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1 EUROPEAN COMMISSION ENTERPRISE DIRECTORATE-GENERAL 2001 년 7 월, 브뤼셀 Working Party on Control of Medicines and Inspections EC GUIDE TO GOOD MANUFACTURING PRACTICE REVISION TO ANNEX 15 제목 : 적격성평가및밸리데이션 초안작성그룹 1 차논의 WPCMI 논의제약위원회의견접수를위해배포의견제출마감최종승인 (Inspector's Working Party) 제약위원회 ( 참고용 ) 시행일자 1999년 9월 16일 1999년 9월 28일 1999년 10월 30일 2000년 2월 28일 2000년 12월 2001년 4월 2001년 9월 1

2 부록 15. 적격성평가및밸리데이션 원칙 (Principle) 1. This Annex describes the principles of qualification and validation which are applicable to the manufacture of medicinal products. It is a requirement of GMP that manufacturers identify what validation work is needed to prove control of the critical aspects of their particular operations. Significant changes to the facilities, the equipment and the processes, which may affect the quality of the product, should be validated. A risk assessment approach should be used to determine the scope and extent of validation. 의약품제조에적용되는적격성평가와밸리데이션의기본원칙을설명한다. GMP 기준에따라, 의약품제조업체는특정작업의중요부분이관리되고있음을증명하기위해필요한밸리데이션업무범위를파악해야한다. 시설, 설비, 공정에중대한변경이발생되고그변경이제품품질에영향을줄수있는경우에는밸리데이션을실시해야한다. 리스크평가 (risk assessment) 를통해밸리데이션범위와규모를결정한다. 밸리데이션계획 (PLANNING FOR VALIDATION) 2. All validation activities should be planned. The key elements of a validation programme should be clearly defined and documented in a validation master plan (VMP) or equivalent documents. 모든밸리데이션업무를사전에계획해야한다. 밸리데이션프로그램의핵심요소를명확히규정하고밸리데이션종합계획서 (VMP) 또는그에상응하는문서를작성해야한다. 3. The VMP should be a summary document which is brief, concise and clear. VMP 는간단하고압축적이고명확하게작성된요약문서이다. 4. The VMP should contain data on at least the following: 적어도다음에관한데이터가 VMP 에포함되어야한다. 2

3 (a) (b) (c) (d) (e) (f) (g) validation policy; 밸리데이션방침 organisational structure of validation activities; 밸리데이션수행을위한조직구조 summary of facilities, systems, equipment and processes to be validated; 밸리데이션대상이되는시설, 시스템, 설비, 공정에대한간단한설명 documentation format: the format to be used for protocols and reports; 문서서식 : 프로토콜과보고서서식 planning and scheduling; 실시계획및일정 change control; 변경관리 reference to existing documents. 참고문서 5. In case of large projects, it may be necessary to create separate validation master plans. 대규모프로젝트인경우에는 VMP 를여러개로만들수있다. 문서 (DOCUMENTATION) 6. A written protocol should be established that specifies how qualification and validation will be conducted. The protocol should be reviewed and approved. The protocol should specify critical steps and acceptance criteria. 적격성평가및밸리데이션실시방법을규정한프로토콜을작성해야한다. 이프로토콜을검토하고승인한다. 중요단계와허용기준이프로토콜에규정되어있어야한다. 7. A report that cross-references the qualification and/or validation protocol should be prepared, summarising the results obtained, commenting on any deviations observed, and drawing the necessary conclusions, including recommending changes necessary to correct deficiencies. Any changes to the plan as defined in the protocol should be documented with appropriate 3

4 justification. 결과를요약하고일탈사항에대해의견을제시하며문제부분의시정에필요한변경의권고를포함해결론을도출한보고서를작성해야하며, 이보고서는적격성평가 / 밸리데이션프로토콜과상호참조가가능해야한다. 프로토콜에규정된계획이변경된경우에는그내용을기록하고타당성을설명해야한다. 8. After completion of a satisfactory qualification, a formal release for the next step in qualification and validation should be made as a written authorisation. 적격성평가가만족스럽게완료되고적격성평가및밸리데이션의다음단계로넘어갈때, 공식적인절차를통해문서로승인을받아야한다. 적격성평가 (QUALIFICATION) 설계적격성평가 (Design qualification) 9. The first element of the validation of new facilities, systems or equipment could be design qualification (DQ). 신규시설, 시스템, 또는설비의밸리데이션에서첫번째요소는설계적격성평가 (DQ) 이다. 10. The compliance of the design with GMP should be demonstrated and documented. 설계상태가 GMP 에부합함을증명하고문서화해야한다. 설치적격성평가 (Installation qualification) 11. Installation qualification (IQ) should be performed on new or modified facilities, systems and equipment. 신규또는변형시설, 시스템, 설비에대해설치적격성평가 (IQ) 를실시해야한다. 12. IQ should include, but not be limited to the following: IQ 는다음을포함하되이에국한되지않는다. (a) installation of equipment, piping, services and instrumentation 4

5 checked to current engineering drawings and specifications; 현재의엔지니어링도면및규격에대비하여설비, 배관, 서비스, 계측 장치의설치상태점검 (b) collection and collation of supplier operating and working instructions and maintenance requirements; 공급업체가제공한운전및작업지시문서와유지관리기준의취합과대조 조사 (c) (d) calibration requirements; 교정기준 verification of materials of construction. 재질의확인 운전적격성평가 (Operational qualification) 13. Operational qualification (OQ) should follow Installation qualification. 설치적격성평가다음에운전적격성평가 (OQ) 를실시한다. 14. OQ should include, but not be limited to the following: OQ 는다음을포함하되이에국한되지않는다. (a) (b) tests that have been developed from knowledge of processes, systems and equipment; 공정, 시스템, 설비에대한지식을바탕으로개발한실험 tests to include a condition or a set of conditions encompassing upper and lower operating limits, sometimes referred to as worst case conditions. 상하한운전기준 (" 최악의조건 " 이라고도함 ) 을포괄하는조건에서의실험 15. The completion of a successful Operational qualification should allow the finalisation of calibration, operating and cleaning procedures, operator training and preventative maintenance requirements. It should permit a formal "release" of the facilities, systems and equipment. OQ가성공적으로종료되면교정, 운전및세척절차, 작업자교육및예방적유지관리기준의마무리작업이이루어져야한다. 해당시설, 시스템, 설비가공식적으로 " 승인 " 된다. 5

6 성능적격성평가 (Performance qualification) 16. Performance qualification (PQ) should follow successful completion of Installation qualification and Operational qualification. 설치적격성평가및운전적격성평가가성공적으로완료된다음에성능적격성평가 (PQ) 를실시한다. 17. PQ should include, but not be limited to the following: PQ 는다음을포함하되이에국한되지않는다. (a) tests, using production materials, qualified substitutes or simulated product, that have been developed from knowledge of the process and the facilities, systems or equipment; 공정및시설, 시스템또는설비에대한지식을바탕으로개발된실험으로서실제생산물품, 적합한대체물품또는시뮬레이션제품을이용한실험 (b) tests to include a condition or set of conditions encompassing upper and lower operating limits. 상하한운전기준을포괄하는조건에서의실험 18. Although PQ is described as a separate activity, it may in some cases be appropriate to perform it in conjunction with OQ. PQ를별도의업무로설명하고있지만, 때로는 OQ와연계하여실시하는것이더적절할수있다. 기존 ( 사용중인 ) 시설, 시스템, 설비의적격성평가 (Qualification of established (inuse) facilities, systems and equipment) 19. Evidence should be available to support and verify the operating parameters and limits for the critical variables of the operating equipment. Additionally, the calibration, cleaning, preventative maintenance, operating procedures and operator training procedures and records should be documented. 사용중인설비의운전변수와중요변수별기준을뒷받침하고확인할수있는 6

7 증거가있어야한다. 또한교정, 세척, 예방적유지관리, 운전절차, 운전자교육 훈련절차및기록이문서화되어있어야한다. 공정밸리데이션 (PROCESS VALIDATION) 공통 (General) 20. The requirements and principles outlined in this chapter are applicable to the manufacture of pharmaceutical dosage forms. They cover the initial validation of new processes, subsequent validation of modified processes and re-validation. 여기서기술하고있는기준과원칙은완제의약품의제조에적용된다. 새로운공정의최초밸리데이션과변형된공정의밸리데이션, 재밸리데이션을대상으로한다. 21. Process validation should normally be completed prior to the distribution and sale of the medicinal product (prospective validation). In exceptional circumstances, where this is not possible, it may be necessary to validate processes during routine production (concurrent validation). Processes in use for some time should also be validated (retrospective validation). 공정밸리데이션은일반적으로의약품의유통및판매에앞서완료되어야한다 ( 예측적밸리데이션 ). 예측적밸리데이션이가능하지않은예외적인경우에는정상적인생산과정중에공정밸리데이션을실시할필요가있다 ( 동시적밸리데이션 ). 기존생산공정또한밸리데이션되어야한다 ( 회고적밸리데이션 ). 22. Facilities, systems and equipment to be used should have been qualified and analytical testing methods should be validated. Staff taking part in the validation work should have been appropriately trained. 예정시설, 시스템, 설비의적격성평가가완료되어있어야하며, 분석방법역시밸리데이션되어야한다. 밸리데이션작업에참여하는작업자에대해적절한교육훈련이실시되어야한다. 23. Facilities, systems, equipment and processes should be periodically evaluated to verify that they are still operating in a valid manner. 시설, 시스템, 설비, 공정을주기적으로평가하여여전히유효한상태를유지하고 7

8 있는지확인해야한다. 예측적밸리데이션 (Prospective validation) 24. Prospective validation should include, but not be limited to the following: 예측적밸리데이션은다음을포함하되이에국한되지않는다. (a) (b) short description of the process; 공정에대한간단한설명 summary of the critical processing steps to be investigated; 조사대상주요공정단계에대한요약설명 (c) list of the equipment/facilities to be used (including measuring/monitoring/recording equipment) together with its calibration status 공정에사용되는설비 / 시설리스트 ( 측정 / 모니터 / 기록장치포함 ) 와교정 상태 (d) (e) (f) finished product specifications for release; 최종제품출하규격 list of analytical methods, as appropriate; 분석방법리스트 proposed in-process controls with acceptance criteria; 예정공정관리 (IPC) 항목과허용기준 (g) additional testing to be carried out, with acceptance criteria and analytical validation, as appropriate; 실시예정인추가시험항목과허용기준, 분석방법밸리데이션 (h) (i) (j) (k) sampling plan; 검체채취계획 methods for recording and evaluating results 결과의기록과평가방법 functions and responsibilities; 업무분장 proposed timetable. 일정 25. Using this defined process (including specified components) a series of 8

9 batches of the final product may be produced under routine conditions. In theory the number of process runs carried out and observations made should be sufficient to allow the normal extent of variation and trends to be established and to provide sufficient data for evaluation. It is generally considered acceptable that three consecutive batches/runs within the finally agreed parameters, would constitute a validation of the process. 확립된공정절차에따라 ( 지정원자재를사용하여 ) 정상생산조건에서일련의배치를생산한다. 이론적으로는정상적인편차와경향을파악하고평가에필요한데이터를충분히확보할수있을정도의횟수로밸리데이션배치를생산해야한다. 최종확정된변수범위이내에서 3회연속배치를생산하여밸리데이션하는것이일반적으로인정된다. 26. Batches made for process validation should be the same size as the intended industrial scale batches. 공정밸리데이션배치의제조단위는예정제조단위와동일해야한다. 27. If it is intended that validation batches be sold or supplied, the conditions under which they are produced should comply fully with the requirements of Good Manufacturing Practice, including the satisfactory outcome of the validation exercise, and with the marketing authorisation. 밸리데이션배치를판매하거나공급할계획인경우, 밸리데이션배치의생산조건은 GMP 기준과판매허가조건에부합해야한다. 밸리데이션결과역시적합해야한다. 동시적밸리데이션 (Concurrent validation) 28. In exceptional circumstances it may be acceptable not to complete a validation programme before routine production starts. 예외적인경우에는실제생산을시작하기전까지밸리데이션프로그램이완료되지않을수도있다. 29. The decision to carry out concurrent validation must be justified, documented and approved by authorised personnel. 허가받은자가동시적밸리데이션의실시결정에대해타당성을입증하고문서화하고승인해야한다. 9

10 30. Documentation requirements for concurrent validation are the same as specified for prospective validation. 동시적밸리데이션의문서기준은예측적밸리데이션의경우와동일하다. 회고적밸리데이션 (Retrospective validation) 31. Retrospective validation is only acceptable for well-established processes and will be inappropriate where there have been recent changes in the composition of the product, operating procedures or equipment. 회고적밸리데이션은확립된공정에대해서만허용되며, 최근에제품조성이나운전절차, 또는설비에변경이발생한경우에는적절하지않다. 32. Validation of such processes should be based on historical data. The steps involved require the preparation of a specific protocol and the reporting of the results of the data review, leading to a conclusion and a recommendation. 확립된공정의회고적밸리데이션은기존자료를바탕으로한다. 회고적밸리데이션을실시할때도프로토콜을만들고자료검토결과를정리하여결론과권고사항을포함한보고서를만든다. 33. The source of data for this validation should include, but not be limited to batch processing and packaging records, process control charts, maintenance log books, records of personnel changes, process capability studies, finished product data, including trend cards and storage stability results. 회고적밸리데이션의검토대상이되는자료는배치가공및포장기록서, 공정관리도, 유지관리기록문서, 작업자변경기록서, 공정성능조사자료, 최종제품품질동향분석과품질관리자료, 안정성결과를포함하되이에국한되지않는다. 34. Batches selected for retrospective validation should be representative of all batches made during the review period, including any batches that failed to meet specifications, and should be sufficient in number to demonstrate process consistency. Additional testing of retained samples may be needed 10

11 to obtain the necessary amount or type of data to retrospectively validate the process. 회고적밸리데이션대상으로선정된배치는검토대상기간동안제조된모든배치를대표할수있어야하며, 규격에부합하지않았던배치도포함시켜야한다. 또한그수는공정의일관성을보여줄수있을정도로충분해야한다. 회고적공정밸리데이션을위해필요한양또는유형의데이터확보를목적으로보관품에대한추가시험이필요할수있다. 35. For retrospective validation, generally data from ten to thirty consecutive batches should be examined to assess process consistency, but fewer batches may be examined if justified. 회고적밸리데이션의경우에공정일관성을평가하기위해일반적으로 10개내지 30개의연속배치자료를검토해야하지만, 타당성이입증되는경우에는더적은수의배치를검토할수도있다. 세척밸리데이션 (CLEANING VALIDATION) 36. Cleaning validation should be performed in order to confirm the effectiveness of a cleaning procedure. The rationale for selecting limits of carry over of product residues, cleaning agents and microbial contamination should be logically based on the materials involved. The limits should be achievable and verifiable. 세척절차의효과확인을위해세척밸리데이션을실시해야한다. 제품잔류물, 세척제, 미생물오염의이월기준은관련물질을바탕으로논리적으로설정해야한다. 이기준은달성가능하고확인가능해야한다. 37. Validated analytical methods having sensitivity to detect residues or contaminants should be used. The detection limit for each analytical method should be sufficiently sensitive to detect the established acceptable level of the residue or contaminant. 잔류물또는오염물질을검출할수있을정도의민감도를지닌밸리데이션된분석방법을사용해야한다. 각분석방법의검출한계는잔류물또는오염물질의허용수준을검출할수있을정도로충분히민감해야한다. 38. Normally only cleaning procedures for product contact surfaces of the 11

12 equipment need to be validated. Consideration should be given to noncontact parts. The intervals between use and cleaning as well as cleaning and reuse should be validated. Cleaning intervals and methods should be determined. 일반적으로는설비의제품접촉표면에대한세척절차만을밸리데이션할필요가있다. 하지만비접촉표면에대한검토도있어야한다. 사용과세척사이의기간과세척과재사용사이의기간도밸리데이션대상이된다. 세척간격과방법을결정해야한다. 39. For cleaning procedures for products and processes which are similar, it is considered acceptable to select a representative range of similar products and processes. A single validation study utilising a worst case approach can be carried out which takes account of the critical issues. 유사한제품과공정의세척절차인경우, 유사제품및공정에서대표적인부분을선정하여밸리데이션하는것도허용된다. 가장중요한사항을고려하여 " 최악의경우 " 방법을활용해단일밸리데이션시험을실시할수도있다. 40. Typically three consecutive applications of the cleaning procedure should be performed and shown to be successful in order to prove that the method is validated. 일반적으로어떤세척절차가밸리데이션되었다고하려면, 세척을 3회연속실시하여모두성공적으로완료되어야한다. 41. "Test until clean" is not considered an appropriate alternative to cleaning validation. " 깨끗할때까지시험 " 하는것은세척밸리데이션의방법으로적당하지않다. 42. Products which simulate the physicochemical properties of the substances to be removed may exceptionally be used instead of the substances themselves, where such substances are either toxic or hazardous. 제거대상성분이독성을갖고있거나위험한경우에는예외적으로그성분의이화학적특성과유사한제품을대신사용할수있다. 변경관리 (CHANGE CONTROL) 12

13 43. Written procedures should be in place to describe the actions to be taken if a change is proposed to a starting material, product component, process equipment, process environment (or site), method of production or testing or any other change that may affect product quality or reproducibility of the process. Change control procedures should ensure that sufficient supporting data are generated to demonstrate that the revised process will result in a product of the desired quality, consistent with the approved specifications. 출발물질, 제품조성, 공정설비, 공정환경 ( 또는사업장 ), 생산또는시험방법, 또는공정의재현성이나제품품질에영향을줄수있는변경이예정된경우에취할조치를기술한절차문서가구비되어있어야한다. 바뀐공정에서도승인된규격에일치하는원하는품질의제품이생산될수있음을증명하는충분한근거자료가변경관리과정에서확보될수있어야한다. 44. All changes that may affect product quality or reproducibility of the process should be formally requested, documented and accepted. The likely impact of the change of facilities, systems and equipment on the product should be evaluated, including risk analysis. The need for, and the extent of, requalification and re-validation should be determined. 제품품질이나공정의재현성에영향을줄수있는모든변경을공식적으로요청하고문서화하고접수한다. 시설, 시스템, 설비의변경이제품에미칠영향을평가해야한다. 이때리스크분석 (RA) 도실시한다. 재적격성평가및재밸리데이션의필요성과그규모를결정해야한다. 재밸리데이션 (REVALIDATION) 45. Facilities, systems, equipment and processes, including cleaning, should be periodically evaluated to confirm that they remain valid. Where no significant changes have been made to the validated status, a review with evidence that facilities, systems, equipment and processes meet the prescribed requirements fulfils the need for revalidation. 시설, 시스템, 설비및공정 ( 세척절차포함 ) 을주기적으로평가하여유효한상태가유지되고있는지확인해야한다. 밸리데이션상태에큰변화가없다면시설, 시스템, 설비, 공정이규정된기준에부합한다는증거에대한검토만으로도재밸리데이션의필요성을충족시킨다. 13

14 용어정의 (GLOSSARY) Definitions of terms relating to qualification and validation which are not given in the glossary of the current EC Guide to GMP, but which are used in this Annex, are given below. 적격성평가및밸리데이션과관련된용어가운데현행 EC GMP 가이드에그의미가규정되어있지않은것의정의는아래와같다. 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 that would ensure and document that the system is maintained in a validated state. 적정분야의자격을갖춘대표자가시설, 시스템, 설비, 또는공정의밸리데이션상태에영향을줄수있는변경안또는변경사항을검토하는공식시스템. 해당시스템이밸리데이션상태를유지하도록보증하고문서화하기위한조치사항을결정해야한다. 세척밸리데이션 (Cleaning Validation) Cleaning validation is documented evidence that an approved cleaning procedure will provide equipment which is suitable for processing medicinal products. 세척밸리데이션은승인된세척절차를통해설비를세척하면의약품처리에적합한상태가된다는점을보여주는문서화된증거이다. 동시적밸리데이션 (Concurrent Validation) Validation carried out during routine production of products intended for sale. 판매를목적으로제품을생산하는도중에실시하는밸리데이션. 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, 설비의설계안이목적용도에적합함을확인하여문서화하는절차. 설치적격성평가 (Installation Qualification (IQ)) The documented verification that the facilities, systems and equipment, as installed 14

15 or modified, comply with the approved design and the manufacturer s recommendations. 설치또는변형된상태의시설, 시스템, 설비가승인된설계문서및제조업체의권고사항에부합함을확인하여문서화하는절차. 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. 설치또는변형된상태의시설, 시스템, 설비가예정운전범위안에서예상대로작동됨을확인하여문서화하는절차. 성능적격성평가 (Performance Qualification (PQ)) The documented verification that the facilities, systems and equipment, as connected together, can perform effectively and reproducibly, based on the approved process method and product specification. 시설, 시스템, 설비가서로연결된상태에서승인된공정방법과제품규격을토대로효과적이고재현성있게성능을발휘할수있음을확인하여문서화하는절차. 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. 설정된범위이내에서작업했을때사전에설정된규격과품질특성에부합하는의약품을효과적이고재현성있게생산할수있음을보여주는문서화된증거. 예측적밸리데이션 (Prospective Validation) Validation carried out before routine production of products intended for sale. 판매용의약품의정식생산에앞서실시하는밸리데이션. 회고적밸리데이션 (Retrospective Validation) Validation of a process for a product which has been marketed based upon accumulated manufacturing, testing and control batch data. 이미시판중에있는제품의공정에대하여축적된제조, 시험, 관리데이터를근거로실시하는밸리데이션. 15

16 재밸리데이션 (Re-Validation) A repeat of the process validation to provide an assurance that changes in the process/equipment introduced in accordance with change control procedures do not adversely affect process characteristics and product quality. 변경관리절차에의거하여도입된공정 / 설비의변경이공정특성및제품품질에부정적인영향을주지않는다는점을보증하기위해공정밸리데이션을반복하는것. 리스크분석 (Risk analysis) Method to assess and characterise the critical parameters in the functionality of an equipment or process. 설비또는공정의기능부분에서중요변수를평가하고특성을파악하는방법.. 시뮬레이션제품 (Simulated Product) A material that closely approximates the physical and, where practical, the chemical characteristics (e.g. viscosity, particle size, ph etc.) of the product under validation. In many cases, these characteristics may be satisfied by a placebo product batch. 밸리데이션대상제품의물리적특성과실질적으로가능한경우에화학적특성 ( 예, 점도, 입도, ph 등 ) 이아주유사한물품. 위약제품배치로이런특성이충족되는경우가많다. 시스템 (System) A group of equipment with a common purpose. 공통의목적을지닌설비그룹. 최악의경우 (Worst Case) A condition or set of conditions encompassing upper and lower processing limits and circumstances, within standard operating procedures, which pose the greatest chance of product or process failure when compared to ideal conditions. Such conditions do not necessarily induce product or process failure. 표준작업절차범위이내의상 / 하한공정기준을포함하는조건으로써, 이상적인조건과비교했을때제품이나공정에이상이발생될가능성이가장큰경우. 반드시제품또는공정이상을유발하는조건일필요는없다. 16