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1 공정밸리데이션 : 일반원칙과실제 (Guidance for Industry: Process Validation: General Principles ) 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) Center for Veterinary Medicine (CVM) January 2011 Current Good Manufacturing Practices (CGMP) Revision 1 1

2 공정밸리데이션 : 일반원칙과실제 (Guidance for Industry: Process Validation: General Principles ) Additional copies are available from: Office of Communications Division of Drug Information, WO51, Room New Hampshire Ave. Silver Spring, MD Phone: ; Fax: druginfo@fda.hhs.gov efault.htm and/or Office of Communication, Outreach and Development, HFM-40 Center for Biologics Evaluation and Research Food and Drug Administration 1401 Rockville Pike, Rockville, MD (Tel) or tion/guidances/default.htm and/or Communications Staff, HFV-12 Center for Veterinary Medicine Food and Drug Administration 7519 Standish Place, Rockville, MD (Tel) rindustry/default.htm 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) Center for Veterinary Medicine (CVM) January 2011 Current Good Manufacturing Practices (CGMP) Revision 1 2

3 [ 목차 ] I. 서론 (INTRODUCTION) II. 배경 (BACKGROUND) A. 공정밸리데이션및의약품품질 (Process Validation and Drug Quality) B. 공정밸리데이션전략 (Approach to Process Validation) III. 공정밸리데이션관련법적기준 (STATUTORY AND REGULATORY IV. REQUIREMENTS FOR PROCESS VALIDATION) 권고사항 (RECOMMENDATIONS) A. 공정밸리데이션공통사항 (General Considerations for Process Validation) B. 1단계 - 공정디자인 (Stage 1 Process Design) 1. 공정지식및이해의확보와축적 (Building and Capturing Process Knowledge and Understanding) 2. 공정관리전략의확립 (Establishing a Strategy for Process Control) C. 2단계 - 공정적격성평가 (Stage 2 Process Qualification) 1. 시설디자인및유틸리티와설비의적격성평가 (Design of a Facility and Qualification of Utilities and Equipment) 2. PPQ(Process Performance Qualification) 3. PPQ 프로토콜 (PPQ Protocol) 4. PPQ 프로토콜실행및보고 (PPQ Protocol Execution and Report) D. 3단계 - 지속적공정베리피케이션 (Stage 3 Continued Process Verification) V. PPQ 배치의동시적출하 (CONCURRENT RELEASE OF PPQ BATCHES) VI. VII. 문서화 (DOCUMENTATION) 분석방법 (ANALYTICAL METHODOLOGY) 용어정의 (GLOSSARY) 참고문헌 (REFERENCES) 3

4 Guidance for Industry 1 Process Validation: General Principles 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 outlines the general principles and approaches that FDA considers appropriate elements of process validation for the manufacture of human and animal drug and biological products, including active pharmaceutical ingredients (APIs or drug substances), collectively referred to in this guidance as drugs or products. This guidance incorporates principles and approaches that all manufacturers can use to validate manufacturing processes. 이가이드문서는 API(active pharmaceutical ingredients) 또는약효성분 (drug substance) 을포함하여사람및동물의약품과생물학적제제 ( 통칭하여 " 의약품 (drug)" 또는 " 제품 (products)") 의제조와관련하여적절한공정밸리데이션요소라고 FDA가 1 This guidance has been prepared by the Division of Manufacturing and Product Quality, Center for Drug Evaluation and Research (CDER), in cooperation with CDER s Office of Pharmaceutical Sciences, the Center for Biologics Evaluation and Research (CBER), the Office of Regulatory Affairs (ORA) and the Center for Veterinary Medicine (CVM) at the Food and Drug Administration. 이가이드문서는 CDER의 OPS, CBER, ORA, CVM과협력하여 CDER의 DMPQ가 작성했다. 4

5 생각하는일반원칙과접근방식을설명한다. 이가이드문서는모든제조업체가제조 공정을밸리데이션할때활용할수있는원칙과접근방식을제시한다. This guidance aligns process validation activities with a product lifecycle concept and with existing FDA guidance, including the FDA/International Conference on Harmonisation (ICH) guidances for industry, Q8(R2) Pharmaceutical Development, Q9 Quality Risk Management, and Q10 Pharmaceutical Quality System. 2 Although this guidance does not repeat the concepts and principles explained in those guidances, FDA encourages the use of modern pharmaceutical development concepts, quality risk management, and quality systems at all stages of the manufacturing process lifecycle. 이가이드문서는 FDA/ICH Q8(R2) " 의약품개발 ", Q9 " 품질리스크관리 ", Q10 " 제약품질시스템 " 을포함한 FDA 가이드문서및제품라이프사이클개념과공정밸리데이션활동을연계시켜설명한다. 이들문서에제시된개념과원칙을이문서에서다시반복하여설명하지않지만, 최신의약품개발개념, 품질리스크관리, 품질시스템을제조공정라이프사이클의모든단계에적용할것을 FDA는권장한다. The lifecycle concept links product and process development, qualification of the 2 To make sure you have the most recent version of a guidance, check the CDER guidance page at ces/default.htm, the CBER guidance page at formation/guidances/default.htm, or the CVM guidance page at anceforindustry/default.htm 아래웹페이지에서최신문서를확인한다. CDER 가이드문서웹페이지 : ces/default.htm, CBER 가이드문서웹페이지 : formation/guidances/default.htm, CVM 가이드문서웹페이지 : anceforindustry/default.htm 5

6 commercial manufacturing process 3, and maintenance of the process in a state of control during routine commercial production. This guidance supports process improvement and innovation through sound science. 라이프사이클개념은제품과공정개발, 상업적제조공정의적격성평가, 그리고일상적인상업적생산시의공정관리상태유지를통합한것이다. 이가이드문서는합리적인과학을통한공정개선과혁신을지원한다. This guidance covers the following categories of drugs: 이가이드문서가적용되는의약품의종류는다음과같다. Human drugs 사람의약품 Veterinary drugs 동물의약품 Biological and biotechnology products 생물학적 / 생명공학제품 Finished products and active pharmaceutical ingredients (API or drug substance) 4 3 In this guidance, the term commercial manufacturing process refers to the manufacturing process resulting in commercial product (i.e., drug that is marketed, distributed, and sold or intended to be sold). For the purposes of this guidance, the term commercial manufacturing process does not include clinical trial or treatment IND material. 이문서에서 " 상업적제조공정 " 이라함은상업적제품 ( 즉, 마케팅, 유통, 판매하기 위한의약품이나판매할의도로만든의약품 ) 을만드는제조공정을의미한다. 이문 서에서임상시험또는치료 IND 물품은 " 상업적제조공정 " 에포함되지않는다. 4 Separate current good manufacturing practice (CGMP) regulations for drug components such as APIs (drug substances) and intermediates have not published as of the date of this guidance, but these components are subject to the statutory CGMP requirements of section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (the Act) (21 U.S.C. 351(a)(2)(B)). Process validation for APIs is discussed in the FDA/ICH guidance for industry, Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients (ICH Q7), available on the Internet at 6

7 완제의약품과 API 또는약효성분 The drug constituent of a combination (drug and medical device) product 복합제품 ( 의약품과의료용구 ) 의의약품구성분 This guidance does not cover the following types of products: 다음제품은이가이드문서의대상이아니다. Type A medicated articles and medicated feed A형약제처리제품과사료 Medical devices 5 의료기기 Dietary supplements 식품보조제 Human tissues intended for transplantation regulated under section 361 of the Public Health Service Act 6 ces/default.htm. Section XII of ICH Q7 describes in detail the principles for validating API processes. API( 약효성분 ) 및중간체등의약품원료의 CGMP 규정이아직까지공표되지않았지만, 이들원료성분에도연방식품의약품화장품법섹션 501(a)(2)(B)(21 USC 351(a)(2)(B)) 의법적 CGMP 기준이적용된다. API의공정밸리데이션은 FDA/ICH 가이드문서 Q7 "API GMP 가이드 " 를참조한다 ( n/guidances/default.htm). ICH Q7의섹션 XII에 API 공정밸리데이션원칙이상세히설명되어있다. 5 Guidance on process validation for medical devices is provided in a separate document, Quality Management Systems Process Validation, edition 2, available at See infra note 6. 의료기기공정밸리데이션은별도의문서에서다룬다. " 품질경영시스템 - 공정 밸리데이션 "(2 판 ). 아래의주 6 참조. 6 See the FDA guidance for industry, Validation of Procedures for Processing of Human Tissues Intended for Transplantation, available on the Internet at ormation/guidances/default.htm. 7

8 PHS 법섹션 361 에의거하여규제되는이식용사람조직 This guidance does not specify what information should be included as part of a regulatory submission. Interested persons can refer to the appropriate guidance or contact the appropriate Center in determining the type of information to include in a submission. 이가이드문서는규제기관제출서류에포함시켜야할정보사항을규정하지않는다. 제출서류에포함시켜야할정보를정할때관련가이드문서를참조하거나관련센터에문의한다. This guidance also does not specifically discuss the validation of automated process control systems (i.e., computer hardware and software interfaces), which are commonly integrated into modern drug manufacturing equipment. This guidance is relevant, however, to the validation of processes that include automated equipment in processing. 또한이가이드문서는자동화공정관리시스템 ( 즉, 컴퓨터하드웨어와소프트웨어인터페이스 ) 의밸리데이션을따로설명하지않는다. 이런부분은일반적으로오늘날의의약품제조설비에통합되어있다. 하지만이가이드문서는자동화설비를포함하는공정의밸리데이션과연관이있다. 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. II. 배경 (BACKGROUND) FDA 가이드문서 " 이식용사람조직가공절차의밸리데이션 " 을참조한다. 8

9 In the Federal Register of May 11, 1987 (52 FR 17638), FDA issued a notice announcing the availability of a guidance entitled Guideline on General Principles of Process Validation (the 1987 guidance). 7 Since then, we have obtained additional experience through our regulatory oversight that allows us to update our recommendations to industry on this topic. This revised guidance conveys FDA s current thinking on process validation and is consistent with basic principles first introduced in the 1987 guidance. The revised guidance also provides recommendations that reflect some of the goals of FDA s initiative entitled Pharmaceutical CGMPs for the 21st Century A Risk-Based Approach, particularly with regard to the use of technological advances in pharmaceutical manufacturing, as well as implementation of modern risk management and quality system tools and concepts. 8 This revised guidance replaces the 1987 guidance. 7 The 1987 guidance was prepared by a working group that included representation from the Center for Devices and Radiological Health (CDRH). Since that time, CDRH elected to reference a process validation guidance prepared in cooperation with the Global Harmonization Task Force (GHTF). The principles and recommendations in that document, Quality Management Systems Process Validation, edition 2 (available on the Internet at are also useful to consider for drug manufacturing processes. 1987년가이드문서는 CDRH를포함한실무그룹이작성했다. 이후 CDRH는 GHTF와협력하여공정밸리데이션가이드문서를발행하기로했다. 이문서 (Quality Management Systems - Process Validation, edition 2)( 에제시된원칙과권고사항은의약품제조공정에도도움이될수있다. 8 See Pharmaceutical cgmps for the 21st Century A Risk-Based Approach: Second Progress Report and Implementation Plan, available at tionsandanswersoncurrentgoodmanufacturingpracticescgmpfordrugs/ucm htm. "21세기제약 CGMP - 리스크기반방식 : 이차진행보고서및구축계획 " 을 참조한다. ( 9

10 1987년 5월 11일자연방관보 (52 FR 17638) 를통해 FDA는가이드문서 (General Principles of Process Validation)(1987년가이드문서 ) 의발행을공표했다. 이후 FDA는규제활동을통해많은경험을축적했으며, 이를통해이주제와관련한권고사항을업데이트할수있게되었다. 이번개정가이드문서는공정밸리데이션에관한 FDA의현행방침을정리한것이며, 1987년가이드문서에서처음제시했던기본원칙과도일치한다. 또한이개정가이드문서는특히의약품제조분야의최신기술과리스크관리및품질시스템도구와개념의적용과관련하여, FDA의 "21세기제약 CGMP - 리스크기반방식 " 프로젝트가정한목적가운데일부를반영한권고사항도제시한다. 이개정가이드문서는 1987년가이드문서를대체한다. FDA has the authority and responsibility to inspect and evaluate process validation performed by manufacturers. The CGMP regulations for validating pharmaceutical (drug) manufacturing require that drug products be produced with a high degree of assurance of meeting all the attributes they are intended to possess (21 CFR (a) and (a)). FDA는제조업체가수행한공정밸리데이션성과를실사하고평가할권한과책임을갖는다. 의약품제조공정밸리데이션과관련된 CGMP 규정에따르면, 의약품은의약품이보유해야 할모든특성기준에부합함을높은수준으로보증하며생산해야한다 (21 CFR (a), (a)). A. 공정밸리데이션및의약품품질 (Process Validation and Drug Quality) Effective process validation contributes significantly to assuring drug quality. The basic principle of quality assurance is that a drug should be produced that is fit for its intended use. This principle incorporates the understanding that the following conditions exist: 효과적인공정밸리데이션은의약품품질보증에유의미하게기여한다. 목적용도에적합한의약품의생산은품질보증의기본원칙이다. 이원칙은다음사항에대한이해를전제로한다. Quality, safety, and efficacy are designed or built into the product. 품질, 안전성, 유효성이제품자체에통합되어야한다. stionsandanswersoncurrentgoodmanufacturingpracticescgmpfordrugs/ucm htm) 10

11 Quality cannot be adequately assured merely by in-process and finishedproduct inspection or testing. 공정도중의검사나시험과최종제품검사나시험으로는품질을적절하게보증할수없다. Each step of a manufacturing process is controlled to assure that the finished product meets all quality attributes including specifications. 최종제품이규격을포함한모든품질특성기준에부합하도록하기위하여제조공정단계각각을관리한다. B. 공정밸리데이션전략 (Approach to Process Validation) For purposes of this guidance, process validation is defined as the collection and evaluation of data, from the process design stage through commercial production, which establishes scientific evidence that a process is capable of consistently delivering quality product. Process validation involves a series of activities taking place over the lifecycle of the product and process. This guidance describes process validation activities in three stages. 이가이드문서에서공정밸리데이션이라함은공정디자인단계부터상업적생산과정까지, 특정공정이고품질의제품을일관되게생산할수있다는과학적증거를확립하는, 데이터의수집과평가를의미한다. 공정밸리데이션은제품및공정라이프사이클전체에걸쳐실시되는일련의활동이다. 이가이드문서는공정밸리데이션활동을다음 3단계로나누어설명한다. Stage 1 Process Design: The commercial manufacturing process is defined during this stage based on knowledge gained through development and scaleup activities. 1단계 - 공정디자인 : 개발및스케일업활동을통해확보한지식에근거하여이단계에서상업적제조공정을규정한다. Stage 2 Process Qualification: During this stage, the process design is evaluated to determine if the process is capable of reproducible commercial manufacturing. 2단계 - 공정적격성평가 : 이단계에서는상업적제조를재현성있게수행할수있는공정디자인인지평가한다. 11

12 Stage 3 Continued Process Verification: Ongoing assurance is gained during routine production that the process remains in a state of control. 3단계 - 지속적공정베리피케이션 : 정규생산을진행하며공정이관리상태에있다는지속적보증을확보한다. This guidance describes activities typical of each stage, but in practice, some activities might occur in multiple stages. 단계별로대표적인활동을설명하지만, 실제로일부활동은여러단계에서반복될수도있다. Before any batch from the process is commercially distributed for use by consumers, a manufacturer should have gained a high degree of assurance in the performance of the manufacturing process such that it will consistently produce APIs and drug products meeting those attributes relating to identity, strength, quality, purity, and potency. The assurance should be obtained from objective information and data from laboratory-, pilot-, and/or commercial-scale studies. Information and data should demonstrate that the commercial manufacturing process is capable of consistently producing acceptable quality products within commercial manufacturing conditions. 생산배치를소비자가사용할수있도록상업적으로유통시키기전에, 제조업체는제조공정이확인, 함량, 품질, 순도, 역가관련품질특성기준에부합하는 API와의약품을일관되게생산할수있다는, 제조공정성능에대한높은수준의보증을확보해야한다. 이러한보증은실험실규모, 파일럿규모, 및 / 또는상업적규모연구활동을통해축적한객관적정보와데이터를통해확보할수있다. 상업적제조조건에서적합한품질의제품을일관되게생산할수있는상업적제조공정임을증명하는정보와데이터를확보해야한다. A successful validation program depends upon information and knowledge from product and process development. This knowledge and understanding is the basis for establishing an approach to control of the manufacturing process that results in products with the desired quality attributes. Manufacturers should: 성공적인밸리데이션프로그램이되기위해서는제품및공정개발활동을통해정보와지식을확보해야한다. 이지식과정보는바람직한품질특성을구비한제품을생산할수있는, 제조공정의적절한관리전략을수립하는데토대가된다. 제조업체는다음사항을 12

13 충족해야한다. Understand the sources of variation 변동의발생원을이해해야한다. Detect the presence and degree of variation 변동의존재와정도를감지해야한다. Understand the impact of variation on the process and ultimately on product attributes 변동이공정과궁극적으로는제품특성요소에미칠영향을이해해야한다. Control the variation in a manner commensurate with the risk it represents to the process and product 변동에따른공정과제품의리스크수준에부합하는방식으로변동요소를관리해야한다. Each manufacturer should judge whether it has gained sufficient understanding to provide a high degree of assurance in its manufacturing process to justify commercial distribution of the product. Focusing exclusively on qualification efforts without also understanding the manufacturing process and associated variations may not lead to adequate assurance of quality. After establishing and confirming the process, manufacturers must maintain the process in a state of control over the life of the process, even as materials, equipment, production environment, personnel, and manufacturing procedures change. 9 각제조업체는충분한정보를확보하여그의제조공정을높은수준으로보증하고제품의상업적유통이타당함을증명할수있는지판단해야한다. 제조공정과관련변동부분에대한이해없이적격성평가활동에만중점을둔다면, 적절한품질보증이가능하지않을것이다. 공정을확립하고확증한다음, 제조업체는물품, 설비, 생산환경, 작업자, 제조 9 The statute and regulations described in section III of this guidance explain the requirement that the methods and facilities used for the manufacturing of drugs be operated and maintained under control sufficient to assure that the identity, strength, purity, and quality of a drug are as they purport or are represented to possess. 이가이드문서의섹션 III에기술된법규에의하면, 의약품제조방법과시설은 의약품이목표로하거나보유하는것으로표시된확인, 함량, 순도, 품질을 보증하기에충분한관리상태로운영되고유지되어야한다. 13

14 절차가변경되더라도라이프사이클전체에걸쳐그공정이관리상태를유지하도록해야 한다. Manufacturers should use ongoing programs to collect and analyze product and process data to evaluate the state of control of the process. These programs may identify process or product problems or opportunities for process improvements that can be evaluated and implemented through some of the activities described in Stages 1 and 2. 제조업체는제품및공정데이터를지속적으로수집하고분석하는프로그램을운영하여, 공정의관리상태를평가해야한다. 이런프로그램을통해공정또는제품관련문제점이나공정개선의기회를파악할수있으며, 이런부분은 1단계와 2단계의활동을통해추진할수있다. Manufacturers of legacy products can take advantage of the knowledge gained from the original process development and qualification work as well as manufacturing experience to continually improve their processes. Implementation of the recommendations in this guidance for legacy products and processes would likely begin with the activities described in Stage 3. 레거시제품제조업체는제조경험과최초의공정개발및적격성평가활동을통해얻은지식을활용하여공정을지속적으로개선할수있다. 레거시제품과공정에대하여이가이드문서에제시된권고사항을이행하고자한다면, 3단계활동부터시작한다. III. 공정밸리데이션관련법적기준 (STATUTORY AND REGULATORY REQUIREMENTS FOR PROCESS VALIDATION) Process validation for drugs (finished pharmaceuticals and components) is a legally enforceable requirement under section 501(a)(2)(B) of the Act (21 U.S.C. 351(a)(2)(B)), which states the following: 의약품 ( 완제의약품과원료 ) 공정밸리데이션은다음과같이규정되어있는법섹션 501(a)(2)(B)(21 USC 351(a)(2)(B)) 에의거하여법적강제성이있는기준이다. A drug... shall be deemed to be adulterated... if... the methods used in, or the facilities or controls used for, its manufacture, processing, packing, or holding do not conform to or are not operated or administered in conformity with current good manufacturing practice to assure that such drug meets the 14

15 requirements of this Act as to safety and has the identity and strength, and meets the quality and purity characteristics, which it purports or is represented to possess. 의약품의제조, 가공, 포장, 또는보관방법이나시설또는이를위한관리대책이 CGMP에부합하지않거나 CGMP에부합하게운영또는관리되지않아그의약품이안전성과관련한이법의기준을충족하며목표로하거나보유하는것으로표시된품질및순도특성과확인및함량기준을충족한다고보장할수없다면, 그의약품은불량의약품으로간주한다. FDA regulations describing current good manufacturing practice (CGMP) for finished pharmaceuticals are provided in 21 CFR parts 210 and 211. 완제의약품 CGMP 와관련한 FDA 규정은 21 CFR 파트 210 과 211 에제시되어있다. The CGMP regulations require that manufacturing processes be designed and controlled to assure that in-process materials and the finished product meet predetermined quality requirements and do so consistently and reliably. Process validation is required, in both general and specific terms, by the CGMP regulations in parts 210 and 211. The foundation for process validation is provided in (a), which states that [t]here shall be written procedures for production and process control designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess... (emphasis added). This regulation requires manufacturers to design a process, including operations and controls, which results in a product meeting these attributes. 공정중물품과최종제품이사전설정품질기준에부합하고일관되고신뢰성있게그렇게되도록제조공정을설계하고관리할것을 CGMP 규정은요구한다. 21 CFR 파트 210 및 211의 CGMP 규정은일반적인표현과구체적인표현으로공정밸리데이션을요구하고있다. 공정밸리데이션의근거가 (a) 에제시되어있는데, 이조항에따르면 " 의약품이목표로하거나보유하는것으로표시한확인, 함량, 품질및순도를보장할수있게설계된생산및공정관리에대한절차문서를구비해야한다." 이규정에따라제조업체는이러한특성요소에부합하는제품을생산하는공정 ( 운영및관리포함 ) 을설계해야한다. Other CGMP regulations define the various aspects of validation. For example, 15

16 (a), Sampling and testing of in-process materials and drug products, requires that control procedures... be established to monitor the output and to validate the performance of those manufacturing processes that may be responsible for causing variability in the characteristics of in-process material and the drug product (emphasis added). Under this regulation, even well-designed processes must include in-process control procedures to assure final product quality. In addition, the CGMP regulations regarding sampling set forth a number of requirements for validation: samples must represent the batch under analysis ( (b)(3)); the sampling plan must result in statistical confidence ( (c) and (d)); and the batch must meet its predetermined specifications ( (a)). 이외에도밸리데이션의다양한측면을정의하고있는 CGMP 규정이있다. 예를들어섹션 (a) " 공정중물품및의약품의검체채취와시험 " 에의하면, " 공정중물품및의약품의특성을변화시킬수있는제조공정작업을밸리데이션하고결과 ( 아웃풋 ) 를모니터하기위한관리절차를확립해야한다." 이규정은잘설계된공정이라도최종제품품질을보증하기위한 IPC 절차를구비해야한다는기준을제시하고있다. 이외에도검체채취에관한 CGMP 규정에밸리데이션기준이다수제시되어있는데, 검체는분석대상배치를대표해야하며 ( (b)(3)), 검체채취계획은통계적신뢰성을구비해야하며 ( (c) and (d)), 배치는미리결정한규격에부합해야한다 ( (a)). In addition to sampling requirements, the CGMP regulations also provide norms for establishing in-process specifications as an aspect of process validation. Section (b) establishes two principles to follow when establishing in-process specifications. The first principle is that... in-process specifications for such characteristics [of in-process material and the drug product] shall be consistent with drug product final specifications.... Accordingly, in-process material should be controlled to assure that the final drug product will meet its quality requirements. The second principle in this regulation further requires that in-process specifications... shall be derived from previous acceptable process average and process variability estimates where possible and determined by the application of suitable statistical procedures where appropriate. This requirement, in part, establishes the need for manufacturers to analyze process performance and control batch-to-batch variability The Agency further explains this principle in the preamble to the final rule on 16

17 검체채취기준이외에도, 공정밸리데이션의한부분으로써공정관리규격의설정에관한기준도 CGMP 규정에제시되어있다. 섹션 (b) 는공정관리규격설정시에준수해야할두가지원칙을제시하고있다. 첫번째원칙은 "[ 공정중물품및의약품의 " 특성요소에대한공정관리규격은의약품최종규격과일관성을갖추어야한다 " 는점이다. 그러므로최종의약품이그의품질기준에부합하도록공정중물품을관리해야한다. 이규정의두번째원칙은공정관리규격을 " 가능하면전에수용가능했던공정평균및공정편차추정치를토대로하며적절한경우에적합한통계적절차를적용하여결정해야한다 " 는점이다. 이기준은부분적으로제조업체가공정성능을분석하고배치간변동성을관리할필요가있음을제시하고있다. The CGMP regulations also describe and define activities connected with process design, development, and maintenance. Section (e) requires that information and data about product quality and manufacturing experience be periodically reviewed to determine whether any changes to the established process are warranted. Ongoing feedback about product quality and process performance is an essential feature of process maintenance. 또한 CGMP 규정에는공정디자인, 개발, 유지관리와관련된활동들이규정되어있다. 섹션 (e) 는제품품질및제조경험과관련한정보및데이터를주기적으로검토하여확립된공정의변경이필요한지결정하도록요구한다. 제품품질과공정성능에관한지속적피드백은공정유지관리의필수적인특징이다. In addition, the CGMP regulations require that facilities in which drugs are manufactured be of suitable size, construction, and location to facilitate proper operations ( ). Equipment must be of appropriate design, adequate size, and suitably located to facilitate operations for its intended use ( ). Automated, mechanical, and electronic equipment must be calibrated, inspected, or checked according to a written program designed to assure proper performance ( ). Current Good Manufacturing Practice in Manufacture, Processing, Packing, or Holding (43 FR at 45052, September 29, 1978) (available on the Internet at " 제조, 가공, 포장, 보관 CGMP" 최종규칙의전문에이원칙이자세히설명되어있다 (43 FR at 45052, September 29, 1978) ( 17

18 이외에도 CGMP 규정은의약품제조시설이적절한작업을용이하게수행할수있는적합한규모, 구조, 위치를갖추어야한다고요구한다 (21 CFR ). 설비는목적용도에맞게작업할수있도록적절한디자인과적절한크기여야하고적합하게위치해야한다 (21 CFR ). 자동화, 기계적, 전자적설비는적절한성능을보장할수있게설계된프로그램문서에따라교정, 검사, 또는점검해야한다 (21 CFR ). In summary, the CGMP regulations require that manufacturing processes be designed and controlled to assure that in-process materials and the finished product meet predetermined quality requirements and do so consistently and reliably. 결국 CGMP 규정은공정중물품과최종제품이미리정한품질기준을충족하고일관되고신뢰성있게그렇게하도록제조공정을설계하고관리할것을요구한다. IV. 권고사항 (RECOMMENDATIONS) In the following sections, we describe general considerations for process validation, the recommended stages of process validation, and specific activities for each stage in the product lifecycle. 공정밸리데이션공통사항, 공정밸리데이션의권장단계, 제품라이프사이클에서단계별활동을아래에서설명한다. A. 공정밸리데이션공통사항 (General Considerations for Process Validation) In all stages of the product lifecycle, good project management and good archiving that capture scientific knowledge will make the process validation program more effective and efficient. The following practices should ensure uniform collection and assessment of information about the process and enhance the accessibility of such information later in the product lifecycle. 제품라이프사이클전체에걸쳐프로젝트관리및문서관리를제대로하면, 과학적지식을확보하고공정밸리데이션프로그램을보다효과적이고효율적으로진행할수있다. 아래에기술한업무방식은공정관련정보를체계적으로수집하고평가하며제품라이프사이클후기단계에이런정보를보다효율적으로활용하는데기여할것이다. 18

19 We recommend an integrated team approach 11 to process validation that includes expertise from a variety of disciplines (e.g., process engineering, industrial pharmacy, analytical chemistry, microbiology, statistics, manufacturing, and quality assurance). Project plans, along with the full support of senior management, are essential elements for success. 공정엔지니어링, 산업약학, 분석화학, 미생물학, 통계학, 제조, 품질보증을포함하여여러분야의전문가로통합적인팀을구성하여공정밸리데이션을추진하는것이바람직하다. 고위경영진의전폭적인지원과함께, 프로젝트계획서가성공의필수요소이다. Throughout the product lifecycle, various studies can be initiated to discover, observe, correlate, or confirm information about the product and process. All studies should be planned and conducted according to sound scientific principles, appropriately documented, and approved in accordance with the established procedure appropriate for the stage of the lifecycle. 제품라이프사이클전체에걸쳐제품과공정에관한정보를발견하고관찰하고상호연계시키고확증하기위한각종연구활동을실시할수있다. 모든연구활동은타당한과학적원칙에따라미리계획을세워실시하고, 적절하게문서화하며, 해당라이프사이클단계에맞는적절한절차문서에따라승인을받아야한다. The terms attribute(s) (e.g., quality, product, component) and parameter(s) (e.g., process, operating, and equipment) are not categorized with respect to criticality in this guidance. With a lifecycle approach to process validation that employs risk based decision making throughout that lifecycle, the perception of criticality as a continuum rather than a binary state is more useful. All attributes and parameters should be evaluated in terms of their roles in the process and impact on the product or in-process material, and reevaluated as new information becomes available. The degree of control over those attributes or parameters should be commensurate with their risk to the 11 This concept is discussed in more detail in FDA s guidance for industry, Quality Systems Approach to Pharmaceutical Current Good Manufacturing Practice Regulations, available at 이개념은 FDA 가이드문서 " 품질시스템방식의제약 CGMP 규정 " 에보다자세히 설명되어있다 ( 19

20 process and process output. In other words, a higher degree of control is appropriate for attributes or parameters that pose a higher risk. The Agency recognizes that terminology usage can vary and expects that each manufacturer will communicate the meaning and intent of its terminology and categorization to the Agency. 이문서에서 " 특성요소 "( 예, 품질, 제품, 원료 ) 와 " 파라미터 "( 예, 공정, 운전, 설비 ) 라는용어는 " 중요도 " 측면에서카테고리를나누지않는다. 라이프사이클전체에걸쳐리스크기반의사결정방식을채택하여추진하는라이프사이클방식의공정밸리데이션에서, 중요도는이분법이아니라일련의연속체로보고접근하는것이보다유용하다. 모든특성요소와파라미터는공정에서의역할과제품또는공정중물품에미칠파급영향을고려하여평가해야하며, 새로운정보가확보됨에따라재평가를실시해야한다. 이러한특성요소나파라미터에대한관리의수준은공정자체와공정결과물에미칠리스크수준을감안하여정한다. 달리말하면, 리스크가더큰특성요소나파라미터에대해서는보다높은수준의관리가적절하다. 업체마다용어의의미가다를수있음을인정하며, 용어와분류체계의의미와취지를제조업체가 FDA에제시할필요가있다. Many products are single-source or involve complicated manufacturing processes. Homogeneity within a batch and consistency between batches are goals of process validation activities. Validation offers assurance that a process is reasonably protected against sources of variability that could affect production output, cause supply problems, and negatively affect public health. 많은제품이싱글소스이거나제조공정이복잡하다. 배치를구성하는제품의균질성과배치사이의일관성이공정밸리데이션활동의목적이다. 생산결과물에영향을주고공급문제를유발하며공중위생에부정적인영향을줄수있는변동발생원으로부터공정이합리적으로보호된다는보증을제공하는활동이밸리데이션이다. B. 1 단계 - 공정디자인 (Stage 1 Process Design) Process design is the activity of defining the commercial manufacturing process that will be reflected in planned master production and control records. The goal of this stage is to design a process suitable for routine commercial manufacturing that can consistently deliver a product that meets its quality attributes. 20

21 공정디자인은상업적제조공정을규정하는활동이며, 그결과물은마스터생산및관리 기록서에반영된다. 이단계의목적은품질특성기준에부합하는제품을일관되게생산할 수있는, 상업적정규제조에적합한공정을설계하는데있다. 1. 공정지식및이해의확보와축적 (Building and Capturing Process Knowledge and Understanding) Generally, early process design experiments do not need to be performed under the CGMP conditions required for drugs intended for commercial distribution that are manufactured during Stage 2 (process qualification) and Stage 3 (continued process verification). They should, however, be conducted in accordance with sound scientific methods and principles, including good documentation practices. This recommendation is consistent with ICH Q10 Pharmaceutical Quality System. 12 Decisions and justification of the controls should be sufficiently documented and internally reviewed to verify and preserve their value for use or adaptation later in the lifecycle of the process and product. 일반적으로초기의공정디자인실험은상업적유통대상의약품에대하여요구되는 CGMP 조건에서수행할필요는없다. 이런의약품은 2단계 ( 공정적격성평가 ) 와 3단계 ( 지속적공정베리피케이션 ) 에서제조된다. 하지만 GDP(good documentation practices) 를포함하여타당한과학적방법과원칙에의거하여실시해야한다. 이권고사항은 ICH Q10 " 제약품질시스템 " 에도부합한다. 관리대책의결정과그타당성에대한설명및근거를충분히문서화하고내부적으로검토하여, 해당제품과공정의이후라이프사이클단계에서사용하거나적용하는데어느정도가치가있는지확인한다. Although often performed at small-scale laboratories, most viral inactivation and impurity clearance studies cannot be considered early process design experiments. Viral and impurity clearance studies intended to evaluate and estimate product quality at commercial scale should have a level of quality unit oversight that will ensure that the studies follow sound scientific methods and principles and the conclusions are supported by the data. 실험실에서작은규모로실시하는경우가많지만, 대다수바이러스불활화및불순물 12 Available at ces/default.htm. 21

22 클리어런스연구는초기공정디자인실험으로볼수없다. 상업적규모에서의제품품질을평가하고추정하기위해실시하는바이러스및불순물클리어런스실험은품질조직의관리하에서실시하여, 타당한과학적방법과원칙에따라실험을수행하고데이터에의해뒷받침되는결론을도출할수있도록해야한다. Product development activities provide key inputs to the process design stage, such as the intended dosage form, the quality attributes, and a general manufacturing pathway. Process information available from product development activities can be leveraged in the process design stage. The functionality and limitations of commercial manufacturing equipment should be considered in the process design, as well as predicted contributions to variability posed by different component lots, production operators, environmental conditions, and measurement systems in the production setting. However, the full spectrum of input variability typical of commercial production is not generally known at this stage. Laboratory or pilotscale models designed to be representative of the commercial process can be used to estimate variability. 제품개발활동을통해공정디자인단계에필요한중요정보 ( 예, 제형, 품질특성요소, 일반적인제조경로 ) 가확보된다. 제품개발단계에서확보된공정정보를공정디자인단계에서활용할수있다. 상업적제조설비의기능과한계, 그리고생산상황에서의서로다른원료로트, 생산작업자, 환경조건, 측정시스템이변동성에기여하는부분도고려해야한다. 하지만상업적생산에서흔히발생하는모든종류의투입요소변동성 (input variability) 부분을이단계에서는다파악하기어렵다. 상업적공정을대표하도록설계된실험실또는파일럿규모모델을활용하여변동성부분을추정할수있다. Designing an efficient process with an effective process control approach is dependent on the process knowledge and understanding obtained. Design of Experiment (DOE) studies can help develop process knowledge by revealing relationships, including multivariate interactions, between the variable inputs (e.g., component characteristics 13 or process parameters) and the resulting outputs (e.g., 13 Component means any ingredient [raw material] intended for use in the manufacture of a drug product, including those that may not appear in such drug product ( 210.3(b)(3)). " 원료 (component)" 는의약품에존재하지않는것을포함하여, 의약품제조에 22

23 in-process material, intermediates, or the final product). Risk analysis tools can be used to screen potential variables for DOE studies to minimize the total number of experiments conducted while maximizing knowledge gained. The results of DOE studies can provide justification for establishing ranges of incoming component quality, equipment parameters, and in-process material quality attributes. FDA does not generally expect manufacturers to develop and test the process until it fails. 효과적인공정관리를갖춘효율적인공정을디자인하려면, 공정지식과이해가필요하다. DOE(Design of Experiment) 연구는각종투입변수 ( 예, 원료특성또는공정파라미터 ) 와산출물 ( 예, 공정중물품, 중간체, 최종제품 ) 사이의다변량상호작용을포함한관계를밝힘으로써공정지식을축적하는데도움이될수있다. 리스크분석도구를활용해 DOE 연구를위한변수들을선별하여, 전체실험횟수를최소화하면서최대한의지식을확보할수도있다. DOE 연구를통해입고원료품질, 설비파라미터, 공정중물품품질특성요소의범위설정에관한근거를확보할수있다. 문제가발생하는지점까지공정개발과테스트를실시해야한다고생각하지는않는다. Other activities, such as experiments or demonstrations at laboratory or pilot scale, also assist in evaluation of certain conditions and prediction of performance of the commercial process. These activities also provide information that can be used to model or simulate the commercial process. Computer-based or virtual simulations of certain unit operations or dynamics can provide process understanding and help avoid problems at commercial scale. It is important to understand the degree to which models represent the commercial process, including any differences that might exist, as this may have an impact on the relevance of information derived from the models. 실험실규모나파일럿규모에서실시하는실험이나증명등기타활동은특정조건을평가하고상업적공정의성능을예측하는데도움이된다. 또한이런활동을통해상업적공정의모델링이나시뮬레이션에활용할수있는정보가확보되기도한다. 특정단위작업이나역학의컴퓨터기반또는가상시뮬레이션은공정정보를확보하고상업적규모에서의문제점을방지하는데도움이된다. 존재가능한차이점을포함하여모델이상업적공정을어느정도대표하는지이해하는것이중요하다. 이런부분은모델에서도출한정보의유의미성에영향을줄수있기때문이다. It is essential that activities and studies resulting in process understanding be 사용되는모든성분 [raw material] 을의미한다 (21 CFR 210.3(b)(3)). 23

24 documented. Documentation should reflect the basis for decisions made about the process. For example, manufacturers should document the variables studied for a unit operation and the rationale for those variables identified as significant. This information is useful during the process qualification and continued process verification stages, including when the design is revised or the strategy for control is refined or changed. 공정이해와관련된활동과연구성과를문서화하는것이중요하다. 공정에대한의사결정의근거를반영하여문서화해야한다. 예를들어단위작업을대상으로연구한변수와특정변수를유의미하다고판단한근거를문서화해야한다. 이런정보는나중에공정디자인을변경하거나관리전략을변경또는구체화하는경우를포함하여, 공정적격성평가 (process qualification) 와지속적공정베리피케이션 (continued process verification) 단계에서큰도움이된다. 2. 공정관리전략의확립 (Establishing a Strategy for Process Control) Process knowledge and understanding is the basis for establishing an approach to process control for each unit operation and the process overall. Strategies for process control can be designed to reduce input variation, adjust for input variation during manufacturing (and so reduce its impact on the output), or combine both approaches. 공정지식과이해는단위작업과공정전체의공정관리전략을수립하기위한토대이다. 투입요소의변동을감소시키거나제조시에투입요소의변동에맞춰조정하거나 ( 그래서산출물에미치는영향을축소하고 ), 아니면이두가지방식을조합하는식으로공정관리전략을설계할수있다. Process controls address variability to assure quality of the product. Controls can consist of material analysis and equipment monitoring at significant processing points ( (c)). Decisions regarding the type and extent of process controls can be aided by earlier risk assessments, then enhanced and improved as process experience is gained. 제품품질을보장하기위하여변동성부분을대상으로공정관리를실시한다. 공정관리는주요공정포인트에서의설비모니터와물품분석으로구성될수있다 ( (c)). 앞서실시한 RA(risk assessment) 결과가공정관리의유형과범위를결정하는데도움이될수있다. 이후에공정경험이축적됨에따라공정관리전략을개선시킨다. 24

25 FDA expects controls to include both examination of material quality and equipment monitoring. Special attention to control the process through operational limits and in-process monitoring is essential in two possible scenarios: 설비모니터와물품품질의검사모두를포함하여관리전략을구비해야할것이다. 다음과같은 2가지상황에서는, 공정한도기준을정하고공정모니터를실시하여공정을관리하는것이특히중요하다. 1. When the product attribute is not readily measurable due to limitations of sampling or detectability (e.g., viral clearance or microbial contamination) or 검체채취또는검출능력의한계때문에 ( 예, 바이러스클리어런스, 미생물오염 ) 제품특성요소를용이하게측정할수없는경우. 2. When intermediates and products cannot be highly characterized and welldefined quality attributes cannot be identified. 중간체와제품의특성을충분하게분석할수없고품질특성요소를충분히파악할수없는경우 These controls are established in the master production and control records (see (a) and (b)(9)). 관리대책을확립하고마스터생산및관리기록서에포함시킨다 (21 CFR (a) and (b)(9)). More advanced strategies, which may involve the use of process analytical technology (PAT), can include timely analysis and control loops to adjust the processing conditions so that the output remains constant. Manufacturing systems of this type can provide a higher degree of process control than non-pat systems. In the case of a strategy using PAT, the approach to process qualification will differ from that used in other process designs. Further information on PAT processes can be found in FDA s guidance for industry on PAT A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance Available at ces/default.htm. Other references that may be useful include ASTM E

26 적시분석과관리루프를활용하여공정조건을조정함으로써산출물의항상성이유지되도록하는다른최신기법 ( 예, PAT(process analytical technology)) 도있다. 비- PAT 시스템에비하여이런종류의제조시스템은보다높은수준의공정관리가가능하다. PAT 전략을채택한경우의공정적격성평가 (process qualification) 방식은다른공정디자인과는다를수있다. PAT에관한자세한사항은 FDA 가이드문서 "PAT - 혁신적의약품개발, 제조, 품질보증프레임워크 " 를참조한다. The planned commercial production and control records, which contain the operational limits and overall strategy for process control, should be carried forward to the next stage for confirmation. 작업한도기준과전반적인공정관리전략을포함하는예정생산및관리기록서를다음확증단계로넘긴다. C. 2 단계 - 공정적격성평가 (Stage 2 Process Qualification) During the process qualification (PQ) stage of process validation, the process design is evaluated to determine if it is capable of reproducible commercial manufacture. This stage has two elements: (1) design of the facility and qualification of the equipment and utilities and (2) process performance qualification (PPQ). During Stage 2, CGMP-compliant procedures must be followed. Successful completion of Stage 2 is necessary before commercial distribution. 15 Products manufactured Standard Practice for Pharmaceutical Process Design Utilizing Process Analytical Technology and ASTM E Standard Guide for Risk Assessment and Risk Control as it Impacts the Design, Development, and Operation of PAT Processes for Pharmaceutical Manufacture. 출처 : ces/default.htm 이외에도 ASTM E "PAT를활용한제약공정디자인업무표준 " 과 ASTM E " 의약품제조를위한 PAT 프로세스의디자인, 개발, 운영과관련된 RA(Risk Assessment) 및 RC(Risk Control) 표준가이드 " 를참조한다. 15 As discussed in section III of this guidance, process validation (including process qualification) is legally enforceable under section 501(a)(2)(B) of the Act. FDA regulations require that process validation procedures be established 26

27 during this stage, if acceptable, can be released for distribution. 공정밸리데이션의공정적격성평가단계에서는공정디자인이재현성있는상업적제조능력을갖고있는지평가한다. 이단계는 (1) 시설디자인및설비와유틸리티의적격성평가와 (2) PPQ(process performance qualification) 등 2개요소로구성된다. 2단계에서는 CGMP에부합하는절차를준수해야하며, 상업적유통에앞서 2단계가성공적으로완료되어야한다. 이단계에서제조된제품이기준에부합한다면출하할수도있다. 1. 시설디자인및유틸리티와설비의적격성평가 (Design of a Facility and Qualification of Utilities and Equipment) Proper design of a manufacturing facility is required under part 211, subpart C, of the CGMP regulations on Buildings and Facilities. It is essential that activities performed to assure proper facility design and commissioning precede PPQ. Here, the term qualification refers to activities undertaken to demonstrate that utilities and equipment are suitable for their intended use and perform properly. These activities necessarily precede manufacturing products at the commercial scale. 21 CFR 파트 211 서브파트 C " 건물및시설 " 은제조시설의적절한디자인을요구한다. PPQ에앞서적절한시설디자인및커미셔닝을위한활동이있어야한다. 유틸리티와설비가목적용도에적합하며적절하게기능을수행한다는점을증명하기위한활동을이가이드문서에서는적격성평가 (qualification) 라고부른다. 상업적규모의제품제조에앞서이런활동을반드시수행해야한다. Qualification of utilities and equipment generally includes the following activities: 유틸리티와설비의적격성평가는일반적으로다음활동을포함한다. Selecting utilities and equipment construction materials, operating principles, and performance characteristics based on whether they are appropriate for and followed ( ) before a batch can be distributed ( and ). 이가이드문서의섹션 III에서설명한바와같이, 공정밸리데이션 ( 공정적격성평가 (process qualification) 포함 ) 은법섹션 501(a)(2)(B) 에의거하여법적으로강제되는것이다. FDA 규정에의하면배치의유통에앞서 (21 CFR and ) 공정밸리데이션절차를확립하고준수해야한다 (21 CFR ). 27

28 their specific uses. 특정용도에적절한지여부를바탕으로유틸리티와설비의제작재질, 운전원리, 성능특성선정. Verifying that utility systems and equipment are built and installed in compliance with the design specifications (e.g., built as designed with proper materials, capacity, and functions, and properly connected and calibrated). 디자인규격에따라유틸리티시스템과설비를제작하고설치했는지확인 ( 예, 설계한바에따라적절한재질, 용량, 기능을갖추도록제작되었고적절하게연결하고교정했는지 ). Verifying that utility systems and equipment operate in accordance with the process requirements in all anticipated operating ranges. This should include challenging the equipment or system functions while under load comparable to that expected during routine production. It should also include the performance of interventions, stoppage, and start-up as is expected during routine production. Operating ranges should be shown capable of being held as long as would be necessary during routine production. 유틸리티시스템과설비가모든예상운전범위에서공정요구기준에맞게작동되는지확인. 이때정규생산시에예상되는것과유사한수준의부하조건에서설비나시스템의기능을챌린지하여테스트한다. 또한예상되는개입조치, 중단, 가동상황도평가한다. 정규생산시에필요할것으로예상되는운전범위가유지됨이증명되어야한다. Qualification of utilities and equipment can be covered under individual plans or as part of an overall project plan. The plan should consider the requirements of use and can incorporate risk management to prioritize certain activities and to identify a level of effort in both the performance and documentation of qualification activities. The plan should identify the following items: 유틸리티와설비의적격성평가활동계획을개별계획서로정리하거나전체프로젝트계획서의일부로정리할수있다. 계획서를작성할때는사용기준을고려해야하며, 리스크관리요소를통합시켜여러활동의우선순위를정하고적격성평가활동수행과문서화의강도를결정할수있다. 다음사항을계획서에명기한다. 28

29 1. the studies or tests to use 수행할실험또는테스트 2. the criteria appropriate to assess outcomes, 성과물평가기준 3. the timing of qualification activities, 적격성평가활동일정 4. responsibilities of relevant departments and the quality unit, and 관련부서및품질조직의업무분장 5. the procedures for documenting and approving the qualification. 적격성평가활동의문서화및승인절차 The project plan should also include the firm s requirements for the evaluation of changes. Qualification activities should be documented and summarized in a report with conclusions that address criteria in the plan. The quality control unit must review and approve the qualification plan and report ( ). 또한변경사항평가에관한기준도포함시킨다. 적격성평가활동을문서화하고보고서로정리한다. 이때계획서에제시되었던기준과관련하여결론을도출한다. QCU(quality control unit) 가적격성평가계획서와보고서를검토하고승인한다 (21 CFR ). 2. PPQ(Process Performance Qualification) The process performance qualification (PPQ) is the second element of Stage 2, process qualification. The PPQ combines the actual facility, utilities, equipment (each now qualified), and the trained personnel with the commercial manufacturing process, control procedures, and components to produce commercial batches. A successful PPQ will confirm the process design and demonstrate that the commercial manufacturing process performs as expected. PPQ(process performance qualification) 는 2단계공정적격성평가의두번째요소이다. PPQ는실제시설, 유틸리티, 설비 ( 적격성평가를거친상태 ), 교육훈련을받은작업자와상업적제조공정, 관리절차, 원료를통합하여상업적배치를생산하는활동이다. 성공적인 PPQ를통해공정디자인이확증되고상업적제조공정이예상했던바에따른성능을발휘한다는점이증명된다. Success at this stage signals an important milestone in the product lifecycle. A 29

30 manufacturer must successfully complete PPQ before commencing commercial distribution of the drug product. 16 The decision to begin commercial distribution should be supported by data from commercial-scale batches. Data from laboratory and pilot studies can provide additional assurance that the commercial manufacturing process performs as expected. 이단계의성공은제품라이프사이클에있어서중요한마일스톤이다. 제조업체는의약품의상업적유통을개시하기전에 PPQ를성공적으로완료해야한다. 상업적유통의개시결정을위해서는상업적규모의배치를생산하고관련데이터를통해뒷받침되어야한다. 상업적제조공정이예상했던바의성능을발휘한다는추가적인보증을실험실과파일럿규모연구데이터가제공할수있다. The approach to PPQ should be based on sound science and the manufacturer s overall level of product and process understanding and demonstrable control. The cumulative data from all relevant studies (e.g., designed experiments; laboratory, pilot, and commercial batches) should be used to establish the manufacturing conditions in the PPQ. To understand the commercial process sufficiently, the manufacturer will need to consider the effects of scale. However, it is not typically necessary to explore the entire operating range at commercial scale if assurance can be provided by process design data. Previous credible experience with sufficiently similar products and processes can also be helpful. In addition, we strongly recommend firms employ objective measures (e.g., statistical metrics) wherever feasible and meaningful to achieve adequate assurance. PPQ 활동은타당한과학과제조업체의전반적인제품및공정이해와증명가능한관리수준을바탕으로실시한다. 모든관련연구 ( 예, DOE; 실험실규모, 파일럿규모, 상업적규모의배치 ) 를통해축적된데이터를활용하여 PPQ를위한제조조건을확립한다. 상업적공정의충분한이해를위해서는스케일의영향을고려할필요가있다. 하지만공정디자인데이터로보증할수있다면, 상업적규모의전체작업범위를연구할필요는없다. 충분히유사한제품과공정을통해확보한예전의신뢰성있는경험도도움이될수있다. 이외에도적절한보증을확보하는데의미가있고타당성이있다면, 객관적인측정 ( 예, 통계학적메트릭 ) 의실시를강력하게권고한다. 16 See section III of this guidance, Statutory and Regulatory Requirements for Process Validation. 이가이드문서의섹션 III " 공정밸리데이션관련법적기준 " 을참조한다. 30

31 In most cases, PPQ will have a higher level of sampling, additional testing, and greater scrutiny of process performance than would be typical of routine commercial production. The level of monitoring and testing should be sufficient to confirm uniform product quality throughout the batch. The increased level of scrutiny, testing, and sampling should continue through the process verification stage as appropriate, to establish levels and frequency of routine sampling and monitoring for the particular product and process. Considerations for the duration of the heightened sampling and monitoring period could include, but are not limited to, volume of production, process complexity, level of process understanding, and experience with similar products and processes. 대개 PPQ 활동을할때는상업적정규생산을할때보다검체채취수준을더높이고추가시험을실시하며공정성능을보다철저하게살펴보아야한다. 모니터및테스트수준은배치전체에걸쳐제품품질의균일성을확증하기에충분해야한다. 이와같은강화된조사, 테스트, 검체채취를공정베리피케이션단계까지계속적용하여, 특정제품및공정의정규검체채취및모니터수준과주기를확립한다. 생산량, 공정복잡성, 공정이해수준, 유사제품및공정경험을포함하되이에국한하지않고여러요소를고려하여, 검체채취및모니터수준을강화해수행할기간을정한다. The extent to which some materials, such as column resins or molecular filtration media, can be re-used without adversely affecting product quality can be assessed in relevant laboratory studies. The usable lifetimes of such materials should be confirmed by an ongoing PPQ protocol during commercial manufacture. 일부물품 ( 예, 칼럼레진, 분자여과매체 ) 의재사용정도 ( 제품품질에대한부정적영향없이 ) 는실험실규모의연구를통해평가할수있으며, 이들물품의가용기간도상업적제조를진행하며진행성 PPQ 프로토콜에의거하여확증한다. A manufacturing process that uses PAT may warrant a different PPQ approach. PAT processes are designed to measure in real time the attributes of an in-process material and then adjust the process in a timely control loop so the process maintains the desired quality of the output material. The process design stage and the process qualification stage should focus on the measurement system and control loop for the measured attribute. Regardless, the goal of validating any manufacturing process is the same: to establish scientific evidence that the process is reproducible and will consistently deliver quality products. PAT를활용하는제조공정은 PPQ를다른방식으로수행해야할수있다. PAT 공정은 31