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近日，F(xiàn)DA發(fā)布了對LCC Ltd.的警告信，其中包含多個(gè)實(shí)驗(yàn)室數(shù)據(jù)完整性問題：

 

在中控實(shí)驗(yàn)室垃圾桶中看到丟棄的原始數(shù)據(jù)（例如pH 測試記錄）。審查發(fā)現(xiàn)測試日期、pH 校準(zhǔn)數(shù)據(jù)與最終測試報(bào)告之間存在差異。

 

在該垃圾桶中還發(fā)現(xiàn)了一份帶有測試數(shù)據(jù)（例如 pH 值、比重）的廢棄實(shí)驗(yàn)記錄，與所報(bào)告的試驗(yàn)記錄相比，測試日期不同。

 

在現(xiàn)場檢查過程中，QC實(shí)驗(yàn)室的高效液相色譜（HPLC）/氣相色譜 （GC）房間中看到垃圾桶裝滿了。后來回到該房間后，檢查人員發(fā)現(xiàn)垃圾桶空了，然后跟隨 QC 人員來到外面的垃圾箱，在那里員工取回了裝有丟棄測試數(shù)據(jù)的垃圾袋。

 

丟棄的測試數(shù)據(jù)包括不合格的 HPLC 分析計(jì)算，但所報(bào)告的結(jié)果是合格的。也未執(zhí)行OOS調(diào)查。

 

在該垃圾桶中還發(fā)現(xiàn)了熔點(diǎn)的原始數(shù)據(jù)，與所記錄的數(shù)據(jù)不完全匹配。

 

FDA要求查看檢驗(yàn)結(jié)果的電子原始數(shù)據(jù)時(shí)，工廠經(jīng)理表示數(shù)據(jù)已丟失。

 

無法提供用于成品藥 COA 報(bào)告的微生物檢測數(shù)據(jù)。

 

FDA在警告信中要求對現(xiàn)任和前任員工進(jìn)行訪談，以確定數(shù)據(jù)不準(zhǔn)確的性質(zhì)、范圍和根本原因。并建議這些訪談?dòng)捎匈Y質(zhì)的第三方進(jìn)行。

 

FDA還要求聘請有資質(zhì)的顧問進(jìn)行廣泛的年度審計(jì)，至少 2 年，以協(xié)助在執(zhí)行數(shù)據(jù)完整性補(bǔ)救協(xié)議后評估 CAPA 的有效性

 

FDA要求其告知是否聘請一名首席誠信官，該首席誠信官完全有權(quán)接收員工報(bào)告數(shù)據(jù)完整性問題的匿名投訴，并有權(quán)確保及時(shí)調(diào)查任何潛在的違規(guī)行為（通過獨(dú)立的質(zhì)量保證職能部門，以及在需要時(shí)來自外部實(shí)體的專業(yè)知識）。

 

翻譯如下：

 

Your firm failed to ensure that laboratory records included complete data derived from all tests necessary to ensure compliance with established specifications and standards (21 CFR 211.194(a)).

 

Your laboratory records lacked complete and trustworthy data to support the analyses performed.

 

你們的實(shí)驗(yàn)室記錄缺乏完整且值得信賴的數(shù)據(jù)來支持所進(jìn)行的檢測。

 

For example:

 

例如：

 

Our investigators observed original data (e.g., pH test     records) discarded in the trash located in your in-process laboratory. A     review of the discarded pH test records found discrepancies between the     test dates, pH calibration data, and the final test report. Additionally,     a discarded worksheet with test data (e.g., pH, specific gravity) was also     found in the trash with different dates for testing compared to the     reported worksheet.

 

我們的檢查人員看到丟棄在中控實(shí)驗(yàn)室垃圾桶中的原始數(shù)據(jù)（例如 pH 測試記錄）。對丟棄的 pH 測試記錄的審查發(fā)現(xiàn)，測試日期、pH 校準(zhǔn)數(shù)據(jù)與最終測試報(bào)告之間存在差異。此外，在垃圾桶中還發(fā)現(xiàn)了一份帶有測試數(shù)據(jù)（例如 pH 值、比重）的廢棄實(shí)驗(yàn)記錄，與所報(bào)告的試驗(yàn)記錄相比，測試日期不同。

 

During a walkthrough by the investigator, a full trash bin was     observed in the high-performance liquid chromatography (HPLC)/gas     chromatography (GC) equipment room of the quality control (QC) laboratory.     Upon later returning to the room, the investigator observed that the trash     bin was then empty, and then followed QC personnel to the outside dumpster     where the employee retrieved the trash bag with discarded test data. The     discarded test data included an HPLC assay calculation that failed     acceptance criteria, but the reported result was found within     specification. No out-of-specification (OOS) investigation was performed.     Additionally, raw data for melting point were also found in the trash and     did not completely match the data recorded.

 

在現(xiàn)場檢查過程中，質(zhì)量控制（QC）實(shí)驗(yàn)室的高效液相色譜（HPLC）/氣相色譜 （GC）設(shè)備房間中看到垃圾桶裝滿了。后來回到該房間后，檢查人員發(fā)現(xiàn)垃圾桶空了，然后跟隨 QC 人員來到外面的垃圾箱，在那里員工取回了裝有丟棄測試數(shù)據(jù)的垃圾袋。丟棄的測試數(shù)據(jù)包括未達(dá)到接受標(biāo)準(zhǔn)的 HPLC 分析計(jì)算，但所報(bào)告的結(jié)果是符合標(biāo)準(zhǔn)的。也未執(zhí)行OOS調(diào)查。此外，在垃圾桶中也發(fā)現(xiàn)了熔點(diǎn)的原始數(shù)據(jù)，與所記錄的數(shù)據(jù)不完全匹配。

 

Upon request to review the electronic raw data for your assay     test results generated for drug products distributed to the U.S. market,     your plant manager indicated the data was lost. In addition, you could not     provide the microbiological test data for testing reported on your     finished drug product COA upon request.

 

在要求查看美國市場藥品的檢驗(yàn)結(jié)果的電子原始數(shù)據(jù)時(shí)，你們的工廠經(jīng)理表示數(shù)據(jù)已丟失。此外，你們無法根據(jù)要求提供用于成品藥 COA 報(bào)告的微生物檢測數(shù)據(jù)。

 

In your response, you acknowledge that your laboratory system lacks appropriate procedures and controls to ensure the integrity of your data. While we acknowledge your commitment to remediate your laboratory system, your response fails to fully consider the gaps and uncertainties in a retrospective review when there is a significant adverse pattern of data that is discarded, lost, or recorded non-contemporaneously. Additionally, your response did not consider plans to assess your manufacturing operation’s documentation system to determine where they are insufficient.

 

在你們回復(fù)中，你們承認(rèn)實(shí)驗(yàn)室系統(tǒng)缺乏適當(dāng)?shù)某绦蚝涂刂拼胧﹣泶_保數(shù)據(jù)完整性。雖然我們知道你們致力于修復(fù)實(shí)驗(yàn)室系統(tǒng)，但當(dāng)存在重大的不合格數(shù)據(jù)被丟棄、丟失或非同期記錄時(shí)，你們的回復(fù)未能充分考慮回顧性審查中的差距和不確定性。此外，你們的回復(fù)沒有考慮評估你們的文件系統(tǒng)以確定它們不足的地方。

 

Reliability of data is fundamentally compromised when there is a failure to record or maintain complete and accurate records of test results, or conditions associated with all tests. Furthermore, the lack of reliable data compromises the QU’s ability to exercise its function of ensuring compliance to applicable standards.

 

當(dāng)未能記錄或維護(hù)測試結(jié)果或與所有測試相關(guān)的條件的完整和準(zhǔn)確記錄時(shí)，數(shù)據(jù)的可靠性會受到根本影響。此外，缺乏可靠的數(shù)據(jù)損害了質(zhì)量部門行使其確保符合適用標(biāo)準(zhǔn)的職能的能力。

 

Data Integrity Remediation

 

數(shù)據(jù)完整性修復(fù)

 

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 documentData Integrity and Compliance With Drug CGMP for guidance on establishing and following CGMP compliant data integrity practices at https://www.fda.gov/media/119267/download.

 

你們的質(zhì)量體系無法充分確保數(shù)據(jù)的準(zhǔn)確性和完整性，以支持所生產(chǎn)的藥物的安全性、有效性和質(zhì)量。請參閱 FDA 指南《藥物 CGMP 數(shù)據(jù)完整性和合規(guī)性》，了解有關(guān)在建立和遵循 CGMP 合規(guī)數(shù)據(jù)可靠性實(shí)踐的指南。

 

We acknowledge that you are using an independent third-party consultant to perform data integrity (DI) training. However, we strongly recommend that you retain an independent third-party qualified consultant to audit your operation and assist in your DI remediation in meeting FDA requirements. In response to this letter, provide:

 

我們知道你們正在使用獨(dú)立的第三方顧問來執(zhí)行數(shù)據(jù)完整性（DI）培訓(xùn)。但是，我們強(qiáng)烈建議你們聘請獨(dú)立的第三方合格顧問來審核你們的操作，并協(xié)助你們的DI 補(bǔ)救以滿足 FDA 要求?；貜?fù)此函請?zhí)峁?/span>

 

A comprehensive investigation into the extent of the     inaccuracies in data records and reporting. Your investigation should     include:

 

對數(shù)據(jù)記錄和報(bào)告中不準(zhǔn)確程度的全面調(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;評估涵蓋的所有實(shí)驗(yàn)室、生產(chǎn)操作和系統(tǒng)的摘要;以及你們提議排除的任何部分的理由。

Interviews of current and former employees to identify the nature, scope, and root cause of data inaccuracies. We recommend that these interviews be conducted by a qualified third party.

 

對現(xiàn)任和前任員工進(jìn)行訪談，以確定數(shù)據(jù)不準(zhǔn)確的性質(zhì)、范圍和根本原因。我們建議這些訪談?dòng)捎匈Y質(zhì)的第三方進(jìn)行。

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.

 

評估你們工廠的數(shù)據(jù)完整性缺陷程度。識別遺漏、更改、刪除、記錄銷毀、非同步記錄和其他缺陷。描述發(fā)現(xiàn)數(shù)據(jù)完整性缺失的工廠操作的所有部分。

A comprehensive retrospective evaluation of the nature of the testing/manufacturing/other data integrity deficiencies. We recommend that a qualified third party with specific expertise in the area where potential breaches were identified should evaluate all data integrity lapses.

 

對檢驗(yàn)/生產(chǎn)/其他數(shù)據(jù)完整性缺陷的性質(zhì)進(jìn)行全面的回顧性評估。我們建議在發(fā)現(xiàn)潛在違規(guī)行為的領(lǐng)域具有特定專業(yè)知識的有資質(zhì)的第三方評估所有數(shù)據(jù)完整性問題。

 

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.

 

對所發(fā)現(xiàn)的失敗對藥物質(zhì)量的潛在影響的當(dāng)前風(fēng)險(xiǎn)評估。你們的評估應(yīng)包括分析因數(shù)據(jù)完整性失效而影響的藥物放行對患者造成的風(fēng)險(xiǎn)，以及分析持續(xù)操作帶來的風(fēng)險(xiǎn)。

 

A management strategy for your firm that includes the details     of your global CAPA plan. Your strategy should include:

 

貴公司的管理策略，包括CAPA 計(jì)劃的詳細(xì)信息。你們的策略應(yīng)包括：

 

A detailed corrective action plan that describes how you intend to ensure the reliability and completeness of all the data you generate including analytical data, manufacturing records, and all data submitted to FDA.

 

一份詳細(xì)的糾正行動(dòng)計(jì)劃，描述你們打算如何確保所生成的所有數(shù)據(jù)的可靠性和完整性，包括檢驗(yàn)數(shù)據(jù)、生產(chǎn)記錄和提交給FDA 的所有數(shù)據(jù)。

A comprehensive description of the root causes of your data integrity lapses, including evidence that the scope and depth of the current action plan is commensurate with the findings of the investigation and risk assessment. Indicate whether individuals responsible for data integrity lapses remain able to influence CGMP-related or drug application data at your firm.

 

對數(shù)據(jù)完整性失效的根本原因的全面描述，包括證明當(dāng)前行動(dòng)計(jì)劃的范圍和深度與調(diào)查和風(fēng)險(xiǎn)評估的結(jié)果相稱的證據(jù)。說明對數(shù)據(jù)完整性失誤負(fù)責(zé)的個(gè)人是否仍然能夠影響貴公司的CGMP 相關(guān)數(shù)據(jù)或藥物應(yīng)用數(shù)據(jù)。

 

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.

 

描述你們?yōu)楸Ｗo(hù)患者和確保藥物質(zhì)量而采取或?qū)⒁扇〉拇胧┑呐R時(shí)措施，例如通知用戶、召回商品、進(jìn)行額外檢測、在穩(wěn)定性計(jì)劃中增加批次以確保穩(wěn)定性、藥物應(yīng)用活動(dòng)和加強(qiáng)投訴監(jiān)控。

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，描述旨在確保公司數(shù)據(jù)完整性的程序、流程、方法、控制、系統(tǒng)、管理監(jiān)督和人力資源（例如，培訓(xùn)、人員配備改進(jìn)）的任何補(bǔ)救工作和改進(jìn)。

A commitment to have a qualified consultant conduct extensive annual audits, for at least 2 years, to assist in evaluating CAPA effectiveness after you have executed your data integrity remediation protocol.

 

承諾聘請有資質(zhì)的顧問進(jìn)行廣泛的年度審計(jì)，至少 2 年，以協(xié)助在執(zhí)行數(shù)據(jù)完整性補(bǔ)救協(xié)議后評估 CAPA 的有效性。

Inform FDA if you will be hiring a Chief Integrity Officer who is fully empowered to receive anonymous complaints from employees reporting data integrity concerns and with the authority to ensure any potential breach is promptly investigated (by independent quality assurance function, along with expertise from outside entities whenever needed).

 

告知FDA你們是否聘請一名首席誠信官，該首席誠信官完全有權(quán)接收員工報(bào)告數(shù)據(jù)完整性問題的匿名投訴，并有權(quán)確保及時(shí)調(diào)查任何潛在的違規(guī)行為（通過獨(dú)立的質(zhì)量保證職能部門，以及在需要時(shí)來自外部實(shí)體的專業(yè)知識）。

A status report for any of the above activities already underway or completed.

 

上述任何已進(jìn)行或已完成的活動(dòng)的狀態(tài)報(bào)告。