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Guidance for Industry OOS 시험결과의조사 (Investigating Out of Specification (OOS) Test Results for Pharmaceutical Production) U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) October 2006 Pharmaceutical CGMPs www..co.kr 1

Guidance for Industry OOS 시험결과의조사 (Investigating Out of Specification (OOS) Test Results for Pharmaceutical Production) Additional copies are available from: Office of Training and Communication Division of Drug Information HFD-240 Center for Drug Evaluation and Research Food and Drug Administration 5600 Fishers Lane Rockville, MD 20857 (Tel) 301-827-4573 http://www.fda.gov/cder/guidance/index.htm U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) October 2006 Pharmaceutical CGMPs www..co.kr 2

[ 목차 ] I. 서론 (INTRODUCTION) II. III. 배경 (BACKGROUND) OOS 시험결과파악및평가 - I 단계 : 시험소조사 (IDENTIFYING AND ASSESSING OOS TEST RESULTS PHASE I: LABORATORY INVESTIGATION) A. 시험자의책임 (Responsibility of the Analyst) B. 관리자의책임 (Responsibilities of the Laboratory Supervisor) IV. OOS 시험결과의조사 - II 단계 : 전면적 OOS 조사 (INVESTIGATING OOS TEST RESULTS - PHASE II: FULL-SCALE OOS INVESTIGATION) A. 생산검토 (Review of Production) B. 추가시험 (Additional Laboratory Testing) C. 시험결과의보고 (Reporting Testing Results) V. 조사종결 (CONCLUDING THE INVESTIGATION) A. 조사결과의해석 (Interpretation of Investigation Results) B. 주의 (Cautions) C. FAR(Field Alert Reports) www..co.kr 3

GUIDANCE FOR INDUSTRY 1 Investigating Out of Specification (OOS) Test Results for Pharmaceutical Production This guidance represents the Food and Drug Administration's (FDA's) current thinking on this topic. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. You can use an alternative approach if the approach satisfies the requirements of the applicable statutes and regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for implementing this guidance. If you cannot identify the appropriate FDA staff, call the appropriate number listed on the title page of this guidance. 이가이드문서는이주제에대한 FDA의방침을제시한다. 이문서는어느누구에게일체의권리를부여하거나인정하지않으며 FDA 또는일반대중을구속하지도않는다. 관련법규에제시된기준을만족시킬수있는다른방법이있다면, 그방법을활용할수도있다. 다른방법을협의하고자한다면, 해당 FDA 담당자에게연락한다. 관련 FDA 담당자가누구인지알수없다면, 이문서의표지에제시된번호로전화를한다. I. 서론 (INTRODUCTION) This guidance for industry provides the Agency s current thinking on how to evaluate out-of-specification (OOS) test results. For purposes of this document, the term OOS results includes all test results that fall outside the specifications or acceptance criteria established in drug applications, drug master files (DMFs), official compendia, or by the manufacturer. The term also applies to all in-process laboratory tests that are outside of established specifications 2. 1 This guidance has been prepared by the Office of Compliance/Division of Manufacturing and Product Quality in the Center for Drug Evaluation and Research (CDER). 이가이드문서는 CDER Office of Compliance/Division of Manufacturing and Product Quality 가작성했다. 2 In certain instances, in-process testing is done solely for purposes of triggering real time equipment or system adjustments to prevent process drift. This guidance does not address these situations. www..co.kr 4

이가이드문서는 OOS(Out of Specification) 시험결과의평가방법에관한 FDA의방침을제시한다. 여기서 OOS 결과라함은의약품신청서류, DMF, 공식공정서에규정된규격또는허용기준, 또는제조업체가설정한규격또는허용기준에서벗어난모든시험결과를의미한다. 또한공정중시험결과가설정규격을벗어난경우에도적용한다. This guidance applies to chemistry-based laboratory testing of drugs regulated by CDER. It is directed toward traditional drug testing and release methods. These laboratory tests are performed on active pharmaceutical ingredients, excipients and other components, in-process materials, and finished drug products 3 to the extent that current good manufacturing practice (CGMP) regulations (21 CFR parts 210 and 211) and the Federal Food, Drug, and Cosmetic Act (the Act) (section 501(a)(2)(B)) apply. The principles in this guidance also apply to in-house testing of drug product components that are purchased by a firm. This guidance can also be used by contract firms performing production and/or laboratory testing responsibilities. Specifically, the guidance discusses how to investigate OOS test results, including the responsibilities of laboratory personnel, the laboratory phase of the investigation, additional testing that may be necessary, when to expand the investigation outside the laboratory, and the final evaluation of all test results. 이가이드문서는 CDER 규제대상의약품의화학적시험에적용한다. 기존의의약품시험및승인방법을대상으로한다. CGMP 규정 (21 CFR Parts 210/211) 및연방식품의약품화장품법 (FD&C법)( 섹션 501(a)(2)(B)) 이적용되는, 활성제약성분, 첨가물, 기타원료, 공정중물품, 최종제품의시험이대상이다. 이가이드문서에제시된원칙을구매하는의약품원료의자체시험에도적용할수있다. 또한생산및 / 또는품질시험업무를수행하는수탁업체도이가이드문서를활용할수있다. 보다구체적으로말하면, 이가이드문서는시험작업자의책임, 시험소차원의조사, 필요한경우에공정표류방지를위하여실시간으로설비또는시스템조정을실시할목적으로공정중시험을실시하는경우도있다. 3 Chemistry-based laboratory testing of biotechnology products that are under the jurisdiction of CDER are within the scope of this guidance. However, this guidance is not intended to address biological assays (e.g., in vivo, immunoassays). CDER 규제대상인생명공학제품의화학적시험은이가이드문서의적용범위에속 한다. 하지만이가이드문서는생물학적분석 ( 예, 체내, 면역분석 ) 은대상으로하지 않는다. www..co.kr 5

실시하는추가시험, 조사범위를시험소이외부분으로확대시키는시점, 모든시험 결과의최종평가를포함하여 OOS 시험결과의조사방법을제시한다. The Agency, in accordance with its August 2002 Pharmaceutical CGMPs for the 21st Century initiative, encourages modern approaches to manufacturing, monitoring, and control to enhance process predictability and efficiency. Process Analytical Technology (PAT) takes a different approach to quality assurance by using process controls and in-process data as the release specification instead of relying on single laboratory determinations to make batch acceptability decisions. This guidance is not intended to address PAT approaches, as routine in-process use of these methods might include other considerations. For information on timely inprocess testing, see the CGMP guidance entitled PAT A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance. 2002년 8월의 "21세기제약 CGMP" 프로젝트에따라, FDA는공정예측성및효율성 증진을위하여현대적인제조, 모니터, 관리방식을권장하고있다. PAT(Process Analytical Technology) 는배치의적합성결정에있어서시험소의결정에만의존하기보다는, 공정관리및공정중데이터를출하승인규격으로활용하는다른품질보증방식을취한다. 이가이드문서는 PAT 접근방식을깊게제시하기위한것이아니다. 이방법을공정관리에정식으로활용하기위해서는다른부분도고려해야하기때문이다. 적시공정중시험에관한자세한사항은, CGMP 가이드문서 ("PAT A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance") 를참조한다. FDA's guidance documents, including this guidance, do not establish legally enforceable responsibilities. Instead, guidances describe the Agency's current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidances means that something is suggested or recommended, but not required. 이가이드문서를포함한 FDA 가이드문서들은법적강제성을지니지않는다. 다만가이드문서는특정주제에대한 FDA의방침을기술하고있으며, 구체적인법적기준이제시되어있지않으면일종의권고사항으로간주한다. FDA 가이드문서에서 "should" 라는표현은어떤것을제안또는권고한다는의미이지반드시그래야한다는의미는아니다. www..co.kr 6

II. 배경 (BACKGROUND) Laboratory testing, which is required by the CGMP regulations ( 211.160 and 211.165), is necessary to confirm that components, containers and closures, inprocess materials, and finished products conform to specifications, including stability specifications. CGMP 규정 ( 211.160 & 211.165) 에따른시험소시험은원료, 용기및마개, 공정중물품, 최종제품이안정성규격을포함하여규격에부합하는지확인하기위한것이다. Testing also supports analytical and process validation efforts. 4 General CGMP regulations covering laboratory operations can be found in part 211, subparts I (Laboratory Controls) and J (Records and Reports). These regulations provide for the establishment of scientifically sound and appropriate specifications, standards, and test procedures that are designed to ensure that components, containers and closures, in-process materials, and finished drug products conform to the established standards. Section 211.165(f) of the CGMP regulations specifies that finished drug products that fail to meet established standards, specifications, or other relevant quality control criteria will be rejected. 또한시험은분석방법밸리데이션및공정밸리데이션을뒷받침하기도한다. 시험소 4 Specifications must be scientifically sound and appropriate ( 211.160(b)), test procedures must be validated as to their accuracy, sensitivity, specificity, and reproducibility ( 211.165(e)), and the suitability of the test procedures under actual conditions of use must be documented ( 211.194(a)(2)). For products that are the subjects of new drug applications (NDAs), abbreviated new drug applications (ANDAs), or investigational new drug applications (INDs), specifications are contained in the application or DMF. Specifications for nonapplication products may be found in official compendia or established by the manufacturer. 규격은과학적으로타당하고적절해야하며 (21 CFR 211.160(b)), 시험절차는 정확성, 민감성, 특이성, 재현성측면에서밸리데이션을실시해야하고 ( 211.165(e)), 실제조건에서시험절차의적합성에관한문서를구비해야한다 ( 211.194(a)(2)). NDA, ANDA, IND 대상제품인경우에규격을신청서류또는 DMF에포함시킨다. 이에해당하지않는제품규격은공식공정서를적용할수있으며, 제조업체가설정할수도있다. www..co.kr 7

작업에관한일반 CGMP 규정은 Part 211, Subpart I( 시험관리 ) 및 J( 기록서및보고서 ) 에제시되어있다. 이들규정에따라원료, 용기및마개, 공정중물품, 최종의약품이설정기준에부합하는지확인할수있도록설계된, 과학적으로타당하고적절한규격, 표준, 시험절차를설정해야한다. CGMP 규정 211.165(f) 는설정표준, 규격또는기타관련품질관리기준에부합하지않는최종의약품은부적합으로처리해야한다고규정하고있다. Both finished pharmaceuticals and active pharmaceutical ingredients (APIs) are to be manufactured in accordance with current good manufacturing practice under section 501(a)(2)(B) of the Act. Current good manufacturing practice for APIs includes the performance of scientifically sound raw material testing, in-process monitoring, release and stability testing, process validation, and adequate investigations of any OOS result obtained from such testing. All citations to part 211 in this document pertain to finished pharmaceuticals, but these referenced regulatory requirements are also consistent with Agency guidance on CGMPs for APIs with respect to laboratory controls, which include out-of-specification investigations. See FDA s guidance for industry Q7A Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients (ICH Q7A) for specific recommendations. 5 최종의약품과 API 모두 FD&C법섹션 501(a)(2)(B) 에의거하여 CGMP에따라제조해야한다. API CGMP는과학적으로타당한원료시험, 공정중모니터, 출하승인및안정성시험, 공정밸리데이션, 그리고그시험에서나온 OOS 결과의적절한조사를포함한다. 이문서에언급한모든파트 211 관련사항은최종의약품에관한것이지만, 이는 OOS 조사를포함한시험관리와관련하여 API CGMP에대한 FDA 가이드라인과도일치한다. 자세한사항은 "Q7A API GMP 가이드문서 (ICH Q7A)" 를참조한다. The responsibility of a contract testing laboratory in meeting these requirements is equivalent to that of a manufacturing firm. 이기준의준수에있어서수탁시험소의책임은제조업체의것과동일하다. 5 We update guidances periodically. To make sure you have the most recent version of a guidance, check the CDER guidance page at http://www.fda.gov/cder/guidance/index.htm. FDA는가이드문서를주기적으로업데이트한다. CDER 가이드문서페이지를방문 하여최신버전인지확인한다. www..co.kr 8

III. OOS 시험결과파악및평가 - I 단계 : 시험소조사 (IDENTIFYING AND ASSESSING OOS TEST RESULTS PHASE I: LABORATORY INVESTIGATION) FDA regulations require that an investigation be conducted whenever an OOS test result is obtained ( 211.192). 6 The purpose of the investigation is to determine the cause of the OOS result. The source of the OOS result should be identified either as an aberration of the measurement process or an aberration of the manufacturing process. Even if a batch is rejected based on an OOS result, the investigation is necessary to determine if the result is associated with other batches of the same drug product or other products. Batch rejection does not negate the need to perform the investigation. The regulations require that a written record of the investigation be made, including the conclusions and follow-up ( 211.192). OOS 시험결과가발생하면조사를실시해야한다. 조사의목적은 OOS 결과의원인을밝혀내는것이다. OOS 결과의원인이측정과정의이상또는제조공정의이상에있는지파악해야한다. OOS 결과에근거하여한배치를부적합처리해도, 그시험결과가동일제품의다른배치또는다른제품과도관계가있는지확인하기위한조사는필요하다. 배치를부적합처리한다고해서조사의필요성이부정되는것은아니다. CGMP 규정에따르면조사결론과사후조치를포함하여조사기록서를작성해야한다 ( 211.192). To be meaningful, the investigation should be thorough, timely, unbiased, welldocumented, and scientifically sound. The first phase of such an investigation should include an initial assessment of the accuracy of the laboratory's data. Whenever possible, this should be done before test preparations (including the composite or the homogenous source of the aliquot tested) are discarded. This way, hypotheses regarding laboratory error or instrument malfunctions can be tested using the same test preparations. If this initial assessment indicates that no meaningful errors were made in the analytical method used to arrive at the data, a full-scale OOS investigation should be conducted. For contract laboratories, the 6 Although the subject of this document is OOS results, much of the guidance may be useful for examining results that are out of trend. 이문서의주제가 OOS 결과이기는하지만, 많은부분은 OOT(out of trend) 결과의 조사에도유용할수있다. www..co.kr 9

laboratory should convey its data, findings, and supporting documentation to the manufacturing firm s quality control unit (QCU), who should then initiate the fullscale OOS investigation. 유의미한조사를위해서는조사를철저하고적시에편견을갖지않고수행하며그내용을문서화하며과학적으로정당해야한다. 이와같은조사작업의첫단계에서는시험데이터의정확성을먼저평가한다. 가능하면시험조제물 ( 시험한것과균질한검체또는복합검체포함 ) 폐기에앞서해야한다. 이때동일시험조제물을사용하여시험소오류나장치의오작동에관련된가설을검증할수있다. 이런초기평가를통해 OOS 데이터가나온분석방법에서유의미한오류가없었다는결론이내려지면, 전면적인 OOS 조사를실시해야한다. 수탁시험소는데이터, 발견사항, 근거문서를제조업체 QCU에전달해야하며, 제조업체 QCU는전면적인 OOS 조사를실시한다. A. 시험자의책임 (Responsibility of the Analyst) The first responsibility for achieving accurate laboratory testing results lies with the analyst who is performing the test. The analyst should be aware of potential problems that could occur during the testing process and should watch for problems that could create inaccurate results. 정확한시험결과를확보할일차적인책임이그시험을수행하는시험자에게있다. 시험자는시험과정에서발생할수있는문제점을인식하고, 부정확한결과를유발할가능성이있는문제점을주시해야한다. In accordance with the CGMP regulations in 211.160 (b)(4), the analyst should ensure that only those instruments meeting established performance specifications are used and that all instruments are properly calibrated. CGMP 규정 ( 211.160(b)(4)) 에의거하여시험자는설정성능규격에부합하는장치만을사용하고, 모든장치가적절하게교정되도록해야한다. Certain analytical methods have system suitability requirements, and systems not meeting these requirements should not be used. For example, in chromatographic systems, reference standard solutions may be injected at intervals throughout chromatographic runs to measure drift, noise, and repeatability. If reference standard responses indicate that the system is not functioning properly, all of the data collected during the suspect time period should be properly identified and www..co.kr 10

should not be used. The cause of the malfunction should be identified and, if possible, corrected before a decision is made whether to use any data prior to the suspect period. 분석방법에따라서는시스템적합성평가가필요하며, 시스템적합성기준을충족시키지못하는시스템을사용해서는안된다. 일례로크로마토그래피시스템은크로마토그래피작업중에참조표준용액을주기적으로주입하여드리프트, 노이즈, 재현성을평가한다. 참조표준용액의반응을통해시스템이적절하게기능을수행하지못하는것으로밝혀지면, 의심스러운기간동안얻은모든데이터를적절하게식별하고사용하지않도록해야한다. 의심기간이전데이터의사용여부를결정하기전에, 오작동의원인을밝히고가능하면시정조치를취해야한다. Analysts should check the data for compliance with test specifications before discarding test preparations or standard preparations. When unexpected results are obtained and no obvious explanation exists, test preparations should be retained, if stable, and the analyst should inform the supervisor. An assessment of the accuracy of the results should be started immediately. 검액이나표준액을폐기하기전에, 시험자는데이터가규격에부합하는지점검해야한다. 예상치않은결과가발생하고그이유를명확하게설명할수없는경우, 검액을보존해야하며 ( 안정한경우 ) 시험자는관리자에게보고해야한다. 결과의정확성평가를즉시시작해야한다. If errors are obvious, such as the spilling of a sample solution or the incomplete transfer of a sample composite, the analyst should immediately document what happened. Analysts should not knowingly continue an analysis they expect to invalidate at a later time for an assignable cause (i.e., analyses should not be completed for the sole purpose of seeing what results can be obtained when obvious errors are known). 검액유출이나검체혼합물의불완전한전달등실수가분명한경우, 시험자는즉시모든사항을기록한다. 명백한이유로인하여나중에무효화될것으로예상되는분석작업을알면서도계속진행해서는안된다 ( 즉명백한실수를알고있는상태에서어떤결과가나올지알아보기위한목적에서분석을진행해서는안된다 ). B. 관리자의책임 (Responsibilities of the Laboratory Supervisor) www..co.kr 11

Once an OOS result has been identified, the supervisor's assessment should be objective and timely. There should be no preconceived assumptions as to the cause of the OOS result. Data should be assessed promptly to ascertain if the results might be attributed to laboratory error, or whether the results could indicate problems in the manufacturing process. An immediate assessment could include reexamination of the actual solutions, test units, and glassware used in the original measurements and preparations, which might provide more credibility for laboratory error hypotheses. 일단 OOS 결과가확인되면, 관리자는적시에객관적으로평가해야한다. OOS 결과의원인에대해미리어떤가정을세워서는안된다. 즉시데이터를평가하여 OOS 시험결과가시험소오류에의한것인지, 아니면제조공정의문제를의미하는지확인한다. 이때최초측정및준비에사용된초자류, 시험검체, 실제시험용액을다시점검하고시험소오류가설을보다철저하게조사한다. The following steps should be taken as part of the supervisor's assessment: 관리자는다음단계를포함하여평가작업을수행한다. 1. Discuss the test method with the analyst; confirm analyst knowledge of and performance of the correct procedure. 시험방법을시험자와협의한다. 시험자가정확한절차를알고있는지, 그대로시행했는지확인한다. 2. Examine the raw data obtained in the analysis, including chromatograms and spectra, and identify anomalous or suspect information. 크로마토그램과스펙트럼을포함하여분석과정에서확보한기초데이터를조사하고비정상적인것또는의심스러운정보사항을파악한다. 3. Verify that the calculations used to convert raw data values into a final test result are scientifically sound, appropriate, and correct; also determine if unauthorized or unvalidated changes have been made to automated calculation methods. 기초데이터값을최종시험결과로전환시키는계산이과학적으로타당하고적절하며정확한지확인한다. 또한자동계산방법을허가없이또는밸리데이션을하지않고변경했는지파악한다. www..co.kr 12

4. Confirm the performance of the instruments. 장치의성능을확인한다. 5. Determine that appropriate reference standards, solvents, reagents, and other solutions were used and that they met quality control specifications. 적절한참조표준품, 용매, 시약및기타용액을사용했는지, 이들시액이품질관리규격에부합하는지확인한다. 6. Evaluate the performance of the test method to ensure that it is performing according to the standard expected based on method validation data and historical data. 시험방법이시험방법밸리데이션데이터및과거데이터에근거한기준에맞는성능을발휘하는지, 시험방법의성능을평가한다. 7. Fully document and preserve records of this laboratory assessment. 이평가결과를문서로남기고보존한다. The assignment of a cause for OOS results will be greatly facilitated if the retained sample preparations are examined promptly. Hypotheses regarding what might have happened (e.g. dilution error, instrument malfunction) should be tested. Examination of the retained solutions should be performed as part of the laboratory investigation. 보관중인검액을즉시조사하면 OOS 결과의원인파악이용이할수있다. 시험중에발생했을사항에대한가설 ( 예, 희석오류, 장치의오작동 ) 을검정해야한다. 시험소조사의일환으로보관중인용액을조사해야한다. 예 (Examples): Solutions can be re-injected as part of an investigation where a transient equipment malfunction is suspected. Such hypotheses are difficult to prove. However, reinjections can provide strong evidence that the problem should be attributed to the instrument, rather than the sample or its preparation. 일시적인설비오작동이의심되는경우, 조사작업의일환으로용액을재주입하는방법이있다. 이가설은증명하기어렵다. 그러나재주입을통해검체자체나 www..co.kr 13

검체의조제과정이아닌장치에문제가있다는강력한증거를확보할수있다. For release rate testing of certain specialized dosage form drugs that are not destroyed during testing, where possible, examination of the original dosage unit tested might determine whether it was damaged during laboratory handling in a way that affected its performance. Such damage would provide evidence to invalidate the OOS test result, and a retest would be indicated. 시험도중에파괴되지않는일부특수제형의방출율시험인경우, 시험대상제품의조사를통해품질성능에영향을주는손상이시험소취급과정에서있었는지확인한다. 이와같은손상이발견되면 OOS 시험결과를무효처리할수있는증거가되며, 그에따라재시험을할수있다. Further extraction of a dosage unit, where possible, can be performed to determine whether it was fully extracted during the original analysis. Incomplete extraction could invalidate the test results and should lead to questions regarding validation of the test method. 최초분석과정에서추출이완전히이루어졌는지확인하기위해추출작업을더진행하는방법도있다. 불완전한추출이확인되면시험결과를무효처리할수있으며, 이렇게되면시험방법밸리데이션과관련하여의문을제기하지않을수없다. It is important that each step in the investigation be fully documented. Laboratory management should ascertain not only the reliability of the individual value obtained, but also the significance these OOS results represent to the laboratory quality assurance program. Laboratory management should be especially alert to developing trends. As part of an effective quality system, a firm s upper management should appropriately monitor these trends and ensure that any problematic areas are addressed. 조사단계별로철저하게기록하는것이중요하다. 관리자는개개측정값의신뢰성뿐만아니라 OOS 결과가전체시험품질보증프로그램에서차지하는의미를검토해야한다. 시험관리자는특히어떤경향이나타나고있는지주의하여살펴보아야한다. 효과적인품질시스템의일환으로, 고위관리자는이러한경향을적절하게모니터하고, 문제영역을파악하여조치하도록해야한다. www..co.kr 14

Laboratory error should be relatively rare. Frequent errors suggest a problem that might be due to inadequate training of analysts, poorly maintained or improperly calibrated equipment, or careless work. Whenever laboratory error is identified, the firm should determine the source of that error and take corrective action to prevent recurrence. To ensure full compliance with the CGMP regulations, the manufacturer also should maintain adequate documentation of the corrective action. 시험소오류는상대적으로드물어야한다. 오류가빈번히발생한다면시험자교육이부적절하거나설비의유지관리나교정이제대로이루어지지않았거나부주의하게작업하고있다는의미일수있다. 시험소오류로파악되면, 그오류의원인을파악하고재발방지를위한시정조치를취해야한다. CGMP 규정준수를위해제조업체는시정조치에대해서도적절하게문서화하여유지해야한다. In summary, when clear evidence of laboratory error exists, laboratory testing results should be invalidated. When evidence of laboratory error remains unclear, a full-scale OOS investigation should be conducted by the manufacturing firm to determine what caused the unexpected results. It should not be assumed that OOS test results are attributable to analytical error without performing and documenting an investigation. Both the initial laboratory assessment and the following OOS investigation should be documented fully. 결국시험소오류라는명확한증거가있는경우, 시험소시험결과를무효처리한다. 시험소오류라는증거가불명확한경우, 예상치못한결과를발생시킨원인을파악하기위한전면적인 OOS 조사를실시해야한다. 조사실시및문서화를추진하지않은상태로 OOS 시험결과를분석오류때문이라고가정해서는안된다. 일차시험소평가와이후의 OOS 조사과정을완벽하게문서화해야한다. IV. OOS 시험결과의조사 - II 단계 : 전면적 OOS 조사 (INVESTIGATING OOS TEST RESULTS - PHASE II: FULL-SCALE OOS INVESTIGATION) When the initial assessment does not determine that laboratory error caused the OOS result and testing results appear to be accurate, a full-scale OOS investigation using a predefined procedure should be conducted. This investigation may consist of a production process review and/or additional laboratory work. The objective of such an investigation should be to identify the root cause of the OOS result and www..co.kr 15

take appropriate corrective and preventative action. 7 A full-scale investigation should include a review of production and sampling procedures, and will often include additional laboratory testing. Such investigations should be given the highest priority. Among the elements of this phase is evaluation of the impact of OOS result(s) on already distributed batches. 초기평가에서 OOS 결과의원인이시험소오류에있다고볼수없고시험결과가정확한것으로나타난경우, 사전에정한절차에따라전면적인 OOS 조사를실시한다. 이조사는생산공정검토및 / 또는추가시험작업으로구성될수있다. 이조사의목적은 OOS 결과의근원을파악하고적절한시정조치및예방조치를취하는것이다. 전면적인조사에는생산및검체채취절차의검토가포함되어야하며, 추가적인시험작업도포함되기도한다. 이조사는최우선의중요도를두고실시해야한다. 이단계에서는 OOS 결과가이미유통된배치에미칠파급효과를평가하는것도포함해야한다. A. 생산검토 (Review of Production) The investigation should be conducted by the QCU and should involve all other departments that could be implicated, including manufacturing, process development, maintenance, and engineering. In cases where manufacturing occurs off-site (i.e., performed by a contract manufacturer or at multiple manufacturing sites), all sites potentially involved should be included in the investigation. Other 7 Please note that 211.192 requires a thorough investigation of any discrepancy, including documentation of conclusions and follow-up. Implicit in this requirement for investigation is the need to implement corrective and preventative actions. Corrective and preventive action is consistent with the FDA s requirements under 21 CFR part 820, subpart J, pertaining to medical devices, as well as the 2004 draft guidance entitled Quality Systems Approach to Pharmaceutical Current Good Manufacturing Practice Regulations, which, when finalized, will represent the Agency s current thinking on this topic. 211.192에의하면, 결론및사후조치의문서화를포함하여, 모든일탈을철저하 게조사해야한다. 조사에대한이기준에는시정조치및예방조치의구축필요성이포함되어있다. 시정조치와예방조치는의료용구와관련된 21 CFR 파트 820, 서브파트 J의기준과 2004년가이드문서초안 ("Quality Systems Approach to Pharmaceutical Current Good Manufacturing Practice Regulations")( 이문서가마무리되면이주제에대한 FDA의방침이된다 ) 에의거한기준과도일치한다. www..co.kr 16

potential problems should be identified and investigated. 조사작업은품질관리조직 (QCU) 이수행하며제조, 공정개발, 유지관리, 엔지니어링등기타관련부서모두가참여해야한다. 제조작업이다른곳에서수행된경우 ( 즉, 계약제조업체가제조했거나, 여러제조사업장에서제조한경우 ), 모든관련사업장이조사에포함되어야한다. 기타잠재문제를파악하고조사한다. The records and documentation of the manufacturing process should be fully reviewed to determine the possible cause of the OOS result(s). 제조공정관련문서와기록서를충분히검토하여 OOS 결과의원인이될만한것을파악한다. A full-scale OOS investigation should consist of a timely, thorough, and welldocumented review. A written record of the review should include the following information. 전면적인 OOS 조사는적시성, 완벽성, 철저한문서화에근거한검토가기본이된다. 다음정보를포함하여검토기록서를만든다. 1. A clear statement of the reason for the investigation. 조사의이유를명확히기술한다. 2. A summary of the aspects of the manufacturing process that may have caused the problem. 문제를유발했을가능성이있는제조공정부분을요약한다. 3. The results of a documentation review, with the assignment of actual or probable cause. 문서검토결과를기술하고실제원인이나가능성있는원인을정한다. 4. The results of a review made to determine if the problem has occurred previously. 그런문제가예전에도발생했었는지검토한다. 5. A description of corrective actions taken. 시정조치사항을기술한다. www..co.kr 17

If this part of the OOS investigation confirms the OOS result and is successful in identifying its root cause, the OOS investigation may be terminated and the product rejected. However, a failure investigation that extends to other batches or products that may have been associated with the specific failure must be completed ( 211.192). If any material was reprocessed after additional testing, the investigation should include comments and the signatures of appropriate production and quality control personnel. 이 OOS 조사단계에서 OOS 결과가확인되고근원을파악하는데성공하면, OOS 조사를종료하고제품을부적합처리할수있다. 하지만이상조사는그이상과관련이있을수있는다른배치나제품까지조사범위를확대하여실시해야한다 ( 211.192). 추가시험을거친다음에어떤물품을재처리한다면, 생산및품질관리작업자의서명과의견도조사에포함되어야한다. OOS results may indicate a flaw in product or process design. For example, a lack of robustness in product formulation, inadequate raw material characterization or control, substantial variation introduced by one or more unit operations of the manufacturing process, or a combination of these factors can be the cause of inconsistent product quality. In such cases, it is essential that redesign of the product or process be undertaken to ensure reproducible product quality. 8 OOS 결과를통해제품또는공정디자인의결함이밝혀질수도있다. 예를들어제품제법의견고성결여, 부적절한원료특성분석이나관리, 제조공정가운데하나이상의단위작업에의해도입된실질적인변동, 또는이들요소의조합이제품품질의비일관성을유발한원인일수있다. 그런경우에는제품또는공정을다시디자인하여, 제품품질의재현성을확보하는것이필수적이다. B. 추가시험 (Additional Laboratory Testing) A full-scale OOS investigation may include additional laboratory testing. A number of practices are used during the laboratory phase of an investigation. These include 8 OOS results might also be the result of the objectionable practice of making unauthorized or unvalidated changes to the manufacturing process. OOS 결과는제조공정을허가없이또는밸리데이션을거치지않고변경한, 바람직하지않은업무의결과일수도있다. www..co.kr 18

(1) retesting a portion of the original sample and (2) resampling. 전면적인 OOS 조사시에추가시험을실시할수있다. 이단계에서취할수있는조사 방법으로는 (1) 최초검체의일부를대상으로한재시험과 (2) 재검체채취가있다. 1. 재시험 (Retesting) Part of the investigation may involve retesting of a portion of the original sample. The sample used for the retesting should be taken from the same homogeneous material that was originally collected from the lot, tested, and yielded the OOS results. For a liquid, it may be from the original unit liquid product or composite of the liquid product; for a solid, it may be an additional weighing from the same sample composite prepared for the original test. 조사작업의일환으로최초검체의일부에대해재시험을할수있다. 재시험용검체는해당로트에서처음채취하여시험해 OOS 결과가발생한것과동일한균질한물품에서취한다. 액체라면최초의단위액체제품또는액체제품혼합물이재시험용검체에해당되며, 고형제인경우에는최초시험을위해조제했던동일검체혼합물에서다시칭량하여재시험용검체를취한다. Situations where retesting is indicated include investigating testing instrument malfunctions or to identify a possible sample handling problem, for example, a suspected dilution error. Decisions to retest should be based on the objectives of the testing and sound scientific judgment. It is often important for the predefined retesting plan to include retests performed by an analyst other than the one who performed the original test. A second analyst performing a retest should be at least as experienced and qualified in the method as the original analyst. 시험장치의오작동조사또는검체취급과정의문제 ( 예, 희석과정에서의오류가의심되는경우 ) 파악을위해재시험을실시하는경우도있다. 재시험결정은시험의목표와타당한과학적결정에근거해야한다. 재시험계획을미리정해놓고, 최초시험자이외의다른시험자가재시험을실시하도록하는것이중요하다. 재시험을수행하는또다른시험자는최초시험자와마찬가지로그시험방법에대한경험이있고자격을갖추어야한다. The CGMP regulations require the establishment of specifications, standards, sampling plans, test procedures, and other laboratory control mechanisms ( www..co.kr 19

211.160). CGMP 규정에따라규격, 표준, 검체채취계획, 시험절차, 기타시험관리메커니즘을 확립해야한다 ( 211.160). FDA inspections have revealed that some firms use a strategy of repeated testing until a passing result is obtained, then disregarding the OOS results without scientific justification. This practice of testing into compliance is unscientific and objectionable under CGMPs. The maximum number of retests to be performed on a sample should be specified in advance in a written standard operating procedure (SOP). The number may vary depending upon the variability of the particular test method employed, but should be based on scientifically sound principles. The number of retests should not be adjusted depending on the results obtained. The firm's predetermined retesting procedures should contain a point at which the additional testing ends and the batch is evaluated. If the results are unsatisfactory at this point, the batch is suspect and must be rejected or held pending further investigation ( 211.165(f)). Any deviation from this SOP should be rare and done in accordance with 211.160(a), which states that any deviations from written specifications, sampling plans, test procedures, or other laboratory control mechanisms shall be recorded and justified. In such cases, before starting additional retesting, a protocol should be prepared (subject to approval by the QCU) that describes the additional testing to be performed and specifies the scientific and/or technical handling of the data. FDA 실사에의하면, 적합결과가나올때까지시험을반복하고, 과학적인타당성입증없이 OOS 결과를무시하는회사도있었다. 이와같은 " 적합할때까지시험 " 하는방법은비과학적이고 CGMP에도맞지않다. 한검체에대해실시할최대재시험횟수를미리 SOP에규정해놓아야한다. 재시험횟수는시험방법의종류에따라달라질수있으나, 과학적으로타당하고근거가있는원칙에따라정해야한다. 시험결과에따라재시험횟수를조정해서는안된다. 사전에정한재시험절차문서에는추가시험을종료하고배치를평가하는시점이포함되어있어야한다. 이시점에서시험결과가부적합하다면해당배치의품질을확신할수없으므로, 그배치를부적합처리하거나추가조사를진행하는동안따로보관해야한다 ( 211.165(f)). 이 SOP의일탈은 211.160(a) 에따라제한적인경우에만실시한다. 211.160(a) 은규격문서, 검체채취계획, 시험절차, 기타시험관리메커니즘문서의일탈사항을기록하고그타당성을제시하도록요구한다. 그런경우에는추가재시험을하기에앞서프로토콜을작성하고 (QCU 승인대상 ), 이프로토콜에 www..co.kr 20

추가시험에관한사항을기술하며데이터의과학적 / 기술적처리에관한사항을규정해야 한다. In the case of a clearly identified laboratory error, the retest results would substitute for the original test result. All original data should be retained, however, and an explanation recorded. This record should be initialed and dated by the involved persons and include a discussion of the error and supervisory comments. (See section III of this guidance for more details on a laboratory investigation.) 명확하게시험소오류로파악된경우, 재시험결과로최초시험결과를대체할수있다. 그러나최초데이터를유지해야하며, 그에대한설명을기록해야한다. 이기록서에관련자가이니셜을기재하고일자를기재하며, 오류에대한설명과관리자의의견을포함시킨다 ( 시험소조사에관한자세한사항은이가이드문서의섹션 III 참조 ). If no laboratory or calculation errors are identified in the first test, there is no scientific basis for invalidating initial OOS results in favor of passing retest results. All test results, both passing and suspect, should be reported 9 and considered in batch release decisions. 첫시험에서시험소오류나계산오류가확인되지않은경우, 재시험결과로적합처리하기위해최초 OOS 결과를무효처리하는것은과학적인근거가전혀없다. 모든시험결과 ( 적합한것이건의심스러운것이건 ) 를보고하며, 배치출하승인단계에서검토해야한다. 2. 재검체채취 (Resampling) While retesting refers to analysis of the original, homogenous sample material, resampling involves analyzing a specimen from any additional units collected as part of the original sampling procedure or from a new sample collected from the batch, should that be necessary. 재시험은최초의균질한검체분석을의미하는반면, 재검체채취는최초검체채취과정의 9 In other words, all data are reported in, for example, quality control reports, batch records, Certificates of Analysis, in accordance with 211.188 and 211.192. 달리말하면, 211.188 및 211.192에의거하여, 모든데이터를예를들어품질 관리보고서, 배치기록서, COA 에기록해야한다. www..co.kr 21

일환으로확보한부분또는필요한경우에는해당배치에서새로검체를채취하여분석하는 것이다. The original sample from a batch should be sufficiently large to accommodate additional testing in the event an OOS result is obtained. In some situations, however, it may be appropriate to collect a new sample from the batch. Control mechanisms for examination of additional specimens should be in accordance with predetermined procedures and sampling strategies ( 211.165(c)). 배치에서처음검체를취할때는 OOS 결과발생시의추가시험을감안해충분한수량을확보한다. 하지만배치에서새로운검체를채취하는것이적절한경우도있다. 추가검체의검사관리메커니즘은사전에설정된절차와검체채취전략에의거해야한다 ( 211.165(c)). When all data have been evaluated, an investigation might conclude that the original sample was prepared improperly and was therefore not representative of the batch quality ( 211.160(b)(3)). Improper sample preparation might be indicated, for example, by widely varied results obtained from several aliquots of an original composite (after determining there was no error in the performance of the analysis). Resampling should be performed by the same qualified, validated methods that were used for the initial sample. However, if the investigation determines that the initial sampling method was inherently inadequate, a new accurate sampling method must be developed, documented, and reviewed and approved by the QCU ( 211.160 and 211.165(c)). 모든데이터를평가한결과, 최초검체가부적절하게처리되어해당배치의품질을대표할수없다는결론이내려지는경우도있다 ( 211.160(b)). 예를들어 ( 분석과정에오류가없다는점을확인한이후 ) 최초혼합물의다수분액에대해시험한결과가다양하게나타나면, 검체조제과정이부적절했다는의미일수있다. 재검체채취는최초검체에적용된것과동일한적합하고밸리데이션된방법을통해실시해야한다. 그러나조사를통해최초검체채취방법이부적절한것으로밝혀지면, 새로운정확한검체채취방법을개발하고문서화한다음에 QCU의검토및승인을받아야한다 ( 211.160 and 211.165(c)). C. 시험결과의보고 (Reporting Testing Results) www..co.kr 22

Practices used in reporting and interpretation of test results include (1) averaging and (2) outlier tests. 시험결과의보고및해석방법으로는 (1) 평균값계산과 (2) 이상점시험이있다. 1. 평균값계산 (Averaging) There are both appropriate and inappropriate uses of averaging test data during original testing and during an OOS investigation: 최초시험과 OOS 조사시에시험데이터의평균값계산을적절하게활용한경우도있고부적절하게활용한경우도있다. a. 적절한활용 (Appropriate uses) Averaging data can be a valid approach, but its use depends upon the sample and its purpose. For example, in an optical rotation test, several discrete measurements are averaged to determine the optical rotation for a sample, and this average is reported as the test result. If the sample can be assumed to be homogeneous, (i.e., an individual sample preparation designed to be homogenous), using averages can provide a more accurate result. In the case of microbiological assays, the U.S. Pharmacopeia (USP) prefers the use of averages because of the innate variability of the biological test system. 시험데이터의평균값을구하는것은유효한방법이될수도있으나, 이방법의사용은검체와시험목적에따라결정된다. 일례로선광도시험에서다수의개개측정값을평균내검체의선광도를정하며, 이때평균값을시험결과로보고한다. 검체가균질하다고가정할수있는경우 ( 즉, 개개검체를균질하게조제한경우 ), 평균값을통해보다정확한결과가나올수있다. 미생물분석인경우에 USP는생물학적시험시스템자체의변동성때문에평균값의활용을선호하고있다. It should be noted that a test might consist of a specific number of replicates to arrive at a result. For instance, an HPLC assay result may be determined by averaging the peak responses from a number of consecutive, replicate injections from the same preparation (usually 2 or 3). The assay result would be calculated using the peak response average. This determination is considered one test and one result. This is a distinct difference from the analysis of different portions from a lot, intended to determine variability within the lot, and from multiple full analyses www..co.kr 23

of the same homogenous sample. The use of replicates to arrive at a single reportable 10 result, and the specific number of replicates used, should be specified in the written, approved test method. Acceptance limits for variability among the replicates should also be specified in the method. Unexpected variation in replicate determinations should trigger remedial action as required by 211.160(b)(4). If acceptance limits for replicate variability are not met, the test results should not be used. 복수시험을통해하나의결과를얻는시험도있다. 예를들어 HPLC 분석은동일검액을연속적으로여러차례주입하여 ( 보통 2 내지 3회 ) 이때나타나는피크값을평균내결과를정하기도한다. 분석결과는피크의평균값을활용하여계산된다. 이런방법은 " 하나의시험 / 하나의결과 " 로간주된다. 이방법은로트자체의변동성을파악하기위해한개로트의여러부분을분석하는것, 그리고균질한동일검체를여러차례분석하는것과는분명히다르다. 복수시험을통해하나의보고대상결과를얻는방법과이때의복수시험횟수가문서로작성하여승인받은시험방법에포함되어있어야한다. 복수시험시의변동성에대한허용기준이규정되어있어야한다. 복수시험에서예상치못한편차가발생하면, 211.160(b)(4) 에의거하여교정조치를취해야한다. 복수시험변동성의허용기준이충족되지않으면, 그시험결과를사용해서는안된다. In some cases, a series of complete tests (full run-throughs of the test procedure), such as assays, are part of the test method. It may be appropriate to specify in the test method that the average of these multiple assays is considered one test and represents one reportable result. In this case, limits on acceptable variability among the individual assay results should be based on the known variability of the method and should also be specified in the test methodology. A set of assay results not meeting these limits should not be used. 일련의완전한시험 ( 시험절차를완전하게시행 )( 예, 함량분석 ) 이시험방법의일부에해당하는경우도있다. 이러한복수분석결과의평균을구하는것이하나의시험으로 10 The term reportable result as used in this document means a final analytical result. This result is appropriately defined in the written approved test method and derived from one full execution of that method, starting from the original sample. 이문서에서말하는 " 보고대상결과 " 라함은, 최종분석결과를의미한다. 이결과를 승인받은시험방법문서에적절하게규정하며, 최초검체부터시작하여, 그방법을 1 회실행하여도출한다. www..co.kr 24

간주되며그평균값이하나의보고대상결과에해당된다는점을시험방법에규정하는것이적절하다. 이런경우에개개분석결과의변동성에대한허용기준은, 그시험방법에대해알고있는변동성에근거하여정해야하며, 또한시험방법에규정되어있어야한다. 이기준에맞지않는분석결과세트는사용하지말아야한다. These appropriate uses of averaging test data should be used during an OOS investigation only if they were used during the original testing that produced the OOS result. OOS 결과를발생된최초시험시에이러한시험데이터의평균값을구하는방법이적절하게사용된경우에만, OOS 조사에서도그러한평균값계산을적용한다. b. 부적절한활용 (Inappropriate uses) Reliance on averaging has the disadvantage of hiding variability among individual test results. For this reason, all individual test results should normally be reported as separate values. Where averaging of separate tests is appropriately specified by the test method, a single averaged result can be reported as the final test result. In some cases, a statistical treatment of the variability of results is reported. For example, in a test for dosage form content uniformity, the standard deviation (or relative standard deviation) is reported with the individual unit dose test results. 평균값에만의존하면개개시험결과사이의편차를은폐하는단점이있다. 이런이유로인해일반적으로는모든개개시험결과를별도로보고해야한다. 여러시험의평균값계산이시험방법에적절하게규정되어있다면, 하나의평균값을최종시험결과로보고할수도있다. 때로는결과의변동성을통계적으로처리하여보고한다. 예를들어최종제품의함량균일성시험에서, 각각의시험결과와함께표준편차 ( 또는상대표준편차 ) 도보고한다. Averaging can also conceal variations in different portions of a batch, or within a sample. For example, the use of averages is inappropriate when performing powder blend/mixture uniformity or dosage form content uniformity determinations. In these cases, testing is intended to measure variability within the product, and individual results provide the information for such an evaluation. 평균값계산방법은검체내부또는배치의서로다른부분에존재하는편차를은폐할수있다. 일례로파우더혼합물의균일성또는제품의함량균일성시험시에평균값을 www..co.kr 25

활용하는것은부적절하다. 이런경우에는제품의변동성을측정하는것이시험의 목적이므로, 개개시험결과를보고해야한다. In the context of additional testing performed during an OOS investigation, averaging the result(s) of the original test that prompted the investigation and additional retest or resample results obtained during the OOS investigation is not appropriate because it hides variability among the individual results. Relying on averages of such data can be particularly misleading when some of the results are OOS and others are within specifications. It is critical that the laboratory provide all individual results for evaluation and consideration by the QCU, which is responsible for approving or rejecting, e.g., drug products, in-process materials ( 211.22) OOS 조사를하면서추가시험을실시하는경우, 조사를시작하게된원인이되었던최초시험결과와 OOS 조사과정에서확보한추가재시험또는재검체시험결과를평균내면, 각시험결과사이의차이를숨기게되므로적절하지않다. 일부시험결과는 OOS이고다른시험결과는규격이내인경우에시험데이터의평균값에의존하면잘못된판단을내릴수있다. 모든시험결과를제시하여 QCU가평가하고검토하도록하는것이중요하다. 그리고 QCU는예를들어의약품, 공정중물품의적 / 부를판단한다 ( 211.22). For example, in an assay of a finished drug with a specification of 90 to 110 percent, an initial OOS result of 89 percent followed by additional retest results of 90 percent and 91 percent would produce an average of 90 percent. While this average would meet specifications 11, the additional test results also tend to confirm the original OOS result. However, in another situation with the same specifications, an initial OOS result of 80 percent followed by additional test results of 85 percent and 105 percent would also produce an average of 90 percent, but present a much different picture. These results do not confirm the original OOS result but show high variability and may not be reliable. In both examples, the individual results, not the average, should be used to evaluate the quality of the product. 예를들어기준이 90 ~ 110% 인최종의약품의함량시험에서, 최초 OOS 결과가 11 When arriving at a batch disposition decision, it is important for a firm to assess whether the low assay value may project to a subpotency failure before the product s labeled expiration date. 배치처리결정을내릴때, 낮은함량분석값이제품표시유효기간이전에역가가 기준이하로떨어질수있다는의미는아닌지평가할필요가있다. www..co.kr 26

89% 이고, 이후의추가재시험결과가 90% 와 91% 인경우, 이들의평균값은 90% 가된다. 이평균값은규격이내에들지만, 추가시험결과도최초결과가 OOS임을뒷받침하는경향이있다. 그러나동일규격에서최초 OOS 결과가 80% 이고, 추가시험에서 85% 와 105% 가나오면, 평균값은 90% 가된다. 하지만앞서의예와는전혀다른상황이라할수있다. 이러한상황은최초결과가 OOS라고확신할수없지만, 큰변동성이있으며신뢰성이떨어진다는의미일수있다. 이두가지예에서는평균값이아니라각각의결과를바탕으로제품품질을평가해야한다. 2. 이상점시험 (Outlier Tests) The CGMP regulations require that statistically valid quality control criteria include appropriate acceptance and/or rejection levels ( 211.165(d)). On rare occasions, a value may be obtained that is markedly different from the others in a series obtained using a validated method. Such a value may qualify as a statistical outlier. An outlier may result from a deviation from prescribed test methods, or it may be the result of variability in the sample. It should never be assumed that the reason for an outlier is error in the testing procedure, rather than inherent variability in the sample being tested. CGMP 규정에따르면통계적으로유효한품질관리기준에는적정허용및 / 또는부적합수준 ( 211.165(d)) 이포함되어야한다. 밸리데이션된방법으로시험하여얻은일련의결과치가운데다른것과현저히다른값이나오는드문경우도있다. 이런결과치는통계적으로이상점이라할수있다. 이상점은지정시험방법의일탈로인해발생하거나, 아니면검체자체의변동성때문일수있다. 이상점이발생한이유를시험대상검체자체의내재적변동성이아닌시험절차의오류로가정해서는절대안된다. Outlier testing is a statistical procedure for identifying from an array those data that are extreme. The possible use of outlier tests should be determined in advance. This should be written into SOPs for data interpretation and be well documented. The SOPs should include the specific outlier test to be applied with relevant parameters specified in advance. The SOPs should specify the minimum number of results required to obtain a statistically significant assessment from the specified outlier test. 이상점시험은일련의시험데이터에서극단적인값을파악하는통계절차이다. 이상점시험의적용여부를미리결정해놓아야한다. 또한데이터의해석에대한 SOP를갖추어야 www..co.kr 27

하며, 그사실을기록해야한다. 미리지정된관련변수를적용할특정이상점시험을 SOP 에포함시켜놓아야한다. 지정이상점시험에서통계적으로유의미한평가에필요한 최소시험결과개수가 SOP 에지정되어있어야한다. For biological assays having a high variability, an outlier test may be an appropriate statistical analysis to identify those results that are statistically extreme observations. The USP describes outlier tests in the general chapter on Design and Analysis of Biological Assays <111>. 12 In these cases, the outlier observation is omitted from calculations. The USP also states that arbitrary rejection or retention of an apparently aberrant response can be a serious source of bias the rejection of observations solely on the basis of their relative magnitudes is a procedure to be used sparingly (USP <111>). 변동성이큰생물학적분석인경우에이상점시험은통계적으로극치에해당하는결과값을파악하는적절한통계분석방법이될수있다. USP의 " 생물학적분석방법설계및분석 <111>" 항목에이상점시험이설명되어있다. 이경우에이상점결과값은계산에서제외한다. 또한 " 명백하게비정상적인결과값을임의로제외하거나포함시키면, 심각한편향문제를유발할수있으며, 상대적크기에만근거하여결과값을제외시키는것도삼가해야한다 " 고 USP에서설명하고있다 (USP <111>). For validated chemical tests with relatively small variance, and if the sample being tested can be considered homogeneous (for example, an assay of a composite of a dosage form drug to determine strength), an outlier test is only a statistical analysis of the data obtained from testing and retesting. It will not identify the cause of an extreme observation and, therefore, should not be used to invalidate the suspect result. Occasionally, an outlier test may be of some value in estimating the probability that the OOS result is discordant from a data set, and this information can be used in an auxiliary fashion, along with all other data from the investigation, to evaluate the significance of the result. 상대적으로편차가적은밸리데이션된화학시험인경우, 그리고시험대상검체가균질하다고볼수있는경우 ( 예를들어완제의약품혼합물의함량분석시험 ), 이상점시험만이시험및재시험결과값을통계적으로분석할수있는방법이다. 이방법으로는극치결과값의원인이파악되지않으므로, 해당데이터의무효처리에적용해서는안된다. 12 The United States Pharmacopeia, 29th Revision, Rockville, MD: The United States Pharmacopeial Convention, 2006. www..co.kr 28

이상점시험은 OOS 결과가데이터세트와조화를이루지않을확률을산출하는데도움이 될수있으며, 조사를통해확보한다른모든데이터와함께이정보를보조적으로 활용하여그결과값의의미를평가할수있다. Outlier tests have no applicability in cases where the variability in the product is what is being assessed, such as for content uniformity, dissolution, or release rate determinations. In these applications, a value perceived to be an outlier may in fact be an accurate result of a nonuniform product. 이상점시험은함량균일성, 용출, 방출율시험같이제품의변동성을평가하는경우에는적용할수없다. 이런경우에이상점으로생각되는결과치가실제로는비균일한제품의정확한결과값일수있다. When using these practices during the additional testing performed in an OOS investigation, the laboratory will obtain multiple results. It is again critical for the laboratory to provide all test results for evaluation and consideration by the QCU in its final disposition decision. In addition, when investigation by a contract laboratory 13 does not determine an assignable cause, all test results should be reported to the customer on the certificate of analysis. OOS 조사과정에서추가시험을실시할때이상의방법을활용하면, 다양한결과를확보하게된다. 시험소는모든시험결과를제공하여 QCU가이들을종합적으로평가하고검토하여최종결정을내릴수있도록하는것이중요하다. 또한수탁시험소가조사를통해뚜렷한원인을파악할수없다면, COA를통해모든시험결과를고객에게보고해야한다. V. 조사종결 (CONCLUDING THE INVESTIGATION) To conclude the investigation, the results should be evaluated, the batch quality should be determined, and a release decision should be made by the QCU. The SOPs should be followed in arriving at this point. Once a batch has been rejected, there is no limit to further testing to determine the cause of the failure so that a corrective action can be taken. 13 The Agency also recommends that OOS investigation reports be provided to the customer. FDA 는 OOS 조사보고서를고객에게제공할것을권고한다. www..co.kr 29

조사를종결하려면결과를평가하고배치품질을결정하며 QCU 가출하승인여부를 결정해야한다. 이시점까지 SOP 를준수한다. 일단어떤배치를부적합처리하면, 사고 원인을밝히고시정조치를취하기위해추가시험을실시하는것에대해서는제한이없다. A. 조사결과의해석 (Interpretation of Investigation Results) The QCU is responsible for interpreting the results of the investigation. An initial OOS result does not necessarily mean the subject batch fails and must be rejected. The OOS result should be investigated, and the findings of the investigation, including retest results, should be interpreted to evaluate the batch and reach a decision regarding release or rejection ( 211.165). QCU는조사결과의해석을책임진다. 초기 OOS 결과가반드시해당배치의부적합처리를의미하지는않는다. OOS 결과를조사하고재시험결과를포함해조사결과를해석하여해당배치를평가하고그배치의적 / 부에대한결정을내려야한다 ( 211.165). In those instances where an investigation has revealed a cause, and the suspect result is invalidated, the result should not be used to evaluate the quality of the batch or lot. Invalidation of a discrete test result may be done only upon the observation and documentation of a test event that can reasonably be determined to have caused the OOS result. 조사를통해원인이밝혀지고의심스러운결과를무효처리하는경우, 그결과를바탕으로해당배치또는로트의품질을평가해서는안된다. OOS 결과를유발한것으로합리적으로판단되는시험상황에대한조사와그내용을기록한문서에근거하여시험결과를무효화해야한다. In those cases where the investigation indicates an OOS result is caused by a factor affecting the batch quality (i.e., an OOS result is confirmed), the result should be used in evaluating the quality of the batch or lot. A confirmed OOS result indicates that the batch does not meet established standards or specifications and should result in the batch's rejection, in accordance with 211.165(f), and proper disposition. For inconclusive investigations in cases where an investigation (1) does not reveal a cause for the OOS test result and (2) does not confirm the OOS result the OOS result should be given full consideration in the batch or lot disposition decision. 조사를통해 OOS 결과가배치품질에영향을주는요소에의해유발된것으로나타나는 www..co.kr 30

경우 ( 즉, OOS 결과가확정된경우 ), 해당시험결과는그배치나로트의품질을평가하는데활용한다. 확정된 OOS 결과는해당배치가설정된표준이나규격에부합하지않으며, 결국 211.165(f) 에의거하여배치를부적합처리하고적절하게처분해야한다는의미이다. 결론이나지않는경우 ((1) 조사과정에서 OOS 시험결과의원인이파악되지않고, (2) OOS 결과를확정하지못한경우 ) 에는 OOS 결과를기록서에기록하고, 해당배치나로트의처리를결정할때그사항을충분히고려해야한다. In the first case (OOS confirmed), the investigation changes from an OOS investigation into a batch failure investigation, which must be extended to other batches or products that may have been associated with the specific failure ( 211.192). 첫번째경우 (OOS 확정 ) 에조사는 OOS 조사에서배치이상조사로전환되며, 이때해당이상사안과관련이있을수있는다른배치나제품까지조사를확대해야한다 ( 211.192). In the second case (inconclusive), the QCU might still ultimately decide to release the batch. For example, a firm might consider release of the product under the following scenario: 두번째경우 ( 미정 ) 에 QCU가궁극적인배치출하승인여부를결정한다. 예를들어제품출하승인과관련하여다음과같은시나리오를생각할수있다. A product has an acceptable composite assay range of 90.0 to 110.0 percent. The initial (OOS) assay result is 89.5 percent. Subsequent sample preparations from the original sample yield the following retest results: 99.0, 98.9, 99.0, 99.1, 98.8, 99.1, and 99.0 percent. A comprehensive laboratory investigation (Phase 1) fails to reveal any laboratory error. Review of events during production of the batch reveals no aberrations or indication of unusual process variation. 14 Review of the manufacturing process and product history demonstrates that the process is robust. The seven passing retest results are all well within the known limits of variability of the method used. Batch results from in-process monitoring, content uniformity, 14 As an example, evaluation of process variation would determine if established equipment, facility, and process control limits were met. 예를들어공정편차평가를통해확립된설비, 시설, 공정관리기준에부합했는지 판단할수있다. www..co.kr 31