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1 EUROPEAN COMMISSION DIRECTORATE-GENERAL FOR HEALTH AND FOOD SAFETY 2015 년 3 월 30 일, 브뤼셀 EudraLex Volume 4 EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use Annex 15: Qualification and Validation Legal basis for publishing the detailed guidelines: Article 47 of Directive 2001/83/EC on the Community code relating to medicinal products for human use and Article 51 of Directive 2001/82/EC on the Community code relating to veterinary medicinal products. This document provides guidance for the interpretation of the principles and guidelines of good manufacturing practice (GMP) for medicinal products as laid down in Directive 2003/94/EC for medicinal products for human use and Directive 91/412/EEC for veterinary use. 세부가이드라인발행의법적근거 : 사람의약품관련 EC 법률에관한디렉티브 2001/83/EC의 47조와동물의약품관련 EC 법률에관한디렉티브 2001/82/EC의 51조. 이문서는사람의약품에대한디렉티브 2003/94/EC와동물의약품에대한디렉티브 91/412/EEC에제시된의약품 GMP의원칙과가이드라인의해석과지침을제공한다. Status of the document: Revision 문서상태 : 개정 Reasons for changes: Since Annex 15 was published in 2001 the manufacturing and regulatory environment has changed significantly and an update is required to this Annex to reflect this changed environment. This revision to Annex 15 takes into account changes to other sections of the EudraLex, Volume 4, Part I, relationship to Part II, Annex 11, ICH Q8, Q9, Q10 and Q11, QWP guidance on process validation, and changes in manufacturing technology. 변경이유 : 2001년에부록 15가발행된이후로, 제조환경과규제환경이크게변했고, 1

2 이와같은변화를반영하여이부록을개정할필요가있다. Eudralex 볼륨 4 파트 I 가운데다른섹션의변경, 파트 II, 부록 11, ICH Q8, Q9, Q10, Q11 과공정밸리데이션에 관한 QWP 가이드라인, 제조기술발달등을고려하여부록 15 를개정한다. Deadline for coming into operation: 1 October 2015 시행일자 : 2015년 10월 1일 2

3 원칙 (Principle) This Annex describes the principles of qualification and validation which are applicable to the facilities, equipment, utilities and processes used for the manufacture of medicinal products and may also be used as supplementary optional guidance for active substances without introduction of additional requirements to EudraLex, Volume 4, Part II. It is a GMP requirement that manufacturers control the critical aspects of their particular operations through qualification and validation over the life cycle of the product and process. Any planned changes to the facilities, equipment, utilities and processes, which may affect the quality of the product, should be formally documented and the impact on the validated status or control strategy assessed. Computerised systems used for the manufacture of medicinal products should also be validated according to the requirements of Annex 11. The relevant concepts and guidance presented in ICH Q8, Q9, Q10 and Q11 should also be taken into account. 의약품제조에사용되는시설, 설비, 유틸리티, 공정의적격성평가와밸리데이션에관한기본원칙을설명한다. 이부록은 EudraLex 볼륨 4 파트 II에새로운기준을추가하는것이아니며, 활성성분제조업체는이부록을보완적인가이드라인으로선택하여활용할수있다. GMP 기준에따라의약품제조업체는제품및공정라이프사이클전체에걸쳐적격성평가와밸리데이션을실시해, 특정공정의중요부분을관리해야한다. 제품품질에영향을미칠가능성이있는시설, 설비, 유틸리티, 공정의변경을추진할때는, 공식적으로문서화하고밸리데이션상태나관리전략에미칠영향을평가한다. 의약품제조에사용되는컴퓨터화시스템을부록 11의기준에따라밸리데이션한다. ICH Q8, Q10, Q11에제시된개념과가이드라인도고려한다. 공통 (General) A quality risk management approach should be applied throughout the lifecycle of a medicinal product. As part of a quality risk management system, decisions on the scope and extent of qualification and validation should be based on a justified and documented risk assessment of the facilities, equipment, utilities and processes. Retrospective validation is no longer considered an acceptable approach. Data supporting qualification and/or validation studies which were obtained from sources outside of the manufacturers own programmes may be used provided that this approach has been justified and that there is adequate assurance that controls were in place throughout the acquisition of such data. 3

4 의약품의라이프사이클전체에걸쳐품질리스크관리방법을적용한다. 품질리스크관리시스템의한부분으로, 시설, 설비, 유틸리티, 공정에대한 RA(risk assessment) 를타당성있게실시하고문서화를한다음에, 이를바탕으로밸리데이션과적격성평가범위와강도를결정한다. 회고적밸리데이션은더이상적합한방법으로간주되지않는다. 제조업체의자체프로그램범위를벗어나는곳에서확보한데이터를활용해적격성평가나밸리데이션실험을뒷받침할수있다. 다만타당성을증명할수있어야하며, 그와같은데이터의확보에관한관리대책이구비되었음을적절하게보증해야한다. 1. 적격성평가및밸리데이션구성및계획 (ORGANISING AND PLANNING FOR QUALIFICATION AND VALIDATION) 1.1. All qualification and validation activities should be planned and take the life cycle of facilities, equipment, utilities, process and product into consideration. 모든적격성평가및밸리데이션활동을미리계획하고, 시설, 설비, 유틸리티, 공정, 제품의라이프사이클을고려하여추진한다 Qualification and validation activities should only be performed by suitably trained personnel who follow approved procedures. 적합하게교육훈련을받은작업자가승인받은절차에의거하여적격성평가와밸리데이션활동을추진한다 Qualification/validation personnel should report as defined in the pharmaceutical quality system although this may not necessarily be to a quality management or a quality assurance function. However, there should be appropriate quality oversight over the whole validation life cycle. 보고대상이반드시품질경영또는품질보증부서일필요는없으나, 적격성평가 / 밸리데이션작업자는제약품질시스템에규정된바에따라보고하며, 밸리데이션라이프사이클전체에걸쳐품질부서의적절한관리가있어야한다 The key elements of the site qualification and validation programme should be clearly defined and documented in a validation master plan (VMP) or equivalent document. 제조소적격성평가 / 밸리데이션프로그램의중요요소를명확히규정하고 VMP(validation master plan) 또는이와동등한문서를작성한다. 4

5 1.5. The VMP or equivalent document should define the qualification/validation system and include or reference information on at least the following: VMP 또는이와동등한문서에적격성평가 / 밸리데이션시스템을규정하고, 적어도다음항목에관한정보를포함시키거나참고정보를기술한다. i. Qualification and Validation policy; 적격성평가 / 밸리데이션방침 ii. The organisational structure including roles and responsibilities for qualification and validation activities; 적격성평가 / 밸리데이션업무에대한역할과책임을포함한조직구조 iii. Summary of the facilities, equipment, systems, processes on site and the qualification and validation status; 제조소의시설, 설비, 시스템, 공정에대한요약정보와적격성평가 / 밸리데이션상태 iv. Change control and deviation management for qualification and validation; 적격성평가 / 밸리데이션의변경관리및일탈관리 v. Guidance on developing acceptance criteria; 허용기준설정가이드라인 vi. References to existing documents; 참고문서 ( 기존문서 ) vii. The qualification and validation strategy, including requalification, where applicable. 적격성평가 / 밸리데이션전략 : 해당되는경우에는재적격성평가포함 1.6. For large and complex projects, planning takes on added importance and separate validation plans may enhance clarity 규모가크고복잡한프로젝트인경우에는기획이더욱중요하며별도의밸리데이션계획문서를만든다면업무가더욱명확해질것이다. 5

6 1.7. A quality risk management approach should be used for qualification and validation activities. In light of increased knowledge and understanding from any changes during the project phase or during commercial production, the risk assessments should be repeated, as required. The way in which risk assessments are used to support qualification and validation activities should be clearly documented. 품질리스크관리방식으로적격성평가와밸리데이션을추진한다. 프로젝트단계나상업적생산시에변경을추진하고지식과이해가축적됨에따라, 필요하면리스크평가를반복한다. 리스크평가를적격성평가와밸리데이션활동에활용하는방식을명확히문서화한다 Appropriate checks should be incorporated into qualification and validation work to ensure the integrity of all data obtained. 확보한모든데이터의완전성보장을위하여, 적격성평가와밸리데이션업무에적절한점검절차를통합시킨다. 2. VMP 를포함한문서 (DOCUMENTATION, INCLUDING VMP) 2.1. Good documentation practices are important to support knowledge management throughout the product lifecycle. 우수문서화절차는제품라이프사이클동안지식관리를뒷받침하는데중요한것이다 All documents generated during qualification and validation should be approved and authorised by appropriate personnel as defined in the pharmaceutical quality system. 적격성평가와밸리데이션과정에서생성된모든문서를제약품질시스템에규정된바에따라지정된자가승인한다 The inter-relationship between documents in complex validation projects should be clearly defined. 복잡한밸리데이션프로젝트인경우에는문서사이의상호관계를명확히규정한다 Validation protocols should be prepared which defines the critical systems, attributes and parameters and the associated acceptance criteria. 6

7 핵심시스템, 특성요소, 파라미터와각각의허용기준을규정한밸리데이션 프로토콜을작성한다 Qualification documents may be combined together, where appropriate, e.g. installation qualification (IQ) and operational qualification (OQ). 적절한경우에적격성평가문서를합칠수있다 ( 예, IQ 와 OQ) 2.6. Where validation protocols and other documentation are supplied by a third party providing validation services, appropriate personnel at the manufacturing site should confirm suitability and compliance with internal procedures before approval. Vendor protocols may be supplemented by additional documentation/test protocols before use. 밸리데이션프로토콜과기타문서를외부밸리데이션서비스업자가제공하는경우, 제조소의적절한자가적합성과내부절차에부합함을확인한다음에승인한다. 벤더의프로토콜인경우에는추가문서 / 테스트프로토콜을작성해보완한다음에사용해야할수도있다 Any significant changes to the approved protocol during execution, e.g. acceptance criteria, operating parameters etc., should be documented as a deviation and be scientifically justified. 승인받은프로토콜을실행도중에중대하게변경하는경우에는 ( 예, 허용기준, 공정파라미터등 ), 이를일탈로간주하고문서화하며과학적으로타당성을제시해야한다 Results which fail to meet the pre-defined acceptance criteria should be recorded as a deviation and be fully investigated according to local procedures. Any implications for the validation should be discussed in the report 사전에규정해놓은허용기준에부합하지않는결과가발생하는경우, 이를일탈로기록하고내부절차에따라충분하게조사하며, 밸리데이션측면에서그의미를보고서에기술한다 The review and conclusions of the validation should be reported and the results obtained summarised against the acceptance criteria. Any subsequent changes to acceptance criteria should be scientifically justified and a final recommendation made as to the outcome of the validation. 7

8 밸리데이션의검토내용과결론을보고하고, 결과를허용기준에대비하여 평가하고요약한다. 허용기준을변경하는경우에는그타당성을과학적으로 제시하고, 밸리데이션결과를바탕으로최종권고사항을정리한다 A formal release for the next stage in the qualification and validation process should be authorised by the relevant responsible personnel either as part of the validation report approval or as a separate summary document. Conditional approval to proceed to the next qualification stage can be given where certain acceptance criteria or deviations have not been fully addressed and there is a documented assessment that there is no significant impact on the next activity. 밸리데이션보고서나별도의요약문서를승인함으로써, 관련책임자가다음적격성평가 / 밸리데이션단계로넘어갈것을공식적으로허가한다. 특정허용기준이나일탈을충분히처리하지못했으나다음활동에미칠영향이크지않은것으로평가되는경우에는그내용을문서화한다음에, 다음적격성평가단계진행을조건부로승인할수있다. 3. 설비, 시설, 유틸리티, 시스템의적격성평가단계 (QUALIFICATION STAGES FOR EQUIPMENT, FACILITIES, UTILITIES AND SYSTEMS) 3.1. Qualification activities should consider all stages from initial development of the user requirements specification through to the end of use of the equipment, facility, utility or system. The main stages and some suggested criteria (although this depends on individual project circumstances and may be different) which could be included in each stage are indicated below: 초기사용자요구기준규격개발부터해당설비, 시설, 유틸리티또는시스템의사용종료시점까지모든단계를고려하여적격성평가활동을추진한다. 중요단계와단계별일부권장기준 ( 프로젝트상황에따라달라질수있음 ) 은다음과같다. URS(User requirements specification) 3.2. The specification for equipment, facilities, utilities or systems should be defined in a URS and/or a functional specification. The essential elements of quality need to be built in at this stage and any GMP risks mitigated to 8

9 an acceptable level. The URS should be a point of reference throughout the validation life cycle. 설비, 시설, 유틸리티, 시스템의규격을 URS나기능규격문서에규정한다. 필수적인품질요소를이단계에서반영시켜 GMP 리스크를허용가능한수준까지완화시킬필요가있다. URS는밸리데이션라이프사이클동안기준점이된다. 설계적격성평가 (Design qualification; DQ) 3.3. The next element in the qualification of equipment, facilities, utilities, or systems is DQ where the compliance of the design with GMP should be demonstrated and documented. The requirements of the user requirements specification should be verified during the design qualification. 설비, 시설, 유틸리티, 시스템의적격성평가에서다음요소는디자인이 GMP에부합함을증명하고문서화하는 DQ이다. URS의기준을 DQ 단계에서확인한다. FAT(Factory acceptance testing) / SAT(Site acceptance testing) 3.4. Equipment, especially if incorporating novel or complex technology, may be evaluated, if applicable, at the vendor prior to delivery. 특히새로운기술이나복잡한기술을채택한설비인경우에는, 해당되는경우에납품에앞서벤더사업장에서평가를실시할수있다 Prior to installation, equipment should be confirmed to comply with the URS/functional specification at the vendor site, if applicable. 해당되는경우에설치에앞서벤더사업장에서설비가 URS/ 기능규격문서에부합하는지확인한다 Where appropriate and justified, documentation review and some tests could be performed at the FAT or other stages without the need to repeat on site at IQ/OQ if it can be shown that the functionality is not affected by the transport and installation. 적절하고타당성이있는경우에는, 운반과설치때문에기능이영향을받지않음을증명할수있으면, IQ/OQ 시에제조소에서반복하지않고 FAT 또는다른단계에서문서검토와일부테스트를실시할수있다 FAT may be supplemented by the execution of a SAT following the receipt 9

10 of equipment at the manufacturing site. 제조소에서설비를인수한다음에 SAT 를실시하여 FAT 를보완할수있다. 설치적격성평가 (Installation qualification; IQ) 3.8. IQ should be performed on equipment, facilities, utilities, or systems. 설비, 시설, 유틸리티, 시스템에대하여 IQ 를실시한다 IQ should include, but is not limited to the following: IQ 항목은다음을포함하되이에국한되지않는다. i. Verification of the correct installation of components, instrumentation, equipment, pipe work and services against the engineering drawings and specifications; 엔지니어링도면및규격문서에대비하여컴포넌트, 계측장치, 설비, 배관, 서비스의정확한설치상태확인 ii. Verification of the correct installation against pre-defined criteria; 사전설정기준에대비하여정확한설치여부확인 iii. Collection and collation of supplier operating and working instructions and maintenance requirements; 공급업체의운전및작업지시문서와유지관리기준의수집및검토 iv. Calibration of instrumentation; 계측장치교정 v. Verification of the materials of construction. 재질확인 운전적격성평가 (Operational qualification; OQ) OQ normally follows IQ but depending on the complexity of the equipment, it may be performed as a combined Installation/Operation Qualification (IOQ). 일반적으로 IQ를끝낸다음에 OQ를실시하지만, 설비의복잡성에따라 IQ/OQ를 10

11 한꺼번에진행할수도있다 (IOQ) OQ should include but is not limited to the following: OQ 항목은다음을포함하되이에국한되지않는다. i. Tests that have been developed from the knowledge of processes, systems and equipment to ensure the system is operating as designed; 시스템이설계했던바와같이작동됨을확인하기위해, 공정, 시스템, 설비에대한지식을바탕으로개발한테스트 ii. Tests to confirm upper and lower operating limits, and /or worst case conditions. 상하한운전기준이나 " 최악의경우 " 에해당되는조건을확인하기위한테스트 The completion of a successful OQ should allow the finalisation of standard operating and cleaning procedures, operator training and preventative maintenance requirements. OQ가성공적으로완료된다음에는, 운전및세척절차, 작업자교육훈련기준, 예방적유지관리기준을마무리한다. 성능적격성평가 (Performance qualification; PQ) PQ should normally follow the successful completion of IQ and OQ. However, it may in some cases be appropriate to perform it in conjunction with OQ or Process Validation. IQ와 OQ가성공적으로완료된다음에 PQ를실시한다. 하지만 OQ나공정밸리데이션과연계하여실시하는편이적절한경우도있다 PQ should include, but is not limited to the following: PQ 항목은다음을포함하되이에국한되지않는다. i. Tests, using production materials, qualified substitutes or simulated product proven to have equivalent behaviour under normal operating conditions with worst case batch sizes. The frequency of sampling used to confirm process control should be justified; 11

12 최악의경우에해당되는배치규모로, 정상공정조건에서동등한동태를나타내는것으로증명된시뮬레이션제품, 적격대체물품, 생산물품을이용한테스트. 공정의관리상태를확인하기위한검체채취주기의타당성을증명할수있어야한다. ii. Tests should cover the operating range of the intended process, unless documented evidence from the development phases confirming the operational ranges is available. 공정범위의적합성을개발단계에서증명한증거문서가없으면, 예정공정범위를대상으로테스트를실시한다. 4. 재적격성평가 (RE-QUALIFICATION) 4.1. Equipment, facilities, utilities and systems should be evaluated at an appropriate frequency to confirm that they remain in a state of control. 설비, 시설, 유틸리티, 시스템을적정주기로평가하여, 관리상태로유지되고있음을확인한다 Where re-qualification is necessary and performed at a specific time period, the period should be justified and the criteria for evaluation defined. Furthermore, the possibility of small changes over time should be assessed. 재적격성평가가필요하고지정주기로실시한다면, 그주기의타당성을제시하고평가기준도규정한다. 또한시간경과에따른변화의가능성을평가한다. 5. 공정밸리데이션 (PROCESS VALIDATION) 공통 (General) 5.1. The requirements and principles outlined in this section are applicable to the manufacture of all pharmaceutical dosage forms. They cover the initial validation of new processes, subsequent validation of modified processes, site transfers and ongoing process verification. It is implicit in this annex that a robust product development process is in place to enable successful process validation. 이섹션의기준과원칙은모든완제의약품제조에적용된다. 새로운공정의최초밸리데이션과이후변형공정의밸리데이션, 사업장이전, 지속적공정 12

13 베리피케이션을대상으로한다. 제품개발이견고하게완료된상태여야공정 밸리데이션을시작할수있다 Section 5 should be used in conjunction with the current EMA guideline on Process Validation. 공정밸리데이션에관한 EMA 가이드라인과함께섹션 5 의기준을적용한다 The guideline on Process Validation is intended to provide guidance on the information and data to be provided in the regulatory submission only. However GMP requirements for process validation continue throughout the lifecycle of the process 공정밸리데이션가이드라인은규제기관제출문서에포함시켜야할정보와데이터에관한것이다. 공정밸리데이션에대한 GMP 기준은공정의라이프사이클전체에걸쳐계속적용된다 This approach should be applied to link product and process development. It will ensure validation of the commercial manufacturing process and maintenance of the process in a state of control during routine commercial production. 제품과공정개발을연계시킨이와같은방식을적용한다. 그래야상업적제조공정의밸리데이션, 그리고상업적생산단계에서공정의관리상태유지를보장할수있다 Manufacturing processes may be developed using a traditional approach or a continuous verification approach. However, irrespective of the approach used, processes must be shown to be robust and ensure consistent product quality before any product is released to the market. Manufacturing processes using the traditional approach should undergo a prospective validation programme, wherever possible, prior to certification of the product. Retrospective validation is no longer an acceptable approach. 전통적방법이나계속적베리피케이션방법으로제조공정을개발할수있다. 어떤방법으로개발하건, 제품의출시에앞서공정이견고하며제품품질을일관되게보장할수있는공정임을증명해야한다. 전통적방법으로제조공정을개발하는경우에는, 가능하면제품출하증명에앞서예측적밸리데이션을실시해야한다. 회고적밸리데이션은더이상인정되지않는다. 13

14 5.4. Process validation of new products should cover all intended marketed strengths and sites of manufacture. Bracketing could be justified for new products based on extensive process knowledge from the development stage in conjunction with an appropriate ongoing verification programme. 새로운제품의공정밸리데이션시에는시판예정인모든함량과제조소를대상으로해야한다. 하지만개발단계에서공정지식을충분히확보하고지속적베리피케이션프로그램을적절히구비한경우에는브라켓방법을적용할수도있다 For process validation of products which are transferred from one site to another or within the same site, the number of validation batches could be reduced by the use of a bracketing approach. However, existing product knowledge, including the content of the previous validation, should be available. Different strengths, batch sizes and pack sizes/container types may also use a bracketing approach, if justified. 한제조소에서다른제조소로이전되거나동일제조소안에서이전되는제품의공정밸리데이션인경우에는브라켓방법을적용하여밸리데이션배치의수를줄일수있다. 하지만과거의밸리데이션데이터를포함하여제품지식이있어야한다. 타당성이있는경우에는함량, 배치규모, 포장크기 / 용기종류가다른경우에브라켓방법을적용할수있다 For the site transfer of legacy products, the manufacturing process and controls must comply with the marketing authorisation and meet current standards for marketing authorisation for that product type. If necessary, variations to the marketing authorisation should be submitted. 레가시제품의제조소이전인경우에는, 제조공정과관리절차가판매허가문서에부합해야하며해당제품에대한현재의허가기준을충족해야한다. 필요하면판매허가변경신청서를제출한다 Process validation should establish whether all quality attributes and process parameters, which are considered important for ensuring the validated state and acceptable product quality, can be consistently met by the process. The basis by which process parameters and quality attributes were identified as being critical or non-critical should be clearly documented, taking into account the results of any risk assessment activities. 14

15 밸리데이션상태와허용제품품질을보장하는데중요하다고생각되는모든품질특성요소와공정파라미터가일관되게충족될수있음을공정밸리데이션을통해확립한다. 리스크평가결과를감안하여, 공정파라미터와품질특성요소를 " 중요 " 또는 " 비중요 " 로구분한근거를명확히문서화한다 Normally batches manufactured for process validation should be the same size as the intended commercial scale batches and the use of any other batch sizes should be justified or specified in other sections of EudraLex, Volume 4. 일반적으로공정밸리데이션시에제조하는배치의규모는예정상업적스케일의배치규모와동일해야하며, 다른배치규모를채택하고자한다면그타당성을증명하거나 EudraLex 볼륨 4의다른섹션에그와같은방식이규정되어있어야한다 Equipment, facilities, utilities and systems used for process validation should be qualified. Test methods should be validated for their intended use. 공정밸리데이션에사용되는설비, 시설, 유틸리티, 시스템의적격성평가를실시하고시험방법도밸리데이션을한다 For all products irrespective of the approach used, process knowledge from development studies or other sources should be accessible to the manufacturing site, unless otherwise justified, and be the basis for validation activities. 어떤방법을채택하건, 달리타당성을제시할수없으면개발단계에서실험을통해축적하거나다른곳에서확보한공정지식을제조소가활용할수있어야하며, 이지식이밸리데이션활동의토대가된다 For process validation batches, production, development, or other site transfer personnel may be involved. Batches should only be manufactured by trained personnel in accordance with GMP using approved documentation. It is expected that production personnel are involved in the manufacture of validation batches to facilitate product understanding. 공정밸리데이션배치의제조시에생산, 개발, 기타제조소이전관련작업자가관여할수있다. 교육훈련을받은작업자가승인받은문서를이용해 GMP 기준에의거하여공정밸리데이션배치를제조한다. 제품이해를촉진하기위하여 15

16 생산작업자가밸리데이션배치의제조에관여해야할것이다 The suppliers of critical starting and packaging materials should be qualified prior to the manufacture of validation batches; otherwise a justification based on the application of quality risk management principles should be documented. 밸리데이션배치의제조에앞서중요출발물질과포장자재공급업체의적격성평가를완료한다. 아니면품질리스크관리원칙에의거해타당성을문서화한다 It is especially important that the underlying process knowledge for the design space justification (if used) and for development of any mathematical models (if used) to confirm a process control strategy should be available. 공정관리전략을확인하는데활용할수학적모델의개발과디자인스페이스의타당성을증명 ( 해당되는경우 ) 하기위한기본적인공정지식을확보하는것이특히중요하다 Where validation batches are released to the market, this should be predefined. The conditions under which they are produced should fully comply with GMP, with the validation acceptance criteria, with any continuous process verification criteria (if used) and with the marketing authorisation or clinical trial authorisation. 밸리데이션배치를출하하는경우에는그부분을미리규정해놓는다. 이런경우에생산조건은 GMP 기준, 밸리데이션허용기준, 계속적공정베리피케이션기준 ( 해당되는경우 ), 판매허가기준또는임상시험허가기준에부합해야한다 For the process validation of investigational medicinal products (IMP), please refer to Annex 13. 임상시험의약품의공정밸리데이션은부록 13 을참조한다. 동시적밸리데이션 (Concurrent validation) In exceptional circumstances, where there is a strong benefit-risk ratio for the patient, it may be acceptable not to complete a validation programme before routine production starts and concurrent validation could be used. 16

17 However, the decision to carry out concurrent validation must be justified, documented in the VMP for visibility and approved by authorised personnel. 환자에대한혜택-리스크평가결과에의거해충분한근거가있는예외적인경우에는, 정규생산을시작하기전까지밸리데이션프로그램을완료하지못한상황도인정할수있으며, 이럴때는동시적밸리데이션방법을적용할수있다. 하지만동시적밸리데이션을추진하기로결정한경우에는그타당성을 VMP에문서화하고허가받은자가승인해야한다 Where a concurrent validation approach has been adopted, there should be sufficient data to support a conclusion that any given batch of product is uniform and meets the defined acceptance criteria. The results and conclusion should be formally documented and available to the Qualified Person prior to certification of the batch. 동시적밸리데이션방법을채택한경우에는, 특정제품배치가균질하고지정허용기준에부합한다는결론을뒷받침하는데이터가충분히있어야한다. 결과와결론을공식적으로문서화하며, 이를 QP가검토한다음에해당배치의출하를증명한다. 전통적밸리데이션방법 (Traditional process validation) In the traditional approach, a number of batches of the finished product are manufactured under routine conditions to confirm reproducibility. 전통적인방법으로진행할때는다수의최종제품배치를일상조건에서제조하여재현성을확인한다 The number of batches manufactured and the number of samples taken should be based on quality risk management principles, allow the normal range of variation and trends to be established and provide sufficient data for evaluation. Each manufacturer must determine and justify the number of batches necessary to demonstrate a high level of assurance that the process is capable of consistently delivering quality product. 배치의수와검체량은품질리스크관리원칙을바탕으로하고, 정상적인변동범위와경향평가가가능하며, 평가에필요한데이터를충분히확보할수있게선정한다. 공정이고품질의제품을일관되게생산할수있음을높은수준으로보증하고증명하는데필요한배치의수를제조업체가결정하고그타당성을제시한다. 17

18 5.20. Without prejudice to 5.19, it is generally considered acceptable that a minimum of three consecutive batches manufactured under routine conditions could constitute a validation of the process. An alternative number of batches may be justified taking into account whether standard methods of manufacture are used and whether similar products or processes are already used at the site. An initial validation exercise with three batches may need to be supplemented with further data obtained from subsequent batches as part of an on-going process verification exercise. 5.19의기준을침해함이없이, 최소 3개연속배치를일상조건에서제조하여공정밸리데이션을진행하면일반적으로인정된다. 표준제조방법을채택하는지, 해당제조소에서비슷한제품을생산하고있거나비슷한공정을이미도입했는지등을검토하여다른배치수의타당성을제시할수있다. 3개배치로밸리데이션을진행한다면, 지속적공정베리피케이션의일환으로이후생산배치에서추가데이터를확보하여보완할필요가있을것이다 A process validation protocol should be prepared which defines the critical process parameters (CPP), critical quality attributes (CQA) and the associated acceptance criteria which should be based on development data or documented process knowledge. CPP와 CQA, 그리고관련허용기준 ( 개발데이터나공정지식을바탕으로설정 ) 을규정한공정밸리데이션프로토콜을작성한다 Process validation protocols should include, but are not limited to the following: 다음항목을포함하되이에국한하지않고밸리데이션프로토콜을작성한다. i. A short description of the process and a reference to the respective Master Batch Record; 공정에대한간단한설명과해당마스터배치기록서에대한정보 ii. Functions and responsibilities; 업무분장 iii. Summary of the CQAs to be investigated; 18

19 조사대상 CQA 요약 iv. Summary of CPPs and their associated limits; CPP와관련기준요약 v. Summary of other (non-critical) attributes and parameters which will be investigated or monitored during the validation activity, and the reasons for their inclusion; 밸리데이션시에조사또는모니터할다른 ( 비중요 ) 특성요소및파라미터와선정이유요약 vi. List of the equipment/facilities to be used (including measuring/monitoring/recording equipment) together with the calibration status; 사용할설비 / 시설리스트 ( 측정 / 모니터 / 기록설비포함 ) 와교정상태 vii. List of analytical methods and method validation, as appropriate. 분석방법및분석법밸리데이션리스트 viii. Proposed in-process controls with acceptance criteria and the reason(s) why each in-process control is selected; 예정 IPC 와허용기준, 그리고각 IPC 항목의선정이유 ix. Additional testing to be carried out with acceptance criteria; 추가시험항목과허용기준 x. Sampling plan and the rationale behind it; 검체채취계획과그근거 xi. Methods for recording and evaluating results; 결과기록및평가방법 xii. Process for release and certification of batches (if applicable). 배치출하승인및증명절차 ( 해당되는경우 ) 계속적공정베리피케이션 (Continuous process verification) 19

20 5.23. For products developed by a quality by design approach, where it has been scientifically established during development that the established control strategy provides a high degree of assurance of product quality, then continuous process verification can be used as an alternative to traditional process validation. QbD 방식으로제품을개발했고확립된공정관리전략으로제품품질을높은수준으로보장할수있음을개발단계에서과학적으로확립한경우에는, 전통적공정밸리데이션대신에계속적공정베리피케이션방법을활용할수있다 The method by which the process will be verified should be defined. There should be a science based control strategy for the required attributes for incoming materials, critical quality attributes and critical process parameters to confirm product realisation. This should also include regular evaluation of the control strategy. Process Analytical Technology and multivariate statistical process control may be used as tools. Each manufacturer must determine and justify the number of batches necessary to demonstrate a high level of assurance that the process is capable of consistently delivering quality product. 공정을베리피케이션하는방법을규정한다. 입고물품의필요특성요소, CQA, CPP에대하여과학적관리전략을수립해제품구현과정을확인한다. 또한관리전략을정기적으로평가한다. PAT와다변량통계적공정관리방법을활용할수있다. 고품질의제품을일관되게생산할수있는공정임을높은수준으로보장하고증명하는데필요한배치의수를제조업체가결정하고그타당성을제시한다 The general principles laid down in above still apply. 상기 의일반원칙을적용한다. 하이브리드방식 (Hybrid approach) A hybrid of the traditional approach and continuous process verification could be used where there is a substantial amount of product and process knowledge and understanding which has been gained from manufacturing experience and historical batch data. 과거배치데이터와제조경험을통해축적한제품 / 공정지식과이해가상당히 20

21 많은경우, 전통적방법과계속적공정베리피케이션을혼합한하이브리드방식을 활용할수있다 This approach may also be used for any validation activities after changes or during ongoing process verification even though the product was initially validated using a traditional approach. 처음에는전통적방법으로밸리데이션한제품이라고하더라도, 변경이후밸리데이션이나지속적공정베리피케이션시에이와같은방식을활용할수있다. 라이프사이클동안지속적공정베리피케이션 (Ongoing Process Verification during Lifecycle) Paragraphs are applicable to all three approaches to process validation mentioned above, i.e. traditional, continuous and hybrid 는앞서설명한 3개공정밸리데이션방법 ( 전통적방법, 계속적방법, 하이브리드방법 ) 에모두적용된다 Manufacturers should monitor product quality to ensure that a state of control is maintained throughout the product lifecycle with the relevant process trends evaluated. 제조업체는제품품질을모니터하여제품라이프사이클동안관리상태가유지되는지확인하고관련공정경향을평가해야한다 The extent and frequency of ongoing process verification should be reviewed periodically. At any point throughout the product lifecycle, it may be appropriate to modify the requirements taking into account the current level of process understanding and process performance. 지속적공정베리피케이션의강도와주기를주기적으로검토한다. 제품라이프사이클동안언제라도공정이해와공정성능수준을감안해적절한경우에는기준을변경할수있다 Ongoing process verification should be conducted under an approved protocol or equivalent documents and a corresponding report should be prepared to document the results obtained. Statistical tools should be used, where appropriate, to support any conclusions with regard to the variability and capability of a given process and ensure a state of control. 21

22 지속적공정베리피케이션을승인받은프로토콜또는이와동등한문서에의거하여실시하고, 결과를정리한보고서를작성한다. 적절한경우에는통계도구를활용해특정공정의능력과변동성에관한결론을뒷받침하고관리상태를확인한다 Ongoing process verification should be used throughout the product lifecycle to support the validated status of the product as documented in the Product Quality Review. Incremental changes over time should also be considered and the need for any additional actions, e.g. enhanced sampling, should be assessed. 제품라이프사이클동안제품품질검토 (Product Quality Review) 시에지속적공정베리피케이션데이터를이용해제품의밸리데이션상태를뒷받침한다. 하지만시간경과에따른점진적변화를고려해야하며, 추가조치의필요성 ( 예, 검체채취강화 ) 을평가한다. 6. 운송베리피케이션 (VERIFICATION OF TRANSPORTATION) 6.1. Finished medicinal products, investigational medicinal products, bulk product and samples should be transported from manufacturing sites in accordance with the conditions defined in the marketing authorisation, the approved label, product specification file or as justified by the manufacturer. 최종의약품, 임상시험의약품, 벌크제품과검체를판매허가문서, 승인받은라벨, 제품규격파일에규정된조건이나제조업체가정한조건에따라운송한다 It is recognised that verification of transportation may be challenging due to the variable factors involved however, transportation routes should be clearly defined. Seasonal and other variations should also be considered during verification of transport 다양한관련요소때문에운송베리피케이션이쉽지않음을인정하지만, 운송경로를명확히규정해야한다. 운송베리피케이션시에계절적변동과기타변동요소를고려한다 A risk assessment should be performed to consider the impact of variables in the transportation process other than those conditions which are continuously controlled or monitored, e.g. delays during transportation, failure of monitoring devices, topping up liquid nitrogen, product 22

23 susceptibility and any other relevant factors. 운송과정에서계속적으로관리또는모니터하는조건이외에다른변수의영향을고려해리스크평가를실시한다 ( 예, 운송시의지연, 모니터장치이상, 액체질소충전, 제품민감성, 기타관련요소 ) Due to the variable conditions expected during transportation, continuous monitoring and recording of any critical environmental conditions to which the product may be subjected should be performed, unless otherwise justified. 운송과정에서여러가지상황이발생할수있으므로, 달리타당성을증명할수없으면제품이노출될가능성이있는중요환경조건을계속적으로모니터하고기록한다. 7. 포장밸리데이션 (VALIDATION OF PACKAGING) 7.1. Variation in equipment processing parameters especially during primary packaging may have a significant impact on the integrity and correct functioning of the pack, e.g. blister strips, sachets and sterile components, therefore primary and secondary packaging equipment for finished and bulk products should be qualified. 특히일차포장과정에서설비공정파라미터의변동은포장 ( 예, 블리스터스트립, 포, 무균컴포넌트 ) 의완전성과기능의정확성에중대한영향을미칠가능성이있으므로, 최종제품과벌크제품의일차 / 이차포장설비에대하여적격성평가를실시해야한다 Qualification of the equipment used for primary packing should be carried out at the minimum and maximum operating ranges defined for the critical process parameters such as temperature, machine speed and sealing pressure or for any other factors. 온도, 기계속도, 밀봉압력등중요공정파라미터에대해규정된최소 / 최대운전범위에서일차포장설비의적격성평가를실시한다. 8. 유틸리티적격성평가 (QUALIFICATION OF UTILITIES) 8.1. The quality of steam, water, air, other gases etc. should be confirmed following installation using the qualification steps described in section 3 23

24 above. 스팀, 용수, 공기, 기타가스등의품질을섹션 3 의적격성평가단계에따라설치 이후에확인한다 The period and extent of qualification should reflect any seasonal variations, if applicable, and the intended use of the utility. 해당되는경우에는계절변동과유틸리티의예정용도를반영하여적격성평가기간과강도를정한다 A risk assessment should be carried out where there may be direct contact with the product, e.g. heating, ventilation and air-conditioning (HVAC) systems, or indirect contact such as through heat exchangers to mitigate any risks of failure. 제품과직접 ( 예, HVAC 시스템 ) 또는간접 ( 예, 열교환기를통해 ) 적으로접촉할가능성이있는경우에는리스크평가를실시하여리스크를완화한다. 9. 시험방법밸리데이션 (VALIDATION OF TEST METHODS) 9.1. All analytical test methods used in qualification, validation or cleaning exercises should be validated with an appropriate detection and quantification limit, where necessary, as defined in Chapter 6 of the EudraLex, Volume 4, Part I. EudraLex 볼륨 4 파트 I의 6장에기술된바에따라, 적격성평가, 밸리데이션또는세척에사용되는모든시험방법을필요한경우에는적절한검출한계와정량한계로밸리데이션을한다 Where microbial testing of product is carried out, the method should be validated to confirm that the product does not influence the recovery of microorganisms. 제품미생물시험을하는경우, 시험방법을밸리데이션하여제품이미생물의회수에영향을주지않음을확인한다 Where microbial testing of surfaces in clean rooms is carried out, validation should be performed on the test method to confirm that sanitising agents do not influence the recovery of microorganisms. 청정실의표면미생물시험을실시하는경우, 시험방법을밸리데이션하여 24

25 소독제가미생물의회수에영향을미치지않음을확인한다. 10. 세척밸리데이션 (CLEANING VALIDATION) Cleaning validation should be performed in order to confirm the effectiveness of any cleaning procedure for all product contact equipment. Simulating agents may be used with appropriate scientific justification. Where similar types of equipment are grouped together, a justification of the specific equipment selected for cleaning validation is expected. 모든제품접촉설비에대하여세척절차의효과를확인하는세척밸리데이션을실시한다. 적절한과학적타당성이있는경우에는시뮬레이션물질을사용할수도있다. 유사한유형의설비를함께묶는다면, 세척밸리데이션대상으로특정설비를선정한이유를타당하게증명해야할것이다 A visual check for cleanliness is an important part of the acceptance criteria for cleaning validation. It is not generally acceptable for this criterion alone to be used. Repeated cleaning and retesting until acceptable residue results are obtained is not considered an acceptable approach. 청결도육안검사가세척밸리데이션의허용기준가운데중요한부분이될수있으나, 이기준만사용하는것은인정되지않는다. 적합한잔류물결과가나올때까지반복하여세척하고재시험하는방법도적합한것으로볼수없다 It is recognised that a cleaning validation programme may take some time to complete and validation with verification after each batch may be required for some products, e.g. investigational medicinal products. There should be sufficient data from the verification to support a conclusion that the equipment is clean and available for further use. 세척밸리데이션프로그램을완료하려면어느정도시간이걸릴수있음을인정하며, 각배치제조이후지속적으로베리피케이션하며밸리데이션을진행할필요도있다 ( 예, 임상시험의약품 ). 설비가깨끗하며다음에사용할수있다는결론을뒷받침하는베리피케이션데이터가충분히있어야한다 Validation should consider the level of automation in the cleaning process. Where an automatic process is used, the specified normal operating range of the utilities and equipment should be validated. 세척공정의자동화수준을고려한다. 자동공정인경우에는설비와유틸리티의 25

26 지정 NOR 을밸리데이션한다 For all cleaning processes an assessment should be performed to determine the variable factors which influence cleaning effectiveness and performance, e.g. operators, the level of detail in procedures such as rinsing times etc. If variable factors have been identified, the worst case situations should be used as the basis for cleaning validation studies. 모든세척공정에대하여평가를실시하여세척효과와성능에영향을미치는여러가지요소를파악한다 ( 예, 작업자, 헹굼횟수등세척절차의구체적인부분 ). 변수요소를파악한다음에는, 최악의경우에해당되는조건을세척밸리데이션실험의토대로활용한다 Limits for the carryover of product residues should be based on a toxicological evaluation 1. The justification for the selected limits should be documented in a risk assessment which includes all the supporting references. Limits should be established for the removal of any cleaning agents used. Acceptance criteria should consider the potential cumulative effect of multiple items of equipment in the process equipment train. 독성학적평가결과를토대로제품잔류물이월기준을설정한다. 잔류물기준의타당성을리스크평가문서에기술하고모든근거참고문헌도포함시킨다. 세척제의제거에대한기준도설정한다. 공정설비트레인의여러설비에의한누적영향가능성을고려하여허용기준을설정한다 Therapeutic macromolecules and peptides are known to degrade and denature when exposed to ph extremes and/or heat, and may become pharmacologically inactive. A toxicological evaluation may therefore not be applicable in these circumstances. 치료고분자와펩타이드는극한의 ph 값이나열에노출되는경우에분해 / 변성되어약리학적비활성상태가될수있다. 그러므로이와같은경우에는독성학적평가를적용하지않을수있다. 1 See EMA Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities 공유시설의여러의약품제조와관련된리스크의파악을위한건강기반노출한도기준설정 EMA 가이드라인 26

27 If it is not feasible to test for specific product residues, other representative parameters may be selected, e.g. total organic carbon (TOC) and conductivity. 특정제품잔류물의시험이가능하지않으면, 다른대표파라미터를선정할수있다 ( 예, TOC, 전도도 ) The risk presented by microbial and endotoxin contamination should be considered during the development of cleaning validation protocols. 세척밸리데이션프로토콜을작성할때, 미생물과엔도톡신오염에따른리스크를고려한다 The influence of the time between manufacture and cleaning and the time between cleaning and use should be taken into account to define dirty and clean hold times for the cleaning process. 제조와세척사이의기간과세척과사용사이의기간에따른영향을고려하여세척공정의 DHT(dirty hold time) 와 CHT(clean hold time) 를규정한다 Where campaign manufacture is carried out, the impact on the ease of cleaning at the end of the campaign should be considered and the maximum length of a campaign (in time and/or number of batches) should be the basis for cleaning validation exercises. 캠페인제조를한다면, 캠페인종료시점의세척용이성에미치는영향을고려해야하며, 최대캠페인생산기간 ( 시간과배치수 ) 을토대로세척밸리데이션방법을정한다 Where a worst case product approach is used as a cleaning validation model, a scientific rationale should be provided for the selection of the worst case product and the impact of new products to the site assessed. Criteria for determining the worst case may include solubility, cleanability, toxicity and potency. 최악의경우에해당되는제품을선정하여세척밸리데이션을진행한다면, 해당제품의선정근거를과학적으로제시하며새로운제품의도입시에는그에따른파급영향을평가한다. 용해성, 세척성, 독성, 역가등을고려하여최악의경우에해당되는제품의선정기준을정할수있다. 27

28 Cleaning validation protocols should specify or reference the locations to be sampled, the rationale for the selection of these locations and define the acceptance criteria. 검체채취위치, 그위치의선정근거, 허용기준을세척밸리데이션프로토콜에자세히규정하거나참고정보를기술한다 Sampling should be carried out by swabbing and/or rinsing or by other means depending on the production equipment. The sampling materials and method should not influence the result. Recovery should be shown to be possible from all product contact materials sampled in the equipment with all the sampling methods used. 스왑이나린스방법으로검체를채취하거나생산설비에따라다른방법으로검체를채취한다. 검체채취물품과방법이결과에영향을미쳐서는안된다. 모든검체채취방법에대하여해당설비의검체채취대상인모든제품접촉재질로부터회수가가능함을증명한다 The cleaning procedure should be performed an appropriate number of times based on a risk assessment and meet the acceptance criteria in order to prove that the cleaning method is validated. 리스크평가결과에근거해적절한횟수로세척절차를진행하며, 세척방법이밸리데이션되었음을증명하려면허용기준에부합해야한다 Where a cleaning process is ineffective or is not appropriate for some equipment, dedicated equipment or other appropriate measures should be used for each product as indicated in chapters 3 and 5 of EudraLex, Volume 4, Part I. 일부설비에서세척절차가효과가없거나적절하지않은것으로밝혀지면, EudraLex 볼륨 4 파트 I의 3장과 5장에규정되어있는바와같이제품별로전용설비를사용하거나다른적절한대책을구비한다 Where manual cleaning of equipment is performed, it is especially important that the effectiveness of the manual process should be confirmed at a justified frequency. 설비의수동세척시에는타당성이입증된주기로수동세척공정의효과를확인하는것이특히중요하다. 28

29 11. 변경관리 (CHANGE CONTROL) The control of change is an important part of knowledge management and should be handled within the pharmaceutical quality system. 변경관리는지식관리에있어서중요한부분이며, 제약품질시스템에의거하여추진한다 Written procedures should be in place to describe the actions to be taken if a planned change is proposed to a starting material, product component, process, equipment, premises, product range, method of production or testing, batch size, design space or any other change during the lifecycle that may affect product quality or reproducibility. 출발물질, 제품컴포넌트, 공정, 설비, 시설, 제품범위, 생산방법이나시험방법, 배치규모, 디자인스페이스등의변경이나라이프사이클동안추진하는제품품질이나재현성에영향을미칠가능성이있는기타변경을추진하고자하는경우에취할조치사항을기술한절차문서를구비한다 Where design space is used, the impact on changes to the design space should be considered against the registered design space within the marketing authorisation and the need for any regulatory actions assessed. 디자인스페이스를운영하는경우, 판매허가문서에규정된디자인스페이스에대비하여변경이디자인스페이스에미칠영향을검토하고규제기관보고등의필요성을평가한다 Quality risk management should be used to evaluate planned changes to determine the potential impact on product quality, pharmaceutical quality systems, documentation, validation, regulatory status, calibration, maintenance and on any other system to avoid unintended consequences and to plan for any necessary process validation, verification or requalification efforts. 품질리스크관리방법으로예정변경사안을평가하여, 제품품질, 제약품질시스템, 문서, 밸리데이션, 허가상태, 교정, 유지관리등에미칠파급영향을파악해, 의도하지않았던상황이발생되지않도록하고, 공정밸리데이션, 베리피케이션또는재적격성평가가필요한경우에는계획을세운다 Changes should be authorised and approved by the responsible persons or 29

30 relevant functional personnel in accordance with the pharmaceutical quality system. 제약품질시스템에의거하여책임자나관련부서에속한자가변경을허가하고승인한다 Supporting data, e.g. copies of documents, should be reviewed to confirm that the impact of the change has been demonstrated prior to final approval. 최종승인에앞서변경의영향을증명하는근거데이터 ( 예, 문서사본 ) 를검토한다 Following implementation, and, where appropriate, an evaluation of the effectiveness of change should be carried out to confirm that the change has been successful. 변경을구축한다음에적절한경우에는변경의효과를평가하여변경이성공적으로구축되었음을확인한다. 12. 용어정의 (GLOSSARY) Definitions of terms relating to qualification and validation which are not given in other sections of the current EudraLex, Volume 4, are given below. 적격성평가및밸리데이션과관련된용어가운데현행 EudraLex 볼륨 4의다른섹션에그의미가규정되지않은것의정의는아래와같다. 브라켓방법 (Bracketing approach). A science and risk based validation approach such that only batches on the extremes of certain predetermined and justified design factors, e.g. strength, batch size and/or pack size, are tested during process validation. The design assumes that validation of any intermediate levels is represented by validation of the extremes. Where a range of strengths is to be validated, bracketing could be applicable if the strengths are identical or very closely related in composition, e.g. for a tablet range made with different compression weights of a similar basic granulation or a capsule range made by filling different plug fill weights of the same basic composition into different size capsule shells. Bracketing can be applied to different container sizes or different fills in the same container closure system. 사전에정해놓은타당성있는디자인요소 ( 예, 함량, 배치규모, 포장크기 ) 가운데극한조건에해당되는배치만을시험하는과학과리스크기반밸리데이션방법. 극한조건에서 30

31 밸리데이션이되면중간조건도밸리데이션이된다고가정하는방법이다. 여러함량의제품을밸리데이션하고자하며조성이동일하거나매우유사한경우에브라켓방법을적용할수있다 ( 예, 유사한기본과립을압축중량만다르게하여제조한정제, 동일한조성을충전량을달리하여여러크기의캡슐에충전하여만든캡슐제품 ). 동일한용기마개시스템이면서용기크기나충전량만다른경우에도브라켓방법을적용할수있다. 변경관리 (Change Control). A formal system by which qualified representatives of appropriate disciplines review proposed or actual changes that might affect the validated status of facilities, systems, equipment or processes. The intent is to determine the need for action to ensure and document that the system is maintained in a validated state. 적정분야의자격을갖춘대표자가시설, 시스템, 설비또는공정의밸리데이션상태에영향을줄수있는예정또는실제변경사항을검토하는공식시스템. 해당시스템이밸리데이션상태를유지하는지확인하고문서화하기위한조치의필요성을결정하는데목적이있다. 세척밸리데이션 (Cleaning Validation). Cleaning validation is documented evidence that an approved cleaning procedure will reproducibly remove the previous product or cleaning agents used in the equipment below the scientifically set maximum allowable carryover level. 세척밸리데이션은승인된세척절차로설비를세척하는경우에그설비에서처리한이전제품이나세척제가, 과학적으로설정한최대허용이월수준이하로재현성있게제거됨을보여주는증거문서를확립하는활동이다. 세척베리피케이션 (Cleaning verification). The gathering of evidence through chemical analysis after each batch/campaign to show that the residues of the previous product or cleaning agents have been reduced below the scientifically set maximum allowable carryover level. 각배치 / 캠페인생산이후에화학적분석을실시해, 이전제품또는세척제잔류물이과학적으로설정한최대허용이월수준이하로감소되었다는증거를수집하는활동이다. 동시적밸리데이션 (Concurrent Validation). Validation carried out in exceptional circumstances, justified on the basis of significant patient benefit, where the validation protocol is executed concurrently with commercialisation of the validation batches. 환자에게유의미한혜택이있음을토대로타당성이입증된예외적인상황에서실시하는 31

32 밸리데이션이며, 밸리데이션배치의상업화와동시에밸리데이션프로토콜에따라 밸리데이션을실시한다. 계속적공정베리피케이션 (Continuous process verification). An alternative approach to process validation in which manufacturing process performance is continuously monitored and evaluated. (ICH Q8) 제조공정성능을계속해서모니터하고평가하는, 공정밸리데이션의한방법. (ICH Q8) 관리전략 (Control Strategy). A planned set of controls derived from current product and process understanding that ensures process performance and product quality. The controls can include parameters and attributes related to drug substance and drug product materials and components, facility and equipment operating conditions, in-process controls, finished product specifications and the associated methods and frequency of monitoring and control. (ICH Q10) 제품및공정에대한현재의지식을바탕으로정하며, 공정성능과제품품질을보장하기위한관리세트. 관리항목으로는원료의약품과의약품원료및자재와관련된파라미터와특성요소, 시설및설비운전조건, IPC, 최종제품규격, 모니터및관리방법과주기등이있다. (ICH Q10) CPP(Critical process parameter). A process parameter whose variability has an impact on a critical quality attribute and therefore should be monitored or controlled to ensure the process produces the desired quality. (ICH Q8) 변동이발생하면 CQA에영향을주므로공정이원하는품질을생산하도록하기위해모니터또는관리해야하는공정파라미터. (ICH Q8) CQA(Critical quality attribute). A physical, chemical, biological or microbiological property or characteristic that should be within an approved limit, range or distribution to ensure the desired product quality. (ICH Q8) 원하는제품품질을보장하기위하여적절한한도, 범위, 또는분포이내에있어야하는, 물리적, 화학적, 생물학적, 또는미생물학적특징이나특성. (ICH Q8) 설계적격성평가 (Design qualification; DQ). The documented verification that the proposed design of the facilities, systems and equipment is suitable for the intended purpose. 시설, 시스템, 설비의예정디자인이목적용도에적합함을확인하고문서화하는절차. 32

33 디자인스페이스 (Design Space). The multidimensional combination and interaction of input variables, e.g. material attributes, and process parameters that have been demonstrated to provide assurance of quality. Working within the design space is not considered as a change. Movement out of the design space is considered to be a change and would normally initiate a regulatory post approval change process. Design space is proposed by the applicant and is subject to regulatory assessment and approval. (ICH Q8) 품질보증과의연관성이증명된공정파라미터와투입변수 ( 예, 물품특성요소 ) 의다차원적조합과상호작용. 디자인스페이스안에서의작업은변경으로간주되지않는다. 디자인스페이스를벗어나는것은변경으로간주되며일반적으로규제기관에변경신청을해야한다. 디자인스페이스는신청업체가제안하며규제기관의평가와승인을받는다 (ICH Q8). 설치적격성평가 (Installation Qualification; IQ). The documented verification that the facilities, systems and equipment, as installed or modified, comply with the approved design and the manufacturer's recommendations. 설치또는변형상태의시설, 시스템, 설비가승인된디자인및제조업체의권고사항에부합함을확인하고문서화하는절차. 지식관리 (Knowledge management). A systematic approach to acquire, analyse, store and disseminate information. (ICH Q10) 정보를체계적으로획득하고분석하고보관하고유포하는방법. (ICH Q10) 라이프사이클 (Lifecycle). All phases in the life of a product, equipment or facility from initial development or use through to discontinuation of use. 초기개발또는사용부터사용중단에이르는제품, 설비또는시설의일생에걸친모든단계. 지속적공정베리피케이션 (Ongoing Process Verification 또는 continued process verification). Documented evidence that the process remains in a state of control during commercial manufacture. 상업적제조시에공정이관리상태에있음을보여주는증거문서. 운전적격성평가 (Operational Qualification; OQ). The documented verification that the facilities, systems and equipment, as installed or modified, perform as intended throughout the anticipated operating ranges. 33

34 설치또는변형상태의시설, 시스템, 설비가예정운전범위에서예상대로작동됨을 확인하고문서화하는절차. 성능적격성평가 (Performance Qualification; PQ). The documented verification that systems and equipment can perform effectively and reproducibly based on the approved process method and product specification. 시스템과설비가승인된공정방법과제품규격을토대로효과적이고재현성있게성능을발휘할수있음을확인하고문서화하는절차. 공정밸리데이션 (Process Validation). The documented evidence that the process, operated within established parameters, can perform effectively and reproducibly to produce a medicinal product meeting its predetermined specifications and quality attributes. 설정파라미터이내에서작업했을때사전설정규격과품질특성에부합하는의약품을효과적이고재현성있게생산할수있음을보여주는증거문서. 제품구현 (Product realisation). Achievement of a product with the quality attributes to meet the needs of patients, health care professionals and regulatory authorities and internal customer requirements. (ICH Q10) 환자, 의료전문가, 규제기관, 내부고객의요구를충족시키는품질특성을갖춘제품의달성. (ICH Q10) 예측적밸리데이션 (Prospective Validation). Validation carried out before routine production of products intended for sale. 판매를목적으로하는제품의생산에앞서실시하는밸리데이션. QbD(Quality by design). A systematic approach that begins with predefined objectives and emphasises product and process understanding and process control, based on sound science and quality risk management. 목적을미리규정하여시작하며과학과품질리스크관리를토대로하여제품과공정이해및공정관리를강조하는체계적인방법. 품질리스크관리 (Quality risk management). A systematic process for the assessment, control, communication and review of risks to quality across the lifecycle. (ICH Q9) 라이프사이클전체에걸쳐품질에대한리스크의평가, 통제, 커뮤니케이션, 검토를위한 34