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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(lián)合修訂并發(fā)布了一份關(guān)于在FDA檢查時，企業(yè)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(chǎn)生一點聯(lián)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(guī)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，F(xiàn)DA每年基于風(fēng)險的模型對其監(jiān)督檢查進行排序。一個工廠被優(yōu)先檢查的頻率是基于多個風(fēng)險因素的（盡管被選中進行檢查不一定表明存在質(zhì)量問題）。此外，如果存在相關(guān)信息，F(xiàn)DA可以基于特定原因?qū)S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(shù)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(guī)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(diào)查員在檢查過程中觀察到問題時，他們在檢查結(jié)束時使用FDA 4833表格記錄他們對CGMP合規(guī)性相關(guān)的觀察結(jié)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(fù)。

 

FDA法規(guī)回顧

 

FDA reviews the following information once an inspection is completed:

一旦檢查完成，F(xiàn)DA會審查以下信息:

 

Form FDA 483, if issued

FDA 483表格，如果已簽發(fā)

 

the establishment inspection report developed by the investigator(s)

由調(diào)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(gòu)活動收集的證據(jù)

 

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(fù) (如果已提供給FDA) ，包括糾正措施計劃

 

other information as appropriate

其他適當?shù)男畔?/span>

 

During the compliance review, the agency also considers:

在合規(guī)性審查期間，該機構(gòu)還考慮:

 

requirements outlined in FDA regulations

FDA法規(guī)中的要求

 

technical standards

技術(shù)標準

 

scientific consultations from across the agency and literature

來自相關(guān)機構(gòu)和文獻的科學(xué)的咨詢

 

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

生產(chǎn)設(shè)施及其生產(chǎn)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(zhì)量偏差風(fēng)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(jù)公司是否符合CGMP的要求將檢查結(jié)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(shè)施處于可接受的合規(guī)狀態(tài)。通常，工廠在檢查結(jié)束時不簽發(fā)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(fā)現(xiàn)了令人不適的狀態(tài)或做法，但工廠已確定對該設(shè)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(jié)束時簽發(fā)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(shè)施處于合規(guī)不可接受狀態(tài)。

 

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(jié)束后90天內(nèi)努力完成其人用藥品設(shè)施的CGMP檢查。機構(gòu)向工廠發(fā)送分類信件(例如: NAI, VAI和OAI信件)，并通常發(fā)布到數(shù)據(jù)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(shè)施的數(shù)據(jù)板包含2009年以來藥品、生物制劑和其他醫(yī)療產(chǎn)品的監(jiān)測和特定原因的檢查信息，以及歷史檢查(包括警告信2)數(shù)據(jù)。

 

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(shè)施，F(xiàn)DA可能會保留:

 

approval of any pending drug applications that list the facility

該設(shè)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(yù)防措施，并通過FDA后續(xù)現(xiàn)場檢查驗證后，F(xiàn)DA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(zhì)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(xù)合規(guī)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(fā)出警告信2，通知工廠違反聯(lián)邦法律的行為，并建議工廠分配適當?shù)馁Y源，全面糾正違規(guī)行為并防止其再次發(fā)生。

 

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

針對CGMP相關(guān)問題發(fā)布一封無標題信1，這封信不一定會發(fā)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(shù)討論時，公司領(lǐng)導(dǎo)層與FDA之間舉行監(jiān)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(guān)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(fēng)險的方法采取監(jiān)管活動，考慮到醫(yī)療需求、短缺風(fēng)險和確保藥品質(zhì)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，F(xiàn)DA可以代表司法部向聯(lián)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(guān)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(nèi)處于供應(yīng)鏈的公司或倉庫中查獲違規(guī)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(gòu)成安全危害或其他健康風(fēng)險的藥物時，作為我們公共衛(wèi)生使命的一部分，我們可能會發(fā)布公開聲明，例如新聞稿或警告，通知醫(yī)療保健從業(yè)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(fā)警告信的情況下FDA發(fā)布的監(jiān)管信函。

 

警告信（warning letter）：在檢查過程中，若發(fā)現(xiàn)嚴重缺陷且對483表格的回復(fù)被認定為不充分時， FDA將簽發(fā)警告信。企業(yè)需在15個工作日內(nèi)予以回復(fù)，警告信通常會發(fā)布在FDA官網(wǎng)上。

 

FDA 483 表格（FDA 483 Form）也稱現(xiàn)場觀察報告，問題嚴重時則不會給483表格，會簽發(fā)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(guān)檢查的結(jié)論、關(guān)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(jiān)管決策。

 

擴展：

 

 

1："FDA認證"并非FDA官方使用術(shù)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(yī)療器械企業(yè)，必須在FDA進行注冊，包括企業(yè)和產(chǎn)品的列名。若未完成注冊，海關(guān)將不予清關(guān)。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(chǎn)品包裝材料的檢測，醫(yī)療產(chǎn)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(chǎn)品的安全性和符合FDA的相關(guān)標準。

 

FDA批準：FDA批準主要涉及藥品領(lǐng)域。當藥品經(jīng)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(yè)或產(chǎn)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(yè)和產(chǎn)品的相關(guān)信息，填寫申請表格，并支付相應(yīng)的注冊費用。FDA審查所提交的資料，并在審核通過后頒發(fā)相應(yīng)的注冊號碼。

 

FDA注冊費用與產(chǎn)品類型和注冊文件復(fù)雜程度有關(guān)，如FDA食品注冊一兩千，如某些高風(fēng)險藥品、醫(yī)療器械，則數(shù)萬至數(shù)百萬不等。

 

注冊號碼是企業(yè)或產(chǎn)品在FDA數(shù)據(jù)庫中的標識，用于驗證合規(guī)性和進一步查詢。此外，注冊號碼的更新和維護也是企業(yè)在市場上持續(xù)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(guān)法律管理委員會的條例。

 

醫(yī)療器械FDA注冊：有效期為一年，需要每年十月進行續(xù)期。根據(jù)FDA的現(xiàn)代化法規(guī)要求，所有從事生產(chǎn)、配制、傳播、合成、組裝、加工或進出口醫(yī)療器械的企業(yè)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(xù)期。激光類產(chǎn)品包括激光筆、激光演示器、激光顯示器、含有激光單元的產(chǎn)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(chǎn)品。

 

藥品FDA注冊：有效期為一年，需要每年十月進行續(xù)期。所有預(yù)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(xù)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(yè)都必須向FDA注冊。

 

Reference document link:

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