最近莫老大哥憑著“483”又火了一把，而且ORA,CDER,CVM,CDRH在6月份聯合修訂并發布了一份關于在FDA檢查時，企業如果延誤，否認，限制或拒絕行為時的指南：<Guidance for Industry Circumstances that Constitute Delaying, Denying, Limiting, or Refusing a Drug or Device Inspection> 。不得不讓人產生一點聯想。

 

因FDA在國際上的影響力和重要性，讓我們一起來看一下FDA時如何評估和確保合規的。

 

CGMP 檢查

 

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.

 

對于上市后檢查，FDA每年基于風險的模型對其監督檢查進行排序。一個工廠被優先檢查的頻率是基于多個風險因素的（盡管被選中進行檢查不一定表明存在質量問題）。此外，如果存在相關信息，FDA可以基于特定原因對工廠進行檢查。

 

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

大多數制造商都符合CGMP要求。事實上，超過90%的檢查顯示工廠的CGMP合規性良好。

 

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.

當FDA調查員在檢查過程中觀察到問題時，他們在檢查結束時使用FDA 4833表格記錄他們對CGMP合規性相關的觀察結果。FDA 483表格不是對是否違反CGMP的最終決定。工廠通常有15個工作日向FDA提交對FDA 483表格的答復。

 

FDA法規回顧

 

FDA reviews the following information once an inspection is completed:

一旦檢查完成，FDA會審查以下信息:

 

Form FDA 483, if issued

FDA 483表格，如果已簽發

 

the establishment inspection report developed by the investigator(s)

由調查員編寫的工廠檢查報告

 

evidence collected during the inspection or via other agency activity

在檢查期間或通過其他機構活動收集的證據

 

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

工廠對FDA 483表格的答復 (如果已提供給FDA) ，包括糾正措施計劃

 

other information as appropriate

其他適當的信息

 

During the compliance review, the agency also considers:

在合規性審查期間，該機構還考慮:

 

requirements outlined in FDA regulations

FDA法規中的要求

 

technical standards

技術標準

 

scientific consultations from across the agency and literature

來自相關機構和文獻的科學的咨詢

 

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

生產設施及其生產藥品的概況

 

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

 

基于對患者或消費者潛在危害的質量偏差風險

 

檢查分類

 

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

FDA根據公司是否符合CGMP的要求將檢查結果分為可接受或不可接受:

 

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.

無需采取措施 (NAI) 分類表明設施處于可接受的合規狀態。通常，工廠在檢查結束時不簽發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) 分類表明檢查發現了令人不適的狀態或做法，但工廠已確定對該設施可以自行糾正其缺陷，并且不會建議采取任何行動。通常，在檢查結束時簽發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) 分類表明設施處于合規不可接受狀態。

 

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在檢查結束后90天內努力完成其人用藥品設施的CGMP檢查。機構向工廠發送分類信件(例如: NAI, VAI和OAI信件)，并通常發布到數據板上。

 

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.

具體設施的數據板包含2009年以來藥品、生物制劑和其他醫療產品的監測和特定原因的檢查信息，以及歷史檢查(包括警告信2)數據。

 

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

 

此外，對于定義為OAI分類的CGMP檢查的設施，FDA可能會保留:

 

approval of any pending drug applications that list the facility

該設施的任何待批準的藥物申請

 

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

打算在美國境外銷售的藥品的出口證明

 

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

準備在美國境外銷售的藥品的CGMP聲明

 

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

 

政府采購合同也可能受到OAI類別的不利影響

 

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.

一般來說，只有在公司實施了全面的糾正和預防措施，并通過FDA后續現場檢查驗證后，FDA才會更改OAI分類。

 

FDA的工具和行動

 

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使用一套強大的工具來促進工廠自愿遵守CGMP要求，并保護患者和消費者免受劣質藥品的侵害。這使工廠有機會自愿采取糾正措施，并朝著可持續合規的方向努力。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

向工廠發出警告信2，通知工廠違反聯邦法律的行為，并建議工廠分配適當的資源，全面糾正違規行為并防止其再次發生。

 

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

針對CGMP相關問題發布一封無標題信1，這封信不一定會發布在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

當FDA希望與公司進行詳細的技術討論時，公司領導層與FDA之間舉行監管會議

 

建議或要求藥物召回

 

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

將公司列入進口警告清單，以阻止其藥品進入美國市場。FDA針對CGMP相關的問題使用60-40等進口警告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基于風險的方法采取監管活動，考慮到醫療需求、短缺風險和確保藥品質量的能力。

 

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:

如果工廠未能解決違反CGMP的問題，FDA可以代表司法部向聯邦法院采取額外行動，例如:

 

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

禁令，包括關閉工廠的同意法令，直到其符合CGMP要求.

 

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

在國內處于供應鏈的公司或倉庫中查獲違規藥物

 

刑事起訴

 

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，當我們意識到可能對消費者構成安全危害或其他健康風險的藥物時，作為我們公共衛生使命的一部分，我們可能會發布公開聲明，例如新聞稿或警告，通知醫療保健從業者和公眾將此類藥物。

 

備注：

 

無標題信（Untitled Letter）：可認為是 嚴重性超過483 表格，但不足以觸發警告信的情況下FDA發布的監管信函。

 

警告信（warning letter）：在檢查過程中，若發現嚴重缺陷且對483表格的回復被認定為不充分時， FDA將簽發警告信。企業需在15個工作日內予以回復，警告信通常會發布在FDA官網上。

 

FDA 483 表格（FDA 483 Form）也稱現場觀察報告，問題嚴重時則不會給483表格，會簽發無標題信或警告信。

 

EIR（Inspectional Observations）：是FDA檢查人員在完成檢查后撰寫的報告，包括有關檢查的結論、關鍵問題的摘要和建議行動計劃。EIR不包括警告信，但是可能會影響注冊或監管決策。

 

擴展：

 

 

1："FDA認證"并非FDA官方使用術語。人們常用"FDA認證"來指代以下三種情況：

 

FDA注冊：對于出口到美國的食品、藥品和醫療器械企業，必須在FDA進行注冊，包括企業和產品的列名。若未完成注冊，海關將不予清關。這是一項強制性要求。

 

FDA檢測：FDA檢測通常指的是對食品接觸材料的安全檢測，產品包裝材料的檢測，醫療產品的生物相容性測試和臨床安全測試等。這些檢測旨在確保產品的安全性和符合FDA的相關標準。

 

FDA批準：FDA批準主要涉及藥品領域。當藥品經過嚴格的研究、試驗和評估后，獲得FDA的批準，才能在美國市場上銷售和使用。

 

通過FDA注冊，企業或產品被認可并合法地在美國市場銷售和流通。注冊過程包括提供企業和產品的相關信息，填寫申請表格，并支付相應的注冊費用。FDA審查所提交的資料，并在審核通過后頒發相應的注冊號碼。

 

FDA注冊費用與產品類型和注冊文件復雜程度有關，如FDA食品注冊一兩千，如某些高風險藥品、醫療器械，則數萬至數百萬不等。

 

注冊號碼是企業或產品在FDA數據庫中的標識，用于驗證合規性和進一步查詢。此外，注冊號碼的更新和維護也是企業在市場上持續銷售的要求之一。

 

2：FDA認證/注冊的有效期：

 

化妝品FDA注冊：認證成功后，有效期是永久有效。一旦獲得注冊，化妝品就可以在美國銷售，無論是本地制造還是國外進口，都需要遵守相關法律管理委員會的條例。

 

醫療器械FDA注冊：有效期為一年，需要每年十月進行續期。根據FDA的現代化法規要求，所有從事生產、配制、傳播、合成、組裝、加工或進出口醫療器械的企業都必須在FDA進行注冊。

 

激光輻射FDA注冊：有效期為一年，需要每年七月進行續期。激光類產品包括激光筆、激光演示器、激光顯示器、含有激光單元的產品（如DVD、CD-ROM、CD播放機、激光打印機等）以及安全防護和救護產品。

 

藥品FDA注冊：有效期為一年，需要每年十月進行續期。所有預期用于疾病的診斷、治療、癥狀緩解、處理或疾病的藥品工廠都必須向FDA進行注冊并申報其所有成分。

 

食品FDA注冊：每兩年進行一次續期。所有從事制造、加工、包裝或儲存將在美國消費的食品或食品原料的美國和非美國企業都必須向FDA注冊。

 

Reference document link:

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