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FDA警告信：哥伦比亚Proquimes S.A.

蒲公英制药论坛 · 公众号 · 药品 · 2021-04-18 10:00

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看起来不是现场检查引起的，只是索取资料审查

Warning Letter 320-21-39

April 5, 2021

Dear Mr. De la Puente:

Your facility is registered with the United States Food and Drug Administration (FDA) as a manufacturer of active pharmaceutical ingredients (API). FDA has reviewed the records you submitted in response to our April 16, 2020, request for records and other information pursuant to section 704(a)(4) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), along with subsequent communication, pertaining to your facility, Proquimes S.A. Productos Quimico Especializados S.A., FEI3010165166, at Carrera 5 Norte No. 52-61, Cali Valle del Cauca.

你们的场所在 FDA 注册为 API 生产商。 FDA 已经审核了你们回复我们 2020 年 4 月 16 日索取 FDCA 第 704(a)(4) 节所要求的记录和其它信息，以及后续关于你们设施 Proquimes S.A.Productos Quimico Especializados S.A., FEI 3010165166, at Carrera 5 Norte No.52-61, Cali Valle del Cauca 的沟通时所提交的记录。

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

本警告信总结了原料药严重违反 CGMP 的行为。

Because your methods, facilities, or controls for manufacturing, processing, packing, or holding do not conform to CGMP, your drug products 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)).

由于你们的原料药生产、加工、包装或保存的方法、场所或控制不符合 CGMP 要求，你们的原料药根据 FDCA 的 501(a)(2)(B) 以及 21 U.S.C. 351(a)(2)(B) 被认为是掺假药品。

1. Failure to demonstrate that your manufacturing process can reproducibly manufacture an API meeting its predetermined quality attributes. 未能证明你们的生产工艺可以重复生产出符合其既定质量属性的 API 。

Your response to our request for records or other information pursuant to section 704(a)(4) indicates that you manufactured and distributed (b)(4) USP API to the United States (U.S.) without validating processes determined to be critical to the quality and purity of the API. For example, in response to our April 16, 2020, request to provide the process validation summary report for all U.S. marketed API, you indicated that you did not perform process validation and therefore did not provide any documents. Our subsequent communication on June 1, 2020, specifically requested process validation for the (b)(4) USP API that you distributed to the United States. You, again, indicated that the manufacturing process for this drug was not validated.

你们对我们索取记录或其它 704(a)(4) 节所要求的信息的要求回复显示你们在没有对工艺进行验证从而确定对 API 质量和纯度关键的参数就使用该工艺生产和销售 XX USP API 销往美国。例如，在对我们 2020 年 4 月 16 日要求提供所有在美国销售的 API 的工艺验证摘要报告的回复中，你们说你们没有执行工艺验证，因此未提供任何文件。我们后续于 2020 年 6 月 1 日的沟通，尤其是索取销往美国的 XX USP API 的工艺验证时，你们再次说该药品的生产工艺未进行验证。

Without process validation documentation, you cannot demonstrate that your manufacturing process can consistently produce API that meet predetermined quality attributes.

没有工艺验证资料，你们就无法证明你们的生产工艺可以持续生产出符合既定质量属性的 API 。

In response to this letter,provide the following for all API intended for the U.S. market:

在回复本函时，请提交准备在美国市场销售的所 API 的以下资料：

• A remediation plan that assures ongoing management oversight throughout the manufacturing lifecycle of all API.Provide a data-driven and scientifically sound program that identifies sources of process variability, and assures that manufacturing, including both production and packaging, operations meet appropriate parameters and quality standards. This includes, but is not limited to, evaluating suitability of equipment for its intended use, ensuring quality of input materials,determining the capability and reliability of each manufacturing process step and its controls, and vigilant ongoing monitoring of process performance and product quality.

• 一份补救计划，保证在所有 API 的整个生产生命周期中会进行持续管理监督。提交一份数据导向和科学合理的计划，识别出工艺波动来源，并保证生产（生产和包装）操作符合适当的参数和质量标准。其中包括但不仅限于设备适合其既定用途的稳定性评估，确保输入原料的质量，确定每个生产工艺步骤及其控制的能力和可靠性，并谨慎持续地监测工艺性能和产品质量。

• A detailed summary of your validation program for ensuring a state of control throughout the product lifecycle, along with associated procedures. Describe your program for process performance qualification, and ongoing monitoring of both intra-batch and inter-batch variation to ensure a continuing state of control.

• 一份对你们工艺验证计划以及相关程序的详细摘要，确保在产品生命周期中其处于受控状态。说明你们的工艺性能确认计划，以及对批间和批内波动的持续监测，从而确保持续受控状态。

• A timeline for performing process performance qualification (PPQ) for each of your marketed API.

• 一份对每个上市 API 实施工艺性能确认（ PPQ ）的时间表

• Include your process performance protocol(s), and written procedures for qualification of equipmentand facilities.

• 提交你们的工艺性能方案，以及设备和设施书面程序

• Provide a detailed program fordesigning, validating, maintaining, controlling and monitoring each of your manufacturing processes that includes vigilant monitoring of intra-batch and inter-batch variation to ensure an ongoing state of control. Also, include your program for qualification of your equipment and facility.

• 为你们每个生产工艺提交一份详细的设计、验证、维护、控制和监测计划，包括对批内和批间波动的谨慎监测，确保持续受控状态。还要包括你们设备和设施确认计划

2. Failure to adequately perform qualification of critical equipment and ancillary systems. 未能充分实施关键设备和辅助系统的确认

You have not conducted qualification of critical manufacturing equipment. For example, in response to our April 16, 2020, communication requesting qualification documentation for the equipment used to manufacture API distributed to the U.S., you indicated that you did not perform equipment qualification and thus could not provide any documents. Our subsequent communication on June 1, 2020, specifically asked whether you had performed qualification of the equipment used in the production of the (b)(4) USP API that you distributed to the United States. You indicated that this information was not available and the equipment was “unqualified.”

你们未对关键生产设备进行确认。例如，在对我们 2020 年 4 月 16 日要求提交用于生产销往美国的 API 所用设备的确认文件的回复中，你们说你们没有做设备确认，因此不能提供任何文件。我们后来在 2020 年 6 月 1 日沟通特别问到是否你们对销往美国的 XX USP API 生产所用设备进行确认，你们说没有这些资料，这些设备“未经确认”。

The continued and suitable performance of manufacturing equipment is important to ensure batch-to-batch consistency during the manufacturing of API.

生产设备的持续适当性能对于确保 API 生产期间的批间一致性是非常重要的。

In response to this letter, conduct a comprehensive evaluation of the equipment used at your facility throughout API manufacturing, and provide a corrective action and preventive action (CAPA) plan that ensures use of only suitably designed and well-controlled equipment.

在回复本函时，请对你们设施中整个 API 生产过程所用的设备进行全面评估，并提交 CAPA 计划确保仅使用经过适当设计和良好控制的设备。

3. Failure to adequately validate written procedures for the cleaning and maintenance of equipment. 未充分验证设备清洁和维护书面程序。

Your process of cleaning shared API manufacturing equipment is not validated. For example, in responseto our April 16, 2020, communication requesting the most recent cleaning validation summary reports for equipment used to manufacture API distributed to the U.S., you indicated that this information was not available and you did not perform cleaning validation. Our subsequent communication on June 1, 2020, specifically requested cleaning validation for the equipment used to manufacture the (b)(4) USP API that you distributed to the United States. You, again, indicated that the cleaning procedure was not validated.

你们的共用 API 生产设备的清洁工艺未经过验证。例如，在对我们 2020 年 4 月 16 日索取销往美国的 API 生产所用设备最近清洁验证总结报告的要求回复中，你们说没有这些资料，你们未进行清洁验证。我们后来在 2020 年 6 月 1 日的沟通，特别要求销往美国的 XX USP API 生产所用设备的清洁验证，你们再次说该清洁程序未经过验证。

Inadequate removal of raw materials and residues from manufacturing equipment during cleaning can result in cross-contamination of your API.

在清洁过程中不能充分清除生产设备中的原料和残留物可能会导致你们 API 产生交叉污染。

In response to this letter, provide the following for all API manufactured to date and intended for the U.S. market:

在回复本函时，请提交截止当前所生产准备销往美国的所有 API 以下资料：

• Appropriate improvements to your cleaning validation program, with special emphasis on incorporating conditions identified as worst case in your drug manufacturing operation. This should include but not be limited to identification and evaluation of all worst-case:

• 对你们清洁验证程序的适当改进，特别要注意将识别为药物生产操作最差情形的条件。其中包括但不仅限于识别和评估所有最差情形：

drugs with higher toxicities
高毒性药物
drugs with higher drug potencies
高效价药物
drugs of lower solubility in their cleaning solvents
在清洁溶剂中溶解度低的药物
drugs with characteristics that make them difficult to clean
难清洁药物
swabbing locations for areas that are most difficult to clean
最难清洁地方的擦拭点
maximum hold times before cleaning
清洁前最长放置时间

In addition, describe the steps that must be taken in your change management system before introduction of new manufacturing equipment or a new product.

另外，说明引入新的生产设备或新产品之前在你们变更管理体系中必须采取的措施。

• A summary of updated SOPs that ensure an appropriate program is in place for verification and validation of cleaning procedures for products, processes, and equipment.

• 一份更新后的 SOP 的摘要，确保订有适当的产品、工艺和设备清洁程序核查和验证计划

4. Failure to test the identity of each batch of incoming production material. 未检测每批进厂生产物料的鉴别

Your incoming raw material used to manufacture API intended for the U.S. market was not adequately tested. For example, in response to our April 16, 2020, communication asking whether you perform at least one specific identity test on each lot of each component, you indicated that an identity test is not performed due to the lack of resources.

你们用于生产准备销往美国市场的 API 所用进厂原料没有经过充分检测。例如，在回复我们 2020 年 4 月 16 日询问你们是否对每批进厂物料是否进行了至少一项专属性鉴别时，你们说因为缺少资源所以没有做鉴别。

Such testing is critical to ensure the identity of each lot of each component used in the manufacture of API prior to their use.

此类测试对于确保用于 API 生产的每批物料在其使用之前进行鉴别至关重要。

In response to this letter, provide the following for all API manufactured to date and intended for the U.S. market:

在回复本函时，请提交截止目前所生产的准备销往美国的所有 API 的以下资料：

• A comprehensive review of your material system to determine whether all suppliers of components, containers, and closures are each qualified and the materials are assigned appropriate expiration or retest dates. The review should also determine whether incoming material controls are adequate to prevent use of unsuitable components, containers, and closures.

• 一份对你们物料系统的全面审核，确定是否所有组份、容器和密闭器的所有供应商均经过确认，物料均被给定了适当的有效期或复验期。审核还应确定进厂物料的控制是否足以防止使用不适合的组份、容器和密闭器

• The chemical and microbiological quality control specifications you use to test and release each incoming lot of component for use in manufacturing.

• 你们用于检测和放行每批进厂组份允许其用于生产的化学和微生物质量控制标准

• A description of how you will test each component lot for conformity with all appropriate specifications for identity, strength, quality, and purity. If you intend to accept any results from your supplier’s Certificates of Analysis (COA) instead of testing each component lot for strength, quality, and purity, specify how you will robustly establish the reliability of your supplier’s results through initial validation as well as periodic re-validation. In addition, include a commitment to always conduct at least one specific identity test for each incoming component lot.

• 说明你们准备如何检测每种组份，确保其符合所有适当的鉴别、含量、质量和纯度标准。如果你们准备接受你们供应商 COA 的所有结果，取代你们自己对每种组份批次的含量、质量和纯度检测，请说明你们准备如何通过初始验证和定期再验证稳固地建立你们供应商质量的可靠性。另外，请提交一份承诺保证你们会一直对每个进厂组份批次执行至少一项专属性鉴别测试。

Additional API Guidance 其它 API 指南

For more information, see FDA’s guidance document Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients , at https://www.fda.gov/media/112426/download . This guidance outlines recommended industry practices and represents FDA’s current thinking regarding CGMP for the manufacture of API.

更多信息，参见 FDA 指南文件 Q7 API 的 GMP 。该指南列出了所建议的行业规范，代表了 FDA 当前对于 API 生产的 CGMP 态度。

CGMP Consultant Recommended CGMP 顾问建议

Based on the nature of the deviations we identified, we strongly recommend engaging a consultant qualifiedas set forth in 21 CFR 211.34 to assist your firm in meeting CGMP requirements. We also recommend that the qualified consultant perform a comprehensive audit of your entire operation for CGMP compliance and evaluate the completion and efficacy of your corrective actions and preventive actions before you pursue resolution of your firm’s compliance status with FDA.

FDA警告信：哥伦比亚Proquimes S.A.

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