Which Batch Size for Validation and Stability Studies?

驗證和穩定性研究的批量大小是多少？

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

制藥技術，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?

問題：我們計劃上市一種新藥(生物技術產品的薄膜包衣片劑，有9種不同的泡罩包裝規格)。為了支持申報，我們必須進行工藝驗證和穩定性試驗。為了盡量減少批次的數量，我們打算生產3個商業規模的片劑批次，然后將每個批次分成3個子批次，共9個‍子批次(每個泡罩包裝規格一個子批次)。然后，我們將從每個泡罩包裝規格中取樣測試穩定性。 這種方法符合要求嗎?

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：你正確地指出，你需要執行工藝驗證并收集每個包裝規格的穩定性數據。要回答的問題是你的批次大小是否符合法規。雖然片劑的批量大小是商業規模，但9個包裝規格中每個子批次的批量僅為商業規模的三分之一。

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.”

全球公認的穩定性測試標準ICH Q1A（R2）新藥用物質和產品的穩定性測試（1）。其中，最小批量的要求是，“批次應達到最小的中試規模。

FDA confirms this requirement (2), stating that these batches can be “either pilot scale or a small scale batch.”

FDA確認了這一要求（2），指出批次可以是“中試規?；蛐≡嚺?rdquo;。

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.

歐洲藥品管理局（EMA）在其“質量：穩定性”網站上引用了ICH指南（3），并在網站上列出的變更指南中提到“中試規模”作為最小批量大小。

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.

注射劑協會 （PDA） 技術報告 60-2 工藝驗證：生命周期方法 – 1附錄 口服固體制劑/半固體劑型（4） 反映了行業最佳實踐，指出應在商業批次規模的 10-15% 下進行穩定性測試。

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.

你所述的批量大小為商業批次大小的三分之一（即33%），目的是證明藥品的穩定性的符合質量要求，因此符合監管期望和法律。

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，在這種規模下，這些批次不能用于批準藥品的工藝驗證。藥品（甚至是仿制藥）的工藝驗證必須通過商業規模（包裝）批次來完成。

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:

原因是工藝驗證必須涵蓋商業規模包裝過程中涉及的所有單元操作。如果在包裝階段將同一批次拆分為不同包裝規格的子批次，則包裝步驟的驗證將不完整。例如，泡罩包裝過程中的取樣需要在商業規模批次包裝的不同時間點（包括開始，中間和結束）進行。商業規模批次的生產可能需要很長時間，可能需要換班，或者可能需要新的鋁箔卷。在減小批量的生產過程中，這些干預可能不會發生。工藝驗證定義如下：

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對工藝驗證的定義（5）：“書面的證據表明，在既定參數內操作的工藝可以有效且可重復地生產符合其預定標準和質量屬性的藥品。

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對工藝驗證的定義（6）：“收集和評估從工藝設計階段到商業生產的數據，以建立工藝能夠始終如一地提供合格產品的科學證據。

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.

盡管歐盟和美國之間對工藝驗證的定義略有不同，但工藝驗證對商業批量大小的要求卻沒有不同。有關詳細信息，請參閱上面引用的兩個文件。