本文轉(zhuǎn)自微信，值得一讀：

2016-03-08 美國FDA新藥和仿制藥注冊

文章來源FDA，由琺成制藥系統(tǒng)工程（上海）有限公司 范宇 翻譯

原創(chuàng)文章，歡迎轉(zhuǎn)帖；尊重原創(chuàng)，從注明出處開始

轉(zhuǎn)帖請注明：GMP驗證及自動化

“FDA-cGMP 問答系列”，該系列選取美國FDA對設(shè)備、設(shè)施、QC等方面的問題和解決方案，并按不同類型分篇章的翻譯。它山之石，可以攻玉，我們希望通過我們的翻譯，讓更多人了解國際通行的cGMP的問題和對策，從而學(xué)習(xí)、反思我們自己平時工作中的不足，提升質(zhì)量管理意識。不積跬步，無以至千里，我們一起努力，為制藥行業(yè)而奮斗吧！

中文翻譯僅供參考，如有異議請以原文為準

1、CGMP要求企業(yè)將設(shè)備狀態(tài)標識與批記錄或者其他文件一起保留嗎？假設(shè)每個設(shè)備對應(yīng)唯一的“清潔使用日記”并恰當保留，那么丟失“快速參考”的設(shè)備標識可以接受嗎？

CGMP條款要求生產(chǎn)商生產(chǎn)藥物成品時，保留非專用設(shè)備的清潔和使用日日志，但并非要求保留作為“快速參考”的和那些臨時的標識。此狀態(tài)標識的例子包括“混批***”，“已清潔，準備用于某天/某月/某年”，“未清潔”。我們認為保留此類標識無任何意義，除了必須的設(shè)備日志或者批記錄文件。該標志是有臨時價值的，那就是肯定的識別設(shè)備的當前情況和物料所在的工藝狀態(tài)。任何標識都應(yīng)是正確的、易讀的、醒目的，并與一部正確的設(shè)備相關(guān)聯(lián)。臨時狀態(tài)標識的信息應(yīng)當與“設(shè)備清潔與使用日志”，或者與上批非專用設(shè)備的記錄一致。

標識僅是一種顯示一部設(shè)備臨時狀態(tài)信息的方式。將設(shè)備臨時狀態(tài)信息在干擦板（白板）或者黑板上也是可行的。并且它適用于FDA調(diào)查員來確認臨時狀態(tài)標識的信息與日志上的一致。

1. Do the CGMPs require a firm to retain the equipment status identification labels with the batch record or other file?  Assuming each major piece of equipment has a unique "Cleaning and Use Log" that is adequately retained, is it acceptable to discard these 'quick reference' equipment labels?

The CGMP regulations for finished pharmaceuticals require the retention of cleaning and use logs for non-dedicated equipment, but no similar requirement exists for retaining what are intended to be "quick reference" or temporary status labels.  Examples of these kinds of status labels include "mixing lot ###"; "clean, ready for use as of d/M/y"; "not clean."  We see no value in the retention of such labels in addition to the required equipment log or batch record documentation.  The labels serve a valuable, temporary purpose of positively identifying the current status of equipment and the material under process.  Any status label should be correct, legible, readily visible, and associated with the correct piece of equipment.  The information on the temporary status label should correspond with the information recorded in the equipment cleaning and use log, or the previous batch record for non-dedicated equipment.

Labels are merely one way to display temporary status information about a piece of equipment.  It is considered acceptable practice to display temporary equipment status information on dry-erase boards or chalkboards.  And it would be appropriate for an FDA investigator to verify that the information on a temporary status label is consistent with the log.

2、 容器、密封件和包裝材料能在倉庫進行接受檢查的取樣嗎？

可以。一般來說，我們認為在標準的藥品生產(chǎn)設(shè)施（一致）倉庫內(nèi)取樣，不會對容器/密封件產(chǎn)生風(fēng)險，或者影響取樣結(jié)果的完整性。但是在倉庫收集樣品第，處理容器時，用“某種設(shè)計阻止容器內(nèi)物品受到污染的方式打開、取樣和密封”是否違反CGMP要求，取決于取樣物料的質(zhì)量屬性和倉庫環(huán)境。對于聲稱是無菌或者無熱源的容器/密封件，取樣條件應(yīng)與物料質(zhì)量需求一致：倉庫環(huán)境不能滿足這種要求（參見 211.94 和 211.113(b)）。如果它們需要檢查微生物污染，這樣做可以保護剩余容器/密封件的適用性和取樣的完整性。在至少，無論任何取樣，都應(yīng)限制取樣時間和樣品移出后（就是擦拭外表面，原包裝打開時限，適當再密封包裝）的暴露時間。關(guān)鍵要素是有規(guī)范的程序并遵守。

要注意的是，CGMP的211.81 條規(guī)定，如果有供應(yīng)商的分析證明和目視鑒定，生產(chǎn)商就可以發(fā)放集裝貨運的容器/密封件。一旦通過驗證供貨商的測試結(jié)果建立了其可靠性，那么生產(chǎn)商就可以在倉庫執(zhí)行全部的目視檢查

2. Can containers, closures, and packaging materials be sampled for receipt examination in the warehouse?

Yes.  Generally, we believe that sampling in a typical drug manufacturing facility warehouse would not represent a risk to the container/closure or affect the integrity of the sample results. But whether the act of collecting a sample in the warehouse violates the CGMPs requirement that containers "be opened, sampled, and sealed in a manner designed to prevent contamination of their contents..." will depend on the purported quality characteristics of the material under sample and the warehouse environment. For container/closures purporting to be sterile or depyrogenated, sampling should be under conditions equivalent to the purported quality of the material: a warehouse environment would not suffice (see 211.94 and 211.113(b)).  This is to preserve the fitness for use of the remaining container/closures as well as ensure sample integrity, if they are to be examined for microbial contamination.  At a minimum, any sampling should be performed in a manner to limit exposure to the environment during and after the time samples are removed (i.e., wiping outside surfaces, limiting time that the original package is open, and properly resealing original package). Well-written and followed procedures are the critical elements.

Note that the CGMPs at 211.84 permit a manufacturer to release for use a shipment of containers/closures based on the supplier's certificate of analysis and a visual identification of the containers/closures.  Once a supplier's reliability has been established by validation of their test results, a manufacturer could perform the visual examination entirely in the warehouse.

3、某企業(yè)培養(yǎng)基灌裝多次失敗。他們的培養(yǎng)基灌裝使用TSB（胰蛋白胨大豆肉湯），打算通過0.2微米的除菌過濾器。調(diào)查沒有顯示任何明顯的原因。污染的來源會是什么？

某公司最近培養(yǎng)基灌裝多次失敗。培養(yǎng)基灌溉運行，模擬生產(chǎn)中灌裝過程，整個過程在隔離器的內(nèi)部進行。公司使用商業(yè)來源的TSB（非無菌原料粉），并通過0.2微米的除菌過濾器。公司進行了調(diào)查，以追查污染源。調(diào)查采用傳統(tǒng)的微生物技術(shù)未能成功地隔離或回收污染微生物，包括使用選擇性（例如，血瓊脂）和非選擇性（例如，TSB和胰酶大豆瓊脂）的培養(yǎng)基，并在顯微鏡下檢查。污染物最終被確定為16S rRNA基因序列的Acholeplasma laidlawii。隨后公司進行的研究證實在很多TSB中會使用Acholeplasma laidlawii。因此，它不是工藝的污染物源，而是培養(yǎng)基的成分。

Acholeplasma laidlawii屬于支原體。支原體只含有細胞膜，無細胞壁。他們不易被β-內(nèi)酰胺類影響，也不易被革蘭氏染色。生物個體是多形性（假設(shè)從球菌形態(tài)到桿狀到細絲狀等不同形態(tài)），大小從0.2到0.3微米或更小。已表明Acholeplasma laidlawii能夠穿透0.2微米的過濾器，但不能穿過0.1微米的過濾器 (see Sundaram, et al.)。已知Acholeplasma laidlawii與動物源性材料有關(guān)，而微生物培養(yǎng)基通常來源于動物。支原體的環(huán)境監(jiān)控需要選擇培養(yǎng)基（肉湯或瓊脂）。

解決方法：

現(xiàn)在，該公司已決定讓培養(yǎng)基灌溉中使用的TSB通過0.1微米的過濾器（注：我們不期望或要求公司經(jīng)常使用0.1微米的過濾器制備培養(yǎng)基）。在未來，當滅菌，輻射可以實現(xiàn)商業(yè)化的時候，公司將使用這些方法處理TSB。（公司的高壓蒸氣滅菌器太小，不足以處理培養(yǎng)基灌溉中使用的TSB，所以這不是一個可行的方法。）公司將繼續(xù)監(jiān)測支原體并重新驗證其潔凈程序以確認是否清除支原體。在這種情況下，公司徹底調(diào)查了導(dǎo)致失敗的原因，并采取適當?shù)募m正措施。

3. A firm has multiple media fill failures. They conducted their media fills using TSB (tryptic soy broth) prepared by filtration through 0.2 micron sterilizing filter. Investigation did not show any obvious causes. What could be the source of contamination?

A firm recently had multiple media fill failures. The media fill runs, simulating the filling process during production, were conducted inside an isolator. The firm used TSB (non-sterile bulk powder) from a commercial source, and prepared the sterile solution by filtering through a 0.2 micron sterilizing filter. An investigation was launched to trace the source of contamination. The investigation was not successful in isolating or recovering the contaminating organism using conventional microbiological techniques, including the use of selective (e.g., blood agar) and nonselective (e.g., TSB and tryptic soy agar) media, and examination under a microscope. The contaminant was eventually identified to beAcholeplasma laidlawii by using 16S rRNA gene sequence. The firm subsequently conducted studies to confirm the presence of Acholeplasma laidlawii in the lot of TSB used. Therefore, it was not a contaminant from the process, but from the media source.

Acholeplasma laidlawii belongs to an order of mycoplasma. Mycoplasma contain only a cell membrane and have no cell wall. They are not susceptible to beta-lactams and do not take up Gram stain. Individual organisms are pleomorphic (assume various shape from cocci to rods to filaments), varying in size from 0.2 to 0.3 microns or smaller. It has been shown that Acholeplasma laidlawii is capable of penetrating a 0.2 micron filter, but is retained by a 0.1 micron filter (see Sundaram, et al.).Acholeplasma laidlawii is known to be associated with animal-derived material, and microbiological media is often from animal sources. Environmental monitoring of mycoplasma requires selective media (PPLO broth or agar).

Resolution:

For now, this firm has decided to filter prepared TSB, for use in media fills, through a 0.1 micron filter (note: we do not expect or require firms to routinely use 0.1 micron filters for media preparation). In the future, the firm will use sterile, irradiated TSB when it becomes available from a commercial supplier. (Firm's autoclave is too small to permit processing of TSB for media fills, so this was not a viable option.) The firm will continue monitoring for mycoplasma and has revalidated their cleaning procedure to verify its removal. In this case, a thorough investigation by the firm led to a determination of the cause of the failure and an appropriate corrective action.

4、有些產(chǎn)品，例如透明貼劑，相比其他產(chǎn)品和工藝，其生產(chǎn)工藝有很高的中間材料廢品率。這樣可以嗎？

也許可以。這取決于廢品率的原因和一致性。與其他的制藥工藝相比，許多透明貼劑的生產(chǎn)工藝會產(chǎn)生更多的廢棄物（理論上說是低產(chǎn)量）。這本身并不是一個問題。浪費產(chǎn)生的原因一般是輥接的積累效應(yīng)，生產(chǎn)線啟動與停機，卷材更換，還有可能較頻繁的過程取樣。工藝上這種情況更多的（高廢棄率）出現(xiàn)在多組分薄層的滾軸壓層時。例如，在滾軸包衣粘合時檢測到卷材的缺陷，只能在整批的最終裝配/壓層時廢棄，這導(dǎo)致了最終工藝的大量浪費。

我們期望，已驗證和控制良好的工藝可以達到批次之間相當一致的廢棄量。若廢棄物超過正常操作水平，可能需要（參見211.192）評估，判定其產(chǎn)生的原因（例如，取樣次數(shù)的增加或者高于正常值的成分缺陷，或者兩者都有）以及對已經(jīng)評估的產(chǎn)品質(zhì)量的影響。我們遇到過小部分異常高的批內(nèi)廢棄/損耗案例，原因在于成分質(zhì)量過度變化和開發(fā)不完善的工藝。

4. Some products, such as transdermal patches, are made using manufacturing processes with higher in-process material reject rates than for other products and processes.  Is this okay?

Maybe.  It depends on the cause and consistency of the reject rate.  Many transdermal patch manufacturing processes produce more waste (i.e., lower yield from theoretical) than other pharmaceutical processes.  This should not of itself be a concern.  The waste is usually due to the cumulative effect of roll splicing, line start-ups and stoppages, roll-stock changes, and perhaps higher rates of in-process sampling.  This is most pronounced for processes involving lamination of rolls of various component layers.  Roll-stock defects detected during adhesive coating of the roll, for example, can often only be rejected from the roll after final fabrication/lamination of the entire patch, which contributes to the final process waste stream.

We expect that validated and well-controlled processes will achieve fairly consistent waste amounts batch-to-batch.  Waste in excess of the normal operating rates may need (see 211.192) to be evaluated to determine cause (e.g., due to increase in sampling or higher than normal component defects... or both) and the consequences on product quality assessed.  We've seen a small number of cases where unusually high intra-batch rejects/losses were due to excessive component quality variability and poorly developed processes.

5、新原料藥或成品藥批準上市之前，CGMPs要求進行三次成功的批次工藝驗證碼？

沒有。CGMP和FDA政策都未指定驗證批次生產(chǎn)工藝的最少值?，F(xiàn)行的API行業(yè)指南（參見針對API的ICH Q7）也沒有指定具體的批次工藝驗證次數(shù)。

FDA認為，一個生產(chǎn)工藝或者工藝變更的驗證，不能簡單的公式化，就依靠三次完整成功的批次。當局承認三批次驗證的理論已經(jīng)流行開來，這在某種程度上是因為其指導(dǎo)文件的語言表述問題。但不管怎樣，F(xiàn)DA現(xiàn)在正在澄清對工藝驗證現(xiàn)行的期望。當前，1987版“工藝驗證一般原則的指導(dǎo)方針” 正在就這個問題進行修訂。對于已驗證的工藝，其重點放在生產(chǎn)商的工藝設(shè)計和開發(fā)研究上，以及展現(xiàn)其大規(guī)模生產(chǎn)的能力，這個目標一直是被期望的。

不管怎樣，沒有規(guī)定生產(chǎn)驗證所需的合格批次的最低數(shù)量。在這一點的選擇上，希望生產(chǎn)商有其可靠的依據(jù)。政府鼓勵使用科學(xué)的方法進行工藝驗證。

2004年3月，F(xiàn)DA修訂“方針遵守指南”（CPG）（490.110 部分）的“待上市批準藥品和原料藥的工藝驗證需求”部分。CPG描述的概念是：在鑒定完成和所有可變性關(guān)鍵源頭之后，生產(chǎn)合規(guī)性批次來證明在正常條件和操作參數(shù)下，工藝能生產(chǎn)出合格的產(chǎn)品。產(chǎn)品上市前,一般要圓滿完成最初的一致性批次驗證，但是，在CPG中也有描述一些例外情況。例如，盡管CPG當局未特別提及供不應(yīng)求的API的同步驗證，但在必要時，如果同步驗證研究符合CPG認同的情況，當局會考慮使用同步驗證，來解決實際的缺貨狀況。（參見4.a-c段落）

CPG概述中的情況包括：為解決缺貨情況，對每批進行的額外檢驗。額外檢驗，若依據(jù)已建立的驗證草案執(zhí)行，則可提供更多的保證，使得API在用于成品藥物之前，批次滿足所有恰當?shù)募榷藴?。此外，可通過增加取樣頻率（批次大規(guī)模代表性取樣）或額外屬性檢驗來獲得對API生產(chǎn)工藝的信任。每批都需要用已驗證的分析方法進行檢驗。即便是早期批次可能已經(jīng)上市流通或者用于藥品成品，當局也希望生產(chǎn)商在多批次完成后，要有一個包含回顧和最終報告的驗證草案。

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

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 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 protocol 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.

6、以無菌工藝生產(chǎn)無菌藥品的生產(chǎn)商在確認設(shè)施時，把ISO 14644-1 和 ISO 14644-2作為唯一的依據(jù)。這種觀念通常可以接受嗎？

不可以。通常不接受這樣的CGMP觀念—“以無菌工藝生產(chǎn)無菌藥品的生產(chǎn)商在確認設(shè)施時，把ISO 14644-1第一部分：空氣潔凈度分析（ISO 14644-1）和 ISO 14644- 2第二部分：證明符合ISO 14644-1的檢測和監(jiān)控規(guī)范（ISO 14644- 2）作為唯一的依據(jù)”。當然，無菌工藝生產(chǎn)商應(yīng)將ISO標準與適當?shù)腇DA條例、指南和其他相關(guān)的參考聯(lián)合起來，確保藥用設(shè)施處在合適的控制下。因此當局希望公司采取適當?shù)拇胧﹣頂U展ISO的建議（例如微生物學(xué)數(shù)據(jù)），以使企業(yè)滿足或超越醫(yī)藥行業(yè)的CGMP。

要注意，ISO 14644-1和 ISO 14644- 2已經(jīng)取代“聯(lián)邦標準209E，潔凈室和潔凈區(qū)空氣懸浮粒子潔凈級別”（FS209E）。在2001年11月，美國聯(lián)邦總署取消FS209E。

然而不是FDA條款或者指南，當局認為ISO 14644-1和 ISO 14644- 2，在促進工業(yè)空氣分級國際協(xié)調(diào)上是有用的，該標準可用于多個行業(yè)（例如，計算機，航天，制藥）中非活性粒子的潔凈度分級。同樣的，F(xiàn)DA在2004年的行業(yè)指南“無菌工藝生產(chǎn)的無菌藥品—CGMP”中采用了這些粒子潔凈度評級。然而，由于無菌工藝生產(chǎn)的無菌藥品其獨特的方面（例如微生物問題），無菌生產(chǎn)商不能僅僅依賴于ISO 14644-1和 ISO 14644- 2進行設(shè)施確認。

6. Is it generally acceptable from a cGMP perspective for a manufacturer of sterile drug products produced by aseptic processing to rely solely on ISO 14644-1 and ISO 14644-2 when qualifying their facility?

No.  It is generally not acceptable from a current good manufacturing practice (“cGMP”) perspective for a manufacturer of sterile drug products produced by aseptic processing to rely solely on ISO 14644-1 Part 1: Classification of Air Cleanliness (“14644-1”) and ISO 14644-2 Part 2: Specifications for Testing and Monitoring to Prove Compliance with ISO 14644-1 (“14644-2”) when qualifying their facility. Rather, a manufacturer of sterile drug products produced by aseptic processing should use these ISO standards in combination with applicable FDA regulations, guidance and other relevant references to ensure a pharmaceutical facility is under an appropriate state of control. Consequently, appropriate measures augmenting ISO’s recommendations (e.g., with microbiological data) would likely be expected for a firm to meet or exceed CGMP in a pharmaceutical facility.

Please understand that 14644-1 and 14644-2 have superseded Federal Standard 209E, Airborne Particulate Cleanliness Classes in Cleanrooms and Clean Zones (“Federal Standard 209E”).  In November 2001, the U.S. General Services Administration canceled Federal Standard 209E.

While not FDA regulations or FDA guidance, the Agency believes 14644-1 and 14644-2 are useful in facilitating the international harmonization of industrial air classification for non-viable particle cleanliness in multiple industries (e.g., computer, aerospace, pharmaceutical).  As such, FDA adopted these particle cleanliness ratings in the 2004 guidance for industry Sterile Drug Products Produced by Aseptic Processing – Current Good Manufacturing Practice.  However, due to the unique aspects of producing sterile drug products by aseptic processing (e.g., microbiological issues) an aseptic processing manufacturer should not rely solely on 14644-1 and 14644-2 when qualifying their facility.