FDA警告信：捷克Interpharm Praha A.S.（节译）

原文网址：http://www.fda.gov/ICECI/Enforce ... /2016/ucm525748.htm

Warning Letter 320-17-02

Via UPS                                                                                

Return Receipt Requested

October 18, 2016

Mr. Yuke Maki

CEO

Interpharm Praha A.S.

Komoranska 955

Praha 4

Modrany, Czech Republic

Dear Mr. Maki:

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Interpharm Praha A.S., at Komoranska 955, Praha, Modrany, from October 12 to 16, 2015.

美国FDA于2015年10月12-16检查了你们位于捷克的生产工厂。

This warning letter summarizes significant deviations from current good manufacturing practice (CGMP) for active pharmaceutical ingredients (API) and significant violations of CGMP regulations for finished pharmaceuticals, 21 CFR parts 210 and 211.

本警告信总结了你工厂原料药和制剂生产严重违背CGMP要求的情况，21CFR第210和211部分。

Because your methods, facilities, or controls for manufacturing, processing, packing, or holding do not conform to CGMP, your drugs are adulterated within the meaning of section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetics Act (the FD&C Act), 21 U.S.C. 351(a)(2)(B).

由于你们生产、加工、包装和保存的方法、设施和控制不符合CGMP要求，你们的药品根据FDCA的定义被认为是掺假药品。

We reviewed your November 6, 2015, response in detail.

我们详细审核了你们于2015年11月6日发来的回复。

During our inspection, our investigator observed specific violations and deviations including, but not limited to, the following.

在我们检查期间，我们的调查人员发现的违规情况包括但不仅限于以下：

API Deviations 原料药偏差

1.    Failure to prevent unauthorized access or changes to data, and to provide adequate controls to prevent manipulation and omission of data.

未能防止未经授权进入或改变数据，未能提供充分控制来防止对数据的篡改和删除。

Your quality control unit did not have basic controls to prevent changes to your electronically-stored laboratory data. Your analysts had user privileges to the Empower-2 system used to generate and analyze chromatographic data that allowed them to eliminate failing, atypical and satisfactory results with no notification; alter peak areas; and add or eliminate samples from sequences without authorization.

贵公司的质量控制部门没有基本的控制来防止对你们电子存贮的实验室数据进行变更。你们的化验员具有EMPOWER-2系统的用户权限，可以生成和分析色谱数据，能够删除不合格、异常和不满意的结果，而不需要通知；可以删除峰；可以增加和删除序列中的样品，不需要批准。

During the inspection, we reviewed an audit trail from your Empower-2 system that stored 8,906 entries. Of these, well over half indicated some form of data deletion or manipulation, including    at least 1,441 instances of deleted results, at least 3,643 instances of manual integration, and at least 194 instances of altered running sample sets. Your personnel confirmed that these actions are common during chromatographic data processing. We found that you did not have a procedure in place to indicate the requirements and level of restrictions for users of the automated system.

在检查期间，我们审核了你们EMPOWER-2系统里的审计追踪，其中存贮了8906条记录。这些记录里，有超过一半显示出数据删除和篡改，包括至少1441次结果删除，至少3643次手动积分，至少194次对运行样品序列的修改。你们的员工确认这些动作在色谱数据处理中是很常见的。我们发现你们没有制订程序，对自动化系统用户的受限层次和要求进行规定。

Your quality unit must review all pertinent analytical data when making batch release decisions. However, your automated system permitted analysts to delete and alter test results without authorization. As a result, your quality unit was presented with incomplete and inaccurate information about the quality of your drugs.

你们的质量部门在做出批放行决定时必须审核所有分析相关数据，而你们的自动化系统允许化验员删除和篡改检验结果，但不需要批准。在这种情况下，你们的质量部门对你们药品的质量的信息是不完整和不准确的。

According to your response, you restricted access and permissions in the Empower 2 automated data system. However, your response does not demonstrate how the specific controls you have implemented prevent deletion or alteration of data, nor have you shown how you will ensure that these permissions are documented, implemented, and followed. Finally, you have not shown how these controls ensure that records relied upon for batch release and other quality review decisions are complete and accurate.

根据你们的回复，你们限制了EMPOWER-2自动化数据系统里的进入和权限。但是，你们的回复没有证据说明你们所实施的具体控制是如何防止数据删除和篡改的，也没有展示你们要如何确保记录、实施和遵守这些许可流程。最后，你们没有展示出这些控制是如何确保这些批放行和其它质量审核决策所依赖的记录是完整和准确的。

2.    Failure to ensure that test procedures are scientifically sound and appropriate to ensure that your API conform to established standards of quality and/or purity.  

未能确保检验程序是科学合理的，适合于确保你们的原料药符合既定的质量和/或纯度标准。

Your laboratory procedures allowed analysts to modify chromatographic sequences and delete results with no justification.

你们的化验室程序允许化验员修改色谱序列和删除结果，不需要论证。

During our review of chromatograms generated during impurities testing for (b)(4), we observed that your analysts conducted many manual integrations. We also found discrepancies in peak integrations, including inconsistent integrations, and peaks that were not integrated at all. Such peaks could represent impurities: they were not included in data packages presented to your quality unit for batch release decisions. Therefore, your quality review and product release decisions were based on incomplete data regarding the quality of your drugs.

在我们审核你们对某产品纯度检验所生成的色谱图时，我我们发现你们的化验员做了许多手动积分。我们还发现峰积分差异，包括积分不一玩笑，有的峰完全没有积分。这些峰可能代表的是杂质，但没有包括在呈交给你们的质量部门批放行单曲循环所用的数据包里。因此，你们的质量审核和产品放行决策是依据不完整的药品质量数据的。

According to your response, you scheduled training on manual integration for all analysts who use Empower-2 software. You have not shown how you will ensure that your test methods are appropriate to determine whether your API conform to established standards and specifications.

根据你们的回复，你们计划对所有使用EMPOWER-2软件的化验员进行手动积分培训。你们没有说明你们要如何确保你们的检验方法适合于决定你们的原料药是否符合既定的标准和质量。

In response to this letter, provide your action plan for developing, validating, and implementing chromatographic test methods to analyze the quality attributes of your drugs. Specify the procedures you will implement to process your chromatographic data related to all test results and audit trail functionality. Detail how you will review chromatographic results as part of the batch release procedure and documentation. Specify the controls you will implement to ensure that any manual integration steps are performed only under defined, limited circumstances according to a protocol approved and supervised by your quality unit.

在回复此函时，请提交你们建立、验证和实施你们药品质量属性分析的色谱分析方法的行动计划。写明你们要实施用以处理你们的与所有检验结果和审计追踪功能的色谱数据的程序。详细说明你们要如何审核作为批放行程序和文件的一部分的色谱结果。写明你们将要实施用以确保所有手动积分步骤只有在预定的有限情形下根据质量部门批准和监管下操作的程序。

Finished Product Violations 制剂违规

1.    Your firm failed to exercise appropriate controls over computer or related systems to assure that only authorized personnel institute changes in master production and control records or other records (21 CFR 211.68(b)).

你们公司未能对计算机和相关系统进行适当控制以确保只有经过授权的人员才能对主生产和检验记录或其它记录进行修改(21 CFR 211.68(b))。

For example, our investigator reviewed an audit trail for impurities testing conducted on (b)(4) validation lot (b)(4), number(b)(4) vial # (b)(4), Injections 1 and 2. The audit trail revealed many deleted results and manual integrations.

例如，我们的调查人员审核了某产品验证批的杂质检验审计追踪，进样瓶XX进样序列1和2。审计追踪显示有许多记录被删除，有手动积分。

As discussed above, deleted and altered analytical test results mean that your quality unit is presented with incomplete and inaccurate information about the quality of your drugs.

如上所讨论，检验结果删除和篡改意味着你们的质量部门收到的是不完整不准确的药品质量信息。

2.    Your firm failed to establish laboratory controls that include scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure that components, drug product containers, closures, in-process materials, labeling, and drug products conform to appropriate standards of identity, strength, quality, and purity (21 CFR 211.160(b)).

贵公司未能建立对化验室的控制，包括科学合理和适当的质量标准、取样计划和检验方法，用以确保药品组份、药品容器、密闭器、在制品、标签和药品符合既定的鉴别、剂量、质量和纯度标准(21 CFR 211.160(b)).

Your laboratory procedures allowed analysts to modify and delete chromatographic results without adequate justification, and to use manual integration in uncontrolled circumstances.

你们的化验室程序让化验员可以修改和删除色谱结果，而没有充分的论证，并且在不受控的情况下使用手动积分。

For example, our investigator found results deleted after repeated manual integrations for (b)(4) stability lots (b)(4). Unjustified, repeated manual integrations and deletions indicate that your laboratory controls are not scientifically sound and appropriate to test your products.

例如，我们的调查人员发现某稳定性样品的色谱数据在反复手动积分之后又删除了结果。没有论证、重复手动积分和删除显示你们化验室的控制是不科学不合理的，不适合于检测你们的产品。

In your response to this letter, describe all steps you will take to ensure that appropriate laboratory controls have been implemented to support product quality review and batch release decisions. Include the controls you will implement for the modification, deletion, and manual integration of chromatographic test results.   

在你们对此函的回复中，请描述你们将要采取的所有用以确保实施适当的化验室控制来支持产品质量审核和批放行决策的措施。包括你们将要实施用以控制色谱检验结果修改、删除和手动积分的程序。

Data Integrity Remediation

Your quality system does not adequately ensure the adequacy and integrity of data to support the safety, effectiveness, and quality of drugs you manufacture. We strongly recommend that you retain a qualified consultant to assist in your remediation.

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 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 your data integrity deficiencies.
• We recommend that a qualified third party with specific expertise in the area where potential lapses were identified should evaluate all data integrity lapses.
  

B.  A current risk assessment of the potential effect 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 in data integrity, and risks posed by ongoing operations.

C.  A management strategy that includes the details of your global corrective action and preventive action plan. Your strategy should include:

• The 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 the FDA.
• 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 data.
• A status report for any of the above activities already underway or completed.
  

Conclusion

Violations and deviations cited in this letter are not intended as an all-inclusive list. You are responsible for investigating these violations and deviations, for determining the causes, for preventing their recurrence, and for preventing other violations and 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.

Until you correct all violations and 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 violations and deviations may also result in FDA refusing admission of articles manufactured at Interpharm Praha A.S., Komoranska 955, Praha 4, Modrany, 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 violations and 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

USA

Please identify your response with FEI 3002807299.

Sincerely,

/S/

Francis Godwin

Acting Director

Office of Manufacturing Quality

Office of Compliance

Center for Drug Evaluation and Research

来源：Julia