IV.INVESTIGATING OOS TEST RESULTS 对OOS结果的调查—

PHASE II: FULL-SCALE OOS INVESTIGATION 第二步：全面OOS调查

When the initialassessment does not determine that laboratory error caused the OOS result andtesting results appear to be accurate, a full-scale OOS investigation using apredefined procedure should be conducted. This investigation may consist of aproduction process review and/or additional laboratory work. The objective ofsuch an investigation should be to identify the root cause of the OOS resultand take appropriate corrective and preventative action.[1] A full-scale investigation should includea review of production and sampling procedures, and will often includeadditional laboratory testing. Such investigations should be given the highestpriority. Among the elements of this phase is evaluation of the impact of OOSresult(s) on already distributed batches.

如果初步评估表明不是实验室错误引起的OOS结果，结果又不正确的话，就要按事先规定的程序进行全面的OOS调查。该调查可能包括生产工艺回顾和／或附加的实验室工作。调查的目的的应是确定引起OOS结果的根本原因并采取适当的改正和预防措施。一个全面的调查应包括对生产和取样程序的回顾，并且经常包括附加的实验室检验。这样的调查有最高的优先权。在这一阶段的内容中，是评估OOS结果对已销售批次的影响。

A. Review of Production 生产情况审核

The investigation shouldbe conducted by the QCU and should involve all other departments that could beimplicated, including manufacturing, process development, maintenance, andengineering. In cases where manufacturing occurs off-site (i.e., performed by acontract manufacturer or at multiple manufacturing sites), all sitespotentially involved should be included in the investigation. Other potentialproblems should be identified and investigated.

调查应由质量管理部门执行，应包括所有涉及的部门，包括生产，工艺发展，维护和工程。如果生产不在当地（也就是由签约生产商生产或在多个生产地生产）调查应包括所有可能的生产地点。其它可能的问题应确定和调查。生产工艺的记录和文件应全部再检查一遍，以确定引起OOS结果的可能原因。

The records anddocumentation of the manufacturing process should be fully reviewed todetermine the possible cause of the OOS result(s).

应对生产记录和文件做全面的审核以确认可能的OOS原因。

A full-scale OOSinvestigation should consist of a timely, thorough, and well-documented review.A written record of the review should include the following information.

一个全面的OOS调查应包括及时的、彻底的及记录完整的审核。审核的书面记录应包括下述信息：

1. A clear statement ofthe reason for the investigation. 明确说明调查的原因。

2. A summary of theaspects of the manufacturing process that may have caused the problem. 对可能导致问题产生的生产工艺的各方面的总结。

3. The results of adocumentation review, with the assignment of actual or probable cause. 对文件和审核结果，包括对实际原因和可能原因的归结。

4. The results of areview made to determine if the problem has occurred previously. 回顾以前生产中是否曾发生相同问题的结果。

5. A description ofcorrective actions taken. 采取的整改措施。

If this part of the OOSinvestigation confirms the OOS result and is successful in identifying its rootcause, the OOS investigation may be terminated and the product rejected.However, a failure investigation that extends to other batches or products thatmay have been associated with the specific failure must be completed (§211.192). If any material was reprocessed after additional testing, theinvestigation should include comments and the signatures of appropriateproduction and quality control personnel.

如果在本部分OOS调查中，OOS结果被确认，且根本原因已被鉴别出，则OOS调查到此结束，该批次产品应被判定不合格。但是，扩展到别的批或产品不合格调查必须继续完成，别的批或产品可能与该结果有关(§ 211.192)。如果有物料在附加检验之后再经过加工，调查应包括适当的生产与质量控制人员的评论与签名。

OOS results may indicatea flaw in product or process design. For example, a lack of robustness inproduct formulation, inadequate raw material characterization or control,substantial variation introduced by one or more unit operations of themanufacturing process, or a combination of these factors can be the cause ofinconsistent product quality. In such cases, it is essential that redesign ofthe product or process be undertaken to ensure reproducible product quality.[2]

OOS结果可能预示了产品或工艺设计的缺点。比如，产品浓度不够，原材料鉴定和控制不够，生产工艺中一个或多个操作单元引入过多的变量，或这些因素的结合，这些都可能是产品质量不稳定的原因。在这些情况下，有必要重新设计产品或工艺以确保产品质量。

B. Additional Laboratory Testing 附加化验室测试

A full-scale OOSinvestigation may include additional laboratory testing. A number of practicesare used during the laboratory phase of an investigation. These include (1)retesting a portion of the original sample and (2) resampling.

一个全面的OOS调查可能包括附加的实验室检验。在调查的实验室阶段，要用到很多规范。这些包括（１）对一部分原样复验和（２）重新取样。

1. Retesting 复测

Part of the investigationmay involve retesting of a portion of the original sample. The sample used forthe retesting should be taken from the same homogeneous material that wasoriginally collected from the lot, tested, and yielded the OOS results. For aliquid, it may be from the original unit liquid product or composite of theliquid product; for a solid, it may be an additional weighing from the samesample composite prepared for the original test.

部分调查可能包括一部分原样的复验。用于复验的样品应该是最初收集检验的、出现OOS结果的样品均质物料的一部分。如果是液体，可以是液体成品的原始单位或液体成品的混合物。如果是固体，可以是分析员制备的相同混合物的额外的称量。

Situations whereretesting is indicated include investigating testing instrument malfunctions orto identify a possible sample handling problem, for example, a suspecteddilution error. Decisions to retest should be based on the objectives of thetesting and sound scientific judgment. It is often important for the predefinedretesting plan to include retests performed by an analyst other than the onewho performed the original test. A second analyst performing a retest should beat least as experienced and qualified in the method as the original analyst.

原样复验旨在调查检测设备故障或确定样品处理上可能存在的问题，例如可疑的稀释错误等。决定复验应依据检验的客观和合理的科学判断。复验计划非常重要的一点是原样复验必须由另一名分析员执行，而不是原先的分析员执行。第二个分析员至少和第一个分析员一样有经验和有资格。

The CGMP regulationsrequire the establishment of specifications, standards, sampling plans, testprocedures, and other laboratory control mechanisms (§211.160).

CGMP要求建立规范，标准，取样计划，检验程序和其它实验室控制体制(§ 211.160)。

FDA inspections haverevealed that some firms use a strategy of repeated testing until a passingresult is obtained, then disregarding the OOS results without scientificjustification. This practice of “testing into compliance” is unscientific and objectionable under CGMPs. The maximum numberof retests to be performed on a sample should be specified in advance in awritten standard operating procedure (SOP). The number may vary depending uponthe variability of the particular test method employed, but should be based onscientifically sound principles. The number of retests should not be adjusteddepending on the results obtained. The firm's predetermined retestingprocedures should contain a point at which the additional testing ends and thebatch is evaluated. If the results are unsatisfactory at this point, the batchis suspect and must be rejected or held pending further investigation (§ 211.165(f)). Any deviation from this SOP should be rare and done inaccordance with § 211.160(a), which states that anydeviations from written specifications, sampling plans, test procedures, orother laboratory control mechanisms shall be recorded and justified. In suchcases, before starting additional retesting, a protocol should be prepared(subject to approval by the QCU) that describes the additional testing to beperformed and specifies the scientific and/or technical handling of the data.

FDA检查显示，有些公司重复检验直到得到满意的结果，然后剔除没有科学依据的OOS结果。按照CGMPs检验至合格是不科学和不充许的。一个样品复验的最多次数应事先在SOP明确规定。不同的检验方法允许复验的次数可能不同，但应遵守科学合理原则。复验次数不能根据结果调整。公司的预先确定的复验程序应包括一个点，在这个点检验终止和进行批评估。如果在这个点结果不满意，则怀疑批，批不合格或待进一步调查(§ 211.165(f))。按照§211.160(a)不应背离SOP，§ 211.160(a)规定，任何背离书面规定，取样计划，检验程序或其它实验室控制制度应予记录和证明是正当的。在这种情况下，在复验前，应准备规程（由质量管理部门批准）描述附加的检验并明确提出数据的科学和／或技术的处理。

In the case of a clearlyidentified laboratory error, the retest results would substitute for theoriginal test result. All original data should be retained, however, and anexplanation recorded. This record should be initialed and dated by the involvedpersons and include a discussion of the error and supervisory comments. (Seesection III of this guidance for more details on a laboratory investigation.)

在明确确定了实验室错误的情况下，原样复验结果合格，再检验结果将取代最初检验结果。应保留所有原始数据，但也应有解释性的记录。应该保留最初结果注明测定结果无效，在OOS调查记录上应有相关人员的签名、日期的标明，并应包括对错误的讨论和主管的注释。(详见本指南第三部分III实验室调查)

If no laboratory orcalculation errors are identified in the first test, there is no scientificbasis for invalidating initial OOS results in favor of passing retest results.All test results, both passing and suspect, should be reported [3] and considered in batch release decisions.

首次检验时若没有实验室错误或统计错误发生，就没有科学基础使原来的OOS结果无效，使复验结果通过。所有的检验结果，通过的和可疑的，都应有报告，在批放行中考虑。

2. Resampling 重新取样

While retesting refers toanalysis of the original, homogenous sample material, resampling involvesanalyzing a specimen from any additional units collected as part of theoriginal sampling procedure or from a new sample collected from the batch,should that be necessary.

重新取样指对已出现不合格结果的样品，按规定的取样规程，从同一批号样品中重新另取的第二组样品，供另外增加化验使用。目的是调查样品可能存在的问题。

The original sample froma batch should be sufficiently large to accommodate additional testing in theevent an OOS result is obtained. In some situations, however, it may beappropriate to collect a new sample from the batch. Control mechanisms forexamination of additional specimens should be in accordance with predeterminedprocedures and sampling strategies (§ 211.165(c)).

同一批的原始的样品应有足够的量，万一出现OOS结果时以供附加的检验。但有的情况下，也可以从同一批中收集新的样品。附加样的检验控制应按照原先确定的程序和取样方法(§ 211.165(c)。

When all data have beenevaluated, an investigation might conclude that the original sample wasprepared improperly and was therefore not representative of the batch quality (§211.160(b)(3)). Improper sample preparation might be indicated, for example, bywidely 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 thatwere used for the initial sample. However, if the investigation determines thatthe initial sampling method was inherently inadequate, a new accurate samplingmethod must be developed, documented, and reviewed and approved by the QCU (§§ 211.160 and 211.165(c)).

对所有的数据评估，调查的结论可能是原来的样品配制不当，所以不具有批质量的代表性(§ 211.160(b)(3)。这可由多种情形判定，如对原样不同部分进行检测，结果大范围波动（确定分析操作没有错误后）。重新取样应按照检测原样所使用的取样方法进行。若调查确定了原来的取样方法不正确，则须开发一个新的正确方法，并由QCU批准颁布实施。(§§211.160和211.165(c))

[1] Pleasenote that § 211.192 requires a thorough investigation of any discrepancy,including documentation of conclusions and follow-up. Implicit in thisrequirement for investigation is the need to implement corrective andpreventative actions. Corrective and preventive action is consistent with theFDA’s requirements under 21 CFR part 820, subpart J, pertainingto medical devices, as well as the 2004 draft guidance entitled Quality SystemsApproach to Pharmaceutical Current Good Manufacturing Practice Regulations,which, when finalized, will represent the Agency’scurrent thinking on this topic.

请注意§ 211.192 要求所有不符都要有一个彻底的调查，包括结论和跟踪的记录文件。此要求对调查而言即是需要实施纠正与预防措施，这些纠正与预防措施与FDA在21CFR 820部分章节J中涉及到医疗器械的要求是一致的，同时2004年起草的指南，名为药品CGMP质量体系方法，最终定稿时将代表当局在此问题上当前的想法。

[2] OOS results might also be the result of theobjectionable practice of making unauthorized or unvalidated changes to themanufacturing process.

OOS结果可能也是由于对生产工艺进行了未经批准或未经验证的变更所产生的负面结果。

[3] In other words, all data are reported in, forexample, quality control reports, batch records, Certificates of Analysis, inaccordance with §§ 211.188 and 211.192.

换而言之，所有数据报告，如质量检测报告，批报告，分析报告应符合211章188和211章192的要求。