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      [GMP] FDA對印度Srikem發布警告信: 數據完整性與實驗室管理問題
      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
      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).
      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).
      We reviewed your January 12, 2016, response in detail and acknowledge receipt of your subsequent correspondence.
      During our inspection, our investigators observed specific deviations, including, but not limited to, the following.
      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.
      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.
      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.
      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.
      2. Failure to follow and document laboratory controls at the time of performance.
      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.
      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.
      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.
       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.

      A.  A comprehensive investigation into the extent of the inaccuracies in data records and reporting. Your investigation should include: 
      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.
      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.
      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.
      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.
      A status report for any of the above activities already underway or completed.
      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
      Please identify your response with FEI 3005048741.
      Francis Godwin
      Acting Director
      Office of Manufacturing Quality
      Office of Compliance
      Center for Drug Evaluation and Research

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