【正文】 investigation and followup ().FDA法規(guī)要求當(dāng)OOS檢驗(yàn)結(jié)果出現(xiàn)時(shí)應(yīng)該進(jìn)行調(diào)查，調(diào)查的目的是確定引起OOS的原因。法規(guī)要求對(duì)調(diào)查包括調(diào)查結(jié)論和隨后采取的措施進(jìn)行記錄()。s data, before test solutions are discarded, whenever possible. This way, hypotheses regarding laboratory error or instrument malfunctions may be tested using the same test solutions. If this initial assessment indicates that no errors were made in the analytical process used to arrive at the data, a plete failure investigation should follow. 更有意義的，調(diào)查必須是完全的，及時(shí)的，不帶有任何偏見(jiàn)的，記錄是完整的和經(jīng)得起科學(xué)推敲的。如果最初的評(píng)估評(píng)估顯示在得到該數(shù)據(jù)的分析過(guò)程中沒(méi)有發(fā)生錯(cuò)誤，必須立即開(kāi)展一個(gè)完全的不合格調(diào)查。檢驗(yàn)員應(yīng)該意識(shí)到在實(shí)驗(yàn)過(guò)程中可能發(fā)生的潛在的問(wèn)題和應(yīng)該注意可能產(chǎn)生OOS結(jié)果的問(wèn)題。 (b)(4)), the analyst should ensure that only those instruments meeting established specifications are used and that all instruments are properly calibrated.Certain analytical methods have system suitability requirements, and systems not meeting such 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 should not be used. The cause of the malfunction should be identified and corrected before a decision is made whether to use any data prior to the suspect period.依據(jù)CGMP (167。某些分析方法有系統(tǒng)適應(yīng)性要求，不符合要求的系統(tǒng)不能使用。如果對(duì)照品響應(yīng)值顯示該系統(tǒng)功能不正常，在可疑的時(shí)間內(nèi)收集的所有數(shù)據(jù)應(yīng)該被適當(dāng)標(biāo)識(shí)并不能使用。Before discarding test preparations or standard preparations, analysts should check the data for pliance with specifications. When unexpected results are obtained and no obvious explanation exists, test preparations should be retained and the analyst should inform the supervisor. An assessment of the accuracy of the results should be started immediately.在丟棄樣品制備液和標(biāo)準(zhǔn)制備液之前，檢驗(yàn)員應(yīng)該核查數(shù)據(jù)對(duì)標(biāo)準(zhǔn)的符合性。應(yīng)該立即開(kāi)始評(píng)估檢驗(yàn)結(jié)果的正確性。檢驗(yàn)員不應(yīng)該有意的繼續(xù)這無(wú)效的分析（也就是，當(dāng)明顯的錯(cuò)誤發(fā)生了，不應(yīng)該帶著會(huì)得出什么結(jié)果的目的去完成分析）。B. Responsibilities of the Supervisor主管的責(zé)任Once an OOS result has been identified, the supervisor39。不應(yīng)該對(duì)OOS結(jié)果的原因進(jìn)行預(yù)想的假定。立即的評(píng)估應(yīng)該包括重新檢測(cè)原溶液、測(cè)試的單位、玻璃器具和溶液制備過(guò)程，這樣可以進(jìn)一步證實(shí)對(duì)OOS結(jié)果屬于實(shí)驗(yàn)室錯(cuò)誤的假設(shè)。s assessment:下面是作為主管應(yīng)評(píng)估的部分步驟：1. Discuss the test method with the analyst。2. Examine the raw data obtained in the analysis, including chromatograms and spectra, and identify anomalous or suspect information.檢查分析的原始數(shù)據(jù)，包括色譜和光譜，并識(shí)別出反?；蚩梢傻男畔?。5. Evaluate the performance of the testing method to ensure that it is performing according to the standard expected based on method validation data.評(píng)估檢驗(yàn)方法的執(zhí)行情況，以保證是按照標(biāo)準(zhǔn)執(zhí)行并有方法驗(yàn)證數(shù)據(jù)。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 (. dilution error, instrument malfunction) can be tested. Examination of the retained solutions can be performed as part of the laboratory investigation.如果及時(shí)檢測(cè)了所保留的樣品制備液，會(huì)極大的促進(jìn)OOS結(jié)果原因的確定。對(duì)被留的溶液的檢驗(yàn)可以作為實(shí)驗(yàn)室調(diào)查的一部分。如果在色譜系統(tǒng)一次進(jìn)樣期間引入了氣泡，而其它的試驗(yàn)進(jìn)行正常，這是可能發(fā)生的。但是，重新進(jìn)樣能有力的證明問(wèn)題與儀器有關(guān)，而不是與樣品或樣品的準(zhǔn)備有關(guān)。這樣的損壞能提供證據(jù)使OOS檢驗(yàn)結(jié)果無(wú)效，這樣就可以進(jìn)行重新檢驗(yàn)。不完全的提取能使檢驗(yàn)結(jié)果無(wú)效，將導(dǎo)致檢驗(yàn)方法驗(yàn)證的問(wèn)題。主管不僅應(yīng)該確定獲得的個(gè)別值的可靠性，也應(yīng)該確定在整個(gè)質(zhì)量保證程序中闡明的OOS結(jié)果的重要性。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 ensure that it does not occur again. To ensure full pliance with the CGMP regulations, the manufacturer also should maintain adequate documentation of the corrective action.In summary, when clear evidence of laboratory error exists, laboratory testing results should be invalidated. When evidence of laboratory error remains unclear, a failure investigation should be conducted to determine what caused the unexpected results. It should not be assumed that failing test results are attributable to analytical error without performing and documenting an investigation. Both the initial laboratory assessment and the following failure investigation should be documented fully.實(shí)驗(yàn)室錯(cuò)誤應(yīng)該是極少發(fā)生的。如果實(shí)驗(yàn)室錯(cuò)誤被確定了，企業(yè)應(yīng)該確定錯(cuò)誤的來(lái)源并采取糾正措施去保證錯(cuò)誤不再發(fā)生。總之，當(dāng)實(shí)驗(yàn)室錯(cuò)誤的證據(jù)已經(jīng)存在，實(shí)驗(yàn)室檢驗(yàn)結(jié)果應(yīng)該作廢。在沒(méi)有進(jìn)行調(diào)查及調(diào)查文件確定之前不應(yīng)該假定失敗的檢驗(yàn)結(jié)果屬于檢驗(yàn)錯(cuò)誤。IV. INVESTIGATING OOS TEST RESULTSOOS結(jié)果調(diào)查When the initial assessment does not determine that laboratory error caused the OOS result and testing results appear to be accurate, a fullscale failure investigation using a predefined procedure should be conducted. The objective of such an investigation should be to identify the source of the OOS result. Varying test results could indicate problems in the manufacturing process, or result from sampling problems. Such investigations present a challenge both to employees and to management and should be given the highest priority.如果最初的評(píng)估不能確定是實(shí)驗(yàn)室錯(cuò)誤造成了OOS結(jié)果且實(shí)驗(yàn)結(jié)果是正確的，應(yīng)按照預(yù)先確定的程序進(jìn)行全方位的不合格調(diào)查。這樣的調(diào)查是對(duì)員工和管理者的挑戰(zhàn)應(yīng)給予極高度的重視。其它的潛在問(wèn)題也應(yīng)該被確定和調(diào)查。A. General Investigational Principles一般調(diào)查原則A failure investigation should consist of a timely, thorough, and welldocumented review. 一個(gè)不合格結(jié)果的調(diào)查在于及時(shí)，徹底，和完善的記錄審核 。2. The manufacturing process sequences that may have caused the problem should be summarized.對(duì)可能引起問(wèn)題的生產(chǎn)工藝流程進(jìn)行了總結(jié)。4. A review should be made to determine if the problem has occurred previously.審核并判斷是否以前發(fā)生過(guò)這類問(wèn)題。B. Laboratory Phase of an Investigation 實(shí)驗(yàn)室階段的調(diào)查A number of practices are used during the laboratory phase of an investigation. These include: (1) retesting a portion of the original sample, (2) testing a specimen from the collection of a new sample from the batch, (3) resampling testing data, and (4) using outlier testing.在實(shí)驗(yàn)室階段的一系列調(diào)查包括：（1）最初樣品一部分的再檢驗(yàn)，（2）從該批中重新取樣樣品的檢驗(yàn)，（3）重新取樣的檢驗(yàn)數(shù)據(jù)，（4）逸出值的檢驗(yàn)1. Retesting重新檢驗(yàn)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 m