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1、1 EUROPEAN COMMISSION ENTERPRISE DIRECTORATE-GENERAL Single market : management - the date and the time of the filling operations; - a reference to the filling station used; - equipment used; - name and reference to the specification of the gas or each gas in a mixture - pre filling operations perfo
2、rmed (see point 7.3.5); - the quantity and size of cylinders before and after filling; - the name of the person carrying out the filling operation; - the initials of the operators for each significant step (line clearance, receipt of cylinders, emptying of cylinders etc); - key parameters that are n
3、eeded to ensure correct fill at standard conditions; - the results of quality control tests and where test equipment is calibrated before each test, the reference gas specification and calibration check results; - results of appropriate checks to ensure the containers have been filled - a sample of
4、the batch code label; - details of any problems or unusual events, and signed authorisation for any deviation from filling instructions; - to indicate agreement, the date and signature of the supervisor responsible for the filling operation. 5 5. Production 5.1.All critical steps in the different ma
5、nufacturing processes should be subject to validation. 5. 2. Bulk production 5.2.1. Bulk gases intended for medicinal use could be prepared by chemical synthesis or obtained from natural resources followed by purification steps if necessary (as for example in an air separation plant). These gases co
6、uld be regarded as Active Pharmaceutical Ingredients (API) or as bulk pharmaceutical products as decided by the national competent authority. 5.2.2. Documentation should be available specifying the purity, other components and possible impurities that may be present in the source gas and at purifica
7、tion steps, as applicable. Flow charts of each different process should be available. 5.2.3.All separation and purification steps should be designed to operate at optimal effectiveness. For example, impurities that may adversely affect a purification step should be removed before this step is reache
8、d. 5.2.4. Separation and purification steps should be validated for effectiveness and monitored according to the results of the validation. Where necessary, in-process controls should include continuous analysis to monitor the process. Maintenance and replacement of expendable equipment components,
9、e.g. purification filters, should be based on the results of monitoring and validation. 5.2.5. If applicable, limits for process temperatures should be documented and in-process monitoring should include temperature measurement. 5.2.6. Computer systems used in controlling or monitoring processes sho
10、uld be validated. 5.2.7. For continuous processes, a definition of a batch should be documented and related to the analysis of the bulk gas. 5.2.8. Gas production should be continuously monitored for quality and impurities. 5.2.9. Water used for cooling during compression of air should be monitored
11、for microbiological quality when in contact with the medicinal gas. 5.2.10. All the transfer operations, including controls before transfers, of liquefied gases from primary storage should be in accordance with written procedures designed to avoid any contamination. The transfer line should be equip
12、ped with a non-return valve or other suitable alternative. Particular attention should be paid to purge the flexible connections and to coupling hoses and connectors. 5.2.11. Deliveries of gas may be added to bulk storage tanks containing the same gas from previous deliveries. The results of a sampl
13、e must show that the quality of the delivered gas is acceptable. Such a sample could be taken from - the delivered gas before the delivery is added; or 6 - from the bulk tank after adding and mixing 5.2.12 Bulk gases intended for medicinal use should be defined as a batch, controlled in accordance w
14、ith relevant Pharmacopoeial monographs and released for filling. 5.3. Filling and labelling 5.3.1. For filling of medicinal gases the batch should be defined. 5.3.2. Containers for medicinal gases should conform to appropriate technical specifications. Valve outlets should be equipped with tamper-ev
15、ident seals after filling. Cylinders should preferably have minimum retention valves in order to get adequate protection against contamination. 5.3.3. The medicinal gases filling manifold as well as the cylinders should be dedicated to a single medicinal gas or to a given mixture of medicinal gases
16、(see also 3.2.2). There should be a system in place ensuring traceability of cylinders and valves. 5.3.4. Cleaning and purging of filling equipment and pipelines should be carried out according to written procedures. This is especially important after maintenance or breaches of system integrity. Che
17、cks for the absence of contaminants should be carried out before the line is released for use. Records should be maintained. 5.3.5. Cylinders should be subject to an internal visual inspection when - they are new - in connection with any hydrostatic pressure test or equivalent test After fitting of
18、the valve, the valve should be maintained in a closed position to prevent any contamination from entering the cylinder. 5.3.6. Checks to be performed before filling should include: - a check to determine the residual pressure (3 to 5 bar) to ensure that the cylinder is not emptied - Cylinders with n
19、o residual pressure should be put aside for additional measures to make sure they are not contaminated with water or other contaminants. These could include cleaning with validated methods or visual inspection as justified. - Assuring that all batch labels and other labels if damaged have been remov
20、ed -visual external inspection of each valve and container for dents, arc burns, debris, other damage and contamination with oil or grease; Cylinders should be cleaned, tested and maintained in an appropriate manner. -a check of each cylinder or cryogenic vessel valve connection to determine that it
21、 is the proper type for the particular medicinal gas involved; -a check of the cylinder “test code date” to determine that the hydrostatic pressure test or equivalent test has been conducted and still is valid as required by national or international guidelines. - a check to determine that each cont
22、ainer is colour-coded according to the relevant standard 7 5.3.7. Cylinders which have been returned for refilling should be prepared with great care in order to minimise risks for contamination. For compressed gases a maximum theoretical impurity of 500 ppm v/v should be obtained for a filling pres
23、sure of 200 bar (and equivalent for other filling pressures). Cylinders could be prepared as follows: - any gas remaining in the cylinders should be removed by evacuating the container at least to a remaining absolute pressure of 150 millibar or - by blowing down each container, followed by purging
24、using validated methods (partial pressurisation at least to 7 bar and then blowing down) For cylinders equipped with residual (positive) pressure valves, one evacuation under vacuum at 150 millibar is sufficient if the pressure is positive. As an alternative, full analysis of the remaining gas shoul
25、d be carried out for each individual container. 5.3.8. There should be appropriate checks to ensure that containers have been filled. An indication that it is filling properly could be to ensure that the exterior of the cylinder is warm by touching it lightly during filling. 5.3.9. Each cylinder sho
26、uld be labelled and colour-coded. The batch number and/or filling date and expiry date may be on a separate label. 6. Quality Control 6.1.Water used for hydrostatic pressure testing should be at least of drinking water quality and monitored routinely for microbiological contamination. 6.2.Each medic
27、inal gas should be tested and released according to its specifications. In addition, each medicinal gas should be tested to full relevant pharmacopoeial requirements at sufficient frequency to assure ongoing compliance. 6.3.The bulk gas supply should be released for filling. (see 5.2.12) 6. 6.4.In t
28、he case of a single medicinal gas filled via a multi-cylinder manifold, at least one cylinder of product from each manifold filling should be tested for identity, assay and if necessary water content each time the cylinders are changed on the manifold. 7. 6.5.In the case of a single medicinal gas fi
29、lled put into cylinders one at a time by individual filling operations, at least one cylinder of each uninterrupted filling cycle should be tested for identity and assay. An example of an uninterrupted filling operation cycle is one shifts production using the same personnel, equipment, and batch of
30、 bulk gas. 6.6.In the case of a medicinal gas produced by mixing two or more different gases in a cylinder from the same manifold, at least one cylinder from each manifold filling operation cycle should be tested for identity, assay and if necessary water content of all of the component gases and fo
31、r identity of the balance gas in the mixture. When cylinders are filled individually, every cylinder should be tested for identity and assay of all of the component gases and at least one cylinder of each uninterrupted filling cycle should be tested for identity of the balance gas in the mixture. 6.
32、7.When gases are mixed in-line before filling (e.g. nitrous oxide/oxygen mixture) continuous analysis of the mixture being filled is required. 8 6.8.When a cylinder is filled with more than one gas, the filling process must ensure that the gases are correctly mixed in every cylinder and are fully ho
33、mogeneous. 6.9.Each filled cylinder should be tested for leaks using an appropriate method, prior to fitting the tamper evident seal. Where sampling and testing is carried out the leak test should be completed after testing. 6.10.In the case of cryogenic gas filled into cryogenic home vessels for de
34、livery to users, each vessel should be tested for identity and assay. 6.11.Cryogenic vessels which are retained by customers and where the medicinal gas is refilled in place from dedicated mobile delivery tanks need not be sampled after filling provided the filling company delivers a certificate of
35、analysis for a sample taken from the mobile delivery tank. Cryogenic vessels retained by customers should be periodically tested to confirm that the contents comply with Pharmacopoeial requirements. 6.12.Retained samples are not required, unless otherwise specified. 7. Storage and release 7.1.Filled
36、 cylinders should be held in quarantine until released by the qualified person. 7.2.Gas cylinders should be stored under cover and not be subjected to extremes of temperature. Storage areas should be clean, dry, well ventilated and free of combustible materials to ensure that cylinders remain clean
37、up to the time of use. 7.3.Storage arrangements should permit segregation of different gases and of full/empty cylinders and permit rotation of stock on a first in first out basis. 7.4. Gas cylinders should be protected from adverse weather conditions during transportation. Specific conditions for s
38、torage and transportation should be employed for gas mixtures for which phase separation occurs on freezing. Glossary Definition of terms relating to manufacture of medicinal gases, which are not given in the glossary of the current PIC/S Guide to GMP, but which are used in this Annex are given belo
39、w. Air separation plant Air separation plants take atmospheric air and through processes of purification, cleaning, compression, cooling, liquefaction and distillation separates the air into the gases oxygen, nitrogen and argon Area Part of premises that is specific to the manufacture of medicinal g
40、ases Blowing down Blow the pressure down to atmospheric pressure Bulk gas Any gas intended for medicinal use, which has completed all processing up to but not including final packaging 9 Compressed gas A gas which when packaged under pressure is entirely gaseous at 50 0 C. (ISO 10286) Container A co
41、ntainer is a cryogenic vessel, a tank, a tanker, a cylinder, a cylinder bundle or any other package that is in direct contact with the medicinal gas. Cryogenic gas Gas which liquefies at 1.013 bar at temperature below 1500 C. Cryogenic vessel A static or mobile thermally insulated container designed
42、 to contain liquefied or cryogenic gases. The gas is removed in gaseous or liquid form. Cylinder A transportable, pressure container with a water capacity not exceeding 150 litres. In this document when using the word cylinder it includes cylinder bundle (or cylinder pack) when appropriate. Cylinder
43、 bundle A set assembly of cylinders, which are fastened together in a frame and interconnec- ted by a manifold, transported and used as a unit. Evacuate To remove the residual gas in a container by pulling a vacuum on it. Gas A substance or a mixture of substances that is completely gaseous at 1,013
44、 bar (101,325 kPa) and +15 0 C or has a vapour pressure exceeding 3 bar (300 kPa) at + 50 0 C. (ISO 10286) Hydrostatic pressure test Test performed for safety reasons as required by national or international guideline in order to make sure that cylinders or tanks can withhold high pressures. Liquefi
45、ed gas A gas which when packaged under pressure, is partially liquid (gas over a liquid) at 50 0 C. Manifold Equipment or apparatus designed to enable one or more gas containers to be emptied and filled at a time. Maximum theoretical residual impurity Gaseous impurity coming from a possible retropol
46、lution and remaining after the cylinders pre-treatment before filling. The calculation of the maximum theoretical impurity is only relevant for compressed gases and supposes that these gases act as perfect gases. 10 Medicinal gas Any gas or mixture of gases intended to be administered to patients fo
47、r therapeutic, diagnostic or prophylactic purposes using pharmacological action and classified as a medicinal product. Minimum pressure retention valve Valve equipped with a non-return system which maintains a definite pressure (about 3 to 5 bars over atmospheric pressure) in order to prevent contam
48、ination during use. Non-return valve Valve which permits flow in one direction only. Purge To empty and clean a cylinder ? by blowing down and evacuating or ? by blowing down, partial pressurisation with the gas in question and then blowing down. Tank Static container for the storage of liquefied or cryogenic gas. Tanker Container fixed on a vehicle for the transport of liquefied or cryogenic gas. Valve Device for opening and closing containers. * * * * * *