FDA印尼警告信：检验在放行之后

9月8日，FDA公布一封针对印度尼西亚企业的警告信。主要的违规项包括产品放行与检验问题、未能有效执行工艺验证，未能独立履行质量部门职责以及稳定性问题。
由于该警告信篇幅较长，PharmLink将分两次翻译连载，供大家参考。

本次重点关注产品放行与检验问题。FDA检查发现，对于某产品，其检验是发生在产品放行之后的。

August 24, 2020
Dear Mr. Jain:

2020年8月24日

尊敬的Jain先生：

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, PT. MegaSurya Mas, FEI 3007801999, at J1 Tambak Sawah 32, Sidoarjo, Jawa Timur, from November 11 to 15, 2019.

2019年11月11日至15日，美国FDA检查了您的药品生产厂PT. MegaSurya Mas，FEI 3007801999, 地址是J1 Tambak Sawah 32, Sidoarjo, Jawa Timur。

This warning letter summarizes significant violations of current good manufacturing practice (CGMP) regulations for finished pharmaceuticals. See Title 21 Code of Federal Regulations (CFR), parts 210 and 211 (21 CFR 210 and 211).

该警告信总结了严重违反制剂CGMP规定的情况。请参阅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 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).

由于您用于生产、加工、包装或储存的方法、设施或控制措施不符合CGMP，因此根据FD＆C法案501(a)(2)(B)条及21 U.S.C.351(a)(2)(B) 条的规定，您的药品被认为是掺假。

We reviewed your December 7, 2019, response to our Form FDA 483 in detail and acknowledge receipt of your subsequent correspondence.

我们已审阅了您于2019年12月7日对FDA 483表格的详细答复，并确认收到您的后续信件。

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

在我们的检查过程中，调查人员发现了具体的违规行为，包括但不限于以下行为。

产品放行问题：

1. You firm failed to have, for each batch of drug product, appropriate laboratory determination of satisfactory conformance to final specifications for the drug product, including the identity and strength of each active ingredient, prior to release and your firm failed to establish the accuracy, sensitivity, specificity, and reproducibility of its test methods (21 CFR 211.165(a) and (e)).

1.您的公司在放行之前未能对每批药品进行适当的实验室检验，以确定是否符合该药品的最终质量标准，包括每种活性成分的鉴别和强度，并且不能建立具有准确性、敏感性、特异性和可重复性的检验方法(21 CFR 211.165(a)和(e))。

Inadequate testing before release放行前检验不足
Your firm released and distributed the over-the-counter (OTC) drug product, (b)(4), to the U.S. on (b)(4), without adequate final product testing. Your batch (b)(4) release document, dated August 14, 2019, recorded an assay result of (b)(4)% (specification (b)(4) – (b)(4)%) of (b)(4). You acknowledged during the inspection that this test was performed in November 2019, after the date of the release document and after the release of the drug product. This discrepancy on batch release documents demonstrates a concern regarding the validity in your CGMP records.

公司放行并分销了非处方(OTC)药品XX（美国的分销渠道为XX），其没有充分的成品检验。批次XX放行文件，日期为2019年8月14日，记录的XX产品检验结果为XX％(质量标准XX- XX％)。在检查过程中您确认，该检验是在2019年11月进行的，这发生在放行文件日期和药物放行之后。批放行文件上的这种偏差，表明CGMP记录存在有效性问题。

Inadequate Method Validation 方法验证不充分
Your firm lacked appropriate validation (or verification, for United States Pharmacopeia (USP) compendial methods) of your analytical test methods used to determine acceptability of your drug product before release for distribution.

您的公司缺乏对分析检验方法的适当验证(或针对USP药典方法的确认)，这些方法用于确定药物产品在分发前是否可接受。

During the inspection, your firm acknowledged that the assay testing for the active ingredient in your finished product is not an USP method, nor has the method been validated for testing by high-performance liquid chromatography (HPLC).

在检查过程中，您的公司承认，对成品中活性成分的检验不是USP方法，也没有通过高效液相色谱(HPLC)对该方法进行验证。

Analytical methods must be validated to show they are suitable for their intended use, and equivalent or better than applicable USP compendial methods. Verifying the accuracy, sensitivity, specificity, and reproducibility of your test methods is essential to determine if the drug products you manufacture meet established specification for chemical and microbial attributes.

分析方法必须经过验证，以表明它们适合其预期用途，并且等效或优于适用的USP药典方法。验证检验方法具有准确性、敏感性、特异性和可重复性，对于确定药品是否符合化学和微生物属性的既定质量标准，是至关重要的。

In your response, you stated that you will purchase a reference standard for the active ingredient, (b)(4), and you will perform validation for specified methods. You also stated that you will perform testing for remaining stock of the (b)(4) by April 30, 2020.

在答复中，您声明将购买活性成分XX的标准品，并将对方法进行验证。您还声明，将在2020年4月30日之前对(b)(4)的剩余库存进行检验。

Your response is inadequate because you did not address your failure to perform adequate release testing on your finished drug products. You also did not provide sufficient information regarding the validation or verification of your test methods for identity and strength of (b)(4). Additionally, your firm lacked a comprehensive assessment and retrospective review of all data generated from all computerized laboratory systems used in CGMP operations.

您的回应不充分，因为您没有解决以下问题：未能对成品执行适当放行检验。您也没有提供充分的信息来，验证或确认XX的鉴别和强度的检验方法。此外，对于CGMP操作中计算机化实验室系统生成的所有数据，您的公司缺乏全面评估和回顾性审查。

In response to this letter, provide the following:

针对此信，请提供：

• A comprehensive independent assessment of your laboratory practices, procedures, methods, equipment, documentation, and analyst competencies. Based on this review, provide a detailed plan to remediate and evaluate the effectiveness of your laboratory system.

•对实验室操作、程序、方法、设备、文档和分析人员的能力，进行全面的独立评估。在此审查的基础上，提供详细计划，以补救和评估实验室系统的有效性。

• A list of chemical and microbial specifications, including test methods, used to analyze each batch of your drug products before batch disposition decisions.

•在决定批次处置之前，用于分析每批药品的化学和微生物质量标准(包括检验方法)列表。

o An action plan and timelines for conducting full chemical and microbiological testing of retain samples to determine the quality of all batches of drug product distributed to the United States within expiry.
 o A summary of all results obtained from testing retain samples from each batch. If such testing reveals substandard quality drug products, take rapid corrective actions, such as notifying customers and product recalls.

O行动计划和时间表：对留样进行全面的化学和微生物检验，以确定分发给美国的药品批次（效期内）质量。

O各留样批次检验结果摘要。如果检验表明药品质量不合格，请采取迅速的纠正措施，例如通知客户和产品召回。

• The actions you will take to determine the overall quality of your U.S. drug product batches within expiry which were previously released without adequate testing, including identity and strength of active ingredients.

•将要采取的措施，来确定美国药品批次（效期内）的总体质量，此前这些批次未经适当检验就已放行，包括有效成分的鉴别和强度。

• Validation summary of all analytical methods you will use to test each batch of U.S. drug product for identity, strength, quality, and purity.

•分析方法的验证摘要，针对将用于检验美国药品的鉴别、强度、质量和纯度的所有方法。

入厂检验问题：
2. Your firm failed to conduct at least one test to verify the identity of each component of a drug product. Your firm also failed to validate and establish the reliability of your component suppliers test analyses at appropriate intervals (21 CFR 211.84(d)(1) and (2)).

2.您的公司未进行至少一项检验，来确认药品中每种成分的鉴别。您的公司也未能在适当的时间间隔内，验证并确定组分供应商检验分析的可靠性(21 CFR 211.84(d)(1)和(2))。

You failed to test the incoming active pharmaceutical ingredient (API), (b)(4), you use in manufacturing your drug product to determine conformance to identity, purity, strength, and other appropriate specifications. Instead, you released API for use in drug production based solely on certificates of analysis (COA) from your supplier without establishing the reliability of the supplier’s analysis through appropriate validation and ensuring that at least one specific identity test is conducted for each lot.

您在生产药品时，未检验入厂API XX，以确定鉴别、纯度、强度和其他适当质量标准。相反，您仅根据供应商提供的分析证书(COA)，放行了用于药品生产的API，而没有通过适当的验证来确定供应商分析的可靠性，并确保至少对每批进行一项特定的鉴别。

In your response, you stated that you will purchase a (b)(4) reference standard, and you will perform identity testing for the existing stock of API.

在答复中，您声明将购买标准品XX，并对现有的API库存执行鉴别检验。

Your response is inadequate because you failed to commit to test all new incoming lots of raw material before you use it in the manufacture of your drug products. In addition, you did not specify how you will establish the reliability of your suppliers’ analyses. Also, you did not take any action for drug products already in the market.

您的回应是不充分的，因为您没有承诺在将其用于药品生产之前，必须对所有新进原料进行检验。此外，您没有说明如何建立供应商分析的可靠性。另外，对于市场上已有的药品，您没有采取任何行动。

In response to this letter, provide the following:

针对此信，请提供：

• A comprehensive, independent 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.

•对物料系统进行全面、独立的审查，以确定所有组分、容器和密封件供应商是否有资质，且为物料指定适当有效期或再验日。对于入厂物料的控制措施，审查还应确定是否足以防止使用不合适的组分、容器和密封件。

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

•每批入厂组分（生产目的），用于检验和放行的化学和微生物质量标准。

• 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 suppliers COA instead of testing each component lot for strength, quality, and purity, specify how you will robustly establish the reliability of your suppliers 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.

•说明如何检验每个批次，确定是否符合有关鉴别、强度、质量和纯度质量标准。如果您打算接受供应商COA的任何结果，而不是检验每个组分批次的强度、质量和纯度，请指定如何进行初始验证和定期在验证，从而稳健地确定供应商结果的可靠性。此外，还应承诺：对于每个入库的组分批次，至少进行一个特定的鉴别检验。

• A summary of results obtained from testing all components to evaluate the reliability of the COA from each component manufacturer. Include your SOP that describes this COA validation program.

•结果摘要：对所有组分进行检验，以评估每个组分生产商的COA可靠性。包括描述此COA验证程序的SOP。

• A summary of your program for qualifying and overseeing contract facilities that test the drug products you manufacture.

•计划摘要：对检验药品的合同设施进行资质确认和监督。

       文章来源：PharmLink

       本网站刊载的所有内容，包括文字、图片、音频、视频、软件等，如非标注为“原创”，则相关版权归原作者所有，如原作者不愿意在本网站刊登相关内容，请及时通知本站，我们将第一时间予以删除。