FDA警告信：印度Hetero

Via UPS

Warning Letter320-17-46

August 15, 2017

Dr. Bandi Parthasarathy Reddy

Chairman and Managing Director

Hetero Labs Limited

7-2-A2, Hetero Corporate Industrial Estates

Sanath Nagar

Hyderabad 500 018, Telangana

India

Dear Dr. Reddy:

The U.S. Food and Drug Administration (FDA) inspectedyour drug manufacturing facility, Hetero Labs Limited, Unit V at PolepallyVillage, Jadcherla Mandal, Mahaboob Nag, Telangana, from December 7–16, 2016.

美國FDA於2016年12月7-16日檢查了你們位於印度特倫甘納州的HETERO生產場所。

This warning letter summarizes significant violations ofcurrent good manufacturing practice (CGMP) regulations for finishedpharmaceuticals. 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 formanufacturing, processing, packing, or holding do not conform to CGMP, yourdrug products are adulterated within the meaning of section 501(a)(2)(B) of theFederal Food, Drug, and Cosmetic Act (FD&C Act), 21 U.S.C. 351(a)(2)(B).

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

We reviewed your January 10, 2017, response in detail andacknowledge receipt of your subsequent correspondence.

我們詳細審核了你們公司2017年1月10日及之後的回復。

During our inspection, our investigators observedspecific 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 investigateany unexplained discrepancy or failure of a batch or any of its components tomeet any of its specifications, whether or not the batch has already beendistributed (21 CFR 211.192).

你公司未能徹底調查所有未能解釋的已銷售或未銷售批產品及其所有組分與其質量標準的差異或不合格，

Your investigations into process deviations andout-of-specification (OOS) laboratory results are insufficient, and do notinclude scientifically-supported conclusions.

你們對工藝偏差和OOS化驗室結果的調查不充分，未包括有科學支持的結論。

For example, you have acted as the contract manufacturerof(b)(4)mg(b)(4)tablets for multiple customers. In February 2016, you received a customercomplaint that lot(b)(4)failed dissolution testing. During your investigation into this complaint, younoted that the(b)(4)usedto manufacture lot(b)(4)was operating at up to(b)(4)%(b)(4),although its specification was not more than (NMT)(b)(4)%(b)(4). You also notedthat the(b)(4)was recorded as 「NMT(b)(4),」which does not indicate if the operating(b)(4)was maintained within the specification of(b)(4)±(b)(4).

例如，你們為多個客戶以CMO的身份生產XXmg的YY片劑。2016年2月，你們收到了一個客戶關於XX批次溶出度測試不合格的投訴。在你們對此投訴的調查期間，你們注意到用於XX生產批次的XX在操作過程中達到XX%YY，而其標準為不超過（NMT）XX%YY。你們也注意到了XX記錄為「NMT XX」，其中沒有說明操作XX是否要維持在標準的XX±YY範圍。

Your March 2016MarketComplaint Investigation Reportconcluded, without scientificjustification, that the(b)(4)and possible(b)(4)deviations during the(b)(4)process for this lot had no relationship to the dissolution test failure.Although the investigation also initially concluded that the failure could be atesting issue involving the use of(b)(4)μm filters, one of your customers found this explanationunacceptable. You subsequently acknowledged to another customer that you hadnot identified the root cause for the failing dissolution results.

你們2016年的市場投訴調查報告結論沒有科學論證，其中說在此批次XX工藝中的XX和可能的YY偏差與溶出度檢測不合格沒有關係。調查在開始也得到結論認為不能接受此解釋。你們之後對另一個客戶說你們沒有發現溶出度結果不合格的根本原因。

Finally, in your April 2016 Closure Report to MarketComplaint Investigation, you indicated that the dissolution failure was due tothe(b)(4)and(b)(4)process.

最後，在你們的2016年4月的市場投訴調查結論報告中說溶出度不合格是由於XX和YY工藝。

Your response states that lot(b)(4)was the onlylot manufactured during a(b)(4)-lotmanufacturing campaign that appeared to be affected by these processing issues.This response is inadequate because it does not provide sufficientjustification for this conclusion, and fails to fully investigate the scope androot causes of the reported dissolution failure.

你們的回復聲稱XX批次是在XX批貌似受過這些工藝問題影響的生產周期中唯一一個批次。此回復是不充分的，因為沒有對此結論給出充分的論證，也沒有充分調查所報告的溶出度不合格的範圍和根本原因。

In response to this letter, provide:

在回複本函時，請提交：

? Updated dissolution testing of all(b)(4)lot retains,and a commitment to add extra lots of the(b)(4)mg tablet to your annual stabilityprogram.

對所有XX批留樣更新後溶出度檢測結果，承諾要在年度穩定性計劃中增加XXmg片劑批次。

? Your detailed retrospective review of allcomplaint, manufacturing, and laboratory investigations associated with eachproduct that you produce for the U.S. market, and all lots that are withinexpiry.

你們對所有與你們為美國市場生產的所有仍在有效期內的產品有關投訴、生產和化驗室調查的詳細回顧性審核。

? Your detailed retrospective review of themanufacturing process validation for each product that can be exported to theU.S., including(b)(4),to ensure your manufacturing processes are capable of consistently yieldingfinished products that meet quality attributes and manufacturing requirements.For each process, identify sources of variability in your raw materials andmanufacturing process, and indicate the steps you have implemented to reducevariability or mitigate its potential effects on the quality of your products.

你們對可能出口至美國的每個產品，包括XX產品，的生產工藝驗證的詳細回顧審核，以確保你們的生產工藝能夠持續產出符合質量屬性和生產要求的製劑成品。針對每個工藝，請識別出你們原料和生產工藝中波動的來源，說明你們實施了哪些步驟來減少波動性或減少其對你們產品質量的潛在影響。

? Your plan to ensure that all futureinvestigations are thorough, scientifically sound, and result in appropriateand effective CAPA.

你們確保未來所有調查都是徹底、科學合理並導向適當有效CAPA的計劃。

2. Your firm failed to clean, maintain, and,as appropriate for the nature of the drug, sanitize and/or sterilize equipmentand utensils at appropriate intervals to prevent malfunctions or contaminationthat would alter the safety, identity, strength, quality, or purity of the drugproduct beyond the official or other established requirements (21 CFR 211.67(a)).

你們公司未能以適當時間間隔對設備和工器具進行清潔、維護，藥品屬性適當時，消毒和/或滅菌，以防止發生可能改變藥品安全性、鑒別、劑量、質量或純度超出官方或其它既定要求的故障和污染(21CFR 211.67(a))。

Our investigators observed multiple(b)(4), which youidentified as clean, containing colored residue and/or in poor condition.

我們調查人員發現你們識別為清潔的多個XX上面有有顏色的殘留和/或狀態不良。

For example,(b)(4)PDE-2095 had white(b)(4)residue on and around a white interior gasket. Our investigator documented agap in the gasket that could allow processed materials to accumulate. The endsof the gasket were also in poor condition.

例如，XXPDE-2095的白色內墊圈上面和周圍有白色XX殘留。我們的調查人員記錄下在墊圈那兒有縫隙使得物料可以累積。墊圈的尾端狀態也很差。

Your response states that you sampled and analyzedresidues to identify and quantify chemical and microbiological contaminants,and the results met microbial attributes. You attributed the white residue to「… part of [the] overall finish of(b)(4)surface」 and the 「…drying of water drops after cleaning.」

你們的回復說你們對殘留物進行了取樣分析，識別並定量了其中的化學和微生物污染物，並且結果符合微生物屬性。你們將白色殘留歸因於「……XX表面的部分拋光」以及「……清潔後水滴乾燥」。

In response to this letter, provide:

在回復此函時，請提交：

? The sampling procedures and analyticalmethods you used to test the white residues. Include validation protocols andvalidation reports.

你們用以測試白色殘留物的取樣程序和分析方法，包括驗證方案和驗證報告。

? Your procedures to install and maintain the「(b)(4)type」 gasket in(b)(4)PDE-2095.Assess all(b)(4)thatuse similar gaskets in product contact areas. Justify the suitability andcontinued use of these gaskets in your(b)(4).

你們用以安裝和維護XXPDE-2095上面「XX型」墊圈的程序。評估所有在產品接觸區域使用類似墊圈的XX。論證在你們的XX中使用這些墊圈的適當性。

? Your plan to ensure that personnelresponsible for cleaning, verifying equipment cleanliness, and maintainingequipment are appropriately trained and capable of performing their assignedduties. Include cleaning validation studies for your(b)(4).

你們用以確保負責清潔、核查設備清潔度、以及維護設備的人員均受到適當培訓，有能力實施其被指派的任務，包括你們XX的清潔驗證驗證研究。

? An overall assessment of the adequacy ofyour cleaning program for all equipment, with special emphasis ondifficult-to-clean parts.

一份你們所有設備的清潔程序充分性的評估，對難以清潔的部分要特別標註。

3. Your firm failed to establish adequatewritten responsibilities and procedures applicable to the quality control unitand to follow such written procedures (21 CFR 211.22(d)).

你們公司未能建立和遵守充分的適用於質量部門的書面職責和程序(21CFR 211.22(d))。

Your firm』s procedures, QM001-04 Quality System Manualand CQA012-01 Product Recall, direct your firm to recall products that fail tomeet specifications, but your quality control unit failed to follow yourwritten procedures regarding the recall of failing products.

你們公司的程序QM001-04質量體系手冊和CQA012-01產品召回，要求你們公司召回不符合質量標準的產品，但你們的質量控制部門並未遵守你們召回不合格產品的書面程序。

For example, on July 8, 2016, you received a complaintthat one tablet in a bottle of 5 mg finasteride tablets, lot FIN16002, wasapproximately double the thickness of the others. You confirmed the defectafter receiving the complaint sample on July 27, 2016, but did not initiate aproduct recall as directed by your own procedures until December 23, 2016. Thiswas nearly a week after our investigators pointed out your failure to takeaction as directed by your own procedures regarding recalls of defectiveproducts.

例如，2016年7月8日，你們收到了一瓶5mg非那雄胺片劑中一片片劑的投訴，批號為FIN16002，該片厚度差不多是其它片的2倍。你們在收到投訴樣品之後於2016年7月27日確認了該瑕疵，但並沒有按你們自己程序的要求啟動產品召回，直到2016年12月23日我們調查人員指出你們沒有按你們自己的程序召回缺陷產品之後近一周才執行召回。

Although you initiated a product recall in response tothe discrepancy raised by our investigators, your response was inadequatebecause you did not explain why you failed to follow your own Quality SystemManual and product recall procedure with respect to this product defect in thefirst instance.

儘管你們啟動了產品召回，應對我們調查人員提出的差異。你們的回復是不充分的，因為你們沒有解釋為什麼你們不遵守你們自己的質量體系手冊和產品召回程序在第一時間召回此產品缺陷。

In response to this letter, provide a list and summaryexplanation for all other instances in which product(s) distributed within thelast five years failed to meet established specifications, but for which youfailed to take actions prescribed by your Quality System Manual and recallprocedure. Provide your planned corrective actions and preventive actions(CAPA) for each such instance and explain your CAPA for ensuring that youfollow your own procedures regarding product quality and recalls.

在回復此函時，請提交一份清單和總結，解釋過去5年內已銷售的不符合標準的產品，而你們並未按你質們質量體系手冊和召回程序所述採取措施的所有其它情況。提交你們制訂的針對每一種此類情形的CAPA計劃，解釋你們的CAPA要如何確保你們會遵守你們自己的產品質量和召回程序。

Process Controls工藝控制

Your firm does not have an adequate ongoing program formonitoring process control to ensure stable manufacturing operations andconsistent drug quality. See FDA』s guidance document, Process Validation:General Principles and Practices, for general principles and approaches thatFDA considers appropriate elements of process validation, at https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM070336.pdf.

你們公司沒有足夠的持續計劃監測工藝控制，以確保生產操作穩定和藥品質量一致。參見FDA指南工藝驗證指南文件。

CGMP Consultant RecommendedCGMP顧問建議

Based upon the nature of the violations we identified atyour firm, we strongly recommend engaging a consultant, qualified as set forthin 21 CFR 211.34, to assist your firm in meeting CGMP requirements. Your use ofa consultant does not relieve your firm』s obligation to comply with CGMP. Yourexecutive management remains responsible for fully resolving all deficienciesand ensuring ongoing CGMP compliance.

根據我們在你們工廠發現的違規情況，我們強烈建議你們聘請一位有能力評估你們操作的顧問，協助你們符合CGMP要求。你們聘用顧問並不能免除你們公司符合CGMP的義務。你們公司的執行管理人員仍保有全面解決所有缺陷，確保持續符合CGMP要求的職責。

Conclusion結論

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

在此函中所引用的偏差並不是全部。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 leadto a disruption in the supply of drugs produced at your facility, FDA requeststhat you contact CDER』s Drug Shortages Staff immediately, at drugshortages@fda.hhs.gov, so thatFDA can work with you on the most effective way to bring your operations intocompliance with the law. Contacting the Drug Shortages Staff also allows you tomeet any obligations you may have to report discontinuances or interruptions inyour drug manufacture under 21 U.S.C. 356C(b) and allows FDA to consider, assoon as possible, what actions, if any, may be needed to avoid shortages andprotect the health of patients who depend on your products.

如果你們正在考慮可能會導致你們工廠所生產的藥品供應中斷的措施，FDA要求你們立即通過上述郵箱聯繫CDER藥物短缺辦公室，使得FDA可以與你們一起，以最高效的方式將你們的運行帶回符合的軌道。與藥物短缺辦公室聯繫還能讓你們完成所你們所承擔的報告你們藥品生產中斷的義務，使得FDA儘可能快地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。

Until you correct all violations completely and weconfirm your compliance with CGMP, FDA may withhold approval of any newapplications or supplements listing your firm as a drug manufacturer.

在你們完全糾正所有違規情況，並由我們確認你們符合CGMP要求之前，FDA可能會暫停所有將你公司列為藥品生產商的新申報和增補。

Failure to correct these violations may also result inFDA refusing admission of articles manufactured at Hetero Labs Limited, Unit Vat Polepally Village, Jadcherla Mandal, Mahaboob Nag, Telangana into the UnitedStates under section 801(a)(3) of the FD&C Act, 21 U.S.C. 381(a)(3). Underthe same authority, articles may be subject to refusal of admission, in thatthe methods and controls used in their manufacture do not appear to conform toCGMP within the meaning 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。

請將你們的電子回複發送至上述郵箱或郵件發至以下地址：

Sincerely,

/s/

Thomas J. Cosgrove, J.D.

Director

Office of Manufacturing Quality

Office of Compliance

Center for Drug Evaluation and Research

喜歡這篇文章嗎？立刻分享出去讓更多人知道吧！