Mr. Hideo Tagashira
Sekisui Medical Co., Ltd.
3-13-5, Nihombashi, Chuo-ku
Dear Mr. Tagashira:
The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Sekisui Medical Co., Ltd., at 4-115 Matsuo, Hachimantai, Iwate, from June 13 to 17, 2016.
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 July 8, 2016, response in detail and acknowledge receipt of your subsequent correspondence.
During our inspection, our investigator observed specific deviations including, but not limited to, the following.
1. Failure to maintain complete data derived from all laboratory tests conducted to ensure compliance with established API specifications and standards.
Our investigator found that you failed to maintain complete data from all laboratory analyses, and that you relied on the incomplete information to determine whether your drugs met established specifications. For example:
a. Numerous data files were found in the recycle bin folder on the computer connected to gas chromatography instruments GC-4 andGC-6. Specifically, our investigator found deleted data for residual solvent testing for (b)(4) lot (b)(4) in the recycle bin. Your records show that you retested the lot without documented justification or an investigation. You retained only the final test result.
b. During the inspection our investigator requested residual solvent release test data for two of your API, (b)(4) and (b)(4).You were unable to retrieve this data.
Any data created as part of a CGMP record must be retained so that it can be evaluated by the quality unit as part of release criteria and maintained for CGMP purposes.
We acknowledge that you commit to revising your SOP for archiving data. Your response is inadequate because it does not explain your failure to maintain complete records prior to the inspection. You also did not address validation of the systems you use to archive your data.
2. Failure to prevent unized access or changes to data, and failure to provide adequate controls to prevent omission of data.
Our investigator observed that your laboratory systems lacked controls to prevent deletion of and alterations to electronic raw data. You do not have adequate controls for seven of (b)(4) high performance liquid chromatography (HPLC) systems and one of (b)(4) gas chromatography systems. For example, the audit trail on HPLC 15 did not record the (b)(4)batch (b)(4) assay. Your records indicate that the assay was performed on March 3, 2014, but your audit trail shows no assays performed between February 28 and March 4, 2014. Moreover, your analyst demonstrated to our investigator that he could change the data, including injection time and date, without the changes being captured in the audit trail, prior to printing the results.
我們的調查人員發現你們化驗室係統缺乏控製，不能防止對電子原始數據的刪除和修改。你們的9台HPLC係統和1台GC係統都沒有充分的控製。例如，HPLC15的審計追蹤沒有記錄某批次的含量。你們的記錄顯示含量是在2014年3月3日檢測的，但你們的審計追蹤顯示在2014年2月28日至3月4日之間都沒有檢測過含量。還有，你們的化驗員向我們的調查人員證實他可以在結果打印之前更改數據，包括進樣時間和日期，並且其操作是審計追蹤無法捕獲的。We acknowledge that you have committed to upgrading your analytical systems to be compliant with CGMP requirements. However, procuring new instruments, installing new and upgraded data acquisition software, and enabling various features on software are not sufficient alone. These steps will be effective only if you implement appropriate procedures and systems to ensure that your quality unit reviews all production and control data and associated audit trails as part of the batch release process.
3. Failure to ensure that your analytical methods used to test API are appropriately validated and verified.
Our investigator found that your microbiological test methods were not adequately verified and that stability test methods were inadequately validated. For example:
a. (b)(4) of your nonsterile API are intended foruse in the manufacture of sterile finished dosage forms for U.S. distribution. You did not appropriately verify your test methods for total aerobic microbial count and total combined yeasts and molds. Specifically, you did not show that these methods are capable of recovering microorganisms in the presence of the API.
b. You did not demonstrate that your stability test methods are capable of detecting and resolving degradants from the main component as well as other (b)(4) components. Specifically, you did not perform forced degradation studies for the related-substance test methods for (b)(4),(b)(4), and (b)(4).
We acknowledge that you have committed to verifying and validating your test methods, but you did not include a plan to evaluate API within expiry that were distributed to the United States.
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 data 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.
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.
B. 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 alapse of data integrity, and risks posed by ongoing operations.
C. A management strategy for your firm that includes the details of your global corrective action and preventive action plan. Your strategy should include:
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.
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.
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.