FDA警告信：存在重大问题，承诺关闭生产

2020年12月29日，FDA公布一封针对美国本土企业（Clientele, Inc.）的警告信。主要的违规项涉及工艺验证不充分、水系统和稳定性问题。

FDA重点指出，该公司的质量单元存在重大问题，未能履行其相关职责。为此，公司承诺停止生产药品，并注销其药品生产商的资格。

Dear Ms. Riley:

赖利女士：

he U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Clientele, Inc., FEI 3012481086, at 14101 NW 4th Street, Sunrise, Florida, from February 3 to 7, 2020.

2020年2月3日至7日，美国FDA检查了你们的药品生产设施Clientele, Inc.，FEI 3012481086，位于佛罗里达州(详略)。

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).

由于你用于生产、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，你们的药品被认为是掺假。

Your firm manufactures the over-the-counter (OTC) drug products “Age Blocker” and “Estro-Lift Day Therapy.”  “Age Blocker” and “Estro-Lift Day Therapy” are misbranded under section 502(c) of the FD&C Act, 21 U.S.C. 352(c).  “Age Blocker” is further misbranded under section 502(a) of the FD&C Act, 21 U.S.C. 352(a). Introduction or delivery for introduction of such products into interstate commerce is prohibited under section 301(a) of the FD&C Act, 21 U.S.C. 331(a).

你们的公司生产非处方(OTC)药品“岁月停滞”和“Esttro-Lift日疗法”。根据FD＆C法案502(c)条及21 U.S.C. 352(c)条的规定，两药品属于标识错误。“岁月停滞”标识错误，也违反了FD＆C法案502(a)及21 U.S.C. 352(a)。根据FD＆C法案301(a)及21 U.S.C. 331(a)，禁止将此类产品引入州际贸易中。

We acknowledge receipt of your July 2, 2020, correspondence. However, you did not provide specific information or evidence of corrective actions to the observations identified during the inspection in our Form FDA 483.

我们确认收到你们2020年7月2日的信件。但是，对于我们在FDA 483表中检查期间发现的观察项，你们没有提供具体信息或纠正措施的证据。

During the inspection, you told the FDA investigator that you would stop making drug products and plan to outsource the manufacture of your drug products to a third-party facility moving forward. In your July 2, 2020, correspondence, you mentioned that you engaged the services of a consultant with expertise in both cosmetic FDA regulations and GMP requirements. You should ensure your consultant is qualified as set forth in 21 CFR 211.34 to advise on compliance with the drug CGMP regulations.

在检查过程中，你们告诉FDA调查员，你们将停止生产药品，并计划将你们的药品生产外包给第三方机构。在2020年7月2日的信函中，你们提到：你们聘请了具有化妆品FDA法规和GMP要求方面专业知识的顾问。你们应确保你们的顾问符合21 CFR 211.34规定的资格，以就遵守药物CGMP法规提出的要求。

质量单元问题
1. Your firm failed to establish an adequate quality unit and the responsibilities, and procedures applicable to the quality control unit were not in writing and fully followed (21 CFR 211.22(a)&(d)).

你们公司未能建立适当的质量单元，对于质量控制单元的职责和程序，没有文件化、且未严格遵循(21 CFR 211.22(a)＆(d))。

Your firm manufactures OTC topical drug products that include sunscreen active ingredients and pain-relieving active ingredients. Your Quality Unit (QU) did not provide adequate oversight for the manufacture of your OTC drug products. For example, your QU failed to ensure the following:

你们公司生产非处方药局部用药，产品涉及防晒活性成分和止痛活性成分。你们的质量部门(QU)对OTC药品生产没有提供充分的监督。例如，你们的QU无法确保以下各项：

-Microbiological testing was performed and reviewed for each batch before release;

进行微生物检测，并在放行前审核每批产品；

-Ongoing stability program was established;

建立了持续的稳定性研究项目；

-Suppliers were adequately qualified;

供应商有充分的资格；

-Out-of-specification (OOS) results were thoroughly investigated and written procedures were established for investigations; and,

对不合格(OOS)结果进行了彻底调查，并建立了书面调查程序；

-Annual product reviews were performed.

进行年度产品回顾。

An adequate QU overseeing all manufacturing operations is necessary to consistently ensure drug quality.

必须有充分的QU来监督所有生产操作，以始终如一地确保药品质量。

Your firm’s quality systems are inadequate. See FDA’s guidance document Quality Systems Approach to Pharmaceutical CGMP Regulations for help implementing quality systems and risk management approaches to meet the requirements of CGMP regulations 21 CFR, parts 210 and 211 at https://www.fda.gov/media/71023/download.

你们公司的质量体系不完善。请参阅FDA指南《药品CGMP法规的质量体系方法》，以帮助实施质量体系和风险管理方法，满足CGMP法规21 CFR第210和211部分的要求，网址为https://www.fda.gov/media/71023/download。

In response to this letter provide a comprehensive assessment and remediation plan to ensure your QU is given the authority and resources to effectively function. The assessment should also include, but not be limited to:

作为对这封信的回应，请提供全面的评估和补救计划，以确保你们的QU拥有有效运作的权限和资源。评估还应包括但不限于：

-A determination of whether procedures used by your firm are robust and appropriate.

确定你们公司使用的程序是否健全和适当。

-Provisions for QU oversight throughout your operations to evaluate adherence to appropriate practices.

整个运营过程中，对QU监督规定的评估，已确定对良好实践的遵守情况。

-A list of chemical and microbial test methods and specifications used to analyze each lot of your drug product before making a lot disposition decision, and the associated written procedures.

在做出批处置决定之前，用于分析每批药品的化学和微生物检测方法和质量标准的列表，以及相关的书面程序。

-A complete and final review of each batch and its related information before the QU disposition decision.

在QU决定处置之前，对每批产品及其相关信息进行完整和最终审查。

-Oversight and approval of investigations and discharging of all other QU duties to ensure identity, strength, quality, and purity of all products.

进行监督和批准，调查并履行所有其他QU职责，以确保所有产品的鉴别、强度、质量和纯度。

-Your consultant’s evaluation of your operations.

你们的顾问对运营的评估。

工艺验证不充分
2. Your firm failed to establish adequate written procedures for production and process control designed to assure that the drug products you manufacture have the identity, strength, quality, and purity they purport or are represented to possess (21 CFR 211.100(a)).

2.公司未建立用于生产和过程控制的书面程序，以确保你所生产的药品具有其声称或代表拥有的鉴别、强度、质量和纯度(21 CFR 211.100(a))。

You failed to adequately validate the processes used to manufacture your drug products. You have not performed process performance qualification (PPQ) studies to support an ongoing program for monitoring process control to ensure stable manufacturing operations and consistent drug quality for products in U.S. distribution. For example, you have not performed studies to support in-process hold times of your drug products.

你们没有充分验证用于生产药品的工艺。你们尚未执行工艺性能确认(PPQ)研究，来支持工艺控制的持续监测项目，以确保稳定的生产操作，保证在美国分销药品的质量始终如一。例如，你们尚未进行研究，以支持药品工艺中的放置时间。

For example, your firm performed at least (b)(4) filling operations of your OTC drug product Age Blocker, lot Q09108, between (b)(4). Your firm stored your bulk drug product in plastic lined buckets that you opened at each filling operation. In addition, you told our investigator that the bulk drug product can be held for filling operations until your stated three-year expiry. During a review of the laboratory test report for this lot, it was noted that only one microbiological test was conducted on June 7, 2019, for total aerobic count. The testing could not be attributed to a specific filling date nor did it include examination for specific objectionable microorganisms. You cannot ensure that lots you release after years of storage in bulk plastic-lined buckets under sporadic monitoring would conform to all your specifications.

例如，公司在XX期间，进行了至少XX次OTC药品Age Blocker同一批次（Q09108）的灌装操作。公司将半成品存储在衬有塑料的桶中，你们在每次灌装操作中都会打开这些桶。此外，你们告诉我们的调查员，该半成品可以放置在容器中，直到三年效期结束为止。在审查该批次的实验室检测报告时，值得注意的是，2019年6月7日仅进行了一项微生物检测，测定总需氧菌计数。该检测不能追溯于特定的灌装日期，也不包括特定有害微生物的检测。你们无法确保在松下的监控下，半成品在塑料衬里的大桶中存放数年后，放行的批次是否仍然符合所有的质量标准。

Process validation evaluates the soundness of design and state of control of a process throughout its lifecycle. Each significant stage of a manufacturing process must be designed appropriately to ensure the quality of raw material inputs, in-process materials, and finished drugs. Failure to conduct these studies could result in product quality attribute failures. Process qualification studies determine whether an initial state of control has been established. Successful process qualification studies are necessary before commercial distribution. Thereafter, ongoing vigilant oversight of process performance and product quality is necessary to maintain a stable manufacturing operation throughout the product lifecycle.

工艺验证会评估整个工艺生命周期中设计的合理性和控制状态。生产工艺中的每个重要阶段都必须进行适当设计，以确保物料输入、在制品和成品的质量。不进行这些研究可能会导致产品质量属性失败。工艺确认研究确定是否已建立初始控制状态。商业放行之前，必须进行成功的工艺确认研究。此后，有必要对工艺性能和产品质量进行持续的监督，以在整个产品生命周期中维持稳定的生产操作。

See FDA’s guidance document Process Validation: General Principles and Practices for general principles and approaches that FDA considers appropriate elements of process validation at https://www.fda.gov/media/71021/download.

请参阅FDA的指南《工艺验证：一般原则和实践》，就FDA考虑的工艺验证适当要素，获取一般原则和方法。

In response to this letter provide the following:

针对此信，请提供：

-An assessment of each drug product process to ensure that there is a data-driven and scientifically sound program that identifies and controls all sources of variability, such that your production processes will consistently meet appropriate specifications and manufacturing standards. This includes, but is not limited to, evaluating suitability of equipment for its intended use, sufficiency of detectability in your monitoring and testing systems (including analytical methods used by you and contract testing labs), quality of input materials, and reliability of each manufacturing process step and control.

对每个药品工艺的评估，以确保有一个数据驱动且科学合理的程序，来识别和控制所有可变性来源，使生产工艺始终符合适当的质量标准和生产规范。这包括但不限于：评估设备的预期用途适用性，监测和检测系统中的可检测性是否充分(包括你们和合同检测实验室使用的分析方法)，输入材料的质量，以及每个生产工艺步骤的可靠性和控制。

-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.

验证计划的详细摘要以及相关程序，以确保整个产品生命周期内的控制状态。描述工艺性能确认计划，并持续监控批内和批间变化，以确保持续的控制状态。

-A timeline for performing PPQ for each of your marketed drug products.

对每种上市药品执行PPQ的时间表。

-Your process performance protocols, and written procedures for qualification of equipment and facilities.

你们的工艺性能草案，以及设备和设施确认的书面程序。

-A detailed program for designing, 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.

用于设计、验证、维护、控制和监测每个生产工艺的详细计划，包括对批内和批间变化进行警惕的监测，以确保持续的控制状态。另外，请包括设备和设施确认计划。

水系统问题
3. Your firm failed to establish laboratory controls that include scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure that components, drug product containers, closures, in-process materials, labeling, and drug products conform to appropriate standards of identity, strength, quality, and purity (21 CFR 211.160(b)).

3.你们的公司未能建立包括科学合理且适当的质量标准、标准、取样计划和检验程序在内的实验室控制措施，以确保组件、药品容器、密封件，在制品、标签和药品符合相关规定，即鉴别、强度、质量和纯度的标准(21 CFR 211.160(b))。

Your firm used (b)(4) water (b)(4) as a component to manufacture your drug products. Your firm failed to routinely monitor your (b)(4) system for all required quality attributes to ensure it consistently produced water suitable for its intended use. You stated to our investigator that sampling at (b)(4) point-of-use (POU) ports were performed on a random basis. You could not provide evidence that two of your POU ports had ever been tested. Furthermore, evidence showed the other (b)(4) POU ports were monitored only twice in 2019. Without routine water monitoring, you cannot ensure that your water meets minimum microbiological and chemical standards suitable for the manufacture of your drug products.

你们的公司使用XX水XX作为生产药品的成分。司未能常规监控XX系统的所有必需质量属性，以确保其始终如一地生产出适合其预期用途的水。你们告诉调查员，在XX使用点(POU)端口的取样是随机进行的。你们无法提供证据，来证明两个POU端口已经过检测。此外，证据显示，其他XX个POU端口在2019年仅进行了两次监测。没有常规的水监控，你们将无法确保你们的水达到适合于生产药品的最低微生物和化学标准。

In addition, our inspection revealed at least two instances of high microbial counts (370 CFU/mL and 446 CFU/mL) from your POU ports. You stated that your microbial specification for (b)(4) at the POU is (b)(4) CFU/mL. This is above the appropriate limits for water intended for pharmaceutical manufacturing.

此外，我们的检查发现，你们的POU端口至少有两个高微生物计数的情况(370 CFU / mL和446 CFU / mL)。你们声明在POU处对XX的微生物指标为XX CFU / mL。这高于用于制药的水的适当限度。

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. The assessment should be retrospective to ensure that products on the market were adequately tested for their quality attributes. Based on this review, provide a detailed plan to remediate and evaluate the effectiveness of your laboratory system.

对你们的实验室操作、程序、方法、设备，文档和分析人员的能力进行全面、独立的评估。评估应该是回顾性的，以确保对市场上的产品进行适当的质量属性检测。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 lot of your drug products before a lot disposition decision.

在做出批处置决定之前，用于分析每批药品的化学和微生物质量标准(包括检测方法)列表。

-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 that are within expiry as of the date of this letter.

行动计划和时间表：对留样进行全面的化学和微生物检测，对于分发给美国的所有效期内（本函件发出之日计）药品批次，确定其质量。

-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.

所有批次的留样检验摘要。如果此类检测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。

-Your plan of action to complete validation (or verification, for compendial methods) for all laboratory methods used together with raw material and drug product testing. In addition, include improved Standard Operating Procedures (SOPs) that require appropriate validation or verification to ensure adequate change management when methods are modified.

你们的行动计划，对于物料和药品检测的所有实验室方法，完成验证(或对于药典方法的确认)。此外，还包括改进的标准操作程序(SOP)，这些操作需要适当的验证或确认，以确保在修改方法时进行适当的变更管理。

-A comprehensive, independent assessment of your water system design, control, and maintenance.

对你们的水系统设计、控制和维护，进行全面，独立的评估。

-A thorough corrective action and preventive action (CAPA) plan to fully remediate and validate a suitable water system.

彻底的纠正和预防措施(CAPA)计划，以全面补救和验证水系统。

-An effective program for ongoing control, maintenance, and monitoring to ensure the remediated system consistently produces water that meets (b)(4), USP monograph specifications and appropriate microbial limits. Regarding the latter, a total count limit lower than 100 CFU/ml would be appropriate for products produced by your firm.

有效的程序，用于持续控制、维护和监测，以确保修复后的系统产生的水始终符合：XX，USP专论规范和适当微生物限度。关于后者，你们公司生产的产品的总计数限度应低于100 CFU / ml。

-The current action/alert limits for total counts and objectionable organisms used for your (b)(4) system. Ensure that the total count limits for your (b)(4) are appropriately stringent considering the intended use of each of the antiseptic drug products produced by your firm.

就XX系统微生物总计数和有害微生物，提供当前行动/警戒限。考虑到你们公司生产的抗菌药品这一预期用途，请确保你们XX总计数限度适当严格。

-A summary of your program for qualifying and overseeing contract facilities that test your raw materials, water, and the drug products you manufacture.

确认和监督合同设施的计划摘要，该设施对你们的物料、水和所生产的药品进行检测。

稳定性问题
4. Your firm failed to establish and follow an adequate written testing program designed to assess the stability characteristics of drug products and to use results of stability testing to determine appropriate storage conditions and expiration dates (21 CFR 211.166(a)).

4.你们的公司未能建立并遵循适当的书面检验程序，以评估药品的稳定性特征；未能使用稳定性检验结果，来确定适当的储存条件和有效期(21 CFR 211.166(a))。

Your firm does not have adequate stability data to show that the chemical and microbiological properties of your drug products remain acceptable throughout the claimed expiry period of three years. You stated that you relied on a study to support your labeled three-year expiry; however, you were unable to provide the study when requested during the inspection. Without appropriate stability data, you cannot ensure your drug products meet established specifications and all pre-determined quality criteria throughout the drug product assigned shelf-life.

你们的公司没有充分的稳定性数据，来证明：你们的药品的化学和微生物特性在所声明的三年有效期内仍然可以接受。你们说你们依靠一项研究来支持三年效期；但是，你们在检查期间无法按要求提供研究数据。没有适当的稳定性数据，你们将无法确保药品在指定的保质期内都符合既定的质量标准和所有预定的质量特性。

In response to this letter, provide the following:

针对此信，请提供：

-A comprehensive, independent assessment and CAPA plan to ensure the adequacy of your stability program. Your remediated program should include, but not be limited to:

全面、独立的评估和CAPA计划，以确保你们的稳定性计划是充分的。你们的补救计划应包括但不限于：

o Stability indicating methods

稳定性指示方法

o Stability studies for each drug product in its marketed container-closure system before distribution is permitted

在分销之前，对市售容器密闭系统中的每种药物进行稳定性研究

o An ongoing program in which representative batches of each product are added each year to the program to determine if the shelf-life claim remains valid

正在进行的计划，每年将每种产品的代表性批次添加到其中，以确定有效期声明是否仍然有效

o Detailed definition of the specific attributes to be tested at each station (timepoint)

每个点(时间点)要检验的特定属性的详细定义

-All procedures that describe these and other elements of your remediated stability program.

针对稳定性补救计划的这些以及其它元素，其所有相关的描述性程序。

Misbranding Violations标识错误的行为(略)

Drug Production Suspended

You committed in a statement provided to the investigator to cease manufacturing drug products and to deregister your facility as a drug manufacturer. If you plan to resume manufacturing or distributing drugs manufactured on your behalf by a contract manufacturer, notify this office before resuming your operations

在向调查员提供的声明中，你们已承诺停止生产药品，并注销你们药品生产商的资格。如果你们打算恢复生产或分销由合同生产商代表你们生产的药品，请在恢复之前通知FDA办公室。

合同生产商的使用
Use of Contract Manufacturers

You stated that you would outsource the production of your OTC drugs to a third-party facility in the future. In response to this letter, provide information regarding the selection of the contract manufacturer you intend to use to manufacture your drug products.

你们说过，将来你们会将OTC药品的生产外包给第三方机构。请回复此信，提供有关药品生产合同生产商选择的信息。

Drugs must be manufactured in conformance with CGMP. FDA is aware that many drug manufacturers use independent contractors such as production facilities, testing laboratories, packagers, and labelers. FDA regards contractors as extensions of the manufacturer.

药品必须按照CGMP生产。FDA意识到许多药品生产商使用独立的合同商，例如生产设施、检测实验室、包装商和贴标签商。FDA将合同商视为生产商的延伸。

If you plan to engage in the use of contract facilities, you are responsible for the quality of your drugs regardless of agreements in place with your contract facilities. You are required to ensure that drugs are made in accordance with section 501(a)(2)(B) of the FD&C Act to ensure safety, identity, strength, quality, and purity. See FDA’s guidance document Contract Manufacturing Arrangements for Drugs: Quality Agreements at https://www.fda.gov/media/86193/download.

如果你们打算使用合同设施，则无论你们与其达成什么协议，都应对药物的质量负责。你们需要确保按照FD＆C法案501(a)(2)(B)节生产药品，以确保安全、鉴别、强度、质量和纯度。请参阅FDA的指南文件 《药品合同生产安排：质量协议》，网址为 https://www.fda.gov/media/86193/download。

The violations cited in this letter are not intended to be an all-inclusive list of violations that exist at your facility. You are responsible for investigating and determining the causes of these violations and for preventing their recurrence or the occurrence of other violations.

本信函中引用的违规行为并非旨在列出与你们的产品相关的所有违规行为。你有责任调查和确定这些违规的原因，并防止其再次发生或发生其它违规情况。

Correct the violations cited in this letter promptly. Failure to promptly correct these violations may result in legal action without further notice including, without limitation, seizure and injunction. Unresolved violations in this warning letter may also prevent other Federal agencies from awarding contracts.

及时纠正此信中引用的违规行为。不及时纠正这些违法行为，可能会导致采取法律行动(恕不另行通知)，包括但不限于：扣押和强制令。此警告信中未解决的违反行为也可能阻止其它联邦机构给予合同。

FDA may also withhold approval of requests for export certificates and approval of pending new drug applications or supplements listing your facility as a supplier or manufacturer until the above violations are corrected. We may re-inspect to verify that you have completed your corrective actions.

FDA还可能拒绝批准出口证书申请，对于新药申请或补充申请，也不会批准将你们的工厂列为供应商或生产商，直到上述违法行为得到纠正。我们可能会重新检查，以确认你已完成纠正措施。

After you receive this letter, respond to this office in writing within 15 working days. Specify what you have done since our inspection to correct your violations and to prevent their recurrence. If you cannot complete corrective actions within 15 working days, state your reasons for delay and your schedule for completion. If you believe that your products are not in violation of the FD&C Act, include your reasoning and any supporting information for our consideration.

收到这封信后，请在15个工作日内以书面形式答复FDA办公室。说明自我们检查以来，你所做的事情，以纠正你们的违规行为，并防止其再次发生。如果你无法在15个工作日内完成纠正措施，请说明延误原因和完成时间表。如果你们认为你们的产品没有违反FD＆C法案，请提供你们的理由和任何支持信息，以供我们考虑。

Ref.:
WARNING LETTER- Clientele, Inc. MARCS-CMS 607476 — DECEMBER 03, 2020. FDA.

       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。