Regulatory compliance in the pharmaceutical and medical-device sectors is paramount for protecting public health. In the United States, the Food and Drug Administration (FDA) enforces laws and regulations to ensure that products meet stringent safety and efficacy standards. To achieve that goal, the FDA conducts inspection of manufacturing and distribution facilities. Authority for such activities derives from the Federal Food, Drug, and Cosmetic (FD&C) Act, particularly section 704, which grants the FDA broad powers to inspect facilities, records, and products.

 

制药和医疗器械行业的法规符合性对于保护公众健康至关重要。在美国，FDA执行法律和法规以确保产品符合严格的安全性和有效性标准。为了实现这一目标，FDA 对制造和分销设施进行检查。此类活动的授权来自FD&C法案，特别是第704 节，该法案授予 FDA 检查设施、记录和产品的广泛权力。

 

The FDA’s guidance documentCircumstances That Constitute Delaying, Denying, Limiting, or Refusing a Drug or Device Inspection outlines the behaviors and actions that can be deemed noncompliant during such inspections (1). The guidance clarifies what constitutes as obstruction of an inspection, helping manufacturers to avoid legal and regulatory repercussions. The document covers a breadth of scenarios, from preannounced inspections to refusals to permit entry, providing a clear framework for understanding FDA expectations.

 

FDA 的指导文件《构成延迟、阻碍、限制或拒绝药品或器械检查的情况》概述了在此类检查期间可能被视为不合规的行为和行动（1）。该指南阐明了什么构成阻碍检查，帮助制造商避免法律和监管影响。该文件涵盖了从预先宣布的检查到拒绝允许进入的广泛场景，为理解FDA 的期望提供了一个清晰的框架。

 

Key Areas of Concern

 

主要关注领域

 

The FDA guidance document identifies several key areas in which facilities must exercise caution to maintain compliance. Such areas include delaying, denying, limiting, or refusing an inspection. Each action can have significant implications for a facility, potentially leading to severe penalties, including the classification of products as adulterated.

 

FDA 指南文件确定了工厂必须谨慎行事以保持合规性的几个关键领域。这些领域包括延迟、阻碍、限制或拒绝检查。每项作都可能对工厂产生重大影响，可能导致严厉的处罚，包括将产品归类为掺假。

 

Delay of Inspections:Preapproval and prelicense inspections tend to be preannounced, as are inspections for foreign facilities. Although the FD&C Act does not mandate preannouncements, they are a common practice to facilitate the inspection process. The FDA usually contacts a facility beforehand to ensure the availability of relevant records and personnel. However, delays in scheduling such inspections can constitute noncompliance, especially if a facility’s management fails to agree on a start date without reasonable explanation.

 

检查延迟：批准前和许可证前检查往往是预先通知的，对国外设施的检查也是如此。虽然FD&C 法案没有强制要求预先通知，但这是促进检查过程的常见做法。FDA通常会事先联系工厂，以确保相关记录和人员准备就绪。但是，延迟安排此类检查可能构成不合规，特别是如果工厂管理层在没有合理解释的情况下未能就开始日期达成一致。

 

Consider a scenario in which a facility is notified of an upcoming preapproval inspection. The FDA attempts to schedule the inspection, but the facility’s management continually requests postponements without providing valid reasons. Eventually, the facility stops responding to FDA communications. In that case, the facility’s actions could be interpreted as a deliberate attempt to delay the inspection, potentially leading to regulatory action. A reasonable explanation, such as ongoing renovations that render a facility inaccessible or unsafe, would mitigate the situation only if properly communicated and documented.

 

考虑这样一种情况：工厂收到即将进行的批准前检查的通知。FDA 试图安排检查，但工厂的管理层不断要求推迟检查，而没有提供正当理由。最终，该工厂停止回应 FDA 的通报。在这种情况下，该设施的行为可能会被解释为故意延迟检查，这可能会导致监管行动。合理的解释，例如正在进行的翻修导致设施无法进入或不安全，只有在适当沟通和记录的情况下才能缓解这种情况。

 

Delay During an Inspection:FDA investigators are authorized to inspect all areas of a facility that bear on whether drugs or devices are adulterated, misbranded, or otherwise in violation of the FD&C Act. Delays during an inspection can arise from restricted access to operational areas, unavailability of necessary personnel, or delays in providing documentation. Such actions can hinder the inspection process significantly.

 

检查期间的延误：FDA 检查人员有权检查设施中所有与药品或器械是否掺假、贴错标签或其他违反 FD&C 法案有关要求。检查期间的延误可能是：进入操作区域受限、缺乏必要人员或延迟提供文件。此类操作会严重阻碍检查过程。

 

During an unannounced inspection, for example, an FDA investigator requests access to a facility’s sterile manufacturing area. The facility’s management, however, insists that the investigator wait several hours before entering, citing ongoing cleaning. Upon investigation, it is revealed that no such cleaning was scheduled, and the delay was an attempt to prevent the investigator from observing specific production activities. Such behavior would be deemed noncompliant because it obstructs the investigator’s ability to conduct a thorough inspection.

 

例如，在突击检查期间，FDA 检查人员要求进入工厂的无菌生产区域。然而，该设施的管理层坚持要求检查人员等待几个小时才能进入，理由是正在进行清洁。经调查，发现没有安排此类清洁，此延迟是为了阻止检查人员观察特定的生产活动。这种行为将被视为不合规，因为它阻碍了检查人员进行彻底检查的能力。

 

Delay in Producing Records:Facilities must be prepared to provide all requested documentation in a timely manner. Delays in producing records, especially without a reasonable explanation, can be considered an attempt to obstruct the inspection. The FDA’s authority extends to both hardcopy and electronic records, and facilities must ensure that such documents are readily accessible.

 

延迟提供记录： 工厂必须准备好及时提供所有要求的文件。延迟提供记录，尤其是没有合理解释，可被视为试图阻碍检查。FDA 的权力涵盖硬拷贝和电子记录，设施必须确保此类文件易于访问。

 

Consider a facility that maintains its financial and production records at an offsite location. During an inspection, the FDA requests specific records, but the facility’s management states that accessing those records will take several days. Such a delay, if not adequately justified, could be considered an obstruction. However, if the facility provides a clear explanation (such as the need to retrieve records from a remote archive) and works to minimize the delay, then it can avoid noncompliance issues.

 

试想一下：一个在异地位置维护其财务和生产记录的设施。在检查期间，FDA 要求提供特定记录，但该设施的管理层表示，访问这些记录需要几天时间。这种延误，如果没有充分的理由，可被视为一种阻碍。但是，如果工厂提供明确的解释（例如需要从远程存档中检索记录）并努力最大限度地减少延迟，那么它可以避免不合规问题。

 

Denial of Inspection:The FDA’s guidance interprets denial broadly, including behavior that prevents an FDA representative from conducting or completing an inspection. This encompasses both active refusals and passive actions that obstruct inspections. Denial can include outright refusals to schedule or allow inspections, as well as misleading or deceptive actions that hinder the inspection process.

 

拒绝检查：FDA 的指南对拒绝检查进行了广泛的解释，包括阻止FDA 人员进行或完成检查的行为。这包括主动拒绝和阻碍检查的被动行动。拒绝包括公然拒绝安排或拒绝允许检查，以及阻碍检查过程的误导性或欺骗性行为。

 

For example, facility management falsely claims that it has ceased all manufacturing operations when FDA investigators arrive for an unannounced inspection. Representatives state that the site is undergoing renovations, and no products are being produced. However, subsequent evidence reveals that the facility had active production lines and was attempting to avoid inspection. Such behavior constitutes a clear denial of inspection because it involves intentionally misleading investigators.

 

例如，当 FDA 检查人员到达现场进行突击检查时，管理部门错误地声称已停止所有生产业务。表示：该场地正在进行翻新，没有生产任何产品。然而，随后的证据表明，该工厂的生产线正在运行，并试图逃避检查。这种行为明显构成拒绝检查，因为它涉及故意误导检查人员。

 

Limiting Inspection: Limiting an inspection involves restricting its scope or extent, such as blocking access to certain areas, restricting observation of specific processes, or withholding information. The FDA considers such actions to be potentially obstructive because they prevent comprehensive evaluation of the facility’s compliance with regulatory standards. Facilities must provide FDA investigators with reasonable access to all areas and processes relevant to the inspection. Limiting access without a valid reason can be interpreted as an attempt to conceal noncompliance. For example, ceasing production during an inspection without reasonable explanation can hinder the FDA’s ability to observe standard operating procedures (SOPs) and manufacturing practices in action.

 

限制检查：限制检查涉及限制其范围或程度，例如阻止访问某些区域、限制对特定过程的观察或隐瞒信息。FDA 认为此类行动具有潜在的阻碍性，因为它们会阻止对工厂是否符合监管标准进行全面评估。企业必须为 FDA 检查人员提供与检查相关的所有区域和工艺的合理访问权限。在没有正当理由的情况下限制访问可以解释为试图掩盖不合规行为。例如，在检查期间在没有合理解释的情况下停止生产可能会阻碍 FDA 观察标准作程序（SOP）和生产实践的能力。

 

Imagine that an FDA inspection team arrives at a facility to conduct a routine inspection. Upon arrival, the team is informed that all production activities have been halted temporarily for maintenance reasons. However, there is no evidence of maintenance work being conducted, and the shutdown appears to have been orchestrated to prevent the inspection team from observing certain processes. Such actions are likely to be viewed as limiting inspection, potentially leading to regulatory action.

 

想象一下，一个 FDA 检查组到达工厂进行例行检查。到达后，团队被告知，由于维护原因，所有生产活动都已暂时停止。然而，没有证据表明正在进行维护工作，而且关闭似乎是经过精心策划的，以防止检查小组观察某些过程。此类行动可能被视为限制检查，并可能导致监管行动。

 

Limiting Photography: Photography during inspections serves as an objective method of documenting facility conditions. The FDA uses photographs to record evidence of compliance or noncompliance, such as the presence of contaminants, inadequate storage conditions, or improper labeling. Limiting the use of photography without legitimate reason can be seen as an attempt to obstruct the inspection.

 

限制拍照：检查期间的拍照是记录设施状况的客观方法。FDA 使用照片来记录合规或不合规的证据，例如存在污染物、储存条件不足或标签不当。在没有正当理由的情况下限制使用拍照可被视为企图阻碍检查。

 

During an inspection, for example, an FDA investigator attempts to photograph a specific area where raw materials are stored. The facility’s management objects, citing concerns about protecting trade secrets and proprietary processes. Although protecting sensitive information is a valid concern, it must be balanced against the need for transparency. The manufacturer should provide a reasonable explanation and offer alternate methods to document conditions without compromising proprietary information.

 

例如，在检查期间，FDA 检查人员试图拍摄储存原辅料的特定区域。该设施的管理层以对保护商业秘密和专有工艺的担忧为由提出反对意见。尽管保护敏感信息是一个合理的担忧，但它必须与透明度的需求相平衡。制造商应提供合理的解释，并提供其他不会影响专有信息的方法来记录情况。

 

Limiting Access to Records:The FDA’s ability to review and copy records is a critical component of its inspection process. Limiting access to records, redacting essential information, or providing incomplete documentation can hinder assessment. Facilities must ensure that all relevant records — including electronic data — are available and accessible to facilitate thorough inspection.

 

限制对记录的访问：FDA 审查和复制记录的权利是其检查过程的关键组成部分。限制对记录的访问、篡改重要信息或提供不完整的文件可能会阻碍检查。企业必须确保所有相关记录（包括电子数据）都可用且可访问，以便于彻底检查。

 

For instance, an FDA investigator might request access to production records, including batch records and quality-control (QC) data. The facility provides some documents but withholds others, claiming that they are not relevant to the inspection. However, upon review, it becomes evident that the withheld records contain critical information about product quality and safety. Such selective disclosure can be considered an attempt to limit inspection, potentially leading to significant regulatory consequences.

 

例如，FDA 检查人员可能会请求访问生产记录，包括批记录和质量控制 （QC） 数据。该设施提供了一些文件，但扣留了另外一些文件，声称这些文件与检查无关。但是，经过审核，很明显，被扣留的记录包含有关产品质量和安全的关键信息。这种选择性披露可被视为试图限制检查，可能导致重大的监管后果。

 

Limiting or Preventing Sample Collection: An integral part of FDA inspections, sample collection enables laboratory analysis and compliance verification. Preventing or limiting collection can disrupt an inspection and raise concerns about product integrity.

 

限制或阻止样品采集：样品采集是 FDA 检查的一个组成部分，可用于实验室分析和合规性验证。阻止或限制收集可能会干扰检验并引起对产品完整性的担忧。

 

During an inspection, for example, FDA investigators request samples of a recently manufactured batch of drug product (DP). The facility’s management refuses, citing that the samples are reserved for internal testing and cannot be released. The refusal to provide samples without a valid reason can be seen as an attempt to prevent the agency from conducting a thorough analysis. Facilities must ensure that all sample requests are met to verify product compliance.

 

例如，在检查期间，FDA 检查人员要求提供最近生产的药品批次的样品。该工厂的管理层拒绝，理由是这些样品是留作内部检测的，不能放行。在没有正当理由的情况下拒绝提供样品可以被视为试图阻止FDA进行彻底分析。工厂必须确保满足所有样品请求，以验证产品合规性。

 

Refusal to permit entry or inspection encompasses both active and passive behaviors that prevent FDA investigators from accessing a facility. This includes not unlocking doors, ignoring FDA communications, or otherwise making it difficult for investigators to conduct their work. Such actions can lead to severe regulatory consequences, including the classification of products as adulterated.

 

拒绝允许进入或检查：包括主动和被动阻止 FDA 检查人员进入设施的行为。这包括锁门、无视 FDA 的沟通或以其他方式使检查人员难以开展工作。此类行为可能导致严重的监管后果，包括将产品归类为掺假商品。

 

Imagine that an FDA inspection team attempts to schedule an inspection with a facility but receives no response despite multiple attempts. When the team arrive at the facility, they find it locked with no staff available to grant entry. The lack of communication and refusal to permit entry can be considered an obstruction of the inspection process. The facility must ensure that appropriate personnel are available to facilitate the inspection and provide necessary access. Acceptable reasons for postponing FDA inspections include emergencies and natural disasters, renovations and other planned shutdowns, cybersecurity incidents, and absence of key personnel.

 

想象一下，FDA 检查组试图安排与工厂进行检查，但尽管多次尝试仍未收到任何回复。当团队到达工厂时，他们发现设施上锁着，没有工作人员可以允许进入。缺乏沟通和拒绝允许进入可被视为对检查过程的阻碍。设施必须确保有适当的人员来协助检查并提供必要的通道。推迟FDA 检查的可接受原因包括紧急情况和自然灾害、装修和其他计划性关闭、网络安全事件以及关键人员不可用。

 

Natural Disasters or Emergency Situations:During events such as the COVID-19 pandemic, companies faced significant disruptions that affected their ability to comply with inspection schedules. Natural disasters (e.g., hurricanes, floods, and earthquakes) also can render facilities temporarily inoperable or unsafe, justifying a request for inspection postponement.

 

自然灾害或紧急情况： 在大流行等事件期间，公司面临重大中断，影响了他们遵守检查计划的能力。自然灾害（例如飓风、洪水和地震）也可能导致设施暂时无法运行或不安全，因此有理由要求推迟检查。

 

Planned Shutdowns or Renovations:If a company already has scheduled a shutdown for maintenance or renovations, and the FDA proposes an inspection date during that period, then the shutdown could be a legitimate reason to request a delay. The FDA itself acknowledges that such planned events, which temporarily disrupt normal operations, may not be considered inspection delays.

 

计划性停工或翻新：如果一家公司已经安排停工进行维护或翻新，然后 FDA 建议在此期间进行检查，那么停工可能是要求延迟的合法理由。FDA 本身承认，此类暂时扰乱正常运营的计划事件可能不被视为检查延误。

 

Cybersecurity Incidents:In rare cases, companies can experience cybersecurity incidents that compromise their operational capabilities. For example, consider a company that experienced a significant cyberattack, leading to postponement of an FDA inspection by about a month. Although such situations typically are not publicized, they provide valid ground for requesting delays, especially when incidents affect access to critical systems or data.

 

网络安全事件：在极少数情况下，公司可能会遇到损害其运营能力的网络安全事件。例如，考虑一家公司遭受了一次重大网络攻击，导致FDA 检查推迟了大约一个月。尽管此类情况通常不会公开，但它们为请求延迟提供了正当理由，尤其是当事件影响对关键系统或数据的访问时。

 

Key Personnel Unavailability:Key staff members, such as those responsible for compliance or production, may become unexpectedly unavailable (e.g., due to illness or urgent personal matters). That could justify a request to postpone inspection. FDA guidance suggests that unavailability of essential personnel can be a reasonable explanation, especially if their presence is critical to inspection.

 

关键人员不可用： 关键员工（例如负责合规或生产的人员）可能会意外不可用（例如，由于疾病或紧急个人事务）。这可能证明推迟检查的请求是合理的。FDA 指南表明，没有必要人员可能是一个合理的解释，特别是如果他们的存在对检查至关重要。

 

Practical Implications and Best Practices

 

实际意义和最佳实践

 

Understanding and adhering to FDA guidelines during inspections is crucial for maintaining compliance and avoiding severe penalties. Facilities must implement best practices to ensure that they are prepared for inspections and can respond appropriately to FDA requests. Below are some practical steps that facilities can take to maintain compliance during inspections.

 

在检查过程中了解并遵守 FDA指南对于保持合规性和避免严厉处罚至关重要。企业必须实施最佳实践，以确保他们为检查做好准备，并能够适当地响应 FDA的要求。以下是工厂可以采取的一些实际步骤，以便在检查期间保持合规性。

 

Preinspection Preparation: Facilities should conduct regular training sessions for staff members to ensure that they are aware of the FDA’s inspection process and the facility’s compliance obligations. That includes training on proper documentation, record-keeping practices, and communication protocols during inspections.

 

检查前准备：企业应定期为员工举办培训课程，以确保他们了解 FDA 的检查流程和企业的合规义务。这包括检查期间有关正确文件、记录保存实践和沟通方案的培训。

 

Maintaining accurate and up-to-date recordsis critical for demonstrating compliance. Facilities should establish robust record-keeping systems that provide easy retrieval of documents during inspections. This includes electronic record systems that are secure, reliable, and accessible to authorized personnel.

 

维护准确和最新的记录对于证明合规性至关重要。工厂应建立强大的记录保存系统，以便在检查期间轻松检索文件。这包括安全、可靠且可供授权人员访问的电子记录系统。

 

Facilities should conductregular internal audits to assess their compliance status and identify potential areas of concern. These audits can help facilities prepare for inspections by ensuring that all areas comply with FDA regulations and that all necessary documentation is readily available.

 

工厂应定期进行内部审计，以评估其合规性状态并确定潜在的关注领域。这些审核可以通过确保所有区域都符合FDA 法规并且所有必要的文件都随时可用，帮助工厂为检查做好准备。

 

Facilities must provide FDA investigators withunrestricted access to all areas and processes relevant to the inspection. That also includes access to secure areas such as cleanrooms or sterile processing zones, following appropriate gowning and safety procedures.

 

企业必须允许 FDA 检查人员不受限制地进入与检查相关的所有区域和流程。这还包括进入安全区域，如洁净室或无菌加工区，遵循适当的更衣和安全程序。

 

Transparencyis key during inspections. Facilities should provide complete, accurate information to FDA investigators and prevent any actions that could be perceived as obstructive. Delays and restrictions must have clear explanations, and information and sample requests still must be met.

 

透明度是检查过程中的关键。企业应向 FDA 人员提供完整、准确的信息，并防止采取任何可能被视为阻碍的行动。延误和限制必须有明确的原因，并且仍然必须满足信息和样品请求。

 

Establishingclear communication protocols can help to facilitate a smooth inspection. That includes designating a point of contact for an inspection team and ensuring that all relevant personnel are available to address questions or concerns raised by investigators.

 

建立明确的沟通方案有助于促进顺利检查。这包括为检查组指定一个联络点，并确保所有相关人员都可以解决调检查员提出的问题或疑虑。

 

Postinspection Follow-Up: Following an inspection, facilities should review the FDA’s findings and take immediate action to address any identified issues. That can include implementing corrective and preventive actions (CAPAs) to address noncompliance and mitigate future occurrences.

 

检查后跟进：检查后，企业应审查 FDA 的检查结果，并立即采取行动解决任何发现的问题。这可能包括实施纠正和预防措施 （CAPA） 来解决不合规问题并减少未来发生的情况。

 

Manufacturers shoulddocument all actions taken in response to inspection findings and report them to the FDA as required. Facilities must provide evidence of corrective actions and demonstrate ongoing compliance with FDA regulations.

 

制造商应记录为应对检查结果而采取的所有行动，并根据需要向 FDA 报告。企业必须提供纠正措施的证据，并证明持续符合 FDA 法规。

 

Continuous improvement is essential for maintaining compliance in the ever-evolving regulatory landscape. Manufacturers should review and update their compliance programs frequently to address new regulations and industry best practices, stay informed about changes in FDA guidance, and participate in industry forums and training programs.

 

持续改进对于在不断变化的监管环境中保持合规性至关重要。制造商应经常审查和更新其合规计划，以应对新的法规和行业最佳实践，随时了解FDA 指南的变化，并参与行业论坛和培训计划。

 

Continued Compliance

 

持续合规

 

Compliance with FDA inspection requirements is a critical aspect of ensuring the safety and efficacy of drugs and medical devices. The guidance document reviewed herein provides a framework for understanding the actions that constitute delaying, denying, limiting, or refusing an inspection. Facilities must understand the guidelines and align their practices with regulatory expectations to avoid severe consequences, including product adulteration designations and potential legal actions. To mitigate potential problems with the FDA, manufacturers should focus on maintaining clear, transparent, and proactive communication with the agency. Below are some specific actions that facility management can take to ensure compliance.

 

遵守 FDA 检查要求是确保药品和医疗器械安全性和有效性的关键方面。本文回顾的指导文件提供了一个框架，用于了解构成延迟、拒绝、限制或拒绝检查的行为。企业必须了解指南，并将其做法与监管要求保持一致，以避免严重后果，包括商品掺假认定和潜在的法律诉讼。为了减轻FDA 的潜在问题，制造商应专注于与FDA保持清晰、透明和主动的沟通。以下是设施管理人员可以采取的一些具体措施来确保合规性。

 

• Communicate all requests for postponement in writing and include detailed explanations supported by evidence, such as maintenance schedules, emergency reports, and medical documentation for key personnel. Documentation not only demonstrates the company’s commitment to transparency, but also helps to prevent misunderstandings.

 

以书面形式传达所有推迟申请，并附上有证据支持的详细解释，例如维护计划、紧急报告和关键人员的医疗文件。文件不仅表明了公司对透明度的承诺，还有助于防止误解。

 

• If an inspection is postponed for good cause, then provide the FDA with regular updates on the situation. For instance, if a facility is recovering from a cyberattack, updates could include the progress of system restorations and interim measures taken to maintain compliance.

 

如果检查因正当理由而推迟，则定期向 FDA 提供有关情况的最新信息。例如，如果设施正在从网络攻击中恢复，则更新可能包括系统恢复的进度和为保持合规性而采取的临时措施。

 

• Develop and regularly update an emergency-preparedness plan with protocols for communicating with the FDA during unforeseen events. The plan should outline how a manufacturer will handle situations such as natural disasters, pandemics, and cybersecurity breaches and keep the FDA informed and involved in real-time decision-making.

 

制定并定期更新应急准备计划，其中包含在意外事件期间与 FDA 沟通的协议。该计划应概述制造商将如何处理自然灾害、流行病和网络安全漏洞等情况，并让 FDA 了解情况并参与实时决策。

 

• In complex situations, consult with regulatory experts who can guide your facility in navigating the scenario. Such professionals can assist with drafting communications, preparing documentation, and strategizing responses to meet FDA expectations.

 

在复杂情况下，请咨询监管专家，他们可以指导你的设施驾驭这种情况。这些专业人员可以协助起草通信、准备文件和制定应对措施策略，以满足FDA 的期望。

 

Maintaining transparency and cooperation during FDA inspections is essential to protecting public health and preserving trust in medical products. Manufacturers should review and update their internal protocols regularly to ensure inspection readiness and foster a culture of compliance. For further guidance, industry professionals should consult the full FDA guidance document referenced below and seek expert advice when necessary. A proactive approach will help facilities to meet their regulatory obligations and uphold the highest standards of product quality and safety.

 

在 FDA 检查期间保持透明度和合作对于保护公众健康和维护对医疗产品的信任至关重要。制造商应定期审查和更新其内部规程，以确保做好检验准备并培养合规文化。如需进一步指导，行业专业人士应查阅下面引用的完整FDA 指导文件，并在必要时寻求专家建议。积极主动的方法将帮助工厂履行其监管义务，并维护最高的产品质量和安全标准。