Attachment No. 3
to the Rules of Good Manufacturing Practice
MANUFACTURE OF RADIOPHARMACEUTICAL MEDICINES
1. Manufacture of radiopharmaceutical medicines shall be organized in accordance with the principles outlined in Chapters III – IV hereof. This Attachment shall set forth special rules of the manufacture of radiopharmaceutical medicines.
2. When applying these Rules, it shall be necessary to take into consideration that:
a) this Attachment does not apply to the manufacture of radiopharmaceutical medicines in pharmacies and veterinary pharmacies;
b) this Attachment applies also to radiopharmaceutical medicines used in clinical studies;
c) radiopharmaceutical medicines shall be transported in accordance with the radiation security requirements of the International Atomic Energy Agency (IAEA) and requirements of the regulatory legal acts of the Russian Federation;
d) it is allowed to use methods other than those specified in this Attachment provided that such other methods allow complying with the product quality assurance requirements. Such methods shall be validated and provide a quality level not below the quality level in accordance with the requirements set forth in this Attachment.
3. (1) Manufacture and handling of radiopharmaceutical medicines are potentially dangerous. The level of risks shall depend, inter alia, on the type of ionizing radiation, radiation energy and radionuclide half-life. Special attention shall be paid to preventing cross contamination, storing residues of radioactive materials and removing waste.
4. (2) As certain radionuclides have a short storage period, radiopharmaceutical medicines containing such radionuclides may be released into circulation before completion of the quality control tests. In such cases a special procedure shall clearly determine in detail the order of the issue of a release permit, including responsibilities of staff members and continuous evaluation of the efficiency of the quality assurance system.
5. (3) The scope of the application of this Attachment shall cover activities of manufacturing facilities, nuclear centers, institutes and PET centers for the manufacture and quality control of the following products:
radiopharmaceutical medicines for PET (positron emission tomography);
radioactive precursors for the manufacture of radiopharmaceutical medicines;
|Type of manufacture||Outside the scope of these Rules <*>||Binding requirements set out in Chapters III – IV of these Rules (requirements becoming more stringent as it comes to the manufacturing of finished products) including corresponding Attachments|
|Products of reactors and cyclotrons <1>||Chemical synthesis||Purification stages||Treatment, preparation, dosing||Aseptic manufacturing or terminal sterilization|
|Radionuclide generators||Products of reactors and cyclotrons <2>||Process operations (assembly of the column, generator, generator charging)|
6. (4) The manufacturer of a finished radiopharmaceutical medicine shall have a description of the process of manufacturing a pharmaceutical substance, a finished medicine and shall specify which of the requirements of these Rules (Chapter III or Chapter IV hereof) apply to various process operations and (or) stages.
7. (5) Radiopharmaceutical medicines shall be manufactured in accordance with the requirements of the radiation security standards.
8. (6) Radiopharmaceutical medicines intended for parenteral administration shall be manufactured in accordance with the requirements set to the sterility of such medicines, subject, where appropriate, to aseptic manufacturing requirements in accordance with Attachment No. 1 hereto.
9. (7) Specifications and methods of control of the quality of radiopharmaceutical medicines shall be stipulated in the State Pharmacopoeia of the Russian Federation or in registration dossiers for such medicines.
10. (8) Manufacture of radiopharmaceutical medicines intended for clinical studies shall be subject also to requirements set out in Attachment No. 13 hereto.
III. QUALITY ASSURANCE
11. (9) Assuring the quality during the manufacture of radiopharmaceutical medicines shall be particularly important because of their specific characteristics, small sizes of batches and, in certain cases, the need for their medical application before completion of the quality control activities.
12. (10) Protection of products from contamination and cross contamination shall be arranged similarly to protection provided during the manufacture of any medicines, subject to additional requirements to protect the process environment and staff from ionizing radiation.
13. (11) It shall be important to duly register the data on the monitoring of premises and processes. Evaluation of such data shall be part of the release of products into circulation.
14. (12) Manufacture of radiopharmaceutical medicines shall be subject to appropriate qualification and validation. The scope of qualification and validation activities shall be determined based on the risk management-based approach, with special attention paid to the combination of requirements of these Rules and radiation security requirements.
15. (13) All process operations shall be performed by staff members who have undergone special radiation security training. Staff members involved in the processes of manufacture, quality control and release of radiopharmaceutical medicines shall undergo training regarding the specifics of the system of assurance of the quality of radiopharmaceutical medicines. The authorized person shall be in charge of release of radiopharmaceutical medicines.
16. (14) Staff members working in the areas of manufacture of radiopharmaceutical medicines (including staff members in charge of cleaning and technical maintenance) shall undergo additional training regarding the specifics of processes and products.
17. (15) If manufacturing premises and equipment are used also for conducting studies, staff members involved in studies shall be trained to apply these Rules. Quality assurance activities shall imply consideration and issue of permits for performing works related to studies in order to exclude their adverse impact on the manufacturing process.
18. (16) Radiopharmaceutical medicines shall be manufactured in controlled areas compliant with requirements to the process environment and radiation security. All manufacturing operations shall be run in special-purpose premises and on special-purpose equipment designed for manufacture of radiopharmaceutical medicines.
19. (17) It shall be necessary to take measures aimed at preventing cross contamination by the staff, starting raw materials and radionuclides. Where practical, it shall be necessary to use closed or isolated equipment. In case of using open-type equipment or when opening equipment, it shall be necessary to take measures minimizing the risk of contamination. Risk assessment shall aim at proving that the cleanliness of the process environment conforms to the requirements applicable to the type of released products.
20. (18) Entry to manufacturing areas shall be authorized through changing rooms (decontamination stations) and shall be allowed only for staff members granted access to such areas.
21. (19) Work stations and the process environment shall be monitored for the level of radiation, concentration of particles and microorganisms. Monitoring procedures shall be set during performance qualification.
22. (20) Precautionary maintenance, calibration and qualification shall be performed in order to ensure that premises and equipment in use conform to the set requirements and have been qualified. Such operations shall be carried out by trained staff; performance of such operations and obtained results shall be documented.
23. (21) It shall be necessary to take measures to protect the process environment from radioactive contamination. It shall be necessary to establish due control of radioactive contamination by means of direct methods with the use of dosimeters or by means of indirect methods – by using smear techniques under established procedures.
24. (22) Product-contacting surfaces of equipment shall not enter into reaction with products, shall not produce any substances and shall not absorb products so as not to change the quality of a radiopharmaceutical medicine.
25. (23) Recirculation of the air from premises where radiopharmaceutical medicines are handled shall not be allowed, except in cases where recirculation is justified. Exhaust systems shall provide protection from environmental contamination with radioactive particles and gases. Controlled areas shall be protected from contamination with particles and microorganisms.
26. (24) For the purpose of excluding dissemination of radioactive particles, in areas with open products it shall be necessary to maintain a negative pressure against surrounding areas. At the same time, products shall be protected against contamination from the process environment, particularly, by using the hurdle technology and pressure-spool air chambers.
27. (25) Sterile radiopharmaceutical medicines shall be divided into two groups: aseptically released medicines and medicines subject to terminal sterilization. The manufacturing process shall be run by maintaining the cleanliness of the process environment at a level corresponding to the type of performed operations. It shall be mandatory to abide by the requirements set out in Attachment No. 1 hereto to the cleanliness of working areas where products or primary packaging may come into contact with the ambient air.
28. (26) Risk assessment methods may be used to define requirements to the differential pressure, the air flow direction and quality.
29. (27) In closed automated systems, which are generally hot chambers with installed chemical synthesis facilities, systems of purification and sterilizing filtration ‘in line’, it shall be sufficient to maintain a C cleanliness class. Closed hot chambers shall be supplied with filtered air of a high cleanliness level. Aseptic operations shall be run in an A Class area.
30. (28) Before the launch of the manufacturing process, operations such as assembly of sterile equipment and components (pipes, sterilizing filters), connection of liquid transmission lines to capped sealed sterile bottles shall be performed aseptically.
31. (29) All documents related to the manufacture of radiopharmaceutical medicines shall be developed, agreed, approved and distributed according to an approved procedure.
32. (30) Requirements to starting raw materials, packing materials, labelling materials, critical intermediate products and finished radiopharmaceutical medicines shall be outlined in specifications. It shall be also necessary to have specifications for critical materials and components (particularly, for auxiliary materials, seals, sterilization filtration kits), which are used in the manufacturing process and may have a critical impact on the product quality.
33. (31) For radiopharmaceutical medicines it shall be necessary to set acceptance criteria, including specifications applicable at the time of release and to the shelf life (for example, with respect to radiochemical purity, volumetric activity, radionuclide purity and specific activity).
34. (32) Records on the use, cleaning, decontamination or sterilization, and technical maintenance of the primary equipment shall contain the date and time of operations, the signature of the operator and, if and where necessary, also the product name and the batch number.
35. (33) Records shall be kept during at least three years unless a different storage period is stipulated by regulatory legal acts of the Russian Federation.
36. (34) Simultaneous manufacturing of different radiopharmaceutical medicines in one working area (hot chamber, laminar zone or cabinet) shall be prohibited in order to minimize the risk of cross contamination with radioactive substances or confusion of materials.
37. (35) Special attention shall be paid to validation, including validation of computerized systems in accordance with Attachment No. 11 hereto. New processes shall be subject to prospective validation.
38. (36) Critical parameters shall be determined before or during validation. It shall be necessary to determine the admissible limits of changes in parameters, necessary for stable manufacturing.
39. (37) Aseptically filled products shall be subject to control of the integrity of membrane filters, considering the need to ensure radiation security and preserved sterility of filters.
40. (38) Given radioactivity of finished products, labels may be applied to primary packages before the manufacturing process starts. Sterile empty closed bottles may be supplied with labels containing partial information before the filling operation, provided that sterility is preserved and nothing impedes visual control of filled bottles.
41. (39) Radiopharmaceutical medicines may be released and used on the basis of an evaluation of batch-related documents before completion of all chemical and microbiological tests.
42. A permit for release of radiopharmaceutical medicines may be executed in two or more stages, before and after the completion of full analytical control:
a) (a) evaluation by the authorized person of the batch manufacturing dossier, covering manufacturing conditions and analytical control until authorization of the transportation of a radiopharmaceutical medicine ‘under quarantine’ to a clinical unit;
b) (b) the authorized person shall issue a permit for release after evaluating the final results of analytical control, all deviations from the normal process, which shall be documented, substantiated and approved. If certain control results cannot be obtained before using a medicine, the authorized person shall issue a provisional permit for release of the medicine before its use by issuing the final permit for release of the medicine after obtaining all control results.
43. (40) Most radiopharmaceutical medicines are used during a short-term period due to a short radionuclide half-life; therefore, the expiration dates of medicines shall be clearly indicated.
44. (41) Radiopharmaceutical medicines containing radionuclides with long half-lives shall be controlled for compliance with all requirements before the authorized person executes a permit for release.
45. (42) Samples shall not have to be necessarily controlled immediately after they are taken so as to let the activity level go down as may be appropriate. All types of control, including sterility control, shall be carried out as soon as possible.
46. (43) Regulations approved by the manufacturer shall set a procedure for the evaluation of products and control results before shipment of products.
47. (44) Products that fail to conform to the established requirements shall be rejected. If reprocessing of materials is envisaged, such reprocessing shall be performed according to a preliminarily approved procedure. Finished products shall comply with the established requirements, which shall be confirmed before their release. It shall not be allowed to reprocess returned products to be handled as radioactive waste.
48. (45) A special procedure shall define steps to be taken by the authorized person upon detecting non-compliance of products with specifications after their shipment prior to the expiration of the shelf life. Such cases shall be investigated and appropriate preventive and corrective actions shall be taken to exclude such situations in future. This process shall be documented.
49. (46) If and where necessary, the manufacturer shall provide information to the responsible staff of a medical organization. For this purpose it shall be necessary to ensure traceability of radiopharmaceutical medicines.
50. (47) It shall be necessary to establish procedures for control of starting raw materials and materials. When selecting and approving the supplier, it shall be necessary to make sure that starting raw materials and materials supplied by such supplier consistently conform to the requirements of specifications. Starting raw materials, packing materials and auxiliary materials for critical process shall be purchased only from approved suppliers.
51. (48) Sufficient quantities of samples shall be taken from each batch of bulk radiopharmaceutical medicines; such samples shall be kept during at least six months from the expiration date of finished products unless otherwise established when using risk management procedures.
52. (49) Samples of starting raw materials used in the manufacturing, excluding solvents, gases and water, shall be kept during at least two years from the product release. This period may be reduced if a shorter stability period is indicated in the specification for raw materials.
53. (50) Other sampling and storage procedures may be determined for sampling and storage of samples of starting raw materials, materials and products if such are customized or manufactured in small quantities or if their storage can cause specific problems.
54. (51) Finished radiopharmaceutical medicines may be sold before obtaining results of all necessary tests provided that such sales are monitored. It shall be necessary to guarantee that such medicines are used in a medical organization only upon obtaining of satisfactory test results and their evaluation by the authorized person.
55. In addition to the terms and definitions stipulated in Chapter II hereof, the following basic terms shall be used for purposes of this Attachment:
hot chamber: an isolated or non-isolated screened working area for the manufacture and handling of radioactive materials;
preparation: preparation of a kit in a medical organization by introducing into it a radionuclide eluated from the generator or with the use of radioactive precursors. Kits, generators and radioactive precursors shall be duly registered;
radioactive precursor: a radioactive substance used for introducing a radionuclide marker to another substance before its application;
radiopharmaceutical medicines: medicines containing one or several radionuclides (radioactive isotopes) in their finished form ready for use <*>.
<*> Paragraph 10 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).