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Guidance for Industry 무균공정에의한무균의약품생산 - CGMP (Sterile Drug Products Produced by Aseptic Processing - Current Good Manufacturing Practice) U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER) Office of Regulatory Affairs (ORA) September 2004 Pharmaceutical CGMPs www..co.kr 1

Guidance for Industry 무균공정에의한무균의약품생산 - CGMP (Sterile Drug Products Produced by Aseptic Processing - Current Good Manufacturing Practice) Additional copies are available from: Office of Training and Communication Division of Drug Information, HFD-240 Center for Drug Evaluation and Research Food and Drug Administration 5600 Fishers Lane Rockville, MD 20857 (Tel) 301-827-4573 http://www.fda.gov/cder/guidance/index.htm or Office of Communication, Training and Manufacturers Assistance, HFM-40 Center for Biologics Evaluation and Research Food and Drug Administration 1401 Rockville Pike, Rockville, MD 20852-1448 http://www.fda.gov/cber/guidelines.htm. (Tel) Voice Information System at 800-835-4709 or 301-827-1800 U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER) Office of Regulatory Affairs (ORA) September 2004 Pharmaceutical CGMPs www..co.kr 2

[ 목차 ] I. 서론 (Introduction) II. 배경 (Background) A. 규제프레임워크 (Regulatory Framework) B. 기술적프레임워크 (Technical Framework) III. IV. 범위 (Scope) 건물및시설 (BUILDINGS AND FACILITIES) A. 핵심지역 (Critical Area) Class 100 (ISO 5) B. 보조청정지역 (Supporting Clean Areas) C. 청정지역분리 (Clean Area Separation) D. 공기여과 (Air Filtration) 1. 멤브레인 (Membrane) 2. HEPA(High-Efficiency Particulate Air) E. 디자인 (Design) V. 작업자 교육, 적격성평가, 모니터링 (PERSONNEL TRAINING, QUALIFICATION, & MONITORING) A. 작업자 (Personnel) B. 시험실작업자 (Laboratory Personnel) C. 모니터링프로그램 (Monitoring Program) VI. 원료및용기 / 마개 A. 원료 (Components) B. 용기 / 마개 (Containers/Closures) 1. 준비 (Preparation) 2. 용기마개시스템검사 (Inspection of Container Closure System) VII. 엔도톡신관리 (ENDOTOXIN CONTROL) VIII. 시간제한 (TIME LIMITATIONS) IX. 무균 공정 및 멸균 공정의 밸리데이션 (VALIDATION of ASEPTIC PROCESSING AND STERILIZATION) A. 공정시뮬레이션 (Process Simulations) 1. 시험디자인 (Study Design) 2. 빈도와횟수 (Frequency and Number of Runs) 3. 기간 (Duration of Runs) www..co.kr 3

4. 규모 (Size of Runs) 5. 라인속도 (Line Speed) 6. 환경조건 (Environmental Conditions) 7. 배지 (Media) 8. 배지충전제품의배양과검사 (Incubation and Examination of Media-Filled Units) 9. 결과의해석 (Interpretation of Test Results) B. 여과효율성 (Filtration Efficacy) C. 설비, 용기, 마개의멸균 (Sterilization of Equipment, Containers, and Closures) 1. 적격성평가및밸리데이션 (Qualification and Validation) 2. 설비제어장치및계측기교정 (Equipment Controls and Instrument Calibration) X. 시험관리 (LABORATORY CONTROLS) A. 환경모니터링 (Environmental Monitoring) 1. 프로그램문서 (General Written Program) 2. 기준설정및경향분석프로그램 (Establishing Levels and a Trending Program) 3. 소독유효성 (Disinfection Efficacy) 4. 모니터링방법 (Monitoring Methods) B. 미생물배지와동정 (Microbiological Media and Identification) C. 여과이전단계의바이오버든 (Prefiltration Bioburden) D. 다른미생물시험방법 (Alternate Microbiological Test Methods) E. 미립자모니터링 (Particle Monitoring) XI. 무균시험 (STERILITY TESTING) A. 미생물시험관리 (Microbiological Laboratory Controls) B. 검체채취와배양 (Sampling and Incubation) C. 양성시험결과의조사 (Investigation of Sterility Positives) XII. 배치기록서검토 : 공정관리문서 (BATCH RECORD REVIEW: PROCESS CONTROL DOCUMENTATION) APPENDIX 1: 무균공정아이솔레이터 (ASEPTIC PROCESSING ISOLATORS) APPENDIX 2: BFS 기술 (BLOW-FILL-SEAL TECHNOLOGY) APPENDIX 3: 충전및밀봉작업이전공정 (PROCESSING PRIOR TO FILLING www..co.kr 4

and SEALING OPERATIONS) 참고문헌 (REFERENCES) 관련가이드문서 (RELEVANT GUIDANCE DOCUMENTS) 용어정의 (GLOSSARY) www..co.kr 5

Guidance for Industry 1 Sterile Drug Products Produced by Aseptic Processing Current Good Manufacturing Practice This guidance represents the Food and Drug Administration's (FDA's) current thinking on this topic. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. You can use an alternative approach if the approach satisfies the requirements of the applicable statutes and regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for implementing this guidance. If you cannot identify the appropriate FDA staff, call the appropriate number listed on the title page of this guidance. 이가이드문서는이주제에대한 FDA의방침을제시한다. 이문서는어느누구에게일체의권리를부여하거나인정하지않으며 FDA 또는일반대중을구속하지도않는다. 관련법규에제시된기준을만족시킬수있는다른방법이있다면, 그방법을활용할수도있다. 다른방법을협의하고자한다면, 해당 FDA 담당자에게연락한다. 관련 FDA 담당자가누구인지알수없다면, 이문서의표지에제시된번호로전화를한다. I. 서론 (Introduction) This guidance is intended to help manufacturers meet the requirements in the Agency's current good manufacturing practice (CGMP) regulations (2l CFR parts 210 and 211) when manufacturing sterile drug and biological products using aseptic processing. This guidance replaces the 1987 Industry Guideline on Sterile Drug Products Produced by Aseptic Processing (Aseptic Processing Guideline). This revision updates and clarifies the 1987 guidance. 이가이드문서는무균공정으로제조되는무균의약품과생물학적제품의제조업체가 FDA CGMP 기준 (21 CFR 파트 210/211) 을준수하는데도움을주기위한것이다. 이가이드문서는 1987년에발행된문서 ("Industry Guideline on Sterile Drug Products 1 This guidance was developed by the Office of Compliance in the Center for Drug Evaluation and Research (CDER) in cooperation with the Center for Biologics Evaluation and Research (CBER) and the Office of Regulatory Affairs (ORA). 이가이드문서는 CBER 및 ORA와협력하여 CDER OC가작성했다. www..co.kr 6

Produced by Aseptic Processing") 를대체한다. 이문서는 1987 년가이드문서의 개정판이며더명확하게작성했다. For sterile drug products subject to a new or abbreviated drug application (NDA or ANDA) or a biologic license application (BLA), this guidance document should be read in conjunction with the guidance on the content of sterile drug applications entitled Guideline for the Submission of Documentation for Sterilization Process Validation in Applications for Human and Veterinary Drug Products (Submission Guidance). The Submission Guidance describes the types of information and data that should be included in drug applications to demonstrate the efficacy of a manufacturer's sterilization process. This guidance compliments the Submission Guidance by describing procedures and practices that will help enable a sterile drug manufacturing facility to meet CGMP requirements relating, for example, to facility design, equipment suitability, process validation, and quality control. NDA 또는 ANDA나 BLA 대상인무균의약품제조업체는무균의약품신청문서의내용에관한가이드문서 ("Guideline for the Submission of Documentation for Sterilization Process Validation in Applications for Human and Veterinary Drug Products")(" 신청가이드문서 ") 와함께이가이드문서를참고한다. 신청가이드문서는멸균공정의유효성증명을위해의약품신청문서에포함시켜야할데이터와정보의종류에관한것이다. 이가이드문서는무균의약품제조시설이예를들어시설디자인, 설비적합성, 공정밸리데이션, 품질관리등과관련한 CGMP 기준을준수하는데도움이되는절차와방법을설명하며, 상기신청가이드문서를보완한다. FDA's guidance documents, including this guidance, do not establish legally enforceable responsibilities. Instead, guidances describe the Agency's current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidances means that something is suggested or recommended, but not required. 이가이드문서를포함한 FDA의가이드문서들은법적강제성을지니지않는다. 다만가이드문서는특정주제에대한 FDA의생각을기술하고있으며, 구체적인법적기준이제시되어있지않으면일종의권고사항으로간주해야한다. FDA 가이드문서에서 "should" 라는표현은어떤것을제안또는권고한다는의미이지반드시그래야한다는의미는아니다. www..co.kr 7

The text boxes included in this guidance include specific sections of parts 210 and 211 of the Code of Federal Regulations (CFR), which address current good manufacturing practice for drugs. The intent of including these quotes in the text boxes is to aid the reader by providing a portion of an applicable regulation being addressed in the guidance. The quotes included in the text boxes are not intended to be exhaustive. Readers of this document should reference the complete CFR to ensure that they have complied, in full, with all relevant sections of the regulations. 이가이드문서에서박스로처리한부분은의약품 CGMP 기준인 CFR 파트 210/211 가운데해당되는항목을정리한것이다. 박스에관련 CGMP 기준을포함시킴으로써, 이가이드문서에서다루는사항에적용되는규정을제시하여해당부분을이해하는데도움이되도록하였다. 박스의인용기준이전부는아니다. 이문서를읽을때는 CFR 전체를참고해야한다. 그래야 CGMP 관련항목을모두준수할수있다. II. 배경 (Background) This section describes briefly both the regulatory and technical reasons why the Agency is developing this guidance document. FDA 가이가이드문서를만든이유를규제와기술측면에서간략하게설명한다. A. 규제프레임워크 (Regulatory Framework) This guidance pertains to current good manufacturing practice (CGMP) regulations (21 CFR parts 210 and 211) when manufacturing sterile drug and biological products using aseptic processing. Although the focus of this guidance is on CGMPs in 21 CFR 210 and 211, supplementary requirements for biological products are in 21 CFR 600-680. For biological products regulated under 21 CFR parts 600 through 680, 210.2(a) and 211.1(b) provide that where it is impossible to comply with the applicable regulations in both parts 600 through 680 and parts 210 and 211, the regulation specifically applicable to the drug product in question shall supercede the more general regulations. 이가이드문서는무균공정에의한무균의약품및생물학적제품제조시의 CGMP 기준 (21 CFR Parts 210/211) 에관한것이다. 이가이드문서가 21 CFR 210/211의 CGMP 기준에중점을두고있지만, 생물학적제품에관한 21 CFR 600-680의기준도고려할필요가있다. 21 CFR 600-680에따라규제를받는생물학적제품인경우, 600- www..co.kr 8

680 과 210/211 의모든규정을준수하기가불가능할때는해당의약품에구체적으로 적용되는규정이보다일반적인것보다우선한다 ( 210.2(a) 및 211.1(b)). B. 기술적프레임워크 (Technical Framework) There are basic differences between the production of sterile drug products using aseptic processing and production using terminal sterilization. 무균공정에의한무균의약품생산과사후멸균방식의생산사이에는기본적으로차이가있다. Terminal sterilization usually involves filling and sealing product containers under high-quality environmental conditions. Products are filled and sealed in this type of environment to minimize the microbial and particulate content of the in-process product and to help ensure that the subsequent sterilization process is successful. In most cases, the product, container, and closure have low bioburden, but they are not sterile. The product in its final container is then subjected to a sterilization process such as heat or irradiation. 사후멸균은일반적으로고품질의환경조건에서제품을충전하고밀봉한다. 이와같은환경에서제품을충전하고밀봉한다면, 반제품의미생물및미립자오염이최소화되고, 이후멸균공정의성공적인수행에도도움이된다. 대개는제품, 용기, 마개의바이오버든이낮은수준이지만, 그렇다고무균상태는아니다. 제품을최종용기에충전한다음에는가열또는방사선조사등멸균공정을거친다. In an aseptic process, the drug product, container, and closure are first subjected to sterilization methods separately, as appropriate, and then brought together. 2 2 Due to their nature, certain products are aseptically processed at an earlier stage in the process, or in their entirety. Cellular therapy products are an example. All components and excipients for these products are rendered sterile, and release of the final product is contingent on determination of sterility. See Appendix III. 제품특성에따라일부제품은공정초기단계에서무균적으로처리하거나공정전체에걸쳐무균공정을적용한다. 세포치료제가대표적인예이다. 세포치료제제조에투입되는모든원료와첨가제를무균상태로만들며, 무균성이확인되어야최종제품의출하승인이결정된다. 부록 III 참조. www..co.kr 9

Because there is no process to sterilize the product in its final container, it is critical that containers be filled and sealed in an extremely high-quality environment. Aseptic processing involves more variables than terminal sterilization. Before aseptic assembly into a final product, the individual parts of the final product are generally subjected to various sterilization processes. For example, glass containers are subjected to dry heat; rubber closures are subjected to moist heat; and liquid dosage forms are subjected to filtration. Each of these manufacturing processes requires validation and control. Each process could introduce an error that ultimately could lead to the distribution of a contaminated product. Any manual or mechanical manipulation of the sterilized drug, components, containers, or closures prior to or during aseptic assembly poses the risk of contamination and thus necessitates careful control. A terminally sterilized drug product, on the other hand, undergoes final sterilization in a sealed container, thus limiting the possibility of error. 3 무균공정에서는제품, 용기, 마개를각기별도로멸균한다음에충전 / 밀봉한다. 충전이후에제품을멸균하는공정이없으므로, 충전및밀봉작업을최고품질수준의환경조건에서하는것이중요하다. 무균공정에는사후멸균공정보다변수가더많다. 무균적으로최종제품을만들기전에최종제품의구성부분각각을각종방법으로멸균한다. 예를들어유리용기를건열멸균하고, 고무마개를습열멸균한다. 액상제제는여과를거친다. 각각의제조공정을밸리데이션하고관리할필요가있다. 공정마다오류가발생할수있으며, 그에따라오염된제품이만들어져시장에유통될가능성도있다. 무균작업이전이나도중에멸균상태의의약품, 원료, 용기또는마개를수작업또는기계적으로조작하므로오염리스크가존재하며, 그렇기때문에치밀한관리가필요하다. 반면사후멸균제품은충전 / 밀봉이후에멸균공정을거치므로오류발생가능성이적다. Sterile drug manufacturers should have a keen awareness of the public health implications of distributing a nonsterile product. Poor CGMP conditions at a manufacturing facility can ultimately pose a life-threatening health risk to a patient. 무균의약품제조업체는비무균제품유통이공중보건에미칠심각한위험성을인식해야한다. 제조시설의 CGMP 상태가부실하면환자에게치명적인건강리스크를유발할수 3 Nearly all drugs recalled due to nonsterility or lack of sterility assurance in the period spanning 1980-2000 were produced via aseptic processing. 1980년부터 2000년사이에비무균또는무균성보증결여로인해리콜된거의모든제품이무균공정으로생산된것이다. www..co.kr 10

있다. III. 범위 (Scope) This guidance document discusses selected issues and does not address all aspects of aseptic processing. For example, the guidance addresses primarily finished drug product CGMP issues while only limited information is provided regarding upstream bulk processing steps. This guidance updates the 1987 Aseptic Processing Guideline primarily with respect to personnel qualification, cleanroom design, process design, quality control, environmental monitoring, and review of production records. The use of isolators for aseptic processing is also discussed. 이가이드문서는무균공정의모든부분을다루지않는다. 일부주제만다룬다. 예를들어기본적으로이문서는완제의약품 CGMP 사항을다루며, 업스트림벌크제조공정에대해서는일부필요한것만제한적으로설명한다. 이가이드문서는작업자적격성평가, 청정실디자인, 공정디자인, 품질관리, 환경모니터링, 생산기록서검토와관련한 1987년무균공정가이드라인을개정한것이다. 아이솔레이터를활용한무균공정부분도살펴본다. Although this guidance document discusses CGMP issues relating to the sterilization of components, containers, and closures, terminal sterilization of drug products is not addressed. It is a well-accepted principle that sterile drugs should be manufactured using aseptic processing only when terminal sterilization is not feasible. However, some final packaging may afford some unique and substantial advantage (e.g., some dual-chamber syringes) that would not be possible if terminal sterilization were employed. In such cases, a manufacturer can explore the option of adding adjunct processing steps to increase the level of sterility assurance. 원료, 용기, 마개의멸균관련 CGMP 부분은설명하지만, 의약품사후멸균은이문서에서다루지않는다. 무균제품은사후멸균이가능하지않은경우에만무균공정으로제조해야한다는것이일반적인원칙이다. 하지만사후멸균방식을채택했을때는가능하지않을몇가지독특하고실질적인이점을제공하는포장방식도있다 ( 예, 일부듀얼챔버주사기 ). 그와같은경우에는보조적인공정단계를추가함으로써무균성보증수준을높이는방법도모색할수있다. www..co.kr 11

A list of references that may be of value to the reader is included at the conclusion of this document. 도움이될만한참고문헌목록이이문서마지막에정리되어있다. 총 138 페이지입니다. 파일 (Printable PDF) 구입을원하시는분은 @hanmail.net 으로연락주시기 바랍니다. www..co.kr 12