Return Receipt Requested
November 8, 2016
Mr. Srinivasan Subramaniam
Managing Director
Srikem Laboratories Pvt. Ltd.
Plot No. 17/24, MIDC Taloja
Navi Mumbai, MH 410208
India
印度Srikem
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.
This warning letter summarizes significant deviations from current good manufacturing practice (CGMP) for active pharmaceutical ingredients (API).
FDA在2015年12月14-18日檢查了你們在孟買的生產場所。本警告信總結了你們原料藥生產CGMP嚴重違規情況。
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).
由於你們生產、加工、包裝和保存的方法、設施和控制不符合CGMP要求，你們的藥品根據FDCA的定義被認為是摻假藥品。
We reviewed your January 12, 2016, response in detail and acknowledge receipt of your subsequent correspondence.
我們詳細審核了你們於2016年1月12日及隨後發來的回覆。
During our inspection, our investigators observed specific deviations, including, but not limited to, the following.
在我們檢查期間，我們的調查人員發現的違規情況包括但不僅限於以下：
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生的完整數據，這些檢測是為了確保藥品符合既定質量標準而實施的。
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批號某產品18個月穩定性檢測有未知雜質含量多個積分，但沒有適當的文件記錄、論證和調查。
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.
你們質量保證部經理認可這些積分是不恰當的。當我們的調查人員要求你們使用適當的積分參數對這些色譜數據進行重新處理時，處理結果顯示未知雜質含量超標。你們的質量部門在做出批放行決策時必須審核所有相關的分析數據，以確定批產品質量。
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.
在你們的回覆中，你們提供了該批號24個月的穩定性結果，承諾要使用自動積分功能。你們的回覆是不充分的，因為回復並沒有對失敗的18個月穩定性結果進行說明，也沒有證明你們要如何確保你們能夠保存所有檢測的準確完整記錄。
2. Failure to follow and document laboratory controls at the time of performance.
未能在實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.
我們的調查人員發現化驗室記錄日期不一致的情況。例如，你們實施的方案記錄顯示24個月穩定性測試樣品是在2015年2月14日進入化驗室的。我們的調查人員要求查看HPLC數據。你們給我們調查人員提供的HPLC圖譜列印件顯示樣品是在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到化驗室的1-2天之前。你們沒有發現對應這些測試的原始數據。HPLC的使用日誌也沒有這些樣品檢驗運行的記錄。
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物質分析列印圖譜裡，日期是2014年8月26日。在你們的電腦系統中存貯的此分析的日期為2013年12月28日：比列印圖譜早了接近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.
在你們的回覆中，你們將數據不一致歸結於軟體故障，斷電和人員換班。你們的回覆是不充分的，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麼，都應確保你們賴以評估你們藥品質量的數據的準確性。
Data Integrity Remediation
數據完整性彌補措施
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.
你們的質量體系不能充分確保數據的準確性和完整性，無法支持你們生產的藥品的安全性、有效性和質量。我們知道你們聘請了顧問來審計你們的操作，協助符合FDA要求。在回復此函時，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:
一份對數據記錄和報告不準確性程度的全面調查。你們的調查應包括：
•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.
詳細的調查方案和方法學；對評估所覆蓋的所有化驗室、生產操作和系統的總結，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 data inaccuracies. We recommend that these interviews be conducted by a qualified third party.
與現有的和已離職的員工進行面談，找出數據不準確的表現、範圍、根本原因。我們建議這些面談由一個有資質的第三方來實施。
•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.
你們工廠數據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現數據完整性問題的所有部分。
• A comprehensive retrospective evaluation of the nature of the 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.
一份對數據完整性缺陷狀況的全面回顧性評估。我們建議由一個有資質的第三方裡具有該領域專業水平的專家評估所有數據完整性問題。
B.
A current risk assessment of the potential effects of the observed failures on the quality of your drugs. Your assessment should include analysesof the risks to patients caused by the release of drugs affected by a lapse of data integrity, and risks posed by ongoing operations.
對你們藥品質量中所發現的不合格情況的潛在影響的當前風險評估。你們的評估應包括由於受到數據完整性問題影響的藥品放行導致的患者風險的分析，以及持續運營所具有的風險。
C.
A management strategy for your firm that includes the details of your global corrective action and preventive action plan. Your strategy should include:
你們公司的管理策略，包括你們全球CAPA計劃詳細情況。你們的策略應包括：
• A detailed corrective action plan that describes how you intend to ensure the reliability and completeness of all of the data you generate, including analytical data, manufacturing records, and all data submitted to FDA.
詳細的CA計劃，描述你們如何確保你們生成的所有數據的可靠性和完整性，包括分析數據、生產記錄和所有提交給FDA的數據。
• 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.
一份完整的描述你們數據完整性問題的根本原因的描述，包括認定當前行動計劃的範圍和深度與調查和風險評估發現相稱的證據。說明是否對數據完整性問題承擔責任的個人仍有能力對你公司對CGMP相關或藥物應用數據產生影響。
• 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，描述你們已採取的行動，或即將採取用以保護患者確保你們藥品質量的努力，例如通知你們的客戶、召回產品、實施額外測試、向穩定性試驗計劃中增加批次以確保穩定性、藥品申報行動以及加強投訴監測。
• 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據完整性的程序、流程、方法、控制、系統、管理監管和人力資源（例如培訓、員工提高）的彌補和提升。
• A status report for any of the above activities already underway or completed.
對上述活動已開展或已經完成的狀態報告。