EU-GMP-Part-II-Annexes-6.pdf
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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
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- EU GMP Part II Annexes
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