FDA警告信：批记录信息不够详细

3月22日，FDA公布一封针对美国本土企业（Honest Globe, Inc.）的警告信。主要的违规项涉及QA职能不独立、批生产记录不够详细、确认与验证存在缺陷。

具体而言，FDA指出该公司QA缺乏独立性：生产人员可以执行生产活动，同时又可以对生产步骤和批放行进行质量批准；在批生产记录缺陷项中，该公司在没有完整指导信息的情况下，使用生产文件，因而不能确保生产信息得到记录。

WARNING LETTER

March 15, 2021

Dear Mr. Kotler:

警告信

2021年3月15日，

科特勒先生：

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Honest Globe, Inc., FEI 3015667771, at 3605 West Macarthur Boulevard, Suite 701, Santa Ana, from October 4 to 8, 2019.

2019年10月4日至8日，美国FDA检查了你们的药品生产设施，Honest Globe，Inc.，FEI 3015667771，位于圣安娜州西麦克阿瑟林荫大道3605号701室。

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).

由于你们用于生产、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，即21 U.S.C.351(a)(2)(B) 条的规定，你们的药品被视为掺假。

Your “ELIXICURE PAIN RELIEF with CBD” products are unapproved new drugs introduced or delivered for introduction into interstate commerce in violation of sections 505(a) and 301(d) of the FD&C Act, 21 U.S.C. 355(a) and 331(d). Furthermore, your “ELIXICURE PAIN RELIEF” products are misbranded drugs introduced or delivered for introduction into interstate commerce in violation of sections 502(a), 502(ee), and 301(a) of the FD&C Act, 21 U.S.C. 352(a), 352(ee), and 331(a).

你们的“含CBD止痛”产品是未经批准的新药，被引入或交付用于州际贸易，违反了FD＆C法案505(a)和301(d)，即21 USC 355(a)和331(d)的规定。此外，你们的“止痛”产品属于标识错误的药物，被引入或交付用于州际贸易，违反FD＆C法案502(a)，502(ee)和301(a)条，即21 USC 352(a)，352(ee)和331(a)。

Currently, a nonprescription drug product containing CBD cannot be legally marketed without an approved new drug application, regardless of whether the CBD is represented on the labeling as an active ingredient or an inactive ingredient. To date, no CBD-containing drug has met applicable FDA requirements to be legally marketed for nonprescription use. As explained below, nonprescription drug products that include CBD as an active ingredient are not generally recognized as safe and effective (GRASE) and are new drugs which require an approved application to be legally marketed.

当前，作为包含CBD的非处方药产品，如果没有通过新药申请而获得批准，就不能合法销售，无论CBD是作为活性成分还是非活性成分出现在标签上。迄今为止，还没有任何含有CBD的药物可符合适用的FDA要求，以便合法销售用于非处方用途。如以下内容所述，以CBD为有效成分的非处方药通常不被认为是安全有效的(GRASE)，而是需要申请并经批准、才能合法销售的新药。

Furthermore, even if CBD could be considered an inactive ingredient in a nonprescription drug product, that product would still need an approved new drug application to be legally marketed, because the product would not meet the general requirements for nonprescription drug products under section 505G of the FD&C Act. In particular, such product would not meet the general requirement with respect to the safety and suitability of inactive ingredients under 21 CFR 330.1(e).

此外，即使可以将CBD视为非处方药产品中的非活性成分，该产品仍属于需要经过批准的新药申请才能合法销售，因为该产品将不符合FD＆C法案第505G条对非处方药产品的一般要求。特别是，此类产品将无法满足21 CFR 330.1(e)中非活性成分的安全性和适用性的一般要求。

Current Good Manufacturing Practice (CGMP) Charges

当前的良好生产规范(CGMP)指控

We reviewed your October 30, 2019, response to our Form FDA 483 in detail.

我们已详细审查了你们对2019年10月30日对FDA 483表格的答复。

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

在我们的检查过程中，调查员发现了具体的违规行为，包括但不限于以下行为。

QA职能不独立
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 Quality Unit (QU) lacked control over your topical over-the-counter drug manufacturing operations and failed to ensure that you had adequate procedures. For example, your QU failed to:

你们的质量单元(QU)对你们的外用非处方药生产业务缺乏控制，并且无法确保你们有充分的程序。例如，你们的QU未能：

Evaluate product quality before batch release. Your firm obtained out-of-specification (OOS) camphor assay release testing results and then sent additional samples from these batches to your contract testing laboratory until passing results were obtained. You reported the passing results and released these batches to the market without investigating release testing assay failures.
批放行前评估产品质量。对于樟脑含量放行检验，你们公司得到了不合格(OOS)结果，之后将这些批次的更多样品送到合同检验实验室进行复验，直到得到合格结果。你们报告了合格的结果，并将这些批次放行到市场上，而没有调查放行检验含量失败的情况。

Exercise adequate independent authority over manufacturing operations. Production staff interchangeably perform manufacturing activities and quality approval of manufacturing steps and batch release.
对生产操作行使充分的独立权限。生产人员可以执行生产活动，同时又可以对生产步骤和批放行进行质量批准。

Establish procedures describing critical oversight responsibilities including, but not limited to, the following: batch review and release, developing and assessing corrective and preventive actions, implementing change controls, and establishing the reliability of component supplier analyses.
建立描述关键监督职责的程序，包括但不限于以下内容：批次审查和放行、制定和评估纠正和预防措施、实施变更控制以及建立组分供应商分析的可靠性。

In your response, you committed to working with your contract laboratory to investigate the cited OOS results and future OOS results. Your response is inadequate because you did not address your responsibilities to investigate potential manufacturing deficiencies that may have led to the OOS results. Your response also failed to evaluate batches with OOS test results that had been distributed and were still within expiry.

在你们的答复中，你们承诺与合同实验室合作，调查上述和将来的OOS结果。你们的回复是不充分的，因为对于可能导致OOS结果的潜在生产缺陷，你们未能阐明调查的责任。对于已分发且仍在有效期内的OOS批次，你们的回复也未能对其进行评估。

Additionally, in your response, you designated (b)(4) to execute the independent Quality Assurance (QA) functions of the organization and committed to revise applicable procedures to reflect QA’s oversight responsibilities. However, the revised QA procedures you proposed only pertain to who is allowed to render final quality decisions. You have not proposed new or revised procedures that govern other deficient aspects of your QU, such as investigating deviations, developing corrective actions and preventive actions, implementing change controls, and auditing component suppliers’ test results.

此外，在你们的回复中，你们指定XX执行独立的QA职能，并承诺修改适用的程序，以反映QA的监督职责。但是，你们修订后的QA程序仅与允许谁做出最终质量决定有关。你们尚未提出新程序或修订程序，用于管理你们QU的其它不足方面，例如调查偏差、制定纠正措施和预防措施、实施变更控制以及审核组分供应商的检验结果。

Without adequate quality procedures and oversight, you cannot ensure the consistency of your manufacturing processes and the purported identity, strength, quality, and purity of drug products released to the market.

没有适当的质量程序和监督，你们将无法确保生产工艺的一致性，以及放行市场药品的鉴别、强度、质量和纯度。

In response to this letter, provide the following:

在回信中，请提供以下信息：

An audit of all released batches for deviations and OOS results that have not been investigated. Also provide the status of any resulting investigations and retain testing, and your action plan to address any product quality or patient safety risks for your drug products in U.S. distribution within expiry, including potential customer notifications and recalls.
审核所有已放行批次的未调查的偏差和OOS结果。并提供所有调查的状态和留样检验，以及你们的行动计划：针对你们在美销售且在效期内的药品，以解决所有的产品质量或患者安全风险，包括潜在的客户通知和召回。

An audit of all incoming component specifications and necessary revisions to ensure that all components have appropriate written specifications for purity, strength, and quality.
审核所有入厂组分质量标准和必要的修订，以确保所有组分都具有关于纯度、强度和质量的适当书面质量标准。

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:
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：

o 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。

o The creation or revision of necessary standard operating procedures (SOPs).

o创建或修订必要的标准操作程序(SOP)。

o Training and effectiveness plans to ensure QU procedures are followed for existing, new, and revised SOPs.

o培训和有效性计划，以确保现有，新的和修订的SOP遵循QU程序。

o Provisions for QU oversight throughout your operations to evaluate adherence to appropriate practices, including but not limited to during manufacturing operations.

o在整个运营过程中对QU进行监督的条款，以评估对适当实践的遵守情况，包括但不限于生产工艺中的行为。

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

o 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。

o 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，调查并履行所有其它QU职责，以确保所有产品的鉴别、强度、质量和纯度。

批生产记录不够详细
2. Your firm failed to prepare batch production and control records with complete information relating to the production and control of each batch of drug product produced. (21 CFR 211.188)

2.你们公司未能准备批生产和控制记录，以提供与每批生产的药品的生产和控制有关的完整信息。(21 CFR 211.188)

Your batch production and control records lack adequate manufacturing details including, but not limited to, the following: weights of charged components, mixing times, mixing speeds, measured temperatures, hold times, amounts removed for in-process testing, in-process observations and testing results, and filling machine settings. Your current practice is to use manufacturing checklists without complete instructions. These checklists do not allow for the documentation of manufacturing information.

你们的批生产和控制记录缺少充分的生产详细信息，包括但不限于以下内容：组分重量、混合时间、混合速度、测量的温度、放置时间、用于控制的取样量、工艺中的观察值和检验结果，以及灌装机设置。你们当前实践是，在没有完整指导信息的情况下，使用生产文件。这些文件不能确保生产信息得到记录。

In your response, you committed to assessing the master production record for only the “ELIXICURE ORIGINAL FORMULA” to ensure steps are adequately defined and documented. Your response is inadequate. Your response does not provide sufficient information about how you plan to identify missing manufacturing information from distributed batches for all products, review your current documentation practices for deficiencies, make updates to master production records for all products, or how you will revise SOPs to comply with CGMP documentation requirements.

在你们的答复中，你们仅承诺评估“ ELIXICURE原始配方”的主生产记录，以确保对步骤进行了充分的定义和记录。你们的回复不充分。你们的回复没有提供充分的信息，说明你们如何计划从所有已分销批次中确定缺失的生产信息，查看当前的文件实践是否存在缺陷，更新所有产品的主生产记录、或如何修改SOP，以符合要求CGMP文件要求。

Completed batch production and control records are necessary to ensure that manufacturing processes are consistently followed and reproducible. Additionally, incomplete manufacturing records deprive you of the ability to adequately investigate deviations and batch failures.

必须有完整的批生产和控制记录，以确保始终遵循并重现生产工艺。此外，不完整的生产记录使你们失去了充分调查偏差和批次问题的能力。

In response to this letter, provide the following:

在回信中，请提供以下信息：

A retrospective analysis and gap assessment of your executed production records for both “ELIXICURE ORIGINAL” and “ELIXICURE LAVENDER” to identify all missing production information.
对你们执行的“ ELIXICURE原始”和“ ELIXICURE薰衣草”生产记录的回顾性分析和差距评估，以识别所有缺失的生产信息。

Revised master production records for all your drug products to demonstrate that, when executed, they fully document each manufacturing step.
对于所有药品，修改后的主生产记录，以证明在执行时它们可以完全记录每个生产步骤。

A complete assessment of documentation systems used throughout your manufacturing and laboratory operations to determine where documentation practices are insufficient. Include a detailed corrective action and preventive action plan that comprehensively remediates your firm’s documentation practices to ensure you retain attributable, legible, complete, original, accurate, and contemporaneous records throughout your operation.
对整个生产和实验室操作中使用的文件系统的完整评估，以确定哪些地方文件实践不充分。包括详细的纠正和预防措施计划，以全面补救公司的文件编制实践，确保你们在整个运营过程中保留可归因、清晰、完整、原始、准确和同期的记录。

确认与验证缺陷
3. 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)).

公司未建立用于生产和过程控制的书面程序，以确保你们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))。

Your firm failed to adequately qualify the equipment and validate the processes used to manufacture your drug products. You have not performed process performance qualification (PPQ) studies, nor do you have an ongoing program for monitoring process control to ensure stable manufacturing operations and consistent drug quality for products in U.S. distribution.

你们公司未能充分确认设备、并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，也没有持续的程序来监视过程控制，以确保稳定的生产操作、保证在美国经销药品质量始终如一。

In your response, you committed to performing Installation Qualification (IQ) and Operational Qualification (OQ) for (b)(4) pieces of equipment and to qualify secondary packaging equipment with the assistance of a CGMP consultant. However, you did not provide details about how you plan to assess and establish equipment requirements for your manufacturing processes and how you will accordingly design appropriate equipment qualification protocols. Finally, you committed to drafting and completing a PPQ protocol but did not provide details about the study design and how it will demonstrate process robustness.

在你们的答复中，你们承诺对XX设备执行安装确认(IQ)和运行确认(OQ)，并在CGMP顾问的协助下对次级包装设备进行确认。但是，你们没有提供有关计划的详细信息，说明如何评估和确定生产工艺中的设备要求、以及如何设计适当的设备确认方案。最后，你们承诺起草并完成PPQ方案，但未提供有关研究设计及其如何证明工艺稳健性的详细信息。

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。

Your PPQ 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 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。

CGMP顾问推荐
CGMP Consultant Recommended

In your response, you noted that you engaged a third-party consultant but you did not define the scope of the relationship. Based upon the nature of the violations we identified at your firm, we strongly recommend engaging a consultant qualified as set forth in 21 CFR 211.34 to assist your firm in meeting CGMP requirements.

在答复中，你们指出你们聘用了第三方顾问，但未定义雇佣范围。根据我们在你们公司发现的违规行为的性质，我们强烈建议聘请符合21 CFR 211.34规定的合格顾问来协助公司满足CGMP要求。

Your use of a consultant does not relieve your firm’s obligation to comply with CGMP. Your firm’s executive management remains responsible for resolving all deficiencies and systemic flaws to ensure ongoing CGMP compliance.

你们聘用顾问并不能免除公司遵守CGMP的义务。你们公司的执行管理层仍然有责任解决所有缺陷和系统缺陷，以确保持续符合CGMP。

未经批准的新药指控(略)
标识错误的药物指控(略)
结论
Conclusion

The violations cited in this letter are not intended to be an all-inclusive list of violations that exist at your facility or an all-inclusive statement of violations that exist in connection with your marketed products. You are responsible for investigating and determining the causes of any violations and for preventing their recurrence or the occurrence of other violations. It is your responsibility to ensure that your firm complies with all requirements of Federal law and FDA regulations.

本信函中引用的违规行为不是要列出你们机构中存在的所有违规行为，也不是与你们所销售的产品有关的所有违规行为声明。你们有责任调查和确定任何违规的原因，并防止其再次发生或发生其它违规情况。你们有责任确保你们公司符合联邦法律和FDA法规的所有要求。

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.

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。

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，以确认你们已完成纠正措施。

This letter notifies you of our findings and provides you an opportunity to address the above deficiencies. After you receive this letter, respond to this office in writing within 15 working days. Specify what you have done since our inspection to address any violations and to prevent their recurrence. In response to this letter, you may provide additional information for our consideration as we continue to assess your activities and practices. If you cannot completely address these violations within 15 working days, state your reasons for delay and your schedule for completion.

这封信通知你们我们的发现，并为你们提供解决上述缺陷的机会。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，你们所做的事情，以纠正你们的违规行为，并防止其再次发生。在回信中，当我们继续评估你们的活动和实践时，你们可以提供其它信息供我们考虑。如果你们无法在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。

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.

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. Honest Globe, Inc. MARCS-CMS 597177 — MARCH 15, 2021.

       文章来源：PharmLink

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