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• 依據(jù)一個假定的實驗室錯誤判定OOS結(jié)果無效

• 濫用離群值檢驗判定另一個OOS結(jié)果無效

• 利用另一份樣品而不是相同樣品的檢驗結(jié)果來判定初始OOS結(jié)果無效

• OOS根本原因沒有確鑿證據(jù)予以論證

• 回復(fù)缺陷時表示玻璃器皿中存在清洗劑殘留會導(dǎo)致API降解，但是沒有提供數(shù)據(jù)支持。

• 發(fā)現(xiàn)嚴(yán)重的色譜系統(tǒng)數(shù)據(jù)完整性問題（數(shù)據(jù)刪除、試驗性進(jìn)樣、未激活審計追蹤、積分不規(guī)范、系統(tǒng)適應(yīng)性非連續(xù)進(jìn)樣和重復(fù)進(jìn)樣）

• 2015年對色譜系統(tǒng)數(shù)據(jù)完整性進(jìn)行自查，發(fā)現(xiàn)數(shù)據(jù)刪除、試驗性進(jìn)樣、未激活審計追蹤等問題，但是沒有將審查范圍進(jìn)一步擴(kuò)大。數(shù)據(jù)完整性糾正預(yù)防措施也無法避免類似問題再次發(fā)生，檢查發(fā)現(xiàn)幾個月后仍有數(shù)據(jù)刪除問題出現(xiàn)。

• 后來擴(kuò)大數(shù)據(jù)完整性自查范圍發(fā)現(xiàn)積分不規(guī)范、系統(tǒng)適應(yīng)性非連續(xù)進(jìn)樣和重復(fù)進(jìn)樣等問題，沒能評估檢驗結(jié)果的有效性。

• 沒能評估數(shù)據(jù)完整性違規(guī)的根本原因

• 車間清潔消毒記錄存在電子數(shù)據(jù)，這些電子數(shù)據(jù)被覆蓋，只保留了粗略的書面記錄。

• 在線粒子系統(tǒng)審計追蹤功能沒有被激活（只關(guān)閉了兩天都能被發(fā)現(xiàn)！）

• 擅自修改在線粒子數(shù)據(jù)，沒有寫明是誰修改和修改了什么

• 無菌操作不規(guī)范（FDA要求給出QA監(jiān)督的頻率）

該警告信缺陷摘譯如下：

1.      Failure to adequately investigate and document out-of-specification results according to a procedure.

未能根據(jù)規(guī)程充分調(diào)查和記錄OOS結(jié)果。 

Our review of your out-of-specification (OOS) investigations found that you lacked adequate procedures for investigating, and scientific justification to invalidate, OOS results.

我們審核了你們的OOS調(diào)查發(fā)現(xiàn)你們?nèi)狈Τ浞值恼{(diào)查程序和無效OOS的科學(xué)論證。

OOS Results for Assay

含量OOS結(jié)果

You initiated an investigation of an initial OOS assay result for (b)(4) batch (b)(4), which was found to be significantly below specification ((b)(4)–(b)(4)%). You also initiated an investigation of an initial OOS assay result for (b)(4) batch (b)(4), which also yielded a test result below specification ((b)(4)–(b)(4)%).

你們對XX批次XX產(chǎn)品發(fā)起了一份含量嚴(yán)重低于標(biāo)準(zhǔn)的OOS結(jié)果調(diào)查。 你們還發(fā)起對（b）（4）批次（b）（4）產(chǎn)品的初始OOS結(jié)果的調(diào)查，其也產(chǎn)生低于標(biāo)準(zhǔn)（（b）（4） - （b）（4）％）的測試結(jié)果。

In both cases, your brief investigations found no anomalies and only stated that it was possible that the sample glassware was not thoroughly cleaned. Although you did not identify a laboratory error and lacked scientific justification, you invalidated the OOS results. Your firm released both batches based on passing retests.

在這兩種情況下，你們簡短的調(diào)查都沒有發(fā)現(xiàn)任何異?，F(xiàn)象，只是說樣品玻璃器皿可能沒有徹底清洗。盡管你們沒有發(fā)現(xiàn)實驗室錯誤，也沒有科學(xué)論證，你們還是判定OOS結(jié)果無效。貴公司依據(jù)復(fù)測的合格結(jié)果放行了這兩批產(chǎn)品。 

Your acceptance of the passing results based on an assumed laboratory error was insufficient to invalidate the original failing result and conclude the investigation.

你們基于假定的實驗室錯誤判定初始OOS結(jié)果無效，結(jié)束調(diào)查并接受復(fù)測結(jié)果是不充分的。

Re-analysis of the actual solutions, test units, and glassware is an integral part of an investigation to determine whether a laboratory error may have occurred. This assessment, in tandem with hypothesis testing if initial re-examinations do not reveal a root cause, is instrumental in determining whether there was a causative laboratory error. Whenever a laboratory investigation lacks conclusive evidence of laboratory error, it is essential that the investigation extends to a thorough investigation of potential manufacturing causes.

重新分析實際溶液，測試單元和玻璃器皿以確定是否可能發(fā)生實驗室錯誤，是調(diào)查中不可或缺的一部分。如果初步重新檢查沒有揭示根本原因，這種評估與假設(shè)檢驗相結(jié)合，有助于確定是否存在成為原因的實驗室錯誤。任何實驗室調(diào)查缺乏與實驗室錯誤的確鑿證據(jù)，都必須將調(diào)查擴(kuò)展到對潛在生產(chǎn)原因的徹底調(diào)查。

Your response acknowledged that there was “no scientific justification or studies performed to evaluate or prove this hypothetical root cause.”

你們的回復(fù)承認(rèn)“沒有執(zhí)行科學(xué)論證或研究來評估或證明這個假設(shè)的根本原因。”

Since our inspection, your indicated that you have shown that the API may degrade in the presence of residual detergent in glassware. However, your response did not include your study data.

自我們檢查以來，你們表示你們已證明API可能會在玻璃器皿中殘留清洗劑的情況下降解。但是，你們的回復(fù)不包括你們的研究數(shù)據(jù)。

OOS Results for Residual Solvent

殘留溶劑OOS結(jié)果

You initiated investigation P201611001 for an initial OOS result of (b)(4) parts per million (ppm) in your (b)(4)residual solvent test (specification: not more than (b)(4) ppm) for (b)(4) API batch (b)(4). The investigation did not reveal laboratory testing anomalies. You tested another sample preparation three times and obtained results very close to the specification upper limit ((b)(4), and (b)(4) ppm). You invalidated the initial failing result, stating that your statistical analysis showed a significant difference between the original value and the retest results. Your investigation lacked further assessment of the root cause of the failing result.

你們對XX批次XX原料殘留溶劑檢驗XXppm的初始OOS結(jié)果發(fā)起調(diào)查。調(diào)查未查出實驗室異常。你們檢驗了另一份樣品三次并得到非常接近標(biāo)準(zhǔn)上限的結(jié)果。你們判定初始OOS結(jié)果無效，并聲明你們的統(tǒng)計學(xué)分析顯示初始值與復(fù)測值有顯著差異。你們的調(diào)查未能進(jìn)一步評估不合格結(jié)果的根本原因。

You released the batch to use as an intermediate in your in-house production of (b)(4) batches of (b)(4) API (batches (b)(4)).

你們放行了這個批次作為中間體用于XX批XX原料藥的生產(chǎn)。

It is not appropriate to use an “outlier test” to invalidate your API test results. Such statistical treatments do not identify the cause of an extreme observation and are only of informational use. In this case, your investigation included multiple retests that were near the upper limit of (b)(4) ppm, similar to the original OOS result.

使用離群值檢驗來判定API檢驗結(jié)果無效是不恰當(dāng)?shù)?。這種統(tǒng)計學(xué)處理未能確定極端原因，僅供信息使用。在此事例中，你們的調(diào)查包括多個接近標(biāo)準(zhǔn)上限的復(fù)測結(jié)果，其實與初始OOS結(jié)果相似。

Furthermore, your OOS investigation procedure, Q0100012.001, was inadequate because it did not adequately address the need to retest the original sample and specify when a new sample should be tested.

此外，你們的OOS調(diào)查規(guī)程也不充分，因為它沒能充分滿足復(fù)測原始樣品的要求并規(guī)定何時應(yīng)該檢驗新的樣品。 

We acknowledge receipt of your revised OOS investigation procedure. However, your response is inadequate because it does not meet CGMP. Your response stated that you can use an outlier test in determining whether to “waive the requirement for conducting appropriate laboratory investigation to determine definitive or potential root cause(s) for the atypical result(s).” It is inappropriate for your procedure to permit waiver of this requirement. Your OOS procedure should specify that outlier tests cannot be used for anything other than auxiliary, informational purposes.

我們收到了你們修訂后的OOS調(diào)查規(guī)程。但是，你們的回復(fù)是不充分的，因為它不符合CGMP。你們的回復(fù)說你們還是允許使用離群值檢驗來決定是否“免去適當(dāng)?shù)膶嶒炇艺{(diào)查以確定異常結(jié)果的確切或潛在根本原因的要求。”你們的規(guī)程允許免去這些要求是不恰當(dāng)?shù)?。你們的OOS規(guī)程應(yīng)規(guī)定離群值檢驗不能用于輔助，信息目的之外的任何其他方面。

Your response also indicated that your firm was retrospectively assessing effects of previously-reported OOS results on your products. However, your response did not provide related records to document your review or summarize findings. It is unclear whether the retrospective review included an evaluation of your use of the statistical outlier test to invalidate OOS results.

你們的回復(fù)還表明貴公司正在回顧性地評估先前報告的OOS結(jié)果對產(chǎn)品的影響。但是，你們的回復(fù)未提供相關(guān)記錄以證實你們的回顧或總結(jié)結(jié)果。目前尚不清楚該回顧性審查是否包括對使用統(tǒng)計學(xué)離群值檢驗判定OOS結(jié)果無效的評估。

2.      Failure of your quality unit to ensure that critical deviations are investigated and resolved.

質(zhì)量部門未能確保關(guān)鍵偏差得到調(diào)查和解決。

You did not adequately investigate findings from your February 2015 retrospective review of analytical chromatography data irregularities (e.g., data deletion, sample trial injections, and missing audit trails). You did not sufficiently expand the scope of your limited review to a larger data set when you found significant data integrity lapses. Your investigation was also insufficient because your corrective actions failed to prevent recurrence of major data integrity deviations. For example, our investigators found that your firm deleted the initial chromatographic injection of (b)(4) API, batch (b)(4), during batch release testing performed several months after the retrospective investigation.

你們沒有充分調(diào)查2015年2月對分析色譜數(shù)據(jù)不合規(guī)（例如，數(shù)據(jù)刪除，樣品試驗性進(jìn)樣和缺少審核跟蹤）的回顧性審查結(jié)果。當(dāng)你們發(fā)現(xiàn)嚴(yán)重的數(shù)據(jù)完整性問題時，你們沒有將審查范圍充分?jǐn)U大到更大的數(shù)據(jù)集。你們的調(diào)查也不充分，因為你們的糾正措施無法防止嚴(yán)重數(shù)據(jù)完整性偏差再次發(fā)生。例如，我們的調(diào)查人員發(fā)現(xiàn)，在該回顧性審查幾個月后進(jìn)行的批放行檢驗期間，貴公司刪除了（b）（4）批（b）（4）API的初始色譜進(jìn)樣。

Your response stated that you performed a further retrospective review (protocol SD-Q0100011.000) of analytical chromatographic data and found further residual solvents results with inappropriate integration, system suitability testing data showing non-consecutive injections of the reference solution, and repeat injections. Your response was inadequate because you did not include sufficient details to demonstrate that you confirmed the validity of initial test results. Such detail would include retest sample testing dates and results, comparison of retest data to original data, and your “comprehensive review records” for the batches included in the assessment. Your response also lacked an assessment of the root cause of data integrity breaches and corrective actions for any products that failed to meet specifications.

你們的回復(fù)表明你們進(jìn)行了進(jìn)一步的分析色譜數(shù)據(jù)回顧性審查（方案：SD-Q0100011.000），發(fā)現(xiàn)了多個殘留溶劑結(jié)果包含不恰當(dāng)積分，系統(tǒng)適用性測試數(shù)據(jù)顯示標(biāo)準(zhǔn)溶液的非連續(xù)進(jìn)樣和重復(fù)進(jìn)樣。你們的回復(fù)不充分，因為你們沒有提供足夠的詳細(xì)信息來證明你們確認(rèn)了初始測試結(jié)果的有效性。這些細(xì)節(jié)包括復(fù)測樣品樣檢驗日期和結(jié)果，重測數(shù)據(jù)與原始數(shù)據(jù)的比較，以及評估中包含的批次的“綜合審查記錄”。你們的回復(fù)還缺乏對數(shù)據(jù)完整性違規(guī)的根本原因評估和對任何未能符合標(biāo)準(zhǔn)的產(chǎn)品的糾正措施。

Additional Concerns Related to Aseptic Processing

其他關(guān)于無菌工藝的問題

Our investigators found additional examples of incomplete data relating to the sterile manufacturing operations evaluated as part of our pre-approval inspection. For instance, your firm failed to maintain electronic data documenting decontamination cycles for the grade A area of workshop (b)(4) where you aseptically manufacture sterile powders. Your firm overwrote the electronic data and kept only a cursory written record.

我們的調(diào)查人員還發(fā)現(xiàn)了的與無菌生產(chǎn)操作相關(guān)的數(shù)據(jù)不完整的其他事例，這也作為我們的預(yù)批準(zhǔn)檢查評估的一部分。例如，貴公司未能保存記錄無菌粉末生產(chǎn)車間A級區(qū)域的清潔消毒周期的電子數(shù)據(jù)。貴公司覆蓋了電子數(shù)據(jù)，只保留了粗略的書面記錄。

You also did not assure reliability of electronic data for monitoring non-viable particles in your manufacturing areas. Our investigators observed that you disabled the electronic audit trail function for your non-viable particle monitoring system for grade A and B areas of workshops (b)(4) and (b)(4) on at least two days in August 2017 when sterile API was manufactured. Also, data files containing particle counts had been modified with no indication of who made the changes or what was modified.

你們還未能確保用于監(jiān)測生產(chǎn)區(qū)域在線粒子的電子數(shù)據(jù)的可靠性。我們的調(diào)查人員發(fā)現(xiàn)， 2017年8月至少有兩天你們的（b）（4）和（b）（4）區(qū)域在線粒子監(jiān)測系統(tǒng)的電子審計跟蹤功能是關(guān)閉的，此時仍有無菌API在生產(chǎn)。此外，修改了包含粒子計數(shù)的數(shù)據(jù)文件，但沒有寫明誰進(jìn)行了修改和修改了什么。

In your response, you provided a review of these findings. Your firm committed to assess the effects on your products of any additional insufficient non-viable particulate monitoring records since the last FDA inspection in March 2015. Your response was inadequate because you did not provide sufficient data to support your conclusions, or commit to a more comprehensive CAPA to assess data systems integrity.

在你們的回復(fù)中，你們提供了對這些缺陷的審查。，貴公司承諾評估自2015年3月上次FDA檢查以來其他任何非活性粒子監(jiān)測記錄不充分對產(chǎn)品的影響。你們的回復(fù)是不充分，因為沒有提供足夠的數(shù)據(jù)來支持你們的結(jié)論，或承諾更多全面的CAPA評估數(shù)據(jù)系統(tǒng)的完整性。

Our inspection also revealed poor aseptic processing operation behaviors. In response to this letter, provide:

我們的檢查還發(fā)現(xiàn)了無菌生產(chǎn)操作不規(guī)范行為?；貜?fù)此函請?zhí)峁?/span>

Your plan to assure appropriate aseptic practices and cleanroom behavior during production. Include specific steps to ensure routine supervisory oversight for all production batches. Also describe the frequency of quality assurance oversight during aseptic processing and other operations.

你們確保在生產(chǎn)過程中適當(dāng)?shù)臒o菌操作和潔凈室行為的計劃。包括確保所有生產(chǎn)批次的日常監(jiān)督監(jiān)管的具體步驟。同時，描述無菌生產(chǎn)和其他操作過程中QA監(jiān)督的頻率。

Comprehensive identification of all contamination hazards with respect to your aseptic processes, equipment, and facilities. Provide a risk assessment that covers all human interactions with the ISO 5 area, equipment placement and ergonomics, air quality in the ISO 5 area and surrounding room, facility layout, personnel flow, and material flow. Also include a detailed CAPA plan, with timelines, to address the findings of the contamination hazards risk assessment. 

全面識別與無菌工藝，設(shè)備和設(shè)施相關(guān)的所有污染危害。提供風(fēng)險評估，涵蓋所有人員對ISO 5區(qū)域（A級）的干擾，設(shè)備裝配和人體工程學(xué)，ISO 5區(qū)域和周圍房間的空氣質(zhì)量，設(shè)施布局，人流和物流。同時，給出詳細(xì)的CAPA計劃，包括時間表，以解決污染危害風(fēng)險評估的結(jié)果。