FDA警告信：临时启动长期稳定性，应付检查？

2月9日，FDA公布一封针对美国本土企业(Allay Pharmaceuticals)的警告信，主要的缺陷项涉及工艺验证、OOS调查、稳定性数据等问题。

FDA表示，对于某个验证批，时隔一年之后，该公司才启动长期稳定性研究（2020年5月1日），而这一决定刚好发生在FDA检查（2020年5月5日）开始前的几天。另外，对于某API，该公司的含量检验结果与供应商COA之间存在明显差异（相差7.8％），但公司没有进行充分的评估；这说明对于来自供应商物料，质量部门未能执行充分的监督。

最后，FDA指出，该公司质量部门未能履行其职责，以确保所生产的药品符合GMP要求，并建议使用CGMP顾问，来解决公司质量问题。

稳定性数据缺陷

3. 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)).

你们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 stability program is inadequate. You failed to have adequate long-term stability data to support the commercial size validation batches manufactured using API from a new supplier. Also, you failed to follow your stability test protocol by not consistently performing disintegration testing. The validation batches using the new API supplier were manufactured from May 16 to June 25, 2019, but not placed into a long-term stability study until May 1, 2020, almost a year later.

你们的稳定性程序不足。你们没有足够的长期稳定性数据，来支持使用新供应商API生产的商业验证批次。另外，你们没有遵循稳定性测试方案，因为没有一致性地执行崩解检验。使用新API供应商的验证批次于2019年5月16日至6月25日生产，但直到将近一年后的2020年5月1日才进行长期稳定性研究。

Stability data is critical for ensuring that products maintain their identity, strength, quality, purity, and safety throughout their labeled shelf-lives.

对于确保产品效期内保持其鉴别、强度、质量、纯度和安全性，稳定性数据至关重要。

In your response, you indicated that you initiated a deviation investigation for the lack of stability testing and that these deficiencies will not reoccur. A stability coordinator will also be hired to oversee the stability program.

在你们的答复中，你们表示由于缺乏稳定性测试而发起了偏差调查，并且这些缺陷将不会再次发生。还将聘请稳定协调员来监督稳定计划。

Your response is inadequate because you did not provide interim measures to address the products in the market that are lacking long term stability data.

你们的答复不充分，因为你们没有提供中期措施，来解决缺乏长期稳定性数据的市售产品问题。

In response to this letter, provide the following:

在针对此信的答复中，提供如下信息：

· 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。

质量部门未履行职责

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

4.质量控制部门未能履行职责，以确保所生产的药品符合CGMP要求，并符合有关鉴别、强度、质量和纯度的既定质量标准(21 CFR 211.22)。

Your quality unit (QU) failed to adequately oversee the quality of components received from your supplier and your drug manufacturing operations. For example:

对于来自供应商和药物生产部门组分的质量，你们质量部门(QU)未能进行充分的监督。例如：

· The variability in API assay results reported by your supplier compared to your testing was not adequately evaluated. The variability observed may compromise the assay and content uniformity of your finished product. For example, your firm’s test results for API lot (b)(4), used in the manufacture of (b)(4) tablets (b)(4) lot (b)(4), had a difference of 7.8% from the API manufacturer’s certificate of analysis (COA). Your firm used your assay result to formulate the finished product. Additionally, the FDA sampled lot (b)(4) and the sample results failed to meet the USP assay specification for active ingredient, (b)(4), and for content uniformity. In your communication dated September 15, 2020, your firm indicated that this lot was not distributed and will be destroyed.

·对于供应商API分析结果与检验结果之间的差异，你们没有充分评估。这种差异性可能会影响成品的含量和含量均匀性。例如，对XX片剂XX批次XX的生产中使用的API批次XX，相比于与API生产商的分析证书(COA)，你们的检验结果相差了7.8％。你们使用你们的含量结果来生产成品。此外，FDA对批次XX进行了其他部分，样品结果不符合USP中API XX的含量和含量均匀性的质量标准。在你们2020年9月15日的沟通信件中，你们公司表示该批次并未分销，将被销毁。

Per the quality agreement with (b)(4), your firm is responsible for the qualification of approved manufacturers. However, during the inspection you had not qualified the new API supplier and you relied on (b)(4) to perform qualification of the supplier, which is contrary to the agreement.

根据与XX达成的质量协议，你们公司负责确认生产商资质。但是，在检查过程中，你们没有确认新的API供应商资质，而是依靠XX对供应商进行资质确认，这违反了协议。

· Computerized systems in the laboratory had inadequate controls.

·实验室中的计算机系统控制不充分。

· Complaints were not adequately reviewed and investigated.

·投诉未得到适当的审查和调查。

In your response you stated that your firm recognizes the need to have more interactions with the API manufacturer. You committed to investigating and communicating to the API manufacturer when API release testing results differ more than 3%. Additionally, you have contacted the manufacturer of your HPLC systems to purchase and validate the necessary equipment. You also indicated that your new complaint procedure includes tracking, trending, and evaluating complaints.

在你们的答复中，你们表示认识到需要与API生产商进行更多的交互。你们承诺：在API放行检验结果相差超过3％时，启动调查并与API生产商沟通。此外，你们已经与HPLC系统的生产商联系，以购买和验证必要的一起。你们还指出，新的投诉程序包括跟踪、趋势化分析和评估投诉。

Your response is inadequate. You did not describe when and how you will requalify your API supplier or provide justification for how you determined when differences in API assay need to be investigated. In addition, you did not perform a retrospective review of the test results for your previous API supplier, (b)(4). Also, you did not perform an assessment to determine the risk from failing to have audit trail enabled controls and unique user passwords.

你们的答复不充分。你们没有描述何时、以及如何重新确认API供应商资质，就何时启动API分析差异调查，也没有提供论证。此外，就以前API供应商XX检验结果，你们没有对进行回顾性审查。此外，对于未能启用审计追踪和使用唯一用户/密码，你们没有执行评估来确定其风险。

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 the following:

在针对此信的答复中，提供如下信息：

· A comprehensive independent review of your material system to determine whether all suppliers of components, containers, and closures are each qualified, and the materials are assigned appropriate expiration or retest dates. The review should also determine whether incoming material controls are adequate to prevent use of unsuitable components, containers, and closures.

·对物料系统进行全面的独立审查，以确定所有组件、容器和密封件供应商是否都具有资质，并对物料指定了适当的效期或再验期。审查还应确定入厂物料控制措施是否充分，以防止使用不合适的组件、容器和封闭件。

· The chemical and microbiological quality control specifications you use to test and release each incoming lot of component for use in manufacturing. Include chemical and microbial test methods used to analyze each of your API, along with the corresponding validation or verification if USP methods are used.

·用于检验和放行每批传入的零件以用于生产的化学和微生物质量控制规范。包括用于分析你们的每个API的化学和微生物检验方法，以及使用USP方法时的相应验证或验证。

· A description of how you will test each component lot for conformity with all appropriate specifications for identity, strength, quality, and purity. If you intend to accept any results from your supplier’s COA instead of testing each component lot for strength, quality, and purity, specify how you will robustly establish the reliability of your supplier’s results through initial validation as well as periodic re-validation. In addition, include a commitment to always conduct at least one specific identity test for each incoming component lot.

·说明如何检验每个批次，确定是否符合有关鉴别、强度、质量和纯度质量标准。如果你们打算接受供应商COA的结果，而不是检验每个组分批次的强度、质量和纯度，请指定如何进行初始验证和定期再验证，从而稳健地确定供应商结果的可靠性。此外，还应承诺：对于每个入库的组分批次，至少进行一个特定的鉴别检验。

· A summary of results obtained from testing all components to evaluate the reliability of the COA from each component manufacturer. Include your standard operating procedure (SOP) that describes this COA validation program.

·结果摘要：对所有组分进行检验，以评估每个组分生产商的COA可靠性。包括描述此COA验证程序的SOP。

· 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，以确保你们QU拥有有效行使职责的授权和资源。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 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。

o 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。

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，调查并履行所有其他QU职责，以确保所有产品的鉴别、强度、质量和纯度。

o 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.

o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，以主动解决新出现的生产/质量问题、并确保持续的控制状态。

· 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:

·详细说明：你们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。包括以下内容：

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

o汇总中期措施，以防止删除和修改数据。

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

O对于使用分析仪器和数据的人员角色和职责，进行定义。

o 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.

o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。

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

o详细说明：每个分析系统所有人员的用户特权。

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

o详细摘要：有关用户角色分配和控制的程序更新和相关培训。

未经批准的新药 (略)

作为合同方的责任

Responsibilities as a Contractor

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方，例如生产设施、检验实验室、包装商和贴标签商。FDA将合同方视为生产商的延伸。

You and your customer (b)(4) have a quality agreement regarding the manufacture of (b)(4). You are responsible for the quality of drugs you produce as a contract facility regardless of agreements in place with product owners. You are required to ensure that drugs are made in accordance with section 501(a)(2)(B) of the FD&C Act for safety, identity, strength, quality, and purity.

就与XX产品的生产，你们和客户XX签订了质量协议。无论与产品所有者达成何种协议，作为合同设施生产，你们应对生产的药品质量负责。你们需要确保按照FD＆C法案第501(a)(2)(B)节的规定生产药物，以确保安全性、鉴别、强度、质量和纯度。

See FDA’s guidance document Contract Manufacturing Arrangements for Drugs: Quality Agreements at https://www.fda.gov/media/86193/download.

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。

建议使用CGMP顾问

CGMP Consultant Recommended

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，来协助你们公司满足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.

你们聘用顾问并不会减轻你们公司遵守CGMP的义务。你们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。

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. 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。你们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。

If you are considering an action that is likely to lead to a disruption in the supply of drugs produced at your facility, FDA requests that you contact CDER’s Drug Shortages Staff immediately, at [e-mail], so that FDA can work with you on the most effective way to bring your operations into compliance with the law. Contacting the Drug Shortages Staff also allows you to meet any obligations you may have to report discontinuances or interruptions in your drug manufacture under 21 U.S.C. 356C(b). This also allows FDA to consider, as soon as possible, what actions, if any, may be needed to avoid shortages and protect the health of patients who depend on your products.

如果你们考虑采取的行动可能会导致你们药物的供应中断，则FDA要求你们立即联系CDER的药物短缺人员([e-mail])，以便FDA可以与你们以最有效的方式沟通，使你们的运营符合法律规定。根据21 USC 356C(b)，与药品短缺人员联系，还可以使你们履行报告药品供应中断的义务。这也使FDA可以尽快考虑可能需要采取什么措施，以避免短缺，并保护依赖你们产品的患者的健康。

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，以确认你们已完成纠正措施。

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，你们所做的事情，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 (or you have complied with FDA regulations), include your reasoning and any supporting information for our consideration.

如果你们认为你们的产品未违反FD＆C法案(或你们认为已遵守FDA法规)，请提供你们的理由和任何支持信息，以供我们考虑。

Ref.: WARNING LETTER- Allay Pharmaceuticals, LLC. MARCS-CMS 609023 — JANUARY 27, 2021. FDA.