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近期，F(xiàn)DA發(fā)布了關(guān)于印度泰米爾納德邦的Malladi Drugs & Pharmaceuticals Limited的警告信Warning Letter 320-18-40，于于2017年9月4-8日對其進(jìn)行了檢查，了發(fā)現(xiàn)其API生產(chǎn)存在嚴(yán)重違反CGMP的行為。

檢查缺陷：

1.Failure to use appropriate precautions to minimize the risk of API contamination where open equipment is used. 

使用開放設(shè)備時(shí)未使用適當(dāng)?shù)念A(yù)防措施以降低API污染風(fēng)險(xiǎn)。

Parts of your facility inwhich API production is conducted are open to the outdoors. Our investigator observed vermin, such as birds and insects, in the facility near open equipment used for drug manufacturing. Their presence puts your drugs at risk of contamination.You failed to take adequate precautions to prevent the risk of contamination while producing drugs using open equipment.

你工廠部分API生產(chǎn)區(qū)域?yàn)槁短飙h(huán)境。我們調(diào)查人員在藥品生產(chǎn)所用的開放設(shè)備附近廠區(qū)發(fā)現(xiàn)有害蟲，如鳥和昆蟲。這使得你們的藥品處于污染風(fēng)險(xiǎn)中。你公司未采取足夠的預(yù)防措施來防止在開放設(shè)備中生產(chǎn)藥品時(shí)的污染風(fēng)險(xiǎn)。

You committed to corrective and preventive actions (CAPA), but your response is inadequate because you failed to address the potential risk to product quality and safety.

你們承諾采取CAPA，但你們的回復(fù)是不充分的，因?yàn)槟銈兾唇鉀Q產(chǎn)品質(zhì)量和安全的潛在風(fēng)險(xiǎn)問題。

In response to this letter, provide a risk assessment for all drugs within their re-test date manufactured and distributed within the United States. Include an evaluation of all (b)(4), drug intermediates, and drugs potentially contaminated by vermin.

在回復(fù)此函時(shí)，請?zhí)峤灰环菰诿绹N售且仍在復(fù)驗(yàn)期內(nèi)的所有藥品的風(fēng)險(xiǎn)評估。其中應(yīng)包括對所有XX、藥品中間體和可能受到害蟲污染的藥品的評估。

2.     Failure to have equipment of the appropriate design and suitability for its intended use and cleaning for the manufacture of API. 

設(shè)備未進(jìn)行適當(dāng)設(shè)計(jì)，適合其既定用途和API生產(chǎn)清潔。

You use (b)(4) vessels in the (b)(4) and (b)(4) stages of your production process. In your response, you indicate that(b)(4) water is used for cleaning the (b)(4) vessels. However, your cleaning processes are insufficient. You lack justification that you can prevent contamination from foreign matter and other impurities that may seep from the (b)(4). Further, your equipment is difficult to reproducibly clean.

你們在你們生產(chǎn)工藝的XX和XX步驟中使用了XX罐。在你們的回復(fù)中，你們說XX罐清潔使用的是XX水。但是，你們的清潔程序是不充分的。你們?nèi)狈φ撟C證明你們可以防止從XX滲入的異物和其它雜質(zhì)。還有，你們的設(shè)備的清潔難以重復(fù)。

Your response also states thatthe (b)(4) is kept partially full with water for up to (b)(4) because the (b)(4) when it is fully dry. Using vessels made of (b)(4) and partially filled with standing water may increase the risk of drug contamination. In addition, equipment surfaces should be easily cleanable, and constructed to prevent additive, absorptive, or reactive characteristics.

你們的回復(fù)還說保持XX裝一部分水直至XX，因?yàn)槿绻蓵?huì)XX。使用XX材質(zhì)的罐并且裝一部分靜止水，可能會(huì)增加藥品污染的風(fēng)險(xiǎn)。另外，設(shè)備表面應(yīng)易于清潔，其結(jié)構(gòu)應(yīng)防止?jié)B出、吸收或反應(yīng)特性。

3.     Failure to demonstrate that your manufacturing process can reproducibly manufacture an API meeting its predetermined quality attributes. 

未能證明你們的生產(chǎn)工藝可以重復(fù)生產(chǎn)出符合其預(yù)定質(zhì)量屬性的API。

During our inspection, you acknowledged that you failed to adequately validate your (b)(4) API drug manufacturing process. In addition, our inspection found that your process lacked adequate control during the (b)(4) step. Twenty-four batches yielded out-of-specification test results for an unspecified impurity over approximately two years. Your firm rejected these nonconforming batches and reprocessed some of them.

在我們檢查期間，你們說你們未對你們的XX API藥品生產(chǎn)工藝進(jìn)行足夠的驗(yàn)證。另外，我們的檢查發(fā)現(xiàn)你們的工藝在XX步驟中缺乏足夠的控制。約2年中有24批均有OOS結(jié)果，檢出非特定雜質(zhì)。你們公司拒收了這些不符合批次，有些批次進(jìn)行了返工。

Prior to the manufacture of process qualification batches, a manufacturer should identify all significant sources of variability and develop robust controls throughout the operation.Your process validation program failed to sufficiently address process parameters and other variables in the commercial manufacturing operation to support process reproducibility. It is essential that your process validation program provide substantial information and data to determine if the process can consistently produce acceptable quality products under commercial manufacturing conditions.

在生產(chǎn)工藝確認(rèn)批次之前，生產(chǎn)商應(yīng)找出所有操作中所有波動(dòng)的來源，并建立穩(wěn)健的控制。你們的工藝驗(yàn)證計(jì)劃未能充分說明商業(yè)化生產(chǎn)操作中工藝參數(shù)和其它變量以支持工藝可重復(fù)性。你們的工藝驗(yàn)證計(jì)劃必須提供實(shí)質(zhì)性信息和數(shù)據(jù)來確定工藝是否可在商業(yè)化生產(chǎn)條件下一致地生產(chǎn)出具有可接受質(zhì)量的產(chǎn)品。

In your response, you also acknowledged that your investigations and timeliness of response to the batch failures was inadequate, and that process changes were initiated without formal change management. You also provided data from many batches that met specifications for impurity and identity. However, this data is not are placement for adequate process design, control, CAPA and change management, and does not sufficiently support your claim that your process is robust.

在你們的回復(fù)中，你們承認(rèn)過去你們的調(diào)查和時(shí)間表是不充分的，工藝變更啟動(dòng)沒有正式變更管理。你們還提供了許多雜質(zhì)和鑒別符合質(zhì)量標(biāo)準(zhǔn)的批次數(shù)據(jù)。但是，這些數(shù)據(jù)并不能取代充分的工藝設(shè)計(jì)、控制、CAPA和變更管理，不足以支持你們聲明說你們的工藝是穩(wěn)健的。

Your firm does not have anadequate ongoing program for monitoring process control to ensure stable manufacturing operations and consistent drug quality. See FDA’s guidance document, Process Validation: General Principles and Practices, for general principles and elements of process validation athttp://www.fda.gov/downloads/Drugs/.../Guidances/UCM070336.pdf.

你們公司沒有充分的持續(xù)計(jì)劃監(jiān)測工藝控制以確保穩(wěn)定性生產(chǎn)操作和一致的藥品質(zhì)量。參見FDA工藝驗(yàn)證指南。

轉(zhuǎn)自：Julia法規(guī)翻譯