FDA 发布 MAPP 5014.1 Rev. 1，说明 CDER 基于风险的选址模型
MAPP 5014.1 Rev. 1 Understanding CDER's Risk-Based Site Selection Model
FDA 发布 MAPP 5014.1 Rev. 1，说明 CDER 药品质量办公室如何管理用于安排常规 CGMP 监督检查的风险导向选址模型。该模型按风险评分为生产场地排序并生成场地监督检查清单（SSIL），风险因子包括场地类型、距上次检查时间、FDA 及所在国家或地区合规历史、患者暴露、危害信号和产品固有风险。
文件说明 CDER 风险导向选址模型的风险因子与检查优先级安排，可帮助理解常规 CGMP 监督检查的排程逻辑。
PDF 文字版；图形和原始排版请参阅官方 PDF。
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MANUAL OF POLICIES AND PROCEDURES
CENTER FOR DRUG EVALUATION AND RESEARCH MAPP 5014.1 Rev. 1
PROGRAM DESCRIPTION
OFFICE OF PHARMACEUTICAL QUALITY
Understanding CDER’s Risk-Based Site Selection Model
Table of Contents
PURPOSE..............................................................................1
BACKGROUND ...................................................................1
POLICY .................................................................................3
RESPONSIBILITIES ...........................................................6
PROCEDURES .....................................................................7
REFERENCES......................................................................8
DEFINITIONS ......................................................................8
EFFECTIVE DATE ..............................................................8
CHANGE CONTROL TABLE............................................9
PURPOSE
This MAPP outlines how the Office of Pharmaceutical Quality (OPQ) will manage the
Site Selection Model (SSM) used by Center for Drug Evaluation and Research (CDER)
staff to prioritize manufacturing sites for routine quality-related surveillance inspections
(i.e., current good manufacturing practice (CGMP) inspections).
BACKGROUND
FDA implemented the risk-based approach to prioritizing human drug
manufacturing sites for routine CGMP surveillance inspection in FY 2005. This
approach was one of many outcomes from the initiative “Pharmaceutical Quality
for the 21st Century — A Risk-Based Approach”. The FY 2005 SSM replaced the
previous approach, which was primarily based on the biennial inspection
frequency for domestic sites as previously established in section 510(h) of the
Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 360(h)).
The Food and Drug Administration Safety and Innovation Act of 2012 amended
section 510(h) of the FD&C Act. This amendment replaced the fixed minimum
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inspection interval for domestic establishments (i.e., sites)1 with the requirement
that FDA inspects domestic and foreign drug establishments “in accordance with
a risk-based schedule” that considers establishments’ “known safety risks.” This
change defined a risk-based inspection frequency for all sites, regardless of
location, to promote parity in inspectional coverage and the effective and efficient
use of FDA resources to address the most significant public health risks. The
statutory change largely adopted the SSM criteria in use since FY 2005; however,
it allowed FDA to place less emphasis on a set frequency of inspection.
The October 2022 update of the Compliance Program 7356.002 — Drug
Manufacturing Inspections added an objective to gain insight into the
effectiveness of a drug manufacturer’s quality system in exceedance of CGMP
requirements.
The Food and Drug Omnibus Reform Act of 2022 amended section 510(h)(4) of
the FD&C Act. It added a risk factor for establishments related to the compliance
history of establishments in the country or region where the establishment is
located.
The Office of Quality Surveillance (OQS), within CDER’s Office of
Pharmaceutical Quality (OPQ), is responsible for producing CDER’s Site
Surveillance Inspection List (SSIL) that prioritizes sites for surveillance
inspections. This list is developed by inputting sites from CDER’s Catalog of
Manufacturing Sites into the SSM. Subject sites are ranked by the CDER SSM so
that higher risk sites are assigned to the Office of Inspections and Investigations
(OII) for surveillance inspection.
The number of sites assigned varies depending on FDA capacity as determined by
multiyear resource planning with OII.
The SSM considers risk related to drug quality (for both drug substance and
finished product) that may arise from violations of the CGMP requirements in
section 501(a)(2)(B) of the FD&C Act (21 U.S.C 351(a)(2)(B)) and related
regulations (e.g., 21 CFR parts 210 and 211).
The list of sites prioritized by the model includes sites in the CDER Catalog of
Manufacturing Sites that are subject to routine surveillance inspections, as
determined by section 510 of the FD&C Act. The CDER Catalog of
Manufacturing Sites comprises sites that commercially manufacture a finished
pharmaceutical (drug product), an in-process material, or an active
pharmaceutical ingredient (API; drug substance) for use in a drug intended for
humans.
1
In this MAPP, the terms establishment, site, and facility are used interchangeably and cover physical
locations subject to FDA drug manufacturing regulations and statutory authority.
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The following types of sites are excluded from prioritization by the CDER SSM
described in this MAPP:
o Human drug compounding outsourcing facilities registered under section
503B of the FD&C Act (21 U.S.C. 353b), because the inspection schedule
for these sites is established by a separate CDER selection process
o Medical gas sites, which are managed by a separate selection process
o Inactive ingredients (excipients) sites (may be inspected when deemed
necessary)
o Sites manufacturing drugs intended for use only in clinical trials (may be
inspected when deemed necessary)
The SSM and the databases it uses are the subject of continuous improvement
programs. OQS solicits internal feedback from its FDA business partners
annually. Additionally, at the time of the last significant revision, the SSM
underwent external peer review by experts in academia. Finally, statistical
analyses are used to assess the correlation between certain outcomes and current
and prospective risk factors. All of this informs continuous improvement of the
model. The current governance structure for the model includes a cross-
functional, model improvement working group and a steering committee that
reviews proposed changes to the model.
POLICY
1. Introduction
1.1 OQS will use the SSM, with defined risk factors, to generate the SSIL.
The SSIL only prioritizes sites for scheduling routine surveillance
inspections, not other inspection types.2 Goals of the surveillance
inspection program, as defined in Compliance Program 7356.002 —
Drug Manufacturing Inspections, are to ensure that sites consistently
manufacture drug products of acceptable quality and minimize
consumers’ exposure to adulterated drug products in accordance with
requirements under sections 510 and 704 of the FD&C Act (21 U.S.C.
360 and 374). More specifically, the objectives of the program are:
2
Inspection types other than surveillance are (1) preapproval, (2) postapproval, and (3) for-cause (see
concept of operations white paper Integration of FDA Facility Evaluation and Inspection Program for
Human Drugs: A Concept of Operations).
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a) Determine whether inspected establishments are operating in
compliance with applicable CGMP requirements and, if not, provide
evidence for actions to prevent adulterated products from entering
the market. As appropriate, remove adulterated products from the
market and take action against persons [(including firms)]
responsible.
b) Provide an assessment of establishments’ conformance to CGMP
requirements for Agency decisions.
c) Gain insight into the effectiveness of a drug manufacturer’s quality
system. Additionally, inform understanding, to the extent possible, of
practices at a facility that not only support meeting CGMP
compliance requirements to establish and maintain a robust state of
control but also promote a quality culture that allows for exceeding
this standard.
d) Provide input to establishments during inspections to improve their
compliance with regulations.
e) Better understand current practices in drug manufacturing to update
CGMP requirements, regulatory policy, and guidance documents.3
1.2 A goal of using the SSM is to achieve parity in inspection frequency for
sites with equivalent risk scores, regardless of product type (e.g., whether
originator, generic, over-the-counter monograph, or biosimilar).
2. Risk Factors
2.1 The SSM will use risk factors consistent with section 510(h)(4) of the
FD&C Act. This provision identifies specific risk factors and allows FDA
to determine additional ones, as follows:
a) The compliance history of the establishment.
b) The record, history, and nature of recalls linked to the establishment.
c) The inherent risk of the drug or device manufactured, prepared,
propagated, compounded, or processed at the establishment.
d) The inspection frequency and history of the establishment, including
whether the establishment has been inspected pursuant to section 704
of the FD&C Act (21 U.S.C. 374) within the last 4 years.
3
This list is a quote from Compliance Program 7356.002 —Drug Manufacturing Inspections.
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e) Whether the establishment has been inspected by a foreign
government or an agency of a foreign government recognized under
section 809 of the FD&C Act (21 U.S.C. 384e).
f) The compliance history of establishments in the country or region in
which the establishment is located that are subject to regulation
under this FD&C Act, including the history of violations related to
products exported from such country or region that are subject to
such regulation.
g) Any other criteria deemed necessary and appropriate by the
Secretary for purposes of allocating inspection resources.4
2.2 OQS will use the SSM to generate a risk score for each site. Risk factors
are based on either empirical evidence collected by FDA, subject matter
experts’ judgment, or a combination of both. The following are currently
identified as risk factors for inclusion in the SSM:
a) Site type (e.g., manufacturer, packager only, control lab only)
b) Time since last surveillance inspection (or if the site was never
previously inspected)
c) FDA compliance history
d) Compliance history of the country or region
e) Foreign regulatory authority inspectional history (with an
authority deemed capable under section 809 of the FD&C Act
f) Patient exposure (using available information such as data
submitted pursuant to section 510(j)(3) of the FD&C Act (21
U.S.C 360(j)(3) as added by the Coronavirus Aid, Relief, and
Economic Security Act (CARES Act))
g) Hazard signals (such as Field Alert Reports, Biological Product
Deviation Reports, MedWatch reports,5 recalls, etc.)
h) Inherent product risk:
i. Dosage form
4
This list is a quote from 510(h)(4) of the FD&C Act, as amended by section 3613 of the Food and Drug
Omnibus Reform Act of 2022.
5
MedWatch collects adverse drug event reports from consumers, physicians, and pharmacists — the
subset of these deemed potentially related to manufacturing quality are forwarded to OQS for individual
evaluation and are also used in the model.
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ii. Route of administration
iii. Products intended to be sterile
iv. API load (i.e., concentration of API in dosage form or unit dose)
v. Biologic drug substance or drug product
vi. Therapeutic class
vii. Therapeutic index or range (e.g., narrow therapeutic index drugs)
viii. Emergency use drugs (e.g., epinephrine)
3. Continuous Improvement of the Model
3.1 The SSM governance process requires that CDER and OII annually
review and approve changes to the SSM. This process encourages
continual improvement by assessing the SSM’s risk factors, weights, and
methodology and then identifying areas for improvement and
modification. Changes are supported scientifically by input from expert
teams and may include updated data, new data sources, and/or revised
methodology. When appropriate, this annual review includes research and
additional studies to better assess the current model and impacts of
change.
RESPONSIBILITIES
OQS provides site and product data for input into the SSM. OQS also implements
the SSM, supports the subsequent program of inspections, and manages review
and continual improvement of the model. In addition, OQS issues the SSIL
assignment within its Surveillance Action Plan (SAP), tracks inspection
accomplishments, and issues quarterly SAP progress reports. Throughout the
year, OQS processes site removal requests from OII.
OII plans, tracks, and conducts inspections.6
6
This MAPP is intended for CDER staff; OII is included for completeness only.
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PROCEDURES
1. Running the SSM and Generating the SSIL
1.1 OQS identifies data discrepancies by reviewing and preparing the SSM.
These are forwarded to the respective data set owners for resolution.
1.2 OQS runs the SSM for sites in the CDER Catalog of Manufacturing Sites.
The SSM generates risk scores for each site that are used to prioritize the
sites.
1.3 OQS performs a quality control assessment of the list.
a) Sites are identified in which the last inspection was classified as final
official action indicated (OAI). The list of OAI sites is reviewed by
OII, OQS, and CDER’s Office of Compliance for concurrence and the
confirmed OAI sites are removed from routine surveillance inspection
planning (i.e., OAI site reinspection is determined as part of the
enforcement effort).
b) Sites currently on import alert are removed from routine surveillance
inspection planning.
c) Any site that is newly registered, or otherwise without any prior
routine surveillance inspection, is assigned and prioritized for
inspection regardless of risk score. OQS may collaborate with OII to
verify that a new site is, in fact, subject to routine surveillance
inspection.
1.4 The SSIL is shared with OII through the SAP.
2. Tracking the Process of Planning and Conducting of Inspections
2.1 OII plans and conducts inspections assigned based on the SSIL.
2.2 OQS tracks the accomplished inspections and provides quarterly updates
through the SAP.
3. Site Removals: OII can request removal of a site from the SSIL.
3.1 OQS will investigate the reasons for the removal request.
3.2 If the request is a result of a recent inspection performed after the SSIL
was generated, the removal will be implemented upon confirmation that
the CGMP inspection has been completed.
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3.3 If the removal is requested because of a change in a site’s operational
status (e.g., the site has gone out of business) or discrepancies between
FDA’s understanding of the site and the site’s claims (e.g., the site claims
to no longer produce drugs for the U.S. market), then the removal can
only take place if the OQS investigation confirms that FDA’s information
needs to be revised and the discrepancy between FDA and the site is
corrected.
REFERENCES
Compliance Program 7356.002 — Drug Manufacturing Inspections (October
2022)
Integration of FDA Facility Evaluation and Inspection Program for Human
Drugs: A Concept of Operations: White Paper (June 2017)
Pharmaceutical CGMPs for the 21st Century — A Risk-Based Approach: Final
Report (September 2004)
Pharmaceutical Quality for the 21st Century — A Risk-Based Approach: Progress
Report (May 2007)
DEFINITIONS
Site Selection Model (SSM): a risk management tool that supports a consistent,
science-based approach for allocating inspectional resources for routine
surveillance CGMP inspections.
Site Surveillance Inspection List (SSIL): the output list of prioritized sites from
the SSM that are selected for inspection as part of the routine surveillance human
drug Compliance Program 7356.002 — Drug Manufacturing Inspections.
Surveillance Action Plan (SAP): the Office of Quality Surveillance product that
includes the SSIL and has quarterly progress reports.
EFFECTIVE DATE
This MAPP is effective upon date of publication.
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CHANGE CONTROL TABLE
Effective Revision Revisions
Date Number
9/26/2018 Initial N/A
6/26/2023 Rev. 1 Updated to include FDORA 2022, CARES Act, and quality system
effectiveness; updated OS to OQS; made nonsubstantive, editorial changes
8/8/2025 N/A Name change reflecting OPQ reorganization. Updated links to websites.
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来源：FDA Pharmaceutical Quality Documents · fda.gov