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).

Your investigations into quality defect complaints of Albuterol Sulfate Inhalation Aerosol were inadequate because they lacked appropriate and timely corrective actions and preventive actions (CAPAs). You also failed to extend your investigations to other potentially affected batches.

FDA认为药厂处理某一气雾剂产品的投诉是不合适的，因为没有制定及时、适当的CAPA，并且没有进一步调查潜在的问题批次。

Your firm received a very high number of complaints (approximately 3,000) from the start of commercial manufacturing in April 2020 to December 2022. In January 2021, you concluded that there was no risk to product quality and patient safety based on a risk assessment. Approximately 91% of these complaints were categorized as “no spray” or “empty/less weight.” Furthermore, many of these complaints remained open for extended periods of time (up to 314 days).

药厂在2年多的时间里收到了很多投诉（将近3000起），大约91%的投诉内容涉及“喷不出来”或“空瓶/重量不足”，然而药厂却评估认为这些投诉对产品质量和患者安全没有风险，并且许多投诉长期未关闭（最长的有314天）。

You concluded that (b)(4) particles from the metered dose inhaler (MDI) valves became lodged in the actuators, blocking drug delivery. The MDI valve manufacturer, (b)(4), identified four valve lots that were potentially affected by this issue. These four valve lots were used to manufacture over (b)(4) batches of Albuterol Sulfate Inhalation Aerosol. In addition, in at least two cases, your investigation into complaints received in 2021 confirmed inhalers were not able to deliver medication due to the defective valve lots.

药厂调查发现产品中所用到的阀门脱落物导致药物递送系统堵塞，阀门厂家称该问题涉及4个批次的阀门，这4批有问题的阀门用于了多个批次药品的生产。并且，药厂在2年前就出现过至少2起同样问题导致的投诉。

While your investigation identified a critical issue with the container-closure system in which particles were blocking the path of the drug delivery, you classified the “Final Severity of Complaint” as “Non-Critical,” determined that no FAR was required, and concluded that no market action was warranted. The impacted Albuterol Sulfate Inhalation Aerosol batches remained on the market through expiry.

药厂评估认为该投诉的级别为非关键投诉，认为不需要向FDA递交FAR（field alert report），决定不需要对市场上在售的产品采取行动。

Inadequate container-closure parts or assembly processes can directly lead to production of poor-quality inhaler medicines with severe functionality or integrity defects, including but not limited to failure to dispense, inadequate dosing, or leaking units. It is essential that your manufacturing processes remain in a continued state of control to ensure that your rescue inhaler products reproducibly deliver the required dose for consumers who rely on your medicines.

不合适的容器密封件或装配操作会导致产品出现严重的功能性和密封性缺陷，比如无法给药、剂量不准确、泄露等。生产工艺能够确保持续稳定地生产出稳定给药的产品是最基本的要求。

In your response, you state there are adequate controls in place and the number of complaints received through December 2022, for product quality issues represent 0.011% of total units distributed. You also state your belief that the two complaints with defective valve components verified in your laboratory investigation were “isolated events.” Furthermore, you indicate that because you anticipate no additional defective units will be present in the market, you did not submit a FAR and no market action was being contemplated.

药厂回复FDA说投诉涉及的产品只占2022年12月份生产产品总量的0.011%，认为阀门问题导致的产品缺陷的这2起投诉是偶发事件，并且推算市场上不会再出现这种缺陷产品的投诉，所以就没有递交FAR，也没对市场上销售的产品采取措施。

Your response is inadequate as the issue with defective valves appears to be unresolved. According to your response, you received numerous additional complaints (about 2,000) between January 2023 and August 2023, with similar issues such as “no spray,” “empty/less weight,” and leaky containers. The batches associated with these complaints used valve lots beyond the four vendor lots previously identified as potentially affected. Many complaints are still under investigation.

FDA不接受药厂的回复，因为并没有解决阀门缺陷的问题。2023年1月至8月期间药厂收到很多类似的产品投诉，这些投诉涉及的产品批次所用到的阀门是在厂家那4批问题阀门之外的，且这些投诉的调查有很多还未关闭。

Your justification for not taking market action is inadequate. The ratio of the number of spontaneous complaints received from customers to the total number of units distributed is not an acceptable indicator of product quality and does not safeguard consumers. You failed to demonstrate that your production design, controls, and input materials are capable of robustly producing units with reliable functionality.

FDA不接受药厂认为不需要采取市场措施的理由，药厂计算投诉产品的占比对于判断产品质量问题是不可接受的，没有保障患者利益。药厂并未证明其生产工艺、过程控制、物料质量水平能够保证持续生产出具有可靠性能的产品。

The number of complaints you received showed a marked and adverse trend of critical drug delivery failures which fundamentally impacted the ability of patients to use your Albuterol Sulfate Inhalation Aerosol. Your complaint system was ineffective. For example, you emphasized the number of complaints verified in your laboratory investigation without appropriately evaluating the severity of the complaints. Also, passing results of retain sample testing cannot be used as a reason to disregard the validity of complaints that are of high severity and occur at a low frequency. For guidance on the principles and application of quality risk management, see FDA’s guidance Q9 Quality Risk Management at https://www.fda.gov/media/167721/download.

市场投诉的数量已经明显说明该产品的药物递送功能缺陷已经影响了患者的使用。经实验室调查确认了投诉数量，但是没有进一步评估投诉的危害性；留样检测结果合格并不能成为忽视该严重投诉投诉、定义该投诉为小概率事件的理由，所以药厂的投诉处理系统是失效的。FDA建议药厂再去学习Q9质量风险管理指南。

We acknowledge your firm initiated a Class I recall on June 27, 2023, for six batches of Albuterol Sulfate Inhalation Aerosol due to a defective valve lot that had a partially missing bottom seat (gasket). However, your firm failed to perform a comprehensive risk assessment by extending the investigations to other batches potentially impacted by defective container-closure components and to adequately determine the scope of the recall.

因为某批次阀门的底座部分缺失从而影响到6批产品，药厂在2023年6月27发起过一次1级召回。然后药厂没有延伸调查其他可能被该密封件问题影响的批次，从而作出综合评估决定召回范围。

In response to this letter, provide the following:

• A comprehensive, independent assessment of your overall system for investigating deviations, discrepancies, complaints, out-of-specification (OOS) results, and failures. Provide a detailed action plan to remediate this system. Your action plan should include, but not be limited to, significant improvements in investigation competencies, scope determination, root cause evaluation, CAPA effectiveness, quality unit (QU) oversight, and written procedures. Address how your firm will ensure all phases of investigations are appropriately conducted.

  FDA要求药厂对偏差、异常事件、投诉、OOS、故障等调查处理系统进行全面、独立的评估，并提供详细的系统改进计划，包括但不限于显著改善调查能力、调查范围确定、根本原因分析、CAPA有效性、QA的监管以及书面规程。说明药厂怎么才能确保所有阶段的调查均会适当开展。

• An independent assessment of your CAPA program. Based on this assessment, provide a plan that evaluates and remediates the program, including but not limited to ensuring robust:

  要求药厂对CAPA系统进行独立的评估，基于评估结果制定改进系统的计划，包括但不限于：

    o Triggers for fulfilling both corrective and preventive objectives

       确保及时触发纠正措施和预防措施的流程；
    o Root cause analysis

       确保分析出根本原因；
    o CAPA effectiveness

       确保CAPA措施的有效性；
    o Analysis of investigations trends on a routine basis

       确保定期分析调查的趋势；
    o CAPA program improvements, whenever needed

       确保CAPA处理流程的持续改进；
    o Implementation of final QU decisions

       确保执行质量部门的决策；
    o Support of the program by executive management.

       确保流程得到高管的支持。

• An independent, retrospective review of all complaints and associated investigations for Albuterol Sulfate Inhalation Aerosol batches manufactured since April 2020. Provide the consultant’s recommendations based on a review that includes but is not limited to an evaluation of:

  要求药厂独立回顾从2020年4月以来该产品所有涉及的投诉以及相关的调查，提供顾问所提出的下述内容的建议：
  

    o All investigations related to “confirmed” and “unconfirmed” container-closure defects, the level of criticality for each defect, all potentially impacted batches (i.e., distributed, undistributed and rejected batches; approved and pending application drug products), and any associated issues identified during both product/process development and via commercial batch experience. 

     所有确定的或待确定的密封件缺陷的调查、每种缺陷的分级、所有潜在受影响的批次、产品开发/商业化生产过程中发生的所有相关的异常事件。

   o The sufficiency (i.e., scope, trend analysis, root cause, CAPA) of the investigations, whether the complaint sample was obtained, all results of analysis of complaint and reserve samples.

      调查的充分性，无论是否可以拿到投诉的样品，无论投诉和留样分析的结果是什么。

• An independent, comprehensive review of your company’s complaint handling program that identifies deficiencies and a corresponding CAPA.

  要求药厂对投诉处理系统进行独立、全面的评估，找出不足，制定CAPA。
  

• A management strategy including the interim measures describing the actions you have taken or will take to protect patients and to ensure the quality of your drugs, such as notifying your customers, recalling product, conducting additional testing, supplier changes, adding batches to your stability program to assure stability, drug application actions, and steps to enhance vigilance in response to serious quality complaints.

  要求药厂提供管理策略，包括描述已经执行的或即将执行的措施以保护患者、确保产品质量的临时措施，例如：通知客户、召回产品、实施额外检测、供应商变更、增加稳定性样品以及对严重影响患者安全的投诉提高警惕性。

总结：从药厂收到的产品投诉为切入点，检查药厂的投诉处理流程以及持续生产出合格产品的能力，从而评价药厂的质量体系。从检查发现的问题来看，药厂对产品投诉很不重视，投诉处理流程很不规范，重点看文中提到的几个点：

1.药厂在2年多的时间里收到将近3000起，大约91%的投诉内容涉及“喷不出来”或“空瓶/重量不足”，然而药厂却评估认为这些投诉对产品质量和患者安全没有风险，并且许多投诉长期未关闭（最长的有314天）。——同一类型的投诉多次发生就说明问题没有得到根本解决，要么是根本原因没有找到，要么是找到了根本原因但解决成本大不愿意去处理。本案例中，问题产品的根本原因是已知的，猜测是企业不想花大成本去解决（召回很多批、已生产未放行的很多批次要报废）。药厂认为该产品缺陷属于低风险，思维太狭隘了，药液喷不出来/空瓶已经属于散失功能了，密封件损坏会造成微生物的污染。在药厂眼里似乎只有假药才是高风险。

2.不合适的容器密封件或装配操作会导致产品出现严重的功能性和密封性缺陷，比如无法给药、剂量不准确、泄露等。生产工艺能够确保持续稳定地生产出稳定给药的产品是最基本的要求。——既然药厂已经调查确认根本原因为供应商提供的阀门质量有缺陷，那么就需要供应商进一步深入调查该阀门出现问题的根本因是什么、阀门厂家历史上出现该问题的频次、阀门厂家放行检测是否有发现该问题（如果出厂前已经发现，为何没主动告知药厂）、潜在受影响的阀门批次（从而进一步评估受影响的药品批次）、阀门厂家如何从根本上解决该问题、重新评估和阀门供应商的质量协议、评估是否需要备选阀门供应商等等，面对该投诉，需要做的事情很多很多。

3.药厂回复FDA说投诉涉及的产品只占2022年12月份生产产品总量的0.011%，认为阀门问题导致的产品缺陷的这2起投诉是偶发事件，并且推算市场上不会再出现这种缺陷产品的投诉。——那么多起该问题的投诉已经说明了该问题不是小概率事件了，药厂拿这种概率计算方式就是自欺欺人了，就难免会给检察官造成很差的印象。如果谈概率问题，药厂更应该在投诉的调查报告中去看厂家阀门出现问题的概率是多少、导致药品给药系统出现问题的概率是多少、药品放行检测发现该问题的概率是多少（解释为何产品放行检测时没有发现该问题）、从而评估市场上可能还有多少产品可能存在该问题，为制定召回行为提供理论支撑。

撰稿人 |  解读FDA483和警告信

责任编辑 | 胡静

审核人 | 何发