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1 공정밸리데이션일반원칙에관한가이드라인 (Guideline on General Principles of Process Validation) MAY, 1987 Prepared by : Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research, and Center for Devices and Radiological Health Food and Drug Administration Maintained by : Division of Manufacturing and Product Quality (HFD-320) Office of Compliance Center for Drug Evaluation and Research Food and Drug Administration 5600 Fishers Lane Rockville, Maryland Reprinted February, 1993 by The Division of Field Investigations Office of Regional Operations Office of Regulatory Affairs U.S.Food and Drug Administration 1

2 [ 목차 ] I. 목적 (PURPOSE) II. 적용범위 (SCOPE) III. 서론 (INTRODUCTION) 용어정의 (Definitions) IV. 기본개념 (GENERAL CONCEPTS) V. 완제의약품 CGMP 기준 (CGMP REGULATIONS FOR FINISHED PHARMACEUTICALS) VI. 의료용구 GMP 기준 (GMP REGULATION FOR MEDICAL DEVICES) VII. 사전검토사항 (PRELIMINARY CONSIDERATIONS) VIII. 공정밸리데이션요소 (ELEMENTS OF PROCESS VALIDATION) A. 예측적밸리데이션 (Prospective Validation) 1. 설비및공정 (Equipment and Process) a. 설비 : 설치적격성평가 (Equipment: Installation Qualification) b. 공정 : 성능적격성평가 (Process: Performance Qualification) c. 제품 : 성능적격성평가 (Product: Performance Qualification) 2. 재밸리데이션을적시에실시하기위한시스템 (System to Assure Timely Revalidation) 3. 문서 (Documentation) B. 회고적공정밸리데이션 (Retrospective Process Validation) IX. 제품시험의인정 (ACCEPTABILITY OF PRODUCT TESTING) 2

3 I. 목적 (PURPOSE) This guideline outlines general principles that FDA considers to be acceptable elements of process validation for the preparation of human and animal drug products and medical devices. 이가이드라인은사람및동물용의약품과의료용구의제조공정밸리데이션과관련하여 FDA가인정하는기본원칙을제시한다. II. 적용범위 (SCOPE) This guideline is issued under Section (21 CFR 10.90) and is applicable to the manufacture of pharmaceuticals and medical devices. It states principles and practices of general applicability that are not legal requirements but are acceptable to the FDA. A person may rely upon this guideline with the assurance of its acceptability to FDA, or may follow different procedures. When different procedures are used, a person may, but is not required to, discuss the matter in advance with FDA to prevent the expenditure of money and effort on activities that may later be determined to be unacceptable. In short, this guideline lists principles and practices which are acceptable to the FDA for the process validation of drug products and medical devices; it does not list the principles and practices that must, in all instances, be used to comply with law. 이가이드라인은 21 CFR 10.90에의거하여발행되는것으로의약품및의료용구제조에적용된다. 이문서는일반적으로적용되는원칙과절차를기술하고있으며, 여기에기술된사항은법적기준은아니지만 FDA 가인정하는것이다. 이 가이드라인을준수하여 FDA의인정을받고자할수도있으며, 다른방법을채택할수도있다. 다른방법을채택하는경우에는강제적인것은아니지만, 사전에 FDA와협의할수가있는데, 이는이후에그방법이부적합한것으로결정될경우입게될시간적 금전적손실을방지하도록하기위함이다. 결국이가이드라인은의약품및의료용구의공정밸리데이션과관련하여 FDA가바람직하다고인정하는원칙과절차를열거하고있다. 그러나법적기준준수를위해모든경우에적용할수있는원칙과절차를제시하고있지는않다. This guideline may be amended from time to time. Interested persons are invited to submit comments on this document and any subsequent revisions. 3

4 Written comments should be submitted to the Dockets Management Branch (HFA-305), Food and Drug Administration, Room 4-62, 5600 Fishers Lane, Rockville, Maryland Received comments may be seen in that office between 9 a.m. and 4 p.m., Monday through Friday. 이가이드라인은수시로개정될수있다. 누구든지이문서와이후의개정판에대해의견을제출할수있다. ( 의견서제출처 : Dockets Management Branch (HFA- 305), Food and Drug Administration, Room 4-62, 5600 Fishers Lane, Rockville, Maryland 20857, U.S.A.). 접수된의견서는월요일부터금요일까지오전 9시부터오후 4시사이에열람할수있다. III. 서론 (INTRODUCTION) Process validation is a requirement of the Current Good Manufacturing Practices Regulations for Finished Pharmaceuticals, 21 CFR Parts 210 and 211, and of the Good Manufacturing Practice Regulations for Medical Devices, 21 CFR Part 820, and therefore, is applicable to the manufacture of pharmaceuticals and medical devices. Several firms have asked FDA for specific guidance on what FDA expects firms to do to assure compliance with the requirements for process validation. This guideline discusses process validation elements and concepts that are considered by FDA as acceptable parts of a validation program. 공정밸리데이션은 21 CFR 파트 210 및 211의완제의약품 CGMP 기준과 21 CFR 파트 820의의료용구 GMP 기준에따라실시해야하는것이므로, 의약품제조업체와의료용구제조업체모두에적용된다. 공정밸리데이션기준을준수하려면어떻게해야하며 FDA는업체가어떻게하기를기대하는지구체적으로문의한업체가많았다. 이에이가이드라인에서는바람직한밸리데이션프로그램이라고 FDA가생각하는공정밸리데이션요소와개념을다루고자한다. The constituents of validation presented in this document are not intended to be all-inclusive. FDA recognizes that, because of the great variety of medical products (drug products and medical devices), processes and manufacturing facilities, it is not possible to state in one document all of the specific validation elements that are applicable. Several broad concepts, however, have general applicability which manufacturers can use successfully as a guide in validating a manufacturing process. Although the 4

5 particular requirements of process validation will vary according to such factors as the nature of the medical product (e.g., sterile vs non-sterile) and the complexity of the process, the broad concepts stated in this document have general applicability and provide an acceptable framework for building a comprehensive approach to process validation. 이문서에제시된밸리데이션구성요소는모든것을포괄하지않는다. 의료관련제품 ( 의약품및의료용구 ), 공정및제조시설이너무나다양하기때문에, 모든경우에적용될수있는구체적인밸리데이션요소모두를하나의문서에서다루는것은불가능하다. 그러나보편적으로적용될수있는몇가지일반적인개념이제시되면, 제조업체는이를토대로하여제조공정밸리데이션을성공적으로수행할수있을것이다. 공정밸리데이션의구체적인기준은의약품의특성 ( 예, 무균제품또는비무균제품 ) 및공정의복잡성등의요소에따라상당히다양할수있으나, 이문서에서제시하는일반적인개념을보편적으로적용할수있으며, 공정밸리데이션수행을위한포괄적인접근방법을구축하는데있어서바람직한토대가될수있다. 용어정의 (Definitions) 설치적격성평가 (Installation qualification) - Establishing confidence that process equipment and ancillary systems are capable of consistently operating within established limits and tolerances. 공정설비및부대시스템이설정된기준과허용범위이내에서일관성있게작동될수있다는신뢰성을수립하는절차. 공정성능적격성평가 (Process performance qualification) - Establishing confidence that the process is effective and reproducible. 공정이효과적이며재현성이있다는신뢰성을수립하는절차. 제품성능적격성평가 (Product performance qualification) - Establishing confidence through appropriate testing that the finished product produced by a specified process meets all release requirements for functionality and safety. 특정공정에의해생산된최종제품이기능과안전성측면에서모든출하승인기준에부합한다는신뢰성을적절한시험을거쳐수립하는절차. 5

6 예측적밸리데이션 (Prospective validation) - Validation conducted prior to the distribution of either a new product, or product made under a revised manufacturing process, where the revisions may affect the product's characteristics. 신제품또는제품특성에영향을줄수있는변경된제조공정에의해제조된제품의출하에앞서실시되는밸리데이션. 회고적밸리데이션 (Retrospective validation) - Validation of a process for a product already in distribution based upon accumulated production, testing and control data. 축적된생산, 시험및관리데이터에근거하여이미유통중인제품에대해실시하는공정밸리데이션. 밸리데이션 (Validation) - Establishing documented evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its pre-determined specifications and quality attributes. 사전에설정된규격과품질특성에부합하는제품을특정공정이일관되게생산할것이라는점을상당한수준으로보증하는증거문서를확립하는절차. 밸리데이션프로토콜 (Validation protocol) - A written plan stating how validation will be conducted, including test parameters, product characteristics, production equipment, and decision points on what constitutes acceptable test results. 시험항목, 제품특성, 생산설비및시험결과의적합여부결정기준을포함하여밸리데이션실시방법을기술한계획문서. 최악의상황 (Worst case) - A set of conditions encompassing upper and lower processing limits and circumstances, including those within standard operating procedures, which pose the greatest chance of process or product failure when compared to ideal conditions. Such conditions do not necessarily induce product or process failure. 이상적인조건과비교했을때, 공정또는제품에문제가발생할가능성이가장큰상 / 하한공정기준및상황 (SOP 범위내에있는조건포함 ) 을포괄하는일련의조건. 그러한조건이반드시제품이나공정에문제를유발하지는않는다. IV. 기본개념 (GENERAL CONCEPTS) Assurance of product quality is derived from careful attention to a number of 6

7 factors including selection of quality parts and materials, adequate product and process design, control of the process, and in-process and end-product testing. Due to the complexity of today's medical products, routine endproduct testing alone often is not sufficient to assure product quality for several reasons. Some end-product tests have limited sensitivity 1. In some cases, destructive testing would be required to show that the manufacturing process was adequate, and in other situations end-product testing does not reveal all variations that may occur in the product that may impact on safety and effectiveness 2. The basic principles of quality assurance have as their goal the production of articles that are fit for their intended use. 제품품질보증을위해서는적합한품질의부품및재료의선정, 적절한제품및공정설계, 공정관리및공정중시험과최종제품시험을포함하여수많은요소를신중하게고려해야한다. 오늘날의약품이너무나복잡하기때문에, 일상적인최종제품시험만으로는여러가지이유때문에제품품질을보증하는데충분하지않다. 일부최종제품시험방법은민감도에있어서한계가있다. 때로는제조공정의적절성을제시하기위해파괴검사가필요하기도하며, 제품의안전성과유효성에영향을줄수있는제품상의모든편차를최종제품시험으로밝히지못할수도있다. 품질보증의기본원칙은목적용도에적합한물품생산을목표로하고있다. These principles may be stated as follows: 1 For example, USP XXI states: "No sampling plan for applying sterility tests to a specified proportion of discrete units selected from a sterilization load is capable of demonstrating with complete assurance that all of the untested units are in fact sterile." 일례로 USP XXI에는 멸균적재물에서일정부분만을선택하여무균시험을실시하 는검체채취방법으로는시험되지않은모든물품이실제로무균상태임을완벽하게 증명할수없다 고기재되어있다. 2 As an example, in one instance a visual inspection failed to detect a defective structural weld which resulted in the failure of an infant warmer. The defect could only have been detected by using destructive testing or expensive test equipment. 예를들어육안검사만으로구조적용접결함을찾아내지못한적이있으며, 그에따 라유아가온장치 (infant warmer) 에문제가발생하기도했다. 이런결함은파괴검 사법이나고가의시험장비를사용해야만찾아낼수있는것이었다. 7

8 기본원칙을다음과같이정리할수있다. (1) quality, safety, and effectiveness must be designed and built into the product; 품질, 안전성, 유효성개념을제품설계및제조과정에포함시켜야한다. (2) quality cannot be inspected or tested into the finished product; and 최종제품의품질은검사나시험만으로확보되지않는다. (3) each step of the manufacturing process must be controlled to maximize the probability that the finished product meets all quality and design specifications. 제조공정각단계를반드시관리하여최종제품이모든품질및설계규격에부합할가능성을극대화하여야한다. Process validation is a key element in assuring that these quality assurance goals are met. It is through careful design and validation of both the process and process controls that a manufacturer can establish a high degree of confidence that all manufactured units from successive lots will be acceptable. Successfully validating a process may reduce the dependence upon intensive in-process and finished product testing. It should be noted that in most all cases, end-product testing plays a major role in assuring that quality assurance goals are met; i.e., validation and end-product testing are not mutually exclusive. 공정밸리데이션은이러한품질보증목표를달성하는데있어서핵심요소이다. 제조업체가일련의모든제조로트가적합할것이라는점에대해상당한정도의신뢰성을수립하기위해서는공정과공정관리모두에대한세심한설계와밸리데이션이필요하다. 어떤공정을성공적으로밸리데이션하면집중적인공정중검사와최종제품시험에대한의존도를낮출수있다. 거의모든경우에있어서, 최종제품시험은품질보증목표를달성하는데중요한역할을한다는점에주목할필요가있다. 즉밸리데이션과최종제품시험은상호배타적인것이아니다. The FDA defines process validation as follows: Process validation is establishing documented evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its pre-determined specifications and quality characteristics. It is important that the manufacturer prepare a written validation protocol which specifies the procedures (and tests) to be conducted and the data to be collected. The 8

9 purpose for which data are collected must be clear, the data must reflect facts and be collected carefully and accurately. FDA는공정밸리데이션을다음과같이정의한다. 공정밸리데이션은사전에설정된규격과품질특성에부합하는제품을특정공정이일관성있게생산할것이라는점을상당한수준으로보증하는증거문서를확립하는절차이다. 제조업체는실시방법 ( 및시험방법 ) 과수집대상데이터를구체적으로명기한밸리데이션프로토콜을작성해야한다. 데이터수집의목적이분명해야하며이들데이터는사실을반영해야하고신중하고정확하게수집해야한다. The protocol should specify a sufficient number of replicate process runs to demonstrate reproducibility and provide an accurate measure of variability among successive runs. The test conditions for these runs should encompass upper and lower processing limits and circumstances, including those within standard operating procedures, which pose the greatest chance of process or product failure compared to ideal conditions; such conditions have become widely known as "worst case" conditions. (They are sometimes called "most appropriate challenge" conditions.) Validation documentation should include evidence of the suitability of materials and the performance and reliability of equipment and systems. 재현성을증명하고일련의공정가동과정에서나타나는편차를정확히측정할수있을정도로충분한공정반복횟수를밸리데이션프로토콜에지정해야한다. 이러한시험조건은이상적인조건과비교했을때공정또는제품에문제가발생할가능성이가장큰상 / 하한공정기준및상황 (SOP 범위내에있는조건포함 ) 이포괄되도록해야하는데, 이러한조건을일반적으로는 최악의상황 (worst case) 조건이라고한다. ( 가장적절한챌린지 조건이라고도한다.) 밸리데이션문서에는재료의적합성, 설비및시스템의성능과신뢰성에대한증거가포함되어야한다. Key process variables should be monitored and documented. Analysis of the data collected from monitoring will establish the variability of process parameters for individual runs and will establish whether or not the equipment and process controls are adequate to assure that product specifications are met. 핵심공정변수를모니터하여문서화해야한다. 모니터를통해획득한데이터를분석하여매운전상황마다공정변수의편차를파악하고, 또한설비및공정관리가규격에적합한제품생산에적절한지도밝혀야한다. 9

10 Finished product and in-process test data can be of value in process validation, particularly in those situations where quality attributes and variabilities can be readily measured. Where finished (or in-process) testing cannot adequately measure certain attributes, process validation should be derived primarily from qualification of each system used in production and from consideration of the interaction of the various systems. 최종제품과공정중시험데이터는공정밸리데이션에서유용한가치를지닐수있는데, 특히품질특성과편차를용이하게측정할수있는상황에서그렇다. 최종 ( 또는공정중 ) 시험으로는어떤품질특성을적절하게측정할수없는경우, 기본적으로생산에활용된각시스템의적격성평가와다양한시스템의상호관계에대한검토를통해공정밸리데이션을실시해야한다. V. 완제의약품 CGMP 기준 (CGMP REGULATIONS FOR FINISHED PHARMACEUTICALS) Process validation is required, in both general and specific terms, by the Current Good Manufacturing Practice Regulations for Finished Pharmaceuticals, 21 CFR Parts 210 and 211. Examples of such requirements are listed below for informational purposes, and are not all-inclusive. 21 CFR 파트 210 및 211의완제의약품 CGMP 기준은일반적이면서구체적인문구로공정밸리데이션의실시를요구하고있다. 참고로공정밸리데이션과관련된기준의예를일부정리하면다음과같다. A requirement for process validation is set forth in general terms in Section Written procedures; deviations -- which states, in part: "There 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." 공정밸리데이션기준은 Sec ( 절차문서 : 일탈 ) 에일반적인수준에서다음과같이제시되어있다. 의약품이목표로하거나보유하는것으로표시한확인, 함량, 품질및순도를확보하도록생산및공정관리에대한절차문서를구비해야한다." Several sections of the CGMP regulations state validation requirements in 10

11 more specific terms. Excerpts from some of these sections are: CGMP 기준가운데여러항목에서보다구체적으로밸리데이션기준을언급하고 있다. 이가운데일부를골라보면다음과같다. Section , Sampling and testing of in-process materials and drug products. (a) "...control procedures shall be established to monitor the output and 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) Sec 공정중물품및의약품의검체채취와시험. (a)... 공정중물품및의약품의특성을변화시킬수있는제조공정작업을밸리데이션하고결과 ( 아웃풋 ) 를모니터하기위한관리절차를확립해야한다. Section , Control of Microbiological Contamination. (b) "Appropriate written procedures, designed to prevent microbiological contamination of drug products purporting to be sterile, shall be established and followed. Such procedures shall include VALIDATION of any sterilization process." (emphasis added) Sec 미생물오염관리 (b) 무균의약품의미생물오염방지를위해적절한절차문서를확립하고이를준수해야한다. 이절차에는멸균공정의밸리데이션사항이포함되어야한다. VI. 의료용구 GMP 기준 (GMP REGULATION FOR MEDICAL DEVICES) Process validation is required by the medical device GMP Regulations, 21 CFR Part 820. Section requires every finished device manufacturer to: "...prepare and implement a quality assurance program that is appropriate to the specific device manufactured...". Section 820.3(n) defines quality assurance as: "...all activities necessary to verify confidence in the quality of the process used to manufacture a finished device." 공정밸리데이션의필요성이의료용구 GMP 기준인 21 CFR 파트 820에규정되어있다. Sec.820.5은모든완제의료용구제조업체가 특정의료용구제조에적절한품질보증프로그램을수립하여구축 해야한다고규정하고있다. 또한 Sec.820.3(n) 에서는품질보증을 완제의료용구제조공정의품질에대한 11

12 신뢰도를입증하는데필요한모든행위 로정의하고있다. When applicable to a specific process, process validation is an essential element in establishing confidence that a process will consistently produce a product meeting the designed quality characteristics. A generally stated requirement for process validation is contained in section : "Written manufacturing specifications and processing procedures shall be established, implemented, and controlled to assure that the device conforms to its original design or any approved changes in that design." 공정밸리데이션은어떤공정이설계품질특성에부합하는제품을일관되게생산할수있다는신뢰성을확립하는데있어서필수적인요소이다. 공정밸리데이션의일반기준이섹션 에다음과같이규정되어있다. 의료용구가원래의설계또는그설계에근거한모든승인받은변경사항에부합하도록하기위해, 제조규격문서및공정절차문서를확립하고그에따라수행하고관리해야한다. Validation is an essential element in the establishment and implementation of a process procedure, as well as in determining what process controls are required in order to assure conformance to specifications. 밸리데이션은공정절차의확립과수행및규격에부합하도록하기위해어떤공정관리가필요한지결정하는데있어서필수적인요소이다. Section (a) (1) states: "...control measures shall be established to assure that the design basis for the device, components and packaging is correctly translated into approved specifications." 섹션 (a)(1) 은 의료용구, 구성요소및포장에대한설계개념이정확하게승인된규격문서로구현될수있게하기위한관리방법이확립되어야한다 고규정하고있다. Validation is an essential control for assuring that the specifications for the device and manufacturing process are adequate to produce a device that will conform to the approved design characteristics. 의료용구및제조공정규격이승인된설계특성에부합하는의료용구생산에적합하도록하는데있어서, 밸리데이션은필수적인관리요소이다. 12

13 VII. 사전검토사항 (PRELIMINARY CONSIDERATIONS) A manufacturer should evaluate all factors that affect product quality when designing and undertaking a process validation study. These factors may vary considerably among different products and manufacturing technologies and could include, for example, component specifications, air and water handling systems, environmental controls, equipment functions, and process control operations. No single approach to process validation will be appropriate and complete in all cases; however, the following quality activities should be undertaken in most situations. 공정밸리데이션을설계하고수행할때는제품품질에영향을주는모든요소를평가해야한다. 이러한요소는제품종류및제조기술에따라상당히다양할수있으며, 예를들어원자재규격, 공기및용수처리시스템, 환경관리, 설비기능, 및공정관리작업등이포함될수있다. 공정밸리데이션을실시하는데있어서모든경우에적용할수있는적절하고완벽한한가지방법은없다. 그러나대부분의경우에다음의품질활동을실시해야한다. During the research and development (R&D) phase, the desired product should be carefully defined in terms of its characteristics, such as physical, chemical, electrical and performance characteristics 3. It is important to 3 For example, in the case of a compressed tablet, physical characteristics would include size, weight, hardness, and freedom from defects, such as capping and splitting. Chemical characteristics would include quantitative formulation/potency; performance characteristics may include bioavailability (reflected by disintegration and dissolution). In the case of blood tubing, physical attributes would include internal and external diameters, length and color. Chemical characteristics would include raw material formulation. Mechanical properties would include hardness and tensile strength; performance characteristics would include biocompatibility and durability. 일례로압축정제의경우에물리적특성에는크기, 무게, 경도, 외관불량 (capping 및 splitting 등 ) 이포함될수있다. 화학적특성에는정량적특성 / 역가등이포함될수있으며, 성능특성에는생체이용률이포함될수있다 ( 붕해도와용출 ). 혈액튜브의경우에물리적특성으로는내경과외경, 길이및색상이있다. 화학적특성에는원료물질조성이포함된다. 기계적특성에는경도와신장강도가있으며, 성능특성에는생 13

14 translate the product characteristics into specifications as a basis for description and control of the product. 연구개발단계에서물리적, 화학적, 전기적, 성능특성등해당제품의바람직한특성을신중하게규정해야한다. 제품특성을제품설명과관리의기준이되는규격으로나타내는것이중요하다. Documentation of changes made during development provide traceability which can later be used to pinpoint solutions to future problems. 개발과정중에발생한변경사항을문서화하면, 이를참조하여이후에발생하게될문제점에대한해결책을정확하게찾아내는데도움이된다. The product's end use should be a determining factor in the development of product (and component) characteristics and specifications. All pertinent aspects of the product which impact on safety and effectiveness should be considered. These aspects include performance, reliability and stability. Acceptable ranges or limits should be established for each characteristic to set up allowable variations 4. These ranges should be expressed in readily measurable terms. 제품 ( 및구성요소 ) 의특성과규격을개발하는데있어서제품의최종용도가결정적인요소이다. 안전성과유효성에영향을주는제품의모든관련측면을검토해야한다. 이러한것으로는성능, 신뢰성및안정성등이있다. 허용편차 (allowable variation) 설정을위해각각의특성별로허용범위또는기준을정해야한다. 이러한허용범위는용이하게측정할수있는방식으로표현되어야 체적합성과내구성이있다. 4 For example, in order to assure that an oral, ophthalmic, or parenteral solution has an acceptable ph, a specification may be established by which a lot is released only if it has been shown to have a ph within a narrow established range. For a device, a specification for the electrical resistance of a pacemaker lead would be established so that the lead would be acceptable only if the resistance was within a specified range. 예를들어경구용액제, 안약또는주사제의허용 ph를보증하기위하여, 좁은범위 의 ph 기준에드는경우에만로트를출하하도록규격을정할수있다. 의료용구의경 우에도페이스메이커리드의전기저항값이특정범위이내인경우에만적합하다고 판정할수있도록규격을정할수있다. 14

15 한다. The validity of acceptance specifications should be verified through testing and challenge of the product on a sound scientific basis during the initial development and production phase. Once a specification is demonstrated as acceptable it is important that any changes to the specification be made in accordance with documented change control procedures. 초기개발및생산단계에서과학적으로타당한근거에의거해제품에대한시험과챌린지를실시하여허용규격의유효성을확인해야한다. 일단규격이적합한것으로증명되면, 규격에대한일체의변경은문서화된변경관리절차에의거하여이루어지도록하는것이중요하다. VIII. 공정밸리데이션요소 (ELEMENTS OF PROCESS VALIDATION) A. 예측적밸리데이션 (Prospective Validation) Prospective validation includes those considerations that should be made before an entirely new product is introduced by a firm or when there is a change in the manufacturing process which may affect the product's characteristics, such as uniformity and identity. The following are considered as key elements of prospective validation. 예측적밸리데이션은완전히새로운제품을도입하거나균일성과확인같은제품특성에영향을줄수있는제조공정상의변경이발생한경우에실시하며, 이때예측적밸리데이션의핵심요소는다음과같다. 1. 설비및공정 (Equipment and Process) The equipment and process(es) should be designed and/or selected so that product specifications are consistently achieved. This should be done with the participation of all appropriate groups that are concerned with assuring a quality product, e.g., engineering design, production operations, and quality assurance personnel. 설비및공정은제품규격을항상맞출수있도록설계및 / 또는선정해야한다. 이를위해제품품질보증에관련된모든그룹, 예를들어엔지니어링설계, 생산작업및품질보증작업자등이참여해야한다. 15

16 a. 설비 : 설치적격성평가 (Equipment: Installation Qualification) Installation qualification studies establish confidence that the process equipment and ancillary systems are capable of consistently operating within established limits and tolerances. After process equipment is designed or selected, it should be evaluated and tested to verify that it is capable of operating satisfactorily within the operating limits required by the process 5. 설치적격성평가는공정설비및부대시스템이설정된기준과허용범위이내에서일관성있게작동될수있다는신뢰성을확립하는절차이다. 공정설비를설계하거나선정한이후, 그설비가공정에서요구되는운전기준이내에서만족스럽게작동된다는점을평가하고시험하여입증해야한다. This phase of validation includes examination of equipment design; determination of calibration, maintenance, and adjustment requirements; and identifying critical equipment features that could affect the process and product. Information obtained from these studies should be used to establish written procedures covering equipment calibration, maintenance, monitoring, and control. 이단계에서실시하는평가항목으로는설비설계에대한점검, 교정 유지관리 조정기준의결정, 공정과제품에영향을줄수있는주요설비특징의파악이있다. 이단계에서확보한정보를활용하여설비교정, 유지관리, 모니터, 관리를포괄하는절차문서를확립해야한다. 5 Examples of equipment performance characteristics which may be measured include temperature and pressure of injection molding machines, uniformity of speed for mixers, temperature, speed and pressure for packaging machines, and temperature and pressure of sterilization chambers. 측정가능한설비성능특성의예로는주사기성형기계의온도와압력, 혼합기의속 도균일성, 포장기계의온도, 속도, 압력, 그리고멸균챔버의온도와압력이있다. 16

17 In assessing the suitability of a given piece of equipment, it is usually insufficient to rely solely upon the representations of the equipment supplier, or upon experience in producing some other product 6. Sound theoretical and practical engineering principles 6 The importance of assessing equipment suitability based upon how it will be used to attain desired product attributes is illustrated in the case of deionizers used to produce Purified Water, USP. In one case, a firm used such water to make a topical drug product solution which, in view of its intended use, should have been free from objectionable microorganisms. However, the product was found to be contaminated with a pathogenic microorganism. The apparent cause of the problem was failure to assess the performance of the deionizer from a microbiological standpoint. USP 정제수생산용탈이온화기의경우에설비의적합성을평가할때바람직한제품 특성의달성을기준으로접근하는것이얼마나중요한지분명하게알수있다. 어떤제조업체는목적용도의관점에서보았을때특정미생물이없어야만하는국소액제의약품제조에정제수를사용한적이있다. 그러나이제품은병원성미생물에오염된것으로밝혀졌다. 이러한문제가발생한이유는미생물학적관점에서탈이온화기의성능을평가하지못했기때문이었다. It is fairly well recognized that the deionizers are prone to build-up of microorganisms -- especially if the flow rates are low and the deionizers are not recharged and sanitized at suitable intervals. Therefore, these factors should have been considered. In this case, however, the firm relied upon the representations of the equipment itself, namely the "recharge" (i.e., conductivity) indicator, to signal the time for regeneration and cleaning. Considering the desired product characteristics, the firm should have determined the need for such procedures based upon pre-use testing, taking into account such factors as the length of time the equipment could produce deionized water of acceptable quality, flow rate, temperature, raw water quality, frequency of use, and surface area of deionizing resins. 탈이온화기는미생물이축적되기쉬운것으로인식되고있으며, 특히유속이낮고탈이온화기를적절한주기로재생및소독되지않는경우에그러하다. 그러므로이들요소를고려했어야했다. 하지만이경우에그회사는설비그자체의표시사항, 즉 재생 지시기 ( 전도도 ) 에만의존하여재생및세척의시기를정했다. 바람직한제품특성을고려하여, 해당설비가적합한품질의탈이온화수를생산할수있는기간, 유 17

18 and considerations are a first step in the assessment. 특정설비의적합성을평가하는데있어서, 일반적으로설비납품업체의주장이나다른제품생산경험에만의존하는것은충분하지않다. 타당한이론적 / 실제적인엔지니어링원칙과검토가평가의첫단계이다. It is important that equipment qualification simulate actual production conditions, including those which are "worst case" situations. Tests and challenges should be repeated a sufficient number of times to assure reliable and meaningful results. All acceptance criteria must be met during the test or challenge. If any test or challenge shows that the equipment does not perform within its specifications, an evaluation should be performed to identify the cause of the failure. 설비적격성평가를할때는실제생산조건을모의하는것이중요한데, 이때 최악의경우 도포함시킨다. 시험결과의신뢰성과유의미성을확보하기위해서는시험과챌린지를충분히반복해서실시해야한다. 시험이나챌린지시에는모든허용기준에부합해야한다. 만약어떤시험이나챌린지에서설비가규격이내에서작동하지않는것으로나오는경우, 그러한문제점의원인을밝히기위한평가작업을실시해야한다. Corrections should be made and additional test runs performed, as needed, to verify that the equipment performs within specifications. The observed variability of the equipment between and within runs can be used as a basis for determining the total number of trials selected for the subsequent performance qualification studies of the process 7. Once the equipment 속, 온도, 원수품질, 사용빈도, 탈이온수지의표면적등의요소를감안해, 사용전 시험결과에근거하여그러한절차의필요성을정했어야했다. 7 For example, the AAMI Guideline for Industrial Ethylene Oxide Sterilization of Medical Devices approved 2 December 1981, states: "The performance qualification should include a minimum of 3 successful, planned qualification runs, in which all of the acceptance criteria are met...( ) 예를들어 1981년 12월 2일자 AAMI의 "EO 가스를이용한의료용구의멸균가이드 18

19 configuration and performance characteristics are established and qualified, they should be documented. 보완조치를취한다음에설비가규격이내에서작동한다는점을입증하기위해필요에따라추가시험가동을실시한다. 시험가동중및시험가동사이에관찰된설비의변화상황을검토하여, 이후그공정에대한성능적격성평가에서시험을몇번실시할지정할수있다. 일단설비구성과성능특성이확립되고그에대한적격성평가가완료되면, 그사항을문서화한다. The installation qualification should include a review of pertinent maintenance procedures, repair parts lists, and calibration methods for each piece of equipment. The objective is to assure that all repairs can be performed in such a way that will not affect the characteristics of material processed after the repair. In addition, special post-repair cleaning and calibration requirements should be developed to prevent inadvertent manufacture of nonconforming product. Planning during the qualification phase can prevent confusion during emergency repairs which could lead to use of the wrong replacement part. 설치적격성평가에는설비별로적절한유지관리절차, 수리부품목록및교정방법등에대한검토도포함되어야한다. 이는수리작업이후에처리된물품의특성이영향을받지않는방식으로수리작업이이루어지도록하기위함이다. 이외에도부적합제품이제조될가능성을예방하기위해, 수리작업이후의특별세척및교정기준을개발해야한다. 적격성평가단계에서이와같은검토 / 기획작업을하게되면, 긴급상황에서수리작업을실시할때잘못된부품을사용하여수리하는경우를예방할수있다. b. 공정 : 성능적격성평가 (Process: Performance Qualification) The purpose of performance qualification is to provide rigorous testing to demonstrate the effectiveness and reproducibility of the 라인 " 에는 성능적격성평가는최소 3 회의적격성평가시험을계획하고실시하여성공 해야하며, 이때모든허용기준에부합해야한다.. ( ) 고규정되어있다. 19

20 process. In entering the performance qualification phase of validation, it is understood that the process specifications have been established and essentially proven acceptable through laboratory or other trial methods and that the equipment has been judged acceptable on the basis of suitable installation studies. 성능적격성평가의목적은엄격한시험을통해해당공정의유효성과재현성을증명하는것이다. 성능적격성평가를시작하기에앞서, 해당공정의규격이설정되고특히시험방법이나기타실험방법을통해적합한것으로증명되어있어야하며, 해당설비가적합한설치시험을통해적합한것으로판정이되어있어야한다. Each process should be defined and described with sufficient specificity so that employees understand what is required. Parts of the process which may vary so as to affect important product quality should be challenged 8. In challenging a process to assess its adequacy, it is important that challenge conditions simulate those that will be encountered during actual production, including "worst case" conditions. The challenges should be repeated 8 For example, in electroplating the metal case of an implantable pacemaker, the significant process steps to define, describe, and challenge include establishment and control of current density and temperature values for assuring adequate composition of electrolyte and for assuring cleanliness of the metal to be plated. In the production of parenteral solutions by aseptic filling, the significant aseptic filling process steps to define and challenge should include the sterilization and depyrogenation of containers/closures, sterilization of solutions, filling equipment and product contact surfaces, and the filling and closing of containers. 예를들어이식용페이스메이커의금속케이스를전기도금할때, 도금대상금속의 청결성보증과전해질의적정조성보증을위한전류밀도와온도값의설정과관리는중요한공정단계로서자세하게규정하고설명하고챌린지시험을해야한다. 무균충전에의한주사제의생산에서는용기 / 마개의멸균과발열성물질제거공정, 약액과충전설비및제품접촉표면의멸균, 충전과용기의밀봉등이자세하게규정하고챌린지시험을해야하는중요한무균충전공정단계에해당된다. 20

21 enough times to assure that the results are meaningful and consistent. Each specific manufacturing process should be appropriately qualified and validated. There is an inherent danger in relying on what are perceived to be similarities between products, processes, and equipment without appropriate challenge 9. 작업자가무엇을해야하는지이해할수있을정도로충분히구체적으로각공정을규정하고기술해야한다. 중요제품품질에영향을줄수있을정도의변화가예상되는공정부분에대해서는챌린지시험을실시해야한다. 어떤공정의적절성을평가하기위한챌린지시험을실시할때, 실제생산과정에서나타날수있는모든조건을모의해야하며, 이때 최악의경우 조건도포함한다. 시험결과가유의미하며 9 For example, in the production of a compressed tablet, a firm may switch from one type of granulation blender to another with the erroneous assumption that both types have similar performance characteristics, and, therefore, granulation mixing times and procedures need not be altered. However, if the blenders are substantially different, use of the new blender with procedures used for the previous blender may result in a granulation with poor content uniformity. This, in turn, may lead to tablets having significantly differing potencies. This situation may be averted if the quality assurance system detects the equipment change' in the first place, challenges the blender performance, precipitates a revalidation of the process, and initiates appropriate changes. In this example, revalidation comprises installation qualification of the new equipment and performance qualification of the process intended for use in the new blender. 예를들어압축정제생산시에과립혼합기를다른종류로교체하면서, 이두종류 의혼합기가유사한성능특성을갖고있으므로, 과립혼합시간과절차를변경할필요가없을것이라고생각할수있다. 그러나혼합기가본질적으로다른경우에는이전혼합기에적용했던절차에따라새로운혼합기를사용하면과립균질성에문제가생길수있다. 또한역가차이가크게나는제품이만들어질수있다. 품질보증시스템이설비의변경을감지하고혼합기의성능을시험한다음에해당공정을재밸리데이션하도록하여적절한변경이이루어지게하면, 이런상황을막을수있다. 이예에서재밸리데이션은신규설비의설치적격성평가와신규혼합기를이용한생산공정의성능적격성평가를포괄한다. 21

22 일관성을유지하도록하기위해챌린지시험을충분히반복해야한다. 특정제조공정의적격성평가와밸리데이션을적절하게수행해야한다. 제품, 공정및설비사이의유사성만보고적절한챌린지시험을하지않는것은위험하다. c. 제품 : 성능적격성평가 (Product: Performance Qualification) For purposes of this guideline, product performance qualification activities apply only to medical devices. These steps should be viewed as pre-production quality assurance activities. Before reaching the conclusion that a process has been successfully validated, it is necessary to demonstrate that the specified process has not adversely affected the finished product. Where possible, product performance qualification testing should include performance testing under conditions that simulate actual use. 이가이드라인에서제품성능적격성평가는의료용구에만적용된다. 제품의성능적격성평가는 생산전품질보증행위 로보아야한다. 어떤공정이성공적으로밸리데이션되었다는결론을내리기에앞서, 그공정이완제품에부정적인영향을주지않았다는점을증명할필요가있다. 가능하면제품성능적격성평가에는실제조건을모방한상황에서의성능시험이포함되어야한다. Product performance qualification testing should be conducted using product manufactured from the same type of production equipment, methods and procedures that will be used for routine production. Otherwise, the qualified product may not be representative of production units and cannot be used as evidence that the manufacturing process will produce a product that meets the pre-determined specifications and quality attributes 10. After actual production units have successfully 10 For example, a manufacturer of heart valves received complaints that the valve-support structure was fracturing under use. Investigation by the manufacturer revealed that all material and dimensional specifications had been met but the production machining process created microscopic scratches 22

23 passed product performance qualification, a formal technical review should be conducted and should include: 제품성능적격성평가시험은실제생산에사용될것과동일한종류의생산설비, 방법및절차에따라제조된제품을대상으로실시해야한다. 그렇지않으면적합한것으로판정된제품이라도실제생산제품을대표하지못할수가있으며, 그제조공정에서사전에설정된규격과품질특성에부합하는제품이생산될것이라는근거로채택될수도없다. 실제생산제품이제품성능적격성평가에서적합한것으로판정되면, 다음사항을포함하여공식적인기술검토를실시한다. Comparison of the approved product specifications and the actual qualified product. 승인된제품규격과실제적격성평가대상제품의비교 on the valve supporting wireform. These scratches caused metal fatigue and subsequent fracture. Comprehensive fatigue testing of production units under simulated use conditions could have detected the process deficiency. In another example, a manufacturer recalled insulin syringes because of complaints that the needles were clogged. Investigation revealed that the needles were clogged by silicone oil which was employed as a lubricant during manufacturing. Investigation further revealed that the method used to extract the silicone oil was only partially effective. Although visual inspection of the syringes seemed to support that the cleaning method was effective, actual use proved otherwise. 예를들어어떤심장밸브제조업체가밸브-서포트구조물이사용중에부러진다는불만을접수한적이있다. 이에대해조사를실시한결과, 모든물질적및치수상의규격에는부합하였으나생산머시닝공정에서밸브서포팅와이어폼에미세한흠이발생했다는점이밝혀졌다. 이러한흠에의해금속이피로해지고그에따라부러지는현상이나타난것이다. 모의사용조건에서생산제품에대한광범위한피로시험을실시했다면, 공정에문제가있다는사실이밝혀졌을것이다. 또한어떤제조업체는주사바늘이막힌다는불만을접수하고인슐린주사기를리콜한적이있다. 제조과정에서윤활유로사용했던실리콘오일에의해바늘이막히는것으로밝혀졌다. 또한실리콘오일추출방법에도문제가있었던것으로나타났다. 주사기에대한육안검사로는세척방법이효과적인것처럼보이겠지만, 실제사용과정에서는그렇지않다는것이증명된예이다. 23

24 Determination of the validity of test methods used to determine compliance with the approved specifications. 승인규격에부합하는지여부를결정하는데사용된시험방법의유효성에대한평가 Determination of the adequacy of the specification change control program. 규격변경관리프로그램의적절성에대한평가 2. 재밸리데이션을적시에실시하기위한시스템 (System to Assure Timely Revalidation) There should be a quality assurance system in place which requires revalidation whenever there are changes in packaging, formulation, equipment, or processes which could impact on product effectiveness or product characteristics, and whenever there are changes in product characteristics. Furthermore, when a change is made in raw material supplier, the manufacturer should consider subtle, potentially adverse differences in the raw material characteristics. A determination of adverse differences in raw material indicates a need to revalidate the process. 제품의유효성이나제품특성에영향을줄수있는포장, 조제, 설비또는공정에변경이발생한경우, 그리고제품특성에변경이발생한때는언제든지재밸리데이션의실시를요구하는품질보증시스템이구비되어있어야한다. 또한원료납품업체가변경되는경우, 제조업체는그러한변경으로인해원료의특성이조금이나마차이가나는지, 부정적인영향을미칠가능성은없는지검토해야한다. 원료물질에바람직하지않은차이가있음이확인되면, 그공정을재밸리데이션할필요가있다는의미가된다. One way of detecting the kind of changes that should initiate revalidation is the use of tests and methods of analysis which are capable of measuring characteristics which may vary. Such tests and methods usually yield specific results which go beyond the mere pass/fail basis, thereby detecting variations within product and process specifications and allowing determination of whether a process is slipping out of control. The quality assurance procedures should 24

25 establish the circumstances under which revalidation is required. 재밸리데이션을실시해야하는그러한종류의변경을밝히는방법중의하나는변화할지모를특성을측정할수있는분석방법과시험을실시하는것이다. 그러한시험과분석을통해단순한적 / 부이상의구체적인결과를얻고, 이결과를바탕으로제품과공정규격의변화를추적하고어떤공정이관리의범위를넘어서는지확인할수있다. 재밸리데이션이필요한상황을규정한품질보증절차가구비되어있어야한다. These may be based upon equipment, process, and product performance observed during the initial validation challenge studies. It is desirable to designate individuals who have the responsibility to review product, process, equipment and personnel changes to determine if and when revalidation is warranted. The extent of revalidation will depend upon the nature of the changes and how they impact upon different aspects of production that had previously been validated. It may not be necessary to revalidate a process from scratch merely because a given circumstance has changed. However, it is important to carefully assess the nature of the change to determine potential ripple effects and what needs to be considered as part of revalidation. 이러한품질보증절차는초기밸리데이션챌린지시험과정에서확인된설비, 공정, 제품성능에근거하여정할수있다. 제품, 공정, 설비및작업자의변경을검토하여재밸리데이션이필요한지, 필요하다면언제해야하는지결정하는담당자를지정해두는것이바람직하다. 재밸리데이션의규모는변경의내용과이러한변경이이미밸리데이션된공정에어떤영향을미치는지에따라달라진다. 단순히어떤상황이변했기때문에공정을 처음부터재밸리데이션 할필요는없다. 그러나변경내용을신중하게 평가하여가능한파급효과와재밸리데이션을실시할때어떠한점을 고려해야하는지결정해야한다. 3. 문서 (Documentation) It is essential that the validation program is documented and that the documentation is properly maintained. Approval and release of the process for use in routine manufacturing should be based upon a 25

26 review of all the validation documentation, including data from the equipment qualification, process performance qualification, and product/package testing to ensure compatibility with the process. For routine production, it is important to adequately record process details (e.g., time, temperature, equipment used) and to record any changes which have occurred. A maintenance log can be useful in performing failure investigations concerning a specific manufacturing lot. Validation data (along with specific test data) may also determine expected variance in product or equipment characteristics. 밸리데이션프로그램을문서화하고이문서를적절하게유지하는것이중요하다. 제조공정에대한승인은모든밸리데이션문서에대한검토결과에의해이루어져야하는데, 여기에는설비적격성평가, 공정성능적격성평가및제품 / 포장재료가해당공정과조화를이루는지확인하는시험을통해얻은데이터가포함된다. 실제생산업무중에는공정세부사항 ( 시간, 온도, 사용설비등 ) 을적절히기록하고발생한모든변경사항을기록하는것이중요하다. 특정제조로트와관련된문제점을조사할때, 유지관리일지가유용할수있다. 밸리데이션데이터 ( 특정시험데이터와함께 ) 를통해제품또는설비특성에있어서예상가능한변화를파악할수있다. B. 회고적공정밸리데이션 (Retrospective Process Validation) In some cases a product may have been on the market without sufficient premarket process validation. In these cases, it may be possible to validate, in some measure, the adequacy of the process by examination of accumulated test data on the product and records of the manufacturing procedures used. 때로는충분한공정밸리데이션을실시하지않은상태로제품이판매되고있는수가있다. 이런경우에는그제품에대해축적된시험데이터와제조작업기록을검토하여공정의적절성을어느정도밸리데이션할수가있다. Retrospective validation can also be useful to augment initial premarket prospective validation for new products or changed processes. In such cases, preliminary prospective validation should have been sufficient to warrant product marketing. As additional data is gathered on production lots, such data can be used to build confidence in the adequacy of the process. 26

27 Conversely, such data may indicate a declining confidence in the process and a commensurate need for corrective changes. Test data may be useful only if the methods and results are adequately specific. 회고적밸리데이션은또한신제품이나변경된공정에대해실시한출시전예측적밸리데이션을보충하는의미로활용할수도있다. 그런경우에는이미실시한예측적밸리데이션이제품판매를보증하기에충분한것이었어야한다. 생산로트에대한추가데이터가확보되면서, 그런데이터를활용하여해당공정의적절성에대한신뢰도를높일수있다. 반대로공정의신뢰도가떨어지는것으로나타나, 그에상응하는보완조치를취해야하는경우도있다. 시험데이터는그방법과결과가적절하고구체적인경우에만유용하다. As with prospective validation, it may be insufficient to assess the process solely on the basis of lot by lot conformance to specifications if test results are merely expressed in terms of pass/fail. Specific results, on the other hand, can be statistically analyzed and a determination can be made of what variance in data can be expected. It is important to maintain records which describe the operating characteristics of the process, e.g., time, temperature, humidity, and equipment settings 11. Whenever test data are used to demonstrate conformance to specifications, it is important that the test methodology be qualified to assure that test results are objective and accurate. 11 For example, sterilizer time and temperature data collected on recording equipment found to be accurate and precise could establish that process parameters had been reliably delivered to previously processed loads. A retrospective qualification of the equipment could be performed to demonstrate that the recorded data represented conditions that were uniform throughout the chamber and that product load configurations, personnel practices, initial temperature, and other variables had been adequately controlled during the earlier runs. 예를들어정확하며정밀한것으로밝혀진기록계에수집된멸균시간과온도자료를 통해, 공정변수가확실하게이전에처리된적재물에적용되었음을알수있다. 설비에대한회고적적격성평가를통해, 기록된데이터가챔버전체에고르게분포했던조건을보여주고있으며제품적재방법, 작업자행위, 초기온도및기타변수가이전멸균작업동안에적절하게관리되었음을증명할수있다. 27

28 예측적밸리데이션과마찬가지로시험결과가단순히적 / 부로표현되는경우에는이결과만을로트간규격적합성의근거로삼아공정을평가하는것은충분하지않을수있다. 반대로구체적인수치로나타나는결과는통계학적으로분석할수있으며, 데이터에서어떠한변화가예상되는지를파악할수도있다. 시간, 온도, 습도, 설비설정값등공정작업특성을기술한기록을유지하는것이중요하다. 시험데이터를활용하여규격에의부합여부를증명하는경우에는, 시험결과가객관적이며정확하다는점을보증할수있도록시험방법의적격성을따져보는것도중요하다. IX. 제품시험의인정 (ACCEPTABILITY OF PRODUCT TESTING) In some cases, a drug product or medical device may be manufactured individually or on a one-time basis. The concept of prospective or retrospective validation as it relates to those situations may have limited applicability, and data obtained during the manufacturing and assembly process may be used in conjunction with product testing to demonstrate that the instant run yielded a finished product meeting all of its specifications and quality characteristics. Such evaluation of data and product testing would be expected to be much more extensive than the usual situation where more reliance would be placed on prospective validation. 의약품또는의료용구를개별적으로또는일회성으로제조하는경우도있다. 그런상황에서는예측적또는회고적밸리데이션개념의적용이제한될수있으며, 제조및조립과정에서얻은데이터와제품에대한시험을통해그런일회적인제조작업의결과로모든제품규격과품질특성에부합하는최종제품이생산된다는점을증명할수도있다. 이때의데이터평가와제품시험은예측적밸리데이션을실시하는일반적인상황보다훨씬더광범위하게이루어져야할것이다. 28