验证报告修改数据、倒签日期，替换页码，QA/QC/生产经理承认，药企回应“由于压力和紧张”！

近日，FDA发布了MMC Healthcare Ltd.的警告信，警告信涉及多个缺陷，包括：

• “工艺验证”报告中添加了数据，倒签日期，并更换了页码。QA经理、QC经理、研发经理和生产经理承认参与了这些活动。另一份“工艺验证”报告的审核也发现了批准盖章和签名存在倒签。该公司在回复中表示“由于压力和紧张，相关人员无意中签了之前的日期而不是当前日期。”，并仅对相关人员进行了培训了事。对此FDA并不接受。

• 用于溶出度检测的紫外-可见(UV-Vis)分光光度计的计算机系统缺乏适当的控制来确保数据完整性，例如审计追踪和规定的用户访问级别。该公司在回复中表示“希望更新UV/Vis [sic]软件”以符合要求，并提供了新软件的报价。FDA不接受该答复并给出了整改的详细要求。

• 该公司的微生物检测方法与USP不同，但未能提供确定所使用的分析方法的充分性的方法验证数据。该公司在回复中表示他们修改了分析方法以符合USP，并对微生物人员进行了再培训。还表示使用修订后的方法重新检验了有效期内大多数批次的xx溶液，全部合格。对此FDA表示该公司没有使用修订后的方法重新检验所有有效期内的产品和批次。

1. Your firm failed to establish an adequate quality control unit with the responsibility and authority to approve or reject all components, drug product containers, closures, in-process materials, packaging materials, labeling, and drug products (21 CFR 211.22(a)).

贵公司未能建立一个足够的质量控制部门以具备责任和权力批准或拒绝所有成分、药品容器、密封部件、中间产品、包装材料、标签和药品（21 CFR 211.22(a)）。

During the inspection of your facility our Investigator observed that your 2021 (b)(4) Tablets “PROCESS VALIDATION” report had data added, backdated signatures, and replaced pages. Your Quality Assurance Manager, Quality Control Manager, Formulation Research & Development Manager, and Production Manager admitted to participating in these practices.

在对你们工厂的检查中，我们的检查人员发现你们2021 xx片剂的“工艺验证”报告中添加了数据，倒签日期，并更换了页码。你们的QA经理、QC经理、研发经理和生产经理承认参与了这些活动。

Review of the (b)(4) Capsules (b)(4) mg “PROCESS VALIDATION” report collected during the inspection also found a backdated approval stamp and signatures.

对检查期间收集的xx胶囊xx mg“工艺验证”报告的审核也发现了批准盖章和签名存在倒签。

In your response, you state that “due to pressure and tensions the concerned team mentioned the back date instead of current date unintentionally.”Additionally, you provide evidence of training conducted with your validation team to prevent such issues from recurring.

在你们回复中，你们说“由于压力和紧张，相关人员无意中签了之前的日期而不是当前日期。”另外，你们提供了对你们的验证人员进行的培训的证据，以防止此类问题再次发生。

Your response is inadequate because you fail to fully review the extent of your practice of backdating CGMP documents. You did not provide adequate evidence to demonstrate that you have conducted a comprehensive assessment of all systems and adequately remediated the deficiencies related to your documentation practices. There is also no indication that you have implemented appropriate and effective corrective actions and preventive actions (CAPAs) throughout your drug manufacturing operations to ensure your manufacturing operation is under control and that your quality unit (QU) is adequately exercising its responsibilities.

你们的回复是不充分的，因为你们没有全面审查你们的CGMP文件倒签的程度。你们没有提供足够的证据来证明你们已经对所有体系进行了全面的评估，并充分纠正了与你们的文件记录相关缺陷。也没有证据表明你们在整个药品生产操作中实施了适当和有效的纠正措施和预防措施(CAPA)，以确保你们的生产操作受控以及你们的质量部门(QU)充分履行职责。

2. Your firm failed to exercise appropriate controls over computer or related systems to assure that only authorized personnel institute changes in master production and control records, or other records (21 CFR 211.68(b)).

贵公司未能对计算机或相关系统实施适当的控制，以确保只有经授权的人员才能对主生产和控制记录或其他记录进行更改(21 CFR 211.68(b))

Your ultraviolet-visible (UV-Vis) spectrophotometer computer system lacked appropriate controls to assure the integrity of electronic test data, such as an audit trail and defined user access levels. This UV-Vis system was used for release testing of drug product batches.

你们的紫外-可见(UV-Vis)分光光度计计算机系统缺乏适当的控制来确保电子检测数据的完整性，例如审计追踪和规定的用户访问级别。该系统用于药品批次的溶出度检测。

In your response, you state that you “would like to update the UV/Vis [sic] software” to be compliant and provide a quote for new software.

在你们的回复中，你们表示“希望更新UV/Vis [sic]软件”以符合要求，并提供了新软件的报价。

Your response is inadequate because it does not provide sufficient details describing:

你们的回复是不充分的，因为它没有提供足够的细节来描述:

• Timeframe for your corrective action.

• 纠正措施的时间表

• Security features of your updated UV-Vis computer system.

• 更新后的UV-Vis计算机系统的安全特性。

• User access levels, access privileges, or authorized users to perform the analyses, collect data, review data, or perform other functions.

• 用户访问级别、访问权限或执行检测、收集数据、查看数据或执行其他功能的授权用户。

• Integrity of data generated by your computerized systems in the interim and any other interim measures, prior to the full implementation of your corrective actions.

• 在你们全面实施纠正措施之前，你们的计算机化系统在过渡期间和任何其他过渡措施中产生的数据的完整性。

• Extent of this practice and how you will fully secure other CGMP computer systems in your facility.

• 这种做法的程度，以及你们将如何完全保护你们工厂其他CGMP计算机系统。

3. Your firm failed to establish the accuracy, sensitivity, specificity, and reproducibility of its test methods (21 CFR 211.165(e)).

贵公司未能建立分析方法的准确性、灵敏度、专属性和可重复性(21 CFR 211.165(e))。

You did not use a United States Pharmacopeia (USP) method to test multiple drug products nor did you show equivalency or superiority for your alternate methods. For example, your E. coli test method for (b)(4) Solution and (b)(4) Tablets drug products only required sub-culturing if turbidity was observed. This differs from the USP method which proceeds with sub-culturing regardless of visual observation of turbidity. Additionally, you could not provide method validation data that established the adequacy of the test methods you use.

你们没有使用美国药典(USP)方法检测多个药品，也没有展示替代方法的等效性或优越性。例如，你们对xx溶液和xx片剂药品的大肠杆菌检测方法只有在观察到（TSB）浑浊时才需要进行传代培养。这与USP方法不同，后者不管是否浑浊都需要进行传代培养。另外，你们未能提供确定你们使用的测试方法的充分性的方法验证数据。

Test methods must be validated to show they are suitable for their intended use, and equivalent or better than applicable USP compendial methods. The reproducibility of your test methods is essential to determine if your drug products meet established specifications for microbial attributes.

分析方法必须经过验证，以表明它们适合其预期用途，并且相当于或优于适用的USP药典方法。分析方法的可重复性对于确定你们的药品是否符合既定的微生物属性标准至关重要。

In your response, you state that you revised your test method to align with the USP and retrained your microbiologists. You also state that you retested most batches of (b)(4) Solution within expiry using the revised method, all of which passed.

在你们的回复中，你们说你们修改了分析方法以符合USP，并对你们的微生物人员进行了再培训。你们还声明你们使用修订后的方法重新检验了有效期内大多数批次的xx溶液，全部合格。

Your response is inadequate. You do not commit to retest all products and batches within expiry with the revised method. In addition, there is no indication that your method is equivalent or superior to the USP. There is also no information to evaluate all your test methods to ensure they are aligned with the USP.

你的答复不充分。你们没有承诺使用修订后的方法重新检验所有有效期内的产品和批次。此外，没有证据表明你们的方法等于或优于USP。也没有信息来评估你们所有的分析方法以确保它们与USP一致。