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：我們計劃在美國和歐盟銷售一種新藥(一種生物技術(shù)產(chǎn)品的薄膜包衣片，有九種不同的泡罩包裝生產(chǎn)規(guī)模)。為了支持上市申請，我們必須執(zhí)行工藝驗證，并且我們需要穩(wěn)定性數(shù)據(jù)。為了盡量減少批次數(shù)量，我們打算生產(chǎn)三個商業(yè)化規(guī)模的片劑批次，然后將每個批次一分為三，創(chuàng)建九個子批次(每個泡罩包裝規(guī)模為一個子批次)。然后，我們將從每個泡罩包裝規(guī)模中取樣以測試穩(wěn)定性。這種方法可行嗎?
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：你說的對，你們確實需要執(zhí)行工藝驗證并收集各種包裝規(guī)模的穩(wěn)定性數(shù)據(jù)。要回答的問題是你的批次規(guī)模是否符合法規(guī)。雖然這些藥片的批次生產(chǎn)規(guī)模達到了商業(yè)規(guī)模，但九種包裝方式中每一種批次的生產(chǎn)規(guī)模僅為商業(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.”
全球公認的穩(wěn)定性測試標準是ICH Q1A(R2)《新原料藥和制劑的穩(wěn)定性測試》。其中，最小批次規(guī)模的要求是“批次應以最小中試規(guī)模生產(chǎn)”。
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，聲明這些批次可以是“中試規(guī)?；蛐∨?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.
EMA在其“質(zhì)量:穩(wěn)定性”網(wǎng)站上引用了ICH指南，其網(wǎng)站上發(fā)布的基于ICH指南略有變化的指南中提到，“中試規(guī)模”可以作為最小批量。
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技術(shù)報告60-2工藝驗證:生命周期方法- 1口服固體劑型/半固體劑型附件，反映了行業(yè)最佳實踐，提到對商業(yè)批量10-15%的批次進行穩(wěn)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.
你們的批量大小為商業(yè)批規(guī)模的三分之一(即33%)，目的是證明藥品在穩(wěn)定性方面的適當質(zhì)量，因此符合監(jiān)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，在這種規(guī)模下，這些批次不能用于在美國或歐盟批準上市的藥品的工藝驗證。藥品的工藝驗證，即使是仿制藥，也必須以商業(yè)規(guī)模(包裝規(guī)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:
原因是工藝驗證必須涵蓋商業(yè)規(guī)模包裝過程中涉及的所有單元操作。如果同一批次在包裝階段被分成不同包裝規(guī)模的子批次，那么包裝步驟的驗證將是不完整的。例如，泡罩包裝期間的取樣需要在商業(yè)規(guī)模批次包裝的不同時間點(包括開始、中間和結(jié)束)進行。完整的生產(chǎn)可能需要很長時間，可能需要換班，或者可能需要新的箔卷。在減少批量生產(chǎn)時，這些干預措施可能不會發(fā)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:“證明該工藝在既定參數(shù)內(nèi)運行，能夠有效地、可重復地生產(chǎn)出符合其預定標準和質(zhì)量屬性的藥品的文件化證據(jù)。”
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:“從工藝設計階段到商業(yè)生產(chǎn)，收集和評估數(shù)據(jù)，建立科學證據(jù)，證明工藝能夠始終如一地提供高質(zhì)量的產(chǎn)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.
盡管歐盟和美國對工藝驗證的定義有所不同，但對工藝驗證的商業(yè)批量大小的要求卻沒有。細節(jié)可以在上面提到的兩個文件中找到。
接下來，我們來看一下中國對穩(wěn)定性測試和工藝驗證批次規(guī)模的要求?！吨袊幍洹?020版第四部9001《原料藥物與制劑穩(wěn)定性試驗指導原則》的要求如下圖所示，內(nèi)容與ICH、FDA和EMA類似。
《中國藥典》2020版第四部9402《生物制品穩(wěn)定性試驗指導原則》的要求如下圖所示，內(nèi)容與ICH、FDA和EMA類似。
中國GMP附錄《確認與驗證》規(guī)定如下：
第二十一條 采用新的生產(chǎn)處方或生產(chǎn)工藝進行首次工藝驗證應當涵蓋該產(chǎn)品的所有規(guī)格。企業(yè)可根據(jù)風險評估的結(jié)果采用簡略的方式進行后續(xù)的工藝驗證，如選取有代表性的產(chǎn)品規(guī)格或包裝規(guī)格、最差工藝條件進行驗證，或適當減少驗證批次。
第二十二條 工藝驗證批的批量應當與預定的商業(yè)批的批量一致。
本文部分內(nèi)容來自Pharmaceutical Technology, 46 (5) (2022)，中文內(nèi)容來自公眾號：GMP干貨。
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).
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