20160516 FDA警告信（德国BBT）节译

Warning Letter 320-16-12

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May 16, 2016


Mr. Hans Peter Oeltze

Head of Quality Assurance

BBT Biotech Gmbh

Arnold-Sommerfeld-Ring 28

Baesweiler, Germany 52499



Dear Mr. Oeltze:



The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, BBT Biotech GMBH at Arnold-Sommerfeld-Ring 28, Baesweiler, Germany, from May 4–7, 2015.

FDA于2015年5月4-7日对你公司德国的工厂进行了检查。

This warning letter summarizes significant deviations from current good manufacturing practice (CGMP) for active pharmaceutical ingredients (API).

本警告信总结了严重的原料药CGMP违规。

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).

  由于你们的方法、设施或生产控制、加工、包装或保存不符合CGMP，你们的原料药被作为掺假药。

We reviewed your May 26, 2015, response in detail and acknowledge receipt of your subsequent responses.

  我们详细审核了你们公司于2015年5月26日的回复，并且我们也收到了你们后面的回复。

During the inspection, our investigators observed specific deviations including, but not limited to, the following.

  我们的调查员在检查期间发现了一些偏差，包括但不仅限于以下：

1.     Failure to follow a documented, on-going stability testing program to monitor the stability characteristics of API and to use the results to confirm appropriate storage conditions and retest or expiry dates.

未能遵守书面的持续稳定性试验计划，监测原料药的稳定性特性，使用结果来确认适当的存贮条件和复验或有效期

You did not follow your stability program, SOP No. Q-0007. According to your SOP, you must fully test at least (b)(4) batch of (b)(4) API (b)(4) for stability at defined stability intervals. Your firm could not provide any stability data to support the (b)(4) expiration date assigned to your (b)(4) API.

你们没有遵守你们的稳定性计划，SOP Q-0007。根据你们的SOP，你们必须对原料药按照既定的稳定性时间间隔至少X批进行稳定性全检，你们公司不能提供任何稳定性数据来支持给定你们原料药的XX有效期。

For example, since January 2012, you shipped approximately (b)(4) batches of (b)(4) API to the United States for which you have no stability data to support your expiration dates. Without stability data for your API, you could not assure that your API met specifications when used by your customers.

例如，自从2012年，你们发运约XX批YY原料药至美国，你们没有稳定性数据来支持你们有效期。没有稳定性数据，你们不能确保你们原料药在你们客户使用时仍符合质量标准。

We acknowledge your commitment to follow your SOP and perform the required stability testing on future batches. However, your response was inadequate because you failed to include any retesting of the API already distributed.

我们知道你们承诺要遵守你们的SOP，承诺对将来批次实施所需的稳定性试验。但是，你们的回复是不充分的，因为你们未能包括已经销售的原料药的复测。

In response to this letter, provide data evaluating whether all API batches potentially in United States supply chain within expiry are stable for the assigned (b)(4) expiration date.

在回复此函时，请提供数据评估是否所有可能在美国供应商的在有效期内的原料药批次在给定的XX有效期内是稳定的。

2.     Failure to establish and follow a change management system evaluating all changes that could affect the production and control of your API, and failure to evaluate the potential effect changes may have on the quality of your API.

未能建立和遵守变更管理系统，评估可能影响你们原料药生产和检验的所有变更，未能评估变更对你们原料药质量的可能影响

Your firm did not have a change management program. You did not require the quality unit to review or approve changes in suppliers. In 2012, your firm changed your crude (b)(4) supplier from (b)(4) to (b)(4). In 2013, you added (b)(4) to your list of suppliers. You did not provide change management documentation or any other documentation for these supplier changes. Without adequate evaluation for critical raw material changes, you could not assure the acceptability of your API manufactured using materials from different suppliers.

你们公司没有变更控制程序。你们没有要求质量部门审核或批准供应商变更。在2012年，你们公司变更了你们的粗XX供应商，从XX改成YY。在2013年，你增加YY到你们的供应商清单中。你们没有提供这些供应商变更的变更控制文件，或任何其它文件记录。对于关键原材料变更没有充分的评估，你不能确保你们采用来自不同供应商的原料生产的原料药的可接受程度。

Your response was inadequate because you failed to provide any information regarding the effect of supplier changes on the distributed API, such as the effect of changes on the impurity profile or the stability of your API.

你们的回复是不充分的，因为未能提供供应商变更对所销售的原料药的影响的信息，例如，变更对你们原料药杂质概况或稳定性的影响。

In response to this letter, provide the following:

在回复此函时，提供以下内容：

a plan to establish and follow a change management program
一份计划，建立和遵守一个变更管理程序
an evaluation of the changes on the impurity profile and stability for your API
一份变更对你们原料药的杂质概况和稳定性的评估
a risk assessment regarding the effects of your supplier changes on the distributed API
一份风险评估，评估你们供应商变更对所销售的原料药的影响
3.     Failure to adequately investigate out-of-specification (OOS) results.

未能充分调查OOS结果

During the inspection, our investigators documented that lot #(b)(4) was rejected after it failed in-process control testing for the (b)(4), which is deemed a critical in-process control (including the control point and method) for your API. Although your investigation identified the supplier change as a possible root cause for the failure, you did not evaluate other lots made with crude (b)(4) from the same supplier. For example, you used the same crude (b)(4) from the new supplier in API lot #(b)(4), which you failed to evaluate before shipping to the United States.

在检查期间，我们的调查人员记录了XX批在中控检验不合格之后被拒收，这是你们原料药的一个关键的中控检验（包括控制点和方法）。尽管你们的调查将供应商变更作为失败的可能根本原因，你们并没有评估采用来自相同供应商的粗XX生产的其它批次。例如，你们在YY批原料药中使用了相同的粗XX，来自新的供应商，你们在发往美国之前未能评估。

We acknowledge your commitment to follow an updated SOP requiring a root cause analysis for in-process OOS results. However, your response was inadequate because it did not assess the effects of the failure to adequately investigate in-process OOS results or indicate how this failure may have affected your API quality.

我们知道你们承诺遵守更新后的SOP，要求对中控OOS结果进行根本原因分析。但是，你们的回复是不充分的，因为它没有评估不充分中控OOS结果调查的影响，或显示此不合格可能如何影响你们的原料药质量。

In response to this letter, provide a comprehensive assessment of all in-process OOS results for (b)(4), including root causes. Extend this assessment to other batches that might have been affected. Also provide a detailed evaluation of all in process attributes and parameters in terms of their roles in the process and impact on the product and in-process material.

在回复此函时，请提供对XX的中控OOS结果的一份全面评估，包括根本原因。将此评估延伸至其它可能受到影响的批次。还要提供一份详细的评估，评估所有中控属性和参数，考虑其在工艺的作用，及对产品和中控原料的影响。

4.     Failure to exercise sufficient controls over computerized systems to prevent unauthorized access or changes to data, and to provide adequate controls to prevent omission of data.

未能对计算机化系统进行充分的控制，防止未经授权进入或改变数据，提供充分的控制来防止删除数据。

Our investigator found that your (b)(4) system used for (b)(4) and (b)(4) testing lacked access controls and audit trail capabilities. For example, all employees had administrator privileges and shared one user name, so actions could not be attributed or traced to specific individuals. This exposed your electronic data to manipulation and/or deletion without traceability.

我们的调查人员发现你们用于AA和BB测试的XX系统缺乏登录控制和审计追踪能力。例如，所有员工均有管理员权限，共用同一个用户名，因此所做的操作无法归属或追溯到特定的个人。这将你们的电子数据暴露于篡改和/或删除风险之下，且没有追溯性。

Our investigator also noted that your firm copied raw data to a CD (b)(4), and then deleted the data from the (b)(4) system to free space on the hard drive. Files copied to the CD were selected manually; the selection process was not supervised. Without audit trail capabilities or supervised file selection, there was no assurance that all raw data files were copied to the CD before they were permanently deleted from the system.

我们的调查人员还注意到你们公司复制了原始数据到CD中，然后将数据从系统中删除，以释放硬盘空间。拷贝到CD上的文件是人工选择的，选择过程没有监管。没有审计追踪能力，没有监管文件选择，在它们从系统上永久删除之前不能确保所有原始数据文件被拷贝到CD上。

We acknowledge your commitment to hire a third-party expert to install audit trails and other controls to ensure that data cannot be deleted from this electronic system. However, your response was inadequate. Simply preventing data deletion is not sufficient. You did not show how these steps will ensure that your firm retains and evaluates all data, including laboratory data, created as part of a CGMP record prior to release of your API.

我们知道你们承诺要雇佣一位第三方专家来安装审计追踪和其它控制来确保数据不会从该电子系统中删除。但是，你们的回复是不充分的。仅是防止数据删除是不够的。你们不能显示出这些步骤如何确保你们公司保存和评估所有数据，包括实验室数据，在你们放行原料药之前创建作为CGMP记录一部分。

In your response to this letter, investigate your retention and review of CGMP data and provide the results. Focus on your firm’s review and retention of laboratory raw data. In addition, provide your interim plan for reviewing and retaining data while your firm is in the process of implementing access controls and audit trail capabilities.

在回复此函时，请调查你们CGMP数据保存和审核情况，提交调查结果。关注你们公司对实验室原始数据的审核的保留。此外，当你们公司在实施权限和审计追踪能力过程中，提交你们审核和保留数据的临时计划。

Conclusion



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.



If, as a result of receiving this warning letter or for other reasons, you are considering a decision that could reduce the number of drugs produced by your manufacturing facility, FDA requests that you contact CDER’s Drug Shortages Staff immediately at drugshortages@fda.hhs.gov so that we 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 in the manufacture of your drug under 21 U.S.C. 356C(a)(1), 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. In appropriate cases, you may be able to take corrective action without interrupting supply, or to shorten any interruption, thereby avoiding or limiting drug shortages.



After you receive this letter, you have 15 business days to respond to this office in writing. 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 business days, state your completion date and reasons for delay.



Until you completely correct all deviations and we confirm your compliance with CGMP, FDA may withhold approval of any new applications or supplements listing your firm as an API manufacturer. Failure to correct these deviations may also result in FDA refusing admission of articles manufactured at BBT Biotech Gmbh, Arnold-Sommerfeld-Ring 28, Baesweiler, 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).



Send your reply to:



Lixin (Leo) Xu, M.D., Ph.D.

Compliance Officer

U.S. Food and Drug Administration

White Oak Building 51, Rm. 4359

10903 New Hampshire Avenue

Silver Spring, MD 20993

USA



Send your electronic reply to CDER-OC-OMQ-Communications@fda.hhs.gov



Please identify your response with FEI # 3005761912.



Sincerely,

/S/

Francis Godwin

Acting Director

Office of Manufacturing Quality

Office of Compliance

Center for Drug Evaluation and Research

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