Attachment No. 13
to the Rules of Good Manufacturing Practice
Содержание
MEDICINES FOR CLINICAL STUDIES
I. PRINCIPLE
1. Medicines for clinical studies shall be manufactured in accordance with these Rules and subject to provisions of relevant regulatory legal acts of the Russian Federation depending on the development stage of the medicine. The methods of work shall be flexible to ensure that it is possible to introduce changes with increasing knowledge about the process and shall correspond to the development stage of the medicine.
2. Clinical studies may result in additional risks for the patients who take part in them as compared to risks for patients who take registered medicines.
3. These Rules shall apply to the manufacture of studied medicines and shall be aimed at excluding risks for patients, as well as preventing insufficient safety, quality or efficacy of the medicine (that result from its improper manufacture) from affecting the results of clinical studies.
4. Equally, these requirements are intended to provide for the consistency of each batch of one and the same studied medicine used in a single clinical study or different studies, as well as documentation and justification of changes in the development of such a medicine.
5. The manufacture of studied medicines is connected with an additional difficulty as compared to the manufacture of registered medicines due to the lack of set procedures, existing differences in plans of clinical studies and, as a result, different requirements to packaging, necessary randomization and coding (marking, use of the ‘blind’ method), as well as a great risk of cross contamination and confusion of medicines. Moreover, the data on the efficacy and toxicity of the medicine may be incomplete, the process validation may be incomplete, or registered medicines that have been repacked or somehow modified may be used. The staff of the manufacturer shall be trained in the application of these Rules with regard to studied medicines. It is necessary to establish relations with sponsors of the clinical studies that are responsible for the organization of the clinical studies, including the quality of the studied medicines. The increased complexity of manufacturing processes requires a highly efficient pharmaceutical quality system.
6. This Attachment also sets requirements to the placement of orders, shipment, transportation and return of medicines intended for clinical studies.
7. Patients may be provided with medicines that are not studied medicines, placebos or comparative medicines. Such medicines may be used as concomitant or medical treatment for prevention, diagnosis or therapy reasons and (or) due to the necessity to provide patients with medical care. Such medicines can also be used pursuant to the protocol of clinical studies to stimulate a physiological reaction. These medicines are not studied medicines and may be provided by the sponsor or the researcher. The sponsor shall guarantee that these medicines correspond to the application for a permit to conduct clinical studies and have the quality required for the purposes of the studies. In addition the sponsor shall take into consideration the source of the medicines, whether these medicines are registered and if they have been repacked. It is recommended to engage an authorized person with this task and take their opinion into account.
Licensing of the manufacturing process and preparation for use
8. Both the whole manufacturing process of studied medicines and its individual stages, as well as different processes of their separation, packaging or their transfer shall be subject to licensing. No license for the manufacture of medicines is required for the preparation for use of the studied medicines in healthcare organizations.
9. For purposes of the above provisions ‘preparation for use’ shall mean a simple process, including:
dilution or dispersion of the studied medicine for its administration to the patient, or
dilution or mixing of the studied medicine(s) with (an)other substance(s) used as the carrier for administration of the medicine.
10. Mixing of several ingredients, including the active substance for obtaining the studied medicine shall not be considered preparation for use.
11. The studied medicine shall be available before the process of preparation for use.
12. The process of preparation for use shall be carried out immediately before administration.
13. This process shall be described in the application for a permit to conduct clinical studies and (or) the dossier of the studied medicine, the protocol of the clinical studies, or the corresponding instructions used in the healthcare organization.
II. TERMS AND DEFINITIONS
14. For purposes of this Attachment the following basic terms shall have the following meaning:
dossier for a medicine: a package of documents containing all information (or references to corresponding documents) required to draw up detailed instructions for manufacture, packaging, quality control, issue of a permit for the release of a batch and shipment of the studied medicine;
order: a task for the manufacture, packaging and (or) delivery of a particular quantity of items of the studied medicine(s);
importer of the studied medicine: an entity having the right to import the studied medicine documented in accordance with regulatory legal acts of the Russian Federation;
researcher: an individual responsible for the clinical studies in a healthcare organization. If clinical studies are conducted in a healthcare organization by a group of persons, the researcher (also known as the chief researcher) shall be the head of the group;
studied medicine: a medicine or placebo studied or used as a comparative medicine in clinical studies. Studied medicines shall also include already registered medicines if their method of administration or manufacture (the pharmaceutical form or packaging) differ from the registered one, or if they are used for indications that have not been approved yet or to get additional information on a pharmaceutical form that has already been registered;
clinical studies: any conducted studies when a human being participates as a subject to detect or prove clinical, pharmaceutical and (or) other pharmacodynamic effects of the studied medicine(s) and (or) to detect its(their) adverse effects, and to study its(their) absorption, distribution, metabolism and excretion in order to evaluate its(their) safety and (or) efficacy;
shipment: operations of packing for shipment and transportation of studied medicines which have been ordered;
comparative medicine: a studied medicine or a registered medicine (for active control) or placebo used for comparison in clinical studies;
randomization code: a list that helps identify what therapy subject to randomization shall be used for each patient;
randomization: the process of dividing patients into groups for treatment or control at random which ensures minimum subjectivity;
‘blind’ method (‘masking’): a method when one party or several parties taking part in the study are not informed of the pursued medical purpose(s). A simple ‘blind’ method shall mean that the patient(s) is(are) not informed, and a double ‘blind’ method shall mean that the patient(s), the researcher(s), observers and in some cases persons analysing the obtained data are not informed. With regard to the studied medicine the ‘blind’ method shall mean intentional masking of the identity of this medicine in accordance with the sponsor’s instructions. Unblinding (unmasking) shall mean disclosure of information that enables identifying the medicine that has been previously masked.
sponsor: a legal entity organizing clinical studies of the medicine for medical application.
III. QUALITY MANAGEMENT
15. (1) A pharmaceutical quality system developed and checked by the manufacturer shall meet the requirements of these Rules related to the studied medicines, shall be documented and available for the sponsor.
16. (2) Specifications and process instructions for the studied medicines may be amended in the process of their development, however it is necessary to ensure their total control and tracing of all changes.
IV. STAFF
17. (3) All staff members whose work is connected with the studied medicines shall be properly trained in terms of the specifics of this type of products.
18. Even if the staff is small, special employees in charge of the manufacturing process and the quality control shall be provided for the manufacture of each batch of the studied medicines.
19. (4) The authorized person shall ensure the availability of appropriate systems pursuant to the requirements hereof. Therefore the authorized person shall be properly trained in the field of development of medicines and clinical studies. The guidelines for the authorized person on the assessment of the studied medicines are given in Items 61 – 65 hereof.
V. PREMISES AND EQUIPMENT
20. (5) In case of work with studied medicines the information on the toxicity, efficacy and sensitization properties may be incomplete, for this reason the manufacturer shall pay special attention to minimizing risks of cross contamination. The design of the equipment and rooms, testing and control methods, as well as limits of acceptable residue concentration after cleaning shall be based on the nature of the said risks. When appropriate, the manufacturer shall take into account the organization of work in manufacturing cycles (sessions). To select a detergent it is necessary to take into consideration the solubility of the medicine for clinical studies.
VI. DOCUMENTS
Specifications and instructions
21. (6) Specifications (for starting raw materials, primary packing materials, intermediate products, bulk and finished products), descriptions, process instructions and packaging instructions shall be as complete as the current level of knowledge about the product allows. In the process of development of medicines they shall be periodically assessed and updated (if necessary). Each new version shall contain the latest data, the technology used at the moment, requirements of the State Pharmacopoeia of the Russian Federation and regulatory legal acts of the Russian Federation. The new version shall also comprise a reference to the previous version to ensure the possibility to trace all changes. The manufacturer shall approve the procedure for any amendments that may influence the quality of the studied medicine, in particular, its stability and bioequivalence.
22. (7) The justifications for introduction of changes shall be documented. The manufacturer shall analyse the influence of introduced changes on the quality of the studied medicine and conducted clinical studies. The results of this analysis shall be documented.
Order
23. (8) An order shall contain a requirement to manufacture and (or) pack a particular quantity of items of products and (or) to ship them. An order to the manufacturer shall be sent by the sponsor or a person acting at the sponsor’s request. The order shall be made in hard and (or) soft copy and shall be sufficiently clear to avoid any discrepancies. The order shall be approved by a person having corresponding powers and shall contain a reference to the dossier for the medicine and the protocol of clinical studies.
Medicine dossier
24. (9) The dossier for a medicine shall be constantly updated while the medicine is developed. In addition the manufacturer shall provide for the possibility to trace previous versions of the medicine dossier.
25. A medicine dossier shall include, without limitation, the following documents (or references thereto):
specifications and analytical procedures for starting raw materials and packing materials;
specifications and analytical procedures for intermediate, bulk and finished products;
process instructions;
control methods in the manufacturing process;
an approved copy of the label;
protocols of clinical studies and, if appropriate, randomization codes;
agreements with contractors specified in Items 237 – 255 of these Rules (if necessary);
data on the stability;
storage and transportation conditions.
26. The above list of documents may be changed depending on the medicine and the stage of its development. The information contained in the dossier shall form the basis for the assessment of the readiness for acceptance and issue of a permit to release a certain batch by the authorized person who shall have access to this information. If different stages of the manufacturing process are performed in different areas where different authorized persons are in charge, it is allowed to draw up separate dossiers with limited information related to the activities in corresponding areas.
Description and process instructions
27. (10) Each processing operation or shipment operation shall be carried out in accordance with clear and sufficiently complete instructions and shall be followed by corresponding records. If an operation is not repeated, it is not necessary to prepare a description and process instructions. Records are greatly important for the preparation of the final versions of documents that will be used in batch manufacturing after a Marketing Authorization for the medicine has been issued.
28. (11) The information in the medicine dossier shall be used for developing detailed instructions for manufacture, packaging, quality control tests, storage and transportation conditions.
Packaging instructions
29. (12) Studied medicines shall be generally packed individually for each patient. The quantity of items of packed products shall be determined before the beginning of packing operations subject to the quantity of items required for the quality control and retention samples for storage. After packing and marking operations it is necessary to draw up the material balance to ensure correct accounting of each type of products for each stage of manufacture.
Records concerning manufacture, control and packaging of a batch of products
30. (13) A dossier for a batch shall contain sufficiently detailed information for accurate tracing of the process sequence. This dossier shall include all significant comments justifying the use of the procedure or introduced changes, giving new information on the medicine and enabling improvement of manufacturing operations.
31. (14) Records concerning the manufacture of a batch of products shall be stored for at least five years after the completion or discontinuation of the last clinical study using this batch.
VII. MANUFACTURING PROCESS
Packing materials
32. (15) Specifications and quality control methods shall indicate special measures aimed at preventing accidental decoding due to differences in the appearance of different batches of packing materials.
Technological operations
33. (16) It is necessary to define at the stage of development of the medicine the critical parameters and types of control in the manufacturing process. Time parameters and types of control in the manufacturing process may be determined based on the acquired experience, including previous development studies. The responsible staff members shall pay special attention to the preparation of required instructions and their constant improvement subject to the experience acquired in the manufacturing process. The set and controlled parameters shall be justified in accordance with the information available at the moment.
34. (17) It is allowed not to perform validation of technological processes of the manufacture of studied medicines to the extent characteristic to batch manufacturing. In any case the premises and equipment shall be qualified. For sterile medicines, validation of sterilization processes shall be performed to the extent similar to that characteristic to registered medicines. If appropriate, to ensure the safety of biotechnological medicines for clinical studies the manufacturer shall prove the effectiveness of inactivation and (or) removal of viruses and (or) other impurities of biological origin pursuant to scientific principles and methods described in corresponding guidelines.
35. (18) Validation of aseptic processes is particularly difficult in case of small sizes of product batches. In such cases the quantity of items of products filled with media may be equal to the maximum size of a batch of products. If possible (including for process imitation), the manufacturer shall fill with media the maximum quantity of items of products to ensure a greater accuracy of the results. Filling and sealing are mainly manual or semi-automated operations representing a risk for sterility. For this reason greater attention shall be paid to the staff training and validation of the methods of aseptic manufacture with the assistance of each operator.
Requirements to the comparative medicine
36. (19) If the comparative medicine is changed, the manufacturer shall provide data (e.g. on the stability, comparative studies of solubility, bioavailability) confirming that these changes will have no material influence on the initial quality parameters of this medicine.
37. (20) The expiration date of the comparative medicine indicated on the primary package may differ from the expiration date of the medicine repacked with some other packaging that does not ensure an equivalent protection level or if this package is incompatible with the medicine. For this reason the sponsor or person acting on the sponsor’s behalf shall define an acceptable date before which the medicine can be used subject to the nature of the medicine, the characteristics of the package and conditions in which this medicine will be stored. The new expiration date shall be justified and shall not exceed the expiration date indicated on the primary package. The expiration date shall correspond to the duration of clinical studies.
Coding operations (‘blind’ method)
38. (21) If studied medicines are coded, it is necessary to develop systems ensuring coding and its preservation, but if necessary enabling identification of the coded (‘blind’) products, including batch numbers of the studied medicine before the coding operation. The manufacturer shall provide for a possibility to quickly identify the studied medicine in case of emergency.
Randomization code
39. (22) Instructions shall describe all procedures for creating, protecting, distributing, processing and storing any randomization code used for packed studied medicines, and decoding methods. The manufacturer shall keep corresponding records.
Packing operations
40. (23) When the studied medicine is packed, it may be necessary to arrange different types of products at one packing line at the same time. The manufacturer shall minimize the risk of confusion of medicines by performing appropriate procedures and (or) using special equipment and properly training the staff.
41. (24) Operations of packing and marking of studied medicines may be more complicated and subject to errors that are difficult to detect than the manufacture of registered medicines. It is particularly so with studied medicines which look alike when the ‘blind’ method is applied. For this reason it is required to take special measures to prevent errors in marking, for example, by drawing up the balance of labels, cleaning the line, ensuring control in the manufacturing process by specially trained staff members.
42. (25) Packaging shall ensure the safety of the studied medicine during transportation and storage in intermediate destination points. Secondary packaging shall immediately show signs of its opening or any other interference during transportation.
Marking
43. (26) Table No. 1 summarizes the requirements specified in Items 43 – 48 hereof. Marking shall ensure protection of the patient, the possibility to trace and identify the medicine and the study and enable correct use of the studied medicine.
44. Labels shall contain the following information, unless its absence is well-grounded (e.g. in case of a centralized electronic system of randomized coding):
а) (a) name, address and telephone number of the sponsor, legal entity engaged by the sponsor for the organization of the clinical study (hereinafter – a contract research organization) or researcher (the main contact for the receipt of information on the medicine, the clinical study and emergency decoding);
b) (b) the pharmaceutical form, the mode of administration, the quantity of dosage units, and in case of a non-blind study – the name and (or) code of the medicine and its dosage and (or) efficacy;
c) (c) the batch number and (or) code to identify the contents and operation by the package;
d) (d) the study number (code) enabling to identify the study, the healthcare organization, the researcher and the sponsor, unless this information is indicated elsewhere;
e) (e) the identification code of the patient and the visit number (if any);
f) (f) the surname and initials of the researcher (unless specified in Sub-items ‘а’ or ‘d’);
g) (g) operation instructions (or a reference to the package leaflet or any other explanatory document intended for the patient or the person administering the medicine);
h) (h) an inscription ‘For clinical studies’;
i) (i) storage conditions;
j) (j) the period of use indicating the month and year so as to avoid any uncertainty (it is possible to state the date before which the medicine shall be used for clinical studies, the expiration date or the date of re-inspection);
k) (k) an inscription ‘Keep out of the reach of children’, except medicines intended for hospital use only.
45. (27) The address and telephone number of the main contact for the provision of information on the medicine, the clinical study and emergency decoding may be omitted on the label, if the patient has been provided with directions for use or a card with these data, and has been instructed to always have them at hand.
46. (28) The data shall be in the Russian language. The data specified in Item 44 hereof shall be enclosed both with the primary and secondary packaging (except cases described in Items 47 – 48 hereof). The requirements to label marking on the primary and secondary packaging are specified in Table 1. Labels may also contain information in other languages.
47. (29) If the studied medicine provided to the patient or the person administering the studied medicine is accompanied by a secondary packaging containing information specified in Item 44 hereof, marking of the primary packaging (or any sealed dosing device with primary packaging) shall comprise the following data:
а) (a) the name of the sponsor, the contract research organization or the researcher;
b) (b) the pharmaceutical form, the mode of administration (may be omitted for solid peroral forms), the quantity of dosage units, and in case of a non-blind study – the name and (or) code of the medicine and its dosage and (or) efficacy;
c) (c) the batch number and (or) code to identify the contents and operation by the package;
d) (d) the study number (code) enabling to identify the study, the healthcare organization, the researcher and the sponsor, unless this information is indicated elsewhere;
e) (e) the identification code of the patient and the visit number (if any).
48. (30) If the primary packaging is a blister or it is small in size (e.g. ampoules that cannot accommodate the data specified in Item 44 hereof), there shall be a secondary packaging with a label containing these data. In this case the primary packaging shall indicate:
а) (a) the name of the sponsor, the contract research organization or the researcher;
b) (b) the mode of administration (may be omitted for solid peroral forms), in case of a non-blind study – the name and (or) code of the medicine and its dosage and (or) efficacy;
c) (c) the batch number and (or) code to identify the contents and operation by the package;
d) (d) the study number (code) enabling to identify the study, the healthcare organization, the researcher and the sponsor, unless this information is indicated elsewhere;
e) (e) the identification code of the patient and the visit number (if any).
Table 1. Summary information on marking (Items 43 – 48)
| а) name, address and telephone number of the sponsor, contract research organization or the researcher (main contact for the receipt of information on the medicine, the clinical study and emergency decoding); | GENERAL CASE
For primary packaging and secondary packaging (Item 44) |
| Information specified in Sub-items ‘а’ <1> – ‘k’ | |
| PRIMARY PACKAGING
If the primary packaging and the secondary packaging are stored together (Item 47) <5> |
|
| b) the pharmaceutical form, the mode of administration, the quantity of dosage units, and in case of a non-blind study the name and (or) code of the medicine and its dosage and (or) efficacy; | Information specified in Sub-items ‘a’ <2> ‘b’ <3> ‘c’ ‘d’ ‘e’ |
| c) the batch number and (or) code to identify the contents and operation by the package; | |
| d) the study number (code) enabling to identify the study, the healthcare organization, the researcher and the sponsor, unless this information is indicated elsewhere; | |
| e) the identification code of the patient and the visit number (if any); | |
| f) the surname and initials of the researcher (unless specified in Sub-items ‘а’ or ‘d’); | |
| g) operation instructions (or a reference to the package leaflet or any other explanatory document intended for the patient or the person administering the medicine); | |
| h) an inscription ‘For clinical studies’; | |
| i) storage conditions; | PRIMARY PACKAGING |
| j) the period of use indicating the month and year so as to avoid any uncertainty (it is possible to state the date before which the medicine shall be used, the expiration date or the date of re-inspection); | Information specified in Sub-items ‘а’ <2> ‘b’ <3>, <4> ‘c’ ‘d’ ‘e’ |
| k) an inscription ‘Keep out of the reach of children’, except medicines intended for hospital use only |
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Notes:
<1> The address and telephone number of the main contact for the receipt of information on the medicine, the clinical study and emergency decoding may be omitted on the label, if the patient has been provided with directions for use of the medicine or a card with these data, and has been instructed to always have them at hand (Item 45 hereof).
<2> The address and telephone number of the main contact for the information on the medicine, the clinical study and emergency decoding is not required.
<3> The mode of administration is not required for solid peroral forms.
<4> The pharmaceutical form and the quantity of dosage units are not required.
<5> If the secondary packaging contains the information specified in Item 44 hereof.
49. (31) Symbols and pictograms may be used to explain the above information. It is possible to provide additional information, warning notes and (or) instructions for use of the medicine.
50. (32) In case of clinical studies when:
а) separate manufacturing or packaging processes are not required;
b) the study is conducted with medicines registered, manufactured or imported in accordance with the law of the Russian Federation;
c) the study is conducted with patients having diseases that correspond to the indications for use approved during registration,
– the following data shall be additionally placed on the primary packaging so as not to cover the original label
(i) the name of the sponsor, the contract research organization or the researcher;
(ii) the study number (code) enabling to identify the healthcare organization, the researcher and the study subject.
51. (33) If it is necessary to change the date before which the studied medicine shall be used, an additional label shall be placed on the package. The additional label shall indicate the new date before which the medicine may be used, and repeat the batch number. The additional label may be placed onto the previous expiration date, but it shall not cover the initial batch number that is required for the quality control. The additional label shall be placed by organizations having a license for the manufacture of medicines or a license for pharmaceutical activities (storage of medicines for medical application). If necessary, the additional label may be placed in a healthcare organization by a pharmaceutical specialist of this organization or under their control, or a medical specialist of a healthcare organization pursuant to the requirements of the law of the Russian Federation. If possible, the additional label may be placed by the monitor of the clinical study who has been appropriately trained. This operation shall be carried out according to these Rules, special and standard operating procedures, and if necessary, entrusted to another organization under a contract. Performance of this operation shall be controlled by another employee. The placement of the additional label shall be carefully recorded both in the documents of the clinical study and the batch dossier.
VIII. QUALITY CONTROL
52. (34) As processes may be determined or validated not in full, special attention shall be paid to studies to ensure that each batch of products corresponds to the specifications.
53. (35) Quality control shall be conducted pursuant to the dossier for the medicine. The manufacturer shall check the coding effectiveness and document obtained results.
54. (36) Samples of studied medicines shall be stored for two purposes: to have an available sample for analytical tests and to have an available sample of the finished medicine. For this reason samples may be divided into two categories:
control sample: samples of a batch of starting raw materials, packing materials, the medicine in the primary packaging and the finished medicine stored for analysis that may be necessary. The manufacturer shall take and keep samples of critical intermediate stages (e.g. stages after which analytical studies shall take place or release permits shall be issued) and samples of intermediate products supplied outside the control area of the manufacturer, if the stability of the samples allows it;
retention sample: a sample in the final packaging taken from a batch of finished products. It shall be stored for the identity test. For example, during the period of storage of the batch it may be necessary to examine the sample or packaging, marking, directions for use, or get the information on the batch number and the expiration date.
55. In most cases control and retention samples of finished goods are identical and are items of products in the final packaging. In such cases control and retention samples may be considered substitutes. Control and retention samples of the studied medicine, including a coded medicine, shall be stored for at least two years after the completion or discontinuation of the last clinical study using this batch (whichever period is longer).
56. The manufacturer shall take care of stored retention samples until the clinical study report has been prepared in order to make it possible to prove the identity of the medicine which it required to investigate unexpected cases or contradicting results of such studies.
57. (37) The place of storage of control and retention samples shall be defined in the agreement between the sponsor and the manufacturer(s). It is necessary to provide timely access for representatives of the authorized federal executive body to these places.
58. Control samples of the finished medicine shall be stored in the Russian Federation or a third country, if there are agreements between the Russian Federation and the third exporting country which guarantee that the manufacturer of the studied medicine observes good manufacturing practices whose requirements are not inferior to the requirements of these Rules. In exceptional cases control samples of the finished medicine may be stored by the manufacturer in a third country. In this case it shall be justified and documented in the form of an agreement between the sponsor, the importer to the Russian Federation and the manufacturer of the medicine in the third country.
59. The number of control samples shall be sufficient for at least two complete analytical studies of the product batch conducted in accordance with the requirements of the medicine dossier submitted to the authorized federal executive body for the issue of a permit for the clinical study.
60. For retention samples it is allowed to store information on the finally packed items of medicines in the form of written or electronic records, if such records ensure sufficient information. In the latter case the storage system shall meet the requirements specified in Attachment No. 11 to these Rules.
IX. ISSUE OF A BATCH RELEASE PERMIT
61. (38) The permit for the release of studied medicines shall not be issued until the authorized person has certified that the set requirements are observed subject to the provisions stipulated in Items 62 – 63 hereof.
62. (39) The fulfilment by the authorized person of their duties with regard to studied medicines may be influences by different factors enumerated below:
а) the medicine has been manufactured in the Russian Federation but has not been registered in the Russian Federation: if an application for a permit for clinical studies has been filed, it is necessary to certify that the studied medicine has been manufactured and tested in accordance with the requirements of these Rules, the medicine dossier and that there is corresponding information provided by the sponsor to the authorized federal executive body;
b) the medicine has been registered in the Russian Federation and is supplied by a wholesale trading organization located in the Russian Federation regardless of where the medicine is manufactured: the requirements indicated in Sub-item ‘а’ hereof are in force, but the amount of provided data may be limited to the confirmation of the fact that the medicine corresponds to the application for a permit for the clinical study and any other subsequent processing for coding, special packaging or marking for this study. The medicine dossier may also be limited in its volume (Items 24 – 26 hereof);
c) the medicine has been imported directly from a third country: it is necessary to confirm that the medicine has been manufactured and tested according to good manufacturing practices whose requirements are not inferior to the requirements of these Rules, the medicine dossier and that there is corresponding information provided by the sponsor to the authorized federal executive body, if an application for a permit for clinical studies has been filed. If studied medicines have been imported from a third country and are a subject of an agreement between the Russian Federation and this country, for example, a mutual recognition agreement, any such agreement shall stipulate that requirements applying to this medicine shall not be inferior to the requirements of these Rules. If there is no mutual recognition agreement the authorized person shall prove that the applied requirements are not inferior to the requirements of these Rules based on the information on the manufacturer’s quality control. As a rule, this information can be received if the authorized person takes part in the audit of the manufacturer’s pharmaceutical quality control system. In both cases the authorized person may carry out the assessment of conformity based on the documents provided by the manufacturer from another country (Item 63 hereof);
d) in case of imported comparative medicines, when it is impossible to guarantee that each batch of products has been manufactured in accordance with the requirements that are not inferior to the requirements of these Rules, the authorized person shall confirm that each manufactured batch has undergone all types of control and tests required for proving its quality, and that there is corresponding information provided by the sponsor to the authorized federal executive body, if an application for a permit for clinical studies has been filed.
63. (40) The following factors, circumstances and documents shall be analysed, if each batch of products is assessed before the issue of a release permit:
the batch dossier, including records concerning the quality control, records concerning control in the manufacturing process and records concerning the release permit evidencing that the batch of products corresponds to the medicine dossier, the order, the study protocol and the randomization code. These records shall contain all deviations or changes introduced according to the ordinary procedure, as well as any additional checks or tests. The records shall be complete and approved by the staff authorized for this purpose in accordance with the pharmaceutical quality system;
the manufacturing environment;
the data on the validation of the equipment, processes and methods;
the inspection of the final packaging;
the results of any analyses or tests conducted after the import, if necessary;
stability reports;
the data on the supplier and examination of the storage and transportation conditions;
reports on audits of the manufacturer’s quality system;
documents confirming the right of the manufacturer to manufacture studied medicines (including comparative medicines) for export provided by the authorized federal executive body;
requirements of regulatory legal acts of the Russian Federation with regard to the registration dossier, applied requirements of these Rules and any confirmations of the authorized federal executive body stating that the requirements of these Rules have been met;
other factors that the authorized person may find significant in terms of the batch quality.
64. The significance of the above factors shall depend on the country where the medicine is manufactured, the manufacturer, the registration status of the medicine (if it is registered in the Russian Federation or a third country), and the stage of the clinical development. The sponsor shall guarantee that all factors taken into account by the authorized person assessing the batch correspond to the information provided to the authorized federal executive body when an application for a permit for the clinical study has been filed (Item 68 hereof).
65. (41) If studied medicines are manufactured and packed in different areas and different authorized persons are responsible for these areas, the requirements specified in Attachment No. 16 to these Rules shall be met.
66. (42) If these Rules and other regulatory legal acts of the Russian Federation state that the operations of packaging or marking shall be performed in a healthcare organization by a pharmaceutical specialist of this organization or under their control, or a medical specialist of a healthcare organization, no certification of these operations on the part of the authorized person shall be required. However the sponsor shall be responsible for proper documentation of these activities, observance of the requirements of these Rules and, if necessary, consultations with the authorized person.
X. TRANSPORTATION
67. (43) Studied medicines shall be controlled by the sponsor until the two-stage procedure of issue of the release permit has been completed: assessment of the conformity by the authorized person and issue by the sponsor of a release permit for clinical studies after all set requirements have been met. Both stages shall be documented, and the records shall be stored by the sponsor or a person acting on the sponsor’s behalf.
68. (44) Studied medicines shall be transported pursuant to the instructions provided by the sponsor or a person acting on the sponsor’s behalf.
69. (45) Before studied medicines have been delivered to the place of the clinical studies, it is necessary to set rules for decoding the medicines by the staff having corresponding powers.
70. (46) It is necessary to keep a detailed list of shipped products drawn up by the manufacturer or the importer. Special attention shall be paid to the accuracy of the stated name and address of the consignee.
71. (47) Studied medicines may be transferred from one place of clinical studies to another only in exceptional cases. The rules for such transfer shall be described in the standard operating procedure. When the medicine is not under the manufacturer’s control, all the data collected in terms of this medicine shall be checked, for example, by means of reports on clinical study monitoring or registration of the storage conditions in the previous place of the clinical studies. Such examination shall be taken into account if the possibility of a transfer of the products is assessed. The authorized person shall take part in this examination. If necessary, the medicine shall be returned to the manufacturer for remarking or its assessment by the authorized person. It is necessary to store all records and ensure a possibility to trace such transfers.
XI. CLAIMS
72. (48) The conclusions on the results of any investigation conducted due to a received claim to the quality of the medicine shall be considered by the manufacturer or the importer and the sponsor (unless it is the same entity). The authorized person and persons in charge of the corresponding clinical study shall be engaged in these activities to assess the possible influence of the claim on the clinical study, development of the medicine and the patients.
XII. WITHDRAWALS AND RETURNS
Withdrawals
73. (49) The procedure for withdrawing studied medicines and documenting these operations shall be approved by the sponsor and the manufacturer or the importer (unless it is the same entity). The researcher and the monitor of the clinical study shall understand their obligations when they carry out the withdrawal procedure.
74. (50) The sponsor shall guarantee that the supplier of any comparative medicine or other medicines used in the clinical study has a system for informing the sponsor that it is necessary to withdraw any supplied medicine.
Returns
75. (51) Studied medicines shall be returned in accordance with the requirements of the sponsor set in corresponding procedures.
76. (52) Returned studied medicines shall be clearly identified. They shall be stored in a specially prepared controlled area. It is necessary to keep accounting records of returned medicines.
XIII. DESTRUCTION
77. (53) The sponsor shall be responsible for the destruction of unused and (or) returned studied medicines. It is prohibited to destroy studied medicines without a written permit of the sponsor.
78. (54) For each healthcare organization conducting a clinical study and each period of the study the sponsor or a person acting on the sponsor’s behalf shall record, draw up a balance and check the quantity of studied medicines that has been supplied, used and returned. Unused studied medicines of a particular healthcare organization or a certain period of the study shall be destroyed only after an investigation has been conducted, a satisfactory explanation for any deviations has been given, and a material balance has been drawn up. The destruction of medicines shall be documented so as to ensure a possibility to prepare a report on all operations. The destruction records shall be stored by the sponsor.
79. (55) If studied medicines have been destroyed, the sponsor shall be provided with a certificate indicating the date or any other document concerning the destruction. These documents shall state the batch number and (or) patient codes (or ensure the possibility of their tracing), and the number of destroyed medicines.