缺陷案例：“MAH”对CMO监管不力，质量体系不完善！

近日，FDA发布了对Sircle Laboratories, LLC的警告信，警告信批评了该公司对其委托的CMO公司的质量监督不力，以及自身缺乏足够的质量体系，例如CMO质量监督、变更控制、产品放行、投诉处理和召回程序等，FDA在警告信中表示：“无论与合同机构签订了何种协议，你们都应对你们药品质量负责。” 警告信缺陷翻译如下：

1. Your firm’s quality control unitfailed to exercise its responsibility to ensure drug products manufactured arein compliance with CGMP, and meet established specifications for identity,strength, quality, and purity. (21 CFR 211.22)

贵公司的质量控制部门未能履行其职责，确保生产的药品符合CGMP，并符合既定的鉴定、含量、质量和纯度标准。（21 CFR 211.22）

Your firm lacks appropriate oversight and procedures to managecontract manufacturing organizations (CMOs) used on behalf of your firm for themanufacturing, packaging, and distribution of your drug products. You areultimately responsible for CGMP activities you perform.

贵公司缺乏适当的监督和程序来管理受托进行药品生产、包装和分销的合同制造组织（CMO）。你们对执行 CGMP 活动负最终责任。

Your firm has failed to follow your established quality unit(QU) procedures, as well as commitments documented in quality agreements (QA).In your response, you maintained that you have CGMP responsibilities,including, but not limited to, having written procedures for your quality unit,handling of consumer complaints, release of drug products, and qualifying andapproving of your CMOs. QU deficiencies include:

贵的公司未能遵守既定质量单位（QU） 程序，以及质量协议 （QA） 中记录的承诺。在答复中，你们坚持认为你们负有 CGMP 职责，包括但不限于建立质量部门的书面程序、处理投诉、放行药品以及确认和批准你们的CMO。QU 的缺陷包括：

Inadequate QU oversight of your CMOs

对 CMO 的 质量监督不足

Your QU lacked adequate oversight and controls for your CMOs,which led to your use of sub-standard CMOs. Since 2017, FDA has taken thefollowing actions in response to CGMP violations found at your CMOs.

你们的质量部门缺乏对你们的 CMO 的充分监督和控制，这导致你们使用低于标准的 CMO。自 2017 年以来，FDA 针对在你们的 CMO 中发现的 CGMP 违规行为采取了以下行动。

For example, (b)(4),was issued a Warning Letter on (b)(4),that included, but not limited to, violations for the failure to establishappropriate time limits for each stage of production, and failure to thoroughlyinvestigate out-of-specification (OOS) results.

例如，于（b）（4）时间向（b）（4）公司发出警告信，其中包括但不限于未能为每个生产阶段规定适当时限的违规行为，以及未能彻底调查OOS的结果。

In your response, you stated that you are in the process ofdeveloping procedures that address the approval process for your CMOs. Yourresponse is inadequate because you did not conduct a retrospective review ofthe lack of QU oversight of your CMOs and product distribution which may impactthe identity, strength, quality, and purity of your drug products.

在回复中，你们表示，你们正在制定处理 CMO 审批流程的程序。你们的回复是不充分的，因为你们没有对 CMO 和产品分销缺乏 QU 监督进行回顾性审查，这可能会影响药品的鉴定、含量、质量和纯度。

Failureto establish and follow QU procedures

未能建立和遵循 QU 程序

• Lack of batch release procedures

• 缺乏批放行程序

Your firm failed to establish adequate written responsibilitiesand procedures for reviewing batches made by your CMO. You also failed toreview production records for each batch for disposition (i.e., reject orapprove) per your QA with (b)(4).You are ultimately responsible for approving or rejecting drug product batchesmanufactured for you by a contract facility. Determining the suitability ofeach batch for release is an essential component of your quality unitresponsibility.

贵公司未能建立足够的书面责任和程序来审查你们的 CMO 所生产的批次。你们也没有审查每批产品的生产记录以由QA按照（b）（4）进行处置（即拒绝或批准）。你们对合同工厂说生产的药品批次的批准或拒绝负最终责任。确定每批产品是否适合放行是你们的质量单位责任的重要组成部分。

In your response, you confirmed that you do not have a writtenprocedure specifying release of drug products from CMOs and stated that you aredeveloping procedures. Your response is inadequate because you did not providedetails on what these procedures entail or how they will be applied.

在你们的回复中，你们确认没有书面程序说明药品从CMOs放行，并表示你们正在制定程序。你们的回复是不充分的，因为你们没有提供这些程序的具体内容或如何应用这些程序的细节。

Failureto follow change control procedures

未能遵循变更控制程序

Your QU failed to ensure your firm follows your change controlprocedure. For example, since the last FDA inspection in March 2019, your firmimplemented changes to your consumer complaints and drug product recallsprocedures without following your change control procedure. In addition, youapproved changes to your drug product labeling without following your changecontrol procedure. In each of these instances, your firm did not adequatelyjustify or document these changes as required in your change control procedure.

你们的QU未能确保公司遵循你们的变更控制程序。例如，自 2019 年 3 月上次 FDA 检查以来，贵公司对你们的投诉和药品召回程序进行了变更，而没有遵循你们的变更控制程序。此外，你们批准变更你们的药物产品标签，而没有遵循你们的变更控制程序。在每种情况下，贵公司都没有按照变更控制程序的要求充分论证或记录这些变更。

In your response, you acknowledge that you have not beenfollowing your change control procedure for the changes your firm hasimplemented. Your response is inadequate in that the forms provided did notinclude an assessment of the impact of the changes, including changes to yourlabeling materials.

在回复中，你们承认你们没有按照贵公司的变更控制程序执行变更。你们的回复是充分的，因为所提供的记录未包含对变更影响的评估，包括标签的变更。

2.Your firm failed to follow establish and follow adequate written proceduresdescribing the handling of all written and oral complaints regarding a drugproduct (21 CFR 211.198(a)).

贵公司未能遵循建立和遵循适当的书面程序，描述如何处理所有关于药品的书面和口头投诉（21 CFR 211.198（a））。

You acknowledge that while you use CMOs on your behalf, youmaintain associated CGMP responsibilities, including, but not limited to,handling customer complaints and inquiries. However, your firm failed toadequately establish and follow your established complaint handling procedure.For example, your procedure stipulated responsibilities for the handling andinvestigating of consumer complaints to your “Drug Safety Specialist” and“Chief Scientific Officer.” During the inspection, these titles and staffpositions did not exist at your firm.

你们承认，虽然你们使用 CMO，但你们仍然承担相关的 CGMP 职责，包括但不限于处理客户投诉和咨询。但是，贵公司未能充分建立并遵循已建立的投诉处理程序。例如，你们的程序规定了你们的"药物安全专家"和"首席科学官"处理和调查投诉的责任。在检查期间，这些职位在贵公司不存在。

Further, your QA with (b)(4) statesthat you will notify (b)(4) ofcomplaints that are likely to result in a field alert and/or recall, and that (b)(4) will conduct and completethe complaint investigation. All quality-related complaints, beyond thoselikely to result in a field alert and/or recall, must be investigated per211.198.

此外，你们的 QA 与（b） （4）指出，你们将通知（b）（4）可能导致现场警报和/或召回的投诉，并且 （b）（4）将执行并完成投诉调查。除可能导致现场警报和/或召回的投诉外，所有与质量相关的投诉都必须按 211.198 进行调查。

In your response, you stated that you revised the complainthandling procedure by removing the non-existent titles and replacing these jobtitles to “Chief Operating Officer.” Your response is inadequate because youdid not provide evidence demonstrating that this individual follows thecomplaint handling procedure and performs reviews to determine whether acomplaint represents a serious and unexpected adverse drug event.

在答复中，你们指出，你们修改了投诉处理程序，删除了不存在的职称，并将这些职称替换为"首席运营官"。你们的回复是不充分的，因为你们没有提供证据证明此人可以遵循投诉处理程序，进行审查以确定投诉是否严重或是意外的药物不良事件。

3.Your firm failed to establish and follow written procedures designed to assurethat correct labels, labeling, and packaging are used for drug products. (21CFR 211.130)

你们公司未能建立和遵守书面程序，以确保药品使用正确的标签、贴签和包装。(21 CFR 211.130)

Your firm reviews and approves the labeling for the drug products manufacturedby your CMOs. Your procedure for reviewing and approving the labels isinadequate. For example, your procedure does not require the verification ofall elements on the labels, such as storage conditions and dispensing volumes.Moreover, your procedure does not include a review or comparison of drugproduct labels against an approved master or reference label.

贵公司审查并批准你们的 CMO 生产的药品的标签。你们审查和批准标签的程序不充分。例如，你们的程序未要求确认标签上的所有元素，如存储条件和配药量。此外，你们的程序未包含对药品标签与批准的主标签或参考标签的审查或比较。

In your response, you stated that you use master labels and thatyou are in the process of revising your label review procedure by July 1, 2021.Your response is inadequate.

在回复中，您声明使用主标签，并且您正在 2021 年 7 月 1 日之前修改标签审查程序。你的回答不够充分。

       文章来源：GMP办公室

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