近日，FDA对Glenmark的警告信中提及稳定性试验样品测试逾期的缺陷：未能在取样品取出后的规定时间内及时完成稳定性测试。很大一部分样品的稳定性测试逾期 3 个月甚至更久。
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Your firm failed to follow an adequate written testing program designed to assess the stability characteristics of drug products (21 CFR 211.166(a)).贵公司未能遵循旨在评估药品稳定性特征的充分书面测试程序（21 CFR 211.166 (a)）。
You failed to follow your written stability procedure for your finished drug products. For example, you did not complete timely stability testing for approximately (b)(4) stability samples for U.S. commercial drug products within the stipulated timeline ((b)(4) after sample pull). Stability testing was overdue by 3 months or longer for a large proportion of your samples.贵公司未能遵循成品药的书面稳定性程序。例如，对于美国市售药品的约（b）（4）个稳定性样品，贵公司未在规定时间内（取样后（b）（4））完成及时性稳定性测试。贵公司很大一部分样品的稳定性测试逾期 3 个月甚至更久。
In your response, you provide details for the backlog of pending stability sample testing, root causes for the delays in stability testing, and state all delayed stability sample testing for U.S. commercial products was completed by December 2024, prior to the inspection. You also implemented quality and executive management oversight for reviewing progress of stability testing, metrics, and upcoming stability testing for resource availability. You developed plans to increase quality control (QC) resources to reduce delayed stability sample testing by increasing QC laboratory capacity, purchasing and qualifying additional equipment, and hiring additional personnel. You plan to perform a stability load assessment for stability samples pulled from March 2025 to December 2025 to evaluate the adequacy of resources in your QC laboratory.在贵公司的回复中，提供了待处理稳定性样品测试的积压详情、稳定性测试延迟的根本原因，并说明在检查前，即 2024 年 12 月前，所有美国市售产品延迟的稳定性样品测试已完成。贵公司还实施了质量和高管管理层监督，以审查稳定性测试的进展、指标以及即将进行的稳定性测试的资源可用性。贵公司制定了增加质量控制（QC）资源的计划，通过提高 QC 实验室容量、购买和确认额外设备以及招聘额外人员来减少稳定性样品测试的延迟。贵公司计划对 2025 年 3 月至 2025 年 12 月抽取的稳定性样品进行稳定性负荷评估，以评估 QC 实验室资源的充足性。
Your response is inadequate. You do not include the test results from the delayed stability analyses or a copy of the investigation report with your written response to demonstrate whether backlogged stability testing was completed and adequately investigated for root cause. Also, you do not provide adequate information on your stability load assessment, with pre-defined criteria, to evaluate adequacy of resources for your stability testing program.贵公司的回复不充分。贵公司的书面回复中未包含被延迟的稳定性分析测试结果或调查报告副本，以证明积压的稳定性测试是否已完成以及是否对根本原因进行了充分调查。此外，贵公司未提供有关稳定性负荷评估的充分信息（包括预定义标准），以评估稳定性测试计划的资源充足性。
Additionally, your impact assessment for the delayed stability analyses does not adequately address the risk to patient safety. Your firm’s failure to perform stability dissolution testing for potassium chloride ER capsules and (b)(4) capsules within the specified testing period led to delays in detecting product quality failures, issuing field alert reports1 and conducting recalls in a timely manner. For example, in multiple instances, potassium chloride ER capsules dissolution failures were not observed for approximately 100 days after stability samples were pulled.此外，贵公司对延迟稳定性分析的影响评估未充分说明对患者安全的风险。贵公司未能在规定测试期内对氯化钾缓释胶囊和（b）（4）胶囊进行稳定性溶出测试，导致检测产品质量不合格、发布现场警报以及及时开展召回工作均出现延迟。例如，在多个案例中，稳定性样品取出约 100 天后才发现氯化钾缓释胶囊的溶出不合格问题。
Without an appropriate ongoing stability program, you lack adequate scientific evidence to support whether your drug products meet established specifications and retain their quality attributes through their labeled expiry.如果没有适当的持续稳定性计划，贵公司就缺乏充分的科学证据来证明贵公司的药品是否符合既定标准，以及在标注的有效期内是否能保持其质量属性。
In response to this letter, provide:针对本函，请提供：
o A copy of the completed stability data from the backlogged stability testing. Include a plan of action for any OOS results found from the stability analyses. o 积压稳定性测试的完整稳定性数据副本。包括针对稳定性分析中发现的任何 OOS 结果的行动计划。
o Your stability load assessment protocol relating to stability samples pulled from March 2025 to December 2025, and the report and CAPA assuring future resource adequacy. o 与 2025 年 3 月至 2025 年 12 月抽取的稳定性样品相关的稳定性负荷评估方案，以及确保未来资源充足的报告和纠正与预防措施（CAPA）。
o A comprehensive, independent assessment and CAPA plan to ensure the adequacy of your stability program. Your remediated program should include, but not be limited to: o 一项全面、独立的评估以及 CAPA 计划，以确保贵公司稳定性计划的充分性。经整改的计划应包括但不限于：
Stability indicating methods.
稳定性指示方法。
Stability studies for each drug product in its marketed container-closure system before distribution is permitted.
在允许分销前，对每种药品在其市售包装容器系统中的稳定性研究。
An ongoing program in which representative batches of each product are added each year to the program to determine if the shelf-life claim remains valid.
一项持续计划，每年将每种产品的代表性批次纳入该计划，以确定保质期声明是否仍然有效。
Detailed definition of the specific attributes to be tested at each station (timepoint).
详细规定每个时间点需测试的特定属性。
All procedures that describe these and other elements of your remediated stability program.
描述经整改的稳定性计划中这些及其他要素的所有程序。
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稳定性试验样品，应取出后在多久内检测？
国外某公司SOP：
< 3 个月样品：10 个工作日
3-6 个月样品：15 个工作日
>6-24 个月样品：21 个工作日
>24 个月样品：30 个工作日
USP 最新发布的通则<1049.1>《生物技术及生物制品稳定性试验》草案中也提及稳定性试验时间零和样品检测时限的要求：
One item of particular importance for biologics is the stability study start date, or time zero. Time zero is defined as the date the material is placed at the applicable storage condition and the stability assessment begins, which may be the date of manufacture as discussed below. The storage condition includes temperature, light, and humidity, as applicable, and is otherwise independent of physical location. Note that regardless of the stability time zero, the expiration date for a batch is based on its date of manufacture and not the stability study start date. A product may have different time zero calendar dates for each storage condition. A change of location for a material while retaining the same storage condition doesnot alter the timezero (i.e. a product moved from a −20° warehouse to a−20°stability chamber doesnot alter the date of time zero because the material is held at the same condition in both locations). Thus, if the product is to be immediately stored after production at the same storage condition planned for long-term stability storage, as is common with biologics stored refrigerated or frozen, itis recommended that time zero is aligned to the date of manufacture.The manufacturer should establish whether it is permissible to leverage batch released at aasthe stability time zero data.
对于⽣物制剂来说，特别重要的⼀项是稳定性研究开始⽇期或时间零。时间零定义为物料置于适⽤的储存条件下并开始稳定性评估的⽇期，它可能是生产⽇期。储存条件包括温度、光照和湿度（如适⽤），且与物理位置⽆关。请注意，⽆论稳定性时间零为何，批次的有效期均基于其⽣产⽇期，⽽不是稳定性试验的开始⽇期。对于每种存储条件，产品可能具有不同的时间零⽇历⽇期。在保持相同存储条件的情况下改变物料的位置不会改变时间零（即，从-20°仓库移动到-20°稳定室的产品不会改变时间零的⽇期，因为物料在两个位置都处于相同的状态）。因此，如果产品在⽣产后要⽴即以所计划的⻓期稳定性相同的储存条件储存，建议将时间零与⽣产⽇期对⻬。制造商应确定是否允许使用批放⾏数据作为稳定性时间零数据。
The pull window is the allowable range around the target pull date to remove the sample from the storage condition and initiate thetesting process. Manufacturers must establish the pull window permissible for each time point. Although manufacturers are expected to describe and manage target pull dates suitable for their product, the industry norm is to require a smaller pull window for shorter test points than longer test points. For example, a 1-month timepoint maybe subject to a shorter pullwindow of 4 days, where as a 24-month timepoint may be subject to a longer pull window. The intent is to ensure the product testing is representative of the time point when the product is removed from the storage condition.
拉动窗⼝是⽬标拉取⽇期左右的允许范围，⽤于将样品从储存条件下取出并启动样品测试过程。制造商必须为每个时间点建⽴允许的拉动窗⼝。尽管制造商应描述和管理适合其产品的⽬标拉动⽇期，但⾏业规范是要求较短的测试点⽐较⻓的测试点使⽤更⼩的拉动窗⼝。例如，1个⽉的时间点可能会受到4天的较短拉取窗⼝的影响，⽽24个⽉的时间点可能会受到较⻓的拉取窗⼝的影响。⽬的是确保产品测试能够代表产品从储存条件下取出的时间点。
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