FDA警告信：印度 Apotex Research Private Limited

最新 08-20

Warning Letter320-18-69August 9, 2018

Dr. Ravinder Kumar,Managing Director

Apotex Research Private Limited

Plot 1 & 2, Bommasandra Industrial Area,4thPhase, Jigani Link Road,Bangalore—560 099,Karnataka,India

Dear Dr. Kumar:

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Apotex Research Private Limited at Plot 1 & 2,Bommasandra Industrial Area, 4thPhase, Jigani Link Road, Bangalore, from November 6 to 17, 2017.

美國FDA於2017年11月6-17日檢查了你們位於印度班加洛爾的ApotexResearch Private Limited生產場所。

This warning letter summarizes significant violations of current good manufacturing practice (CGMP) regulations for finished pharmaceuticals. See 21 CFR, parts 210 and 211.

本警告信總結了製劑生產嚴重違反CGMP的行為。參見21CFR第210和211部分。

Because your methods, facilities, or controls for manufacturing, processing, packing, or holding do not conform to CGMP, your drug products are adulterated within the meaning of section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), 21 U.S.C. 351(a)(2)(B).

由於你們的原料葯生產、加工、包裝或保存的方法、場所或控制不符合CGMP要求，你們的原料葯根據FDCA的501(a)(2)(B)以及21U.S.C. 351(a)(2)(B)被認為是摻假藥品。

We reviewed your December 11, 2017, response in detail and acknowledge receipt of your subsequent correspondence.

我們已詳細審核了你公司2017年12月11日的回復，並此告知已收悉後續函件。

During our inspection, our investigators observed specific violations including, but not limited to, the following.

檢查期間，我們的調查人員發現的具體問題包括但不僅限於以下：

1. Your firm failed to thoroughly investigate any unexplained discrepancy or failure of a batch or anyof its components to meet any of its specifications, whether or not the batch has already been distributed (21 CFR 211.192).你公司未能徹底調查所有放行或未放行銷售批次或其組分無法解釋的不一致情況，或不符合其質量標準的情況。(21CFR 211.192)

Your investigations into out-of-specification (OOS) laboratory results and manufacturing deviations are insufficient and do not include scientifically-supported conclusions. For example:

你們對化驗室OOS結果和生產偏差的調查是不充分的，並未包括有受科學支持的結論。例如：

A. You tested (b)(4) for (b)(4) capsule samples collectedat (b)(4) locations during the manufacture of(b)(4) capsules, (b)(4) mg, batch (b)(4). The relative standarddeviation (RSD) was OOS: (b)(4)% (specification is not more than (b)(4)%).You then tested reserve capsules and obtained additional OOS results for this batch. One unit assayed at (b)(4)% (specification is (b)(4)–(b)(4)%), and the RSD was (b)(4)% (specification is not more than (b)(4)%).Your firm excluded the individual sub potent assay OOS result and recalculated the RSD results as passing with a new value of (b)(4)%.

你們在XX膠囊XXmg的XX批次生產期間對XX位置所取樣品進行了XX檢測。相對標準偏差（RSD）值為OOS：XX%（標準要求不得過XX%）。然後你們檢測了留樣膠囊，得到了該批次更多的OOS結果。一個單位含量為XX%（標準為XX-XX%），RSD為XX%（標準為不得過XX%）。你們公司排除了單個含量不合格的OOS結果重新計算RSD結果為合格，重新計算結果為XX%。

You did not test the reserve capsulesand investigate the failing (b)(4) capsule (b)(4) results until approximately one and a half months after you used the same batch of (b)(4) capsules for in-vivo bioavailability studies on December 17, 2016.

直到2016年12月17日你們將相同批次XX膠囊用於體內生物等效性研究之後一個半月，你們才檢查了留樣膠囊，並調查不合格的XX膠囊XX結果。

Your response is inadequate. You attributed this failure toan 「unknown lab error.」 You claimed that the low individual assay test resultwas an outlier and that the most probable root cause was analytical error.Outlier tests have no applicability in cases where the variability in theproduct is what is being assessed, suchas for (b)(4). You did notprovide sufficient justification for disregarding the low result or supporting your unspecific conclusion of unknown laboratory root cause.

你們的回復是不充分的。你們將此不合格歸因於「未知化驗室錯誤」。你們聲稱單個含量值偏低的檢測結果是離群結果，最可能的根本原因是檢驗錯誤。如果產品本身的波動性是受評估的對象，如XX，那麼離群測試是不適用的。你們並未提交足夠的論證用以支持忽略低含量結果或支持你們未知化驗室根本原因的非特定原因。

B. You initiated an investigation into OOS and out-of-trend (OOT) assay results for (b)(4) tablets, (b)(4)mg and (b)(4) mg, three-month stability samples (batches (b)(4) and (b)(4)). Your May 2017 investigation states that you also obtained low OOT assay values at the one-month time point. You concluded the OOS and OOT results were due to analyst error during sampling preparation but lacked data to support your conclusion. Your testing associated with the investigation did not demonstrate that sample preparation caused the aberrant results as assay values did not differ substantially when you varied sample preparation.

你們啟動了對XXmg和XXmg的XX片劑3個月穩定性樣品（批號XX和XX）的OOS和OOT含量結果的調查。你們在2017年5月的調查聲稱你們在1個月的時間點亦得到了較低的OOT含量值。你們做出結論說該OOS和OOT結果是由於化驗員的取樣製備錯誤，但缺乏數據來支持你們的結論。你們與調查有關的檢測並未證明樣品製備會導致異常結果，因為當你們改變樣品製備時含量值並未發現有顯著差異。

You did not extend the investigation to manufacturing, although your Site Incident Response Committee requested initiation of this part of the investigation. Notably, you performed the manufacturing phase of the investigation after our inspection.

雖然你們的工廠事件響應委員會要求啟動生產部分調查，但你們並未將該調查延伸至生產。值得注意的是，你們在我們檢查之後執行了生產階段調查。

Your response explains that a third party performed a retrospective review of nine invalidated OOS investigations and that in 「all cases, the investigations were found to be thorough and robust and the findings were sufficiently justified.」 However, this is not fully consistent with your third-party report. Regarding this specific OOS investigation, your third-party report says it 「did not believe sufficient scientific evidence was presented in the laboratory OOS investigation process to justify retesting. Only retesting and obtaining passing results are the basis of conclusions.」

你們的回復解釋說一個第三方單位對9個被宣布無效的OOS調查進行了回顧性審核，「在所有案例中均發現調查是徹底可靠的，發現的問題經過了科學論證」。但是，這與你們的第三方報告並不完全一致。關於此具體的OOS調查，你們的第三方報告說他們「並不認為在化驗室OOS調查過程中有足夠的科學證據來對復驗進行支持。結論的基礎只有復驗和獲得的合格結果」。

C. Variance investigation checklists (VIC) and variance investigation reports (VIR) used to investigate poor chromatography and failing results are inadequate. These VIC and VIR investigations are not subject to your OOS investigational procedures, and you do not track and trend them. Our inspection identified that you used test results obtained with your VIC and VIR investigations to replace original results. Further, your personnel stated that they retested a sample as part of a VIR investigation because they did not want to show low results to a customer.

用於調查不良色譜和不合格結果的差異調查檢查清單（VIC）和差異調查報告（VIR）不充分。這些VIC和VIR調查未遵守你們的OOS調查程序，你們並未追蹤並進行趨勢分析。我們在檢查中發現你們使用了你們VIC和VIR調查中所獲得的檢測結果來取代原始結果。另外，你們的人員聲稱他們作為VIR調查的一部分對一份樣品進行了複測，因為他們不想給客戶顯示出低結果。

Your response is inadequate. You have not provided the retrospective review of all VIC and VIR investigations.

你們的回復是不充分的，你們並未提交對所有VIC和VIR調查的回顧性審核。

D. On August 8 and 9, 2017, you observed capped and edge-worn tablets in two batches of(b)(4) tablets, (b)(4)mg. You rejected a substantial number of units from each batch due to these defects. You opened an investigation, which closed September 7, 2017, and concluded the most probable root cause was high (b)(4) force. You lackedscientific evidence to support this root cause as other batches had been successfully produced in that range. After observing a third batch with capped (b)(4) tablets, (b)(4) mg, inOctober 2017, you initiated another investigation.

在2017年8月8日和9日，你們發現XX片劑XXmg兩個批次中有已頂裂以及邊緣破損的片子。由於該缺陷，你們拒收了每個批次中相當多的數量。你們開啟了一個調查，該調查於2018年9月7日關閉，結論是最可能的根本原因是高XX力。你們缺乏科學證據來支持該根本原因，因為在該範圍內成功生產其它批次。在2017年10月發現第三批頂裂XX片劑XXmg之後，你們啟動了另一個調查。

Your response acknowledges that the tablet defects may be due to multiple root causes and you continue to investigate the issue. However, your response lacks a detailed update on the investigations into the capped tablets. You also did not include corrective action and preventive actions (CAPA) initiated in association with the investigations.

你們的回復說知曉片劑缺陷可能是由於多個根本原因，你們將繼續調查此問題。但是，你們的回復缺乏對頂裂片劑的調查情況的更新細節。你們亦未包括在相關調查中啟動的CAPA。

In response to this letter:在回復此函時：

Explain why (b)(4) mg capsule batch (b)(4) was shipped and used for your bioequivalence studies before testing and investigational activities were completed. Also, describe whether your procedures require all testing and investigations to be completed prior to batch release.

請解釋為何在完成檢測和調查活動之前已將XXmg膠囊批次XX發運，並用於你們的生物等效性研究。亦請說明你們的程序是否要求在批放行之前完成所有檢測和調查。

Perform a three-year retrospective review to determine whether outlier tests have been used in previous OOS investigations, and determine whether you used them to improperly invalidate OOS results.

對過去三年進行回顧性審核以確定在之前的OOS調查中是否有使用離群檢查，並確定你們是否使得它們來不恰當地宣布了OOS結果無效。

Provide the report and associated CAPAs for your retrospective review of all VIRs and VICs initiated since January 1, 2015. Include a third-party assessment of each of the VIRs and VICs, and of your firm』s final report.

請提交一份對自2015年1月1日開始所有VIR和VIC的回顧性審核的報告和相關CAPA。在其中包括一份第三方對每份VIR和VIC的評估，以及對你們公司最終報告的評估。

Assess the procedures you use to evaluate (b)(4) uniformity, including collecting and testing samples and evaluating results.

對你們用於評估XX均一性的程序的評估，包括樣品採集和檢測以及對結果的評估。

Provide a comprehensive, independent assessment of your overall system for investigations of laboratory and manufacturing-related deviations, discrepancies, complaints, OOS results, and failures. Your CAPA plan should include but not be limited to improvements in investigation competencies, root cause analysis, written procedures, and quality unit oversight. Also, include an improved process for evaluating CAPA effectiveness.

提交一份對你們化驗室和生產相關偏差、不符合、投訴、OOS結果和不合格調查的總體系統的全面獨立評估。你們的CAPA計劃應包括但不僅限於對調查能力、根本原因分析、書面程序和質量部門監管的改進。還應包括改進後的CAPA有效性評估程序。

For more information about handling failing,out-of-specification, out-of-trend, or other unexpected results and documentation of your investigations, see FDA』s guidance document,InvestigatingOut-of-Specification (OOS) Test Results for Pharmaceutical Production, athttps://www.fda.gov/downloads/drugs/guidances/ucm070287.pdf.

更多信息參見FDA官網OOS調查指南。

2. Your firm failed to establish valid in-process specifications (21 CFR 211.110(b)).你公司未建立有效的中控標準（21 CFR 211.110(b)）。

Your firm failed to establish appropriate in-process specifications to ensure the quality of (b)(4). During our inspection, your management explained that (b)(4) could not be tested (b)(4) because the material was not (b)(4) and could fail assay specifications. OOS (b)(4) should not be (b)(4) with other batches for the purpose ofmeeting specifications.

你公司未能建立適當的中控質量標準，以確保XX的質量。在我們檢查期間，你們的管理人員解釋說XX不能檢測XX，因為該物料不是XX，含量可能不符合標準。OOS的XX不應與其它批次XX以達成符合質量標準的目的。

Your response included a process flow diagram which showsthat (b)(4) of (b)(4) undergo separate dispensing, (b)(4), and (b)(4) steps, and are not tested separately (b)(4). You stated that assay testing at the (b)(4) stage is not a critical quality attribute because the (b)(4) is incomplete. You also acknowledged thatyou did not perform this (b)(4) testing during process validation studies.This response is inadequate. (b)(4) should be individually tested and found to meet appropriate specifications (b)(4).

你們的回復包括有一個工藝流程圖，其中顯示了XX的XX有分散、XX和XX步驟，且並未分別檢測XX。你們聲稱在XX步驟的含量檢測並不是關鍵質量屬性，因為XX是不完整的。你們亦知曉你們在工藝驗證期間並未執行此XX檢測。該回復是不充分的。XX應該單獨檢測並應符合適當的質量標準XX。

In response to this letter, remediate your current procedures to ensure that(b)(4)are tested for appropriate quality attributes(b)(4). Provide us with any updates made to your procedures.Provide a list of all products manufactured in a similar manner and include an assessment of the effects on any batches produced in this manner which are within expiry.

在回復此函時，請對你們當前程序進行彌補以確保檢測XX的適當質量屬性XX。向我們提供你們程序所做的所有更新。提交一份以類似方式生產的所有產品清單，並包括一份對所有以此方式生產且仍在效期內批次的影響性評估。

Quality Unit Authority質量部門權力

Your inspectional history indicates that your quality unit does not fully exercise authority, such as ensuring that appropriate investigations are performed with sound conclusions, identifying root causes,and supporting scientific justification. Your firm must provide your quality unit with appropriate authority, sufficient resources, and staff to carry out its responsibilities and consistently ensure drug quality.

你們的檢查歷史顯示你們質量部門並不具有全面的履責權力，例如確保進行適當的調查並得出合理結論、識別根本原因，以及支持性科學論證。你公司必須為你們質量部門提供適當的權力、足夠的權力和人員來履行其職責，持續確保藥品質量。

Quality Systems質量體系

Your firm』s quality systems are inadequate. For guidance onestablishing and following CGMP compliant quality systems, see FDA』s guidancefor industry:

你們公司的質量體系是不充分的。建立和遵守符合CGMP要求的質量體系請參見FDA行業指南Q8/Q9/Q10

Q8(R2) Pharmaceutical Development, athttps://www.fda.gov/downloads/drugs/guidances/ucm073507.pdf;

Q9 Quality Risk Management, athttps://www.fda.gov/downloads/Drugs/Guidances/ucm073511.pdf; and

Q10 Pharmaceutical Quality System, athttps://www.fda.gov/downloads/drugs/guidances/ucm073517.pdf.

Repeat Violations and Deviations at Multiple Sites多個工廠重複違規和偏差

FDA has cited similar CGMP violations and deviations at this and other facilities in your company』s network. In the last five years, FDA has taken the following actions in response to CGMP violations and deviations at Apotex facilities.

FDA在你們公司網路中此工廠和其它工廠發現了類似的CGMP違規和偏差情況。在過去5年內，FDA已經採取了以下措施來響應APOTEX工廠的CGMP違規和偏差情況：

1. FDA placed Apotex Pharmachem India Private Limited on Import Alert on April 1, 2014, and issued a warning letter on June 16, 2014, which cited failure to investigate and document OOS results.FDA於2014年4月1日將Apotex PharmachemIndia Private Limited置於進口禁令中，並於2014年6月16日簽發了警告信。

2. FDA placed Apotex Research Private Limited on Import Alert on September 22, 2014, and issued a warning letter on January 30, 2015, which cited failure to follow written procedures applicable to the quality control unit.FDA於2014年9月22日將Apotex Research Private Limited置於進口禁令中，並於2015年1月30日簽發了警告信，其中引用了不遵守質量部門所適用書面程序的問題。

FDA has previously communicated about the need for appropriate and global quality oversight to Apotex senior management during several regulatory meetings.These repeated failures at multiplesites demonstrate that management oversight and control over the manufacture of drugs is inadequate.

FDA之前在幾次法規會議中已與APOTEX的高級管理層溝通過需要有適當的全球質量監管事宜。這些在多個工廠發現的重複違規情況說明管理層對藥品生產的監管和控制是不充分的。

Your quality system has not implemented effective correctiveactions to ensure the accuracy and integrity of the data generated at your facility, which is necessary to ensure the safety, effectiveness, and quality of the drug products you manufacture. There will be additional communications from CDER』s Office of Pharmaceutical Quality regarding theseissues. The Office of Generic Drugs may subsequently provide comment regarding the effect of these findings on(b)(4)if needed.

你們的質量體系並未執行有效的糾正措施來確保在你們工廠所產生的數據的準確性和完整性，而這些數據是確保你們所生產藥品的安全性、有效性與質量所必須的。CDER的藥品質量辦公室將就此問題進行另外的溝通。必要時，仿製葯辦公室可能會在後續提供對這些缺陷的看法。

CGMP consultant recommendedCGMP顧問建議

Because you failed to correct repeat violations, we strongly recommend engaging a consultant qualified as set forth in 21 CFR 211.34, to assist your firm in meeting CGMP requirements. Your use of a consultant does not relieve your firm』s obligation to comply with CGMP. We also recommend that the qualified consultant perform a comprehensive audit of your entire operation for CGMP compliance, and evaluate the completion and effectiveness of any corrective actions and preventive actions you have implemented before you pursue resolution of your firm』s compliance status with FDA. Your firm』s executive management remains responsible for fully resolving all deficiencies and ensuring ongoing CGMP compliance.

由於你們未能糾正重複的違規情況，我們強烈建議你們使用一位有21 CFR211.34所述資質的顧問來協助你們公司符合CGMP要求。我們還建議具備資質的顧問對你們全面操作進行CGMP合規性綜合審計，並在你公司尋求符合FDA法規要求解決方案之前評估所有已實施CAPA的完整性和有效性。你們公司的高級管理層仍負有義務全面解決所有缺陷，確保持續CGMP符合性。

Conclusion結論

Violations cited in this letter are not intended as an all-inclusive list. You are responsible for investigating these violations, for determining the causes, for preventing their recurrence, and for preventing other violations in all your facilities.

此函中所引用的違規並不是全部。你們有責任對這些偏差進行調查，確定原因，防止其再次發生，防止其它偏差的發生。

If you are considering an action that is likely to lead to a disruption in the supply of drugs produced at your facility, FDA requests thatyou contact CDER』s Drug Shortages Staff immediately, at drugshortages@fda.hhs.gov, so that FDA can work with you on the most effectiveway to bring your operations into compliance with the law. Contacting the DrugShortages Staff also allows you to meet any obligations you may have to reportdiscontinuances or interruptions in your drug manufacture under 21 U.S.C.356C(b) and allows FDA to consider, as soon as possible, what actions, if any,may be needed to avoid shortages and protect the health of patients who dependon your products.

如果你們在考慮要採取的措施可能會導致你們工廠所生產的藥品供應中斷，FDA要求你立即聯繫CDER藥品短缺負責人員，這樣FDA可以與你們一起採用最為高效的方式引導你們的操作符合法規要求。聯繫藥品短缺負責人員還能讓你滿足依據21 U.S.C. 356C(b)你可能必須報告你們藥品中止或中斷的義務，讓FDA儘快考慮是否需要採取何種措施來避免短缺，保護依賴於你們藥品的患者健康。

FDA placed your firm on Import Alert 66-40 on April 12,2018.

FDA已於2018年4月12日將你置於進口禁令66-40項下。

Until you correct all violations completely and we confirmyour compliance with CGMP, FDA may withhold approval of any new applications orsupplements listing your firm as a drug manufacturer.

在貴公司未能完成所有偏差糾正並且由我們確認你們符合CGMP之前，FDA可能會擱置所有將你公司列為藥品生產的新申報和增補申報的批准。

Failure to correct these violations may also result in FDAcontinuing to refuse admission of articles manufactured at Apotex ResearchPrivate Limited at Plot 1 & 2, Bommasandra Industrial Area, 4thPhase, Jigani Link Rd., Bangalore, into the United States under section801(a)(3) of the FD&C Act, 21 U.S.C. 381(a)(3). Under the same authority,articles may be subject to refusal of admission, in that the methods andcontrols used in their manufacture do not appear to conform to CGMP within themeaning of section 501(a)(2)(B) of the FD&C Act, 21 U.S.C. 351(a)(2)(B).

未能糾正這些偏差可能還會導致FDA依據FDCA第801(a)(3)條和21 U.S.C. 381(a)(3)拒絕接受在上述地址生產的產品進入美國。

After you receive this letter, respond to this office inwriting within 15 working days. Specify what you have done since our inspectionto correct your violations and to prevent their recurrence. If you cannotcomplete corrective actions within 15 working days, state your reasons fordelay and your schedule for completion.

在收到此函後，請在15個工作日內回復至本辦公室。在回復中說明自從檢查後，你們做了哪些工作來糾正你們的偏差，防止其再次發生。如果不能在15個工作日內完成糾正措施，說明延遲的原因以及完成計劃。

Brooke K. Higgins

Compliance Officer

U.S. Food and Drug Administration

White Oak Building 51, Room 4359

10903 New Hampshire Avenue

Silver Spring, MD 20993

USA

Sincerely,

/S/

Francis Godwin

Acting Director