Which Batch Size for Validation and Stability Studies?

驗(yàn)證和穩(wěn)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(shù)，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(jì)劃上市一種新藥(生物技術(shù)產(chǎn)品的薄膜包衣片劑，有9種不同的泡罩包裝規(guī)格)。為了支持申報(bào)，我們必須進(jìn)行工藝驗(yàn)證和穩(wěn)定性試驗(yàn)。為了盡量減少批次的數(shù)量，我們打算生產(chǎn)3個(gè)商業(yè)規(guī)模的片劑批次，然后將每個(gè)批次分成3個(gè)子批次，共9個(gè)‍子批次(每個(gè)泡罩包裝規(guī)格一個(gè)子批次)。然后，我們將從每個(gè)泡罩包裝規(guī)格中取樣測(cè)試穩(wěn)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(zhí)行工藝驗(yàn)證并收集每個(gè)包裝規(guī)格的穩(wěn)定性數(shù)據(jù)。要回答的問題是你的批次大小是否符合法規(guī)。雖然片劑的批量大小是商業(yè)規(guī)模，但9個(gè)包裝規(guī)格中每個(gè)子批次的批量?jī)H為商業(yè)規(guī)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(rèn)的穩(wěn)定性測(cè)試標(biāo)準(zhǔn)ICH Q1A（R2）新藥用物質(zhì)和產(chǎn)品的穩(wěn)定性測(cè)試（1）。其中，最小批量的要求是，“批次應(yīng)達(dá)到最小的中試規(guī)模。

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

FDA確認(rèn)了這一要求（2），指出批次可以是“中試規(guī)模或小試批次”。

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.

歐洲藥品管理局（EMA）在其“質(zhì)量：穩(wěn)定性”網(wǎng)站上引用了ICH指南（3），并在網(wǎng)站上列出的變更指南中提到“中試規(guī)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(xié)會(huì) （PDA） 技術(shù)報(bào)告 60-2 工藝驗(yàn)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(yè)最佳實(shí)踐，指出應(yīng)在商業(yè)批次規(guī)模的 10-15% 下進(jìn)行穩(wěn)定性測(cè)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(yè)批次大小的三分之一（即33%），目的是證明藥品的穩(wěn)定性的符合質(zhì)量要求，因此符合監(jiān)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(guī)模下，這些批次不能用于批準(zhǔn)藥品的工藝驗(yàn)證。藥品（甚至是仿制藥）的工藝驗(yàn)證必須通過商業(yè)規(guī)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(yàn)證必須涵蓋商業(yè)規(guī)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(guī)格的子批次，則包裝步驟的驗(yàn)證將不完整。例如，泡罩包裝過程中的取樣需要在商業(yè)規(guī)模批次包裝的不同時(shí)間點(diǎn)（包括開始，中間和結(jié)束）進(jìn)行。商業(yè)規(guī)模批次的生產(chǎn)可能需要很長(zhǎng)時(shí)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(chǎn)過程中，這些干預(yù)可能不會(huì)發(fā)生。工藝驗(yàn)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(duì)工藝驗(yàn)證的定義（5）：“書面的證據(jù)表明，在既定參數(shù)內(nèi)操作的工藝可以有效且可重復(fù)地生產(chǎn)符合其預(yù)定標(biāo)準(zhǔn)和質(zhì)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(duì)工藝驗(yàn)證的定義（6）：“收集和評(píng)估從工藝設(shè)計(jì)階段到商業(yè)生產(chǎn)的數(shù)據(jù)，以建立工藝能夠始終如一地提供合格產(chǎn)品的科學(xué)證據(jù)。

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(guó)之間對(duì)工藝驗(yàn)證的定義略有不同，但工藝驗(yàn)證對(duì)商業(yè)批量大小的要求卻沒有不同。有關(guān)詳細(xì)信息，請(qǐng)參閱上面引用的兩個(gè)文件。