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In a recent FDA Warning Letter, the FDA criticized inadequate process validation for a semi-solid dosage form. What exactly did the FDA find inadequate?
在最近的FDA警告信中，FDA批评了某公司半固体剂型的工艺验证不足。 FDA究竟发现了什么不足之处？
The validation studies were criticized for not reflecting inter- and intra-batch variability. In particular, there was criticism that the sampling was random. The viscosity sampling scheme does not lead to statistical confidence in process performance. 验证研究因没有反映批次间和批次内的差异而受到批评。特别是，批评了抽样是随机的。粘度取样方案未能使工艺性能具有统计置信度。
In a second Process Performance Qualification (PPQ) study, the influence of a critical excipient on viscosity was to be shown. Again, the FDA criticized that no inter-batch variability was demonstrated. This is not surprising, since only one run was performed. 在第二阶段工艺性能确认（PPQ）研究中，显示了关键辅料对粘度的影响。FDA再次批评没有证明批间差异。这并不奇怪，因为只执行了一批。
As measures, the FDA requires: 作为措施，FDA要求：
a validation programme, starting with product development, the validation itself and the control/monitoring of the processes with regard to intra- and inter-batch variability 从产品开发开始，对批次内和批次间差异的控制/监控，以及验证 an equipment and premises qualification programme 设备和设施资格确认计划 a programme for Process Performance Qualification and Continued Process Verification measures. 过程性能确认和持续工艺确认措施的计划。
警告信原文如下：
Your firm failed to establish adequate written procedures for production and process control designed to assure that the drug products you manufacture have the identity, strength, quality, and purity they purport or are represented to possess (21 CFR 211.100(a)). 贵公司未能为生产和工艺控制建立适当的书面程序，以确保您生产的药品具有其声称的特性、含量、质量和纯度（21 CFR 211.100（a））。
Your firm failed to adequately validate the manufacturing process for(b)(4) gel (b)(4)%. Specifically, your process validation lacks an evaluation of inter-batch and intra-batch variability for (b)(4) gel (b)(4)%. Your initial process performance qualification for this drug product only tested (b)(4) random tube for viscosity taken from tubes collected at the (b)(4) of filling for each of the three validation batches. This study did not evaluate variability within the batch, and it is not described in the validation report where the (b)(4) tube was collected. This sampling plan for viscosity does not result in statistical confidence in your process performance. 贵公司未能充分验证（b）（4）凝胶（b）（4）%的制造工艺。具体而言，工艺验证缺乏对（b）（4）凝胶（b）（4）%的批次间和批次内变异性的评估。你们对该药品的初始工艺性能确认仅测试了 （b）（4） 随机样品的粘度，这些样品取自三个验证批次中每个批次在灌装（b）（4） 处收集的管（样品）中的粘度。该研究未评估批次内的变异性，并且在收集（b）（4）管（样品）的验证报告中也没有描述。该粘度取样计划未能对工艺性能产生统计置信度。 A second process performance qualification study was conducted to qualify a critical excipient used to control the viscosity of the drug product. The study included one batch and therefore inter-batch variability could not be assessed to ensure the process consistently produces quality drug products. You rejected five batches between 2020 and 2021 for failure to meet viscosity specifications of(b)(4) gel (b)(4)%. 你们进行了第二次工艺性能确认研究，以确认用于控制药品粘度的关键辅料。该研究包括一个批次，因此无法评估批次间变异性以确保该工艺始终如一地生产出高质量的药品。你们在 2020 年至 2021 年期间拒绝了五批不符合 （b）（4） 凝胶 （b）（4）% 粘度标准（的产品）。
In response to this letter, provide the following: 回复此函，请提供以下：
Provide a detailed program for designing, validating, maintaining, controlling and monitoring each of your manufacturing processes that includes vigilant monitoring of intra-batch and inter-batch variation to ensure an ongoing state of control. Also, include your program for qualification of your equipment and facility. 提供详细的程序以设计、验证、维护、控制和监控你们的每个制造过程，包括监控批次内和批次间的变异性以确保持续的受控状态。此外，请包括设备和设施确认计划。 A detailed summary of your validation program for ensuring a state of control throughout the product lifecycle, along with associated procedures. Describe your program for process performance qualification, and ongoing monitoring of both intra-batch and inter-batch variation to ensure a continuing state of control. 详细的验证程序摘要以确保整个产品生命周期中的控制状态以及相关程序。描述你们的工艺性能确认计划，以及对批次内和批次间变异性的持续监控以确保持续的受控状态。
工艺验证，三批是否足够？
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?
[size=1.125]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。
[size=1.125]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。
[size=1.125]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。
[size=1.125]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)。
[size=1.125]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。
[size=1.125] References: [size=1.125]· 21 CFR 211.100:Written procedures; deviations [size=1.125]· 21 CFR 211.110:Sampling and testing of in-process materials and drug products [size=1.125]· Compliance Policy Guide Sec. 490.100 Process Validation Requirements for Drug Products andActive Pharmaceutical Ingredients Subject to Pre-Market Approval [size=1.125]· FDA Guidance for Industry, 2001, ICH Q7 GoodManufacturing Practice Guidance for Active Pharmaceutical Ingredients [size=1.125]· FDA Guidance for Industry, 2011, Process Validation: General Principles and Practices
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发表于 2023-3-3 08:50:20
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