| [GMP] FDA對印度Srikem發(fā)布警告信: 數(shù)據(jù)完整性與實(shí)驗室管理問題 |
Your Preferred Partner to Compliance
November 8, 2016
Mr. Srinivasan Subramaniam
Managing Director
Srikem Laboratories Pvt. Ltd.
Plot No. 17/24, MIDC Taloja
Navi Mumbai, MH 410208
India
Dear Mr. Subramaniam:
The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Srikem Laboratories Pvt. Ltd., Plot No. 17/24, MIDC Taloja, Navi Mumbai, from December 14 to 18, 2015.
FDA在2015年12月14-18日檢查了你們在孟買的生產(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)了你們原料藥生產(chǎn)CGMP嚴(yán)重違規(guī)情況。
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).
由于你們生產(chǎn)、加工、包裝和保存的方法、設(shè)施和控制不符合CGMP要求，你們的藥品根據(jù)FDCA的定義被認(rèn)為是摻假藥品。
We reviewed your January 12, 2016, response in detail and acknowledge receipt of your subsequent correspondence.
我們詳細(xì)審核了你們于2016年1月12日及隨后發(fā)來的回復(fù)。
During our inspection, our investigators observed specific deviations, including, but not limited to, the following.
在我們檢查期間，我們的調(diào)查人員發(fā)現(xiàn)的違規(guī)情況包括但不僅限于以下：
1. Failure to have laboratory control records that include complete data derived from all laboratory tests conducted to ensure compliance with established specifications and standards.
化驗室檢驗記錄沒有來自所有化驗室檢驗中產(chǎn)生的完整數(shù)據(jù)，這些檢測是為了確保藥品符合既定質(zhì)量標(biāo)準(zhǔn)而實(shí)施的。
The audit trail for High Performance Liquid Chromatography (HPLC) instrument QCIEQPI40 showed multiple integrations conducted on the 18-month stability tests for unknown impurity content for (b)(4), USP lots (b)(4), without appropriate documentation, justification, and investigation.
HPLC儀器QCIEQP140儀器的審計追蹤顯示某USP批號某產(chǎn)品18個月穩(wěn)定性檢測有未知雜質(zhì)含量多個積分，但沒有適當(dāng)?shù)奈募涗?、論證和調(diào)查。
Your quality assurance manager agreed that these integrations were inappropriate. When our investigator asked you to reprocess the chromatograms using appropriate integration parameters, the results were out-of-specification for unknown impurity content. Your quality unit must review all pertinent analytical data when making batch release decisions in order to determine batch quality.
你們質(zhì)量保證部經(jīng)理認(rèn)可這些積分是不恰當(dāng)?shù)?。?dāng)我們的調(diào)查人員要求你們使用適當(dāng)?shù)姆e分參數(shù)對這些色譜數(shù)據(jù)進(jìn)行重新處理時，處理結(jié)果顯示未知雜質(zhì)含量超標(biāo)。你們的質(zhì)量部門在做出批放行決策時必須審核所有相關(guān)的分析數(shù)據(jù)，以確定批產(chǎn)品質(zhì)量。
In your response, you provided passing 24-month stability results for (b)(4) lots (b)(4), and committed to use the auto integration function. Your response is inadequate because it does not address the failing 18-month stability results for these lots and does not demonstrate how you will ensure that you retain complete and accurate records of all tests.
在你們的回復(fù)中，你們提供了該批號24個月的穩(wěn)定性結(jié)果，承諾要使用自動積分功能。你們的回復(fù)是不充分的，因為回復(fù)并沒有對失敗的18個月穩(wěn)定性結(jié)果進(jìn)行說明，也沒有證明你們要如何確保你們能夠保存所有檢測的準(zhǔn)確完整記錄。
2. Failure to follow and document laboratory controls at the time of performance.
未能在實(shí)施檢驗時遵守和記錄化驗室檢驗情況。
Our investigator observed inconsistently-dated laboratory records. For example, your executed protocol records show that a 24-month time-point stability testing sample of (b)(4), USP batch (b)(4), entered the laboratory on February 14, 2015. Our investigator requested the HPLC data. You provided our investigator HPLC chromatogram printouts showing that the sample was tested on February 12 and 13, 2015: one or two days before your protocol shows that the samples even entered the lab. You were unable to find any raw data corresponding to these tests. The use-log of the HPLC does not contain entries for these runs.
我們的調(diào)查人員發(fā)現(xiàn)化驗室記錄日期不一致的情況。例如，你們實(shí)施的方案記錄顯示24個月穩(wěn)定性測試樣品是在2015年2月14日進(jìn)入化驗室的。我們的調(diào)查人員要求查看HPLC數(shù)據(jù)。你們給我們調(diào)查人員提供的HPLC圖譜打印件顯示樣品是在2015年2月12日和13日檢測的，在你們的方案顯示樣品甚至還沒進(jìn)到化驗室的1-2天之前。你們沒有發(fā)現(xiàn)對應(yīng)這些測試的原始數(shù)據(jù)。HPLC的使用日志也沒有這些樣品檢驗運(yùn)行的記錄。
In another example, a printed chromatogram from related substance analysis performed by gas chromatography for (b)(4), batch (b)(4), was dated August 26, 2014. The data saved to your computer system from this analysis was dated December 28, 2013: nearly eight months before the date on the printed chromatogram.
在另一個例子中，GC對某批號所做的有關(guān)物質(zhì)分析打印圖譜里，日期是2014年8月26日。在你們的電腦系統(tǒng)中存貯的此分析的日期為2013年12月28日：比打印圖譜早了接近8個月。
In your response, you attributed data discrepancies to software malfunctions, power outages, and personnel shift changes. Your response is inadequate because you have not sufficiently explained how you are improving controls, notwithstanding these claimed sources of discrepancies, to ensure the reliability and accuracy of the data you rely on to evaluate the quality of your drugs.
在你們的回復(fù)中，你們將數(shù)據(jù)不一致歸結(jié)于軟件故障，斷電和人員換班。你們的回復(fù)是不充分的，因為你們沒有充分地解釋你們要如何改善你們的控制，不管這些所聲明的不一致的原因是什么，都應(yīng)確保你們賴以評估你們藥品質(zhì)量的數(shù)據(jù)的準(zhǔn)確性。
Data Integrity Remediation 數(shù)據(jù)完整性彌補(bǔ)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. We acknowledge that you are using a consultant to audit your operation and assist in meeting FDA requirements. In response to this letter, provide the following. 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。我們知道你們聘請了顧問來審計你們的操作，協(xié)助符合FDA要求。在回復(fù)此函時，提供以下資料： A. A comprehensive investigation into the extent of the inaccuracies in data records and reporting. Your investigation should include: 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。你們的調(diào)查應(yīng)包括： A detailed investigation protocol and methodology; a summary of all laboratories, manufacturing operations, and systems to be covered by the assessment; and a justification for any part of your operation that you propose to exclude. 詳細(xì)的調(diào)查方案和方法學(xué)；對評估所覆蓋的所有化驗室、生產(chǎn)操作和系統(tǒng)的總結(jié)，以及對你們意在排除的操作中所有部分的論證。 Interviews of current and former employees to identify the nature, scope, and root cause of da ta inaccuracies. We recommend that these interviews be conducted by a qualified third party. 與現(xiàn)有的和已離職的員工進(jìn)行面談，找出數(shù)據(jù)不準(zhǔn)確的表現(xiàn)、范圍、根本原因。我們建議這些面談由一個有資質(zhì)的第三方來實(shí)施。 An assessment of the extent of data integrity deficiencies at your facility. Identify omissions, alterations, deletions, record destruction, non-contemporaneous record completion, and other deficiencies. Describe all parts of your facility’s operations in which you discovered data integrity lapses. 你們工廠數(shù)據(jù)完整性缺陷的程度的評估。識別出省略、修改、刪除、記錄銷毀、不同步記錄填寫和其它缺陷。描述你們工廠操作中發(fā)現(xiàn)數(shù)據(jù)完整性問題的所有部分。數(shù)據(jù)完整性問題的根本原因的描述，包括認(rèn)定當(dāng)前行動計劃的范圍和深度與調(diào)查和風(fēng)險評估發(fā)現(xiàn)相稱的證據(jù)。說明是否對數(shù)據(jù)完整性問題承擔(dān)責(zé)任的個人仍有能力對你公司對CGMP相關(guān)或藥物應(yīng)用數(shù)據(jù)產(chǎn)生影響。 Interim measures describing the actions you have taken or will take to protect patients and to ensure the quality of your drugs, such as notifying your customers, recalling product, conducting additional testing, adding lots to your stability programs to assure stability, drug application actions, and enhanced complaint monitoring. 臨時描述，描述你們已采取的行動，或即將采取用以保護(hù)患者確保你們藥品質(zhì)量的努力，例如通知你們的客戶、召回產(chǎn)品、實(shí)施額外測試、向穩(wěn)定性試驗計劃中增加批次以確保穩(wěn)定性、藥品申報行動以及加強(qiáng)投訴監(jiān)測。Long-term measures describing any remediation efforts and enhancements to procedures, processes, methods, controls, systems, management oversight, and human resources (e.g., training, staffing improvements) designed to ensure the integrity of your company's data. 長期措施，其中描述所有對用以確保你們公司數(shù)據(jù)完整性的程序、流程、方法、控制、系統(tǒng)、管理監(jiān)管和人力資源（例如培訓(xùn)、員工提高）的彌補(bǔ)和提升。
A status report for any of the above activities already underway or completed.
對上述活動已開展或已經(jīng)完成的狀態(tài)報告。
Conclusion
Deviations cited in this letter are not intended as an all-inclusive list. You are responsible for investigating these deviations, for determining the causes, for preventing their recurrence, and for preventing other deviations in all your facilities.
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 that you contact CDER’s Drug Shortages Staff immediately, at drugshortages@fda.hhs.gov, so that FDA can work with you on the most effective way to bring your operations into compliance with the law. Contacting the Drug Shortages Staff also allows you to meet any obligations you may have to report discontinuances 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 depend on your products.
FDA placed your firm on Import Alert 66-40 on July 6, 2016.
Until you correct all deviations completely and we confirm your compliance with CGMP, FDA may withhold approval of any new applications or supplements listing your firm as a drug manufacturer.
Failure to correct these deviations may also result in FDA continuing to refuse admission of articles manufactured at Srikem Laboratories Pvt. Ltd. Plot No. 17/24, MIDC Taloja, Navi Mumbai, MH 410208, into the United States under section 801(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 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).
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.
Send your electronic reply to CDER-OC-OMQ-Communications@fda.hhs.gov or mail your reply to:
Carlos Gonzalez, Compliance Officer
U.S. Food and Drug Administration
White Oak, Building 51 Room 4359
10903 New Hampshire Avenue
Silver Spring, MD 20993
USA
Please identify your response with FEI 3005048741.
Sincerely,
Francis Godwin
Acting Director
Office of Manufacturing Quality
Office of Compliance
Center for Drug Evaluation and Research
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