最近莫老大哥凭着“483”又火了一把，而且ORA,CDER,CVM,CDRH在6月份联合修订并发布了一份关于在FDA检查时，企业如果延误，否认，限制或拒绝行为时的指南：<Guidance for Industry Circumstances that Constitute Delaying, Denying, Limiting, or Refusing a Drug or Device Inspection> 。不得不让人产生一点联想。

 

因FDA在国际上的影响力和重要性，让我们一起来看一下FDA时如何评估和确保合规的。

 

CGMP 检查

 

For postmarket inspections, each year FDA prioritizes its surveillance inspections using a risk-based model. The frequency at which a facility is prioritized for inspection is based on multiple risk factors (although being selected for an inspection does not necessarily signal a quality issue). Additionally, FDA can inspect facilities on a for-cause basis if information warrants it.

 

对于上市后检查，FDA每年基于风险的模型对其监督检查进行排序。一个工厂被优先检查的频率是基于多个风险因素的（尽管被选中进行检查不一定表明存在质量问题）。此外，如果存在相关信息，FDA可以基于特定原因对工厂进行检查。

 

Most manufacturers comply with CGMP requirements. In fact, more than 90% of inspections found facilities to have acceptable CGMP compliance.

大多数制造商都符合CGMP要求。事实上，超过90%的检查显示工厂的CGMP合规性良好。

 

When FDA investigators observe issues during an inspection, they use Form FDA 4833 to document their observations related to CGMP compliance at the conclusion of the inspection. A Form FDA 483 does not constitute a final agency determination of whether any condition violates CGMP. A company generally has 15 business days to provide FDA with a voluntary response to the Form FDA 483.

当FDA调查员在检查过程中观察到问题时，他们在检查结束时使用FDA 4833表格记录他们对CGMP合规性相关的观察结果。FDA 483表格不是对是否违反CGMP的最终决定。工厂通常有15个工作日向FDA提交对FDA 483表格的答复。

 

FDA法规回顾

 

FDA reviews the following information once an inspection is completed:

一旦检查完成，FDA会审查以下信息:

 

Form FDA 483, if issued

FDA 483表格，如果已签发

 

the establishment inspection report developed by the investigator(s)

由调查员编写的工厂检查报告

 

evidence collected during the inspection or via other agency activity

在检查期间或通过其他机构活动收集的证据

 

the company’s response to the Form FDA 483 (if provided to FDA), including plans for corrective actions

工厂对FDA 483表格的答复 (如果已提供给FDA) ，包括纠正措施计划

 

other information as appropriate

其他适当的信息

 

During the compliance review, the agency also considers:

在合规性审查期间，该机构还考虑:

 

requirements outlined in FDA regulations

FDA法规中的要求

 

technical standards

技术标准

 

scientific consultations from across the agency and literature

来自相关机构和文献的科学的咨询

 

profile of the manufacturing facility and the drug(s) they produce

生产设施及其生产药品的概况

 

risk of the quality deviations based on the potential for patient or consumer harm

 

基于对患者或消费者潜在危害的质量偏差风险

 

检查分类

 

FDA classifies inspections based on a company’s state of compliance as acceptable or unacceptable with respect to CGMP requirements:

FDA根据公司是否符合CGMP的要求将检查结果分为可接受或不可接受:

 

No action indicated (NAI) classification indicates a facility is in an acceptable state of compliance. The facility, usually, was not issued a Form FDA 483 at the conclusion of the inspection.

无需采取措施 (NAI) 分类表明设施处于可接受的合规状态。通常，工厂在检查结束时不签发FDA 483表格。

 

Voluntary action indicated (VAI) classification indicates the inspection found objectionable conditions or practices but the agency has determined the facility can voluntarily correct its deficiencies and will not recommend any action. Usually, the facility was issued a Form FDA 483 at the conclusion of the inspection.

 

自愿采取措施 (VAI) 分类表明检查发现了令人不适的状态或做法，但工厂已确定对该设施可以自行纠正其缺陷，并且不会建议采取任何行动。通常，在检查结束时签发FDA 483表格。

 

Official action indicated (OAI) classification indicates a facility is in an unacceptable state of compliance.

 

官方需要采取措施 (OAI) 分类表明设施处于合规不可接受状态。

 

FDA strives to complete its CGMP classification of human drug facility inspections within 90 days of the end of the inspection. The agency sends the facility a letter with the classification (examples: NAI, VAI and OAI letters) and generally posts the classification to the data dashboard.

FDA在检查结束后90天内努力完成其人用药品设施的CGMP检查。机构向工厂发送分类信件(例如: NAI, VAI和OAI信件)，并通常发布到数据板上。

 

The facility-specific data dashboard contains information on surveillance and for-cause inspections for drugs, biologics and other medical products dating back to 2009, as well as data on a facility’s inspection history, including warning letters2.

具体设施的数据板包含2009年以来药品、生物制剂和其他医疗产品的监测和特定原因的检查信息，以及历史检查(包括警告信2)数据。

 

Additionally, for facilities with an OAI-classified CGMP inspections, FDA may withhold:

 

此外，对于定义为OAI分类的CGMP检查的设施，FDA可能会保留:

 

approval of any pending drug applications that list the facility

该设施的任何待批准的药物申请

 

export certificates for drugs intended for distribution outside of the U.S.

打算在美国境外销售的药品的出口证明

 

CGMP declarations for drugs intended for distribution outside of the U.S.

准备在美国境外销售的药品的CGMP声明

 

Government purchasing contracts may also be adversely impacted by an OAI classified inspection.

 

政府采购合同也可能受到OAI类别的不利影响

 

Generally, FDA will only change an OAI inspection classification after a company implements comprehensive corrective and preventive actions that are verified through an onsite follow-up FDA inspection.

一般来说，只有在公司实施了全面的纠正和预防措施，并通过FDA后续现场检查验证后，FDA才会更改OAI分类。

 

FDA的工具和行动

 

FDA uses a robust set of tools to promote prompt voluntary compliance with CGMP requirements and to protect patients and consumers from poor quality drugs. This gives the facility an opportunity to take voluntary corrective actions and work towards sustainable compliance. Examples include:

FDA使用一套强大的工具来促进工厂自愿遵守CGMP要求，并保护患者和消费者免受劣质药品的侵害。这使工厂有机会自愿采取纠正措施，并朝着可持续合规的方向努力。例子包括:

 

issuing a warning letter2 to a facility to notify a firm of federal law violations, and recommend a facility allocate appropriate resources to fully correct the violations and prevent their recurrence

向工厂发出警告信2，通知工厂违反联邦法律的行为，并建议工厂分配适当的资源，全面纠正违规行为并防止其再次发生。

 

issuing an untitled letter1 for CGMP-related issues, which are not necessarily posted to FDA.gov

针对CGMP相关问题发布一封无标题信1，这封信不一定会发布在FDA.gov上

 

having a regulatory meeting between company leadership and FDA when the agency wants to conduct a detailed technical discussion with the company

当FDA希望与公司进行详细的技术讨论时，公司领导层与FDA之间举行监管会议

 

建议或要求药物召回

 

placing a company on import alert to help stop their drugs from entering the U.S. market. FDA uses import alert 66-40 and others for CGMP-related concerns

将公司列入进口警告清单，以阻止其药品进入美国市场。FDA针对CGMP相关的问题使用60-40等进口警告66-40。

 

FDA takes a risk-based approach to its regulatory activities taking into account medical need, risk of shortage and ability to assure drug quality.

FDA基于风险的方法采取监管活动，考虑到医疗需求、短缺风险和确保药品质量的能力。

 

The agency may take additional action brought in federal court by the Department of Justice on behalf of FDA if a facility fails to address CGMP violations, such as:

如果工厂未能解决违反CGMP的问题，FDA可以代表司法部向联邦法院采取额外行动，例如:

 

injunctions, including consent decrees, which can shut down a facility until it complies with CGMP requirements

禁令，包括关闭工厂的同意法令，直到其符合CGMP要求.

 

seizures of violative drugs in the domestic supply chain from a company or warehouse

在国内处于供应链的公司或仓库中查获违规药物

 

刑事起诉

 

Additionally, when we become aware of drugs that may present a safety hazard or other health risk to consumers, we may issue public statements, such as a press release or an alert, to notify health care practitioners and the public regarding such drugs as part of our public health mission.

此外，当我们意识到可能对消费者构成安全危害或其他健康风险的药物时，作为我们公共卫生使命的一部分，我们可能会发布公开声明，例如新闻稿或警告，通知医疗保健从业者和公众将此类药物。

 

备注：

 

无标题信（Untitled Letter）：可认为是 严重性超过483 表格，但不足以触发警告信的情况下FDA发布的监管信函。

 

警告信（warning letter）：在检查过程中，若发现严重缺陷且对483表格的回复被认定为不充分时， FDA将签发警告信。企业需在15个工作日内予以回复，警告信通常会发布在FDA官网上。

 

FDA 483 表格（FDA 483 Form）也称现场观察报告，问题严重时则不会给483表格，会签发无标题信或警告信。

 

EIR（Inspectional Observations）：是FDA检查人员在完成检查后撰写的报告，包括有关检查的结论、关键问题的摘要和建议行动计划。EIR不包括警告信，但是可能会影响注册或监管决策。

 

扩展：

 

 

1："FDA认证"并非FDA官方使用术语。人们常用"FDA认证"来指代以下三种情况：

 

FDA注册：对于出口到美国的食品、药品和医疗器械企业，必须在FDA进行注册，包括企业和产品的列名。若未完成注册，海关将不予清关。这是一项强制性要求。

 

FDA检测：FDA检测通常指的是对食品接触材料的安全检测，产品包装材料的检测，医疗产品的生物相容性测试和临床安全测试等。这些检测旨在确保产品的安全性和符合FDA的相关标准。

 

FDA批准：FDA批准主要涉及药品领域。当药品经过严格的研究、试验和评估后，获得FDA的批准，才能在美国市场上销售和使用。

 

通过FDA注册，企业或产品被认可并合法地在美国市场销售和流通。注册过程包括提供企业和产品的相关信息，填写申请表格，并支付相应的注册费用。FDA审查所提交的资料，并在审核通过后颁发相应的注册号码。

 

FDA注册费用与产品类型和注册文件复杂程度有关，如FDA食品注册一两千，如某些高风险药品、医疗器械，则数万至数百万不等。

 

注册号码是企业或产品在FDA数据库中的标识，用于验证合规性和进一步查询。此外，注册号码的更新和维护也是企业在市场上持续销售的要求之一。

 

2：FDA认证/注册的有效期：

 

化妆品FDA注册：认证成功后，有效期是永久有效。一旦获得注册，化妆品就可以在美国销售，无论是本地制造还是国外进口，都需要遵守相关法律管理委员会的条例。

 

医疗器械FDA注册：有效期为一年，需要每年十月进行续期。根据FDA的现代化法规要求，所有从事生产、配制、传播、合成、组装、加工或进出口医疗器械的企业都必须在FDA进行注册。

 

激光辐射FDA注册：有效期为一年，需要每年七月进行续期。激光类产品包括激光笔、激光演示器、激光显示器、含有激光单元的产品（如DVD、CD-ROM、CD播放机、激光打印机等）以及安全防护和救护产品。

 

药品FDA注册：有效期为一年，需要每年十月进行续期。所有预期用于疾病的诊断、治疗、症状缓解、处理或疾病的药品工厂都必须向FDA进行注册并申报其所有成分。

 

食品FDA注册：每两年进行一次续期。所有从事制造、加工、包装或储存将在美国消费的食品或食品原料的美国和非美国企业都必须向FDA注册。

 

Reference document link:

https://www.fda.gov/drugs/guidance-compliance-regulatory-information/pharmaceutical-inspections-and-compliance