本月FDA更新了这个曾经搅动行业神经，进而带了数据完整性风暴的OOS指南
当然，我还有一点就要看完了，稍后审核完也放在这一篇里，生得看官您还要再点击一次。
食言了，原因见尾部，但今天都已经发完。
另一篇地址：FDA OOS指南 修订版（2022.05）（下） - 博普智库 (bopuyun.com)
Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production
Guidance for Industry1
药品生产OOS检测结果调查 行业指南【1】
本指南代表了食品和药物管理局(FDA或Agency)在这一主题上的当前思想。它不为任何人确立任何权利，对FDA 或公众没有约束力。如果满足适用的法律法规的要求，您可以使用另一种方法。如需讨论替代方法，请联系如标题页所列的FDA负责本指南的办公室。
I.INTRODUCTION
简介
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
本行业指南提供了fda当前对如何评估OOS检测
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 products3 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.
本指南适用于CDER规管的药物的化学实验室检测。它是针对传统的药物测试和释放方法。在当前良好生产规范(CGMP)法规(21 CFR部分210和211)和联邦食品、药品和化妆品法案(Act)(第501(a)(2)(B))适用的范围内，对活性药物成分、辅料和其他成分、中控材料和制剂进行实验室检测【3】。本指南中的原则也适用于公司购买的药品组件的内部测试。本指南也可适用于履行生产和/或实验室检测职责的合同公司。具体来说，该指南讨论了如何调查OOS检测结果，包括实验室人员的职责、实验室阶段的调查、可能需要增加的检测、何时扩大实验室外的调查以及对所有检测结果的最终评估。
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
【1 This guidance has been prepared by the Office of Pharmaceutical Quality in the Center for Drug Evaluation and Research (CDER). You may submit comments on this guidance at any time. Submit comments to Docket No. FDA-1998-D-0019 (available at https://www.regulations.gov/docket/FDA-1998-D-0019
本指南由药物评价和研究中心(CDER)的药物质量办公室编写。您可以在任何时候提交对本指南的意见。提交意见到No. FDA-1998-D-0019卷宗号记事表，可在上述网址检索。】
【2In certain instances, in-process testing is done solely to determine the need for real-time equipment or system adjustments to prevent process drift. This guidance does not address these situations.
在某些情况下，进行中间控制测试只是为了确定设备或系统实时调整的必要性，以防止过程漂移。本指南不评述这些情况。】
【3Chemistry-based laboratory testing of biotechnology products that are under the jurisdiction of CDER is within the scope of this guidance. While this guidance is not intended to address biological assays (e.g., in vivo, immunoassays) it does briefly discuss Design and Analysis of Biological Assays (USP<111>).
CDER规管下的生物技术产品的基础化学实验室测试在本指南的范围内。虽然本指南不打算评述生物测定(例如，体内免疫测定)，但它简要讨论了生物测定的设计和分析（详见USP<111>）】
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 in-process testing, see the CGMP guidance entitled PAT — A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance (September 2004).
FDA根据其2002年8月的“21世纪制药cGMP”倡议，鼓励采用现代方法来生产、监控和控制，以提高过程的可预测性和效率。过程分析技术(PAT)采用了一种不同的质量保证方法，使用过程控制和中控数据作为放行规范，而不是依赖单一的实验室决定来做出批可接受性决定。本指南不打算讨论PAT方法，因为这些方法的日常过程中使用可能包括其他考虑因素。有关及时过程检测的信息，请参见CGMP指南PAT -创新药物开发、生产和质量保证框架(2004年9月)。
The contents of this document do not have the force and effect of law and are not meant to bind the public in any way, unless specifically incorporated into a contract. This document is intended only to provide clarity to the public regarding existing requirements under the law. FDA guidance documents, including this guidance, should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidance means that something is suggested or recommended, but not required.
本文件的内容不具有法律效力，不以任何方式约束公众，除非明确纳入合同。本文件旨在向公众明确法律规定的现有要求。FDA指导文件，包括本指南，应仅作为建议，除非引用了具体的监管或法定要求。在机构指南中使用“应该”一词意味着有建议或推荐，但不是必需的。
II.BACKGROUND
背景
Laboratory testing, which is required by the CGMP regulations (§§ 211.160 and 211.165), is necessary to confirm that components, containers and closures, in-process materials, and finished products conform to specifications, including stability specifications.
CGMP法规（§§211.160和211.165）要求进行实验室测试，以确认组件、容器和密封件、过程中材料和成品符合规范，包括稳定性规范。
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 must be rejected.
测试还支持分析和工艺验证工作【4】。涉及实验室操作的通用CGMP法规可在第211部分第I子部分（实验室控制）和第J子部分（记录和报告）中找到。这些法规规定建立科学合理的规范、标准和测试程序，以确保成分、容器和密封件、过程中材料和成品符合既定标准。CGMP法规第211.165（f）节规定，不符合既定标准、规范或其他相关质量控制标准的成品必须拒收。
【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 suitabilityof 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 drugapplications (INDs), specifications are contained in the application or DMF.Specifications for nonapplication products may be found in official compendiaor established by the manufacturer. 标准规范必须科学合理和适当(211.160(b))，测试程序必须验证其准确性、灵敏度、专属性和重复性(211.165(e))，必须记录测试程序在实际使用条件下的适用性(211.194(a)(2))。对于作为新药申报(nda)、仿制药申报(anda)或新药研究申报(ind)这类产品，标准规格包含在申报或DMF中。非申报相关标准规范可在药典中找到或由制造商制定。】
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.
制剂和原料药(API)都应按照cGMP并根据法案501(a)(2)(B)进行生产。原料药cGMP包括科学合理的原材料测试、过程监控、放行和稳定性测试、工艺验证，以及对从这些测试中获得的任何OOS结果的充分调查。
All citations to part 211 in this document pertain to finished pharmaceuticals, but these referenced regulatory requirements are also consistent with Agency guidance on CGMP for APIs with respect to laboratory controls, which include out-of-specification investigations. See FDA’s guidance for industry Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients (September 2016) (ICH Q7) for specific recommendations.5
本文件第211部分的所有引用均与成品药有关，但这些引用的监管要求也与有关实验室控制的API CGMP的机构指南一致，其中包括不符合规范的调查。见FDA行业指南Q7活性药物成分良好生产规范指南（2016年9月）（ICH Q7）中的具体建议【5】。
The responsibility of a contract testing laboratory in meeting these requirements is equivalent to that of a manufacturing firm.
合同测试实验室在满足这些要求方面的责任等同于制造公司的责任。
【5We update guidances periodically. To make sure you have the most recent version of a guidance, check the CDER guidance page at https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs.
我们定期更新指南。要确保您拥有最新版本的指南，请查看CDER指南网址。】
III.IDENTIFYING AND ASSESSING OOS TEST RESULTS — PHASE I: LABORATORY INVESTIGATION
识别和评估OOS测试结果——第一阶段：实验室调查
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).
FDA法规要求，无论何时获得OOS检测结果，都应进行调查（§211.192）【6】。调查的目的是确定OOS结果的原因。OOS结果的来源应确定为测量过程的偏差或制造过程的偏差。即使一批因OOS结果而被拒绝，也有必要进行调查，以确定该结果是否与同一药品或其他产品的其他批次有关。批量拒收并不意味着不需要进行调查。条例要求对调查进行书面记录，包括结论和后续行动（§211.192）。
【6Although the subject of this document is OOS results, much of the guidance may be useful for examining results that are out of trend.
虽然本文档的主题是OOS结果，但本指南大部分内容对于检查不符合趋势的结果可能有用。】
To be meaningful, the investigation should be thorough, timely, unbiased, well-documented, 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 causative 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 laboratory should convey its data, findings, and supporting documentation to the manufacturing firm’s quality unit (QU). The manufacturing firm’s QU should then initiate the Phase 2 (full-scale) OOS investigation, whenever no clearly causative laboratory error was identified.
为确保有意义的调查，调查工作应该彻底、及时、公正、有充分的文件记录，并且科学合理。此类调查的第一阶段应包括对实验室数据准确性的初步评估。如果可能，应在丢弃试验制剂（包括被测试混合物或同源分离物）之前进行。这样，关于实验室错误或仪器故障的假设可以使用相同的测试准备液进行测试。如果初步评估表明，用于获取数据的分析方法中未出现任何因果错误，则应进行全面的OOS调查。对于合同实验室，实验室应将其数据、调查结果和支持文件传达给制造公司的质量部门（QU）。如果没有发现明显的实验室错误原因，则制造公司的QU应启动第2阶段（全面）OOS调查。
A.Responsibility of the Analyst
分析员的责任
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.
实现准确实验室测试结果的首要责任在于执行测试的分析员。分析员应注意测试过程中可能出现的潜在问题，并应注意可能产生不准确结果的问题。
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.
根据§211.160（b）（4）中的CGMP规定，分析员应确保仅使用符合既定性能规范的仪器，且所有仪器均已正确校准。
某些分析方法有系统适用性要求，不应使用不符合这些要求的系统。例如，在色谱系统中，可在整个色谱过程中每隔一段时间注入参考标准溶液，以测量漂移、噪声和重复性。如果参考标准响应表明系统运行不正常，则应正确识别可疑时间段内收集的所有数据，且不应使用这些数据。在决定是否在可疑期之前使用任何数据之前，应确定故障原因，并在可能的情况下予以纠正。
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.
在丢弃试验液或标准液之前，分析员应检查数据是否符合试验规范。当获得意外结果且不存在明显解释时，应保留试验准备液（如果稳定），分析员应通知主管。应立即开始评估结果的准确性。
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).
如果错误很明显，例如样品溶液溢出或样品混合物转移不完全，分析员应立即记录所发生的情况。分析员不应故意继续进行他们预期在以后某个时间因可分配的原因而失效的分析（即，完成分析的唯一目的不应是查看在已知明显错误时可以获得什么结果）。
B.Responsibilities of the Laboratory Supervisor
实验室主管的职责
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 re-examination of the actual solutions, test units, and glassware used in the original measurements and preparations, which might provide more credibility for laboratory error hypotheses.
一旦OOS结果被识别到，主管的评估应客观及时。对于OOS结果的原因，不应有任何先入为主的假设。应立即评估数据，以确定结果是否可能归因于实验室错误，或结果是否可能表明制造过程中存在问题。立即评估可能包括重新检查原始测量和准备液中使用的实际溶液、测试装置和玻璃器皿，这可能为“实验室错误”的假设提供更可靠的依据。
The following steps should be taken as part of the supervisor's assessment:
作为主管评估的一部分，应采取以下步骤：
1.Discuss the test method with the analyst; confirm analyst knowledge of and performance of the correct procedure.
与分析员讨论测试方法；确认分析员对正确程序的了解和执行情况。
2.Examine the raw data obtained in the analysis, including chromatograms and spectra, and identify anomalous or suspect information.
检查分析中获得的原始数据，包括色谱图和光谱，并识别异常或可疑信息。
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.
核实用于将原始数据值转换为最终测试结果的计算是否科学合理、适当和正确；还要确定是否对自动计算方法进行了未经授权或未经验证的更改。
4.Confirm the performance of the instruments.
确认仪器的性能。
5.Determine that appropriate reference standards, solvents, reagents, and other solutions were used and that they met quality control specifications.
确定使用了适当的参考标准品、溶剂、试剂和其他溶液，并符合质量控制规范。
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.
根据方法验证数据和历史数据，评估测试方法的性能，以确保其按照预期标准执行。
7.Fully document and preserve records of this laboratory assessment.
完整记录调查过程并保存实验室评估的记录。
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.
如果及时检查保留的样品制备样，将大大有助于确定OOS结果的原因。应对可能发生的情况（例如稀释误差、仪器故障）的假设进行测试。保留溶液的检查应作为实验室调查的一部分进行。
Examples:例如
•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.
在怀疑存在瞬时设备故障的情况下，可以重新注入溶液，作为调查的一部分。这样的假设很难证明。然而，回注可以提供强有力的证据，证明问题应归咎于仪器，而不是样品或其制备。
•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.
对于某些在检测过程中未被销毁的特定剂型药物的释放率检测，如果可能，对被检测的原始剂型进行检查可能会确定该剂型在实验室处理过程中是否受到损害，从而影响其性能。这种损坏将为OOS检测结果无效提供证据，需要重新检测。
•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.
在可能的情况下，可以对剂量单位进行进一步提取，以确定在原始分析中该剂量单位是否被充分提取。不完全提取可能使试验结果无效，并应导致有关试验方法验证的问题。
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.
调查中的每一步都要有完整的记录，这一点很重要。实验室管理层不仅应确定获得的单个值的可靠性，还应确定这些OOS结果对实验室质量保证计划的重要性。实验室管理人员应特别注意事件发展趋势。作为有效质量体系的一部分，公司的高层管理人员应适当监控这些趋势，并确保解决任何问题。
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.
实验室误差应该相对较少。频繁出现的错误表明问题可能是由于分析人员培训不足、设备维护不当或校准不当或工作粗心造成的。一旦发现实验室错误，公司应确定该错误的来源，并采取纠正措施防止再次发生。为确保完全符合CGMP法规，制造商还应保存足够的纠正措施文件。
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.
总之，当存在实验室错误的明确证据时，实验室测试结果应无效。当实验室错误的证据尚不清楚时，制造公司应进行全面的OOS调查，以确定导致意外结果的原因。
OOS test results should not be attributed to analytical error without completing an investigation that clearly establishes a laboratory root cause. Both the initial laboratory assessment and the following OOS investigation should be documented fully.
在没有完成明确确定实验室根本原因的调查之前，OOS检测结果不应归因于分析错误。初始实验室评估和后续OOS调查均应完整记录。
IV.INVESTIGATING OOS TEST RESULTS — PHASE II: FULL-SCALE OOS INVESTIGATION
调查OOS测试结果——第二阶段：全面OOS调查
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. The objective of such an investigation should be to identify the root cause of the OOS result and take appropriate corrective action and preventive 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.
当初始评估未确定实验室错误导致OOS结果，且测试结果似乎准确时，应使用预定义程序进行全面OOS调查。此类调查的目的应是确定OOS结果的根本原因，并采取适当的纠正措施和预防措施【7】。全面调查应包括对生产和取样程序的审查，并通常包括额外的实验室测试。这种调查应该得到最高优先级对待。
【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 actions and preventive actions. Corrective action and preventive action are consistent with the principles in ICH guidance for industry Q10 Pharmaceutical Quality System (April 2009).
请注意211.192要求对任何差异进行彻底的调查，包括结论和后续行动的记录。这一调查要求隐含了实施纠正措施和预防措施的必要性。纠正措施和预防措施符合ICH行业指南Q10药品质量体系(2009年4月)中的原则。】
Among the elements of this phase is evaluation of the impact of OOS result(s) on already distributed batches.
该阶段的内容包括评估OOS结果对其它批次的扩散影响。
A.Review of Production生产回顾
The investigation should be conducted by the QU 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 potential problems should be identified and investigated.
调查应由质量部门进行，并应涉及可能涉及的所有其他部门，包括制造、工艺开发、维护和工程。如果生产发生在外部（即，由合同制造商或多个生产现场进行），则调查中应包括所有可能涉及的现场。应确定并调查其他潜在问题。
The records and documentation of the manufacturing process should be fully reviewed to determine the possible cause of the OOS result(s).
应全面审查制造过程的记录和文件，以确定OOS结果的可能原因。
A full-scale OOS investigation should consist of a timely, thorough, and well-documented review. A written record of the review should include the following information.
全面的OOS调查应包括及时、彻底和记录良好的审查。审查的书面记录应包括以下信息。
1.A clear statement of the reason for the investigation.
对调查原因的明确陈述。
2.A summary of the aspects of the manufacturing process that may have caused the problem.
制造过程中可能导致问题的方面的总结。
3.The results of a documentation review, with the assignment of actual or probable cause.
文件审查的结果，以及实际或可能原因的分配。
4.The results of a review made to determine if the problem has occurred previously.
为确定该类问题之前是否发生而进行的审查的结果。
5.A description of corrective actions taken.
对所采取的纠正措施的描述。
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 personnel, including production and QU personnel.
如果这部分OOS调查确认了OOS结果，并成功地确定了其根本原因，则OOS调查可能会终止，产品将被拒绝。但是，必须完成对可能与特定失效有关的其他批次或产品的失效调查(§211.192)。如果在额外测试后对任何材料进行返工，调查应包括相关人员的意见和签名，包括生产和质量控制部门人员。
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结果可能表明产品或工艺设计中存在缺陷。例如，产品配方中缺乏稳健性、原材料特性或控制不足、生产过程中的一个或多个单元操作引入的重大变更，或这些因素的组合可能是导致产品质量不一致的原因。在这种情况下，为确保可重现的产品质量，对产品或工艺进行重新设计是至关重要的【8】。
【8 OOS结果也可能是对生产工艺进行未经授权或未经验证的更改的不良做法的结果。】
