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12月24日，F(xiàn)DA發(fā)布了Viatris, Inc.（Viatris為Mylan(邁蘭)和Pfizer(輝瑞)子公司Upjohn(普強(qiáng))合并而成的新公司，中文名為暉致）的警告信，其中記錄了嚴(yán)重的數(shù)據(jù)完整性和實(shí)驗(yàn)室調(diào)查不當(dāng)問題，并在隨后發(fā)現(xiàn)工廠的現(xiàn)場(chǎng)質(zhì)量負(fù)責(zé)人、質(zhì)量控制負(fù)責(zé)人、質(zhì)量保證負(fù)責(zé)人、調(diào)查負(fù)責(zé)人和負(fù)責(zé)包材實(shí)驗(yàn)室的經(jīng)理違反了數(shù)據(jù)完整性政策，并被該公司辭退，F(xiàn)DA批評(píng)該公司質(zhì)量體系為無效的質(zhì)量體系：

 

組件（包材）放行檢測(cè)存在數(shù)據(jù)完整性問題。檢查人員查看了四張記錄并發(fā)現(xiàn)了異常。

 

該公司的考勤記錄為生物識(shí)別訪問記錄，其中記錄了包材檢測(cè)人員在檢測(cè)期間沒有實(shí)際出現(xiàn)在工廠。盡管他們不在，但他們記錄了測(cè)試過程和結(jié)果，就好像他們已經(jīng)進(jìn)行了檢測(cè)一樣。隨后該公司表示已查明出勤記錄無法支持分析人員在場(chǎng)完成他們所簽名的檢測(cè)。

 

在檢查之后，該公司擴(kuò)大了調(diào)查范圍，發(fā)現(xiàn)工廠的現(xiàn)場(chǎng)質(zhì)量負(fù)責(zé)人、質(zhì)量控制負(fù)責(zé)人、質(zhì)量保證負(fù)責(zé)人、調(diào)查負(fù)責(zé)人和負(fù)責(zé)包材實(shí)驗(yàn)室的經(jīng)理違反了數(shù)據(jù)完整性政策，并被該公司辭退。

 

在18個(gè)月和3個(gè)月的長(zhǎng)期穩(wěn)定性時(shí)間點(diǎn)的HPLC溶出度試驗(yàn)中分別出現(xiàn)OOS和OOT結(jié)果。分析人員在咨詢其主管后，在沒有提供充分論證的情況下中止了HPLC樣品組序列。也缺乏證據(jù)來證實(shí)根本原因。

 

將含量均勻性O(shè)OT結(jié)果歸因于HPLC柱泄漏。然而，儀器的審計(jì)追蹤并沒有記錄該問題（HPLC柱泄漏），并且使用了另一個(gè)的樣品和儀器進(jìn)行了復(fù)測(cè)。

 

FDA批評(píng)該公司質(zhì)量體系為無效的質(zhì)量體系：除了對(duì)實(shí)驗(yàn)室操作缺乏有效的管理監(jiān)督外，質(zhì)量部門無法行使適當(dāng)?shù)臋?quán)力和/或沒有充分履行其職責(zé)。

 

FDA提醒該公司有責(zé)任糾正在質(zhì)量保證程序?qū)徲?jì)（包括自檢）中發(fā)現(xiàn)的缺陷。

 

FDA要求該公司對(duì)過去五年內(nèi)所有質(zhì)量保證程序?qū)徲?jì)（包括自檢）和檢查進(jìn)行回顧，并提供完成審計(jì)中確定的所有相關(guān)糾正措施的時(shí)間表。認(rèn)證和/或時(shí)間表應(yīng)由Viatris，Inc.的首席執(zhí)行官簽署。

 

警告信翻譯如下：

 

Dear Mr. Smith:

 

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Mylan Laboratories Limited, Inc., “a Viatris company,” FEI 3010453141, located at Plot No. 11, 12 & 13, Indore SEZ Pharma Zone, Phase-II, Sector-III, Pithampur, Dhar, Madhya Pradesh, India, from June 14 to 26, 2024.

 

FDA于2024年6月14日至26日檢查了你們的藥品生產(chǎn)工廠Mylan Laboratories Limited， Inc.(“Viatris公司”，注冊(cè)號(hào)FEI 3010453141，位于印度中央邦達(dá)爾Pithampur印度經(jīng)濟(jì)特區(qū)制藥區(qū)ii期iii區(qū)第11、12和13號(hào)地塊。

 

This warning letter summarizes significant violations of Current Good Manufacturing Practice (CGMP) regulations for finished pharmaceuticals. See Title 21 Code of Federal Regulations (CFR), parts 210 and 211 (21 CFR parts 210 and 211).

 

本警告信總結(jié)了成品藥品嚴(yán)重違反現(xiàn)行良好生產(chǎn)規(guī)范（CGMP）規(guī)定的情況。參見21 CFR第210和211部分。

 

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

 

由于你們的生產(chǎn)、加工、包裝或保存的方法、設(shè)施或控制不符合CGMP，你們的藥品根據(jù)FD&C Act第501(a)(2)(B)條，21 U.S.C. 351(a)(2)(B)條被認(rèn)定為摻假。

 

We reviewed your July 18, 2024, response to our Form FDA 483 in detail and acknowledge receipt of your subsequent correspondence.

 

我們?cè)敿?xì)審查了你們2024年7月18日對(duì)FDA表格483的回復(fù)，并確認(rèn)收到了你們隨后的來信。

 

During our inspection, our investigators observed specific violations including, but not limited to, the following.

 

在我們的檢查中，檢查人員發(fā)現(xiàn)了具體的違規(guī)行為，包括但不限于以下情況。

 

1. Your firm failed to establish adequate written responsibilities and procedures applicable to the quality control unit and to follow written procedures applicable to the quality control unit (21 CFR 211.22(d)).

 

貴公司沒有建立足夠的適用于質(zhì)量控制部門的書面職責(zé)和程序，也沒有遵循適用于質(zhì)量控制部門的書面程序（21 CFR 211.22(d)）。

 

You failed to ensure the reliability and integrity of quality control data during component release testing at your facility. Our investigators identified anomalies in four worksheets that reported passing results for(b)(4) identification testing by chemical analysis.

 

你們未能確保組件放行檢測(cè)期間的質(zhì)量控制數(shù)據(jù)的可靠性和完整性。我們的檢查人員在四張記錄中發(fā)現(xiàn)了異常，這些記錄報(bào)告了通過化學(xué)分析進(jìn)行xx鑒定測(cè)試的合格結(jié)果。

 

Biometric access records documented that the responsible analysts were not physically present at the facility during testing. Despite their absence, they documented both the testing process and results as if they had conducted the analyses.

 

生物識(shí)別訪問記錄記錄了負(fù)責(zé)的分析人員在檢測(cè)期間沒有實(shí)際出現(xiàn)在工廠。盡管他們不在，但他們記錄了測(cè)試過程和結(jié)果，就好像他們已經(jīng)進(jìn)行了檢測(cè)一樣。

 

Data integrity is critical throughout the CGMP data life cycle, including in the creation, modification, processing, maintenance, archival, retrieval, transmission, and disposition of data after the record’s retention period ends.

 

數(shù)據(jù)完整性在整個(gè)CGMP數(shù)據(jù)生命周期中是至關(guān)重要的，包括數(shù)據(jù)的創(chuàng)建、修改、處理、維護(hù)、存檔、檢索、傳輸和在記錄保存時(shí)間結(jié)束后的處置。

 

In your response, you “…confirmed that certain test data generated in the Packaging Material Laboratory were not reliable…” and “…determined that attendance records did not support that the analyst was present to complete the testing for which they signed.” You commit to implement a Data Integrity Remediation Plan, which includes appointing a Data Integrity Lead to oversee and enhance compliance efforts.

 

在你們的回復(fù)中，你們“……確認(rèn)在包材實(shí)驗(yàn)室產(chǎn)生的某些測(cè)試數(shù)據(jù)不可靠……”并“……已查明出勤記錄無法支持分析人員在場(chǎng)完成他們所簽名的檢測(cè)。”你們承諾實(shí)施數(shù)據(jù)完整性補(bǔ)救計(jì)劃，其中包括任命一名數(shù)據(jù)完整性主管來監(jiān)督和加強(qiáng)合規(guī)工作。

 

We acknowledge that you suspended testing in the Packaging Material Laboratory, and initiated reserve sample testing for components. We also acknowledge that after the inspection, you expanded your investigations, which identified that the facility’s Site Head of Quality, Head of Quality Control, Head of Quality Assurance, Head of Investigations, and the Manager responsible for the packaging materials laboratory had violated your data integrity policies and were removed from your organization.

 

我們知道你們暫停了在包材實(shí)驗(yàn)室的測(cè)試，并開始了對(duì)組件的留樣樣品進(jìn)行測(cè)試。我們也知道，在檢查之后，你們擴(kuò)大了調(diào)查范圍，發(fā)現(xiàn)工廠的現(xiàn)場(chǎng)質(zhì)量負(fù)責(zé)人、質(zhì)量控制負(fù)責(zé)人、質(zhì)量保證負(fù)責(zé)人、調(diào)查負(fù)責(zé)人和負(fù)責(zé)包材實(shí)驗(yàn)室的經(jīng)理違反了你們的數(shù)據(jù)完整性政策，并被你們的組織辭退。

 

Your response is inadequate. It fails to provide sufficient details regarding the extent of the identified data integrity issues, and the thoroughness of your proposed corrective and preventive actions (CAPAs) is unclear.

 

你的答復(fù)是不充分的。它未能提供關(guān)于已識(shí)別數(shù)據(jù)完整性問題程度的足夠細(xì)節(jié)，并且不清楚你們所提議的糾正和預(yù)防措施（CAPA）的徹底性。

 

In subsequent communications following the inspection, you disclosed that both your site and global quality organization became aware of the data integrity issues related to component testing in January 2024. FDA is concerned that you did not adequately investigate or begin to implement holistic corrective actions until after the subsequent FDA inspection.

 

In response to this letter, provide:

 

在檢查后的后續(xù)溝通中，你們披露你們的工廠和全球質(zhì)量組織都在2024年1月意識(shí)到與組件測(cè)試相關(guān)的數(shù)據(jù)完整性問題。FDA擔(dān)心你們?cè)谟蠪DA檢查之后才充分調(diào)查或開始實(shí)施整體糾正措施。

 

2. Your firm failed to thoroughly investigate any unexplained discrepancy or failure of a batch or any of its components to meet any of its specifications, whether or not the batch has already been distributed (21 CFR 211.192).

 

你們公司未能徹底調(diào)查批次或其任何成分出現(xiàn)的任何無法解釋的差異或不符合標(biāo)準(zhǔn)，無論該批次是否已經(jīng)放行（21 CFR 211.192）。

 

Your investigations into discrepancies and out-of-specification (OOS) results lacked adequate scientific rationale to support root cause determinations. Specifically,

 

你們對(duì)差異和OOS結(jié)果的調(diào)查缺乏足夠的科學(xué)依據(jù)來支持根本原因的確定。具體的,

 

A.(b)(4) mg tablets, batches (b)(4) and (b)(4), exhibited OOS and out-of-trend (OOT) results during the dissolution test by high-performance liquid chromatography (HPLC) at the 18-month and 3-month long-term stability timepoints, respectively. The analyst, after consulting their supervisor, aborted the HPLC sample set sequence without providing adequate justification. You also lacked evidence to substantiate the root cause of improper (b)(4) of (b)(4).

 

(b)(4) mg片劑、批號(hào)XX和xx在18個(gè)月和3個(gè)月的長(zhǎng)期穩(wěn)定性時(shí)間點(diǎn)的高效液相色譜（HPLC）溶出度試驗(yàn)中分別出現(xiàn)OOS和OOT結(jié)果。分析人員在咨詢其主管后，在沒有提供充分論證的情況下中止了HPLC樣品組序列。你們也缺乏證據(jù)來證實(shí)根本原因。

 

B. You invalidated OOT assay results and during retest subsequently dismissed an anomalous content uniformity result for(b)(4) mg Capsules, batch (b)(4), attributing the original issue to HPLC column leakage. However, the equipment's audit trail did not document such an error, and you conducted retesting using different samples and equipment.

 

你們判定OOT測(cè)定結(jié)果無效，隨后在復(fù)測(cè)期間，你們駁回了xx批次xx mg膠囊的異常含量均勻性結(jié)果，并將最初的問題歸因于HPLC柱泄漏。然而，儀器的審計(jì)追蹤并沒有記錄該問題（HPLC柱泄漏），并且你們使用了另一個(gè)的樣品和儀器進(jìn)行了復(fù)測(cè)。

 

In your response, you acknowledge your inadequate laboratory investigations and data handling practices. Additionally, you commit to perform an extended evaluation across the rest of the laboratory to evaluate your laboratory practices and controls.

 

在你們的回復(fù)中，你們承認(rèn)你們的實(shí)驗(yàn)室調(diào)查和數(shù)據(jù)處理不充分。另外，你們承諾在實(shí)驗(yàn)室的其余部分執(zhí)行擴(kuò)大評(píng)估，以評(píng)估你們的實(shí)驗(yàn)室實(shí)踐和控制。

 

Your response is inadequate. The conclusions of your OOS investigations lack the necessary rigor and scope to thoroughly identify root causes, assess the extent of deviations, and evaluate their impact on drug products. You repeatedly accepted these conclusions, despite insufficient justification.

 

你們的答復(fù)是不充分的。你們OOS調(diào)查的結(jié)論缺乏必要的嚴(yán)謹(jǐn)性和范圍，無法徹底識(shí)別根本原因，評(píng)估偏差的程度，并評(píng)估其對(duì)藥品的影響。你一再接受這些結(jié)論，盡管沒有充分的理由。

 

For more information about handling failing, out-of-specification, out-of-trend, or other unexpected results and documentation of your investigations, see FDA’s current guidance documentInvestigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production at https://www.fda.gov/media/158416/download.

 

有關(guān)處理不合格、不符合標(biāo)準(zhǔn)、不符合趨勢(shì)或其他意外結(jié)果和調(diào)查文件的更多信息，請(qǐng)參閱FDA當(dāng)前的指導(dǎo)文件調(diào)查藥品生產(chǎn)不符合規(guī)格（OOS）的測(cè)試結(jié)果，網(wǎng)址為https://www.fda.gov/media/158416/download。

 

Ineffective Quality Systems

 

無效的質(zhì)量體系

 

Significant findings in this letter demonstrate that your firm does not operate an effective quality system in accord with CGMP. In addition to the lack of effective management oversight of your laboratory operations, we found your QU is not enabled to exercise proper authority and/or has insufficiently implemented its responsibilities. Executive management should immediately and comprehensively assess your company’s global manufacturing operations to ensure that your systems, processes, and products conform to FDA requirements.

 

此函中的重要發(fā)現(xiàn)證明你們公司沒有按照CGMP運(yùn)行有效的質(zhì)量體系。除了對(duì)你們的實(shí)驗(yàn)室操作缺乏有效的管理監(jiān)督外，我們還發(fā)現(xiàn)你們的質(zhì)量部門無法行使適當(dāng)?shù)臋?quán)力和/或沒有充分履行其職責(zé)。執(zhí)行管理層應(yīng)立即全面評(píng)估你們公司的全球生產(chǎn)運(yùn)營(yíng)，以確保你們的體系、流程和產(chǎn)品符合FDA的要求。

 

CGMP Consultant Recommendation

 

CGMP顧問推薦

 

We strongly recommend that your firm engage a consultant qualified as set forth in 21 CFR 211.34 to assist your firm in meeting CGMP requirements. 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.

 

我們強(qiáng)烈建議你們公司聘請(qǐng)符合21 CFR 211.34規(guī)定的顧問來協(xié)助你們公司滿足CGMP要求。你們使用顧問并不解除你們公司遵守CGMP的義務(wù)。你們公司的執(zhí)行管理層仍然有責(zé)任解決所有缺陷和系統(tǒng)性不足，以確保持續(xù)的CGMP符合性。

 

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/regulatory-information/search-fda-guidance-documents/data-integrity-and-compliance-drug-cgmp-questions-and-answers.

 

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，以支持你們生產(chǎn)的藥品的安全性、有效性和質(zhì)量。關(guān)于建立和遵循CGMP合規(guī)數(shù)據(jù)完整性實(shí)踐的指導(dǎo)，請(qǐng)參閱FDA指南：數(shù)據(jù)完整性和藥品CGMP合規(guī)性，網(wǎng)址為https://www.fda.gov/regulatory-information/search-fda-guidance-documents/data-integrity-and-compliance-drug-cgmp-questions-and-answers。

 

Quality Assurance Program Audits

 

質(zhì)素保證程序?qū)徲?jì)

 

FDA reminds Viatris, Inc. of their responsibility as a matter of CGMP to correct deficiencies found during quality assurance program audits, also referred to as “internal audits” in your correspondence with the FDA.

 

FDA提醒Viatris， Inc.有責(zé)任糾正在質(zhì)量保證程序?qū)徲?jì)中發(fā)現(xiàn)的缺陷，在你們與FDA的通信中也被稱為“內(nèi)審”。

 

In response to this letter, conduct a review of all quality assurance program audits and inspections within the last five years at all Viatris, Inc. facilities. Provide written certification that required corrective actions for such audits and inspections have been taken. If, upon your review or the review by any pertinent party working on your behalf, it is determined that actions have not been taken, provide a timeline for completion for all related corrective actions identified in the audits. The certification and/or timeline should be signed by the CEO of Viatris, Inc.

 

回復(fù)此函，對(duì)過去五年內(nèi)所有Viatris， Inc.工廠的所有質(zhì)量保證程序?qū)徲?jì)和檢查進(jìn)行回顧。提供書面證明，證明已對(duì)此類審計(jì)和檢查采取了糾正措施。如果經(jīng)貴司或代表貴司工作的任何相關(guān)方回顧確定未采取措施，請(qǐng)?zhí)峁┩瓿蓪徲?jì)中確定的所有相關(guān)糾正措施的時(shí)間表。認(rèn)證和/或時(shí)間表應(yīng)由Viatris， Inc.的首席執(zhí)行官簽署。