原文：https://www./gmp-news/recent-gmp-defects-in-process-validation

引用的警告信：https://www./inspections-compliance-enforcement-and-criminal-investigations/warning-letters/laboratoires-clarins-568157-04232019

先上雙語對照譯文：

What are the authorities' requirementsregarding process validation? Regulatory GMP inspection reports are useful inanswering that question. The 'Freedom of Information Act' obliges theUS FDA to publish inspection results. The FDA does that particularly when itcomes to warning letters.

監(jiān)管機構(gòu)對工藝驗證的要求是什么,？監(jiān)管機構(gòu)的GMP檢查報告有助于回答這一問題?！缎畔⒆杂煞ò浮反偈姑绹鴩揖郑‵DA）公布檢查結(jié)果,。當(dāng)提到警告信時，F(xiàn)DA特別會公布檢查結(jié)果,。

As is customary when it comes todeficiencies regarding process validation, the FDA cites 21 CFR 211.100. TheFDA criticised the insufficient process validation and the inadequatelyqualified equipment. They particularly took issue with the processqualification studies and the ongoing monitoring program, which shows processstability and ensures constant product quality. Although the drug manufacturerpledged that they would improve their process validation program and qualifyall current and future equipment, the FDA wasn't satisfied.

當(dāng)提到工藝驗證相關(guān)的缺陷時,，F(xiàn)DA習(xí)慣上引用21CFR第211.100條款。FDA曾批評過不充分的工藝驗證和不適當(dāng)?shù)脑O(shè)備確認(rèn),。FDA特別對工藝確認(rèn)研究和持續(xù)監(jiān)測計劃持異議,，這兩者顯示工藝穩(wěn)定性，確保恒定的產(chǎn)品質(zhì)量。盡管藥品制造企業(yè)保證過會改進工藝驗證計劃,，保證確認(rèn)所有當(dāng)前的和將來要用的設(shè)備,，但FDA仍不滿意。

They stated that the manufacturer couldnot show the process to be reproducible and functional regarding all quality attributes. Theydemand a validation plan guaranteeing a state of control throughout the wholeproduct life cycle. This includes a process performance qualification as wellas monitoring of batch to batch variations. They further asked for the processperformance protocols and corresponding studies.

FDA稱,，制造企業(yè)不能證明就所有質(zhì)量屬性而言工藝將是能重現(xiàn)的和有函數(shù)性的,。FDA要求一個保證在整個產(chǎn)品生命周期處于受控狀態(tài)的驗證計劃。這包括工藝性能確認(rèn)以及批間變異監(jiān)測,。FDA進一步要求了工藝性能方案和相應(yīng)的研究,。

Conclusion: in the recent past,mentions of the process validation life cycle in FDA warning letters haveincreased. Especially defects connected with Step 3 'Continued/OngoingProcess Verification' are criticised more often. And this time, a Europeanmanufacturer is involved.

結(jié)論：最近，“工藝驗證生命周期”的提法在FDA警告信中有所增加,。特別是與第三步“持續(xù)的工藝確證”有關(guān)的缺陷受到了更頻繁的批評,。這次涉及了一家歐洲制造企業(yè)。

思考與分析

關(guān)于第三步“持續(xù)的工藝確證”(Stage3 ― Continued Process Verification)的提法出自FDA于2011年發(fā)布的工藝驗證行業(yè)指南：https://www./regulatory-information/search-fda-guidance-documents/process-validation-general-principles-and-practices

2015年3月發(fā)布的歐盟GMP附錄十五中也有類似概念,，稱為“OngoingProcess Verification”,，并且該附錄明確提出回顧性驗證不再被被視為一種可接受的方式。

此文中提到的“functional”一詞在ICHQ8《制藥開發(fā)》和ICHQ11《原料藥制造和開發(fā)》中均有提及,，例如：

“Determiningthe functional relationships that link material attributes and processparameters to product CQAs”;

“Determining thefunctional relationships that link material attributes and process parametersto drug substance CQAs”.

“functional”源自“function”,。在中國清代數(shù)學(xué)家李善蘭(1811—1882)翻譯的《代數(shù)學(xué)》一書中，首次用中文把“function”翻譯為“函數(shù)”,，此譯名沿用至今,。故上述ICH要求可理解為：

“明確與藥品關(guān)鍵質(zhì)量屬性相關(guān)聯(lián)的物料屬性與工藝參數(shù)之間的函數(shù)關(guān)系”；

“明確與原料藥關(guān)鍵質(zhì)量屬性相關(guān)聯(lián)的物料屬性與工藝參數(shù)之間的函數(shù)關(guān)系”,。

正如ICHQ11提到的,，確定合適的物料質(zhì)量標(biāo)準(zhǔn)及工藝參數(shù)范圍需要遵循以下步驟：

s   確認(rèn)工藝變化的潛在源頭；

s   確認(rèn)可能會對原料藥質(zhì)量產(chǎn)生最大影響的物料屬性及工藝參數(shù),。這可以基于之前的知識和風(fēng)險評估工具,；

s   設(shè)計并進行研究(例如，機理和/或動力學(xué)評價,、多變量試驗設(shè)計,、模擬、建模)來識別與確定物料屬性和工藝參數(shù)與原料藥關(guān)鍵質(zhì)量屬性之間的關(guān)聯(lián)和關(guān)系,；

s   對數(shù)據(jù)行分析與評估,，來設(shè)定合適的范圍，包括必要時建立的設(shè)計空間,。

綜上所述，工藝驗證要合規(guī),，源頭在工藝開發(fā)階段要做規(guī)范,，這涉及大量的試驗和數(shù)據(jù)。希望這篇警告信幫助制藥企業(yè)更好地了解監(jiān)管機構(gòu)對工藝驗證的當(dāng)前要求。

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