Q. We are planning to market a new drug (film coated tablets of the biotech product in nine different blister pack sizes) in the United States and the European Union. In support of the application, we must perform process validation and we will need to have stability data. To minimize the number of batches, we intend to manufacture three commercial-size batches of the tablets, then split each batch into three to create nine sub batches (one batch for each blister pack size). We will then take samples from each blister pack size to test stability. Is this a compliant approach?
问：我们计划在美国和欧盟销售一种新药(一种生物技术产品的薄膜包衣片，有九种不同的泡罩包装生产规模)。为了支持上市申请，我们必须执行工艺验证，并且我们需要稳定性数据。为了尽量减少批次数量，我们打算生产三个商业化规模的片剂批次，然后将每个批次一分为三，创建九个子批次(每个泡罩包装规模为一个子批次)。然后，我们将从每个泡罩包装规模中取样以测试稳定性。这种方法可行吗?
A. You correctly state that you need to perform process validation and collect stability data for the various pack sizes. The question to answer is whether your batch sizes are in compliance with the regulations. Though the batch size for the tablets is at commercial scale, the batch size for each of the nine packaging runs is only a third of commercial scale.
答：你说的对，你们确实需要执行工艺验证并收集各种包装规模的稳定性数据。要回答的问题是你的批次规模是否符合法规。虽然这些药片的批次生产规模达到了商业规模，但九种包装方式中每一种批次的生产规模仅为商业规模的三分之一。
The globally accepted standard for stability testing is International Council for Harmonisation (ICH) Q1A(R2) Stability Testing of New Drug Substances and Products (1). Herein, the minimum batch size requirement is, “The batches should be manufactured to a minimum of pilot scale.”
全球公认的稳定性测试标准是ICH Q1A(R2)《新原料药和制剂的稳定性测试》。其中，最小批次规模的要求是“批次应以最小中试规模生产”。
FDA confirms this requirement (2), stating that these batches can be “either pilot scale or a small scale batch.”
FDA确认了这一要求，声明这些批次可以是“中试规模或小批量”。
The European Medicines Agency (EMA) refers to the ICH guidance on their “quality: stability” website (3) and mentions “pilot scale” as the minimum batch size in their variation guidance listed on this website.
EMA在其“质量:稳定性”网站上引用了ICH指南，其网站上发布的基于ICH指南略有变化的指南中提到，“中试规模”可以作为最小批量。
The Parenteral Drug Association’s (PDA) Technical Report 60-2 Process Validation: A Lifecycle Approach–1 Oral Solid Dosage/Semisolid Dosage Forms Annex (4), which reflects industry best practices, refers to batches for stability testing at 10–15% of commercial batch volume.
PDA技术报告60-2工艺验证:生命周期方法- 1口服固体剂型/半固体剂型附件，反映了行业最佳实践，提到对商业批量10-15%的批次进行稳定性测试。
Your batch size of a third (i.e., 33%) of commercial batch size, with the aim to demonstrate the appropriate quality of the drug product on stability, is thus compliant with regulatory expectations and the laws.
你们的批量大小为商业批规模的三分之一(即33%)，目的是证明药品在稳定性方面的适当质量，因此符合监管期望和法律的要求。
At this scale, however, these batches cannot be used for process validation for a drug product to be approved for marketing in either the US or the EU. Process validation for a drug product, even a generic-drug product, has to be done with commercial scale (packaging) batches.
然而，在这种规模下，这些批次不能用于在美国或欧盟批准上市的药品的工艺验证。药品的工艺验证，即使是仿制药，也必须以商业规模(包装规模)批次完成。
The reason is that process validation has to cover all the unit operations involved in the packaging process at the commercial scale. If the same batch is split at the packaging stage into sub-batches for different pack sizes, then validation of the packaging step will be incomplete. For example, sampling during blister packaging needs to be done at different time points (including beginning, middle, and end) of packaging of a commercial size batch. Full-scale manufacturing may take so long that shift changes may be required, or new rolls of foil may be required. These interventions may not happen during the manufacture at the reduced batch size. Process validation is defined as follows:
原因是工艺验证必须涵盖商业规模包装过程中涉及的所有单元操作。如果同一批次在包装阶段被分成不同包装规模的子批次，那么包装步骤的验证将是不完整的。例如，泡罩包装期间的取样需要在商业规模批次包装的不同时间点(包括开始、中间和结束)进行。完整的生产可能需要很长时间，可能需要换班，或者可能需要新的箔卷。在减少批量生产时，这些干预措施可能不会发生。工艺验证定义如下：
EMA definition of process validation (5): “The documented evidence that the process, operated within established parameters, can perform effectively and reproducibly to product a medicinal product meeting its predetermined specifications and quality attributes.”
EMA对工艺验证的定义:“证明该工艺在既定参数内运行，能够有效地、可重复地生产出符合其预定标准和质量属性的药品的文件化证据。”
FDA definition of process validation (6): “The collection and evaluation of data, from the process design stage through commercial production, which establishes scientific evidence that a process is capable of consistently delivering quality products.”
FDA对工艺验证的定义:“从工艺设计阶段到商业生产，收集和评估数据，建立科学证据，证明工艺能够始终如一地提供高质量的产品。”
Although the definition of process validation differs somewhat between the EU and US, the requirements for commercial batch size for process validation do not. The details can be found in the two documents referenced above.
尽管欧盟和美国对工艺验证的定义有所不同，但对工艺验证的商业批量大小的要求却没有。细节可以在上面提到的两个文件中找到。
接下来，我们来看一下中国对稳定性测试和工艺验证批次规模的要求。《中国药典》2020版第四部9001《原料药物与制剂稳定性试验指导原则》的要求如下图所示，内容与ICH、FDA和EMA类似。
《中国药典》2020版第四部9402《生物制品稳定性试验指导原则》的要求如下图所示，内容与ICH、FDA和EMA类似。
中国GMP附录《确认与验证》规定如下：
第二十一条 采用新的生产处方或生产工艺进行首次工艺验证应当涵盖该产品的所有规格。企业可根据风险评估的结果采用简略的方式进行后续的工艺验证，如选取有代表性的产品规格或包装规格、最差工艺条件进行验证，或适当减少验证批次。
第二十二条 工艺验证批的批量应当与预定的商业批的批量一致。
本文部分内容来自Pharmaceutical Technology, 46 (5) (2022)，中文内容来自公众号：GMP干货。
References
1. ICH, Q1A(R2)Stability Testing of New Drug Substances and Products, www.ich.org (ICH, February 2003).
2. FDAQuestions and Answers on Quality-Related Controlled
Correspondence, FDA.gov, Sept. 23, 2021.
3. EMA,Quality: Stability, ema.europa.eu, accessed April 8, 2022.
4. PDA,Technical Report 60-2 Process Validation: A Lifecycle
Approach - 1 Oral Solid Dosage/Semisolid Dosage Forms Annex (PDA, March 2017).
5. EMA,Guideline on Process Validation for Finished Products–Information and Data to be Provided in Regulatory Submissions, EMA/CHMP/CVMP/QWP/BWP/70278/2012-Rev1,Corr.1, Nov. 21, 2016.
6. FDA,Guidance for Industry, Process Validation: General Principles and Practices (CDER, CBER, January 2011).
