THE RULES OF GOOD MANUFACTURING PRACTICE

Содержимое (Table of Contents)

THE RULES OF GOOD MANUFACTURING PRACTICE

I. GENERAL PROVISIONS

1. The Rules of Good Manufacturing Practice (hereinafter – the Rules) shall set forth requirements to the organization of manufacture and quality control of medicines for purposes of medical and veterinary application.

2. The Rules shall apply to all types of medicines and shall define the general requirements to the organization of their manufacture and quality control as well as special requirements to the organization of manufacture of individual types of medicines.

3. These Rules shall not cover issues related to the occupational health and safety of the staff involved in the manufacturing processes, assurance of industrial, fire, explosion, chemical, hygiene and other safety during manufacture of medicines and environmental protection. Taking appropriate measures in connection with the foregoing shall be the manufacturer’s direct responsibility, subject to the regulatory legal acts of the Russian Federation.

II. TERMS AND DEFINITIONS

4. Basic terms used for purposes hereof:

tank: a container, generally cylindrical, for pressurized, liquefied or dissolved gas, with fixtures to regulate spontaneous discharge of gas under atmospheric pressure and at indoor temperature;

biological agents: microorganisms, including those derived by means of gene engineering techniques, cell cultures and endoparasites, either pathogenic or non-pathogenic;

bioreactor: a closed system such as a fermenter, in which biological agents alongside other raw materials are introduced so as to cause their multiplication or production by them of other substances through interaction with other raw materials. Bioreactors are generally supplied with adjusters and controllers and with fixtures for adding and removing substances;

validation: formalized activities providing a high degree of assurance that a method, a process, equipment, material, an operation or a system complies with set requirements and that their use shall invariably bring about results corresponding to acceptance criteria set in advance;

return: return of a medicine to its manufacturer or supplier;

air chamber: restricted space with two or several doors, between two or several rooms, for example, of different contamination classes, intended for separating air media in rooms when entering them and used for movement of the staff as well as for relocation of materials;

highly potent substances: chemical compounds that have an effect on the human body in low concentrations;

highly potent medicines: medicines that give a pharmacological effect in low dosage (concentrations);

finished products (finished product): a medicine after all process stages, including final packaging;

record: a document finalizing the implementation of various activities to evidence their compliance with instructions;

isolated area: an area supplied with necessary filters and air units for preventing contamination of the external environment with biological agents present in the area;

isolation: activities aimed at restricting dissemination of biological agents or other contaminants beyond a certain area;

secondary isolation: an isolation system preventing penetration of a biological agent into the external environment or other operating areas by means of using rooms/premises with special air systems, air chambers and (or) sterilizers for delivering materials outside, alongside process safety procedures. In many cases the secondary isolation is used for increasing the efficiency of the primary isolation;

primary isolation: an isolation system preventing penetration of a biological agent into the external environment directly adjacent to an operating area, by means of using closed containers or boxes for safe performance of biological activities, alongside process safety procedures;

infected: infected with foreign biological agents and, therefore, able to spread infection;

starting raw materials: a general term used to denote source materials, reagents and solvents used to manufacture intermediate products or a pharmaceutical substance;

calibration: demonstrating that measurements by a certain instrument or device are within the set limits against measurements obtained with the use of a reference standard or a reference element comparable to the standard or measurement standard throughout the corresponding range of measurements;

quarantine: the status of starting raw materials, packing materials, intermediate, bulk or finished products, isolated physically or in any other effective manner, until it is decided to approve or reject them;

qualification: activities certifying and documenting that equipment or auxiliary systems are duly assembled, properly function and really bring about the expected results. ‘Validation’ is a broader term and sometimes covers ‘qualification’;

cell culture: cell mass obtained as a result of in vitro growth of cells isolated from multicellular organisms;

collector: a device or equipment designed for one or several tanks (containers) and making it possible to simultaneously clean a tank (container) and fill it with gas;

computerized system: a process or an operation integrated in a computer system, which comprises input of data, their electronic processing and output of data used for documentation and (or) automatic control;

controlled area: an area built and operated in a way so as to control possible contamination and accidental spreading of living microorganisms, which is used in case of negative pressure against adjacent classified premises and makes it possible to efficiently eliminate minor quantities of contamination sources in the air; the degree of the on-going control depends on the type of the microorganism used in the process;

in-process control (interoperational control): control implemented during the manufacturing process for the purpose of checking the compliance of intermediate products and (or) products with the set requirements, following which it may be required to adjust the process parameters. Environmental control or equipment control may be regarded as an element of the in-process control;

quality control: quality control includes sampling, testing, checks for the compliance with requirements of specifications, procedures for the organization, documenting and issue of release permits;

cryogenic vessel: a vessel used for storing liquefied gas at extremely low temperatures;

medicinal plant: a whole plant or its parts used for medical purposes;

medicines: substances or their combinations, which come into contact with the human body or animal organism, penetrate into human or animal organs, tissues, are used for purposes of prevention, diagnosis (excluding substances or their combinations that do not contact the human body or animal organism), treatment of diseases, rehabilitation, for pregnancy maintenance, prevention or termination, and which are obtained from blood, blood plasma, from human or animal tissues, plants, minerals by means of synthesis methods or with the use of biological technologies. Medicines include pharmaceutical substances and pharmaceuticals <*>;

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<*> Paragraph 1 Article 4 of Federal Law No. 61-FZ dated 12 April 2010 “On Circulation of Medicines” (Collection of Legislative Acts of the Russian Federation, 2010, No. 16, Art. 1815).

hermedicinal product produced or manufactured from one or several types of herbal raw materials and sold in secondary (consumer) packaging <*>;

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<*> Paragraph 15 Article 4 of Federal Law No. 61-FZ dated 12 April 2010 “On Circulation of Medicines” (Collection of Legislative Actbal medicinal product: a s of the Russian Federation, 2010, No. 16, Art. 1815).

material balance: the balance between the quantity of products or materials, which theoretically can be used in and result from the manufacturing process, and the quantity of products or materials, which has been actually used in and resulted from the manufacturing process, considering admissible variations;

bulk products: any products that have gone through all the process stages, excluding consumer packaging;

batch (lot) number: a unique combination of figures, characters and (or) symbols, which identify a batch (lot) and allow tracing the history of its manufacture and sale. Batches are numbered with Arabic figures; the last four figures in the batch number indicate the month and the year of the medicine manufacture;

cross contamination: contamination of starting raw materials, materials or products with other starting raw materials, materials or products;

reprocessing: reprocessing of a batch or part of a batch of products that does not meet the set requirements, starting from a certain manufacturing stage – introducing intermediate products or a pharmaceutical substance, including those not meeting standards or specifications, in the manufacturing process and repeating the stage of crystallization or other chemical or physical manipulations (for example, distillation, filtration, chromatographic run, disintegration), which are a stage of the established manufacturing process. Continuation of a stage of the manufacturing process after the in-process control has revealed that the stage has not been completed is deemed as a part of the normal process, and not as reprocessing;

recovery: introducing a previously manufactured batch of products (or its part) of the required quality in another batch of products at a certain manufacturing stage;

inoculum:

inoculum system: a system implying that successive product batches are manufactured from the same main inoculum with a certain number of reinoculations (passages). For the usual manufacturing process the working inoculum is prepared out of the main inoculum. Based on the requirements to safety and effectiveness during manufacture of finished products, which are obtained from the working inoculum, it is prohibited to use more passages from the main inoculum than for a vaccine that has undergone clinical trials. The origin and the number of passages of the main inoculum and the working inoculum are required to be documented;

main inoculum: a culture of microorganisms dispersed from one volume of the inoculum in a receptacle during one operation in a way so as to ensure homogeneity, prevent contamination and guarantee stability. The main inoculum in liquid state is generally stored at or below -70 °C, in lyophilized state – at a known temperature ensuring stability;

working inoculum: a culture of microorganisms obtained from the main inoculum and used in the manufacturing process. The working inoculum is dispersed in a receptacle and is stored in the conditions as described above for main inocula;

products: intermediate, bulk and finished products;

manufacturer: a manufacturer of medicines – a legal entity manufacturing medicines in accordance with requirements of Federal Law No. 61-FZ dated 12 April 2010 “On Circulation of Medicines” <*>;

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<*> Collection of Legislative Acts of the Russian Federation, 2010, No. 16, Art. 1815.

manufacture: activities conducted by medicine manufacturers for manufacture of medicines at one, several or all process stages, including storage and sales of manufactured medicines<*>, which include operations and control activities related to acceptance of materials, the manufacturing process, packaging, re-packaging, marking, re-marking, release, storage and sale of manufactured medicines and pharmaceutical substances;

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<*> Paragraph 31 Article 4 of Federal Law No. 61-FZ dated 12 April 2010 “On Circulation of Medicines” (Collection of Legislative Acts of the Russian Federation, 2010, No. 16, Art. 1815).

intermediate products: in-process starting raw materials subject to subsequent manufacturing stages before becoming bulk products. With respect to pharmaceutical substances – material that is obtained at stages of the pharmaceutical substance manufacturing process and undergoes further molecular transformations or is subject to purification before becoming a pharmaceutical substance. With respect to pharmaceutical substances, in the course of the manufacturing process intermediate products can be separated or remain unseparated;

procedure: a finalized description of operations to be carried out, precautions and activities directly or indirectly related to the manufacture of intermediate products, pharmaceutical substances or medicines;

herbal raw materials: fresh or dried plants or their parts, used for the manufacture of medicines by medicine manufacturers or for the manufacture of medicines by pharmacies, veterinary pharmacies, individual entrepreneurs holding pharmaceutical licenses <*>;

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<*> Paragraph 13 Article 4 of Federal Law No. 61-FZ dated 12 April 2010 “On Circulation of Medicines” (Collection of Legislative Acts of the Russian Federation, 2010, No. 16, Art. 1815).

batch (lot): a certain quantity of starting raw materials, packing materials or products, processed through one or several successive processes so as to expect homogeneity of products within a set range; in terms of the finished product control, a batch is a total of medicine units of dosage (pharmaceutical) form, which are manufactured from one volume of the starting material and have undergone the same sequence of manufacturing operations or the same sterilization cycle; in case of continuous manufacture – all units manufactured within a set time interval. For the completion of certain manufacturing stages, sometimes it is necessary to divide a batch into a certain number of sub-batches, which later on are joined to form the final homogeneous batch. For continuous manufacture, the term ‘batch’ should refer to a certain part of products characterized by homogeneity. In such case the batch size can be determined either as a fixed quantity or as a quantity manufactured within a certain time interval;

liquefied gases: gases stored in tanks in liquefied form at the standard temperature and filling pressure;

system: a combination of interrelated actions and technical facilities that form an integrated whole for the organization of manufacture and quality control of medicines;

cell bank system: a system implying that successive product batches are manufactured from cell cultures from the main cell bank fully defined for authenticity and absence of contaminations. A certain number of receptacles of the main cell bank is used for generating a working cell bank. The cell bank system is required to be validated for a certain number of passages or population duplications, prior to which they can be used in the on-going manufacturing process;

specification: a list of tests, references to analytical methods and acceptance criteria, which are index ranges, intervals, or other criteria for relevant tests. A specification defines a set of criteria, which a material should meet to be deemed as suitable for its intended use. ‘Compliant with the specification’ means that a material that has been tested according to the listed analytical methods meets the specified acceptance criteria;

sterility: absence of living organisms. Sterility control requirements are given in corresponding general pharmacopoeial monographs and/or normative documents;

manufacturing process: all operations connected with the manufacture of a medicine or a pharmaceutical substance, from acceptance of starting raw materials, including processing, packaging, and to release of finished products;

packaging: all operations, including pre-packing and marking, carried out with respect to bulk products to obtain finished products. Filling of sterile products is generally excluded from the process of packaging because products are dosed in primary packaging but are not finally packaged;

packing material: any material used for packaging of medicines, pharmaceutical substances or intermediate products, except for any shipping containers for storage, transportation or shipment. Packing materials are divided into primary and secondary, depending on whether or not there is direct contact with medicines;

authorized person: a medicine manufacturer’s officer, who has higher pharmaceutical, chemical or biological education, or, in case of manufacture of veterinary medicines, veterinary education, at least five years of work experience in the manufacture and quality control of medicines, and has been qualified according to the procedure established by the authorized federal executive authority <*>;

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<*> Part 7 Article 45 of Federal Law No. 61-FZ dated 12 April 2010 “On Circulation of Medicines” (Collection of Legislative Acts of the Russian Federation, 2010, No. 16, Art. 1815).

clean area: an area built and operated in a way so as to minimize penetration, generation and accumulation of contaminants in the form of particles and microorganisms. Clean area classes are defined in Attachment No. 1 hereto;

clean contained area: an area built and operated in a way so as to be used simultaneously as a clean and contained area;

exotic organism: a biological agent, which provokes a disease not observed in the given country or geographical area, or which is subject to preventive measures or a programme on its elimination in the given country or geographical area.

III. BASIC REQUIREMENTS TO THE ORGANIZATION OF MANUFACTURE AND QUALITY CONTROL OF MEDICINES (PART I <*>)

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<*> Here and elsewhere herein numbers in brackets are numbers of the structural text units according to GMP EC rules.

PHARMACEUTICAL QUALITY SYSTEM (CHAPTER 1)

Principle

5. The manufacturer shall manufacture medicines so as to guarantee their consistency with the intended purposes, compliance with requirements of the registration dossier or the clinical trial protocol and to exclude the risk associated with unsatisfactory safety, quality and efficacy. Responsibility for the compliance with these requirements shall be borne by the manufacturer’s management. Their compliance shall imply proper fulfilment of duties by the staff members from different units of the manufacturer at all levels as well as by suppliers and wholesalers of medicines. For these purposes, the manufacturer shall develop and ensure due functioning of a pharmaceutical quality system, which shall incorporate compliance with the requirements of these Rules and implementation of quality risk management. The manufacturer shall document the pharmaceutical quality system and monitor its efficiency. To ensure the functioning of all elements of the pharmaceutical quality system, the manufacturer shall see about providing qualified staff, appropriate premises, equipment and technical facilities. The main principles of managing the quality of the organization of manufacture and quality control and managing quality risks shall be inter-related.

Pharmaceutical quality system

6. (1.1) In a broad sense, quality management shall cover all aspects that influence, in whole or in particular, the quality of products and is understood to be a set of organizational measures aimed at assuring consistency of the quality of medicines with their intended purposes.

7. (1.2) These Rules shall apply to all stages of the life cycle of medicines: manufacture of medicines for clinical studies, technology transfer, commercial manufacture, and discontinuation of manufacture of medicines. The manufacturer may apply the pharmaceutical quality system to a stage of the life cycle of medicines such as pharmaceutical development, which promotes innovations and contributes to continuous improvement and strengthening of the link between pharmaceutical development and manufacture.

8. (1.3) When developing a new pharmaceutical quality system or when revising the existing system, it shall be required to take into account the scope and complexity of the manufacturer’s activity. Certain aspects of the pharmaceutical quality system may be applied to the manufacturer’s activity on the whole, others – only to particular production sites. The efficiency of the implementation of the pharmaceutical quality system is generally manifested at the production site level.

9. (1.4) The pharmaceutical quality system for manufacture of medicines shall guarantee:

a) (i) that release of medicines with appropriate quality indicators is ensured through development, planning, implementation, maintenance and continuous enhancement of the system;

b) (ii) that information about medicines and their manufacturing process is used throughout all life cycle stages;

c) (iii) that medicines are developed and studied subject to the requirements set forth herein;

d) (iv) that operations related to the manufacture and control have been established and comply with the requirements set forth herein;

e) (v) that responsibilities and duties of staff members are clearly defined;

f) (vi) implementation of measures ensuring manufacture, supply and use of proper starting raw materials and packing materials, and implementation of measures aimed at selection and control of suppliers and at verifying that each supply is made via an approved supply chain;

g) (vii) integration of processes ensuring control of activities delegated to another organization (outsourcing management);

h) (viii) establishment and maintenance of continuously monitored conditions by means of developing and using effective monitoring and control systems with respect to the process efficiency and medicine quality;

i) (ix) that the results of monitoring of medicines and processes are taken into account at the time of batch release, during investigations into deviations and for taking preventive measures to avoid potential deviations;

j) (x) due control of intermediate products, in-process control and validation;

k) (xi) continuous enhancement through introduction of improvements based on the actual knowledge about the process and products;

l) (xii) implementation of measures for a long-term evaluation of planned changes and their approval before implementation, subject to notification of and approval by the authorized federal executive authority, if and where necessary;

m) (xiii) on-going evaluation of made changes after their implementation for the purpose of confirming that the purpose of the changes has been attained and that it has not affected the product quality;

n) (xiv) that investigations into deviations, including versions suggesting defects in products and other problems, are based on an appropriate analysis of the main reasons for such inconsistencies. The reasons may be identified by using quality risk management principles. If it is impossible to identify the true reason for an inconsistency, it is required to determine the most probable reason. If such reason is suspected or established to be human error, it should be proven to guarantee that there are no process, procedural or system errors or problems. Appropriate corrective and (or) preventive measures shall be taken based on the results of the investigation. The efficiency of such measures shall be checked and assessed by the manufacturer in accordance with the quality risk management principles;

o) (xv) that it shall not be allowed to put medicines into civil circulation before the authorized person issues a release permit. The authorized person shall certify that each batch of medicines has been manufactured and controlled in accordance with the requirements of the registration dossier and these Rules;

p) (xvi) that taken measures assure the quality of medicines throughout their shelf-life during their storage and subsequent circulation;

q) (xvii) development of self-inspection and (or) quality audit procedures for the regular assessment of the efficiency and suitability of the pharmaceutical quality system.

10. (1.5) The management shall be responsible for having an effective pharmaceutical quality system and necessary resources as well as for making sure that duties, responsibilities and powers are defined, are brought to the knowledge of each staff member and are applied in all units of the manufacturer. The management shall be widely involved in the pharmaceutical quality system to guarantee that the staff members at all levels and in all units of the manufacturer contribute to the pharmaceutical quality system and are motivated to ensure its functioning.

11. (1.6) It shall be necessary to make periodic reviews of the functioning of the pharmaceutical quality system with the involvement of the management for purposes of continuous improvement of products, processes and the system itself.

12. (1.7) The pharmaceutical quality system shall be finalized. The manufacturer shall approve quality guidelines or a similar document describing the quality management system and defining, inter alia, responsibility of the management.

Organization of manufacture and quality control

of medicines

13. (1.8) Organization of manufacture and quality control of medicines shall be part of quality management ensuring that products are manufactured and controlled on a continuing basis according to the quality standards consistent with their intended purposes and in compliance with the requirements of the registration dossier, the clinical trial protocol and the specification for the given products.

14. The main requirements of these Rules:

a) (i) all manufacturing processes shall be regulated, systematically revised considering accumulated experience and verified for ensuring continuous manufacture of medicines of the required quality according to the specifications;

b) (ii) critical stages of the manufacturing process and major changes in the process shall be subject to validation;

c) (iii) to comply with the requirements set forth herein it shall be necessary to ensure appropriate conditions, including, inter alia:

duly trained staff of appropriate qualification;

appropriate areas and rooms;

appropriate equipment and maintenance;

appropriate starting raw materials and packing materials;

approved procedures and instructions in accordance with the pharmaceutical quality system;

appropriate storage and transportation conditions;

d) (iv) instructions and procedures shall be precise, uniquely and clearly defined in writing;

e) (v) staff members shall be duly trained to carry out procedures;

f) (vi) the manufacturing process shall be carried out being supported by records (hand-written and (or) with the use of technical means) providing documentary evidence of the actual completion of stages required in accordance with established methods and instructions and that the quantity and the quality of products correspond to established standard rates;

g) (vii) deviations shall be documented and investigated into for the purpose of identifying reasons for the deviations and taking corresponding corrective and preventive measures;

h) (viii) a batch dossier, including sales-related documents, shall allow tracking the full history of the batch manufacture, shall be intelligibly worded and kept at hand;

i) (ix) for purposes of sales of medicines, it shall be required to minimize all quality risks and take into account the Rules of Wholesale Trade of Medicines for Medical Application <*>;

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<*> Order of the Ministry of Healthcare and Social Development of the Russian Federation No. 1222n dated 28 December 2010 “On the Approval of the Rules of Wholesale Trade of Medicines for Medical Application” (registered with the Ministry of Justice of the Russian Federation on 4 February 2011, Registration No. 19698).

j) (x) it shall be required to arrange a system for withdrawing any batch of medicines from circulation;

k) (xi) it shall be obligatory to review claims with respect to the quality of sold medicines, to investigate into the reasons for defects and to take appropriate measures both with respect to low-quality medicines and for preventing similar situations.

Quality control

15. (1.9) Quality control shall include sampling, tests, checks for the compliance with requirements of the specifications, procedures for the organization, documenting and issue of release permits. Quality control shall be aimed at preventing the use or sale of materials or products that fail to meet the set requirements.

16. The main requirements to quality control:

a) (i) availability of appropriate rooms and equipment, trained staff and approved methods for sampling, control and testing of starting raw materials and packing materials, intermediate, bulk and finished products, and, where appropriate, for monitoring the conditions of the process environment in pursuance hereof;

b) (ii) samples of starting raw materials and packing materials, intermediate, bulk and finished products shall be taken by qualified staff in accordance with the methods approved by the quality control unit;

c) (iii) test procedures shall be validated;

d) (iv) it shall be obligatory to make records (hand-written and (or) with the use of technical means) to provide documentary evidence that all the necessary activities related to sampling, control and test procedures have really been conducted. All deviations shall be documented and investigated into;

e) (v) finished products shall contain pharmaceutical substances corresponding to the registration dossier by the qualitative and quantitative composition, shall be of the required purity, properly packaged and properly marked;

f) (vi) records made on the basis of the results of control and testing of starting raw materials and packing materials, intermediate, bulk and finished products, shall be compared with the requirements of the specifications. Evaluation of products shall include review and evaluation of corresponding manufacturing documents and analysis of deviations from established procedures;

g) (vii) no product batch shall be put into civil circulation before the authorized person certifies its compliance with the established requirements as per Attachment No. 16 hereto;

h) (viii) it shall be necessary to retain a sufficient quantity of control samples of starting raw materials, packing materials and finished products for the purpose of conducting, if and where necessary, tests in future as per Attachment No. 18 hereto. Samples of finished products shall be stored in the final packaging, except for samples of large volumes, weight or size.

Product quality review

17. (1.10) The manufacturer shall make regular reviews of the quality of all manufactured medicines, including pharmaceuticals manufactured for export only, for the purpose of confirming the constancy of the existing process, compliance with the effective specifications both for starting raw materials and for finished products, for the purpose of identifying tendencies and possibilities for improving products and the process. Such reviews shall be documented and shall be made, as a rule, on an annual basis, considering previous reviews.

18. Quality reviews shall include as minimum:

a) (i) a review of starting raw materials and packing materials used in the manufacturing process, especially those coming from new suppliers, and a separate review of the traceability of pharmaceutical substance supply chains;

b) (ii) a review of the critical control points in the manufacturing process and the results of control of finished products;

c) (iii) a review of all batches that failed to correspond to the established specifications and the results of corresponding investigations;

d) (iv) a review of all material deviations or inconsistencies, a review of investigations in this connection, the effectiveness and the efficiency of implemented corrective and preventive measures;

e) (v) a review of all changes made to the processes or analytical methods;

f) (vi) a review of suggested, approved or rejected changes to the registration dossier, and a review of changes to the dossier for medicines intended for export only;

g) (vii) a review of the results of the stability and adverse tendency monitoring programme;

h) (viii) a review of all returns, claims and withdrawals, related to the product quality, and investigations conducted in this connection;

i) (ix) a review of the adequacy of any previously implemented corrective measures with respect to the manufacturing process or equipment;

j) (x) a review of postmarketing commitments in case of receipt of new Marketing Authorizations or in case of changes made to the registration dossier;

k) (xi) the status of qualification of the corresponding equipment and technical facilities, for example, the heating, ventilation and air conditioning, water supply, liquefied gas supply systems;

l) (xii) a review of any contracts/agreements mentioned in Items 237255 hereof for the purpose of confirming their compliance with the effective requirements.

19. (1.11) Within the framework of the pharmaceutical quality system the manufacturer and the legal entity, in the name of which the Marketing Authorization has been issued (if such legal entity is not the manufacturer) shall analyse results of product quality reviews to decide whether or not it is necessary to implement corrective and preventive measures or to carry out re-validation. It shall be necessary to develop procedures for managing and analysing such measures; the efficiency of such procedures shall be checked during self-inspections.

20. Quality reviews may be grouped by product type (for example, solid dosage forms, liquid dosage forms, sterile medicines), if scientifically justified.

21. If the legal entity, in the name of which the Marketing Authorization has been issued, is not the manufacturer, such legal entity and the manufacturer shall conclude an agreement stipulating relevant obligations of the parties with respect to the preparation of quality reviews.

Quality risk management

22. (1.12) Quality risk management shall be a systematized process of assessing risks for the quality of medicines, their monitoring, transfer of information and preparation of reviews of such risks. This process may be run either on a perspective or retrospective basis.

23. (1.13) Quality risk management principles:

а) (i) assessment of quality risks shall be based on scientific knowledge, operational experience with respect to the process and shall be ultimately targeted at the patient protection;

b) (ii) the level of efforts, formalization and documenting of the quality risk management process shall correspond to the level of risk.

STAFF (CHAPTER 2)

Principle

24. Organization and functioning of a proper quality assurance system and proper medicine manufacture depend on the human factor. For this reason, in order to solve all the tasks the manufacturer is in charge of, the manufacturer shall have sufficient quantities of qualified staff. Each staff member shall know and understand his/her job duties, which shall be stipulated in documentary form. All staff members shall be acquainted with provisions of these Rules, related to their activities, and shall undergo primary and further continuous training, including hygiene briefing.

General requirements

25. (2.1) The manufacturer shall have sufficient quantities of staff possessing necessary qualifications and operational experience. The scope of job duties for each staff member shall not be too wide in order to exclude potential risks for the product quality.

26. (2.2) The manufacturer shall have a clearly-established organizational structure. Job duties of staff members holding positions of responsibility shall be stipulated in job descriptions. Such staff members shall be entitled to enjoy powers necessary for the fulfilment of their assigned functions. Their job duties may be delegated to other designated substitutes possessing appropriate qualifications. When determining job duties of its staff members, the manufacturer shall exclude unreasonable overlapping of duties and functions of its staff members and prevent situations where any duties related to fulfilment of the requirements set forth herein fail to be assigned to any staff member.

Designated staff

27. (2.3) The designated staff shall include the manufacture manager, the head of the quality control unit and the authorized person(s) if powers of such authorized person(s) are not assigned to the manufacture manager and (or) the head of the quality control unit. The designated staff shall generally work full-time. Manufacture managers and heads of quality control units shall be independent from one another. Large manufacturers may delegate part of the duties stipulated in Items 30 — 32 hereof to other staff members.

28. (2.4) Duties of the authorized person:

a) (a) the authorized person shall confirm that each batch of medicines produced in the Russian Federation has been manufactured and tested in accordance with the effective legislation of the Russian Federation and the requirements of the registration dossier;

b) (b) with respect to medicines released outside the Russian Federation, the authorized person shall confirm that each imported batch of products has been tested according to the procedure established in the Russian Federation;

c) (c) the authorized person shall confirm in documentary form that the manufacturing process has been run in accordance with these Rules and shall certify that before the issue of each release permit each batch of products has been manufactured and (or) tested in accordance with the requirements of the registration dossier.

29. Qualifications of the authorized person shall comply with the requirements established by the legislation of the Russian Federation. The authorized person shall be on the manufacturer’s staff. The authorized person’s duties may be delegated only to other authorized person(s).

30. (2.5) Main duties of the manufacture manager:

a) (i) to ensure the manufacturing process and storage of products in accordance with the approved documents for assuring the necessary quality;

b) (ii) to approve instructions concerning manufacturing operations and to ensure their accurate performance;

c) (iii) to ensure evaluation and signing of manufacturing records by duly authorized staff members before they are delivered to the quality control unit;

d) (iv) to monitor the work of the subordinate organizational unit, maintenance of premises, operation and technical maintenance of equipment;

e) (v) to ensure implementation of appropriate validation;

f) (vi) to ensure the conduct of the necessary primary and further continuous training of the staff from the subordinate organizational unit.

31. (2.6) Main duties of the head of the quality control unit:

a) (i) to approve or reject starting raw materials, packing materials, and also intermediate, bulk and finished products;

b) (ii) to evaluate batch dossiers;

c) (iii) to ensure the conduct of all necessary tests;

d) (iv) to approve specifications, sampling instructions, test methods and other quality control procedures;

e) (v) to approve and monitor contractors under contracts mentioned in Items 237 — 255 hereof (contract tests);

f) (vi) to monitor the work of the subordinate organizational unit, maintenance of premises, operation and technical maintenance of equipment;

g) (vii) to ensure implementation of appropriate validation;

h) (viii) to ensure the conduct of the necessary primary and further continuous training of the staff from the subordinate organizational unit.

32. (2.7) Manufacture managers and heads of quality control units shall have common or jointly performed quality-related duties, which shall include, inter alia:

approval of procedures and other documents, including introduction of amendments thereto;

process environment monitoring and control;

occupational health control;

process validation;

staff training;

approval and monitoring of suppliers of starting raw materials and packing materials;

approval and monitoring of contractors under contracts mentioned in Items 237 — 255 hereof (contract manufacturer);

determination and monitoring of the conditions of storage of starting raw materials and products;

record keeping;

monitoring of the compliance with the requirements set forth herein;

inspection, examination and sampling for purposes of monitoring factors that can influence the product quality.

Training

33. (2.8) The manufacturer shall provide for the training of the staff members whose job duties imply working in processing areas or control laboratories (including technicians, maintenance staff and cleaners) and also of other staff members whose work may influence the product quality.

34. (2.9) In addition to the basic training including theoretical and practical application of these Rules, newly employed staff members shall undergo the primary training according to their assigned duties. The manufacturer shall also conduct further continuous training of the staff by regularly evaluating its practical effectiveness. The staff training shall be conducted according to training programs approved by the manufacture manager or the head of the quality control unit, respectively. The manufacturer shall keep training-related documentation.

35. (2.10) Staff members working in the areas subjected to contamination, for example, in clean areas or in areas of operations with highly active, toxic, infecting or sensitizing substances shall undergo special training.

36. (2.11) Visitors or staff members, who have not undergone training, shall not be admitted to processing areas and quality control areas. In case of need to visit such areas, the specified persons shall be preliminarily briefed, in particular, for personal hygiene regulations and use of protective clothing. Such persons shall be subject to close supervision.

37. (2.12) Training shall comprise detailed explanations and discussions of the quality assurance principles as well as any and all measures facilitating their understanding and implementation.

Staff hygiene

38. (2.13) The manufacturer shall develop and implement a complex of occupational hygiene activities considering specifics of particular manufacturing processes. The said complex of activities shall incorporate procedures concerning the compliance with health requirements, sanitary regulations and requirements to staff clothes. Each staff member whose job duties imply staying in processing areas and quality control areas shall be aware of and strictly abide by such procedures. The managerial staff shall be responsible for the observance by staff members of the personal hygiene rules and for organization of the necessary training.

39. (2.14) Newly employed persons shall undergo medical examinations. The manufacturer shall approve instructions ensuring its awareness of the health conditions of the staff members, which may influence the product quality. The primary medical examination shall be followed by subsequent regular medical check-ups of staff members.

40. (2.15) The manufacturer shall take measures not to admit persons with infectious diseases or open injuries on open skin areas to the manufacture of medicines.

41. (2.16) Persons entering processing areas shall wear protective clothes, appropriate for operations performed in such areas.

42. (2.17) It shall be prohibited to take meals, drinks, chew or smoke, keep foodstuffs, beverages, tobacco products and personal medicines in processing areas and storage areas. It shall be prohibited to conduct in processing and other premises any activities that violate the established hygiene requirements and may affect the product quality.

43. (2.18) Staff members shall be required to avoid direct hand contact with open products as well as with any part of the equipment contacting products.

44. (2.19) Staff members shall undergo hand washing briefing.

45. (2.20) Special requirements to the hygiene of staff members involved in the manufacture of special product groups (for example, sterile medicines) shall be outlined in Attachment No. 1 and Attachment No. 5 hereto.

PREMISES AND EQUIPMENT (CHAPTER 3)

Principle

46. Premises and equipment shall be located, designed, constructed, equipped and operated in a way so as to ensure their consistency with performed operations. Their spatial arrangement and design shall minimize the risk of errors and allow effective cleaning and maintenance for the purpose of excluding cross contamination, dust accumulation and any factors adverse for the product quality.

Premises

General requirements

47. (3.1) Given observance of all process safety measures, environment in premises shall minimize the risk of contamination of materials or products.

48. (3.2) Operation, technical maintenance and repair of premises shall not affect the product quality. Premises shall be cleaned and disinfected according to detailed instructions approved by the manufacturer.

49. (3.3) Light fixtures, temperature, humidity and ventilation shall be consistent with the purpose of premises and shall have no direct or indirect adverse effect on medicines during their manufacture and storage and/or on the proper functioning of equipment.

50. (3.4) During design and operation premises shall be protected against penetration of insects or animals.

51. (3.5) Persons who have no right of access to premises shall not be admitted to premises. Processing areas, storage areas and quality control areas shall not be used for the walk-through of staff members who do not work in such areas.

Processing area

52. (3.6) In order to minimize the risks for human health due to cross contamination during manufacture of certain medicines such as sensitizing substances (for example, penicillins) or biological medicines (for example, from living microorganisms), it shall be required to provide specially designated separate premises, equipment and facilities for their maintenance. It shall be prohibited to use the same premises for manufacture of certain types of antibiotics, certain hormones, cytotoxins, highly potent medicines and products other than medicines. In exceptional cases such medicines shall be allowed to be manufactured in the same premises subject to production cycles with time sharing and given special precautions and appropriate validation.

53. It shall be prohibited to manufacture technical poisons such as pesticides and herbicides in premises used for manufacture of medicines.

54. (3.7) The spatial arrangement of premises shall ensure the compliance with the cleanness requirements and, where possible, shall be consistent with the logical sequence of manufacturing operations.

55. (3.8) The spatial arrangement of processing areas and in-process storage areas shall provide for consistent and logical location of equipment and materials by minimizing the risk of confusion of different medicines and their components, excluding cross contamination and minimizing the risk of skipping or improper performance of any stage during manufacture or control.

56. (3.9) In premises where starting raw materials and primary packing materials, intermediate or bulk products are exposed to the processing environment, inside surfaces (walls, floors and ceilings) shall be smooth, without cracks and splits at joints, shall not produce any fractions and shall be easily and effectively cleaned and, if and where necessary, disinfected.

57. (3.10) Pipelines, light fixtures, ventilation units and other maintenance systems shall be designed and arranged in a way so as to exclude cavities making it difficult to clean them. Where possible, access to the foregoing for maintenance purposes shall be from outside of processing areas.

58. (3.11) Points of connection to sewage effluents shall be of appropriate dimensions and shall be supplied with fixtures to prevent backflow. Where possible, it shall be recommended to avoid open discharge channels; should such appear to be necessary, they shall be shallow to facilitate cleaning and disinfection.

59. (3.12) Processing areas shall be equipped with an effective ventilation system supplied with fixtures to control air parameters (including temperature and, where appropriate, humidity and filtration), depending on the type of released products, performed operations and environment.

60. (3.13) Starting raw materials shall be generally weighed in separate premises specially designated for this purpose.

61. (3.14) In case of dust accumulation (for example, during sampling, weighing, mixing, process operations, packaging of dry products) it shall be required to take special precautions to prevent cross contamination and facilitate cleaning.

62. (3.15) Premises for packaging of medicines shall be specially designed and arranged in a way so as to prevent confusion or cross contamination.

63. (3.16) Processing areas shall be well lighted, especially in sections subject to continuous visual control.

64. (3.17) In-process control may be conducted in the processing area provided that it creates no risks for the manufacturing process.

Storage areas

65. (3.18) Storage areas shall have storage capacity sufficient for storing various categories of materials and products: starting raw materials and packing materials, intermediate, bulk and finished products, products under quarantine, products permitted for release, rejected, returned or withdrawn products.

66. (3.19) When designing and equipping storage areas, it shall be necessary to provide proper storage conditions. Storage areas shall be clean and dry, with a required temperature maintained in them. In case of need for special storage conditions (for example, temperature, humidity), such conditions shall be created, checked and monitored.

67. (3.20) In places of acceptance and shipment starting raw materials, packing materials and products shall be protected from the weather effect. Acceptance areas shall be designed and equipped in a way so that containers with the coming starting raw materials and packing materials could be cleaned before storing.

68. (3.21) In cases where products under quarantine are stored in separate areas, such areas shall be clearly marked and access to such areas shall be allowed only to those staff members who have appropriate powers. Any other system replacing physical quarantine shall ensure equal safety.

69. (3.22) Samples of starting raw materials and primary packing materials shall be generally taken in a separate area. Sampling carried out in a storage area shall be carried out in a way so as to prevent contamination or cross contamination.

70. (3.23) Isolated areas shall be arranged for storage of rejected, withdrawn or returned starting raw materials, packing materials or products.

71. (3.24) Highly potent substances and medicines subject to special storage conditions in accordance with regulatory legal acts of the Russian Federation shall be stored in safe and protected areas.

72. (3.25) It shall be necessary to provide safe and secure storage of printed packing materials as such are deemed as critical for ensuring compliance of medicines with the established requirements.

Quality control areas

73. (3.26) Quality control laboratories shall be separated from processing areas. This is especially important for laboratories for control of biological and microbiological medicines and radioisotopes — they shall be also separated from one another.

74. (3.27) Control laboratories shall be designed in a way so as to comply with the requirements to operations performed in them. Laboratories shall occupy areas sufficient to exclude confusion and cross contamination and to store samples and records.

75. (3.28) Separate rooms shall be provided for sensitive instruments that need to be protected against vibration, electromagnetic fields, atmospheric humidity and other exposures.

76. (3.29) If regulatory legal acts of the Russian Federation envisage special requirements to laboratories used for handling specific substances, for example, biological or radioactive materials, such requirements shall be binding.

Auxiliary areas

77. (3.30) Rooms for recreation and meals shall be separated from other areas.

78. (3.31) Changing rooms, toilet rooms and show cubicles shall be easily accessible; their layout and dimensions shall correspond to the staff size. Toilet rooms shall not be directly inter-connected with processing or storage areas.

79. (3.32) Workshops shall be separated, if and where possible, from processing areas. If spare parts and instruments are stored in a processing area, they shall be kept in specially designated rooms or lockers.

80. (3.33) Animal facilities shall be isolated from other areas, shall be supplied with separate entrances (access to animals) and individual air handling systems.

Equipment

81. (3.34) The design, assembly and technical maintenance of manufacturing equipment shall correspond to its intended purpose.

82. (3.35) Works related to repair and technical maintenance of equipment shall not affect the product quality.

83. (3.36) The design of manufacturing equipment shall facilitate its thorough cleaning. Cleaning shall be made according to detailed instructions approved by the manufacturer. Equipment shall be kept clean and dry.

84. (3.37) Implements and accessories for cleaning and decontamination shall not provoke contamination.

85. (3.38) Equipment shall be installed in a way so as to prevent any risk of errors or contamination.

86. (3.39) Manufacturing equipment shall not affect the quality of or threaten products. Parts of manufacturing equipment that come into contact with products shall not provoke any chemical reactions, produce or absorb substances affecting the product quality.

87. (3.40) The accuracy and the operating range of balances and other instruments of measurement shall be consistent with the manufacturing and control operations, in which they are used.

88. (3.41) Balances and other instruments of measurement, recording and control devices shall be calibrated and adjusted at certain time intervals by using appropriate methods. Results of the calibration and adjustment shall be documented and kept.

89. (3.42) Permanent pipelines shall bear marking indicating substances that flow through them and, if appropriate, flow directions.

90. (3.43) Pipelines for purified water, water for injections (distilled, deionized) and, if and where necessary, pipelines for other water shall be subject to sanitary treatment according to instructions approved by the manufacturer, which shall indicate microbial contamination limits and measures to be taken if such limits are exceeded.

91. (3.44) Faulty equipment shall be removed from the processing area and the quality control area or, at least, clearly marked as faulty.

DOCUMENTATION (CHAPTER 4)

Principle

92. Documentation shall constitute an integral part of the pharmaceutical quality system and shall be a key element in the organization of manufacture and quality control of products in accordance with these Rules. The manufacturer’s quality management system shall clearly define different types of used documents and data media. Documentation may exist in various forms, including in hard copy, soft copy or on other media. The main purpose of the applied documentation system shall be creation, management, control and registration of all activities that may directly or indirectly influence all aspects of the quality of medicines. The quality management system shall contain sufficiently detailed instructions for ensuring due documentation of various processes and evaluation of any observations. Such instructions shall facilitate the general understanding of requirements for demonstrating their observance.

93. Documents shall be divided into two main groups: documents for the compliance with the requirements set forth herein, i.e. regulatory documents, and documents for the registration of their compliance, i.e. registration documents. The manufacturer shall ensure due preparation of such documents, depending on the document type.

94. The manufacturer shall carry out control activities for the purpose of ensuring the accuracy, integrity, availability and coherence of documents. Regulatory documents shall be accessible, i.e. recorded or otherwise fixed on data media, from which data may be obtained in a legible form, and shall not contain errors.

Document types

95. The master dossier of a production site shall be a document describing the organization of manufacture and quality control of medicines in accordance with the requirements of these Rules.

96. A batch dossier shall be a document describing the process of manufacture of each product batch, including issue of a permit for its release, and all factors influencing the quality of finished products.

97. Regulatory documents shall include:

specifications – documents containing detailed requirements to starting raw materials, packing materials and products used or obtained during the manufacturing process. They shall form the basis for the assessment of the quality of medicines;

process description, process instructions, including packaging instructions, test procedures – documents containing detailed information about all used starting raw materials, equipment and computerized systems (if any), including all instructions on manufacturing processes, packaging, sampling and testing. Where applicable, it shall be required to indicate all control points in the manufacturing process and the applied process analytical technologies with acceptance criteria;

procedures (may be also referred to as instructions or standard operating procedures (hereinafter – SOP)) – documents containing instructions for performing certain operations;

protocols (plans) – documents containing instructions for performing and registering individual operations (for example, validation protocol, validation master plan);

contracts – agreements concluded between customers and contractors for works performed by outside organizations (outsourcing).

98. Registration documents (records and (or) reports) shall include:

records – documents fixing the completion of various activities for evidencing their compliance with instructions, for example, events, incidents, investigations. With respect to a batch, records shall contain the history of each product batch, including its sale. Records shall contain source data used for generation of other records. If records are kept in electronic format, software users in charge of keeping such records shall identify which data should be used as source ones. As minimum, all data on the basis of which quality-related decisions are made shall be used as source data;

documents certifying quality (certificates, worksheets and other similar documents) – documents summarizing the results of tests of samples of products or starting raw materials and packing materials and assessing the compliance with the established specification. If a process analytical technology (PAT) is used during the manufacture of a batch, assessment of the compliance of the batch with the requirements of the registration dossier may be based (in full or in part) on an analysis of data, parameters and results obtained on a real-time basis (summaries and deviation reports);

reports – documents accompanying the accomplishment of specific tasks, projects or investigations and containing results, conclusions and recommendations.

Preparation and control of documents

99. (4.1) The manufacturer shall develop all types of documents and ensure their observance. Requirements shall be equally applied to all types of data media. A comprehensive system shall be intelligible, duly documented and validated, with established adequate control. Certain documents (instructions and (or) records) may be mixed in their format when one part of a document exists in soft copy while the other part is in hard copy. Cross links and control measures with respect to the originals of documents, accounting copies, data processing and records shall be clearly stated for all documentation systems, either mixed or homogeneous in form. Accounting of copies shall be maintained in a manner determined by the manufacturer. It shall be required to introduce appropriate control activities with respect to electronic documents such as templates, forms and source documents. Appropriate control activities shall be carried out for ensuring the integrity of records during their period of storage.

100. (4.2) It shall be required to establish procedures for the development, execution, issue and withdrawal of documents and for the introduction of amendments thereto. Documents shall comply with the requirements of the registration dossier and conform to documents submitted for obtaining a license for the manufacture of medicines. Reproduction of original documents for obtaining accounting copies shall not lead to any errors during copying.

101. (4.3) Regulatory documents shall be approved and signed by persons granted the signing authority and shall be dated. Contents of documents shall be non-ambiguous. It shall be necessary to provide unique identification of documents and set document validity terms.

102. (4.4) Regulatory documents shall be logically structured to facilitate their inspection. The style of presentation of information in documents shall correspond to their intended purpose.

103. (4.5) Documents shall be regularly revised and updated; the use of outdated versions shall be discontinued.

104. (4.6) It shall not be recommended to maintain documents in hand-written form. If a document suggests introduction of hand-written records, there should be enough space for such records.

Due documentation rules

105. (4.7) Hand-written records shall be made in a clear and legible form so that recorded data cannot be deleted.

106. (4.8) Records shall be kept for each operation, in a way so as to trace all relevant activities related to the manufacture of medicines.

107. (4.9) Any change made to a document shall be signed and dated. Changes shall be made in a way so as to allow reading the original data. Where applicable, it shall be necessary to specify the cause of the change.

Storage of documents

108. (4.10) It shall be required to clearly define which records are related to a certain type of manufacturing activities and where they are stored. It shall be necessary to envisage control measures to ensure the integrity of records throughout the period of their storage. If and where necessary, such measures shall be validated.

109. (4.11) Special requirements shall be set to batch-related documents, which shall be kept during one year upon the expiration of the shelf life of the batch or during at least five years upon assessment by the authorized person of the compliance of the batch (whichever is longer). For medicines intended for clinical studies, batch-related documents shall be kept during at least five years upon termination or discontinuation of the clinical studies, in which the batch has been used.

110. (4.12) The period of storage for other types of documents shall depend on the types of the activities supported by such documents. Critical documents, including source data (for example, concerning validation or stability), which support data in the registration dossier, shall be kept throughout the validity term of the Marketing Authorization. It shall be allowed to destroy certain documents (for example, source data, accompanying validation or stability reports) if data have been replaced with a full package of new data. Reasons for such actions shall be documented. It shall be necessary to consider the requirements to storing batch-related documents, for example, with respect to process validation data accompanying source data it shall be necessary to keep the data at least as long as documents for all batches, for which the release permit is supported by the data of such validation studies.

Specifications

111. (4.13) The manufacturer shall have duly approved specifications for starting raw materials, packing materials and finished products, with an indication of the approval date.

Specifications for starting raw materials and packing materials

112. (4.14) Specifications for starting raw materials and packing materials shall contain the following information (or appropriate references, where applicable):

a) (a) a description of starting raw materials or packing materials, including:

name and internal code (where necessary);

reference to a pharmacopoeial monograph and/or normative document;

names of approved suppliers and the manufacturer of starting raw materials or packing materials;

sample of printed materials;

b) (b) sampling and testing instructions;

c) (c) qualitative and quantitative characteristics with specification of thresholds;

d) (d) storage conditions and precautions;

e) (e) shelf life.

Specifications for intermediate and bulk products

113. (4.15) Specifications for intermediate and bulk products shall be available at the time of acquisition or shipment of products and when using data on intermediate products during the assessment of the quality of finished products. These specifications shall be identical to the specifications either for starting raw materials or finished products, respectively.

Specifications for finished products

114. (4.16) Specifications for finished products shall contain the following information:

a) (a) medicine name and code (where necessary);

b) (b) composition of the medicine or a reference to a corresponding pharmacopoeial monograph and/or normative document;

c) (c) description of the pharmaceutical form and detailed information about packaging;

d) (d) sampling and testing instructions;

e) (e) qualitative and quantitative characteristics with specification of thresholds;

f) (f) storage conditions and precautions during usage (where applicable);

g) (g) shelf life.

Process description and process instructions

115. It shall be required to have a process description approved by the chief officer of the medicine manufacturer and process instructions for each manufactured medicine and each batch volume.

116. (4.17) The process description shall contain a list of the pharmaceutical substances and excipients, used quantities of each of them, data on the equipment used, descriptions of the manufacturing process and control methods at all stages of the manufacture of medicines. General requirements to the structure and other requirements to the contents of process descriptions shall be stipulated by corresponding regulatory legal acts of the Russian Federation.

117. (4.18) Process instructions shall contain:

a) (a) data on the site of the process and the primary equipment required to be used;

b) (b) methods or references to methods that are used for preparation of the manufacturing equipment (for example, cleaning, assembly, calibration, sterilization);

c) (c) instructions for verifying that equipment and workstations are clear from previous products, documents and materials unnecessary for the planned process, and instructions for inspecting the cleanness of equipment and its preparedness for the next process;

d) (d) a detailed description of each operation (for example, inspection of materials, preprocessing, raw materials charging, critical process parameters (time, temperature));

e) (e) instructions for in-process control types with permissible limits of controlled parameters;

f) (f) requirements to the storage of bulk products, including containers, labelling and special storage conditions where required;

g) (g) special precautions.

Packaging instructions

118. (4.19) For each medicine, package size and type it shall be required to have approved packaging instructions, which shall contain the following data (or references to the following data):

a) (a) medicine name, including the number of the batch of bulk products and finished products;

b) (b) a description of the pharmaceutical form and dosage (where applicable);

c) (c) quantity of the medicine in the final packaging, in pieces, weight or volume units;

d) (d) a full list of all necessary packing materials, including their quantity, dimensions and types, with the code or number related to specifications for each packing material;

e) (e) where applicable, a sample or a copy of appropriate printed packing materials and samples indicating the place of the application of the batch number and product shelf life;

f) (f) instructions for checking that the used equipment and workstations have been cleared from previous products, documents or materials unnecessary for performing planned packaging operations (line purity) and that the equipment is clean and prepared for use;

g) (g) precautions, including thorough inspection of the packaging area and equipment, to guarantee that the packaging line has been cleaned before operations;

h) (h) a description of the packaging process, including all important auxiliary operations and equipment used;

i) (i) a description of the in-process control with sampling instructions and thresholds.

Batch dossier

119. A batch dossier shall contain records on the batch manufacture, records on the batch packaging, other documents confirming that the batch has been manufactured in accordance with these Rules and documents for the sale of the batch.

Batch manufacture records

120. (4.20) For each manufactured batch it shall be required to keep batch manufacture records, which shall be based on process descriptions and process instructions and shall contain the following information:

a) (a) name and number of the product batch;

b) (b) dates and time of the commencement and termination of the manufacturing process and the main intermediate stages;

c) (c) initials and last name(s) of the operator(s) of each main manufacturing operation and, if and where necessary, of the person who checked each of such operations;

d) (d) batch number and (or) analytical control number, and the actually weighed quantity of starting raw materials of each type (including the batch number and the quantity of any added regenerated or reprocessed raw materials);

e) (e) main manufacturing operations or actions and the primary equipment used;

f) (f) in-process control records, executors and obtained results;

g) (g) output at different manufacturing stages;

h) (h) a description of deviations from the process description and process instructions, dated and signed by the authorized person;

i) (i) signature of the person in charge of the manufacturing process, with the date stated.

121. Product batch manufacture records shall be made at the time a corresponding operation is run.

122. If the validated process is subject to continuous monitoring and control, automatically generated reports may be limited to a general compliance report and reports on deviations and (or) departures from the specification.

Batch packaging records

123. (4.21) For each manufacture batch or part of a batch it shall be required to keep batch packaging records. Such records shall be based on corresponding sections of packaging instructions.

124. Batch packaging records shall contain the following data:

a) (a) name and number of the medicine batch;

b) (b) date(s) and time of packaging operations;

c) (c) initials and last name(s) of the operator(s) of each main manufacturing operation and, if and where necessary, of the person who has checked each of such operations;

d) (d) records on the inspection of identify and compliance with packaging instructions, including results of the in-process control;

e) (e) information about performed packaging operations, including references to equipment and packaging lines used;

f) (f) samples of the used printed packing material, including samples with a marked batch number, shelf life and other supplementary identification data;

g) (g) a description of deviations from packaging instructions, dated and signed by the authorized person;

h) (h) the quantity and a reference to the number or name of all printed packing materials and bulk products, released, used, destroyed or returned to the warehouse, and the quantity of finished products for the preparation of the material balance. Such data may be omitted if there is electronic control during packaging;

i) (i) signature of the person in charge of the packaging process, with the date stated.

Procedures and records

Acceptance

125. (4.22) The manufacturer shall have approved procedures and supporting records for acceptance of each supply of every type of starting raw materials (including bulk, intermediate or finished products) and also of the primary, secondary and printed packing materials.

126. (4.23) Acceptance records shall contain:

a) (a) material name in the waybill and on the container;

b) (b) factory name (if the factory name is different from the name as per ‘a’ of this item) and (or) material code (where necessary);

c) (c) acceptance date;

d) (d) supplier and manufacturer;

e) (e) the manufacturer’s batch number;

f) (f) the total quantity of received materials and the number of package units;

g) (g) the batch number assigned upon acceptance, where applicable;

h) (h) any substantive comments.

127. (4.24) The manufacturer shall approve procedures for the factory labelling, quarantine and storage of starting raw materials, packing and, if and where necessary, other materials.

Sampling

128. (4.25) The manufacturer shall approve sampling procedures describing methods and equipment used, quantities to be sampled and any precautions to be taken for avoiding contamination of materials or any deterioration of their quality.

Testing

129. (4.26) The manufacturer shall approve procedures for testing starting raw materials, packing materials and products at various manufacturing stages by describing methods and equipment used. Completed tests shall be documented.

Other operations

130. (4.27) The manufacturer shall approve procedures for the release and rejection of raw materials and products, specifically, for the issue by the authorized person(s) of finished product release permits. All records shall be available to the authorized person. It shall be required to introduce a system for describing special observations and any changes with respect to critical data.

131. (4.28) The manufacturer shall maintain and keep records on sales of each product batch for facilitating withdrawals of batches if necessary.

132. (4.29) It shall be required to have written finalized principles, procedures, plans, reports and related records with respect to undertaken actions or made conclusions, where applicable, regarding:

validation and qualification of processes, equipment and systems;

assembly and calibration of equipment;

technology transfer;

technical maintenance, cleaning and disinfection;

staff, including signature identification, familiarization with these Rules, technical training, changing and hygiene regulations, and training efficiency monitoring;

activities aimed at monitoring the appearance and spread of parasites;

claims;

withdrawals of products;

returns of products;

control of changes;

investigations of deviations and inconsistencies;

internal quality audit and (or) compliance with requirements of these Rules;

generalization of records (for example, product quality review), if and where necessary;

evaluation made, inter alia, at the place of the supplier’s activities (hereinafter – the supplier evaluation).

133. (4.30) The manufacturer shall approve clear instructions for operation of main units of the manufacturing and control and analytical equipment.

134. (4.31) The manufacturer shall keep logbooks with respect to the most crucial or critical manufacturing and control and analytical equipment and with respect to premises wherein products have been manufactured. Such logbooks shall be used for the chronological registration of any use of such premises, equipment and methods, calibration works, technical maintenance, cleaning or repair, with specification of dates and persons in charge.

(4.32) The manufacturer shall maintain documentation accounting as part of the quality management system.

MANUFACTURE (CHAPTER 5)

Principle

135. Manufacturing operations shall be carried out according to clearly defined procedures, shall comply with these Rules for obtaining output of the required quality and conform to the license for the manufacture of medicines and the registration dossier.

General requirements

136. (5.1) The manufacturing process shall be run and controlled with the employment of qualified staff.

137. (5.2) All operations performed with starting raw materials, packing materials and products, such as acceptance, quarantine, sampling, storage, labelling, release to production, manufacturing process, packaging and sales, shall be carried out according to procedures or instructions approved by the manufacturer and shall be documented.

138. (5.3) All received starting raw materials and packing materials shall be inspected in order to ensure that supplies conform to the order. Package items shall be cleaned (if and where necessary) and supplied with labels containing required data.

139. (5.4) Events of damage to containers and packaging and any other problems that may affect the quality of starting raw materials and packing materials shall be subject to investigation and documentation and shall be reported to the quality control unit.

140. (5.5) Received starting raw materials, packing materials and manufactured finished products shall be immediately put under quarantine, subject to separate storage or organizational measures, and shall remain under quarantine until obtaining of a permit for use of starting raw materials or a permit for release of finished products.

141. (5.6) Acceptance of purchased intermediate and bulk products shall be carried out according to the rules applicable to starting raw materials.

142. (5.7) All starting raw materials, packing materials and products shall be stored in appropriate conditions designated by the manufacturer, subject to a certain procedure implying separation by batches and established priority of the use of stock reserves.

143. (5.8) The manufacturer shall verify outputs and the material balance to make sure that there are no deviations exceeding permissible limits.

144. (5.9) Simultaneous or consecutive operations with different products in the same premises shall be prohibited except where there is no risk of confusion or cross contamination.

145. (5.10) Products, starting raw materials and packing materials shall be protected against microbial and other contamination at all manufacturing stages.

146. (5.11) Dry materials and products shall be handled given special precautions for preventing dust generation and dispersal. This condition shall be especially important for handling highly potent and sensitizing substances.

147. (5.12) Throughout the manufacturing process all used starting raw materials, packing materials, containers for bulk products, main equipment units and, where appropriate, premises shall be marked with labels or otherwise for identification of the manufactured products or processed starting raw materials and packing materials, dosage (where applicable) and product batch numbers. Such labelling shall also indicate the manufacturing process stage (where applicable).

148. (5.13) Labels attached to containers, equipment or premises shall be legible and unambiguous and correspond to the form established by the manufacturer. In addition to the label data, for status identification purposes it shall be recommended to use colour marking.

149. (5.14) The manufacturer shall control the accuracy of connections of pipelines and other parts of the equipment used for transportation of products from one area to another.

150. (5.15) Any deviations from instructions or procedures shall be prohibited. Should a deviation be allowed, such deviation is required to be authorized by a person granted appropriate powers, with the involvement, where necessary, of the quality control unit.

151. (5.16) Only those staff members who are allowed access to processing areas shall be admitted to processing areas.

152. (5.17) Premises and equipment intended for the manufacture of medicines may not be used for the manufacture of products other than medicines.

Prevention of cross contamination during manufacture

153. (5.18) Contamination of starting raw materials or products with other starting raw materials or products shall be excluded. The risk of accidental cross contamination results from uncontrolled dispersion of dust, gases, vapours, aerosols or microorganisms, from processing of starting raw materials and products, due to residues remaining on equipment and clothes of the staff. The level of risk shall depend on the type of contaminants and contaminated products. The most dangerous contaminants include substances of high sensitizing power, biological medicines containing living microorganisms, certain hormones, cytotoxic medicines and other highly potent substances. The most dangerous contamination is contamination of medicines intended for injections and of medicines administered in high doses and (or) during continuous periods of time.

154. (5.19) For the purposes of preventing cross contamination it shall be required to envisage appropriate technical and (or) organizational measures, including:

a) (a) implementation of the manufacturing process in designated areas (it shall be mandatory for products such as penicillins, live vaccines, medicines containing living microorganisms and some other biological medicines) or implementation of the manufacturing process on a manufacturing cycle basis (time-sharing sessions) subject to subsequent appropriate decontamination;

b) (b) provision of air chambers and exhaust systems;

c) (c) minimization of the risk of contamination caused by recirculation or repeated flow of non-treated or insufficiently treated air;

d) (d) storage of protective clothing inside the premises used for the processing of products provoking extremely high risks of cross contamination;

e) (e) usage of cleaning and decontamination methods with known effectiveness as ineffectively cleaned equipment usually provokes cross contamination;

f) (f) usage of “closed” manufacturing systems;

g) (g) control over residues and usage of labels indicating the equipment cleanout status.

155. (5.20) The manufacturer shall regularly check the implementation of activities aimed at preventing cross contamination and their effectiveness, according to approved procedures.

Validation

156. (5.21) Validation activities shall form the basis for the due organization of manufacture and quality control of medicines in accordance with these Rules. Such activities shall be carried out according to established procedures. Obtained results and conclusions shall be documented.

157. (5.22) In case of introduction of a new process description or a new manufacture method, it shall be necessary to prove their suitability for batch manufacturing. It shall be proved that the given manufacturing process with the use of prescribed starting raw materials, packing materials and equipment allows continuous manufacture of products of the required quality.

158. (5.23) Material changes in the manufacturing process, including any changes in equipment or starting raw materials and packing materials, which may influence the product quality and (or) the process repeatability, shall be subject to validation.

159. (5.24) Processes and procedures shall be subject to periodic re-validation to ensure that processes and procedures remain suitable for achieving planned targets.

Starting raw materials

160. (5.25) Purchase of starting raw materials shall be an important operation to be performed with the involvement of staff members possessing detailed and complete information about suppliers.

161. (5.26) Starting raw materials shall be purchased only from approved suppliers specified in a corresponding specification and, if and where possible, directly from manufacturers of starting raw materials, which shall be suppliers of starting raw materials. It shall be recommended to have specifications established by the medicine manufacturer for starting raw materials agreed with suppliers. All aspects related to the manufacture and control of starting raw materials as regards handling, labelling, packaging, rejection and claims consideration requirements shall be agreed between the medicine manufacturer and the supplier.

162. (5.27) Each supply shall be checked for the integrity of packaging and seals, consistency of the data specified in the waybill with the data indicated on the supplier’s labels.

163. (5.28) If a supply of starting raw materials comprises different batches, each batch shall be regarded as a separate batch for purposes of sampling, testing and issue of permits for use.

164. (5.29) The starting raw materials stored in the storage area shall be appropriately labelled (Item 148 hereof). Labels shall contain, inter alia:

the product name and, where necessary, the factory code;

the manufacturer’s batch number and (or) the batch number assigned during acceptance;

where applicable, the status of contents (for example, ‘under quarantine’, ‘under test’, ‘authorized’, ‘rejected’);

the expiration date or, where applicable, the date after which re-verification is required.

If fully computerized storage systems are used, it shall not be obligatory to indicate all these data on labels.

165. (5.30) The manufacturer shall approve procedures or measures ensuring the authenticity of contents of each container with starting raw materials. Containers from which samples have been taken shall be labelled (Item 216 hereof).

166. (5.31) The manufacturer shall use only those starting raw materials that have been approved by the quality control unit and have not expired.

167. (5.32) Starting raw materials shall be issued solely to specially designated persons according to an approved procedure in order to make sure that appropriate starting raw materials have been accurately weighed or measured in clean and duly labelled containers.

168. (5.33) All issued starting raw materials, their weights and volumes shall be subject to independent inspections. Inspection results shall be documented.

169. (5.34) Starting raw materials issued for each batch shall be stored together and clearly labelled.

Manufacturing operations: intermediate and bulk products

170. (5.35) Before running any manufacturing operation, it shall be required to take measures ensuring that the working area and equipment have been cleaned and cleared from any starting raw materials, products, residues of products or documents not related to the planned operation.

171. (5.36) Intermediate and bulk products shall be stored in proper conditions.

172. (5.37) Critical processes shall be subject to validation (Items 156 — 159 hereof).

173. (5.38) All necessary in-process and process environment control activities shall be carried out and documented.

174. (5.39) Any material deviation from the expected product output shall be documented and investigated.

Packing materials

175. (5.40) Equal priority shall be given to purchase, control and handling of primary and printed packing materials and starting raw materials.

176. (5.41) Special attention shall be given to printed materials. They shall be stored in safe conditions excluding access of unauthorized persons. Split labels and fragmented printed materials shall be stored and transported separately, in closed containers, so as to exclude their confusion. A permit to use packing materials shall be issued only to specially designated persons according to an approved procedure.

177. (5.42) An identification number or identification mark shall be assigned to each supply or batch of primary or printed packing materials.

178. (5.43) Expired or unusable printed or primary packing materials shall be destroyed and such destruction shall be documented.

Packaging operations

179. (5.44) Packaging operations plans shall be made by prioritizing the minimization of the risk of cross contamination, confusion or substitution. It shall not be allowed to package different types of products in the immediate vicinity of one another, except in cases where physical separation is required.

180. (5.45) Before commencing packaging operations, it shall be required to take measures ensuring that the working area, packaging lines, printing machines and other equipment are clean and clear from any previously used medicines, packing materials or documents unless such are needed for the planned operation. The line shall be cleaned according to an approved procedure.

181. (5.46) The name and the number of the batch of products being packaged shall be indicated on each package or line.

182. (5.47) Upon receipt of products and packing materials in the packaging area, it shall be necessary to check their quantity, identify and conformity to the packaging instructions.

183. (5.48) Primary packaging materials shall be cleaned before the filling operation. Any contamination, such as glass fragments and metallic particles, shall be prevented and removed.

184. (5.49) Labelling shall be recommended to be made as soon as possible after pre-packaging and capping. It shall be necessary to take appropriate measures excluding confusion or wrong labelling.

185. (5.50) The accuracy of any printing operations (for example, application of batch numbers, expiration dates) run either as individual manufacturing operations or as operations making part of the packaging process shall be subject to thorough control and documentation. Special attention shall be paid to manual labelling, which shall be subject to regular revalidation.

186. (5.51) Special precautions shall be observed when using split labels and applying marking outside the packaging line. For avoiding confusion of printed materials, it shall be recommended to use roll labels instead of split ones.

187. (5.52) The manufacturer shall make inspections to guarantee proper functioning of all electronic code readers, label counters and similar devices.

188. (5.53) Labels applied to packing materials by means of printing or embossing shall be legible and resistant to discolouring or erasure.

189. (5.54) The control of the process of the product packaging in the line shall aim at checking, inter alia:

a) (a) the general design of packaging;

b) (b) the package completeness;

c) (c) the use of appropriate types of products and packing materials;

d) (d) the accuracy of the application of any labelling;

e) (e) the proper functioning of control devices in the line.

190. Samples from the packaging line shall not be required to be returned to the line.

191. (5.55) In case of unexpected situations during product packaging, the products may be put back to the manufacturing process only after a special inspection, an investigation and with the authorization of the person granted corresponding powers. The foregoing shall be documented in the form of a protocol to be duly kept.

192. (5.56) In case of material or unusual discrepancies between the quantity of bulk products, printed packing material and the quantity of manufactured items of finished products, revealed during the preparation of the material balance, it shall be necessary to carry out an investigation to identify the reason for such discrepancies before the issue of the release permit.

193. (5.57) Upon completion of packaging operations, any remaining packing materials with an applied batch number shall be destroyed and such destruction shall be documented. Unlabelled packing materials shall be returned to the warehouse according to an approved procedure.

Finished products

194. (5.58) Until the issue of the release permit, finished products shall be kept in quarantine, in the conditions set by the manufacturer.

195. (5.59) Before the issue of the release permit, it shall be necessary to assess the quality of finished products and appropriate documents according to the procedure set out in Items 202 — 236 hereof.

196. (5.60) After the issue of the release permit, finished products shall be stored as marketable products, in the conditions set by the manufacturer.

Rejected, re-used and returned materials and products

197. (5.61) Rejected materials and products shall bear clear labelling and shall be separately stored in restricted access areas. They shall be subject to be returned to the supplier, to re-processing (if allowed) or to destruction. Any actions undertaken shall be documented and authorized by persons granted appropriate powers.

198. (5.62) Reprocessing of rejected products shall be allowed in exceptional cases provided that the quality of finished products is not affected and all requirements of the specifications are fulfilled. Reprocessing shall be carried out according to an approved process description after the assessment of the potential risk, subject to further documentation.

199. (5.63) Re-use of a whole batch or part of previously manufactured batches of a corresponding quality through joining them to a batch of the same products at a certain manufacturing stage envisaged by the process description shall be authorized in advance, on the basis of the assessment of the associated risks, including any possible effect on the expiration date. Operations related to such re-use shall be documented.

200. (5.64) Whether or not additional control is needed with respect to any finished products after reprocessing or with respect to products, to which re-used products have been joined, shall be determined by the quality control unit.

201. (5.65) Products that are returned from the market and are no longer controlled by the manufacturer shall be destroyed unless their quality is proved to comply with the established requirements. It may be decided to re-sell, re-label or re-use products only after a special analysis is made by the quality control unit according to an approved procedure. In such cases it shall be necessary to take into account the type of products, their history, condition, observance of special storage conditions and the time expired from the date of release. In case of any doubts about the quality of products, re-use or re-release of such products shall be prohibited; however, such products may be used for their chemical reprocessing for regeneration of active ingredients. All performed operations shall be documented.

QUALITY CONTROL (CHAPTER 6)

Principle

202. Quality control shall include sampling, testing and inspections for compliance with the requirements of specifications, instructions and other documents, organization of the operating process, documentation and issue of release permits. Quality control shall be aimed at preventing the use or sale of materials or products that fail to conform to the set requirements. Quality control shall not be limited to laboratory research, it shall support all decisions related to the product quality. A fundamental principle for the efficient performance of the quality control unit shall be its independence from manufacturing units (Items 5 — 23 hereof).

General requirements

203. (6.1) Each manufacturer’s organizational structure shall comprise a quality control unit independent from the other units. The head of the said unit shall have appropriate qualifications and operational experience and shall have under his/her command one or several control laboratories. The unit shall be supplied with sufficient resources to ensure that all quality control activities are effective and reliable.

204. (6.2) The main duties of the head of the quality control unit shall be listed in Items 2445 hereof. The quality control unit may be in charge of other duties, including development, validation and implementation of all quality control procedures, storage of control samples of starting raw materials, packing materials and products, assurance of proper labelling of packages with starting raw materials and products, product stability monitoring, participation in investigations of claims regarding the product quality. The said duties shall be performed in accordance with approved procedures and, if and where necessary, shall be documented.

205. (6.3) Evaluation of the quality of finished products shall imply considering all relevant factors, including manufacturing conditions, in-process control results, review of manufacturing documents (including packaging documents), compliance with specifications for finished products and inspection of the final packaging of finished products.

206. (6.4) The staff of the quality control unit shall be granted access to processing areas for taking samples and conducting necessary tests.

Good laboratory quality control practice

207. (6.5) Premises and equipment of control laboratories shall conform to the general and special requirements set to the quality control areas and stipulated in Items 46 — 91 hereof.

208. (6.6) The staff, premises and equipment of laboratories shall correspond to the type and scope of the manufacturing process. In individual cases it shall be allowed to use outside laboratories provided that such outside laboratories conform to the requirements set out in Items 237 — 255 hereof and corresponding records are made in quality control documents.

Documents

209. (6.7) Documents of control laboratories shall conform to the requirements set out in Items 92 — 134 hereof. A material part of such documents shall be related to quality control.

210. Documents of the quality control unit, required to be easily accessible:

specifications;

sampling procedures;

methods and documents related to conducted tests (including worksheets and (or) laboratory notebooks);

analytical reports and (or) documents certifying quality;

results of the process environment monitoring, where required;

test validation protocols, where applicable;

procedures and protocols of instrument calibration and equipment maintenance.

211. (6.8) Any quality control documents related to records on the manufacture of product batches shall be kept during one year upon the expiration of the batch shelf life and during at least five years upon due assessment of the batch conformity by the authorized person (‘c’, Item 28 hereof).

212. (6.9) For certain categories of data (for example, results of analytical tests, output, process environment parameters) it shall be recommended to keep records in a form allowing analysing parameter changing tendencies.

213. (6.10) In addition to the data making part of the batch dossier, other source data such as laboratory notebooks and (or) records shall be kept and shall be easily accessible.

Sampling

214. (6.11) The manufacturer shall take samples according to approved procedures defining:

sampling methods;

equipment used;

quantities of samples to be taken;

procedures for dividing a taken sample into parts (where necessary);

type and condition of containers used for sampling;

identification of containers with taken samples and of containers from which samples have been taken;

any precautions to be observed, especially during sampling of sterile and hazardous substances;

storage conditions;

procedures for cleaning and storage of sampling equipment.

215. (6.12) Taken control samples shall be representative samples of a batch of starting raw materials, packing materials or finished products. Additional samples may be taken for purposes of monitoring the most crucial process stages (for example, its launch or termination).

216. (6.13) The label of a container with taken samples shall indicate its contents, batch number, sampling date and designation of the package from which the given samples have been taken.

217. (6.14) Additional requirements to control and retention samples shall be outlined in Attachment No. 18 hereto.

Testing

218. (6.15) Quality control procedures shall be validated. All tests specified in the registration dossier shall be conducted according to approved procedures.

219. (6.16) Obtained test results shall be documented and verified to ensure their consistency with one another. All calculations shall be thoroughly checked.

220. (6.17) Conducted tests shall be registered by documenting, inter alia:

a) (a) the name of starting raw materials, packing materials or products and, if and where necessary, the pharmaceutical form;

b) (b) the batch number assigned during acceptance and, where applicable, the manufacturer’s batch number, the manufacturer and (or) the supplier;

c) (c) a reference to corresponding specifications and test procedures;

d) (d) results of tests, including observations, calculations and references to all documents containing results of made analyses;

e) (e) test dates;

f) (f) initials and last names of the persons who conducted tests;

g) (g) initials and last names of the persons who checked the conduct of tests and computations, where applicable;

h) (h) a conclusive opinion on the approval of the permit issue or rejection of products (or other decision on the product status), the date and the signature of the person in charge.

221. (6.18) All in-process control operations, including operations performed in the processing area by the process staff, shall be carried out in accordance with procedures approved by the quality control unit and results of such operations shall be documented.

222. (6.19) Special attention shall be paid to the quality of laboratory reagents, volumetric apparatus, standard solutions, reference samples and media, which shall be prepared and arranged according to requirements of approved instructions.

223. (6.20) Laboratory reagent solutions shall be labelled with the specification of the preparation date and signatures of executors. The label shall indicate the expiration date of unstable reagents and media and specific conditions of their storage. For standard solutions it shall be necessary to indicate the date of the last standardization and the appropriate adjustment factor.

224. (6.21) If and where necessary, containers shall indicate the date of receipt of each substance used in tests (for example, reagents and reference samples), and corresponding instructions on their usage and storage. In some cases it may be necessary to test a reagent (after its receipt or before its use) for identify and (or) other parameters.

225. (6.22) Animals used for control of components, starting raw materials or products shall be put, where applicable, under quarantine before commencing any operations with them. Animal management and control shall be organized so as to ensure their usability for intended purposes. Animals shall be labelled; data on any previous operations with animals shall be documented.

Follow-up stability studies programme

226. (6.23) After a medicine is released into circulation, the medicine stability shall be monitored according to a programme allowing identifying problems with the stability of the medicine of the given composition in consumer packaging (for example, changes in the contents of impurities or solution profile).

227. (6.24) Such follow-up stability studies programme shall be aimed at monitoring the medicine throughout its shelf life and identifying whether the medicine conforms to its specification if the storage conditions indicated in the label are observed.

228. (6.25) The above requirements shall apply mainly to finished medicines in consumer packaging; however, also bulk products shall be included in the follow-up stability studies programme. In particular, if bulk products are kept for a long period of time before packaging and (or) relocation from the processing area to the packaging area, this factor shall be analysed and assessed for its influence on the stability of finished products at corresponding environmental parameters. The said requirement shall be applied also to intermediate products stored and used during a continuous period of time. The stability of a medicine prepared immediately before its usage shall be studied at the time of the medicine development. Such medicines shall not be required to be included in the follow-up stability studies programme. At the same time, the stability of such medicines may be subject to follow-up studies where applicable.

229. (6.26) The follow-up stability studies programme shall be documented according to the requirements set out in Items 92 — 134 hereof and the results shall be presented in the form of a report. Equipment used for stability studies (for example, stability chambers) shall be qualified and shall be maintained according to the requirements set out in Items 46 — 91 hereof and Attachment No. 15 hereto.

230. (6.27) A report on activities under the follow-up stability studies programme shall cover the entire period until the product expiration date and shall contain, inter alia, the following information:

number(s) of batch(es) for various doses and different batch sizes, where applicable;

data on physical, chemical, microbiological and biological test procedures;

acceptance criteria;

references to test procedures;

packaging description;

testing frequency (time control points);

a description of storage conditions (it shall be required to use conditions for long-time stability testing, which are standardized in regulatory legal acts of the Russian Federation and correspond to the data in the registration dossier);

other appropriate parameters specific for the given medicine.

231. (6.28) The report on activities under the follow-up stability studies programme may differ from the initial long-time stability testing report contained in the registration dossier given justification and documentation in the report (including variances in the testing frequency).

232. (6.29) The number of batches and the testing frequency shall provide for ample data for analysis of change tendencies. The follow-up studies programme shall annually include at least one batch of a manufactured medicine in every dosage and in each type of the primary packaging, excluding cases where no batches of the given medicine are manufactured during the year unless otherwise substantiated by the manufacturer. For medicines, with respect to which the follow-up stability studies require using animals and there exist no alternative validated methods, the control frequency may be determined on the basis of risk assessment. Framework or array structures may be used for documentation purposes provided that the applicability of such structures is duly scientifically justified.

233. (6.30) In certain cases the follow-up stability studies shall cover additional batches. Specifically, it shall be required to conduct follow-up stability studies after any material change or material deviation in the manufacturing or packaging process. The same shall apply to any operations related to re-processing, processing or regeneration.

234. (6.31) The results of the follow-up stability studies shall be made available to the designated staff and to the specially authorized person(s). If follow-up stability studies are carried out at a place other than the place of manufacture of bulk or finished products, a corresponding agreement shall be concluded between the parties involved. Results of the follow-up stability studies shall be kept at the place of manufacture for their submission to the authorized federal executive authority.

235. (6.32) The manufacturer shall analyse events of shifts beyond the specification and significant untypical tendencies. Any confirmed beyond-the-specification shit or significant adverse tendencies shall be reported to the authorized federal executive authority. In accordance with the requirements set out in Items 256 — 272 hereof and also during communication with the authorized federal executive authority it shall be necessary to consider possible steps with respect to batches launched on the market.

236. (6.33) Opinions on stability studies, including intermediate conclusions, shall be documented. Stability data shall be subject to regular review.

ACTIVITIES DELEGATED TO ANOTHER ORGANIZATION (OUTSOURCING) (CHAPTER 7)

Principle

237. Any activity which is covered by these Rules and which is delegated to another (outside) organization (outsourcing) shall be duly determined, agreed and monitored for the avoidance of controversies that may affect the quality of products or works performed. The contract between the customer and the contractor shall clearly define specified obligations of each of the parties and shall stipulate procedures and liability of the authorized person for the issue of a release permit for each product batch.

238. The requirements set out in Items 237 — 255 hereof shall not prejudice the corresponding obligations of manufacturers regarding preparation of the registration dossier and obtaining a license for manufacture of medicines. They shall not define liabilities of the contractor and the customer to the consumer, which are stipulated by other regulatory legal acts of the Russian Federation.

General requirements and recommendations

239. (7.1) The outsourcing contract shall be recommended to incorporate references to products, works or services subject to outsourcing as well as all technical or other agreements to the contract in connection with such outsourcing.

240. (7.2) The outsourcing contract and all suggested amendments to technical or other agreements shall comply with the legislation of the Russian Federation and the registration dossier for corresponding products.

241. (7.3) If the legal entity in whose name the Marketing Authorization has been issued is not the manufacturer, such legal entity and the manufacturer shall conclude corresponding agreements subject to the provisions stipulated in Items 237255 hereof.

Customer

242. (7.4) The pharmaceutical quality system of the customer shall include control and inspection of any outsourced activity. The customer shall guarantee control of the outsourced activity. Such control shall incorporate the quality risk management principles and the requirements outlined below.

243. (7.5) Before outsourcing an activity, the customer shall verify the contactor’s legal capacity (in particular, whether the contractor holds a license required in accordance with the legislation of the Russian Federation), competence and ability to properly fulfil its contractual obligations in accordance with the requirements of these Rules. The contract shall be recommended to incorporate also provisions ensuring compliance with the requirements of these Rules.

244. (7.6) The customer shall furnish to the contractor all information and materials necessary for the proper fulfilment of the contractual obligations in accordance with the legislation of the Russian Federation and the registration dossier. The customer shall guarantee that the contractor is fully aware of any and all factors that are associated with the products or outsourced activity and may threaten its premises, equipment, staff, starting raw materials or other products.

245. (7.7) The customer shall control and inspect the contractor’s actions, including any necessary improvements implemented by the contractor.

246. (7.8) The customer shall be responsible for the examination and evaluation of records and results related to the outsourced activity. The customer shall see to it, either on its own or on the basis of a confirmation by the contractor’s authorized person, that all products and materials supplied to it by the contractor have been manufactured in accordance with these Rules and the registration dossier.

Contractor

247. (7.9) The contractor shall have the necessary knowledge, experience, qualified staff and appropriate premises and equipment for the proper fulfilment of the contractual obligations.

248. (7.10) The contractor shall make sure that all products, starting raw materials, packing materials and information, provided to it, are suitable to be used for intended purposes.

249. (7.11) The contractor shall not transfer the works or services contracted thereto to any third party without prior review and approval by the customer. When entering into agreements with third parties, the contractor shall ensure that information, including information about third party conformity assessment, is presented in the same manner as between the original customer and the contractor.

250. (7.12) The contractor shall not introduce unauthorized changes beyond the scope of the contract as such may affect the quality of works performed for the customer.

251. (7.13) The contractor shall understand that the outsourced works, including contract analysis under, are controlled by authorized federal executive authorities.

Contract

252. (7.14) The customer and the contractor shall conclude a contract, which is recommended to stipulate their mutual obligations and procedures for the exchange of information related to the outsourced activity. Technical aspects of the contract shall be elaborated by persons possessing appropriate knowledge in relation to the outsourced activity and these Rules. Provisions of the contract, agreed between the parties, and all technical or other agreements related to the contract shall comply with the legislation of the Russian Federation and the registration dossier.

253. (7.15) The contact shall be recommended to stipulate which party is responsible for each stage of the outsourced activity (for example, knowledge management, technology transfer, ensuring supply chains, conclusion of contracts with third parties, purchase of starting raw materials, materials and their quality, testing, issue of permits for use of starting raw materials and packing materials, manufacturing process and quality control procedures (including in-process control, sampling and sample analysis)).

254. (7.16) All records in connection with the outsourced activity, for example, records on the manufacturing process, analysis and sales of products, and corresponding control samples shall be kept with the customer, or the customer shall be allowed access to such records. In case of filed claims, assumed non-compliance with requirements or in case of investigations regarding assumed product falsification, any records related to the evaluation of the product quality shall be made available to the customer and clearly defined in its corresponding procedures.

255. (7.17) It shall be recommended to stipulate in the contract the customer’s right to the audit of the outsourced activity, such audit being conducted by the contractor or a mutually agreed third party.

CLAIMS AND WITHDRAWAL OF PRODUCTS (CHAPTER 8)

Principle

256. All claims and information related to potentially defective medicines shall be thoroughly investigated in accordance with approved procedures. The manufacturer shall have a system for the prompt and effective withdrawal from the marker of products with revealed or assumed quality defects.

Claims

257. (8.1) The manufacturer shall designate an officer to be in charge of claims consideration and decision-making, entitled to employ staff members as may be necessary. If such officer is not the authorized person, the authorized person shall be informed about all filed claims, investigations and product withdrawals.

258. (8.2) Activities related to consideration of claims regarding potentially defective medicines and making of product withdrawal decisions shall be stipulated in corresponding approved procedures.

259. (8.3) Any claim regarding the product quality shall be registered, with source data stated, and shall be thoroughly investigated. Such activities shall be generally conducted with the participation of the person in charge of the product quality control.

260. (8.4) If the quality of a product batch is revealed or suspected to fail to conform to the established requirements, it shall be decided to check similar batches and also batches that may include products obtained during the reprocessing of the defective batch.

261. (8.5) Decisions and measures taken as a result of the consideration of any claim shall be registered and included in a corresponding batch dossier.

262. (8.6) Claim consideration records shall be regularly analysed for the purpose of identifying specific and recurrent factors that require special attention and may lead to the product withdrawal.

263. (8.7) Special attention shall be paid to analysing whether a claim is caused by product falsification.

264. (8.8) If the manufacturer takes steps as a result of possible errors in the manufacturing process, deterioration of the product quality, detection of falsified products or other serious problems related to the product quality, such steps shall be reported to the corresponding authorized federal executive authority.

Product withdrawal

265. (8.9) The manufacturer shall designate an officer to be in charge of timely withdrawal of products from the market, entitled to employ staff members as may be necessary. Such officer shall be, as a rule, independent from the sales and marketing units. If such officer is not the authorized person, the authorized person shall be informed about all events of the product withdrawal.

266. (8.10) The rules of withdrawing products shall be regulated by an approved procedure, which shall be regularly verified and, if and where necessary, revised.

267. (8.11) Product withdrawals shall be carried out in a quick and effective manner, at any time.

268. (8.12) Competent authorities of all the countries, in which products have been released, shall be immediately notified of the decision to withdraw the products due to suspected or revealed defects in their quality.

269. (8.13) Shipment records shall be available to the person(s) in charge of the product withdrawal and shall contain sufficient data on wholesalers and direct customers of medicines (addresses, telephone and (or) fax numbers, during and outside working hours, batch numbers and supply volumes), including export supplies and supplies of medicine samples.

270. (8.14) Withdrawn products shall be labelled and separately stored in a secure area until it is decided to use or destroy them.

271. (8.15) The sequence of actions in case of the product withdrawal shall be documented. The final report shall contain the material balance between supplied and returned quantities of products.

272. (8.16) The effectiveness of product withdrawal activities shall be regularly analysed.

SELF-INSPECTION (CHAPTER 9)

Principle

273. Self-inspections shall be conducted for the purpose of checking the manufacturer’s compliance with the requirements set forth in these Rules and suggesting appropriate corrective actions.

274 (9.1) Issues related to the staff, premises, equipment, documents, manufacturing process, quality control sales of medicines, claim-related activities, product withdrawals and self-inspections shall be regularly analysed according to a preliminarily approved programme, as per an established schedule for checking their conformity to the principles of the pharmaceutical quality system.

275. (9.2) A self-inspection shall be independently conducted with due diligence by specially designated qualified staff members of the manufacturer. Where necessary, an independent audit of the manufacturer may be conducted by experts of outside organizations.

276. (9.3) Results of self-inspections shall be documented. Reports prepared on the basis of results of self-inspections shall include all obtained information and appropriate corrective actions (where applicable). Actions undertaken on the basis of results of conducted self-inspections shall be documented.

IV. BASIC REQUIREMENTS TO PHARMACEUTICAL SUBSTANCES USED AS STARTING RAW MATERIALS (PART II)

INTRODUCTION (1)

277. Legal entities, in whose name Marketing Authorizations are issued, and manufacturers shall use for starting raw materials only those pharmaceutical substances that have been manufactured in accordance with these Rules.

Purpose (1.1)

278. This chapter shall set requirements concerning due manufacture of pharmaceutical substances with an appropriate quality management system. It shall be applicable also for the purpose of assuring the quality and purity of active substances, in accordance with the set requirements.

279. In this chapter the term ‘manufacture’ shall imply all types of operations with pharmaceutical substances: acceptance of materials, manufacture, packaging, re-packaging, labelling, re-labelling, quality control, issue of the release permit, storage and sales, and corresponding control measures. The requirements set forth in this chapter shall be binding unless Attachments to these Rules stipulate other requirements to be applied in appropriate cases and/or unless the specified requirements can be substituted by alternative actions ensuring as minimum an equivalent level of the product quality.

280. These Rules shall not define requirements set for the registration of pharmaceutical substances. The manufacturer shall abide by all requirements set for the inclusion of pharmaceutical substances in the state register of medicines.

Scope of application (1.2)

281. This chapter shall set requirements to the manufacture of pharmaceutical substances used in the manufacture of medicines for medical and veterinary application, specifically, to the manufacture of pharmaceutical substances obtained from donated blood or plasma used as starting raw materials. The chapter shall apply to all starting active substances, alongside Attachments No. 27 hereto, outlining additional requirements for certain types of active substances.

282. Items 622644 hereof shall contain requirements applicable only to the manufacture of pharmaceutical substances used for obtaining medicines intended for clinical studies.

283. Requirements set out in this chapter shall be applicable to the manufacture of sterile pharmaceutical substances only until the sterilization stage.

284. This chapter shall not apply to the processes of sterilization and aseptic manufacture of sterile pharmaceutical substances. Such processes shall be run according to the principles of these Rules, the requirements set out in Attachment No. 1 hereto and in other regulatory legal acts of the Russian Federation.

285. This chapter shall not apply to whole donated blood and plasma as blood drawing and testing requirements are stipulated in corresponding regulatory legal acts of the Russian Federation, and/or to bulk medicines (‘in bulk’). If regulatory legal acts of the Russian Federation stipulate special requirements for assuring the quality during manufacture of veterinary medicines against ectoparasites, such requirements shall be binding.

286. Starting raw materials for manufacture of pharmaceutical substances shall be starting raw materials, intermediate products or other pharmaceutical substances, which are used in the manufacture of pharmaceutical substances and which are added to the structure of a pharmaceutical substance as an important structural fragment. Starting raw materials for manufacture of pharmaceutical substances may be purchased on a contractual basis from one or several suppliers or may be produced independently. Starting raw materials for manufacture of pharmaceutical substances generally have the established chemical properties and structure.

287. The manufacturer shall determine the starting stage of the manufacture of a pharmaceutical substance and substantiate it in documentary form. For synthesis processes such stage shall be determined as the stage of launching starting raw materials for manufacture of pharmaceutical substances in the manufacturing process. For other processes (for example, fermentation, extraction, purification), such stage shall be determined on the basis of specifics of the manufacturing process. Table No. 1 shall contain the criteria as regards the moment when starting raw materials for manufacture of pharmaceutical substances are generally introduced in the process. As of this stage, the requirements set out in this chapter shall be applicable to the specified intermediate products and (or) stages of the manufacture of pharmaceutical substances. They shall include validation of critical stages of the manufacturing process that influence the quality of pharmaceutical substances. However, a stage of the manufacturing process selected by the manufacturer for validation shall not be necessarily a critical stage. Requirements of this chapter shall generally apply to the stages given in Table No. 1 in grey background. It does not mean that all the stages mentioned in this table should be carried out during the manufacturing process. The stringency of the requirements of this chapter shall increase from early stages of the manufacture of pharmaceutical substances to final stages of the manufacturing process, purification and packaging. Physical processing of pharmaceutical substances, such as granulation, coating or physical changing of the particle size (for example, coarse and fine grinding) shall be run as minimum according to the requirements of these Rules. This chapter shall not apply to stages preceding the introduction in the process of substances defined as starting raw materials for manufacture of pharmaceutical substances.

288. The term ‘pharmaceutical substance’ (PS), used in this chapter, shall be deemed as interchangeable with the term ‘active pharmaceutical ingredient’ (API). The terms used in this chapter and their definitions (given in Item 645 hereof) shall be used solely for purposes of this chapter.

Table No. 1. Application of Chapter IV of these Rules to the manufacture of pharmaceutical substances

Type of manufacturing process PS manufacture stages subject to Chapter IV of these Rules (in grey background)
Chemical manufacture Manufacture of starting raw materials for PS Introduction of starting raw materials for manufacture of PS in the process Manufacture of intermediate products (OM) Downstream Physical processing and packaging
PS obtained from animal-based raw materials Collection of organs, liquids or tissues Cutting, mixing and (or) primary processing Introduction of starting raw materials for manufacture of PS in the process Downstream Physical processing and packaging
PS obtained from plant-based raw materials Collection of plants Cutting and primary extraction Introduction of starting raw materials for manufacture of PS in the process Downstream Physical processing and packaging
Plant extracts used as PS Collection of plants Cutting and primary extraction Subsequent extraction Physical processing and packaging
PS composed of ground or powdered plants Collection of plants and (or) cultivation and collection Cutting and (or) grinding Physical processing and packaging
Biotechnology: fermentation and (or) cultivation of cells Generation of the main and working cell banks Maintenance of the working cell bank Cultivation of cells and (or) fermentation Downstream Physical processing and packaging
‘Classical’ fermentation for manufacture of PS Generation of the cell bank Maintenance of the cell bank Introduction of cells in the fermentation process Downstream Physical processing and packaging
Strengthening of requirements

QUALITY MANAGEMENT (2)

Principles (2.1)

289. (2.10) All staff members involved in the manufacturing process shall be responsible for quality.

290. (2.11) Each manufacturer shall develop, finalize and implement an effective quality management system with the participation of the managerial and process staff.

291. (2.12) The quality management system shall cover the organizational structure, procedures, processes and resources, including activities aimed at ensuring the conformity of PS to all requirements of corresponding specifications regarding quality and purity. The manufacturer shall determine and document all types of quality-related activities.

292. (2.13) The manufacturer shall have units in charge of quality assurance and control functions, which shall be independent from the manufacturing unit. The said functions may be either performed by separate quality assurance and control units or assigned to one person or a group of persons, depending on the company’s size and structure.

293. (2.14) It shall be necessary to designate persons authorized to issue permits for release of intermediate products and PS.

294. (2.15) All quality-related actions shall be documented immediately while implemented.

295. (2.16) Any deviation from the established procedures shall be documented and justified. It shall be required to investigate into critical deviations and document such investigations and conclusions made.

296. (2.17) Starting raw materials for manufacture of pharmaceutical substances and materials shall be permitted to be released or used only after obtaining a positive opinion on the basis of an evaluation made by the quality unit(s) if the manufacture does not have appropriate systems authorizing such use (for example, release under quarantine as described in Item 472 hereof, or use of starting raw materials or intermediate products whose quality assessment is still in progress).

297. (2.18) The manufacturer shall develop procedures for the timely notification of the managerial staff of inspections by the authorized federal executive authority, drawbacks regarding the compliance with the requirements of these Rules, defects in products and implementation of corresponding measures (for example, consideration of quality claims, product withdrawals, steps taken by the authorized federal executive authority).

298. (2.19) For achieving the quality management objectives, it shall be necessary to integrate a comprehensively elaborated and consistent quality system comprising the organization of activities according to these Rules, including quality control and the quality risk management system.

Quality risk management system (2.2)

299. (2.20) Quality risk management shall be a systematic process of evaluation, control and transfer of information and review of risks for the quality of PS. The said process may be run both on a perspective or retrospective basis.

300. (2.21) The quality risk management system shall aim to ensure that:

the risk assessment is made on the basis of scientific knowledge, manufacturing experience and is ultimately aimed at the patient protection through exchange of data with the acquirer of PS;

the level of efforts, formalization and finalization of the quality risk management process is comparable to the level of risks.

Duties of the quality unit(s) (2.3)

301. (2.30) The quality unit(s) shall participate in addressing all quality-related issues.

302. (2.31) The quality unit(s) shall review and approve all documents related to the product quality.

303. (2.32) The main duties of the independent quality unit(s) may not be delegated to other units. Such main duties shall be documented and shall comprise, inter alia:

a) (1) issue of permits for release or rejection of all PS, and issue of permits for release or rejection of intermediate products whose intended usage is outside the manufacturer’s control;

b) (2) creation of a system of the issue of permits for release or rejection of starting raw materials, intermediate products, packing materials and labelling materials;

c) (3) inspection of made batch manufacture records and laboratory control documents with respect to critical process stages before the issue of permits for release of PS;

d) (4) arrangement of investigations into reasons for critical deviations and their elimination;

e) (5) agreement or approval of all specifications and main process instructions;

f) (6) agreement or approval of all procedures that may influence the quality of intermediate products or PS;

g) (7) arrangement of internal audits (self-inspections);

h) (8) approval of manufacturers of intermediate products and PS, engaged on a contractual basis;

i) (9) approval of changes that may potentially influence the quality of intermediate products or PS;

j) (10) verification and approval of validation protocols and reports;

k) (11) arrangement of investigations and decision-making with respect to quality-related claims;

l) (12) control of timely technical maintenance, calibration and adjustment of critical equipment;

m) (13) arrangement of appropriate tests of starting raw materials and documenting of results;

n) (14) ensuring availability of stability data for confirming the dates set for repeated tests or expiration dates, and also conditions of storage of PS and (or) intermediate products where applicable;

o) (15) product quality reviews (Items 307308 hereof).

Duties regarding manufacturing activities (2.4)

304. The duties regarding manufacturing activities shall be documented and shall comprise, inter alia:

a) (1) development, revision, approval and distribution of instructions on the manufacture of intermediate products or PS according to an approved procedure;

b) (2) manufacture of PS and, if and where necessary, intermediate products according to preliminarily approved instructions;

c) (3) review of all product batch manufacture records and confirmation of their completeness and signing;

d) (4) ensuring mandatory documenting of all deviations from the manufacturing process, their assessment, investigation into all critical deviations and documenting of conclusions made;

e) (5) ensuring cleanness of manufacturing facilities and, if and where necessary, their disinfection;

f) (6) arrangement of the necessary calibrations, maintenance and keeping of records;

g) (7) ensuring service of premises and equipment, maintenance and keeping of records;

h) (8) ensuring verification and approval of validation protocols and reports;

i) (9) evaluation of suggested changes with respect to products, the process or equipment;

j) (10) ensuring qualification of new and, if and where necessary, upgraded premises and equipment.

Internal audits (self-inspection) (2.5)

305. (2.50) In order to confirm the conformity of the manufacture of PS to the requirements of these Rules, the manufacturer shall regularly conduct internal audits according to an approved schedule.

306. (2.51) Results of internal audits and subsequent corrective actions shall be documented and reported to the manufacturer’s managerial staff. Agreed corrective actions shall be implemented in due course in an effective manner.

Product quality review (2.6)

307. (2.60) For the purpose of confirming the continuity of the manufacturing process, it shall be necessary to make regular reviews of the quality of PS. Such quality reviews shall be generally made on an annual basis, subject to subsequent documenting. Such quality reviews shall comprise as minimum:

reviews of the results of the in-process control by critical points and tests of FS according to the critical parameters;

reviews of all batches that fail to conform to the approved specifications;

reviews of all critical deviations or inconsistencies and investigations in this connection;

reviews of any changes made to the processes or analytical methods;

review of results of the stability studies programme;

reviews of all returns, claims and withdrawals in connection with quality;

reviews of the adequacy of corrective actions.

308. (2.61) It shall be necessary to analyse results of the said reviews and to evaluate whether corrective actions or re-validation is needed. Justification of such corrective actions shall be documented. Agreed corrective actions shall be implemented in due course in an effective manner.

STAFF (3)

Staff qualifications (3.1)

309. (3.10) The manufacturer shall have a sufficient number of staff members possessing appropriate education, training and (or) work experience for the manufacture of intermediate products and PS and supervision over such manufacture.

310. (3.11) The duties of all staff members involved in the manufacture of intermediate products and PS shall be clearly defined and stipulated in writing.

311. (3.12) The manufacturer shall regularly train its staff members by employing qualified experts in all spheres related to specific operations performed by its staff members and to requirements of these Rules connected with the functional duties of staff members. The manufacturer shall keep training records and organize periodic training evaluation.

Staff hygiene (3.2)

312. (3.20) Staff members shall abide by sanitary regulations.

313. (3.21) Staff members shall wear clean clothes according to their jobs. When needed, staff clothes shall be changed. For the purpose of protecting intermediate products and PS from contamination, where necessary, staff members shall use additional protective clothing covering heads, faces, arms and hands.

314. (3.22) Staff members shall avoid any direct contact with intermediate products or PS.

315. (3.23) It shall be allowed to smoke, take meals, drinks, chew and store foodstuffs only in specially designated areas separated from processing areas.

316. (3.24) If a staff member has an infectious disease or open injuries on open skin areas, such staff member shall be suspended from work not to compromise the quality of PS. Any staff member with marked symptoms of a disease or with open skin injuries (according to a medical examination or screening) shall be suspended from works, during which the staff member’s health conditions may affect the quality of PS, until the staff member recovers or obtains a medical conclusion that his/her participation in the manufacturing process does not compromise the safety or quality of PS.

Consultants (3.3)

317. (3.30) Consultants for the manufacture and control of intermediate products or PS shall have appropriate education, training and work experience or any combination of the foregoing to be able to provide consultations on the issues planned to be solved with their participation.

318. (3.31) It shall be necessary to keep records by specifying first names, patronymics (if any), last names, addresses and qualifications of consultants, and the type of services provided by them.

BUILDINGS AND PREMISES (4)

Design and construction (4.1)

319. (4.10) Buildings and premises used in the manufacture of intermediate products and PS shall be located, designed and constructed so as to allow their cleaning, maintenance and operation according to the type and stage of the manufacturing process. Premises shall be designed so as to minimize possible contamination. If there are set specifications with respect to microbiological parameters of intermediate products or PS, premises shall be designed so as limit, where possible, the risk of adverse microbial contamination.

320. (4.11) Buildings and premises shall be large enough for the proper arrangement of equipment, storage and relocation of materials, in order to prevent confusion and contamination.

321. (4.12) If equipment (for example, closed or isolated systems) serves to ensure safe protection of materials, it may be installed outside premises.

322. (4.13) Relocation of materials and movement of the staff in buildings and premises shall be arranged so as to prevent confusion and contamination.

323. (4.14) There shall be designated specific areas or other control systems for the following operations:

acceptance, identification, sampling and quarantine of coming materials before the issue of a permit for use or before rejection;

storage of intermediate products and PS in quarantine until the issue of a permit for use or until rejection;

taking of samples of intermediate products and PS;

storage of rejected starting raw materials and packing materials until their disposal (for example, return, reprocessing or destruction);

storage of materials authorized for use;

process operations;

packaging and labelling operations;

laboratory tests.

324. (4.15) The manufacturer shall provide for necessary facilities for staff (for example, for hand washing) and a sufficient number of toilet rooms and keep them clean. Such facilities shall be supplied with hot and cold water, soap or other cleansers, blowers and disposable towels. Washing facilities and toilet rooms shall be separated from processing areas but shall be easily accessible. It shall be necessary to provide for changing rooms and, if and where necessary, showers.

325. (4.16) Laboratory areas, sites of laboratory works shall be recommended to be separated from processing areas. Certain laboratory areas, for example areas used for the in-process control, may be arranged in processing areas provided that process operations do not affect the accuracy of laboratory measurements and that laboratory works do not affect the manufacturing process, intermediate products or PS.

Utility systems (4.2)

326. (4.20) All utility systems that may influence the product quality (for example, vapour, gas, compressed air supply systems, heating, ventilation and air conditioning systems) shall be subject to qualification. The functioning of such systems shall be duly controlled; if the admissible limits of controlled parameters are exceeded, appropriate measures shall be taken. The manufacturer shall have drawings of such utility systems.

327. (4.21) If and where necessary, it shall be required to provide appropriate ventilation and air filtration systems and exhaust units. Such systems shall be designed and constructed so as to minimize the risk of contamination and cross contamination. Such systems shall be also supplied with equipment for the air pressure control, control of microorganisms (where needed), dust content, humidity and temperature, if such is required for the given manufacturing stage. Special attention shall be paid to areas wherein PS are exposed to the process environment.

328. (4.22) In manufacturing facilities with air recirculation it shall be necessary to provide for measures aimed at preventing the risk of contamination and cross contamination.

329. (4.23) Permanent pipelines shall be duly identified – with the use of labelling of individual pipelines, appropriate documents, computer control systems or otherwise. Pipelines shall be arranged so as to avoid the risk of contamination of intermediate products or PS.

330. (4.24) Permanent pipelines shall be of appropriate dimensions and shall be supplied with air lock systems or, if and where necessary, with backflow lock fixtures.

Water (4.3)

331. (4.30) The water used in the manufacture of PS shall correspond to the intended purpose. Observance of this requirement shall be confirmed by the quality unit.

332. (4.31) The quality of the water used in the manufacturing process shall conform to the requirements of the regulatory legal acts of the Russian Federation, set to the quality of potable water.

333. (4.32) If the potable water parameters are not sufficient to ensure the quality of PS and the requirements to chemical and (or) microbiological properties of water need to be tightened, it shall be necessary to develop appropriate specifications for water in terms of physical properties, chemical properties, the total number of microorganisms, inadmissible microorganisms and (or) endotoxin levels in water.

334. (4.33) If for the purpose of achieving a certain quality the manufacturer uses special treatment for the water used in the manufacturing process, such treatment shall be subject to validation and control considering the set limits.

335. (4.34) If the manufacturer of a non-sterile PS plans to use its products for the further manufacture of a sterile medicine or declares that its products are suitable for obtaining a sterile medicine, the water used at the final downstream stages shall be monitored and controlled for the total number of microorganisms, inadmissible microorganisms and endotoxins.

Area separation (4.4)

336. (4.40) Products with high sensitizing power such as penicillins or cephalosporins shall be manufactured in specially dedicated processing areas, which may incorporate premises, equipment for air treatment and process equipment.

337. (4.41) Specially dedicated processing areas shall be provided also for substances with infectious properties, with a high pharmacological activity or toxicity (for example, certain steroids or cytotoxic antitumour drugs), except in cases where established validated inactivation and (or) purification procedures are used.

338. (4.42) The manufacturer shall develop and introduce measures necessary for preventing cross contamination by the staff, starting raw materials, packing materials, intermediate products, equipment and other objects relocated from one dedicated area to another.

339. (4.43) Any process operations (including weighing, grinding or packaging) with highly toxic non-pharmaceutical substances such as herbicides and pesticides shall be prohibited to be carried out in the same buildings and (or) on the same equipment as are used for the manufacture of PS. Such highly toxic non-pharmaceutical substances shall be handled and stored separately from PS.

Lighting (4.5)

340. (4.50) All areas shall be supplied with lighting systems to facilitate cleaning, technical maintenance and proper run of operations.

Discharges and waste (4.6)

341. (4.60) Discharges, waste and other used materials (for example, solid, liquid and gaseous byproducts) inside and outside buildings and directly in the adjacent territory shall be in due course removed to ensure safety and to comply with sanitary regulations. Waste containers and (or) discharge pipes shall be clearly labelled.

Sanitary treatment and technical maintenance (4.7)

342. (4.70) Buildings used for the manufacture of intermediate products and PS shall be properly maintained, repaired and kept clean.

343. (4.71) The manufacturer shall develop documents defining responsibility for sanitary treatment, containing clean-up schedules and listing methods, equipment and materials used for the cleaning of buildings and premises.

344. (4.72) If and where necessary, for the avoidance of contamination of equipment, starting raw materials, packing materials and labelling materials, intermediate products and PS, it shall be also required to develop procedures for the use of rodenticides, insecticides, fungicides, fumigants and cleansers and disinfectants of PS.

PROCESS EQUIPMENT (5)

Design and assembly (5.1)

345. (5.10) Equipment used for the manufacture of intermediate products and PS shall be appropriately designed, be of appropriate dimensions and arranged according to its intended purpose so that the staff could clean, disinfect (where necessary) and service such equipment.

346. (5.11) Equipment surfaces contacting starting raw materials, intermediate products or PS shall not affect the quality of intermediate products and PS and change their characteristics by shifting them beyond the permissible limits set in the specifications.

347. (5.12) The process equipment shall be used only within the operating ranges determined during qualification.

348. (5.13) The primary equipment (for example, reactors, storage containers) and permanent manufacturing lines used in the manufacture of intermediate products or PS shall be duly identified.

349. (5.14) Any substances necessary for the functioning of equipment such as lubricants, heating liquids or coolants shall not come into contact with intermediate products or PS so as not to change their quality. The manufacturer shall analyse any deviations from this requirement to make sure that such materials do not cause any adverse effect on the usability of intermediate products or PS. Where possible, lubricants and oils designed for the food-manufacturing industry shall be used.

350. (5.15) In all cases where applicable, it shall be required to use closed or hermetically sealed equipment. Open equipment shall be used or opened by taking precautions to minimize the risk of contamination.

351. (5.16) The manufacturer shall have an up-to-date package of drawings of the equipment in use as well as of critical interlink systems (for example, control and measuring instruments, auxiliary systems).

Technical maintenance and cleaning of equipment (5.2)

352. (5.20) Preventive maintenance of equipment shall be conducted according to approved schedules and procedures defining responsibility for their implementation.

353. (5.21) The manufacturer shall develop instructions on cleaning equipment and obtaining afterwards a permit for its use in the manufacture of intermediate products and PS. Cleaning procedures shall be given in sufficient detail to enable operators to clean any type of equipment in a reproducible and effective manner. Such procedures shall define:

responsibility for equipment cleaning;

clean-up schedules including (if and where necessary) sanitary treatment schedules;

a full description of methods and materials, specifically, preparation of means used for equipment cleaning;

instructions on the disassembly and assembly of each (where necessary) equipment unit for proper clean-up;

instructions on removing labels of the previous batch;

instructions on protecting clean equipment from contamination before its use;

procedures for inspection of the cleanness of equipment immediately before its use, if practicable;

a maximum (where applicable) time interval between the end of the process and the clean-up of equipment.

354. (5.22) Equipment and accessories shall be cleaned, stored and, if and where necessary, put under sanitary treatment or sterilization for the purpose of preventing contamination or transfer of materials that may shift the quality of intermediate products and PS beyond the limits set in the specifications.

355. (5.23) Equipment intended for the continuous manufacturing process or for the manufacture in sessions (manufacturing cycles) of consecutive batches of the same intermediate products or the same PS shall be cleaned at regular time intervals in order to avoid accumulation and migration of contaminants (for example, degradants or inadmissible quantities of microorganisms).

356. (5.24) Equipment used for the manufacture of different materials shall be cleaned in the intervals between their changeover for the avoidance of cross contamination.

357. (5.25) The manufacturer shall set and validate acceptance criteria with respect to residues. The manufacturer shall select and validate its choice of cleaning procedures and detergents.

358. (5.26) Equipment shall be duly labelled for its contents and the clean-up status.

Calibration (5.3)

359. (5.30) Measuring and control and analytical equipment (including balances and monitoring devices), which is critical for ensuring the quality of intermediate products or PS, shall be calibrated according to approved instructions and an established schedule.

360. (5.31) Calibration shall be made on the basis of appropriate certified standards or a reference standard or a reference element comparable to the standard (if any).

361. (5.32) Calibration records shall be subject to safe-keeping.

362. (5.33) The current status of the calibration of critical equipment shall be known and allow its verification.

363. (5.34) It shall be prohibited to use instruments/devices that fail to conform to the calibration criteria.

364. (5.35) Deviations from the approved calibration standards for critical instruments/devices shall be investigated to identify whether such deviation has effected the quality of intermediate products and PS manufactured with the use of the given equipment after its last successful calibration.

Computerized systems (5.4)

365. (5.40) Computerized systems used for purposes hereof shall be subject to validation. The scope of validation shall depend on the variety, complexity and criticality of application of computerized systems.

366. (5.41) Due qualification of assembly and qualification of performance shall prove that computer equipment and software are suitable for the attainment of set objectives.

367. (5.42) If the software used has been qualified, it shall not be required to be tested at the same level. If an existing system failed to be validated during installation, retrospective validation may be conducted provided that there are appropriate documents.

368. (5.43) Computerized systems shall be provided with a sufficient level of control to prevent unauthorized access to data or changes in data. It shall be necessary to provide for data loss protection (for example during computer shutdown). Information about any changes in data, the last input of data, who and when changed/entered data shall be subject to registration.

369. (5.44) The manufacturer shall have approved procedures for the operation and technical maintenance of computerized systems.

370. (5.45) If critical data are entered manually, the accuracy of their entry shall be subject to additional verification. Such verification may be made by a secondary operator or by the system itself.

371. (5.46) Failures in the performance of computerized systems, which may affect the quality of intermediate products or PS, the reliability of records or test results, shall be subject to documenting and investigation.

372. (5.47) Modifications introduced to computerized systems shall be introduced according to procedures for the introduction of modifications, shall be officially authorized, documented and tested. Records on all changes, including modification and upgrade of computer equipment, software and other critical system components, shall be subject to safe-keeping. Such records shall serve as evidence that the system is maintained validated.

373. (5.48) If a failure or breakdown of the system results in permanent loss of records, the manufacturer shall provide a backup system. All computerized systems shall be supplied with facilities ensuring data protection.

374. (5.49) Besides being stored in computer systems, data may be recorded also by using other methods.

DOCUMENTS AND RECORDS (6)

Documentation system and specifications (6.1)

375. (6.10) All documents related to the manufacture of intermediate products or PS shall be drawn up, checked, approved and distributed according to procedures approved by the manufacturer. Such documents may be executed either in writing or in electronic format.

376. (6.11) Issue, revision, replacement or withdrawal of any documents shall be controlled by keeping information about their previous versions.

377. (6.12) The manufacturer shall organize a system for the safe-keeping of all documents (for example, development reports, scaling reports, technology transfer reports, process validation reports, training records, manufacturing records, control documents and sales records) by specifying periods of storage of such documents.

378. (6.13) All records related to the manufacturing process, control and sales shall be kept during at least 1 (one) year from the batch expiration date. Records containing data on repeated testing of PS shall be kept during at least 3 (three) years after the batch is fully sold.

379. (6.14) Records shall be made in indelible ink, in specially designated placed, immediately after an operation is conducted; the person who has made a record shall be specified. Corrections in records shall be signed, with the date stated. Such corrections shall allow reading the original records.

380. (6.15) During the period of their storage originals or copies of records shall be easily accessible at the manufacturing site where the recorded operations were performed. Records may be promptly obtained also from other places of storage by using electronic or other means.

381. (6.16) Specifications, instructions, procedures and records may be kept either in the original or as copies such as photocopies, microfilms, microfiches or other forms of exact reproduction of the original records. In case of use of the original size reduction methods, for example, microfilming, or electronic records, it shall be required to have appropriate reading equipment and machines for making printed copies.

382. (6.17) The manufacturer shall develop and document specifications for starting raw materials, intermediate products (where necessary), PS and materials for labelling and packaging. Additionally, the manufacturer may need to have specifications for other specific materials (for example, auxiliary materials, insertions) used in the manufacture of intermediate products or PS as may be critical for their quality. It shall be necessary to set and document acceptance criteria for the in-process control.

383. (6.18) Electronic signatures used in documents shall be identified and protected.

Equipment clean-up and use records (6.2)

384. (6.20) Records on the use, clean-up, sanitary treatment and (or) sterilization and technical maintenance of the primary equipment shall specify the date, time (where necessary), product item, the number of each batch manufactured with the use of the given equipment, and the person in charge of the equipment clean-up and technical maintenance.

385. (6.21) It shall not be required to make separate equipment clean-up and use records if equipment is intended specifically for the manufacture of one item of an intermediate product or PS and batches of such intermediate product or PS are manufactured in a traceable sequence. In case of use of equipment intended for specific purposes, records on its clean-up, technical maintenance and operation may be incorporated in the batch dossier or constitute a separate document.

Records on starting raw materials, intermediate products, packing materials and materials for labelling of pharmaceutical substances (6.3)

386. (6.30) It shall be necessary to keep records on starting raw materials, intermediate products, packing materials, materials for labelling of PS, which shall specify:

the manufacturer, ID and quantity of each supply of each batch of starting raw materials, intermediate products or packing materials and materials for labelling of PS;

the supplier; the control number(s) of the supplier (if known) or other ID number; the number assigned during acceptance and the acceptance date;

results of all conducted tests or inspections, and conclusions made on their basis;

records for tracing the use of materials;

documents related to evaluation and inspection of packing materials and materials for labelling of PS for their compliance with the established specifications;

the final decision regarding rejected starting raw materials, intermediate products or packing materials and materials for labelling of PS.

387. (6.31) The manufacturer shall keep the approved samples of labels to check if they match the manufactured labels.

Process description and process instructions (6.4)

388. (6.40) For ensuring batch-to-batch homogeneity, the manufacturer shall develop process descriptions for each type of PS, which shall be approved by the manufacturer’s chief officer and shall be independently checked, signed and dated by an officer from the quality unit. Process descriptions shall form the basis for developing process instructions for each stage of the manufacturing process and (or) for each type of intermediate products; such instructions shall be signed and dated by one person and shall be independently checked, signed and dated by an officer from the quality unit. The process description shall list materials used by specifying quantities of each of them, contain information about the equipment used, the manufacturing process and control methods at all stages of the manufacture of PS. The general requirements to the structure and other requirements to the contents of process descriptions shall be stipulated in corresponding regulatory legal acts of the Russian Federation.

389. (6.41) Process instructions shall specify:

the name of the manufactured intermediate products or PS, stages of the manufacturing process and, where applicable, the corresponding document code;

a full list of starting raw materials and intermediate products with their names or codes specific enough to identify and determine any special quality characteristics;

the exact quantity or ratio of each name of the used starting raw materials or intermediate products and units of measurement. If such quantity is not fixed, instructions shall contain calculations for each batch size or manufacturing mode. Instructions shall also list deviations from the specified quantities, if such are justified;

the site of the manufacturing process and the primary process equipment used;

detailed process operations, including:

the sequence required to be observed;

ranges of the process parameters used;

sampling and in-process control guidelines, with acceptance criteria where necessary;

deadlines of individual stages of the manufacturing process and (or) the entire process where necessary;

expected ranges of the output at corresponding process stages or at a certain time;

special guidelines and precautions to be observed, or corresponding cross references thereto, where necessary;

guidelines on the storage of intermediate products or PS for ensuring their usability, including packing and labelling materials, and special storage conditions with storage periods, where appropriate.

Batch dossier (manufacturing and quality control records) (6.5)

390. (6.50) Each intermediate product or PS shall be accompanied with a product batch dossier comprising full data on the manufacturing process and quality control of each batch. The form issued for making manufacturing records shall correspond to the process instruction and shall be up-to-date. If the form for records on the batch manufacture is drawn up on the basis of a separate section of the process instruction, such document shall contain a reference to the valid process instruction in use.

391. (6.51) Forms for records shall be numbered with specification of a certain batch number or ID number and shall be dated and signed when issued. In case of continuous manufacture, the product code and the date and time of release may be regarded as unique identifiers until the final batch number is assigned.

392. (6.52) Upon completion of each important manufacturing stage, the batch dossier (manufacturing and quality control records) shall contain the following data:

the date and, where applicable, time;

the primary equipment used (for example, reactors, driers, mills);

specific ID of each batch, including weight, units of measurement, numbers of batches of starting raw materials, intermediate products or any materials that have been reprocessed during the manufacturing process;

registered actual results of the critical process parameters;

data on any sampling made;

signatures of persons in charge of each critical stage and of persons in charge of direct supervision or inspection;

results of in-process tests and laboratory tests;

the actual output at corresponding stages or at a certain time;

a description of packaging and labelling for intermediate products or PS;

a sample of the label for PS or intermediate products if such are made for sale;

any observed deviation and its analysis, information about the conducted investigation (where necessary) or a reference to such investigation if relevant documents are kept separately;

results of control at the time of the issue of the release permit.

393. (6.53) The manufacturer shall develop and approve procedures to be observed when investigating into critical deviations or inconsistencies of batches of intermediate products or PS from their specifications. Such investigation shall cover also other batches, to which such inconsistencies or deviations may be related.

Laboratory control documents (6.6)

394. (6.60) Laboratory control documents shall contain full information about data obtained in the course of all the tests conducted for the purpose of confirming the conformity to the established specifications and the general pharmacopoeial monograph, pharmacopoeial monograph and/or regulatory document, including investigations and quantitative measurements, namely:

a description of samples obtained for testing purposes, including the name of starting raw materials, the place of sampling, the batch number or other indicative code, the date of sampling and, where applicable, the sample quantity presented for testing and the date of its receipt;

a description of each used testing procedure or a reference to such procedure;

the sample weight and other units of measurement for the sample used for each test, according to the described procedure; data on the preparation and testing of standard samples, reagents and reference solutions, or corresponding cross references;

full records of all source data obtained in the course of each test, in addition to schedules, charts and spectra obtained with the use of laboratory instruments, duly identified for a specific substance and batch tested;

records of all calculations made in connection with testing, including units of measurement, conversion and equivalence factors;

test results and their conformity to the established acceptance criteria;

the signature of the person who conducted each test and the test date(s);

the date and the signature of the person who confirmed that the original records were verified for their accuracy, completeness and compliance with the established requirements.

395. (6.61) It shall be also necessary to keep full records specifying:

any changes in the established analytical methods;

regular calibration of laboratory equipment, machines, measuring instruments and recording devices;

all tests of PS for stability;

investigations into deviations from specifications.

Batch dossier review (6.7)

396. (6.70) In order to determine the conformity of intermediate products or PS to the established specifications before the issue of the permit for release of the batch or before its sale it shall be necessary to develop procedures to be observed at the time of review and approval of records on the manufacture and laboratory control of batches, including packaging and labelling.

397. (6.71) Records on the manufacture of batches and laboratory control of the critical process stages shall be verified and confirmed by the quality unit(s) before the issue of the release permit or before the sale of each batch of PS. Records on the manufacture and laboratory control for non-critical process stages may be checked by qualified staff members of the manufacturing unit or other units, according to the procedures approved by the quality unit(s).

398. (6.72) All deviations, reports on investigations and deviations of results from specifications shall be analysed at the time of the review of the batch dossier before the issue of the permit for release of the given batch.

399. (6.73) The quality unit(s) may delegate to the manufacturing unit its duties and powers for the issue of a permit for use of intermediate products, except in cases where products are intended to be supplied outside the scope of the manufacturer’s control.

OPERATIONS WITH STARTING RAW MATERIALS (7)

General control (7.1)

400. (7.10) The manufacturer shall approve documents outlining acceptance, identification, placement under quarantine, storage, handling, sampling, testing, approval or rejection of starting raw materials.

401. (7.11) Manufacturers of intermediate products and (or) PS shall have a system of evaluation of suppliers of starting raw materials critical for quality.

402. (7.12) Starting raw materials shall be supplied by suppliers approved by the quality unit(s), in accordance with agreed specifications.

403. (7.13) If the supplier of critical starting raw materials is not their manufacturer, the manufacturer of intermediate products and (or) PS shall know the name and the address of the manufacturer of such starting raw materials.

404. (7.14) Suppliers of critical starting raw materials may be changed as per Items 540547 hereof.

Acceptance and quarantine (7.2)

405. (7.20) During receipt and before acceptance each package item with starting raw materials or a group of package items shall be visually inspected for the correctness of labelling (including the consistency of names used by the supplier and the customer if they differ) and for damages to containers, damaged seals, signs of outside interference or contamination. Starting raw materials shall be kept under quarantine until sampling, inspection or testing and until obtaining a permit for their use.

406. (7.21) Before received starting raw materials are joined to the available stock (for example, solvents or stocks in storage bins), such received starting raw materials shall be marked as compliant with the requirements to the given starting raw materials, appropriately tested, if applicable, and authorized for use. It shall be necessary to develop procedures for preventing loading of received starting raw materials to the existing stock by mistake.

407. (7.22) The manufacturer shall exclude possible cross contamination of ‘bulk’ supplies if such are made in containers not specially designed for such supplies. This may be confirmed by one or several of the following:

a document confirming clean-up;

testing for impurities;

supplier evaluation.

408. (7.23) Large storage tanks and pipelines servicing them, filling and unloading lines shall be appropriately labelled.

409. (7.24) Each package item or a group of package items with starting raw materials (a batch of starting raw materials) shall be identified with an indicative code, batch number or the number assigned during acceptance. The said number shall be used during registration of the location of each batch. It shall be necessary to use a system for identification of the status of each batch.

Sampling and testing of received starting raw materials and materials (7.3)

410. (7.30) For the purpose of confirming identification of each batch of starting raw materials and materials (excluding starting raw materials and materials specified in Item 412 hereof) it shall be necessary to conduct at least one test. If the manufacturer has a supplier evaluation system, instead of conducting tests the manufacturer may use the supplier’s document certifying quality.

411. (7.31) The supplier approval procedure shall include evaluation of the manufacturer’s capability of supplying raw materials and materials conforming to specifications (for example, data on the quality of previous supplies) on a continuous basis. Before reducing the scope of tests during incoming control, the manufacturer shall make a full analysis of at least three batches. In any case it shall be required to make such full analysis at regular time intervals and to compare its results with the data from the supplier’s document certifying quality. Reliability of such documents certifying quality shall be regularly verified.

412. (7.32) Processing additives, hazardous or highly toxic raw materials, other special materials or materials transferred to another unit under the customer’s control shall not be subject to control provided that there is the manufacturer’s document certifying the quality and compliance of such raw materials with the established requirements. Such materials shall be identified by means of visual inspection of package items, labels and registration of batch numbers. Non-conduct of any on-site control of such raw materials shall be justified and documented.

413. (7.33) Samples shall be representative for the batch of starting raw materials, from which they are taken. Sampling procedures shall specify the number of package items, from which samples are required to be taken, and that part of a package item, from which a sample is taken, and also the quantity of raw materials to be taken from each package item. The number of package items for sampling and the sample size shall be specified in the sampling plan, which shall be prepared considering the criticality of raw materials, variability of properties of raw materials, the previous experience of dealing with the supplier as regards the quality, and quantities necessary for analysis.

414. (7.34) Samples shall be taken in designated places and in accordance with instructions aimed at preventing contamination of taken samples and other materials.

415. (7.35) Package items, from which samples are taken, shall be opened with care and immediately closed after a sample is taken. Such package items shall bear labelling indicating that samples have been taken.

Storage (7.4)

416. (7.40) Starting raw materials shall be handled and stored so as to prevent their decomposition, contamination and cross contamination.

417. (7.41) Starting raw materials stored in fiber drums, bags or boxes shall not be arranged on the floor. Such raw materials shall be located so as to make it possible, if and where necessary, to clean and inspect them.

418. (7.42) The conditions in which and the period of time during which starting raw materials are stored shall not affect their quality. It shall be recommended to see to it that earlier received starting raw materials are used first.

419. (7.43) Certain starting raw materials in appropriate package items may be stored outside premises provided that their identification labels remain legible and their package items are duly cleaned before being opening and use.

420 (7.44) In order to prevent unauthorized use of rejected starting raw materials in the manufacturing process, such rejected starting raw materials shall be labelled and kept under control in quarantine.

Re-evaluation (7.5)

421. (7.50) If and where necessary, starting raw materials shall be subject to re-evaluation in order to determine their usability (for example, after long-term storage or exposure to heat or humidity).

MANUFACTURING PROCESS AND IN-PROCESS CONTROL (8)

Process operations (8.1)

422. (8.10) Starting raw materials for the manufacture of intermediate products and PS shall be weighed or measured in appropriate conditions that do not affect their usability. The accuracy of balances and volumetric instruments shall correspond to their intended purposes.

423. (8.11) If starting raw materials are divided into several portions for their further use in process operations, the container, in which starting raw materials are received, shall be suitable for such purpose and labelled accordingly to indicate the following data:

the name and (or) code of starting raw materials;

the number assigned during acceptance or the control number;

the weight or the volume of staring raw materials in a new container;

if and where necessary, the re-evaluation or re-test date.

424. (8.12) The critical operations of weighing, measuring or division shall be monitored; performance of such operations shall be subject to certification or equivalent control. Before using starting raw materials, the process staff shall make sure that such starting raw materials are really the raw materials specified in the form for records on the manufacture of the batch for the given intermediate products or PS.

425. (8.13) Other critical operations shall be carried out also under control of a second specialist or shall be subject to equivalent control.

426. (8.14) At certain stages of the manufacturing process the actual outputs shall be comparable to the expected ones. The expected outputs within appropriate ranges shall be determined on the basis of the results of the previously conducted laboratory, pilot or commercial tests. The reasons for deviations from the expected output, connected with the critical process stages, shall be investigated for determining their effect (or possible effect) on the quality of corresponding batches.

427. (8.15) Any deviation shall be documented and explained. Any critical deviation shall be investigated.

428. (8.16) The process status of the primary equipment units shall be indicated either on certain equipment units or in corresponding documents, either with the use of computer control systems or with the help of alternative methods.

429. (8.17) The manufacturer shall control materials intended for retreatment or reprocessing for the purpose of preventing unauthorized use.

Time restrictions for operations (8.2)

430. (8.20) If the process instruction (Item 389 hereof) sets time restrictions, such restrictions shall be observed for assuring the quality of intermediate products and PS. The manufacturer shall document and evaluate deviations from such restrictions. Such restrictions may appear to be unnecessary when the manufacturing process aims at reaching set parameters (for example, the necessary pH level, hydrogenation, drying to a preset parameter value) as the completion of reactions or process stages is determined by means of in-control sampling and testing.

431. (8.21) Intermediate products intended for further processing shall be stored in specific conditions to ensure their further usability.

In-process sampling and control (8.3)

432. (8.30) The manufacturer shall develop and approve instructions on monitoring the process and controlling the implementation of those process stages that cause the changeability of quality parameters of intermediate products and PS. The in-process control procedures and appropriate acceptance criteria shall be determined on the basis of the data obtained at the development stage, or on the basis of the previous manufacturing experience.

433. (8.31) Acceptance criteria, the type and scope of testing may depend on the nature of intermediate products and PS released, the reaction or process stage and the extent of the effect of the manufacturing process on the changeability of the product quality. The initial process stages may be accompanied by less strict in-process control whereas the subsequent process stages (for example, the downstream stage) require more strict control.

434. (8.32) The critical in-process control stages and monitoring of the critical processes, including control points and methods, shall be outlined in writing and approved by the quality control unit.

435. (8.33) The in-process control shall be carried out by qualified process staff. The process may be changed and adjusted without preliminary authorization of the quality unit provided that such adjustment is made within the pre-set limits approved by the quality unit. All tests and their results shall be fully documented as part of the batch dossier.

436. (8.34) Sampling methods for in-process materials, intermediate products and PS shall be given in instructions approved by the manufacturer. Sampling plans and methods shall be based on scientifically grounded sampling procedures.

437. (8.35) The manufacturer shall carry out the in-process sampling by using procedures ensuring prevention of contamination of sampled materials and other intermediate products or PS. It shall be necessary to develop procedures for maintaining the integrity of samples after their taking.

438. (8.36) It shall not be generally required to investigate into inconsistencies with specifications during the in-process testing carried out for purposes of the process monitoring and (or) adjustment.

Mixing of batches of intermediate products or pharmaceutical substances (8.4)

439. (8.40) For purposes of this chapter mixing shall imply joining substances compliant with requirements of one specification for obtaining homogeneous intermediate products or PS. The in-process mixing of parts of one and the same batch (for example, joining several centrifuge loads from one batch obtained upon crystallization) or joining of parts of different batches for their further processing shall constitute part of the manufacturing process and shall not be deemed as mixing.

440. (8.41) It shall be prohibited to mix batches that fail to conform to the requirements of specifications with other batches for ensuring conformity to specifications. Each batch making part of the mixture shall be manufactured according to an established technology, shall be individually tested and correspond to the established specifications before mixing.

441. (8.42) Mixing operations shall be used, in particular, for:

mixing small batches in order to increase the batch size;

mixing residues (i.e. relatively small quantities of an isolated substance) of batches of the same intermediate products or the same PS for obtaining a single batch.

442. (8.43) The manufacturer shall control and document mixing processes. The batch obtained as a result of mixing shall be tested, where applicable, for its compliance with specifications.

443. (8.44) The dossier for a batch connected with mixing shall allow tracing back individual batches forming the mixture.

444. (8.45) In cases where physical characteristics of PS are critical (for example, PS used for obtaining solid dosage forms or oral suspensions), mixing operations shall be validated in order to guarantee the homogeneity of a joined batch. Validation shall include testing of critical characteristics (for example, distribution of particles by size, tapped density and bulk density) that may be influenced by the mixing process.

445. (8.46) If mixing may affect stability, the manufacture shall test stability of the final batches obtained as a result of mixing.

446. (8.47) The expiration date or the re-test date of a batch obtained as a result of mixing shall be determined on the basis of the date of manufacture of the oldest residues or the oldest batch in the mixture.

Contamination control (8.5)

447. (8.50) Residues of substances (specifically, residues stuck to the wall of the blender, a layer of damp crystals remaining on the walls of the centrifuge bowl after discharge, residues formed as a result of partial discharge of liquids or crystals from the process receptacle during the transport of a substance to the next process stage) may be joined to the subsequent batches of the same intermediate products or PS given due control. Such joining shall not entail any transfer of degradants or microbial contamination, which may affect the specified profile of impurities of PS.

448. (8.51) Process operations shall be carried out in a way so as to prevent contamination of intermediate products or PS with other substances.

449. (8.52) For the purpose of preventing contamination, the manufacturer shall observe special precautions when handling PS after purification.

PACKAGING AND IDENTIFICATION LABELLING OF PHARMACEUTICAL SUBSTANCES AND INTERMEDIATE PRODUCTS (9)

General requirements (9.1)

450. (9.10) The manufacturer shall approve procedures defining rules of acceptance, identification, placement under quarantine, sampling, research and (or) testing, and issue of permits for the use of packing materials and labelling materials, and procedures for handling such materials.

451. (9.11) Packing materials and labelling materials shall comply with specifications. Those packing/labelling materials that fail to comply with specifications shall be rejected for preventing their use during operations, for which they are not suitable.

452. (9.12) The manufacturer shall keep records for each supply of labels and packing materials by recording data on their acceptance, inspection or testing, their approval or rejection.

Packing materials (9.2)

453. (9.20) Containers shall ensure due protection against spoilage or contamination of intermediate products or PS during transportation and storage in specified conditions.

454. (9.21) Containers shall be clean and, if required by the nature of intermediate products or PS, shall be subject to sanitary treatment to ensure their usability for intended purposes. Such containers shall not be chemically active, shall not have any absorbing properties or be a source of foreign impurities in order not to cause any shifts in the quality of intermediate products or PS beyond the limits set in the specification.

455. (9.22) Reusable containers shall be cleaned according to approved instructions; all previously attached labels shall be erased or removed.

Issue of labels and control (9.3)

456. (9.30) Access to label storage areas shall be granted only to persons vested with appropriate powers.

457. (9.31) The manufacturer shall use procedure for comparing the quantities of issued, used and returned labels to analyse the differences between the quantities of labelled packages and the quantities of issued labels. Such differences shall be investigated and the obtained results shall be approved by the quality unit(s).

458. (9.32) All unused labels with batch numbers or other printed data related to such batches shall be destroyed. Returned labels shall be stored and kept so as to prevent their confusion and ensure due identification.

459. (9.33) Outdated labels shall be destroyed.

460. (9.34) The manufacturer shall control the equipment used for printing labels during packaging operations for the purpose of ensuring that all imprints correspond to the printed text contained in the batch manufacturing records.

461. (9.35) Printed labels issued for a certain batch shall be carefully checked for their authenticity and conformity to the established requirements. Results of such checks shall be documented.

462. (9.36) A printed label sample corresponding to used labels shall be incorporated in the batch manufacturing records.

Packaging and labelling operations (9.4)

463. (9.40) The manufacturer shall approve instructions aimed at ensuring consistent use of packing materials and labels.

464. (9.41) Procedures for labelling operations shall exclude confusion of labelling materials. Operations related to different intermediate products or PS shall be physically or spatially separated.

465. (9.42) Labels used for labelling external surfaces of containers with intermediate products or PS shall bear the name or ID code, the product batch number and storage conditions if such data are critical for ensuring the quality of intermediate products or PS.

466. (9.43) If intermediate products or PS are planned to be transported outside the area of control of the manufacturer’s materials management system, the label shall also indicate the manufacturer’s name and address, quantities of contents, special transportation conditions and any special requirements set by pharmacopoeial monographs and/or normative documents. For intermediate products and PS with set expiration dates, the label and the document certifying quality shall indicate the expiration date of the shelf life. For intermediate products and PS with set re-test dates, such dates shall be indicated on the label and (or) in the document certifying quality.

467. (9.44) The manufacturer shall inspect premises and equipment for packaging and labelling immediately before their use to make sure that all materials not needed for the next packaging operation have been removed. Such inspection shall be documented in the batch manufacturing records, in the premises and equipment operation logbook or in any other documentation system.

468. (9.45) The manufacturer shall inspect packaged and labelled intermediate products or PS to make sure that the primary and secondary packaging for the batch is consistently labelled. Such inspection shall be part of the packaging operation. Results of such inspection may be recorded in the batch manufacturing records or in control documents.

469. (9.46) Packages with intermediate products or PS to be transported outside the area of the manufacturer’s control shall be sealed so that in case of seal integrity violation or in case of absence of seals the receiver could notice possible changes in contents.

STORAGE AND SALES (10)

Warehouse storage (10.1)

470. (10.10) The manufacturer shall provide premises and technical facilities necessary for storage of all materials according to the set conditions (for example, controlled temperature and humidity where necessary). It shall be required to keep records of parameters of such conditions if they are critical for retaining properties of materials.

471. (10.11) The manufacturer shall allocate separate areas for temporary storage of materials under quarantine, for rejected, returned or withdrawn materials until such materials are approved for use, unless the manufacturer has another system for preventing unintended or unauthorized use of such materials.

Sales (10.2)

472. (10.20) PS and intermediate products shall be sold to third parties only after the quality unit(s) issue(s) a permit for their release and the authorized person confirms the batch compliance. PS and intermediate products under quarantine may be transferred to another unit within the area of the manufacturer’s control provided that such transfer is authorized by the quality unit(s) and given appropriate control and documents.

473. (10.21) Conditions of transportation of PS and intermediate products shall not affect their quality.

474. (10.22) Special conditions of transportation or storage of PS or intermediate products shall be indicated on the label.

475. (10.23) The manufacturer shall see to it that the contractor in charge of transportation of PS or intermediate products is aware of and abides by transportation and storage conditions.

476. (10.24) The manufacturer shall have a system allowing prompt identification of the chains of sales of each batch of intermediate products and (or) PS to be able to withdraw them.

LABORATORY CONTROL (11)

General control (11.1)

477. (11.10) The independent quality unit(s) shall have appropriate laboratory premises and equipment.

478. (11.11) The manufacturer shall approve instructions on sampling, testing, approval or rejection of materials, documenting and safe-keeping of laboratory data. Laboratory records shall be kept in accordance with the requirements set out in Items 394395 hereof.

479. (11.12) All specifications, sampling plans and testing procedures shall be scientifically grounded and guarantee that starting raw materials, intermediate products, PS, labels and packing materials conform to general pharmacopoeial monographs, pharmacopoeial monographs and/or normative documents in terms of quality and (or) purity. Specifications and testing procedures shall comply with the requirements of the registration dossier. The manufacturer may also approve specifications supplementing the specifications of the registration dossier. Specifications, sampling plans and testing procedures, including amendments thereto, shall be drawn up by a corresponding unit of the manufacturer and shall be checked and approved by the quality unit(s).

480. (11.13) The manufacturer shall approve specifications for PS, compliant with the general pharmacopoeial monographs, pharmacopoeial monographs and/or normative documents and consistent with the manufacturing process. Specifications shall contain requirements to the control of impurities (for example, organic and inorganic impurities and residual solvents). If there microbiological purity specifications for PS, it shall be necessary to set limits for the total quantity of microorganisms and inadmissible microorganisms entailing measures to be taken according to procedures approved by the manufacturer. If there are endotoxin level specifications for PS, it shall be necessary to set appropriate limits entailing measures to be taken according to procedures approved by the manufacturer.

481. (11.14) All laboratory control procedures shall be carried out according to approved instructions and shall be written down while implemented. Any deviations from the above procedures shall be documented and supported with relevant explanations.

482. (11.15) Any obtained data on the non-conformity to the specification shall be investigated and documented according to an approved procedure. Such procedure shall be used for analysing the data, determining if there are critical problems, identifying appropriate corrective actions and making conclusions. Any repeated sampling and (or) repeated testing after obtaining data on the non-conformity to the specification shall be carried out according to an approved procedure.

483. (11.16) The manufacturer shall prepare and label reagents and reference solutions according to approved instructions. Dishes with analytical reagents or reference solutions (where appropriate) shall indicate the date until which they may be used (‘best before’).

484. (11.17) Primary standard samples shall be necessary for the manufacture of PS (where necessary). The source of each primary standard sample shall be documented. It shall be necessary to keep records on the storage of each primary standard sample and its use according to the supplier’s recommendations. Primary standard samples obtained from officially recognized sources and stored according to the supplier’s recommendations shall be used as a rule without being tested.

485. (11.18) If no primary standard samples are available with officially recognized sources, it shall be necessary to develop an ‘internal’ primary standard sample. Appropriate tests shall be carried out for reliable authentication and establishment of purity of such primary standard sample. Documents related to such tests shall be subject to safe-keeping.

486. (11.19) The manufacturer shall duly prepare, identify, test, approve and store secondary standard samples. Before the first use, each batch of the secondary standard sample shall be identified for usability by being compared to the primary standard sample. Each batch of the secondary standard sample shall be regularly re-qualified according to the protocol.

Testing of intermediate products and pharmaceutical substances (11.2)

487. (11.20) Appropriate laboratory tests shall be conducted for each batch of intermediate products and PS for the purpose of confirming their compliance with specifications.

488. (11.21) As a rule, for each PS it shall be necessary to set an impurity profile describing identified and non-identified impurities present in a typical batch obtained as a result of a specific controlled manufacturing process. The impurity profile shall include identification or any qualitative analytical characteristic (for example, retention time), content limits of each detected impurity and classification of each identified impurity (for example, organic and inorganic impurities, solvent). The impurity profile shall generally depend on the specifics of the manufacturing process and the origin of PS. In most cases it shall not be required to define any impurity profile for plant- or animal-based PS.

489. (11.22) The impurity profile shall be compared at regular time intervals to the impurity profile outlined in the registration dossier or to the previously obtained data in order to track changes in PS resulting from changes in starting raw materials, parameters of the equipment performance or manufacturing process.

490. (11.23) The manufacturer shall conduct appropriate microbiological tests for each batch of intermediate products and PS if their microbiological impurity is subject to limitation.

Validation of analytical methods (11.3)

491. Analytical methods shall be validated as per Items 511539 hereof.

Documents certifying quality (11.4)

492. (11.40) For each batch of intermediate products or PS the original document certifying quality shall be issued on request.

493. (11.41) The document certifying quality shall specify the name of intermediate products or PS, including if and where necessary, grade, batch number and date of release. If there is an established expiration date for intermediate products or PS, such date shall be indicated on the label and in the document certifying quality. If there is an established re-test date for intermediate products or PS, such date shall be indicated on the label and (or) in the document certifying quality.

494. (11.42) The document certifying quality shall list all tests conducted in accordance with the requirements of the general pharmacopoeial monograph, pharmacopoeial monograph and/or normative document, and also with the requirements of the buyer of PS or intermediate products, including admissible thresholds and observed numeric values (where applicable).

495. (11.43) The document certifying quality shall be signed by officers of the quality unit(s) granted appropriate powers, with the date stated, and shall contain the name, address and phone number of the original manufacturer. If tests have been made by an organization performing re-packaging or reprocessing operations, the document certifying quality shall specify its name, address, phone number and the original manufacturer.

496. (11.44) If organizations performing re-packaging and (or) reprocessing operations issue new documents certifying quality, such documents shall specify the name, address and telephone number of the laboratory that conducted tests. Such documents certifying quality shall contain a reference to the name and address of the original manufacturer and to the original document certifying quality, a copy of which shall be attached.

Pharmaceutical substance stability control (11.5)

497. (11.50) The manufacturer shall develop a finalized continued testing programme aimed at controlling the stability of characteristics of PS. Observed results shall be used for confirming proper storage conditions and re-test dates or expiration dates.

498. (11.51) Testing procedures used for stability studies shall be validated and allow obtaining necessary stability data.

499. (11.52) Samples for stability testing shall be stored in containers modelling consumer containers (packaging). For example, if PS are sold in bags packaged in fiber drums, samples for stability testing may be packaged in bags of the same material, placed in smaller drums made of a material similar or identical to the material of the fiber drums, in which PS are released for sale.

500. (11.53) For the purpose of confirming the re-test dates or expiration dates, the stability monitoring programme shall generally cover the first three batches sold. If preliminary studies show that PS can retain stability at least during two years, less than three batches may be used.

501. (11.54) Afterwards, the continued stability testing programme shall cover at least one manufactured batch of PS a year (except in cases where no batches are manufactured during the year), required to be tested for stability at least once a year.

502. (11.55) Tests with respect to PS with short shelf lives shall be conducted more often. For example, for biotechnological, biological and other PS whose storage period is one year or less, it shall be necessary to take samples for stability testing and conduct tests on a monthly basis during the first three months, and then every three months. If there are data confirming that PS retain stability, time intervals between tests may be extended (for example, to nine months).

503. (11.56) While conducting stability tests it shall be recommended to ensure the observance of the storage conditions as per the Guidelines of the International Conference on Harmonization “Studies of Stability of New Medicinal Substances and Drugs” (ICH Q1A) <*>.

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<*> For reference: Guidelines of the International Conference on Harmonization “Studies of Stability of New Medicinal Substances and Drugs” (ICH Q1A) published in the Internet at: http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q1A_R2/Step4/Q1A_R2_Guideline.pdf

Expiration dates and re-test dates (11.6)

504. (11.60) If intermediate products are intended to be transferred outside the scope of control of the manufacturer’s materials management system and there are set expiration dates or re-test dates for such products, it shall be required to have data confirming their stability (for example, published data, test results).

505. (11.61) Expiration dates or re-test dates of PS shall be based on the results of the evaluation of the data obtained during stability studies. Usually re-test dates instead of expiration dates are used for PS.

506. (11.62) Preliminary expiration dates or re-test dates of PS may be based on the results observed for trial batches if: 1) manufacturing methods and procedures used for trial batches model the final process of commercial manufacture and 2) the quality of PS corresponds to the quality of the substance to be commercially released.

507. (11.63) Representative samples shall be taken for conducting re-tests.

Retention samples (11.7)

508. (11.70) Retention samples shall be packaged and stored for the possible future evaluation of the quality of PS batches but not for conducting stability tests.

509. (11.71) Duly labelled retention samples of each PS batch shall be kept during one year from the expiration date of the batch, to be determined by the manufacturer, or during three years from the sale of the batch, whichever is longer. Retention samples of PS with a set re-test date shall be kept during three years after the batch is fully sold by the manufacturer.

510. (11.72) For purposes of storing retention samples, it shall be necessary to use the same system of packaging used for storing PS or a system of packaging equivalent to the packaging system that is designed for sale or ensures safer protection. The manufacturer shall keep retention samples in a quantity sufficient for at least two comprehensive analyses as per the general pharmacopoeial monograph, the pharmacopoeial monograph, or, if no pharmacopoeial monograph is available, for two comprehensive analyses according to the normative documents.

VALIDATION (12)

Validation policy (12.1)

511. (12.10) The manufacturer shall have a documented general validation policy, defining its objectives and principles, including validation of manufacturing processes, cleaning procedures, analytical methods, in-process control, computerized systems and persons in charge of development, inspection, approval and documenting of each validation stage.

512. (12.11) Critical parameters and (or) characteristics shall be generally determined at the development stage or on the basis of the preliminary operational experience data; it shall be also necessary to determine ranges of values for such critical parameters and (or) characteristics necessary for ensuring the process repeatability. For these purposes it shall be necessary to:

determine critical characteristics of PS as products;

specify the process parameters that may influence the critical parameters of the quality of PS;

set a range of values for each critical process parameter planned to be used in the batch manufacturing and process control.

513. (12.12) Operations deemed as critical for the quality and purity of PS shall be subject to validation.

Validation documents (12.2)

514. (12.20) A validation protocol shall be drawn up for each process subject to validation. Such protocol shall be checked and approved by the quality unit(s) and other corresponding units.

515. (12.21) The validation protocol shall define the critical process stages and acceptance criteria, the type of validation (for example, retrospective, prospective, concurrent validation) and the number of manufacturing cycles.

516. (12.22) The validation report shall contain cross references to the validation protocol and summarize obtained results, explain any detected deviations and present corresponding conclusions, including recommended changes for elimination of defects.

517. (12.23) Any deviations from the validation protocol shall be documented and justified.

Qualification (12.3)

518. (12.30) Before starting activities related to the process validation, it shall be necessary to complete qualification of the critical equipment and auxiliary systems. Qualification shall be generally performed by the following stages (on an individual or joint basis):

design qualification: a documented confirmation that the proposed design of manufacturing premises, equipment or systems is suitable for the intended purposes.

installation qualification: a documented confirmation that premises, systems and equipment (installed or modified) have been assembled in accordance with the approved design, the manufacturer’s recommendations and (or) the medicine manufacturer’s requirements.

operational qualification: a documented confirmation that premises, systems and equipment (installed or modified) function according to their intended purposes in all specified operating modes.

performance qualification: a documented confirmation that, when jointly operated, premises, systems and equipment demonstrate effective performance with reproducible parameters according to established requirements and process characteristics.

Process validation approaches (12.4)

519. (12.40) The process validation shall be performed to evidence that the process run within the ranges of the set parameters ensures the effective manufacturing with reproducible parameters of intermediate products or PS compliant with the preliminary set specifications and quality characteristics. The results of the process validation shall be documented.

520. (12.41) There are three validation approaches: prospective validation, concurrent validation and retrospective validation. Prospective validation shall be the recommended approach, except in cases where the other approaches may be used.

521. (12.42) Prospective validation shall be recommended to be performed for all processes related to the manufacture of PS as outlined in Item 513 hereof. Prospective validation performed for a process related to the manufacture of PS shall be completed before sales of the finished medicine produced from such PS.

522. (12.43) Concurrent validation may be performed in the absence of data for repeat manufacturing cycles if a limited number of PS batches was released, if PS batches were seldom released or were manufactured by using a validated process that was modified. Before concurrent validation of a PS batch is completed, the PS batches may be released and used for the manufacture of a medicine intended for sales, given complete control of the PS batches.

523. (12.44) In exceptional cases, retrospective validation may be performed for well-organized processes, to which no significant changes have been made for producing PS of the required quality due to changes in starting raw materials, equipment, systems, technical facilities or the manufacturing process. This validation approach may be used if:

a) (1) there are determined critical quality parameters and critical process parameters;

b) (2) there are duly set acceptance and in-process control criteria;

c) (3) there were no material failures during the process or defects in products for reasons other than operator errors or equipment failures;

d) (4) there are determined impurity profiles for the given PS.

524. (12.45) Batches selected for retrospective validation shall form a representative sampling of all the batches manufactured during the tested period, including any batches that fail to conform to the specifications. The number of such batches shall be sufficient to evidence the process continuity. Retention samples may be tested for obtaining data for retrospective process validation.

Process validation programme (12.5)

525. (12.50) The number of manufacturing cycles necessary for validation shall depend on the process complexity or on the significance of the process changes to be analysed. Retrospective and concurrent validation shall imply using data obtained for three consecutive batches of products of the required quality. However, additional manufacturing cycles (for example, compound PS or long-time manufacturing processes) may appear to be necessary for evidencing the process continuity. The evaluation of the process continuity in case of retrospective validation shall generally imply analysing data for 10 – 30 consecutive batches, or fewer batches given appropriate justification.

526. (12.51) While conducting process validation studies, it shall be necessary to control and check its critical parameters. The process parameters not related to quality, for example, variables controlled for the purpose of reducing electric power consumption or equipment use, may be excluded from the process validation.

527. (12.52) The process validation shall confirm that the impurity profile for each PS is within the set limits. The impurity profile shall be similar to (or better than) the earlier observed profile and (where applicable) the impurity profile determined at the time of the development of the process or batches used for main clinical and toxicological studies.

Periodic inspection of validated systems (12.6)

528. (12.60) Systems and processes shall be regularly inspected for the purpose of verifying their consistent performance and functioning. As a rule, no re-validation shall be needed if no significant changes have been made to a process or a system and the quality review has confirmed that the system or the process continuously ensures the manufacturing of a material compliant with specifications.

Cleaning validation (12.7)

529. (12.70) Cleaning procedures shall be normally subject to validation. The cleaning validation shall be performed in cases where the quality of PS is most compromised by contamination or transfer of substances. For example, the validation of the equipment cleaning procedures at the initial stages of the manufacturing process may appear to be unnecessary if the residual matters are removed at subsequent cleaning stages.

530. (12.71) The validation of cleaning procedures shall reflect the actual type of use of equipment. If different PS or different intermediate products are manufactured with the use of the same equipment and such equipment is cleaned by using the same method, representative intermediate products or PS may be selected for the cleaning validation. Such selection shall be based on the solubility data, information about cleaning problems, and calculations of the maximum content of residues considering their activity, toxicity and stability.

531. (12.72) The cleaning validation protocol shall specify the equipment subject to cleaning, procedures, materials, admissible cleaning levels, controlled and adjustable parameters and analytical methods. The protocol shall also specify the types of samples taken, sampling and labelling methods.

532. (12.73) For detecting both insoluble and soluble residues, the sampling methods shall include, as the case may be, smearing, wipe sampling or other methods (for example, direct extraction). The applied sampling methods shall allow quantitative measurements of the levels of residues on equipment surfaces after cleaning. Sampling such as smear taking may appear to be impracticable if the product-contacting surfaces are not easily accessible due to design features of equipment (for example, inside surfaces of hoses, transport pipelines, reactor tanks with narrow hatches, and small complex equipment, for example, micronizators and micro dispensers) and (or) if there are process limitations (for example, processing of toxic substances).

533. (12.74) It shall be required to use validated analytical methods with sufficient sensitivity for detecting residues or contaminants. Detection limits of each analytical method shall be adequate for detecting certain acceptable levels of residues or contaminants. An achievable substance extraction level shall be set for a method. The residues content limits shall be specific, achievable and verifiable and shall be based on the content of the most harmful residue. The limits may be set on the basis of the minimum quantity of PS or its most harmful component with a known pharmacological, toxicological or physiological activity.

534. (12.75) For processes that require reducing the total quantity of microorganisms or endotoxins in PS or for other processes for which such contamination may be significant (for example, manufacture of non-sterile PS used for the manufacture of sterile medicines), the cleaning studies and (or) sanitary treatment of equipment shall be required to be performed with respect to contamination with microorganism and endotoxins.

535. (12.76) The manufacturer shall monitor the cleaning procedures at certain time intervals after validation in order to make sure that such procedures are effective when used during the current manufacturing process. Where practicable, the cleanness of equipment shall be controlled by means of analytical tests and visual inspection. Visual inspection allows detecting considerable formations of contaminants within small areas, which may fail to be detected by using any other method during sampling and (or) analysis.

Validation of analytical methods (12.8)

536. (12.80) The applied analytical methods shall be subject to validation. Nevertheless, the applicability of all used testing methods shall be verified in the field based setting; the results shall be documented.

537. (12.81) Validation of methods shall be performed considering characteristics given in the guidelines for validation of analytical methods. The scope of the analytical validation shall depend on the purpose of the analysis and the stage of the PS manufacturing process.

538. (12.82) Before the validation of analytical methods, the analytical equipment shall be duly qualified.

539. (12.83) It shall be necessary to keep full records of any changes in a validated analytical method. Such records shall specify the cause of the change and the relevant data for confirming that the change brings about results as accurate and reliable as the results obtained with the use of the established method.

CHANGE CONTROL (13)

540. (13.10) The manufacturer shall develop a change control system for evaluating all changes that may influence the manufacturing process and control of intermediate products and PS.

541. (13.11) The manufacturer shall approve procedures for identification, documenting, appropriate inspection and approval of changes with respect to starting raw materials, specifications, analytical methods, premises, auxiliary systems, equipment (including computer equipment), process stages, packing materials, labelling materials and also software.

542. (13.12) Any proposals as regards changes concerning the organization of manufacture and quality control of medicines shall be prepared, checked and approved by corresponding units, and afterwards checked and approved by the quality unit(s).

543. (13.13) It shall be necessary to analyse the potential effect of a proposed change on the quality of intermediate products or PS. Change classification procedures may be used to facilitate determining the scope of testing, validation and documentation required for substantiation of changes made to a validated process. Changes may be classified (for example, as material or minor changes) depending on their type and scope and effect that they may have on the process. Based on a substantiated opinion, the manufacturer shall decide which additional validation tests and studies need to be performed for substantiating such changes.

544. (13.14) When introducing approved changes, it shall be necessary to revise all the documents whose contents may be influenced by such changes.

545. (13.15) The introduction of a change shall be followed by an evaluation of the first batches manufactured or tests after the introduction of such change.

546. (13.16) The manufacturer shall evaluate the potential effect of critical changes on stability and, hence, on the set re-test dates or expiration dates. If and where necessary, samples of intermediate products or PS that have been manufactured by running a changed process may be incorporated in the accelerated stability studies and (or) stability monitoring programme(s).

547. (13.17) The manufacturer shall notify corresponding medicine manufacturers of changes in established manufacturing processes and process control procedures, which may influence the quality of PS.

REJECTION AND RECOVERY OF MATERIALS (14)

Rejection (14.1)

548. (14.10) Intermediate products and PS that fail to conform to the approved specifications shall be clearly labelled as may be appropriate and kept under quarantine. Such intermediate products or PS may be subject to reprocessing or retreatment. The final decision with respect to rejected materials shall be documented.

Retreatment (14.2)

549. (14.20) Re-introduction in the process of intermediate products or PS, including products that fail to conform to specifications, and their retreatment by repeating the crystallization stage or other corresponding stages of chemical or physical treatment (for example, distillation, filtration, chromatographic run, disintegration), making part of the established manufacturing process, shall be normally regarded as acceptable. However, if retreatment is used for most batches, it shall be integrated as part of the standard manufacturing process.

550. (14.21) Continuation of a stage of the manufacturing process after the in-process control reveals that the stage has not been completed shall be deemed as part of the normal process and not as retreatment.

551. (14.22) Re-introduction of an unreacted substance in the process and repeated carrying out of the chemical reaction shall be deemed as retreatment unless it is part of the established process. Such retreatment shall be preceded by a thorough evaluation to guarantee that it shall not affect the quality of intermediate products or PS due to possible formation of byproducts and substances that have reacted beyond the set standard limits.

Reprocessing (14.3)

552. (14.30) Before it is decided to reprocess batches that fail to conform to specifications, reasons for such failure shall be investigated.

553. (14.31) Batches decided to be reprocessed shall be subject (if there are indications) to appropriate evaluation, testing, stability studies and documenting in order to ensure that by quality the reprocessed products are equivalent to the products manufactured in the course of the originally established manufacturing process. The most appropriate validation approach to reprocessing procedures shall be concurrent validation. This approach allows making records on the reprocessing procedure, determining the order of its performance and expected results. If only one batch is subject to reprocessing, a written report may be drawn up and the batch may be approved for release immediately after its quality is confirmed.

554. (14.32) The manufacturer shall approve procedures for comparing impurity profiles of every reprocessed batch to impurity profiles of batches manufactured in the course of the established process. If the applied analytical methods do not provide for due analysis of a reprocessed batch, additional methods shall be used.

Regeneration of materials and solvents (14.4)

555. (14.40) Regeneration (for example, from mother liquid or filtrates) of reagents, intermediate products or PS shall be deemed as acceptable provided that there are approved regeneration procedures and that regenerated materials conform to the specifications applicable for the intended use of such materials.

556. (14.41) It shall be allowed to regenerate and re-use solvents in the same or other processes provided that regeneration procedures are controlled and verified for ensuring compliance of solvents with specifications before their re-use or mixing with other approved materials.

557. (14.42) It shall be allowed to mix new and regenerated solvents and reagents if the appropriate tests have proved their usability for all manufacturing processes, in which they may be used.

558. (14.43) The use of regenerated solvents, mother liquids and other regenerated substances shall be documented.

Return (14.5)

559. (14.50) The manufacturer shall duly label returned intermediate products or returned PS and keep them under quarantine.

560. (14.51) If the manufacturer has doubts about the observance of proper conditions of storage or transportation of returned intermediate products or returned PS before or during their return or about the condition of containers as regards potential influence on quality, returned intermediate products or returned PS shall be subject to retreatment, reprocessing or destruction, as the case may be.

561. (14.52) The manufacturer shall keep records on returns of intermediate products or PS. Data to be documented for each return:

the name and address of the receiver;

the name of intermediate products or PS, the batch number and the returned quantity;

the cause of return;

directions for use or destruction of returned intermediate products or PS.

CLAIMS AND WITHDRAWALS (15)

562. (15.10) The manufacturer shall document and investigate according to approved instructions all quality claims received by it, regardless of the form of such claims (oral or written).

563. (15.11) Claim review records shall contain:

the name and address of the claimant;

the first name, patronymic (if any) and last name and, where necessary, position of the claimant and his/her phone number;

the subject-matter of the claim (including the PS name and batch number);

the date of the claim;

initially taken measures, with the date and the person who took such measures;

further actions for the claim review;

the answer sent to the claimant (including the date of sending such answer);

the final decision about the batch or lot of intermediate products or PS.

564. (15.12) Claim review records shall be kept for analysing tendencies, the frequency of the receipt of claims and their materiality for taking additional and, if and where necessary, immediate corrective actions.

565. (15.13) The manufacturer shall approve procedures for identifying circumstances, under which it shall be required to consider withdrawing intermediate products or PS.

566. (15.14) The withdrawal procedure shall define who should participate in the evaluation of information, how to launch the withdrawal procedure, who should be informed about withdrawal and what to do with withdrawn materials.

567. (15.15) In case of serious situations or situations potentially threatening human life the manufacturer shall notify the authorized federal executive authority and competent authorities of the countries, to which products have been released.

CONTRACTUAL MANUFACTURE (INCLUDING LABORATORIES) (16)

568. (16.10) All contractors working on a contractual basis (including laboratories) shall abide by the requirements of these Rules. Special attention shall be paid to preventing cross contamination and ensuring traceability.

569. (16.11) The customer shall evaluate the contractor engaged on a contractual basis (including laboratories) for determining compliance of specific operations performed at the manufacturing sites of the contractor engaged on a contractual basis with the requirements of these Rules.

570. (16.12) The contract signed between the customer and the contractor shall be recommended to stipulate in detail the obligations of the parties regarding compliance with the requirements of these Rules, including quality assurance activities to be implemented by each of the parties.

571. (16.13) It shall be recommended to stipulate in the contract the customer’s right to audit the contractor’s activities for compliance with the requirements of these Rules.

572. (16.14) It shall be recommended to stipulate in the contract that the contractor may employ third parties for the performance of the contract only upon consent of the customer.

573. (16.15) Manufacturing and laboratory records shall be kept at the manufacturing site where works were performed. Such records shall be easily accessible.

574. (16.16) It shall be recommended to stipulate in the contract that the contractor may not introduce changes or modifications in the manufacturing process, equipment, testing procedures and specifications, agreed by the parties, as well as to other provisions of the contract without the customer’s consent.

ORGANIZATIONS SPECIALIZING IN REPACKAGING AND (OR) RELABELING (17)

Scope of application (17.1)

575. (17.10) The requirements set forth in Items 575589 hereof shall apply to organizations that are not the original manufacturers of PS or intermediate products but specialize in repackaging and (or) relabeling.

576. (17.11) Organizations specializing in repackaging and (or) relabeling shall abide by the requirements of this chapter.

Traceability of sold pharmaceutical substances and intermediate products (17.2)

577. (17.20) Organizations specializing in repackaging and (or) relabeling shall ensure complete traceability of PS and intermediate products sold by them. For these purposes it shall be required to have and keep the following documents and information:

the name of the original manufacturer;

the address of the original manufacturer;

supply orders;

waybills (shipping documents);

acceptance documents;

the name or designation of PS or intermediate products;

the batch number assigned by the manufacturer;

information about transportation and sales;

all original documents certifying quality, including documents certifying quality that are obtained after repackaging and (or) relabeling and documents received from the original manufacturer;

the re-test date or the expiration date.

Quality management (17.3)

578. (17.30) Organizations specializing in repackaging and (or) relabeling shall develop and implement an effective quality management system as set forth in Items 289308 hereof and keep all necessary documents.

Repackaging, relabeling and storage of pharmaceutical substances and intermediate products (17.4)

579. (17.40) PS and intermediate products shall be repackaged, relabelled and stored in accordance with the requirements of these Rules for the purpose of avoiding confusion or loss of authenticity or purity of PS or intermediate products.

580. (17.41) Repackaging shall be carried out in an appropriate process environment for the purpose of preventing contamination or cross contamination.

Stability (17.5)

581. (17.50) In cases where PS or intermediate products are repackaged in containers (primary packaging) of a type other than the container type used by the manufacturer of PS or intermediate products, it shall be necessary to study stability in order to substantiate the set expiration date or re-test date.

Communication of information (17.6)

582. (17.60) Organizations specializing in repackaging and (or) labelling shall communicate all information about quality and decisions of the authorized federal executive authority, received from the manufacturer of PS or intermediate products, to the buyer, and information from the buyer – to the manufacturer of PS or intermediate products.

583. (17.61) When selling PS or intermediate products to the buyer, organizations specializing in repackaging and (or) relabeling shall specify the name of the original manufacturer of PS or intermediate products and the number(s) of the batch supplied.

584. (17.62) Upon request of the authorized federal executive authority, organizations specializing in repackaging and (or) labelling shall furnish information about the original manufacturer of PS or intermediate products. The original manufacturer may directly furnish such information to the authorized federal executive authority or communicate it via its representatives.

585. (17.63) Documents certifying quality shall be subject to the special requirements set out in Items 492496 hereof.

Dealing with claims and withdrawals (17.7)

586. (17.70) Organizations specializing in repackaging and (or) labelling shall keep records on claim reviews and withdrawals according to the rules set out in Items 562567 hereof, with respect to all claims and withdrawals within their operational scope.

587. (17.71) If and where necessary, organizations specializing in repackaging and (or) labelling shall review claims in cooperation with the original manufacturer of PS or intermediate products in order to determine whether it is necessary to take further steps together with other buyers that might receive the same PS or intermediate products, or with the authorized federal executive authority, or with all concerned parties. Investigations into reasons for claims or withdrawals shall be carried out and documented by a corresponding party.

588. (17.72) If a claim concerns the original manufacturer of PS or intermediate products, the claim review records kept by organizations specializing in repackaging and (or) labelling shall incorporate all and any answers received from the original manufacturer of PS or intermediate products (including the date and information furnished).

Dealing with returns (17.8)

589. (17.80) Returns of products shall be handled in accordance with the requirements set out in Item 561 hereof. Organizations specializing in repackaging and (or) labelling shall keep documents regarding returned PS and intermediate products.

SPECIAL GUIDELINES ON PHARMACEUTICAL SUBSTANCES MANUFACTURED BY MEANS OF CELL CULTIVATION OR FERMENTATION (18)

General requirements (18.1)

590. (18.10) Items 590 — 621 hereof shall set forth special requirements to control of PS or intermediate products manufactured by means of cell cultivation or fermentation with the use of natural or recombinant organisms. The said requirements shall be considered in combination with the other requirements because the requirements outlined in other items of these Rules are also applicable to such products. ‘Classical’ processes of obtaining low molecular substances and processes using recombinant and non-recombinant organisms for production of proteins and (or) polypeptides shall be subject to identical fermentation principles, even though with a different level of control. If practically observed, such differences shall be specified in the said items. The level of control of biotechnological processes used for production of proteins and polypeptides shall be higher than for classical fermentation processes.

591. (18.11) The term ‘biotechnological process’ shall refer to the use of cells or organisms obtained or modified by means of the rDNA, hybridoma or other technology for manufacture of PS. PS obtained by means of biotechnological processes shall be generally composed of high molecular compounds such as proteins and polypeptides subject to the special requirements set out in Items 590621 hereof. The rDNA technology may be used also for obtaining certain PS with a low molecular weight such as antibiotics, amino acids, vitamins and carbohydrates. The level of control of such types of PS shall be similar to the level of control used for classical fermentation.

592. (18.12) The term ‘classical fermentation’ shall refer to processes of obtaining PS, in which natural microorganisms and (or) microorganisms modified with the use of conventional methods (for example, by means of radiation exposure or chemical mutagenesis) are used. PS obtained by means of ‘classical fermentation’ are generally products with a low molecular weight such as antibiotics, amino acids, vitamins and carbohydrates.

593. (18.13) Manufacture of PS or intermediate products from cell cultures or by means of fermentation shall comprise processes such as cell cultivation or extraction and purification of the material obtained from living organisms. Such processes may include additional stages making part of the manufacturing process, such as physical and chemical modification. Starting raw materials (media, buffer components) that are used may allow growth of contaminating microorganisms. Depending on the source, the method of production and the intended application of PS or intermediate products, it may be necessary to ensure control of the bioburden, contamination with viruses and (or) endotoxins during the manufacturing process and monitoring at appropriate stages.

594. (18.14) For ensuring the quality of intermediate products and (or) PS, due control shall be provided at all manufacturing stages. Although this chapter applies to stages starting from cell cultivation or fermentation, preceding stages (for example, creation of a cell bank) shall be subject to due in-process control. This chapter shall cover cell cultivation or fermentation, from the moment of the extraction from the cell bank of the bottle with a cell culture to be used in the manufacturing process.

595. (18.15) For minimizing the risk of contamination, the manufacturer shall use appropriate equipment and control the process environment. Acceptance criteria for the quality of the process environment and the control frequency shall depend on the stages and conditions of the manufacturing process (open, closed or isolated systems).

596. (18.16) In-process control shall imply:

maintenance of the working cell bank (if any);

accurate culture inoculation and growth;

control of the critical performance parameters during cell cultivation or fermentation;

control over the cell growth process, cell viability (for most cell cultivation processes) and productivity, where applicable;

collection and purification procedures aimed at removing cells, cell residues and media components alongside protecting intermediate products or PS from contamination (especially microbiological contamination) and quality deterioration;

control of the bioburden and levels of endotoxins (where necessary) at corresponding stages of the manufacturing process;

viral safety.

597. (18.17) Where applicable, it shall be proved that media components, host cell proteins, other impurities and contaminants associated with the process and related to products are removed.

Maintenance of the cell bank and record keeping (18.2)

598. (18.20) Access to cell banks shall be allowed only to persons granted appropriate powers.

599. (18.21) Cell banks shall be stored in conditions specially designated for ensuring maintenance of the cell viability and preventing contamination.

600. (18.22) The manufacturer shall maintain and keep records on the use and conditions of storage of bottles from cell banks.

601. (18.23) If and where necessary, cell banks shall be subject to periodic inspections for determining their usability.

602. (18.24) If regulatory legal acts of the Russian Federation set special requirements to the maintenance of cell banks, such requirements shall be binding.

Cell cultivation or fermentation (18.3)

603. (18.30) If cell substrates, media, buffers and gases need to be aseptically added, where possible, closed or isolated systems shall be used. If the inoculation in the original receptacle or subsequent transfers or additions (in particular, of media, buffers) are carried out in open receptacles, it shall be necessary to implement control and appropriate procedures in order to minimize the risk of contamination.

604. (18.31) In cases where microbial contamination may affect the quality of PS, operations with the use of open receptacles shall be carried out in a box ensuring biological safety or in a similarly controlled process environment.

605. (18.32) When handling cell cultures, staff members shall wear special clothes and observe special precautions.

606. (18.33) For the purpose of ensuring the continuity of the established process, the manufacturer shall control critical performance parameters (for example, temperature, pH, mixing rate, gas addition, pressure). The manufacturer shall also control the growth, viability (for most cell cultivation processes) and, where applicable, productivity of cells. The critical parameters shall vary from process to process and in case of classical fermentation controlling certain parameters (for example, cell viability) may appear to be unnecessary.

607. (18.34) After being used, equipment used for cell cultivation shall be cleaned and sterilized. If and where necessary, fermentation equipment shall be also subject to cleaning, sanitary treatment or sterilization.

608. (18.35) Before being used, growth media shall be sterilized to prevent any adverse effect on the quality of PS.

609. (18.36) The manufacturer shall approve procedure for detecting contamination and determining actions to be performed. Such procedures shall include procedures for identifying the effect of contamination on products and procedures for decontaminating equipment and bringing it back to a state allowing using the equipment for manufacture of subsequent batches.

610. If and where necessary, the manufacturer shall identify foreign organisms detected during fermentation processes and evaluate the effect of their presence on the product quality. Results of such evaluations shall be taken into account when deciding on the usability of the obtained material.

611. (18.37) The manufacturer shall keep records on detected contamination.

612. (18.38) The cleaning of the general-purpose equipment (designed for manufacture of many types of products) between manufacturing cycles for production of different products may be required to be followed by additional testing for the purpose of minimizing the risk of cross contamination.

Collection, extraction and purification (18.4)

613. (18.40) Collection stages both for removing cells or cell components and for collecting cell components after breakdown shall be carried out with the use of equipment and in areas designated for minimizing the risk of contamination.

614. (18.41) Collection and purification procedures allowing removing or inactivating the microorganism-producer, cell residues and media components (at minimized breakdown, contamination and quality deterioration) shall ensure obtaining intermediate products or PS of a consistent quality.

615. (18.42) After being used, all equipment shall be subject to cleaning and sanitary treatment according to established procedures. It shall be allowed to manufacture several consecutive batches of intermediate products and PS without cleaning the equipment provided that their quality is not affected.

616. (18.43) In case of use of open systems, cleaning shall be made in controlled conditions of the process environment, preserving the product quality.

617. (18.44) If equipment is used for manufacturing different types of products, additional control measures may be applied, such as use of special chromatographic resins or additional tests.

Virus removal or inactivation stages (18.5)

618. (18.50) If regulatory legal acts of the Russian Federation set special requirements to virus removal or inactivation, such requirements shall be binding.

619. (18.51) The virus removal and inactivation stages shall be critical processing stages for certain processes and shall be performed within the limits of validated parameters.

620. (18.52) The manufacturer shall take appropriate precautions to prevent potential viral contamination of products that have undergone the virus removal or inactivation stages with products that have not undergone these stages. For this purpose, processing operations in open systems shall be carried out in areas separated from other manufacturing stages and supplied with individual air treatment systems.

621. (18.53) Normally it shall not be recommended to use the same equipment at different purification stages. In case of need to use the same equipment, before being re-used such equipment shall be duly cleaned and subject to sanitary treatment. The manufacturer shall take appropriate precautions to prevent potential transfer of viruses from the previous stages (for example, via equipment or the process environment).

PHARMACEUTICAL SUBSTANCES INTENDED FOR CLINICAL STUDIES (19)

General requirements (19.1)

622. (19.10) Not all types of control outlined in the previous items of this chapter shall be applicable during manufacture of the original PS intended for conducting studies during its development. Items 622644 hereof shall outline special requirements to such PS.

623. (19.11) Control performed during manufacture of PS intended for clinical studies shall correspond to the phase of the development of the medicine, in which the PS is a component. The process and methods of studies shall be flexible to allow introducing changes upon accumulation of the knowledge about the process and advancing of the studies of the medicine from pre-clinical to clinical studies. When the medicine development process reaches a stage of obtaining PS for being used in the medicine intended for clinical studies, manufacturers shall guarantee that PS have been manufactured with the use of appropriate technical facilities and subject to appropriate manufacturing and control procedures necessary for ensuring the quality of PS.

Quality (19.2)

624. (19.20) PS intended for clinical studies shall be manufactured subject to the corresponding requirements of these Rules and appropriate procedures for approval of each batch.

625. (19.21) It shall be necessary to set up a quality unit (units), independent from processing units, which shall approve or reject each of batch of PS intended for clinical studies.

626. (19.22) Certain testing functions generally performed by the quality unit(s) may be performed in other units.

627. (19.23) Quality-related activities shall comprise a system of testing of starting raw materials, packing materials, intermediate products and PS.

628. (19.24) The manufacturer shall analyse problems related to the manufacture and quality of PS intended for clinical studies.

629. (19.25) The text of labels for PS intended for clinical studies shall be duly controlled. Such text shall indicate that the substance is intended for studies.

Premises and equipment (19.3)

630. (19.30). All phases of clinical studies, including use of trial areas or laboratories for the manufacture of PS batches intended for clinical studies, shall be implemented according to established procedures ensuring that equipment has been calibrated, cleaned and corresponds to its intended purposes.

631. (19.31) Procedures for the operation of equipment shall ensure that operations with starting raw materials are carried out in a way so as to minimize the risk of contamination and cross contamination.

Control of starting raw materials (19.4)

632. (19.40) Starting raw materials used in the manufacture of PS intended for clinical studies shall be evaluated by means of testing or accepted together with results of tests conducted by the supplier. The manufacturer shall also test starting raw materials for authenticity. If a substance is deemed as hazardous, the test conducted by the supplier shall be sufficient.

633. (19.41) In some cases the suitability of starting raw materials may be determined before use on the basis of results of a small reaction (i.e. operational suitability tests); the latter option shall be preferable to analytical tests.

Manufacture (19.5)

634. (19.50) Manufacture of PS intended for clinical studies shall be recorded in laboratory notebooks, in batch records or otherwise as may be appropriate. Such documents shall include information about the use of materials, about equipment, the manufacturing process and scientific observations.

635. (19.51) The expected outputs may differ from and be less definite than the expected outputs in the processes performed on a commercial scale. It shall not be required to investigate into reasons for deviations from the expected output.

Validation (19.6)

636. (19.60) If one batch of PS is manufactured or if changes to the process during the PS development render the batch reproduction difficult or inaccurate, it shall be usually unnecessary to validate the process of the manufacture of PS intended for clinical studies. At this development stage the quality of PS shall be assured by means of combining control, calibration and, where necessary, qualification of equipment.

637. (19.61) If batches are manufactured for commercial use, the process shall be validated as per Items 511539 hereof even if such batches are manufactured on a pilot or pilot-and-commercial scale.

Changes (19.7)

638. (19.70) The manufacturer shall introduce appropriate changes in the course of the development upon accumulation of new knowledge and expansion of the scale of operations. Each change in the manufacturing process, specifications or testing procedures shall be duly registered.

Laboratory control (19.8)

639. (19.80) Even if not yet validated, analytical methods used for evaluation of a PS batch intended for clinical studies shall be scientifically grounded.

640. (19.81) The manufacturer shall organize a system of storage of retention samples of all batches. Such system shall ensure preservation of a sufficient quantity of each retention sample during a set period of time after approval, closure or withdrawal of the marketing authorization application.

641. (19.82) Determination of the expiration date and the re-test date as set out in Items 504507 hereof shall be applicable to the existing PS intended for clinical studies. Generally, the requirements specified in Items 504507 hereof shall not apply to new PS at early stages of clinical studies.

Documentation (19.9)

642. (19.90) The documentation system shall ensure that the information obtained in the course of the development and manufacture of PS intended for clinical studies shall be duly documented and available for use.

643. (19.91) Development and application of analytical methods used for the confirmation of the release of PS batches intended for clinical studies shall be documented.

644. (19.92) The manufacturer shall develop and implement a system of safe-keeping of manufacturing and control records and appropriate documents. Such system shall ensure safe-keeping of records and documents during a set period of time after approval, closure or withdrawal of the marketing authorization application.

TERMS AND DEFINITIONS (20)

645. For purposes of this chapter, in addition to the terms and definitions given in Chapter II hereof, the following basic terms shall be used:

bioburden: the level and the type of microorganisms (for example, inadmissible or admissible microorganisms) that may be present in starting raw materials, starting raw materials for the manufacture of a pharmaceutical substance, intermediate products or a pharmaceutical substance. Bioburden shall not be regarded as contamination if its levels are within the set limits or if no microorganisms defined as inadmissible are detected;

excipients: materials, excluding solvents, which are auxiliary in the manufacture of intermediate products or pharmaceutical substances and do not participate as such in chemical or biological reactions (for example, filtering materials, charcoal);

expected output: a quantity of a material or percent of the theoretical output expected at any corresponding stage of the manufacturing process and based on the data preliminarily obtained in the course of the manufacture of the given material in laboratory, trial or industrial setting;

theoretical output: a quantity that is determined on the basis of the quantity of the material used and may be produced at any corresponding stage of the manufacturing process provided that there are no losses or deviations in the conditions of the real manufacturing process;

expiration date: the date specified on the packaging and (or) labels of a pharmaceutical substance, denoting a period of time during which characteristics of the pharmaceutical substance during storage in specified conditions are supposed to remain within the limits of specifications and upon the expiry of which the pharmaceutical substance may no longer be used;

re-test date: the date of the repeated control of a material for confirming its further usability;

starting raw materials for manufacture of a pharmaceutical substance: raw materials, intermediate products or other pharmaceutical substances that are used for manufacture of pharmaceutical substances and make part of the structure of the pharmaceutical substance as an important structural fragment. Starting raw materials for manufacture of a pharmaceutical substance may be purchased by the manufacturer under a contract from one or several suppliers, or may be independently produced by the manufacturer. Starting raw materials for manufacture of a pharmaceutical substance generally have the established chemical properties and structure;

computer system: a group of hardware components and appropriate software, designed and installed so as to fulfil a certain function or a set of functions;

contamination: unwanted introduction of chemical or microbiological impurities or foreign substances in starting raw materials, intermediate products or PS during the manufacturing process, sampling, packaging or repackaging, storage or transportation;

acceptance criteria (permissible rates): numeric limits, intervals or other appropriate measures for accepting test results;

critical: a term referring to a manufacturing stage, a condition of the manufacturing process, a test criteria or any other material parameter or object, subject to control within the limits of the set criteria for ensuring the compliance of a medicine and (or) a pharmaceutical substance with the approved specification;

material: a general term denoting raw materials (starting raw materials, reagents, solvents), excipients, intermediate products, pharmaceutical substance, packing materials, labelling materials;

mother liquid: residual liquid after crystallization or extraction processes. Mother liquid may contain unreacted substances, intermediate products, certain quantities of a pharmaceutical substance and (or) impurities. It may be used for further processing;

quality assurance: a combination of all organizational activities aimed at ensuring that all medicines and (or) pharmaceutical substances possess the quality required for their intended application and all quality systems are maintained in good working order;

deviation: a departure from an approved instruction or an established standard;

processing: performance of one or several stages different from the established manufacturing process for the purpose of processing an intermediate product or a pharmaceutical substance that fails to conform to standards or specifications in order to obtain an intermediate product or a pharmaceutical substance of an acceptable quality (for example, recrystallization by using another solvent);

signed, signature: the signature of the person who performed a certain action or made an inspection. Such signature may be given in the form of initials, a full hand-written name (first name, patronymic (if any) and last name), a hand-written signature, a personal seal or an authentic protected electronic signature;

quality unit(s): a unit that is independent from processing units and performs duties related both to the quality assurance and quality control. It may be either separate quality assurance and quality control units or one person or a group of persons, depending on the company’s scope and structure;

impurity: any unwanted component present in an intermediate product or a pharmaceutical substance;

contract manufacturer: a manufacturer engaged in a certain manufacturing activity by order of the original manufacturer;

validation protocol: a documented plan that contains validation guidelines and defines acceptance criteria. In particular, the protocol of validation of the manufacturing process shall specify the process equipment, the critical parameters and operational modes of the process, product characteristics, sampling, test data to be collected, the number of validation cycles and acceptable test results;

impurity profile: a description of identified and unidentified impurities present in a pharmaceutical substance;

solvent: an inorganic or organic liquid used as the medium for preparation of solutions or suspensions during manufacture of intermediate products or pharmaceutical substances;

standard sample, secondary: a substance of an established quality and purity, which is proved by means of comparison to the primary standard sample, used as a standard sample for the current laboratory tests;

standard sample, primary: a substance that is an authentic substance, which is proved by means of extended analytical tests, and is required to have a high level of purity. Such standard may be: 1) obtained from an officially recognized source, or 2) obtained by means of independent synthesis, or 3) obtained from a substance with a high level of purity, used in the manufacturing process, or 4) prepared by means of subsequent purification of a substance used in the manufacturing process;

pharmaceutical substances (PS): medicines in the form of active ingredients of biological, biotechnological, mineral or chemical origin, with a pharmacological activity, intended for production, manufacture of medicines and determining their efficacy <*>.

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<*> Paragraph 2 Article 4 of Federal Law No. 61-FZ dated 12 April 2010 “On Circulation of Medicines” (Collection of Legislative Acts of the Russian Federation, 2010, No. 16, Art. 1815).

Attachment No. 1 MANUFACTURE OF STERILE MEDICINES

Attachment No. 2 MANUFACTURE OF BIOLOGICAL (INCLUDING IMMUNOBIOLOGICAL) PHARMACEUTICAL SUBSTANCES AND MEDICINES

Attachment No. 3 MANUFACTURE OF RADIOPHARMACEUTICAL MEDICINES

Attachment No. 4 PARTICULARITIES OF MANUFACTURE OF MEDICINES FOR VETERINARY APPLICATION (EXCEPT IMMUNOBIOLOGICAL MEDICINE FOR VETERINARY APPLICATION)

Attachment No. 5 PARTICULARITIES OF MANUFACTURE OF IMMUNOBIOLOGICAL MEDICINES FOR VETERINARY APPLICATION

Attachment No. 6 MANUFACTURE OF MEDICAL GASES

Attachment No. 7 MANUFACTURE OF HERBAL MEDICINAL PRODUCTS

Attachment No. 8 SAMPLES OF STARTING RAW MATERIALS AND PACKING MATERIALS

Attachment No. 9 MANUFACTURE OF LIQUIDS, CREAMS AND OINTMENTS

Attachment No. 10 MANUFACTURE OF DOSAGE AEROSOL MEDICINES UNDER PRESSURE FOR INHALATIONS

Attachment No. 11 COMPUTERIZED SYSTEMS

Attachment No. 12 USE OF IONIZING RADIATION IN THE MANUFACTURE OF MEDICINES

Attachment No. 13 MEDICINES FOR CLINICAL STUDIES

Attachment No. 14 MANUFACTURE OF MEDICINES FROM DONATED BLOOD AND PLASMA

Attachment No. 15 QUALIFICATION AND VALIDATION

Attachment No. 16 CONFIRMATION BY THE AUTHORIZED PERSON OF THE CONFORMITY OF A BATCH OF PRODUCTS TO THE PURPOSE OF THEIR RELEASE

Attachment No. 17 PARAMETER-BASED RELEASE

Attachment No. 18 (19) CONTROL AND RETENTION SAMPLES