Attachment No. 6
to the Rules of Good Manufacturing Practice
Содержание
MANUFACTURE OF MEDICAL GASES
I. PRINCIPLE
1. This Attachment governs the manufacture of gases as pharmaceutical substances (PS) and the manufacture of gases for medical application (hereinafter – medical gases). Medical gases related to medicines shall be manufactured pursuant to corresponding regulatory legal acts of the Russian Federation.
2. This Attachment shall not apply to manufacture and circulation of medical gases in healthcare organizations, if this process is not industrial production.
3. Differentiation between the manufacture of PS and the manufacture of medicines shall be clearly defined in each registration dossier. As a rule, stages of gas manufacture and treatment are related to the manufacture of PS. Gases are considered medicines from the moment of the first preservation of gas intended for such application.
4. In exceptional cases continuous processes when intermediate storage between the manufacture of PS and the manufacture of medicines is impossible shall be deemed the production of medicines and it shall be clearly specified in the registration dossier.
II. MANUFACTURE OF GASES AS PHARMACEUTICAL SUBSTANCES
5. Gases as pharmaceutical substances may be manufactured by chemical synthesis or from natural source, including by their purification (e.g. at factories separating gases from the air).
6. (1) The manufacturer shall perform technological processes of gas production in accordance with the above methods pursuant to the requirements of Chapter IV of these Rules, however:
а) (a) requirements to starting raw materials for pharmaceutical substances (Items 400 – 421 of these Rules) shall not apply to the manufacture of pharmaceutical substances in the form of gases by the air separation method (but the manufacturer shall guarantee that the quality of the used air corresponds to the set quality and any change in the quality of the air from the external environment will not affect the quality of gases manufactured as PS);
b) (b) requirements to the continuous study of the stability of gases as pharmaceutical substances (Items 497 – 503 of these Rules) conducted in order to confirm the storage conditions and the expiration date or the date of re-inspection (Items 487 – 490 of these Rules), shall not apply if the initial study of the stability was based on the data from the scientific literature;
c) (c) requirements to control and retention samples (Items 508 – 510 of these Rules) shall not apply to gases as pharmaceutical substances, unless otherwise stated in regulatory legal acts of the Russian Federation.
7. (2) The manufacturer shall conduct steady monitoring of the quality of gases as pharmaceutical substances manufactured by the continuous method (e.g. air separation). The monitoring results shall be stored in a form that enables trend assessment.
8. (3) (a) Transportation and delivery conditions of bulk gases as pharmaceutical substances shall meet the requirements set for medical gases (Items 29 – 31 hereof);
9. (b) Filling of tanks or portable cryogenic vessels with gases as pharmaceutical substances shall be performed pursuant to the requirements set for medical gases (Items 32 – 48 hereof) and the requirements set in Items 450 – 469 of these Rules.
III. MANUFACTURE OF MEDICAL GASES
10. Medical gases are generally manufactured in closed equipment. For this reason the risk of contamination of these products from the process environment is minimum. However there is a risk of contamination or cross contamination with other gases, especially in case of repeated use of containers.
11. (4) Requirements to tanks shall also cover groups (bundles) of tanks (except when stored or transported in special containers).
12. (5) The staff engaged in the manufacture and sale of medical gases shall be trained in the organization of manufacture and quality control of medicines with regard to this type of products. The staff shall know about critical aspects and the possible danger of medicines in the form of medical gases. Drivers transporting medical gases shall also be properly trainer.
13. (6) The staff employed under contractor agreements and able to influence the quality of medical gases (e.g. the staff performing the maintenance of tanks or valves) shall be properly trainer.
14. (7) Tanks and portable cryogenic vessels shall be checked, prepared, filled and stored in areas separated from areas intended for operations with non-medical gases. It is prohibited to exchange tanks and portable cryogenic vessels between these areas. However it is acceptable to control, prepare, fill and store medical and non-medical gases in the same areas, if the requirements to non-medical gases correspond to the requirements to medical gases, and processing operations with non-medical gases are carried out pursuant to the requirements of these Rules.
15. (8) Rooms where operations of processing, testing and storage of medical gases take place shall have sufficient space to prevent any risk of confusion. The layout of the rooms shall ensure:
а) (a) separate marked areas for different gases;
b) (b) definite marking and separation of empty tanks and (or) portable cryogenic vessels, as well as tanks and (or) portable cryogenic vessels at different manufacturing stages (e.g. ‘to be checked’, ‘to be filled’, ‘quarantine’, ‘approved’, ‘rejected’, ‘ready for shipment’).
16. The separation techniques shall depend on the nature, scope and complexity of the manufacturing process. Separation measures may include use of areas with floor marking, walls, barriers and symbols.
17. (9) Empty tanks and (or) portable cryogenic vessels that have been sorted and maintained, and filled tanks and (or) portable cryogenic vessels shall be stored in a shed protecting them from unfavourable weather conditions. Filled tanks and (or) portable cryogenic vessels shall be stored under conditions that guarantee their delivery in a clean state corresponding to the conditions for their use.
18. (10) The manufacturer shall ensure special storage conditions in accordance with the requirements of the registration dossier (e.g. for gas mixtures with phase separation in case of freezing).
19. (11) The equipment shall be designed so as to guarantee that gas is pushed into the right container. As a rule, there shall be no connections between pipelines with different gases. If such connections are necessary (e.g. equipment used for filling with gas mixtures), the manufacturer shall conduct appropriate qualification in order to guarantee that there is no risk of cross contamination with different gases. In addition to this requirements supply manifolds shall be equipped with specific connection elements. If regulatory legal acts of the Russian Federation set requirements to the use of supply manifolds and their connections with tank valves, these requirements shall be met. Use of connections corresponding to different standards in one processing area shall be closely controlled, as well as the use of adapters that are necessary in some cases for connection of special filling systems.
20. (12) Reservoirs for storage and portable tankers for delivery shall be used only for one type of gas of a definite quality. Medical gases may be stored and transported in the same reservoirs as similar non-medical gases provided that the quality of the latter is at least equivalent to the quality of medical gases and the requirements of these Rules are met. In such cases the manufacturer shall perform and document risk management procedures.
21. (13) A common gas distribution system with medical and non-medical collector shall be acceptable only in case of a validated method preventing the gas from flowing back from the non-medical system into the medical one.
22. (14) The manufacturer shall have filling collectors intended for one medical gas or a certain mixture of medical gases. In exceptional cases it is acceptable to fill gases for other medical purposes with the help of collectors intended for medical gases, if the possibility of this operation is proven and this process is controlled. In these cases the quality of the non-medical gas shall be at least equivalent to the quality of the medical gas and the requirements of these Rules shall be met. Filling operations shall be performed according to the principle of organization of production cycles.
23. (15) Repair and maintenance of equipment (including cleaning and purging) shall not affect the quality of medical gases. In particular, the manufacturer shall develop and document measures taken after repairs and maintenance leading to system depressurization. The manufacturer shall guarantee that the equipment is free from any contamination that may affect the quality of the finished product before its release. The manufacturer shall keep records on the conducted works.
24. (16) The manufacturer shall develop and document procedures performed when a tanker is returned to the area of works with medical gases after transportation of non-medical gas under conditions specified in Item 20 hereof or after maintenance. This procedure shall include analytical tests.
25. (17) Data indicated in the dossier for each batch of filled tanks (portable cryogenic vessels) shall enable tracing of the information on all basic parameters of corresponding filling stages for each filled tank.
26. The dossier for a batch shall contain the following information (if applicable):
а) (a) the name of the product;
b) (b) the batch number;
c) (c) the date and time of the filling operation;
d) (d) the staff members who perform the main process stages (e.g. line cleaning, acceptance of materials, filling line preparation, filling operations);
e) (e) the reference to the number(s) of the gas batch(es) used for the filling operations pursuant to Item 32 hereof, including their status (permit for filling);
f) (f) used equipment (e.g. the filling collector);
g) (g) the number of tanks and (or) portable cryogenic vessels before the filling operation, including the identification details of each tank and its geometric volume;
h) (h) operations performed before filling (Item 41 hereof);
i) (i) key parameters required for confirming the correctness of the filling operation under standard conditions;
j) (j) results of corresponding inspections proving that tanks and (or) portable cryogenic vessels have been filled;
k) (k) a template of the batch label;
l) (l) specifications of the medicine and the quality control results (including references to the current calibration status of the equipment applied for testing);
m) (m) the number of rejected tanks and (or) portable cryogenic vessels with their individual identification details and rejection causes;
n) (n) detailed information on all problems and deviations, an approved permit for any deviation from filling instructions;
o) (o) a dated and signed permit of an authorized person for the release of the batch.
27. (18) The manufacturer shall keep a dossier for each gas batch intended for filling reservoirs in healthcare organizations. The dossier shall contain the following information (if applicable):
а) (a) the name of the product;
b) (b) the batch number;
c) (c) the reference to the identification number of the vessel (tanker) in which the batch is permitted to be sold;
d) (d) the date and time of the filling operation;
e) (e) the staff members filling the vessel (tanker);
f) (f) data on the vessel (tanker) from which the gas is taken, the information on the gas used for the filling operation;
g) (g) data on all significant details of the filling operation;
h) (h) specifications of the finished medicine and the quality control results (including references to the current calibration status of the equipment applied for testing);
i) (i) detailed information on all problems and deviations, an approved permit for any deviation from filling instructions;
j) (j) a dated and signed permit of an authorized person for the release of the batch.
28. If regulatory legal acts of the Russian Federation set special requirements to the contents of the above dossier, these requirements shall be met.
Relocation and delivery of cryogenic and liquefied gases
29. (19) Relocation of cryogenic and liquefied gases from the place of initial storage, including control before relocation, shall be carried out in accordance with validated procedures developed to prevent possible contamination. Pipelines for gas transportation shall have a holding valve or any other appropriate device. Flexible connections, temporary connecting tubes and connection means shall be cleaned with a flow of appropriate gas before use.
30. (20) Tubes used for filling reservoirs and tankers shall have connection means specially intended for this type of products. Use of adapters enabling connection of reservoirs and tankers shall be properly controlled.
31. (21) Supply of gas into reservoirs containing similar gas of the same quality level shall be performed in case of positive quality test results of the supplied gas. A sample may be taken either from supplied gas or from the reservoir after the gas supply has been completed. Special conditions concerning the quality control in case of filling of reservoirs at the acquirer’s site are described in Item 56 hereof.
Filling and marking of tanks and portable
cryogenic vessels
32. (22) Before tanks and portable cryogenic vessels have been filled, the gas batch(es) shall be identified, checked pursuant to the specifications and approved for the filling operation.
33. (23) In case of continuous processes it is necessary to set relevant production control points to ensure the conformity of the gas to the specifications.
34. (24) Tanks, portable cryogenic vessels and valves shall correspond to the set technical specifications and meet the requirements of the registration dossier. They shall be intended only for one medical gas or a certain mixture of medical gases. Tanks shall have colour marking pursuant to the set requirements. To avoid contamination tanks shall be equipped with minimum pressure containment valves and mechanisms preventing any reverse flow.
35. (25) Tanks, portable cryogenic vessels and valves shall be checked before their first use in the manufacturing process and properly maintained. In case of use of medical products their technical maintenance shall be performed pursuant to the instructions of the manufacturer of the tanks, portable cryogenic vessels and valves.
36. (26) Operations of inspection and maintenance shall not affect the quality and safety of the medicine. Water used for testing tanks under hydrostatic pressure shall meet the requirements to the quality of drinking water.
37. (27) To guarantee absence of contamination, the internal state of tanks shall undergo visual inspection to ensure that there is no water or other contaminants left before the valve has been installed. The above operation shall be performed as part of inspections and maintenance. It shall be carried out:
with regard to new tanks used for medical gases for the first time;
after testing under hydrostatic pressure or any equivalent tests with the valve removal;
every time the valve is replaced.
38. After the valve has been installed, it shall be closed to prevent any contamination. In case of any doubts in terms of the internal state of the tank, the valve shall be removed and the internal state of the tank shall be inspected to ensure that there is no contamination.
39. (28) The manufacturer shall maintain and repair tanks, portable cryogenic vessels and valves. If these works are performed under a contract, these works shall be performed only by the contractor indicated in the contract. It is recommended to include in contracts for work outsourcing technical requirements for such works. The manufacturer shall check that contractors observe the conditions of the contract, including conditions of compliance with the requirements of these Rules.
40. (29) The manufacturer shall develop a system that enables tracing tanks, portable cryogenic vessels and valves.
41. (30) Inspections conducted before the filling operation shall include:
а) (a) an examination of tanks according to the approved procedure in terms of the presence of residual excessive pressure for each tank:
if the tank is equipped with a minimum pressure containment valve, and there is no signal indicating that there is residual excessive pressure, the valve shall be checked; if the valve functions incorrectly, the tank shall be sent for maintenance;
if the tank has no minimum pressure containment valve and there is no residual excessive pressure in the tank, this tank shall be sent for additional testing to check the absence of contamination by water or other substances; additional measures may include a visual inspection of the internal state of the tank which shall be conducted after cleaning by means of a validated method;
b) (b) an examination of the absence of identification labels of the previous batch;
c) (c) an examination of removal and replacement of all damaged identification labels of the product;
d) (d) an external visual examination of each tank, portable cryogenic vessel and valve in order to detect cavities, welding burnings, other damages and contamination with oils, and cleaning, if necessary;
e) (e) an examination of the tube connection of each tank or portable cryogenic vessel for compliance with the type of connection for the filled gas;
f) (f) an examination of the date of the following valve test (for valves subject to periodic checks);
g) (g) an examination of tanks or portable cryogenic vessels with regard to completion of all required tests (e.g. testing under hydrostatic pressure or any equivalent tests) which are required pursuant to regulatory legal acts of the Russian Federation, and an examination of the accuracy of results of these tests;
h) (h) an examination of the colour marking of each tank in accordance with the registration dossier (colour codes pursuant to the set requirements).
42. (31) The batch size shall be defined depending on the filling operation.
43. 32) Tanks returned for refilling shall be thoroughly prepared to minimize the risk of contamination according to the set procedures. Techniques including pumping and (or) purging procedures shall be validated. The theoretical impurity level for pressurized gases under the filling pressure of 200 bar shall equal no more than 500 volume parts per million at the temperature of 15 °C. Equivalent values shall be determined for other pressure.
44. (33) To minimize the risk of contamination portable cryogenic vessels returned for refilling shall be carefully prepared according to the approved procedures. In particular, portable vessels free from residual pressure shall be prepared with the help of a validated method.
45. (34) The manufacturer shall perform appropriate examinations to ensure correct filling of each tank and (or) portable cryogenic vessel.
46. (35) Before the first opening control device has been installed (Item 47 hereof), each filled tank shall be checked for leakage with the help of an appropriate method. The used control method shall not lead to contamination of the surface of the tube of the tank valve. If possible, this examination shall take place after all samples for the quality control have been taken.
47. (36) After the filling operation, the tubes of tank valves shall be closed with caps to prevent contamination. First opening control devices shall be installed on tanks and portable cryogenic vessels.
48. (37) Each tank or portable cryogenic vessel shall be marked with labels. The batch number and expiration date may be indicated on a separate label.
49. (38) When medical gases are manufactured by mixing two or more different gases (in the filling line or in tanks), the manufacturer shall use a validated mixing method that can guarantee that gases have been properly mixed in each tank and ensures the homogeneity of the mixture.
50. (39) Each batch of medical gas (tanks, portable cryogenic vessels, reservoirs in healthcare organizations) shall be checked in accordance with the set requirements. A release permit shall be provided for each batch by an authorized person.
51. (40) The sampling plan and the scope of conducted tests shall meet the following requirements in terms of tanks (unless otherwise stated in the procedures):
а) (a) if only one medical gas is pushed into tanks with the help of a collector to which several tanks are connected at the same time, the gas shall be tested at least from one tank in order to determine authenticity and quantitative measurement; samples shall be taken in each filling cycle when tanks connected to the collector are changed;
b) (b) if only one medical gas is pushed into tanks during one period of time of one production cycle, at least one tank in each continuous filling cycle shall be checked for authenticity and quantitative content. An example of a continuous filling cycle shall be the manufacture during one shift by the same staff members with the help of the same equipment and one gas batch that is used to fill containers;
c) (c) if the medical gas is made by mixing in the tank of two or more different gases from one and the same supply manifold, gas from each tank shall be checked for authenticity and quantitative content of all components of the gas mixture. For excipients (if any) the test for authenticity may be conducted for one tank from the filling cycle (or for each continuous filling cycle). Fewer tanks may be tested, if validated automated filling systems are used;
d) (d) in case of gases mixed before the filling operation, it is required to observe the same principles as in case of filling with one gas, when the mixture of gases used for the filling operation is constantly controlled at the line.
52. In case of gases mixed before the filling stage, it is necessary to observe the same principles as in case of gases mixed in tanks, when the mixture of gases used for the filling operation is not constantly controlled at the line.
53. Unless otherwise stated by the manufacturer, tests for water content shall be conducted.
54. It is allowed to use other sampling and testing methods, if they ensure the same quality level.
55. (41) Final tests of portable cryogenic vessels shall include tests for authenticity and quantitative measurement in each vessel, unless otherwise indicated in the set requirements. Random batch inspection may be used only it has been proven that the critical characteristics of the residual gas in each tank remain the same before refilling.
56. (42) After cryogenic vessels of acquirers have been refilled in the place of use (reservoirs in healthcare organizations or portable cryogenic vessels) from specially intended tankers, no samples shall be taken, if there is a document confirming the quality of the contents of the used tankers. In this case the manufacturer shall prove that after consecutive refilling operations the quality of the gas in the vessels is kept at the set level.
57. (43) Control and retention samples of a batch of products shall be kept only if it is required according to the documents.
58. (44) No continued stability studies are required, if the initial study of the stability has been replaced by the data from the scientific literature.
59. (45) Filled gas tanks and portable cryogenic vessels shall be protected during transportation, in particular, they shall be delivered to clients clean according to the conditions of their further use.
IV. TERMS AND DEFINITIONS
60. For purposes hereof, in addition to the terms and definitions stipulated in Chapter II of these Rules, the following basic terms are used:
ambulatory cryogenic vessel: a portable thermally isolated container designed for storing liquefied oxygen and using oxygen gas at the patient’s;
gas: a substance or a mixture of substances which are in a completely gaseous state under the pressure of 1.013 bar and at the temperature of +20 °C or at +50 °C the pressure of their vapours exceeds 3 bar;
gas as a pharmaceutical substance: a gas intended to be used as a pharmaceutical substance for the manufacture of a medicine;
group (bundle) of tanks: tanks grouped and joined together, connected through a supply manifold, transported and used as a whole;
test under hydrostatic pressure: a test conducted in order to ensure safety in accordance with the set requirements by checking that tanks and reservoirs can sustain the planned high pressure;
valve: a device for opening and closing a container;
residual pressure containment valve: a valve installed on a tank and maintaining above atmospheric pressure in the used tank to prevent contamination of the internal volume of the tank;
container: a cryogenic vessel (a tank, tanker or portable cryogenic vessel of any other type), a tank, a bundle of tanks or any other package that is in direct contract with the medical gas;
cryogenic gas: a gas liquefied under pressure of 1.013 bar and at the temperature below -150 °C;
maximum theoretical impurity residual level: a gaseous impurity from a probable reverse flow of gases that remains after preliminary treatment of tanks before their filling. The calculation of the maximum theoretical impurity level is important only for pressurized gases with an assumption that these gases behave like perfect gases;
medical gas: any gas or a mixture of gases that are a medicine;
holding valve: a valve that lets the flow go only in one direction;
to pump out: to remove residual gas from a container and (or) system with the help of vacuum under pressure of less than 1.013 bar;
portable cryogenic vessel: a portable thermally isolated container designed for storing liquid substances. For purposes hereof this term shall not include the term ‘tanker’;
purging: removal of residual gas from a container and (or) system by initial pressurization with the help of the used gas and subsequent depressurization of the gas to 1.013 bar;
air separation: separation of the atmospheric air into its gas components by means of fractional distillation at cryogenic temperatures;
supply manifold: equipment or a device designed for simultaneously emptying or filling with gas one or more containers;
reservoir: a fixed thermally isolated container for storing liquefied or cryogenic gas, also called ‘a fixed cryogenic vessel’;
depressurization: an operation aimed at removing residual gas from a container and (or) system till the residual pressure reaches 1.013 bar and carried out by connecting the container and (or) system to the atmospheric air;
pressurized gas: gas packaged under pressure for transportation which remains completely gaseous at the temperature above -50 °C;
liquefied gas: gas packaged under pressure for transportation which remains partially liquid or solid at the temperature above -50 °C;
tanker: a thermally isolated container fixed to a vehicle to transport liquefied and cryogenic gas.