中文字幕一级黄色A级片|免费特级毛片。性欧美日本|偷拍亚洲欧美1级片|成人黄色中文小说网|A级片视频在线观看|老司机网址在线观看|免费一级无码激情黄所|欧美三级片区精品网站999|日韩av超碰日本青青草成人|一区二区亚洲AV婷婷

• 依據(jù)一個(gè)假定的實(shí)驗(yàn)室錯(cuò)誤判定OOS結(jié)果無(wú)效

• 濫用離群值檢驗(yàn)判定另一個(gè)OOS結(jié)果無(wú)效

• 利用另一份樣品而不是相同樣品的檢驗(yàn)結(jié)果來(lái)判定初始OOS結(jié)果無(wú)效

• OOS根本原因沒(méi)有確鑿證據(jù)予以論證

• 回復(fù)缺陷時(shí)表示玻璃器皿中存在清洗劑殘留會(huì)導(dǎo)致API降解，但是沒(méi)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(wèn)題（數(shù)據(jù)刪除、試驗(yàn)性進(jìn)樣、未激活審計(jì)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(duì)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(yàn)性進(jìn)樣、未激活審計(jì)追蹤等問(wèn)題，但是沒(méi)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(wú)法避免類(lèi)似問(wèn)題再次發(fā)生，檢查發(fā)現(xiàn)幾個(gè)月后仍有數(shù)據(jù)刪除問(wèn)題出現(xiàn)。

• 后來(lái)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(wèn)題，沒(méi)能評(píng)估檢驗(yàn)結(jié)果的有效性。

• 沒(méi)能評(píng)估數(shù)據(jù)完整性違規(guī)的根本原因

• 車(chē)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(shū)面記錄。

• 在線粒子系統(tǒng)審計(jì)追蹤功能沒(méi)有被激活（只關(guān)閉了兩天都能被發(fā)現(xiàn)?。?/span>

• 擅自修改在線粒子數(shù)據(jù)，沒(méi)有寫(xiě)明是誰(shuí)修改和修改了什么

• 無(wú)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(wú)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(duì)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(duì)（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(cè)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(jiǎn)短的調(diào)查都沒(méi)有發(fā)現(xiàn)任何異?，F(xiàn)象，只是說(shuō)樣品玻璃器皿可能沒(méi)有徹底清洗。盡管你們沒(méi)有發(fā)現(xiàn)實(shí)驗(yàn)室錯(cuò)誤，也沒(méi)有科學(xué)論證，你們還是判定OOS結(jié)果無(wú)效。貴公司依據(jù)復(fù)測(cè)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(shí)驗(yàn)室錯(cuò)誤判定初始OOS結(jié)果無(wú)效，結(jié)束調(diào)查并接受復(fù)測(cè)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(shí)際溶液，測(cè)試單元和玻璃器皿以確定是否可能發(fā)生實(shí)驗(yàn)室錯(cuò)誤，是調(diào)查中不可或缺的一部分。如果初步重新檢查沒(méi)有揭示根本原因，這種評(píng)估與假設(shè)檢驗(yàn)相結(jié)合，有助于確定是否存在成為原因的實(shí)驗(yàn)室錯(cuò)誤。任何實(shí)驗(yàn)室調(diào)查缺乏與實(shí)驗(yàn)室錯(cuò)誤的確鑿證據(jù)，都必須將調(diào)查擴(kuò)展到對(duì)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(méi)有執(zhí)行科學(xué)論證或研究來(lái)評(píng)估或證明這個(gè)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(lái)，你們表示你們已證明API可能會(huì)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(duì)XX批次XX原料殘留溶劑檢驗(yàn)XXppm的初始OOS結(jié)果發(fā)起調(diào)查。調(diào)查未查出實(shí)驗(yàn)室異常。你們檢驗(yàn)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(wú)效，并聲明你們的統(tǒng)計(jì)學(xué)分析顯示初始值與復(fù)測(cè)值有顯著差異。你們的調(diào)查未能進(jìn)一步評(píng)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(gè)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(yàn)來(lái)判定API檢驗(yàn)結(jié)果無(wú)效是不恰當(dāng)?shù)摹＿@種統(tǒng)計(jì)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(gè)接近標(biāo)準(zhǔn)上限的復(fù)測(cè)結(jié)果，其實(shí)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?yàn)樗鼪](méi)能充分滿(mǎn)足復(fù)測(cè)原始樣品的要求并規(guī)定何時(shí)應(yīng)該檢驗(yàn)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?yàn)樗环螩GMP。你們的回復(fù)說(shuō)你們還是允許使用離群值檢驗(yàn)來(lái)決定是否“免去適當(dāng)?shù)膶?shí)驗(yàn)室調(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(yàn)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(píng)估先前報(bào)告的OOS結(jié)果對(duì)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(shí)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(duì)使用統(tǒng)計(jì)學(xué)離群值檢驗(yàn)判定OOS結(jié)果無(wú)效的評(píng)估。

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

質(zhì)量部門(mén)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(méi)有充分調(diào)查2015年2月對(duì)分析色譜數(shù)據(jù)不合規(guī)（例如，數(shù)據(jù)刪除，樣品試驗(yàn)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(wèn)題時(shí)，你們沒(méi)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?yàn)槟銈兊募m正措施無(wú)法防止嚴(yán)重?cái)?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(gè)月后進(jìn)行的批放行檢驗(yàn)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(gè)殘留溶劑結(jié)果包含不恰當(dāng)積分，系統(tǒng)適用性測(cè)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?yàn)槟銈儧](méi)有提供足夠的詳細(xì)信息來(lái)證明你們確認(rèn)了初始測(cè)試結(jié)果的有效性。這些細(xì)節(jié)包括復(fù)測(cè)樣品樣檢驗(yàn)日期和結(jié)果，重測(cè)數(shù)據(jù)與原始數(shù)據(jù)的比較，以及評(píng)估中包含的批次的“綜合審查記錄”。你們的回復(fù)還缺乏對(duì)數(shù)據(jù)完整性違規(guī)的根本原因評(píng)估和對(duì)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(wú)菌工藝的問(wèn)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(wú)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(píng)估的一部分。例如，貴公司未能保存記錄無(wú)菌粉末生產(chǎn)車(chē)間A級(jí)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(shū)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(cè)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(cè)系統(tǒng)的電子審計(jì)跟蹤功能是關(guān)閉的，此時(shí)仍有無(wú)菌API在生產(chǎn)。此外，修改了包含粒子計(jì)數(shù)的數(shù)據(jù)文件，但沒(méi)有寫(xiě)明誰(shuí)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(duì)這些缺陷的審查。，貴公司承諾評(píng)估自2015年3月上次FDA檢查以來(lái)其他任何非活性粒子監(jiān)測(cè)記錄不充分對(duì)產(chǎn)品的影響。你們的回復(fù)是不充分，因?yàn)闆](méi)有提供足夠的數(shù)據(jù)來(lái)支持你們的結(jié)論，或承諾更多全面的CAPA評(píng)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(wú)菌生產(chǎn)操作不規(guī)范行為?；貜?fù)此函請(qǐng)?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(guò)程中適當(dāng)?shù)臒o(wú)菌操作和潔凈室行為的計(jì)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(shí)，描述無(wú)菌生產(chǎn)和其他操作過(guò)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(shí)別與無(wú)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(xiǎn)評(píng)估，涵蓋所有人員對(duì)ISO 5區(qū)域（A級(jí)）的干擾，設(shè)備裝配和人體工程學(xué)，ISO 5區(qū)域和周?chē)块g的空氣質(zhì)量，設(shè)施布局，人流和物流。同時(shí)，給出詳細(xì)的CAPA計(jì)劃，包括時(shí)間表，以解決污染危害風(fēng)險(xiǎn)評(píng)估的結(jié)果。