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1 EUROPEAN COMMISSION ENTERPRISE DIRECTORATE-GENERAL 2008 년 11 월 25 일, 브뤼셀 EudraLex The Rules Governing Medicinal in the European Union Volume 4 EU Guidelines to Good Manufacturing Practice Medicinal for Human and Veterinary Use Annex 1 Manufacture of Sterile Medicinal (corrected version) 문서변경내역 2003 년 5 월 30 일자문서시행 2003 년 9 월 청정실등급구분표정리, 배지시뮬레이션, 바이오버든 모니터, 바이알캐핑관련가이드라인포함 2005 년 11 월 ~2007 년 12 월 시행일자및이전문서폐지일자 2009 년 3 월 1 일 1 바이알캐핑관련부분이수정되었음! 1 주 : 바이알캐핑작업에관한조항은 2010 년 3 월 1 일부터시행한다. 1

2 부록 1. 무균의약품제조 원칙 (Principle) The manufacture of sterile products is subject to special requirements in order to minimize risks of microbiological contamination, and of particulate and pyrogen contamination. Much depends on the skill, training and attitudes of the personnel involved. Quality Assurance is particularly important, and this type of manufacture must strictly follow carefully established and validated methods of preparation and procedure. Sole reliance for sterility or other quality aspects must not be placed on any terminal process or finished product test. 무균제품제조시에는미생물, 미립자, 발열성물질오염을최소화하기위해특별한기준이필요하다. 많은부분이관련작업자의기술, 훈련, 기본자세에달려있다. 품질 보증체계 (Quality Assurance) 가특히중요하며, 이런종류의제조작업시에는 체계적으로정립되고밸리데이션된절차와방법을정확하게준수해야한다. 최종제품의 무균상태나여타품질측면을최종공정이나최종제품시험에만의존해서는안된다. 주 (Note): This guidance does not lay down detailed methods for determining the microbiological and particulate cleanliness of air, surfaces etc. Reference should be made to other documents such as the EN/ISO Standards. 이가이드라인은공기, 표면등의미생물과미립자청정도를결정짓는구체적인방법을제시하지않는다. 이에대한사항은 EN/ISO 표준같은다른문서를참고한다. 공통 (General) 1. The manufacture of sterile products should be carried out in clean areas entry to which should be through airlocks for personnel and/or for equipment and materials. Clean areas should be maintained to an appropriate cleanliness standard and supplied with air which has passed through filters of an appropriate efficiency. 무균제품제조작업은작업자및 / 또는설비와물품이에어록을통해이동되는 2

3 청정지역에서실시되어야한다. 청정지역은적정청정기준에맞게유지되어야 하며적정효율의필터를통해공기를공급해야한다. 2. The various operations of component preparation, product preparation and filling should be carried out in separate areas within the clean area. Manufacturing operations are divided into two categories; firstly those where the product is terminally sterilised, and secondly those which are conducted aseptically at some or all stages. 원자재준비, 제품조제, 충전등의작업은청정지역내의별도지역 (separate areas) 에서실시해야한다. 제조작업은제품을사후멸균하는경우와제조공정전부또는일부단계를무균적으로실시하는경우등두종류로구분할수있다. 3. Clean areas for the manufacture of sterile products are classified according to the required characteristics 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 contamination of the product or materials being handled. 필요환경특성을바탕으로무균제품제조를위한청정지역을분류한다. 각각의제조작업마다취급대상제품또는물품의미생물또는미립자오염위험을 최소화하기위해, 작업상태 (operational state) 에서적정청정도수준을 유지해야한다. In order to meet in operation 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 personnel present. The in operation state is the condition where the installation is functioning in the defined operating mode with the specified number of personnel working. 작업상태 (in operation condition) 의청정도기준을만족시키기위해서는, 우선휴지상태 (at rest condition) 에서지정청정도기준에맞도록작업지역을설계해야한다. 휴지상태 (at rest state) 라함은생산설비의설치등모든설치가완료되고작업자없이설비가작동중인상태를의미한다. 작업상태 (in 3

4 operation state) 라함은지정작업자가있는상태에서정해진바에따라작업이 진행중인상태를말한다. The in operation and at rest states should be defined for each clean room or suite of clean rooms. 각각의청정작업실또는청정작업실그룹별로 " 작업상태 " 및 " 휴지상태 " 의기준을규정해야한다. For the manufacture of sterile medicinal products 4 grades can be distinguished. 무균의약품제조작업과관련하여, 일반적으로 4 개청정도등급이있다. 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 homogeneous air speed in a range of m/s (guidance value) at the working position in open clean room applications. The maintenance of laminarity should be demonstrated and validated. A 등급 : 충전지역, 마개보관통, 노출상태의앰플과바이알, 무균연결조작같이위험성이높은작업이진행되는곳. 일반적으로층류작업대 (laminar air flow work station) 를구비하여이런조건을확보한다. 층류시스템은개방청정작업실상황에서작업부위에 m/s( 참고치 ) 의균질한풍속을제공해야한다. 층류상태의유지를증명하고밸리데이션해야한다. A uni-directional air flow and lower velocities may be used in closed isolators and glove boxes. 폐쇄형아이솔레이터및글로브박스에서는단일방향공기흐름을확보하면서보다느린풍속상태로작업할수도있다. Grade B: For aseptic preparation and filling, this is the background environment for the grade A zone. B 등급 : 무균준비및충전작업을하는경우에, A 등급지역의배경환경에해당된다. 4

5 Grade C and D: Clean areas for carrying out less critical stages in the manufacture of sterile products. C 및 D 등급 : 무균제품의제조에서중요성이덜한단계의작업을수행하는청정지역. 청정실및청정공기장치분류 (Clean room and clean air device classification) 4. Clean rooms and clean air devices should be classified in accordance with EN ISO Classification should be clearly differentiated from operational process environmental monitoring. The maximum permitted airborne particle concentration for each grade is given in the following table. 청정실및청정공기장치의등급을 EN ISO 에따라분류한다. 작업상태의공정환경모니터와등급분류를명확히구분해야한다. 등급별최대허용부유미립자농도는다음표와같다. 등급 Maximum permitted number of particles/m 3 equal to or greater than the tabulated size 휴지상태 (at rest) 작업상태 (in operation) 0.5 m 5.0 m 0.5 m 5.0 m A 3, , B 3, ,000 2,900 C 352,000 2,900 3,520,000 29,000 D 3,520,000 29,000 not defined not defined 5. For classification purposes in Grade A zones, a minimum sample volume of 1 m 3 should be taken per sample location. For Grade A the airborne particle classification is ISO 4.8 dictated by the limit for particles 5.0 μm. For Grade B (at rest) the airborne particle classification is ISO for both considered particle sizes. For Grade C (at rest & in operation) the airborne particle classification is ISO 7 and ISO 8 respectively. For Grade D (at rest) the airborne particle classification is ISO 8. For classification purposes EN/ISO methodology defines both the minimum number of sample locations and the sample size based on the class limit of the 5

6 largest considered particle size and the method of evaluation of the data collected. A 등급지역의청정도분류시에검체채취위치별로최소 1 m 3 의검체를취해야한다. A 등급의부유미립자기준은 5.0 μm의미립자한도기준을적용한 ISO 4.8이다. B 등급 ( 휴지상태 ) 인경우에는부유미립자기준이두가지미립자크기모두에대하여 ISO 5를적용한다. C 등급 ( 휴지상태 & 작업상태 ) 인경우에는부유미립자기준이각각 ISO 7과 ISO 8이다. 등급분류목적에서의고려대상최대입자크기의기준에근거한검체량과최소검체채취위치수, 그리고수집한데이터의평가방법이 EN/ISO 에제시되어있다. 6. Portable particle counters with a short length of sample tubing should be used for classification purposes because of the relatively higher rate of precipitation of particles 5.0 μm in remote sampling systems with long lengths of tubing. Isokinetic sample heads shall be used in unidirectional airflow systems. 등급분류시에는검체튜빙의길이가짧은휴대용미립자계수장치를사용한다. 긴튜빙을구비하여먼거리에서검체를취하는시스템인경우에는 5.0 μm 입자의침전율이상대적으로높아지기때문이다. 단일방향기류시스템에서는등속성샘플헤드를사용한다. 7. In operation classification may be demonstrated during normal operations, simulated operations or during media fills as worst-case simulation is required for this. EN ISO provides information on testing to demonstrate continued compliance with the assigned cleanliness classifications. " 작업상태 " 등급은정상작업, 시뮬레이션작업, 또는메디아필과정중에증명할수있다. 이경우에는 " 최악의경우 " 시뮬레이션이요구되기때문이다. 지정청정도기준의지속적준수를증명하는테스트에관한정보가 EN ISO 에기술되어있다. 청정실과청정공기장치모니터 (Clean room and clean air device monitoring) 8. Clean rooms and clean air devices should be routinely monitored in operation and the monitoring locations based on a formal risk analysis 6

7 study and the results obtained during the classification of rooms and/or clean air devices. 청정실과청정공기장치를작업상태에서모니터하며, 작업실및 / 또는청정공기장치의등급분류과정에서획득한결과와공식리스크분석조사결과에근거하여모니터위치를정한다. 9. For Grade A zones, particle monitoring should be undertaken for the full duration of critical processing, including equipment assembly, except where justified by contaminants in the process that would damage the particle counter or present a hazard, e.g. live organisms and radiological hazards. In such cases monitoring during routine equipment set up operations should be undertaken prior to exposure to the risk. Monitoring during simulated operations should also be performed. The Grade A zone should be monitored at such a frequency and with suitable sample size that all interventions, transient events and any system deterioration would be captured and alarms triggered if alert limits are exceeded. It is accepted that it may not always be possible to demonstrate low levels of 5.0 μm particles at the point of fill when filling is in progress, due to the generation of particles or droplets from the product itself. A 등급지역은설비조립을포함하여핵심가공기간전체에걸쳐미립자모니터를실시한다. 다만미립자계수장치를손상시키거나위험을발생시킬수있는공정중의오염물 ( 예, 살아있는생물체와방사학적위험 ) 을감안해타당성이있는경우에는예외를인정한다. 이런경우에는정규설비셋업작업시의모니터를리스크노출이전에실시해야한다. 시뮬레이션작업도중의모니터도실시해야한다. 모든개입상황, 일회적이벤트, 시스템상태저하를포착하고경계기준을초과하면경보가발생될수있는정도의빈도로적합한검체량을채취하여 A 등급지역모니터를실시한다. 제품자체에서발생하는미립자나물방울때문에충전작업이진행중인상태에서충전지점의 5.0 μm 미립자가낮은수준임을증명하기가항상가능하지않을수도있음을인정한다. 10. It is recommended that a similar system be used for Grade B zones although the sample frequency may be decreased. The importance of the particle monitoring system should be determined by the effectiveness of the segregation between the adjacent Grade A and B zones. The Grade B 7

8 zone should be monitored at such a frequency and with suitable sample size that changes in levels of contamination and any system deterioration would be captured and alarms triggered if alert limits are exceeded. 검체채취빈도를감소시킬수는있지만, B 등급지역도유사한방식으로모니터할것을권고한다. 인접한 A 등급지역과 B 등급지역사이분리의효과를감안하여미립자모니터시스템의중요도를결정한다. 시스템상태저하와오염수준의변화를포착하고경계기준을초과하면경보가발생될수있는정도의빈도로적합한검체량을채취하여 B 등급지역의모니터를실시한다. 11. Airborne particle monitoring systems may consist of independent particle counters; a network of sequentially accessed sampling points connected by manifold to a single particle counter; or a combination of the two. The system selected must be appropriate for the particle size considered. Where remote sampling systems are used, the length of tubing and the radii of any bends in the tubing must be considered in the context of particle losses in the tubing. The selection of the monitoring system should take account of any risk presented by the materials used in the manufacturing operation, for example those involving live organisms or radiopharmaceuticals. 부유미립자모니터시스템은독립적인미립자계수장치, 하나의미립자계수장치가있고매니폴드를통해순차적으로여러검체채취포인트가연결되는네트워크시스템, 또는이둘의조합으로구성될수있다. 모니터대상미립자크기에적절한시스템을선정한다. 원격검체채취시스템을사용한다면, 미립자가튜빙에남아정확히측정되지않을가능성이있으므로, 튜빙의길이와튜빙가운데구부러진부분의반경을검토해야한다. 제조작업에사용되는물품에의한리스크, 예를들어살아있는생물체나방사성의약품관련리스크를고려하여모니터시스템을선정한다. 12. The sample sizes taken for monitoring purposes using automated systems will usually be a function of the sampling rate of the system used. It is not necessary for the sample volume to be the same as that used for formal classification of clean rooms and clean air devices. 자동화시스템을이용하여모니터목적으로채취하는검체량은일반적으로그시스템의검체채취속도를감안하여정한다. 청정실및청정공기장치의공식 8

9 등급분류시에취했던검체량과모니터목적의검체량이반드시같을필요는 없다. 13. In Grade A and B zones, the monitoring of the 5.0 μm particle concentration count takes on a particular significance as it is an important diagnostic tool for early detection of failure. The occasional indication of 5.0 μm particle counts may be false counts due to electronic noise, stray light, coincidence, etc. However consecutive or regular counting of low levels is an indicator of a possible contamination event and should be investigated. Such events may indicate early failure of the HVAC system, filling equipment failure or may also be diagnostic of poor practices during machine set-up and routine operation. A 등급과 B 등급지역의경우에 5.0 μm 미립자모니터는문제점을조기에파악할수있는중요한진단도구이므로특별한의미를갖는다. 전자노이즈, 미광, 계수손실등으로인하여 5.0 μm 미립자의수가이따금잘못된수치로나타날수있다. 하지만낮은수준이연속적으로나주기적으로발생한다면, 이는오염징후이므로조사를실시해야한다. HVAC 시스템의이상이나충전설비이상을조기에알려주는징후일수있으며, 또는기계셋업과정규작업과정의잘못된행위를의미할수도있다. 14. The particle limits given in the table for the at rest state should be achieved after a short clean up period of minutes (guidance value) in an unmanned state after completion of operations. 표의 " 휴지상태 " 미립자기준은작업완료이후사람이없는상태에서 15-20분 ( 참고치 ) 동안의짧은 " 클린업 " 기간이후에달성되어야한다. 15. The monitoring of Grade C and D areas in operation should be performed in accordance with the principles of quality risk management. The requirements and alert/action limits will depend on the nature of the operations carried out, but the recommended clean up period should be attained. 작업상태의 C 등급과 D 등급지역모니터는품질리스크관리원칙에따라실시한다. 수행작업의특성을감안하여기준과경계 / 조치기준을정하지만, 권장 " 클린업 " 기간이달성되어야한다. 9

10 16. Other characteristics such as temperature and relative humidity depend on the product and nature of the operations carried out. These parameters should not interfere with the defined cleanliness standard. 온도나상대습도같은다른특성요소는수행작업의특성과제품을감안하여정한다. 이들변수로인해지정청정도기준이훼손되어서는안된다. 17. Examples of operations to be carried out in the various grades are given in the table below (see also paragraphs 28 to 35): 청정도등급별작업의예를정리하면아래의표와같다. (28 내지 35 항참조 ) 등급 A C D 사후멸균제품인경우 (examples of operations for terminally sterilized products)(28-30항참조 ) 제품충전 ( 특히위험한경우 )(filling of products, when unusually at risk) 용액조제 ( 특히위험한경우 ), 제품충전 (preparation of solutions, when unusually at risk. Filling of products) 충전작업을위한용액및원자재준비 (preparation of solutions and components for subsequent filling) 등급 A C D 무균작업으로제조되는제품의경우 (examples of operations for aseptic preparations)(31-35항참조 ) 무균적준비및충전 (aseptic preparation and filling) 여과할용액의조제 (preparation of solutions to be filtered) 세척이후자재의취급 (handling of components after washing) 18. Where aseptic operations are performed monitoring should be frequent using methods 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 10

11 release. Surfaces and personnel should be monitored after critical operations. Additional microbiological monitoring is also required outside production operations, e.g. after validation of systems, cleaning and sanitisation. 무균작업을하는곳에서는낙하균 (settle plate), 부유미생물 (volumetric air), 표면균 (surface sampling; swabs & contact plates) 검사등미생물모니터를자주실시해야한다. 작업중의미생물모니터 ( 검체채취방법 ) 때문에해당지역의청정도가훼손되어서는안된다. 최종제품출하승인을위한배치문서검토시에환경모니터결과를점검해야한다. 중요작업이끝난뒤에는표면과작업자를모니터해야한다. 생산작업이외에도위생처리, 세척, 시스템밸리데이션이후에추가적인미생물모니터가필요하다. 19. Recommended limits for microbiological monitoring of clean areas during operation: 작업도중의청정지역미생물모니터권장기준. 미생물오염권고기준 (recommended limits for microbial contamination)(a) 등급 부유미생물 (air sample: cfu/m 3 ) 낙하균 (settle plates (diam. 90 mm), cfu/4 hours) (b) 표면균 (contact plates (diam. 55 mm), cfu/plate) 장갑 (glove print 5 fingers, cfu/glove) A < 1 < 1 < 1 < 1 B C D 주 (Notes) (a) (b) These are average values. 평균값임. Individual settle plates may be exposed for less than 4 hours. 개개플레이트 (settle plates) 는 4시간미만노출시킨다. 20. Appropriate alert and action limits should be set for the results of particulate and microbiological monitoring. If these limits are exceeded operating procedures should prescribe corrective action. 11

12 미립자및미생물모니터결과에대하여적절한경계기준 (alert limit) 과조치 기준 (action limit) 을설정해야한다. 환경관리결과가이기준을초과하는 경우에취할조치사항도규정되어있어야한다. 아이솔레이터기술 (Isolator technology) 21. The utilisation of isolator technology to minimize human interventions in processing areas may result in a significant decrease in the risk of microbiological contamination of aseptically manufactured products from the environment. There are many possible designs of isolators and transfer devices. The isolator and the background environment should be designed so that the required air quality for the respective zones can be realised. Isolators are constructed of various materials more or less prone to puncture and leakage. Transfer devices may vary from a single door to double door designs to fully sealed systems incorporating sterilization mechanisms. 제조작업지역에서작업자의개입을최소화하기위해아이솔레이터기술 (isolator technology) 을활용하면, 무균적으로제조된제품이제조환경의미생물에의해오염될위험성을크게줄일수있다. 아이솔레이터와이송장치 (transfer devices) 는다양한방식으로디자인할수있다. 아이솔레이터와주변환경은해당지역의필요공기품질수준을달성할수있도록설계해야한다. 아이솔레이터는구멍이나거나누출되는정도가다양한여러종류의재질로만든다. 이송장치 (transfer devices) 의디자인도단일문에서이중문에이르기까지다양하며, 멸균메커니즘을통합한완전밀봉시스템도있다. 22. The transfer of materials into and out of the unit is one of the greatest potential sources of contamination. In general the area inside the isolator is the local zone for high risk manipulations, although it is recognised that laminar air flow may not exist in the working zone of all such devices. 아이솔레이터장치에물품을반입하거나장치에서물품을반출할때오염이발생할가능성이매우크다. 모든아이솔레이터장치의작업지역에층류가존재하지않을수도있음이인정되고있지만, 일반적으로아이솔레이터내부지역은고위험조작을위한국소지역이다. 12

13 23. The air classification required for the background environment depends on the design of the isolator and its application. It should be controlled and for aseptic processing it should be at least grade D. 아이솔레이터주변의환경기준은아이솔레이터의디자인과이의용도에따라다르다. 하지만주변환경을관리해야하며무균작업인경우에는적어도 D 등급은되어야한다. 24. Isolators should be introduced only after appropriate validation. Validation should take into account all critical factors of isolator technology, for example the quality of the air inside and outside (background) the isolator, sanitisation of the isolator, the transfer process and isolator integrity. 적절한밸리데이션을거친다음에아이솔레이터를도입해야한다. 밸리데이션을할때는아이솔레이터내부와외부 ( 주위 ) 의공기품질, 아이솔레이터의위생처리, 이송방법, 아이솔레이터의완전성등아이솔레이터기술 (isolator technology) 의핵심요소모두를고려해야한다. 25. Monitoring should be carried out routinely and should include frequent leak testing of the isolator and glove/sleeve system. 모니터를일상적으로실시해야하며아이솔레이터와작업자와의연결부위 (glove/sleeve system) 에대해서는누출시험을자주실시해야한다. BFS(blow/fill/seal) 기술 (Blow/fill/seal technology) 26. Blow/fill/seal units are purpose built machines in which, in one continuous operation, containers are formed from a thermoplastic granulate, filled and then sealed, all by the one automatic machine. Blow/fill/seal equipment used for aseptic production which is fitted with an effective grade A air shower may be installed in at least a grade C environment, provided that grade A/B clothing is used. The environment should comply with the viable and non viable limits at rest and the viable limit only when in operation. Blow/fill/seal equipment used for the production of products which are terminally sterilised should be installed in at least a grade D environment. BFS(Blow/Fill/Seal) 장치는하나의자동기계를이용하여일련의연속작업으로열가소성입자 (thermoplastic granulate) 로용기를만들고충전및밀봉작업을 13

14 실시하는특수목적기계이다. A 등급에어샤워를장착한무균생산용 BFS 장치는, 최소한 C 등급환경에설치할수있다. 다만 A/B 등급작업복을착용해야한다. 작업환경은휴지상태에서의미생물및미립자기준과작업상태에서의미생물기준에적합해야한다. 사후멸균제품생산용 BFS 장치는적어도 D 등급의환경에설치해야한다. 27. Because of this special technology particular attention should be paid to, at least the following: 기술적특수성때문에적어도다음사항에대하여특별한주의가요구된다. equipment design and qualification 설비디자인및적격성평가 validation and reproducibility of cleaning-in-place and sterilisation-inplace CIP 및 SIP의밸리데이션과재현성 background clean room environment in which the equipment is located 설비가위치한청정실배경환경 operator training and clothing 작업자의교육훈련과복장 interventions in the critical zone of the equipment including any aseptic assembly prior to the commencement of filling. 충전작업시작전의모든무균조립을포함하여설비의중요지역에대한개입 사후멸균제품 (Terminally sterilised products) 28. Preparation of components and most products should be done in at least a grade D environment in order to give low risk of microbial and particulate contamination, suitable for filtration and sterilisation. Where the product is at a high or unusual risk of microbial contamination, (for example, because the product actively supports microbial growth or must be held for a long period before sterilisation or is necessarily processed not mainly in closed vessels), then preparation should be carried out in a grade C environment. 원자재와제품대다수의준비작업은미생물과미립자오염을최소화하기위해 14

15 적어도 D 등급의환경에서실시해야하며여과와멸균에적합해야한다. 하지만 ( 제품이미생물성장에적당하거나멸균하기전에오랫동안보관해야하거나, 밀폐된용기에서반드시처리되지않는경우와같이 ), 제품의미생물오염위험이높거나비정상적으로존재하는경우에는상기준비작업을 C 등급환경에서실시해야한다. 29. Filling of products for terminal sterilisation should be carried out in at least a grade C environment. 사후멸균제품의충전작업은적어도 C 등급환경에서실시해야한다. 30. Where the product is at unusual risk of contamination from the environment, for example because the filling operation is slow or the containers are wide-necked or are necessarily exposed for more than a few seconds before sealing, the filling should be done in a grade A zone with at least a grade C background. Preparation and filling of ointments, creams, suspensions and emulsions should generally be carried out in a grade C environment before terminal sterilisation. 충전속도가느리거나용기의입구가넓거나밀봉하기전에몇초이상노출되는경우와같이제품의오염위험이높은경우에충전작업은 A 등급의지역에서해야하며주위환경은적어도 C 등급이어야한다. 연고제, 크림제, 현탁제, 유제의조제및충전은일반적으로사후멸균하기전에 C등급의환경에서실시해야한다. 무균제조 (Aseptic preparation) 31. Components after washing should be handled in at least a grade D environment. Handling of sterile starting materials and components, unless subjected to sterilisation or filtration through a micro-organism-retaining filter later in the process, should be done in a grade A environment with grade B background. 세척이후의원자재는적어도 D 등급환경에서다루어야한다. 무균출발물질과원자재의취급은, 이들이이후공정에서멸균되거나미생물제거효율이있는필터를통해여과를거치지않는경우, A 등급환경에서실시해야하며주위환경은 B 등급이어야한다. 15

16 32. Preparation of solutions which are to be sterile filtered during the process should be done in a grade C environment; if not filtered, the preparation of materials and products should be done in a grade A environment with a grade B background. 제균여과공정을거치는용액의조제는 C 등급환경에서실시한다. 제균여과공정을거치지않는경우에는물품및제품의조제작업을 A 등급환경에서실시하며주위환경은 B 등급이어야한다. 33. Handling and filling of aseptically prepared products should be done in a grade A environment with a grade B background. 무균적으로준비한제품의취급및충전은 A 등급환경에서해야하며주위환경은 B 등급이어야한다. 34. Prior to the completion of stoppering, transfer of partially closed containers, as used in freeze drying should be done either in a grade A environment with grade B background or in sealed transfer trays in a grade B environment. 동결건조제품처럼반타전된제품을완전밀봉하기전에이송할때는 A 등급환경과 B 등급의주위환경에서하거나, B 등급환경에서밀폐된이송트레이에담아이송해야한다. 35. Preparation and filling of sterile ointments, creams, suspensions and emulsions should be done in a grade A environment, with a grade B background, when the product is exposed and is not subsequently filtered. 제품이노출되고이후에여과를거치지않는다면, 무균연고제, 크림제, 현탁제, 유제의조제및충전은 A 등급환경에서실시하며주위환경은 B 등급이어야한다. 작업자 (Personnel) 36. Only the minimum number of personnel required should be present in clean areas; this is particularly important during aseptic processing. Inspections and controls should be conducted outside the clean areas as far as possible. 16

17 청정지역에는최소한의작업자만있어야한다. 이원칙은특히무균공정의 경우에특히중요하다. 공정관리및검사는청정지역으로부터가능한한멀리 떨어진곳에서해야한다. 37. All personnel (including those concerned with cleaning and maintenance) employed in such areas should receive regular training in disciplines relevant to the correct manufacture of sterile products. This training should include reference to hygiene and to the basic elements of microbiology. When outside staff who have not received such training (e.g. building or maintenance contractors) need to be brought in, particular care should be taken over their instruction and supervision. 청정지역내작업자 ( 청소및유지관리업무관련작업자포함 ) 에대하여무균제품의올바른제조와관련된사항을정기적으로훈련시켜야한다. 위생및미생물학기본개념에관한사항도훈련내용에포함시킨다. 이런훈련을받지않은외부인 ( 예, 건물관리또는유지관리위탁업체 ) 이작업장안으로들어갈필요가있는경우, 작업장안에서준수해야할사항을주지시키고감독하는등특별한주의조치를취해야한다. 38. Staff who have been engaged in the processing of animal tissue materials or of cultures of micro-organisms other than those used in the current manufacturing process should not enter sterile-product areas unless rigorous and clearly defined entry procedures have been followed. 현제조공정에사용되는것이외의다른동물세포나미생물배양작업을수행한작업자는, 엄격하고명확히규정된출입절차를준수하지않으면무균제품작업지역에들어갈수없다. 39. High standards of personal hygiene and cleanliness are essential. Personnel involved in the manufacture of sterile preparations should be instructed to report any condition which may cause the shedding of abnormal numbers or types of contaminants; periodic health checks for such conditions are desirable. Actions to be taken about personnel who could be introducing undue microbiological hazard should be decided by a designated competent person. 높은수준의개인위생및청결이필수적이다. 무균제품제조관련작업자는 17

18 비정상적인수나유형의오염물질을발산시킬수있는모든상태를보고하도록지도해야한다. 주기적으로작업자의건강을점검하는것도바람직하다. 부적절한미생물위험을일으킬소지가있는작업자에대해취할조치사항을지정책임자가결정해야한다. 40. Wristwatches, make-up and jewellery should not be worn in clean areas. 손목시계, 화장, 장신구를착용하고청정지역에들어가서는안된다. 41. Changing and washing should follow a written procedure designed to minimize contamination of clean area clothing or carry-through of contaminants to the clean areas. 복장이나물품반입에의해청정지역이오염되는것을최소화할수있도록절차문서에따라갱의와세척을실시해야한다. 42. The clothing and its quality should be appropriate for the process and the grade of the working area. It should be worn in such a way as to protect the product from contamination. 작업복과작업복의품질은작업지역의환경등급과해당공정에적절해야한다. 작업복은제품이오염되지않게하는방식으로착용해야한다. 43. The description of clothing required for each grade is given below: 청정등급별로필요한작업복은다음과같다. Grade D: Hair and, where relevant, beard should be covered. A general protective suit and appropriate shoes or overshoes should be worn. Appropriate measures should be taken to avoid any contamination coming from outside the clean area. D 등급 : 머리카락과해당되는경우에턱수염을가려야한다. 일반보호복장과적절한신발또는덧신을착용해야한다. 청정지역외부에서들어오는오염물질을방지하기위해적절한조치가있어야한다. Grade C: Hair and where relevant beard and moustache should be covered. A single or two-piece trouser suit, gathered at the wrists and with high neck and appropriate shoes or overshoes should be 18

19 worn. They should shed virtually no fibres or particulate matter. C 등급 : 머리카락과해당되는경우에턱수염및콧수염을가려야한다. 적당한신발이나덧신, 그리고목위로올라오고손목부위에서묶을수있는원피스나투피스형작업복을착용해야한다. 이들은섬유질이나미립자를방출해서는안된다. Grade A/B: Headgear should totally enclose hair and, where relevant, beard and moustache; it should be tucked into the neck of the suit; a face mask should be worn to prevent the shedding of droplets. Appropriate sterilised, non-powdered rubber or plastic gloves and sterilised or disinfected footwear should be worn. Trouser-legs should be tucked inside the footwear and garment sleeves into the gloves. The protective clothing should shed virtually no fibres or particulate matter and retain particles shed by the body. A/B 등급 : 모자는머리카락과해당되는경우에턱수염및콧수염을완전히가려야하며, 작업복의목부위로밀어넣어야한다. 얼굴에는비말이날리지않도록마스크를써야한다. 적절하게멸균된비분말형 (nonpowdered) 고무또는플라스틱장갑과멸균또는소독된신발을착용한다. 바지하단은신발안으로쑤셔넣고소매는장갑속으로넣는다. 이런보호복장은섬유질이나미립자를방출하지않아야하며, 몸에서떨어지는미립자가유포되지않도록해야한다. 44. Outdoor clothing should not be brought into changing rooms leading to grade B and C rooms. For every worker in a grade A/B area, clean sterile (sterilised or adequately sanitised) protective garments should be provided at each work session. Gloves should be regularly disinfected during operations. Masks and gloves should be changed at least for every working session. 일반복장을 B 및 C 등급작업실로이어지는갱의실에반입해서는안된다. A와 B 등급지역에서일하는모든작업자에게작업기간마다청정무균 ( 멸균또는적절하게위생처리한 ) 보호복장을제공해야한다. 작업중에는주기적으로장갑을소독한다. 마스크와장갑은적어도매작업시마다교체해야한다. 45. Clean area clothing should be cleaned and handled in such a way that it 19

20 does not gather additional contaminants which can later be shed. These operations should follow written procedures. Separate laundry facilities for such clothing are desirable. Inappropriate treatment of clothing will damage fibres and may increase the risk of shedding of particles. 청정지역복장을세척하고취급할때는, 오염물이작업복에붙어있다가나중에떨어지는일이생기지않도록해야한다. 세척과취급작업은절차문서에따라실시해야한다. 별도의세탁시설을갖추는것이바람직하다. 작업복을부적절하게처리하면섬유에손상을주어입자방출위험성이커진다. 시설 (Premises) 46. In clean areas, all exposed surfaces should be smooth, impervious and unbroken in order to minimize the shedding or accumulation of particles or micro-organisms and to permit the repeated application of cleaning agents, and disinfectants where used. 청정지역의모든노출표면은미생물이나미립자의방출또는축적을최소화하고반복적으로세척제와소독제를사용할수있도록, 매끄럽고불침투성이며파손되지않아야한다. 47. To reduce accumulation of dust and to facilitate cleaning there should be no uncleanable recesses and a minimum of projecting ledges, shelves, cupboards and equipment. Doors should be designed to avoid those uncleanable recesses; sliding doors may be undesirable for this reason. 먼지가쌓이지않고청소하기쉽도록하기위해, 청소하기힘든후미진부위가없도록하고돌출부와선반, 컵보드, 설비는최소화해야한다. 출입문도청소하기힘든후미진부위가없도록설계해야한다. 이런점에서미닫이문은바람직하지않을수있다. 48. False ceilings should be sealed to prevent contamination from the space above them. 보조천장 (false ceiling) 은그위의공간에서오염물질이떨어지는것을방지하기위해밀봉해야한다. 49. Pipes and ducts and other utilities should be installed so that they do not 20

21 create recesses, unsealed openings and surfaces which are difficult to clean. 파이프와덕트, 여타유틸리티시설은청소하기힘든표면, 밀봉되지않은개구부, 후미진곳이생기지않도록설치해야한다. 50. Sinks and drains should be prohibited in grade A/B areas used for aseptic manufacture. In other areas air breaks should be fitted between the machine or sink and the drains. Floor drains in lower grade clean rooms should be fitted with traps or water seals to prevent backflow. 무균제조작업을하는 A/B 등급지역에싱크대와배수시설을해서는안된다. 다른지역에는기계또는싱크대와배수시설사이에에어브레이크 (air break) 를설치해야한다. 낮은등급의청정작업실은역류방지를위해바닥배수구에트랩 (trap) 또는수밀봉 (water seal) 을갖추어야한다. 51. Changing rooms should be designed as airlocks and used to provide physical separation of the different stages of changing and so minimize microbial and particulate contamination of protective clothing. They should be flushed effectively with filtered air. The final stage of the changing room should, in the at-rest state, be the same grade as the area into which it leads. The use of separate changing rooms for entering and leaving clean areas is sometimes desirable. In general hand washing facilities should be provided only in the first stage of the changing rooms. 갱의실은갱의단계에따라물리적으로구분하고미생물과미립자에의한보호복장의오염을최소화할수있도록사용해야하며에어록방식으로설계해야한다. 갱의실에는여과된공기를효과적으로공급해야한다. 갱의실의마지막단계는갱의실을통해들어가는작업지역의휴지상태청정기준과동일해야한다. 때로는청정지역에들어갈때와나올때의갱의실을별도로두는것이바람직하다. 일반적으로수세시설은갱의실의첫단계에만설치해야한다. 52. Both airlock doors should not be opened simultaneously. An interlocking system or a visual and/or audible warning system should be operated to prevent the opening of more than one door at a time. 에어록이설치된문은양쪽이동시에열리지않아야한다. 동시에양쪽문이같이열리는것을방지하기위해, 시각및 / 또는청각적경보장치를설치하거나인터록 21

22 시스템을갖추어야한다. 53. A filtered air supply should maintain a positive pressure and an air flow relative to surrounding areas of a lower grade under all operational conditions and should flush the area effectively. Adjacent rooms of different grades should have a pressure differential of pascals (guidance values). Particular attention should be paid to the protection of the zone of greatest risk, that is, the immediate environment to which a product and cleaned components which contact the product are exposed. The various recommendations regarding air supplies and pressure differentials may need to be modified where it becomes necessary to contain some materials, e.g. pathogenic, highly toxic, radioactive or live viral or bacterial materials or products. Decontamination of facilities and treatment of air leaving a clean area may be necessary for some operations. 모든작업조건에서주위의낮은등급지역에대해양압상태의공기흐름이유지되도록여과된공기를공급해야하며, 해당지역을효과적으로환기할수있어야한다. 서로다른등급의인접작업실간에는 10 ~ 15 파스칼 ( 참고치 ) 정도의차압을유지해야한다. 고위험지역, 즉제품과접촉하는깨끗한자재와제품이노출되는지역의보호를위해특히주의해야한다. 병원성제품, 독성제품, 방사성또는생바이러스나세균성물품또는제품의봉쇄필요성이있는경우, 급기와차압에대한권고사항이다양하게조정될수있다. 작업에따라시설의정화작업과청정지역에서배출되는공기의처리가필요할수도있다. 54. It should be demonstrated that air-flow patterns do not present a contamination risk, e.g. care should be taken to ensure that air flows do not distribute particles from a particle-generating person, operation or machine to a zone of higher product risk. 공기흐름패턴으로인한오염위험성이없다는점을증명해야한다. 즉공기흐름때문에작업자, 작업또는기계에서발생한미립자가제품위험성이큰지역으로퍼지지않게주의해야한다. 55. A warning system should be provided to indicate failure in the air supply. Indicators of pressure differences should be fitted between areas where these differences are important. These pressure differences should be 22

23 recorded regularly or otherwise documented. 급기에이상이발생했을경우에이를알려주는경보장치가설치되어있어야한다. 작업실간차압이중요한경우, 실간차압을보여주는인디케이터가구비되어야한다. 차압을정기적으로기록하거나다른방식으로문서화한다. 설비 (Equipment) 56. A conveyor belt should not pass through a partition between a grade A or B area and a processing area of lower air cleanliness, unless the belt itself is continually sterilised (e.g. in a sterilising tunnel). 컨베이어벨트는터널식멸균기처럼벨트자체가연속해서멸균되는경우가아니면, A 또는 B 등급작업지역과이보다낮은등급의작업지역사이를통과해서는안된다. 57. As far as practicable equipment, fittings and services should be designed and installed so that operations, maintenance and repairs can be carried out outside the clean area. If sterilisation is required, it should be carried out, wherever possible, after complete reassembly. 가능하면설비, 장치물, 서비스시설은운전, 유지관리, 보수를청정지역외부에서수행할수있도록설계하고설치한다. 멸균이필요한경우에는가능하면완전히재조립한후에실시한다. 58. When equipment maintenance has been carried out within the clean area, the area should be cleaned, disinfected and/or sterilised where appropriate, before processing recommences if the required standards of cleanliness and/or asepsis have not been maintained during the work. 설비유지관리를청정지역안에서하는경우, 그작업도중에청정도와무균상태유지가되지않았다면제조작업을다시시작하기전에그작업지역을적절하게청소, 소독, 및 / 또는멸균해야한다. 59. Water treatment plants and distribution systems should be designed, constructed and maintained so as to ensure a reliable source of water of an appropriate quality. They should not be operated beyond their designed capacity. Water for injections should be produced, stored and distributed in 23

24 a manner which prevents microbial growth, for example by constant circulation at a temperature above 70 C. 수처리시설과분배시스템은적정품질의믿을수있는용수를공급할수있도록설계, 시공, 유지관리되어야한다. 설계용량범위이상으로가동해서는안된다. 주사용수 (WFI) 는미생물성장을방지할수있는방식으로, 예를들어 70 C 이상에서연속순환하는식으로생산, 보관, 공급해야한다. 60. All equipment such as sterilisers, air handling and filtration systems, air vent and gas filters, water treatment, generation, storage and distribution systems should be subject to validation and planned maintenance; their return to use should be approved. 멸균기, 공조및여과시스템, 배기및가스필터, 용수처리, 생산, 보관, 분배시스템등모든설비를밸리데이션하고계획에의거하여유지관리해야한다. 이들설비를다시사용하는것도승인을받아야한다. 위생관리 (Sanitation) 61. The sanitation of clean areas is particularly important. They should be cleaned thoroughly in accordance with a written programme. Where disinfectants are used, more than one type should be employed. Monitoring should be undertaken regularly in order to detect the development of resistant strains. 청정지역의위생관리가특히중요하다. 청정지역은문서화된프로그램에의거하여철저하게청소해야한다. 소독제를사용하는경우에는한가지이상의소독제를채택해야한다. 소독제내성균발생여부를확인하기위해주기적으로모니터를실시해야한다. 62. Disinfectants and detergents should be monitored for microbial contamination; dilutions should be kept in previously cleaned containers and should only be stored for defined periods unless sterilised. Disinfectants and detergents used in Grades A and B areas should be sterile prior to use. 소독제와세정제의미생물오염여부를모니터해야한다. 희석액은미리세척한용기에보관해야하며, 멸균하지않고사용한다면일정기간동안만보관해야 24

25 한다. A/B 등급지역에사용하는소독제와세정제는사용전에반드시무균 상태여야한다. 63. Fumigation of clean areas may be useful for reducing microbiological contamination in inaccessible places. 청정지역의훈증은접근하기힘든곳의미생물오염감소에유용할수있다. 공정 (Processing) 64. Precautions to minimize contamination should be taken during all processing stages including the stages before sterilisation. 멸균이전단계를포함하여모든제조공정에서오염최소화를위해주의가필요하다. 65. Preparations of microbiological origin should not be made or filled in areas used for the processing of other medicinal products; however, vaccines of dead organisms or of bacterial extracts may be filled, after inactivation, in the same premises as other sterile medicinal products. 미생물유래물질의취급작업을다른의약품작업지역에서하거나충전해서는안된다. 하지만사백신이나세균추출물백신은불활화단계이후에다른무균의약품과동일시설에서충전할수있다. 66. Validation of aseptic processing should include a process simulation test using a nutrient medium (media fill). Selection of the nutrient medium should be made based on dosage form of the product and selectivity, clarity, concentration and suitability for sterilisation of the nutrient medium. 무균공정밸리데이션을할때는영양배지를활용한공정시뮬레이션테스트를실시해야한다 ( 메디아필 ). 영양배지의종류는해당제품의제형과영양배지의멸균적합성, 농도, 투명도, 선택성을토대로결정한다. 67. The process simulation test should imitate as closely as possible the routine aseptic manufacturing process and include all the critical subsequent manufacturing steps. It should also take into account various interventions known to occur during normal production as well as worstcase situations. 25

26 이공정시뮬레이션테스트는최대한실제무균제조공정에가까워야하며, 중요 제조단계를모두포함해야한다. " 최악의경우 " 상황과정상적인생산작업중에 발생할수있는다양한개입부분을고려해야한다. 68 Process simulation tests should be performed as initial validation with three consecutive satisfactory simulation tests per shift and repeated at defined intervals and after any significant modification to the HVAC-system, equipment, process and number of shifts. Normally process simulation tests should be repeated twice a year per shift and process. 초기밸리데이션의일환으로작업조 (shift) 별로공정시뮬레이션테스트를 3회연속실시해적합한결과가나와야하며, 이후에도주기적으로실시해야한다. 또한 HVAC 시스템, 설비, 공정, 작업조인원의중요변경이있을때도실시해야한다. 일반적으로공정시뮬레이션테스트를 1년에 2회, 작업조및공정별로실시한다. 69. The number of containers used for media fills should be sufficient to enable a valid evaluation. For small batches, the number of containers for media fills should at least equal the size of the product batch. The target should be zero growth and the following should apply: 메디아필충전수량은유효한평가를가능하게할정도로충분해야한다. 소규모배치인경우에는메디아필충전수량이적어도실제제품배치규모와동일해야한다. "0" 성장을목표로잡아야하며다음사항을적용한다. When filling fewer than 5000 units, no contaminated units should be detected 개보다적은수를충전하는경우, 오염이전혀검출되지않아야한다. When filling 5,000 to 10,000 units: 5,000 ~ 10,000개를충전하는경우. a) One (1) contaminated unit should result in an investigation, including consideration of a repeat media fill; 1개제품이오염되면조사를실시해야하며, 메디아필의반복을고려한다. b) Two (2) contaminated units are considered cause for 26

27 revalidation, following investigation. 2 개제품이오염된것으로나타나면, 조사를실시한다음에 재밸리데이션을할이유가있다고간주한다. When filling more than 10,000 units: 10,000개이상을충전하는경우. a) One (1) contaminated unit should result in an investigation; 1개제품이오염되면조사를실시한다. b) Two (2) contaminated units are considered cause for revalidation, following investigation. 2개제품이오염된것으로나타나면, 조사를실시한다음에재밸리데이션을할이유가있다고간주한다. 70. For any run size, intermittent incidents of microbial contamination may be indicative of low-level contamination that should be investigated. Investigation of gross failures should include the potential impact on the sterility assurance of batches manufactured since the last successful media fill. 어떤작업규모이건, 미생물오염이간헐적으로발생한다면, 이는낮은수준의오염이있다는징후로볼수있고조사를실시해야한다. 조사를할때는메디아필이성공적으로끝났던시점이후에제조된배치의무균성보장에대한영향가능성도조사해야한다. 71. Care should be taken that any validation does not compromise the processes. 밸리데이션으로인해해당공정이훼손되지않도록주의해야한다. 72. Water sources, water treatment equipment and treated water should be monitored regularly for chemical and biological contamination and, as appropriate, for endotoxins. Records should be maintained of the results of the monitoring and of any action taken. 수원, 수처리설비, 처리수를대상으로화학적및생물학적오염시험을정기적으로실시해야하며, 또한적절한경우에는엔도톡신시험을실시해야한다. 모니터결과와조치결과에대한기록서를유지해야한다. 27

28 73. Activities in clean areas and especially when aseptic operations are in progress should be kept to a minimum and movement of personnel should be controlled and methodical, to avoid excessive shedding of particles and organisms due to over-vigorous activity. The ambient temperature and humidity should not be uncomfortably high because of the nature of the garments worn. 청정지역과특히무균조작을수행하는지역에서의활동을최소화해야하며, 과도한활동으로인하여미립자와미생물이지나치게방출되지않도록, 작업자의움직임을통제하고정해진방법대로작업하게해야한다. 작업자가착용하는작업복의특성을감안하여, 주위온도와습도는불쾌감을줄정도로높아서는안된다. 74. Microbiological contamination of starting materials should be minimal. Specifications should include requirements for microbiological quality when the need for this has been indicated by monitoring. 출발물질의미생물오염을최소화해야한다. 모니터결과에의거하여필요하다고판단되는경우, 출발물질규격에미생물학적품질기준을포함시켜야한다. 75. Containers and materials liable to generate fibres should be minimised in clean areas. 섬유질을방출하기쉬운용기와물품을청정지역에서는최소화해야한다. 76. Where appropriate, measures should be taken to minimize the particulate contamination of the end product. 적절한경우에는최종제품의미립자오염을최소화할수있는대책을구비해야한다. 77. Components, containers and equipment should be handled after the final cleaning process in such a way that they are not recontaminated. 원자재, 용기, 설비를최종세척한이후에는다시오염되지않도록취급해야한다. 78. The interval between the washing and drying and the sterilisation of components, containers and equipment as well as between their sterilisation and use should be minimized and subject to a time-limit 28

29 appropriate to the storage conditions. 원자재, 용기, 설비의세척및건조와멸균사이의기간, 그리고이들의멸균이후사용까지의기간을최소화해야하며, 보관조건을감안하여적절한기한을설정해야한다. 79. The time between the start of the preparation of a solution and its sterilisation or filtration through a micro-organism-retaining filter should be minimised. There should be a set maximum permissible time for each product that takes into account its composition and the prescribed method of storage. 용액의조제시작부터멸균또는제균여과작업까지의시간을최소화해야한다. 제품조성과지정보관방법을고려하여제품별로최대허용기간을설정한다. 80. The bioburden should be monitored before sterilisation. There should be working limits on contamination immediately before sterilisation, which are related to the efficiency of the method to be used. Bioburden assay should be performed on each batch for both aseptically filled product and terminally sterilised products. Where overkill sterilisation parameters are set for terminally sterilised products, bioburden might be monitored only at suitable scheduled intervals. For parametric release systems, bioburden assay should be performed on each batch and considered as an in-process test. Where appropriate the level of endotoxins should be monitored. All solutions, in particular large volume infusion fluids, should be passed through a micro-organism-retaining filter, if possible sited immediately before filling. 멸균하기전에바이오버든을모니터해야한다. 멸균방법의효율성을감안하여멸균직전의오염기준이설정되어있어야한다. 무균충전제품과사후멸균제품모두, 각배치에대하여바이오버든분석을실시한다. 사후멸균제품에대하여오버킬멸균변수를설정한경우, 적합한주기로만바이오버든모니터를실시할수있다. 변수기반출하승인시스템인경우, 배치별로바이오버든분석을실시하고, 이를공정검사로간주한다. 적절한경우에는엔도톡신수준도모니터한다. 모든용액은 ( 특히대용량수액제의경우 ) 제균여과를해야하며, 가능하면충전직전에한다. 29

30 81. Components, containers, equipment and any other article required in a clean area where aseptic work takes place should be sterilised and passed into the area through double-ended sterilisers sealed into the wall, or by a procedure which achieves the same objective of not introducing contamination. Non-combustible gases should be passed through microorganism retentive filters. 무균작업을하는청정지역에서사용할원자재, 용기, 설비및기타물품은멸균을한다음에벽을가로질러부착되어있으며이중문을장착한멸균기를통해반입하거나, 오염물질의유입차단이라는목표를달성할수있는방법으로반입해야한다. 불연성가스는제균여과필터를통과해야한다. 82. The efficacy of any new procedure should be validated, and the validation verified at scheduled intervals based on performance history or when any significant change is made in the process or equipment. 새로운절차는그효율성을밸리데이션해야하며, 공정또는설비에주요변경이발생하거나성능이력을감안하여일정주기로밸리데이션상태를확인해야한다. 멸균 (Sterilisation) 83. All sterilisation processes should be validated. Particular attention should be given when the adopted sterilisation method is not described in the current edition of the European Pharmacopoeia, or when it is used for a product which is not a simple aqueous or oily solution. Where possible, heat sterilisation is the method of choice. In any case, the sterilisation process must be in accordance with the marketing and manufacturing authorisations. 모든멸균공정을밸리데이션해야한다. 채택하고있는멸균방법이유럽약전최신판에기술된것이아닌경우, 또는해당제품이단순한액상이나유성액체가아닌경우에는특히주의해야한다. 가능하면열멸균 (heat sterilisation) 방법이가장적당하다. 멸균공정은판매및제조허가사항과일치해야한다. 84. Before any sterilisation process is adopted its suitability for the product and its efficacy in achieving the desired sterilising conditions in all parts of each type of load to be processed should be demonstrated by physical measurements and by biological indicators where appropriate. The validity 30

31 of the process should be verified at scheduled intervals, at least annually, and whenever significant modifications have been made to the equipment. Records should be kept of the results. 멸균공정을도입하기전에그멸균공정이해당제품에적합하며멸균적재유형별로모든부분에서기대한만큼의멸균조건을달성하는데효과적이라는점을물리적측정방법과적절한경우에는생물학적지시물 (biological indicator) 을사용하여증명해야한다. 해당공정의유효성을적어도 1년에한번씩주기적으로확인해야하며설비의중요변경이있을때도실시해야한다. 그결과에대한기록서도유지해야한다. 85. For effective sterilisation the whole of the material must be subjected to the required treatment and the process should be designed to ensure that this is achieved. 효과적인멸균을위해물품모두에대하여필요한처리를해야하며, 그에맞도록공정을설계해야한다. 86. Validated loading patterns should be established for all sterilisation processes. 모든멸균공정에대하여밸리데이션된적재패턴을설정해야한다. 87. Biological indicators should be considered as an additional method for monitoring the sterilisation. They should be stored and used according to the manufacturer s instructions, and their quality checked by positive controls. If biological indicators are used, strict precautions should be taken to avoid transferring microbial contamination from them. 생물학적지시물 (BI) 은멸균공정모니터를위한부가적인방법으로생각해야한다. 제조원의설명서에따라 BI를보관하고사용하며, 양성대조로 BI의품질을점검한다. BI를사용하는경우에는이로인해미생물오염이일어나지않도록특히주의해야한다. 88. There should be a clear means of differentiating products which have not been sterilized from those which have. Each basket, tray or other carrier of products or components should be clearly labelled with the material name, its batch number and an indication of whether or not it has been sterilised. 31

32 Indicators such as autoclave tape may be used, where appropriate, to indicate whether or not a batch (or sub-batch) has passed through a sterilisation process, but they do not give a reliable indication that the lot is, in fact, sterile. 멸균된것과멸균되지않은것을구분할수있는명확한방법이있어야한다. 제품또는원자재를담는바구니, 트레이, 기타운반용구에품명, 배치번호, 멸균여부를명확하게기재한표시서를부착한다. 배치 ( 또는서브배치 ) 가멸균공정을거쳤는지표시하기위해적절한경우에는멸균테이프같은지시물을사용할수도있다. 하지만이것은그로트가실제로무균상태라는신뢰할수있는표시는아니다. 89. Sterilisation records should be available for each sterilisation run. They should be approved as part of the batch release procedure. 매멸균작업마다멸균기록서가있어야한다. 배치출하승인절차의일부로멸균기록서를승인해야한다. 열에의한멸균 (Sterilisation by heat) 90. Each heat sterilisation cycle should be recorded on a time/temperature chart with a sufficiently large scale or by other appropriate equipment with suitable accuracy and precision. The position of the temperature probes used for controlling and/or recording should have been determined during the validation, and where applicable also checked against a second independent temperature probe located at the same position. 열멸균사이클을충분히큰스케일의시간 / 온도차트에기록하거나, 적합한정확도와정밀도를지닌적절한장비를사용해기록해야한다. 관리또는기록을위한온도프로브의위치는밸리데이션을거쳐결정해야하며, 필요한경우에는동일한위치에별도의온도프로브를위치시켜점검한다. 91. Chemical or biological indicators may also be used, but should not take the place of physical measurements. 화학적또는생물학적지시물을사용할수도있지만, 물리적측정을대신할수는없다. 32

33 92. Sufficient time must be allowed for the whole of the load to reach the required temperature before measurement of the sterilising time-period is commenced. This time must be determined for each type of load to be processed. 적재물전체가필요온도수준에도달한다음에멸균기간측정을시작하도록충분한시간을두어야한다. 적재유형별로이시간을결정해야한다. 93. After the high temperature phase of a heat sterilisation cycle, precautions should be taken against contamination of a sterilised load during cooling. Any cooling fluid or gas in contact with the product should be sterilised unless it can be shown that any leaking container would not be approved for use. 열멸균사이클고온단계이후에는냉각기간동안에멸균된적재물이오염되지않도록주의해야한다. 누출용기는사용을승인하지않는다는점을증명할수없다면, 제품과접촉하는냉각용액체나가스도멸균해야한다. 습열 (Moist heat) 94. Both temperature and pressure should be used to monitor the process. Control instrumentation should normally be independent of monitoring instrumentation and recording charts. Where automated control and monitoring systems are used for these applications they should be validated to ensure that critical process requirements are met. System and cycle faults should be registered by the system and observed by the operator. The reading of the independent temperature indicator should be routinely checked against the chart recorder during the sterilisation period. For sterilisers fitted with a drain at the bottom of the chamber, it may also be necessary to record the temperature at this position, throughout the sterilization period. There should be frequent leak tests on the chamber when a vacuum phase is part of the cycle. 온도와압력으로공정을모니터해야한다. 제어장치는모니터장치및기록차트로부터독립되어있어야한다. 자동제어및모니터시스템을사용하는경우, 핵심공정기준이충족된다는점을밸리데이션을통해확인해야한다. 시스템과사이클이상을시스템자체가기록하고작업자가확인할수있어야한다. 멸균중에별도의온도표시장치에나타난사항과기록지에나타난것을점검해야 33

34 한다. 챔버하단에배수장치가갖추어진멸균기인경우, 전체멸균기간동안이 부분의온도를기록할필요가있다. 멸균사이클중에진공단계가있으면, 챔버에대하여누출시험 (leak test) 을빈번하게실시해야한다. 95. The items to be sterilised, other than products in sealed containers, should be wrapped in a material which allows removal of air and penetration of steam but which prevents recontamination after sterilisation. All parts of the load should be in contact with the sterilizing agent at the required temperature for the required time. 밀봉용기에담긴제품이외의다른멸균대상물품은, 공기의제거와스팀의침투가용이하고멸균이후재오염을방지할수있는재질로포장해야한다. 적재되는모든물품은필요시간동안필요온도에서멸균인자 (sterilizing agent) 와접촉상태를유지해야한다. 96. Care should be taken to ensure that steam used for sterilisation is of suitable quality and does not contain additives at a level which could cause contamination of product or equipment. 멸균에사용되는스팀은적합한품질이어야하며제품이나설비를오염시킬수준의첨가물이함유되지않도록주의해야한다. 건열 (Dry heat) 97. The process used should include air circulation within the chamber and the maintenance of a positive pressure to prevent the entry of non-sterile air. Any air admitted should be passed through a HEPA filter. Where this process is also intended to remove pyrogens, challenge tests using endotoxins should be used as part of the validation. 이멸균방법을사용하는경우에는챔버내의공기가순환되어야하며비무균공기의유입을방지하기위해양압을유지해야한다. 공기는 HEPA 필터를통해서만유입되어야한다. 이공정이발열성물질제거를목적으로하는경우에는밸리데이션의일부로엔도톡신을이용한챌린지시험을실시해야한다. 방사선멸균 (Sterilisation by radiation) 34

35 98. Radiation sterilisation is used mainly for the sterilisation of heat sensitive materials and products. Many medicinal products and some packaging materials are radiation-sensitive, so this method is permissible only when the absence of deleterious effects on the product has been confirmed experimentally. Ultraviolet irradiation is not normally an acceptable method of sterilisation. 방사선멸균은열에민감한물품과제품의멸균에주로사용된다. 많은의약품과일부포장자재는방사선에민감하다. 그래서방사선이제품에유해한영향을미치지않는다는점이실험적으로증명되었을경우에만이방법을사용한다. 자외선조사는일반적으로적절한멸균방법이아니다. 99. During the sterilisation procedure the radiation dose should be measured. For this purpose, dosimetry indicators which are independent of dose rate should be used, giving a quantitative measurement of the dose received by the product itself. Dosimeters should be inserted in the load in sufficient number and close enough together to ensure that there is always a dosimeter in the irradiator. Where plastic dosimeters are used they should be used within the time-limit of their calibration. Dosimeter absorbances should be read within a short period after exposure to radiation. 멸균과정중에방사능조사량을측정해야한다. 이를위해선량율 (dose rate) 과는별도의선량계인디케이터 (dosimetry indicators) 를사용하여제품자체가받은선량을양적으로측정할수있어야한다. 충분한수의선량계를적재물에삽입해야하며, 충분히서로밀착하도록하여방사선조사장치 (irradiator) 에항상선량계가있도록해야한다. 플라스틱선량계를쓰는경우에는이들은정해진교정기한내에서만사용한다. 방사선노출이후단시간안에선량계흡광도를읽어야한다 Biological indicators may be used as an additional control. 부가적으로생물학적지시물을사용할수도있다 Validation procedures should ensure that the effects of variations in density of the packages are considered. 밸리데이션시에는포장재의밀도차이에따른영향을고려해야만한다. 35