FDA警告信：OOS调查不能随意

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9月22日，FDA公布一封针对美国本土企业的警告信。主要的违规项设计OOS调查问题和未能执行工艺验证研究，在此基础上FDA认为该企业的质量部门失效，并存在严重的数据完整性问题。

FDA重点指出，与OOS结果相关的原始数据已被重写，无法查看；公司OOS调查中唯一可用的信息是某检验结果很高，出现OOS。

Ref: Case 607359

Dear Dr. Potini:

参考：案例607359

亲爱的波蒂尼博士：

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, HNC Products Inc., FEI 3000205427, at 8631 Sunset Road, Clinton, Illinois, from March 10 to 17, 2020.

2020年3月10日至17日，美国FDA检查了你的药品生产设施HNC Products Inc，FEI 3000205427，位于伊利诺伊州克林顿的8631 Sunset 路。

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，你的药品被认为是掺假。

Our inspection also revealed that your firm failed to fulfill its registration and listing obligations under section 510 of the FD&C Act, which is prohibited under section 301(p), 21 U.S.C. 360 and 331(p). As a result, your drugs are misbranded under section 502(o) of the FD&C Act, 21 U.S.C. 352(o).

我们的检查还显示，你的公司未履行FD＆C法案第510条规定的注册和上市义务，331(p)条对此予以禁止(即21 U.S.C. 360 和 331(p) 条款)。因此，根据FD＆C法案第502(o)(即21 U.S.C. 352(o))，你的药品属于表示错误。

We reviewed your April 3, 2020, response to our Form FDA 483 in detail and acknowledge receipt of your subsequent correspondence.

我们详细审查了你2020年4月3日对FDA 483表格的答复，并确认收到你的后续信件。

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。

OOS调查问题

1. Your firm failed to thoroughly investigate any unexplained discrepancy or failure of a batch or any of its components to meet any of its specifications, whether or not the batch has already been distributed (21 CFR 211.192).

1. 无论是否已经分发，对于这些批次或其中任何组件无法解释的差异或故障、无法满足其质量标准，公司未能彻底调查 (21 CFR 211.192)。

You failed to thoroughly investigate an out-of-specification (OOS) assay test result, a critical product attribute, for one of your sunscreen drug products. Specifically, your investigation into the OOS result for (b)(4) batch (b)(4) lacked critical information in sufficient detail, such as sample and standard preparation, root cause analysis, conclusion of investigation, and corrective action and preventive action (CAPA).

对于你的一种防晒药品，你无法彻底调查其超标(OOS)含量检验结果，而这是一种关键的产品属性。具体来说，对于XX批次 的OOS结果的调查, 你缺少足够详细的关键信息，例如样品和标准品的制备、根本原因分析、调查结论以及纠正措施和预防措施(CAPA)。

In addition, original data associated with the OOS result was overwritten and unavailable for review. Furthermore, the only information available in your investigation was that (b)(4) results were high and OOS. Your rationale for invalidating the test failure lacked a substantive scientific evaluation and did not follow your procedure for investigating OOS results.

此外，与OOS结果相关的原始数据已被重写，无法查看。此外，你的调查中唯一可用的信息是XX结果很高，出现OOS。你使检验OOS无效，但理由缺乏实质性的科学评估，也没有遵循调查OOS结果的程序。

Your response acknowledged that you did not have a formalized written review and investigation into the OOS result, and that your procedure lacked a requirement for root cause analysis and CAPA determination. You stated that you updated the (b)(4) method on the software to prevent deleting or overwriting results, although the quality control (QC) manager still retains the ability to do so.

你的回答承认：你没有对OOS结果进行正式的书面审查和调查，并且你的程序缺少根本原因分析和CAPA确定的要求。你声明了在软件上更新了XX方法，以防止删除或覆盖结果，尽管QC经理仍然保留了这样做的能力。

Your response is inadequate because your revised procedure for OOS investigation provided in response to this violation continued to lack sufficient details on how your firm will meaningfully investigate OOS occurrences. We also note that your laboratory manager still retains the ability to delete and overwrite results, which is unacceptable. It is your fundamental GMP responsibility to ensure that laboratory records include complete data derived from all tests necessary to assure compliance with established specifications and standards.

你的回应不充分，原因是，关于公司将如何有意义地调查OOS事件，针对此违规行为提供的OOS调查修订程序仍然缺乏足够详细信息。我们还注意到你的实验室经理仍然保留删除和覆盖结果的功能，这是无法接受的。GMP的基本职责是：确保实验室记录包含了从所有必要检验中获得的完整数据，以确保符合既定的质量标准和规范。

The lack of control over the integrity of your data raises questions about the authenticity and reliability of your analytical data and the quality of your drug products.

缺乏对数据完整性的控制，会引发了有关分析数据的真实性和可靠性、以及药品质量的问题。

For more information about handling out-of-specification, out-of-trend, or other unexpected results and documentation of your investigations, see FDA’s guidance document Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production at https://www.fda.gov/media/71001/download.

有关处理OOS、OOT或其他意外结果的更多信息，以及调查的文件化要求，请参阅FDA的指南《调查药品生产中的超标(OOS)检验结果》，网址为(见上)。

In response, provide the following:

作为回应，提供以下内容：

a. A retrospective review of all invalidated OOS (including in-process and release/stability testing) results for products currently in the U.S. for the last three years from the initial date of inspection and a report summarizing the findings of the analysis, including the following for each OOS:

对自检查之日起最近三年内在美国产品的所有无效OOS(包括过程中和放行/稳定性检验)结果，进行的回顾性审查，并总结分析结果的报告，包括每个OOS的以下内容：

i. Determine whether the scientific justification and evidence relating to the invalidated OOS result conclusively or inconclusively demonstrates causative laboratory error

确定与无效的OOS结果相关的科学依据和证据，是否说明了实验室错误是结论性的、还是不确定性的

ii. For investigations that conclusively establish laboratory root cause, provide rationale and ensure that all other laboratory methods vulnerable to the same or similar root cause are identified for remediation

对于最终确定实验室根本原因的调查，应提供理由，并确保确定了所有其他易受相同或相似根本原因影响的实验室方法，以进行补救

iii. For all OOS results found by the retrospective review to have an inconclusive or no root cause identified in the laboratory, include a thorough review of production (e.g., batch manufacturing records, adequacy of the manufacturing steps, suitability of equipment/facilities, variability of raw materials, process capability, deviation history, complaint history, batch failure history). Provide a summary of potential manufacturing root causes for each investigation, and any manufacturing operation improvements.

对于回顾性审查发现的所有OOS结果，如果在实验室中无法确定或没有根本原因，需要包括对生产进行彻底的审查(例如，批生产记录、生产步骤是否适当、设备/设施的适用性、原材料的可变性、过程能力、偏差历史记录、投诉历史记录、批次失败历史记录)。提供摘要信息：每个调查获得的潜在生产根本原因、以及任何生产操作改进。

b. A comprehensive review and remediation plan for your OOS result investigation systems. The CAPA should include but not be limited to addressing the following:

OOS结果调查系统的全面审查和补救计划。该CAPA应包括但不限于满足以下：

i. Quality unit oversight of laboratory investigations

实验室调查的质量部门监督

ii. Identification of adverse laboratory control trends

确定不利的实验室控制趋势

iii. Resolution of causes of laboratory variation

解决实验室波动的原因

iv. Initiation of thorough investigations of potential manufacturing causes whenever a laboratory cause cannot be conclusively identified

当无法确定实验室原因时，就开始对潜在生产原因进行彻底调查

v. Adequate scoping of each investigation and its CAPA

对每个调查及其CAPA，进行适当范围界定

vi. Revised OOS investigation procedures with these and other remediations

基于这些和其他补救措施，修订OOS调查程序

c. A complete assessment of documentation systems used throughout your manufacturing and laboratory operations to determine where documentation practices are insufficient. Include a detailed CAPA 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档系统的完整评估，以确定哪些地方文档实践不充分。包括一份详细的CAPA计划，该计划全面地修正了公司的文件编制惯例，以确保你在整个运营过程中保留可归因的、清晰的、完整的、原始的、准确的和同步的记录。

d. A detailed description of how your firm will implement an effective system to ensure retention and review of written and electronic laboratory data. Include the following:

有关贵公司将如何实施有效系统，以确保保留和审查书面和电子实验室数据的详细说明。包括以下内容：

i. Summarize your interim controls to prevent deletion and modification of data.

汇总临时控制措施，以防止删除和修改数据。

ii. Define the roles and responsibilities of personnel who have access to analytical instruments and data.

对于分析仪器和数据，定义授权人员的角色和职责。

iii. Establish a procedure to ensure that all analytical data including but not limited to sample and standard preparation are documented in accordance with CGMP requirements.

建立程序，以确保所有分析数据(包括但不限于样品和标准品)均按照CGMP要求进行记录。

iv. Detail the user privileges for all staff for each of your analytical systems.

详细说明分析系统的用户权限。

v. Provide a detailed summary of your procedural updates and associated training for user role assignments and controls.

就有关用户角色分配和控制的程序更新和相关培训，提供详细摘要。

生产和过程控制

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, and your firm's quality control unit did not review and approve those procedures, including any changes (21 CFR 211.100(a)).

2.你的公司未建立适当的书面生产和过程控制程序，以确保你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，而质量控制部门没有审查并批准这些程序，包括任何变更(21 CFR 211.100(a))。

You did not perform process validation studies for your sunscreen products. During the inspection, you were not able to provide documentation that process performance qualification (PPQ) studies had been conducted to establish that your processes are capable of consistently delivering quality product. Furthermore, you did not have an ongoing program for monitoring process control to ensure stable manufacturing operations and consistent drug quality.

你没有对防晒产品执行工艺验证研究。在检查过程中，你无法提供证明已进行工艺性能确认(PPQ)研究，以证明工艺能够始终如一地交付优质产品。此外，你没有正在进行的计划，来监视工艺控制，以确保稳定的生产操作和一致的药品质量。

In your response, you provided a new procedure for process validation. Your response is inadequate because it failed to include a detailed process performance protocol and actions to identify all sources of variability. Additionally, your response did not provide a timeline for completion of PPQ studies for each of your drug products.

在你的答复中，你提供了一个新的工艺验证程序。你的回答不充分，因为它没有包括详细的工艺性能草案、及识别所有可变性来源的措施。此外，你的回应并未提供完成每种药品PPQ研究的时间表。

Successful process qualification studies are necessary before commercial distribution. Thereafter, ongoing vigilant oversight of process performance and product quality is necessary to ensure you maintain a stable manufacturing operation throughout the product lifecycle.

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，以确保你在整个产品生命周期中保持稳定的生产运营。

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的指导性文件《工艺验证：一般原则和惯例》，以获取FDA关于工艺验证适当要素的一般原则和方法。

In response, provide the following:

作为回应，提供以下内容：

a. A detailed summary of your validation program for ensuring a state of control throughout the product lifecycle, along with associated procedures. Describe how your program ensures appropriate design, how you approach process performance qualification studies, and how you perform vigilant monitoring of both intra-batch and inter-batch variation to ensure an ongoing state of control.

验证计划的详细摘要(以确保整个产品生命周期内的控制状态)，以及相关程序。描述该计划如何确保适当的设计，如何进行工艺性能确认研究，以及如何对批内和批间变化进行警惕的监视，以确保持续的控制状态。

b. A timeline for performing appropriate process performance qualification (PPQ) for each of your marketed drug products.

为每种上市药品执行适当的工艺性能确认(PPQ)的时间表。

c. Include your PPQ protocols, and written procedures for qualification of equipment and facilities.

包含你的PPQ草案，以及用于确认设备和设施的书面程序。

d. For the PPQ studies, include the statistical basis for intensively evaluating the sources of variation in your manufacturing operation, number of batches per product, and other important parameters of your study.

d。对于PPQ研究，需包括统计依据(以集中评估生产操作中的波动因素)、每种产品的批数、以及研究中的其他重要参数。

质量部门失效

3. Your firm failed to establish an adequate quality control unit with the responsibility and authority to approve or reject all components, drug product containers, closures, in-process materials, packaging materials, labeling, and drug products (21 CFR 211.22(a)).

3.你的公司未能建立适当的质量控制部门，以负责和拒绝批准或拒绝所有组件、药品容器、密封件、在制品、包装材料、标签和药品(21 CFR 211.22(a)) )。

You failed to establish an independent and effective quality unit. For example, you failed to perform adequate quality unit (QU) responsibilities, such as the review of OOS investigations and equipment qualification. In addition, your firm failed to establish a change management and annual product review program.

你未能建立独立有效的质量部门。例如，你没有履行适当的质量单位(QU)职责，例如对OOS调查和设备确认的审查。此外，你的公司未能建立变更管理和年度产品回顾计划。

Your response indicated that you do not have the resources to allow for a formal QU and that increased organization, documentation, and cross-checking will improve your QU. You also indicated that you updated existing procedures; created new ones, such as a procedure for investigations; and planned to implement annual product review.

你的回答表明你没有资源来使用正式的QU，你认为对组织、文档的增强和交叉检查，将改善你的QU。你还表示已更新了现有程序；创建了新的程序，例如调查程序；并计划实施年度产品回顾。

Your response is inadequate because you failed to provide documentation to demonstrate that you have implemented an effective QU capable of performing QU responsibilities. You also failed to provide copies of the procedures you updated or created, and a timeline for the remaining procedures.

你的答复不充分，因为你未能提供文档来证明：你已实施了能够执行其职责的有效QU。你还没有提供更新或创建的程序的副本、以及其余程序的时间表。

Establishing an adequate QU is essential to ensuring that your operations associated with all systems (facilities and equipment, materials, production, laboratory controls, and packaging and labeling) are appropriately planned, approved, conducted, and monitored, and ultimately ensures that your firm is capable of consistently producing drug products of acceptable quality.

建立适当的QU对确保适当计划、批准、执行和监控与所有系统(设施和设备、物料、生产、实验室控制以及包装和标签)相关的操作至关重要，并最终确保你的公司：能够始终如一地生产出质量合格的药品。

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.

请参阅FDA的指南《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，以满足CGMP法规21 CFR第210和211部分的要求，网址为(见上)。

In response, provide the following:

作为回应，提供以下内容：

a. 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:

全面的评估和补救计划，以确保你的QU拥有有效运行的权限和资源。该评估还应包括，但不限于：

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

确定贵公司所使用的程序是否健全和适当

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

在整个运营过程中对QU进行监督的规定，以评估对适当实践的遵守情况

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

QU处置决策之前，对每批产品及其相关信息进行完整的最终审查

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

监督和批准调查并履行所有其他QU职责，以确保所有药品的鉴别、强度、质量和纯度

v. Also describe how top management supports quality assurance and reliable operations, including but not limited to timely provision of resources to proactively address emerging manufacturing/quality issues and to assure a continuing state of control

还应描述高层管理人员如何支持质量保证和可靠的运营，包括但不限于：及时提供资源，以主动解决新兴的生产/质量问题，并确保持续的控制状态

b. Information collected during the inspection indicated that bulk products are shipped outside of your firm’s control, prior to receipt of final laboratory test results. State whether your firm has discontinued this practice and provide the list of lots shipped and distributed prior to final receipt of laboratory results and QU clearance.

在检查过程中收集的信息表明，在收到最终实验室检验结果之前，半产品已运输，并超出你公司的控制范围。在最终收到实验室结果和QU许可之前，请说明你的公司是否已停止这种做法，并提供已装运和已分发批次的清单。

数据完整性问题

Your quality system does not adequately ensure the accuracy and integrity of data to support the safety, effectiveness, and quality of the drugs you manufacture. See FDA’s guidance document Data Integrity and Compliance With Drug CGMP for guidance on establishing and following CGMP compliant data integrity practices at https://www.fda.gov/media/119267/download.

你的质量体系无法充分确保数据准确性和完整性，无法支持所生产药物的安全性、有效性和质量。有关建立和遵循CGMP数据完整性实践的指导，请参阅FDA的指南《数据完整性和CGMP合规性》。

We strongly recommend that you retain a qualified consultant to assist in your remediation.

我们强烈建议你聘请有资质顾问，来协助你进行补救。

In response to this letter, provide the following:

针对此信，请提供：

• A comprehensive investigation into the extent of the inaccuracies in data records and reporting including results of the data review for drugs distributed to the United States. Include a detailed description of the scope and root causes of your data integrity lapses.

•全面调查数据记录和报告中不准确的程度，包括分发至美国药物的数据审查结果。包括有关数据完整性失效范围和根本原因的详细说明。

• A current risk assessment of the potential effects of the observed failures on the quality of your drugs. Your assessment should include analyses of the risks to patients caused by the release of drugs affected by a lapse of data integrity and analyses of the risks posed by ongoing operations.

•对于观察到的失效可能对药物质量产生潜在影响，进行当前风险评估。你的评估应包括：数据完整性错误影响下，药物放行对患者的风险分析，以及对正在进行的操作造成的风险进行分析。

• A management strategy for your firm that includes the details of your global corrective action and preventive action plan. The detailed corrective action plan should describe how you intend to ensure the reliability and completeness of all data generated by your firm including microbiological and analytical data, manufacturing records, and all data submitted to FDA.

•你公司的管理策略，其中包括全球CAPA计划的详细信息。详细的纠正措施计划应描述：你打算如何确保公司生成的所有数据(包括微生物和分析数据、生产记录以及所有提交给FDA的数据)的可靠性和完整性。

质量单元授权

Significant findings in this letter indicate that your quality unit is not able to fully exercise its authority and/or responsibilities. Your firm must provide the quality unit with the appropriate authority and sufficient resources to carry out its responsibilities and consistently ensure drug quality.

这封信中的重大发现表明：你的质量部门无法充分行使其权限和/或职责。你的公司必须向质量部门提供适当的权限和足够的资源，以履行其职责，并始终如一地确保药品质量。

CGMP顾问推荐

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.

根据我们在你公司中发现的违规行为的性质，我们强烈建议雇用一名符合21 CFR 211.34规定的合格顾问，以帮助你的公司满足CGMP要求。

We also recommend a consultant assist you in identifying which of your products are drugs, and therefore subject to the pharmaceutical CGMPs (21 CFR 210 and 211).

我们还建议顾问帮助你确定哪些产品是药物，并因此受制于药物CGMP要求(21 CFR 210和211)。

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.

你聘用顾问并不能免除公司遵守CGMP的义务。你公司的执行管理层仍然负责解决所有缺陷和系统性缺陷，以确保持续符合CGMP。

Drug Registration Violation 违反药品注册(略)

结论

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.

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。

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