Attachment No. 12
to the Rules of Good Manufacturing Practice
1. The manufacturer of products for which ionizing radiation is a part of the manufacturing process shall also observe the regulatory legal acts of the Russian Federation governing the use of ionizing radiation in the manufacture of medicines.
2. Ionizing radiation may be used in the manufacturing process for different purposes, including decrease of the bioburden degree and sterilization of staring raw materials, components of packages or products, as well as treatment of blood preparations.
3. Two types of ionizing radiation are used: gamma radiation from a radioactive source and high energy electron radiation (beta radiation) obtained by an accelerator.
4. In case of gamma radiation two different processing modes may be used:
а) (i) the batch mode: products are placed in a fixed position around the source of radiation and may not be loaded or unloaded while the source of ionizing radiation is open;
b) (ii) the continuous mode: an automated system transports products into the exposure chamber by an open source of ionizing radiation, moves them at the appropriate rate along the set route and then takes out of the chamber.
5. Radiation plants with electron accelerators: products are moved through a continuous or pulsing bunch of high-energy electrons (beta radiation), whose sweep is made in both directions perpendicular to the movement of products.
6. (1) Radiation treatment of medicines may be performed directly by its manufacturer or an organization possessing a radiation plant under a contract with this manufacturer. Both of them shall have a corresponding license for the manufacture of medicines.
7. (2) The manufacturer shall be responsible for the quality of products, including the results of exposure to ionizing radiation. The organization performing the radiation treatment shall be responsible for exposing each package to a dose determined by the manufacturer (including the package with products that is the farthest from the source of radiation).
8. (3) The required dose and reasoned limits shall be specified in the registration dossier for the medicine.
9. (4) Dosimetry is the measurement of the absorbed dose of ionizing radiation with the help of dosimeters. Understanding of the principles of work and correct use of equipment have great importance for validation, commissioning of the plant and process monitoring.
10. Calibration of each batch of working dosimeters shall be traceable up to the national or international standards. The validity period of calibration shall be set, well-grounded and strictly observed.
11. (6) To detect any changes in the readings of operating dosimeters after exposure and during their calibration one and the same instrument shall be used. If different instruments are use, they shall be calibrated in absolute absorbance units.
12. (7) Depending on the type of used dosimeters it is necessary to take into account the possible sources of errors, including humidity, temperature changes, the period of time between exposure and measurement, and the absorbed dose rate.
13. (8) The wave length of the instrument used to measure changes in the absorption of dosimeters and the instrument used to measure the thickness of dosimeters shall be periodically checked by calibration in particular periods of time set based on the stability, intended use and method of application of the instrument.
14. (9) Validation is an action proving that the process, or exposure of the products to a set absorbed dose, has achieved expected results. If in case of use of ionizing radiation in the manufacture of medicines regulatory legal acts of the Russian Federation set additional requirements to validation, these requirements shall be met.
15. (10) Validation shall include preparation of a dose field map to determine the distribution of the absorbed dose inside the exposed container with products arranged there in a particular way.
16. (11) Technical specifications of the irradiation process shall include, in particular, the following:
а) (a) detailed information on the product packaging;
b) (b) arrangement of products inside the container for irradiation. If the irradiated container contains different types of products, special attention shall be paid to ensure that firm products get the full dose and do not shield other products. Each method of arranging different types of products in a container shall be determined in the corresponding procedure and validated;
c) (c) the arrangement of containers around the source (the batch mode) or the route of exposed objects inside the exposure chamber (the continuous mode);
f) (f) other parameters of the process, including the absorbed dose rate, the maximum exposure time, the number of exposures, and the number of exposure cycles.
17. If irradiation is performed under a contract, it is recommended to include into this contract at least Sub-items ‘d’ and ‘e’ of Item 16 hereof that contain technical specifications for the irradiation process.
18. (12) Commissioning is documented evidence obtained by experiment proving that the radiation plant operating in accordance with the technical specifications for the process will always function within pre-set limits. According to this Attachment pre-set limits shall mean the maximum and minimum threshold doses intended to be absorbed by the exposed container. Any changes in the operation of the plant that may lead to a situation when values of the dose absorbed by the container go outside these limits shall be never omitted by the operator.
19. (13) Commissioning shall consist of the following elements:
а) (a) planning;
b) (b) preparation of a dose field map;
c) (c) documentation;
d) (d) determination of requirements to re-commissioning of the plant;
20. (14) The dose absorbed by a particular part of the exposed container in any certain point around the radiation source shall depend, without limitation, on the following factors:
а) (a) the activity and shape of the radiation source;
b) (b) the distance from the source to the container;
c) (c) the time of exposure controlled by the timer or the speed at which the conveyor moves;
d) (d) the composition and density of the material, including other products between the source and a certain part of the container.
21. (15) The total absorbed dose shall also depend on the route along which containers move in case of the continuous mode, or the loading pattern in case of the batch mode of irradiation, as well as the number of exposure cycles.
22. (16) In case of a determined route (continuous irradiation) or a set loading pattern (batch mode of irradiation), a constant output of the source and the type of products, the main parameter of the plant controlled by the operator shall be the speed of the conveyor or the time set on the timer.
23. (17) During the preparation of a dose field map the exposure chamber shall be filled with containers and models or samples of products of uniform density. Dosimeters shall be placed in at least three full containers moving through the radiation source. These containers shall be surrounded with similar containers or models of products. It products are not arranged evenly, dosimeters shall be placed in a greater number of containers.
24. (18) The position of dosimeters shall depend on the size of the exposed container. For example, for containers of 1 x 1 x 0.5 m dosimeters may be placed in points of a three-dimensional lattice at 20 cm from each other subject to the external surface of the container. If probable areas with the maximum and minimum doses have been detected during previous experiments, a number of dosimeters may be taken from areas with mean dose values and put into areas with extreme dose values at 10 cm from each other.
25. (19) This procedure shall result in determining the minimum and maximum doses absorbed by the products and the surface of the container at the set parameters of the plant, density of the products and the loading pattern.
26. (20) Ideally, it is recommended to use reference dosimeters to determine the dose field map as they have a greater accuracy. It is also allowed to apply ordinary dosimeters, but it is recommended to place at their side reference dosimeters in areas where minimum and maximum doses are expected and in the usually controlled area in each dummy container for exposure. The measured values of the absorbed dose will include random errors that may be determined by numerous measurements.
27. (21) The minimum observed dose measured by an ordinary dosimeter and required to guarantee that all exposed containers have absorbed the minimum required dose shall be set based on the random measurement error of operating dosimeters.
28. (22) During preparation of the dose field map parameters of the plant shall be kept unchanged, controlled and registered. These records, the dosimetry results and other obtained records shall be stored.
29. (23) The absorbed dose of ionizing radiation in products shall depend on the following main factors:
а) (a) the characteristics of the bunch, namely: the electron energy, the average flow of the bunch, the width of the sweep and the even arrangement of the bunch across the sweep;
b) (b) the conveyor speed;
c) (c) the composition and density of the products;
d) (d) the composition, density and thickness of the material placed between the output window and the exposed part of the products;
e) (e) the distance from the output window to the container.
30. (24) The main parameters controlled by the operator shall be the characteristics of the bunch and the conveyor speed.
31. (25) During the preparation of a dose field map dosimeters shall be placed between layers of a homogeneous absorber representing the real products or between layers of samples of products of uniform density so as at least 10 measurements are taken within the limits of the maximum path of electrons. It is also necessary to meet the requirements specified in Items 24 – 27 hereof.
32. (26) During preparation of the dose field map parameters of the radiation plant shall be kept unchanged, controlled and registered. These records, the dosimetry results and other obtained records shall be stored.
33. (27) The re-commissioning procedure shall be repeated every time when there are changes in the process or parameters of the radiation plant that can influence the distribution of the absorbed dose inside the exposed container (e.g. when the rod of the radiation source is replaced). The scope of re-commissioning works shall depend on the degree of changes in the design of the radiation source of the radiation plant or the boot configuration. If there are any doubts, the re-commissioning of the plant shall be performed again
34. (28) Rooms shall be designed and used so as to separate irradiated containers from those that have not been irradiated in order to prevent cross contamination. If materials are processed in closed irradiation containers, it is not necessary to separate pharmaceutical and non-pharmaceutical materials from one another provided that there will be no risk of their contamination in future.
35. Any possibility of contamination of the products by radionuclides shall be excluded.
36. (29) Containers with products shall be loaded according to the loading pattern(s) set in the process of validation.
37. (30) During the process the radiation dose for irradiated containers shall be controlled with the help of certified measuring techniques. The dependence between this dose and the dose absorbed by the products inside the container shall be determined during the process validation and commissioning of the radiation plant.
38. (31) To differentiate between irradiated and non-irradiated containers, it is necessary to use ionizing radiation indicators. However such indicators shall not be used as the only differentiating means or as the only indication of satisfactory results of processing.
39. (32) Different types of products may be loaded and simultaneously treated in the radiation chamber only if according to the results of the plant operation or other data the absorbed dose in each individual container remains within the set limits.
40. (33) If the required dose of radiation is absorbed in more than one exposure or more than one passage through the radiation chamber, it shall be approved by the legal entity in whose name the Marketing Authorization has been issued. In this case the specified dose shall be absorbed within the pre-set period of time. The legal entity in whose name the Marketing Authorization has been issued shall be informed of unplanned pauses in the irradiation process if they prolong the process to a period of time exceeding the one previously agreed.
41. (34) Irradiated products shall be always separated from non-irradiated ones. Methods ensuring such separation shall include the use of radiation indicators (Item 38 hereof), and appropriate layout of the premises (Item 34 hereof).
42. (35) In case of the continuous mode dosimeters shall be placed so as to ensure that during the whole process at least two dosimeters are simultaneously exposed to radiation.
43. (36) In case of the batch mode at least two dosimeters shall be exposed to ionizing radiation in the area where the minimum dose is absorbed.
44. (37) In case of the continuous mode there shall be an indication of the required operating position of the source. The position of the source and the movement of the conveyor shall be connected by a block system. The conveyor speed shall be constantly controlled and registered.
45. (38) In case of the batch mode of irradiation the movement of the source and the time of exposure of each batch of products shall be controlled and registered.
46. (39) To get the required dose it is necessary to adjust the time of exposure and the speed of the conveyor subject to the decay or recharge of the source of radiation. The validity period of the plant parameter and the conveyor speed shall be documented and strictly observed.
47. (40) A dosimeter shall be put into each container.
48. (41) It is necessary to constantly register the mean value of the bunch flow, the electron energy, the width of the sweep and the conveyor speed. These parameters, except the conveyor speed, shall be controlled within the set limits determined during commissioning, as they are subject to spontaneous variations.
49. (42) The number of received containers and the number of irradiated containers transported from the production site shall be equal and correspond to the values indicated in the supporting documents. Any deviations shall be registered and investigated into.
50. (43) The operator of the radiation plant shall confirm in writing the range of values of doses absorbed by each container in case of each loading or batch of products.
51. (44) Process records and control records for each irradiated batch of products shall be checked, signed by a specially appointed person and stored. The method and place of storage shall be agreed between the organization performing the irradiation and the legal entity in whose name the Marketing Authorization for the medicine has been issued.
52. (45) Documents related to the validation of the radiation plant shall be stored for one year after the expiry date or at least within five years after the release of the last products irradiated in this plant whichever period is longer.
53. (46) The manufacturer of the medicines shall be in charge of the microbiological control. This monitoring may include monitoring of the process environment and product inspection before irradiation as specified in the registration dossier.