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1、EUROPEAN COMMISSION ENTERPRISE DIRECTORATE-GENERAL Single market : management firstly those where the product is terminally sterilised, and secondly those which are conducted aseptically at some or all stages. 3. Clean areas for the manufacture of sterile products are classified according to the req
2、uired charac- teristics of the environment. Each manufacturing operation requires an appropriate environmental cleanliness level in the operational state in order to minimise the risks of particulate or microbial con- tamination of the product or materials being handled. In order to meet “in operati
3、on” conditions these areas should be designed to reach certain specified air-cleanliness levels in the “at rest” occupancy state. The “at-rest” state is the condition where the installation is installed and operating, complete with production equipment but with no operating per- sonnel present. The
4、“in operation” state is the condition where the installation is functioning in the de- fined operating mode with the specified number of personnel working. The “in operation” and “at rest” states should be defined for each clean room or suite of clean rooms. For the manufacture of sterile medicinal
5、products 4 grades can be distinguished. Grade A : The local zone for high risk operations, e.g. filling zone, stopper bowls, open ampoules and vials, making aseptic connections. Normally such conditions are provided by a laminar air flow work station. Laminar air flow systems should provide a homoge
6、neous air speed in a range of 0.36 0.54 m/s (guidance value) at the working position in open clean room applications. The maintenance of laminarity should be demonstrated and validated. A uni-directional air flow and lower velocities may be used in closed isolators and glove boxes. Grade B : For ase
7、ptic preparation and filling, this is the background environment for the grade A zone. Grade C and D: Clean areas for carrying out less critical stages in the manufacture of sterile products. The airborne particulate classification for these grades is given in the following table. at rest (b)in oper
8、ation (b) Grademaximum permitted number of particles/m3 equal to or above (a) 0.5 m (d)5 m0.5 m (d)5 m A3 5001 (e)3 5001 (e) B (c)3 5001 (e)350 0002 000 C (c)350 0002 0003 500 00020 000 D (c)3 500 00020 000not defined (f)not defined (f) Notes: (a) Particle measurement based on the use of a discrete
9、airborne particle counter to measure the concentration of particles at designated sizes equal to or greater than the threshold stated. A continuous measurement system should be used for monitoring the concentration of particles in the grade A zone, and is recommended for the surrounding grade B area
10、s. For routine testing the total sample volume should not be less than 1 m3 for grade A and B areas and preferably also in grade C areas. (b) The particulate conditions given in the table for the “at rest” state should be achieved after a short “clean up” period of 15-20 minutes (guidance value) in
11、an unmanned state after completion of op- erations. The particulate conditions for grade A “in operation” given in the table should be main- tained in the zone immediately surrounding the product whenever the product or open container is exposed to the environment. It is accepted that it may not alw
12、ays be possible to demonstrate conformity with particulate standards at the point of fill when filling is in progress, due to the gen- eration of particles or droplets from the product itself. (c) In order to reach the B, C and D air grades, the number of air changes should be related to the size of
13、 the room and the equipment and personnel present in the room. The air system should be provided with appropriate terminal filters such as HEPA for grades A, B and C. (d) The guidance given for the maximum permitted number of particles in the “at rest“ and “in opera- tion” conditions correspond appr
14、oximately to the cleanliness classes in the EN/ISO 14644-1 at a particle size of 0.5 m. (e) These areas are expected to be completely free from particles of size greater than or equal to 5 m. As it is impossible to demonstrate the absence of particles with any statistical significance the limits are
15、 set to 1 particle / m3. During the clean room qualification it should be shown that the ar- eas can be maintained within the defined limits. (f) The requirements and limits will depend on the nature of the operations carried out. Other characteristics such as temperature and relative humidity depen
16、d on the product and nature of the operations carried out. These parameters should not interfere with the defined cleanliness stan- dard. Examples of operations to be carried out in the various grades are given in the table below. (see also par. 11 and 12) GradeExamples of operations for terminally
17、sterilised products. (see par. 11) AFilling of products, when unusually at risk CPreparation of solutions, when unusually at risk. Filling of products DPreparation of solutions and components for subsequent filling GradeExamples of operations for aseptic preparations. (see par. 12) AAseptic preparat
18、ion and filling. CPreparation of solutions to be filtered. DHandling of components after washing. 4. The areas should be monitored during operation, in order to control the particulate cleanliness of the various grades. 5. Where aseptic operations are performed monitoring should be frequent using me
19、thods such as settle plates, volumetric air and surface sampling (e.g. swabs and contact plates). Sampling methods used in operation should not interfere with zone protection. Results from monitoring should be considered when reviewing batch documentation for finished product release. Surfaces and p
20、ersonnel should be monitored after critical operations. Additional microbiological monitoring is also required outside production operations, e.g. after validation of systems, cleaning and sanitisation. Recommended limits for microbiological monitoring of clean areas during operation. Recommended li
21、mits for microbial contamination (a) Gradeair sample cfu/m 3 settle plates (diam. 9 0 mm), cfu/4 hours (b) contact plates (diam. 55 mm), cfu/plate glove print 5 fingers cfu/glove A3 to 5 bar) to ensure that the cylinder is not emptied - Cylinders with no residual pressure should be put aside for add
22、itional 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 removed -visual external inspection of each valve an
23、d 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 is the proper type for the particular medicina
24、l 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 container is colour-coded according to the relevant
25、 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 pressure of 200 bar (and equivalent for other filli
26、ng 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 using validated methods (partial pressurisation
27、 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 should be carried out for each individual container.
28、 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 should be labelled and colour-coded. The batch num
29、ber 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 medicinal gas should be tested and released accordin
30、g 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 the case of a single medicinal gas filled via a
31、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 filled put into cylinders one at a time by indivi
32、dual 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 bulk gas. 6.6.In the case of a medicinal gas p
33、roduced 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 for identity of the balance gas in the mixture. W
34、hen 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. 6.7.When gases are mixed in-line before filling (
35、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 homogeneous. 6.9.Each filled cylinder should be t
36、ested 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 delivery to users, each vessel should be tested f
37、or 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 analysis for a sample taken from the mobile del
38、ivery 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 cylinders should be held in quarantine until r
39、eleased 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 up to the time of use. 7.3.Storage arrangements
40、 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 storage and transportation should be employed fo
41、r 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 below. Air separation plant Air separation plants t
42、ake 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 gases Blowing down Blow the pressure down to atm
43、ospheric 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 container is a cryogenic vessel, a tank, a tanker
44、, 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 to contain liquefied or cryogenic gases. The g
45、as 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 bundle A set assembly of cylinders, which are
46、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 bar (101,325 kPa) and +15 0 C or has a vapour
47、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. Liquefied gas A gas which when packaged under pressure
48、, 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 retropollution and remaining after the cylinders pre-tr
49、eatment 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 for 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 contamination during use. Non-return