1. Failure to ensure all productiondeviations are reported and evaluated, and that critical deviations areinvestigated and the conclusions are recorded. 未能確保報告及評估所有生產偏差，調查關鍵偏差並記錄其結論。
Your firm failed to follow your written procedures forproduction and to report, evaluate, and investigate deviations from productionprocedures. For example, your (b)(4) batch records specify an in-processassay for (b)(4). You did not perform these in-process assay tests forat least five batches in 2016, but had no explanation for the failure toconduct these tests. Additionally, your (b)(4) batch records specify ayield reconciliation formula to (b)(4). Without any justification, youfailed to use the specified formula for at least three batches in2016.
你公司未能遵守自己的生產偏差報告、評估和調查程序。例如，你們的XX批記錄顯示XX有一個中控含量，但你們在2016年至少有5個批次並沒有執行此中控含量測試，對未執行此測試也沒有解釋。此外，你們的XX批記錄寫明了XX的收率計算公式，但在2016至少有3個批次你們未經論證沒有使用該指定公式。
In your response, you stated that the 「for informationonly」 in-process assay requirement for (b)(4) was 「occasionallyperformed, without any rationale」 because the (b)(4) in-process testprovided similar information and was within specifications for those batches.You also stated that you revised your master production records to remove thein-process assay test requirement: you only require it when (b)(4)values are out of specification. You also admitted that the (b)(4) yieldformula in the master production record was incorrect.
在你們的回覆中，你們說XX的中控含量「僅供參考」，只是「偶爾執行，不需要理由」因為XX中控測試能提供類似的信息，並且這些批准都是在標準以內的。你們還說，你們會修訂你們的主生產記錄，刪除此中控含量測試要求，你們只要求在XX值超出標準時才要求對該項進行測試。你們也承認主生產記錄中的XX收率公式是不正確的。
Your response is inadequate. You did not review allyour production records to determine if other steps were 「occasionallyperformed, without any rationale,」 or if master batch record formulas for anyof your other drugs were incorrect.
你們的回覆是不充分的。你們沒有審核你們所有的生產記錄以確定是否其它步驟是「偶爾執行，沒有任何理由」，或者是否你們其它藥品的主批記錄公式是不正確的。
In your response to this letter, conduct and providethe results of a review of your firm’s production records to identify instancesof production deviations for all drugs distributed in the United States withinexpiry. Conduct a risk analysis to determine the product quality effects of anysuch identified failures, and indicate the specific steps you will take toinvestigate and respond to any critical deviations.
在你們對此函的回覆中，請對你們公司的生產記錄進行審核，識別出所有銷售至美國的藥品生產偏差的情況，並提交結果。進行風險分析以確定所有此類識別出的失敗對產品質量的影響，寫明你們將採取的具體調查措施，以及對關鍵偏差所做出的響應。
2. Failure to adequately documentthe completion of each significant step in the batch production records withsignatures of the persons performing and directly supervising or checking eachcritical step in the operation.未能充分記錄批生產記錄中每個重要步驟的完成情況，連同其執行人員和直接監管或對操作中每個關鍵步驟檢查的人員籤名。
Your batch production records omitted signature fieldsto document who performed, directly supervised, and checked each critical stepin your manufacturing process. For example, the batch production record for (b)(4)batch (b)(4), Section E, Packing Details, indicates a grossweight of (b)(4), a tare weight of (b)(4), and a calculated netweight of (b)(4) for 「Drum No. 4.」 The correct calculated net weightshould be (b)(4). There are no signatures to identify who performed theweighing operation and who subsequently verified it. We also observed that the「done by」 and 「checked by」 fields in many of your other batch productionrecords were completed by the same person. During the inspection, you statedthat it was general practice for supervisors to initial or sign for operators.
你們的批生產記錄裡沒有記錄執行、直接監管和檢查你們生產工藝中每個關鍵步驟的人員籤字的地方。例如，XX批XX產品的批生產記錄，第E部分，包裝詳情，顯示有一個XX的毛重、XX的淨重、第4桶XX的計算淨重。正確的計算淨重應為XX。這裡沒有籤名來識別出是誰執行的稱重操作，又是誰在之後對此進行核查。我們還發現在你們的很多其它批生產記錄中，「操作人」和「覆核人」都是由同一個完成的。在檢查期間，你們聲稱一般都是由主管代替操作人員籤名或首字母籤名。
In your response, you stated that you revised your (b)(4)batch records to include space for operators and verifiers to sign. Youexplained that supervisors were signing for operators because the operators』「hands were dirty」 and your corrective action and preventive action (CAPA) wasto provide operators with gloves. Additionally, you noted that your batchrecords were in English but many of your operators only understand Hindi. Thus,you proposed bilingual English and Hindi batch records to improve operatorunderstanding and compliance.
在你們的回覆中，你們聲稱你們修訂了你們的XX批記錄，在其中放進了操作人員和覆核人員籤名的地方。你們解釋說主管代替操作人員籤名是因為操作人員的「手很髒」，你們的CAPA是為操作人員提供手套。另外，你們提到你們的批記錄是英文，而你們許多操作人員只懂印地語，因此，你們擬採用雙語批記錄來改進操作人員的理解水平和合規性。
Your response is inadequate. Your revision of thebatch record for (b)(4) was insufficient because you did not review allbatch records for all of your drugs to identify any additional critical steps(besides weighing) that may have been inadequately performed, documented, andreviewed or checked. Your CAPA of providing gloves to operators and proposal togenerate bilingual batch records did not directly address the observeddeficiency of supervisors signing records on behalf of operators who performedcritical steps.
你們的回覆是不充分的。你們對XX批記錄的修訂是不足夠的，因為你們並沒有審核所有的藥品批記錄中是否還有其它的關鍵步驟（除了稱重）可能會執行、記錄、審核和檢查不充分。你們的CAPA是提供手套給操作人員，並擬製作雙語批記錄，並未直接解決所發現的主管代替關鍵步驟操作人員籤字的缺陷。
In your response to this letter, provide the resultsof a retrospective investigation of batch records for all of your APIdistributed to the U.S. that are within expiry. Your review should identify anyinstances in which your batch records indicate inadequate performance,documentation, or review of critical steps in the operation, and should includea risk assessment to determine the impact on the quality of your API for anysuch identified instances. Also provide the specific actions you have taken toensure that current and future batch records for all products are adequate andsigned correctly, such as establishing a documented system of regular, periodicquality unit audits of your batch records.
在你們對此函的回覆中，請提交對所有你們銷售至美國仍在有效期的原料藥的批記錄回顧性調查的結果。你們的審核應識別出你們批記錄中所有顯示關鍵操作步驟中表現、文件記錄和審核的情形，應包括一份風險評估來確定此類識別出的情形對你們API質量的影響。還要提交你們為確保當前和未來所有產品批記錄內容充分籤字正確所採取的措施，例如建立一個書面的體系，由質量部門對你們批記錄進行常規定期審計。
3. Failure to adequately investigateand document out-of-specification results and implement appropriate correctiveactions. 未能充分調查和記錄OOS結果並實施適當的糾正措施。
Your firm ignored aberrant analytical test resultsrather than investigating them, determining the root cause, and implementingappropriate corrective actions. You relied on these out-of-specification (OOS)results to assign 「expiration dates」 to your API. For example, our investigatorreviewed your 48-month stability gas chromatography (GC) test results for (b)(4)content in (b)(4) validation batches (b)(4), (b)(4),and (b)(4).
你們公司忽略了異常分析結果，沒有對其進行調查以確定根本原因並實施適當的糾正措施。你們依據這些OOS結果來制訂你們原料藥的「有效期」。例如，我們調查人員審核了你們XX產品驗證3個驗證批次的48個月穩定性XX含量GC檢測結果。
Our investigator observed that all three chromatogramsfor these batches displayed an unknown peak at an earlier retention time thanthe internal standard peak. The unknown peak did not appear in the internalstandard blank run. Prior to our inspection, you did not initiate aninvestigation into this OOS result, nor did your firm determine the root causeor assess the effects of the unknown peak on the quality of your drugs.Instead, you reviewed, approved, and used the stability data for these batchesto determine the 「expiration date」 for your commercial (b)(4) APIbatches.
我們的調查人員發現這些批次的所有3個色譜圖均在保留時間靠右前的地方顯示有未知峰，但並不是內標峰。該未知峰在內標空白中並沒有。在我們調查之前，你們並沒有啟動對此OOS結果的調查，也沒有確定根本原因，或評估此未知峰對你們藥品質量的影響。相反，你們審核、批准、使用了這些批次的這些穩定性數據來確定你們商業批次XX原料藥的「有效期」。
In your response, you stated that you performed aretrospective investigation, and determined that the unknown peak was due to「injector contamination」 of (b)(4) precipitation in the needle of the GCinjector. You concluded that the unknown peaks were isolated, and did notreflect systemic product quality deviations or affect the reported values of (b)(4)or labeled expiration dates. You revised your procedures to require chemists todocument and investigate OOS results, and stated that you would purchase new GCequipment.
在你們的回覆中，你們聲稱你們進行了回顧性調查，確定未知峰是因為GC進樣針中XX沉澱物對「進樣器汙染」所造成的。你們得出結論說未知峰是孤立的情況，不能反映出系統的產品質量偏差，或對XX報告值及所標示有效日期的影響。你們修訂了你們的程序，要求化驗員記錄和調查OOS結果，並聲稱說你們會購買新的GC儀器。
Your response is inadequate. You did not expand thescope of your investigation to determine if other drugs tested on the same GCequipment were affected by similar 「injector contamination」 events. You alsofailed to explain why you neglected to investigate these aberrant test resultsin the first instance, or relied on OOS results to assign 「expiration dates」 toyour API.
你們的回覆是不充分的。你們沒有將你們調查的範圍進行擴展，以確定是否有其它在同一臺GC儀器上的受試藥品受到類似「進樣器汙染」的影響。你們也沒有解釋為什麼你們沒有在第一時間對些異常測試結果進行調查，而是依賴於這些OOS結果來為你們原料藥給定「有效期」。
In your response to this letter, provide yourinvestigation report and risk analysis for all drugs tested on the affected GCequipment since 2015. Indicate the steps you will take for any analytical testresults you identify as having been affected by needle contamination orcarryover. Also provide your revised stability program to indicate how you willensure that your 「expiration dates」 are based only on analytical data thatmeets scientifically valid and appropriate specifications.
在你們的回覆中，請提交你們自2015年以來在這臺受到影響的GC儀器上所檢測的所有藥品的調查報告和風險分析。說明你們對於受到進樣針汙染或殘留影響的所有分析結果要採取的措施。也請提交你們修訂後的穩定性計劃來說明你們要如何確保你們的「有效期」只基於符合科學有效和適當標準的分析數據來制訂。
4. Failure of your quality unit toadequately perform annual product reviews. 你們質量部門未能充分實施年度產品回顧。
We reviewed your annual product reviews (APR) formultiple products and observed a variety of deficiencies. For example, thestability data from your 2016 (b)(4) APR was identical to the dataincluded in your 2015 APR for the same API. Your 2016 (b)(4) APR alsoincluded stability data that could not have been generated at the time pointsprovided in the APR. Your 2016 APR for (b)(4) also included multipleerrors. For example, the mean values for product quality attributes such aswater content, impurities, and optical rotation exceed the maximum values.Product quality tables of numerical minimum values also reported maximum valuesas 「not detected.」 In another instance, mean values were reported for a singlebatch.
我們審核了你們多個產品的年度產品回顧（APR），發現了大量的缺陷。例如，你們2016年XX產品APR的穩定性數據與2015年APR同一原料藥的穩定性數據是相同的。你們的XX產品2016年APR中包括有在APR所提供的時間點不可能生成的數據。你們的2016年XX產品APR裡面還有多個錯誤。例如，產品質量屬性如水份、雜質和旋光的平均值超出了最大值。產品質量表中最小數字值也報告最大值為「未檢出」。另一個地方，平均報告的是一個批號。
Such reporting errors are repeat deviations from FDA’s2013 inspection of this site.
這些報告錯誤是該場所2013年FDA檢查中重複問題。
In your response, you attributed these APR errors topersonnel using the previous year’s APR as a template. You revised yourprocedures to include a blank template. You also stated that 「all the error wastranscription error and review error by all managers of concerned departments.」You indicated that you would avoid such errors in the future by usingenterprise resource planning to compile QMS data online.
在你們的回覆中，你們將這些APR錯誤歸罪於使用之前年度APR作為模板的人員。你們修訂了你們的程序，在其中包括了一個空白模板。你們還聲稱「所有錯誤均是相關部門經理的抄錄錯誤和審核錯誤」。你們說你們在未來通過使用企業資源規劃來匯整QMS在線數據以避免此類錯誤。
Your response is inadequate. You did not explain howyour use of an enterprise resource planning system will prevent APR errors inthe future. Further, you did not perform a retrospective review of all APR toensure that there were no errors that may have compromised or obscured indiciaof drug quality.
你們的回覆是不充分的。你們並未解釋在未來你們使用企業資源規劃系統如何來防止APR錯誤。另外，你們也沒有對所有APR進行回顧性審核，以確保其中沒有錯誤，這些錯誤可能會使得藥品質量受損或標記模糊。
In your response to this letter, conduct a retrospectivereview of all APR for the past three years, and provide a tabular summary ofyour review. Also provide annotated copies of your revised 2015 and 2016 (b)(4)and (b)(4) APR, referencing the underlying data along with copies of therecords containing the underlying data.
在你們對此函的回覆中，請對過去3年所有APR進行回顧性審核，提交一份你們審核的是表格式總結。也請提交你們修訂後的2015年和2016年XX產品和XX產品APR，對基礎數據的引用以及包括基礎數據的記錄的副本。
Repeat deviations at multiple sites多場所重複偏差
FDA cited similar CGMP deviations at other facilitiesin your firm’s network. Specifically, when FDA inspected Vital LaboratoriesPrivate Limited Plant-I (formerly known as Vital Healthcare Private Limited) inVapi, Gujarat, in 2015, it was classified as unacceptable for drugmanufacturing as a result of observations that were similar to those observedduring Plant-II’s inspection. These repeated failures at multiple sitesdemonstrate that your company’s oversight and control over the manufacture ofdrugs is inadequate.
FDA在對你們公司旗下其它場所檢查中發現有類似的CGMP偏差。具體來說，2015年在吉拉特邦一廠區檢查時，該工廠因發現與此次二廠類似偏差而被列為不可接受。多個工廠重複失敗的情況證明你們公司藥品生產的監管和控制是不足夠的。
Your executive management remains responsible forfully resolving all deficiencies and ensuring ongoing CGMP compliance. Youshould immediately and comprehensively assess your company’s globalmanufacturing operations to ensure that systems, processes, and ultimately,manufactured products, conform to FDA requirements.
你們的執行管理人員對於全面解決所有這些缺陷負有義務，應確保持續的CGMP合規性。你們應立即全面評估你們公司的全球生產操作，以確保系統、工藝以及最終生產的產品符合FDA要求。