FDA警告信：包装线清场问题

9月22日，FDA公布一封针对美国本土企业的警告信。主要的违规项包括包装线清场问题、清洁验证未能科学选择最差产品，并基于偏差调查问题，提出公司质量部门未能履行职责。

在清场观察项中，FDA表示，在包装区域内和下方，FDA调查员观察到各种不同的片剂和胶囊，而批记录表明已经执行了生产线清洁检查。

September 15, 2020

Dear Mr. Shafer:

2020年9月15日，

谢弗先生：

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Coupler Enterprises, FEI 3003734940, at 125 Titus Avenue. Suite 200, Warrington, Pennsylvania, from February 26 to March 10, 2020.

2020年2月26日至3月10日，美国FDA检查了你处的药品生产设施，Coupler企业，FEI 3003734940，位于宾夕法尼亚州沃灵顿。

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，你药品被认为是掺假。

We reviewed your March 31, 2020, response to our Form FDA 483 in detail.

我们详细审查了你对2020年3月31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。

清场问题
1. Your firm does not adequately inspect the packaging and labeling facilities immediately before use to assure that all drug products have been removed from the previous operations (21 CFR 211.130(e)).

1.在使用前，你公司没有充分检查包装和标签设施，以确保所有药品均已从先前的操作中去除（21 CFR 211.130（e））。

Your firm operates as a human drug repackager. During the inspection walk-through, our investigator observed a variety of different tablets and capsules on and under the (b)(4) and (b)(4) packaging area. Your batch records indicated that line clearance was performed and the “Repackaging Room Cleaning Checklist” indicated the room was fully cleaned on February 14, 2020. The presence of tablets and capsules of various drugs on and under the packaging machinery indicates that line clearance was not adequately performed and increases the risk for potentially dangerous drug product mix-ups.

你公司是一家人药包装商。在检查过程中，在 XX和 XX包装区域内和下方，我们的调查员观察到各种不同的片剂和胶囊。你批记录表明已经执行了生产线清洁检查，并且“分包装室清洁核对表”表明该房间已在2020年2月14日完全清洁过。包装机上和下方的各种片剂和胶囊剂，表明生产线清场没有充分执行，这增加了潜在的、危险性的药品混淆的风险。

In your response, you stated that operators had been re-trained on line-clearance and a timelier cleaning schedule for the production area was developed. However, the standard operating procedure (SOP) for line clearance was not provided and your SOP for Production Room Cleaning Requirements lacks sufficient detail.

在你答复中，你说过对操作员进行了在线清场方面的培训，并为生产区域制定了更及时的清洁计划。但是，没有提供生产线清场的标准操作程序（SOP），并且你的“生产车间清洁要求”SOP缺少足够的细节。

In your response to this letter, provide your SOP for line clearance and a comprehensive written evaluation of packaging and labeling operation, with emphasis on failure modes, capability, and design sufficiency. Provide an analysis including but not limited to, all human interactions with equipment before, during, and after (e.g., clearance) operations to identify all points with potential for human error.

在你对这封信的答复中，请提供生产线清场SOP，并对包装和贴标操作进行全面的书面评估，重点是失效模式、功能和设计充分性。提供分析，包括但不限于在操作（例如，清场）之前、期间和之后，所有的人机交互，以识别所有可能造成人为错误的点。


清洁验证
2. Your firm failed to establish and follow adequate written procedures for cleaning and maintenance of equipment (21 CFR 211.67(b)).

2.你公司未建立并遵循适当的书面程序，来清洁和维护设备(21 CFR 211.67(b))。

You failed to demonstrate that your cleaning practices are adequate to remove residue from shared equipment used to manufacture your drug products. You were unable to provide scientific justification for the selection of drug products used in your cleaning validation studies. You stated that the “most powdery” products were selected for cleaning validation studies rather than selecting products based on adequate scientific rationale.

对于清洁实践足以清除药品共用生产设备上的残留，你无法证明。对于清洁验证研究中使用药物的选择，你无法为其提供科学依据。你表示，“粉状”产品被选择用于清洁验证研究，但不是根据充分的科学原理选择产品。

Although you committed to working with your third party consultant to address your deficiencies, you have not provided adequate details on your progress.

尽管你承诺与你第三方顾问一起解决你不足，但是你没有提供足够的进度细节。

In your response to this letter, provide the following:

针对此信，请提供：

• Appropriate improvements to your cleaning validation program, with special emphasis on incorporating conditions identified as worst case in your drug manufacturing operation. This should include but not be limited to identification and evaluation of all worst-case:

对清洁验证程序进行了适当的改进，特别着重于纳入在药品生产过程中确定为最差情况的条件。最差情况的识别和评估，应包括但不限于：

o products with higher toxicities

o products with higher potencies

o products of lower solubility in your cleaning solvents

o products with characteristics that make them difficult to clean

o swabbing locations for areas that are most difficult to clean

o maximum hold times before cleaning

o具有较高毒性的

o产品具有较高活性的

o产品在清洁溶剂中溶解度较低的产品

o具有使其难以清洁的特性的产品

o 清洁最困难区域的擦拭位置

o清洁前的最长放置时间

In addition, describe the steps that must be taken in your change management system before introduction of new manufacturing equipment or a new product.

另外，描述在引入新的生产设备或新产品之前，变更管理系统必须采取的步骤。

• A summary of updated SOPs that ensure an appropriate program is in place to verify and validate cleaning procedures for products, processes, and equipment.

更新的SOP的摘要，以确保制定适当的程序，来验证和确认产品、工艺和设备的清洁程序。

质量部门未履行职责
3. 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).

3.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)。

During the inspection, our investigator observed that your quality unit (QU) did not provide adequate oversight for the manufacture of your drug products. Your QU failed to ensure that all deviations were investigated. For example, contrary to your firm’s Deviation SOP, you lacked adequate investigations into 11 deviations. Instead, the 11 batch records in question were placed in a folder labeled “deviations” without appropriate deviation forms or adequate investigation. Additionally, your QU failed to ensure all equipment was qualified. For example, you did not adequately qualify the air compressor used in your operations.

在检查过程中，我们的调查员发现你质量部门（QU）对药品生产没有提供足够的监督。QU无法确保对所有偏差进行调查。例如，与公司的偏差SOP的要求相反，你缺乏对11个偏差的充分调查。相反，有问题的11个批记录被放置在标有“偏差”的文件夹中，而没有适当的偏差表或充分的调查。此外，你QU无法确保所有设备都已被确认。例如，你没有对操作中使用的空气压缩机进行充分确认。

In your response you provided a master list of 11 investigations. However, you did not provide the completed individual investigations. You also failed to address the product impact of the 11 deviations. Additionally, the qualification of your air compressor was still pending.

在你答复中，你提供了11个调查的主清单。但是，你没有提供完成的单个调查。你还没有解决11个偏差对产品的影响。此外，你空气压缩机的确认仍在进行中。

In response to this letter, provide the following:

针对此信，请提供：

• A risk analysis to show quality impact of inadequate equipment qualification on currently distributed drugs.

风险分析，以显示设备确认不足对当前已分发的药物的质量影响。

• 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：

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

确定贵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。

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。

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.

如果你认为你产品未违反FD＆C法案（或你已遵守FDA法规），请提供你理由和任何支持信息，以供我们考虑。

       文章来源：PharmLink

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