成人午夜又粗又硬又长_鲁一鲁AV2019在线_欧美深深色噜噜狠狠yyy_www.91色.com_色影音先锋av资源网_特级做A爰片久久毛片A片喷水_99精品无人区乱码1区2区3区_国产人妻久久精品一区_欧美午夜精品久久久久久浪潮_av免费无码天堂在线_蜜桃色欲AV久久无码精品软件_日美一级毛片_久久久久久久久性潮_国产乱对白精彩_日韩精品免费一区二区_亚洲欧美精品在线_无码国产69精品久久久久_开心五月综合激情综合五月_干一夜综合_亚洲中文有码字幕日本

來(lái)源：知藥學(xué)社

第一問(wèn)

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

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

FDA認(rèn)為，驗(yàn)證一個(gè)生產(chǎn)工藝或變更生產(chǎn)工藝，不能簡(jiǎn)單公式化，僅依靠完成3次完整成功的批次。FDA當(dāng)局承認(rèn)3個(gè)驗(yàn)證批次的概念已流行開(kāi)來(lái)，這在某種程序上是由于指導(dǎo)文件的語(yǔ)言表述問(wèn)題。但是，F(xiàn)DA現(xiàn)在正在澄清對(duì)工藝驗(yàn)證現(xiàn)行的期望。當(dāng)前正在修訂1987版《工藝驗(yàn)證一般原則的指導(dǎo)方針》來(lái)解決這個(gè)問(wèn)題。證實(shí)經(jīng)過(guò)驗(yàn)證的工藝，其重點(diǎn)應(yīng)放在生產(chǎn)商的工藝設(shè)計(jì)與開(kāi)發(fā)研究上，另外還證實(shí)，一起期望實(shí)現(xiàn)大規(guī)模生產(chǎn)的可重現(xiàn)性這一目標(biāo)。

但是，未規(guī)定生產(chǎn)工藝驗(yàn)證所需的最小批次數(shù)。在這點(diǎn)上，希望生產(chǎn)商對(duì)自己選定的批次數(shù)有可靠的論據(jù)。FDA當(dāng)局鼓勵(lì)使用科學(xué)的方法進(jìn)行工藝驗(yàn)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(zhǔn)前工藝驗(yàn)證的規(guī)范》。CPG描述的理念：對(duì)所有關(guān)鍵的變異性來(lái)源進(jìn)行識(shí)別并且進(jìn)行控制后，應(yīng)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(méi)有明確提到對(duì)供不應(yīng)求的API進(jìn)行同步驗(yàn)證，但是為了解決實(shí)際的缺貨狀況，F(xiàn)DA當(dāng)局考慮在必要時(shí)使用同步驗(yàn)證以及同步驗(yàn)證研究是否符合CPG中認(rèn)同的情況。

CPG中概述的情況包括：對(duì)解決短貨情況的每個(gè)批次進(jìn)行額外檢驗(yàn)。額外檢驗(yàn)，依據(jù)驗(yàn)證方案進(jìn)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(biāo)準(zhǔn)。此外，對(duì)API生產(chǎn)工藝的信任，可通過(guò)增加取樣（增加有代表性的樣本量）以及可能增加對(duì)額外屬性的檢驗(yàn)來(lái)獲得。每批檢驗(yàn)需要用驗(yàn)證過(guò)的分析方法，包括驗(yàn)證批次。FDA當(dāng)局還期望生產(chǎn)商生產(chǎn)多個(gè)批次后做一份驗(yàn)證方案，包含回顧和最終報(bào)告，即使早期的批次可能已經(jīng)銷(xiāo)售或者用于成品生產(chǎn)了。

注：本問(wèn)答摘自FDA官網(wǎng) Q&A on CGMPs。

第二問(wèn)

咨詢(xún)內(nèi)容：關(guān)于新增原輔料供應(yīng)商，應(yīng)該做小樣檢測(cè)、供應(yīng)商審計(jì)、小試、工藝驗(yàn)證。如果做3批工藝驗(yàn)證，那么3批批物料對(duì)應(yīng)3批工藝驗(yàn)證么？還是1批物料用來(lái)做3批工藝驗(yàn)證？

回復(fù)：3批批物料對(duì)應(yīng)3批工藝驗(yàn)證。

注：本問(wèn)答摘自國(guó)家藥品監(jiān)督管理局食品藥品審核查驗(yàn)中心互動(dòng)交流欄中的問(wèn)題回復(fù)。

第三問(wèn)

咨詢(xún)內(nèi)容：老師您好，凍干粉針劑品種車(chē)間同時(shí)購(gòu)入兩臺(tái)同型號(hào)同容量?jī)龈蓹C(jī)，兩臺(tái)凍干機(jī)已分別進(jìn)行設(shè)備驗(yàn)證包括性能驗(yàn)證，如果兩臺(tái)凍干機(jī)性能無(wú)明顯差異，對(duì)同一個(gè)品種的同一批量生產(chǎn)工藝驗(yàn)證可否一臺(tái)凍干機(jī)生產(chǎn)2批，另一臺(tái)凍干機(jī)生產(chǎn)1批，共同完成3批工藝驗(yàn)證？

回復(fù)：你好，需要根據(jù)具體情況而定。

注：本問(wèn)答摘自國(guó)家藥品監(jiān)督管理局食品藥品審核查驗(yàn)中心互動(dòng)交流欄中的問(wèn)題回復(fù)。

第四問(wèn)

咨詢(xún)內(nèi)容：老師你好，工藝驗(yàn)證過(guò)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(guò)程中也插入了一批B產(chǎn)品是否可以。

回復(fù)：你好，一般是可以的。

注：本問(wèn)答摘自國(guó)家藥品監(jiān)督管理局食品藥品審核查驗(yàn)中心互動(dòng)交流欄中的問(wèn)題回復(fù)。

第五問(wèn)

問(wèn):企業(yè)對(duì)影響藥品制備因素的變更，應(yīng)當(dāng)進(jìn)行驗(yàn)證或確認(rèn)，如果物料包材的產(chǎn)地發(fā)生變化，需要進(jìn)行3批產(chǎn)品的工藝驗(yàn)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(jìn)行至少三批包裝工藝驗(yàn)證，

點(diǎn)評(píng)：有時(shí)或者很多時(shí)候，包材供應(yīng)商的變化（包括產(chǎn)地的變化）可能會(huì)引起包裝工藝中一些參數(shù)的變化，如機(jī)速、熱合溫度（泡軍包裝）變化，甚至可能會(huì)引起成型后包裝的密閉性，所以通常需要進(jìn)行三批產(chǎn)品的工藝驗(yàn)證。成品還應(yīng)進(jìn)行持續(xù)穩(wěn)定性考察。

注：本問(wèn)答摘自2010年版GMP疑難問(wèn)題解答（國(guó)家食品藥品監(jiān)督管理局高級(jí)研修學(xué)院組織編寫(xiě)）。

第六問(wèn)

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

答：工藝驗(yàn)證有前驗(yàn)證和同步驗(yàn)證，前驗(yàn)證需要預(yù)先完成連續(xù)三批后，才能進(jìn)行正式生產(chǎn)，對(duì)于同步再驗(yàn)證，需要進(jìn)行至少三批工藝驗(yàn)證，在確保設(shè)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(yàn)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(gè)批次后完成再驗(yàn)證報(bào)告。如前驗(yàn)證采用同步驗(yàn)證的方式，需要預(yù)先完成連續(xù)三批的工藝驗(yàn)證，才允許三批產(chǎn)品放行。

點(diǎn)評(píng)：前驗(yàn)證系指在任一工藝、設(shè)備或方法等正式使用前按照預(yù)定驗(yàn)證方案逬行的驗(yàn)證，其適用條件：如果沒(méi)有充分的理由，任何工藝、過(guò)程、設(shè)備或物料必須進(jìn)行前驗(yàn)證。

同步再驗(yàn)證系指在正常工藝運(yùn)行的同時(shí)進(jìn)行的驗(yàn)證，允許產(chǎn)品逐批放行。由于此類(lèi)驗(yàn)證的風(fēng)險(xiǎn)較大，通常僅適用于生產(chǎn)工藝成熟的非無(wú)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(yàn)證過(guò)的工藝發(fā)生變更。

注：本問(wèn)答摘自2010年版GMP疑難問(wèn)題解答（國(guó)家食品藥品監(jiān)督管理局高級(jí)研修學(xué)院組織編寫(xiě)）。