FDA警告信:QA指示软件供应商修改电子批记录,多批次稳定性实验出现OOS!

4 月 28 日，FDA 发布一则警告信；值得关注的是，该企业已有多款进口药品在中国获批上市。

检查对象：Intas Pharmaceuticals Limited（英塔斯）

检查日期：2025年9月8日 — 2025年9月17日

483回复提交时间：2025年10月8日

FDA 警告信日期：2026年3月30日

During our inspection, our investigators observed specific violations including, but not limited to, the following.

在本次检查中，我方检查员观察到多项具体违规行为，包括但不限于以下内容。

1.Your firm failed to thoroughly investigate any unexplained discrepancy or failure of a batch or any of its components to meet any of its specifications, whether or not the batch has already been distributed (21 CFR 211.192).

你公司未能对某一批次或其任何组分存在的任何无法解释的偏差或不符合质量标准情况进行彻底调查，无论该批次是否已上市销售（21 CFR 211.192）。

Your investigations into out-of-specification (OOS) assay results were inadequate. Your corrective and preventive actions (CAPAs) to address your persistent OOS assay results for (b)(4) tablets were not robust, as evidenced by the continued trend of subpotent assay stability failures and multiple (b)(4) to drug product expiry period.

你公司对含量测定超标（OOS）结果的调查不充分。针对 (b)(4) 片剂持续出现的含量测定 OOS 结果，你公司所采取的纠正预防措施（CAPA）不够有效，这一点体现为含量不足的稳定性试验失败趋势持续存在，且在药品有效期内多次出现 (b)(4) 情况。

For example, since 2023, your testing has shown multiple confirmed stability OOS results for (b)(4) batches. You (b)(4) your expiry period from (b)(4) to (b)(4), and then further (b)(4) it to the current (b)(4). We acknowledge your decision to recall (b)(4) batches of (b)(4) tablets in response to stability OOS results since 2024.

例如，自 2023 年以来，你公司检测显示多个 (b)(4) 批次的稳定性试验 OOS 结果已确认。你公司将有效期从 (b)(4)(b)(4) 至 (b)(4)，随后进一步 (b)(4) 至当前的 (b)(4)。我方注意到你公司针对 2024 年以来稳定性试验 OOS 结果，决定召回 (b)(4) 批次的 (b)(4) 片剂。

Multiple CAPAs included changes to batch processing to prevent further degradation of the active pharmaceutical ingredient. You also implemented modifications to your assay sample preparation procedures. However, you still experienced OOS assay results.For example, you tested 12-month long term stability batch (b)(4) and had a confirmed OOS result of (b)(4)% (specification is (b)(4)%). Your investigation of this 12-month stability failure was inadequate.

你公司实施了多项 CAPA，包括调整批次生产工艺以防止活性药物成分进一步降解，也修改了含量测定样品制备程序，但仍出现含量测定 OOS 结果。例如，你公司对 (b)(4) 批次进行 12 个月长期稳定性试验，检测得到确认的 OOS 结果为 (b)(4)%（标准为 (b)(4)%）。你公司对该 12 个月稳定性试验失败的调查不充分。

You identified the root cause as “product behavior” and recalled this batch. You did not adequately evaluate the reserves of all distributed batches or reserve batches using the same API lot to determine if market 行动 is warranted, as required.

你公司将根本原因归为 “产品特性” 并召回该批次，但未按要求充分评估所有已上市批次的留样及使用同一活性成分批次的留样，以判断是否需要采取市场处置措施。

After the initial OOS result, you proceeded to test samples from the same batch and other previously OOS batches, using a revised analytical method with a different sample preparation and obtained different results.Despite using the revised analytical method, two batches ((b)(4) and (b)(4), (b)(4) tablets USP (b)(4) mcg and (b)(4) mcg) remained out of specification.Your investigation failed to evaluate why these batches still failed or assess whether the analytical method itself contributes to result variability. Attributing a failure to inherent drug product behaviors is not scientifically sound when a change in the test method yields a different outcome.

在首次出现 OOS 结果后，你公司采用经修订、样品制备方式不同的分析方法，继续检测同批次及此前出现 OOS 的其他批次样品，并得到不同结果。尽管使用了修订后的分析方法，仍有两个批次（(b)(4) 和 (b)(4)，(b)(4) 片剂 USP (b)(4) mcg 及 (b)(4) mcg）仍不符合标准。你公司的调查未评估这些批次仍不合格的原因，也未评估分析方法本身是否导致结果波动。当检测方法改变会得到不同结果时，将不合格原因归为药品固有特性在科学上不成立。

Additionally, after you implemented your revised method in July 2025 you continued to experience low assay results.For example, you invalidated an assay result of (b)(4)% for a sample batch ((b)(4)) used as a control due to “solution preparation error” without conclusive supporting evidence, despite the sample preparation analysis being deemed “satisfactory” during the laboratory Phase I investigation.You did not issue a CAPA plan for analyst training. You also discarded the initial OOS with insufficient supporting documentation and did not include it in your final reporting of the assay result.

此外，你公司于 2025 年 7 月实施修订方法后，仍持续出现含量偏低结果。例如，你公司以 “溶液配制错误” 为由，作废某对照批次 (b)(4) 的 (b)(4)% 含量测定结果，但无确凿证据支持；尽管实验室第一阶段调查判定样品配制分析 “合格”。你公司未制定针对检验人员培训的 CAPA 计划，且在支持文件不足的情况下丢弃首次 OOS 数据，未将其纳入含量测定最终报告。

In your response, you attribute the low assay values to the analytical limitation in the assay method, specifically incomplete extraction of the active pharmaceutical ingredient. You state it is not “totally due to actual product degradation.”You discuss your submission of a (b)(4) to the Agency to address the assay OOS results. Using the revised method, your new assay results appeared to be closer to the lower specification end. The variability in the new results does not clearly explain why these results are outside of the target assay value.

你公司在回复中将含量偏低归因为含量测定方法的分析局限性，具体为活性药物成分提取不完全，并声称并非 “完全由产品实际降解导致”。你公司提及已向监管机构提交 (b)(4) 以解决含量测定 OOS 问题。采用修订方法后，新的含量测定结果更接近标准下限，但新结果的波动无法清晰解释为何结果超出目标含量值。

Additionally, you initiated testing of all (b)(4) distributed batches of (b)(4) tablets USP (all strengths) within their approved shelf-life for the U.S. market. All batches met the specification criteria.

此外，你公司已启动对美国市场所有在有效期内的 (b)(4) 已上市 (b)(4) 片剂 USP（所有规格）的检测，所有批次均符合标准。

Your response is inadequate. Your response does not address why the extraction limitation was not identified during the original method validation or explain what failures in your method validation process allowed this critical deficiency.In addition, your impact assessment of the evaluation of the extraction method did not extend to all assay values specifically which were on the higher end of the specification. Your response does not review or correlate market complaints or adverse events with low assay batches, which would be critical for a patient safety assessment.

你公司的回复不充分，未说明为何在原始方法验证中未发现该提取局限性，也未解释方法验证过程中哪些缺陷导致该关键问题未被识别。此外，你公司针对提取方法的影响评估未覆盖所有含量测定结果，尤其是标准上限附近的结果。你公司的回复未回顾或关联市场投诉、不良事件与含量偏低批次的关系，而这对患者安全评估至关重要。

In response to this letter, provide the following:

针对本函，请提交以下资料：

• An impact assessment of (b)(4) tablet batches within expiry that showed assay results below your target assay.This assessment can coincide with your protocol for impact assessment for batches in the U.S. market that have stability testing assay results below (b)(4)%. Identify any common variables leading to the low assay values.Provide the OOS investigations for batch (b)(4) and all OOS assay failures for (b)(4) tablets since the FDA inspection.

• 对有效期内含量测定结果低于目标值的 (b)(4) 片剂批次进行影响评估。该评估可与你公司针对美国市场稳定性试验含量结果低于 (b)(4)% 的批次所制定的影响评估方案保持一致，识别导致含量偏低的共同变量。提供 (b)(4) 批次的 OOS 调查，以及自 FDA 检查以来 (b)(4) 片剂所有含量测定 OOS 不合格的调查资料。

• An assessment of each drug product process to ensure that there is a data-driven and scientifically sound program that identifies and controls all sources of variability, such that your production processes, and will consistently meet appropriate specifications and manufacturing standards.This includes, but is not limited to, evaluating suitability of equipment for its intended use, sufficiency of detectability in your monitoring and testing systems, quality of input materials, and reliability of each manufacturing process step and control.

• 对每个药品生产工艺进行评估，确保建立以数据为支撑、科学合理的程序，识别并控制所有波动来源，使生产工艺持续符合适用标准与生产规范。该评估包括但不限于：评估设备是否适用于预定用途、监测与检测系统的检出能力是否充分、原辅料质量，以及各生产工艺步骤与控制措施的可靠性。

• A comprehensive, independent assessment of your overall system for investigating deviations, discrepancies, complaints, OOS results, and failures.Provide a detailed action plan to remediate this system. Your action plan should include, but is not limited to, significant improvements in investigation competencies, scope determination, root cause evaluation, CAPA effectiveness, quality assurance oversight, and written procedures.Address how your firm will ensure all phases of investigations are appropriately conducted.

• 对你公司用于调查偏差、异常、投诉、OOS 结果及不合格项的整体体系开展全面、独立评估。提供详细的体系整改行动计划，应包括但不限于在调查能力、范围界定、根本原因评估、CAPA 有效性、质量保证监督及书面程序方面的重大改进。说明你公司将如何确保调查各阶段均得到规范执行。

• An independent third-party assessment and remediation plan for your CAPA program.Provide a report that evaluates whether the program includes effective root cause analysis, ensures CAPA effectiveness, analyzes investigations trends, improves the CAPA program when needed, implements final quality assurance decisions, and is fully supported by executive management.

• 对你公司 CAPA 体系开展独立第三方评估并制定整改计划。提供一份评估报告，判断该体系是否包含有效的根本原因分析、确保 CAPA 有效性、分析调查趋势、按需改进 CAPA 体系、执行质量保证最终决定，并得到最高管理层充分支持。

2.Your firm’s quality control unit failed to exercise its responsibility to ensure drug products manufactured are in compliance with CGMP and meet established specifications for identity, strength, quality, and purity (21 CFR 211.22).

你公司质量控制部门未履行职责，未能确保所生产药品符合 CGMP 要求，且未达到既定的鉴别、效价、质量与纯度标准（21 CFR 211.22）。

Your firm lacks controls to assure the integrity of electronic batch record data. Your quality assurance employee instructed your software vendor to make changes to your electronic batch record which were not captured in the audit trail or managed through your quality system.

你公司缺乏确保电子批记录数据完整性的控制措施。你公司质量保证人员指示软件供应商对电子批记录进行修改，此类修改未在审计追踪中记录，也未通过质量体系进行管理。

During the inspection, you provided written communication from a quality assurance employee to the software vendor that discussed multiple changes and modifications made to the electronic batch record. One of the changes included the replacement of an employee identification number with another employee number for “Dispensed by” in (b)(4) tablets USP (b)(4) mcg batch record (b)(4). The change was not recorded in the audit trail, nor was it noted in the electronic batch record. Additionally, your firm lacked detailed procedural controls to assure the integrity of electronic batch record data when modifications are made after completion of the batch record.

检查期间，你方提供了质量保证人员发给软件供应商的书面沟通记录，其中提及对电子批记录进行的多项修改。其中一项修改为：在 (b)(4) 片剂 USP (b)(4) mcg 批记录 (b)(4) 中，将 “分发人” 对应的员工编号替换为另一员工编号。该修改未在审计追踪中记录，也未在电子批记录中备注。此外，你公司缺乏详细的程序控制，无法确保批记录完成后进行修改时电子批记录数据的完整性。

In your response, you indicate that the changes the software vendor made in the electronic batch record corrected inaccuracies only. You state your requests to software vendors to modify data have been terminated. You commit to conducting formal interviews with employees who contacted the vendors to request the data changes and to initiating deviation investigations. You commit to performing a retrospective review of all group and individual email messages sent to the software vendor to determine which email messages contained CGMP instructions. You also commit to conducting a review of the audit trails of all U.S. batches.

你方在回复中称，软件供应商对电子批记录所做修改仅为纠正错误信息。你方称已停止向软件供应商提出数据修改请求。你方承诺对联系供应商请求修改数据的员工开展正式访谈，并启动偏差调查。你方承诺回溯审核发给该软件供应商的所有群组及个人邮件，判定哪些邮件包含涉及 CGMP 的指令。你方还承诺审核所有销往美国批次的审计追踪数据。

Your response is inadequate. You fail to provide documentation of the deviations, interview transcripts, or discussion held with the employees who requested changes to electronic batch record data. You fail to explain why Quality Assurance did not initiate a deviation upon finding discrepancies or why the batch record contained no comments or remarks about the employee identification change. Additionally, your retrospective review of email requests to software vendors for data changes did not include an assessment of communications with other software vendors such as (b)(4).

你方回复不充分。你方未提供偏差文件、访谈记录或与请求修改电子批记录数据员工的讨论记录。你方未解释质量保证部门发现差异后为何未启动偏差，也未解释批记录中为何未对员工编号修改添加任何注释或说明。此外，你方对发给软件供应商的数据修改邮件请求的回溯审核，未包含与 (b)(4) 等其他软件供应商的沟通评估。

In response to this letter, provide the following:

针对本函，请提交以下内容：

• A retrospective review of all software related communications and correlated audit trail between your Intas Dehradun facility and software support vendors. Provide any updated deviations and related CAPA reports.

• 对你方 Intas Dehradun 厂区与软件支持供应商之间所有与软件相关的沟通记录及对应审计追踪进行回溯审核。提供所有更新后的偏差及相关 CAPA 报告。

• A product impact assessment for identified communications related to changes in batch record data and process parameters.

• 对已识别出的、与批记录数据及工艺参数修改相关的沟通记录进行产品影响评估。

• Effectiveness checks for the CAPAs implemented in your “Data Integrity Risk Assessment” of software applications, conducted by third party consultants in 2024.

• 对 2024 年由第三方顾问在软件应用系统 “数据完整性风险评估” 中所实施 CAPA 的有效性进行核查。

• Performance qualification deviations for your (b)(4) filling machine ((b)(4), Model (b)(4), equipment ID: DP-38). Include a report discussing the discrepancies in entries in the data sheet versus audit trail data, including maximum (b)(4). This equipment is related to a (b)(4) for (b)(4) solution (b)(4).

• 你公司 (b)(4) 灌装机（(b)(4)，型号 (b)(4)，设备编号：DP‑38）的性能确认偏差。包含一份报告，说明数据记录表中录入项与审计追踪数据之间的差异，包括最大值 (b)(4)。该设备与 (b)(4) 溶液 (b)(4) 的 (b)(4) 相关。

• A comprehensive assessment and remediation plan to ensure your quality unit (QU) is given the authority and resources to effectively function. The assessment should also include, but is not limited to:

• 一份全面评估及整改计划，确保你方质量部门（QU）被赋予有效履职所需的权限与资源。该评估还应包括但不限于：

o A determination of whether procedures used by your firm are robust and appropriate

o 判定你公司所用程序是否健全、适当

o Provisions for QU oversight throughout your operations to evaluate adherence to appropriate practices

o 为质量部门全程监督运营活动、评估合规执行情况提供保障

o A complete and final review of each batch and its related information before the QU disposition decision

o 在质量部门做出放行决定前，对每一批次及其相关信息完成完整最终审核

o Oversight and approval of investigations and discharging of all other QU duties to ensure identity, strength, quality, and purity of all products

o 监督并批准调查，履行质量部门其他全部职责，确保所有产品的鉴别、效价、质量与纯度

o Also describe how top management supports quality assurance and reliable operations, including but not limited to timely provision of resources to proactively address emerging manufacturing/quality issues and to assure a continuing state of control.

o 同时说明最高管理层如何支持质量保证与可靠运营，包括但不限于及时提供资源，主动应对新出现的生产 / 质量问题，并确保持续受控状态。