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法规专家分享专栏 | 法规监管实验室如何准备FDA审计（一）

安捷伦科技（中国）有限公司

2022.9.23

制药行业法规监管实验室（如 QC 实验室）应如何应对 FDA 审计呢？迷茫、困惑、不知道如何入手？别急，安捷伦将邀请法规专家分享tips。

第一期隆重邀请安捷伦全球资深法规专家 Paul Smith 为大家深入浅出阐述如何准备 FDA 审计。由于篇幅限制，本系列主题将分期刊登，本期为第一期。

第一期

保罗•史密斯 Paul Smith

安捷伦全球法规策略顾问

Paul 有 20 多年的法规实验室相关指导经验，现在是安捷伦全球法规策略顾问，监察全球法规变化和不合规趋势，并分享这些信息于客户和同事。

Paul 是 GAMP 的活跃成员、英国 GAMP 实践社区的指导委员会成员，专注于分享知识和学习，提供了良好的实践指南且为实践做出了贡献。

本期分享亮点：

拒绝合理的审计请求将导致 FDA 警告信

在进行 FDA 审计之前，实验室需要关注的领域

必须避免试图“隐藏”问题和“假装性”的合规

需有一个“可信的”计划来解决每个实验室合规符合性差距

法规监管实验室应是“随时可查”的，因此，原则上似乎没有必要“为审计而准备”。但事实却非如此，FDA 及其他监管机构持续地给出不合规性缺陷项，这一事实清晰地说明：基本合规问题通常与数据完整性和/或超出标准结果(OOS)的管理相关。那么，一旦实验室收到审计信函（FDA 4821表格“检查通知”），他们可以做什么？又应该做哪些来”应对 FDA 审计”呢？

FDA 的透明性意味着大量 FDA 信息可以作为联邦法案(CFR)2 和工业指南3 的补充，受监管实验室可以审查这些 FDA 信息以帮助自己了解法规要求。然而，虽然这些信息对经验丰富的实验室有帮助，但法规信息太多，且法规通常是“建议遵守什么”而不是“如何遵守”，这就意味着实验室将不确定哪些是“应对审计”的优先工作。

一些公司用来应对 FDA 审计的措施之一是：拒绝支持审计或拒绝提供审计期间所要求的信息。实验室应该参考“审计范围”和 FDA 482 表格来识别哪些是审计范围之外的内容，但正如 FDA 所引用的工业指南4 提到的：拒绝合理的请求（或审计）将导致 FDA 警告信。因此不推荐使用该措施。

在 FDA 审计之前，实验室能做到哪些程度，取决于他们能用的时间、资源和所具备的专业知识。 在进行 FDA 审计之前，实验室需要关注的领域包括：

Regulated laboratories should be “inspection ready” and therefore, in principle, there is no need to “Prepare for an Audit” (because they are “inspection ready”). The fact is that continued non-compliance findings by the FDA and other regulators clearly indicate that this is not the case, because of fundamental compliance problems typically related to Data Integrity and/or management of Out of Specification (OOS) results. So, what can and should labs. do to “Prepare for an FDA Audit”, once they receive the letter (“Notice of Inspection” FDA form 4821) ?

FDA transparency means that a wealth of information is available to supplement the Code of Federal Regulations (CFR)2 and Guidance for Industry3 – that labs. could review to help understand their compliance requirements. However, although helpful to experienced regulated labs., there is too much information, and it typically advises of what to comply with and not how to be compliant. This can mean that labs. are not sure how to prioritise audit preparation.

One of the options some companies used with the FDA is to refuse to support the audit or refused to provide information requested during the audit. The scope of the audit and the FDA form 482 should be used to identify any areas that are outside the scope of the audit, but refusing a reasonable request (or for the audit) will result in a guaranteed FDA Warning Letter, as referenced by FDA Guidance for Industry4, therefore, this option is not recommended.

What can be achieved before the audit, depends on the resource, expertise, and time available. Some of the areas that labs. need to focus on before an FDA audit include:

1、cGMP 再培训

2、培训——在 FDA 审计期间如何回答问题

3、每个人——必须参考他们的工作和岗位描述审查他们的培训记录

4、了解实验室产生的所有 OOS 结果

5、了解仪器合规性

1、cGMP Refresher Training

2、Training – in how to respond to questions during an FDA Audit

3、Everyone – must review their training records against their work and job description

4、Understanding of all OOS results generated by the Lab.

5、Understanding of instrument compliance

5.1►Standard Operating Procedures 标准操作程序 (SOP’s)

所有仪器均具有标准操作程序（SOP）？
这些SOPs是否为最新版本？
这些SOPs是否经过批准且受控？
是否有管理色谱积分的 SOP？
Do all instruments have a Standard Operating Procedure (SOP)
Are the SOP’s up to date
Are they approved and controlled?
Is there an SOP for chromatographic integration?

5.2►Maintenance and Qualification 维护与确认

所有仪器是否都得到维护（如预防性维护PM）?
所有仪器是否经过确认（以及确认测试范围是否覆盖仪器使用范围）？
Are all instruments maintained (e.g. PM) ?
Are all instruments qualified (and does it cover the range of use) ?

5.3►Software Validation 软件验证

仪器控制软件是否得到验证，以证明适用于其预定用途？
分析程序 – 分析方法/ 程序是否经过验证，以证明其适用于样品测试和对分析结果的判断？
Is instrument control software validated for intended use ?
Analytical Procedures – are the analytical methods / procedures validated for the samples tested and the decisions made on the analytical results ?

不可避免地——为了识别以上主题的合规状态，该方法将产生一些清单。实验室应该有这个认识：对于尚未“准备好检查”的实验室，想在审计之前对识别出来的潜在问题进行“有意义的修复”是极不可能的。必须避免试图“隐藏”问题和“假装性”的合规。

相反，实验室必须了解任何合规符合性方面的差距，并优先安排解决这些差距的工作。如果在审计之前无法完成这些工作——需有一个“可信的”计划来解决每个合规符合性差距。这可能意味着两件事：一是能够为潜在的问题“为什么会发生这种情况”提供“实际的回复”（原则上是为了防止它再次发生）；二是提供可信的、解决缺陷的行动计划（例如，不要只承诺修复问题，而要提供细节以增加计划的可信度，并能够回答计划的相关问题）。

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Inevitably – this kind of approach generates lists – which identify the status of compliance against the subject. It should be recognised that for a lab that is not “inspection ready”, it is extremely unlikely that all of the potential issues identified can be “fixed” in a meaningful way before the audit. Trying to “hide” problems must be avoided and “pretending”.

Instead, labs. must have an understand of any compliance gaps and prioritise any work to address these gaps. Where work cannot be complete before the audit – there must be a “believable” plan to address each compliance gap. This can mean two things – being able to provide a realistic answer to the potential question “Why” this occurred (in principle to prevent it occurring again) and a believable action plan to address the deficiency (e.g. don’t just promise to fix the issue, provide details that add credibility to the response – and be able to answer questions about the plan).

未完待续，我们下期再见！

参考文献 References：

1.What should I expect during an inspection? https://www.fda.gov/industry/fda-basics-industry/what-should-i-expect-during-inspection

2.Code of Federal Regulations: https://www.ecfr.gov/

3.FDA Guidance for Industry: https://www.fda.gov/animal-veterinary/guidance-regulations/guidance-industry

4.Guidance for Industry Circumstances that Constitute Delaying, Denying, Limiting, or Refusing a Drug Inspection: https://www.fda.gov/media/86328/download