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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(jì)追蹤顯示某USP批號(hào)某產(chǎn)品18個(gè)月穩(wěn)定性檢測(cè)有未知雜質(zhì)含量多個(gè)積分，但沒(méi)有適當(dāng)?shù)奈募涗洝⒄撟C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(duì)這些色譜數(shù)據(jù)進(jìn)行重新處理時(shí)，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(shí)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(hào)24個(gè)月的穩(wěn)定性結(jié)果，承諾要使用自動(dòng)積分功能。你們的回復(fù)是不充分的，因?yàn)榛貜?fù)并沒(méi)有對(duì)失敗的18個(gè)月穩(wěn)定性結(jié)果進(jìn)行說(shuō)明，也沒(méi)有證明你們要如何確保你們能夠保存所有檢測(cè)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(yàn)時(shí)遵守和記錄化驗(yàn)室檢驗(yàn)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(yàn)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(gè)月穩(wěn)定性測(cè)試樣品是在2015年2月14日進(jìn)入化驗(yàn)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(cè)的，在你們的方案顯示樣品甚至還沒(méi)進(jìn)到化驗(yàn)室的1-2天之前。你們沒(méi)有發(fā)現(xiàn)對(duì)應(yīng)這些測(cè)試的原始數(shù)據(jù)。HPLC的使用日志也沒(méi)有這些樣品檢驗(yàn)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(gè)例子中，GC對(duì)某批號(hào)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(gè)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?yàn)槟銈儧](méi)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(píng)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(wú)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(qǐng)了顧問(wèn)來(lái)審計(jì)你們的操作，協(xié)助符合FDA要求。在回復(fù)此函時(shí)，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(duì)數(shù)據(jù)記錄和報(bào)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(duì)評(píng)估所覆蓋的所有化驗(yàn)室、生產(chǎn)操作和系統(tǒng)的總結(jié)，以及對(duì)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?dòng)梢粋€(gè)有資質(zhì)的第三方來(lái)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(píng)估。識(shí)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(wèn)題的所有部分。數(shù)據(jù)完整性問(wèn)題的根本原因的描述，包括認(rèn)定當(dāng)前行動(dòng)計(jì)劃的范圍和深度與調(diào)查和風(fēng)險(xiǎn)評(píng)估發(fā)現(xiàn)相稱的證據(jù)。說(shuō)明是否對(duì)數(shù)據(jù)完整性問(wèn)題承擔(dān)責(zé)任的個(gè)人仍有能力對(duì)你公司對(duì)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(shí)描述，描述你們已采取的行動(dòng)，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(cè)試、向穩(wěn)定性試驗(yàn)計(jì)劃中增加批次以確保穩(wěn)定性、藥品申報(bào)行動(dòng)以及加強(qiáng)投訴監(jiān)測(cè)。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(zhǎng)期措施，其中描述所有對(duì)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(duì)上述活動(dòng)已開(kāi)展或已經(jīng)完成的狀態(tài)報(bào)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