第一篇：美國(guó)FDA清洗驗(yàn)證檢查指南

美國(guó)FDA清洗驗(yàn)證檢查指南

Ⅰ.簡(jiǎn)介

對(duì)于清洗程序的驗(yàn)證的討論，已經(jīng)在FDA原料藥檢查指南和生物制品檢查指南中有了簡(jiǎn)要地解釋。這些官方文件明確表達(dá)了清洗驗(yàn)證的期望。

本指南通過(guò)討論一些可接受（或不可接受）的實(shí)例來(lái)建立檢查的連貫性和一致性。同時(shí)我們必須意識(shí)到清洗驗(yàn)證同其他過(guò)程的驗(yàn)證一樣，都有不止一種的方法進(jìn)行驗(yàn)證。最后驗(yàn)證證明，是否有科學(xué)數(shù)據(jù)表明系統(tǒng)確實(shí)如預(yù)期穩(wěn)定，并滿足預(yù)設(shè)規(guī)定的結(jié)果。

這個(gè)指南僅涉及對(duì)設(shè)備化學(xué)殘留物的清洗。

Ⅱ.背景

FDA對(duì)于設(shè)備使用前的清洗沒(méi)有什么新要求，1963GMP規(guī)范中（133.4部分）有以下陳述“設(shè)備***應(yīng)保持清潔和有序的狀態(tài)***”。在1978cGMP規(guī)范的設(shè)備清潔中有非常類似的章節(jié)。當(dāng)然，設(shè)備清洗的主要目的是為了防止藥品的污染和混淆。歷史上，F(xiàn)DA檢查員發(fā)現(xiàn)由于設(shè)備的清洗和維護(hù)的不充分及不良的灰塵控制系統(tǒng)帶來(lái)總體上的不衛(wèi)生。歷史上來(lái)說(shuō)，F(xiàn)DA更關(guān)注非青霉素類受青霉素類的污染和高活性的類固醇或激素對(duì)藥物的交叉污染。過(guò)去的幾十年里，許多產(chǎn)品由于實(shí)際存在或潛在的青霉素交叉污染而召回。

1998年消膽胺樹(shù)脂USP制劑的召回事件使FDA對(duì)由于不充分的清洗程序造成的潛在交叉污染更為重視。產(chǎn)品生產(chǎn)中用到的化學(xué)原料藥有低量的中間體和農(nóng)業(yè)殺蟲(chóng)劑的降解物污染。那個(gè)事件中交叉污染被認(rèn)為來(lái)自回收溶劑的套用過(guò)程?；厥杖軇┑奈廴臼怯捎谌鄙賹?duì)溶劑罐重復(fù)使用的控制。殺蟲(chóng)劑生產(chǎn)過(guò)程中存放回收溶劑的罐子隨后用于存放樹(shù)脂生產(chǎn)過(guò)程中的回收溶劑。公司對(duì)這些溶劑罐未嚴(yán)格管理，對(duì)存放的溶劑未充分檢測(cè)，對(duì)罐子的清洗程序未驗(yàn)證。

殺蟲(chóng)劑污染了的原料藥運(yùn)到另一個(gè)地方提供給第二個(gè)工廠最后加工。這對(duì)后一個(gè)工廠流化床干燥器上用到的捕塵袋造成殺蟲(chóng)劑污染。這反過(guò)來(lái)導(dǎo)致在這里生產(chǎn)的多個(gè)批次交叉污染，而這里正常情況下沒(méi)有殺蟲(chóng)劑生產(chǎn)。

FDA在1992年對(duì)外國(guó)原料藥廠家發(fā)出進(jìn)口警告，針對(duì)的是用普通設(shè)備生產(chǎn)高活性的類固醇和非類固醇類產(chǎn)品的廠家。這個(gè)公司是一個(gè)生產(chǎn)多種原料藥的廠家。FDA考慮到潛在交叉污染的嚴(yán)重性，可能對(duì)公眾造成嚴(yán)重的健康危害。這個(gè)公司僅僅在最近檢查的時(shí)候開(kāi)始清洗驗(yàn)證程序，而它被FDA認(rèn)為是不合適的。認(rèn)為他們做得不合適的理由之一是公司僅尋找無(wú)前期成份的化合物的證據(jù)。這個(gè)公司通過(guò)沖洗液的TLC測(cè)試證明存在反應(yīng)副產(chǎn)物的殘留和前面過(guò)程的降解物。

Ⅲ.常規(guī)要求

FDA專家希望公司有SOP來(lái)詳細(xì)敘述設(shè)備不同部分的清洗過(guò)程。如果公司用一個(gè)清洗程序清

洗不同批次的同一產(chǎn)品，用不同程序清洗不同的產(chǎn)品，應(yīng)在SOP中予以說(shuō)明。同樣的，如果公司有除去水溶性殘留物的程序和除去非水溶性殘留物的另一種程序，SOP中應(yīng)強(qiáng)調(diào)說(shuō)明使其在執(zhí)行時(shí)明確。原料藥廠可能采用特定設(shè)備用于一些特定的化學(xué)生產(chǎn)過(guò)程，這些化學(xué)過(guò)程能產(chǎn)生難以從設(shè)備上除去的焦油狀或膠質(zhì)的殘留物。流化床干燥器的捕塵袋是設(shè)備的另一個(gè)例子，它們難以清洗并經(jīng)常用于一種特定產(chǎn)品。清潔過(guò)程本身帶來(lái)的任何殘留物（洗滌劑，溶劑等）也必須從設(shè)備上除去。

FDA希望公司有一個(gè)總的關(guān)于如何進(jìn)行清洗驗(yàn)證的書(shū)面計(jì)劃。

總驗(yàn)證計(jì)劃能明確誰(shuí)負(fù)責(zé)執(zhí)行和批準(zhǔn)驗(yàn)證研究、可接受標(biāo)準(zhǔn)、再驗(yàn)證周期等。

FDA希望公司對(duì)每一個(gè)生產(chǎn)系統(tǒng)或設(shè)備預(yù)先準(zhǔn)備專門的驗(yàn)證方案，以明確取樣程序，運(yùn)用的分析方法及其靈敏性等。

FDA希望公司按驗(yàn)證方案進(jìn)行驗(yàn)證，并將驗(yàn)證結(jié)果進(jìn)行歸檔。

FDA希望由經(jīng)理批準(zhǔn)的最終驗(yàn)證報(bào)告，闡明清洗程序是否有效。數(shù)據(jù)應(yīng)能充分支持殘留物減少到可接受水平的結(jié)論。

Ⅳ.清洗驗(yàn)證評(píng)價(jià)

第一步關(guān)注驗(yàn)證過(guò)程的客觀性，我們發(fā)現(xiàn)一些公司難以做到這點(diǎn)。常見(jiàn)廠商按照清洗程序大范圍的抽樣和檢測(cè)而沒(méi)有真正地評(píng)價(jià)設(shè)備清洗步驟的有效性。在評(píng)價(jià)清洗程序時(shí)需要強(qiáng)調(diào)幾個(gè)問(wèn)題。例如，怎樣才能說(shuō)一臺(tái)設(shè)備或系統(tǒng)是干凈的？必須用手擦洗嗎？手洗比僅用溶劑清洗在什么方面有效？批與批之間，產(chǎn)品與產(chǎn)品之間手工清洗有何區(qū)別？由于要確定過(guò)程的總體效果，這些問(wèn)題的答案對(duì)于檢查和評(píng)價(jià)清洗程序明顯是很重要的。這些問(wèn)題的答案也能明確可去除的步驟，以提高效率、節(jié)省公司資源。

確定每一臺(tái)設(shè)備清洗程序的數(shù)目。理想的情況下，一臺(tái)設(shè)備或一套系統(tǒng)有一個(gè)清洗程序，但是這將取決于生產(chǎn)的產(chǎn)品和清洗是否在同產(chǎn)品不同批之間（相對(duì)于一個(gè)較長(zhǎng)的生產(chǎn)周期）或不同產(chǎn)品之間。當(dāng)清洗程序僅用于相同產(chǎn)品不同批（或原料藥過(guò)程中相同中間體的不同批）之間時(shí)，公司僅需要滿足設(shè)備“目測(cè)干凈”的標(biāo)準(zhǔn)。這種在批之間的清洗程序不需要驗(yàn)證。

1.設(shè)備設(shè)計(jì)

檢查設(shè)備的設(shè)計(jì)，尤其在那些運(yùn)用半自動(dòng)或全自動(dòng)的在線清洗系統(tǒng)及關(guān)鍵的大型系統(tǒng)中。例如，可以使用無(wú)球閥的潔凈管線。當(dāng)使用非衛(wèi)生球閥時(shí)，清洗很困難，這在原料藥企業(yè)中很普遍。檢查時(shí)如發(fā)現(xiàn)使用后一種設(shè)備，應(yīng)了解操作者在清洗時(shí)是否知道這一設(shè)備的問(wèn)題，針對(duì)這一系統(tǒng)及球閥是否進(jìn)行專門培訓(xùn)以及培訓(xùn)的水平，是否有清洗經(jīng)驗(yàn)等是非常重要的。也要檢查書(shū)面和驗(yàn)證過(guò)的清洗程序，以確定這類系統(tǒng)是否被專門說(shuō)明和驗(yàn)證。

在大型系統(tǒng)中，如那些使用長(zhǎng)管線的設(shè)備，要核對(duì)流程圖和管線圖以確定閥門和清潔SOP。管道和閥門應(yīng)被標(biāo)記，易被清洗操作員辨認(rèn)。有時(shí)，由于圖上及現(xiàn)場(chǎng)閥門標(biāo)識(shí)不清楚，不易識(shí)別，易導(dǎo)致不正確的清潔操作。

要現(xiàn)場(chǎng)核對(duì)清洗程序文件中的一個(gè)重要問(wèn)題，確定和控制操作結(jié)束和每個(gè)清潔步驟之間相距的時(shí)間。這對(duì)于外用藥、混懸劑、原料藥的操作尤其重要。殘留物干燥將直接影響清洗的效果。無(wú)論在線清洗系統(tǒng)是否用在過(guò)程設(shè)備的清潔，都應(yīng)該考慮到設(shè)備清洗的微生物檢測(cè)。這包括大量的預(yù)防措施而不是在發(fā)生污染后再去清除。應(yīng)該有一些證據(jù)證明日常清潔和設(shè)備貯存不會(huì)讓微生物繁殖。例如，設(shè)備應(yīng)在貯存前干燥，清洗操作后不允許設(shè)備有淤水。

當(dāng)設(shè)備用作無(wú)菌工藝，或非無(wú)菌工藝，所生產(chǎn)的產(chǎn)品易滋生微生物時(shí)，設(shè)備清潔過(guò)程后須經(jīng)滅菌或消毒程序。而這樣的滅菌或消毒程序超出這個(gè)指南范圍，必須指出，設(shè)備通過(guò)適當(dāng)?shù)那逑春唾A存以控制生物負(fù)載，對(duì)于確保滅菌或消毒程序能取得必要的無(wú)菌保證是很重要的。從無(wú)菌工藝控制熱原的觀點(diǎn)來(lái)說(shuō)，這尤其重要，因?yàn)樵O(shè)備滅菌程序可能未明顯的滅活或除去熱原。

2．清洗SOP的撰寫

程序和文件

對(duì)于驗(yàn)證過(guò)的清洗過(guò)程，應(yīng)檢查程序的細(xì)節(jié)、特殊性及必備文件的數(shù)量。我們已經(jīng)看過(guò)總的SOPs，并看過(guò)其它一些用于執(zhí)行每一步驟所需的專門文件類型，如批生產(chǎn)記錄及日志。執(zhí)行不同清洗步驟或程序所必需的文件數(shù)量，取決于系統(tǒng)和清洗過(guò)程的復(fù)雜性、操作者的能力和培訓(xùn)程度。

當(dāng)需要較復(fù)雜的清洗程序時(shí)，制定關(guān)鍵的清洗步驟（像原料藥的合成過(guò)程）是重要的。在這方面，關(guān)于設(shè)備本身具體的文件包括誰(shuí)清潔和何時(shí)清潔是必要的。但是，對(duì)于相對(duì)簡(jiǎn)單的清潔操作，執(zhí)行總的清洗程序的文件就夠了。

其他因素如清洗歷史、清洗后殘留物水平和測(cè)試結(jié)果的可變性都會(huì)決定要求的文件數(shù)量。例如，在執(zhí)行認(rèn)為是可接受的清洗程序后殘留物檢測(cè)數(shù)據(jù)變化，則必須進(jìn)一步建立更有效的程序且使操作者可執(zhí)行。適當(dāng)評(píng)價(jià)是需要的，當(dāng)操作者操作存在問(wèn)題時(shí)，要求有更多的文件（指南）和培訓(xùn)。

3.分析方法

應(yīng)確定用來(lái)測(cè)定殘留或污染的分析方法的專屬性和靈敏性。隨著分析技術(shù)的進(jìn)展，生產(chǎn)和清潔過(guò)程的殘留物能在很低的水平檢測(cè)出來(lái)。如果污染或殘留物的水平不能檢出，這并不意味著清潔后沒(méi)有殘留污染。這僅意味著樣品中污染水平比分析方式的靈敏度或檢測(cè)限低。公司應(yīng)在取樣確實(shí)能覆蓋設(shè)備表面污染的情況下做挑戰(zhàn)分析，例如在50%回收率，90%回收率的水平分析。這在得出結(jié)論前是必要的。一種不好的取樣技術(shù)也可以導(dǎo)致反面的結(jié)果。（見(jiàn)下文）

4.取樣

通常有兩種取樣方法可被接受。最可取的是從設(shè)備表面直接取樣。另一種方法用沖洗溶液法。a.直接表面取樣-確定使用的取樣材料類型和對(duì)測(cè)試結(jié)果的影響。如用于刷條的粘合劑被發(fā)現(xiàn)能干擾樣品的分析。因此，在早期驗(yàn)證時(shí)，要確保取樣媒介和溶劑（溶媒中提取用）是適當(dāng)?shù)募耙资褂玫摹?/p>

直接取樣的優(yōu)點(diǎn)是能評(píng)價(jià)最難清洗和易接近的區(qū)域，從而建立每個(gè)給定表面區(qū)域上的污染物或殘留物的水平。此外，“干燥的”或不溶性的殘留物能通過(guò)這種物理方式取樣。

b.沖洗溶液取樣-使用沖洗溶液取樣的兩個(gè)優(yōu)點(diǎn)是能在更大表面取樣，不易進(jìn)入的系統(tǒng)或不能常規(guī)拆卸取樣的系統(tǒng)可以被取樣和評(píng)價(jià)。

沖洗取樣的缺點(diǎn)是殘留物或污染不能被溶解或可能在設(shè)備里結(jié)垢時(shí)不能被評(píng)價(jià)。相似的情況也發(fā)生在“死角”。死角清洗的評(píng)價(jià)中，尤其對(duì)于有干燥殘留物，不能通過(guò)沖洗水去判斷是否干凈，而是應(yīng)該用目測(cè)。

檢查發(fā)現(xiàn)當(dāng)清洗驗(yàn)證時(shí)直接測(cè)沖洗水殘留物和污染情況。僅測(cè)試沖洗水的水質(zhì)（在簡(jiǎn)要測(cè)試中確實(shí)遇到）而不測(cè)試其中潛在的污染是不可接受的。

c.常規(guī)生產(chǎn)過(guò)程控制

監(jiān)測(cè)-間接取樣，當(dāng)清洗程序被驗(yàn)證過(guò)，這對(duì)常規(guī)檢測(cè)是有價(jià)值的，如電導(dǎo)率測(cè)試。對(duì)原料藥廠家尤其如此，其中反應(yīng)器、離心機(jī)和大型設(shè)備間的管線只能沖洗液取樣。任何間接測(cè)試方法必須與設(shè)備情況相關(guān)。在驗(yàn)證中，公司應(yīng)對(duì)間接測(cè)試中不潔凈設(shè)備測(cè)試得出的不合格結(jié)果進(jìn)行歸檔。

V.限度的建立

FDA不會(huì)去設(shè)定可接受的標(biāo)準(zhǔn)或方法來(lái)決定一個(gè)清洗程序是否被驗(yàn)證。因?yàn)檎麄€(gè)原料藥和制劑工業(yè)中使用的設(shè)備和產(chǎn)品具有廣泛的多樣性，這樣做尤其不現(xiàn)實(shí)。公司建立殘留物限度的標(biāo)準(zhǔn)應(yīng)建立在廠商對(duì)涉及物料了解的邏輯基礎(chǔ)上，而且是實(shí)際的，可行的，可證實(shí)的。為了制定合理的限度，定義分析方法的靈敏性是重要的。工業(yè)界已在文獻(xiàn)提出一些限度要求，包括分析檢測(cè)水平如10ppm，生物活性水平如1/1000的普通治療劑量和感官水平如無(wú)可見(jiàn)殘留物。

核對(duì)建立限度的方式。不像制劑的化學(xué)殘留鑒定是已知的（如活性物質(zhì)，非活性物質(zhì)，降解物質(zhì)），原料藥過(guò)程有部分反應(yīng)物和多余的副產(chǎn)物可能無(wú)法用化學(xué)鑒定。在建立殘留限度中，僅關(guān)注主要的反應(yīng)物是不夠的，因?yàn)槠渌鞣N化學(xué)成分可能更難去除。除化學(xué)分析以外有些情況需要薄層掃描。在原料藥的生產(chǎn)工藝中，尤其是高活性的化學(xué)品如一些類固醇，如果設(shè)備不專用就要考慮副產(chǎn)物。檢查的目的是確保任何限度的基礎(chǔ)是科學(xué)公正的。

VI．其他問(wèn)題

a.安慰劑產(chǎn)品

為了評(píng)價(jià)和驗(yàn)證清洗程序，一些廠家在設(shè)備中生產(chǎn)一批安慰劑產(chǎn)品，基本上是按照原藥物同樣的操作參數(shù)生產(chǎn)。安慰劑批次的取樣就為了測(cè)試殘留的污染物。但是，我們記錄幾個(gè)重要的問(wèn)題，當(dāng)使用安慰劑產(chǎn)品驗(yàn)證清洗程序時(shí)這些是需要指出的。

不能保證污染物在整個(gè)系統(tǒng)中分散的一致。例如，如果出口閥或攪拌機(jī)的槳被污染了，污染物可能不會(huì)均勻分散在安慰劑中，它最可能集中在批次的最開(kāi)始排出的部分。此外，如果污染物或殘留物是大顆粒的，它可能不能均勻分散在安慰劑中。

一些公司假設(shè)殘留污染物在設(shè)備表面均勻的逐漸減少，這也是錯(cuò)誤的結(jié)論。最終，檢測(cè)效果也隨著污染物的稀釋極大的降低。因?yàn)檫@樣的問(wèn)題，沖洗和擦拭取樣應(yīng)與安慰劑的方法相結(jié)合進(jìn)行。

b.清潔劑

如果清潔中使用清潔劑或肥皂試檢測(cè)殘留物時(shí)，判斷和分析將變得很困難。在清潔劑的使用中最常見(jiàn)問(wèn)題是它的成分。許多清潔劑的供應(yīng)商不能提供具體成分，這使用戶難以判斷殘留物。對(duì)于產(chǎn)品殘留，生產(chǎn)商評(píng)價(jià)清洗程序去除殘留的效果是重要的，也是能做到的。但是，不同于產(chǎn)品殘留，我們希望清潔后沒(méi)有清潔劑存在（或者嚴(yán)格分析方法-很低）。清潔劑不是生產(chǎn)過(guò)程的一個(gè)部分，僅在清洗過(guò)程中添加到清潔設(shè)備中。因此，它們應(yīng)該容易被去除。否則，就要選擇另外一種不同的清潔劑。

c.測(cè)試到清潔

應(yīng)檢查和評(píng)價(jià)測(cè)試水平與再測(cè)試結(jié)果，因?yàn)闇y(cè)試到清潔被一些廠商作為概念使用。他們測(cè)試，再取樣，再測(cè)試設(shè)備或系統(tǒng)直至達(dá)到可接受的殘留物水平。對(duì)于已做過(guò)清洗程序的系統(tǒng)或設(shè)備，不應(yīng)該再取樣，這僅在很少的情況下被接受。連續(xù)的再測(cè)試和再取樣是能表明清洗程序沒(méi)有被驗(yàn)證，因?yàn)檫@些再測(cè)試實(shí)際記錄了無(wú)效的清洗程序、不可接受的殘留物和污染物的存在。

出處：浙江藥品認(rèn)證中心

作者：不詳

注釋：這份文件是檢查員和其他FDA人員的參考資料。這份文件不約束FDA，不授予任何人任何權(quán)力、特權(quán)、利益或豁免權(quán)。僅供學(xué)習(xí)參考

第二篇：FDA新版工藝驗(yàn)證指南培訓(xùn)總結(jié)

南京綠葉思科藥業(yè)培訓(xùn)總結(jié)

參加美國(guó)FDA2011工藝驗(yàn)證指南解讀講座總結(jié)

6月16日我公司生產(chǎn)、質(zhì)量部共9人參加了中國(guó)藥科大學(xué)組織的FDA2011工藝驗(yàn)證指南的講座。本講座由FDA總部藥品評(píng)價(jià)和研究中心官員主講，講座內(nèi)容如下：

此版指南將產(chǎn)品生命周期概念和工藝驗(yàn)證活動(dòng)結(jié)合起來(lái)，將工藝驗(yàn)證分為工藝設(shè)計(jì)、.工藝確認(rèn)、持續(xù)的工藝驗(yàn)證三個(gè)階段。

工藝驗(yàn)證是指從工藝設(shè)計(jì)階段到商業(yè)生產(chǎn)的整個(gè)過(guò)程中，對(duì)數(shù)據(jù)進(jìn)行收集和評(píng)價(jià)，建立能夠使工藝始終如一的傳遞到優(yōu)質(zhì)產(chǎn)品中的科學(xué)證據(jù)。

對(duì)已經(jīng)上市的產(chǎn)品則直接執(zhí)行持續(xù)工藝核實(shí)這一階段的工作。制作商應(yīng)該保持持續(xù)的信息收集和對(duì)工藝的定期評(píng)價(jià)，以發(fā)現(xiàn)常見(jiàn)的工藝變異情況，進(jìn)而增加對(duì)工藝和變異的理解，評(píng)價(jià)和控制工藝參數(shù)，并建立科學(xué)的參數(shù)評(píng)價(jià)方法，在商品生產(chǎn)這一階段內(nèi)做到對(duì)工藝的逐步改進(jìn)（如縮小參數(shù)范圍等）。在此階段如發(fā)現(xiàn)有重大變異或工藝有較大改動(dòng)，而現(xiàn)有數(shù)據(jù)不足以進(jìn)行分析時(shí)，可以回到工藝設(shè)計(jì)或工藝確認(rèn)階段。

提出的建議：

1.試驗(yàn)批量：商品正式流通時(shí)的生產(chǎn)批量

2.方案設(shè)計(jì)：取消關(guān)鍵參數(shù)的概念，擴(kuò)大了考察面積，希望制造商能夠?qū)に?/p>

全面的重視，取樣頻率和監(jiān)控參數(shù)必須結(jié)合風(fēng)險(xiǎn)評(píng)估和統(tǒng)計(jì)學(xué)

分析再做出決定。

取消最差條件的概念，工藝確認(rèn)應(yīng)在生產(chǎn)可能遇到的真實(shí)情況

下進(jìn)行，不建議人為創(chuàng)造極端情況。

3.結(jié)果判斷：所有的決定應(yīng)該建立在足夠的數(shù)據(jù)基礎(chǔ)上，這些數(shù)據(jù)可以來(lái)自于

產(chǎn)品生命周期的全過(guò)程，并且需要通過(guò)統(tǒng)計(jì)學(xué)家或受過(guò)專業(yè)訓(xùn)

練的人員進(jìn)行科學(xué)的統(tǒng)計(jì)學(xué)分析。

4.放行標(biāo)準(zhǔn)：必須在工藝性能確認(rèn)所收集到的數(shù)據(jù)進(jìn)行完整的統(tǒng)計(jì)學(xué)分析、驗(yàn)

證報(bào)告得到審批后方可放行，不建議同步放行。

5.上市條件：在正式上市流通前必須完成工藝確認(rèn)，向FDA證明工藝是穩(wěn)定的。而工藝確認(rèn)階段的結(jié)束標(biāo)志則由制造商自行決定。（也就是

說(shuō)工藝確認(rèn)應(yīng)該進(jìn)行多少次的商品批量試驗(yàn)而認(rèn)為收集到了足

1/4

夠的數(shù)據(jù)，是由制造商決定的）

6.監(jiān)控要求：在上市的初期階段應(yīng)保持一段時(shí)間高頻率多項(xiàng)目（與工藝確認(rèn)時(shí)

期相同）的監(jiān)控，直到有足夠的數(shù)據(jù)來(lái)進(jìn)行統(tǒng)計(jì)學(xué)分析保證工

藝的完全可靠，才可以通過(guò)定期對(duì)工藝評(píng)價(jià)來(lái)調(diào)整監(jiān)測(cè)項(xiàng)目。

以下內(nèi)容是學(xué)習(xí)培訓(xùn)講義和2011工藝驗(yàn)證指南的收獲。

1.法規(guī)要求

設(shè)計(jì)要求：在CGMP210和211節(jié)中要求生產(chǎn)商必須從操作和控制兩方面設(shè)計(jì)工藝，以保證得到鑒別，含量，質(zhì)量，純度都符合企業(yè)向FDA所申報(bào)標(biāo)準(zhǔn)的產(chǎn)品。

建立中間生產(chǎn)工藝規(guī)程：同時(shí)工藝設(shè)計(jì)也應(yīng)針對(duì)中間生產(chǎn)工藝建立控制程序，中間生產(chǎn)工藝規(guī)程是在試驗(yàn)批量與成品生產(chǎn)批量一致的原則上以數(shù)據(jù)統(tǒng)計(jì)分析（已認(rèn)可的參數(shù)和對(duì)未知的可能變異的參數(shù)的估計(jì)）為基礎(chǔ)建立的。本項(xiàng)法規(guī)同時(shí)對(duì)生產(chǎn)商提出了分析工藝性能和控制批間變異的要求。

設(shè)備要求：對(duì)所使用的機(jī)械和電子設(shè)備必須有書(shū)面的計(jì)劃來(lái)保證校準(zhǔn)能夠如期完成，以保證設(shè)備符合原有的設(shè)計(jì)要求。

抽樣要求：1.樣品必須代表接受分析的批次；2.抽樣方法必須產(chǎn)生統(tǒng)計(jì)學(xué)置信度；3.批次必須符合其預(yù)設(shè)規(guī)格。

產(chǎn)品質(zhì)量回顧：通過(guò)定期對(duì)產(chǎn)品質(zhì)量回顧來(lái)確定工藝變更的合理性。這里的產(chǎn)品質(zhì)量回顧是對(duì)有關(guān)產(chǎn)品質(zhì)量和制造經(jīng)驗(yàn)的信息和數(shù)據(jù)進(jìn)行定期的審核。通過(guò)產(chǎn)品質(zhì)量回顧可以將工藝的影響不斷的反饋至產(chǎn)品質(zhì)量上，從而開(kāi)展對(duì)工藝的維護(hù)。

2.建議

2.1 總體要求

在組織工藝驗(yàn)證時(shí)建議采用來(lái)自多學(xué)科的綜合團(tuán)隊(duì)（如：工藝學(xué)，制藥工程，分析化學(xué)，微生物學(xué)，統(tǒng)計(jì)學(xué)，制造以及質(zhì)量保證），所有啟動(dòng)的研究都應(yīng)該根據(jù)可靠的，科學(xué)的原則來(lái)計(jì)劃，實(shí)施。妥善記錄各種活動(dòng)，保證完整地收集與工藝有關(guān)的信息，及時(shí)對(duì)這些信息進(jìn)行可靠的評(píng)價(jià)。這都要求該團(tuán)隊(duì)做好項(xiàng)目

管理和文件歸檔。

在選擇研究對(duì)象時(shí)，取消了原有關(guān)鍵參數(shù)的概念，而是使用了基于風(fēng)險(xiǎn)的決策生命周期方法進(jìn)行工藝驗(yàn)證。關(guān)鍵程度應(yīng)該是連續(xù)的，而不該是二元的。

風(fēng)險(xiǎn)評(píng)估應(yīng)該從屬性或參數(shù)在工藝中發(fā)揮的作用和對(duì)產(chǎn)品的影響角度來(lái)進(jìn)行評(píng)估。在工藝變更后，這些項(xiàng)目都必須進(jìn)行重新評(píng)估。

不論如何，批間和批次間的一致性都是工藝驗(yàn)證的基本目標(biāo)。

2.2 工藝設(shè)計(jì)

A.建立和捕獲工藝知識(shí)并理解

通過(guò)早期實(shí)驗(yàn)室產(chǎn)品開(kāi)發(fā)時(shí)累積的數(shù)據(jù)來(lái)加強(qiáng)對(duì)工藝的理解。利用分析和統(tǒng)計(jì)學(xué)知識(shí)來(lái)選擇在實(shí)驗(yàn)室階段研究工藝的潛在變異。

可以建立小試或中試模型來(lái)估計(jì)變異，變異的估計(jì)可以從以下幾個(gè)角度來(lái)考慮：1.設(shè)備的設(shè)計(jì)功能和局限性，2.批量變化，2.生產(chǎn)操作人員，3.環(huán)境條件變化，4，檢測(cè)系統(tǒng)

這些數(shù)據(jù)都應(yīng)被記錄和保存，是工藝決策（參數(shù)和質(zhì)量范圍的界定）和將來(lái)工藝確認(rèn)和持續(xù)核實(shí)階段的數(shù)據(jù)基礎(chǔ)。

B.建立工藝控制策略

工藝控制可以由重要工藝控制點(diǎn)的物料分析和設(shè)備監(jiān)控組成，通過(guò)減少輸入變異和在生產(chǎn)中調(diào)整輸入變異來(lái)達(dá)到控制目標(biāo)。

在產(chǎn)品屬性不易測(cè)量和中間體和產(chǎn)品不易界定的情況下可以通過(guò)工作極限和中間工藝監(jiān)控來(lái)控制工藝。

2.3 工藝確認(rèn)

在本指南中工藝確認(rèn)包括兩部分內(nèi)容：

A.廠房設(shè)施設(shè)計(jì)以及公用設(shè)施與設(shè)備確認(rèn)，包括這些設(shè)施或設(shè)備的4Q，其中

PQ應(yīng)是在可與日常生產(chǎn)預(yù)期相比的負(fù)荷下進(jìn)行，還應(yīng)包括預(yù)期的日常生產(chǎn)條件下干預(yù)/停止和啟動(dòng)功能。

B.工藝性能驗(yàn)證（PPQ），PPQ必須在上一階段完成后才可以進(jìn)行。

C.PPQ的目的：為工藝可重現(xiàn)和始終如一的產(chǎn)出優(yōu)秀產(chǎn)品建立科學(xué)證據(jù)。

來(lái)自所有相關(guān)研究的累積數(shù)據(jù)應(yīng)用于PPQ中建立正式的生產(chǎn)條件，在此階段將有較高的取樣和額外的檢測(cè)水平。

在方案中應(yīng)體現(xiàn)取樣方案的設(shè)計(jì)，包括樣品數(shù)應(yīng)足以對(duì)批內(nèi)和批間的質(zhì)量分析提供足夠的樣本進(jìn)行統(tǒng)計(jì)學(xué)置信度分析。所選定的置信水平以風(fēng)險(xiǎn)分析為基礎(chǔ)。

方案中的決策標(biāo)準(zhǔn)應(yīng)包括：所用的統(tǒng)計(jì)學(xué)方法描述，和偏離數(shù)據(jù)的處理方法。偏離數(shù)據(jù)不得隨便舍去。

2.4持續(xù)工藝驗(yàn)證

本階段的目標(biāo)是：在商品化生產(chǎn)期間持續(xù)保證工藝處于受控狀態(tài)。收集和評(píng)估關(guān)于工藝性能的信息和數(shù)據(jù)，發(fā)現(xiàn)變異，提前預(yù)防和防止問(wèn)題。

在日常的持續(xù)工藝驗(yàn)證中，收集與產(chǎn)品質(zhì)量相關(guān)的數(shù)據(jù)進(jìn)行趨勢(shì)分析，（分析所用的統(tǒng)計(jì)學(xué)方法，數(shù)據(jù)收集方案由經(jīng)過(guò)統(tǒng)計(jì)學(xué)工藝控制技術(shù)方面訓(xùn)練的人員制定），并定期根據(jù)分析結(jié)果對(duì)工藝進(jìn)行評(píng)估。

工藝變異的來(lái)源：缺陷投訴，不合格品的調(diào)查結(jié)果，工藝偏移報(bào)告，工藝產(chǎn)率差異，批生產(chǎn)報(bào)告，原料報(bào)告，不良事件報(bào)告。這些變異應(yīng)定期評(píng)價(jià)，并相應(yīng)的對(duì)監(jiān)測(cè)做出調(diào)整。

生產(chǎn)工藝的變更，必須建立在所收集的變異或數(shù)據(jù)的統(tǒng)計(jì)學(xué)基礎(chǔ)上，并在實(shí)施前由質(zhì)量部門進(jìn)行審批。如變更對(duì)產(chǎn)品質(zhì)量有重大影響的需要回到工藝設(shè)計(jì)或工藝確認(rèn)階段進(jìn)一步收集數(shù)據(jù)，并正式通知FDA。

同樣，廠房設(shè)施的狀態(tài)必須通過(guò)日常檢查，校準(zhǔn)進(jìn)行維護(hù)，相關(guān)數(shù)據(jù)定期評(píng)估，以確定是否應(yīng)該重新確認(rèn)，維護(hù)和校準(zhǔn)頻率應(yīng)給予評(píng)估所得到的反饋予以調(diào)整。

學(xué)習(xí)小組

2011-06-24

第三篇：美國(guó)FDA關(guān)于制劑藥廠cGMP的檢查指南-93-10

Dosage Form Drug Manufacturers cGMPs(10/93)GUIDE TO INSPECTIONS OF DOSAGE FORM DRUG MANUFACTURER'S-CGMPR'S

Note: This document is reference material for investigators and other FDA personnel.The document does not bind FDA, and does no confer any rights, privileges, benefits, or immunities for or on any person(s).I.INTRODUCTION

This document is intended to be a general guide to inspections of drug manufacturers to determine their compliance with the drug CGMPR's.This guide should be used with instructions in the IOM, other drug inspection guides, and compliance programs.A list of the inspection guides is referenced in Chapter 10 of the IOM.Some of these guides are:

o Guide to Inspections of Bulk Pharmaceutical Chemicals.o Guide to Inspections of High Purity Water Systems.o Guide to Inspections of Pharmaceutical Quality Control Laboratories.o Guide to Inspections of Microbiological Pharmaceutical Quality Control Laboratories.o Guide to Inspections of Lyophilization of Parenterals.o Guide to Inspections of Validation of Cleaning Processes.o Guide to Inspections of Computerized Systems in Drug Processing.o Guideline on General Principles of Process Validation.II.CURRENT GOOD

MANUFACTURING PRACTICE

REGULATIONS

Prescription vs.Non-prescription

All drugs must be manufactured in accordance with the current good manufacturing practice regulations otherwise they are considered to be adulterated within the meaning of the FD&C Act, Section 501(a)(2)(B).Records relating to prescription drugs must be readily available for review in accordance with Sec.704(a)(1)(B)of the FD&C Act.If the product is an OTC drug which is covered by an NDA or ANDA, FDA may review, copy and verify the records under Sec.505(k)(2)of the FD&C Act.However, if the product is an OTC drug for which there is no application filed with FDA, the firm is not legally required to show these records to the investigator during an inspection being conducted under Section 704 of the FD&C Act.Nonetheless, all manufacturers of prescription and OTC drugs must comply with the drug CGMPR requirements, including those involving records.The investigator should review these records as part of the inspection in determining the firm's compliance with the CGMP regulations.On rare occasions, a firm may refuse to allow review of OTC records stating they are not legally required to.While the firm may be under no legal obligation to permit review of such records, this does not relieve the firm of its statutory requirement to comply with the good manufacturing practices under section 501(a)(2)(B)of the Food Drug and Cosmetic Act, including the requirements for maintaining records.If a firm refuses review of OTC records, the investigator should determine by other inspectional means the extent of the firm's compliance with CGMPR's.Inspectional observations and findings that CGMPR's are not being followed are to be cited on a List of Inspectional Observations, FDA-483, for both prescription and non-prescription drugs.Organization and Personnel [21 CFR 211 Subpart B]

The firm must have a quality control department that has the responsibility and authority as described in the referenced CFR.The quality control department must maintain its independence from the production department, and its responsibilities must be in writing.Obtain the name, title and individual responsibilities of corporate officers and other key employees as indicated in the IOM.In the drug industry, an employee's education and training for their position has a significant impact on the production of a quality product.Report whether the firm has a formalized training program, and describe the type of training received.The training received by an employee should be documented.Quality control must do product annual review on each drug manufactured, and have written annual review procedures.Review these reports in detail.This report will quickly let you know if the manufacturing process is under control.The report should provide a summary all lots that failed in-process or finished product testing, and other critical factors.Investigate any failures.Quality control must validate the manufacturing process for each drug manufactured.Review and evaluate this data.Buildings and Facilities [21 CFR 211 Subpart C]

Review the construction, size, and location of plant in relation to surroundings.There must be adequate lighting, ventilation, screening, and proper physical barriers for all operations including dust, temperature, humidity, and bacteriological controls.There must be adequate blueprints which describe the high purity water, HEPA, and compressed air systems.The site must have adequate locker, toilet, and hand washing facilities.The firm must provide adequate space for the placement of equipment and materials to prevent mix-ups in the following operations:

o receiving, sampling, and storage of raw materials;

o manufacturing or processing;

o packaging and labeling;

o storage for containers, packaging materials, labeling, and finished products;

o production and control laboratories.Equipment [21 CFR 211 Subpart D]

Review the design, capacity, construction, and location of equipment used in the manufacturing, processing, packaging, labeling, and laboratories.Describe the manufacturing equipment including brief descriptions of operating principles.Consider the use of photographs, flow charts, and diagrams to supplement written descriptions.New equipment must be properly installed, and operate as designed.Determine if the equipment change would require FDA pre-approval and/or revalidation of the manufacturing process.The equipment must be cleaned before use according to written procedures.The cleaning must be documented and validated.The equipment should not adversely effect the identity, strength, quality, or purity of the drug.The material used to manufacture the equipment must not react with the drug.Also, lubricants or coolants must not contaminate the drug.The equipment should be constructed and located to ease cleaning, adjustments, and maintenance.Also, it should prevent contamination from other or previous manufacturing operations.Equipment must be identified as to its cleaning status and content.The cleaning and maintenance of the equipment are usually documented in a log book maintained in the immediate area.Determine if the equipment is of suitable capacity and accuracy for use in measuring, weighing, or mixing operations.If the equipment requires calibration, they must have a written procedure for calibrating the equipment and document the calibration.Components and Product Containers [21 CFR 211 Subpart E]

Inspect the warehouse and determine how components, drug product containers, and closures are received, identified, stored, handled, sampled, tested, and approved or rejected.They must have written procedures which describe how these operations are done.Challenge the system to decide if it is functioning correctly.If the handling and storage of components are computer controlled, the program must be validated.The receiving records must provide traceability to the component manufacturer and supplier.The receiving records for components should contain the name of the component, manufacturer, supplier if different from the manufacturer, and carrier.In addition, it should include the receiving date, manufacturer's lot number, quantity received, and control number assigned by the firm.Check sanitary conditions in the storage area, stock rotation practices, retest dates, and special storage conditions(protection from light, moisture, temperature, air, etc.).Inspect glandular and botanical components for insect infestation.Components or finished product adulterated by rodents, insects, or chemicals must be documented and submitted for seizure.Collect the evidence even if the firm plans to voluntarily destroy the product.Be alert for components, colors, and food additives that may be new drug substances, appear to have no use in the plant or appear to be from an unknown supplier.Check the colors against the Color Additives Status List in the IOM Determine if the color is approved for its intended use, and required statements are declared on the drug label.Components might be received at more than one location.Components must be handled in accordance with the drug CGMP's including components used in the research and development lab.Determine how components are identified after receipt and quarantined until released.Components must be identified so the status(quarantine, approved, or rejected)is known.Review the criteria for removing components from quarantine and challenge the system.Determine what records are maintained in the storage area to document the movement of components to other areas, and how rejected components handled.The component container has an identification code affixed to it.This unique code provides traceability from the component manufacturer to its use in the finished product.Review the sampling and testing procedures for components, and the process by which approved materials are released for use.Decide if these practices are adequate and followed.Determine the validity, and accuracy of the firm's inventory system for drug components, containers, closures and labeling.Challenge the component inventory records by weighing a lot and comparing the results against the quantity remaining on the inventory record.Significant discrepancies in these records should be investigated.Evaluate the following to determine whether the firm has shown that the containers and closures are compatible with the product, will provide adequate protection for the drug against deterioration or contamination, are not additive or absorptive, and are suitable for use:

o Specifications for containers, closures, cotton filler, and desiccant, etc.o What tests or checks are made(cracks, glass particles, durability of material, metal particles in ointment tubes, compliance with compendium specifications, etc.).o Cleaning procedures and how containers are stored.o Handling of preprinted containers.Are these controlled as labeling, or as containers? The firm must review the labeling for accuracy.Production and Process Controls [21 CFR Subpart F]

1.Critical Manufacturing Steps [21 CFR 211.101]

Each critical step in the manufacturing process shall be done by a responsible individual and checked by a second responsible individual.If such steps in the processing are controlled by automatic mechanical or electronic equipment, its performance should be verified.Critical manufacturing steps include the selection, weighing, measuring and identifying of components, and addition of components during processing.It includes the recording of deviations from the batch record, mixing time and testing of in-process material, and the determination of actual yield and percent of theoretical yield.These manufacturing steps are documented when done, and not before or after the fact.2.Equipment Identification [21 CFR 211.105]

All containers and equipment used in to manufacture a drug should be labeled at all times.The label should identify the contents of the container or equipment including the batch number, and stage of processing.Previous identification labels should be removed.The batch should be handled and stored to prevent mixups or contamination.3.In-Line and Bulk Testing [21 CFR 211.110]

To ensure the uniformity and integrity of products, there shall be adequate in-process controls, such as checking the weights and disintegration time of tablets, the fill of liquids, the adequacy of mixing, the homogeneity of suspensions, and the clarity of solutions.Determine if in-process test equipment is on site and the specified tests are done.Be alert for prerecording of test results such as tablet weight determinations.The bulk drug is usually held in quarantine until all tests are completed before it is released to the packaging and labeling department.However, the testing might be done after packaging.product.4.Actual Yield [21 CFR 211.103]

Determine if personnel check the actual against the theoretical yield of each batch of drug manufactured.In the event of any significant unexplained discrepancies, determine if there is a procedure to prevent distribution of the batch in question, and related batches.5.Personnel Habits

Observe the work habits of plant personnel.Determine:

Their attitudes and actions involving the jobs they perform.(Careless, lackadaisical, disgruntled, etc.).Their dress.(Clean dresses, coats, shirts and pants, head coverings, etc.If proper equipment is used for a given job or whether short cuts are taken(i.e.use of hands and arms to mix or empty trays of drug components).If there are significant written or verbal language barriers that could affect their job performance.Tablet and Capsule Products

Become familiar with the type of equipment and its location in the tableting operation.The equipment may include rotary tableting machines, coating and polishing pans, punches and dies, etc.The equipment should be constructed and located to facilitate maintenance and cleaning at the end of each batch or at suitable intervals in the case of a continuous batch operation.If possible, observe the cleaning and determine if the cleaning procedure is followed.The ingredients in a tablet are the active ingredient, binders, disintegrators, bases, and lubricants.The binder is added to the batch to keep the tablet together.Excess binder will make the tablet too hard for use.The disintegrator is used to help disintegration of the tablet after administration.The base should be an inert substance which is compatible with the active ingredient and is added to provide size and weight.The lubricant helps in the flow of granulated material, prevents adhesion of the tablet material to the surface of punches and dies, and helps in tablet ejection from the machine.Tablets and capsules are susceptible to airborne contamination because of the manipulation of large quantities of dry ingredients.To prevent cross-contamination in the tableting department, pay close attention to the maintenance, cleaning, and location of equipment, and the storage of granulations and tablets.To prevent cross-contamination, the mixing, granulation, drying and/or tableting operation should be segregated in enclosed areas with its own air handling system.Determine what precautions are taken to prevent cross-contamination.When cross-contamination is suspect, investigate the problem and collect in-line samples(INV)and official samples of the suspect product.Determine what temperature, humidity, and dust collecting controls are used by the firm in manufacturing operations.Lack of temperature and humidity controls can affect the quality of the tablet.Observe the actual operation of the equipment and determine whether powders or granulations are processed according to the firm's specifications.The mixing process must be validated.The drying ovens should have their own air handling system which will prevent cross-contamination.Does the firm record drying time/temperature and maintain recording charts including loss on drying test results? Review the in-line tests performed by production and/or quality control.Some in-process tests are tablet weight, thickness, hardness, disintegration , and friability.Evaluate the disposition of in-process samples.Capsules may be either hard, or soft type.They are filled with powder, beads, or liquid by machine.The manufacturing operation of powders for capsules should follow the same practice as for tablets.Determine manufacturing controls used, in-line testing, and basis for evaluating test results for the filling operations.Sterile Products

Typically, a sterile drug contains no viable microorganisms and is non-pyrogenic.Drugs for intravenous injection, irrigation, and as ophthalmic preparations, etc., meet this criteria.In addition, other dosage forms might be labeled as sterile.For instance, an ointment applied to a puncture wound or skin abrasion.Parenteral drugs must be non-pyrogenic, because the presence of pyrogens can cause a febrile reaction in human beings.Pyrogens are the products of the growth of microorganisms.Therefore, any condition that permits bacterial growth should be avoided in the manufacturing process.Pyrogens may develop in water located in stills, storage tanks, dead legs, and piping, or from surface contamination of containers, closures, or other equipment.Parenterals may also contain chemical contaminants that will produce a pyretic response in humans or animals although there are no pyrogens present.There are many excellent reference materials which should be reviewed before the inspection.Some of these are the “Guideline on Sterile Drug Products Produced by Aseptic Processing,” and chapter 84 on pyrogens in the Remington's Pharmaceutical Sciences.Determine and evaluate the procedures used to minimize the hazard of contamination with microorganisms and particulates of sterile drugs.o Personnel

Review the training program to ensure that personnel performing production and control procedures have experience and training commensurate with their intended duties.It is important that personnel be trained in aseptic procedures.The employees must be properly gowned and use good aseptic techniques.o Buildings

The non-sterile preparation areas for sterile drugs should be controlled.Refer to Subpart C of the proposed CGMPR's for LVP's;however, deviations from these proposed regulations are not necessarily deviations from the CGMPR's.Evaluate the air cleanliness classification of the area.For guidance in this area, review Federal Standard #209E entitled “Airborne Particulate Cleanliness Classes in Cleanrooms and Clean Zones.” Observe the formulation practices or procedures used in the preparation areas.Be alert for routes of contamination.Determine how the firm minimizes traffic and unnecessary activity in the preparation area.Determine if filling rooms and other aseptic areas are constructed to eliminate possible areas for microbiological/particulate contamination.For instance, dust-collecting ledges, porous surfaces, etc.Determine how aseptic areas are cleaned and maintained.1.Air

Air supplied to the non-sterile preparation or formulation area for manufacturing solutions prior to sterilization should be filtered as necessary to control particulates.Air being supplied to product exposure areas where sterile drugs are processed and handled should be high efficiency particulate air(HEPA)filtered under positive pressure.Review the firm's system for HEPA filters, determine if they are certified and/or Dioctyl Phthalate(DOP)tested and frequency of testing.Review the compressed air system and determine if it is filtered at the point of use to control particulates.Diagrams of the HEPA filtered and compressed air systems should be reviewed and evaluated.2.Environmental Controls

Specifications for viable and non-viable particulates must be established.Specifications for viable particulates must include provisions for both air and surface sampling of aseptic processing areas and equipment.Review the firm's environmental control program, specifications, and test data.Determine if the firm follows its procedure for reviewing out-of-limit test results.Also, determine if review of environmental test data is included as a part of the firm's release procedures.Note: In the preparation of media for environmental air and surface sampling, suitable inactivating agents should be added.For example, the addition of penicillinase to media used for monitoring sterile penicillin operations and cephalosporin products.o Equipment

Determine how the equipment operates including the cleaning and maintenance practices.Determine how equipment used in the filling room is sterilized, and if the sterilization cycle has been validated.Determine the practice of re-sterilizing equipment if sterility has been compromised.Determine the type of filters used.Determine the purpose of the filters, how they are assembled, cleaned, and inspected for damage.Determine if a microbial retentive filter, and integrity testing is required.o Water for Injection

Water used in the production of sterile drugs must be controlled to assure that it meets U.S.P.specifications.Review the firm's water for injection production, storage, and delivery system.Determine that the stills, filters, storage tanks, and pipes are installed and operated in a manner that will not contaminate the water.Evaluate the firm's procedures and specifications that assure the quality of the water for injection.As reference material, review the “FDA Guide to Inspecteons of High Purity Water Systems” before initiating an inspection.o Containers and Closures

Determine how containers and closures are handled and stored.Decide if the cleaning, sterilization, and depyrogenization are adequate, and have been validated.o Sterilization

1.Methods

Determine what method of sterilization is used.A good source of reference material on validation of various sterilization processes is the Parenteral Drug Association Technical Reports.For instance, Technical Report #1 covers “Validation of Steam Sterilization Cycles.” Review and evaluate the validation data whatever the method employed.If steam under pressure is used, an essential control is a mercury thermometer and a recording thermometer installed in the exhaust line.The time required to heat the center of the largest container to the desired temperature must be known.Steam must expel all air from the sterilizer chamber to eliminate cold spots.The drain lines should be connected to the sewer by means of an air break to prevent back siphoning.The use of paper layers or liners and other practices which might block the flow of steam should be avoided.Charts of time, temperature, and pressure should be filed for each sterilizer load.If sterile filtration is used, determine the firm's criteria for selecting the filter and the frequency of changing.Review the filter validation data.Determine if the firm knows the bioburden of the drug, and examine their procedures for filter integrity testing.Filters might not be changed after each batch is sterilized.Determine if there is data to justify the integrity of the filters for the time used and that “grow through” has not occurred.If ethylene oxide sterilization is used, determine what tests are made for residues and degradation.Review the ETO sterilization cycle including preconditioning of the product, ETO concentration, gas exposure time, chamber and product temperature, and chamber humidity.2.Indicators

Determine the type of indicator used to assure sterility.Such as, lag thermometers, peak controls, Steam Klox, test cultures, biological indicators, etc.Caution: When spore test strips are used to test the effectiveness of ethylene oxide sterilization, be aware that refrigeration may cause condensation on removal to room temperature.Moisture on the strips converts the spore to the more susceptible vegetative forms of the organism which may affect the reliability of the sterilization test.The spore strips should not be stored where they could be exposed to low levels of ethylene oxide.If biological indicators are used, review the current U.S.P.on sterilization and biological indicators.In some cases, testing biological indicators may become all or part of the sterility testing.Biological indicators are of two forms, each of which incorporates a viable culture of a single species of microorganism.In one form, the culture is added to representative units of the lot to be sterilized or to a simulated product that offers no less resistance to sterilization than the product to be sterilized.The second form is used when the first form is not practical as in the case of solids.In the second form, the culture is added to disks or strips of filter paper, or metal, glass, or plastic beads.During the inspection of a firm which relies on biological indicators, review background data complied by the firm to include:

o Surveys of the types and numbers of organisms in the product before sterilization.o Data on the resistance of the organism to the specific sterilization process.o Data used for selecting the most resistant organism and its form(spore or vegetative cell).o Studies of the stability and resistance of the selected organism to the specific sterilization process.o Studies on the recovery of the organism used to inoculate the product.o If a simulated product or surface similar to the solid product is used, validation of the simulation or similarity.The simulated product or similar surface must not affect the recovery of the numbers of indicator organisms applied.o Validation of the number of organisms used to inoculate the product, simulated product, or similar surface, to include stability of the inoculum during the sterilization process.Since qualified personnel are crucial to the selection and application of these indicators, review their qualifications including experience dealing with the process, expected contaminants, testing of resistance of organisms, and technique.Review the firm's instructions regarding use, control and testing, of the biological indicator by product including a description of the method used to demonstrate presence or absence of viable indicator in or on the product.Review the data used to support the use of the indicator each time it is used.Include the counts of the inoculum used;recovery data to control the method used to demonstrate the sterilization of the indicator organism;counts on unprocessed, inoculated material to

indicate the stability of the inoculum for the process time;and

results of sterility testing specifically designed to demonstrate the presence or absence of the indicator organism for each batch or filling operation.In using indicators, you must assure yourself that the organisms are handled so they don't contaminate the drug manufacturing area and product.3.Filled Containers

Evaluate how the filled vials or ampules leave the filling room.Is the capping or sealing done in the sterile fill area? If not, how is sterility maintained until capped?

Review the tests done on finished vials, ampules, or other containers, to assure proper fill and seal.For instance, leak and torque tests.Review examinations made for particulcte contamination.You can quickly check for suspected particulate matter by using a polariscope.Employees doing visual examinations on line must be properly trained.If particle counts are done by machine, this operation must be validated.4.Personnel Practices

Check how the employees sterilize and operate the equipment used in the filling area.Observe filling room personnel practices.Are the employees properly dressed in sterile gowns, masks, caps, and shoe coverings? Observe and evaluate the gowning procedures, and determine if good aseptic technique is maintained in the dressing and filling rooms.Check on the practices after lunch and other absences.Is fresh sterile garb supplied, or are soiled garments reused?

Determine if the dressing room is next to the filling area and how employees and supplies enter the sterile area.o Laboratory Controls

For guidance on how to inspect micro and chemistry labs, review the “FDA Guide to Inspections of Pharmaceutical Quality Control Laboratories” and “FDA Guide to Inspections of Microbiological Pharmaceutical Quality Control Laboratories.”

1.Retesting for Sterility See the USP for guidance on sterility testing.Sterility retesting is acceptable provided the cause of the initial non-sterility is known, and thereby invalidates the original results.It cannot be assumed that the initial sterility test failure is a false positive.This conclusion must be justified by sufficient documented investigation.Additionally, spotty or low level contamination may not be identified by repeated sampling and testing.Review sterility test failures and determine the incidence, procedures for handling, and final disposition of the batches involved.2.Retesting for Pyrogens

As with sterility, pyrogen retesting can be performed provided it is known that the test system was compromised.It cannot be assumed that the failure is a false positive without documented justification.Review any initial pyrogen test failures and determine the firm's justification for retesting.3.Particulate Matter Testing

Particulate matter consists of extraneous, mobile, undissolved substances, other than gas bubbles, unintentionally present in parenteral solutions.Cleanliness specifications or levels of non-viable particulate contamination must be established.Limits are usually based on the history of the process.The particulate matter test procedure and limits for LVP's in the U.S.P.can be used as a general guideline.However, the levels of particulate contamination in sterile powders are generally greater than in LVP's.LVP solutions are filtered during the filling operation.However, sterile powders, except powders lyophilized in vials, cannot include filtration as a part of the filling operation.Considerable particulate contamination is also present in sterile powders which are spray dried due to charring during the process.Review the particulate matter test procedure and release criteria.Review production and control records of any batches for which complaints of particulate matter have been received.o Production Records

Production records should be similar to those for other dosage forms.Critical steps, such as integrity testing of filters, should be signed and dated by a second responsible person.Review production records to ensure that directions for significant manufacturing steps are included and reflect a complete history of production.Ointments, Liquids, and Lotions

Major factors in the preparation of these drugs are the selection of raw materials, manufacturing practices, equipment, controls, and laboratory testing.Following the basic drug inspection fundamentals, fully evaluate the production procedures.In addition, evaluate specific information regarding:

o The selection and compatibility of ingredients.o Whether the drug is a homogeneous preparation free of extraneous matter.o The possibility of decomposition, separation, or crystallization of ingredients.o The adequacy of ultimate containers to hold and dispense contents.o Procedure for cleaning the containers before filling.o Maintenance of homogeneity during manufacturing and filling operations.The most common problem associated with the production of these dosage forms is microbiological contamination caused by faulty design and/or control of purified water systems.During inspections, evaluate the adequacy of the water system.Review and evaluate the micro/chemistry test results on the routine monitoring of the water system including validation of the water system.Review any microbiological tests done on the finished drug including in-process testing.Some of these drugs have preservatives added which protect them from microbial contamination.The preservatives are used primarily in multiple-dose containers to inhibit the growth of microorganisms introduced inadvertently during or after manufacturing.Evaluate the adequacy of preservative system.Preservative effectiveness testing for these products should be reviewed.For additional information, review the “Antimicrobial Preservatives-Effectiveness” section of the U.S.P..Equipment employed for manufacturing topical drugs is sometimes difficult to clean.This is especially true for those which contain insoluble active ingredients, such as the sulfa drugs.The firm's equipment cleaning procedures including cleaning validation data should be reviewed and evaluated.Packaging and Labeling [21 CFR Subpart G]

Packaging and labeling operations must be controlled so only those drugs which meet the specifications established in the master formula records are distributed.Review in detail the packaging and labeling operations to decide if the system will prevent drug and label mix-ups.Approximately 25% of all drug recalls originate in this area.Evaluate what controls or procedures the firm has to provide positive assurance that all labels are correct.Determine if packaging and labeling operations include:

o Adequate physical separation of labeling and packaging operations from manufacturing process.o Review of:

1.Label copy before delivery to the printer.2.Printer's copy.3.Whether firm's representative inspects the printer.4.Whether or not gang printing is prohibited.5.Whether labels are checked against the master label before released to stock.Determine who is responsible for label review prior to release of the labels to production.Also, whether the labels are identical to the labeling specified in the batch production records.o Separate storage of each label(including package inserts)to avoid mixups.o Inventory of label stocks.Determine if the printer's count is accepted or if labels are counted upon receipt.o Designation of one individual to be responsible for storage and issuance of all labels.o Receipt by the packaging and labeling department of a batch record, or other record, showing the quantity of labels needed for a batch.Determine if the batch record is retained by the packaging supervisor or accompanies the labels to the actual packaging and labeling line.o Adequate controls of the quantities of labeling issued, used, and returned.Determine if excess labels are accounted for and if excess labels bearing specific control codes, and obsolete or changed labels are destroyed.o Inspection of the facilities before labeling to ensure that all previously used labeling and drugs have been removed.o Assurance that batch identification is maintained during packaging.o Control procedures to follow if a significant unexplained discrepancy occurs between quantity of drug packaged and the quantity of labeling issued.o Segregated facilities for labeling one batch of the drug at a time.If this is not practiced, determine what steps are taken to prevent mix-ups.o Methods for checking similar type labels of different drugs or potencies to prevent mixing.o Quarantine of finished packaged products to permit adequate examination or testing of a representative sample to safeguard against errors.Also, to prevent distribution of any batch until all specified tests have been met.o An individual who makes the final decision that the drug should go to the warehouse, or the shipping department.o Utilization of any outside firms, such as contract packers, and what controls are exercised over such operations.Special attention should be devoted to firms using “rolls” of pressure sensitive labels.Investigators have found instances where:

o Paper chips cut from label backing to help running the labels through a coder interfered with the code printer causing digits in the lot number to be blocked out.o Some rolls contained spliced sections resulting in label changes in the roll.o Some labels shifted on the roll when the labels were printed resulting in omitting required information.The use of cut labels can cause a significant problem and should be evaluated in detail.Most firms are replacing their cut labels with roll labels.Review prescription drugs for which full disclosure information may be lacking.If such products are found, submit labels and other labeling as exhibits with the EIR See 21 CFR 201.56 for the recommended sequence in which full disclosure information should be presented.Review labels of OTC products for warnings required by 21 CFR 369.A control code must be used to identify the finished product with a lot, or control number that permits determination of the complete history of the manufacture and control of the batch.Determine:

o The complete key(breakdown)to the code.o Whether the batch number is the same as the control number on the finished package.If not, determine how the finished package control number relates, and how it is used to find the identity of the original batch.Beginning August 3, 1994 the following new requirements will become effective:

o Use of gang-printed labels will be prohibited unless they are adequately differentiated by size, shape or color.(211.122(f))o If cut labels are used one of the following special control procedures shall be used(211.122(g)):

(1)Dedication of packaging lines.(2)Use of electronic or electromechanical equipment to conduct a 100-percent examination of finished product.(3)Use of visual inspection to examine 100-percent of the finished product for hand applied labeling.The visual examination will be conducted by one person and independently verified by a second person.o Labeling reconciliation required by 211.125 is waived for cut or roll labeling if a 100-percent examination is performed according to 211.22(g)(2).Holding and Distribution [21 CFR subpart H]

Check the finished product storage and shipping areas for sanitary condition, stock rotation, and special storage conditions needed for specific drugs.Evaluate any drugs that have been rejected, or are on hold for other than routine reasons.Laboratory Controls [21 CFR Subpart I]

Laboratory controls should include adequate specifications and test procedures to assure that components, in-process and finished products conform to appropriate standards of identity, strength, quality, and purity.In order to permit proper evaluation of the firm's laboratory controls, determine:

o Whether the firm has established a master file of specifications for all raw materials used in drug manufacture.This master file should include sampling procedures, sample size, number of containers to be sampled, manner in which samples will be identified, tests to be performed, and retest dates for components subject to deterioration.o The firm's policies about protocols of assay.These reports are often furnished by raw material suppliers;however, the manufacturer is responsible for verifying the validity of the protocols by periodically performing their own complete testing and routinely conducting identity tests on all raw materials received.o Laboratory procedure for releasing raw materials, finished bulk drugs or packaged drugs from quarantine.Determine who is responsible for this decision.Raw material specifications should include approved suppliers.For NDA or ANDA drugs, the approved suppliers listed in their specifications should be the same as those approved in the NDA or ANDA.o If the laboratory is staffed and equipped to do all raw material, in-process, and finished product testing that is claimed.o Whether drug preparations are tested during processing.If so, determine what type of tests are made and whether a representative sample is obtained from various stages of processing.o Specifications and description of laboratory testing procedures for finished products.o Procedures for checking the identity and strength of all active ingredients including pyrogen and sterility testing, if applicable.o If the laboratory conducts pyrogen tests, safety tests, or bioassays;determine the number of laboratory animals and if they are adequately fed and housed.Determine what care is provided on weekends and holidays.o Sterility testing procedures.Entries should be permanently recorded and show all results, both positive and negative.Examine representative samples being tested and their records.When checking the sterility testing procedures, determine:

1.Physical conditions of testing room.The facility used to conduct sterility testing should be similar to those used for manufacturing products.2.Laboratory procedures for handling sterile sample.3.Use of ultra-violet lights.4.Number of units tested per batch.5.Procedure for identifying test media with specific batches.6.Test media's ability to support growth of organisms.7.Length of incubation period.8.Procedure for diluting products to offset the effects of bacteriostatic agents.o Pyrogen testing procedures

Determine if animals involved in positive pyrogen tests are withdrawn from use for the required period.If the L.A.L.Test is used, review the FDA “Guideline on Validation of the Limulus Amebocyte Lysate Test ***.”

o If any tests are made by outside laboratories, report the names of the laboratories and the tests they perform.Determine what precautions the firm takes to insure that the laboratories' work is bona fide.o Methods used to check the reliability, accuracy, and precision of laboratory test procedures and instrumentation.o How final acceptance or rejection of raw materials, intermediates, and finished products is determined.Review recent rejections and disposition of affected items.o The provisions for complete records of all data concerning laboratory tests performed, including dates and endorsements of individuals performing the tests, and traceability.o For components and finished product, the reserve sample program and procedures should be evaluated.Challenge the system and determine if the samples are maintained and can be retrieved.The storage container must maintain the integrity of the product.o Whether stability tests are performed on:

1.The drug product in the container and closure system in which marketed.2.Solutions prepared as directed in the labeling at the time of dispensing.Determine if expiration dates, based on appropriate stability studies, are placed on labels.o If penicillin and non-penicillin products are manufactured on the same premises, whether non-penicillin products are tested for penicillin contamination.Obtain copies of laboratory records, batch records, and any other documents that show errors or other deficiencies.Control Records [21 CFR Subpart J]

1.Master Production and Control Records [21 CFR 211.186]

The various master production and control records are important because all phases of production and control are governed by them.Master records, if erroneous, may adversely affect the product.These records must be prepared according to the drug CGMPR's outlined in 21 CFR 211.186.These records might not be in one location, but should be readily available for review.2.Batch Production and Control Records [21 CFR 211.188]

The batch production and control records must document each significant step in the manufacture, labeling, packaging, and control of specific batches of drugs.21 CFR 211.188 provides the basic information the batch records must provide.A complete production and control record may consist of several separate records which should be readily available to the investigator.Routinely check the batch record calculations against the master formula record.Give special attention to those products on which there have been complaints.Be alert for transcription errors from the master formula record to the batch record.Be alert for transcription or photocopying errors involving misinterpretation of symbols, abbreviations, and decimal points, etc.It is important that batch production records be specific in terms of equipment(v-blender vs.ribbon blender)and processing times(mixing time and speed).The equipment should have its own unique identification number.The manufacturing process for these products must be standardized, controlled, and validated.3.Distribution [21 CFR 211.196]

Complete distribution records should be maintained per 21 CFR 211.196.Be alert for suspicious shipments of products subject to abuse or which have been targeted for high priority investigation by the agency.These include steroids, counterfeits, diverted drugs(i.e.;physician samples, clinical packs, etc.).Determine and evaluate if the firm checks on the authenticity of orders received.What references are used, e.g.current editions of the AMA Directory, Hays Directory, etc.4.Complaint Files [21 CFR 211.198] CFR 211.198 requires that records of all written and oral complaints be maintained.Although FDA has no authority to require a drug firm, except for prescription drugs, to open its complaint files, attempt to review the firm's files.The complaint files should be readily available for review.Do a follow-up investigation on all applicable consumer complaints in the firm's district factory jacket.Review and evaluate the firm's procedures for handling complaints.Determine if all complaints are handled as complaints and not inappropriately excluded.Review the complaints and determine if they were fully investigated.Evaluate the firm's conclusions of the investigation, and determine if appropriate corrective action was taken.Determine if the product should be recalled, or warrant a comprehensive investigation by FDA

Returned Drug Products [21 CFR Subpart K]

Returned drugs often serve as an indication that products may have decomposed during storage, are being recalled or discontinued.Determine how returned drug items are handled.For example, are they quarantined, destroyed after credit, or returned to storage?

If an abnormally large amount of a specific drug item is on hand, determine why.Check if returned drug items are examined in the laboratory, and who makes the ultimate decision as to the use of the returned drugs.Note: Dumping salvage drugs in the trash is a potentially dangerous practice.Advise management to properly dispose of the drugs to preclude salvage.Drugs should be disposed of in accordance with E.P.A.regulations.

第四篇：FDA檢查指南

美國(guó)FDA關(guān)注的問(wèn)題

1.原料

2.工廠的每日衛(wèi)生檢查

3.HACCP計(jì)劃

4.HACCP計(jì)劃中列明的所有記錄

5.對(duì)出口美國(guó)的途徑、方式、進(jìn)口商的情況也很關(guān)心

6.此外，F(xiàn)DA官員對(duì)培訓(xùn)、加工過(guò)程中的溫度時(shí)間的控制等也表現(xiàn)出了相當(dāng)?shù)年P(guān)注。

FDA HACCP官方驗(yàn)證的內(nèi)容和方法

1.進(jìn)行初次訪談（具備一定資格的官方驗(yàn)證人員要事先了解有關(guān)情況，必要時(shí)進(jìn)行初次訪談。第一次初訪應(yīng)表明你的身份，要確定在檢查期間所涉及的產(chǎn)品，時(shí)間盡可能短。）了解有關(guān)信息，主要包括：

（1）企業(yè)生產(chǎn)加工的食品品種；

（2）當(dāng)天正在加工的產(chǎn)品情況；

（3）HACCP小組成員及培訓(xùn)情況；

（4）被驗(yàn)證企業(yè)制定和實(shí)施食品

HACCP體系、SSOP的情況； 企業(yè)最近一次驗(yàn)證或體系審核情況，特別是存在的問(wèn)題和整改措施。

2.官方驗(yàn)證人員進(jìn)行自己的危害分析

官方驗(yàn)證人員在對(duì)食品生產(chǎn)加工企業(yè)HACCP計(jì)劃驗(yàn)證前本人首先應(yīng)進(jìn)行危害分析，通過(guò)比較，對(duì)企業(yè)危害分析的完整性和準(zhǔn)確性做出判斷

自己的危害分析最好在檢查工廠期間進(jìn)行，檢驗(yàn)檢疫機(jī)構(gòu)的官方驗(yàn)證人員要通過(guò)觀察和交談，盡可能多的收集有關(guān)加工過(guò)程和工廠控制方面的材料。

官方驗(yàn)證人員開(kāi)展危害分析的前提條件：

本人要有食品生產(chǎn)加工及檢驗(yàn)的知識(shí)和工作經(jīng)驗(yàn)；

深入生產(chǎn)實(shí)際，熟悉整個(gè)加工過(guò)程，能主動(dòng)向企業(yè)管理人員和操作人員了解情況。

? 繪制或核查工廠提供的生產(chǎn)工藝流程圖，并對(duì)每一個(gè)工序的描述進(jìn)行核查；

? 觀察生產(chǎn)加工過(guò)程；

? 可以向企業(yè)管理和操作人員了解有關(guān)的一些內(nèi)容；

? 對(duì)生產(chǎn)加工過(guò)程每一工序存在的生物、化學(xué)、物理危害的可能性進(jìn)行分析；

? 了解企業(yè)對(duì)生產(chǎn)加工中可能發(fā)生的危害是否采取了預(yù)防控制措施以控制危害的發(fā)生；

? 官方驗(yàn)證人員進(jìn)行危害分析時(shí)，要特別注意企業(yè)在安全衛(wèi)生方面存在的問(wèn)題。

? 對(duì)生產(chǎn)加工過(guò)程中觀察和了解到的信息資料做出評(píng)價(jià)并將有關(guān)信息記錄于危害分析工作單中。

? 對(duì)在生產(chǎn)加工過(guò)程中觀察了了解過(guò)程中確認(rèn)的危害及控制產(chǎn)生質(zhì)疑時(shí)，應(yīng)該查閱有關(guān)法規(guī)、技術(shù)資料或向有關(guān)專家咨詢。對(duì)食品生產(chǎn)加工中的顯著危害、預(yù)防控制措施和關(guān)鍵控制點(diǎn)做出判斷（可利用判斷樹(shù)進(jìn)行），完成自己的危害分析工作單 3.審查評(píng)價(jià)企業(yè)的危害分析和控制措施

將自己的危害分析與工廠的危害分析進(jìn)行比較。要爭(zhēng)取看到工廠的書(shū)面的危害分析。工廠對(duì)顯著危害的判斷可能與自己不同。并需要討論你的判斷并審查工廠是基于何種情況做出此判斷。在這個(gè)階段，相互交流是關(guān)鍵 ? 比較生產(chǎn)工藝流程圖 ? 比較危害分析

? 危害分析存在差異的原因

4.評(píng)價(jià)企業(yè)的HACCP計(jì)劃

? 當(dāng)檢驗(yàn)檢疫機(jī)構(gòu)的官方驗(yàn)證人員就顯著危害達(dá)成一致后，要評(píng)價(jià)工廠書(shū)面的HACCP計(jì)劃。評(píng)價(jià)期間，檢驗(yàn)檢疫機(jī)構(gòu)的官方驗(yàn)證人員要就關(guān)鍵限值和監(jiān)控程序等是否適當(dāng)做出判斷。

? 制定、重新評(píng)估和修改計(jì)劃的人員必須接受過(guò)HACCP原理應(yīng)用方面的培訓(xùn)，或是通過(guò)修完標(biāo)準(zhǔn)的課程，或者擁有相當(dāng)?shù)膶?shí)踐經(jīng)驗(yàn)。

官方驗(yàn)證人員主要是審查生產(chǎn)加工企業(yè)是否正確的制定和實(shí)施HACCP計(jì)劃

? HACCP計(jì)劃的簽署和發(fā)布實(shí)施必須是企業(yè)的最高負(fù)責(zé)人或更高一級(jí)的職員。

食品生產(chǎn)加工企業(yè)首次制定的HACCP計(jì)劃或計(jì)劃修改或每年審核后都應(yīng)簽署發(fā)布

? HACCP計(jì)劃的簽署和發(fā)布實(shí)施必須是企業(yè)的最高負(fù)責(zé)人或更高一級(jí)的職員。

食品生產(chǎn)加工企業(yè)首次制定的HACCP計(jì)劃或計(jì)劃修改或每年審核后都應(yīng)簽署發(fā)布

對(duì)HACCP計(jì)劃評(píng)價(jià)的技術(shù)要求 分析評(píng)價(jià)時(shí)應(yīng)考慮以下內(nèi)容 : ? 計(jì)劃是否將官方驗(yàn)證企業(yè)危害分析時(shí)確定的關(guān)鍵控制點(diǎn)和顯著危害列入；

? 計(jì)劃是否對(duì)各關(guān)鍵控制點(diǎn)建立了關(guān)鍵限值；

? 計(jì)劃中建立的關(guān)鍵限值是否合理； 計(jì)劃中是否制定了對(duì)關(guān)鍵限值的監(jiān)控程序 ? 分析評(píng)價(jià)時(shí)應(yīng)考慮以下內(nèi)容 : ? 計(jì)劃中的監(jiān)控程序的方式和頻率是否合理；

? 計(jì)劃中對(duì)各關(guān)鍵限值是否建立了糾偏程序；

? 計(jì)劃中所列的糾偏程序是否適用；

? 分析評(píng)價(jià)時(shí)應(yīng)考慮以下內(nèi)容 : ? 計(jì)劃中對(duì)監(jiān)控設(shè)備是否有校準(zhǔn)程序；

? 計(jì)劃中所列的監(jiān)控設(shè)備校準(zhǔn)程序的方法和頻率是否合適；

? 計(jì)劃中是否將用于監(jiān)控、驗(yàn)證的記錄列入； ? 計(jì)劃是否將支持HACCP計(jì)劃的有關(guān)文件列入。對(duì)HACCP計(jì)劃中的危害和關(guān)鍵控制點(diǎn)的審查

? 即使食品生產(chǎn)加工企業(yè)在HACCP計(jì)劃中未將官方驗(yàn)證點(diǎn)人員認(rèn)定的顯著危害和關(guān)鍵控制點(diǎn)列出，但還是應(yīng)按照雙方預(yù)先確定的顯著危害和關(guān)鍵控制點(diǎn)進(jìn)行審查。

? 審查監(jiān)控程序

? 審查記錄

? 審查糾偏措施

? 審查驗(yàn)證程序

5.確定HACCP計(jì)劃是否正確地執(zhí)行

? 檢驗(yàn)檢疫機(jī)構(gòu)的官方驗(yàn)證人員將評(píng)價(jià)工廠HACCP計(jì)劃執(zhí)行的情況。這個(gè)評(píng)價(jià)最好通過(guò)觀察生產(chǎn)線上所發(fā)生的事情來(lái)完成。在一定程度上，這是最初巡查工廠的繼續(xù)。目的是看HACCP計(jì)劃中包含的監(jiān)控程序是否完成和這個(gè)計(jì)劃在執(zhí)行中是否走樣。

? 觀察 ? 詢問(wèn)

? 詢問(wèn)和觀察的目的不僅在于確定生產(chǎn)加工企業(yè)是否正確實(shí)施HACCP計(jì)劃，而且可以向驗(yàn)證人員審查有關(guān)記錄時(shí)提供有價(jià)值的信息。

HACCP計(jì)劃要素的驗(yàn)證 包含以下內(nèi)容： ? 監(jiān)測(cè)監(jiān)控是否按照計(jì)劃規(guī)定進(jìn)行；

? 監(jiān)測(cè)監(jiān)控是否按規(guī)定頻率進(jìn)行；

? 有無(wú)檢測(cè)監(jiān)控設(shè)備；

? 監(jiān)測(cè)監(jiān)控設(shè)備是否處于良好操作狀態(tài)；

? 監(jiān)測(cè)監(jiān)控設(shè)備是否按計(jì)劃規(guī)定校準(zhǔn)；

? 監(jiān)測(cè)監(jiān)控結(jié)果記錄是否及時(shí)準(zhǔn)確。

? 關(guān)鍵限值偏離時(shí)是否采取了糾偏措施。糾偏措施應(yīng)糾正偏離的原因，確保無(wú)不安全食品出售；

? 糾偏措施是否如實(shí)準(zhǔn)確地記錄；

? 其它驗(yàn)證程序，如：是否每周對(duì)成品按規(guī)定進(jìn)行檢測(cè)； 如果需要，還應(yīng)對(duì)企業(yè)的驗(yàn)證程序是否有準(zhǔn)確的記錄進(jìn)行核查 ? 驗(yàn)證人員抽取成品食品送檢驗(yàn)檢疫機(jī)構(gòu)認(rèn)可的實(shí)驗(yàn)室進(jìn)行檢測(cè)，以驗(yàn)證企業(yè)對(duì)HACCP體系實(shí)施的有效性。

6.審查記錄

? 主要評(píng)價(jià)工廠的HACCP記錄，如監(jiān)控記錄、糾偏記錄、驗(yàn)證記錄等。

? 官方驗(yàn)證人員對(duì)HACCP體系驗(yàn)證時(shí)必須審查相關(guān)記錄，記錄審查最好在驗(yàn)證即將結(jié)束時(shí)進(jìn)行，這可使驗(yàn)證人員在生產(chǎn)加工中能親眼目睹記錄形成的過(guò)程。對(duì)記錄的審查意味著對(duì)HACCP審核工作的即將完成。

? 關(guān)鍵限值的監(jiān)控記錄 ? 糾偏行動(dòng)記錄 ? 驗(yàn)證記錄

? HACCP計(jì)劃的支持性文件資料等記錄 ? 監(jiān)控和糾正記錄

? 驗(yàn)證活動(dòng)的相關(guān)記錄

審查記錄的選擇

? 官方驗(yàn)證人員首先必須選擇足夠數(shù)量的監(jiān)控記錄、糾偏活動(dòng)記錄和驗(yàn)證記錄，對(duì)這些記錄按照以下要求做出評(píng)價(jià)：

? 記錄是否完整、準(zhǔn)確；

? 操作是否符合關(guān)鍵限值；

當(dāng)關(guān)鍵限值偏離時(shí)，是否采取了糾偏行動(dòng)

? 檢測(cè)監(jiān)控設(shè)備是否進(jìn)行了校準(zhǔn)并符合HACCP計(jì)劃的要求，是否對(duì)成品食品及其生產(chǎn)加工過(guò)程的中間品進(jìn)行了檢測(cè)；

? 記錄是否按要求的時(shí)間進(jìn)行審核。

? 官方驗(yàn)證人員選擇某一生產(chǎn)日期的全套記錄包括衛(wèi)生監(jiān)控記錄進(jìn)行審查。

? 官方驗(yàn)證人員應(yīng)當(dāng)選擇當(dāng)天正在生產(chǎn)加工食品的記錄進(jìn)行審查，這樣會(huì)使驗(yàn)證人員了解記錄形成的全過(guò)程。

? 審查記錄的選擇方法：

? 確定所選審查記錄的生產(chǎn)天數(shù)及具體日期，可從最后一次審查開(kāi)始算起，也可從HACCP計(jì)劃開(kāi)始執(zhí)行之日算起。

? 將所先生產(chǎn)日的天數(shù)開(kāi)平方根，即得出驗(yàn)證所需審查記錄的生產(chǎn)日天數(shù)，但所選天數(shù)不得少于12天。

? 將所選的天數(shù)分配到生產(chǎn)的各個(gè)月。

? 在同一個(gè)月內(nèi)應(yīng)選取最不良狀況下的生產(chǎn)日期。

在開(kāi)始審查記錄時(shí)，如果遇到重大問(wèn)題，驗(yàn)證人員應(yīng)從發(fā)現(xiàn)問(wèn)題的期間大量選取記錄，一直到確定了問(wèn)題所涉及的范圍及問(wèn)題得到解決時(shí)為止。在審查記錄中要對(duì)出現(xiàn)的問(wèn)題加以分析，從而對(duì)問(wèn)題發(fā)生的偶然性或?qū)龠`法事件做出判斷 ? 監(jiān)控記錄的審查 ? 糾偏記錄的審查

? 驗(yàn)證記錄的審查

? 虛假記錄的審查

? 復(fù)印記錄

7.審查企業(yè)的衛(wèi)生監(jiān)控

? 官方驗(yàn)證人員在審查評(píng)價(jià)被驗(yàn)證食品生產(chǎn)加工企業(yè)的衛(wèi)生標(biāo)準(zhǔn)操作程序（SSOP）時(shí)，主要對(duì)衛(wèi)生監(jiān)控、衛(wèi)生糾正、監(jiān)控和糾正的記錄保持等進(jìn)行核查，核查的內(nèi)容至少包括前面講到的SSOP的八個(gè)方面。

8.違反HACCP的報(bào)告

? 主要對(duì)涉及安全衛(wèi)生和HACCP計(jì)劃方面的問(wèn)題應(yīng)特別注意。

? 美國(guó)FDA海產(chǎn)品HACCP法規(guī)（21CFR 123）等。填寫不符合項(xiàng)的要求

? 屬實(shí)，即實(shí)際觀察到的。不受個(gè)人意見(jiàn)和假設(shè)影響。報(bào)告實(shí)際的結(jié)論，不能報(bào)告未經(jīng)本人證實(shí)的不可靠的結(jié)論。

? 以簡(jiǎn)明和直接的方式書(shū)寫，書(shū)寫應(yīng)使接收表格的人員容易理解。

? 與觀察到的潛在問(wèn)題有顯著關(guān)聯(lián)，潛在問(wèn)題應(yīng)有 理由可能發(fā)生。

? 簡(jiǎn)潔，歸納相似的現(xiàn)象以防累贅，重要的是事項(xiàng)（不符合項(xiàng)）的顯著性而非數(shù)量。對(duì)不是顯著的缺陷，可以以口頭方式建議，不必記入報(bào)告。

? 不要寫入相關(guān)法規(guī)、規(guī)定的內(nèi)容。

? 當(dāng)觀察記錄特別長(zhǎng)的時(shí)候，應(yīng)首先將缺陷或問(wèn)題放在觀察記錄的開(kāi)頭部分。這樣可以直接突出問(wèn)題而不是把它放在長(zhǎng)篇累牘之中。

如何判斷被驗(yàn)證企業(yè)是否合格？

? 驗(yàn)證中要樹(shù)立體系觀念?？幢或?yàn)證企業(yè)是否在體系上存在重大問(wèn)題？

? 是否是嚴(yán)重地違反法規(guī)或安全衛(wèi)生問(wèn)題？

? 驗(yàn)證人員的經(jīng)驗(yàn)非常重要

? 小組討論的結(jié)果

? 為避免誤判、錯(cuò)判，應(yīng)盡可能地多收集證據(jù)，從各個(gè)方面、各個(gè)角度去論證

第五篇：美國(guó)FDA藥品質(zhì)量控制實(shí)驗(yàn)室檢查指南1 9 9 3年

美國(guó)FDA 藥品質(zhì)量控制實(shí)驗(yàn)室

檢查指南 1 9 9 3年 1.導(dǎo)言

藥品質(zhì)量控制實(shí)驗(yàn)室是藥品生產(chǎn)及管理的最重要的職能部門之一。現(xiàn)行藥品生產(chǎn)質(zhì)量管理規(guī)范(21CFR211)中很多篇章均與質(zhì)量控制實(shí)驗(yàn)和產(chǎn)品檢驗(yàn)有關(guān)。類似的概念也適用于原料藥。

本檢查指南增補(bǔ)了—些含在其他機(jī)構(gòu)檢查指南文件中的內(nèi)容。例如要求新藥批準(zhǔn)前進(jìn)行的新藥申請(qǐng)或簡(jiǎn)略的新藥申請(qǐng)檢查的7346·832號(hào)文件中，含有進(jìn)行產(chǎn)品新藥申請(qǐng)或簡(jiǎn)略的新藥申請(qǐng)檢查審計(jì)的—般指導(dǎo)，以衡量是否符合新藥申請(qǐng)和現(xiàn)行藥品生產(chǎn)質(zhì)量管理規(guī)范的要求。這些要求包括對(duì)半成品和成品檢驗(yàn)實(shí)驗(yàn)室的檢查。

2．目的

檢查之前應(yīng)當(dāng)講明該檢查的特別目的。對(duì)實(shí)驗(yàn)室的檢查可以限定在—些特定的方面，也可以圍繞實(shí)驗(yàn)室是否符合現(xiàn)行藥品生產(chǎn)質(zhì)量管理規(guī)范方面進(jìn)行—次綜合評(píng)價(jià)。每個(gè)藥品質(zhì)量控制實(shí)驗(yàn)驗(yàn)室至少第二年要進(jìn)行一次這樣的綜合評(píng)價(jià)，以此作為法定檢查職責(zé)的一部分。

——般來(lái)說(shuō)這些檢查包括：

一—將用于新產(chǎn)品檢驗(yàn)的特殊方法；

—一實(shí)驗(yàn)室是否符合藥品生產(chǎn)質(zhì)量管理規(guī)范的全面評(píng)價(jià)；

——特定的實(shí)驗(yàn)室操作。

3.檢查前的準(zhǔn)備

FDA的檢查指南是建立在組隊(duì)檢查方式基礎(chǔ)上的。我們對(duì)實(shí)驗(yàn)室的檢查也是如此。為了力求獲得相關(guān)—致的檢查結(jié)果，我們希望由—位具有專業(yè)知識(shí)并有實(shí)踐經(jīng)驗(yàn)的實(shí)驗(yàn)室分析專家對(duì)復(fù)雜的、高技術(shù)的、專門的化驗(yàn)設(shè)備、化驗(yàn)程序、數(shù)據(jù)處理及科學(xué)化實(shí)驗(yàn)室操作進(jìn)行評(píng)價(jià)。檢查人員的委派由地區(qū)主管部門確定，然而我們希望，調(diào)查人員、分析人員和其他人員能組成—個(gè)檢查組，并在需要時(shí)為了完成—項(xiàng)有意義的檢查，可建議主管部門增加有關(guān)方面的專家。

參加新藥審批前檢查的小組成員必須閱讀并熟悉7346·832號(hào)文件即審批前檢查或調(diào)查文件的內(nèi)容。檢查前應(yīng)當(dāng)審查新藥申請(qǐng)或簡(jiǎn)略的新藥申請(qǐng)的有關(guān)部分，如果該申請(qǐng)書(shū)不能從別的來(lái)源得到，可對(duì)由公司提供的副本進(jìn)行審查。

如果可能的話，小組成員在檢查之前就應(yīng)當(dāng)集中，以討論檢查方法，明確每位組員的角色，并確定目標(biāo)以完成委派的任務(wù)。檢查前還要確定負(fù)責(zé)起草各報(bào)告，包括準(zhǔn)備FDA483文件的責(zé)任。

藥品評(píng)價(jià)和研究中心(CDER)可能已經(jīng)發(fā)出有關(guān)缺陷信件，列舉出存在的各種問(wèn)題。要求受檢企業(yè)必須在新藥申請(qǐng)或簡(jiǎn)略的新藥申請(qǐng)和補(bǔ)充文件被批準(zhǔn)前予以改正。希望檢查組審查這些已經(jīng)在FDA地區(qū)辦公室歸檔的信件，并向藥廠要求了解這些信件的內(nèi)容。檢查組還要評(píng)價(jià)藥廠對(duì)這些信件的答復(fù)，以確保數(shù)據(jù)的準(zhǔn)確和真實(shí)。即使藥廠沒(méi)有對(duì)這些信件作出答復(fù)，或者認(rèn)為藥廠的答復(fù)不充分，也應(yīng)當(dāng)完成這項(xiàng)檢查工作。

4．檢查方法

A.總則

除了采用對(duì)藥品進(jìn)行現(xiàn)行藥品生產(chǎn)質(zhì)量管理規(guī)范的—般檢查方法之外，對(duì)實(shí)驗(yàn)室的檢查還要采用觀察實(shí)驗(yàn)操作和檢查原始數(shù)據(jù)的方法，以評(píng)價(jià)其符合現(xiàn)行藥品生產(chǎn)質(zhì)量管理規(guī)范的情況，以及實(shí)現(xiàn)申請(qǐng)書(shū)中或者藥品工藝檔案中約定的義務(wù)。對(duì)實(shí)驗(yàn)室進(jìn)行綜合檢查時(shí)，應(yīng)評(píng)價(jià)實(shí)驗(yàn)室操作的各個(gè)方面。

實(shí)驗(yàn)室記錄和實(shí)驗(yàn)記錄本是不可缺少的資料來(lái)源，從這些資料中可以全面了解從業(yè)人員的技術(shù)能力和全部質(zhì)量控制程序。標(biāo)準(zhǔn)操作程序應(yīng)當(dāng)是全面而恰當(dāng)?shù)模瑢?shí)驗(yàn)室的操作應(yīng)當(dāng)與書(shū)面的規(guī)程相—致。規(guī)格標(biāo)準(zhǔn)和分析程序應(yīng)當(dāng)合適，而且也符合申請(qǐng)中記載的內(nèi)容及法定方法的要求。

要評(píng)價(jià)原始實(shí)驗(yàn)數(shù)據(jù)、實(shí)驗(yàn)程序和方法、實(shí)驗(yàn)室設(shè)備，包括設(shè)備的維護(hù)和校正，以及實(shí)驗(yàn)方法的驗(yàn)證數(shù)據(jù)，以確定實(shí)驗(yàn)室操作的總體質(zhì)量和符合現(xiàn)行藥品生產(chǎn)質(zhì)量管理規(guī)范的能力。檢查色譜和光譜圖譜以發(fā)現(xiàn)是否存在雜質(zhì)、是否存在操作失當(dāng)或者有儀器未校正的情況的證據(jù)。

大多數(shù)生產(chǎn)企業(yè)具有對(duì)實(shí)驗(yàn)室不合格檢驗(yàn)結(jié)果進(jìn)行調(diào)查的體系。通常這些調(diào)查結(jié)果記錄在某種實(shí)驗(yàn)記錄本上。要求查看幾批不符合規(guī)格標(biāo)準(zhǔn)產(chǎn)品的測(cè)試結(jié)果。審查幾批被復(fù)檢、報(bào)廢或返工的產(chǎn)品的分析數(shù)據(jù)。對(duì)于某些批次的產(chǎn)品，當(dāng)實(shí)驗(yàn)室結(jié)果表明該產(chǎn)品不能滿足規(guī)格標(biāo)準(zhǔn)而被發(fā)放時(shí)，應(yīng)當(dāng)評(píng)價(jià)該發(fā)放決定并查明由準(zhǔn)決定發(fā)放了這些批次的產(chǎn)品。

B．審批前檢查

有關(guān)產(chǎn)品處方、原料藥的合成、產(chǎn)品規(guī)格標(biāo)準(zhǔn)、產(chǎn)品分析和其他方面的文件在總部審查工藝過(guò)程時(shí)進(jìn)行檢查。然而這些檢查和評(píng)價(jià)依賴那些能真正代表產(chǎn)品的準(zhǔn)確而又真實(shí)的數(shù)據(jù)。

審批前檢查是為了確定藥廠在申請(qǐng)中提供的數(shù)據(jù)是否真實(shí)和準(zhǔn)確，以及申請(qǐng)中所列出的程序是否是實(shí)際上用來(lái)產(chǎn)生這些數(shù)據(jù)的程序。此外，審批前的檢查也是為了進(jìn)—步證實(shí)藥廠(包括質(zhì)量控制實(shí)驗(yàn)室)是否符合現(xiàn)行藥品生產(chǎn)質(zhì)量管理規(guī)范的要求。

藥物申請(qǐng)的分析部分通常只包含化驗(yàn)結(jié)果和用來(lái)獲得這些結(jié)果的方法，并不要求負(fù)責(zé)人提交所有的化驗(yàn)數(shù)據(jù)，因?yàn)檫@樣做會(huì)使提交的資料體積太大，并可導(dǎo)致提供過(guò)多不必要的資料。負(fù)責(zé)人可能有意無(wú)意地選擇并報(bào)告那些能顯示藥物安全有效并能得到批準(zhǔn)的數(shù)據(jù)，而不報(bào)告那些證明該產(chǎn)品不能滿足預(yù)先制定的規(guī)格標(biāo)準(zhǔn)的數(shù)據(jù)。檢查組必須確定這樣做是否存在有效的、科學(xué)的解釋。

企業(yè)總部與生產(chǎn)現(xiàn)場(chǎng)的協(xié)調(diào)一致對(duì)完成藥物申請(qǐng)和藥廠的全面審查是必不可少的。當(dāng)發(fā)現(xiàn)有關(guān)規(guī)格和標(biāo)準(zhǔn)的問(wèn)題時(shí)，有經(jīng)驗(yàn)的凋查人員和分析人員可以同參加審查的化學(xué)家聯(lián)系(由合適的主管人員協(xié)助)。

檢查時(shí)應(yīng)將提交的分析結(jié)果與所生產(chǎn)的其他批次的分析結(jié)果比較。評(píng)價(jià)這些方法并且注意實(shí)際使用的程序或設(shè)備與申請(qǐng)中所列的程序和設(shè)備有無(wú)例外，要進(jìn)—步證實(shí)申請(qǐng)中所列的方法與實(shí)際用的方法是相同的。希望分析人員評(píng)價(jià)對(duì)參檢批次(小試與臨床試驗(yàn)樣品)所檢驗(yàn)

得到的原始實(shí)驗(yàn)數(shù)據(jù)，并將該原始數(shù)據(jù)與申請(qǐng)中的數(shù)據(jù)比較。

5.不合格[不符合規(guī)格標(biāo)準(zhǔn)(Out—of—specification))的實(shí)驗(yàn)室結(jié)果

評(píng)價(jià)公司用來(lái)調(diào)查實(shí)驗(yàn)室檢驗(yàn)結(jié)果不合格的系統(tǒng)。這些調(diào)查對(duì)于決定一種產(chǎn)品是被發(fā)放或是報(bào)廢起著至關(guān)重要的作用，它也是復(fù)檢、重新取樣的基礎(chǔ)。

在最近一次法院的裁決中，法官用術(shù)語(yǔ)“不符合規(guī)格標(biāo)準(zhǔn)(OOS)”的實(shí)驗(yàn)室結(jié)果代替FDA調(diào)查人員和檢驗(yàn)人員更習(xí)慣的術(shù)語(yǔ)“產(chǎn)品不合格”。法官裁定，—項(xiàng)不符合規(guī)格標(biāo)準(zhǔn)結(jié)果如經(jīng)調(diào)查或者經(jīng)outlier檢驗(yàn)(系指一數(shù)據(jù)超出一般偏差，為決定是否可以不采用而做的檢驗(yàn))，發(fā)現(xiàn)是由實(shí)驗(yàn)室誤差所致，或復(fù)檢結(jié)果符合規(guī)定，則并不表示產(chǎn)品不合格。

不符合規(guī)格標(biāo)準(zhǔn)結(jié)果可以分成三類：

一——實(shí)驗(yàn)室誤差；

——一非生產(chǎn)工藝性誤差或者稱為操作者誤差；

———和生產(chǎn)工藝有關(guān)的誤差或者稱為生產(chǎn)工藝誤差；

A．實(shí)驗(yàn)室誤差

實(shí)驗(yàn)室誤差產(chǎn)生于下列情況：化驗(yàn)員未能正確地按分析方法操作；使用不正確的標(biāo)準(zhǔn)和(或)簡(jiǎn)單地算錯(cuò)了數(shù)據(jù)。實(shí)驗(yàn)室誤差必須通過(guò)一項(xiàng)調(diào)查來(lái)確定，以便鑒定不符合規(guī)格標(biāo)準(zhǔn)的原因?！┎环弦?guī)格標(biāo)準(zhǔn)結(jié)果的性質(zhì)被確定了，就可以把它歸入上述三類中的一類。由于調(diào)查的目的不一樣，查詢可能很不相同。

B.實(shí)驗(yàn)室調(diào)查

要確定化驗(yàn)員誤差或差錯(cuò)的確切原因是困難的，同時(shí)希望化驗(yàn)員誤差總能確定和記錄下來(lái)是不現(xiàn)實(shí)的。然而，一項(xiàng)實(shí)驗(yàn)室調(diào)查并不僅限于進(jìn)行復(fù)試，無(wú)法有把握地鑒別誤差原因會(huì)影響復(fù)檢的程序，而不影響對(duì)最初的不符合規(guī)格標(biāo)準(zhǔn)結(jié)果所要求的調(diào)查詢問(wèn)。

藥廠化驗(yàn)員應(yīng)當(dāng)遵循書(shū)面的調(diào)查程序，如同完成分析過(guò)程—樣，核對(duì)每一操作步驟。

我們希望實(shí)驗(yàn)室檢驗(yàn)數(shù)據(jù)能直接記在記錄本上，避免使用紙片或活頁(yè)紙。這些常識(shí)性方法可以增強(qiáng)數(shù)據(jù)的準(zhǔn)確性和完整性。

審查和評(píng)價(jià)實(shí)驗(yàn)室用于進(jìn)行產(chǎn)品不合格調(diào)查的標(biāo)準(zhǔn)操作程序，對(duì)單一和多個(gè)不符合規(guī)格標(biāo)準(zhǔn)結(jié)果的調(diào)查應(yīng)遵循不同的程序。對(duì)單一不符合規(guī)格標(biāo)準(zhǔn)結(jié)果，調(diào)查應(yīng)包括下列步驟，并且這些調(diào)查應(yīng)當(dāng)在該樣品被復(fù)檢之前進(jìn)行：

進(jìn)行檢驗(yàn)的化驗(yàn)員應(yīng)向主管人報(bào)告不符合規(guī)格標(biāo)準(zhǔn)結(jié)果；

化驗(yàn)員和主管人應(yīng)進(jìn)行一次非正式的實(shí)驗(yàn)室調(diào)查。

調(diào)查范圍如下：

(1）討論檢驗(yàn)程序；

(2)討論汁算過(guò)程；

(3)檢查儀器；

(4)審查包含不符合規(guī)格標(biāo)準(zhǔn)結(jié)果的記錄本。

如果對(duì)不合格結(jié)果的凋查不能查明原因，—種可以使最初的不符合規(guī)格標(biāo)準(zhǔn)結(jié)果歸于無(wú)效的變通方法是outliertest。但是使用這種檢驗(yàn)應(yīng)有特別的限制：

(1）公司不能經(jīng)常以此為基礎(chǔ)否定化驗(yàn)結(jié)果；

(2)美國(guó)藥典標(biāo)準(zhǔn)規(guī)定outlier test只用于特定的情況；

(3)該檢驗(yàn)不適用于化學(xué)分析結(jié)果”；

(4)以統(tǒng)計(jì)為基礎(chǔ)的檢驗(yàn)(如含量均勻度和溶出度檢驗(yàn))不能用outliertest。

確定藥廠是否使用outliertest，并評(píng)價(jià)其不符合規(guī)格標(biāo)準(zhǔn)。

確定對(duì)多個(gè)不符合規(guī)格標(biāo)準(zhǔn)結(jié)果是否做了全面的查詢，這種查詢不僅與實(shí)驗(yàn)室工作人員有關(guān)，也涉及到質(zhì)量控制和質(zhì)量保證人員，以便確定誤差是否與生產(chǎn)工藝有關(guān)。

當(dāng)實(shí)驗(yàn)室調(diào)查不能得出結(jié)論(誤差原因不明)時(shí)，該藥廠：

(1)不得進(jìn)行兩次復(fù)檢和根據(jù)三次化驗(yàn)的平均值對(duì)產(chǎn)品進(jìn)行發(fā)放；

(2)不能用。outlinertest做化學(xué)檢驗(yàn)；

(3)不能用重復(fù)取樣的辦法假定取樣或制備過(guò)程誤差；

(4)當(dāng)確認(rèn)可以復(fù)檢時(shí)(見(jiàn)另外的標(biāo)準(zhǔn))，可以取同一樣品中的不同藥片做復(fù)檢。

C．正式調(diào)查

超出廠實(shí)驗(yàn)室范圍的正式調(diào)查，必須依照一個(gè)提綱進(jìn)行，并要特別注意整改措施。

公司應(yīng)當(dāng)：

(1)闡明調(diào)查的理由；

(2)提供可能引起問(wèn)題的生產(chǎn)工藝的各個(gè)步驟；

(3)提出必要的可保留該批藥品，并防止類似問(wèn)題再發(fā)生的整改措施；

(4)列出其他可能受影響的批次和產(chǎn)品，對(duì)這些批次和產(chǎn)品的調(diào)查結(jié)果及各項(xiàng)整改措施，特別是檢查由臨時(shí)工或代用機(jī)器生產(chǎn)的其他批次產(chǎn)品，檢查臨時(shí)加工或操作生產(chǎn)的其他產(chǎn)品；

(5)保存好所有曾參加調(diào)查及批準(zhǔn)使用再檢后返工物料的生產(chǎn)和質(zhì)量控制人員的評(píng)語(yǔ)和簽字。

D．調(diào)查記錄

化驗(yàn)員的差錯(cuò)，如未被發(fā)現(xiàn)的計(jì)算誤差，應(yīng)當(dāng)詳細(xì)說(shuō)明并提供證據(jù)。調(diào)查及取得的結(jié)論要以書(shū)面文件形式保存，文件中應(yīng)列出調(diào)查的每一步。如有評(píng)估、結(jié)論和整改措施的話，應(yīng)當(dāng)保存在調(diào)查報(bào)告里，并存人中心檔案。

E．調(diào)查時(shí)限

全部對(duì)不合格結(jié)果的調(diào)查應(yīng)當(dāng)在問(wèn)題產(chǎn)生起20個(gè)工作日內(nèi)完成，并且要記錄和寫進(jìn)對(duì)不合格結(jié)果的調(diào)查報(bào)告中去：

6．產(chǎn)品不合格

—個(gè)不符合規(guī)格標(biāo)準(zhǔn)實(shí)驗(yàn)室結(jié)果如果被證明為實(shí)驗(yàn)室誤差所致，就可以被認(rèn)定為無(wú)效。然而，由于操作者的差錯(cuò)、設(shè)備(實(shí)驗(yàn)室設(shè)備除外)故障、欠缺的生產(chǎn)工藝(如不恰當(dāng)?shù)幕旌蠒r(shí)間)等引起的與生產(chǎn)工藝無(wú)關(guān)和有關(guān)的誤差，則意味著產(chǎn)品不合格。用上述指南第五部分作指導(dǎo)，檢查調(diào)查結(jié)果，評(píng)估對(duì)產(chǎn)品的發(fā)放、復(fù)檢或返工的決定。

7．復(fù)檢

評(píng)價(jià)公司復(fù)檢的標(biāo)準(zhǔn)操作規(guī)程是否依照了科學(xué)上正確、合適的程序。最近的一次法庭判決所做出的重要裁決提供了一套程序用來(lái)指導(dǎo)復(fù)檢項(xiàng)目。這項(xiàng)地方法院的裁決為評(píng)價(jià)藥品實(shí)驗(yàn)室的某些方面提供了出色的指導(dǎo)，但該裁決尚不能被視為法律、法規(guī)或有約束力的法律判例。法庭認(rèn)為公司應(yīng)具備一套預(yù)先確定的檢驗(yàn)程序，應(yīng)確定檢驗(yàn)終止和產(chǎn)品評(píng)估的時(shí)間，如果結(jié)果不令人滿意，產(chǎn)品將被拒收。

此外，公司應(yīng)根據(jù)該產(chǎn)品一切記錄文件考慮所有復(fù)檢結(jié)果，包括該產(chǎn)品的歷史數(shù)據(jù)、所進(jìn)行的檢驗(yàn)類型、以及生產(chǎn)過(guò)程中檢驗(yàn)的結(jié)果。不能單純因?yàn)樗幤泛烤鶆蚨鹊慕Y(jié)果可以接受，就無(wú)視不合格的含量測(cè)定結(jié)果。

在藥廠得出結(jié)論，認(rèn)為一項(xiàng)無(wú)法解釋的不符合規(guī)格標(biāo)準(zhǔn)結(jié)果無(wú)效或產(chǎn)品不能予以接受之所進(jìn)行的復(fù)檢次數(shù)是個(gè)科學(xué)判斷的問(wèn)題。復(fù)檢的目的是為了剔除不符合規(guī)格標(biāo)準(zhǔn)結(jié)果，但不能無(wú)限制地復(fù)檢。

至于與生產(chǎn)工藝有關(guān)和無(wú)關(guān)的差錯(cuò)，復(fù)檢值得懷疑。因?yàn)樵谶@些情況下，最初的檢驗(yàn)是真實(shí)的，附加檢驗(yàn)本身無(wú)益于產(chǎn)品的質(zhì)量。法庭承認(rèn)某些復(fù)檢可能是在與生產(chǎn)工藝有關(guān)或無(wú)關(guān)的誤差發(fā)現(xiàn)之前進(jìn)行的。盡管如此，以測(cè)定產(chǎn)品是否符合規(guī)格標(biāo)準(zhǔn)與目的的附加復(fù)檢是不能接受的。

例如在為檢測(cè)混料或片劑的差異性而設(shè)計(jì)的含量均勻度檢驗(yàn)中，合格和不合格的檢驗(yàn)結(jié)果在本質(zhì)上并非毫不相關(guān)，經(jīng)過(guò)數(shù)次復(fù)檢而獲得過(guò)的結(jié)果并不排除一種可能性，即這批藥品不均勻。作為調(diào)查的—部分，藥廠應(yīng)參照前幾個(gè)批次的記錄，因?yàn)椴煌沃邢嗨苹蛳嚓P(guān)的不合格結(jié)果也許是由同一原因所致。

法庭認(rèn)為對(duì)不符合規(guī)格標(biāo)準(zhǔn)結(jié)果進(jìn)行的復(fù)檢只有在此種情況下才是適合的，即對(duì)不合格的調(diào)查正在進(jìn)行且該調(diào)查部分地決定廠復(fù)檢是否合適。當(dāng)調(diào)查發(fā)現(xiàn)不符合規(guī)格標(biāo)準(zhǔn)結(jié)果確由化驗(yàn)員誤差所致或?qū)?yàn)員工作的復(fù)查是“無(wú)結(jié)論性的(inconclusive)”情況下，復(fù)檢是合適的。而對(duì)于眾所周知，沒(méi)有爭(zhēng)議的與生產(chǎn)過(guò)程有關(guān)或無(wú)關(guān)的錯(cuò)誤，復(fù)檢是不合適的。

對(duì)于復(fù)檢，法庭規(guī)定：

必須使用原樣品，不得用其他樣品；

可以使用與第一等份式樣同一來(lái)源樣品中的第二等份試樣；

可以使用以前為實(shí)驗(yàn)?zāi)康亩〉耐獋€(gè)樣品中的一部分。

8．再取樣

藥廠不得依賴再取樣來(lái)發(fā)放經(jīng)檢驗(yàn)和復(fù)檢均不合格的產(chǎn)品，除非對(duì)不合格結(jié)果的調(diào)查查出證據(jù)表明原樣品不具有代表性或準(zhǔn)備不當(dāng)。

評(píng)價(jià)每次再取樣活動(dòng)是否遵照廠本指南。

9．平均分析結(jié)果

當(dāng)考察的對(duì)象是全批產(chǎn)品的含量測(cè)定時(shí)，平均法不失為一種合理的、有效的方法。但作為—般性原則，應(yīng)避免使用平均法，因?yàn)槠骄鶖?shù)掩蓋廠每個(gè)測(cè)試結(jié)果的差異性。當(dāng)檢驗(yàn)既得出不符合規(guī)格標(biāo)準(zhǔn)結(jié)果，也有單個(gè)合格的結(jié)果，而平均結(jié)果又合乎規(guī)格標(biāo)準(zhǔn)時(shí)，這種現(xiàn)象特別麻煩，這里，不對(duì)單個(gè)不符合規(guī)格標(biāo)準(zhǔn)結(jié)果進(jìn)行審查和解釋就信任平均數(shù)，極易造成誤導(dǎo)，而且是不能接受的。

含量均勻度和溶出度結(jié)果不允許采用平均法以獲得通過(guò)。

至于含量測(cè)定的微生物濁度分析法和培養(yǎng)皿分析法，美國(guó)藥典優(yōu)先采用平均值，在這種

情況下，將不符合規(guī)格標(biāo)準(zhǔn)結(jié)果包括在平均數(shù)內(nèi)較好，除非outliertest(微生物法含量測(cè)定)表明不符合規(guī)格標(biāo)準(zhǔn)結(jié)果異常。

10．混料的取樣和檢驗(yàn)

實(shí)驗(yàn)室極其重要的一項(xiàng)功能就是檢驗(yàn)混料，在提高發(fā)現(xiàn)劣等產(chǎn)品批次的可能性方面，混料檢驗(yàn)必不可少。不能因偏好于依賴對(duì)成品的檢驗(yàn)而放棄對(duì)混料均勻度的檢驗(yàn)，因?yàn)槌善窓z驗(yàn)有其局限性。

某法庭規(guī)定，因取樣量影響最終混料檢驗(yàn)的結(jié)果，取樣量應(yīng)與制劑取樣量相當(dāng)，其他任何做法只會(huì)混淆混料各部分之間的區(qū)別，從而無(wú)法達(dá)到檢驗(yàn)?zāi)康?。如果樣品的首次取樣量必須大于使用的單位量，則應(yīng)仔細(xì)取出與制劑取樣量相當(dāng)?shù)牡确萦糜跈z驗(yàn)、復(fù)檢及留樣。顯然，最初的大用量樣品在等份被取出前不易另行攪拌或處理，否則會(huì)掩蓋樣品的非均勻性。用作混料均勻度測(cè)試的數(shù)個(gè)樣品，如果采自不同區(qū)域，則相互之間不得混合，除非在以含量測(cè)定為目的而不是為了考察其差異性的情況下，才允許混合。

如果藥廠的樣品不是取自混合器，則應(yīng)通過(guò)驗(yàn)證證明其取樣技術(shù)能反映混料各個(gè)部分和總體的特征。也就是說(shuō)，這些樣品必須能夠代表生產(chǎn)中可能發(fā)生問(wèn)題的位點(diǎn)，如混料中的薄弱點(diǎn)或過(guò)熱點(diǎn)。

11．微生物方面

對(duì)制劑產(chǎn)品微生物學(xué)數(shù)據(jù)的審查最好由微生物學(xué)家(化驗(yàn)員)完成。應(yīng)審查的數(shù)據(jù)包括防腐劑的有效性測(cè)試、生物負(fù)荷數(shù)據(jù)以及特定產(chǎn)品的微生物檢驗(yàn)及其方法。

從細(xì)菌內(nèi)毒素與無(wú)菌性兩方面審查過(guò)濾前和(或)滅菌前產(chǎn)品的生物負(fù)荷狀況。對(duì)于原料藥檢驗(yàn)實(shí)驗(yàn)室，要評(píng)價(jià)其方法驗(yàn)證以及無(wú)菌性和細(xì)菌內(nèi)毒素檢驗(yàn)、環(huán)境監(jiān)測(cè)、濾器及過(guò)濾方法驗(yàn)證的原始數(shù)據(jù)。此外，還要評(píng)價(jià)實(shí)驗(yàn)室檢驗(yàn)及確定生物負(fù)荷量所采用的方法。

參考《微生物學(xué)檢驗(yàn)指南》，以便獲取更多關(guān)于檢查微生物實(shí)驗(yàn)室的資料。

12．取樣

在藥品審批前檢查時(shí)采集樣品。依照CP7346．832第三部分，第五、六頁(yè)上關(guān)于取樣的指導(dǎo)進(jìn)行取樣。

13．實(shí)驗(yàn)室記錄和文件

審查化驗(yàn)員保存的實(shí)驗(yàn)室個(gè)人分析記錄，并將其與工作單及總實(shí)驗(yàn)室記錄比較。為廠準(zhǔn)確與可靠起見(jiàn)，準(zhǔn)備檢查所有記錄與工作單，核實(shí)確已保留下來(lái)的原始數(shù)據(jù)，以便保證從實(shí)驗(yàn)室結(jié)果中得出的結(jié)論。

參照生產(chǎn)日期的順序?qū)彶閷?shí)驗(yàn)室記錄的分析順序。檢驗(yàn)的日期應(yīng)與樣品確實(shí)存在于實(shí)驗(yàn)室的日期相符合。如果使用電腦數(shù)據(jù)庫(kù)，應(yīng)確定改變數(shù)據(jù)的方案，對(duì)數(shù)據(jù)變更應(yīng)建立跟蹤審計(jì)程序。

我們希望原始實(shí)驗(yàn)數(shù)據(jù)能成冊(cè)保存(避免散亂或用零碎紙張記錄)，或以書(shū)本、或以事先編號(hào)可以計(jì)數(shù)的化驗(yàn)單的形式保存。大多數(shù)生產(chǎn)企業(yè)復(fù)印的多套記錄或“原始數(shù)據(jù)”中，不乏未標(biāo)明頁(yè)碼的散紙片。一些公司使用磁盤或磁帶記錄并儲(chǔ)存原始數(shù)據(jù)，只要表述明確(原始數(shù)據(jù)予以標(biāo)明)，且經(jīng)過(guò)驗(yàn)證，這樣的系統(tǒng)是可以接受的。

仔細(xì)檢查并評(píng)價(jià)實(shí)驗(yàn)室工作記錄、工作單和其他記錄，其中包括諸如稱量、稀釋、儀器狀態(tài)、計(jì)算等原始數(shù)據(jù)。注意原始數(shù)據(jù)有無(wú)遺失，記錄是否經(jīng)過(guò)改寫，是否使用廠涂改液來(lái)掩蓋失誤。結(jié)果變更必須有解釋。將被更改過(guò)的數(shù)據(jù)互相參照以證實(shí)其真實(shí)性。未經(jīng)凋查得出科學(xué)的、有效的依據(jù)，不得隨意將不符合規(guī)格標(biāo)準(zhǔn)的實(shí)驗(yàn)室結(jié)果貼上“實(shí)驗(yàn)誤差”的標(biāo)簽，產(chǎn)品不得以此種方式“被檢驗(yàn)合乎要求”。

不得只抄錄檢驗(yàn)結(jié)果而不保留原記錄，也不得有選擇地記錄檢驗(yàn)結(jié)果。例如有調(diào)查發(fā)現(xiàn)藥廠用散頁(yè)紙有選擇地抄錄理想數(shù)據(jù)代替化驗(yàn)單和(或)工作記錄薄的作法，有的吸收度值和計(jì)算數(shù)字竟然寫在臺(tái)歷上。

對(duì)沒(méi)有進(jìn)針顯示的剪切下的圖表、在直接數(shù)據(jù)輸入系統(tǒng)中的對(duì)文件的刪除、未經(jīng)驗(yàn)證就間接輸入的數(shù)據(jù)以及無(wú)視程序特征而改變計(jì)算機(jī)程序的行為應(yīng)仔細(xì)檢查。這些作法應(yīng)引起對(duì)數(shù)據(jù)整體質(zhì)量的懷疑。

藥廠應(yīng)對(duì)遺失的進(jìn)針記錄，尤其是應(yīng)對(duì)從正式的工作單或卷宗內(nèi)遺失連續(xù)的進(jìn)針記錄作出書(shū)面解釋。多次記錄下的進(jìn)針記錄必須保存于連續(xù)的文件內(nèi)，并具有連續(xù)記錄的時(shí)間。

希望看到對(duì)各種文件的刪除作出的書(shū)面的正確解釋。

確定藥廠的檢驗(yàn)程序是否充分，是否能保證藥廠在原輔料的接受、生產(chǎn)過(guò)程、成品和保留的穩(wěn)定性樣品等方面已考慮過(guò)所有有效的實(shí)驗(yàn)數(shù)據(jù)。對(duì)照實(shí)驗(yàn)室工作記錄和文件可能會(huì)發(fā)現(xiàn)某些數(shù)據(jù)被藥廠刪除了，藥廠決定發(fā)放產(chǎn)品而對(duì)表明產(chǎn)品不符合規(guī)格標(biāo)準(zhǔn)的檢驗(yàn)結(jié)果又不能做出任何令人滿意的解釋。對(duì)這種無(wú)視檢驗(yàn)結(jié)果(表明產(chǎn)品不符合規(guī)格標(biāo)準(zhǔn))的行為所作的解釋進(jìn)行評(píng)價(jià)。

14．實(shí)驗(yàn)室標(biāo)準(zhǔn)溶液

確定(實(shí)驗(yàn)室)是否使用了適當(dāng)?shù)臉?biāo)準(zhǔn)品，如在有效期內(nèi)且保存適當(dāng)。檢查是否未確定其穩(wěn)定性就再次使用儲(chǔ)備液。儲(chǔ)備液通常存放于實(shí)驗(yàn)室冰箱內(nèi)。檢查實(shí)驗(yàn)室冰箱內(nèi)的溶液，核對(duì)區(qū)別標(biāo)記是否適當(dāng)。審查制備標(biāo)準(zhǔn)溶液的記錄以確信文件完整而準(zhǔn)確。任何藥廠幾乎都不可能“準(zhǔn)確地、始終如一地稱量到”同樣的微克數(shù)。因此，反映這種水平的標(biāo)準(zhǔn)化或模式的數(shù)據(jù)值得懷疑，應(yīng)予以仔細(xì)調(diào)查。

15．檢驗(yàn)方法的驗(yàn)證

對(duì)檢驗(yàn)方法驗(yàn)證資料的評(píng)價(jià)應(yīng)仔細(xì)考察其完整性、準(zhǔn)確性和可靠性。尤其是當(dāng)有—種法定方法存在，而藥廠卻采用其他方法時(shí)，應(yīng)將兩種方法進(jìn)行比較，并證明所用內(nèi)控方法與正式程序相比，其效果相當(dāng)，甚至更佳。藥廠還應(yīng)證明法定方法是在實(shí)際使用條件下使用的。

有幾種途徑可以驗(yàn)證檢驗(yàn)方法。美國(guó)藥典中的方法被視為已經(jīng)過(guò)驗(yàn)證；被批準(zhǔn)的簡(jiǎn)略的新藥申請(qǐng)方法也視為經(jīng)過(guò)驗(yàn)證。藥廠也可以對(duì)他們的方法進(jìn)行驗(yàn)證研究，但系統(tǒng)適應(yīng)性數(shù)據(jù)本身不足以也不構(gòu)成對(duì)方法的驗(yàn)證。

在審查方法驗(yàn)證數(shù)據(jù)時(shí)，希望復(fù)檢的數(shù)據(jù)具有一致性，受檢溶液的濃度變化應(yīng)能夠得出線性結(jié)果?，F(xiàn)在，許多含量分析和雜質(zhì)檢驗(yàn)都使用高效液相色譜儀，在系統(tǒng)適當(dāng)性檢驗(yàn)中，這些分析的精確性應(yīng)等同于或低于RSD的精度，美國(guó)藥典第22章(1225頁(yè))列舉的分析參數(shù)，標(biāo)題為“法定方法的驗(yàn)證”可以用作確定方法驗(yàn)證中的分析參數(shù)(如準(zhǔn)確性、精密度、線性、可靠性等)的指導(dǎo)。

16.儀器設(shè)備

檢查實(shí)驗(yàn)室設(shè)備的使用、維護(hù)狀況、校正記錄、維修記錄及維護(hù)的標(biāo)準(zhǔn)操作規(guī)程。確認(rèn)是否備有在分析方法中使用的專用設(shè)備，注意其狀況。核實(shí)當(dāng)檢驗(yàn)各批次產(chǎn)品時(shí)，所用儀器確實(shí)存在并處于良好的工作狀態(tài)。確定儀器是否使用正確。

除此之外，如果某儀器參與了臨床試驗(yàn)樣品或小試樣品的分析，則應(yīng)核實(shí)該儀器在所有使用中是否均處于良好的工作狀態(tài)，因?yàn)槿藗儠?huì)懷疑從一臺(tái)失靈的儀器中得出的數(shù)據(jù)。所以，繼續(xù)使用該儀器并據(jù)此發(fā)放產(chǎn)品是對(duì)現(xiàn)行藥品生產(chǎn)質(zhì)量管理規(guī)范的嚴(yán)重違反。

17．原料檢驗(yàn)

有的調(diào)查還包括原料藥生產(chǎn)廠。制劑的安全性與有效性在很大程度上取決于原料藥的純度與質(zhì)量，考查原料藥分析的原始數(shù)據(jù)，其中包括純度檢驗(yàn)、圖表等。核查用于小試和臨床試驗(yàn)樣品的原料藥雜質(zhì)分析結(jié)果，以確定其是否與生產(chǎn)整批產(chǎn)品所用的原料藥結(jié)果相同。確定生產(chǎn)廠家是否有審查原料藥分析證書(shū)的項(xiàng)目規(guī)程，如果有，考查這些檢驗(yàn)結(jié)果。如發(fā)現(xiàn)雜質(zhì)分析結(jié)果與其他檢測(cè)結(jié)果有實(shí)質(zhì)上的區(qū)別，應(yīng)給以報(bào)告。

一些老的法定測(cè)試方法可能測(cè)不出產(chǎn)品的雜質(zhì)含量，而雜質(zhì)含量的分析又是控制生產(chǎn)過(guò)程所不可缺少的。已經(jīng)研究出—些新測(cè)試法可以檢測(cè)這些產(chǎn)品。這些新方法必須經(jīng)驗(yàn)證以確保它們能滿足對(duì)控制和驗(yàn)證原料藥生產(chǎn)過(guò)程進(jìn)行分析的目的。藥品生產(chǎn)企業(yè)必須完全了解生產(chǎn)過(guò)程和最終產(chǎn)品中可能出現(xiàn)的潛在雜質(zhì)。沒(méi)有一種適當(dāng)?shù)?、?jīng)過(guò)驗(yàn)證的方法就無(wú)法評(píng)價(jià)這些雜質(zhì)。

物理檢測(cè)，比如原料的粒徑、膏藥的粘連測(cè)試、注射劑擠壓測(cè)試等對(duì)于保證生產(chǎn)和控制系統(tǒng)的連續(xù)操作，保證產(chǎn)品的質(zhì)量與藥效來(lái)說(shuō)是必不可少的。這些檢測(cè)右的已列入新藥申請(qǐng)文件中，其他的可以通過(guò)藥品生產(chǎn)方案來(lái)建立。對(duì)這些檢測(cè)力法的驗(yàn)證，與對(duì)藥物的化學(xué)特性的檢測(cè)同等重要。

物理性能的檢測(cè)經(jīng)常要求有專門的設(shè)備和方法規(guī)程，這些檢測(cè)在其他實(shí)驗(yàn)室可能不能重復(fù)。因此，有必要進(jìn)行現(xiàn)場(chǎng)評(píng)價(jià)。

18.生產(chǎn)過(guò)程控制及規(guī)格標(biāo)準(zhǔn)

評(píng)價(jià)在生產(chǎn)區(qū)域或?qū)嶒?yàn)室內(nèi)完成的生產(chǎn)過(guò)程檢測(cè)結(jié)果，看其是否符合制定的取樣、檢驗(yàn)方案、分析方法和規(guī)格標(biāo)準(zhǔn)，例如評(píng)價(jià)重量差異、硬度和脆度。這些檢測(cè)可以在壓片或裝膠囊過(guò)程中每15或30分鐘進(jìn)行一次。各項(xiàng)檢測(cè)應(yīng)遵循現(xiàn)行藥品生產(chǎn)質(zhì)量管理規(guī)范的要求。

藥品申請(qǐng)書(shū)中可能包括某些生產(chǎn)過(guò)程檢測(cè)計(jì)劃，其中包括檢測(cè)方法及規(guī)格標(biāo)準(zhǔn)。調(diào)查必須核實(shí)生產(chǎn)過(guò)程中的檢測(cè)已按計(jì)劃進(jìn)行，且檢測(cè)結(jié)果符合規(guī)格標(biāo)準(zhǔn)。對(duì)較長(zhǎng)時(shí)間檢測(cè)的實(shí)驗(yàn)室工作也應(yīng)予以審查。

生產(chǎn)過(guò)程中檢測(cè)所用的方法可能不同于藥品發(fā)放檢測(cè)方法。一般說(shuō)來(lái)，無(wú)論方法異同，生產(chǎn)過(guò)程中檢測(cè)的規(guī)格標(biāo)準(zhǔn)可能更嚴(yán)格些。如某產(chǎn)品發(fā)放的含量檢測(cè)標(biāo)準(zhǔn)90.0％-110.0％，而其生產(chǎn)過(guò)程中的混料規(guī)格標(biāo)準(zhǔn)可能需限制在95.0％-105.0％之間。生產(chǎn)過(guò)程中所做的檢驗(yàn)也可能不同于發(fā)放檢驗(yàn)。例如藥廠可以把崩解測(cè)試作為生產(chǎn)過(guò)程中檢測(cè)，而將溶出測(cè)試作為發(fā)放檢測(cè)。

希望各批次內(nèi)部和基于同一處方或生產(chǎn)工藝的不同批次之間(包括研制批次與樣品批次)的生產(chǎn)過(guò)程中檢測(cè)的結(jié)果具有一致性。如果檢測(cè)結(jié)果之間并無(wú)一致性，希望看到科學(xué)的數(shù)據(jù)對(duì)其中的差異能作出合理的解釋。

19．穩(wěn)定性

必須用一種能顯示穩(wěn)定性的方法來(lái)檢測(cè)產(chǎn)品的樣品，如果沒(méi)有顯示穩(wěn)定性的含量測(cè)定方法，則應(yīng)采用其他方法，如薄層層析，作為一般含量測(cè)定方法的補(bǔ)充。應(yīng)提供證據(jù)表明該方法可以顯示產(chǎn)品的穩(wěn)定性，法定方法也不例外。生產(chǎn)企業(yè)可能會(huì)被要求做產(chǎn)品的加速或強(qiáng)迫分解試驗(yàn)，以表明該項(xiàng)測(cè)試可以顯示產(chǎn)品的穩(wěn)定性。在某些情況下，簡(jiǎn)略的新藥申請(qǐng)的負(fù)責(zé)人可以查找文獻(xiàn)，找到關(guān)于某種特殊方法的背景數(shù)據(jù)。這方面的資料也可從原料藥供應(yīng)商處得到，這樣驗(yàn)證就變得相對(duì)簡(jiǎn)單明了了。在美國(guó)藥典的第1225節(jié)還列出了驗(yàn)證可應(yīng)用的法定方法的典型參數(shù)。

評(píng)價(jià)生產(chǎn)商關(guān)于穩(wěn)定性測(cè)試的驗(yàn)證報(bào)告，同時(shí)還應(yīng)復(fù)審原始實(shí)驗(yàn)數(shù)據(jù)和在不同地方進(jìn)行檢測(cè)所得出的結(jié)果，核實(shí)實(shí)際報(bào)告的數(shù)據(jù)是否與現(xiàn)場(chǎng)記錄的數(shù)據(jù)相符。

評(píng)價(jià)用于審報(bào)文件的原始數(shù)據(jù)，從而了解所用檢測(cè)方法是否能顯示產(chǎn)品的穩(wěn)定性并廠解雜質(zhì)含量。

20．計(jì)算機(jī)實(shí)驗(yàn)數(shù)據(jù)獲取系統(tǒng)

使用計(jì)算機(jī)實(shí)驗(yàn)數(shù)據(jù)獲取系統(tǒng)不是什么新事物，以下幾處現(xiàn)行藥品生產(chǎn)質(zhì)量管理規(guī)范指導(dǎo)文件中均有閘述。

《政策遵循指南〉7132a．07”計(jì)算機(jī)化藥品生產(chǎn):輸入與輸出檢驗(yàn)”；

《政策遵循指南》7132a.03“計(jì)算機(jī)化藥品生產(chǎn):批生產(chǎn)與控制記錄中“人”的識(shí)別；

《政策遵循指南》7132a．11“計(jì)算機(jī)化藥品生產(chǎn):現(xiàn)行藥品生產(chǎn)質(zhì)量管理規(guī)范應(yīng)用硬件和軟件”；

《政策遵循指南≥7132a.12“計(jì)算機(jī)化藥品生產(chǎn)：供應(yīng)商的責(zé)任”；

《政策遵循指南》7132a．15“計(jì)劈：機(jī)化藥品生產(chǎn)：生產(chǎn)控制應(yīng)用程序源碼”；

《藥品生產(chǎn)過(guò)程計(jì)算機(jī)系統(tǒng)檢查指南》。

對(duì)于計(jì)算機(jī)系統(tǒng)和非計(jì)算機(jī)系統(tǒng)來(lái)說(shuō)，很重要的是要限定收集數(shù)據(jù)的范圍、收集程序和證明其準(zhǔn)確性的方法。同樣重要的是審計(jì)數(shù)據(jù)和計(jì)劃以及糾正誤差的程序。評(píng)價(jià)計(jì)算機(jī)化實(shí)驗(yàn)室系統(tǒng)時(shí)，應(yīng)注意的事項(xiàng)包括數(shù)據(jù)收集、處理、數(shù)據(jù)的完整性和可靠性。

只有在數(shù)據(jù)可靠、原始數(shù)據(jù)未遺失及數(shù)據(jù)不能被篡改的情況下，處理過(guò)程才被認(rèn)為是充分的。該計(jì)算機(jī)系統(tǒng)必須確保原始數(shù)據(jù)得到儲(chǔ)存并切實(shí)地處理。

制定規(guī)章，做到只有經(jīng)過(guò)授權(quán)的人才能輸入數(shù)據(jù)；

數(shù)據(jù)條目不得刪除，只能以修正的形式改動(dòng)；

數(shù)據(jù)庫(kù)應(yīng)盡可能具有防篡改功能；

標(biāo)準(zhǔn)操作程序應(yīng)描述確保數(shù)據(jù)有效性的方法。

對(duì)實(shí)驗(yàn)室計(jì)算機(jī)化數(shù)據(jù)獲取系統(tǒng)進(jìn)行驗(yàn)證的一個(gè)基本方面，就是將由基本一分析儀器得到的數(shù)據(jù)與通過(guò)系統(tǒng)電子傳遞和打印機(jī)上顯示的同—數(shù)據(jù)進(jìn)行比較。為保證計(jì)算機(jī)系統(tǒng)得出連貫的、有效的結(jié)果，應(yīng)在足夠長(zhǎng)的時(shí)間內(nèi)進(jìn)行數(shù)據(jù)比較，只有以此為前提，定期進(jìn)行的數(shù)據(jù)比較才是充分的。

21．實(shí)驗(yàn)室管理

對(duì)實(shí)驗(yàn)室的工作和實(shí)驗(yàn)室人員的全面管理及對(duì)分析結(jié)果的評(píng)價(jià)是評(píng)價(jià)質(zhì)控實(shí)驗(yàn)室的重要內(nèi)容。主管人員的職責(zé)范圍、人員的素質(zhì)、化驗(yàn)貝的調(diào)整，以及實(shí)驗(yàn)室的責(zé)任范圍等，都是決定全面管理和工作監(jiān)督質(zhì)量所要考察的重要事項(xiàng)。只有在這些因素單獨(dú)或整體地致使現(xiàn)行藥品生產(chǎn)質(zhì)量管理規(guī)范所要求的工作任務(wù)無(wú)法完成時(shí)，它們才可成為實(shí)驗(yàn)室管理不合格的依據(jù)。

審查實(shí)驗(yàn)室日記，以確定分析順序和生產(chǎn)順序的符合情況。檢查實(shí)驗(yàn)室記錄和日記，以了解有關(guān)職員的技術(shù)水平及實(shí)驗(yàn)室質(zhì)量控制程序的重要信息。

觀察化驗(yàn)員按照申請(qǐng)書(shū)中描述的操作演示，沒(méi)有其他方法能代替親眼觀看操作并注意化驗(yàn)員是否技術(shù)良好。不應(yīng)站在化驗(yàn)員身旁，可以在稍遠(yuǎn)處觀察并評(píng)價(jià)其操作。

有時(shí)候，公司的職員因缺乏足夠的訓(xùn)練或時(shí)間，意識(shí)不到實(shí)驗(yàn)中存在需要進(jìn)一步調(diào)查和解釋的問(wèn)題。他們會(huì)不經(jīng)努力去鑒別無(wú)法解釋的色譜峰就加以接受。他們也許會(huì)接受藥品穩(wěn)定性分析中，隨著時(shí)間的推移含量明顯遞增的檢測(cè)結(jié)果，卻不提出任何明確的疑問(wèn)。同樣，在進(jìn)行高效液相色譜分析時(shí)，當(dāng)系統(tǒng)穩(wěn)定幾小時(shí)后，重復(fù)能力衰減的現(xiàn)象也會(huì)被不加思索地接受。

藥品生產(chǎn)質(zhì)量管理規(guī)范要求有積極的培訓(xùn)計(jì)劃及對(duì)化驗(yàn)員培訓(xùn)的書(shū)面評(píng)價(jià)。

刪除文件的權(quán)力和越過(guò)計(jì)算機(jī)系統(tǒng)的權(quán)力應(yīng)當(dāng)被嚴(yán)格審查。評(píng)估對(duì)計(jì)算程序加以更改的歷史數(shù)據(jù)。有些更改可能要求管理者對(duì)已發(fā)放產(chǎn)品的數(shù)據(jù)進(jìn)行重新審查。

(美國(guó)食品藥物管理局

法規(guī)事務(wù)辦公室

地方業(yè)務(wù)辦公室

現(xiàn)場(chǎng)調(diào)查部)

(朱

艷、朱世斌譯

賴婉楓校)