FDA警告信：香港联华药业有限公司 20180406

Warning Letter   320-18-44

April 06, 2018

Ms. Mimi Shun, CEO and Managing Director

Luen Wah (HK) Medicine Ltd.

12 Ka Yip Street, 412 Room, Paramount Building 406, ChaiWan, Hong Kong Island, Hong Kong SAR

Dear Ms. Shun:

The U.S. Food and Drug Administration (FDA) inspectedyour drug manufacturing facility, Luen Wah (HK) Medicine Ltd. at 12 Ka YipStreet, Paramount Building 406, 412 Room, Chai Wan, Hong Kong Island, fromSeptember 25 to 28, 2017.

  美国 FDA 于 2017 年 9 月 25 日 28 日 检查了你 们位于香港柴湾嘉业街 12 号百乐门大厦 4 楼 406-412 室的香港联华药业有限公司生产场所。

This warning letter summarizes significant violationsof current good manufacturing practice (CGMP) regulations for finishedpharmaceuticals. See 21 CFR, parts 210 and 211.

本警告信总结了制剂生产严重违反 CGMP 的行为。参见 21CFR 第 210 和 211 部分。

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

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

We reviewed your October 17, 2017, response in detailand acknowledge receipt of your subsequent correspondence.

我们已详细审核了你公司于 2017 年 10 月 17 日的回复并此告知已收到后续的通信。

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

检查期间，我们的调查人员发现的具体问题包括但不仅限于以下：

1.  Your firm failed to perform, for each batchof drug product, appropriate laboratory determination of satisfactoryconformance to final specifications for the drug product, including theidentity and strength of each active ingredient, prior to release, and for eachbatch of drug product required to be free of objectionable microorganisms,appropriate laboratory testing, as necessary (21 CFR 211.165(a) and (b)).   你公司未能在放行对每批药品进行适当的化验室检测，确定其是否符合药品最终质量标准，包括每种活性鉴别和剂量，以及对不得检出致病菌的每批药品在必要时进行适当的化验室检测 (21 CFR 211.165(a) and (b)) 。

Your firm released your over-the-counter (OTC) drugproducts to the United States market without testing identity and strength ofeach active ingredient. In addition, you released these drug products withouttesting for total aerobic microbial count and objectionable micro-organisms.Testing is essential to ensuring that the drug products you manufacture meetestablished specifications for the chemical and microbial attributes theypurport to possess.

你公司未检测每种活性成份的鉴别和剂量即放行了你们的 OTC 药品于美国市场。另外，你们未检测总需氧菌和致病菌即放行了这些药品。为确保你们生产的药品符合其理当具备的既定化学和微生物属性，进行检测是必须的。

Your response states that you will create new samplingprocedures for your drug manufacturing processes. Your response is inadequate.Your response failed to provide details for establishing your finished productspecifications for your OTC   (b)(4)  drug products. You also did notprovide details for the associated test methods or any comparability studies todemonstrate that your test methods are equivalent to or better than USP testmethods. In addition, your response does not address whether your firm willconduct retrospective testing of your retain samples of drug productsdistributed to the U.S. to assure specifications are met.

你们的回复中声称你们将为你们的药品生产工艺建立新的取样程序。你们的回复是不充分的。你们的回复未提交建立你们 XX 成品 OTC 药品标准的细节，亦未提供相关检测方法或任何可比性研究以证明你们的检测方法等同或优于 USP 检测方法的细节。另外，你们的回复未说明你们公司是否将对已销于美国的药品留样进行回顾检测以确保其符合质量标准。

In response to this letter, provide yournewly-established test methods and specifications intended to analyze eachbatch of drug product prior to release. Also, provide a summary of your testresults obtained from full testing of retains for all batches of your drugproducts distributed to the U.S. market still within expiry. If you find thatyou released any batch for which results are out of specification (OOS),indicate the corrective actions you will take, such as customer notificationsand product recalls.

  在回复此函时，请提交你们新建立将用于放行前分析每批药品的检测方法和质量标准，亦请提交一份你们对所有销往美国市场的所有批次药品留样检测所得的结果荡总。如果你们发现你们放行的药品中有任何批次结果为 OOS ，指明你们将采取的纠正措施，如通知客户和召回产品。

2.  Your firm failed toconduct at least one test to verify the identity of eachcomponent of a drugproduct. Your firm also failed to establish thereliability of component supplier analyses on whichyou rely in lieu of certain tests throughappropriate validation of the supplier's test results atappropriate intervals. (21 CFR 211.84(d)(1) and (2)).   你公司未执行至少一项检测来确认药品的每种成分的鉴别。你公司说未通过对供应商检测结果以适当时间间隔进行验证的方式来建立组份供应商分析的可靠性却依赖于其结果替代某些检测 (21 CFR 211.84(d)(1) and (2)) 。

Your firm failed to test incoming activepharmaceutical ingredients (API) and other components used to manufacture yourOTC drug products to determine their identity, purity, strength, and otherappropriate quality attributes. Instead, your firm relied solely oncertificates of analysis (COA) from unqualified suppliers.

你公司未检测 OTC 药品和平所用进厂 API 和其它成分以确定其鉴别、纯度、含量和其它适当的质量属性，而只是依赖于未经确认的供应商的 COA 。

Your response states that you will conduct identitytesting on incoming API and other components, and that you will establishsampling procedures. Your response is inadequate. Your response failed toprovide a list of all active ingredients and components to be tested for yourOTC drug products. You also did not provide details for the associated testmethods for your active ingredients and components demonstrating that your testmethods are equivalent to or better than USP methods.

你们的回复声称你们将对进厂 API 和其它成分执行鉴别测试，并将建立取样程序。你们的回复是不充分的。你们的回复未提交一份将进行检测的 OTC 药品所有 API 和成分的清单。你们亦未提交 API 和组份相关检测方法的详细信息以证明你们的检测方法等同或优于 USP 方法。

In response to this letter, provide a summary of thetest results obtained from fully testing each of your active ingredients andother incoming components to validate suppliers’ COA. In addition, provide yourspecifications for all API and incoming components. Include a description ofthe sampling and testing to be performed.

在回复此函时，请提交一份对你们的 API 和其它进厂成分的全检结果汇总以验证供应商的 COA 。另外，请提交你们所有 API 和进厂组份的质量标准，包括一份将执行的取样和检测描述。

3.  Your firm failed to ensure that its drugproduct bore an expiration date that was supported by appropriate stabilitytesting (21 CFR 211.137(a)).   你公司未能确保其药品具备受恰当稳定性测试支持的有效期  (21 CFR 211.137(a)) 。

Your firm has not established a stability program. Youlack data to demonstrate that the chemical and physical properties of your OTC   (b)(4)drug products will remain acceptable throughout their labeled   (b)(4)expiry period.

你公司未建立稳定性程序。你们缺乏数据证明你们 OTC 药品的理化特性在其所标识的 XX 有效期内将保持可接受。

Your response states that you will perform acceleratedstability testing and establish a stability program. Your response isinadequate. Your response failed to include your stability protocols whichincludes timelines. You also failed to address whether you will perform a riskassessment or conduct testing to address the drug products distributed to theUS with an expiry not supported by stability data.

你们的回复声称你们将执行加速稳定性测试并建立稳定性程序。你们的回复是不充分的，你们的回复未能包括含有时间表的稳定性方案。你们亦未说明你们是否会执行风险评估或执行检测以解决销往美国仍在效期内无稳定性数据支持的药品问题。

In response to this letter, provide stability data todemonstrate that all your OTC drug products distributed to the U.S. meet theirspecifications throughout their assigned shelf lives. Also, provide yourprocedure describing your ongoing stability program.

在回复此函时，请提交稳定性数据以支持所有销往美国的 OTC 药品在其给定货架期内符合其质量标准，亦请提交你们的程序描述你们的正在进行的稳定性计划。  

4.  Your firm failed to establish adequatewritten procedures for production and process control designed to assure thatthe drug products you manufacture have the identity, strength, quality, andpurity they purport or are represented to possess (21 CFR 211.100(a)).   你公司未建立设计用以确保你们生产的药品具备其理应具备的鉴别、剂量、质量和纯度的生产和工艺控制书面程序 (21 CFR 211.100(a)) 。

Your firm has not validated the processes used tomanufacture your drug products. You failed to perform process qualificationstudies, and lacked an ongoing program for monitoring process control to ensurestable manufacturing operations and consistent drug quality.

你公司未验证用于生产你们的药品的工艺。你们未能执行工艺确认研究，缺乏持续计划监测工艺控制以确保生产操作稳定和药品质量一致。

Your response states that you will evaluate yourmanufacturing processes to determine the critical production steps. You alsostate that you will perform concurrent validation of your manufacturingprocesses which will include modification of your master batch records. Yourresponse is inadequate. Your response failed to provide your validationprotocols. You also did not provide your revised batch records based on yournewly-established manufacturing process parameters.

你们的回复声称你们将评估你们的生产工艺以确定关键生产步骤。你们还声称你们将对你们的生产工艺执行同步验证，其中包括修订你们的主批记录。你们的回复是不充分的，其中未提交你们的验证方案，亦未提交你们你们依据新建立的生产工艺参数修订后的批记录。

In response to this letter, provide timelines forprocess performance qualification for each of your   (b)(4)  drug products.In addition, provide a detailed summary of your approach for routinelymonitoring intra- and inter-batch variation. Also provide drafts of yourrevised batch record with newly-defined process parameters, such as