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Rules of conducting the expertise of medicines, medical devices and medical equipment

About amending the order of Ministry of health of the Republic of Kazakhstan of November 18, 2009 # 736 «About approval of Rules of conducting the expertise of medicines, medical devices and medical equipment»

Order of Ministry of health of the Republic of Kazakhstan of June 15, 2018 # 374. Registered in the Ministry of Justice of the Republic of Kazakhstan on July 12, 2018 # № 17185

      According to clauses 63 of the Code of the Republic of Kazakhstan of September 18, 2009 “About public health and healthcare system” I ORDER:

      1. Amend the order of Ministry of health of the Republic of Kazakhstan of November 18, 2009 # № 736 «About approval of Rules of conducting the expertise of medicines, medical devices and medical equipment» (registered in the Register of State registration of regulatory and legal acts with # № 5926, published in the Collection of acts of central executive and other central state bodies of the Republic of Kazakhstan, #5, 2010) in the following way:

Rules of conducting the expertise of medicines, approved by this order, put in the new edition according to Appendix 1 to this order;

Rules of conducting the expertise of medical devices and medical equipment, approved by this order, put in the new edition according to Appendix 2.

      2. Committee of pharmacy of Ministry of health of the Republic of Kazakhstan in the established by the legislation of the Republic of Kazakhstan order is to provide the following:

      1) state registration of this order in the Ministry of justice of the Republic of Kazakhstan;

      2) in term of ten calendar days since the date of state registration of this order send the copy of it in paper and electronic form in Kazakh and Russian languages to Republican state enterprise on the right of economic use “Republican center of legal information” for official publishing and inclusion to the Reference control bank of regulatory and legal acts of the Republic of Kazakhstan;

      3) in term of ten calendar days since the date of state registration of this order send the copy of it for official publishing to different periodicals;

      4) place this order on the internet site of Ministry of health of the Republic of Kazakhstan after its official publishing;

      5) in term of ten working days after state registration of this order present to the Department of legal services of Ministry of health of the Republic of Kazakhstan the information about execution of activities, envisaged by sub-paragraphs 1), 2), 3) and 4) of this paragraph.

      3. Control for the execution of this order is to be performed by vice-minister of health of the Republic of Kazakhstan, Tsoy A.V.

      4. This order enter into power after ten calendar days after its first official publishing.

Minister of Health

of the Republic of Kazakhstan

E. Birtanov
Appendix 1
to the order of Minister of health
of the Republic of Kazakhstan
of June 15, 2018 # 374
Approved by the
order of Minister of health
of the Republic of Kazakhstan
of November 18, 2009 # 736

Rules of conducting the expertise of medicines

Clause 1. General provisions

      1. This Rules of conducting the expertise of medicines (hereinafter referred to as the Rules) are developed in accordance with clause 63 of Code of the Republic of Kazakhstan of September 18, 2009 «About public health and healthcare system” (hereinafter referred to as the Code) and define to order of conducting the expertise of medicines.

      2. The expertise of medicines according to paragraph 2 of clause 63 of the Code is conducted by the state republican enterprise on the right of economic use (hereinafter referred to as the state expert organization), performing manufacturing and economic activities in the healthcare field for provision of safety, efficiency and quality of medicines.

      3. Medicines, manufactured in the Republic of Kazakhstan and imported to the territory of the Republic, are to be put to expertise.

      4. Expertise is not conducted for medicines with the same name but different composition of active substances. Expertise for medicines, manufactured in the Republic of Kazakhstan for export purposes, is conducted according to decision of the manufacturers from the Republic of Kazakhstan.

      5. Before application for expertise, the applicant receives in the state expert organization the scientific and pre-registration consultation on contract basis regarding the questions, connected to the conducting of the expertise.

      6. To conduct the expertise of medicines of blood and blood components, the state expert organization attracts specialists from profile organization, working in blood services.

      7. These Rules use the following terms and definitions:

      1) bioavailability – rate and extent, with which active substance is absorbed from the dosage form and becomes available in the place of action;

      2) biological equivalency (bioequivalency) – absence of significant differences in rate and extent, with which active substance or active part of the molecule of active substance of pharmaceutical equivalents of pharmaceutical alternatives becomes available in the place of its action, being injected in the same molar dose under similar conditions in the studies with appropriate design;

      3) biosimilar – biotechnological medicine, similar to the originally produced (original) medicine by quality, safety, efficiency, and presented to the registration after expiration of the patent of original medicine;

      4) biopharmaceutical classification system (hereinafter referred to as BCS) – scientific system of classification of active substances on the basis of their solubility in media with certain pH level and extent of ingress through intestine walls;

      5) original medicine – medicine, which is represented by or contains new active substances, efficiency and safety of which is confirmed by the results of pre-clinical and clinical studies, and registered on the basis of full dossier;

      6) hybrid medicine – medicine, which does not fall under the definition of reproduced medicine with impossibility to prove its bioequivalency using bioavailability studies, and also in the case when this preparation has undergone changes of active substance (substances), dosage units, dosage forms or ways of administration, compared to the original medicine;

      7) homeopathic preparations – medicines, containing substances of natural origin in small doses and manufactured according to the special technology;

      8) medicines – drugs, represented by or which contain pharmacological active substances, which substances come into contact with human body or ingress to its organs or tissues, and designed for preventing, diagnostics and treatment of the diseases, and also changing the state and functions of the body: medical substance, medical raw material, bulk products of medicines, medical preparations;

      9) conclusion about safety, efficiency and quality of the medicine – document, which contains results of expertise of aforementioned medicine;

      10) non-reasonable combination of composition of the medicines – composition of the medicine, which does not correspond to the assumed pharmacological properties and action;

      11) instructions for medical use of the medicine – document, which contains information for the user and which accompany the medicine in the package;

      12) regulatory document for quality and safety control of the drugs (hereinafter referred to as the regulatory safety document) – document, which establishes the complex of requirements to the quality of the medicine, methods of determining the quality, which provide their uniform parameters of safety and quality;

      13) medical substance – drug or combination of drugs, regardless of the nature of origin, which has certain pharmacological activity, intended for production and manufacturing the medicines;

      14) standard samples of medical substances and their impurities – reference drugs, which are used for conducting the expertise of tested medicines;

      15) manufacturer of the medicine – individual entrepreneur or legal entity, which performs manufacture or one or more stages of manufacture;

      16) herbal medical raw material – fresh or dried plants or their parts, used for production and manufacture of the medicines;

      17) well studied medical use – medical use of the active substance, which constitutes the part of the medicine, efficiency of which is well studied, acknowledged, safety extent is acceptable and proven by detailed bibliography references to the published data about post-registration, epidemiology studies, and not less than 15 years passed since the date of first systematic and documented use of the medicine;

      18) immune-biological preparations – preparations for specific prevention, diagnostics and treatment of infection and immune diseases (including allergic diseases), with the aid of immunological methods of other and physiological states, means for indication of infection agents and their antigens in the objects of outer environment, blood preparations (regardless of method of obtaining), and also preparations, which case treatment and prevention through immune system;

      19) reproduced medicine (generic) – medical preparation, identical to the original medicine by composition of active substances, medical formulation, quality, safety and efficiency parameters, manufactured by different manufacturers;

      20) plan of risk management – detailed description of the system of risk management;

      21) periodical safety report – form and contents of the report for presentation of evaluation of risk/benefit ratio of the medicine by holder of registration authorization during certain periods of time in post-registration stage of medicine;

      22) countries of the region of International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) – countries, regulatory bodies of which are founders or constant members of ICH (European Union countries, United States of America, Japan, Switzerland, Canada) (hereinafter referred to as the ICH region countries);

      23) Expert council of state expert organization (hereinafter referred to as the expert council) – collegial body, created in state expert organization for review of arguable questions regarding the results of expertise, groundings (reasons) of issue of negative conclusions on the efficiency, safety and quality of medicines, medical devices and medical equipment and making the final decision.

      24) orphan medicines – preparations for diagnostic and pathogenetical treatment of orphan (rare) diseases;

      25) production site – territorially isolated complex, intended for execution of whole process of manufacture of medicine, medical device or medical equipment, or certain stages of it;

      26) applicant – developer, manufacturer, registration authorization holder or their trusted person, authorized to submit application, documents and materials, and performs actions, envisaged by the power of attorney of the principal to conduct expertise during registration, re-registration and amending the registration dossier of the medicines;

      27) reference medicine – medicine, which is used as the comparison preparation and represents the standard, by which the properties of medicine are determined (regulated);

      28) registration dossier – set of documents and materials of established composition, presented to the application for expertise;

      29) amending the registration dossier – amendments, made by the applicant to the registration dossier during the term of registration authorization, which does not have negative effect on the safety, efficiency and quality of the medicine, which are also subject to the expertise according to these Rules;

      30) good manufacture practice (GMP) – constituent part of the quality assurance system, which guarantees manufacture and quality control of the medicine according to standards conforming to their designation and requirements of registration dossier;

      31) registration authorization holder – manufacturer, organization, which has the document from the manufacturer to own the registration authorization;

      32) equivalency study – study, which determines equivalency between generic and original medicine with the use of in vivo (inside the organism) and (or) in vitro (outside the organism) studies;

      33) “biowaiver” procedure – procedure, according to which the determination of equivalency of reproduced medicine (generic) is conducted basing on the bio-pharmaceutical classification system and results of comparative studies outside the organism (in vitro) with the use of “Solubility” study, and is used for hard medical preparations of instant release (1 and 3 class according to the bio-pharmaceutical classification system).

Clause 2. Order of presenting the registration dossier for conducting the expertise of the medicine

      8. For conducting the expertise of the medicine, the applicant enters into the contract with state expert organization for conducting the expertise, and presents the following documents to the customers service center of the state expert organization (hereinafter referred to as Customers service):

      1) application for conducting the expertise of the medicine (hereinafter referred to as the application) in the form according to Appendix 1 to these Rules;

      2) registration dossier in electronic medium:

      list of the documents, presented for the expertise by the manufacturers from the Republic of Kazakhstan in the form according to Appendix 2 to these Rules;

list of the documents, presented for the expertise by the foreign manufacturers in the form according to Appendix 3 to these Rules;

      3) samples of the medicines, standard samples of chemical substances, standard samples of biological preparations, test strains of the micro-organisms, cell cultures in the amounts, suitable for triple laboratory tests with remaining time to expiration date not less than six months;

      4) specific reagents, consumables, used during conducting laboratory tests of the medicines;

      5) copy of the document proving the payment by the applicant of the amount of money to the checking account of the state expert organization.

      Forming the application for conducting the expertise of the medicines with appended list of documents, presented to the expertise by manufacturers from the Republic of Kazakhstan, according to Appendix 2 to these Rules or the list of documents, presented to the expertise by foreign manufacturers, according to Appendix 3 to these Rules, is performed by the applicant within information system of state expert organization with the use of individual password.

      9. Materials of registration dossier of the medicine, presented for the expertise by foreign manufacturers, correspond to Appendix 1 of the Rules of registration and expertise of the medical preparations for medical use, approved by Decree of the Council of Euro-Asian economic commission of November 3, 2016 # 78.

      10. Specialist of the Customer service in term of one working day after the receipt of the documents, provided by paragraph 8 of these Rules:

      1) preforms the registration of the applicant in the software;

      2) places information on the official site of state expert organization about presented for expertise medicines (trade name, international non-patented name, dosage form, dosage units, concentration, manufacturer, country);

      3) checks the remaining period to expiration date of the samples of medicines, standard samples of chemical substances, standard samples of biological preparations, test strains of the micro-organisms, cell cultures, specific reagents, consumables, required for reproducibility of methods of laboratory tests of the medicine, and enters the data to the software.

      To keep the storage conditions (temperature, humidity), samples of the medicines, including narcotics, psychotropic drugs and precursors are presented directly to the test laboratory.

      11. The applicant presents applications and registration dossier for each medical formulation to the expertise of different medical formulations of the same medicine.

      12. In the case of simultaneous application to the expertise the medicine in one medical formulation with different dosage units, concentration, volume, the applicant presents one application and registration dossier with appendix of layout of the packages, labels for each dosage unit, concentration, volume and amount of dosages in the package, and also regulatory document for quality in the case of different control methods.

      13. In the case of presentation of reproduced medicine by domestic manufacturer for expertise without equivalency study data, the applicant in registration dossier presents the project of protocol and guarantee letter in free form about presentation the report of clinical studies. With this, the period of time for conducting test studies is not the part of period of time for conducting the expertise at registration.

      14. During the expertise of orphan medicines, the applicant presents the program of the testwork, results of which are the grounding for re-evaluation of risk-benefit ratio, conforming to the use of medicine under strict control of the therapist, and emergent provision of card-messages about side effects, serious side effects and about lack of efficiency of the medicine to the state body in the form, provided by the Rules of conducting the pharmacological surveillance and monitoring of side effects of medicines, medical devices and medical equipment, approved by the order of Minister of health and social development of the Republic of Kazakhstan of May 29, 2015 # 421 (registered in the Register of state registration of regulatory legal acts under # 11485).

      15. In the cases of provision by the applicant the incomplete set of the documents, and also not keeping to the conditions, envisaged by paragraph 8 of these Rules, the specialist of Customer service refuses to accept the application.

Clause 3. The order of conducting of the medicines

Paragraph 1. Stages of conducting the expertise of the medicines

      16. Expertise of the medicine consists of the following stages:

      1) initial expertise (validation of registration dossier);

      2) specialized expertise;

      3) laboratory testwork.

      17. The expertise is conducted with the use of electronic program of state expert organization “Expertise of medicines, medical devices and medical equipment”, integrated with the uniform database “System of medical provision management” of Uniform information system of health care.

Paragraph 2. The order of conducting the initial expertise (validation of registration dossier) of the medicine

      18. After the acceptance of the application by the expert, the initial expertise is performed (validation of registration dossier) for the medicine in the terms, envisaged by clause 6 of these Rules.

      19. During initial expertise (validation of registration dossier) of the medicine, the evaluation of completeness, complexity and correctness of the paperwork, presented by the applicant in the registration dossier regarding proofs of safety, efficiency and quality of the medicine is performed.

      20. In the case of presence of remarks to the documents of registration dossier, to the applicant the letter is sent stating the revealed remarks and requirement to amend them during the period less than sixty calendar days.

      21. In the case of non amending such, the state expertise organization sends the applicant the note message (in free form) about termination of expertise of the medicine.

      22. According to the results of initial expertise (validation of registration dossier) of the medicine with taking into account the stated remarks, the report for initial expertise (validation of registration dossier) is produced according to Appendix 4 to these Rules, or initial expertise report (validation of registration dossier) about amendments, put into registration dossier of the medicine according to the Appendix 5 to these Rules.

Paragraph 3. The order of conducting the special expertise of the medicines

      23. The positive result of initial expertise (validation of registration dossier) of the medicine is the grounding for conducting the special expertise of the medicine during the terms, envisaged by Clause 6 of these Rules.

      24. Special expertise of the medicine includes the study of the documents of registration dossier for the issues of safety, efficiency and quality of the medicine by evaluation of pre-clinical (non-clinical), clinical studies for bio-equivalency, analysis of information about the quality of the medicine, including the evaluation of pharmacokinetic and (or) pharmacodynamics interaction for the conformity to the List of unreasonable combination of the medicines according to Appendix 6 to these Rules.

      25. Special expertise of the medicine is performed by the group of experts of the state expert organization with attraction (if needed) of the freelance profile experts.

      26. According to the results of the study of documents of registration dossier at the stage of special expertise, the consolidated request is sent to the applicant (in free form) about safety, efficiency and quality of the medicine.

      27. The applicant in the term of sixty calendar days send the answer and required materials according to the request of the state expertise organization.

      In the case of appearance of additional questions regarding information, presented by the applicant in the answer to the previous request, the applicant in the term of thirty calendar days since the moment of receipt of the request send the answer and required documents to the additional request from the state expert organization.

      28. In the case of not presenting by the applicant to the request of state expert organization in the established term according to paragraph 27 of these Rules, and also in the case of presenting the incomplete report and required materials, the negative consolidated report is produced by the experts of evaluation of the medicine, and the materials are sent to the Expert council for making the decision about declining and termination of the expertise of the medicine.

      Expert council reviews the incoming materials once a month and the results of the decisions are forwarded to the applicant in the term of ten calendar days.

      29. According to the results of the special expertise, the consolidated report from the experts for evaluation of the medicines is completed according to the form from Appendix 7 to these Rules, and consolidated report of experts for evaluation of the medicine under amendments made into registration dossier according to Appendix 8 to these Rules. In the report of the experts for evaluation of the medicines all aspects of safety, efficiency and quality of the medicine are reflected.

Paragraph 4. The order of conducting the laboratory tests of the medicines

      30. In the case of positive response of special expertise, the laboratory tests of the medicine are conducted in the terms, envisaged by clause 6 of these Rules.

      31. Laboratory tests of the medicine are performed in the test labs of the state expertise organization for proving the conformity of the quality and safety indicators of the medicine and include:

      1) test of the samples of the medicine;

      2) determination of reproducibility of analysis methods.

      Tests of the samples of the medicines with the use of complex of physical and chemical, biological tests, is designed for determination of quantitative and qualitative content of active substances and conjugates, impurities, and also extent of biological safety (microbiological purity, toxicity, pyrogenicity).

      Determination of reproducibility of the methods of analysis for control over the quality of medicine is performed for confirmation of their conformity, envisaged by regulatory quality documents.

      32. Laboratory tests are not conducted during:

      1) prolongation of the active term of the registration authorization of the medicine (in the case of absence of reclamations for the quality of the medicine and according to the results of pharmacological surveillance for the safety of the medicine), manufactured under good manufacture practice and presents on the pharmaceutical market of the Republic of Kazakhstan for not less than 8 years;

      2) expertise of the medicine, produced in ICH region countries;

      3) expertise of the medicines, pre-qualifies by World Health Organization;

      4) prolongation of the term of the registration authorization of the medicine, manufactured in the Republic of Kazakhstan.

      33. In the case of determining the remarks regarding the results of laboratory tests, to the applicant the letter is sent stating all the determined remark and requirement to fix them in the term not more than ninety calendar days.

      34. In the case of non presentation by the applicant of the answers, the established in the letter of state expert organization remarks in the established term according to paragraph 33 of these Rules and negative results of laboratory tests, the materials are sent to the expert council to make decision about refusal and termination of the expertise of the medicine.

      35. According to the results of the laboratory tests of the medicine, the test laboratory creates the protocol of the test according to the form presented in Appendix 9 to these Rules.

      36. In the case of impossibility of conducting the laboratory tests of the samples of the medicines in the test laboratory of state expert organization, including their attribution to the orphan category, psychotropic, narcotic, including the ones designed for treatment of expensive nosologies as the results of their high cost, impossibility of keeping the transportation conditions of the aforementioned samples to the territory of the Republic of Kazakhstan and (or) their storage, lack of special equipment and consumables in state expert organization, if regulatory documents about the quality of the products state the need for additional tests, connected to large expenses of manufacturer’s costs, expensive value of the samples, with samples, which require special transportation conditions, specific equipment and additional measures, laboratory tests are conducted in the presence of representatives of the expert organization in the quality control laboratory of the manufacturer, or in the contract laboratory, named by the manufacturer.

      According to the results of laboratory tests, the Report about results of conducting the laboratory tests in the contract laboratory is completed, which laboratory is used by the manufacturer according to the Appendix 10 to these Rules.

Clause 4. The order of formulation of the results of finally conducted expertise of the medicine

37. After the end of the expertise (initial expertise – validation of the registration dossier, special expertise and laboratory tests), the applicant in term of thirty calendar days, which are not the part of the period of expertise is agreed with state expert organization on general (administrative) information about the medicine, final documents (regulatory safety document, instruction for medical use and markings of layout of the packages, labels, stickers).

      The agreement is performed in the electronic mode with the use of individual password through personal cabinet or by presenting the agreement sheet.

      38. According to the results of conducted expertise of the medicine the state expert organization prepares the conclusion about safety, efficiency and quality of the medicine, applied for the expertise according to the Appendix 11 to these Rules, and the conclusion about safety, efficiency and quality of the medicine, applied for the expertise with amendments put into registration dossier according to the Appendix 12 to these Rules.

      39. State expert organization sends in the electronic mode with electronic-digital signatures of the head (or authorized person) and responsible people, who conducted the expertise, to the state body:

      conclusion about safety, efficiency and quality of the medicine;

      regulatory document for quality, approved by the applicant and agreed with the expert organization;

      instruction for medical use of the medicine in Kazakh and Russian languages, being developed according to the Rules of completing and layout of the instructions for medical use of medicines and medical devices, approved by the order of the Minister of health and social development of the Republic of Kazakhstan of May 2015, # 414 (registered in the register of state registration of regulatory and other expert information;

      layouts of the packages, labels and stickers of the medicine in Kazakh and Russian languages, agreed by the expert organization.

      40. Conclusion about safety, efficiency and properties of the medicine are valid for one hundred and eighty days. In the case of expiration of this period. The applicant again applies application, documents and materials, envisaged by clause 8 of these Rules.

      41. For the medicines of domestic manufacture, produced for export purposes and domestic market of the country under different trade names, the expertise is conducted resulting in one conclusion about safety, efficiency and quality.

      42. The groundings to give the negative conclusion about safety, efficiency and quality are the following:

      1) non presentation the full set of registration dossier after issue of the remarks to the applicant in the process of conducting the expertise in terms, established by these Rules;

      2) untrustworthy data is provided by the applicant;

      3) lower safety and efficiency compared to the earlier registered similar products;

      4) lower safety and quality indices, regulated by the State Pharmacopeia of the Republic of Kazakhstan of pharmacopeias, deemed to be active on the territory of the Republic of Kazakhstan, or compared to the earlier registered similar products;

      5) presence in the composition of the medicine the substances and materials, prohibited for use in the Republic of Kazakhstan;

      6) receipt of negative results from one of the stages of the expertise;

      7) Discrepancy of the actual manufacturing conditions and system of quality assurance to the conditions, providing stated safety, efficiency and quality according to the results of evaluation of manufacture and quality assurance system;

      8) refusal of the manufacturer to attend enterprises (manufacturing sites) with the aim to evaluate the conditions of the manufacture and quality assurance system according to the requirements of legislation of the Republic of Kazakhstan.

      43. In the cases of negative conclusion about safety, efficiency and quality of the medicine, or recall by the applicant of the application for expertise after the start of conducting the expertise, the cost of conducting the expert works is not returned to the applicant.

      44. According to the results of the expertise the state expert organization completes the consolidated report about safety, efficiency and quality of the medicine, in accordance to the Appendix 13 to these Rules, part of which is placed on the internet site of state expert organization.

      45. After finishing the expertise procedure the state expert organization forms electronic archive copy of the registration dossier, which contains documents and materials from the results of expertise (additional materials, supplied by the applicant according to the request from state expert organization, report of validation of registration dossier, final consolidated report from the experts about critical evaluation of the medicines, protocols of the test laboratory), conclusion about the safety, efficiency and quality, approved instruction for medical use, regulatory document for the quality of the medicine with individual number, approved layouts of the packages, labels, stickers, contained in electronic archive.

      During the active period of registration authorization the archive registration dossier is completed with the registration dossier, applied for inclusion of amendments, containing documents and materials of the results of expertise.

      Registration dossier is stored in electronic form on the electronic media for the term of ten years.

Clause 5. Special features of conducting the expertise of the medicine

      46. Explanations or refinements, appearing during conducting the expertise between state expert organization and applicant, are executed through Customer service by forming the electronic document according to the individual password of the applicant through informational system with electronic and digital signature of the applicant and state expert organization, or in paper.

      During the time of presentation by the applicant the requested documents the expertise is stopped.

      47. Under the expertise scope, the state expert organization performs the verification of authenticity of the translation to Kazakh language of the instructions for medical use, markings of the layouts of package, labels, and stickers.

      48. Information in the instruction for medical use of original medicine, presented for the Republic of Kazakhstan, corresponds to the information, stated in the general characteristics of the medicine.

      In the instruction for medical use of the medicine the information is reflected about conjugates, their nominal content in the medicine, and also limits of use of the medicine according to the Appendix 14 to these Rules.

      49. Instruction for medical use of reproduced medicine and biosimilar corresponds to overall characteristics of original medicine. In the case of differences in the instruction for medical use between reproduced medicine and biosimilar from original preparation by the indication for use in the expanding way, or dosage schedule or admission routes, the results of corresponding clinical studies are appended.

      50. Registration authorization holder of the original preparation applies for amending the instruction for medical use in the term of ninety calendar days after updating the general characteristics of the medicine in the country of manufacturer or registration authorization holder.

      51. State expert organization after amending the instruction of original medicine or in the case of determining by international routes and results of pharmacological surveillance the changes in general characteristic of the original medicine, notifies through information resources all of the registration authorization holders for generics about requirement to put corresponding amendments to the instruction for medical use through the procedure of amendments in the term of ninety calendar days after amending the instruction of original preparation regarding safety information, and in the term of twelve month in other cases. Holder of registration authorization of the original preparation amends the instruction for medical use basing on the notification (in free form) from state expert organization for discrepancies, determined as the result of pharmacological surveillance, and according to international official sources for the term of ninety days.

      52. In the case of non-fulfilling conditions, stated in paragraphs 50 and 51 of these Rules, the state expert organization notifies (in free form) the state body in the field of circulation of medicines, medical devices and medical equipment (hereinafter referred to as the state body) about requirement to suspend the action of the registration authorization.

      53. For medicines, which have unlimited registration authorization, the state expert organization performs periodical evaluation of risk/benefit ratio on the basis of the pharmacological surveillance with compensation of the costs of the state expert organization basing on the contract between the applicant and state expert organization.

      54. The expertise of changes, being put into the registration dossier, is performed for the medicine in the period of registration authorization being active and when it does not have any negative effect to the risk/benefit ratio of the medicine.

      55. Changes are classified according to the List of changes, amending the registration dossier of the medicine, according to the Appendix 15 to these Rules for:

      1) type IA changes – ones which do not require new registration (insignificant changes, which has a slight effect or no effect at all on the quality, safety and efficiency of the medicine, and are about amending the content of the material of registration dossier, applied during the term of registration authorization of the medicine;

      2) type IБ changes – ones which do not require new registration (slight changes, which are not changes of types IA and II);

      3) type II changes – any changes to the materials of registration dossier, which do not require new registration of the medicine and which may influence the quality, safety and efficiency of it greatly;

      4) urgent changes, regarding safety of the medicine – urgent temporary limitations, connected to the safety of use of the medicine, which are implied by the applicant in the case of determining the risk for public health with the use of registered (re-registered) medicine. The holder of registration authorization in the term of twenty four hours notifies the state body about limitations used. In case in the term of twenty four hours from receipt of such information no objections were received from the state body, urgent limitation connected to the safety are deemed to be accepted. Terms of realization of the limitations are negotiated by the holder of registration authorization with the state body.

      Urgent limitation connected to the safety are initiated by the state body in the case of risk for life or health of the person.

      Application for amending regarding urgent limitations (initiated by the holder of registration authorization or state body) is sent by the holder of registration authorization for review not later than sixty calendar days since the date of notificationя.

      56. Each change is subjected to the expertise, even if all of them are introduced simultaneously.

      57. In the case of amendments which are not classifies in these Rules, the applicant refers to the state expert organization through consultation procedure with the aim to receive recommendations about classification of amendment.

      State expert organization in the term of thirty calendar days after the receipt of the request forwards the answer to the applicant in electronic and (or) paper form.

      58. In the case of type IА amendments:

      1) type IА amendments are to be evaluated by the state expert organization without conducting the special expertise. The applicant presents the application in the form according to the Appendix 1 to these Rules and documents proving the amendments done in the term of twelve months since the date of introducing the corresponding amendments according to the Appendix 15 of these Rules;

      2) the applicant notifies the state expert organization in the case of type IА amendments, requiring immediate notification with the aim of constant control of the medicine;

      3) registration authorization holder under the limits of one application states several insignificant type IА amendments regarding one registration authorization;

      4) state expert organization in the term of thirty calendar days since the date of receipt of the payment conducts the evaluation of the type IА amendments and notifies registration authorization holder about safety, efficiency and quality of the medicine, presented for expertise for amending the registration dossier in the form according to the Appendix 11 to these Rules;

      5) in the case of amendments, which require change of the information in the registration authorization, the state body issues new registration authorization with the same old number for the residual term of the registration authorization.

      59. In case of IБ type amendments:

      1) the applicant presents the application in the form according to Appendix 1 to there Rules and documents according to Appendix 15 to these Rules;

      2) holders of registration authorization under the scope of one application may notify about several type IБ amendments regarding one registration authorization, or group one or several type IБ amendments with other type IА amendments, connected to the registration authorization, in the case such grouping conforms to the conditions, listed in the Appendix 15 to these Rules;

      3) in the case of amendments, which require change of the information in the registration authorization, the state body issues new registration authorization with the same old number for the residual term of the registration authorization.

60. In case of type IБ amendment, which results into other sequential type IА and type IБ amendments, one application is submitted, containing all the sequential amendments of type I.

      61. In the case of serious type II amendments:

      1) the applicant presents the application in the form according to Appendix 1 to there Rules and documents according to Appendix 15 to these Rules;

      2) the application contains one type II amendments. In the case of having several type II amendments, separate application is submitted regarding each amendment, each application has references to each other;

      3) in the case when type II amendment leads to other sequential type II amendments, one application includes all sequential changes with their description of correspondence between such sequential type II amendments.

      State expertise organization during type II amendments in the term of ninety calendar days after acceptance of the application conducts the expertise of the documents.

      62. Consolidated report for evaluation of introduced amendments to the medicine with changes, introduced to the registration dossier of type I and type II, which do not require new registration, is completed in the form according the Appendix 8 to there Rules.

      63. According to the results of conducted expertize, the state expert organization completes the conclusion about safety, efficiency and quality of the medicine, presented for expertise of the amendments, introduced into registration dossier in the form according to the Appendix 12 to there Rules.

Clause 6. Terms of conducting the expertise of the medicine

      64. Expertise of the medicine, excluding medicines produced in the Republic of Kazakhstan of ICH region countries, is performed in the term not more than two hundred and ten calendar days, including:

      1) initial expertise (validation of registration dossier) of the medicine – thirty calendar days;

      2) special expertise – ninety calendar days (including the verification of authenticity or translation to Kazakh language of the instruction for medical use, markings of the package, labels, stickers, during twenty calendar days);

      3) laboratory tests – seventy calendar days;

      4) forming the conclusion about safety, efficiency and quality – twenty calendar days.

      65. Expertise of the medicine with prolonged active term of registration authorization is conducted during one hundred and twenty days, including:

      1) initial expertise (validation of registration dossier) of the medicine – twenty calendar days;

2) special expertise – ninety calendar days (including the verification of authenticity or translation to Kazakh language of the instruction for medical use, markings of the package, labels, stickers, during fifteen calendar days);

      3) forming the conclusion about safety, efficiency and quality – ten calendar days.

      66. Expertise of the amendments, introduced to the registration dossier, type ІА, is performed in the term not more than thirty calendar days, which includes:

      1) initial expertise (validation of registration dossier) of the medicine – ten calendar days;

      2) verification of authenticity or translation to Kazakh language of the instruction for medical use, markings of the package, labels, stickers, during ten calendar days;

      3) forming the conclusion about safety, efficiency and quality – ten calendar days.

      67. Expertise of the amendments, introduced into registration dossier, type ІБ and II, is conducted in the term not more than ninety calendar days with the stage of conducting the laboratory testwork, including:

      1) initial expertise (validation of registration dossier) of the medicine – fifteen calendar days;

      2) special expertise – sixty five calendar days (including the verification of authenticity or translation to Kazakh language of the instruction for medical use, markings of the package, labels, stickers, during ten calendar days);

      3) forming the conclusion about safety, efficiency and quality – ten calendar days.

      68. Expertise of amendments, introduced into the registration dossier, type ІБ and II, is performed in the term not more than sixty calendar days without the stage of conducting the laboratory testwork, including:

      1) initial expertise (validation of registration dossier) of the medicine – ten calendar days;

      2) special expertise – forty calendar days (including the verification of authenticity or translation to Kazakh language of the instruction for medical use, markings of the package, labels, stickers, during ten calendar days);

      3) forming the conclusion about safety, efficiency and quality – ten calendar days.

      69. Expertise of the medicine, produced in the Republic of Kazakhstan, is performed for one hundred and eighty calendar days, including:

      1) initial expertise (validation of registration dossier) of the medicine – twenty calendar days;

      2) special expertise – ninety five calendar days (including the verification of authenticity or translation to Kazakh language of the instruction for medical use, markings of the package, labels, stickers, during twenty calendar days);

      3) laboratory testwork – fifty calendar days;

      4) forming the conclusion about safety, efficiency and quality – fifteen calendar days.

      70. Expertise of the medicine, produced in the Republic of Kazakhstan, in the case of prolongation of action of registration authorization, is conducted during one hundred days, including:

      1) initial expertise (validation of registration dossier) of the medicine – fifteen calendar days;

      2) special expertise – seventy calendar days (including the verification of authenticity or translation to Kazakh language of the instruction for medical use, markings of the package, labels, stickers, during fifteen calendar days);

      3) forming the conclusion about safety, efficiency and quality – fifteen calendar days.

      71. Expertise of amendments, introduced to the registration dossier, type ІА, for medicines produced in the Republic of Kazakhstan, is performed in term not more than thirty calendar days, including:

      1) initial expertise (validation of registration dossier) of the medicine – ten calendar days;

      2) forming the conclusion about safety, efficiency and quality (including verification of authenticity or translation to Kazakh language of the instruction for medical use, markings of the package, labels, stickers) – twenty calendar days.

      72. Expertise of amendments, introduced into registration dossier, type ІБ and II for the medicine, produced in the Republic of Kazakhstan, is performed during ninety calendar days with the stage of laboratory testwork, including:

      1) initial expertise (validation of registration dossier) of the medicine – fifteen calendar days;

      2) special expertise – sixty calendar days (including the verification of authenticity or translation to Kazakh language of the instruction for medical use, markings of the package, labels, stickers, during ten calendar days);

      3) forming the conclusion about safety, efficiency and quality – fifteen calendar days.

      73. Expertise of amendments, introduced to the registration dossier, type ІБ and II for the medicine produced in the Republic of Kazakhstan is performed during sixty days without the stage of laboratory testwork, including:

      1) initial expertise (validation of registration dossier) of the medicine – ten calendar days;

      2) special expertise – forty calendar days (including the verification of authenticity or translation to Kazakh language of the instruction for medical use, markings of the package, labels, stickers, during ten calendar days);

      3) forming the conclusion about safety, efficiency and quality – ten calendar days.

      74. Expertise of the medicines, produced in ICH region countries is conducted during on hundred and eighty days, including:

      1) initial expertise (validation of registration dossier) of the medicine – thirty calendar days;

      2) special expertise – one hundred and twenty calendar days (including the verification of authenticity or translation to Kazakh language of the instruction for medical use, markings of the package, labels, stickers, during twenty calendar days);

      3) forming the conclusion about safety, efficiency and quality – thirty calendar days.

      75. Expertise of the medicines, produced in ICH region countries, in case of prolongation of action of registration authorization, is performed during one hundred calendar days, including:

      1) initial expertise (validation of registration dossier) of the medicine – twenty calendar days;

      2) special expertise – seventy calendar days (including the verification of authenticity or translation to Kazakh language of the instruction for medical use, markings of the package, labels, stickers, during fifteen calendar days);

      3) forming the conclusion about safety, efficiency and quality – ten calendar days.

      76. Expertise of the amendments, introduced to the registration dossier, type ІА, for medicines, produced in ICH region countries, is performed during thirty days, including:

      1) initial expertise (validation of registration dossier) of the medicine – twenty calendar days;

      2) forming the conclusion about safety, efficiency and quality (including verification of authenticity or translation to Kazakh language of the instruction for medical use, markings of the package, labels, stickers) – twenty calendar days.

      77. Expertise of amendments, introduced to the registration dossier, type ІБ and II for medicines, produced in the ICH region countries, is performed during sixty days without the state of laboratory testwork, including:

      1) initial expertise (validation of registration dossier) of the medicine – ten calendar days;

      2) special expertise – forty calendar days (including the verification of authenticity or translation to Kazakh language of the instruction for medical use, markings of the package, labels, stickers, during ten calendar days);

      3) forming the conclusion about safety, efficiency and quality – ten calendar days.

      78. Terms of conducting the expertise do not include the following:

      1) time of replenishing the incompleteness of registration dossier;

      2) time of presentation documents and materials according to the request on any stage of the expertise by the applicant;

      3) time of organization of conducting the evaluation of the conditions of the manufacture and quality assurance system in the manufacturer company, conditions of conducting pre-clinical and (or) clinical studies, system of pharmacological surveillance of the holder of registration authorization;

      4) terms of provision of the report about clinical studies with conforming to the conditions, defined by paragraph 13 of these Rules. With this, the terms of provision of the report cannot exceed one hundred and twenty calendar days since the date of start of special expertise;

      5) organization and holding the Expert council;

      6) agreement by the applicant on the final documents.

Appendix 1

to the Rules of conducting the expertise of medicines

Form

Application for conducting the expertise of medicine *

1. Trade name In Kazakh
In Russian
In English
2. Export trade name (for domestic manufacturers) In Kazakh In Russian In English Country
3. International non-patented name In Kazakh
In Russian
In English
4. Dosage form In Kazakh
In Russian
5. Dosage units/concentration (Filled in case of presence. Volume is filled in the package) Concentration is stated for liquid, soft and gas-form medicines
6. Anatomical Therapeutic Chemical Classification Code number
Name in Kazakh
Name in Russian
7. Type of the medicine (filled for the appropriate medicine)
1) ☐ Original medicine
☐ One-component ☐ Multicomponent
☐ Biological medicine ☐ Bulk product
☐ Active pharmaceutical substance, not manufactured under GMP conditions, or herbal medical raw material
2) ☐ Reproduced medicine
☐ One-component ☐ Multicomponent
☐ Bulk product
Original medicine:
Name of the medicine, dosage, dosage form
Holder of the registration authorization (company, to the name of which registration authorization is given), date of registration, number of registration authorization, state, where the original medicine is registered
Reference medicine for domestic manufacturer, which was used in equivalency studies (if such were performed):
Name of the medicine, dosage, dosage forms
Holder of the registration authorization (company, to the name of which registration authorization is given), date of registration, number of registration authorization, state, where the reference medicine is registered
Present the groundings of use of reference medicine in case it is different from original medicine
Note. This part is required for each medicine, which was used in equivalency studies.
3) ☐ Biosimilar medicine (biosimilar)
☐ Bulk product
Original biological medicine:
Name of the medicine, dosage, dosage forms
name of medicinal product, dosage, dosage form
holder of registration certificate (the company in whose name the registration certificate was issued), registration date, number of the registration certificate, the state where the original medicinal product is registered
Reference biological medicinal product:
name of medicinal product, dosage, dosage form
holder of registration certificate, registration date, number of the registration certificate, the state where the reference medicinal product is registered
differences in comparison with the reference biological medicinal product (if any): ☐ differences in the source material;

☐ differences in the production process;

☐ other indications for use;

☐ differences in dosage form;

☐ another dosage;

☐ (quantitative changes in the active pharmaceutical substance);

☐ another way of administration;

☐ other differences
___________________________________
_____________________________________

4) ☐ Hybrid medicinal product
☐ Single — component ☐ Multi — component
☐ Bulk product
Original medicinal product:
name of medicinal product, dosage, dosage form
holder of registration certificate, registration date, number of the registration certificate, the state where the original medicinal product is registered
Differences in comparison with the original medicinal product: ☐ changes in the active pharmaceutical substance;

☐ another dosage form;

☐ other dosage (s) (quantitative changes in the active pharmaceutical substance);

☐ other administration method (s);

☐ other pharmacokinetics (including other bioavailability);

☐ another indication for use;

☐ other differences
____________________________________
_____________________________________

5) ☐ Combined medicinal product
☐ known combination ☐ new combination
☐ Bulk product
Original medicinal product: (in case of known combination)
name of medicinal product, dosage, dosage form
holder of registration certificate, registration date, number of the registration certificate, the state where the original medicinal product is registered
6) ☐ Medicinal product with a well-studied medical use
☐ Bulk product
name of medicinal product, dosage, dosage form
holder of registration certificate, registration date, number of the registration certificate.
7) ☐ Radiopharmaceutical medicinal product
☐ Bulk product
☐ radiopharmaceutical set
☐ precursor of radionuclide
source of radionuclide (primary and secondary) (if available)
generator
8) ☐ Homeopatic medicinal product
☐ new homeopathic product ☐ homeopathic product included in pharmacopoeias and monographs
9) ☐ Herbal medicinal product
binominal scientific name of the plant (genus, species, sort)
source of origin of raw materials (laboratory code)
parts of producing plant
name (definition) of a substance of phytogenic origin and other names (synonyms specified in Pharmacopoeias)
10) ☐ Orphan medicinal product
Has the medicinal product been given the status of an orphan medicinal product in the Republic of Kazakhstan?

No

In the process of consideration

Yes
Date
number of the registration certificate of orphan medicinal product
Refused to assign the status of an orphan medicinal product
Date
Resolution number
Application for assignment of status withdrawn: date
8. Form of medicinal product in the applicant’s country By medical prescription
Without medical prescription
9. Administration methods
10. Information on administration devices
11. Package (list of values to be filled in)
No. Type (primary or secondary) Name Size (if available) Volume (if available) Number of units in package Short description
1. Primary
2. Secondary
3 Secondary Packing Barcode (GTIN) Indicate the barcode for each dosage / concentration
12. Full qualitative and quantitative composition (list of values to be filled in)
No. Type of substance (active or excipient) Name Amount per unit dosage form Normative document regulating quality or the Pharmacopoeia with indication of the year of publication Manufacturer, country and address of the production site (for active substances) Controlled by the International Narcotics Control Board (marked if available) Presence of poisonous substances (marked if available) Wild or cultivated (for medicinal plant material) and the place of vegetation Sign of human or animal origin (marked if available)
1. Active II tab.
III tab.
IV tab.
1 list
2 list
2. Excipient
13. Name of active pharmaceutical substance
14. Shelf life of medicinal product suggested shelf life
suggested use period (after first opening of container)
suggested use period (after dissolution or delution)
15. Transportation conditions
16. Storage conditions suggested storage conditions
suggested storage conditions after first opening of package
17. Registration in the manufacturer country and other countries
1. Country name Registration certificate number (to be indicated if available) Date of issue Term of validity
2.
18. Presence of a title of protection for an invention or utility model, trademark
Name of title of protection Number of title of protection Date of issue Term of issue
19. Manufacture 1) Completely in this production site

2) Partially in this production site

3) Completely in other production site

20. Manufacturer (s) of the medicinal product and production site (s) (including production sites of any component (including the dosage form solvent) that is part of the medicinal product)
No. Manufacturer type Name, country (in Kazakh, Russian, English) No., date and period of validity of the authorization document Legal address Physical address Phone, fax, e-mail Full name, position of the head Full name, position of contact person
1) Manufacturer
2) License holder Data on the production license issued by the authorized body of the manufacturer country
3) Holder of registration certificate
4) Packing company
5) Applicant or representative office Power of attorney data
6) Authorized person for pharmacovigilance in the Republic of Kazakhstan
21. Laboratory of the manufacturer country for quality control of blood products and vaccines, responsible for quality control / production of the series
name of laboratory
address of place of business
country
telephone/fax
e-mail
22. Number of registration certificate issued in the Republic of Kazakhstan (with extension of validity period of the registration certificate)
23. Changes to the registration dossier of medicinal product (indicate the changes introduced)
Type of change Version before making changes Making changes
24. Data on contract for examination of medicinal products
1. Contract No.
2. Execution date
3. Term of validity
25. Entity paying for examination
1. Name
2. Country
3. Legal address
4. Physical address
5. Full name, position of head
6. Telephone
7. Fax
8. e-mail
9. Business Identification Number
10. Individual Identification Number
11. Bank
12. Settlement account
13. Currency account
14. Code
15. Bank Identification Code
Date
Full name and position of Applicant’s authorized person
Signature, stamp

      Note:

      * This form of application is also provided upon extension of validity period of registration certificate issued by authorized health authority of the Republic of Kazakhstan in accordance with the Rules of state registration, re-registration and modification of registration dossier of medicinal product, medical devices and medical equipment approved by the order of the Minister of Health of the Republic of Kazakhstan dated November 18, 2009 No. 735 (registered in the Register of the State Registration of regulatory legal acts under No. 5935) and with changes made to the registration dossier.

Appendix 2
to the Rules of examination of medicinal products

List of documents to be submitted for examination by manufacturers of the Republic of Kazakhstan

Sr. No. Document name
1 2
Part І General Documentation *
IA1. GMP certificate (indicating date and notarized results of the last inspection), if available
I А2. Copy of the state license for pharmaceutical activities (notarized)
I А3. Appendix to the license (for vegetable raw materials — permission to harvest for domestic manufacturers)
I А4. If several manufacturers participate in the production process, the documents of points IА2, ІА3, ІА4 are provided per all participants of manufacture
I А5. License contract (agreement) for the right to manufacture (before the expiration of the patent for the original product)
I А6-1 notarized copy of the title of protection for an invention or utility model of the original medicinal product (provided by the patent holder of the title of protection);
I А6-2 guarantee letter on non-infringement of exclusive rights by third parties for an invention or utility model (provided when examining a generic medicinal product)
I А7. Document confirming quality of the active substance (certificate of substance analysis from manufacturer, certificate of compliance with monograph of the European Pharmacopeia, protocol of analysis, the analytical passport)
I А8. Document confirming the quality of finished product of three industrial series (certificate of analysis, analysis protocol), one series of which coincides with a series of samples of the medicinal product submitted for registration
I А 9. Document on prion safety for substances of animal origin from the manufacturer
I А 10. Copy of registration certificate of the Republic of Kazakhstan (for renewal of validity period of registration certificate)
I.В.1. Draft instruction on medical use in electronic format «doc»
1.В.2 Marking text for primary and secondary packaging, stickers, labels in Kazakh and Russian
1.В.3 Color layouts of consumer packages, labels, stickers in electronic format «jpeg»
I.С Brief description of pharmacovigilance system of the registration certificate holder includes:
information that the registration certificate holder has at its disposal an authorized person for global pharmacovigilance; contact details of the authorized person for global pharmacovigilance; declaration signed by the registration certificate holder that it has a pharmacovigilance system to perform tasks and responsibilities for post-registration control of medicinal product safety; link to the location (address) where the master file of the pharmacovigilance system is stored.
I.D Document confirming the availability of a qualified person responsible for pharmacovigilance for the collection and recording of adverse reactions detected in the territory of the Republic of Kazakhstan
Part II Chemical, pharmaceutical and biological documentation *
II Contents
II А Composition
II А 1 The qualitative and quantitative composition of the medicinal product (active, excipient substances, the composition of the tablet shell or the capsule body)
II А 2 Package description
II А 3 Pharmaceutical development (justification of the choice of composition, primary packaging)
II В Information about the production:
II В 1 production formula
II В 2 description of production technology
II В 3 control in the production process (operational control)
II В 4 primary examination of production processes
II С methods of control of source materials
II С 1 active substances
II С 1.1 certificates of quality for active substances
II С 2 excipient substances
II С 2.1 certificates of quality for excipient substances
II С 3 packaging material (primary and secondary packaging)
II С 3.1 certificates of quality of packaging material with atttachment of documents regulating their quality
II D methods of quality control of intermediate products (if necessary)
II Е specification of quality and methods of control of the finished product with an authentic translation from the manufacturer’s language into Russian
II E 1 regulatory document of the manufacturer on the quality and safety control of the medicinal product in electronic «doc» format, an explanatory note to it
II E 2 primary examination of medicinal product testing methods (except pharmacopeia methods) (when re-registered, additionally a copy of the regulatory document on quality, approved in the Republic of Kazakhstan)
II F stability test results for at least three industrial or experimental-industrial (pilot) series
II G information on the dissolution profile (for solid dosage forms)
II Н animal control data
II K data on the likely environmental hazard for products containing genetically modified organisms
II L periodic security report update (when re-registered)
II M. additional information confirming the quality (if necessary)
Part III. Pharmacological and toxicological documentation
III. Contents
III А. Data on toxicity (acute and chronic), (medical immunobiological preparation — toxicity with a single administration and administration of repeated doses)
III В. Influence on reproductive function
III С. Data on embryotoxicity and teratogenicity
III D. Data on mutagenicity
III Е. Data on carcinogenicity
III F. Pharmacodynamics (medical geneobiological preparation — reactogenicity)
III G. Pharmacokinetics (medical immunobiological preparation — specific activity)
III H. Data on local irritant effect (medical immunobiological preparation — immunogenicity for vaccines)
III Q. Additional information confirming safety (if necessary)
Part IV. Clinical documentation
IV. Contents
IV А. Data on clinical pharmacology (pharmacodynamics, pharmacokinetics), bioequivalence studies for generics
IV В Clinical, immunological effectiveness
IV С Diagnostic effectiveness
IV D Results of clinical trials, scientific publications, reports
IV D 1 Post-registration experience data (if available)
IV Q Additional information confirming the effectiveness

Note:

      * When extending the validity of the registration certificate issued by the authorized body in the field of medical care in the Republic of Kazakhstan in accordance with the Rules of state registration, re-registration and modification of the registration dossier of the medicinal product, medical devices and medical equipment approved by the order of the Minister of Health of the Republic of Kazakhstan dated November 18, 2009 No. 735 (registered in the Register of state registration of regulatory legal acts under No. 5935) parts I and II of this list are presented.

Appendix 3
to the Rules of examination of medicinal products

List of documents provided for examination by foreign manufacturers

Sr. No. Document name
Part 1.*
1.1. General documentation
1.2.1 Certificate for a pharmaceutical product according to the recommendation of the World Health Organization (notarized).
In the absence, the following is presented:
Certificate (registration certificate) on registration in the manufacturer country (notarized)
GMP certificate (with the date and results of the last inspection) (notarized)
Certificate allowing free sale (export)
1.2.2. Certificate of origin (for domestic manufacturers)
1.2.3. License contract (agreement) for the right to manufacture (before the expiration of the patent for the original product)
1.2.4. Information on the registration of medicinal product in other countries, indicating the number and date of the registration certificate (or a copy of the certificate or registration certificate)
1.3. Brief description of the medicinal product, labeling (color layout) and instructions for medical use
1.3.1. Brief description of the medicinal product with the date of the last revision
1.3.2. Approved instruction on the medical use of the medicinal product (for organizations-manufacturers of the Commonwealth of Independent States), certified by the manufacturer
1.3.3. Draft instruction on the medical use of the medicinal product
1.3.4 The text of the labeling of primary and secondary packaging, labels, stickers in Kazakh and Russian languages
1.3.5. Color layouts of consumer packages, labels, stickers in electronic jpeg format in 1: 1 scale
1.4. Information about experts
1.4.1. Information about the quality expert
1.4.2. Information about the expert on preclinical data
1.4.3. Information on the expert on clinical data
1.5. Special requirements for different types of applications
1.6. Assessment of potential environmental hazards
1.6.1 Medicinal products containing or derived from genetically modified organisms
1.7. Information on pharmacovigilance of the applicant in the Republic of Kazakhstan
1.7.1 Brief description of pharmacovigilance system of the registration certificate holder includes:
information that the registration certificate holder has at its disposal an authorized person for global pharmacovigilance; contact details of the authorized person for global pharmacovigilance; declaration signed by the registration certificate holder that it has a pharmacovigilance system to perform tasks and responsibilities for post-registration control of medicinal product safety; link to the location (address) where the master file of the pharmacovigilance system is stored.
1.7.2 Document confirming that the applicant has a responsible person for pharmacovigilance in the territory of the Republic of Kazakhstan
Part 2.*
Summary of the general technical document
2.1. Content of parts 2.3.4.5
2.2. Introduction to the general technical document
2.3. General quality report
2.4. Pre-clinical data review
2.5. Clinical data review
2.6. Pre-clinical data report
2.6.1. Pharmacological data report in text format
2.6.2. Pharmacological data report in table format
2.6.3. Pharmacokinetic data report in text format
2.6.4. Pharmacokinetic data report in table format
2.6.5. Toxicological data report in text format
2.6.6. Toxicological data report in table format
2.7. Clinical data report
2.7.1. Report of biopharmaceutical research and related analytical methods
2.7.2. Report of research on clinical pharmacology
2.7.3. Clinical effectiveness report
2.7.4. Clinical safety report
2.7.5. Copy of the literature list used
2.7.6. Short reviews of individual tests
Part 3. Quality*
3.1. Contents
3.2. Basic data
3.2.S. Drug substance (for medicinal products that contain more than one active substance, information is provided in full on each of them) **
3.2.S.1. General information**
3.2.S.1.1. Name**
3.2.S.1.2. Structure**
3.2.S.1.3. General characteristics**
3.2.S.2. Manufacture
3.2.S.2.1. Manufacturer**
3.2.S.2.2. Description of the production process and its control
3.2.S.2.3. Control of source materials
3.2.S.2.4. Control of critical stages and intermediate products
3.2.S.2.5. Primary examination of the process and / or its assessment
3.2.S.2.6. Development of the production process
3.2.S.3. Characteristics**
3.2.S.3.1. Proof of structure and characteristics
3.2.S.3.2. Admixtures**
3.2.S.4. Active substance control **
3.2.S.4.1. Specification**
3.2.S.4.2. Analytical methods **
3.2.S.4.3. Primary examination of analytical methods
3.2.S.4.4. Series analysis**
3.2.S.4.5. Justification of specification
3.2.S.5. Standard samples or substances
3.2.S.6. Packaging / sealing system **
3.2.S.7. Stability**
3.2.S.7.1. Summary of stability and conclusions **
3.2.S.7.2. Protocol of post-registration study of stability and obligations regarding stability **
3.2.S.7.3. Stability data **
3.2.Р. Medicinal product
3.2.Р.1. Description and composition of the medicinal product
3.2.Р.2. Pharmaceutical development
3.2.Р.2.1. Composite substances of the medicinal product
3.2.Р.2.1.1. Drug substance
3.2.Р.2.1.2. Excipients
3.2.Р.2.2. Medicinal product
3.2.Р.2.2.1. Development of the composition
3.2.Р.2.2.2. Surplus
3.2.Р.2.2.3. Physico-chemical and biological properties
3.2.Р.2.3. Development of the production process
3.2.Р.2.4. Packaging / sealing system
3.2.Р.2.5. Microbiological characteristics
3.2.Р.2.6. Compatibility
3.2.Р.3. Manufacture
3.2.Р.3.1. Manufacturer (s)
3.2.Р.3.2. Composition per series
3.2.Р.3.3. Description of the production process and process control
3.2.Р.3.4. Control of critical stages and intermediate products
3.2.Р.3.5. Primary examination of the process and / or its assessment
3.2.Р.4. Control of excipients
3.2.Р.4.1. Specifications
3.2.Р.4.2. Analytical methods
3.2.Р.4.3. Primary examination of analytical methods
3.2.Р.4.4. Justification of specifications
3.2.Р.4.5. Excipients of human and animal origin
3.2.Р.4.6. New excipients
3.2.Р.5. Control of medicinal product
3.2.Р.5.1. Specification (s)
3.2.Р.5.2. Analytical methods
Approved normative document on quality and safety control in electronic doc format (when re-registered, additionally a copy of the approved normative document in the Republic of Kazakhstan)
3.2.Р.5.3. Primary examination of analytical methods
3.2.Р.5.4. Series analysis
3.2.Р.5.5. Admixtures characteristics
3.2.Р.5.6. Justifications of specification (s)
3.2.Р.6. Standard samples and substances
3.2.Р.7. Packaging / sealing system
3.2.Р.8. Stability
3.2.Р.8.1. Summary and stability conclusion
3.2.Р.8.2. Protocol of post-registration study of stability and obligation regarding stability
3.2.Р.8.3. Stability data
3.2.А. Additions
3.2.А.1. Technical means and equipment
3.2.А.2. Safety assessment of foreign microorganisms
3.2.А.3. New excipients
3.2.R. Regional information
3.3. Copy of the literature list used
Part 4. Pre-clinical (non-clinical) studies reports
4.1. Contents
4.2. Study reports
4.2.1. Pharmacology
4.2.1.1. Primary pharmacodynamics
4.2.1.2. Secondary pharmacodynamics
4.2.1.3. Pharmacology of safety
4.2.1.4. Pharmacodynamic drug interactions
4.2.2. Pharmacokinetics
4.2.2.1. Analytical methods and report on their primary expertise
4.2.2.2. Absorbing
4.2.2.3. Distribution
4.2.2.4. Metabolism
4.2.2.5. Demedication
4.2.2.6. Pharmacokinetic drug interactions (pre-clinical)
4.2.2.7. Other pharmacokinetic studies
4.2.3. Toxicology
4.2.3.1. Toxicity with administration of a single dose
4.2.3.2. Toxicity with administration of repeated doses
4.2.3.3. Genotoxicity (in vitro, in vivo, toxicokinetic assessment)
4.2.3.4. Carcinogenicity (long-term studies, short-term or medium-term studies)
4.2.3.5. Reproductive and ontogenetic toxicity: ability to reproduce offspring and early embryonic development; fetal embryo development; intrauterine and postnatal development; studies in which offspring (growing animals) were given a certain dose and / or were assessed later.
4.2.3.6. Local tolerance
4.2.3.7. Other toxicity studies: antigenicity; immunotoxicity; mechanical studies; addiction; metabolites; admixtures.
4.3. Copy of the literature list used
Part 5. Reports on clinical studies and (or) trials
5.1. Contents
5.2. List of all clinical trials in table format
5.3. Clinical trials reports
5.3.1. Biopharmaceutical studies reports: report on bioavailability studies; report of comparative studies on bioavailability and bioequivalence; report on the correlation of in-vitro in-vivo studies; report on bioanalytical and analytical methods;
5.3.2. Reports on studies on pharmacokinetics in the use of human biomaterials: report on protein binding studies; report on studies of hepatic metabolism and interactions; report on research using human biomaterials.
5.3.3. Reports on pharmacokinetic studies in humans: report of pharmacokinetics studies in healthy volunteers and a study of primary tolerability; report of pharmacokinetic studies in patients and a study of primary tolerability; report of studies of the internal factor of pharmacokinetic studies; report of studies of the external factor of pharmacokinetic studies; report of pharmacokinetics studies in various populations;
5.3.4. Reports on pharmacodynamic studies in humans: report of studies of pharmacodynamics and pharmacokinetics / pharmacodynamics in healthy volunteers; report on pharmacodynamics and pharmacokinetics / pharmacodynamics studies in patients;
5.3.5. Reports on study of efficacy and safety: report of controlled clinical trials on the claimed indications; report of uncontrolled clinical trials; data analysis reports from more than one study, including any formal integrated analyzes, meta-analyzes and cross-analyzes; reports on other studies
5.3.6. Reports on the post-registration experience of the use
5.3.7. Samples of individual registration forms and individual patient lists
5.4. Copy of the literature list used

Note:

      * When extending the validity of the registration certificate issued by the authorized body in the field of health care in the Republic of Kazakhstan in accordance with the Rules of state registration, re-registration and modification of the registration dossier of the medicinal product, medical devices and medical equipment approved by the order of the Minister of Health of the Republic of Kazakhstan dated November 18, 2009 No. 735 (registered in the Register of state registration of regulatory legal acts under No. 5935) parts I-III of this list are presented.

      **The minimum amount of information required for submission in section 3.2.S.

If parts of the documentation are not included in the dossier, a justification must be provided in the relevant section.

      For animal products in Section 3.2.S, the following additional information should be provided: data on the species, age, diet of animals from which raw materials are obtained; data on the nature (category) of the tissue from which the raw material for production of the medicinal product is derived, in terms of its danger with regard to the content of prions; technological scheme for processing raw materials with an indication of extractants and technological parameters; methods of quality control of raw materials, including methods for identifying prions in a medicinal product (if necessary). It is allowed to provide documents of Parts 3, 4, 5 in English with the translation into Kazakh and Russian of the following sections of Part 3: specifications (3.2.P.5.1.), analytical methods (3.2.P.5.2.), justification of specifications (3.2. R.5.6.).

Appendix 4
to the Rules of examination of medicinal products
Form

Initial examination report (validation of the registration dossier) of the medicinal product

1. Initial examination (validation of the registration dossier) of the medicinal product is carried out
1) Full name of expert
2) Position of expert
2. Information about the medicinal product
1) Number and date of application
2) Trade name of the product
3) International non-proprietary name (hereinafter — INN)
4) Dosage form
5) Dosage rate
6) Concentration
7) Administration method
 3. Package
No. Package name Type of packaging (primary, secondary) Volume Number of units in package
1)
2)
4. Manufacturer data
No. Type of organization or production site Name of organization Country Legal address
1) Applicant
2) Manufacturer
3) Packer
4) Holder of the registration certificate
5. Dispatch procedure
1) Dispatch conditions:
(tick the necessary)
☐ by medical prescription
☐ without medical prescription
6. In the Republic of Kazakhstan, under the indicated trade name, another medicinal product with a different composition of active substances
1) ☐ no ☐ yes
7. Evaluation of fullness, completeness of registration dossier and correctness of execution of submitted documents
1) Dossier is divided into sections, the pages are numbered, the list of documents is compiled ☐ no
☐ yes
2) Set of documents corresponds to the approved list ☐ no
☐ yes
3) Presence of color layouts of packages and the fact of their certification by the applicant’s seal, compliance of the medicinal product package with the Rules for the Marking of Medicinal Products, Medical Devices and Medical Equipment approved by Order No. 227 of the Minister of Health and Social Development of the Republic of Kazakhstan dated 16 April 2015 (registered in the Register of State Registration of regulatory legal acts under No. 11088) (hereinafter — Order No. 227) ☐ no
☐ yes
4) Text of marking of samples of layouts of packing, labels, stickers corresponds to Order No. 227 ☐ no
☐ yes
 8. Evaluation of medicinal product composition
1) Presence in the composition of the medicinal product of prohibited dyes and other excipients ☐ no
☐ yes
2) Presence in the composition of the medicinal product of substances derived from blood, organs and tissues of humans and animals ☐ no
☐ yes
3) Presence of narcotic drugs, psychotropic substances and precursors in the composition (if necessary, specify the Table, number of the line) ☐ no
☐ yes
9. Evaluation of the name of the medicinal product for lack in it of the following:
1) similarity with previously registered medicinal products and words with cacophonous expressions ☐ no
☐ yes
2) ability to mislead about the true composition and effect of the medicinal product ☐ no
☐ yes
3) similarity of INN and / or similar names for a medicinal product of a different chemical composition or effect ☐ no
☐ yes
10. Evaluation of information about pharmacological effect of the medicinal product
1) Accordance of the structure and execution of the instruction for medical use of the medicinal product with the Rules for preparation and execution of instructions for medical use of medicinal products and medical items approved by the order No. 414 of the Minister of Health and Social Development of the Republic of Kazakhstan dated May 29, 2015 (registered in the Register of State Registration of regulatory legal acts under No. 11495)
11. Conclusions:
1) refuse further examination (with justification)
2) continue examination

     Head of structural unit ____________ _______________________
signature       Full name
Expert _____________ __________________________________________________________
signature       Full name

      Date ______________

      L.S.

Appendix 5
to the Rules of examination of medicinal products
Form

Report of the initial examination (validation of registration dossier) of changes made to the registration dossier of the medicinal product

1. Initial examination (validation of registration dossier) of the changes made to the registration dossier of the medicinal product
1) Full name of expert
2) Position of expert
2. Declared changes are of:
type I: type I А, type I B Indicate changes to be made
type II Indicate changes to be made
3. Information about medicinal product
1) Number and date of application
2) Trade name of the product
3) International Nonproprietary name
4) Pharmaceutical form
5) Dosage
6) Concentration
7) Administration method
8) Organization-manufacturer
9) No. of product license
4. Packaging
No. Packaging name Packaging (immediate, secondary) Volume Units per packaging
1)
2)
5. Data on manufacturer
No. Type of organization or production site Name of organization Country Legal address
1) Applicant
2) Manufacturer
3) Packager
6. List of changes
1) Document name Earlier revision Revised version
7. Evaluation of completeness of registration dossier and correctness of execution of submitted documents
1) The dossier is divided into sections, the pages are numbered, the inventory of documents is completed ☐ no
☐ yes
2) The set of documents corresponds to the approved list ☐ no
☐ yes
8. Conclusion:
1) refuse further expert evaluation (with justification)
2) continue expert evaluation

     Head of structural unit ____________ _______________________
signature       Surname, name, patronymic (if any)

Expert ______ __________________________________________________________
signature                   Surname, name, patronymic (if any)

      Date ______________

      Place of seal

Annex 6
to the Rules for conducting
in expert evaluation of medicines

The list of non-rational combinations of medicines

No. Name of medicine, combination
1. Fixed combinations of vitamins with tranquilizers
2. Fixed combinations of atropine/atropine-like medicines with analgesics and antipyretics
3. Fixed combinations of yohimbine with testosterone and vitamins
4. Fixed combinations of iron with yohimbine
5. Fixed combinations of antihistamines with antidiarrheal medicines
6. Fixed combinations of penicillins with sulfonamides
7. Fixed combinations of vitamins with analgesics (with the exception of paracetamol with vitamin C, acetylsalicylic acid with vitamin C)
8. Fixed combinations of quinolones with any other medicines, with the exception of preparations for external use
9. Fixed combinations of corticosteroids with any other oral medication
10. Fixed combinations of chloramphenicol with any other oral medication
11. Fixed combinations of vitamins with anti-tuberculosis drugs, with the exception of isoniazid with pyridoxine hydrochloride (vitamin B6)
12. Combinations of steroid anabolics with other drugs
13. Fixed combinations of sedative/hypnotics/anxiolytic drugs with analgesics-antipyretics/non-steroidal anti-inflammatory drugs
14. Fixed combinations of H2-histamine-receptor antagonists/proton pomp inhibitors with antacids
15. Fixed combinations containing more than one antihistamine drug substance
16. Fixed combinations of anthelmintic medicines with laxatives
17. Fixed combinations of drugs with bronchodilator action with antitussive drugs of central action and/or antihistamines
18. Fixed combinations of mucolytics/expectorants with antitussive drugs and/or antihistamines
19. Fixed combinations of laxatives and/or spasmolytic drugs with enzyme preparations
20. Fixed combinations of anti-emetic drugs of dopamine receptor inhibitors with drugs that have systemic absorption
21. Fixed combinations of antitussive drugs of central action with antihistamine drugs
22. Fixed combinations containing pectin and/or kaolin with any medicinal substances that are absorbed into the systemic circulation from the gastrointestinal tract, with the exception of combinations of pectin and/or kaolin with drugs without systemic absorption
23. Fixed combinations of antidiarrhoeal drugs with electrolytes
24 Fixed combinations of oxyphenbutazone or phenylbutazone with any other drugs
25. Fixed combinations of analgin with any other drugs
26. Fixed combinations of non-steroidal anti-inflammatory drugs/paracetamol/analgin with atropine-like drugs/antispasmodics
27. Fixed combinations of non-steroidal anti-inflammatory drugs/paracetamol/analgin with opioid analgesics/opioid-non-opioid analgesics
28. Fixed combinations of two or more non-steroidal anti-inflammatory drugs
29. Fixed combinations of paracetamol with barbiturates, tranquilizers and other drugs, enzyme inducers of the cytochrome liver system.
30. Fixed combinations of paracetamol (above 200 mg in a single dose) with non-steroidal anti-inflammatory drugs, except for short-term medications
31. Fixed combinations of penicillin with streptomycin in parenteral dosage forms
32. Fixed combinations of pancreatin or pacralipase containing amylase, protease and lipase, with any other enzymes, including bovine bile, hemicellulose
33. Fixed combinations of nitrofurantoin and trimethoprim
34. Fixed combinations of barbiturates with other drugs, except for plant origin
35. Fixed combinations of drugs that depress the central nervous system with stimulants of the central nervous system
36. Fixed combinations of barbiturates with hyoscyamine and/or hyoscyline, belladonna and other atropine-like drugs
37. Fixed combinations of barbiturates with ergotamine
38. Fixed combinations of haloperidol with any anticholinergic drugs
39. Fixed combinations of antibacterial and antiprotozoal drugs
40. Fixed combinations of loperamide hydrochloride with furazolidone
41. Fixed combinations of antibacterial drugs and probiotics, prebiotics
42. Fixed combinations of cyproheptadine with lysine or peptone
43. Fixed combinations of non-steroidal anti-inflammatory drugs/paracetamol/acetylsalicylic acid and antacids/H2-blockers/proton pomp inhibitors
Annex 7
to the Rules for conducting
in expert evaluation of medicines
Form

Summary experts report on the evaluation of the medicinal product

      1. Examination of the registration dossier of the medicinal product

1. Surname, name, patronymic (if any) and position of experts
2. Scientific degree, rank
3. Application name
4. Date
5. Preparation commercial name
6. International non-proprietary name (hereinafter — INN)
7. Medical product is ☐ Original medical product
☐ Reproduced medical product
☐ Biosimilar medical product
☐ Hybrid medical product
☐ Biological medical product
☐ Combined medical product
☐ Medicinal product with a well-studied medical application
☐ Radiopharmaceutical medicinal product or precursor
☐ Homeopathic medical product
☐ Herbal medicine
☐ Orphan medical product
☐ Active pharmaceutical substance produced not in GMP conditions
☐ Medical bulk product
☐ Biological bulk product
☐ Medical natural raw material (not pharmacopeial)
Studies of aqueous solutions of generic drugs in vitro
Introduction of the transfer of production and technological processes
8. For generic, indicate the name of the original medicinal product
9. Pharmaceutical form
10. Dosage
11. Concentration
12. Therapeutic class
13. Code in accordance with the anatomic-therapeutic-chemical classification (hereinafter — anatomic-therapeutic-chemical)
14. Availability ☐ with/without prescription

      2. Packaging

No. Packaging name Packaging (immediate, secondary) Volume Units per packaging No. Brief description
1.
2.

      3. Data on manifacturer

No. Type of organization or production site Name of organization Country Legal address
1. Applicant
2. Manufactured by
3. Packed by
4. Production section
5. Registration certificate holder

4. Registration in the manufacturer’s country and other countries

No. Country Registration certificate No. Issued on Validity term
1.
2.

5. In the result of the expertise the following was established:

1) Formula of the medicinal product and conclusion on its efficiency and compatibility of ingredients (drug substances and auxiliary matters, including preservatives, medication shell compounds shall be given):

No. Name Quantity per pharmaceutical form Medicinal Product Quality and Safety Control Regulatory Instrument, or State Pharmacopeia of the Republic of Kazakhstan, foreign pharmacopeias acknowledged effective in the territory of the Republic of Kazakhstan
1. Drug substance(s):
2. Auxiliary matters:
3. Formula of pill shell or capsule body:

2) For medicinal herbs

No. Latin botanic names of plants in the harvest composition Medicinal Product Quality and Safety Control Regulatory Instrument, or State Pharmacopeia of the Republic of Kazakhstan and foreign pharmacopeias acknowledged effective in the territory of the Republic of Kazakhstan Wild or cultivated Place of vegetation
1.
2.

6. Producers of active substances in the medicinal product composition

No. Name of substance in the medicinal product composition Name of producer in Russian and English languages Country* Address of manufacturing facility in Russian and English languages
1.
2.

7. In case of a substance in the medicinal product subjected to control according to the Law of the Republic of Kazakhstan dated July 10, 1998 “On narcotic drugs, psychotropic substances, their analogues and precursors, and countermeasures on their illegal trafficking and abusing”:

1) Conclusion on appurtenance to the controlled substances (based on studying the international nonproprietary name, trade name, chemical name, structural formula on appurtenance to the controlled substances stating the entry in the List Table, whether the substance is a stereoisomer of narcotic drugs of Table II, in cases when the existence of such isomers is possible in the framework of the certain chemical notation (if those are not excluded explicitly), salt of all narcotic drugs given in Table II, including isomer salts, as set forth above, in all cases when the existence of such salts is possible; salt of psychotropic substances in Table II and Table III when the existence of such salts is possible.
2) Scientifically grounded risk evaluation of abuse: high risk of abuse, or no risk of abuse, or negligible risk;

Determination of maximum allowable content of narcotic drugs, psychotropic substances and precursors in medicinal products.

3) Conclusion on the possibility or impossibility of easy extraction of the controlled substance in quantities sufficient for the abuse.
4) Conclusion on clearing certain control measures with regard to the product.

8. Analysis of data about the origin, registration in the Republic of Kazakhstan, quality and conclusions on the possibility of substance usage (without GMP Certificate)

_____________________________________________________________________________

9. Analysis of data about quality, quantity with conclusions on the admissibility of usage of the utilized auxiliary matters

_____________________________________________________________________________

10. Conclusion about production (production formula, description of production technology, production control, primary expertise of production processes)

_____________________________________________________________________________

11. Characteristics of the ready product (correspondence of the presented parameters in the Finished Product Quality Certificate or Manufacturing Company Certificate to the described quality control methods in the regulatory documentation, correspondence of the series of presented specimens to those given in the certificate)

_____________________________________________________________________________

12. Conclusion about marking and packaging as for their sufficiency for providing the preservation of quality of the medicinal product during storage and transportation (necessity in additional inscriptions), availability of specifications on the primary and secondary packaging. Sanitary conclusion for the packaging (for domestic producers)

____________________________________________________________________________

13. Conclusion on the availability or absence in the medicinal product name of the following:

1) Graphic similarities with the previously registered medicinal products and words with cacophonous expressions;

2) Possibility of misleading about the true content and effect of the product;

3) Similarity of the INN and/or names similar to them for the medicinal product with another chemical composition or effect.

14. Specifications of the finished product

_____________________________________________________________________________

15. Conclusion about the data of chemical, pharmaceutical and biological (in-vitro) equivalence given on the medicinal product by the company

_____________________________________________________________________________

16. Conclusion of stability of the medicinal product, supportability of the given shelf life

_____________________________________________________________________________

17. Analysis and evaluation of drafts of the instructions for medical use of the medicinal product, packaging and label mock-ups, verification on the equivalence of instructions about storage and transportation conditions given in the draft of the medicinal product quality and safety regulatory document with the above drafts

____________________________________________________________________________

18. Conclusion on medicinal product storage and transportation conditions, and the necessity in introducing additional requirements for providing the medicinal product quality preservation

_____________________________________________________________________________

19. Analysis of the medicinal product quality and safety regulatory document of the producer and finished product quality control methods

____________________________________________________________________________

20. Comparison with analogues registered in the Republic of Kazakhstan. Comparative characteristics of the main quality figures

____________________________________________________________________________

21. Analysis of accuracy of the qualitative and quantitative composition of active and auxiliary substances given in the instructions for medical use comparing with the stated composition in the statement, analytical regulatory document and packaging mock-up

________________________________________________________________

22. Evaluation of pharmacologic compatibility of components, in case of registration of the reproduced medicinal product the comparison with the original product composition shall be given

____________________________________________________________________________

23. * Analysis of documentation on pre-clinical research: toxicity (acute, chronic, LD50, LD100), carcinogenicity, embryotixicity, teratogenicity, mutagenity, local irritation, effect on the immune system, specific pharmacologic (biological) activity.

Note: when evaluating the biosimilars the product of comparison used at all stages of comparative research (from pharmaceutical development to clinical examinations) shall be given: name, active substance, manufacturer, manufacturing country, series, shelf life __________________________________________

24. * Analysis of clinical examination documentation (phases of clinical examinations, post-marketing research, minutes and reports, conclusions of the Ethic Commission). The place, date, sponsor of examination, aim, design, examination duration, quantity, sex and age of those tested, regime of product dosing, monitoring of side effects in the course of the clinical research, correspondence of the report to the minutes, conclusion on the “benefit-risk” relation.

Note: when evaluating the biosimilars the product of comparison used at all stages of comparative research (from pharmaceutical development to clinical examinations) shall be given: name, active substance, manufacturer, manufacturing country, series, shelf life.

25. According to the requirements of the present Rules the registration dossier includes:

Report of comparative pharmacokinetic research (bioequivalence research)

____________________________________________________________________________

Report of comparative pharmacodynamic clinical research

____________________________________________________________________________

Report of comparative research of therapeutic equivalence

_____________________________________________________________________________

Report on comparative in-vitro research

____________________________________________________________________________

1) The applicant, possessing the document which confirms the correspondence of production of the good manufacturing practice of countries-regions of ICH, PIC/S, Republic of Kazakhstan, is not required to provide the in-vivo equivalence research reports

____________________________________________________________________________

2) In case of differences in the composition of auxiliary substances the applicant shall prove that during their usage there will be no safety and/or efficiency impact of the medicinal product; if the applicant is unable to provide such information and has no access to the corresponding data, it shall perform the duly examinations (pharmaceutical or pre-clinical, or clinical) in order to prove the absence of impact of various auxiliary substances or auxiliary designs on safety and/or efficiency impact of the medicinal product

_____________________________________________________________________________

3) The applicant shall provide the proof of in-vivo equivalence if there is a risk, that possible differences in bioavailability result in therapeutic inequivalence of the generic to the reference product (according to the requirements of this order)

4) For generics in instant release solid oral dosage forms and concentration of the active substance, which can be measured in the biological body fluids (blood plasma, urine) the bioequivalence research data shall be given.

For generics in instant release solid oral dosage forms, the concentration of the active substance which cannot be measured in the biological body fluids, the comparative pharmacodynamic clinical research data or comparative therapeutic equivalence research data shall be given

_____________________________________________________________________________

5) For generics quoted in the biowaiver procedure

_____________________________________________________________________________

6) During the evaluation of domestic generic products base on complete transfer of production and engineering processes, the registration dossier provides the proofs that the production conditions at the production facility in the Republic of Kazakhstan completely corresponds the production conditions of the facility outside Kazakhstan:

1) Agreement on transfer of production and engineering processes with the right of use of all documents and registration dossiers, including the bioequivalence research, clinical research data between domestic producer and foreign manufacturer ________________________________;

2) Results and intervals of the audit of production conditions at the domestic production facility by the foreign manufacturer handing over its production and engineering processes ______________________________;

3) Primary expertise of production processes at the domestic production facility ___________________________________________;

4) Confirmation that the quality of the starting raw material (active substance, auxiliary substances, etc.) used at the domestic facility does not influence the process or finished product _________________________________________;

5) Control of the quality of products produced at the domestic production facility and products of the foreign producer is made as per the only specifications (same admixture profile, pharmacokinetic dilution profile (for solid dosage forms), and other in-vitro research)

__________________________________________________________________;

6) Reports on bioequivalence research, clinical research of medicinal products produced at the production facilities outside Kazakhstan;

7) Report of the inspection by the authorized body of the domestic production facility and production facility of the foreign manufacturer confirming the conditions of transfer observance ________________________________________.

8) * Analysis of data on in-vivo research equivalence (minutes and reports, conclusions of the Ethic Commission). The place, date, sponsor of examination, aim, examination duration, tested product, reference product, pharmaceutical form, dosing regime, administration route, quantity, sex and age of those tested, monitoring of side effects, correspondence of the report to the minutes, bioanalytical methods of the research, internal standard, individual chromatograms, pharmacokinetic curves, static data on pharmacokinetic parameters (in the form of tables), bioequivalence conclusion. Correspondence of the bioequivalence research to the requirements of the Republic of Kazakhstan.

Note: when providing the in-vivo equivalence research (pharmacodynamic or therapeutic equivalence): aim, design, duration of examination, monitoring of side effects in the course of clinical research, correspondence of the report to the minutes, conclusion about comparable efficiency and safety of the generic with the reference product.

26. * Separate types of medicinal products:

1) For the expertise of herbal medicinal products the results of the corresponding pharmacologic, toxicologic and clinical research shall be given. Materials and documents on pre-clinical (non-clinical) and/or clinical research shall include the following:

Materials of pre-clinical (non-clinical) specific activity research

___________________________________________________________________________;

Materials of acute and chronic toxicity research

__________________________________________________________________________

Data on local irritation

_____________________________________________________________________;

Data on allergenic properties

__________________________________________________________________;

Experience of clinical usage in the manufacturing country or other countries.

For the harvest of the medicinal herbal raw materials, phyto-teas the review of scientific literature on medicinal herbs in their composition shall be presented.

2) For the expertise of medicinal products containing vitamins and/or presenting a complex of vitamins and/or vitamins and minerals the applicant shall provide one of the below documents and materials:

Bibliographic review of data on safety of medicinal products together with the expert’s report, including the information about the expert

_____________________________________________________________________;

Scientific publications on the applied product _________________________________;

Data about acute and/or chronic toxicity research

___________________________________________________________________.

3) For the expertise of homeopathic preparations the applicant shall provide documents and materials, that include the following information on Parts 4 and 5 or Parts 3 and 4 of the List:

for the products of long-term experience of application: review of data of scientific literature about efficiency and safety of the homeopathic preparation in the declared application area

_____________________________________________________________________;

For new homeopathic preparations not stated in pharmacopeias and monographs: data of toxicologic research, substantiation of selection of various potencies, data of clinical experience of application __________________________________;

instructions for medical use stating that the medicinal product is a homeopathic product

____________________________________________.

4) For the medicinal products, which active substance is studied well in the medical application, the following data are presented:

1) Factors to be taken into account when defining the well-studied medical use of components of the medicinal products:

time during which the active substance is used in medical practice

______________________________________________________________________

quantitative aspects of use of the active substance

____________________________________________________________________

degree of scientific interest and relevance of use of the active substance during the last 5 years before the application was filed (with reference to the published scientific sources)

_________________________________________________________________

consistency of scientific assessments __________________________________________

For determining the well-studied application of various active substances the assessment for the different periods of time may be required. The period of time, required for determining the well-studied medical application of the active substance, shall be at least 15 years from the date of the first systematic and documented use of such active substance as a medicinal product.

2) Materials of the registration dossier presented by the applicant shall compose of all aspects of safety and efficiency assessment, contain or provide a reference to the review of the corresponding literature taking into account the pre- or post-registration research and published scientific literature related to the results of epidemiologic examinations and, in particular, comparative epidemiologic examinations, all documentation both positive and negative. The bibliographic reference to other sources of proofs (post-registration examinations, epidemiologic examinations), besides the data related to the control and test methods, can be a proof of safety and efficiency of the medicinal product provided that the materials of the registration dossier clearly explained and substantiated the use of such sources of information __________________________________________________________;

3) It should be substantiated why the admissible level of safety and/or efficiency can be considered as proven despite the absence of certain examinations

___________________________________________________________________;

4) In pre-clinical and/or clinical reviews the significance of any presented data related to the already registered medicinal product different from the one proposed for the reregistration must be explained. The substantiation on whether the declared medicinal product can be considered as similar to the already registered medicinal product shall be given despite the existing discrepancies ______________________________________________________;

5) Post-registration experience of use may contain the information about the use of other medicinal products containing the same components;

6) Periodically updated report on medicinal product safety for the last 5 years before the application was filed, and confirmation of its intensive utilization in the manufacturing country for the last 5 years before the application was filed (for foreign producers) _________________________________________________________________

27. Assessment of the source of origin (blood, human and animal organs and tissues) and specific activity for immunological products

___________________________________________________________________

28. * Assessment of the medicinal product safety and efficiency based on the results of clinical research with regard to the declared age groups of sick persons, substantiation of the choice of indications for use, contraindications, admonitions when using the product, profile of side effects

_____________________________________________________________________

29. To be filled in only in case if the application is filed for the state reregistration of the medicinal product

_______________________________________________________________.

Evaluation of safety and efficiency of the medicinal product based on the data of safety reports updated on a regular basis — analysis of the safety profile, recording new side effects, contraindications in the brief characteristics of the medicinal product and instructions for medical use or refusal on reregistration of the product, amendments in the product registration status in other countries, updated data about the measures taken by the regulatory authority or producer for security reasons, changes in the information on the product safety, sale volumes, quantity of patients obtained the product for the reported period, studying the description of individual cases and the list of side effects and consolidated tables, individual cases of developing side effects found by the registration certificate holder, the nature and quantity of serious side effects and those not registered by the company earlier. General evaluation of safety based on the data of periodically updated safety reports and conclusion about safety profile preservation or change, introducing new side effects, contraindications into the instructions for medical use or on reregistration of the product.

Note: conduction of the expertise of products-biosimilars according to the requirements:

For the expertise in case of state reregistration of the biological medicinal product, including the biosimilar, Parts 1-3 of the List, from Part 5 shall be presented:

1) Periodically updated safety report or periodic report

_____________________________________________________________________

2) Results of monitoring of the Plan of risk management and risk mitigation, immunogenicity when using the biological medicinal product, including in the Republic of Kazakhstan, obtained in the result of:

post-registration observational research of safety and efficiency of the medicinal product (by means of active monitoring method, random control method or cohort retrospective and/or prospective studies) _______________________

Analysis of registers of patients obtaining treatment using the certain biological medicinal product

__________________________________________________

Post-marketing clinical research _________________________________

Conduction of training events on raising awareness of physicians, pharmaceutists and patients in order to decrease the risks related to the application of the biological medicinal product in the Republic of Kazakhstan.

30. Evaluation of safety and efficiency of the medicinal product taking into account the “benefit-risk” relation — contraindications, warning and admonitions when using the product. Particular attention shall be paid to the childhood age, pregnant and breastfeeding women, elderly people, patients with renal or hepatic failure

____________________________________________________________________

31. Expertise of the instructions for medical use is performed in comparison with the brief characteristic of the medicinal product. Conclusion shall be made about the correspondence or non-correspondence of indications for use, side effects, contraindications, specific indications, drug interactions, overdosage stated in the instructions for medical use of the medicinal product, brief characteristic of the medicinal product.

_____________________________________________________________

32. Conclusion on the availability or absence in the medicinal product name of the following:

1) Graphic similarities with the previously registered medicinal products and words with cacophonous expressions

________________________________________________________________

2) Possibility of misleading about the true content and effect of the product ___________________________________________________________

3) Similarity of the INN and/or names similar to them for the medicinal product with another chemical composition or effect

______________________________________________________________

33. Assessment of correctness of code assignment of the Anatomical Therapeutic Chemical (hereinafter referred to as ATC) Classification, correspondence of the pharmacotherapeutic group to the ATC Classification code, pharmacological action, indications for use. In case of the incorrectly declared ATC code and pharmacotherapeutic group, those recommended by the expert shall be stated

__________________________________________________________________

34. Verification of adequacy of declared doses and dosing regime according to the pharmacokinetic parameters (half-life period, degree of blood plasma and protein fixation, effect on liver enzyme activity, bacteriostatic/bactericidal concentration hold time in case of antimicrobial drugs). Attention should be paid to the doses recommended for children, elderly people, sick people having kidney and liver function disorders

______________________________________________________________

35. Verification of correspondence of the declared shelf life, given in the statement, in brief characteristics of the medicinal product, to the instructions for medical use, packaging mock-ups with the shelf life set forth in the regulatory document

36. Correspondence of the presented instrucitons for medical use to the effective legislation of the Republic of Kazakhstan.

37. Detailed description of the pharmacovigilance and risk management system:

1) Brief characteristic of the pharmacovigilance system of the registration certificate holder shall contain the following elements:

proof that the holder of the registration certificate has at command a responsible person for global pharmacovigilance

__________________________________________________________________

contact data of the responsible person for global pharmacovigilance ____________

declaration signed by the holder of the registration certificate that it has the pharmacovigilance system for fulfilling the tasks and obligations on post-registration control of medicinal product safety __________________

reference to the place (address) where the master file of the pharmacovigilance system is stored _______

2) Contact person for local pharmacovigilance in the Republic of Kazakhstan:

document confirming appointment of the responsible person for pharmacovigilance in the Republic of Kazakhstan

_____________________________________________

Contact data of the responsible person for pharmacovigilance in the Republic of Kazakhstan

__________________________________________________________________

3) Risk management plan in case medical application of the medicinal product, applied for registration/reregistration or amendments (for the original products, biosimilars, vaccines, blood products, generic products requiring special control)

Conclusion:

positive or negative (with substantiation)

Note:

sections with the * mark shall be filled in case of extension of the validity term of the registration certificate

Date of arrival of documents to expert
Date of finish of document expertise

All data, provided in the expert conclusion, are accurate and meet the up-to-date requirements, that is confirmed by the personal signature.

Last name, given name, patronymic (if any) of experts

___________________________

Signature ____________________

Date
Supplement 8

to the Rules of medicinal product expertise

Form

Consolidated report of experts on the assessment of the medicinal product in case of amendments made in the registration dossier

1. Last name, given name, patronymic (if any) and position of expert
2. Academic degree, capacity
3. Application No.
4. Date
5. Trade name of the product
6. International nonproprietary name
7. Medicinal product ☐ Original medicinal product

☐ Reproduced medicinal product

☐ Biosimilar medicinal product (biosimilar)

☐ Hybrid medicinal product

☐ Biological medicinal product

☐ Combined medicinal product

☐ Medicinal product with well-studied medicinal application

☐ Radiopharmaceutical medicinal product or precursor

☐ Homeopathic medicinal product

☐ Herbal medicinal product

☐ Orphan medicinal product

☐ Active pharmaceutical substance not produced in GMP conditions

☐ Medicinal bulk product

☐ Biological bulk product

☐ Medicinal natural raw material (non-pharmacopoeial)

examinations of aqueous solutions of in-vitro generic products
introduction of transfer of production and engineering processes
8. In case of the reproduced medicinal product or biosimilar the name of the original medicinal product shall be given
9. Pharmaceutical form
10. Dosage
11. Concentration
12. Pharmacotherapeutic group
13. Code as per the Anatomical Therapeutic Chemical Classification
14. Dispensing method ☐ On prescription ☐ OTC

2. Packaging

No. Name of packaging Type of packaging (primary, secondary) Size Volume Units in package
1.

3. Data about manufacturer

No. Type of organization or production section Name of organization Country Legal address
1. Applicant
2. Manufactured by
3. Packed by
4. Production section
5. Registration certificate holder

4. Registration in the manufacturer’s country and other countries

No. Country Registration certificate No. Issued on Validity term
1.
2.

5. 1) Formula of the medicinal product (drug substances and auxiliary matters, including preservatives, medication shell compounds shall be given):

No. Name Quantity per pharmaceutical form Medicinal Product Quality and Safety Control Regulatory Instrument, or State Pharmacopeia of the Republic of Kazakhstan, foreign pharmacopeias acknowledged effective in the territory of the Republic of Kazakhstan
1. Drug substance(s):
2. Auxiliary matters:
3. Formula of pill shell or capsule body:

2) For medicinal herbs

No. Latin botanic names of plants in the harvest composition Medicinal Product Quality and Safety Control Regulatory Instrument, or State Pharmacopeia of the Republic of Kazakhstan and foreign pharmacopeias acknowledged effective in the territory of the Republic of Kazakhstan Wild or cultivated Place of vegetation
1.
2.

6. Producers of active substances in the medicinal product composition

No. Name of substance in the medicinal product composition Name of producer in Russian and English languages Country* Address of manufacturing facility in Russian and English languages
1.
2.

7. 1) Formula of the medicinal product (drug substances and auxiliary matters, including preservatives, medication shell compounds shall be given):

No. Name Quantity per pharmaceutical form Medicinal Product Quality and Safety Control Regulatory Instrument, or State Pharmacopeia of the Republic of Kazakhstan, foreign pharmacopeias acknowledged effective in the territory of the Republic of Kazakhstan
1. Drug substance(s):
2. Auxiliary matters:
3. Formula of pill shell or capsule body:

2) For medicinal herbs

No. Latin botanic names of plants in the harvest composition Medicinal Product Quality and Safety Control Regulatory Instrument, or State Pharmacopeia of the Republic of Kazakhstan and foreign pharmacopeias acknowledged effective in the territory of the Republic of Kazakhstan Wild or cultivated Place of vegetation
1.
2.

8. Producers of active substances in the medicinal product composition

No. Name of substance in the medicinal product composition Name of producer in Russian and English languages Country* Address of manufacturing facility in Russian and English languages
1.
2.

9. Type of changes

1) Type of amendments according to Annex 17 Introduced amendments Old version New version

10. Assessment of the registration dossier on the quality, safety and efficiency aspects ___________________________________________________________________

Recommendations:

1) Declared amendments of type _______ (give the type) do not produce influence on the quality, safety and efficiency of medicinal products. Declared amendment can be recommended for the registration. Conditions for introducing amendments under the declared type of amendments are observed.
2) Declared amendments of type _______ (give the type) produce influence on the quality, safety and efficiency of medicinal products. Declared amendment cannot be recommended for the registration.
3) According to the declared amendments the documents of the registration dossier are not presented in full according to Annex 17, or the conditions for introducing amendments under the declared type of amendments are not observed. Documents shall be reviewed for the second time after additional materials on expert’s demand are presented:

Date of arrival of documents to expert _______________________

Date of finish of document expertise ______________________

All data, provided in the expert conclusion, are accurate

and meet the up-to-date requirements, which is confirmed by the personal signature.

Last name, given name, patronymic (if any) of experts _______________

Signature _______________

Date

Annex 10
to the Rules for Conducting of Drug Products Expertise
Form

Report on laboratory test results in the manufacturer’s quality control laboratory or in the contract laboratory used by the manufacturer

      1. Summary

Drug product name
Name, address and requisites of manufacture site
Name, address and requisites of quality control laboratory and / or quality control contract laboratory
Basis for laboratory test conduct
License numbers (if any), certificates, applications for testing at state registration
Summary of quality control laboratory activities Laboratory tests conduct
Start of drug products series sale
Other (please specify)
Date (s) of laboratory test
Experts surname, name and patronymic (if any), title

      2. Background Information

Short description of quality control laboratory
Availability of documented test procedures
Compliance with the requirements of documented test procedures
Purpose of laboratory test
Testing objects
Personnel of quality control laboratory participating the laboratory test
Documents submitted by the manufacturing organization and/or quality control laboratory before assessment of production conditions and quality assurance system

      3. Observations and laboratory test results

Normative document, references
Serial number, manufacture date
Indicator Normative document requirements Actual results С, humidity Complies / does not comply

      4. Annexures

Documents (primary data, test reports) and samples taken during the laboratory test

      5. Recommendations and conclusions

Recommendations
Conclusions

Remark:

      * It is necessary to attach the report on laboratory test results, copy of analysis certificate and/or test report for the products issued by the manufacturer’s quality control laboratory or contract laboratory used by the manufacturer. All annexes to the report are an integral part of it.

      Committee heads:
____________ ___________________________________________________________________
(signature)                         Surname, name, patronymic (if any), title
committee members:
____________ ___________________________________________________________________
(signature)                         Surname, name, patronymic (if any), title
____________ ___________________________________________________________________
(signature)                         Surname, name, patronymic (if any), title
«____» _______________________20____ .

      Approved by:
___________ _________ ___________________________________________________________
(title) (signature)             Surname, name, patronymic (if any), title
___________ _________ ___________________________________________________________
(title) (signature)             Surname, name, patronymic (if any), title

Annex 11

to the Rules for Conducting of Drug Products Expertise

Conclusion on safety, efficacy and quality of drug product claimed for testing

      1. The Republican State Enterprise on the right of economic management «National Center for Expertise of Drug products, Medical Devices and Medical Equipment» of the Ministry of Health of the Republic of Kazakhstan reports on the results of safety, efficacy and quality of Drug product expertise.

Number and date of application
Trade name of the drug product (indicating dosage form, dosage, concentration and volume of filling, number of doses in the package for the drug product)
Manufacturer organization, country of origin
Conclusion made by initial expertise (master file validation) (positive or negative)
Conclusion made by testing laboratory: date and protocol number, (positive or negative)
Conclusion made by specialized expertise (positive or negative)

      2. Conclusion (positive): Materials and documents of the Drug Master File (trade name of the drug product, indicating dosage form, dosage, concentration and volume of filling, number of doses in the package) claimed for expertise, comply with the requirements, safety, efficacy and quality of the drug products are confirmed by appropriate materials and tests conducted.

      Conclusion (negative): Materials and documents of the Drug Master File (trade name of the drug product, indicating dosage form, dosage, concentration and volume of filling, number of doses in the package) claimed for expertise, do not comply with the requirements, safety, efficacy and quality of the drug products are not confirmed by appropriate materials and tests conducted.

      Head of the State Expert Organization:
____________________________________________________________________
Signature                         Surname, name, patronymic (if any), title
Date ____________
Stamp here

Annex 12

to the Rules for Conducting of Drug Products Expertise

Form

Conclusion on safety, efficacy and quality of drug product claimed for testing of changes made to the master file

      1. The Republican State Enterprise on the right of economic management «National Center for Expertise of Drug products, Medical Devices and Medical Equipment» of the Ministry of Health of the Republic of Kazakhstan reports on the results of safety, efficacy and quality of Drug product expertise.

Number and date of application
Trade name of the drug product (indicating dosage form, dosage, concentration and volume of filling, number of doses in the package for the drug product)
Manufacturer organization, country of origin
Changes are classified as Type I, Type I B, Type II
Conclusion made by initial expertise (master file validation) of drug product (positive or negative)
Conclusion made by testing laboratory: date and protocol number, (positive or negative)
Conclusion made by specialized examination (positive or negative)

      2. Conclusion (positive): Materials and documents of the Drug Master File remained unchanged (trade name of the drug product, indicating dosage form, dosage, concentration and volume of filling, number of doses in the package) claimed for expertise, comply with the requirements, safety, efficacy and quality of the drug products are confirmed by appropriate materials and tests conducted.

Conclusion (negative): Materials and documents of the Drug Master File (trade name of the drug product, indicating dosage form, dosage, concentration and volume of filling, number of doses in the package) claimed for expertise of changes, do not comply with the requirements, safety, efficacy and quality of the drug products are not confirmed by appropriate materials and tests conducted.

     Head of the State Expert Organization:
_________________________________________________
signature                   Surname, name, patronymic (if any), title

Date ______________

Stamp here

Annex 13

to the Rules for Conducting of Drug Products Expertise

Form

      Date __________ Stamp here

Қазақстан Республикасы Денсаулық сақтау министрлігінің «Дәрілік заттарды, медициналық мақсаттағы бұйымдарды және медицина техникасын сараптау ұлттық орталығы» шаруашылық жүргізу құқығындағы республикалық мемлекеттік кәсіпорны The Republican State Enterprise on the right of economic management » National Center for Expertise of Drug products, Medical Devices and Medical Equipment» of the Ministry of Health of the Republic of Kazakhstan
__________________

Summary report on safety, efficacy and quality of the drug product

«Name of the drug», manufacturer, country

      Confidential information was excluded from the report

      1. Reference information about the procedure

      1.1. Submission of master file

      2. Scientific discussion

      2.1 Quality aspects

      2.1.1 Active pharmaceutical substance: analysis of origin and quality information and conclusions on substance use potential

      2.1.2. Excipients: analysis of quality and quantity information including conclusions on allowability of use

      2.1.3 Conclusion on medical product about production, quality specification and stability

      2.2. Non-clinical aspects

      2.3 Clinical aspects

      2.4 Benefit-risk analysis

      2.5 Pharmacovigilance Description of Pharmacovigilance System Risk Management Plan

      2.6 Prescription status

Annex 14

to the Rules for Conducting of Drug Products Expertise

Information about excipients, its nominal content in medical products, as well as restrictions on drug product use

Name of Excipients Administration route Permissible limits of excipients content Information to be included in the instructions for medical use Comments **
1 2 3 4 5 6
1. Aprotinin Topical * Hypersensitivity or a serious allergic reaction
2. Peanut oil Topical, oral, parenteral * Contraindicated to persons with allergic reaction to nuts or soy Purified peanut oil ,may contain protein
3. Aspartame (Е951) Oral * Contains phenylalanine, contraindicated to persons with phenylketonuria May cause harm to persons with phenylketonuria
4. Azo dyes:

1) E 102 Tartrazine

2) Е 110 Yellow sunset (FCF)

3) E 122 Azorubin, Carmoisin

4) E 124 Ponso 4R (crimson 4R), Cochineal red A

5) Е 151 Diamond black BN, black PN

Oral * Allergic reactions E 102, E 110, E 122 are prohibited for use in drug products for children
5. Erythrosin (E127) Oral 0 — 0,1 mg/kg Drug cannot be prescribed and administered to the patients with thyroid pathology Prohibited for use in drug products for children
6. Peru balsam Topical * Skin reactions are possible
7. Benzalkonium chloride Ophthalmic dosage forms * Irities are possible;

Avoid contact with soft contact lenses;

Remove contact lenses before use and wait at least 15 minutes after instillation;

Does not apply in children under 8 years old

Benzalkonium chloride discolours soft contact lenses
Topical * Skin reactions
Inhalation 10 μg / 1 dose Bronchospasm
8. Benzoic acid and benzoates:
1) E210 benzoic acid

2) E211 sodium benzoate

3) E212 potassium benzoate

Topical * Irritation of skin, eyes and mucous membranes
Parenteral * Contraindicated to newborn infants High risk of jaundice in newborns
9. Benzyl alcohol Parenteral If dose of less than 90 mg / kg / day Contraindicated to preterm, newborn and children under 3 years;

adverse effect — anaphylactoid reactions;

the amount of benzyl alcohol in the preparation (mg/ml)

Possible cases of toxic and allergic reactions in children under 3 years
If dose of less than 90 mg / kg / day Contraindicated to preterm, newborn and children under 3 years;

when benzyl alcohol is used at doses of 90 mg /kg/day and higher, risk of fatal toxic reactions increases

10. Bergampton Bergampton Oil Topical * Increased sensitivity to ultra-violet rays (both to natural and artificial rays) Not used if oil contains bergapten
11. Bronopol Topical * Local skin reactions (contact dermatitis)
12. Butylhydroxyanisole Е320 Topical * Local skin reactions (contact dermatitis), eye and mucous membrane irritation
13. Butylhydroxytoluene Е321 Topical * Local skin reactions (contact dermatitis), eye and mucous membrane irritation
14. Castor oil, polyethoxylated;
castor oil, polyethoxylated hydrogenated
Parenteral * Serious allergic reactions
Oral * Gastrointestinal tract disease and diarrhea
Topical * Skin reactions
15. Cetostearyl alcohol;
cetyl alcohol
Topical * Local skin reactions (contact dermatitis)
16. Chlorcresol Topical Parenteral * Allergic reactions
17. Dimethylsulfoxide Topical * Skin Irritations
18. Ethanol Oral и parenteral Content of ethanol in a single dose of less than 100 mg Drug contains a low level of ethanol Containing ethanol, less than 100 mg in a single dose
from 100 mg to 3 g of ethanol in a single dose Contraindicated:

to persons suffering from alcoholism, epilepsy, children, pregnant and lactating women, patients with liver diseases

Oral и parenteral 3 g in a single dose of the drug Contraindicated:

to persons suffering from alcoholism, epilepsy, children, pregnant and lactating women and patients with liver diseases; effects on ability to drive and use machines; effects and alters other drugs effect

Quantity of ethyl alcohol in these drugs can influence and alter other drugs effect
19. Formaldehyde Topical * There are cases of local skin reactions (contact dermatitis)
Oral * Gastrointestinal tract disease and diarrhea
20. Fructose Oral * Before prescribing of drugs it is necessary to test the fructose tolerability; Contraindicated for patients with hereditary intolerance to fructose
Parenteral 5 g Amount of fructose in in a single drug dose, g;
do not prescribe to patients with diabetes mellitus
Oral liquid, chewable tablet * Harmful to the teeth In case of long-term use for two or more weeks
21. Galactose Parenteral * Contraindicated for persons with hereditary intolerance to galactose, galactosemia
Oral * Contraindicated for persons with hereditary intolerance to galactose, galactosemia, or malabsorption of glucosogalactose
Oral Parenteral 5 g Amount of galactose in a drug single dose, g;
Be careful when prescribing to the patients with diabetes mellitus
22. Glucose Oral * Contraindicated for persons with glucose-galactose malabsorption
Oral Parenteral 5 g Amount of galactose in a drug single dose, g;
Be careful when prescribing to the patients with diabetes mellitus
Oral solutions Sucking and chewable tablets * Harmful to the teeth This information is included in the instruction for medical use, in case of long-term use (two or more weeks)
23. Glycerol Oral 10 g / 1 dose Adverse reactions: headache, disorders of the gastrointestinal tract, diarrhea
Rectal 1 g Lapactic effect
24. Heparin (as an auxiliary substance) Parenteral * Allergic reactions, decreased coagulability: contraindicated for persons with an allergic reaction to heparin
25. Hydrogenated glucose syrup (or maltitol liquid) Oral * Contraindicated for persons with hereditary intolerance to fructose
10 g Moderate lapactic effect; caloric value of hydrogenated glucose 2.3 kcal/g is indicated
26. Inverted sugar Oral Contraindicated for persons with hereditary intolerance to fructose or malabsorption of glucose-galactose
5 g Amount of galactose in a drug single dose, g;
Be careful when prescribing to the patients with diabetes mellitus
Oral solutions Sucking and chewable tablets * Harmful to the teeth In case of long-term use (for two or more weeks)
27. Lactitol Е 966 Oral * Contraindicated for persons with hereditary intolerance to fructose, galactose, galactosemia or malabsorption of glucose-galactose
10 g Moderate lapactic effect; caloric value of hydrogenated glucose 2.3 kcal/g is indicated
28. Lactose Oral * Contraindicated for persons with hereditary intolerance to fructose, deficiency of enzyme Lapp (LAPP) -lactase, malabsorption of glucose-galactose
5 g Amount of galactose in a drug single dose, g;
Be careful when prescribing to the patients with diabetes mellitus
29. Lanolin (Wool Fat) Topical * Local skin reactions (contact dermatitis)
30. E 965 Maltitol;

E 953 Isomaltiltol;

Maltite liquid (hydrogenated glucose syrup)

Oral * Contraindicated for persons with hereditary intolerance to fructose
10 g Moderate lapactic effect; caloric value of hydrogenated glucose 2.3 kcal/g is indicated
31. Mannitol (mannitol) E421 Oral 10 g Moderate lapactic effect
32. Organic compounds of mercury:

1) thiomersal

2) phenyl mercury nitrate

3) phenyl mercuric acetate

4) phenyl mercury borate

Ophthalmic dosage forms * Allergic reactions
Topical * Local skin reactions (contact dermatitis), skin depigmentation
Parenteral * Allergic reactions
33. Parahydroxybenzoates and their ethers:

1) ethylpara- hydroxybenzoate (E 214)

2) propyl parahydroxybenzoate (E 216)

3) sodium propyl parahydroxybenzoate (E 217)

4) methyl parahydroxybenzoate (E 218)

5) sodium methyl parahydroxybenzoate (E 219)

Oral; Ophthalmic dosage forms;
topical
* Delayed allergic reactions
Parenteral; inhalation * Delayed allergic reactions, bronchospasm
34. Phenylalanine Topical, oral, parenteral * Contraindicated for persons with phenylketonuria
35. Potassium Parenteral Content of potassium is less than 1 mmol in a single dose Amount of potassium in a single drug dose is indicated, mmol (or mg) Information on potassium content indicated in the instructions, is based on total potassium content in the drug;
less than 1 mmol (39 mg) in a single dose, is considered drugs free of potassium; it is particularly important when applied in pediatric practice, when low-potassium drugs are prescribed
Parenteral Oral Content of potassium is less than 1 mmol in a single dose Amount of potassium is indicated, mmol (or mg) in a single dose of the drug; be careful when prescribe for persons with reduced renal function or who are controlled by the intake of potassium from food
Intravenous injection 30 mmol/l Injection site pain
36. Propylene glycol and its ethers Topical * Skin irritation
Oral Parenteral 400 mg/kg — for adults 200 mg / kg for children Effects similar to the effects of alcohol
37. Sesame seed oil All administration routes Rare cases of serious allergic reactions
38. Sodium Parenteral Content of sodium is less than 1 mmol in a single dose of the drug Amount of sodium in a single dose of the drug is indicated, mmol (or mg) Information on sodium content indicated in the instructions, is based on total potassium content in the drug;
less than 1 mmol (23 mg) in a single dose, is considered drugs free of sodium; it is particularly important when applied in pediatric practice, when low-sodium drugs are prescribed
Parenteral; oral Content of sodium is 1 mmol in a single dose Indicate amount of sodium in a single drug dose, mmol (or mg); Be careful when prescribing to people who follow a salt-free diet
39. Sorbic acid and its salts Topical * Local skin reactions (contact dermatitis)
40. Sorbitol Е420 Oral Parenteral * Contraindicated for patients with hereditary intolerance to fructose
Oral 10 g Moderate lapactic effect;
caloricity of sorbitol is indicated — 2.6 kcal / g
41. Soybean oil,

Hydrogenated soybean oil

All administration routes * Local skin reactions (contact dermatitis)
42. Stearyl alcohol Topical * Local skin reactions (contact dermatitis)
43. Sucrose Oral * Contraindicated for persons with hereditary intolerance to fructose, malabsorption of glucose-galactose, deficiency of enzyme sucrase-isomaltase
5 g Amount of sucrase in a single drug dose is indicated, g;
Be careful when prescribing to the patients with diabetes mellitus
Oral solutions Sucking and chewable tablets * Harmful to the teeth This information is included in the instructions when the drug is intended for long-term use (two or more weeks)
44. Sulphites, including metabisulfites:

1) Sulfur dioxide E 220

2) Sodium sulfite E 221

3) sodium bisulfite E 222

4) sodium metabisulphite E 223

5) potassium metabisulphite E 224

6) potassium bisulphite E 228

Oral;
parenteral;
inhalation
* Serious allergic reactions and bronchospasm
45. Wheat starch Oral * Contraindicated for persons with allergic reactions to wheat starch Wheat starch may contain Gluten (traces)
46. Xylitol Oral 10 g Moderate lapactic effect;
caloricity of xylitol is indicated — 2.4 kcal / g

      Abbreviations used:

mg — milligram;

kg-kilogram;

μg — microgram;

g — gram;

kcal — kilocalorie;

mmol — milimole;

l — liter.

Note:      * Regardless of the assay content of excipients, information in column 5 is indicated in the instructions for medical use.

     Information indicated in column 6 is intended for experts when conducting a specialized expertise of drug product.

Annex 15

to the Rules for Conducting of Drug Products Expertise

List of changes made in master file of drug product

      А. administrative changes

А.1 Change of Marketing Authorisation Holder Name and (or) address Conditions Documents and data Procedure
1 1, 2 IA
Conditions
1. Marketing Authorisation Holder is a legal entity.
Documents
1. Document issued by the relevant authorized body (for example, by the tax authority), which indicates a new name or address.
2. Revised information on drug product.
А. Change of drug product (trade) name Conditions Documents and data Procedure
а) Drug products 1 IB
Conditions
Documentation
1. Revised information on the drug product.
А.3 Change of active pharmaceutical ingredients name Conditions Documents and data Procedure
1 1, 2 IA

1. Pharmaceutical ingredient / excipient remain unchanged.
Documents
1. Approval certificate issued by the World Health Organization (hereinafter WHO) or copy of International Nonproprietary Name List. Confirmation that the change corresponds to the State Pharmacopoeia of the Republic of Kazakhstan, if applicable. Declaration that name of herbal drug products of vegetable origin corresponds to the documents of the Republic of Kazakhstan.

2. Revised information on drug product.

Annex 14

to the Rules for drug expertise

Information on excipients, their declared content in drugs and limits for drug application

№ п/п Name of excipient Administration route Acceptable excipient limits Information to be disclosed in Medical Use Instruction Comments**
1 2 3 4 5 6
1. Aprotinin Local * Hypersensitivity or severe allergy
2. Peanut oil Local, oral, parenteral * Not recommended to people having allergy for nuts or soybeans Clarified peanut oil may contain protein
3. Aspartam (Е951) Parenterally * Contains phenylanin, not recommended to people suffering from phenylketonuria May cause harm to people suffering from phenylketonuria
4. Azoic colours:
1) Е 102 Tartrazine
2) Е 110 Sunset Yellow (FCF)
3) Е 122 Azorubine, Carmoisine
4) Е 124 Ponceau 4R (ponceau 4R), Red Cochinea А
5) Е 151 Brilliant Black BN, black PN
Parenterally * Allergy Е 102, Е 110, Е 122 are prohibited for use in drugs for children
5. Erythrosin (E127) Parenterally 0 – 0.1 mg/kg the drug cannot be prescribed and administered to patients suffering from thyroid pathology Prohibited for use in drugs for children
6. Peruvian Balsam Local * Skin reactions are possible
7. Benzalkonium chloride Ophthalmological pharmaceutical forms * Iritis is possible;
it is recommended to avoid contact with soft contact lenses;
remove contact lenses before use and wait about 15 minutes after instillation;
not applicable in children under 8 years
Benzalkonium chloride decolourizes soft contact lenses
Local * Skin reactions
Pulmonary 10 mkg/in1 dose Bronchial spasm
8. Benzoic acid and benzoates:
1) Е210 benzoic acid
2) Е211 sodium benzoate
3) Е212 potassium benzoate
Local * Irritation of skin, eyes and mucosa
Parenterally * Not recommended for nrewborns High risk of newborn jaundice
9. Benzyl alcohol Parenterally At a dose below 90 mg/kg/day Not recommended for premature children, newborns and children under 3 years;
adverse reaction – anaphylactoid reactions;
an amount of benzyl alcohol in the drug (mg/ml)
There may be cases of toxic and allergic reactions in children under 3 years
At a dose 90 mg/kg/day Not recommended for premature children, newborns and children under 3 years;
in case of administration of benzyl alcohol at a dose 90 mg/kg/day and more, there is an increased risk of fatal toxic responses
10. Bergamot oil

Bergapten

Local * Increased sensitivity to UV rays (both natural and artificial) Not used if there is bergapten in oil
11. Bronopol Local * Local skin reactions (contact dermatitis)
12. Butylhydroxyanisole Е320 Local * Local skin reactions (contact dermatitis), irritation of eyes and mucosa
13. Butylhydroxytoluol Е321 Local * Local skin reactions (contact dermatitis), irritation of eyes and mucosa
14. Polyethoxylated castor oil;
gydrogenated polyethoxylated castor oil
Parenterally * Heavy allergic reactions
Oral * Gastrointestinal tract disorders and diarrhea
Local * Skin reactions
15. Cetostearyl alcohol;
Cetyl alcohol
Local * Local skin reactions (contact dermatitis)
16. Chlorocresol Local

Parenteral

* Allergy
17. Dimethylsulfoxide Local * Skin irritation
18. Ethanol Oral and parenteral Ethanol content in a single dose is less than 100 vg The drug has low ethanol level Ethanol content is less than 100 mg in a single doze
From 100 mg to 3 g of ethanol in a single dose Not recommended to people suffering from alcoholism, epilepsy, as well as to children, pregnant women and breastfeeding women, patients with hepatic disorders
Oral and parenteral 3 g in a single dose Not recommended to people suffering from alcoholism, epilepsy, as well as to children, pregnant women and breastfeeding women, patients with hepatic disorders; influences the ability to drive vehicles and use machinery; influences the effect of other drugs The amount of ethanol in these drugs can influence or change the activity of other drugs.
19. Formaldehyde Local * Cases of local skin reactions (contact dermatitis) are possible
Oral * Gastrointestinal tract disorders and diarrhea
20. Fructose Oral * Before prescription of drugs, it is recommended to identify fructose tolerance; contraindicated to people with hereditary fructose intolerance
Parenteral 5 g The amount of fructose in g in a single dose of the drug;
the drug should not be prescribed to patients suffering from diabetes mellitus
Liquids for internal use, chewable tablets * Harmful for teeth In case of long-term intake within two or more weeks
21. Galactose Parenteral * Contraindicated to people with hereditary galactose intolerance, galactosemia
Oral * Contraindicated to people with hereditary galactose intolerance, galactosemia or malabsorption of glucose-galactose
Oral

Parenteral

5 g The amount of galactose in g in a single dose of the drug;
the drug should be prescribed to patients suffering from diabetes mellitus with care
22. Glucose Oral * Contraindicated to people with malabsorption of glucose-ogalactose
Oral

Parenteral

5 g The amount of glucose in g in a single dose of the drug;
the drug should be prescribed to patients suffering from diabetes mellitus with care
Oral solutions, chewable and orodispersible tablets * Damaging action on teeth This information is included into the Instruction in case of long-term intake (within two or more weeks)
23. Glycerol Oral 10 g/in 1 dose Adverse reactions: headache, gastrointestinal tract disorders and diarrhea
Rectal 1 g Laxative action
24. Heparin (as an excipient) Parenteral * Allergic reactions, decrease of blood clotting ability: contraindicated to people with allergic reaction for heparin
25. Hydrogenized glucose syrop (or liquid maltitol) Oral * Contraindicated to people with hereditary fructose intolerance
10 g Moderate laxative action; Hydrogenized glucose energy value is 2.3 kcal/g
26. Invert sugar Oral Contraindicated to people with hereditary fructose intolerance or malabsorption of glucose-galactose
5 г The amount of glucose and fructose in g in a single dose of the drug;
the drug should be prescribed to patients suffering from diabetes mellitus with care
Oral solutions, chewable and orodispersible tablets * Damaging action on teeth In case of long-term intake (within two or more weeks)
27. Lactitol Е 966 Oral * Contraindicated to people with hereditary fructose and galactose intolerance, galactosemia or malabsorption of glucose-galactose
10 g Moderate laxative action; lactitol energy value is 2.3 kcal/g
28. Lactose Oral * Contraindicated to people with hereditary fructose intolerance, LAPP-lactase enzyme deficiency, malabsorption of glucose-galactose
5 g The amount of lactose in g in a single dose of the drug is established;
the drug should be prescribed to patients suffering from diabetes mellitus with care
29. Lanolin (Wool fat) Local * Local skin reactions (contact dermatitis)
30. Е 965 Maltitol;
Е 953 Isomaltitol;
Liquid maltitol (hydrogenized glucose syrop)
Oral * Contraindicated to people with hereditary fructose intolerance
10 g Moderate laxative action; hydrogenized glucose energy value is 2.3 kcal/g
31. Mannitol (mannite) Е421 Oral 10 g Moderate laxative action
32. Organomercury compounds:
1) thiomersal
2) phenyl-mercuric nitrate
3) phenyl-mercuric acetate
4) phenyl-mercuric borate
Ophthalmological pharmaceutical forms * Allergic reactions
Local * Local skin reactions (contact dermatitis), skin depigmentation
Parenteral * Allergic reactions
33. Parahydroxybenzoates and their ethers:
1) ethyl parahydroxybenzoate (Е 214)
2) propyl-parahydroxybenzoate (Е 216)
3) sodium propylparahydroxybenzoate (Е 217)
4) methyl-parahydroxybenzoate (Е 218)
5) sodium methylparahydroxybenzoate (Е 219)
Oral; Ophthalmological pharmaceutical forms;
Local
* Delayed allergic reactions
Parenteral; Pulmonary * Delayed allergic reactions, bronchial spasm
34. Phenylanine Local, oral, parenteral * Contraindicated to people suffering from phenyl ketonuria
35. Potassium Parenteral Potassium content is less than 1 mmol in a single dose The amount of potassium in mmol (or mg) in a single dose of the drug In the instruction, information regarding potassium content is based on general content of potassium in the drug;
drugs that contain less than 1 mmol (39 mg) in a single dose are potassium-free; this is particularly important for pediatric practice where drugs with low potassium level are prescribed.
Parenteral

Oral

Potassium content is 1 mmol in a single dose The amount of potassium in mmol (or mg) in a single dose of the drug shall be specified; the drug shall be carefully prescribed to people suffering from impaired kidney function or to those requiring potassium intake control
Intravenous administration 30 mmol/l Injection site pain
36. Propylene-glycol and its ethers Local * Skin irritation
Oral

Parenteral

400 mg/kg – for adults, 200 mg/kg – for children Effects similar with alcohol influence
37. Sesame oil All administration ways Rare cases of serious allergic reactions
38. Sodium Parenteral Sodium content less than 1 mmol in a single dose of the drug The amount of sodium in mmol (or mg) in a single dose of the drug shall be specified. In the instruction, information regarding sodium content is based on general content of sodium in the drug;
drugs that contain less than 1 mmol (23 mg) in a single dose are sodium-free; this is particularly important for pediatric practice where drugs with low sodium level are prescribed.
Parenteral

Oral

Sodium content in 1 mmol in a single dose The amount of sodium in mmol (or mg) in a single dose of the drus shall be specified; it shall be carefully prescribed to people keeping low-salt diet
39. Sorbic acid and its salts Local * Local skin reactions (contact dermatitis)
40. Sorbitol Е420 Oral

Parenteral

* Contraindicated to patients with hereditary fructose intolerance
Oral 10 g Moderate laxative action;
Sorbitol energy value is 2.6 kcal/g
41. Soybean oil,
hydrogenized soybean oil
All administration ways * Local skin reactions (contact dermatitis)
42. Stearyl alcohol Local * Local skin reactions (contact dermatitis)
43. Sucrose Oral * Contraindicated to people with hereditary fructose intolerance, malabsorption of glucose-galactose, socrose-isomaltase enzyme deficiency
5 g The amount of sucrose in grams in a single dose of the drud shall be specified;
the drug should be carefully prescribed to patients suffering from diabetes mellitus
Oral solutions, chewable and orodispersible tablets * Damaging action on teeth This information is included into the Instruction in case of long-term intake (within two or more weeks)
44. Suphites, including metabisulphites:
1) sulphurous dioxide Е 220
2) sodium sulphite Е 221
3) sodium bisulphite Е 222
4) sodium metabisulphite Е 223
5) potassium metabisulphite Е 224
6) potassium bisulphite Е 228
Oral
Parenteral
Pulmonary
* Serious allergic reactions and bronchial spasm
45. Wheat powder Oral * Contraindicated to people with allergic reactions for wheat powder Wheat powder may contain gluten (traces)
46. Xylitol Oral 10 g Moderate laxative action;
Xylitol energy value is 2.4 kcal/g

Abbreviations used:

      mg – milligram;

      kg – kilogram;

      мкг – микрограмм;

      g– gram;

     kcall – kilo-calorie;

      mmol – millimole;

      l – liter.

      Note:

* Regardless quantitative content of excipients, information provided in column 5 is disclosed in the instructions for medical use.

** Information provided in column 6 is intended for experts in conduction of specialized examination of medicinal product.

Annex 15

to the Rules for drug expertise

List of changes to medical product registration dossier

А. Administrative changes

А.1 Change of name and (or) address of the Marketing Authorization Holder Conditions Documents and data Procedure
1 1, 2 IA
Conditions
1. The Marketing Authorization Holder is a juridical person.
Documentation
1. A document from correspondent authorized body (e.g. tax authority), specifying new name or address.
2. Revised product information.
А. 2 Change of (commercial) name of the medical product Conditions Documents and data Procedure
а) medical products 1 IB
Conditions
Documentation
1. Revised product information.
А.3 Change of name of active pharmaceutical ingredients or excipients Conditions Documents and data Procedure
1 1, 2 IA
Conditions
1. Pharmaceutical ingredients/excipients are not changed.
Documentation
1. Certificate of approval of the World Health Organization (hereinafter referred to as – the WHO) or a copy of the list of the International non-propriety name. If applicable, confirmation of conformity of the change to the State Pharmacopoeia of the Republic of Kazakhstan. Declaration of correspondence of the name of herbal medicinal products to the documents of the Republic of Kazakhstan.
2. Revised product information.
А. 4 Change in the name and (or) address of the manufacturer (including, if applicable, quality control sites) or the holder of the master file of active pharmaceutical substance (hereinafter referred to as – the HMFAPS), or the supplier of active pharmaceutical ingredients, starting materials, reagents or intermediate products used in production of active pharmaceutical ingredients (if specified in technical dossier), if there are no certificates of correspondence of Ph. Eur., or the manufacturer of a new excipient (if specified in the technical dossier). Conditions Documents and data Procedure
1 1, 2, 3 IA
Conditions
1. Manufacturing site and operations are not changed.
Documentation
1. An official document from an authorized body (e.g. tax authority) specifying new name and (or) address.
2. The amendment to the correspondent section (-s) of the dossier.
3. In case of change of the HMFAPS name, an updated «access permit» shall be provided.
А. 5 Change in the name and (or) address of the manufacturer, including release sites and quality control sites Conditions Documents and data Procedure
а) Actions, for which the manufacturer/importer is responsible, do not include batch release 1 1,2 IA
Conditions
1. There are no changes in manufacturing process and actual location of the site, in the normative document on control of quality and safety of medical product.
Documentation
1. A copy of an amended manufacturing approval (if any) or an official document from an authorized body, where new name and (or) address are specified.
2. If applicable, an amendment to the correspondent section (-s) of the dossier, including revised product information.
А. 6 Change of Anatomic Therapeutic Chemical (hereinafter referred to as — ATC) classification Conditions Required documentation Type of procedure
1 1, 2 IA
Conditions
1. Change due to approval or modification of ATC code by the WHO.
Documentation
1. WHO certificate of approval or a copy of the list of ATC codes.
2. Revised product information.
А. 7 Elimination of manufacturing site (including sites for active pharmaceutical ingredients, intermediate products, medicinal product, a packer, a manufacturer responsible for release of the batch, quality control of a batch or a supplier of the starting material, reagent or excipient (if specified in the dossier). Conditions Required documentation Type of procedure
1, 2 1, 2 IA
Conditions
1. There remains at least one previously approved manufacturing site/manufacturer, performing the same functions as those to be excluded. If applicable, there remains at least one manufacturer responsible for manufacturing of a batch, capable to certify product testing for release of a batch in the Republic of Kazakhstan.
2. The exclusion is not a consequence of critical shortfalls in manufacturing.
Documentation
1. The form of application for changes shall clearly specify «current» and «offered» manufacturers, listed in the application for registration.
2. The Amendment to correspondent section (-s) of the dossier, including revised product information.
A. 8 Change of audit date for verification of correspondence of a manufacturer of active pharmaceutical ingredients to the Rules of Good Manufacturing Practice. Conditions Required documentation Type of procedure
1 IA
Documentation
1. A written confirmation of product manufacturer, containing an order for verification of compliance of a manufacturer of active pharmaceutical ingredients to the Rules of Good Manufacturing Practice of the Republic of Kazakhstan.

      Б. Quality change

      Б.I Active pharmaceutical ingredient

      Б.I. а) Manufacturing

Б.I.а.1 Change of a manufacturer of starting material/reagent/intermediate product, used in the process of manufacturing of active pharmaceutical ingredients or change of a manufacturer of active pharmaceutical ingredients (including, if applicable, quality control sites), if there is no Certificate of Conformity to the European Pharmacopoeia in the registration dossier. Conditions Required documentation Type of procedure
а) An offered manufacturer belongs to the same pharmaceutical group as an approved manufacturer. 1, 2, 3 1, 2, 3, 4, 5, 6, 7 IA
б) Adding a new manufacturer of active pharmaceutical ingredients, approved by the HMFAPS. II
в) An offered manufacturer uses starkly different method of synthesis or manufacturing conditions, which change important quality indicators of active pharmaceutical ingredients, such as qualitative and (or) quantitative impurity profiling, requiring qualification, or physical and chemical properties, influencing bioavailability. II
г) New material manufacturer, requiring assessment of viral safety and (or) the risk of Transmittable Spongiform Encephalopathy (hereinafter referred to as – TSE) II
д) The change affects biological active pharmaceutical ingredients or starting material/reagent/intermediate product, used in manufacturing of biological/immunological drug. II
е) Change of the order of quality control for active pharmaceutical ingredients: replacement or adding a site where control/testing of a batch is performed. 2, 4 1, 5 IA
ж) Adding new manufacturer of active pharmaceutical ingredients, which do not have HMFAPS and require significant renewal of existing dossier section related to active pharmaceutical ingredients. II
з) Inclusion of an alternative site for sterilization of active pharmaceutical ingredients using the method of State Pharmacopoeia of the Republic of Kazakhstan. 1, 2, 4, 5, 8 IB
и) Adding a new micronization site. 2, 5 1, 4, 5, 6 IA
к) Changes in agreements for testing of quality control of a biological active pharmaceutical ingredients: replacement or adding a site where batch control/testing is carried out, including the biological/immunological/immunochemical method. II
л) New site for storage of the main cell bank and (or) working cell banks. 1, 5 IB
Conditions
1. Specifications of starting materials and reagents (including in-process controls, methods for analysis for all materials) are identical to those previously approved. Specifications (including in-process control, methods of analysis for all materials), methods of preparation (including the size of the batch) and detailed method of synthesis of intermediate products and active pharmaceutical ingredients are identical to those previously approved.
2. Active pharmaceutical ingredient is not biological/immunological or sterile.
3. If materials of human or animal origin are used in production process, the manufacturer does not involve new supplier for which viral safety assessment and compliance with the State Pharmacopoeia of the Republic of Kazakhstan is required to minimize the risk of transmission of agents of spongiform encephalopathy of animals through drugs for medical and veterinary use.
4. Transfer of the method from the old site to the new one has taken place successfully.
5. Specification for particle size of active pharmaceutical ingredients and relevant analytical method do not change.
Documentation
1. If applicable, the Amendment to the appropriate section (-s) of the dossier.
2. Declaration of the Marketing Authorization Holder or the Holder of HMFAPS, correspondingly, confirming that procedures of quality control of synthesis method (or for herbal medicinal products (correspondingly): preparation method, geographic source, manufacturing of herbal pharmaceutical ingredients and manufacturing process) and specifications of active pharmaceutical ingredients and starting material/reagent/intermediate product in the process of manufacturing of active pharmaceutical ingredients (if applicable) do not differ from those previously approved.
3. Either European Pharmacopoeia certificate for TSE for any new source of material, or (if applicable) documentary evidence of previous investigation of the source of material at TSE risk by the authorized body and its compliance with the State Pharmacopoeia of the Republic of Kazakhstan has been confirmed to minimize the risk of transmitting agents of spongiform encephalopathy of animals through drugs for medical and veterinary use. It is necessary to provide the following information: manufacturer’s name; types of animals and tissues from which the material has been taken; country of origin of animals, its use and acceptability in the past.
4. Data of batch analysis (in the form of comparative table) of, at least, two batches (at least, pilot-scale) of active pharmaceutical ingredients received from current and offered manufacturers/sites.
5. «Current» and «offered» manufacturers shall be clearly specified in the form of change application as indicated in section 2.5 of the application form.
6. If active pharmaceutical ingredients are used as starting material, declaration of qualified person of each holder of the production license specified in the application and qualified person of each holder of the production license specified in the application as responsible for the release of the batch. It is necessary to indicate in the declaration that the manufacturer (-s) of active pharmaceutical ingredients specified in the application carries out his activities in accordance with the Rules of Good Manufacturing Practices of the Republic of Kazakhstan with respect to starting materials. Under certain circumstances, it is allowed to submit one declaration (see note to the amendment Б.II.б.1).
7. A letter of guarantee (if necessary) of the manufacturer of an active pharmaceutical ingredients to notify the Marketing Authorization Holder about any change in manufacturing process, specifications and analytical methods of active pharmaceutical ingredients.
8. Confirmation of proper licensing of each offered site with regard to each examined pharmaceutical form, drug or manufacturing operation.
Б.I.а.2 Changes in manufacturing process of active pharmaceutical ingredients Conditions Required documentation Type of procedure
а) Insignificant change of manufacturing process of active pharmaceutical ingredients 1, 2, 3, 4, 5, 6, 7 1, 2, 3 IA
б) Significant change of manufacturing process of active pharmaceutical ingredients, which can have a significant impact on quality, safety or effectiveness of the drug. II
в) The change relates to biological/immunological substance or use of another substance, obtained by means of chemical synthesis in the course of manufacturing of biological/immunological drug, which can have significant influence on quality, safety or effectiveness of the drug and has no relation to the protocol. II
г) The change affects a herbal drug, namely: a geographic source, production or preparation method. II
д) Insignificant change of the closed part of the HMFAPS. 1, 2, 3, 4 IB
Conditions
1. There are no undesirable changes of quantitative or quantitative impurity profiling or physical and chemical properties.
2. Synthesis method remains the same, i.e. intermediate products do not change and there are no new reagents, catalysts and solvents. Geographic source, preparation of herbal raw material and method of preparation of herbal medicinal products do not change.
3. Specifications of active pharmaceutical ingredients and intermediate products do not change.
4. The change is fully described in the opened part (the Applicant’s part) of the HMFAPS (if applicable).
5. Active pharmaceutical ingredients are not biological/immunological ingredients.
6. The change does not affect geographic source, production method or preparation of herbal medicinal product.
7. The change does not affect closed part of the HMFAPS.
Documentation
1. The amendment to the corresponding section (-s) of the dossier, including direct comparison of current and new processes.
2. Data of batch analysis (in the form of comparative table) of, at least, two batches (at least, pilot-scale), manufactured with the help of approved and offered processes.
3. Copies of approved specifications of active pharmaceutical ingredients.
4. Declaration of the Marketing Authorization Holder or the Holder of the HMFAPS, correspondingly, confirming that qualitative and quantitative impurity profiling or physical and chemical properties, synthesis method, specifications of active pharmaceutical ingredients and intermediate products do not change.
Note к Б.I.а.2.б) Substantial changes in active pharmaceutical ingredients obtained by means of chemical synthesis involve changes in synthesis method and production conditions that can change important quality indicators of active pharmaceutical ingredients, such as qualitative and (or) quantitative impurity profiling requiring qualification, or the physical and chemical properties, affecting the bioavailability.
Б.I.а.3 Change in the size of a batch (including size range of a batch) of active pharmaceutical ingredients or intermediate product used in production of active pharmaceutical ingredients. Conditions Required documentation Type of procedure
а) Increase of the size of a batch up to 10 times in comparison with the registered size. 1, 2, 3, 4, 5, 6, 7, 8 1, 2, 5 IA
б) 10-time disaggregation 1, 2, 3, 4, 5 1, 2, 5 IA
в) The change requires compatibility analysis of biological/immunological active pharmaceutical ingredients. II
г) Increase of the size of a batch by more than 10 times in comparison with the registered size. 1, 2, 3, 4 IB
д) Increase/decrease of manufacturing scale of biological/immunological active pharmaceutical ingredients without manufacturing process change (e.g., line duplication) 1, 2, 3, 4 IB
Conditions
1. All changes in manufacturing methods affect only those necessary for consolidation or disaggregation, for example, use of equipment of another size.
2. It is necessary to provide test results according to the specifications of at least two batches of offered batch size.
3. The drug in question is not a biological/immunological drug.
4. The change does not undesirably influence process repeatability.
5. The change should not be the result of unforeseen situations arose in the course of manufacturing, or destabilization.
6. Specifications of active pharmaceutical ingredients/intermediate products do not change.
7. Active pharmaceutical ingredients are not sterile.
8. The size of the batch is within 10-time range of batch size, provided in registration or after the following change that was not the change of IA type.
Documentation
1. The Amendment to the corresponding section (-s) of the dossier.
2. The serial numbers of tested batches have offered size of the batch.
3. The analysis data of the batch (in the form of comparative table) of, at least, one industrial batch of active pharmaceutical ingredient or intermediate product, correspondingly, produced in the approved and offered size. It is necessary to provide data on the following two complete industrial batches upon request; the holder shall report if the results of the analysis do not fit specification and provide an action plan.
4. Copies of approved specifications of active pharmaceutical ingredients (and intermediate products, if applicable).
5. Declaration of the Marketing Authorization Holder or the Holder of the HMFAPS, confirming that all changes in manufacturing methods affect only those necessary for consolidation or disaggregation, for example, the use of equipment of another size; the change does not undesirably affect the reproducibility of the process; the change is not a consequence of unforeseen situations arising in the course of manufacturing, or distabilization; specifications of active pharmaceutical ingredients/intermediate products are not changed.
Б.I.а.4 Changes in in-process tests or acceptance criteria used in manufacturing of active pharmaceutical ingredients. Conditions Required documentation Type of procedure
а) Stiffening of in-process acceptance criteria. 1, 2, 3, 4 1, 2 IA
б) Adding new in-process tests or criteria. 1, 2, 5, 6 1, 2, 3, 4, 6 IA
в) Exclusion of insignificant in-process test. 1, 2, 7 1, 2, 5 IA
г) Expansion of approved in-process acceptance criteria, which significantly influence overall quality of active pharmaceutical ingredients. II
д) Exclusion of an in-process test, which can significantly influence overall quality of active pharmaceutical ingredients. II
е) Addition or replacement of in-process test for safety or quality reasons. 1, 2, 3, 4, 6 IB
Conditions
1. The change is not a consequence of any commitment, made according to the results of previous examinations with the purpose of analysis of specification acceptance criteria (for example, in the course of registration or modification of type II).
2. The change is not a consequence of unforeseen situations arising in the course of manufacturing, for example, new unqualified impurity, change of limits for impurity content.
3. Any change shall be within the range of acting approved acceptance criteria.
4. Analytical methods do not change or just slightly change.
5. No new test method is based on a new non-standard methodology or standard methodology used on a new.
6. A new test method is not biological/immunological/immunochemical method or a method that uses a biological reagent for a biologically active pharmaceutical ingredient (except standard pharmacopeia microbiological methods).
7. The parameter of specification does not affect the critical parameter, for example, any of the following: quantification, impurities (unless a certain solvent is used in manufacturing of active pharmaceutical ingredients), any critical physical characteristic, for example, particle size, bulk density before and after compaction, on authenticity, water, any request for change in test frequency.
Documentation
1. The Amendment to the corresponding section of the dossier.
2. Comparative table of current and offered in-process tests.
3. Detailed description of new non-pharmacopoeia analytical procedure and data of primary expertise (in relevant cases).
4. The analysis data of two industrial batches (three industrial batches for biologically active pharmaceutical ingredients, in case of absence of proper justification) of active pharmaceutical ingredients for all specification parameters.
5. Justification/assessment of risks from the part of the Marketing Authorization Holder or the Holder of the MFAFS, respectively, confirming that in-process parameters are insignificant or outdated.
6. Justification of new in-process tests and limits from the part of the Marketing Authorization Holder or the Holder of the MFAFS, respectively.
Б.I.а.5 Change of active pharmaceutical ingredients of seasonal, pre-pandemic or pandemic vaccine for prevention of influenza Conditions Required documentation Type of procedure
а) Replacement of the strain (-s) of seasonal, pre-pandemic or pandemic vaccine for prevention of influenza. II

      Б.I. б) Control of quality of active pharmaceutical ingredients

Б.I.б.1 Change of specification parameters and (or) acceptance criteria of active pharmaceutical ingredients, starting material/intermediate product/reagent used in the process of manufacturing of active pharmaceutical ingredients. Conditions Required documentation Type of procedure
а) Stiffening of acceptance criteria for specification of medicinal products that subject to release by the official control authority. 1, 2, 3, 4 1, 2 IAНУ
б) Stiffening of specification acceptance criteria. 1, 2, 3, 4 1, 2 IA
в) Adding a new parameter and relevant test method into the specification. 1, 2, 5, 6, 7 1, 2, 3, 4, 7 IA
г) Exclusion of insignificant specification parameter (e.g., exclusion of an outdated parameter). 1, 2, 8 1, 2, 6 IA
д) Exclusion of specification parameter, which can significantly influence overall quality of active pharmaceutical ingredients and (or) the drug. II
е) A change that is beyond the approved range of specification acceptance criteria for active pharmaceutical ingredients. II
g)  Expansion of approved specification acceptance criteria for starting materials/intermediate products that significantly influence overall quality of active pharmaceutical ingredients and/or the drug. II
h) Addition or replacement (excluding biological and immunological ingredients) of specification parameter and its corresponding test method for safety or quality reasons. 1, 2, 3, 4, 5, 7 IB
  1. If there is no article for active pharmaceutical ingredients in the State Pharmacopoeia of the Republic of Kazakhstan, replacement of own specification data by the data of an unofficial pharmacopoeia or pharmacopoeia of the third country.
1, 2, 3, 4, 5, 7 IB
Conditions
1. The change is not a consequence of any commitment, made according to the results of previous examinations with the purpose of analysis of specification acceptance criteria (for example, in the course of registration or modification of type II).
2. The change is not a consequence of unforeseen situations arising in the course of manufacturing, for example, new unqualified impurity, change of limits for impurity content.
3. Any change shall be within the range of acting approved acceptance criteria.
4. Analytical methods do not change or just slightly change.
5. No new test method is based on a new non-standard methodology or standard methodology used on a new.
6. A new test method is not biological/immunological/immunochemical method or a method that uses a biological reagent for biologically active pharmaceutical ingredients (except standard pharmacopeia microbiological methods).
7. The change in any material does not influence genotoxic impurity. If active pharmaceutical ingredients are involved, with the exception of residual solvents that should comply with the limits of the corresponding article of the State Pharmacopeia of the Republic of Kazakhstan, the control of any new admixture should comply with the State Pharmacopoeia of the Republic of Kazakhstan.
8. The parameter of specification does not affect the critical parameter, for example, any of the following: quantification, impurities (unless a certain solvent is used in manufacturing of active pharmaceutical ingredients), any critical physical characteristic, for example, particle size, bulk density before and after compaction, on authenticity, water, any request for change in test frequency.
Documentation
1. The Amendment to the corresponding section of the dossier.
2. Comparative table of current and offered specifications.
3. Detailed description of any new analytical procedure and data of primary expertise (in relevant cases).
4. The analysis data of two industrial batches (three industrial batches for biologically active pharmaceutical ingredients, in case of absence of proper justification) of active pharmaceutical ingredients for all specification parameters.
5. In relevant cases, the data of the test of comparative dissolution kinetics of a drug, containing active pharmaceutical ingredients, at least, from a pilot –scale butch, corresponding to acting and offered specifications. In respect to herbal medicinal products, data on comparative disintegration is sufficient.
6. Justification of new specification parameters and acceptance criteria from the part of the Marketing Authorization Holder or the Holder of the MFAFS.
Б.I.б.2 Change of analytical procedure of active pharmaceutical ingredients or starting material/intermediate product/reagent used in the process of manufacturing of active pharmaceutical ingredients. Conditions Required documentation Type of procedure
а) Insignificant changes of approved analytical procedure. 1, 2, 3, 4 1, 2 IA
б) Exclusion of analytical procedure of active pharmaceutical ingredients or starting material/intermediate products/reagent, if an alternative analytical procedure has already been approved. 7 1 IA
в) Other changes in the analytical procedure (including replacement or addition) of the reagent that does not have a significant effect on overall quality of active pharmaceutical ingredients. 1, 2, 3, 5, 6 1, 2 IA
г) Substantial modification or replacement of biological/immunological/immunochemical test method or method in which biological reagent is used for biological active pharmaceutical ingredients. II
д) Other changes in analytical procedure (including addition or replacement) of the active pharmaceutical ingredients or starting material/intermediate product. 1, 2 IB
Conditions

1. Necessary primary expertise confirming that updated analytical methodology is, at least, equivalent to the previous one, has been done.

2. Limits of impurity content have not been changed, new unqualified impurities have not been detected.

3. The analysis method has not changed (for example, change of column length or temperature, but not another type of column or method).

4. The test method is not biological/immunological/immunochemical method or method that uses biological reagent for biologically active pharmaceutical ingredients (except standard pharmacopeia microbiological methods).

5. No new test method is based on a new non-standard methodology or standard methodology used on a new.
6. Active pharmaceutical ingredients are not biological/immunological.
7. Alternative analytical procedure for specification parameter is already approved; herewith this procedure has not been included by means of IA-notification.

Documentation
1. The Amendment to the relevant section (-s) of the dossier, including description of analytical procedure, summary of primary expertise data, revised specifications for impurities (if applicable).
2. Comparative results of primary expertise or, if justification is available, comparative results of analysis, confirming that current and offered tests are equivalent. This requirement is not applied, if new analytical method is added.

      Б.I. в) Container closure system

Б.I.в.1 Change of primary packing of active pharmaceutical ingredients Conditions Required documentation Type of procedure
а) Qualitative and (or) quantitative compound. 1, 2, 3 1, 2, 3, 4, 6 IA
б) Qualitative and (or) quantitative compound for sterile or ambient biological/immunological active pharmaceutical ingredients. II
в) Liquid active pharmaceutical ingredients (unsterile) 1, 2, 3, 5, 6 IB
Conditions
1. According to the relative properties, the offered packaging material should at least be equivalent to the approved packaging material.
2. Relevant stability studies have been started in accordance with the established requirements and at the moment of introduction of changes the applicant has analyzed relevant stability parameters for at least two pilot industrial or industrial batches, and he has satisfactory results of at least 3-month stability study at his disposal. However, if offered packaging is more stable compared to the registered one, then three-month stability data are not required. Upon completion of such studies, if the results do not fit specification or potentially do not fit specification at the end of the expiration date/retest period, they should be immediately provided to the authorized body along with the offered action plan.
3. Excluding sterile, liquid and biological/immunological active pharmaceutical ingredients.
Documentation
1. The amendment to relevant section (-s) of the dossier.
2. The required data on new packing (e.g. comparative data on permeability, e.g., for O2, CO2, moisture, etc.), including an approval of correspondence of material to the relevant pharmacopeia requirements for plastic materials and objects, contacting with food products.
3. In relevant cases it is necessary to provide confirmation that interaction between the content and the packaging material does not occur (for example, there is no movement of components of the offered material into its content, the components of the drug do not move into package), including confirmation that the material corresponds relevant pharmacopoeia requirements for plastic materials and objects, contacting food products.
4. Declaration of the Marketing Authorization Holder or the Holder of the HMFAPS, that relevant stability studies have been started in accordance with the established requirements (with indication of a batch number); and that (in relevant cases) at the moment of introduction of changes he had necessary minimal satisfactory data regarding stability at his disposal; and that the available data did not indicate any problems. Also it is necessary to provide confirmation of study completion, and also to confirm that if the results do not fit specification or potentially do not fit specification at the end of the expiration date/retest period, they will be immediately provided to the authorized body along with the offered action plan.

5. The results of stability studies carried out in accordance with the established requirements for significant stability parameters in at least two pilot industrial or industrial batches covering at least three months and confirmation that these studies will be completed and if the results do not fit specifications or potentially fail to meet the specifications for the end of the expiration date/retest period, they will be immediately presented to the authorized body along with the offered action plan.
6. Comparison of acting and offered specifications of primary packing (if applicable).

Б.I.в. 2 Change of specification parameters and (or) acceptance criteria of primary packing of active pharmaceutical ingredients Conditions Required documentation Type of procedure
а) Stiffening of specification acceptance criteria. 1, 2, 3, 4 1, 2 IA
б) Addition of new parameter and its relevant test method into specification. 1, 2, 5 1, 2, 3, 4, 6 IA
в) Exclusion of insignificant specification parameter (e.g. exclusion of outdated parameter). 1, 2 1, 2, 5 IA
г) Addition or replacement of specification parameter for safety and quality reasons. 1, 2, 3, 4, 6 IB
Conditions
1. The change is not a consequence of any commitment, made according to the results of previous examinations with the purpose of analysis of specification acceptance criteria (for example, in the course of registration or modification of type II), unless it has previously been examined and approved as a measure for following observation.
2. The change is not a consequence of unforeseen situations arising in the course of manufacturing of packing material or in storage of active pharmaceutical ingredients.
3. Any change shall be within the range of acting approved acceptance criteria.
4. Analytical methods do not change or just slightly change.
5. No new test method is based on a new non-standard methodology or standard methodology used on a new.
Documentation
1. The Amendment to the corresponding section of the dossier.
2. Comparative table of current and offered specifications.
3. Detailed description of any new analytical procedure and data of primary expertise (in relevant cases).
4. Analysis data for two batches of packing material for all specification parameters.
5. Justification/assessment of risks from the part of the Marketing Authorization Holder or the Holder of the MFAFS, respectively, confirming that an in-process parameter is insignificant or outdated.
6. Justification from the part of the Marketing Authorization Holder or the Holder of the MFAFS regarding new specification parameter and acceptance criteria.
Б.I.в. 3 Change of analytical test procedure for primary packing of active pharmaceutical ingredients. Conditions Required documentation Type of procedure
а) Insignificant changes of approved analytical procedure. 1, 2, 3 1, 2 IA
б) Other changes of analytical procedure (including addition and replacement). 1, 3, 4 1, 2 IA
в) Exclusion of analytical procedure in case of approval of its alternative procedure. 5 1 IA
Conditions
1. According to the relevant documents of the Republic of Kazakhstan, necessary primary expertise, confirming that updated analytical methodology is at least equivalent to the previous one, has been performed.
2. The analysis method has not changed (for example, change of column length or temperature, but not another type of column or method).
3. No new test method is based on a new non-standard methodology or standard methodology used on a new.
4. Active pharmaceutical ingredients are not biological/immunological.
5. Alternative analytical procedure for specification parameter is already approved; herewith this procedure has not been included by means of IA-notification.
Documentation
1. The Amendment to the relevant section (-s) of the dossier, including description of analytical procedure, summary of primary expertise data.
2. Comparative results of primary expertise or, if justification is available, comparative results of analysis, confirming that current and offered tests are equivalent. This requirement is not applied, if new analytical method is added.

      Б.I. г) Stability.

Б.I.г. 1 Change of the period of retest/storage or conditions of storage of active pharmaceutical ingredients,

if there is no Certificate of Conformity to the European Pharmacopoeia in a registration dossier.

Conditions Required documentation Type of procedure
а) Period of retest/storage.
1. Reduction.
1 1, 2, 3 IA
2. Increase of retest period by means of extrapolation of stability data, that does not correspond to the documents of the Republic of Kazakhstan (*). II
3.  Increase of storage period of biological/immunological active pharmaceutical ingredients, which do not correspond to the approved stability program. II
4.  Increase or introduction of the retest period/storage period, confirmed by natural storage data. 1, 2, 3 IB
б) Storage conditions
  1. Replacement of storage conditions of active pharmaceutical ingredients by stricter conditions.
1 1, 2, 3 IA
  1. Change of storage conditions for biological/immunological active pharmaceutical ingredients if stability studies are not conducted in accordance with the current approved protocol of stability.
II
3. Change of storage conditions for active pharmaceutical ingredients. 1, 2, 3 IB
в) Change of approved stability program. 1, 2 1, 4 IA
Conditions
1. The change is not a consequence of unforeseen situations arising in the course of manufacturing or stability change.
2. Changes do not lead to extension of eligibility criteria for test parameters, elimination of stability parameters or reduction of test frequency.
Documentation
1. Amendment to the relevant section (-s) of the dossier. It is necessary to present the results of relevant real-time stability studies carried out in accordance with the relevant stability guidelines for at least two (three batches for biological medicinal products) pilot industrial or industrial batches of active pharmaceutical ingredients packed with the use of registered packaging material and covering the entire offered retest period or offered storage conditions.
2. Confirmation that stability studies are conducted in accordance with the current approved program. The results of the study should confirm that the relevant approved specifications continue to be observed.
3. Copies of approved specifications for active pharmaceutical ingredients.
4. Justification of offered changes.
(*) Note Retest period is not applied to biological/immunological active pharmaceutical ingredients.

      Б.I. д) Design space and protocol of post-registration changes

Б.I.д.1 Introduction of new design space or expansion of approved design space of active pharmaceutical ingredients, including: Conditions Required documentation Type of procedure
а) one operating unit of the process for manufacturing of active pharmaceutical ingredients, including appropriate in-process controls and (or) analytical procedures. 1, 2, 3 II
б) analytical procedures for starting materials/intermediate products and (or) active pharmaceutical ingredients. 1, 2, 3 II
Documentation
1. The design space was developed on the basis of relevant established requirements and international scientific guidelines. The results of product, process and analytical methodology research studies (for example, interaction of different parameters forming the design space to be studied, including risk assessment and multidimensional studies, respectively), confirming that holistic mechanistic understanding of material quality and process parameters for critical indicators of quality of active pharmaceutical ingredients has been achieved.
2. Description of design space in a tabular form, including variables (material properties and manufacturing process parameters) and their proposed ranges.
3. The amendment to the relevant section (-s) of the dossier.
Б.I.д.2 Introduction of post-registration protocol of change management affecting active pharmaceutical ingredients. Conditions Required documentation Type of procedure
1, 2, 3 II
Documentation

1. Detailed description of an offered change.
2. Protocol of change management, affecting active pharmaceutical ingredients.
3. The amendment to the relevant section (-s) of the dossier.

Б.I.д. 3 Exclusion of post-registration protocol of change management affecting active pharmaceutical ingredients. Conditions Required documentation Type of procedure
1 1, 2 IA
Conditions
1. Exclusion of post-registration protocol of change management affecting active pharmaceutical ingredients is not a consequence of unforeseen situations or non-conformity of specification in the course of introduction of changes described in the protocol and does not have any effect on approved information included into the registration dossier.
Documentation
1. Justification of an offered exclusion.
2. The amendment to the relevant section (-s) of the dossier.
Б.I.д. 4 Changes of the approved protocol of change management Conditions Required documentation Type of procedure
а) Significant changes of the protocol of change management II
б) Insignificant changes of the protocol of change management, that do not affect a strategy described in the protocol 1 IB
Documentation
1. Declaration confirming that any change should fit the range of acting approved acceptance criteria. In addition, the declaration confirming that there is no need to provide comparability assessment, required for biological / immunological drugs.
Б.I.д. 5 Change implementation provided by the approved protocol of change management Conditions Required documentation Type of procedure
а) Change implementation does not require additional data 1 1, 2, 4 IA
б) Change implementation requires additional data 1, 2, 3, 4 IB
в) Change implementation for biological/immunological medicinal product 1, 2, 3, 4, 5 IB
Conditions
1. Offered change is performed in full correspondence with the approved protocol of change management.
Documentation
1. Reference to the approved protocol of change management.
2. Declaration about correspondence of the change to the approved protocol of change management and correspondence of the results of the study to acceptance criteria specified in the protocol. Besides this, declaration confirming that no comparability assessment is required for biological/immunological drugs.
3. The results of studies performed in accordance with the approved protocol of change management.
4. The amendment to the relevant section (-s) of the dossier.
5. Copy of approved specifications for active pharmaceutical ingredients.

      Б.II Medical product.

      Б.II. а) Appearance and composition.

Б.II.а. 1 Change or addition of impressions, engravings or other signs, including replacement or addition of ink used in the manufacture of medicinal product Conditions Required documentation Type of procedure
а) Change of impressions, engravings or other signs 1, 2, 3, 4 1, 2 IA
б) Change of engravures/score lines, provided for division into equal doses. 1, 2, 3 IB
Conditions
1. Specifications of the drug for the period of release and the end of shelf life do not change (except appearance).

2. All inks shall comply with applicable pharmaceutical legislation.

3. Engravures/score lines are not intended for division into equal doses.

4. Signs of medicinal product used for determination of dosages are not completely removed.

Documentation
1. The amendment to the relevant section (-s) of the dossier, including detailed graphical or narrative description of current and new appearance, as well as corresponding review of information regarding medicinal product.
2. In relevant cases, samples of medicinal product.
3. The results of corresponding studies in the field of the State Pharmacopoeia of the Republic of Kazakhstan, certifying equivalency of properties/dosage correctness.
Б.II.а. 2 Change of form or size of pharmaceutical form Conditions Required documentation Type of procedure
а) Tablets, capsules, suppositories and peccaries of immediate release. 1, 2, 3, 4 1, 4 IA
б) Medicinal forms of delayed, modified or prolonged release and tablets with engravure intended for division into equal doses. 1, 2, 3, 4, 5 IB
в) Adding a new set for radiopharmaceutical medicinal product with different filling volume. II
Conditions
1. Dissolution profile of changed medicinal product is comparable to the old one, if applicable. If dissolution test is not possible, disintegration time of new medicinal product in comparison with the unchanged one.
2. Specifications of medicinal product for release and at the end of shelf life have not changed (except the size of pharmaceutical form).

3. Qualitative and quantitative composition and average mass have not changed.

4. The change does not relate tablets with engravures, intended for separation of pharmaceutical form into doses.

Documentation
1. The amendment to the relevant section (-s) of the dossier, including detailed graphical indication of current and offered status, as well as review of information regarding medicinal product.
2. Comparative dissolution data for at least one pilot-industrial batch with current and offered sizes (no significant differences as for comparability — see the Rules for Conducting of Bioequivalence Studies of Medicinal Products (hereinafter referred to as – the Rules for Conducting of Bioequivalence Studies). For herbal medicinal products, comparative disintegration data are acceptable.
3. Justification for failure to submit the results of new bioequivalence study according to the Rules for conducting of bioequivalence studies.

4. In relevant cases, samples of medicinal products.

5. Results of relevant tests of the State Pharmacopoeia of the Republic of Kazakhstan, confirming the equivalence of properties/dosing correctness.

(*) Note Для Б.II.а. 2. в), any change of «dosage» of medicinal product requires submission of an application for expansion of registration.
Б.II.а. 3 Change of composition (excipients) of medicinal product Conditions Required documentation Type of procedure
а) Change of flavor or color composition.
1. Addition, exclusion or replacement. 1, 2, 3, 4, 5, 6, 7, 9 1, 2, 4, 5, 6 IA
2. Content increase or decrease. 1, 2, 3, 4 1, 2, 4 IA
б) Other excipients.
1. Any insignificant corrections of qualitative compound of excipients. 1, 2, 4, 8, 9, 10 1, 2, 7 IA
2. Qualitative or quantitative changes of one or more excipients that significantly influence quality, safety or effectiveness of medicinal product. II
3. Change, relating to biological/immunological medicinal product. II
4.  Any new excipients that can use materials of human or animal origin, requiring evaluation of viral safety data and/or TSE risk. II
5. Change justified by the results of bioequivalence study. II
6. Replacement of one auxiliary excipient by similar excipient with the same functional characteristics and in similar amount. 1, 3, 4, 5, 6, 7, 8, 9 IB
Conditions
1. Changes of functional characteristics of pharmaceutical form, for example, disintegration time, dissolution profile, are absent.
2. Any minor correction of composition to maintain the total mass should be done with the use of auxiliary excipients, which currently constitutes the main part of the medicinal product.
3. Specification of medicinal product is updated with regard to appearance/odor/taste and, if necessary, authenticity test, is excluded.
4. The corresponding stability studies have been initiated in accordance with the established requirements (indicating batch numbers); The corresponding stability parameters are analyzed for at least two pilot-industrial or industrial batches; the applicant has satisfactory results of at least 3-month stability study (at the time of introduction of IA type changes and notification of IB type changes); Stability profile is similar to the currently approved profile. Confirmation that the studies will be completed and that if the results at the end of the validity period do not fit specifications or potentially fall outside specification, they will be immediately presented to the authorized body along with the offered action plan. In addition, a photostability test should be carried out, if necessary.
5. All new components shall meet the requirements of the relevant documents of the Republic of Kazakhstan concerning colors, used in food industry and flavor additives.
6. No new component assumes the use of materials of human or animal origin requiring evaluation of viral safety data or compliance with the current requirements of the State Pharmacopoeia of the Republic of Kazakhstan to minimize the risk of transmitting agents of spongiform encephalopathy of animals through the drugs for medical and veterinary use.
7. In appropriate cases, changes do not affect differences between dosages and do not adversely affect the taste characteristics of medicinal products intended for children.
8. Dissolution profile of at least two pilot-industrial batches of the new drug is comparable to unchanged one (no significant differences as for comparability — see the Rules for Conducting Bioequivalence Studies). If dissolution test with herbal medicinal products is not possible, the disintegration time of the new drug is comparable to that one of the unchanged drug.
9. Change is not a consequence of instability and (or) should not affect safety, i.e. differences between dosages.
10. The drug in question is not a biological / immunological drug.
Documentation
1. The amendment to the relevant section (s) of the dossier, including methods for testing of the validity of all new colors (if applicable), as well as revising information on medicinal product, respectively.
2. Declaration confirming that required stability studies have been initiated in accordance with the established requirements (indicating batch numbers); and that (where appropriate) at the time of introduction of changes, the required minimum satisfactory stability data was at its disposal; and that the available data did not indicate any problem. It is also necessary to provide confirmation that in case if the studies are completed and in case if the results do not fit specifications or potentially fall outside the specification at the end of the expiration date, they will be immediately presented to the authorized body along with the proposed action plan.
3. The results of stability studies carried out in accordance with the established requirements for significant stability parameters in, at least, two pilot industrial or industrial batches covering not less than 3 months and confirmation that in case if these studies are completed, and in case if the results do not fit specifications or potentially do not fit specification at the end of the expiration date, they will be immediately presented to the authorized body along with the proposed action plan.
4. In relevant cases, samples of new medicinal product.
5. Either the certificate of conformity of the European Pharmacopoeia on TSE to any new source of material, or (if applicable) documentary evidence that the source of material subject to the TSE risk was previously verified by the authorized body; and its compliance with the current article of the State Pharmacopoeia of the Republic of Kazakhstan on minimizing the risk of transmitting agents of spongiform encephalopathy of animals through the drug for medical and veterinary use was confirmed. For each such material, the following information should be provided: the name of the manufacturer; types of animals and tissues from which the material is taken; country of origin of animals and its use.
6. Where appropriate, evidence that new excipient does not interact with the analytical procedures of drug specification shall be provided.
7. It is necessary, through appropriate pharmaceutical development (including stability and antimicrobial conservation, if applicable), to provide justification for replacement/selection of excipients, etc.
8. Comparative data of dissolution profile for solid dosage forms rearding at least two pilot-industrial batches of the drug of new and old formulations. Comparative disintegration data are sufficient for herbal medicinal products.
9. Justifications for non-submission of the results of new bioequivalence study in accordance with the Rules for Conducting of Bioequivalence Studies.
4. The change does not affect the tablet with a scoreline, intended to separate the dosage form into equal doses.
Documentation
1. Amendment to the relevant section (s) of the dossier, including a detailed graphical representation of the current and proposed provision, as well as revision of the information on the medicinal product, respectively.
2. Comparative dissolution data for at least one test output batch of current and proposed sizes (no significant differences in comparability terms — see Rules for Conducting DP Bioequivalence Studies, hereinafter — Rules for Conducting Bioequivalence Studies). Comparative dissolution data are acceptable for herbal medicinal products.
3. Rationales for non-submission of results of a new bioequivalence study according to Rules for Conducting Bioequivalence Studies.
4. Where appropriate, samples of a drug product.
5. Results of relevant tests in accordance with State Pharmacopoeia of the Republic of Kazakhstan, confirming the equivalence of properties / the correctness of dosage.
(*) Note. For B.II.а. 2. c) any «dosage» change of the drug product requires submission of application for registration extension.
B.II.а. 3 Change of drug product composition (excipients) Conditions Documentation Required Type of procedure
а) Change in the composition of flavor additives (flavors) or dyes
1. Addition, exclusion or replacement 1, 2, 3, 4, 5, 6, 7, 9 1, 2, 4, 5, 6 IA
2. Content increase or decrease 1, 2, 3, 4 1, 2, 4 IA
b) Other excipients
1. Any minor correction of quantitative composition of drug product excipients 1, 2, 4, 8, 9, 10 1, 2, 7 IA
2. Qualitative or quantitative changes in one or more excipients that significantly affect the quality, safety or efficacy of drug product II
3. Change affecting biological / immunological product II
4. Any new excipient involving use of materials of human or animal origin that require evaluation of viral safety data and / or TSE risk II
5. Change, based on results of bioequivalence study II
6. Replacement of one excipient with a similar substance with same functional characteristics and a similar volume 1, 3, 4, 5, 6, 7, 8, 9 IB
Conditions
1. Changes of dosage form functional characteristics, for example, disintegration time, dissolution profile are absent.
2. Any minor correction of composition to maintain the total mass should be carried out using an excipient, which currently is a main part of the drug product.
3. Drug product specification is updated in terms of appearance / odor / taste and, if necessary, identification test is excluded.
4. Corresponding stability studies have been initiated in accordance with established requirements (indicating batch numbers); corresponding stability parameters of at least two test output batches or industrial batches are analyzed; applicant has satisfactory results of at least a 3-month stability study (at the time of IA changes introduction and IB changes notification); stability profile is similar to currently approved profile. Confirmation that studies will be completed and that if results at the end of expiration date do not correspond to specifications or potentially fall outside specification range, they will be immediately presented to authorized body along with the proposed plan of action. In addition, where applicable a photostability test has to be carried out.
5. All new components must meet requirements stated in relevant documents of the Republic of Kazakhstan concerning dyes used in the food industry and flavor additives.
6. New components do not involve use of human or animal origin materials requiring evaluation of viral safety data or compliance with the current requirements of the State Pharmacopoeia of the Republic of Kazakhstan to minimize risk of transmitting agents of animal spongiform encephalopathy through drug products for medical and veterinary use.
7. Where appropriate, changes do not affect dosage differences and do not adversely affect taste characteristics of drug products intended for use in children.
8. Dissolution profile of at least one test output batch of new drug product is comparable to profile of unaltered drug product (no significant differences in comparability terms — see Rules for Conducting Bioequivalence Studies). If herbal medicinal product dissolution test is not possible to conduct, the disintegration time of new drug product is comparable to that of unaltered drug product.
9. Change is not a consequence of instability and (or) should not affect safety, i.e. differences in dosages.
10. Analyzed drug product is not a biological / immunological drug product.
Documentation
1. Amendment to the relevant section (s) of the dossier, including identification tests of all new dyes (if applicable), as well as revision of information on medicinal product, respectively.
2. Declaration confirming that required stability studies are initiated in accordance with the established requirements (indicating batch numbers); and that (where appropriate) at the time of changes introduction, applicant has minimum satisfactory stability study results; and that the available data did not indicate a problem. It is also necessary to provide confirmation that the studies will be completed and that if at the end of expiration date results do not correspond to specifications or potentially fall outside specification range, they will be immediately presented to authorized body along with the proposed plan of action.
3. Results of stability studies performed for not less then 3 months in accordance with established requirements for significant stability parameters of at least two test output batches or industrial batches, also confirmation that the studies will be completed and that if at the end of expiration date results do not correspond to specifications or potentially fall outside specification range, they will be immediately presented to authorized body along with the proposed plan of action.
4. Where appropriate, samples of a new drug product.
5. Either European Pharmacopoeia Certificate of Conformity on TSE for any new material source, or (if applicable) documentary evidence that material source subject to the risk of TSE was previously verified by an authorized body; and its compliance with the current article of the State Pharmacopoeia of the Republic of Kazakhstan on minimizing the risk of transmitting agents of animals spongiform encephalopathy through medications for medical and veterinary use was confirmed. For each such material, the following information must be provided: name of manufacturer; species of animals and tissues from which the material is obtained; animals country of origin and its use.
6. Where appropriate, evidence that new excipient does not interact with drug product specification analytical techniques.
7. Appropriate pharmaceutical development (including stability and antimicrobial conservation, if applicable) is necessary to provide rationale for replacement / selection of excipients, etc.
8. Comparative data of solid dosage forms dissolution profile for at least two test output batches of drug product of new and current formulations. Comparative dissolution data are sufficient for herbal medicinal products.
9. Rationales for non-submission of results of a new bioequivalence study according to Rules for Conducting Bioequivalence Studies.
B.II.а. 4 Change in shell mass of dosage forms for oral administration or change in capsule shell mass Conditions Documentation Required Type of procedure
a) Solid dosage forms for oral administration 1, 2, 3, 4 1, 2 IA
b) Dosage forms with delayed, modified or prolonged release, in which shell is the key release factor II
Conditions
1. Dissolution profile of at least one test output batch of new drug product is comparable to profile of current drug product. If herbal medicinal product dissolution test is not possible to conduct, the disintegration time of new drug product is comparable to that of current drug product.
2. The shell is not a key factor in the release mechanism.
3. Specification of drug product has been updated only in terms of mass and size (if applicable).
4. Corresponding stability studies have been initiated in accordance with established requirements for least two test output batches or industrial batches; applicant has satisfactory results of at least a 3-month stability study (at the time of changes introduction); confirmation that the study will be completed. If at the end of expiration date results do not correspond to specifications or potentially fall outside specification range, they will be immediately presented to authorized body along with the proposed plan of action.
Documentation
1. Amendment to relevant section (s) of the dossier.
2. Declaration confirming that required stability studies are initiated in accordance with the established requirements (indicating batch numbers); and that (where appropriate) at the time of changes introduction, applicant has minimum satisfactory stability study results; and that the available data did not indicate a problem. It is also necessary to provide confirmation that the studies will be completed and that if at the end of expiration date results do not correspond to specifications or potentially fall outside specification range, they will be immediately presented to authorized body along with the proposed plan of action. In addition, where applicable a photostability test has to be carried out.
B.II.а. 5 A concentration change of a single-dose, fully administered parenteral drug product when active pharmaceutical substance content per dose unit (i. e. dosage) remains unaltered. Conditions Documentation Required Type of procedure
II
B.II.а. 6 Exclusion of solvent / diluent container from the packaging Conditions Documentation Required Type of procedure
1, 2 IB
Documentation
1. Exclusion rationale, including solvent / diluent alternative preparation methods for safe and effective use of a drug product.
2. Revised information on a drug product.

      B.II. b) Manufacturing process

B.II.b. 1 Change of manufacturing site for part or all of manufacturing processes of a drug product Conditions Documentation Required Type of procedure
а) Secondary packaging site 1, 2 1, 3, 8 IA
b) Primary packaging site 1, 2, 3, 4, 5 1, 2, 3, 4, 8, 9 IA
c) Manufacturing site of biological / immunological drug products or dosage forms manufactured via complex manufacturing processes, with the exception of batches release, quality control and secondary packaging II
d) A site requiring a primary inspection or a product-specific inspection II
e) A site where manufacturing operations for non-sterile drug products are carried out, except for batch release, quality control, primary and secondary packaging 1, 2, 3, 4, 5, 6, 7, 8, 9 IB
f) A site where manufacturing operations are carried out for sterile drug products manufactured using aseptic methods (excluding biological / immunological drugs), except for batch release, quality control and secondary packaging 1, 2, 3, 4, 5, 7, 8 IB
Conditions
1. Good Manufacturing Practice (GMP) certificate for manufacturing site of the transferring and accepting parties.
2. Site is licensed in accordance with the established procedure (for analyzed dosage form or drug product manufacturing).
3. Analyzed drug product is not sterile.
4. Where appropriate, for example, for suspensions or emulsions, scheme for primary expertise is introduced or, according to the current protocol, a primary expertise of a new manufacturing site using at least three industrial batches has been successfully carried out.
5. Analyzed drug product is not a biological / immunological drug product.
Documentation
1. Documentary evidence that proposed site is licensed in accordance with the established procedure for analyzed dosage form or drug product manufacturing.
2. Where appropriate, it is necessary to indicate batch numbers, corresponding batch size and batch manufacturing date (3) used in validation study, and provide primary expertise data or the primary expertise report (s) to be submitted.
3. It is necessary to clearly indicate «current» and «proposed» drug product manufacturers in Application Form for Change Introduction (according to section 2.5 of application form).
4. Copies of approved specifications for release and expiration date (if applicable).
5. The analysis data of one industrial batch and two test output batches that simulate manufacturing process (or two industrial batches) and comparative data of three batch manufactured at the previous manufacturing site. If requested, it is necessary to provide data on two complete industrial batches; it is necessary to inform if analysis results do not correspond to specification, and propose an plan of action.
6. Relevant data from the primary expertise, including particle size distribution microscopy results and soft and liquid dosage forms morphology, where pharmaceutical substance is in an undissolved state.
7. If on the new manufacturing site an active pharmaceutical ingredient is used as raw material, declaration of a manufacturing site authorized person responsible for batches manufacturing process is needed to confirm that active pharmaceutical ingredient is produced in accordance with the Rules of Good Manufacturing Practice of the Republic of Kazakhstan for raw materials.
8. Amendment to relevant section (s) of the dossier.
9. If manufacturing site and site conducting primary packaging are different sites, it is necessary to describe and validate conditions for transportation and storage of bulk preparation.
Note. In case of change of a manufacturing site or introduction of a new manufacturing site not in the Republic of Kazakhstan but in the country which has no agreement on mutual recognition of GMP, before submitting the notification holders are advised to consult authorized body and provide information on all previous inspections for last 2-3 years and (or) all scheduled inspections, including inspection dates, categories of inspected products, supervisory authority and other information. Declarations of authorized person, concerning the active pharmaceutical ingredient.
Manufacturing authorization holders are required to use only active pharmaceutical ingredients manufactured in accordance with GMP as raw material, therefore, each manufacturing authorization holder is required to declare that usage of active pharmaceutical ingredient manufactured in accordance with GMP as raw material. In addition, since authorized person responsible for the batch certification assumes overall responsibility for each batch, if site where batches are manufactured differs from the site stated above, authorized person responsible for batch certification must submit an additional declaration.
In many cases, only one manufacturing authorization holder is involved, so only one declaration will be required. However, if several manufacturing authorization holder are involved, instead of filing several declarations, it is allowed to file one declaration signed by one authorized person. This is permissible provided that:
the declaration clearly states that it is signed on behalf of all authorized persons involved.
B.II.b.2 Change of importer, batch release agreements and drug product quality control tests Conditions Documentation Required Type of procedure
a) Change or addition of a site where quality control / batch testing is carried out 1, 2, 3 1, 2, 5 IA
b) Change or addition of a manufacturer responsible for producing biological / immunological drug product batches and for any on-site biological / immunological test methods II
b) Change or addition of a manufacturer responsible for batch manufacturing process
1. Except for quality control / batch testing 1, 3 1, 2, 3, 4 IA
2. Including quality control / batch testing 1, 2, 3 1, 2, 3, 4 IA
3. Including quality control / testing of the biological / immunological drug product and one of biological / immunological / immunochemical on-site test methods II
Conditions
1. Site is licensed in accordance with the established procedure.
2. Drug product is not a biological / immunological drug product.
3. Technology transfer from the old to a new manufacturing site or a new test laboratory performed successfully.
Documentation
1. A copy of manufacturing authorizations or, if absent, a GMP certificate issued within the last three years by the appropriate authorized body.
2. It is necessary to indicate «current» and «proposed» drug product manufacturers in Application Form for Change Introduction (according to section 2.5 of application form).
3. Declaration of the authorized person responsible for batch certification, where it is stated that the manufacturer (s) of active pharmaceutical ingredient specified in the registration dossier, operates in accordance with the Rules of Good Manufacturing Practice of the Republic of Kazakhstan for raw materials. Under certain circumstances it is allowed to submit one declaration (see note to the amendment B.II.b.1).
4. Amendment to relevant section (s) of the dossier, including information on drug product.
B.II.b.3 Change in drug product manufacturing process, including an intermediate product used in the manufacture of a drug product Conditions Documentation Required Type of procedure
a) Minor changes in manufacturing process 1, 2, 3, 4, 5, 6, 7 1, 3, 4, 5, 6, 7, 8 IA
b) Significant changes inmanufacturing process, which have a significant impact on quality, safety and efficacy of drug product II
c) Drug is biological / immunologic drug product, and change requires an assessment of comparability II
d) Introduction of a non-standard terminal sterilization method II
e) Introduction or increase of excess used for active pharmaceutical ingredient II
f) Minor change in manufacturing process of an aqueous suspension for oral administration 1, 2, 4, 6, 7, 8 IB
Conditions
1. There are no changes in qualitative or quantitative profile of impurities or physicochemical properties.
2. Change concerns a solid oral dosage form / immediate-release solution and analyzed drug product is not biological / immunological or herbal.
3. Manufacturing principle, including its stages, does not change, for example, intermediate products processing, any solvents used in the manufacturing process remain unaltered.
4. Currently registered production process is monitored by in-house controls, and changes to such controls (expansion or exclusion of eligibility criteria) are not required.
5. Drug product and intermediate products specifications do not change.
6. As a result of new process, drug product identical to current drug product in terms of all aspects of quality, safety and efficacy should be manufactured.
7. According to relevant documents of the Republic of Kazakhstan, relevant stability studies of at least one test output batch or industrial batch have been initiated; applicant has satisfactory results of at least a 3-month stability study. Confirmation that the studies will be completed and that if at the end of expiration date results do not correspond to specifications or potentially fall outside specification range, they will be immediately presented to authorized body along with the proposed plan of action.
Documentation
1. Amendment to relevant section (s) of the dossier.
2. In regard to soft and liquid dosage forms containing active pharmaceutical ingredient undissolved: appropriate primary expertise of changes, including particle microscopy for visual changes in morphology; comparative data on particle size distribution (dispersity) obtained using an appropriate method.
3. In regard to solid dosage forms: data on dissolution profile for one representative industrial batch and comparative data for last three batches manufactured using previous process. If requested, it is necessary to provide data on two complete industrial batches or to inform if the results do not correspond to specification, and propose a plan of action. Comparative dissolution data are sufficient for herbal medicinal products.
4. Rationales for non-submission of results of a new bioequivalence study according to Rules for Conducting RK Bioequivalence Studies.
5. In the cases of changes in process parameter(s) considered as not affecting the drug product quality: declaration stating that these were achieved during previous approved risk assessment.
6. Copies of specifications for release and expiration date.
7. Data of analysis (as a comparative table) of at least one batch manufactured using approved and proposed process. If requested, it is necessary to provide data on two complete industrial batches; it should be reported if analysis results do not correspond to specification, and propose a plan of action.
8. Declaration stating that appropriate studies of stability were initiated according to documents of the Republic of Kazakhstan (indication batch numbers) and required stability parameters were studied for at least one test output batch or industrial batch, and that the applicant, at the time of notification, had available satisfactory results of at least a 3-month stability study, and the stability profile is similar to currently registered situation. Confirmation is provided that the studies will be completed and that if at the end of expiration date results do not correspond to specifications or potentially fall outside specification range, they will be immediately presented to authorized body along with the proposed plan of action.
B.II.b.4 Change in drug product batch size (including batch size ranges) Conditions Documentation Required Type of procedure
a) Up to 10-fold upsizing vs. approved 1, 2, 3, 4, 5, 7 1, 4 IA
b) Up to 10-fold downsizing 1, 2, 3, 4, 5, 6 1, 4 IA
c) The change requires an analysis of comparability of biological/immunological drug product, ot change in batch size requires a new bioequivalency study II
d) The change affects all other dosage forms manufactured using integrated manufacturing process II
d) 10-fold upsizing vs. approved (oral) immediate release dosage form batch size 1, 2, 3, 4, 5, 6 IB
e) Scale of nanufacturing biological/immunological drug product increased/decreased with no changes in manufacturing process (e.g., line duplication) 1, 2, 3, 4, 5, 6 IB
Conditions
1. The change does not affect reproducibility and (or) stability of drug product quality.
2. The change affects standard oral immediate release dosage forms or non-sterile liquid dosage forms.
3. Any changes in manufacturing methods and (or) in-process controls are only needed for batch size changes, e.g. use of equipment having different dimensions.
4. Scheme for primary expertise is available or, according to the current protocol and applicable requirements, a primary expertise of manufacture performed for least three industrial new size batches.
5. Analyzed drug product is not a biological / immunological drug product.
6. The change should not be due to unforeseen situations emerged during the production, or due to changes in stability.
7. Batch size falls into 10-fold range specified at registration or after further change other than type IA change.
Documentation
1. Amendment to relevant section (s) of the dossier.
2. Data of analysis (as a comparative table) of at least one industrial batch manufactured in registered and proposed sizes. If requested, it is necessary to provide data on two complete industrial batches; MA holder is obliged to report if analysis results do not correspond to specification, and propose a plan of action.
3. Copies of approved specifications for release and expiration date.
4. Where appropriate, it is necessary to indicate batch numbers, corresponding batch size and batch manufacturing date (3) used in validation study, or provide primary expertise report (scheme).
5. Primery expertise results must be provided.
6. Results of stability study performed in accordance with RK documents in regard to the relevant stability parameters for at least one test output batch or industrial batch encompassing at least three months; confirmation that such studies will be completed and that if at the end of expiration date results do not correspond to specifications or potentially fall outside specification range, they will be immediately presented to authorized body along with the proposed plan of action. For biological/immunological drugs: declaration stating that no comparability assessment is required.
B.II.b. 5 Change in in-process tests or acceptance criteria used during drug production Conditions Documentation Required Type of procedure
a) Strengthening in-process acceptance criteria 1, 2, 3, 4 1, 2 IA
b) Addition of new tests or acceptance criteria 1, 2, 5, 6 1, 2, 3, 4, 5, 7 IA
c) Exclusion of non-essential in-process test 1, 2, 7 1, 2, 6 IA
d) Exclusion of in-process test that might significantly affect total drug product quality II
e) Expanding approved in-process acceptance criteria significantly affecting total drug product quality II
f) Addition or replacement of in-process test for safety or quality reasons 1, 2, 3, 4, 5, 7 IB
Conditions
1. The change is not due to any obligation undertaken based on previous expertizes in order to analyze specification acceptance criteria (e.g., during registration or introducing type II changes)
2. The change is due to unforeseen situations emerged during the production, e.g. new raw impurity, change in total impurities content limits.
3. Any change should fall into the range of currently approved acceptance criteria.
4. Analytical method undergoes no or insugnificant changes.
5. Neither new test method is based on new non-standard procedures or standard procedures used in a new fashion.
6. New test method is not a biological / immunological / immunochemical method and does not use biological reagents for biological active pharmaceutical substance (except of standard microbiological pharmacopoeia method)
7. In-process test does not affect control of critical parameter, for example:
quantification
impurities (provided that specific solvent is definitely not used in manufacture)
any critical physical parameter (particle size, bulk density and tapped density)
identification test (with no siutable alternative control)
Microbiological control (provided that it is not required for a specific dosage form)
Documentation
1. Amendment to relevant section (s) of the dossier.
2. Comparative table of current and proposed in-process tests and acceptance criteria.
3. Detailed description of a new analytical method and primary expertise data (as appropriate).
4. Data of analysis of two industrial drug product batches (three batches, if no proper proof available for biological active pharmaceutical subatances) in regard of all specification parameters.
5. As appropriate, comparatve data of drug product dissolution profile for at least one test output batch manufactured using current and new in-process tests. Comparative dissolution data are sufficient for herbal medicinal products.
6. Risk justification/assessment confirming that the in-process test is non-essential or obsolete.
7. Proof of new in-process test and acceptance criteria.

      B. II. c) Excipient quality controls

B.II.c.1 Change in excipient specification parameter and (or) acceptance criteria Conditions Documentation Required Type of procedure
a) Strengthening specification acceptance criteria 1, 2, 3, 4 1, 2 IA
b) Supplementing the specification with a new parameter and corresponding test method 1, 2, 5, 6, 7 1, 2, 3, 4, 6, 8 IA
c) Exclusion of non-essential specification parameter (e.g., exclusion of an obsolete parameter) 1, 2 1, 2, 7 IA
d) Change falling outside the approved specification acceptance criteria II
d) Exclusion of a specification parameter that might significantly affect total drug product quality II
f) Addition or replacement (except for biological and immunological drug) of a specification parameter abd corresponding test method for safety or quality reasons 1, 2, 3, 4, 5, 6, 8 IB
g) change in proprietary data of specification of unofficial pharmacopeia or third country pharmacopeia, if no article for the excipient included into RK pharmacopeia 1, 2, 3, 4, 5, 6, 8 IB
Conditions
1. The change is not due to any obligation undertaken based on previous expertizes in order to analyze specification acceptance criteria (e.g., during drug product registration or introducing type II changes)
2. The change is due to unforeseen situations emerged during the production, e.g. new raw impurity, change in total impurities content limits.
3. Any change should fall into the range of currently approved acceptance criteria.
4. Analytical method undergoes no or insugnificant changes.
5. Neither new test method is based on new non-standard procedures or standard procedures used in a new fashion.
6. New test method is not a biological / immunological / immunochemical method and does not use biological reagents for biological active pharmaceutical substance (except of standard microbiological pharmacopoeia method)
7. The change is not related to a genotoxic impurity.
Documentation
1. Amendment to relevant section (s) of the dossier.
2. Comparative table of current and proposed specifications.
3. Detailed description of any new analytical method and primary expertise data (as appropriate).
4. Data of analysis of two industrial excipient batches (three batches, if no proper proof available for biological active pharmaceutical subatances) in regard of all specification parameters.
5. As appropriate, data of comparative drug product dissolution kinetic test for at least one test output batch containing the excipient meeting current and proposed specifications. Comparative dissolution data are sufficient for herbal medicinal products.
6. Rationales for non-submission of results of a new bioequivalence study according to Rules for Conducting RK Bioequivalence Studies.
7. Risk justification/assessment confirming that the parameter is non-essential or obsolete.
8. Proof of new specification parameter and acceptance criteria.
B.II.c. 2 Change of analytical method for excipient Conditions Documentation Required Type of procedure
a) Minor changes in approved analytical method 1, 2, 3, 4 1, 2 IA
b) Exclusion of the analytical method if an alternative method is already approved 5 1 IA
c) Replacement of biological/immunological/immunochemical test method or method involving a biological reagent II
d) Other changes in analytical method (including addition or replacement) 1, 2 IB
Conditions
1. Accorging to the relevant documents, the required validation studies performed confirming that the updated analytical method is at least equivalent to the previous one.
2. Total impurities content limits are unchanged, no new raw impurities identified.
3. Analytical method is unchanged (e.g., change in column length or temperature but not other column type or method).
4. New test method is not a biological / immunological / immunochemical method and does not use biological reagents (except of standard microbiological pharmacopoeia method)
5. An alternative analytical method for the specification parameter is already approved, and such method was included otherwise than using IA/ notification.
Documentation
1. Amendment to relevant section (s) of the dossier, including the description of analytical procedures, summary of primary expertise data, revised specifications for impurities (if applicable).
2. Comparative results of primary expertise or, if the proof is available, comparative results of analysis confirming the equivalency of the current and proposed tests. This requirement is not applicable if a new analytical method is added.
B.II.c. 3 Change of the source of excipient or reagent with TSE risk Conditions Documentation Required Type of procedure
а) From a material with TSE risk for a material of plant or synthetic origin
1. For excpients or reagents not used in manufacture of biological/immunological active pharmaceutical ingredient or biological/immunological drug product 1 1 IA
2. For excpients or reagents used in manufacture of biological/immunological active pharmaceutical substance or biological/immunological drug product 1, 2 IB
b) Change or introduction of a material with TSE risk or replacement of a material with TSE risk with other material with TSE risk having no TSE certificate II
Conditions
1. Specifications for release and expiration date of excipient and drug product are unchanged.
Documentation
1. Declaration of material manufacturer or Marketing Authorization holder stating that they are completely of plant or synthetic origin.
2. Material equivalency study anf effect on manufacture of final material and drug product characteristics (e.g., dissolution parameters).
B.II.c. 4 Change in synthesis or preparation of a non-pharmacopoeial excipient (if described in a registration dossier) or new excipient Conditions Documentation Required Type of procedure
a) Non-essential change in synthesis or preparation of a non-pharmacopoeial excipient or new excipient 1, 2 1, 2, 3, 4 IA
b) Specifications changed or there is a change in physicochemical properties of the excipient affecting drug product quality II
c) The excipient is a biological/immunological substance II
Conditions
1. Method of synthesis and specifications are identical, with no qualitative and quantitative changes in impurities profile (except of residual solvents provided that theay are controlled in accordance of limits specified in RK documents) or physicochemical properties.
2. Except of adjuvants.
Documentation
1. Amendment to relevant section (s) of the dossier.
2. Data of analysis (as a comparative table) of at least two (at least test output) batches of the excipient manufactured using old and new processes.
3. As appropriate, data of comparative drug product dissolution kinetic test for at least two (at least test output) batches. Comparative dissolution data are sufficient for herbal medicinal products.
4. A copy of approved and new (if applicable) specifications of the excipient.

      B. II. d) Drug product quality control

B.II.d.1 Change in drug product specification parameters and (or) acceptance criteria Conditions Documentation Required Type of procedure
a) Strengthening specification acceptance criteria 1, 2, 3, 4 1, 2 IA
b) Strengthening specification acceptance criteria for drugs to be batch released by an official control authority 1, 2, 3, 4 1, 2 IA
c) Supplementing the specification with a new parameter and corresponding test method 1, 2, 5, 6, 7 1, 2, 3, 4, 5, 7 IA
d) Exclusion of non-essential specification parameter (e.g., exclusion of an obsolete parameter) 1, 2 1, 2, 6 IA
e) Change falling outside the approved specification acceptance criteria II
f) Exclusion of a specification parameter that might significantly affect total drug product quality II
g) Addition or replacement (except for biological and immunological drug) of a specification parameter abd corresponding test method for safety or quality reasons 1, 2, 3, 4, 5, 7 IB
h) Updating dossier to meet regulations of updated general article of Republic of Kazakhstan State Pharmacopoeia for the drug product (*) 1, 2, 3, 4, 7, 8 1, 2 IA
i) An article “Dosing consistency” or “Weight consistency” or “Content consistency” is added to Republic of Kazakhstan State Pharmacopoeia in order to replace currently registered method 1, 2, 10 1, 2, 4 IA
Conditions
1. The change is not due to any obligation undertaken based on previous expertizes in order to review specification acceptance criteria (e.g., during drug product registration or introducing type II changes), provided that the proof documents were not verified and approved previously within another procedure.
2. The change is due to unforeseen situations emerged during the production, e.g. new raw impurity, change in total impurities content limits.
3. Any change should fall into the range of currently approved acceptance criteria.
4. Analytical method undergoes no or insugnificant changes.
5. Neither new test method is based on new non-standard procedures or standard procedures used in a new fashion.
6. New test method is not a biological / immunological / immunochemical method and does not use biological reagents for biological active pharmaceutical substance (except of standard microbiological pharmacopoeia method)
7. The change does not affect any impurities (including genotoxic ones) or dissolution.
8. The change affects update of microbiological control acceptance criteria to meet the applicable Pharmacopeia, and currently registered microbiological control acceptance criteria do not include any additional controls included in the specification, except of pharmacopeial requirements related to the specific dosage form
9. Specification parameter does not affect a critical parameter, for example:
quantification
impurities (provided that specific solvent is definitely not used in drug product manufacture)
any critical physical characteristics (uncoated tablet durability or fragility, size)
any request for test omission
10. Proposed control completely conforms to a table in the article of Republic of Kazakhstan State Pharmacopoeia and does not include alternative proposals of dosing consistency test using variation in weight or content consistency if the latter are specified in the article.
Documentation
1. Amendment to relevant section (s) of the dossier.
2. Comparative table of current and proposed specifications.
3. Detailed description of any new analytical method and primary expertise data (as appropriate).
4. Data of analysis of two industrial drug product batches (three batches, if no proper proof available for biological active pharmaceutical subatances) in regard of all specification parameters.
5. As appropriate, data of comparative drug product dissolution kinetic test for at least one test output batch meeting current and proposed specifications. Comparative dissolution data are sufficient for herbal medicinal products.
6. Risk justification/assessment confirming that the parameter is non-significant.
7. Proof of new specification parameter and acceptance criteria.
(*) Note. need to notify competent authorities about updated article of RK State Pharmacopoeia, if the registered drug product dossier refers to “current edition”. In this regard, such change is applicable in the case of no references to the updated pharmacopoeial article available in the technical dossier, and the change is performed in order to include the reference to the updated version.
B.II.d.2 Change in the drug product analytical method Conditions Documentation Required Type of procedure
a) Non-essential changes in the approved analytical method 1, 2, 3, 4 1, 2 IA
b) Exclusion of the analytical method if an alternative method is already approved 4 1 IA
c) Change in (replacement of) a biological/immunological/immunochemical test method or method involving a biological reagent, or replacement of the reference biological drug not covered with approved protocol II
d) Other changes in analytical method (including addition or replacement) 1, 2 IB
e) Updating the analytical method to conform to the updated general articlle in Republic of Kazakhstan State Pharmacopoeia 2, 3, 4, 5 1 IA
f) To reflect the conformity with Republic of Kazakhstan State Pharmacopoeia and to exclude a reference to obsolete proprietary analytical method and its number (*) 2, 3, 4, 5 1 IA
Conditions
1. Accorging to the relevant documents, the required validation studies performed confirming that the updated analytical method is at least equivalent to the previous one.
2. Total impurities content limits are unchanged, no new raw impurities identified.
3. Analytical method is unchanged (e.g., change in column length or temperature but not other column type or method).
Conditions
1. According to the relevant documents, the necessary validation studies have been carried out, confirming that the updated analytical methodology is at least equivalent to the previous one.

2. Limits content of the impurities amount have not changed, new unqualified impurities are not detected.

3. The analytical method has not changed (e.g., changing of the column length or temperature, but not changing of column type or method).

4. The new test method is not biological/immunological/immunochemical or a method using a biological reagent (with the exception of standard pharmacopeia microbiological methods).

5. The registered analytical method already refers to the general article of the State Pharmacopoeia of the RK, and any changes are insignificant and require updating of the technical dossier.

Documentation
1. Amendment to the relevant section(s) of the dossier, including a description of analytical methods, a summary of the primary expert examination data, revised specifications for impurities (if applicable).

2. Comparative results of the primary expert examination or, if justification is available, comparative analysis results confirming that the current and proposed test are equivalent. If a new analytical method is added, this requirement does not apply.

(*) Note If a «current edition» is mentioned in the registered medicinal product master file, there is no need to notify the authorized bodies about the updated article of the State Pharmacopeia of the Republic of Kazakhstan.
B.II.d.3 Change affecting the introduction of a real-time release or release by parameters in the manufacture process of a medicinal product. Conditions Documentation required Type of procedure
II

      B. II. e) Container closure system

B.II.e.1 Change of the medicinal product primary packaging Conditions Documentation required Type of procedure
а) Qualitative and quantitative composition
1. Solid dosage forms 1, 2, 3 1, 2, 3, 4, 6 IA
2. Soft and non-sterile liquid dosage forms 1, 2, 3, 5, 6 IB
3. Sterile medical drugs and biological/immunological drugs II
4. The change affects packaging with less protective properties in simultaneously changing of storage conditions and (or) with the shelf life reduction. II
b) Changing of the container type or adding of a new container
1. Solid, soft and non-sterile liquid dosage forms 1, 2, 3, 5, 6, 7 IB
2. Sterile medical drugs and biological/immunological drugs II
3. Exclusion of the primary packaging container, which does not result in the complete exclusion of the strength or dosage form 4 1, 8 IA
Conditions
1. The change affects only one type of package/container (e.g., blister — blister).

2. Significant properties of the proposed packaging material are at least equivalent to ones of the approved packaging material.

3. Appropriate stability studies have been initiated in accordance with the established requirements. At the time of introduction of changes the applicant has the relevant stability parameters analyzed in at least two test output or industrial series and satisfactory results of at least 3-month stability studies available. However, if the proposed packaging is more stable than approved one, three-month stability data are not required. The studies are to be completed, if their results do not fit into the specification or potentially do not fit into the specification at the end of the expiry date, they must be immediately presented to the authorized body along with the proposed action plan.

4. The remaining form(s) of the release of the medicinal product must comply with the dosage recommendations and the duration of treatment specified in the summary of the product characteristics.

Documentation
1. Amendment to the relevant section(s) of the dossier.

2. Required data on the new packaging (e.g., comparative data on permeability, for example, for O2, CO2, moisture, etc.).

3. Where appropriate, it should be confirmed that interaction between the contents and the packaging material does not occur (for example, the components of the proposed material do not get absorbed by its contents, the components of the drug do not soak into the package), including confirmation that the material meets the relevant pharmacopeia requirements or the legislation of the Republic of Kazakhstan on plastic food contact materials and objects.

4. Declaration on the required stability studies have been initiated in accordance with the established requirements (indicating the series numbers); and on the required minimum satisfactory stability data (where appropriate) available at the applicant’s disposal at the time of the changes introduction; and that the available data did not detect any problem. It is also necessary to provide confirmation that the studies are to be completed and that if the results do not fit into the specifications or potentially fall outside the specification at the end of the expiration date, they will be immediately presented to the authorized body along with the proposed action plan.

5. Appropriate stability studies have been initiated in accordance with the established requirements. At the time of introduction of changes the applicant has the relevant stability parameters analyzed in at least two test output or industrial series and satisfactory results of at least 3-month stability studies available. The studies are to be completed, if their results do not fit into the specification or potentially do not fit into the specification at the end of the expiry date, they must be immediately presented to the authorized body along with the proposed action plan.

6. Comparison of current and proposed specifications of primary packaging (if applicable).

7. Samples of a new container/closure, if applicable.

8. Declaration that the remaining package sizes correspond to the dose regimen and the duration of treatment and comply with the dosing recommendations provided in the summary of the product characteristics.

Note For B.II.E.1.b) — if a change leads to «the formation of a new dosage form», such a change requires filing of an application for extension of registration.
B.II.e.2 Change of specification parameters and (or) acceptability criteria of the medicinal product primary packaging Conditions Documentation required Type of procedure
a) Stiffening of the acceptance criteria for the specification 1, 2, 3, 4 1, 2 IA
b) Adding of a new parameter and corresponding analytical method to the specification 1, 2, 5 1, 2, 3, 4, 6 IA
c) Elimination of a non-essential specification parameter (for example, exclusion of an obsolete parameter) 1, 2 1, 2, 5 IA
d) Addition or replacement of the specification parameter for safety or quality reasons 1, 2, 3, 4, 6 IB
Conditions
1. The change is not a consequence of any commitment made based on the results of previous expert examinations to analyze the criteria for the acceptability of the specification (for example, during the registration of a medicinal product or the introduction of Type II changes).

2. The change is not a consequence of unforeseen situations arising in the manufacture process.

3. Any change should be within the range of the currently approved eligibility criteria.

4. The analytical methodology does not change or changes insignificantly.

5. No new test method is based on a new non-standard methodology or a standard methodology used in a new way.

Documentation
1. Amendment to the relevant section (s) of the dossier.

2. Comparative table of current and proposed specifications.

3. Detailed description of the new analytical method and data of the primary expert examination (as appropriate).

4. Data analysis of two series of packaging material by all parameters (indicators) of the specification.

5. Risk justification/assessment, which confirms that the parameter is insignificant.

6. Justification of a new specification parameter and acceptance criteria.

B.II.e.3 Change in the analytical method for the primary packaging of the medical product Conditions Documentation required Type of procedure
a) Minor changes in the approved analytical method 1, 2, 3 1, 2 IA
b) Other changes in the analytical method (including replacement or addition) 1, 3, 4 1, 2 IA
c) Exclusion of the analytical method, if the alternative method has already been approved 5 1 IA
Conditions
1. According to the relevant documents, the necessary primary expertise carried out confirms, that the updated analytical methodology is at least equivalent to the previous one.

2. The analysis method has not changed (e.g., changing of the column length or temperature, but not changing of column type or method).

3. No new test method is based on a new non-standard methodology or a standard methodology used in a new way.

4. Active pharmaceutical substance/medicinal product is not biological/immunological.

5. An alternative analytical method for the specification parameter has already been approved, and this method was not included by IA/notification.

Documentation
1. Amendment to the relevant section(s) of the dossier.

2. Comparative results of the primary examination or, if there is justification, comparative analysis results confirming that the current test is equivalent to the proposed one. This requirement does not apply if a new analytical technique is added.

B.II.e. 4 Changing of the shape or dimensions of the primary packaging or closure (primary packaging) Conditions Documentation required Type of procedure
а) Non-sterile medical products 1, 2, 3 1, 2, 4 IA
b) Change of shape or size affects key features of the packaging material that significantly affect delivery, use, safety or stability of the drug II
c) Sterile medical products 1, 2, 3, 4 IB
Conditions
1. Amendment to the relevant section(s) of the dossier, including description, detailed drawing and composition of the container or closure material, as well as the revision of the information on the medicinal product.

2. If applicable, samples of a new container/closure.

3. Repeated validation studies of sterile preparations undergoing terminal sterilization were conducted. If applicable, the series numbers used in the validation studies should be indicated.

4. If the free space or the ratio of the surface to the volume change, declaration on the required stability studies initiated in accordance with the established requirements (indicating the series numbers) is necessary; and on the satisfactory results of stability studies available, as appropriate, at the time of the notification of the IA type change and the notification of the change of the IB type; and the available data do not indicate any problems. It is also necessary to provide confirmation that the studies are to be completed, and that if the results do not fit into the specifications or potentially fall outside the specification at the end of the expiration date, they will be immediately presented to the authorized body along with the proposed action plan.

Documentation
1. Amendment to the relevant section(s) of the dossier, including description, detailed drawing and composition of the container or closure material, as well as the revision of the information on the medicinal product.

2. If applicable, samples of a new container/closure.

3. Repeated validation studies of sterile preparations undergoing terminal sterilization were conducted. If applicable, the series numbers used in the validation studies should be indicated.

4. If the free space or the ratio of the surface to the volume change, declaration on the required stability studies initiated in accordance with the established requirements (indicating the series numbers) is necessary; and on the satisfactory results of stability studies available, as appropriate, at the time of the notification of the IA type change and the notification of the change of the IB type; and the available data do not indicate any problems. It is also necessary to provide confirmation that the studies are to be completed, and that if the results do not fit into the specifications or potentially fall outside the specification at the end of the expiration date, they will be immediately presented to the authorized body along with the proposed action plan.

B.II.e.5 Change of the medical product’s package size. Conditions Documentation required Type of procedure
a) Change of the number of units of the dosage form (e.g., tablets, ampoules, etc.) in the package
1. Change is within the approved range of package sizes 1, 2 1, 3 IA
2. The change is not within the approved package size range 1, 2, 3 IB
b) Change in the size(s) of package(s) 3 1, 2 IA
c) Change in nominal mass/nominal volume of sterile multi-dose (or single-dose with partial extraction) parenteral drugs and biological/immunologic multidose parenteral drugs II
d) Change in nominal mass/nominal volume of non-parenteral multidose (or single-dose with partial extraction) drugs 1, 2, 3 IB
Conditions
1. The new size of the package should correspond to the dosage regimen and the duration of treatment indicated in the summary of product characteristics.

2. The material of the primary package does not change.

3. The remaining forms of release comply with the recommendations on dosing and duration of treatment specified in the summary of product characteristics.

Documentation
1. Amendment to the relevant section(s) of the dossier, including revision of information on the medicinal product.

2. Justification that the new/remaining dimensions of the packages correspond to the dosage regimen and duration of treatment indicated in the summary of product characteristics.

3. Declaration on that if it is expected to affect stability, stability studies will be initiated in accordance with the relevant established requirements. The data must be submitted (with the proposed action plan) only if they do not fit into the specification.

Note: For B.II.e.5.c) and d) — If the change leads to a change in the «strength» of the drug, such a change requires the filing of an application for registration extension.
B.II.e. 6 Change in any component of the (primary) package that is not in direct contact with the product (e.g., the color of the removable caps, the colored code rings on the ampoules, the change of the cap protecting the needle (use of another plastic)) Conditions Documentation required Type of procedure
a) A change affecting the information on the medicinal product 1 1 IA
b) A change that does not affect the information on the medicinal product 1 1 IA
Conditions
1. The change does not affect those parts of the packaging material affecting the delivery, use, safety or stability of the drug.
Documentation
1. Amendment to the relevant section (s) of the dossier, including revision of information on the medicinal product.
B.II.e.7 Changing of the supplier of components for the package or device (if specified in the dossier) Conditions Documentation required Type of procedure
а) Exclusion of supplier 1 1 IA
b) Substitution or addition of a supplier 1, 2, 3, 4 1, 2, 3 IA
c) Any change in the suppliers of dispensers of metered-dose inhalers II
Conditions
1. No exclusion of the component of the package or product.

2. The qualitative and quantitative composition of the components of the package/product and sketch specifications do not change.

3. Specifications and quality control methods are at least equivalent.

4. The sterilization method and its conditions do not change (if applicable).

Documentation
1. Amendment to the relevant section(s) of the dossier.

2. Confirmation of the registration of a medical device in the Republic of Kazakhstan with respect to medical devices attached to a medicinal product.

3. Comparison table of current and proposed specifications (if applicable).

B.II.e. 8 Change of the labeling design of primary and secondary packaging Conditions Documentation required Type of procedure
1 1,2 IA
Conditions
1. The qualitative and quantitative composition of the components of the package/product and sketch specifications do not change.
Documentation
1. Amendment to the relevant section(s) of the dossier.

2. Layout of packages in the previous design.

      B.II. f) Stability

B.II.f. 1 Change of medicinal product the shelf life or storage conditions Conditions Documentation required Type of procedure
a) Reduction of the shelf life of the medicinal product
1. Packed in commercial packaging 1 1, 2, 3 IA
2. After the first opening 1 1, 2, 3 IA
3. After dilution or reconstitution 1 1, 2, 3 IA
b) Increased shelf life of the medicinal product
1. Packed in commercial packaging (confirmed by real-time data) 1, 2, 3 IB
2. After the first opening (confirmed by real-time data) 1, 2, 3 IB
3. After dilution or recovery (confirmed by real-time data) 1, 2, 3 IB
4. Extension of the expiration date by extrapolation of stability data that does not correspond to the documents of the Republic of Kazakhstan (*) II
5. Increase in the storage period of the biological/immunological drug in accordance with the approved stability program 1, 2, 3 IB
c) Change in storage conditions for biological/immunological drugs if stability studies are not conducted in accordance with the current approved stability study program II
d) Change in the storage conditions of the drug or drug after dilution/ reconstitution 1, 2, 3 IB
e) Modification of the approved stability protocol 1, 2 1, 4 IA
Conditions
1. The change should not be a consequence of unforeseen situations arising in the course of manufacture process or due to changes in stability.

2. The changes do not lead to an extension of the eligibility criteria for the test parameters, the elimination of the stability parameter, or the reduction of the test frequency.

Documentation
1. Amendment to the relevant section(s) of the dossier. It should contain the results of relevant real-time stability studies (covering the entire shelf life) carried out in accordance with the relevant RK documents in at least two test output series (1) of the medicinal product packaged with the registered packaging material, and/or respectively after first opening or dilution; in appropriate cases, it is necessary to present the results of microbiological tests.

2. Revised information on the medicinal product.

3. Copies of the approved specifications at the end of the expiration date and, if applicable, the specifications after dilution/reconstitution or after the first opening.

4. Justification of the proposed changes.

(*) Note: Extrapolation is not applicable with respect to a biological/immunological drug.
(1) If there is an obligation to check the expiration date on industrial series, test output series are allowed.

      B. II. g) Design space and protocol of post-marketing changes

B.II.g. 1 Introduction of a new design space or the expansion of an approved design space of a medicinal product (excepting biological), affecting: Conditions Documentation required Type of procedure
a) One or more separate operations of the medicinal product manufacturing process, including appropriate in-house controls and (or) analytical methods 1, 2, 3 II
b) Analytical procedures for excipients/intermediates and (or) medicinal product 1, 2, 3 II
Documentation
1. The results of drug and process development studies (including risk assessment and multivariate studies, respectively), confirming that a complete mechanistic understanding of the quality of materials and process parameters on critical drug quality parameters has been achieved.

2. Description of the design space in a tabular form, including variables (material properties and production process parameters) and their proposed ranges.

3. Amendment to the relevant section(s) of the dossier.

B.II.g. 2 Introduction of a post-registration protocol for managing changes affecting a medicinal product Conditions Documentation required Type of procedure
1, 2, 3 II
Documentation
1. Detailed description of the proposed change.

2. Protocol for the management of changes affecting the medicinal product.

3. Amendment to the relevant section(s) of the dossier.

B.II.g. 3 Exclusion of an approved protocol for managing changes affecting a medicinal product Conditions Documentation required Type of procedure
1 1 IA
Conditions
1. Exclusion of the post-marketing change management protocol affecting the medicinal product is not a consequence of unforeseen situations or inconsistency of the specification during the introduction of the changes described in the protocol, and does not affect the approved information included in the dossier in any way.
Documentation
1. Justification of the proposed exclusion.
2.
B.II.g. 4 Changes to the approved change management protocol Conditions Documentation required Type of procedure
a) Significant changes to the change management protocol II
b) Minor changes in the change management protocol that do not change the strategy described in the protocol 1 IB
Documentation
1. A declaration on that any change should fit within the range of valid approved eligibility criteria. In addition, a declaration on that biological/immunological drugs do not require comparability assessment.
B.II.g. 5 Implementation of changes envisaged by the approved change management protocol Conditions Documentation required Type of procedure
a) Implementation of the change does not require additional auxiliary data 1 1, 2, 4 IA
b) Implementation of the change requires additional auxiliary data 1, 2, 3, 4 IB
c) Realization of the change of the biological/immunological medicinal product. 1, 2, 3, 4, 5 IB
Conditions
1. The proposed change was implemented in full compliance with the approved change management protocol, which requires immediate notification after its implementation.
Documentation
1. Reference to the approved change management protocol.

2. The declaration on that the change corresponds to the approved change management protocol and the results of the study satisfy the eligibility criteria specified in the protocol. In addition, the declaration that comparability is not required for biological/immunological products.

3. Results of studies conducted in accordance with the approved change management protocol.

4. Amendment to the relevant section(s) of the dossier.

5. A copy of the approved specifications for the medicinal product.

      B. II. з Safety in respect of extraneous agents

B.II.з.1 Update of the information «Safety assessment with respect to extraneous agents» (section 3.2.A.2 of the registration dossier) Conditions Documentation required Type of procedure
a) Studies affecting production phases studied for the first time for one or more extraneous agents II
b) Replacement of out-of-date studies that affect production stages and extraneous agents previously included in the dossier
1. with a change in the risk assessment II
2. without any change in the risk assessment 1, 2, 3 IB
Documentation
1. Amendment to the relevant section(s) of the dossier, including the introduction of new studies aimed at examining the ability of production stages to inactivate/eliminate extraneous agents.

2. Justification that study does not change the assessment of risks.

3. Amendment to information on the medicinal product (if applicable).

      B.III Certificate of compliance with the European Pharmacopoeia (CEP) (if available)/TSE/ monographs

B.III.1 Submission of a new or updated Certificate of Conformity to European Pharmacopoeia or exclusion of the Certificate of Conformity to European Pharmacopoeia Conditions Documentation required Type of procedure
For a pharmaceutical substance

For raw material/reagent/intermediate product used in the pharmaceutical substance manufacturing process

For an excipients

a) Certificate of conformity to the European Pharmacopeia with the relevant monograph of the European Pharmacopoeia
1. A new certificate from a previously approved manufacturer 1, 2, 3, 4, 5, 6, 9 1, 2, 3, 4, 5 IA
2. Updated certificate from a previously approved manufacturer 1, 2, 3, 4, 6 1, 2, 3, 4, 5 IA
3. New certificate from the new manufacturer (replacement or addition) 1, 2, 3, 4, 5, 6, 9 1, 2, 3, 4, 5 IA
4. Exclusion of certificates (if several certificates were attached to the material) 8 3 IA
5. A new certificate for a non-sterile active pharmaceutical substance to be used in a sterile drug when water is used at the last stage of the synthesis, and the absence of endotoxins 1, 2, 3, 4, 5 IB
b) Certificate of conformity to the European Pharmacopoeia on TSE regarding active pharmaceutical substance/raw material/reagent/intermediate/excipients
1. A new certificate for an active pharmaceutical substance from a new or previously approved manufacturer 3, 5, 9 1, 2, 3, 4, 5 IA
2. New certificate for pharmaceutical substance/ raw material/reagent/intermediate product/ excipients from a new or previously approved manufacturer 3, 6, 7 1, 2, 3, 4, 5 IA
3. Updated certificate from a previously approved manufacturer 7 1, 2, 3, 4, 5 IA
4. Exclusion of certificates (if several certificates were attached to the material) 8 3 IA
5. New/updated certificate from a previously approved /new manufacturer using materials of human or animal origin in regard of which an assessment for the risk of potential contamination by extraneous agents is required. II
Conditions
1. Specifications for the release and for the shelf life of the medicinal product do not change.

2. Unspecified (excluding stiffening) additional specifications (to the State Pharmacopoeia of the Republic of Kazakhstan) for impurities (excluding residual solvents, provided they meet the requirements of the Republic of Kazakhstan) product-specific requirements (for example, particle size profiles, polymorphic forms), if applicable.

3. Manufacture process of an active pharmaceutical substance, raw material/reagent/intermediate does not include the use of materials of human or animal origin for which viral safety data analysis is required.

4. Exclusively for an active pharmaceutical substance: it will be tested immediately before use if the re-test period is not included in the certificate of conformity to European Pharmacopoeia or the data justifying the re-test period are no longer included in the dossier.

5. The active pharmaceutical substance/raw material/reagent/intermediate/excipients are non-sterile.

6. Herbal pharmaceutical substances: method of production, physical state, extracting solvent and extraction ratio of the medicinal product do not change.

7. If the composition of the drug for parenteral administration includes bone gelatin, its production must be carried out exclusively in accordance with the requirements of the concerned country.

8. At least one producer of this substance remains in the dossier.

9. If the active pharmaceutical substance is non-sterile but will be used as part of a sterile drug, then in accordance with CEP, water canot be used at the last stage of the synthesis or, if this occurs, it is necessary to ensure the absence of bacterial endotoxins in the active pharmaceutical substance.

Documentation
1. A copy of the current (updated) certificate of conformity to European Pharmacopoeia.

2. When adding a production site in the form of an application for changes, it is necessary to clearly identify «registered» and «proposed» producers, as indicated in section 2.5 of the application form.

3. Amendment to the relevant section(s) of the dossier.

4. If applicable, a document, containing information on all materials that are within the scope of the article of the State Pharmacopoeia of the Republic of Kazakhstan on minimizing the risk of transmitting agents of spongiform encephalopathy of animals through medications for human and veterinary use, including those used in the manufacture of active pharmaceutical substances/excipients. The following information must be provided for each such material: name of the manufacturer; species of animals and tissues from which the material is obtained; country of origin of animals and its use.
5. With respect to an active pharmaceutical substance: the declaration of the authorized person of each licensed manufacturer, specified in the application, using the active pharmaceutical substance as the raw material and the authorized person of each licensed manufacturer specified in the application as responsible for the series release. In the declarations it is necessary to indicate that the manufacturer(s) of the active pharmaceutical substance, indicated in the application, carries out its/their activities in accordance with the Rules of Good Manufacturing Practices of the Republic of Kazakhstan with respect to the raw materials. Under certain circumstances it is allowed to submit one declaration (see note to the amendment B.II.b.1). If any updates to certificates for active pharmaceutical substances and intermediates are affected, a declaration of the authorized person from the manufacturer of the intermediate products also required; the declaration of the authorized person is needed only if there is a change in the existing production sites included in the list, compared with the previously registered version of the certificate.

B.III.2 Changes made in order to comply with the State Pharmacopoeia of the Republic of Kazakhstan Conditions Documentation required Type of procedure
a) Changing the specification (s) of a previously non-pharmacopeia substance in order to comply with the State Pharmacopoeia of the Republic of Kazakhstan
1. Active pharmaceutical substance 1, 2, 3, 4, 5 1, 2, 3, 4 IA
2. Excipients/raw material of active pharmaceutical substance 1, 2, 4 1, 2, 3, 4 IA
b) Changes in order to comply with the updated relevant article of the State Pharmacopoeia of the Republic of Kazakhstan 1, 2, 4, 5 1, 2, 3, 4 IA
c) Change of specifications in the State Pharmacopoeia of the Republic of Kazakhstan 1, 4, 5 1, 2, 3, 4 IA
Conditions
1. The change is carried out solely for the purposes of full compliance with the pharmacopoeia. All tests in the specification must comply with the pharmacopeia standard after the change, excepting any additional supporting tests.

2. Additional specifications for the pharmacopeia for product-specific properties do not change (for example, particle size profiles, polymorphic form or, for example, biological methods, aggregates).

3. There are no significant changes in the qualitative and quantitative profiles of impurities (excepting specifications stiffening).

4. Additional primary expert examination of a new or modified pharmacopoeia method is not required.

5. Herbal pharmaceutical substances: method of production, physical condition, extracting agent and the extraction ratio of the medicinal product do not change.

Documentation
1. Amendment to the relevant section(s) of the dossier.

2. Comparative table of current and proposed specifications.

3. The series analysis data (in the comparison table format) of at least two test output series of the relevant substance(s) for all tests of the new specification and, if applicable, the results of the comparative dissolution kinetics test for at least one test series of medicinal product. Comparative disintegration data are sufficient for medicinal herbal preparations.

4. Data confirming the suitability of the monograph for the substance quality control, for example, comparison of potential impurities with the transparency note of the monograph.

      B. IV Medical devices

B.IV.1 Modification of a measuring device or device for administration Conditions Documentation required Type of procedure
a) Addition or replacement of a product that is not a part of the primary packaging
1. Medical products registered in the Republic of Kazakhstan 1, 2, 3, 5, 6 1, 2, 3 IA
2. Spacers of metered-dose inhalers or other devices that may have a significant effect on the delivery of the pharmaceutical substance of the drug (e.g., nebulizer) II
b) Exclusion of device 4 1, 4 IA
c) Adding or replacing of the product that is a part of the primary packaging II
Conditions
1. The proposed measuring product must accurately measure the required dose of the drug according to the approved method of use. The results of such studies should be provided.

2. The new product is compatible with the drug.

3. The change should not lead to a significant change in labeling on the medicinal product.

4. The drug can continue to be accurately dosed.

5. The medical device is not used as a solvent for the drug.

6. If a measuring function is provided, it must be included in the dossier of such a device.

Documentation
1. Amendment to the relevant section(s) of the dossier, including a detailed sketch and composition of the material of the product and the supplier, if applicable, as well as the relevant revision of the medicinal product labeling.

2. Confirmation of registration of a medical device in the Republic of Kazakhstan.

3. Samples of a new product, if applicable.

4. Justification of the product exclusion.

Note: For B.IV.1.c) — if the change leads to «formation of a new dosage form», such a change requires filing an application for an extension of registration.

      B. V Changes in the registration dossier due to other regulatory procedures

      B.V. a) PMF/VAMF

B.V.a.1 Inclusion of a new, updated or corrected plasma master file in the registration dossier of the medicinal product (PMF procedure, the 2nd stage) Conditions Documentation required Type of procedure
a) First inclusion of a new plasma master file that affects the properties of the drug II
b) The first inclusion of a new plasma master file that does not affect the properties of the drug 1, 2, 3, 4 IB
c) Inclusion of an updated/corrected plasma master file: changes affect the properties of the drug 1, 2, 3, 4 IB
d) Inclusion of an updated/corrected plasma master file: the changes do not affect the properties of the drug 1 1, 2, 3, 4 IA
Conditions
1. A certificate of conformity to the legislation of the Republic of Kazakhstan has been issued for the updated or amended PMF.
Documentation
1. Declaration on that the PMF certificate and the expert report are fully applicable to the registered medicinal product, the holder of the PMF presented to the MAH (if MAH and holder of the PMF are not the same person) PMF certificate, the expert report and PMF dossier, the PMF certificate and the expert report replaces the previous PMF documentation for the specific drug.

2. PMF certificate and expert report.

3. An expert’s declaration describing all the changes introduced by the certified PMF and assessing their potential impact on medicines, including product-specific risks assessments.

4. In the form of a declaration of change, the «current» and «proposed» PMF certificate (code number) in the registration dossier should be clearly reflected. If applicable, an application for changes should also clearly list all other PMFs which the medication refers to, even if they are not the subject of the application.

B.V.a. 2 Inclusion of a new, updated or corrected vaccine antigen master file (hereinafter referred to as the VAMF) in the registration dossier of the medicinal preparation (VAMF procedure, the 2nd stage) Conditions Documentation required Type of procedure
a) First inclusion of a new vaccine antigen master file II
b) Inclusion of an updated/amended vaccine antigen master file: changes affect the properties of the medicinal product 1, 2, 3, 4 IB
c) Inclusion of the updated/amended vaccine antigen master file: the changes do not affect the properties of the medicinal product 1, 2, 3, 4 IA
Conditions
1.
Documentation
1. Declaration on that the VAMF certificate and the expert report are fully applicable to the registered medicinal product, the holder of the VAMF presented to the MAH (if MAH and holder of the VAMF are not the same person) VAMF certificate, the expert report and VAMF dossier, the VAMF certificate and the expert report replaces the previous VAMF documentation for the specific drug.

2. VAMF certificate and expert report.

3. An expert’s declaration describing all the changes introduced by the certified VAMF and assessing their potential impact on medicines, including product-specific risks assessments.

4. In the form of a declaration of change, the «current» and «proposed» VAMF certificate (code number) in the registration dossier should be clearly reflected. If applicable, an application for changes should also clearly list all other VAMFs which the medication refers to, even if they are not the subject of the application.

      B.V. b) Appeal to the expert committee

B.V.b.1 Update of the quality dossier, aimed at implementing of the expert committee conclusion Conditions Documentation required Type of procedure
a) The amendment implements the opinion of the expert committee 1 1, 2 IA
b) Harmonization of the quality dossier was not a part of the expert committee conclusion, and the update is aimed at its harmonization II
Conditions
1. The result does not require any further expertise.
Documentation
1. An application for an amendment attached to the covering letter: a reference to the considered opinion of the expert committee.

2. In the dossier it is necessary to clearly identify the changes made during the expert committee appeal procedure.

      C. Safety, efficacy and pharmacovigilance changes

      C.I Medical products for human use

C.I.1 Change in summary of product characteristics and labeling of the medicinal product, aimed at the implementation of the expert committee conclusion Conditions Documentation required Type of procedure
a) The medicinal product is covered by the expert committee appeal procedure. 1 1, 2, 3 IA
b) The medicinal product is not covered by the expert committee appeal procedure, but changes are implemented by the conclusion of the the expert committee conclusion, new data are not provided by the MAH 1, 2, 3 IB
c) The medicinal product is not covered by the procedure for contacting the expert committee, but changes are implemented by the expert committee conclusion, the MAH presented new additional data 1, 3 II
Conditions
1. The amendment implements the wording requested by the authorized body, and does not require the submission of additional information and (or) further examination.
Documentation
1. An application for an amendment attached to a covering letter: a reference to the expert committee’s opinion with an attached information on the medicinal product, labeling or summary of product characteristics.

2. Declaration that the relevant sections of the proposed general characteristics of the medicinal product and labeling are identical to those attached to the expert committee conclusion.

3. Revised information on the medicinal product.

C.I.2 Change in general characteristic of the drug, labeling of the reproduced/hybrid/biosimilar drug after evaluating the same change in the reference medicinal product Conditions Documentation required Type of procedure
a) Implementation of the change(s) which the holder of the registration certificate is not required to submit new additional data for. 1, 2 IB
b) Implementation of the change(s) requiring the submission of the new additional data by the holder to justify such change(s) (for example, comparability) II
Documentation
1. An application for amendment attached to a covering letter: the request of the national authorized body (if applicable).

2. Revised information on the medicinal product.

C.I.3 Change(s) of the general characteristics of the medicinal product, labeling of the medicinal product for human use, aimed at the implementation of the procedure result affecting the PSUR or post-marketing safety study. Conditions Documentation required Type of procedure
a) Introduction of the wording agreed upon by the authorized body 1 1, 2 IA
b) Introduction of changes requiring the submission by the MAH of the new additional data supporting such changes 2 II
Conditions
3. The amendment implements the wording requested by the authorized body, and does not require the submission of additional information and (or) further examination.
Documentation
1. An application for an amendment attached to a covering letter: reference to the approval/ assessment of the authorized body.
2. Revised information on the medicinal product.
C.I.4 Changes that mean a significant change of the general characteristics of the drug due to new quality data, preclinical, clinical or pharmacovigilance data. Conditions Documentation required Type of procedure
II
Note: this change does not apply if the new data is submitted in accordance with the change in BI.13. In such cases, the change in the general characteristic of the medicinal product and labeling fall within the scope of application of the change B.I.13.
C.I.5 Change in the conditions for the medicinal product dispensing Conditions Documentation required Type of procedure
a) Reproduced/hybrid/biosimilar drugs after changing of the dispensing conditions of the reference medication 1, 2 IB
b) Other reasons for changing the dispensing conditions II
Documentation
1. Confirmation of the change in conditions for the reference medicinal product release, attached to a covering letter of the application for change.

2. Revised information on the medicinal product.

C.I. 6 Change in therapeutic indications Conditions Documentation required Type of procedure
a) Introduction of a new indication or modification of the earlier approved one II
b) Exclusion of indication IB
Note If addition or change of the indication is due to the implementation of the expert committee’s conclusion or changes in the drug information of the reproduced/hybrid/biosimilar drug after examination of the same change in the reference medicinal product, the changes in B.I.1 and B.I.2 are applied, respectively.
C.I.7 Exception: Conditions Documentation required Procedure
Note: This amendment covers the introduction of PSMF, regardless of the availability of a Detailed description of the pharmacovigilance system in the technical part of the registration dossier.

Change of the contact person for pharmacovigilance, including contact details (telephone and fax numbers, postal address and e-mail address) and change of the location of PSMF (street, city, zip code, country) are allowed to be updated exclusively through the Republic of Kazakhstan Register (no need for modifications).

If a marketing authorization holder resorts to the possibility of updating the above mentioned information through the Register of the Republic of Kazakhstan, it must be indicated in the registration dossier that the updated information of this data is included to the Register of the Republic of Kazakhstan.

C.I. 9 Modification of the existing pharmacovigilance system according to the detailed description of the pharmacovigilance system (hereinafter — DDPS) Conditions Documentation required Type of procedure
а) Change of the qualified person responsible for pharmacovigilance, and (or) contact details, and (or) reservation procedure 1 1 IA
b) Change of the security database and (or) the main contractual agreements in order to fulfill pharmacovigilance responsibilities and (or) change of the location of the pharmacovigilance activities 1, 2, 3 1 IA
c) Other changes of the DDPS that do not affect functioning of the pharmacovigilance system (e. g. change of the main storage/archive location, administrative changes) 1 1 IA
d) Making changes in the DDPS based on the results of the DDPS examination of the same MAH for another pharmaceutical. 4 1, 2 IA
Conditions
1. The pharmacovigilance system itself does not change.

2. The database system has passed the primary expert evaluation (if applicable).

3. Data transfer from other database systems has been validated (if applicable).

4. The same changes in DDPS were introduced for all medicinal products of the same MAH (the same final version of DDPS).

Documentation
1. The latest version of DDPS and the latest version of the drug-specific supplement, if applicable. They should include a) a brief biography of a new qualified person responsible for pharmacovigilance, b) a new statement of the MAH and of a new qualified person responsible for pharmacovigilance on their capability and ways of adverse reactions reporting, signed by the new qualified person responsible for pharmacovigilance and by MAH, and reflecting other consequent changes, e.g. in the organizational chart.

If a qualified person responsible for pharmacovigilance and/or his/her contact details were not initially included in the DDPS or no DDPS exists, there is no need to submit a revised DDPS, only the application form is required.

2. Reference to the application/procedure and to the medicinal product for which the changes were approved.

C.I. 10 Change of the interval and/or date of submission of the periodic safety update report (PSUR) on medicinal products for human use Conditions Documentation required Type of procedure
1 1, 2 IA
Conditions
1. The change of the interval and (or) the date of the PSUR submission has been agreed upon by the national authorized body.
Documentation
1.An application on amendments attached to a covering letter: a reference to the authorized body approval.

2. The revised interval and/or date of the PSUR submission.

Note This change applies only if the PSUR cycle is listed in the registration dossier in ways other than specifying the reference to the list of reporting dates, and, if necessary, the PSUR submission.
C.I.11 Introduction or modification of the obligations and conditions of registration, including a risk management plan Conditions Documentation required Type of procedure
а) Implementation of the wording agreed upon with the authorized body 1 1, 2 IA
b) Implementation of changes requiring the submission of new additional data by the MAH, that require expert examination by the authorized body

(*)

II
Conditions
1. The change implements the action requested by the authorized body, and does not require the submission of additional information and (or) further examination.
Documentation
1. An application on amendments attached to a covering letter: a reference to the authorized body decision.
2. Revised information on a medicinal product.
Note This change only covers the situation when the amendment introduced only affects the conditions and/or registration obligations, including the risk management plan and the conditions and (or) obligations of registration under exceptional circumstances and conditional registration.
(*) The introduction of a risk management plan, requested by the authorized body, always requires a substantial examination.
C.I. 12 Inclusion or exclusion of a black symbol or explanatory notes for medicinal products, included to the list of drugs that are subject to additional monitoring. Conditions Documentation required Type of procedure
1 1, 2 IA
Conditions
1. The medicinal preparation is included or excluded from the list of medicinal products subject to additional monitoring (respectively).
Documentation
1. An application on amendments attached to a covering letter: a reference to the list of medicinal products subject to additional monitoring.
2. Revised information on the medicinal product.
Note This change covers the situation where the inclusion or exclusion of a black symbol or explanatory note is not carried out under another regulatory procedure (e.g., the procedure for extending or change of the information on the medicinal product).
C.I. 13 Other changes, that are not described elsewhere in this Addendum, including the submission of studies to the authorized body (*) Conditions Documentation required Type of procedure
II
Note If the examination of the submitted data by the authorized body leads to a change in the general characteristics of the medicinal product and labeling, this amendment covers the relevant amendments to the general characteristics of the medicinal product and labeling.
(*) This change does not apply to changes that are accepted as changes to the IB type by default in accordance with any other section of this Addendum.

      D. DMF/MFVA

D. 1 Change of the name and (or) of address of the MFVA certificate holder Conditions Documentation required Type of procedure
1 1 IA
Conditions
1. The holder of the MFVA certificate must be the same legal entity.
Documentation
1. An official document from the relevant authorized body (for example, the tax authority), which indicates a new name or address.
D. 2 Change of the name and (or) of address of the DMF certificate holder Conditions Documentation required Type of procedure
1 1 IA
Conditions
1. The holder of the DMF certificate must be the same legal entity.
Documentation
1. An official document from the relevant authorized body (for example, the tax authority), which indicates a new name or address.
D. 3 Change or transfer of the DMF certificate from the current holder to the new holder of the DMF certificate — i.e. to another legal entity Conditions Documentation required Type of procedure
1, 2, 3, 4, 5, 6 IA
Documentation
1. The document, including the identification (name and address) of the current DMF holder (the transferor) and the identification (name and address) of the person receiving the transfer (the transferee), as well as the proposed date of the transaction signed by both companies.

2. Copy of the last page of the DMF certificate. Confirmation of registration of a new holder (an extract from the register of legal entities and its translation into Russian), signed by both companies.

3. Confirmation of the transfer of all DMF documentation starting from the first certification of the DMF to the transferee, signed by both companies.

4. Power of attorney, including contact information of the person responsible for communication between the authorized body and the DMF holder, signed by the transferee.

5. Letter of commitment to fulfill all open and remaining obligations (if any), signed by the transferee.

D. 4 Change of the name and/or address of blood facilities, including blood/plasma collection centers Conditions Documentation required Type of procedure
1, 2 1, 2, 3 IA
Conditions
1. The blood facility should remain the same legal entity.
2. The change should be administrative (for example, merger, acquisition); change the name of the institution/center of the blood collection, given the blood institution remains the same.
Documentation
1. A signed declaration that a change does not include a change of the quality system of a blood institution.

2. A signed declaration that the list of collection centers was not changed.

3. Updated relevant sections and additions to the DMF.

D. 5 Replacing or adding of a blood/plasma collection center as a part of a blood facility included to the DMF Conditions Documentation required Type of procedure
1, 2, 3 IB
Documentation
1. Epidemiological data on viral markers affecting the blood/plasma collection center, covering 3 years. With respect to the newly opened center (s) or, in case of the data absence, a declaration that the epidemiological data are to be presented in the next annual update.

2. Indication that the center operates under the same conditions as other centers belonging to the blood institution, in accordance with the provisions of the standard contract between the blood institution and the DMF holder.

3. Updated relevant sections and additions to the DMF.

D. 6 Elimination or change of the status (functioning/non-functioning) of the blood center/institution (s) used for blood/plasma collection or for blood, plasma and plasma pools testing. Conditions Documentation required Type of procedure
1, 2 1 IA
Conditions
1. The reasons for exclusion or change of status are not caused by problems related to GMP.

2. The institution(s)/center(s) must comply with the inspection law when the status changes from non-functioning to functioning.

Documentation
1. Updated relevant sections and additions to the DMF.
D. 7 Inclusion of a new blood institution for the blood/plasma collection, that is not included in the DMF. Conditions Documentation required Type of procedure
II
D. 8 Replacement or inclusion of a new blood center for blood donations, plasma and/or plasma pools testing within an institution included in the DMF. Conditions Documentation required Type of procedure
1, 2 IB
Documentation
1. Indication that the tests are carried out according to the same approved SOP and/or test methods.

2. Updated relevant sections and additions to the DMF.

D. 9 Inclusion of a new blood center for blood donations, plasma and/or plasma pools testing within an institution, not included in the DMF. Conditions Documentation required Type of procedure
II
D. 10 replacement or inclusion of a new blood institution or the center(s) for plasma storage. Conditions Documentation required Type of procedure
1, 2 IB
Documentation
1. Indication that the storage center operates in accordance with the same SOP approved in the institution.

2. Updated relevant sections and additions to the DMF.

D. 11 Exclusion of the blood facility or of the center(s) for plasma storage. Conditions Documentation required Type of procedure
1 1 IA
Conditions
1. The reason for an exclusion should not be caused by problems related to GMP.
Documentation
1. Updated relevant sections and additions to the DMF.
D. 12 Replacement or inclusion of an organization involved to the plasma transportation. Conditions Documentation required Type of procedure
1 IB
Documentation
1. Updated relevant sections and additions to the DMF, including all blood facilities using this transport organization, a summary of the current system providing transportation under appropriate conditions (time, temperature and compliance with GMP) and confirmation that the transportation conditions are validated.
D. 13 Exclusion of an organization involved to the plasma transportation Conditions Documentation required Type of procedure
1 1 IA
Conditions
1. The reason for an exclusion should not be caused by problems related to GMP.
Documentation
1. Updated relevant sections and additions to the DMF.
D. 14 Inclusion of a test system registered in the Republic of Kazakhstan as a medical device for the purpose of the individual donations of blood and plasma testing as a new test system Conditions Documentation required Type of procedure
1 1, 2 IA
Conditions
1. A new test system has been registered in the Republic of Kazakhstan as a medical device.
Documentation
1. List of test sites where the test system is being used.
2. Updated relevant sections and additions to the DMF, including updated information on tests in accordance with the requirements of the Republic of Kazakhstan for compiling the DMF.
D. 15 Inclusion of a test system, not registered in the Republic of Kazakhstan as a medical device for the purpose of the individual donations of blood and plasma testing as a new test system. Conditions Documentation required Type of procedure
а) A new testing system was not previously approved by the DMF for any blood center for blood and plasma donation tests II
b) A new testing system was previously approved by the DMF for any blood center for blood and plasma donation tests 1, 2 IA
Documentation
1. List of test centers where the test system is being used, and a list of test centers where it will be used.

2. Updated relevant sections and additions to the DMF, including updated information on tests in accordance with the requirements of the Republic of Kazakhstan for compiling the DMF.

D. 16 Change of the test system/method used for pools testing (antibody, antigen, or nucleic acid amplification test) Conditions Documentation required Type of procedure
II
D. 17 Introduction or expansion of the quarantine storage procedure Conditions Documentation required Type of procedure
1 1 IA
Conditions
1. The quarantine storage procedure is more strict (e.g., release only after a second check of donors).
Documentation
1. Updated relevant sections and additions to the DMF, including the grounds for introducing or expanding of the quarantine storage procedure, the sites where quarantine and procedure changes are implemented, decision tree, including new conditions.
D. 18 Exclusion of the period of quarantine or reduction of its duration Conditions Documentation required Type of procedure
1 IB
Documentation
1. Updated relevant sections of the DMF.
D. 19 Replacement or addition of containers for blood (e.g., bags, vials) Conditions Documentation required Type of procedure
а) New containers for blood are registered in the Republic of Kazakhstan as medical devices 1, 2 1 IA
b) New containers for blood are not registered in the Republic of Kazakhstan as medical devices II
Conditions
1. The container is registered in the Republic of Kazakhstan as a medical device.

2. The criteria of quality of the blood contained in the container are not changed.

Documentation
1. Updated relevant sections and additions to the DMF, including name of the container, manufacturer, specification of the anticoagulant solution, confirmation of registration in the Republic of Kazakhstan and name of the blood institution where the container is being used.
D. 20 Storage/transportation change Conditions Documentation required Type of procedure
а) storage and (or) transportation conditions 1 1 IA
b) maximum shelf life of plasma 1, 2 1 IA
Conditions
1. The change should toughen the conditions and meet the requirements of the State Pharmacopoeia of the Republic of Kazakhstan, applied to the human plasma intended for fractionation.

2. The maximum shelf life is shorter than the previous one.

Documentation
1. Updated relevant sections and additions to the DMF, including a detailed description of the new conditions, confirmation of the primary expert examination of the storage/transportation conditions and the name of the blood institution(s) where the change occurs (if applicable)
D. 21 Introduction of a test for viral markers, if such an introduction would have a significant impact on the viral risks evaluation. Conditions Documentation required Type of procedure
II
D. 22 Change in the plasma pool preparation (e.g., production method, pool size, storage of plasma pool samples) Conditions Documentation required Type of procedure
1 IB
Documentation
1. Updated relevant sections of the DMF.
D. 23 Change of measures taken in retrospective detection that donations of blood and plasma are subject to exclusion from treatment (a retrospective analysis procedure) Conditions Documentation required Type of procedure
II
Annex 2
to the Order of the Minister of Public Health

of the Republic of Kazakhstan No 374
of June 15, 2018

Approved by
the Order of the Minister of Health

of the Republic of Kazakhstan No. 736
of November 18, 2009

Rules for the expertise of medical devices and medical equipment

Chapter 1. General Provisions

1. The present Procedure for the expertise of Medical Devices and Medical Equipment (hereinafter referred to as Procedure) are developed in accordance with Article 63 of the Code of the Republic of Kazakhstan dated September 18, 2009 «On the Health of the People and the Healthcare System» (hereinafter referred to as the Code) and determine the procedure for conducting product expertise medical purpose and medical equipment.

2. The expertise of medical devices and medical equipment in accordance with paragraph 2 of Article 63 of the Code is carried out by the republican state enterprise on the right of economic management (hereinafter referred to as the state expert organization) engaged in production and economic activities in the field of health care to ensure the safety, efficiency and quality of medical devices destination and medical equipment.

3. Expertise shall be made in the Republic of Kazakhstan, as well as medical products and medical equipment imported to its territory.

4. Prior to submitting an application for expertise of a medical device and medical equipment, the applicant, at his request, receives scientific and pre-registration advice from the state expert organization on a contractual basis on issues related to the expertise of medical devices and medical equipment.

5. For the expertise of medical devices and medical equipment used in the blood service, the state expert organization attracts specialists from profile organizations that carry out activities in the blood service sphere.

6. The following terms and definitions are used in the present Procedure:

1) medical products / medical equipment for invitro diagnostics — instruments, apparatus, devices, equipment, materials, reagents, calibrators, control materials and other products used for medical purposes separately or in combination, and together with accessories necessary for the use of these products for their intended purpose (including special software), and intended for use in invitro studies of human biological material samples and to obtain information concerning a physiological or pathological condition, congenital disorders, predisposition to certain clinical condition or disease, tissue compatibility with potential recipients, predicting responses to therapeutic effects, selection of therapeutic agents and (or) the control treatment;

2) the name of medical devices and medical equipment — the verbal designation of medical devices and medical equipment, defining the model, variety, modification, type;

3) component for medical devices and medical equipment — a product that is not a medical product or medical equipment or accessories, including blocks, parts, components of the product, materials, spare parts intended by the manufacturer of medical devices and medical equipment for application in or with the composition;

4) belonging to medical devices and medical equipment — a product that is not a medical device or medical equipment intended for use jointly with one or more medical devices or medical equipment for use in accordance with their purpose;

5) safety of medical devices and medical equipment — the absence of unacceptable risk associated with the possibility of harming life, human health and the environment;

6) a conclusion on the safety, efficiency and quality of medical devices and medical equipment — a document containing the results of expertise of the declared medical devices and medical equipment;

7) expendable material for medical devices and medical equipment — products and materials used for the use of medical devices and medical equipment, providing manipulation in accordance with the functional purpose of medical devices and medical equipment;

8) the manufacturer (manufacturer) of medical devices and medical equipment is a legal entity or an individual registered as an individual entrepreneur responsible for the development and manufacture of a medical device and medical equipment and making it available for use on its own behalf, developed and (or) produced (manufactured) a medical device and medical equipment by this person or on his behalf by another person (persons) responsible for its safety, quality, efficiency and in whose name the registration certificate of the Republic of Kazakhstan is issued;

9) the quality of medical devices and medical equipment — the degree of compliance of the set of properties and characteristics of medical devices and medical equipment affecting their ability to act as intended;

10) the effectiveness of medical devices and medical equipment — a set of characteristics that ensure the achievement of preventive, diagnostic, therapeutic and (or) rehabilitation effect;

11) regulatory document for the control of the quality and safety of medical devices (hereinafter referred to as the normative document) is a document that establishes a set of requirements for the quality of medical devices, as well as the methods for determining it, ensuring their identical safety and quality parameters;

12) The Expert Council of the State Expert Organization (hereinafter referred to as the Expert Council) is a collegial body set up in the state expert organization to review disputes in the results of the expertise, grounds (reasons) for issuing negative conclusions on the effectiveness, safety and quality of medicines, medical devices and medical equipment and final decision making;

13) model — alphabetic, numeric or alphanumeric designation of one unit of medical devices and medical equipment;

14) modification — a variety, a version of medical products and medical equipment developed on the basis of the main product for the purpose of improving, expanding or specializing in medical applications and having common design features with the main product;

15) production site — a territorially detached complex, designed to perform the entire process of manufacturing a medical device and medical equipment or its specific stages;

16) authorized representative of the manufacturer — a legal or natural person registered as an individual entrepreneur who is a resident of the Republic of Kazakhstan authorized by the power of attorney of the manufacturer of a medical device and medical equipment to represent his interests on the issues of circulation of a medical device and medical equipment on the territory of the Republic of Kazakhstan in accordance with current legislation of the Republic of Kazakhstan in the field of health;

17) the applicant is a manufacturer or their representative authorized to submit an application, documents and materials for expertise of medical devices and medical equipment for registration, re-registration, introduction of changes to the registration dossier;

18) standard series — a number of products with a single design, a common technological process, of the same material, a general functional purpose, differing in size, diameter, depth, weight, volume, color and shape;

19) registration dossier — a set of documents and materials of specified content submitted to the application for expertise of medical devices and medical equipment;

20) introduction of changes in the registration dossier — changes made by the applicant in the registration dossier during the validity of the registration certificate, which do not affect the safety, efficiency and quality of medical devices and medical equipment and are subject to expertise in accordance with the present Procedure.

Chapter 2. The procedure for providing a registration dossier for the expertise of medical devices and medical equipment

7. For the expertise of medical devices and medical equipment, the applicant concludes an expert agreement with the state expert organization and provides the following documents to the Center for the Servicing of Applicants of the State Expert Organization (hereinafter referred to as «the CSA»):

1) application for expertise of the medical device and medical equipment in the form in accordance with Annex 1 to the present Procedure;

2) the registration dossier containing the list of documents of the registration dossier for the expertise of medical devices and medical equipment in accordance with Annex 2 to the present Procedure;

3) samples of medical devices, standard samples of chemicals, test-strains of microorganisms, cell cultures, specific reagents, consumables required for the reproducibility of laboratory test methods for a medical device in quantities sufficient for triplicate tests with a shelf life of at least six months;

4) a copy of the document confirming payment by the applicant of the amount for the expertise to the settlement account of the state expert organization.

8. Forming an application for expertise of medical devices and medical equipment with the Annex of the list of documents of the registration dossier for the expertise of medical devices and medical equipment in accordance with Annex 2 to this Regulation is carried out in the information system of the state expert organization (hereinafter — the information system) by an individual password.

9. Specialist of the CSA after receiving the documents provided for in paragraph 7 of the present Procedure within one working day:

1) performs registration of the application in the information system;

2) uploads the electronic registration dossier to the information system;

3) checks the remaining shelf life of samples of medical devices, standard samples of chemical substances, test-strains of microorganisms, cell cultures, specific reagents, consumables required for the reproducibility of laboratory test methods for medical devices and adds data to the information system.

To comply with storage conditions (temperature regime, humidity), samples of medical devices are provided purposely directly to the testing laboratory.

10. With simultaneous submission for expertise of several modifications of medical devices and medical equipment belonging to one type of medical device and medical equipment manufactured by one manufacturer, different changes in the equipment and / or technical parameters that do not affect the operating principle and functional purpose, relating to one class of potential risk of use, the applicant submits one application and one registration dossier.

11. In cases of submission by the applicant of an incomplete set of documents, as well as failure to comply with the conditions stipulated in clause 7 of the present Procedure, the specialist of the CSA refuses to accept the application.

Chapter 3. The procedure for the expertise of medical devices and medical equipment

 Paragraph 1. Stages of expertise of medical devices and medical equipment

12. Expertise of medical devices or medical equipment consists of the following stages:

1) initial expertise (validation of the registration dossier);

2) laboratory tests for medical devices;

3) specialized expertise.

13. Expertise is carried out using the information system of the state expert organization «Expertise of medicines, medical products and medical equipment» integrated with the unified database «Drug Supply Management System» of the Unified Health Information System.

Paragraph 2. The procedure for the initial expertise (validation of the registration dossier) of medical devices and medical equipment

14. After receiving the application, the expert conducts an initial expertise (validation of the registration dossier) of a medical device or medical equipment within the time limits provided for in Chapter 6 of the present Procedure.

15. At the initial expertise (validation of the registration dossier) of a medical device or medical equipment, an assessment is made of the composition, completeness and correctness of the documents submitted by the applicant in the registration dossier regarding evidence of safety, efficiency and quality of medical devices or medical equipment, medical devices and standard samples for carrying out laboratory tests for compliance with the conditions imposed on medical devices for laboratory tests in accordance with Annex 3 to this Regulation.

16. If there are any comments in the registration dossier, the applicant is sent a letter indicating the remarks that have been revealed and the need to eliminate them within a period not exceeding sixty calendar days.

17. In case of non-elimination of remarks and failure to respond in due date provided for in clause 16 of the present Procedure, the state expert organization shall send the applicant a notification (in any form) of termination of expertise of the medical device or medical equipment.

18. Based on the results of the initial expertise (validation of the registration dossier), a report of the initial expertise (validation of the registration dossier) of a medical device or medical equipment is made, for according on the basis of prescription 4 to this Regulation or reports on the audit (validation of the registration dossier) entered in the registration dossier of a medical device or medical equipment in accordance with Annex 5 to this Regulation.

Paragraph 3. Procedure for conducting laboratory tests of medical devices

19. In the case of a positive initial expertise report (validation of the registration dossier), laboratory tests of samples of medical devices are carried out within the time limits provided for in Chapter 6 of this Regulation.

20. Laboratory tests of samples of medical devices are carried out in testing laboratories of the state expert organization in order to confirm compliance of the safety and quality indicators of medical devices declared in the manufacturer’s standard document and include:

1) testing of samples of medical devices;

2) determination of reproducibility of analysis techniques.

Tests of samples of medical devices are carried out by carrying out physicochemical, biological and technical tests in order to confirm the compliance of the safety and quality indicators of medical devices.

When testing samples of a medical device, biological safety or an evaluation of biological action, physical and mechanical indices, functional, technical and physico-chemical indicators are determined.

Determination of the reproducibility of the methods of analysis for the quality control of medical devices is carried out in order to confirm their compliance, as stipulated by the regulatory document of the manufacturer.

21. Laboratory tests are not carried out with the extension of the validity period of the registration certificate in case of presence on the pharmaceutical market of the Republic of Kazakhstan medical products manufactured under the conditions of ISO (ISO) 13485 or GMP (GMiPi), no less than ten years without claims for its safety, efficiency and quality.

22. In case of revealing remarks on the results of laboratory tests, the applicant shall be sent a letter indicating the identified remarks and the need for their elimination within a period not exceeding ninety calendar days.

23. If the applicant fails to provide a response to the observations made in the letter of the state expert organization within the prescribed period provided for in paragraph 22 of the present Procedure and the negative results of laboratory tests, the materials are sent to the Expert Council for making a decision to refuse and terminate the expertise of medical devices.

24. Based on the results of laboratory tests of medical devices, the test laboratory shall prepare a test report to the form according to Annex 6 to this Regulation.

25. For samples of medical devices requiring special transportation and testing conditions using specific equipment and auxiliary equipment, laboratory tests are conducted in the manufacturer’s quality control laboratory or in a contract laboratory used by the manufacturer in the presence of representatives of the state expert organization.

Based on the results of the tests, a report is prepared on the results of the laboratory test in the manufacturer’s quality control laboratory or in the contract laboratory used by the manufacturer in accordance with Annex 7 to this Regulation.

Paragraph 4. The procedure for conducting a specialized expertise of medical devices and medical equipment

26. In the case of a positive result of laboratory tests, a specialized expertise of a medical device and medical equipment is carried out within the time limits provided for in Chapter 6 of the present Procedure.

27. Specialized expertise is conducted by studying the documents of the registration dossier for their safety, efficiency, quality, including:

1) an assessment of the safety, efficacy and quality of medical devices and medical equipment;

2) assessing the impact of changes in the registration dossier on the safety, efficacy and quality of medical devices and medical equipment;

3) analysis of data on the development and production of medical devices and medical equipment (schemes of production processes, the main stages of production, packaging, testing and the procedure for the production of the final product);

4) analysis of reports based on the evaluation results of production conditions and quality assurance system for state registration of medical devices and medical equipment;

5) analysis of biological safety of medical devices based on analysis of all materials of animal or human origin included in medical products, as well as information on the selection of sources (donors), material selection, processing, storage, testing, primary examination of testing procedures, and handling of tissues, cells, substances of animal or human origin, cultures of microorganisms and viruses;

6) analysis of the report of clinical trials, experience in the use in clinical practice of medical devices and medical equipment of class 2b (increased risk), class 3 (high-risk), medical devices intended for getting, storage, blood transfusion and its components, clinical and laboratory tests of medical devices and medical equipment for in vitro diagnostics irrespective of the risk class;

7) analysis of the stability of the medical device and (or) the medicinal product included in the composition of medical devices declared in the registration dossier;

8) expertise of compliance of safety and quality indicators specified in the normative document of the producer organization with standards (national, regional, international);

9) analysis of the protocol of the testing laboratory, evaluation of the results of laboratory tests;

10) study the validity of software based on analysis of data on its verification and initial expertise, including information on its development and testing at the enterprise and in multicenter studies, data on identification and marking of the operating system;

11) analysis of the procedure and methods for sterilization of medical devices, materials justifying the method of sterilization, proposed methods for quality control and determination of sterilizing agent residues using a chemical method of sterilization;

12) analysis of the safety and efficacy of the medicinal product in the medical device and medical equipment, its effect on the functionality of the medical device and medical equipment, the compatibility of the medicinal product with the medical device and medical equipment (with the exception of medical devices and medical equipment for in-vitro diagnostics;

13) assessment of the reliability of the data specified in the application and documents of the registration dossier with respect to the class, depending on the degree of the potential risk of using medical devices and medical equipment;

14) analysis of the conformity of the text of the draft instruction on the medical use of the medical device to the original instruction from the manufacturing organization and the design of the draft instruction in accordance with the present Procedure for the preparation and execution of instructions for the medical use of medicines and medical products approved by the order of the Minister of Health and Social Development of the Republic of Kazakhstan from May 29, 2015, No. 414 (registered in the Registry of regulatory legal acts under No. 11495) (hereinafter — order No. 41 4);

15) evaluation of the information contained in the operational document of medical equipment;

16) analysis of information contained on samples of packaging models, labels, stickers of medical devices in accordance with the requirements of the legislation of the Republic of Kazakhstan in the sphere of circulation of medicines, medical devices and medical equipment;

17) analysis of information provided by the manufacturer on the presence or absence of reports of accidents and recalls from the market of medical devices and medical equipment, on undesirable events and (or) accidents involving the use of medical devices and medical equipment, product safety notifications medical devices and medical equipment, the approach to the consideration of these problems and their solutions by manufacturers in each of these cases, the description of the corrective actions taken in response to these cases, as well as the ratio of sales and the number of accidents and reviews of medical devices and medical equipment from circulation.

28. During the period of the specialized expertise, if there are any comments, the applicant is sent a letter indicating the remarks that have been identified and the need to eliminate them within a period not exceeding sixty calendar days.

29. If additional questions arise concerning the information provided by the applicant in response to the previous request, the applicant shall within thirty calendar days from the receipt of the request, forward the response and the necessary materials to an additional request of the state expert organization.

30. If the applicant does not provide answers to the letter of the state expert organization, as well as providing an incomplete answer and the necessary materials within the timeframes provided for in paragraphs 28 and 29, the materials of the specialized expertise are sent to the Expert Council to decide on the refusal and termination of examination of medical devices and medical techniques.

The expert council considers the received materials monthly and the results of the decision the state expert organization sends to the applicant within ten calendar days.

31. In the case of a positive report of a specialized expertise, an expert report of a specialized expertise of a medical device and medical equipment is drawn up in accordance with Annex 8 to this Regulation or an expert report of a specialized expertise on the effect of changes in the registration dossier on the safety, efficiency and quality of medical devices and medical equipment form, in accordance with Annex 9 to this Regulation.

Chapter 4. The order of forming the results of the expertise of medical devices and medical equipment

32. At the end of the examination, the applicant, within thirty calendar days not entering the examination period, agrees with the state expert organization information on the medical device or medical equipment and final documents (normative document on quality, instructions for medical use and labeling of packaging models, labels, stickers).

The reconciliation is carried out electronically on an individual password through a personal cabinet or by providing an approval sheet.

33. Based on the results of the examination of the medical device and medical equipment, the state expert organization draws up an opinion on the safety, efficacy and quality of medical devices and medical equipment declared for examination in accordance with Annex 10 to this Regulation and an opinion on the safety of efficacy and quality of medical devices appointment and medical equipment in case of changes made to the registration dossier in accordance with Annex 11 to this Regulation, a subscription is done by the head of the state expert organization or an authorized person.

34. The state expert organization sends in electronic form to the state body:

1) a conclusion on the safety, efficiency and quality of medical devices and medical equipment;

2) instructions for the medical use of medical devices in Kazakh and Russian languages, developed in accordance with Order No. 414 and agreed upon by the expert organization;

3) models of packages, labels, stickers of medical products, agreed by the state expert organization in Kazakh and Russian languages.

35. Based on the results of the expertise, the state expert organization forms a consolidated report on the safety, efficiency and quality of medical devices and medical equipment in accordance with Appendix 12 to this Regulation, part of which is posted on the Internet resource of the state expert organization.

36. The conclusion on the safety, efficiency and quality of medical devices and medical equipment is valid for one hundred and eighty calendar days. If the conclusion on the safety, effectiveness and quality of medical devices and medical equipment expires, the applicant re-submits the application, documents and materials for the expertise in accordance with the present Procedure.

37. A negative conclusion on the safety, efficiency and quality of medical devices, medical equipment is issued in the following cases:

1) failure to submit a complete set of the registration dossier after the issuance of comments to the applicant in the process of the expertise within the time limits established by the present Procedure;

2) submission of unreliable information by the applicant;

3) lower safety, efficiency and quality of medical devices and medical equipment in comparison with previously registered analogues;

4) negative conclusion about the safety, efficiency and quality of the medical device and medical equipment by the results of any stage of the expertise;

5) inconsistencies between the actual production conditions and the quality assurance system for the conditions ensuring the declared safety, efficiency and quality of medical devices and medical equipment, based on the results of the production evaluation and the quality assurance system of the manufacturer of the registration;

6) the applicant’s refusal to organize a visit to the enterprise (production site) in order to assess the production conditions and the quality assurance system, in accordance with the requirements of the legislative acts of the Republic of Kazakhstan.

38. In cases of a negative conclusion on the safety, efficiency and quality of a medical device, medical equipment or the applicant’s withdrawal of an application for expertise after the commencement of the expertise, the cost of conducting expert works shall not be returned to the applicant.

39. After completion of the expertise procedure, the state expert organization forms an electronic archive copy of the registration dossier containing documents and materials of the expertise result (additional materials provided by the applicant at the request of the state expert organization, the conclusion of the initial expertise, specialized expertise, the protocols of the testing laboratory) effectiveness and quality, the approved instruction on the medical use of the medical device appointments, approved layouts of packages, labels, stickers and stored in an electronic archive.

During the validity of the registration certificate, the archival registration dossier is supplemented with copies of registration certificates for making changes with all attached documents of the applicant in electronic form.

The registration dossier is stored in an electronic archive in compliance with confidentiality requirements, regardless of the results of the examination.

The registration dossier of a medical device and medical equipment on electronic media is stored for ten years.

Chapter 5. Features of the expertise of medical devices and medical equipment

40. Clarifications or refinement arising during the examination period between the state expert organization and the applicant are carried out through the CSA by forming an electronic document on the applicant’s individual password through an information system with an electronic digital signature of the applicant and the state expert organization or on paper carriers.

41. In the course of expertise of medical devices and medical equipment, the state expert organization determines the conformity of the declared class, depending on the degree of potential risk of application in accordance with the present Procedure for the classification of safety of medical devices and medical equipment approved by Order No. 764 of the Minister of Health of the Republic of Kazakhstan of November 24, 2009 (registered in the Register of state registration of regulatory legal acts under No. 5936).

42. For medical devices and medical equipment with an unlimited registration certificate, the state expert organization periodically assesses the benefit / risk ratio on the basis of continuous safety monitoring with an annual reimbursement by the applicant of costs on the basis of an agreement between the applicant and the state expert organization.

43. The expertise of the belonging of products to medical devices and medical equipment and the need for its state registration in the Republic of Kazakhstan is carried out by the state expert organization in accordance with the contract concluded between the applicant and the state expert organization.

44. Expertise of changes made to the registration dossier is carried out on medical devices and medical equipment during the validity period of the registration certificate and does not reduce the safety and quality of medical devices and medical equipment.

45. The changes are classified in accordance with the list of changes made to the registration dossier of a medical device and (or) medical equipment during the validity period of the registration certificate in accordance with Annex 13 to the present Procedure. Changes not included in the specified list are subject to new registration in accordance with the present Procedure.

46. ​​The applicant shall, within two months after the approval of the changes introduced by the manufacturer, submit an application for expertise of the medical device and medical equipment in accordance with Annex 1 to this Regulation.

47. The application for changes in the registration dossier of a medical device and medical equipment shall be accompanied by documents and materials necessary for making changes, in accordance with the List of changes made to the registration dossier of a medical device and (or) medical equipment during the validity period of the registration certificate in accordance with Annex 13 to the present Procedure.

48. Based on the results of the expert expertise, the state expert organization draws up an expert report on the impact of the changes in the registration dossier on the safety, efficiency and quality of medical devices and medical equipment in accordance with Annex 9 to the present Procedure, signed by the head of the structural unit and an expert who conducted expertise.

49. The manufacturer or authorized representative of the manufacturer of a medical device or medical equipment shall make changes to the registration dossier based on a notification in an arbitrary form to the state expert organization based on information from international sources and results of security monitoring.

The state expert organization, when identifying the grounds for international sources and the results of security monitoring, notifies all producers and authorized representatives of the manufacturer through information resources about the need to make appropriate changes to the instruction on medical application or operational document through the procedure for making changes to the registration dossier within ninety calendar days.

The state expert organization, when identifying the grounds for international sources and the results of security monitoring, notifies all producers and authorized representatives of the manufacturer through information resources about the need to make appropriate changes to the instruction on medical application or operational document through the procedure for making changes to the registration dossier within ninety calendar days.

50. If the condition specified in paragraph 49 of the present Procedure is not met, the state expert organization shall notify (in an arbitrary form) the state agency in the sphere of circulation of medicines, medical devices and medical equipment about the need to suspend the validity of the registration certificate.

Chapter 6. Period of expertise of medical devices and medical equipment

51. Period for the expertise of medical devices and medical equipment are as follows:

1) when expertise medical products of Class 1 and Class 2a in terms not exceeding ninety calendar days, including:

Initial expertise (validation of the registration dossier) — ten calendar days;

laboratory tests — thirty calendar days;

specialized expertise — forty calendar days (including confirmation of authenticity or translation into the Kazakh language of marking of mock-ups of packages, labels, stickers, instructions for medical use, within ten calendar days);

formation of an opinion on safety, efficiency and quality — ten calendar days;

2) when expertise a medical device of class 2b (increased risk) and class 3 (high risk) within a period not exceeding one hundred and sixty calendar days, including:

45. Amendments shall be classified in accordance with the list of changes made to the registration dossier for the medical device and (or) medical equipment within the period of validity of marketing according to Annex 13 to the Rules. Changes not included to the above list are subject to new registration in accordance with the Rules.

      46. Two months after approval of the changes by the manufacturer, the Applicant shall submit an application for carrying out expert examination of medical devices and medical equipment in the form complying for Annex 1 to the Rules.

      47. The application for amending registration dossier of medical device or medical equipment shall be submitted along with the documents and materials necessary for amending, in accordance with the List of changes to be made in registration dossier of medical device and (or) medical equipment within the period of validity of marketing according to Annex 13 to the Rules.

      48. Based on examination results, the state expert organization shall elaborate an expert report on the impact of the changes in the registration dossier on safety, efficiency and quality of medical devices and medical equipment, in accordance with Annex 9 to the Rules, signed by the head of the structural unit and the expert who conducted the examination.

      49. The manufacturer or authorized representative of the manufacturer of a medical device or medical equipment shall make changes to the registration dossier based on a notification in an arbitrary form to the state expert organization, based on information from international sources and the results of safety monitoring.

      In case of evidence identified in international sources or from safety monitoring, State expert organization shall inform all the manufacturers and authorized representatives of the manufacturers via information resources on the need to make correspondent changes in the instruction on medical use or operating procedure in accordance with the procedure on amending registration dossier within ninety calendar days.

      50. In case of failure to comply with the requirement stipulated in section 49 of the Rules, State expert organization shall inform (in arbitrary form) the Government agency in the field of movement of drug products, medical devices and medical equipment on the need to marketing authorization suspension.

Chapter 6. Terms for carrying out expert examination of medical devices and equipment

      51. Terms for carrying out expert examination of medical devices and equipment are as follows:

      1) in case of expert examination of I and IIa class medical devices, the duration shall not exceed 90 calendar days, including:

      initial expert examination (validation of the registration dossier) — ten calendar days;

      laboratory tests — thirty calendar days;

      specific expert examination — forty calendar days (including confirmation of authenticity, or translation into the Kazakh language of mock-ups labels for packages, labels, stickers, package leaflets, within ten calendar days);

      elaboration of conclusions on safety, effectiveness and quality — ten calendar days;

      2) in case of expert examination of IIb (increased risk) and III (high risk) class medical devices, the duration shall not exceed 160 calendar days, including:

      initial expert examination (validation of the registration dossier) — twenty calendar days;

      laboratory tests — sixty calendar days;

      specific expert examination — seventy calendar days (including confirmation of authenticity, or translation into the Kazakh language of mock-ups labels for packages, labels, stickers, package leaflets, within ten calendar days);

      elaboration of conclusions on safety, effectiveness and quality — ten calendar days;

      3) amending to the registration dossier of a medical device and medical equipment (without conducting laboratory tests) within a period not exceeding sixty calendar days, including:

      initial expert examination (validation of the registration dossier) — ten calendar days;

      specific expert examination — forty calendar days (including confirmation of authenticity, or translation into the Kazakh language of mock-ups labels for packages, labels, stickers, package leaflets, within ten calendar days;

      elaboration of conclusions on safety, effectiveness and quality — ten calendar days.

      4) I type changes to the registration dossier of a medical device (with laboratory tests) within a period not exceeding eighty calendar days, including:

      initial expert examination (validation of the registration dossier) — ten calendar days;

      laboratory tests — twenty calendar days;

      specific expert examination — forty calendar days (including confirmation of authenticity, or translation into the Kazakh language of mock-ups labels for packages, labels, stickers, package leaflets, within ten calendar days);

      elaboration of conclusions on safety, effectiveness and quality — ten calendar days;

      5) in case of expert examination of medical equipment (independently of a class) the duration shall not exceed 90 calendar days, including:

      initial expert examination (validation of the registration dossier) — ten calendar days;

      specific expert examination — seventy calendar days;

      elaboration of conclusions on safety, effectiveness and quality — ten calendar days.

      52. Terms for carrying out expert examination of
medical devices and equipment shall not include:

      1) time for completing the incompleteness of the registration dossier;

      2) time the applicant submits documents and materials upon request in the course of the examination in a timely manner;

      3) time of organization and assessment of manufacturing environment;

      4) approval by the applicant of the final documents;

      5) organization and holding of the Expert Council.

Appendix 1 to the Rules of expert examination of
medical devices and equipment
Form

Application for carrying out expert examination of medical devices and equipment*

1. Type (check as appropriate) Medical device

Medical equipment

2. Trade name In Kazakh:
in Russian
3. Identification code in accordance with Global nomenclature established for medical devices (if available)
4. Identification code in accordance with nomenclature established for the Republic of Kazakhstan
5. Domain of usage In Kazakh:
in Russian
6. Intended use In Kazakh:
in Russian
7. Type of medical device (check as appropriate) Closed system:
Yes

no

Manufacturer’s justification (indicate the number of a page in marketing authorization)
8. Specification summary (upon software availability, please, include data related to the software) In Kazakh:
in Russian
9. Class in accordance with the degree of a potential risk associated with usage (check as appropriate) Class 1 — associated with low degree of risk
Class 2a — associated with moderate degree of risk
Class 2b — associated with elevated degree of risk
Class 3 — associated with high degree of risk
10. Medical device or medical equipment is (check as appropriate) Measuring instrument

Sterile

Bulk

Medical device or medical equipment for diagnostic in vitro

11. Includes therapeutic agent Yes

no

12. Assembly of medical device and medical equipment
No Name Model Manufacturer State
1. Basic unit
(if available)
2. Fittings (if available)
3. Options (if available)
4. Software (if available)
5. Expandable materials (if available)
13. Package
No Type (primary and secondary) Name Dimensions Sample size Number of units per package Brief description
1. Primary
2. Secondary
14. Shelf life (for medical device)/ guarantee service life (for medical equipment) For therapeutic agents: lot, terms
15. Transportation terms and conditions
16. Storage conditions
17. Registration in country of manufacture and in other country
1. Name of the country No of marketing authorization (if any) Date of issue Period of validity
18. Manufacturing process Completely on the manufacturing facility

Partly on the manufacturing facility

Completely on other manufacturing facility

19. The manufacturer (s) of medical devices and medical equipment and the manufacturing site (s) (including production areas of any component that is a part of medical device and medical equipment)
No Type of manufacturer Name, country 1,2 (in Kazakh, in Russian and in English) No, date and duration of an approval document Legal address Current address Telephone, fax, e-mail Full name (if available), position of a manager Full name (if available) of a contact person
1. Manufacturer
2. Authorized representative of the manufacturer
3. Contact details of an authorized person responsible for the monitoring of adverse events (incidents) on the territory of the Republic of Kazakhstan
4. Manufacturing area
5 Applicant Information by deputy
20. Number of marketing authorization issued in the Republic of Kazakhstan (in case of marketing authorization renewal)
21. Changes to be made in registration dossiers (fill if the application type is “Amending”) (indicate changes to be made)
No Version before amending Changes to be made
22. Data related to the Contract for carrying out expert examination
1. Contract No
2. Date of conclusion
3. Period of validity
23. An entity that shall pay for carrying out expert examination
1. Name of juridical person
2. Country
3. Legal address
4. Current address
5. Full name (if available)
6. Telephone
7. Fax
8. E-mail
9. Business identification number
10. Individual identification number
11. Bank
12. Business account
13. Currency account
14. Code
15. Bank identification number
Date
Full name (if available)
of the Applicant
Signature, stamp (if available)

      Note:

      * This application form shall be also submitted in renewal of registration dossier issued by authorized body in the field of healthcare of the Republic of Kazakhstan in accordance with the Rules on marketing authorization, recognition renewal and amending registration dossier of drug products, medical devices and medical equipment approved by the Order No. 735 of the Minister of Healthcare dated as November 19th, 2009 (registered in the Registry of the state registration of regulations with the number 5935) as well as in case of changes to the registration dossier.

Appendix 2
to the rules for carrying out expert examination
of medical devices and equipment

List of documents from registration dossier necessary for expert examination of medical devices and equipment*

Ser. No. Name of a document Class 1 Class 2a Class 2b Class 3 Medical devices and medical equipment for diagnostic in vitro (regardless of class of potential risk associated with the usage) Note
1 2 3 4 5 6 7 8
1. Document approving the registration in the country of manufacture or in the manufacturing area (marketing authorization, Free Sale (Certificate for export)). The document shall be authoritatively translated into Russian and notarized. + + + + + In accordance with international standards of attestation or standards of attestation established in the Republic of Kazakhstan: Pdf format
2. Copy of an approval document for right to manufacture on the territory of the country of manufacture (if any) with Annexes + + + + + In accordance with international standards of attestation or standards of attestation established in the Republic of Kazakhstan: Pdf format
3. Copy of the document certifying the registration in other countries (if any) + + + + + Shall be certified by a manufacturer or it’s representative: Pdf format
4. Copies of certificates for quality management system of the manufacturer of medical devices (ISO) 13485, GMP or appropriate regional or national standard)
(except for sterile)

(except for sterile)
+ + + Format: Pdf format
5. Declaration of conformity to the requirements of safety and efficacy of medical devices and medical equipment or equivalent document (if any) + + + + + Format: Pdf format
6. Document certifying the class depending on the degree of a potential risk associated with the usage (Declaration of conformity, justification letter issued by the manufacturer) + + + + + Shall be certified by a manufacturer or it’s representative Format: Pdf format
7. Information related to the therapeutic agents which are components of medical device and/or medical equipment (composition of therapeutic agent, amount, data on compatibility of a therapeutic agent with a medical device, document certifying the quality of a therapeutic agent) + + + + Shall be certified by a manufacturer or it’s representative Format: Pdf format
8. Report (protocol) of toxicological and hygienic testing with the authoritative translation of results and conclusions of the test into Russian + + + + +
9. Report (protocol) of technical testing with the authoritative translation of results and conclusions of the test into Russian + + + + + Shall be certified by a manufacturer or it’s representative Format: Pdf format
10. Specificity and sensitivity test report applicable for medical devices intended to diagnostic in vitro including those incorporated in medical equipment for closed-type diagnostic in vitro + Shall be certified by a manufacturer or it’s representative Format: Pdf format
11. Report of stability testing justifying the shelf life (for medical devices, including those incorporated in medical equipment, sterile components of medical devices and medical equipment), with the authoritative translation of results and conclusions of the test into Russian + + + + + Shall be certified by a manufacturer or it’s representative Format: Pdf format
12. Report of stability testing performed for reagents and raw materials included in medical equipment for closed-type diagnostic in vitro + Shall be certified by a manufacturer or it’s representative Format: Pdf format
13. Data related to clinical (clinical laboratory) testing (studies) with the authoritative translation of results and conclusions of the test into Russian or available clinical data (use, comments, scientific publications) + (in presence of therapeutic agent) + + + Shall be certified by a manufacturer or it’s representative Format: Pdf format
14. Information related to the monitoring of undesirable and adverse events (the information shall not be submitted for first-ever developed or designed medical devices and medical equipment):
1) List of adverse events/accidents related to the usage of the device. Determination of event duration;
2) Summary of each event type. Indicate total number of each reported event type (in presence of high incidence);
3) List of recalled medical devices and medical equipment and/or advisory notices with provision of the analysis of corrective actions and measures taken.
+ + + + + Shall be certified by a manufacturer or it’s representative Format: Pdf format
15. Regulatory document: international, national or in-house standard (technical specifications, specifications for finished product control methods) with the authoritative translation of the specifications and analytical methods into Russian + + + + + Shall be certified by a manufacturer or it’s representative Format: Pdf format
16. Information on specific software (if any) + + + + + Shall be certified by a manufacturer or it’s representative Format: Pdf format
17. Reference including the description of scope of use, indications and brief description of a medical device and medical equipment, design style and accessories (on the form) + + + + + Shall be certified by a manufacturer or it’s representative Format: pdf, doc, xis
18. Operating procedure for medical device in Kazakh and in Russian + + + + + Shall be certified by a manufacturer or it’s representative Format: Pdf format
19. Instruction for use of a medical device approved in the country of manufacture with the authoritative translation into Russian + + + + + Shall be certified by a manufacturer or it’s representative Format: Pdf format
20. Draft of the instruction for medical use of the medical device in Kazakh and in Russian + + + + + The Applicant shall certify the format: pdf, doc
21. Samples of a medical device/raw materials and accessories for medical equipment considered to be a medical device + + + + +
22. Standard samples (if their use is indicated in a statutory document) + + + + +
23. Diagram of a label for the medical device + + + + + Shall be certified by a manufacturer or it’s representative Format: Pdf format
24. Description of the package of medical device (information on quality, including for primary, secondary, multiple, shipping, intermediate package; such information as material, composition, dimensions shall be provided).
Documents regulating the quality of packaging materials used for package of medical devices (specification for quality, certificate of analysis for primary packaging).
+ + + + + Shall be certified by a manufacturer or it’s representative Format: Pdf format
25. Photo (shall reflect the appearance of the device, its components and expandable materials) + + + + + Shall be certified by a manufacturer or it’s representative Format: (jpeg)
26. Colored mock-ups and labels (for primary and secondary packaging) supplied by a manufacturer of medical devices or if necessary its components (the design of package draft shall be submitted in expanded form).
In the presence of a large number of typical sizes and colors it is possible to provide one typical mock-up for one of the sizes, colors (in case when the mock-ups are identical)
+ + + + + Shall be certified by the manufacturer or his authorized representative, format: pdf, jpeg
27. Draft text for mock-up, label and sticker for medical device Kazakh and in Russian (in the presence of a large number of typical sizes and colors it is possible to approve one mock-up using abbreviation) Shall be certified by a manufacturer or it’s representative Format: pdf, doc, jpeg
28. Copy of marketing authorization in the Republic of Kazakhstan (in case of reregistration) + + + + + Format: Pdf format
29. Justification letter on type of medical device (opened or closed system) + + + + + Shall be certified by a manufacturer or it’s representative Format: Pdf format
30. Data on biological safety (if available). + + + + + Shall be certified by a manufacturer or it’s representative Format: Pdf format
31. Data on sterilization procedure including the information related to primary expert evaluation process, results of testing on microorganisms content (degree of bioburden), pyrogenicity and sterility (if necessary) testing with specification of testing methods and data related to primary expert evaluation of the package. + + + + + (except for 1 class) Shall be certified by a manufacturer or it’s representative Format: Pdf format
32. Manufacturer’s details: name, type of activity, legal address, form of ownership, list of subsidiary and affiliated companies with specification of their status, powers and authority + + + + + Shall be certified by a manufacturer or it’s representative Format: Pdf format
33. Information on development and manufacturing: manufacturing process charts, charts of main manufacturing stages, packaging and testing processes as well as charts of finished product release procedures. + + + + + Shall be certified by a manufacturer or it’s representative Format: Pdf format
34. List of documents in registration dossier + + + + + Format: Pdf format
35. List of standards to which medical device and medical equipment correspond (with indication of information about such standards) + + + + + Shall be certified by a manufacturer (it’s representative)
36. Plan for collection and analysis of data on safety and efficacy of medical devices and medical equipment in postmarketing period + + + + + Shall be certified by a manufacturer (it’s representative)
37. Risk evaluation report (if available) + + + + (except for 1 class) Shall be certified by a manufacturer (it’s representative)
38. Information on marketing (history provided that medical device and medical equipment are available on the market within the period exceeding 2 years) (if available) + + +
(except for
1 and 2а class)
Shall be certified by a manufacturer (it’s representative)

Preparation of a certificate for medical equipment and medical devices**

Name Manufacturer (producer), country
Manufacturing site, country
Authorized representative of the manufacturer, country
Completeness Recommended use, application Specification summary
Description of component parts Model Manufacturer Country
Main unit

(if any)

Accessories

(if any)

Components

(if any)

Consumables

(if any)

Software

(if any)

      Note:

      * This list is also submitted for renewal of a marketing3,0 authorization, issued by an authorized healthcare body of the Republic of Kazakhstan in compliance with the Regulations on marketing authorization, recognition renewal and introduction of changes into the registration dossier of drug products, medical equipment and medical devices, approved by the Order No.735 of the Minister of Health of the Republic of Kazakhstan of 19th November 2009 (registered in the register of state registration of laws and regulations under Ref. No. 5935).

      **This form is filled additionally for expert examination of medical equipment.

Appendix 3
To the Regulations for the Expert Examination of medical equipment and medical devices
Form

Requirements to samples of medical devices for laboratory tests

      1. Applicant, prior to submission of the Application for expert examination, shall calculate the number of samples needed for three-stage analysis during laboratory tests.

      2. Number of samples of medical devices submitted for laboratory tests is determined based on the requirements of regulatory documents, compliance to which is checked by the tests.

      3. Homogeneity of the submitted products, representativeness in the content and quantity, compliance of samples to identification characteristics of this product representing its quality attributes are taken into account in order to determine the required number of samples.

      4. Number of submitted samples in composition reflects the aggregate of the submitted homogeneous product, taking into account the differences between qualities of different types (models, brands) of such aggregate.

      5. For homogeneous products which differ only in dimension range, only samples of the largest, medium and smallest dimensions shall be submitted.

      6. If different types of the selected medical devices differ only in color, submission of samples of the same color shall be sufficient.

      7. Samples of medical devices are not returned after tests.

Appendix 4
To the Regulations for the Expert Examination of medical equipment and medical devices
Form

Report of the initial expert examination (registration dossier validation) of medical devices or medical equipment submitted for tests.

Initial expert examination (registration dossier validation) of medical devices or medical equipment (as applicable) submitted for tests has been performed.

1. Surname, name, patronymic (if any) of the examiner
2. Ref. No and date of the Application
3. Date of submission of documents for the initial expert examination
4. Trade name of medical devices or medical equipment
5. Intended use of medical devices or medical equipment
6. Scope of application
7. Class depending on the level of the potential risk of application
8. Applicant

      Manufacturer data:

No. Type of business or production area Business name Country Legal address
1. Manufacturer
2. Manufacturing site
3 Authorized representative of the manufacturer
4. Packer (where applicable)
5 Contact information of an authorized officer for monitoring of adverse events (incidents) in the territory of the Republic of Kazakhstan

      1. Initial expert examination of completeness of the registration dossier and satisfactory form of the documents submitted (remarks on incompleteness of the dossier and unsatisfactory form of the documents shall be made)

___________________________________________________________________________

      2. Registration in the country of origin (of the manufacturer) and in other countries:

No. Country Ref. No. of a registration document Date of issue Examiner’s notes

      3. Compliance of the class of medical devices based on the level of the potential risk of application specified in the Application and documents of the registration dossier:

No. Class according to the Application Class according to the documents of the registration dossier Description of the documents of the registration dossier which specify class Examiner’s notes

4. Compliance of the samples submitted for laboratory tests:

Description of samples (including volume and size) Series Number of samples submitted (in units of measurement: vials, pcs., packs) Shelf life Remaining shelf life of samples of the product Storage (transportation) conditions Packing (type)

      5. Assessment of the labeling text of a draft package design, labels, stickers for compliance to legal requirements:

      __________________________________________________________________________

      6. Compliance of standard samples submitted to the regulatory documents of the manufacturer (provided that their application is specified in a regulatory document):

Description of standard samples Number of standard samples submitted (in units of measurement: vials, pcs., packs) Shelf life Remaining shelf life of samples of the product Storage (transportation) conditions Packing (type)

      7. Conclusion:

Deny further expert examination (with justification)
Continue expert examination of medical devices or medical equipment

      Business unit supervisor _______ ___________________________________
signature surname, name, patronymic (if any)
Examiner______ _________________________________________________________________
signature                         Surname, name, patronymic (if any)
Date ______________

Appendix 5
To the Regulations for the Expert Examination of medical equipment and medical devices
Form

Report of the initial expert examination (registration dossier validation) of changes introduced into the registration dossier of medical devices or medical equipment.

Initial expert examination (registration dossier validation) of medical devices or medical equipment (as applicable) submitted for tests upon introduction of changes into the registration dossier has been performed.

1. Surname, name, patronymic (if any) of the examiner
2. Ref. No. and date of an Application
3. Date of submission of the documents for the initial expert examination
4. Trade name of medical devices or medical equipment
5. Intended use of medical devices or medical equipment
6. Scope of application
7. Class depending on the level of potential risk of application
8. Applicant

      Manufacturer data:

No. Type of business or production area Business name Country Legal address
1. Manufacturer
2. Manufacturing site
3 Authorized representative of the manufacturer
4. Packer (where applicable)
5 Contact information of an authorized officer for monitoring of adverse events (incidents) in the territory of the Republic of Kazakhstan

      1. Initial expert examination of completeness of the registration dossier and satisfactory form of the documents submitted (remarks on incompleteness of the dossier and unsatisfactory form of the documents are made).

      _________________________________________________________________________

      2. Registration in the country of origin (of the manufacturer) and in other countries:

No. Country Ref. No. of a registration document Date of issue Examiner’s notes

3. Compliance of the class of medical devices based on the level of potential risk of application specified in the Application and documents of the registration dossier:

No. Class according to the Application Class according to the documents of the registration dossier Description of the documents of the registration dossier which specify class Examiner’s notes

     4. Compliance of the samples submitted for laboratory tests:

Description of samples (including volume and size) Series Number of samples submitted (in units of measurement: vials, pcs., packs) Shelf life Remaining shelf life of samples of the product Storage (transportation) conditions Packing (type)

      5. Assessment of the labeling text of a draft package design, labels, stickers for compliance to legal requirements:

___________________________________________________________________________

      6. Type of changes introduced

Edition before introduction of changes Edition after introduction of changes

 7. Compliance of standard samples submitted to regulatory documents of the manufacturer (provided that their application is specified in a regulatory document):

Description of standard samples Number of standard samples submitted (in units of measurement: vials, pcs., packs) Shelf life Remaining shelf life of samples of the product Storage (transportation) conditions Packing (type)

8. Conclusion:

Deny further expert examination (with justification)
Continue expert examination

Business unit supervisor _______ ___________________________________
signature surname, name, patronymic (if any)
Examiner _________________________________________________________________
signature                         Surname, name, patronymic (if any)
Date ______________

Appendix 6
To the Regulations for the Expert Examination of medical equipment and medical devices
Form

Ministry of Healthcare of the Republic of Kazakhstan

            _______________________________________________________________________
Name of the state expert organization

__________________________________________________________________________
Accreditation certificate of the test laboratory (No., date of expiry)
__________________________________________________________________________
Address, telephone number of the expert organization (test laboratory)

Test record sheet No. ________ of «____» ____________

            Page ____ /Number of pages __

      Applicant (name for a legal entity / full name for a physical entity (if any) and address):
_____________________________________________________________________________Product description: _______________________________________________________
Mode of test: ________________________________________________________________
Basis: ___________________________________________________________________
Producer/manufacturer, country: ________________________________________
Series, batch: ____________ Manufacture date: ___________ Shelf life: ___________
Test start and completion date: __________________________________________
Number of samples: ___________________________________________________________
Designation of a regulatory quality assessment document for the product quality:
_____________________________________________________________________________
Designation of a regulatory quality assessment document for test methods:
_____________________________________________________________________________

Test results

Indicator description Requirements of regulatory documents Factual results obtained Temperature °C and humidity (%)
1 2 3 4

Conclusion: The submitted results comply/do not comply with the requirements of regulatory documents and test methods are reproduced / are not reproduced (as appropriate). (Underline as appropriate).

      Methods are not reproduced in the following criteria: ____________________________
Signatures of authorized officers
____________ ___________________________________________________
(position) (signature)                   (Surname, name, patronymic (if any)
__________________ ___________________________________________________
(position) (signature)                   (Surname, name, patronymic (if any)
__________ ___________________________________________________________
(position) (signature)                   (Surname, name, patronymic (if any)
Stamp here

Appendix 7
To the Regulations for the Expert Examination of medical equipment and medical devices
Form

Report on the results of laboratory tests conducted in the quality control laboratory of the manufacturer or a contract laboratory used by the manufacturer*

      1. Summary

Description of medical devices
Name, address and requisites of a manufacturing site
Name, address and requisites of a quality control laboratory and/or a contract quality control laboratory
Basis for laboratory tests
Number of licenses (if any), certificates, applications for expertise
Summary of activities of the quality control laboratory Conduction of laboratory tests
Commercialization of a series of medical devices
Other (please specify)
Date(s) of laboratory tests conduction
Full names (if any) of examiners (panel members), positions

      2. Introductory information

Brief summary of the quality control laboratory
Availability of documented testing procedures
Fulfillment of documented testing procedures
Objective of laboratory tests
Test units
Personnel of the quality control laboratory, taking part in the laboratory tests
Documents submitted by the manufacturer and/or quality control laboratory prior to assessment of conditions of production and quality assurance system

      3. Observations and results of laboratory tests

Reference to a regulatory document
Series number, date of manufacture
Characteristic Requirements of a quality assessment regulatory document Factual results Т, humidity Fulfills/fails to meet the requirements

      4. Appendices

Documents (primary data, test record sheets) and samples selected during laboratory tests

      5. Conclusion

Positive
Negative (with justification)

      Note

* The Report of laboratory test results shall be appended by a copy of an analysis certificate and (or) a test record sheet for the product issued by the quality control laboratory of the manufacturer or contract laboratory used by the manufacturer. All appendices to the report shall make an integral part thereof.

Head of panel ________________________________________________
(signature)       (Surname, name, patronymic (if any)
Members of panel: _____________ ___________________________________

(signature)                   (Surname, name, patronymic (if any)
_________________________________________________

(signature)                   (Surname, name, patronymic (if any)
«______» _______________________20____.

 Approved on:
___________ ___________ _________________________________

(position) (signature)             Surname, name, patronymic (if any)
___________ ___________ _________________________________

(position) (signature)             Surname, name, patronymic (if any)

Appendix 8

To the Regulations for the Expert Examination of medical equipment and medical devices

Form

Expert Report on a specialized examination of medical devices and medical equipment

1. Surname, name, patronymic (if any) of the examiner
2. Academic degree, title
3. Ref. No. and date of an Application
4. Date of submission of documents for a specialized examination
5. Trade name of medical devices/medical equipment
6. GMDN Code (if any)
7. Code of the Medical Device Nomenclature of the Republic of Kazakhstan
8. Specifications of medical devices/medical equipment
9. Intended use of medical devices/medical equipment
10. Scope of application

Documents of the registration dossier describing safety, efficiency and quality of medical devices/medical equipment have been assessed by the expert examination.

      1. Manufacturer data concerning medical devices/medical equipment, including consumables and components, as part of medical devices:

No. Type of business or production area Business name Country Legal address
1. Manufacturer
2. Manufacturing site
3 Authorized representative of the manufacturer (if any)
4. Packer (where applicable)
5 Contact information of an authorized officer for monitoring of adverse events (incidents) in the territory of the Republic of Kazakhstan

      2. Registration in the country of origin (of the manufacturer) and other countries

No. Country Ref. No. of a registration document Date of issue Examiner’s notes
1

      3. Fidelity assessment of the class of medical devices and medical equipment specified in the Application and documents of the registration dossier depending on the potential risk of application in compliance with the legislative requirements of the Republic of Kazakhstan in the field of movement of medicines, medical devices or medical equipment.

Class according to the Application Class according to the documents of the registration dossier Compliance of the specified class to the legislative requirements of the Republic of Kazakhstan Examiner’s notes

      4. Characteristics of the system of criteria determining safety, efficiency and quality of medical devices/medical equipment, including consumables and components, as part of medical devices:

      1) Quality management systems ISO, GMP of the manufacturing organization, including consumables and components, as part of medical devices:

No. Name of the document No. of the document

Date of issue

Date of expiry Examiner’s notes

      2) Quality of medical devices/medical equipment, including consumables and components, as part of medical devices (technical conditions, company standards):

No. Name of the document No. of the document

Date of issue

Date of expiry Examiner’s notes

      3) Confirmation of compliance of medical devices/medical equipment with the requirements of national or international regulatory documents (Declaration of Conformity; Certificate of Conformity):

No. Name of the document No. of the document

Date of issue

Date of expiry Examiner’s notes

      4) Analysis of data obtained during tests (toxicity, technical, clinical) in the country of origin (reports, conclusions) and data obtained during the previous stages of expert examination in the Republic of Kazakhstan (initial expert examination, laboratory tests):

No. Name of the document Assessment of completeness and quality of the information in the document Examiner’s notes

      5) Conclusion on stability of medical devices, substantiation of the specified shelf life:

No. Specified shelf life Analysis of the submitted stability report Examiner’s notes

      6) Assessment of the draft patient information leaflet for the medical devices, including consumables and components to medical equipment, as part of such equipment, and exploitative document on medical equipment:

No. Analysis Assessment of the examiner
1. Completeness of the text content of the draft patient information leaflet for medical devices
2. Conformity of the draft text content to the original patient information leaflet of the manufacturer
3. Conformity of the design of the draft patient information leaflet to the legislative requirements of the Republic of Kazakhstan in the field of movement of medicines
4. Information contained in the exploitative document on the application of medical equipment

      7) Assessment of the design of package and label

No. Analysis Assessment of the examiner
1. Conformity of the design of text of the draft labeling to the legislative requirements of the Republic of Kazakhstan in the field of movement of medicines, medical devices and medical equipment
2. Identity of instructions on storage and transportation conditions specified in the standardization document for medical devices and in the draft patient information leaflet

      8) Analysis of data on the development and manufacturing of medical devices and medical equipment (schemes of production process, main stages of production, packing, tests and final product output). Conclusion concerning the conformity of the development, production process and quality control to the procedure of manufacturing of safe and quality products

No. Analysis Assessment of the examiner
1. Assessment of the data provided by the Applicant concerning the development and production, including the analysis of the production inspection report (if any);
2. Conclusion concerning the compliance of the development, production process and quality control to the procedure of manufacturing of safe and quality products

      9) Assessment of biological safety of medical devices based on the analysis of all material of animal or human origin, being part of medical devices, as well as based on the analysis of the information concerning selection of sources (donors), material take off, processing, storage, testing, initial expert examination of testing procedures, as well as of handling tissues, cells, substances of animal or human origin, germ and cultures and viruses (if any):

No. Analysis Assessment of the examiner
1. Assessment of data provided by the Applicant on the biological safety analysis

      10) Assessment of the initial expert examination of the software based on the analysis of the information concerning its verification and initial expert examination, including information concerning its development and testing within the company and during multicenter studies, information concerning identification and labeling of the operating system:

No. Analysis Assessment of the examiner
1. Assessment of data provided by the Applicant

      11) Assessment of the procedure and methods of sterilization of medical devices, materials, substantiating the way of sterilization, proposed quality control methods and ways of detection of sterilizing agent reminder during chemical sterilization:

No. Analysis Assessment of the examiner
1. Assessment of data provided by the Applicant

      12) Assessment of safety and efficiency of a drug product used as a component of medical devices and medical equipment, its influence on the functions of medical devices and medical equipment, compatibility of a drug product with medical devices and medical equipment (except for medical devices and medical equipment used for in vitro diagnostics). Information concerning registration of a drug product in the country of origin of such drug product:

No. Analysis Assessment of the examiner
1. Assessment of data provided by the Applicant

      13) Analysis of the information provided by the manufacturer concerning presence or absence of notices of accidents, incidents and withdraw from the market of medical devices and medical equipment, concerning unwanted event and (or) accidents connected with the use of medical devices and medical equipment, security notifications concerning medical devices and medical equipment, attitude to consideration of these issues and solutions taken by the manufacturer in each separate case, description of corrective actions taken in response to such cases, as well as the proportion of proportion sales and number of accidents and withdrawals of medical devices and medical equipment from circulation:

No. Analysis Assessment of the examiner
1. Assessment of data provided by the Applicant

      14) Assessment of the Data Collection and Analysis Plan concerning safety and efficiency of medical devices and medical equipment at the after-sales stage and Risk Analysis Report

No. Analysis Assessment of the examiner
1. Assessment of data provided by the Applicant

      5. Conclusion of the examiner

1. Positive
2. Negative (with justification)

      All information provided in the expert opinion is true and comply with the applicable requirements, which is confirmed by the personal signature of the:

      Business unit supervisor _______ ___________________________________
signature             Surname, name, patronymic (if any)

Examiner _____________________________________________________
signature                   Surname, name, patronymic (if any)
Date ______________
Stamp here

Appendix 9
To the Regulations for the Expert Examination of medical equipment and medical devices
Form

Expert Report on a specialized examination of the influence of changes introduced into the registration dossier on safety, efficiency and quality of medical devices and medical equipment

1. Surname, name, patronymic (if any) of the examiner
2. Academic degree, title
3. Ref. No. and date of an Application
4. Date of submission of documents for a specialized examination
5. Trade name of medical devices and medical equipment

Documents of the registration dossier describing the influence of changes introduced into the registration dossier on safety, efficiency and quality of medical devices and medical equipment have been assessed by the expert examination.

      Expert examination found the following:

No. Edition before introduction of changes Changes introduced

     Influence of changes introduced on safety, efficiency and quality of medical devices and medical equipment:

No. Changes (specify as applicable) Assessment (affects/does not affect)

In case of a negative assessment, justification shall be provided

      Conclusion of the examiner:

1. Positive
2. Negative (with justification)

All information provided in the expert opinion are true and comply with the applicable requirements, which is confirmed by the personal signature of the:

      Business unit supervisor _______ ___________________________________
signature           Surname, name, patronymic (if any)

Examiner _______ _________________________________________________________________
signature                   Surname, name, patronymic (if any)
Date ______________
Stamp here

Appendix 10
To the Regulations for the Expert Examination of medical equipment and medical devices
Form

Conclusion concerning safety, efficiency and quality of medical devices and medical equipment submitted for the expert examination

      1. Republican State Enterprise on the Right of Economic Use «National Centre for Expertise of Medicines, Medical Devices and Medical Equipment» under the Ministry of Healthcare of the Republic of Kazakhstan hereby informs on the results of the expert examination of safety, efficiency and quality of medical devices and medical equipment:

Trade name of medical devices or medical equipment
Manufacturer, country of origin
Manufacturing site, country
Authorized representative, country
Type (of medical devices or medical equipment)
Type of expert examination
Class based on the potential risk of application
Code of the Medical Device Nomenclature of the Republic of Kazakhstan
Configuration of medical devices/medical equipment (number of components, if any) (Table)
Conclusion of the initial expert examination (validation of the registration dossier) (positive, negative)
Conclusion of the test laboratory: date and number of the test report (positive, negative)
Conclusion of a specialized examination (to recommend/not to recommend the medical device/medical equipment)
Table

      Configuration of medical devices and medical equipment

Description Model Manufacturer Country

      2. Conclusion:

      (Positive) Materials and documents of the registration dossier for medical devices/medical equipment submitted for the expert examination comply with the requirements to safety, efficiency and quality of medical devices/medical equipment, which is proved by appropriate materials and tests conducted.

      (Negative) Materials and documents of the registration dossier for medical devices/medical equipment submitted for the expert examination do not comply with the requirements to safety efficiency and quality of medical devices/medical equipment, which is proved by appropriate materials and tests conducted.

      Head of the state expert organization (or authorized person):
____________________________________________________________
Signature                   Surname, name, patronymic (if any)
Date ______________
Stamp here

Appendix 11
To the Regulations for the Expert Examination of medical equipment and medical devices
Form

Conclusion concerning safety, efficiency and quality of medical devices and medical equipment after changes introduced into the registration dossier

      1. Republican State Enterprise on the Right of Economic Use «National Centre for Expertise of Medicines, Medical Devices and Medical Equipment» under the Ministry of Healthcare of the Republic of Kazakhstan hereby informs on the results of the expert examination of the influence of changes introduced into the registration dossier on safety, efficiency and quality of the medical device/medical equipment:

Trade name of the medical device (medical equipment)
Manufacturer, country or origin
Manufacturing site, country
Authorized representative, country
Changes introduced
Conclusion of the initial expert examination (validation of the registration dossier) (positive or negative)
Conclusion of the test laboratory: date and number of the test report (positive or negative)
Conclusion of a specialized examination (introduction of changes into the registration dossier is recommended/not recommended)

      2. Conclusion:

      (Positive) Materials and documents for medical devices (medical equipment) submitted for the introduction of changes into the registration dossier comply with the applicable requirements, influence on safety, efficiency and quality of medical devices (medical equipment) is proved by appropriate materials and tests conducted.

      The changes are registered with (without) the issue of a new marketing authorization.

      (Negative) Materials and documents for medical devices (medical equipment) submitted for the introduction of changes into the registration dossier do not comply with the applicable requirements, have negative influence on safety, efficiency and quality of medical devices (medical equipment).

      Changes are not registered.

     Head of the state expert organization (or authorized person):
______________________________________________________________________
Signature                         Surname, name, patronymic (if any)
Date ______________
Stamp here

Appendix 12
To the Regulations for the Expert Examination of medical equipment and medical devices
Form
Қазақстан Республикасы Денсаулық сақтау министрлігінің «Дәрілік заттарды, медициналық мақсаттағы бұйымдарды және медицина техникасын сараптау ұлттық орталығы» шаруашылық жүргізу құқығындағы республикалық мемлекеттік кәсіпорны Republican State Enterprise on the Right of Economic Use «National Centre for Expertise of Medicines, Medical Devices and Medical Equipment» Ministry of Healthcare of the Republic of Kazakhstan

Summary bridging report on safety, efficiency and quality of medical devices and medical equipment

      «Description of medical devices», manufacturer, country

     Confidential information has been removed from the report

      Table of content

      1. Scope of application of medical devices

      2. Intended use of medical devices

      3. Specification summary of medical devices

      4. Safety class

      5. Manufacturer information

      6. Determination (conclusion)

      7. Registration information

      8. Storage conditions for IVD

Appendix 13
To the Regulations for the Expert Examination of medical equipment and medical devices

List of changes introduced into the registration dossier of medical devices and (or) medical equipment during the validity of the marketing authorization

Changes Conditions/notes List of documents and materials necessary for introduction of changes
1 2 3
1.Change of information of the manufacturer / manufacturing site of medical devices/ medical equipment Main condition is an issue of a new manufacturing authorization by an authorized organization of the country of origin (of the manufacturer).
Manufacturing site was not changed.

Production process or specifications including testing methods were not changed.

1. Document certifying registration of medical equipment/ medical devices in the country of origin (marketing authorization, notarized Certificate of Free Sale (FreeSale), Export Certificate) with the changes introduced
2. Document certifying introduction of changes (with a date of changes) issued by an authorized body of the country of origin
3. Notarized document certifying compliance of the conditions of production with the national and/or international standards GMP; ISO
4. Notarized document certifying compliance of medical equipment with the national and/or international regulatory documents, class based on the level of potential risk of application (Declaration of Conformity; Certificate of Conformity)
5. Copy of the Marketing Authorization issued in the Republic of Kazakhstan
6. Letter of the manufacturer certifying that the process or production, quality control and monitoring of safety of the final product shall be remained unchanged, specifying the date of changes introduced
7. Draft patient information leaflet of medical devices/ operating manual for the medical equipment (on electronic media such as CD in doc. format).
8. Draft labeling (on electronic media such as CD in jpeg format)
9. List of documents
2.Change of the information concerning the authorized representative, including the information about re-organization of a legal entity, about change of its name, change of a surname, name and patronymic (if any), of a residential address of an individual entrepreneur Introduction of changes into the marketing authorization does not affect the efficiency and safety of medical devices/ medical equipment 1. Copy of a document confirming the authorization of the manufacturer’s representative
2. Copy of the Marketing Authorization
3. Documents confirming changed introduced
4. List of documents
3.Change of name of medical devices and/or medical equipment Well-reasoned grounds for the necessity of change of name of medical devices and/or medical equipment, which do not affect its functional and technical features 1. Application for the introduction of changes made in the approved form (on electronic media such as CD in doc. format)
2. Notarized document certifying registration of medical equipment/ medical devices in the country of origin (marketing authorization, Certificate of Free Sale (FreeSale), Export Certificate with the changes introduced
3. Copy of the Marketing Authorization issued in the Republic of Kazakhstan.
4. Letter of the manufacturer (producer) containing well-reasoned grounds for the necessity of change of name of medical devices and(or) medical equipment, which do not affect functional and technical features of medical devices/medical equipment
5. Draft patient information leaflet of medical devices/ exploitative document for the medical equipment (on electronic media such as CD in doc. format)
6. Draft labeling (on electronic media such as CD in jpeg format)
7. Photographic image of a general view of medical devices/medical equipment together with accessories necessary for the intended application (size should be at least 18 x 24 centimeters)
8. List of documents
4.Change of the set of accessories and (or) components and (or) consumables, update (installation of a new version) of software Absence of influence on the functional features of medical devices and medical equipment 1. Application for the introduction of changes made in the approved form (on electronic media such as CD in doc. format)
2. Copy of the Marketing Authorization issued in the Republic of Kazakhstan
3. Letter of the manufacturer (producer), containing well-reasoned grounds for the necessity of change of the set of components and with a specification of a new list of components, proving absence of influence on the functional features of medical devices and medical equipment (including broadening of a spectrum of detected analytes of medical devices and medical equipment for in vitro diagnostics).
4. Draft patient information leaflet of medical devices /exploitative document in the Kazakh and Russian languages
5. Updated specification with a list of components and consumables in the approved form
6. List of documents
7. If a new component has been added as a part of medical devices – samples of such medical devices (in case of a sterile one, the whole set shall be submitted) and a regulatory document
5. Change of the instructions of medical use; scope of application; counter-indications;
side effects
Safety of use of medical devices and/or medical equipment shall be remained and proved by clinical study data for the safety and efficiency 1. Application for the introduction of changes made in the approved form (on electronic media such as CD in word. format)
2. Copy of the Marketing Authorization issued in the Republic of Kazakhstan
3. Letter of the manufacturer (producer), containing well-reasoned grounds for the necessity of change of the instruction of usage
4. Draft patient information leaflet of medical devices in compliance with the one established under legislation (on electronic media such as CD in doc. format)
5. Previously approved instructions of medical use
6. Colorful package design, labels, stickers (where applicable) (on electronic media such as CD in jpeg format)
7. Clinical trial results reflecting the changes introduced
8. List of documents
6. Change of the manufacturer of the components, accessories, consumables Technical specifications and quality control of the components and/or consumables should not compromise the quality of the final product 1. Application for the introduction of changes made in the approved form (on electronic media such as CD in doc. format)
2. Notarized document certifying the conformity of the conditions of production with the national and/or international standards GMP, ISO of the components and/or consumables
3. Copy of the Marketing Authorization issued in the Republic of Kazakhstan
4. Letter of the manufacturer, confirming that the production process, quality control and monitoring of safety of the final product have remained unchanged
5. Draft patient information leaflet for the medical use of medical devices (where applicable) (on electronic media such as CD in doc. format)
6. List of documents
7. Extension/ reduction of shelf life of medical devices Well-reasoned grounds for the change of terms 1. Application for the introduction of changes made in the approved form (on electronic media such as CD in doc. format)
2. Copy of the Marketing Authorization issued in the Republic of Kazakhstan
3. Letter of the manufacturer, confirming that the production process quality control and monitoring of safety of the final product have remained unchanged
4. Information concerning stability (for medical devices) of at least three series) (report substantiating the time of shelf life)
5. Draft patient information leaflet for medical device (where applicable): (on electronic media such as CD in doc. format)
6. Colorful package design, labels, stickers (on electronic media such as CD in jpeg format)
7. List of documents
8.Change of storage conditions Well-reasoned grounds for the change of storage conditions 1. Application for the introduction of changes made in the approved form (on electronic media such as CD in doc. format)
2. Copy of the Marketing Authorization issued in the Republic of Kazakhstan
3. Justification letter of the manufacturer (producer) concerning the change of storage conditions made on the letterhead of the manufacturer in compliance with the one established under legislation
4. Information concerning stability (for medical devices) of at least three series)
5. Draft patient information leaflet for medical devices (where applicable); (on electronic media such as CD in doc. format)
6. Colorful package design, labels, stickers (on electronic media such as CD in jpeg format)
7. List of documents
9. Change of the quality control procedure of the final medical device Well-reasoned grounds for the change of quality control procedure 1. Application for the introduction of changes made in the approved form (on electronic media such as CD in word. format)
2. Copy of the Marketing Authorization issued in the Republic of Kazakhstan
3. Letter of the manufacturer confirming that the production process has remained unchanged
4. Letter of the manufacturer confirming that the specified monitoring procedure does not compromise the quality and safety of the final product
5. Regulatory documentation with the changes introduced, regulating the quality of the product, notarized Certificate of Analysis of the quality control procedure of the final product
6. Samples, standard samples for laboratory tests (where applicable)
7. List of documents
10. Change of the packaging of medical devices:
of the initial packaging of medical devices;
secondary and/or multiple packaging, transport packaging, intermediate packaging
Well-reasoned grounds of the influence/non-influence of the change of packaging on stability, quality of medical devices; reciprocal interaction between the packaging and medical devices 1. Application for the introduction of changes made in the approved form (on electronic media such as CD in doc. format)
2. Copy of the Marketing Authorization issued in the Republic of Kazakhstan
3. Letter of the manufacturer confirming that the changes introduced into the initial packaging do not affect stability, quality of the medical devices
4. Regulatory documentation with the changes introduced
5. Colorful package design, labels, stickers of the new and old design (on electronic media such as CD in jpeg format)
6. Photo of medical equipment
7. Samples for sterile medical devices, standard samples for laboratory tests in case of change of the initial packaging (where applicable)
8. List of documents
11. Change of imprints, primers or other marking, stamps and tests, including addition or change of colors used for marking of medical devices. Well-reasoned grounds for the introduction of changes into the marking 1. Application for the introduction of changes made in the approved form (on electronic media such as CD (СД) in word. format)
2. Copy of the Marketing Authorization issued in the Republic of Kazakhstan
3. Justification letter of the manufacturer concerning the changes introduced
4. Colorful package design, labels, stickers of the new and old design (on electronic media such as CD in jpeg format)
5. Photo of medical equipment
6. List of documents

© 2012. Republican State Enterprise on the Right of Economic Use of the Republican Center of the Legal Information under the Ministry of Justice of the Republic of Kazakhstan

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