What was FDA criticized on process validation?

 

关于工艺验证，FDA批评了什么？

 

Correlation between Validation Master Plan and Validation Protocols

 

验证主计划和验证方案之间的相关性

 

In warning letter 320-25-43, FDA found that although there were requirements in the Validation Master Plan for process validation and hold times, no operating conditions such as bulk hold times, process limits or acceptance criteria for process parameters were specified in the validation protocol itself.

 

在警告信320-25-43中，FDA 发现，尽管验证主计划中对工艺验证和保持时间有要求，但验证方案本身并未指定操作条件，例如待包装产品保持时间、工艺限度或工艺参数的接受标准。

 

 

Inadequate Process Validation

工艺验证不充分

 

You did not have data to demonstrate that you adequately validate your manufacturing processes used to manufacture your OTC drug products and demonstrate that your processes are reproducible and controlled to consistently yield drugs of uniform character and quality. For example, your validation plan, “VALIDATOIN MASTER PLAN (VMP),” describes requirements for process validation and hold time studies. However, the protocol implementing your validation planed, “PROCESS VALIDATION PROTOCOL,” failed to include operating parameters, such as bulk hold times, or processing limits, such as acceptance criteria for process parameters.

 

你们没有数据证明充分验证了用于生产药品的制造工艺，并证明该工艺是可重复的和可控的，可以始终如一地生产出具有一致特性和质量的药物。例如，你们的 “验证主计划（VMP）”描述了工艺验证和保持时间研究的要求。但是，实施验证计划的 “工艺验证方案”未能包括作参数（如批保持时间）或工艺限度（如工艺参数的接受标准）。

 

In response, the inspected company submitted an updated validation protocol which, according to the FDA, still failed to address hold times and other details, such as information on sampling and the batch report that is used for the first validation batch. Subsequently, the FDA refers to its process validation guideline and describes the content of the guideline in a short section of the warning letter. 

 

作为回复，被检查的公司提交了一份更新的验证方案，根据 FDA 的说法，该方案仍然未能解决保持时间和其他细节，例如取样信息和用于第一个验证批次的批次报告。随后，FDA 引用了其工艺验证指南，并在警告信的一小节中描述了指南的内容。

 

Another point of criticism was the equipment. Contrary to the intended use, the circulation of the (water) system was stopped when it was not in operation. There was also a lack of monitoring of both chemical and microbiological parameters in accordance with the US Pharmacopoeia (USP). The response of the inspected company to operate the system permanently in the future is not sufficient. The entire system design is still to be assessed and monitoring introduced. In addition, the FDA requires interim measures and an investigation into the impact of the incorrectly validated system on product quality.

 

另一个批评点是设备。不符合预期使用，（水）系统在未运行时，循环被停止。此外，还缺乏根据美国药典（USP） 对化学和微生物参数的监测。被检查公司在未来永久运行该系统的回复是不够的。整个系统设计仍有待评估和监控。此外，FDA 要求采取临时措施并调查验证错误的系统对产品质量的影响。

 

Inadequate Control of(b)(4) System

对 （b）（4） 系统的控制不足

 

Your firm uses(b)(4) as a component to manufacture your OTC drug product. You failed to ensure that your (b)(4) system is suitable for producing (b)(4) used in the formulation of your drug product. For example, you turned your (b)(4) system off when not in use, stopping its circulation, which deviates from its design use as a continuously recirculating system. In addition, you failed to demonstrate that your (b)(4) system is adequately monitored to ensure it consistently produces (b)(4) that meets appropriate chemical and microbial attributes.

 

贵公司使用 （b）（4） 作为生产药物的组成部分。你们未能确保你们的（b）（4）系统适合生产。例如，你们在不使用时关闭了（b）（4）系统，停止了其循环，这偏离了其作为连续循环系统的设计用途。此外，你们未能证明你们的（b）（4）系统受到充分监控，以确保其始终产生符合适当化学和微生物属性的（b）（4）。

 

The FDA also expects a validation program, detailed PPQ plans, timelines for the PPQ, maintenance information, a description of monitoring and an assessment of the impact of defects on customer information and recalls.

 

FDA 还希望有一个验证计划、详细的 PPQ计划、PPQ 的时间表、维护信息、监控描述以及对缺陷对用户和召回影响的评估。

 

来源：GMP办公室

关键词： 工艺验证 FDA警告信