Which Batch Size for Validation and Stability Studies?

验证和稳定性研究的批量大小是多少？

Pharmaceutical Technology, Pharmaceutical Technology, May 2022, Volume 46, Issue 5

制药技术，2022 年 5 月，第 46 卷，第 5 期

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?

问题：我们计划上市一种新药(生物技术产品的薄膜包衣片剂，有9种不同的泡罩包装规格)。为了支持申报，我们必须进行工艺验证和稳定性试验。为了尽量减少批次的数量，我们打算生产3个商业规模的片剂批次，然后将每个批次分成3个子批次，共9个‍子批次(每个泡罩包装规格一个子批次)。然后，我们将从每个泡罩包装规格中取样测试稳定性。 这种方法符合要求吗?

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：你正确地指出，你需要执行工艺验证并收集每个包装规格的稳定性数据。要回答的问题是你的批次大小是否符合法规。虽然片剂的批量大小是商业规模，但9个包装规格中每个子批次的批量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ICH Q1A（R2）新药用物质和产品的稳定性测试（1）。其中，最小批量的要求是，“批次应达到最小的中试规模。

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（2），指出批次可以是“中试规模或小试批次”。

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.

欧洲药品管理局（EMA）在其“质量：稳定性”网站上引用了ICH指南（3），并在网站上列出的变更指南中提到“中试规模”作为最小批量大小。

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.

注射剂协会 （PDA） 技术报告 60-2 工艺验证：生命周期方法 – 1附录 口服固体制剂/半固体剂型（4） 反映了行业最佳实践，指出应在商业批次规模的 10-15% 下进行稳定性测试。

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.

你所述的批量大小为商业批次大小的三分之一（即33%），目的是证明药品的稳定性的符合质量要求，因此符合监管期望和法律。

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，这些批次不能用于批准药品的工艺验证。药品（甚至是仿制药）的工艺验证必须通过商业规模（包装）批次来完成。

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。如果在包装阶段将同一批次拆分为不同包装规格的子批次，则包装步骤的验证将不完整。例如，泡罩包装过程中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。商业规模批次的生产可能需要很长时间，可能需要换班，或者可能需要新的铝箔卷。在减小批量的生产过程中，这些干预可能不会发生。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（5）：“书面的证据表明，在既定参数内操作的工艺可以有效且可重复地生产符合其预定标准和质量属性的药品。

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（6）：“收集和评估从工艺设计阶段到商业生产的数据，以建立工艺能够始终如一地提供合格产品的科学证据。

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.

尽管欧盟和美国之间对工艺验证的定义略有不同，但工艺验证对商业批量大小的要求却没有不同。有关详细信息，请参阅上面引用的两个文件。