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 來自：JULIA法規(guī)翻譯

Warning Letter 320-20-39
June 17, 2020
Dear Mr. Kurre:
The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Vega Life Sciences Private Limited, FEI 3015658387, at Plot No. D-15, 16, 21 & 22, Phase-I, I.D.A.Pashamylaram, Patencheru (M), Sangareddy District, Telangana, from November 25 to 28, 2019.

美國FDA于2019年11月25日至28日檢查了你們位于印度的Vega Life Sciences Private Limited（FEI 3015658387）生產(chǎn)場所。

This warning letter summarizes significant deviations from current good manufacturing practice (CGMP) for active pharmaceutical ingredients (API).
本警告信總結(jié)了原料藥生產(chǎn)嚴(yán)重違反CGMP的行為。

Because your methods, facilities, or controls for manufacturing, processing, packing, or holding do not conform to CGMP, your API 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).

由于你們的原料藥生產(chǎn)、加工、包裝或保存的方法、場所或控制不符合CGMP要求，你們的原料藥根據(jù)FDCA的501(a)(2)(B)以及21 U.S.C.351(a)(2)(B)被認(rèn)為是摻假藥品。

We reviewed your December 19, 2019, response to our Form FDA 483 in detail and acknowledge receipt of your subsequent correspondence.
我們已詳細(xì)審核了你公司2019年12月19日對我們FDA483表格的回復(fù)，并此告知已收到后續(xù)通信。

During our inspection, our investigators observed specific deviations including, but not limited to, the following.
檢查期間，我們的調(diào)查人員發(fā)現(xiàn)的具體問題包括但不僅限于以下：

1. Failure to control and monitor solvent recovery procedures to ensure that solvents meet appropriate standards before reuse in API manufacturing. 未能控制和監(jiān)測溶劑回收程序，從而確保溶劑在重新用于API生產(chǎn)之前符合適當(dāng)?shù)臉?biāo)準(zhǔn)。

Our inspection found that your firm acts as acontract solvent recovery facility for your customer’s (b)(4) API manufacturing operations. Solvents recovered at your facility include (b)(4).
我們檢查發(fā)現(xiàn)你公司受委托為你們客戶的XX API生產(chǎn)操作回收溶劑。在你們場所回收的溶劑包括XX。

Your firm failed to establish and follow procedures to evaluate and control impurity risks associated with your solvent recovery operations. For example:
你公司未能建立和遵守評估和控制與你們?nèi)軇┗厥詹僮饔嘘P(guān)的雜質(zhì)風(fēng)險的程序。例如
Inadequate Testing of Recovered Solvents 對回收溶劑檢測不充分

Your firm failed to follow your gas chromatography (GC) test method procedure for recovered (b)(4). The procedure requiresuse of a standard for ensuring the batch meets the Identification by GC recovered solvent specification. We reviewed analytical data packages for approximately (b)(4) batches of recovered (b)(4) processed by your firm in 2019 and found they lacked chromatograms representing the use of a standard. Furthermore, your firm stated to the investigators that standards were never run during GC analysis of recovered (b)(4) in 2018 and 2019.

你公司未能遵守你們對回收XX的GC檢測方法。該方法要求使用一種對照品確保批次符合回收溶劑質(zhì)量標(biāo)準(zhǔn)中的GC鑒別。我們審核了你公司在2019年約XX批次回收XX的分析數(shù)據(jù)包，發(fā)現(xiàn)其中缺少使用對照品的圖譜。另外，你公司向檢查員承諾2018-2019年間在GC分析時從未使用對照品運(yùn)行GC分析。

In your response, you provided no explanation for this deviation and made no commitment to investigate the scope of this deficiency to determine if other test methods or procedures were not followed. Your response also lacked a risk assessment to determine potential product impact.
在你們的回復(fù)中，你們沒有為該偏差提交解釋，亦未承諾要調(diào)查該缺陷的范圍，從而確定是否未遵守其它檢測方法或程序。你們的回復(fù)亦未進(jìn)行風(fēng)險評估來確定對產(chǎn)品的潛在影響。

Failure to Establish an Impurity Profile for Recovered Solvents or Investigate Extraneous Peaks in Chromatograms
未能建立回收溶劑的雜質(zhì)概況或調(diào)查色譜圖中的外源峰

Your firm failed to establish an impurity profilefor recovered solvents and maintain appropriate oversight of your operations for the control of unknown impurities. Extraneous peaks were observed in morethan (b)(4) batches of recovered (b)(4) processed at your facility between 2018 and 2019. The batches were released by your firm without investigation and you failed to inform your customer of any potential impurities. You stated that your customer instructed you to focus only on the peak representing the recovered solvent, however this is not adequate. Unknown peaks observed in chromatograms of recovered solvents may represent unanticipated impurities that can impact the quality of your customer’s API and should be thoroughly investigated.

你公司未能建立回收溶劑雜質(zhì)譜，并對你們操作中未知雜質(zhì)的控制進(jìn)行適當(dāng)監(jiān)管。在2018-2019年間在你們場所加工的多個批次回收XX中發(fā)現(xiàn)有外源峰。你們未進(jìn)行調(diào)查就放行這些批次，你們未將潛在雜質(zhì)問題通知給你們客戶。你們聲稱你們的客戶指令你們僅關(guān)注回收溶劑峰，但這是不夠的。回收溶劑色譜圖中的未知峰可能代表了意外雜質(zhì)，可能會影響你們客戶API的質(zhì)量，應(yīng)進(jìn)行徹底調(diào)查。

Your response is inadequate. Your evaluation of the extraneous peaks observed in recovered solvent chromatograms was not comprehensive and did not include a thorough manufacturing evaluation to determine if your solvent recovery operations contributed impurities to the recovered solvent.

你們的回復(fù)是不充分的。你們對回收溶劑色譜圖中外源峰的評估不全面，其中未包括徹底的生產(chǎn)評估，從而確定你們的溶劑回收操作是否影響了回收溶劑的雜質(zhì)。

During the inspection, your firm provided a written statement indicating that you had terminated processing recovered solvents for customers. However in your response you indicated that all future customer products would include quality agreements, which suggests that you may resume such operations in the future. Your firm has not provided sufficient details or procedures to demonstrate the capability of predicting, controlling, testing, and preventing impurities or cross contamination associated with your solvent recovery processes.

在檢查期間，你們公司提交了一份書面聲明，說你們已停止為客戶回收溶劑。但是在你們的回復(fù)中，你們說所有未來客戶產(chǎn)品會包括有質(zhì)量協(xié)議，這表示你們未來可能恢復(fù)此類操作。你公司未提交足夠詳細(xì)的信息或程序，來證明你們預(yù)測、控制、檢測和預(yù)防溶劑回收工藝雜質(zhì)與交叉污染的能力。

In response to this letter, provide the following: 在回復(fù)本函時請?zhí)峤灰韵沦Y料

• A comprehensive investigation into your firm’sfailure to follow internal procedures including test methods. Include a detailed description of the scope and root causes of your lapses and list all associated corrective actions with timeframes for completion.

• 一份對你們公司未遵守內(nèi)部程序，包括檢測方法的全面調(diào)查。包括對你們問題范圍和根本原因的詳細(xì)描述，以及所有相關(guān)糾正措施和完成時限的清單

• A detailed plan describing how you will implement an ongoing program for evaluating the effectiveness of your solvent recovery operations monitoring process control to ensure stable manufacturing and prevention of unanticipated impurities during solvent recovery operations.

• 一份詳細(xì)的計劃，說明你們會持續(xù)評估你們?nèi)軇┗厥詹僮饔行裕O(jiān)測工藝控制，以確保生產(chǎn)的穩(wěn)定性，防止溶劑回收操作中的意外雜質(zhì)

• A procedure requiring an impurity profile analysis and risk assessment for all solvent recovery operations. The scope of the procedure should include recovered solvents for internal and external use.

• 一份要求進(jìn)行雜質(zhì)概況分析，對所有溶劑回收操作進(jìn)行風(fēng)險評估的程序。程序的范圍應(yīng)包括內(nèi)部和外部使用的回收溶劑。

• An updated procedure for handling unknown peaks in chromatograms.

• 一份處理色譜中未知峰的程序

2. Failure to have adequate cleaning procedures to prevent contamination or carry-over of a material that would alter the quality of the API. 未制訂足夠的清潔程序，防止可能改變API質(zhì)量的污染或物料殘留

The cleaning of your nondedicated manufacturing equipment used to recover customer solvents including (b)(4) is inadequate. Your firm failed to ensure that your cleaning procedure was sufficient to prevent carryover or contamination for nondedicated equipment used to recover spent solvents. Your firm stated during the inspection that these requirements were not met. Additionally, your firm stated that there were no records to document cleaning of nondedicated equipment used to process recovered solvents including product changeover cleaning.

你們用于回收客戶溶劑的非專用生產(chǎn)設(shè)備的清潔包括XX是不充分的。你公司未能確保你們的清潔程序足以防止用于回收廢溶劑的非專用設(shè)備的殘留或污染。你公司在檢查期間聲稱不符合這些要求。另外，你公司聲稱沒有記錄回收溶劑的非專用設(shè)備的清潔，包括更換產(chǎn)品的清潔。

In your response, you provided examples of equipment cleaning records but did not include an explanation or justification regarding why you told our investigators during the inspection that these documents did not exist.

在你們的回復(fù)中，你們提交了一份設(shè)備清潔記錄的例子，但并未解釋或說明為何你們在檢查期間告訴我們檢查員沒有記錄。

Your response also failed to include a thorough evaluation designed to ensure that all equipment including nondedicated storage, receiving, and charging tanks were properly cleaned according to approved procedures.

你們的回復(fù)亦未對設(shè)計用以確保所有設(shè)備包括非專用存貯、接收和加料罐未能按已批準(zhǔn)程序進(jìn)行恰當(dāng)清潔進(jìn)行徹底評估。

In response to this letter, provide the following:

在回復(fù)本函時請?zhí)峤灰韵沦Y料：

• A corrective action and preventive action (CAPA) plan, based on the retrospective assessment, that includes appropriate remediations to your cleaning processes and practices, and timelines for completion. Providea detailed summary of vulnerabilities in your process for lifecycle management of equipment cleaning. Describe improvements to your cleaning program including enhancements to cleaning effectiveness, improved ongoing verification of proper cleaning execution for all products and equipment, and all other needed remediations.

• 一份基于回顧性評估的CAPA計劃，其中要包括對你們清潔工藝和做法的適當(dāng)補(bǔ)救，以及完成時限。提交一份對你們工藝在設(shè)備清潔生命周期管理中的薄弱點。說明對你們清潔程序的改進(jìn)，包括改進(jìn)清潔有效性，改進(jìn)所有產(chǎn)品和設(shè)備執(zhí)行適當(dāng)清潔的持續(xù)確認(rèn)，以及其它所需補(bǔ)救措施

• Appropriate improvements to your cleaning program,with special emphasis on incorporating conditions identified as worst case in your drug manufacturing operation. In addition, describe the steps that must be taken in your change management system before introduction of new manufacturing equipment or new manufacturing operations.
• 對你們清潔程序的適當(dāng)改進(jìn)，特別要強(qiáng)調(diào)你們藥品生產(chǎn)操作的最差情形。另外，說明你們變更管理體系中在引入新的生產(chǎn)設(shè)備或新的生產(chǎn)操作之前必須采取的措施

• A summary of updated SOPs that ensure an appropriate program is in place for cleaning procedures for products, processes, and equipment.
• 一份更新后的SOP摘要，確保制訂有適當(dāng)?shù)漠a(chǎn)品、工藝和設(shè)備清潔程序

• A comprehensive investigation into your firm’s CGMP documentation practices. Include a detailed description of the scope and root causes of your documentation lapses and list all associated corrective actions with timeframes for completion.
• 一份對你們公司CGMP文件規(guī)范的全面調(diào)查。包括一份對你們文件問題范圍和根本原因的詳細(xì)描述，以及所有相關(guān)糾正措施的清單及完成時限

3. Failure to exercise sufficient controls over computerized systems to prevent unauthorized access or changes to data andfailure to have adequate controls to prevent omission of data. 未能對計算機(jī)化系統(tǒng)進(jìn)行足夠的控制從而防止未經(jīng)授權(quán)進(jìn)入或改變數(shù)據(jù)，未能充分防止數(shù)據(jù)遺漏

Your firm failed to implement adequate controls toensure the integrity of data generated at your facility including:
你公司未能實施足夠的控制，從而確保在你們工廠所生產(chǎn)的數(shù)據(jù)的完整性，包括：

• Missing raw data files associated with recovered solvent testing were observed in folders on the local hard drive of the operating system connected to the GC instrument. Your firm indicated that the files appear to have been deleted.

• 在連接GC儀器的操作系統(tǒng)的本地硬盤文件夾中發(fā)現(xiàn)與回收溶劑檢測有關(guān)的原數(shù)據(jù)文件缺失，你公司說文件已刪除

• Quality Control analysts shared the same user nameand password for the operating system on each workstation and the analyticalsoftware for the GC.
• QC化驗員共用工作站操作系統(tǒng)和GC分析軟件的用戶名和密碼

• Recovered solvent data on the stand-alone computerized system for the GC were not backed up as required per your approved procedure.
• 單機(jī)版本計算機(jī)化系統(tǒng)中的回收溶劑GC分析數(shù)據(jù)未按你們已批準(zhǔn)的程序備份

• Your firm did not have a procedure governing the audit trail or its retention. During the inspection, the GC analytical software was configured to retain the audit trail for only (b)(4).
• 你公司沒有程序?qū)徲嬜粉櫦捌浔４媲闆r進(jìn)行管理。在檢查期間，GC分析軟件的參數(shù)設(shè)置為審計追蹤僅保存XX

Your firm failed to include a comprehensive, systematic plan for evaluating your practices and procedures to ensure data integrity controls are applied throughout your firm. Additionally, you failed to conduct a risk assessment addressing potential impacts to product as a result of the inadequate data integrity controls.

你公司未包括一份評估你們做法和程序的全面系統(tǒng)化計劃，從而確保在整個公司對數(shù)據(jù)完整性進(jìn)行了控制。另外，你們未能執(zhí)行風(fēng)險評估，解決數(shù)據(jù)完整性控制不充分對產(chǎn)品的潛在影響問題。

Data Integrity Remediation 數(shù)據(jù)完整性補(bǔ)救措施

Your quality system does not adequately ensure the accuracy and integrity of data to support the safety, effectiveness, and quality of the drugs you manufacture. See FDA’s guidance document Data Integrity and Compliance With Drug CGMP for guidance on establishing and following CGMP compliant data integrity practices at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/data-integrity-and-compliance-drug-cgmp-questions-and-answers-guidance-industry.

你們的質(zhì)量體系不能充分確保數(shù)據(jù)的準(zhǔn)確性和完整性，無法支持你們生產(chǎn)的藥品的安全性、有效性和質(zhì)量。參見FDA指南文件“數(shù)據(jù)完整性和藥品GMP合規(guī)”指導(dǎo)建立和遵守CGMP合格數(shù)據(jù)完整性規(guī)范。

We strongly recommend that you retain a qualified consultant to assist in your data integrity remediation. In response to this letter, provide the following:
我們強(qiáng)烈建議你們正聘用顧問對你們的操作進(jìn)行審計并協(xié)助你們符合FDA要求。在回復(fù)此函時請?zhí)峤灰韵滦畔ⅲ?br />
• A comprehensive investigation into the extent of the inaccuracies in data records and reporting including results of the data review for drugs distributed to the United States. Include a detailed description of the scope and root causes of your data integrity lapses.

• 一份對數(shù)據(jù)記錄和報告不準(zhǔn)確性程度的全面調(diào)查。其中要包括一份對你們數(shù)據(jù)完整性問題范圍和根本原因的詳細(xì)說明。

• A current risk assessment of the potential effects of the observed failures on the quality of your drugs. Your assessment should include analyses of the risks to patients caused by the release of drugs affected by a lapse of data integrity and analyses of the risks posed by ongoing operations.

• 你們藥品質(zhì)量中所發(fā)現(xiàn)的不合格情況的潛在影響的當(dāng)前風(fēng)險評估。你們的評估應(yīng)包括由于受到數(shù)據(jù)完整性問題影響的藥品放行導(dǎo)致的患者風(fēng)險的分析，以及持續(xù)運(yùn)營所具有的風(fēng)險。

• A management strategy for your firm that includesthe details of your global CAPA plan. The detailed corrective action plan should describe how you intend to ensure the reliability and completeness of all data generated by your firm including microbiological and analytical data, manufacturing records, and all data submitted to FDA.
• 你們公司的管理策略，包括你們?nèi)駽APA計劃詳細(xì)情況。應(yīng)有一份詳細(xì)的CA計劃，說明你們準(zhǔn)備如何確保你們生成的所有數(shù)據(jù)的可靠性和完整性，包括分析數(shù)據(jù)、生產(chǎn)記錄和所有提交給FDA的數(shù)據(jù)。

CGMP Consultant Recommended CGMP顧問建議

Based upon the nature of the deviations we identified at your firm, we strongly recommend engaging a consultant qualified to evaluate your operations and to assist your firm in meeting CGMP requirements if your firm intends to resume manufacturing drugs for the U.S.market. We also recommend that the qualified consultant perform a comprehensive audit of your entire operation for CGMP compliance and that the consultant evaluates the completion and efficacy of your corrective actions and preventive actions before you pursue resolution of your firm’s compliance status with FDA.

鑒于我們在你公司所發(fā)現(xiàn)的違規(guī)情況，我們強(qiáng)烈建議你們使用一位有21 CFR 211.34所述資質(zhì)的顧問來協(xié)助你們公司符合CGMP要求。我們亦建議該具備資質(zhì)的顧問對你們整體運(yùn)營情況進(jìn)行藥品CGMP合規(guī)情況全面審計，并由其在你們尋求滿足FDA合規(guī)要求之前對你們CAPA的完成情況和有效性進(jìn)行評估。

Your use of a consultant does not relieve your firm’s obligation to comply with CGMP. Your firm’s executive management remains responsible for resolving all deficiencies and systemic flaws to ensure ongoing CGMP compliance.

你們使用顧問并不能解除你們公司符合CGMP的義務(wù)。你們公司的高級管理層仍負(fù)有義務(wù)全面解決所有缺陷，確保持續(xù)CGMP符合性。
Solvent Recovery Operations Terminated 停止溶劑回收操作

We acknowledge your commitment to terminate processing recovered solvents for customers at this facility for the U.S.market. If you plan to resume producing recovered solvents for the U.S. supply chain, notify this office in writing.

我們了解到你們承諾會停止在該場所為美國市場客戶回收溶劑。如果你們計劃繼續(xù)為美國供應(yīng)鏈回收溶劑，請書面通知本辦公室。

Conclusion 結(jié)論

The deviations cited in this letter are not intended to be an all-inclusive list of deviations that exist at your facility.You are responsible for investigating and determining the causes of these deviations and for preventing their recurrence or the occurrence of other deviations.

此函中所引用的違規(guī)并不是全部。你們有責(zé)任對這些偏差進(jìn)行調(diào)查，確定原因，防止其再次發(fā)生，防止你們設(shè)施內(nèi)其它偏差的發(fā)生。
FDA placed your firm on Import Alert 66-40 on April14, 2020.

FDA已于2020年4月14日將你公司置于進(jìn)口禁令66-40中。

Until you correct all deviations completely and we confirm your compliance with CGMP, FDA may withhold approval of any new drug applications or supplements listing your firm as a drug manufacturer.

在貴公司未能完成所有偏差糾正并且由我們確認(rèn)你們符合CGMP之前，F(xiàn)DA可能會擱置所有將你公司列為藥品生產(chǎn)商的新申報和增補(bǔ)申報的批準(zhǔn)。

Failure to correct these deviations may also resultin the FDA continuing to refuse admission of articles manufactured at Vega Life Sciences Private Limited at Plot No. D-15, 16, 21 & 22, Phase-I, I.D.A.Pashamylaram, Patencheru (M), Sangareddy District, Telangana into the United States under section 801(a)(3) of the FD&C Act, 21 U.S.C. 381(a)(3).Articles under this authority may be subject to refusal of admission, in that the methods and controls used in their manufacture do not appear to conform to CGMP 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(dǎo)致FDA依據(jù)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(chǎn)的產(chǎn)品進(jìn)入美國。

After you receive this letter, respond to this office in writing within 15 working days. Specify what you have done since our inspection to correct your deviations and to prevent their recurrence. If you cannot complete corrective actions within 15 working days, state your reasons for delay and your schedule for completion.

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

Send your electronic reply to CDER-OC-OMQ-Communications@fda.hhs.gov
Please identify your response with FEI 3015658387and ATTN: Rory Geyer.
Sincerely,
/S/
Francis Godwin
Director
Office of Manufacturing Quality
Office of Compliance
Center for Drug Evaluation and Research