Do CGMPs require three successfulprocess validation batches before a new active pharmaceutical ingredient (API)or a finished drug product is released for distribution?

在新的原料药(API)或制剂放行之前，CGMP是否要求三个成功的工艺验证批次?

No. Neither the CGMP regulations nor FDA policy specifies a minimum number ofbatches to validate a manufacturing process. The current FDA guidance on APIs(see guidance for industry ICH Q7 for APIs) also does not specify aspecific number of batches for process validation. 

不。无论是CGMP法规还是FDA政策都没有规定生产工艺验证的最小批数。目前的FDA原料药指南(见ICH Q7原料药行业指南)也没有规定工艺验证的具体批数。

FDArecognizes that validating a manufacturing process, or a change to a process,cannot be reduced to so simplistic a formula as the completion of threesuccessful full-scale batches. The Agency acknowledges that the idea ofthree validation batches became prevalent in part because of language used inpast Agency guidance. FDA's process validation guidance now recommends aproduct lifecycle approach. The emphasis for demonstrating validated processesis placed on the manufacturer’s process design and development studies inaddition to its demonstration of  reproducibility at scale, a goal that has always been expected. 

FDA认识到，一个生产工艺的验证，或一个工艺的变更，不能简化为完成三个成功的批次那样简单的公式。当局也承认，三批验证的想法变得普遍，部分原因是过去指南中使用的语言。FDA的工艺验证指南现在推荐一种产品生命周期方法。除了证实商业化的可重现性之外，工艺验证的重点放在制造商的工艺设计和开发研究上，这是人们一直期望的目标。

However,a minimum number of conformance (a.k.a. validation) batches necessary  tovalidate the manufacturing processes is not specified.  The manufactureris expected to have a sound rationale for its choices in this regard.  TheAgency encourages the use of science-based approaches to process validation.

然而，并没有规定验证生产工艺所需的最低符合性(即验证)批次数量。制造商在这方面的选择应该有一个合理的理由。当局鼓励使用基于科学的方法进行工艺验证。

InMarch 2004, FDA revised the Compliance Policy Guide (CPG) Sec. 490.100 on Process Validation Requirements for Drug Products andActive Pharmaceutical Ingredients Subject to Pre-Market Approval. The CPG describes the concept that, after having identified and establishingcontrol of all critical sources of variability, conformance batches areprepared to demonstrate that under normal conditions and operating parameters,the process results in the production of an acceptable product. Successful completion of the initial conformance batches would normally beexpected before commercial distribution begins, but some possible exceptionsare described in the CPG.  For example, although the CPG does notspecifically mention concurrent validation for an API in short supply, theAgency would consider the use of concurrent validation when it is necessary toaddress a true short-supply situation, and if the concurrent validation studyconforms to the conditions identified in the CPG (see paragraph 4, a-c).

2004年3月，FDA修订了符合性政策指南(CPG)第490.100节关于上市前批准的药品和活性药物成分的工艺验证要求。CPG描述的概念是，在确定和建立对所有关键的可变性来源的控制之后，通过生产合格的批次以证明在正常条件和操作参数下，该工艺可生产出可接受的产品。正常情况下，在商业销售开始之前，要求成功完成初始的合格批次，但CPG中描述了一些可能的例外情况。例如，尽管CPG未提及供应短缺的API的同步验证，当局将考虑使用同步验证必要时应对真正的短缺情况，如果同步验证研究中确定符合条件的CPG(见段4,a - c)。

Theconditions outlined in the CPG include expanded testing for each batch intendedto address a short-supply situation.  Expanded testing conducted accordingto an established validation protocol could provide added assurance that thebatch meets all established and appropriate criteria before the API is used inthe finished drug product.  Additionally, confidence in the APImanufacturing process may be gained by enhanced sampling (larger sample sizerepresentative of the batch) and perhaps the testing of additionalattributes.  Validated analytical methods are needed for testing everybatch, including validation batches.  The Agency would also expect themanufacturer to use a validation protocol that includes a review and finalreport after multiple batches are completed, even though the earlier batchesmay have been distributed or used in the finished drug product.

CPG概述的条件包括为解决供应短缺的情况，对每批进行扩大检测。根据已建立的验证方案进行的放大检测可以提供额外的保证，即在API用于成品之前，该批符合所有已建立的适当标准。此外，对API生产过程的信心可以通过加强取样(更大的样品容量代表批次)和可能的额外属性测试来获得。每个批次，包括验证批次，都需要已验证的分析方法。FDA还希望生产商在多个批次完成后使用包含评审和最终报告的验证方案，即使较早的批次可能已经在成品中分发或使用。

 References:

·      21 CFR 211.100:Written procedures; deviations

·      21 CFR 211.110:Sampling and testing of in-process materials and drug products

·      Compliance Policy Guide Sec. 490.100 Process Validation Requirements for Drug Products andActive Pharmaceutical Ingredients Subject to Pre-Market Approval

·      FDA Guidance for Industry, 2001, ICH Q7 GoodManufacturing Practice Guidance for Active Pharmaceutical Ingredients

·      FDA Guidance for Industry, 2011, Process Validation: General Principles and Practices