來源：知藥學社

第一問

Question：Do CGMPs require three successful process validation batches before a new active pharmaceutical ingredient (API) or a finished drug product is released for distribution?

Answer：No. Neither the CGMP regulations nor FDA policy specifies a minimum number of batches to validate a manufacturing process. The current industry guidance on APIs (see ICH Q7A for APIs) also does not specify a specific number of batches for process validation.

FDA recognizes that validating a manufacturing process, or a change to a process, cannot be reduced to so simplistic a formula as the completion of three successful full scale batches. The agency acknowledges that the idea of three validation batches has become prevalent, in part due to language in its own guidance documents. However, FDA is now clarifying current expectations on process validation. The 1987 Guideline of General Principles of Process Validation （譯者注：實為 Guideline on General Principles of Process Validation） is currently being revised to address this issue. The emphasis for demonstrating validated processes is placed on the manufacturer’s process design and development studies in addition to its demonstration of reproducibility at scale, a goal that has always been expected.

However, a minimum number of conformance (a.k.a. validation) batches necessary to validate the manufacturing processes is not specified. The manufacturer is expected to have a sound rationale for its choices in this regard. The agency encourages the use of science based approaches to process validation.

In March 2004, FDA revised the Compliance Policy Guide (CPG) (Sec. 490.100) on Process Validation Requirements for Drug Products and Active Pharmaceutical Ingredients Subject to Pre-Market Approval. The CPG describes the concept that, after having identified and establishing control of all critical sources of variability, conformance batches are prepared to demonstrate that under normal conditions and operating parameters, the process results in the production of acceptable product. Successful completion of the initial conformance batches would normally be expected before commercial distribution begins, but some possible exceptions are described in the CPG. For example, although the CPG does not specifically mention concurrent validation for an API in short supply, the agency would consider the use of concurrent validation when it is necessary to address a true short-supply situation, and if the concurrent validation study conforms to the conditions identified in the CPG (See paragraph 4.a-c).

The conditions outlined in the CPG include expanded testing for each batch intended to address a short-supply situation. Expanded testing, conducted according to an established validation could provide added assurance that the batch meets all established and appropriate criteria before the API is used in the finished drug product. Additionally, confidence in the API manufacturing process may be gained by enhanced sampling (larger sample size representative of batch) and perhaps the testing of additional attributes. Validated analytical methods are needed for testing every batch, including validation batches. The agency would also expect the manufacturer to use a validation protocol which includes a review and final report after multiple batches are completed, even though the earlier batches may have been distributed or used in the finished drug product.

問：cGMP要求新原料藥（API）或新制劑放行銷售前,，需要有3次成功的工藝驗證批次嗎？

答：沒有,。cGMP條例和FDA法規(guī)都未指定生產(chǎn)工藝驗證的最少批次數(shù),。API現(xiàn)行的行業(yè)指南中（參見ICHQ7A）也未指定具體的工藝驗證批次數(shù)。

FDA認為,，驗證一個生產(chǎn)工藝或變更生產(chǎn)工藝,，不能簡單公式化，僅依靠完成3次完整成功的批次,。FDA當局承認3個驗證批次的概念已流行開來,，這在某種程序上是由于指導文件的語言表述問題。但是,，F(xiàn)DA現(xiàn)在正在澄清對工藝驗證現(xiàn)行的期望,。當前正在修訂1987版《工藝驗證一般原則的指導方針》來解決這個問題,。證實經(jīng)過驗證的工藝，其重點應放在生產(chǎn)商的工藝設計與開發(fā)研究上,，另外還證實,，一起期望實現(xiàn)大規(guī)模生產(chǎn)的可重現(xiàn)性這一目標。

但是,，未規(guī)定生產(chǎn)工藝驗證所需的最小批次數(shù),。在這點上，希望生產(chǎn)商對自己選定的批次數(shù)有可靠的論據(jù),。FDA當局鼓勵使用科學的方法進行工藝驗證,。

2004年3月，F(xiàn)DA修訂了《符合性政策指南》（CPG）（490.100部分）關(guān)于《制劑和原料藥上市批準前工藝驗證的規(guī)范》,。CPG描述的理念：對所有關(guān)鍵的變異性來源進行識別并且進行控制后,，應能生產(chǎn)出一致性批次，以此證明在正常的條件和操作參數(shù)下,，按工藝能生產(chǎn)出合格的產(chǎn)品,。上市前通常期望最終幾批能順利完成、符合要求,，但是有一些可能的例外在CPG中也有描述,。例如，盡管CPG中沒有明確提到對供不應求的API進行同步驗證,，但是為了解決實際的缺貨狀況,，F(xiàn)DA當局考慮在必要時使用同步驗證以及同步驗證研究是否符合CPG中認同的情況。

CPG中概述的情況包括：對解決短貨情況的每個批次進行額外檢驗,。額外檢驗,，依據(jù)驗證方案進行，可提供更多的保證：活性藥物成分（API）用于制劑成品前,，批次符合所有制定的適合的標準,。此外，對API生產(chǎn)工藝的信任,，可通過增加取樣（增加有代表性的樣本量）以及可能增加對額外屬性的檢驗來獲得,。每批檢驗需要用驗證過的分析方法，包括驗證批次,。FDA當局還期望生產(chǎn)商生產(chǎn)多個批次后做一份驗證方案,，包含回顧和最終報告，即使早期的批次可能已經(jīng)銷售或者用于成品生產(chǎn)了,。

注：本問答摘自FDA官網(wǎng) Q&A on CGMPs,。

第二問

咨詢內(nèi)容：關(guān)于新增原輔料供應商，應該做小樣檢測,、供應商審計,、小試,、工藝驗證。如果做3批工藝驗證,，那么3批批物料對應3批工藝驗證么,？還是1批物料用來做3批工藝驗證？

回復：3批批物料對應3批工藝驗證,。

注：本問答摘自國家藥品監(jiān)督管理局食品藥品審核查驗中心互動交流欄中的問題回復,。

第三問

咨詢內(nèi)容：老師您好，凍干粉針劑品種車間同時購入兩臺同型號同容量凍干機,，兩臺凍干機已分別進行設備驗證包括性能驗證,，如果兩臺凍干機性能無明顯差異，對同一個品種的同一批量生產(chǎn)工藝驗證可否一臺凍干機生產(chǎn)2批,，另一臺凍干機生產(chǎn)1批,，共同完成3批工藝驗證？

回復：你好,，需要根據(jù)具體情況而定,。

注：本問答摘自國家藥品監(jiān)督管理局食品藥品審核查驗中心互動交流欄中的問題回復。

第四問

咨詢內(nèi)容：老師你好,，工藝驗證過程中產(chǎn)品連續(xù)三批是指A產(chǎn)品必須不間斷的生產(chǎn)三批,。如果A產(chǎn)品三批生產(chǎn)過程中也插入了一批B產(chǎn)品是否可以。

回復：你好,，一般是可以的,。

注：本問答摘自國家藥品監(jiān)督管理局食品藥品審核查驗中心互動交流欄中的問題回復。

第五問

問:企業(yè)對影響藥品制備因素的變更,，應當進行驗證或確認,，如果物料包材的產(chǎn)地發(fā)生變化，需要進行3批產(chǎn)品的工藝驗證,？

答：如果包材的變化影響到關(guān)鍵工藝參數(shù)及產(chǎn)品質(zhì)量，需要進行至少三批包裝工藝驗證,，

點評：有時或者很多時候,，包材供應商的變化（包括產(chǎn)地的變化）可能會引起包裝工藝中一些參數(shù)的變化，如機速,、熱合溫度（泡軍包裝）變化,，甚至可能會引起成型后包裝的密閉性，所以通常需要進行三批產(chǎn)品的工藝驗證,。成品還應進行持續(xù)穩(wěn)定性考察,。

注：本問答摘自2010年版GMP疑難問題解答（國家食品藥品監(jiān)督管理局高級研修學院組織編寫）。

第六問

問：每年生產(chǎn)1?2批的產(chǎn)品如何做工藝驗證?驗證方法用什么,？

答：工藝驗證有前驗證和同步驗證,，前驗證需要預先完成連續(xù)三批后,，才能進行正式生產(chǎn)，對于同步再驗證,，需要進行至少三批工藝驗證,，在確保設備性能、工藝,、原輔料等不變的倩況下,，允許每批生產(chǎn)結(jié)束后,，按工藝驗證方案的要求，整理好該批資料,，如符合要求，放行該批次產(chǎn)品,，直至累積三個批次后完成再驗證報告,。如前驗證采用同步驗證的方式，需要預先完成連續(xù)三批的工藝驗證,，才允許三批產(chǎn)品放行,。

點評：前驗證系指在任一工藝、設備或方法等正式使用前按照預定驗證方案逬行的驗證,，其適用條件：如果沒有充分的理由,，任何工藝、過程,、設備或物料必須進行前驗證,。

同步再驗證系指在正常工藝運行的同時進行的驗證，允許產(chǎn)品逐批放行,。由于此類驗證的風險較大,，通常僅適用于生產(chǎn)工藝成熟的非無菌藥品。歐盟GMP規(guī)定的適用條件：

1,、生產(chǎn)批數(shù)有限,；

2、不經(jīng)常生產(chǎn),；

3,、已驗證過的工藝發(fā)生變更。

注：本問答摘自2010年版GMP疑難問題解答（國家食品藥品監(jiān)督管理局高級研修學院組織編寫）,。