最近在工艺验证中发现的GMP缺陷

mandy53wiuq5i6 2020-01-01

展开全文

原文：https://www./gmp-news/recent-gmp-defects-in-process-validation

引用的警告信：https://www./inspections-compliance-enforcement-and-criminal-investigations/warning-letters/laboratoires-clarins-568157-04232019

先上双语对照译文：

What are the authorities' requirementsregarding process validation? Regulatory GMP inspection reports are useful inanswering that question. The 'Freedom of Information Act' obliges theUS FDA to publish inspection results. The FDA does that particularly when itcomes to warning letters.

监管机构对工艺验证的要求是什么？监管机构的GMP检查报告有助于回答这一问题。《信息自由法案》促使美国国家局（FDA）公布检查结果。当提到警告信时，FDA特别会公布检查结果。

As is customary when it comes todeficiencies regarding process validation, the FDA cites 21 CFR 211.100. TheFDA criticised the insufficient process validation and the inadequatelyqualified equipment. They particularly took issue with the processqualification studies and the ongoing monitoring program, which shows processstability and ensures constant product quality. Although the drug manufacturerpledged that they would improve their process validation program and qualifyall current and future equipment, the FDA wasn't satisfied.

当提到工艺验证相关的缺陷时，FDA习惯上引用21CFR第211.100条款。FDA曾批评过不充分的工艺验证和不适当的设备确认。FDA特别对工艺确认研究和持续监测计划持异议，这两者显示工艺稳定性，确保恒定的产品质量。尽管药品制造企业保证过会改进工艺验证计划，保证确认所有当前的和将来要用的设备，但FDA仍不满意。

They stated that the manufacturer couldnot show the process to be reproducible and functional regarding all quality attributes. Theydemand a validation plan guaranteeing a state of control throughout the wholeproduct life cycle. This includes a process performance qualification as wellas monitoring of batch to batch variations. They further asked for the processperformance protocols and corresponding studies.

FDA称，制造企业不能证明就所有质量属性而言工艺将是能重现的和有函数性的。FDA要求一个保证在整个产品生命周期处于受控状态的验证计划。这包括工艺性能确认以及批间变异监测。FDA进一步要求了工艺性能方案和相应的研究。

Conclusion: in the recent past,mentions of the process validation life cycle in FDA warning letters haveincreased. Especially defects connected with Step 3 'Continued/OngoingProcess Verification' are criticised more often. And this time, a Europeanmanufacturer is involved.

结论：最近，“工艺验证生命周期”的提法在FDA警告信中有所增加。特别是与第三步“持续的工艺确证”有关的缺陷受到了更频繁的批评。这次涉及了一家欧洲制造企业。

思考与分析

关于第三步“持续的工艺确证”(Stage3 ― Continued Process Verification)的提法出自FDA于2011年发布的工艺验证行业指南：https://www./regulatory-information/search-fda-guidance-documents/process-validation-general-principles-and-practices

2015年3月发布的欧盟GMP附录十五中也有类似概念，称为“OngoingProcess Verification”，并且该附录明确提出回顾性验证不再被被视为一种可接受的方式。

此文中提到的“functional”一词在ICHQ8《制药开发》和ICHQ11《原料药制造和开发》中均有提及，例如：

“Determiningthe functional relationships that link material attributes and processparameters to product CQAs”;

“Determining thefunctional relationships that link material attributes and process parametersto drug substance CQAs”.

“functional”源自“function”。在中国清代数学家李善兰(1811—1882)翻译的《代数学》一书中，首次用中文把“function”翻译为“函数”，此译名沿用至今。故上述ICH要求可理解为：

“明确与药品关键质量属性相关联的物料属性与工艺参数之间的函数关系”；

“明确与原料药关键质量属性相关联的物料属性与工艺参数之间的函数关系”。

正如ICHQ11提到的，确定合适的物料质量标准及工艺参数范围需要遵循以下步骤：

s 确认工艺变化的潜在源头；

s 确认可能会对原料药质量产生最大影响的物料属性及工艺参数。这可以基于之前的知识和风险评估工具；

s 设计并进行研究(例如，机理和/或动力学评价、多变量试验设计、模拟、建模)来识别与确定物料属性和工艺参数与原料药关键质量属性之间的关联和关系；

s 对数据行分析与评估，来设定合适的范围，包括必要时建立的设计空间。