Identification of Out-of-Trend Stability Results, Part II PhRMA CMC Statistics, Stability Expert Teams Oct 2, 2005 By: PhRMA CMC Statistics, Stability Expert Teams Pharmaceutical Technology
High-quality stability data are critical to the pharmaceutical and biopharmaceutical industries. These data form the basis for justifying specification limits (also called acceptance criteria in the International Conference on Harmonization [ICH] Q1 and Q6 guidances), for setting and extending product expiration dates, and for establishing product label storage statements. Annual, routine stability studies also can be used to support product or process modifications and are vital for ensuring the continuous quality of production batches. To facilitate the prompt identification of potential issues, and to ensure data quality, it is advantageous to use objective (often statistical) methods that detect potential out-of-trend (OOT) stability data quickly. 高质量的稳定性数据对于制药企业和生物制药企业是很重要，是证实合理的质量规格、设置和延长有效期、以及确定产品标签储存说明的依据。每年，常规的稳定性数据也可用于支持产品或工艺的改进，对保证持续的生产批质量有着举足轻重的作用。为了促进及时确定潜在的问题和保证数据质量，应该使用能够快速发现潜在超趋势（OOT）稳定性数据的客观方法(常为统计方法)。 In general, OOT stability data can be described as a result or sequences of results that are within specification limits but are unexpected, given the typical analytical and sampling variation and a measured characteristic's normal change over time (e.g., an increase in degradation product on stability). 通常，OOT稳定性数据是指在给定典型分析和取样变化，以及标准特性随时间正常变化的情况下，产生的在质量规格限度内，但是超出预期期望的一个结果或一系列结果（比如稳定性降解产物的增加）。 OOT stability results may have a significant business and regulatory impact. For example, if an OOT result occurs in the annual production batch placed on stability, the entire year's production could be affected, depending on the OOT alert level. Systems that are useful for detecting OOT results provide easy access to earlier results so that they can track stability data and trigger an alert when a potential OOT situation arises. Procedures describing OOT limits, responsibilities for all aspects of an OOT system, and investigational directions are all components of a company's quality system. OOT稳定性数据对企业有着重要的商业和管理影响。例如在每年放入稳定性试验的生产批中出现OOT结果，根据OOT警戒标准，全年的生产都要受到影响。能够发现OOT结果的系统才能够提供早期结果，以便可以追踪稳定性数据，并在潜在OOT情况发生时引起警惕。描述OOT限度，OOT系统各个方面的职责以及调查方向的程序是一个公司质量系统的组成部分。 Representatives from the US Food and Drug Administration and 77 individuals from more than 30 Pharmaceutical Research and Manufacturers of America (PhRMA) member companies met in October 2003 to address important stability OOT alert issues. Their discussions underscored the need to track OOT stability data, associated issues, and potential statistical or other approaches to establish OOT alert limits. Breakout sessions captured participants' perspectives on FDA expectations and guidances, acceptable OOT identification methodologies, and implementation challenges. 美国FDA代表和来自美国药品研究与制造商协会成员公司的77位代表在2003年10月召开会议，致力于重要的稳定性OOT警戒问题。讨论强调了追踪OOT稳定性数据的必要性，相关问题，以及确定OOT警戒限可以使用的统计学方法和其他方法。分组讨论把与会者的观点集中在FDA的期望和指导，可接受的OOT证实方法学以及实施过程中的挑战性等方面。 Workshop attendees concluded that the main focus for OOT identification and investigation should be annual, routine production stability studies rather than primary new drug application (NDA) batches because historical data are usually needed to determine appropriate OOT alert limits. 专题小组的与会者认为，OOT确定和调查的主要焦点应该是年度常规的生产稳定性研究，而不是最初新药的申请批次。因为通常需要历史数据来确定合适的OOT警戒限。 In addition, attendees clearly expressed a desire for a simple approach to tracking stability data that would allow at-the-bench, real-time detection of OOT results. This capability is important from an implementation standpoint so that a timely investigation can be initiated. Timeliness is especially important when an analytical error is suspected of causing OOT results. It was recognized that an efficient approach with such properties might be difficult to achieve. 另外，与会者明确表示他们希望能有一个简单的方法用来追踪稳定性数据，该方法允许在试验台前实时检测OOT结果。从实施角度而言，这个性能是非常重要的，以便可以及时展开调查。在怀疑是因为分析原因造成OOT结果时，及时展开调查很重要。同时大家也知道，很难得到这样一个及时有效的方法。 Another recommendation was the need for standard operating procedures (SOPs) that address how to handle (e.g., identify, investigate, conclude, take action) OOT data. Workshop participants believed that a separate FDA guidance is not needed to develop such SOPs because the existing out-of-specification (OOS) guidance should suffice. 另一个建议是通过建立SOP来说明如何处理（例如确定，调查，断定和采取措施）OOT数据的必要性。 专题小组与会者认为不需要单独的FDA指南来开发这样的SOP，因为现在的OOS指南有能力做到这一点。 Three types of OOT results—which determine the degree and scope of an OOT investigation—were identified at the workshop. This article expounds on these outcomes and addresses other questions raised during the workshop and in a previous article (1). Recommendations put forward in this article are not requirements, but rather, are possible alternatives for handling OOT data. 专题小组确定了三种类型的OOT结果，可以用来确定OOT调查的程度和范围。本文对这些结果做了详细说明，并致力于小组讨论期间和以前文章中提出的其他问题。本文提出的建议不是要求必备的条件，应是处理OOT数据时可以选用的方法。
Figure 1: An analytical alert (theoretical data, see endnote). OOT alerts can be classified into three categories to help identify the appropriate depth for an investigation. In this article, OOT stability alerts are referred to as analytical, process control and compliance alerts, in order of implied severity. As the alert level increases from analytical to process control to compliance alert, the depth of investigation should increase. OOT警戒可以分为三种类型，用来确定调查的适当程度。本文所说的OOT稳定性数据是指分析，工艺控制和符合性警戒。因为警戒水平从分析到工艺控制再到符合性警戒逐步增加，调查的程度也应该增加。
Figure 2: A process control alert (theoretical data, see endnote). Results from multiple time points for a study do not follow the same trend over the 36-month shelf-life expiration as do other studies. The study is not expected to fall below the specification limit through the 36-month expiration. Historical data are needed to identify OOT alerts. An analytical alert is observed when a single result is aberrant but within specification limits (i.e., outside normal analytical or sampling variation and normal change over time) (see Figure 1). OOT警戒需要用历史数据来确定。当某单一结果异常，但还在质量规格内时，属于分析警戒。（例如在常规分析或取样变化以及随时间的正常变化之外）（见图1） A process control alert occurs when a succession of data points shows an atypical pattern that was possibly caused by changes to the laboratory or manufacturing process. These data points might originate from the same stability study (see Figure 2) or from multiple studies assayed within a reasonably close timeframe (within a few weeks) (see Figure 3). As these Figures 2 and 3 indicate, the trends for the batches in question vary substantially from those of comparable batches. Despite the deviating trends, no pending potential OOS situation occurs. 当一连串的数据点显示可能由实验室或生产工艺变化引起了非典型模式时，表示出现了工艺控制警戒。数据点可能来自同一稳定性研究或来自近期内的多重研究（几周内）。如图2和图3所示，问题批的趋势变化明显与对照批不同。尽管背离了趋势，没有产生潜在的OOS。 Lastly, a compliance alert defines a case in which an OOT result suggests the potential or likelihood for OOS results to occur before the expiration date within the same stability study (or for other studies) on the same product (see Figures 4 and 5). 最后符合性警戒是指，同一产品的同一（或其他）稳定性研究产生的OOT结果显示，在有效期内有产生OOS的潜在性或可能性的情况。
Similarly, tests with multiple stages can be classified into the three OOT alert levels, but this task is much more challenging and less straightforward. For example, consider the three-stage USP dissolution test. If Stage 2 testing is rarely required, then an analytical alert for USP dissolution testing might be a single, unusual minimum or average dissolution. If the product usually passes Stage 1 and a new stability study goes to Stage 2 several times, then this result might signal a process control alert. If the study's dissolution average shows a decreasing trend with time that indicates difficulty remaining above the registered Q-value through expiration, this fact could indicate a compliance alert. 同样，多阶段检测也可分为三种OOT警戒水平，但是这项任务太具有挑战性，不是那么简单。例如，USP中溶出度的三阶段测定。如果很少要求第二阶段的测定，那么USP溶出度测定的分析警戒可能是一个单个的，非寻常最小值或平均溶出度。如果该产品通过了第一阶段，并且第二阶段也进行了几次新的稳定性研究，那么这个结果有可能是一个工艺控制警戒信号。如果所研究的溶出度平均值显示随时间的下降趋势，该趋势预示了在有效期内保持高于所注册Q值的难度，这种事实可能预示符合性警戒。
Very minimal guidance was provided on this topic at the workshop, though some attendees believed it is an area that lacks clarity and consistency. 专题小组很少对本主题提供指南，尽管一些与会者认为这是一个缺乏清晰度和一致性的领域
SOP requirements SOP要求 The workshop attendees suggested that companies develop SOPs for the review and investigation of OOT stability results. FDA participants pointed out that current good manufacturing practices (CGMPs) require a written stability-testing program to assess the stability characteristics of drug products (211.166) and require written procedures for conducting a thorough investigation of any unexplained discrepancy (211.192). Moreover, CGMPs require written procedures for evaluating the quality standards of each drug product at least annually (211.180). A review of the OOT alert procedures' performance might coincide with the annual product review. When preparing an SOP for handling OOT test results, it is prudent to consider risks to product quality when determining the company's assessment of OOT test results. The depth of an investigation and the corrective measures taken may depend on the potential or implied risk to product quality. 专题小组的与会者建议公司编写SOP来对OOT结果进行审核和调查。FDA的参与者指出，现行的 cGMP要求有书面的稳定性检测程序来评估药品的稳定特性， 并要求有书面的程序来对任何不明原因的差异进行彻底的调查。此外，cGMP还要求按照书面程序对每个药品的质量标准每年至少评估一次。OOT警戒程序执行情况的审核可能符合年度产品审核。在编写处理OOT检测结果的SOP过程中，在确定公司对OOT测试结果的评估时， 要谨慎考虑产品质量的风险。调查的程度和所采取的纠正措施取决于产品质量的潜在风险。 The following five SOP topics are areas that companies may want to address. These points were not discussed by conference participants. 以下五个SOP主题是公司意图致力的领域。与会者没有讨论这些问题点。
Figure 4: A compliance alert (theoretical data, see endnote). Results from multiple time points for a study do not follow the same trend as other studies. The study is at risk of falling below the specification limit before the 36-month shelf-life expiration. How to set alert limits. SOPs may identify scientifically sound approaches to determine procedures with associated limits for the identification of each type of OOT alert for stability test attributes such as assay and degradation products. Once an approach is identified, some potential topics to be included in the SOP are data requirements, personnel responsible for setting the limits, and methods used to detect each type of OOT alert. 如何设置警戒限度：SOP应指定科学合理的方法，用相关的限度来对稳定性试验属性，如含量和降解产物等规定每一种OOT警戒的鉴定程序。一旦指定了方法，SOP应包含以下潜在内容：数据要求，负责设定限度的人员，用来测定每种OOT警戒的方法。 For new products, available stability data will be limited. Established products often will have sufficient historical data. The methods for detecting OOT results may vary depending on the type of OOT alert. Ideally, a method for each OOT type should be specified. 对于新产品，可以得到的稳定性数据有限。既定产品的通常有足够的历史数据。确定OOT结果的方法可以根据OOT警戒类型的不同而有所不同。理想地认为，应指定每一种OOT的确定方法。 How to use limits. The SOP may contain a section about how OOT alert limits are applied and which personnel will be responsible for comparing new stability results with the OOT alert criteria and timeliness of the review. 如何使用限度：本SOP可以包含关于如何应用OOT警戒限的部分，以及什么人负责将新的稳定性数据和OOT警戒标准进行对比和及时进行审核。
Figure 5: A compliance alert (theoretical data, see endnote). After two analytical alert results in a study, a result is observed right on the specification limit at the 30-month expiration time point. Because this study may represent many other batches, it is a potential compliance concern. Investigation. Investigation requirements could include personnel responsibilities with defined timelines, documentation requirements, and proper internal notification requirements. The investigation's depth required for each OOT alert will depend on potential risks to product quality. The SOP should not be overly prescriptive because the steps taken to investigate OOT results will depend on the nature of the initial finding and the investigation findings. Nonetheless, SOPs should provide basic criteria for conducting the investigations. Moreover, the steps taken to investigate OOT results should be scientifically defensible, and the rationale for the investigation's depth should be documented. Although an OOT result usually will be investigated as soon as possible after it is identified, it also can be addressed more broadly during the annual product review. The notification requirements and the department responsible for performing the annual product reviews also could be included. 调查研究：调查要求应包括人员职责， 并指定时间，文件要求以及适当的内部通知要求。每个OOT警戒调查的程度取决于对产品质量的潜在风险。SOP不应是过分说明性的，因为OOT结果调查所采取的步骤取决于最初发现和调查发现的性质。虽然如此，SOP应该提供进行调查的基本标准。此外，OOT结果调查所采取的步骤应科学有理有据，调查程度的原理应有文件记录。尽管，OOT结果一旦确定就应该尽快对其展开调查，也可以在年度产品审核时对其进行广泛处理。通知要求和负责执行年度审核的部门也要包括在SOP中。 Limits for truncated data. The SOP may specifically address truncated data such as for degradation products, whereas the approaches discussed in this article may not be appropriate because of the truncation. An example of truncated data is unreported data that are lower than the ICH reporting threshold. Degradant results may be higher or lower than the ICH reporting threshold from time point to time point. In addition, results may be reportable only at later time points as the levels increase depending on the amount of truncation (ICH reporting threshold). Setting data-driven OOT alert limits in such situations may not be possible. To facilitate the quantitative evaluation of the data, it is suggested that degradation product and impurity results be available to at least two decimal places. 截短数据的界限：SOP应明确说明截短的数据，如对于降解产物，但是因为数据切断，本文章中讨论的方法可能不适用。截短数据的一个例子就是低于ICH报告限而未报道的数据。降解产物的结果在不同的时间点可能会高于或低于ICH的报告限。另外，可能只有后面时间点的结果是可报告的，因为水平由于截短数量（ICH报告限）而增加。 在这种情况下，不可能设置数据驱动的OOT警戒线。为了方便进行数据的定量评估，建议降解产物和杂质结果至少保存两位小数。 Periodic review of limits. SOPs may specify a periodic review process for OOT alert limits. The frequency of the review and the personnel responsible for completing it may be addressed in the SOPs. This assessment can involve identifying a previous result that was once within trend but is now an OOT result. Or, it may find that a previous OOT result is now within trend. It is natural that earlier conclusions be revised in light of new information because developing OOT alert criteria is an active and continuing process. 限度的周期审核：SOP可以规定OOT警戒限的一个周期性审核程序。SOP应指定审核的频率和负责完成审核的人员。这个评估包括识别一个以前的结果，该结果曾经符合趋势，但现在是OOT。或是发现以前是OOT的结果，现在符合趋势。早期的结论根据新的标准被修订是很自然的事情，因为OOT警戒标准的开发是一个主动持续的过程。
Depth of investigation 调查的程度 It is important to point out that by itself, an alert provided by a method designed to detect unexpected events or degradation patterns is no proof that the batch in question has a deviating trend. The alert is only a signal to begin an investigation. The alert is not intended to make any conclusions. A conclusion can only be reached after the investigation of OOT stability data that follows. 这一点很重要，就是用检测非期望事件或降解方式的方法提出警戒，不是证明讨论批有背离趋势。警戒只是启动调查的一个信号。警戒不是要做出什么结论。只有接下来对OOT稳定性数据进行调查以后才可以做出结论。 An investigation's depth may depend on the nature of the data, the product history and characteristics being measured, the potential risk to product quality, and the potentially related safety or efficacy implications. The CGMP regulations in CFR 211.166 require an assessment of drug stability, whereas 21 CFR 211.192 requires an investigation of unexplained discrepancies by the quality control unit. 调查的程度取决于数据的性质，产品历史和所检测的特性，对产品质量的潜在风险以及对有关安全性和有效性的潜在影响。CFR 211.166 的CGMP 法规要求对药品稳定性做出评估，而21 CFR 211.192 要求质量控制部门对不明原因的差异进行调查。 If an analytical alert is observed, a laboratory investigation may be performed. If the laboratory investigation is inconclusive, then the supervisor may take no further action at that time and monitor subsequent time points closely. A review of results for related or correlated test attributes also can facilitate the investigation. Depending on the product, history, and nature of the analytical alert data, the company may decide to investigate whether a manufacturing error occurred in cases in which a laboratory error is not conclusive. More data (i.e., the next stability test point) may be needed to indicate whether the result is part of a long-term trend (process control alert) or just an isolated result. If subsequent results within the study and across other studies are not out of trend, then the initial analytical alert result may be an isolated incident that requires no further investigation. 如果观察到的是分析警戒，应进行实验室调查。如果实验室调查没有结论，主管人当时可以不采取进一步措施，但是要密切检测后面的时间点。有关检测属性的结果审核也有助于调查。根据产品，历史和分析警戒数据的性质，在确定不是实验室误差的情况下，公司可以决定调查是否存在生产误差。可能需要更多的数据（如下一次稳定性测试点的数据）来说明该结果是否是长期趋势（工艺控制警戒）的一部分或者仅仅是一个孤立结果。如果该研究以后的结果和其他的横向结果都没有超出趋势，那么最初的分析警戒有可能就是一个孤立事件，没必要对其做进一步的调查。 A process control alert may indicate unexpected changes in product or assay performance. A stability study with an unusual trend may reveal that a characteristic's stability profile changed, whereas multiple analytical alerts may suggest that the measurement process is no longer in control. When a process control alert is evident, the investigation will often begin with an assessment of the effect of potential changes to the laboratory process (e.g., changes in instrument, column, integration technique, or standard). It also may extend to the manufacturing process (e.g., looking for changes in materials, personnel, equipment, and procedures). 工艺控制警戒可能预示产品或分析性能的意外变化。有着不同寻常趋势的稳定性研究可能显示某一特性的稳定情况发生了改变，而多重分析警戒可能暗示测量过程不再受控。当工艺控制警戒很明显时，调查通常从评估实验室工艺可能存在的变化的影响开始（例如仪器的变化，色谱柱的变化，集成技术的变化，标准的变化等 ）。也可延伸到生产工艺（如检查材料，人员，设备和工艺有无变化）。 Because a compliance alert identifies a situation in which a particular study (or several related studies) may not meet specification limits during the expiration period, one may need to conduct a thorough investigation. In general, this investigation begins with the laboratory process and expands to the manufacturing process if no conclusive laboratory root cause is identified. The manufacturing investigation might include other batches (from the same or related products) that may be associated with this predicted failure to identify whether the discrepancy is isolated or systematic. The investigation also could assess whether more analytical testing, an investigation into the manufacturing process, a product recall, or shorter dating is required. An investigation of a compliance alert aims for the early detection of potentially failing product and the identification of possible causes. If a root cause is determined, then appropriate action should be taken such as the identification of potential preventative actions. 因为符合性警戒是指某一特定研究（或一些相关研究）在有效期内可能不符合质量标准限度，因此需要进行全面彻底的调查。通常这种调查从实验室工艺开始，如果不能最终确定根本原因，进一步扩大到生产工艺。生产调查可能会包括与本次预示性失败有关的其他批次（同一产品或相关产品），以确定这种偏差是孤立的还是系统的。调查也要评估是否需要进行另外的分析检测，生产工艺调查，产品召回和减短检测间隔。符合性警戒调查的目的是及早发现潜在的失败产品和确定可能引起失败的原因。如果确定了根本原因，应采取适当的措施，例如确定可能采取的预防措施。
Identification of Out-of-Trend Stability Results - A Review of the Potential Regulatory Issue and Various Approaches, PhRMA CMC Statistics and Stability Expert Teams http://www.pharmtech.com/pharmtech/article/articleDetail.jsp?id=52982
Identification of Out-of-Trend Stability Results, Part II PhRMA CMC Statistics, Stability Expert Teams http://www.pharmtech.com/pharmtech/article/articleDetail.jsp?id=190315
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