FDA警告信：发货、放行与检验时间都不对！

9月15日，FDA公布一封针对美国本土企业的警告信，包括了制剂和API违反GMP的情况。对于制剂产品，FDA检查发现某产品放行时间存在重大问题：

· 2019年12月5日：发货
· 2019年12月17日：产品放行
· 2019年12月20日：获得产品检验结果
· 2019年12月23日：审核批记录

FDA特别提到，在2017年11月的先前检查中，同样发现该公司没有适当的操作程序。FDA进而认为，这种屡次失效表明，该公司对药品生产的管理监督和控制是不足的。

Ms. Tabor:

塔博尔女士：

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Kalchem International, Inc., FEI 1000149906 (formerly FEI 1000160137), at 224 S. Main Street, Suite B, Lindsay, Oklahoma from February 10 to 21, 2020.

2020年2月10日至21日，美国FDA检查了您药品生产设施Kalchem International，Inc.，FEI 1000149906(此前为FEI 1000160137)，位于(美国)俄克拉荷马州。

This warning letter summarizes significant violations of current good manufacturing practice (CGMP) regulations for finished pharmaceuticals, Title 21 Code of Federal Regulations CFR parts 210 and 211 (21 CFR 210 and 211), and significant deviations from CGMP for active pharmaceutical ingredients (API).

该警告信总结了严重违反制剂CGMP规定的情况，见21CFR第210和211部分；同时也总结了有效活性成分(API)GMP的偏差情况。

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).

由于您用于生产、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，您的药品被认为是掺假。

Your firm manufactures and introduces, or delivers for introduction into interstate commerce, “(b)(4),” an unapproved new drug that is in violation of section 505(a) of the FD&C Act, 21 U.S.C. 355(a). This product is also misbranded under section 502 of the FD&C Act, 21 U.S.C. 352. Introduction or delivery for introduction of such a product into interstate commerce is prohibited under sections 301(d) and (a) of the FD&C Act, 21 U.S.C. 331(d) and (a), respectively. These additional violations are described in more detail below in the CGMP violation and deviation sections of this letter.

您的公司生产、引入或交付用于州际贸易的“ XX”，这是一种未经批准的新药，违反了FD＆C法案505(a)条，即21 USC 355(a)条。根据FD＆C法案502条，即21 USC 352条，该产品也属于标识错误。根据FD＆C法案301(d)和(a) 条，即21 USC 331(301) (d)和(a) 条，禁止将此类产品引入州际贸易。这些额外的违规行为，将在下文的CGMP违规和偏差部分中详细介绍。

We reviewed your March 10, 2020, response to our Form FDA 483 in detail.

对于您2020年3月10日对FDA 483表格的回复, 我们进行了详细审查。

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。

制剂的CGMP违规行为：
Your firm failed to have, for each batch of drug product, appropriate laboratory determination of satisfactory conformance to final specifications for the drug product, including the identity and strength of each active ingredient, prior to release (21 CFR 211.165(a)).

公司没有对每批药品进行适当的实验室确认，以确定其是否符合最终产品的质量标准要求，包括放行之前的每种活性成分的鉴别和强度(21 CFR 211.165(a))。

On December 5, 2019, your firm shipped the over-the counter (OTC) drug product “(b)(4)” three days before you received the certificate of analysis (COA) with assay results from your contract laboratory for the active ingredient, (b)(4). While you received the COA on December 20, 2019, you indicated to your customer that the batch was released on December 17, 2019.

在2019年12月5日，在收到合同实验室提供的API含量结果COA的三天前，公司已将OTC药品“ XX” 发货。在2019年12月20日收到COA时，您向客户说明该批已在2019年12月17日放行。

In addition, you did not review and approve the batch records until December 23, 2019, after the batch had been released.

此外，在批次放行之后，直到2019年12月23日，您才审阅和批准批记录。

In your response, you committed to perform a full and prompt batch review by the Quality Unit (QU) prior to product release and shipment to your customers.

在您的答复中，您承诺在产品放行并交付给客户之前，由质量部门(QU)进行全面、及时的批审查。

Your response is inadequate. You did not describe your corrective action and preventive action (CAPA) to ensure that all batch testing is reviewed before release or rejection.

您的回应不充分。您没有描述CAPA，以确保在放行或拒绝之前审查所有的批检验数据。

In response to this letter, provide the following:

针对此信，请提供：

1) A list of chemical and microbial specifications, including test methods, used to analyze each batch of your drug products before a batch disposition decision. Also include:

在决定批次处置之前，用于分析每批药品的化学和微生物质量标准(包括检验方法)列表。还包括：

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 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验，以确定分发给美国的药品批次(本函发出之日仍在效期内)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.
各留样批次检验结果摘要。如果检验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。

2) A comprehensive independent assessment of your laboratory practices, procedures, methods, equipment, documentation, and analyst competencies. Based on this review, provide a detailed plan to remediate and evaluate the effectiveness of your laboratory system.

对实验室操作、程序、方法、设备、文档和分析人员的能力，进行全面的独立评估。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。

3) 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:

全面的独立评估和补救计划，以确保您的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;
 Provisions for QU oversight throughout your operations to evaluate adherence to appropriate practices;
 A complete and final review of each batch and its related information before the QU disposition decision; and,
 Oversight and approval of investigations and discharging of all other QU duties to ensure identity, strength, quality, and purity of all products.
确定公司所使用的程序是否健全和适当
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
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
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；


API的 CGMP偏差：
Failure of your quality unit to exercise its responsibility to ensure the API manufactured at your facility are in compliance with CGMP.

您的质量部门未能履行职责，来确保在您的工厂生产的API符合CGMP。

Your facility repacks and relabels API. Your QU failed to perform adequate functions to ensure that the API you supply met CGMP requirements.

您的设施分包装并重新贴标了API。您的QU无法执行适当的功能，以确保您提供的API满足CGMP要求。

For example, your QU failed to ensure that records are maintained and reviewed for each API that is relabeled. In addition, you lacked a procedure for relabeling API.

例如，就每个API重新贴标的活动，您的QU无法确保维护并检查记录。此外，您缺少重新贴标API的相关程序。

It was a common practice for your firm to relabel and distribute lots without a written procedure and documentation.

在没有书面程序和文件的情况下，重新贴标和分销批次是贵公司的惯例。

You also failed to adequately review your re-packaging batch records before release. For example, one lot of Lidocaine HCL was re-packaged with an incorrect lot number and shipped. Your QU reviewed the Chemical Repackaging record six days after the product had been shipped. The error was not detected until the FDA investigator found it during our inspection.

在放行之前，您也没有充分检查分包装批记录。例如，分包装了一批利多卡因盐酸盐，虽然批号不正确，但也发货了。在产品发货六天后，您的QU才检查了化学分包装记录。直到FDA调查员在检查期间发现错误后，才意识到有问题。

In your response, you stated that you will create a new procedure for relabeling API and will revise your re-packaging procedure. You also committed that your QU will be responsible to approve or reject your drugs prior to shipments to customers.

在答复中，您声明将建立一个用于重新贴标API的新程序，并将修改您的分包装程序。您还承诺，在给客户发货之前，您的QU将负责批准或拒绝药品。

Your response is inadequate because you did not include a comprehensive risk assessment of potentially undetected hazards due to inadequate documentation and oversight for both current relabeled API inventory and distributed API. In addition, you failed to provide a copy of the new and the revised procedures.

您的回应是不充分的，因为对于重新贴标的现有API库存和已分销API，就其文档和监督不足而导致的、尚未发现的潜在危害，公司没有进行全面的风险评估。此外，您没有提供新程序和修订程序的副本。

In response to this letter, provide the following:

针对此信，请提供：

1) 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，以确保您的QU拥有有效运行的权限和资源。评估还应包括但不限于：

 A determination of whether procedures used by your firm are robust and appropriate;
 Provisions for QU oversight throughout your operations to evaluate adherence to appropriate practices;
 A complete and final review of each lot and its related information before the QU disposition decision; and,
 Oversight and approval of investigations and discharging of all other QU duties to ensure identity, strength, quality, and purity of all drugs. 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.
确定贵公司使用的程序是否健全和适当；
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QU处置决定之前，对每个批次及其相关信息进行完整的最终审查；和，
监督和批准调查以及履行所有其他QU职责，以确保所有药物的标识，强度，质量和纯度。另外，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。
2) A risk assessment addressing the hazards posed by inadequate documentation and oversight for both the distributed and current inventory of relabeled drugs. Also, provide a copy of your new and revised procedures for relabeling and repackaging.

进行风险评估，以阐述其文档和监督不足而导致的危害，需要针对重新贴标的现有API库存和已分销药物。另外，请提供重新贴标和分包装的新程序和修订程序的副本。

API Misbranding Violation API错误标识的违规行为(略)

Unapproved New Drug and Misbranding Violations未经批准的新药和错误标识的违规行为(略)

在工厂重复观察
In a previous inspection, dated November 2017, you were also cited for not having appropriate procedures in place for your operations. You proposed specific remediation for these observations in your written response at the time.

在日期为2017年11月的先前检查中，同样发现您没有适当的操作程序。您当时在书面答复中，提出了针对这些意见的具体补救措施。

Repeated failures demonstrate that executive management oversight and control over the manufacture of drugs is inadequate.

屡次失效表明，对药品生产的管理监督和控制不足。

API CGMP指南：
FDA considers the expectations outlined in ICH Q7 in determining whether API are manufactured in conformance with CGMP. See FDA’s guidance document, Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients, for guidance regarding CGMP for the manufacture of API, at https://www.fda.gov/media/71518/download.

FDA在确定API是否按照CGMP进行生产时，考虑了ICH Q7中概述的期望。请参阅FDA的指指南《Q7：关于活性药物成分的GMP指南》，以获取有关API的CGMP的指导，网址为https://www.fda.gov/media/71518/download。

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.

根据我们在您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，以帮助您的公司满足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.

您聘用顾问并不能免除公司遵守CGMP的义务。您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：
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您的产品相关的所有违规行为。您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 drugshortages@fda.hhs.gov, 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.

如果您考虑采取的行动可能会导致您药物的供应中断，则FDA要求您立即联系CDER的药物短缺人员(drugshortages@fda.hhs.gov)，以便FDA可以与您以最有效的方式沟通，使您的运营符合法律规定。根据21 USC 356C(b)，与药品短缺人员联系，还可以使您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，并保护依赖您产品的患者的健康。

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，也不会批准将您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，以确认您已完成纠正措施。

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，您所做的事情，以纠正您的违规行为，并防止其再次发生。如果您无法在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。

       文章来源：PharmLink

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