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FDA于6月12日发布了对河南利华制药有限公司的警告信，全是数据可靠性问题，包含纸质和电子数据和记录：
1. Failure of your quality unit to review and approve all appropriate quality-related documents. 你们的质量部门未能审核和批准所有质量相关的文件。
Our investigator observed numerous blank batch manufacturing records in an open cabinet in your manufacturing workshop office. Among these were multiple blank, product release forms marked with a red quality assurance release stamp as “Permitted to Leave [the] Factory.” Our investigator also observed two record issuance stamps for batch and page number in the open cabinet.
检查官在车间办公室的一个打开的柜子里，发现了很多空白批生产记录。在这些空白的记录中，由很多空白的产品放行单，盖有红色质量保证放行章——“允许出厂”。检查官还在这个柜子里面发现了两个记录发放用章，分别是批号章和页码章。
These blank records and stamps were uncontrolled, although your standard operating procedure states that your quality unit is responsible for release of blank CGMP records. Your quality unit failed to control these records to assure that information entered on these forms is accurate and reliable. The use of uncontrolled records without quality unit review and approval poses a risk to data integrity and adequate assurance of product quality. FDA recommends that, if used, blank forms be controlled by the quality unit or by another document control method.
虽然你们的SOP规定质量部门负责空白CGMP记录的发放，但是这些空白记录和章没有受控，你们的质量部门未能控制这些记录，以保证填入到这些表格中的信息是准确的和可靠的。使用不受控的、未经质量部门审核和批准的记录，造成了对数据可靠性和充分保障产品质量的风险。FDA建议，如使用空白记录，则应受控于质量部门，或者受控于其它文件控制手段。
In your response, you said the product release form was “stamped in advance for convenience of release and warehousing of products” from your facility. You also said the quality unit record controller “did not realize the risk of the damaged lock” on the cabinet containing the records and stamps.
在你们的回复中，解释产品放行单“提前盖章，便于放行和产品入库”。你们还解释质量部门文件控制人员“没有意识到放置记录和章的柜子上的损坏的锁所带来的风险”。
We note you revised your standard operating procedures and re-trained your quality personnel. Your response is inadequate because it does not provide assurance that your employees are adequately qualified and trained to perform their duties.
我们注意到你们修订了SOP，并再次培训了你们的质量人员。但是你们的回复不够充分，由于没能提供保证，确保你们的员工经过充分地资质确认和培训，来开展他们的职责。
2. Failure to maintain complete data derived from all laboratory tests conducted to ensure your API complies with established specifications and standards. 为能保存所有实验室测试的完整数据，以确保你们的API符合既定标准。
You used a (b)(4) instrument (FK03011) for stability testing for multiple API, including (b)(4) and (b)(4). You subsequently used the same instrument and software to perform in-process analytical testing. Our investigator reviewed the audit trail on this instrument and observed that the software was configured to permit continuous use of the “preview run” function and routine overwriting of previous runs. Only the final “preview run” (b)(4) in each project folder was retained.
你们使用XX仪器（FK03011）进行多个API的稳定性测试，包括XX产品和XX产品。你们随后i也使用这台仪器和软件进行生产过程样品的分析检测。检查官审核了这台仪器上的审计追踪，发现该软件被配置为允许连续使用“预览运行”功能，并程序性地覆盖之前的运行记录。只有每个项目文件中的最后一次“预览运行”被保存。
Our review of the audit trail demonstrated that multiple distinct (b)(4) were performed and that the length of each (b)(4) was consistent with the time required to perform blank, sample, and standard (b)(4). It is essential to retain raw data to ensure the ability to reconstruct CGMP activities and to review raw data, as necessary, for CGMP control testing.
对审计追踪的审核显示XX产品明显进行了多次检测，并且每次检测的时长与进行空白、样品、和标准品的进样时间一致。对于CGMP质量控制检测，必须保留原始数据，保证重现CGMP活动的能力，并在必要时可以审核原始数据。
In your response, you stated the software did not allow retrieval of “non-data acquisition (b)(4),” and you did not realize that you needed to retain the preview run data. We acknowledge that you intend to replace the affected (b)(4) instruments. 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 you retain data as required so that your quality unit can review production and control data and associated audit trails as part of evaluating whether your API complies with all established criteria for in-process and stability testing.
在你们的回复中，声明这个软件不允许恢复“XX的无数据采集”，并且你们没有意识到需要保留预览运行数据。我们知道你们打算替换受影响的XX仪器。然而，仅仅通过获取新仪器，安装新的升级了的数据采集软件，和在软件上使用多项新特性，是不够的。只有当你们实施了适当的规程和体系，保证了所有需要的数据都被保留，以便于质量部门审核生产和检测数据以及相关的审计追踪数据，作为评价你们的API（不管是生产过程样品还是稳定性样品）是否符合所有既定标准限度的一部分的情况下，这些步骤才会有效。
Data Integrity Remediation 数据可靠性补救措施
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 committed to using a consultant to assist in meeting FDA requirements. In response to this letter, provide the following.
你们的质量体系不能充分保证数据的准确性和可靠性，以支持你们生产的药品的安全性、有效性和质量。我们知道你们承诺使用顾问，来帮助你们符合FDA的要求。在对本警告信的回复中，提供下列信息：
A. A comprehensive investigation into the extent of the inaccuracies in data records and reporting. Your investigation should include:
一份针对数据记录的不准确性的程度的综合调查和报告。你们的调查应包括：
- 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.
- 一份详尽的调查方案和方法；一份调查所覆盖的所有实验室、生产操作和系统的汇总；以及针对你们想要将任何一部分排除在调查之外的解释说明。
- 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.
- 与现在及离职了的员工谈话，识别数据不准确的本质、范围以及根本原因。我们建议这些谈话由一个有资质的第三方来进行。
- 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.
- 一份你们工厂数据可靠性缺陷程度的评估。识别遗漏、修改、删除、记录毁坏、不及时记录及其它缺陷。描述所有发现数据可靠性问题的操作的所有方面。
- A comprehensive retrospective evaluation of the nature of the testing and manufacturing 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.
- 一份对检测和生产数据可靠性问题的本质的综合性、回顾性的评估。我们建议由有资质的第三方，具备在发现问题领域特殊专业知识的人员，来评估所有的数据可靠性问题。
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 a lapse of data integrity, and risks posed by ongoing operations.
一份当前风险评估，评估所发现的问题对于你们生产的药品质量的潜在影响。你们的评估应包含由于放行了受数据可靠性漏洞影响的药品而对病人的风险的分析，以及由于当前活动所产生的风险。
C. A management strategy for your firm that includes the details of your global corrective action and preventive action plan. Your strategy should include:
一份你们公司的管理策略，包括你们整体纠正和预防措施计划的细节。你们的策略应包括：
- 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.
- 一份详细的修正预防措施计划，描述你们将怎样保证所有你们产生的数据的可靠性和完整i性，包括分析数据、生产数据、和所有递交给FDA的数据。
- 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.
- 一份对你们数据可靠性漏洞产生的根原因的综合性描述，包括可以证明你们所采取的行动的范围和深度与调查所发现的问题和风险评估相匹配的证据。明确需要为数据可靠性漏洞负责的相关人员是否可以继续在你们公司影响CGMP相关数据或药品申报数据。
- 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.
- 描述你们已经采取的行动，或者将要采取的行动，以保护病人和保证药品质量的过渡性措施。如通知你们的客户，召回产品，进行额外测试，增加稳定性研究的批次，以保证药品稳定性、药品申报行为、和提高合规监测。
- 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.
- 描述所有补救努力和提高规程、流程、方法、控制、系统、管理层监管和所设计的用于保证你们公司数据的可靠性的人力资源（如培训、人员改进）的长期措施。
- A status report for any of the above activities already underway or completed.
- 一份针对任何上述活动已经在进行中或已经完成的状态报告。
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发表于 2018-6-27 11:45:35
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