FDA 发布药品生产检查合规计划 7356.002 修订版，2022 年 10 月 17 日实施
Drug Manufacturing Inspections (7356.002)
FDA 发布药品生产检查合规计划 7356.002 修订版，新增 ICH Q9、Q10、Q12 相关要素、亚硝胺杂质控制和设施评估替代工具等内容。该文件签发日为 2022 年 9 月 16 日，实施日期为 2022 年 10 月 17 日，适用于人用药品的 CGMP 监督检查和有因检查。
材料列出该合规计划修订新增的 ICH Q9、Q10、Q12 要素与亚硝胺杂质控制内容，便于读者对照检查覆盖与报告要求。
PDF 文字版；图形和原始排版请参阅官方 PDF。
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FOOD AND DRUG ADMINISTRATION
COMPLIANCE PROGRAM PROGRAM 7356.002
CHAPTER 56—DRUG QUALITY ASSURANCE
SUBJECT: IMPLEMENTATION DATE:
Drug Manufacturing Inspections 10/17/2022
REVISION: Revised to add elements of International Council for
Harmonisation (ICH) guidances for industry Q9 Quality Risk
Management, Q10 Pharmaceutical Quality System, and Q12
Technical and Regulatory Considerations for Pharmaceutical
Product Lifecycle Management; 1 control of nitrosamine
impurities; and alternative tools for evaluating facilities.
DATA REPORTING
PRODUCT CODES PRODUCT/ASSIGNMENT CODES
All Human Drugs Domestic/Foreign current good manufacturing practice (CGMP)
inspections covered under this compliance program, 7356.002,
Industry codes:
include inspection of any establishment that does not have a specific
50, 54-56, 59, 60-66 program:
PAC Type Subject
56002 Full Drug Process Inspections (DPI)
56002H Abbreviated Drug Process Inspections (DPI)
Report CGMP coverage of the programs specified below under
PACs as follows (using the appropriate compliance program):
PAC Type Subject
56002A Full DPI/Small Volume Parenterals (compliance
program 7356.002A—Sterile Drug Process
Inspections)
56002I Abbreviated DPI/Small Volume Parenterals (compliance
program 7356.002A)
56002B Full DPI/Drug Repackers and Relabelers
56002J Abbreviated DPI/Drug Repackers and Relabelers
56002C Full DPI/Radioactive Drugs
56002K Abbreviated DPI/Radioactive Drugs
56002F Full Active Pharmaceutical Ingredient Process
Inspections
56002L Abbreviated Active Pharmaceutical Ingredient Process
Inspections
1
We update guidances periodically. For the most recent version of a guidance, check the FDA guidance web page at
https://www.fda.gov/regulatory-information/search-fda-guidance-documents.
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56002P Full Drug Process Inspections - PET Domestic
(compliance program 7356.002P—PET
CGMP Drug Process and Pre-Approval
Inspections/Investigations)
56002Q Abbreviated Drug Process Inspections - PET Domestic
(compliance program 7356.002P)
Note: The following surveillance programs are reported under single
PACs; there are no full or abbreviated specific PACs:
PAC Subject
56002E DPI/Medical Gas Manufacturers (compliance program
7356.002E—Compressed Medical Gases)
56002M DPI/Therapeutic Biological Product Inspections
(compliance program 7356.002M—Surveillance
Inspections of Protein Drug Substance Manufacturers)
56002S Drug Process Inspections - Biosimilars
56R927 Remote Interactive Evaluation (RIE) Activities - Human
Drugs
56R928 704a4 Activities - Human Drugs
FIELD REPORTING REQUIREMENTS:
The Office of Regulatory Affairs (ORA) division completes the establishment inspection report
(EIR), including an inspection classification consistent with Field Management Directive (FMD)
86 and FDA policies governing pharmaceutical quality, including this compliance program,
within ORA established timeframes. The ORA division files the inspection documents
electronically no later than 45 calendar days from the close of the inspection using the specific
module (eNSpect, or Compliance Management System (CMS)) accessible to both ORA and
CDER (Center for Drug Evaluation and Research).
ORA divisions should, as soon as practical, report significant inspection issues into eNSpect, as
per the Investigations Operations Manual (IOM). For inspections initially classified as Official
Action Indicated (OAI) due to failure to comply with CGMP requirements, submit the written
classification analysis and electronic documents to CDER’s Office of Compliance (OC), Office
of Manufacturing Quality (OMQ) for evaluation via CMS. 2
ORA staff (e.g., preapproval program managers (PAMs)) are responsible for timely reporting of
potential OAI (pOAI) alerts into Panorama as per current procedures. 3 The ORA PAM should
consider the following when entering a pOAI alert into Panorama:
2
For further information, see Part V—Regulatory/Administrative Strategy.
3
Panorama is a component of the CDER Informatics Platform that is used to manage workflow and documents.
Refer to Panorama step-by-step guides for creating, editing and closing pOAI alerts.
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1. For CGMP (surveillance or for-cause) coverage that may result in an OAI status, enter a
pOAI alert into Panorama, as soon as practical, but at most within 2 days of closing the
inspection.
2. Enter a pOAI alert for the refusal of an inspection. 4
3. If surveillance and preapproval coverage are provided during the same inspection:
a. Do not enter a pOAI alert for significant application-specific preapproval issues that
do not impact marketed product; refer to compliance program 7346.832—
Preapproval Inspections.
b. Do enter a pOAI alert for significant CGMP issues (see point 1).
The ORA PAM must remove the pOAI alert in Panorama as soon as practical if the ORA
division decides to change the initial recommendation of OAI. If OMQ decides to change the
initial OAI recommendation, OMQ must update or remove the pOAI alert associated with that
initial classification in Panorama as soon as practical.
During an inspection, if an inspection team obtains information pertaining to inadequate adverse
drug experience reporting, unapproved drug issues, or postapproval reporting violations (e.g.,
failing to submit application supplements, field alert reports (FARs)), or the team observes
significant findings pertinent to the quality information provided in the site dossier, the
inspection team should notify the Office of Quality Surveillance (OQS), in CDER’s Office of
Pharmaceutical Quality (OPQ), and the Office of Compliance in a timely manner by emailing
[email protected] and [email protected] and, for biological
products, copying [email protected]. Notifications should include a
summary of the findings and any unreported changes the team believes should have been
submitted to FDA per 21 CFR 314.70 or 601.12 (i.e., an annual reportable change, a change
being effected supplement, or a prior approval supplement). The inspection team should not
request manufacturing supplements to be submitted unless CDER confirms that such a
submission is appropriate. The inspection team should also document its findings under
separate captions in the EIR. Data system information about these inspectional activities should
be reported under separate product/assignment codes (PACs). Expansion of coverage under these
programs into a CGMP inspection 5 should be reported under this compliance program.
The ORA divisions should use this revised compliance program for all CGMP inspections
satisfying the statutory obligation for periodic risk-based inspections of drug production. The
instructions provided in this section and elsewhere in this compliance program governing ORA
and CDER interactions supersede the instructions in the other compliance programs for the 5600
PACs (e.g., 7356.002A, 7356.002F—Active Pharmaceutical Ingredient (API) Process
Inspection, 7356.002P).
Note that active pharmaceutical ingredient (API) and positron emission tomography (PET) drug
inspections are performed to verify conformance with different quality standards and have their
4
See guidance for industry Circumstances That Constitute Delaying, Denying, Limiting, or Refusing a Drug
Inspection.
5
In this compliance program, CGMP inspections include surveillance and for-cause inspections.
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own compliance programs. API inspections per compliance program 7356.002F are conducted to
verify adherence to section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (FD&C
Act) using ICH guidance for industry Q7 Good Manufacturing Practice Guidance for Active
Pharmaceutical Ingredients as a guideline. PET inspections per compliance program 7356.002P
are conducted to verify adherence to 21 CFR part 212.
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CONTENTS
PART I—BACKGROUND .......................................................................................................................... 7
PART II—IMPLEMENTATION ................................................................................................................. 9
1. Objectives ...................................................................................................................................... 9
2. Strategy ......................................................................................................................................... 9
A. Inspection of Manufacturing Establishments ........................................................................... 9
B. Inspection of Systems ............................................................................................................ 10
C. Scheme of Systems for the Manufacture of Drugs/Drug Products ........................................ 10
3. Program Management Instructions ............................................................................................. 12
A. Definitions.............................................................................................................................. 12
B. Inspection Planning ................................................................................................................ 14
C. Profiles ................................................................................................................................... 15
PART III—INSPECTIONAL ..................................................................................................................... 16
1. General ........................................................................................................................................ 16
2. Inspection Approaches ................................................................................................................ 17
A. Selecting the Full Inspection Option ...................................................................................... 17
B. Selecting the Abbreviated Inspection Option ......................................................................... 17
C. Inspection Coverage ............................................................................................................... 18
3. System Inspection Coverage ....................................................................................................... 18
A. Quality System ....................................................................................................................... 18
B. Facilities and Equipment System ........................................................................................... 21
C. Materials System .................................................................................................................... 23
D. Production System ................................................................................................................. 24
E. Packaging and Labeling System ............................................................................................ 25
F. Laboratory Control System .................................................................................................... 26
4. Sampling ..................................................................................................................................... 27
5. Inspection Teams......................................................................................................................... 27
6. Reporting ..................................................................................................................................... 28
PART IV—ANALYTICAL ....................................................................................................................... 29
1. Analyzing Laboratories ............................................................................................................... 29
2. Analysis ....................................................................................................................................... 29
PART V—REGULATORY/ADMINISTRATIVE STRATEGY .............................................................. 30
1. Quality System ............................................................................................................................ 31
2. Facilities and Equipment ............................................................................................................. 31
3. Materials System ......................................................................................................................... 31
4. Production System....................................................................................................................... 32
5. Packaging and Labeling .............................................................................................................. 32
6. Laboratory System ...................................................................................................................... 32
PART VI—REFERENCES, ATTACHMENTS, PROGRAM CONTACTS, AND ACRONYMS .......... 34
1. References ................................................................................................................................... 34
2. Attachments ................................................................................................................................. 36
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3. Contacts ....................................................................................................................................... 36
A. Office of Regulatory Affairs .................................................................................................. 36
B. Center for Drug Evaluation and Research ............................................................................. 37
Acronyms .................................................................................................................................... 37
PART VII—CDER AND ORA RESPONSIBILITIES OVERVIEW ........................................................ 39
1. Surveillance Inspection Responsibilities ..................................................................................... 39
2. For-Cause Inspection Responsibilities ........................................................................................ 39
ATTACHMENT A: REMOTE REGULATORY ASSESSMENTS .......................................................... 41
1. FDA Records and Other Information Requests Under Section 704(a)(4) of the FD&C Act
(Statutorily Authorized RRA) ..................................................................................................... 41
2. Remote Interactive Evaluation (Voluntary RRA) ....................................................................... 42
ATTACHMENT B: EXAMPLES OF INDICATORS OF AN ADVANCED QUALITY SYSTEM ....... 43
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PART I—BACKGROUND
Until 2012, FDA was required to inspect domestic establishments 6 that manufacture drugs
marketed in the United States every 2 years, but there was no comparable requirement for
inspecting foreign establishments. The Food and Drug Administration Safety and Innovation Act
(FDASIA), 7 which amended section 510(h) of the FD&C Act, eliminated this distinction,
directing FDA to take a risk-based approach to inspecting both domestic and foreign drug
manufacturing establishments. The selection of both domestic and foreign establishments for
routine surveillance inspections is now driven by a risk-based site selection model. In 2015, FDA
formalized its process for selecting establishments for inspection based on risk factors specified
by section 510(h) of the FD&C Act.
FDASIA also amended the FD&C Act to provide FDA the authority to enter into agreements to
recognize drug inspections conducted by foreign regulatory authorities if FDA determines those
authorities are capable of conducting inspections that meet U.S. requirements. Under section
809(a)(1) of the FD&C Act, FDA may enter into arrangements and agreements with a foreign
government or an agency of a foreign government to recognize the inspection of a foreign
establishment registered under section 510(i) of the FD&C Act to facilitate risk-based
inspections in accordance with the schedule established in paragraph (2) or (3) of section 510(h)
of the FD&C Act.
This compliance program provides CGMP inspection coverage of drug manufacturing
establishments to determine whether they are complying with CGMP requirements per section
501(a)(2)(B) of the FD&C Act, implementing regulations and corrective actions. The focus of
CGMP inspections is on system-wide controls that ensure manufacturing processes consistently
produce quality drugs. Systems examined during these inspections include those related to
quality, facilities and equipment, materials, production, packaging and labeling, and laboratory
controls. Inspections under this compliance program serve a core role in determining an
establishment’s compliance with CGMP requirements.
FDA expects that establishments that comply with CGMP requirements are those that operate in
a state of control and consistently manufacture drug products of acceptable quality. FDA will use
information gathered from inspections under this compliance program to assess an
establishment’s compliance with CGMP requirements, including, among other things, evaluating
the effectiveness of the establishment’s quality system. 8 FDA will also use this information to
assess whether the quality system exceeds CGMP requirements. In total, this information will
support the implementation of ICH Q12 and help FDA assess manufacturing establishments.
6
In this compliance program, the synonymous terms establishment, person, site, firm, and facility cover entities
subject to FDA drug manufacturing regulations and statutory authority.
7
See https://www.gpo.gov/fdsys/pkg/PLAW-112publ144/pdf/PLAW-112publ144.pdf, page 1067.
8
In this compliance program, the term quality system refers to the pharmaceutical quality system (PQS) as described
in ICH Q10 and the Pharmaceutical Inspection Co-operation Scheme (PIC/S) recommendation PI 054-1 How To
Evaluate and Demonstrate the Effectiveness of a Pharmaceutical Quality System in Relation to Risk-Based Change
Management, https://picscheme.org/docview/4294. The PQS is a management system to direct and control a
pharmaceutical company with regard to quality.
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To facilitate FDA’s initiative to enhance the regulation of pharmaceutical manufacturing and
product quality, FDA may use additional information sources to inform its regulatory oversight.
This may include the following: (1) other inspections conducted by FDA (e.g., preapproval and
postapproval inspections); (2) existing inspection reports requested from trusted foreign
regulatory partners through mutual recognition agreements (MRAs) and other confidentiality
agreements; 9 and (3) remote regulatory assessments (RRAs), 10 including (a) records or other
information requested directly from facilities and other inspected entities under section 704(a)(4)
of the FD&C Act, and (b) remote interactive evaluations (RIEs) conducted where appropriate.
The inspectional guidance and instructions in this compliance program are structured to provide
for efficient use of resources devoted to routine surveillance inspections, recognizing that in-
depth coverage of all systems and all processes is not feasible or required for all establishments
and inspections. This compliance program also provides instruction for conducting for-cause
inspections as appropriate (see Part II.3—Program Management Instructions).
9
For existing FDA MRAs with the European Union and the United Kingdom, this includes the use of official
inspection reports issued by a recognized authority for manufacturing facilities located inside and outside the
territory of the issuing authority. For more information, see https://www.fda.gov/international-
programs/international-arrangements/mutual-recognition-agreement-mra.
10
An RRA is an examination of an FDA-regulated establishment and/or its records, conducted entirely remotely, to
evaluate compliance with applicable FDA requirements. RRAs assist in protecting human health, informing
regulatory decisions, and verifying certain information submitted to the Agency.
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PART II—IMPLEMENTATION
1. Objectives
The goal of this compliance program’s activities is to ensure that establishments consistently
manufacture drug products of acceptable quality and minimize consumers’ exposure to
adulterated drug products.
Under this compliance program, inspections, investigations, sample collections, sample analyses,
and regulatory or administrative follow-up are made to identify quality problems and adverse
trends at establishments, so that FDA can develop strategies to mitigate them. In addition to
inspections conducted by FDA staff and inspections conducted by foreign regulatory authorities
under MRAs, when appropriate, FDA may also use RRAs as part of the regulatory oversight
program to support regulatory decisions, inform inspection planning, and verify certain
information submitted to the Agency (see Attachment A for RRAs).
The objectives of this compliance program follow:
• Determine whether inspected establishments are operating in compliance with applicable
CGMP requirements and, if not, provide the evidence for actions to prevent adulterated
products from entering the market. As appropriate, remove adulterated products from the
market, and take action against persons responsible.
• Provide an assessment of establishments’ conformance to CGMP requirements for
Agency decisions.
• Gain insight into the effectiveness of a drug manufacturer’s quality system. In addition, it
may 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.
• Provide input to establishments during inspections to improve their compliance with
regulations.
• Better understand current practices in drug manufacturing for the purpose of updating
CGMP requirements, regulatory policy, and guidance documents.
2. Strategy
A. Inspection of Manufacturing Establishments
Drug products are manufactured using many physical operations that bring together components,
containers, and closures to make a product that is released for distribution. Drug manufacturing
can be organized into sets of operations and related activities, called systems. Control of all
systems helps to ensure the establishment will produce drugs that are safe and that meet the
identity, strength, quality, and purity characteristics as intended.
This compliance program applies to all pharmaceutical manufacturing operations at the
establishment, which includes repackaging, contract testing, labeling, and other operations.
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It is not practical for FDA to audit every aspect of CGMP in every manufacturing establishment
during every inspection visit. Profile classes generalize inspection coverage from a small number
of specific products to all the products in that class. Reporting coverage for every profile class as
defined in eNSpect, for each inspection, provides the most broadly resource-efficient approach.
This compliance program uses a risk-based systems approach to further generalize inspection
coverage from a small number of profile classes to an overall evaluation of the establishment.
Risk-based inspectional approaches allow updating of all profile classes.
The inspection is defined as audit coverage of two or more systems, with mandatory coverage of
the quality system (see system definitions below). Depending on the purpose of the inspection,
inspection coverage may include different numbers of systems. Inspecting the minimum number
of systems, or more systems as deemed necessary by the ORA division, will provide the basis for
an overall CGMP classification decision.
B. Inspection of Systems
Inspections of drug manufacturers should be made and reported using the system definitions and
industry codes in this compliance program. Focusing on systems, rather than profile classes, will
increase efficiency in conducting inspections because the systems are often applicable to
multiple profile classes. System inspection coverage should represent all profile classes at the
establishment and determine their acceptability/non-acceptability.
Coverage of a system should be sufficiently detailed, with specific examples selected, so that the
system inspection outcome reflects the state of control in that system for every profile class. If a
particular system is adequate, it should be adequate for all profile classes manufactured by the
establishment. For example, the way an establishment handles “materials” (i.e., receipt,
sampling, testing, acceptance, etc.) should be the same for all profile classes. An inspection does
not have to include every profile class attribute when covering a given system provided that
inspection coverage includes related controls for all types of drugs and operations. Likewise in
the production system, there are general requirements like use of standard operating procedures
(SOPs), charge-in of components, equipment identification, in-process sampling, and testing that
can be evaluated through selection of example products in various profile classes. Under each
system, there may be something unique for a particular profile class: e.g., under the materials
system, the production of Water for Injection USP (United States Pharmacopeia) for use in
manufacturing. Selecting unique functions within a system will be at the discretion of the lead
investigator. Any given inspection need not cover every system. See Part III of this compliance
program.
Complete inspection of one system may necessitate further follow up of some items within the
activities of other systems to fully document the findings. However, this coverage does not
constitute nor require complete coverage of these other systems.
C. Scheme of Systems for the Manufacture of Drugs/Drug Products
The overall theme in devising the following scheme of systems was the subchapter structure of
the 21 CFR part 211 CGMP regulations. Every effort was made to group whole subchapters
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together in a rational set of six systems numbered below that incorporates the general scheme of
pharmaceutical manufacturing operations.
The organization and personnel, including appropriate qualifications and training, employed in
any given system will be evaluated as part of that system’s operation. Production, control, and
distribution records required to be maintained by the CGMP regulations and selected for review
should be included for inspection audit within the context of each of the six systems. Inspections
of contract companies should be within the system for which the product or service is contracted
as well as their quality system.
A general scheme of systems for auditing the manufacture of drugs and drug products consists of
the following:
1. Quality System. This system ensures overall compliance with CGMP and internal
procedures and specifications. A robust quality system relies on documentation and
strong senior management oversight of CGMP operations and quality-related matters,
supports and facilitates the activities conducted under all of the six systems, monitors its
effectiveness, and ensures a commitment to an established quality policy. 11 This system
also includes the quality unit and its review and approval duties (e.g., quality agreements,
change management, risk management, reprocessing, batch release, annual record review,
investigations, continued process verification, validation protocols and reports). It
includes product defect evaluations and evaluations of returned and salvaged drug
products. See the CGMP regulations, 21 CFR part 211, subparts B, E, F, G, I, J, and K.
2. Facilities and Equipment System. This system includes the measures and activities that
provide an appropriate physical environment and resources used in the production of
drugs or drug products. It includes the following:
a. Buildings and facilities along with maintenance
b. Equipment qualifications (installation and operation), equipment calibration and
preventive maintenance, and cleaning and validation of cleaning processes as
appropriate; process performance qualification will be evaluated as part of the
inspection of the overall process validation, which is done within the system where the
process is employed
c. Utilities that are not intended to be incorporated into the product, such as HVAC,
compressed gases, steam, and water systems
See the CGMP regulations, 21 CFR part 211, subparts B, C, D, and J.
3. Materials System. This system includes measures and activities to control finished
products, components (including water or gases that are incorporated into the product),
containers, and closures. It includes validation of computerized inventory control
processes; management of lifecycle risks from components, containers, and closures;
11
Quality policy is defined as the overall intentions and direction of an organization related to quality as formally
expressed by senior management. See ICH Q10.
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drug storage; distribution controls; and records. See the CGMP regulations, 21 CFR part
211, subparts B, E, H, and J.
4. Production System. This system includes measures and activities to control the
manufacture of drugs and drug products, including batch compounding, dosage form
production, in-process sampling and testing, and process validation. It also includes
establishing, following, and documenting performance of approved manufacturing
procedures. See the CGMP regulations, 21 CFR part 211, subparts B, F, and J.
5. Packaging and Labeling System. This system includes measures and activities that
control the packaging and labeling of drugs and drug products. It includes written
procedures, label examination and usage, label storage and issuance, packaging and
labeling operations controls, and validation of these operations. See the CGMP
regulations, 21 CFR part 211, subparts B, G, and J.
6. Laboratory Control System. This system includes measures and activities related to
laboratory procedures, testing, analytical methods development and validation or
verification, and the stability program. See the CGMP regulations, 21 CFR part 211,
subparts B, I, J, and K.
3. Program Management Instructions
A. Definitions
(1) Surveillance Inspections
(a) Full Inspection Option
The full surveillance inspection option is a CGMP inspection meant to provide a broad and in-
depth evaluation of the establishment’s conformance with CGMP requirements. A full inspection
may change to an abbreviated inspection with concurrence of the ORA division. During the
course of a full inspection, verification of quality system activities may require limited coverage in
other systems. The full inspection option will normally include an inspection audit of at least four
of the systems, one of which must be the quality system (the system that includes management’s
responsibility for overseeing an ongoing state of control).
(b) Abbreviated Inspection Option
The abbreviated surveillance inspection option is a CGMP inspection meant to provide an
efficient, updated evaluation of an establishment’s conformance with CGMP requirements. The
abbreviated inspection will provide documentation for continuing an establishment in a
satisfactory CGMP compliance status. Generally, this will be done when an establishment has a
record of satisfactory CGMP compliance, with no significant recall, or product defect or alert
incidents, or with little shift in the manufacturing profiles of the establishment since the last
inspection. See Part III.2.B—Selecting the Abbreviated Inspection Option. An abbreviated
inspection may change to a full inspection, upon findings of objectionable conditions (as listed in
Part V) in one or more systems, with ORA division concurrence. The abbreviated inspection
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option normally will include an inspection audit of at least two of the systems, one of which must
be the quality system (the system that includes management’s responsibility for overseeing an
ongoing state of control). The ORA division drug program managers should ensure that the
optional systems are rotated in successive abbreviated inspections. During the course of an
abbreviated inspection, verification of quality system activities may require limited coverage in
other systems. Some establishments participate in a limited part of the production of a drug or
drug product, e.g., a contract laboratory. Such establishments may employ only two of the
systems defined. In these cases, the inspection of the two systems will comprise inspection of the
entire establishment and will be considered the full inspection option.
(c) Selecting Systems for Coverage
The ORA division will select systems for coverage based on the establishment’s specific
operation, history of previous coverage, history of compliance, or other priorities determined by
the ORA division.
(2) For-Cause Inspections
For-cause inspections include (a) follow-up CGMP compliance inspections performed to verify
corrective actions after a regulatory action has been taken; and (b) CGMP inspections performed
in response to specific events or information (e.g., FARs, biological product defect reports
(BPDRs), industry complaints, recalls, other indicators of defective products) that bring into
question the compliance or quality of a manufacturing practice, facility, process, or drug.
For-cause inspections that are to be initiated and reported under this compliance program fall
under the category of follow-up CGMP compliance inspections performed to verify corrective
actions after a regulatory action has been taken. Follow-up CGMP compliance inspections
provide focused coverage and include the areas of concern, the proposed corrective action plan
for impacted operations, any implemented corrective actions, and/or the deficiencies noted on
Form FDA 483 for a previous inspection. The decision to add systems coverage is made on a
case-by-case basis.
For-cause inspections in response to FARs are to be initiated and performed under compliance
program 7356.021—Drug Quality Reporting System (DQRS) (MedWatch Reports); NDA Field
Alert Reports (FARs). 12
Other for-cause inspections (e.g., industry complaints, other indicators of defective products)
may be initiated per ORA internal procedures but expanded to include CGMP coverage for the
purpose of updating overall compliance status.
(3) State of Control
A drug establishment is considered to be operating in a state of control when it employs
conditions and practices that comply with section 501(a)(2)(B) of the FD&C Act and the
portions of the CGMP regulations that pertain to its systems. An establishment in a state of
12
NDA=new drug application.
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control produces finished drug products for which there is an adequate level of assurance of
quality, strength, identity, and purity.
An establishment is out of control if any one system is out of control. A system is out of control
if the quality, identity, strength, and purity of the products resulting from one or more systems
cannot be adequately ensured. Documented CGMP deficiencies provide the evidence for
concluding that a system is not operating in a state of control. See Part V—
Regulatory/Administrative Strategy for a discussion of compliance actions based on inspection
findings demonstrating an out-of-control system or systems.
(4) Drug Process
A drug process is a related series of operations that result in the preparation of a drug or drug
product. Major operations or steps in a drug process may include mixing, granulation,
encapsulation, tableting, chemical synthesis, fermentation, aseptic filling, sterilization, packaging,
labeling, testing, and so forth.
(5) Drug Manufacturing Inspection
A drug manufacturing inspection is an establishment inspection in which two or more systems,
including the quality system, are evaluated to determine if manufacturing is occurring in a state
of control.
B. Inspection Planning
ORA will conduct drug manufacturing inspections using a risk-based approach and will maintain
profiles or other monitoring systems. The ORA division is responsible for determining the depth
of coverage given to each drug establishment. The depth of inspection coverage should be
determined by the establishment’s compliance history, the manufacturing technology employed,
and the characteristics of the products. CGMP inspectional coverage must be sufficient to assess
the state of control and compliance for each establishment.
Before scheduling the surveillance coverage of the newly registered establishment, the
investigator should consult with their ORA division to determine whether there have been any
requests for preapproval or postapproval inspections that should be included in the inspectional
coverage. In advance of a scheduled surveillance inspection, OQS prepares an up-to-date site
dossier that includes, but is not limited to, quality information on establishment inspection
history, recalls, shortages, customer complaints, foreign regulator inspection outcomes,
information on submitted FARs or BPDRs, a listing of all products manufactured at the site, and,
where applicable, CGMP elements identified as at risk. When a system is inspected, the
inspection of that system may be considered applicable to all products that use it. Investigators
should select an adequate number and type of products to accomplish coverage of the system.
Selection of products should be made so that coverage is representative of the establishment’s
overall abilities in manufacturing within CGMP requirements.
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Products posing special challenges, such as low dose products, narrow therapeutic range drugs,
combination products, 13 modified release products, biological products, and new products
manufactured under recently approved drug applications, should be considered first in selecting
products for coverage. Refer to IOM chapter 5, section 5.5.1.2—Inspectional Approach. 14
The health significance of certain CGMP deviations may be lower when the drug product
involved has no major systemic health effect or no dosage limitations such as in products like
calamine lotion. Such products should be given inspection coverage with appropriate priority.
Inspections for this compliance program may be performed during visits to an establishment
when operations are being performed for other compliance programs or other investigations.
C. Profiles
The inspection findings will be used as the basis for updating all profile classes in the profile tab
in eNSpect as per the IOM. Normally, an inspection under this risk-based systems approach will
result in all profile classes being updated.
13
Combination products are subject to the CGMP requirements outlined in 21 CFR part 4. See guidance for industry
and FDA staff Current Good Manufacturing Practice Requirements for Combination Products and compliance
program 7356.000 Inspections of CDER-Led or CDRH-Led Combination Products.
14
See https://www.fda.gov/downloads/ICECI/Inspections/IOM/UCM150576.pdf.
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PART III—INSPECTIONAL
1. General
The investigator should review and use the CGMP regulations for finished pharmaceuticals (21
CFR parts 210 and 211) and related guidance for industry to evaluate manufacturing processes.
The investigator should conduct inspections according to Part II.2—Strategy of this compliance
program. Recognizing that drug establishments vary greatly in size and scope, and
manufacturing systems are more or less sophisticated, the approach to inspecting each
establishment should be carefully planned. The complexity and variability necessitate a flexible
inspection approach—one that allows the investigator to choose the inspection focus and depth
appropriate for a specific establishment, but also one that directs the performance and reporting
on the inspection within a framework that will provide for a uniform level of CGMP assessment,
efficient communication, and evaluation of findings. Performance and documentation under this
compliance program may be facilitated by the use of applicable eNSpect inspection protocols
along with the collection of evidence.
Inspectional observations noting CGMP deficiencies should be related to a requirement. CGMP
requirements for manufacture of drug products (dosage forms) are in section 501(a)(2)(B) of the
FD&C Act and the regulations and are amplified by guidance, case precedents, and so forth.
CGMP requirements apply to the manufacture of all human drugs, which include prescription
and nonprescription drug products, drug products that are the subject of pending applications,
drug products used in clinical trials, and products not requiring approval.
API and PET drug inspections are performed to verify conformance with different quality
standards than 21 CFR parts 210 and 211 and have their own compliance programs. API
inspections are conducted under compliance program 7356.002F, which employs ICH Q7 as a
quality standard and establishes compliance to the statutory requirement of section 501(a)(2)(B)
of the FD&C Act. Establishments that follow ICH Q7 generally will be considered to comply
with the statutory requirement. PET inspections under compliance program 7356.002P are
conducted to verify adherence to 21 CFR part 212.
Guidance documents are not to be referred to as the justification for an inspectional observation.
The justification comes from the statute and the CGMP regulations. Current guides to inspection
and guidance documents provide interpretations of requirements, which may assist in the
evaluation of the adequacy of CGMP systems. Guidance documents do not establish
requirements.
Current inspectional observation policy as stated in the IOM says that Form FDA 483, when
issued, should be specific and contain only significant items. For this compliance program,
inspection observations should be organized under separate captions by the systems defined in
this compliance program. List the observations in order of importance within each system.
Where repeated or similar observations are made, they should be consolidated under a unified
observation. A limited number of observations can be common to more than one system (e.g.,
organization and personnel, including appropriate qualifications and training). In these instances,
put the observation in the first system reported on Form FDA 483 and in the text of the EIR, and
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PROGRAM 7356.002
reference the applicability to other systems where appropriate. This is being done to
accommodate the structure of eNSpect, which allows individual citation once per Form FDA
483. Refrain from using unsubstantiated conclusions. Do not use the term inadequate without
explaining why and how. Refer to policy in IOM chapter 5, section 5.2.3—Reports of
Observations, for further guidance on the content of inspectional observations.
Specific, specialized inspectional guidance may be provided in addition to this compliance
program or in requests for inspection, assignments, and so forth.
2. Inspection Approaches
This compliance program provides two CGMP inspection options: Full and abbreviated. See the
definitions of the inspection options in Part II of this compliance program.
A. Selecting the Full Inspection Option
The full inspection option will include inspection of at least four of the systems listed in Part
II.2—Strategy, one of which must be the quality system.
• Select the full inspection option for an initial FDA inspection of newly registered
establishments. Inspection coverage should include all systems as appropriate to the
operations. A full inspection may change to an abbreviated inspection, with ORA division
concurrence and where appropriate.
• Select the full inspection option when the establishment has a history of fluctuating into
and out of compliance. To determine if the establishment meets this criterion, the ORA
division should use all information at its disposal, such as inspection results, results of
sample analyses, complaints, defects, DQRS reports and BPDRs, recalls, and any
compliance actions resulting from them or from past inspections.
• Evaluate whether important changes have occurred by comparing current operations
against the EIR for the previous full inspection. The following types of changes are
typical of those that warrant the full inspection option:
o New potential for cross-contamination arising through change in process or product
line
o Use of new technology requiring new expertise, significant new equipment, or new
facilities
• A full inspection may also be conducted based on CGMP findings at the ORA division’s
discretion.
B. Selecting the Abbreviated Inspection Option
The abbreviated inspection option normally will include an inspection audit of at least two
systems, one of which must be the quality system. During the course of an abbreviated
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inspection, verification of quality system activities may require limited coverage in other
systems.
• This option involves inspecting the manufacturer to maintain surveillance over the
establishment’s manufacturing practices and quality performance and to evaluate whether
the establishment is maintaining and improving the CGMP level of assurance of product
quality.
• Select the abbreviated inspection option with ORA division concurrence when an
establishment has a record of sustained acceptable compliance history, a strong risk
management program, and a lack of significant marketed product quality defects.
• Abbreviated inspection coverage may be changed to full inspection coverage at the
discretion of the ORA division.
C. Inspection Coverage
It is not anticipated that full inspections (4 to 6 systems coverage) can be conducted every time.
To build comprehensive information on the establishment’s manufacturing activities, ORA
divisions should consider selecting different systems for inspection coverage during successive
abbreviated inspections.
Follow-up inspections to a warning letter or other significant regulatory actions are considered
for-cause inspections and, as a result, the related for-cause assignments can request either full
systems coverage or individual system coverage. In addition, coverage can be added on a case-
by-case basis at the discretion of the ORA division before or during the inspection.
3. System Inspection Coverage
A. Quality System
For the purposes of this compliance program, quality system refers to the system (i.e., policies,
procedures, controls, activities, etc.) satisfying the specific quality control and quality assurance
requirements outlined under 21 CFR 211.22, as well as other quality-related requirements in 21
CFR part 211 and under the FD&C Act.
The quality system, typically described in an establishment’s quality manual, should provide for
effective senior management oversight of drug quality and support the establishment’s quality
unit. This includes, but is not limited to, quality policies, quality planning, quality resource
management, and quality management review. When effectively implemented with an
established quality policy endorsed by senior management, a quality system provides for
coordination and direction of the organization’s activities related to producing quality drugs,
helps establish and maintain a state of control, promotes robust risk management, and facilitates
continual improvement throughout a product’s lifecycle. To ensure the implementation of a
CGMP-compliant quality system, manufacturers should use knowledge management and quality
risk management tools to conduct operations, in whole or in part, consistent with
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recommendations in guidance for industry Quality Systems Approach to Pharmaceutical CGMP
Regulations and ICH Q9, Q10, and Q12.
Additionally, an inspection conducted under this compliance program provides an opportunity
for investigators to observe and document examples of mature quality practices that exceed
CGMP requirements and are indicative of an advanced quality system. To aid investigators,
Attachment B provides some examples of these practices that, when properly implemented, are
indicators of an advanced quality system. The information from this compliance program, when
combined with information on mature quality practices gathered from other sources, provides
FDA with a more comprehensive understanding of a firm’s quality system. This knowledge is
used by the Agency to support regulatory decisions, including the use of more flexible
approaches in our regulatory oversight. 15
As described in 21 CFR 314.70(a) (for NDAs) and 314.97(a) (for ANDAs), applicants of
approved products “must notify FDA about each change in each condition established in an
approved [A]NDA beyond the variations already provided for in the [A]NDA.” Similar
requirements exist for biologics license application products in 21 CFR 601.12. ICH Q12 and the
draft guidance for industry ICH Q12: Implementation Considerations for FDA-Regulated
Products (ICH Q12 implementation guidance) 16 provide an opportunity for applicants to
specifically define established conditions (ECs) to gain clarity around which elements of the
product, manufacturing process, facilities and equipment, and control strategy in their
applications are considered to be ECs and therefore require reporting if changed. Proposing ECs
in the application is entirely voluntary, but where proposed, they must be approved with the
application to be implemented. Some applicants also have approved reporting categories for
changes to ECs following the principles outlined in ICH Q12. Applicants include the list of ECs,
their reporting categories, and any comparability protocols in the product lifecycle management
(PLCM) document. 17 The implementation of a robust change management system that evaluates
manufacturing changes in a manner commensurate with the level of risk imposed by a proposed
change is a basic element of the quality system and is necessary to support ICH Q12 tools,
including ECs, reporting categories for changes to ECs, and comparability protocols.
Inspectional assessment of the quality system is two-phased. The first phase is to evaluate
whether the quality unit has fulfilled the responsibility to review and approve all procedures
related to manufacturing, quality control, and quality assurance and ensure the procedures are
adequate for their intended use as outlined under 21 CFR 211.22(a) and 211.22(c). This also
includes the associated recordkeeping systems. The second phase is to assess the data collected
to identify quality problems that may link to other major systems for inspectional coverage.
For each of the following, the establishment should have written and approved procedures and
documentation resulting therefrom. The establishment’s adherence to written procedures should
be verified through observation whenever possible. These areas are not limited to finished
15
See ICH Q10, ICH Q12, and OPQ’s white paper Quality Management Maturity: Essential for Stable U.S. Supply
Chains of Quality Pharmaceuticals.
16
When final, the ICH Q12 implementation guidance will represent FDA’s current thinking on this topic.
17
Comparability protocols may also be described as postapproval change management protocols (PACMP) as
described in ICH Q12. These are equivalent terms.
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products but may also incorporate components and in-process materials. These areas may
indicate deficiencies not only in this system but also in other major systems that would warrant
expansion of coverage. All areas under this system should be covered; however, the depth of
coverage may vary depending on inspectional findings.
• Quality oversight of contracted operations and material suppliers: Effective monitoring
strategy has been implemented; incoming material monitoring, lifecycle qualification
program, quality agreements, and timely communication mechanisms are included
• Management oversight of the development, implementation, monitoring, and continual
improvement of the quality system: Quality risk management and knowledge
management 18 are incorporated (e.g., providing an early warning system for appropriate
resource allocation)
• Quality risk management program:
o Documented and implemented to ensure hazards (e.g., cross-contamination,
adulteration, hazardous impurities such as nitrosamines, 19 nitrosating agents, nitrites,
nitrates, and azides) are identified, evaluated, addressed, communicated (to the
establishment’s management and FDA), and continuously reviewed as needed
throughout a product’s lifecycle
o Hazardous impurity risk is assessed and control strategies are implemented to
mitigate the risk (e.g., actions to address sources of variability, release testing,
reduction or elimination of impurities, cleaning validation); control strategies are
reviewed following changes and throughout a product’s lifecycle
• Product reviews: Conducted at least annually; product quality is reviewed to assess risk
and determine the need for changes, such as changes in drug product specifications,
manufacturing, or control procedures; statistical analysis is conducted to identify areas
(e.g., trends, patterns, correlations, anomalies) for action and improvement; refer to 21
CFR 211.180(e)
• Complaint reviews (quality and medical): Documented; evaluated; investigated in a
timely manner; corrective action is included where appropriate
• Discrepancy and failure investigations: Documented; investigated in a timely manner
using scientific evidence to identify the root cause; corrective actions and preventive
actions (CAPAs) are included and effectiveness of the CAPAs is evaluated
• Change management for the manufacturing of all products: Documented (with
justification); quality risk management 20 is used to evaluate proposed changes for
18
Effective knowledge management (e.g., acquiring, analyzing, storing, and disseminating information) supports
effective risk management, along with timely risk review, corrective actions and preventive actions, and change
management.
19
See guidance for industry Control of Nitrosamine Impurities in Human Drugs.
20
See PIC/S recommendation PI 054-1 How To Evaluate and Demonstrate the Effectiveness of a Pharmaceutical
Quality System in Relation to Risk-Based Change Management.
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potential risks (e.g., hazardous impurities) and impact on product quality; reviewed by
subject matter experts; approved before implementation; evaluated for effectiveness;
revalidated, reverified, requalified as needed; changes are reported to FDA as appropriate
• Reporting of changes for approved application products: Changes to ECs are documented
and reported as defined by the PLCM document in the application or as described in the
regulations and existing guidance 21
• Rejects: Investigation is expanded where warranted; CAPAs are implemented where
appropriate
• Stability failures: Investigation is expanded where warranted; need for FARs, BPDRs,
and recalls are evaluated; disposition is documented
• Quarantine products
• Validation: Approval of required validation/revalidation (e.g., computer, manufacturing
process, laboratory methods) is documented
• Training/qualification of employees in CGMP: Includes coverage of quality functions,
risk management, and specific CGMP operations assigned to individual employees
• Programs for the ongoing monitoring of process performance and product quality
throughout a product’s lifecycle: Significant issues are escalated to senior management
• Reprocess/Rework: Evaluation is conducted and approval is documented; impact on
validation and stability is assessed
• Returns/Salvages: Assessment is conducted; investigation is expanded where warranted;
disposition is completed
B. Facilities and Equipment System
For each of the following, the establishment should have written and approved procedures and
documentation resulting therefrom. The establishment’s adherence to written procedures should
be verified through observation whenever possible. These areas are not limited to finished
products but may also incorporate components and in-process materials. These areas may
indicate deficiencies not only in this system but also in other systems that would warrant
expansion of coverage. When this system is selected for coverage in addition to the quality
system, all areas listed below should be covered; however, the depth of coverage may vary
depending on inspectional findings.
21
See e.g., FDA’s Scale-Up and Postapproval Changes (SUPAC) guidances and the guidances for industry Changes
to an Approved Application for Specified Biotechnology and Specified Synthetic Biological Products, Changes to an
Approved NDA or ANDA, Chemistry, Manufacturing, and Controls Changes to an Approved Application: Certain
Biological Products, and CMC Postapproval Manufacturing Changes To Be Documented in Annual Reports.
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(1) Facilities
• Cleaning and maintenance
• Facility layout and air handling systems for prevention of cross-contamination (e.g.,
penicillin, beta-lactams, steroids, hormones, cytotoxics)
• Specifically designed areas for the manufacturing operations performed by the
establishment to prevent cross-contamination or mix-ups
• General air handling systems
• Control system for implementing changes in the building
• Lighting, potable water, washing and toilet facilities, sewage and refuse disposal
• Sanitation of the building, use of rodenticides, fungicides, insecticides, cleaning and
sanitizing agents
• Oversight of facility infrastructure and suitability of manufacturing operations by
responsible operations managers
(2) Equipment
• Equipment installation and operational qualification where appropriate
• Adequacy of equipment design, size, and location
• Equipment surfaces that are not reactive, additive, or absorptive
• Appropriate use of equipment operations substances (e.g., lubricants, coolants,
refrigerants) contacting products/containers
• Cleaning procedures and cleaning validation for reusable or multiproduct equipment
• Controls to prevent contamination, particularly with pesticides or other toxic materials, or
other drug or non-drug chemicals
• Qualification, calibration, and maintenance of storage equipment (e.g., refrigerators,
freezers) for ensuring that standards, raw materials, reagents, and so forth are stored at
the proper temperatures
• Equipment qualification, calibration, and maintenance, including computer
qualification/validation and security
• Control system for implementing changes in the equipment
• Equipment identification practices (where appropriate)
• Documented investigation into unexpected discrepancies
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C. Materials System
For each of the following, the establishment should have written and approved procedures and
documentation resulting therefrom. The establishment’s adherence to written procedures should
be verified through observation whenever possible. These areas are not limited to finished
products but may also incorporate components and in-process materials. These areas may
indicate deficiencies not only in this system but also in other systems that would warrant
expansion of coverage. When this system is selected for coverage in addition to the quality
system, all areas listed below should be covered; however, the depth of coverage may vary
depending on inspectional findings.
• Training/qualification of personnel
• Identification of components, containers, and closures
• Inventory of components, containers, and closures
• Storage conditions
• Storage under quarantine until tested or examined and released
• Representative samples collected, tested, or examined using appropriate means
• At least one specific identity test conducted on each lot of each component
• Visual identification conducted on each lot of containers and closures
• Testing or validation of supplier’s test results for components, containers, and closures
• Rejection of components, containers, and closures not meeting acceptance requirements
• Full investigation of the establishment’s procedures for verification of the source of
components
• Appropriate retesting/reexamination of components, containers, and closures
• First in—first out use of components, containers, and closures
• Quarantine of rejected materials
• Water and process gas supply, design, maintenance, validation, and operation
• Containers and closures are not additive, reactive, or absorptive to the drug product
• Control system for implementing changes in the materials handling operations
• Qualification/validation and security of computerized or automated processes
• Finished product distribution records by lot
• Documented investigation into unexpected discrepancies
• Risk management program for components: Documented when unacceptable levels of
hazardous impurities are identified by the establishment and updated as needed
throughout the product’s lifecycle
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D. Production System
For each of the following, the establishment should have written and approved procedures and
documentation resulting therefrom. The establishment’s adherence to written procedures should
be verified through observation whenever possible. These areas are not limited to finished
products but may also incorporate components and in-process materials. These areas may
indicate deficiencies not only in this system but also in other systems that would warrant
expansion of coverage. When this system is selected for coverage in addition to the quality
system, all areas listed below should be covered; however, the depth of coverage may vary
depending on inspectional findings.
• Training/qualification of personnel
• Control system for implementing changes in processes
• Adequate procedure and practice for charge-in of components
• Formulation/manufacturing at not less than 100 percent
• Identification of equipment with contents and, where appropriate, phase of manufacturing
or status
• Validation and verification of cleaning/sterilization/depyrogenation of containers and
closures
• Calculation and documentation of actual yields and percentage of theoretical yields
• Contemporaneous and complete batch production documentation
• Established time limits for completion of phases of production
• Implementation and documentation of in-process controls, tests, and examinations (e.g.,
pH, adequacy of mix, weight variation, clarity)
• Justification and consistency of in-process specifications and drug product final
specifications
• Prevention of objectionable microorganisms in non-sterile drug products
• Adherence to preprocessing procedures (e.g., set-up, line clearance)
• Equipment cleaning and use logs
• Master production and control records
• Batch production and control records
• Process validation, including validation and security of computerized or automated
processes
• Ongoing statistical evaluations (e.g., batch control data, periodic capability analysis) to
identify processes that exhibit higher variability and trigger needed improvements
• Change control; the need for revalidation evaluated
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• Investigation into unexpected discrepancies
• Effective control strategy established for operations at risk of forming hazardous
impurities
E. Packaging and Labeling System
For each of the following, the establishment should have written and approved procedures and
documentation resulting therefrom. The establishment’s adherence to written procedures should
be verified through observation whenever possible. These areas are not limited to finished
products but may also incorporate components and in-process materials. These areas may
indicate deficiencies not only in this system but also in other systems that would warrant
expansion of coverage. When this system is selected for coverage in addition to the quality
system, all areas listed below should be covered; however, the depth of coverage may vary
depending on inspectional findings.
• Training/qualification of personnel
• Acceptance operations for packaging and labeling materials
• Control system for implementing changes in packaging and labeling operations
• Adequate storage for labels and labeling, both approved and returned after issued
• Control of labels that are similar in size, shape, and color for different products
• Finished product cut labels for immediate containers that are similar in appearance
without some type of 100 percent electronic or visual verification system or the use of
dedicated lines
• Gang printing of labels is not done, unless they are differentiated by size, shape, or color
• Control of filled unlabeled containers that are later labeled under multiple private labels
• Adequate packaging records that will include specimens of all labels used
• Control of issuance of labeling, examination of issued labels, and reconciliation of used
labels
• Examination of the labeled finished product
• Adequate inspection (proofing) of incoming labeling
• Use of lot numbers, destruction of excess labeling bearing lot/control numbers
• Physical/spatial separation between different labeling and packaging lines
• Monitoring of printing devices associated with manufacturing lines
• Line clearance, inspection, and documentation
• Adequate expiration dates on the label
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• Conformance to tamper-resistant packaging requirements (see 21 CFR 211.132 and CPG
Sec. 450.500 Tamper-Resistant Packaging Requirements for Certain Over-the-Counter
Human Drug Products) 22
• Validation of packaging and labeling operations, including validation and security of
computerized processes
• Documented investigation into unexpected discrepancies
F. Laboratory Control System
For each of the following, the establishment should have written and approved procedures and
documentation resulting therefrom. The establishment’s adherence to written procedures should
be verified through observation whenever possible. These areas are not limited to finished
products but may also incorporate components and in-process materials. These areas may
indicate deficiencies not only in this system but also in other systems that would warrant
expansion of coverage. When this system is selected for coverage in addition to the quality
system, all areas listed below should be covered; however, the depth of coverage may vary
depending on inspectional findings.
• Training/qualification of personnel
• Adequacy of staffing for laboratory operations
• Adequacy of equipment and facility for intended use
• Calibration and maintenance programs for analytical instruments and equipment
• Validation and security of computerized or automated processes
• Reference standards; source, purity, and assay and tests to establish equivalency to
current official reference standards as appropriate
• System suitability checks on chromatographic systems (e.g., gas chromatography, high-
performance liquid chromatography)
• Specifications, standards, and representative sampling plans
• Control strategy established for hazardous impurities if identified in components or the
finished product, or as a degradant, throughout the product’s lifecycle
• Adherence to the written methods of analysis
• Validation/verification of analytical methods
• Control system for implementing changes in laboratory operations
• Required testing performed on the correct samples
• Documented investigation into unexpected discrepancies
22
See https://www.fda.gov/iceci/compliancemanuals/compliancepolicyguidancemanual/ucm074391.htm.
Date of Issuance: 09/16/2022 Page 26 of 44
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• Complete analytical records from tests and summaries of results
• Quality and retention of raw data (e.g., chromatograms and spectra)
• Correlation of result summaries to raw data; presence of unused data
• Adherence to an adequate out-of-specification (OOS) procedure that includes timely
completion of the investigation
• Adequate reserve samples; documentation of reserve sample examination
• Stability testing program, including demonstration of stability indicating capability of the
test methods
4. Sampling
Samples of defective product constitute persuasive evidence that significant CGMP problems
exist. Physical samples may be an integral part of a CGMP inspection where control deficiencies
are observed. Physical samples should be correlated with observed control deficiencies. Contact
the program coordinator (chemistry, microbiology) in the Office of Medical Products, Tobacco,
and Specialty Laboratory Operations (OMPTSLO) in ORA’s Office of Regulatory Science
(ORS) identified in Part VI.3—Contacts for guidance and types of samples (in-process or
finished product) to be collected and for the appropriate servicing laboratory. Documentary
samples may be submitted when the documentation illustrates the deficiencies better than a
physical sample. ORA divisions may elect to collect, but not analyze, physical samples or to
collect documentary samples to document CGMP deficiencies. Physical sample analysis is not
necessary to document CGMP deficiencies.
When a large number of products have been produced under deficient controls, collect physical
or documentary samples of products that have the greatest therapeutic significance, narrow
therapeutic range, or low dosage strength. Include samples of products of minimal therapeutic
significance only when they illustrate highly significant CGMP deficiencies.
For sampling guidance, refer to IOM chapter 4—Sampling.
5. Inspection Teams
An inspection team (see IOM chapter 5, section 5.1.2.5—Team Inspections) is composed of
experts from across ORA, and in certain cases CDER, when specific expertise and experience
are needed. Contact ORA’s Office of Pharmaceutical Quality Operations if technical assistance
is needed (see also FMD 142). ORA leads the inspection with CDER participation, when
requested by ORA. Participation of an analyst (chemist or microbiologist) on an inspection team
is also encouraged, especially where laboratory issues are extensive or complex. Contact your
drug servicing laboratory or ORA/ORS. Each inspection team member is responsible for
preparing for, executing, and documenting the inspection, including contributing to the EIR,
which documents the items covered during the inspection, within established timeframes.
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6. Reporting
If ORA observes critical conditions (e.g., conditions that may result in an imminent health
hazard), as appropriate and if feasible, they may be discussed between ORA and OMQ before
the inspection closes. The ORA Director of the Investigations Branch or designee, the
investigator(s), and OMQ collaboratively decide whether to continue the inspection to gather
additional information or to close the inspection to initiate prompt regulatory action.
The investigator will use IOM subchapter 5.11—Reporting for guidance in reporting of
inspectional findings. Identify systems covered in the summary of findings. Identify and explain
in the body of the report the rationale for inspecting the profile classes covered. Report and
discuss in full any adverse findings by systems under separate captions. Add additional
information as needed or desired, for example, a description of any significant changes that have
occurred since previous inspections. Each report should include a description of operations,
products, and controls covered during the inspection in sufficient detail to enable appropriate
regulatory decision-making following the inspection and to inform future inspections.
FDA’s pharmaceutical CGMP inspection program and resulting inspection reports are of interest
to counterpart inspectorates and regulators worldwide who use and rely on FDA inspections and
inspection reports, as does FDA of their inspections and reports.
Reports with specific, specialized information required should be prepared as instructed within
the individual assignment/attachment.
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PART IV—ANALYTICAL
1. Analyzing Laboratories
The types of analyses that may be performed under this compliance program include (but are not
limited to):
• Routine analyses: Assay, impurities, dissolution, identification
• Routine microbiological analyses: Sterility, endotoxin, nonsterile examination
• Other microbiological examinations
• Chemical cross contamination
• Antibiotics
• Bioassays
• Particulate matter in injectables
Email ORS/OMPTSLO at [email protected] for servicing
laboratories for chemical and microbiological testing. When contacting ORS for servicing
laboratories, provide a product description, lots to be tested, analyses to be performed, and a
reason for the sample collection. Servicing laboratories will be identified based on lab
specialization, technology and testing expertise, and laboratory capacity.
Note: The Laboratory Servicing Table (LST) Dashboard is not sufficiently detailed to accurately
identify laboratories and should not be used for selecting servicing laboratories under this
compliance program.
2. Analysis
1. Samples are to be examined for compliance with applicable specifications as they relate
to deficiencies noted during the inspection. All analyses will be performed by the official
regulatory methods or, when no official method exists, by other validated procedures
identified by ORS/OMPTSLO.
2. The presence of cross-contamination should be confirmed by a mass spectroscopic
method.
3. Ensure the analysis for the dissolution rate is performed by a second dissolution-testing
laboratory.
4. Microbiological examinations should be based on appropriate sections of USP and ORA’s
Pharmaceutical Microbiological Manual. 23
23
See https://www.fda.gov/downloads/scienceresearch/fieldscience/ucm397228.pdf.
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PART V—REGULATORY/ADMINISTRATIVE STRATEGY
Inspection findings that demonstrate that an establishment is not operating in a state of control
may be used as evidence for taking appropriate advisory, administrative, or judicial actions.
The initial classification should be based on the ORA division’s assessment of the seriousness of
the CGMP problem.
The endorsement of the inspection report should point out the actions by the establishment that
have been taken or will be taken and when. All deficiencies noted in inspections/audits under this
compliance program must be addressed by stating the establishment’s corrective actions,
accomplished or projected, for each as established in the discussion with management at the
close of the inspection.
All corrective actions proposed by establishments are monitored and managed collaboratively by
the ORA division and OMQ. These approaches may range from shutdown of operations, recall
of products, conducting of testing programs, development of new procedures, or modifications of
plants and equipment to simple and immediate corrections of conditions. CDER OPQ suboffices
(Office of Pharmaceutical Manufacturing Assessment (OPMA) and/or OQS) will also assist
ORA divisions as requested.
If an inspection report documents that one or more of the establishment’s systems are out of
control, the inspection should receive an initial OAI classification. Issuing a warning letter or
taking other regulatory or advisory actions pursuant to a CGMP inspection should result in the
classification of all profile classes as unacceptable. Also, the inspection findings will be used as
the basis for updating profile classes in eNSpect.
If there are significant concerns about the quality system, and particularly about the change
management system, from an inspection that is classified as OAI at an establishment where ECs
have been approved, CDER offices will collaborate to evaluate the significant findings and the
firm’s response for the potential impact on approved ECs. If approved ECs are impacted, CDER
will notify the applicant that the reporting categories previously approved in the application for
that facility will revert to reporting categories consistent with the risk-based paradigm in the
regulations and as recommended in guidance.
Requests and review of records, documents, and other information from RRA activities may
reveal potentially violative practices. In such cases, OMQ’s evaluation of a pOAI
recommendation will use approaches aligned with those discussed in this section during review
of the case.
FDA laboratory tests that demonstrate effects of absent or inadequate CGMP are strong evidence
for supporting regulatory actions. Such evidence development should be considered as an
inspection progresses and deficiencies are found. However, the lack of violative physical
samples is not a barrier to pursuing regulatory or administrative action provided that CGMP
deficiencies have been well documented. Likewise, physical samples found to be in compliance
are not a barrier to pursuing action under CGMP charges.
Evidence to support significant deficiencies or a trend of deficiencies within a system covered
could demonstrate system failure and should result in an OAI referral to OMQ. When deciding
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the type of action to recommend, the initial decision should be based on the seriousness or
frequency of the problems. Examples of such problems include the following:
1. Quality System
• Pattern of failure to implement an adequate quality system
• Pattern of failure to formalize a quality risk management program
• Pattern of failure to review/approve/follow procedures
• Pattern of failure to document execution of operations as required
• Pattern of failure to review documentation
• Pattern of failure to conduct investigations and resolve discrepancies/failures/
deviations/complaints
• Pattern of failure to establish/follow an effective change management system for
implementing changes across all systems/operations
• Pattern of failure to establish and maintain a state of control and facilitate needed
improvements throughout a product’s lifecycle.
• Pattern of failure to assess other systems to ensure compliance with CGMP requirements
and internal SOPs
2. Facilities and Equipment
• Contamination with filth, objectionable microorganisms, toxic chemicals, or other drug
chemicals, or a reasonable potential for contamination, with demonstrated avenues of
contamination, such as airborne or through unclean equipment
• Pattern of failure to validate cleaning procedures for nondedicated equipment; lack of
demonstration of effectiveness of cleaning for dedicated equipment
• Pattern of failure to document investigation of discrepancies
• Pattern of failure to establish/follow a control system for implementing changes in the
equipment
• Pattern of failure to qualify equipment, including computers
3. Materials System
• Release of materials for use or distribution that do not conform to established
specifications
• Pattern of failure to conduct one specific identity test for components
• Pattern of failure to document investigation of discrepancies
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• Pattern of failure to establish/follow a control system for implementing changes in
materials handling operations
• Lack of validation of water systems as required depending on the intended use of the
water
• Lack of validation of computerized processes
4. Production System
• Pattern of failure to establish/follow a control system for implementing changes in
production system operations
• Pattern of failure to document investigation of discrepancies
• Lack of process validation
• Lack of validation of computerized processes
• Pattern of incomplete or missing batch production records
• Pattern of nonconformance to established in-process controls, tests, or specifications
5. Packaging and Labeling
• Pattern of failure to establish/follow a control system for implementing changes in
packaging or labeling operations
• Pattern of failure to document investigation of discrepancies
• Lack of validation of computerized processes
• Lack of control of packaging and labeling operations that may introduce a potential for
mislabeling
• Lack of packaging validation
6. Laboratory System
• Pattern of failure to establish/follow a control system for implementing changes in
laboratory operations
• Pattern of failure to document investigation of discrepancies
• Lack of validation of computerized or automated processes
• Pattern of inadequate sampling practices
• Lack of validated analytical methods
• Pattern of failure to follow approved analytical procedures
• Pattern of failure to follow an adequate OOS procedure
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• Pattern of failure to retain raw data
• Lack of stability-indicating methods
• Pattern of failure to follow stability programs
Follow up to a warning letter or other significant regulatory action as a result of an abbreviated
inspection should warrant full inspection coverage as defined in this compliance program.
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PART VI—REFERENCES, ATTACHMENTS, PROGRAM CONTACTS, AND
ACRONYMS
1. References
• Code of Federal Regulations
o 21 CFR parts 4, 210, and 211, as revised
o Preamble to 21 CFR parts 210 and 211, General Comments (1978)
o 21 CFR part 11, Electronic Records: Electronic Signatures
• Compliance Programs 24
o 7346.832—Preapproval Inspections
o 7356.000—Inspections of CDER-Led or CDRH-Led Combination Products
o 7356.002A—Sterile Drug Process Inspections
o 7356.002E—Compressed Medical Gases
o 7356.002F—Active Pharmaceutical Ingredient (API) Process Inspection
o 7356.002M—Surveillance Inspections of Protein Drug Substance Manufacturers
o 7356.002P—PET CGMP Drug Process and Pre-Approval Inspections/Investigations
o 7356.021—Drug Quality Reporting System (DQRS) (MedWatch Reports); NDA Field
Alert Reports (FARs)
o 7356.843—Postapproval Inspections
• FD&C Act, as amended
• FDA Guidance for Industry 25
o Chemistry, Manufacturing, and Controls Changes to an Approved Application:
Certain Biological Products (June 2021)
o CMC Postapproval Manufacturing Changes for Specified Biological Products To Be
Documented in Annual Reports (December 2021)
o Changes to an Approved Application for Specified Biotechnology and Specified
Synthetic Biological Products (July 1997)
o Circumstances that Constitute Delaying, Denying, Limiting, or Refusing a Drug
Inspection (October 2014)
24
See https://www.fda.gov/drugs/guidance-compliance-regulatory-information/drug-compliance-programs.
25
See https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm. CDER
guidance documents related to pharmaceutical quality are generally found under the following topics:
pharmaceutical quality; chemistry, manufacturing, and controls; current good manufacturing practice; and
microbiology.
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PROGRAM 7356.002
o Control of Nitrosamine Impurities in Human Drugs, Rev. 1 (February 2021)
o Current Good Manufacturing Practice Requirements for Combination Products
(January 2017)
o Quality Systems Approach to Pharmaceutical CGMP Regulations (September 2006)
o Remote Interactive Evaluations of Drug Manufacturing and Bioresearch Monitoring
Facilities During the COVID-19 Public Health Emergency (April 2021)
*Also see FDA’s Scale-Up and Postapproval Changes (SUPAC) guidances for industry
o ICH Guidance for Industry
Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical
Ingredients (September 2016)
Q8(R2) Pharmaceutical Development (November 2009)
Q9 Quality Risk Management (June 2006)
Q10 Pharmaceutical Quality System (April 2009)
Q12 Technical and Regulatory Considerations for Pharmaceutical Product
Lifecycle Management and its Annexes (May 2021)
o Draft Guidance for Industry 26
Conducting Remote Regulatory Assessments: Questions and Answers (July 2022)
ICH Q12: Implementation Considerations for FDA-Regulated Products (May
2021)
Postapproval Changes to Drug Substances (September 2018)
• Inspection Guides 27
o Computerized Systems in Drug Establishments
o Dosage Form Drug Manufacturers CGMPs
o Pharmaceutical Quality Control Labs
o High Purity Water Systems
o Validation of Cleaning Processes
• Integration of FDA Facility Evaluation and Inspection Program for Human Drugs: A
Concept Of Operations,
https://www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofGlobalRegulatoryOpe
rationsandPolicy/ORA/UCM574362.pdf
26
When final, these guidances will represent FDA’s current thinking on these topics.
27
See https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/inspection-
references/inspection-guides.
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PROGRAM 7356.002
• Investigations Operations Manual, https://www.fda.gov/inspections-compliance-
enforcement-and-criminal-investigations/inspection-references/investigations-operations-
manual
• Manual of Compliance Policy Guides, Chapter 4—Human Drugs,
https://www.fda.gov/inspections-compliance-enforcement-and-criminal-
investigations/manual-compliance-policy-guides/chapter-4-human-drugs
• Pharmaceutical Inspection Co-operation Scheme (PIC/S) recommendation PI 054-1 How
To Evaluate and Demonstrate the Effectiveness of a Pharmaceutical Quality System in
Relation to Risk-Based Change Management, https://picscheme.org/docview/4294
• Pharmaceutical Microbiological Manual, ORA.007,
https://www.fda.gov/downloads/scienceresearch/fieldscience/ucm397228.pdf
• Quality Management Maturity: Essential for Stable U.S. Supply Chains of Quality
Pharmaceuticals, https://www.fda.gov/media/157432/download
• Regulatory Procedures Manual, https://www.fda.gov/inspections-compliance-
enforcement-and-criminal-investigations/compliance-manuals/regulatory-procedures-
manual
2. Attachments
Attachment A: Remote Regulatory Assessments
Attachment B: Indicators of an Advanced Quality System
3. Contacts
A. Office of Regulatory Affairs
For technical questions concerning inspections, contact:
Office of Medical Products and Tobacco Operations (OMPTO)
Division of Medical Products and Tobacco Program Operations (DMPTPO)
301-796-0358
[email protected]
Office of Regulatory Science/Office of Medical Products, Tobacco, and Specialty Laboratory
Operations (OMPTSLO)
[email protected]
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B. Center for Drug Evaluation and Research
CGMP or Quality-Related Policy Questions
For CGMP or quality-related policy questions, technical or scientific questions, or information
needs, including questions about this compliance program, please send an email to the following
address and it will be handled as a top priority:
[email protected]
Postapproval Change Management Questions
For postapproval change management questions related to the impact and reporting of a change
on an approved product, whether it should have been reported, or whether it was submitted
appropriately (e.g., supplement vs. annual report), please send an email to the following address
and it will be triaged to the appropriate CDER assessor:
[email protected]
cc: [email protected] (biological products)
Enforcement-Related Guidance or Policy
For enforcement-related guidance or policy, including evidence need and sufficiency, citations,
and case evaluation/recommendation advice, please send an email to the following address and it
will be handled as a top priority:
[email protected]
Labeling Requirements and Policies
Office of Unapproved Drugs and Labeling Compliance, see FDA’s SharePoint site for contacts
[FDA Organizations | CDER | CDER Offices | Office of Compliance | Office of Unapproved
Drugs and Labeling Compliance]
Registration and Drug Listing Requirements
CDER Office of Compliance, see FDA’s SharePoint site for contacts [FDA Organizations |
CDER | Office of Communications | “CDER: Who’s the Lead” link (on resulting page, scroll
down to the Drug Registration and Listing entry under Office of Compliance)]
Acronyms
API: active pharmaceutical CMS: Compliance Management
ingredient System
BPDR: biological product defect report DQRS: Drug Quality Reporting System
CAPA: corrective action and EC: established condition
preventive action
EIR: establishment inspection report
CDER: Center for Drug Evaluation and FAR: field alert report
Research
FD&C Act: Federal Food, Drug, and
CGMP: current good manufacturing Cosmetic Act
practice
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PROGRAM 7356.002
FDASIA: Food and Drug Administration OPQ: Office of Pharmaceutical
Safety and Innovation Act Quality
FMD: Field Management Directive OQS: Office of Quality Surveillance
ICH: International Council for ORA: Office of Regulatory Affairs
Harmonisation ORS: Office of Regulatory Science
IOM: Investigations Operations PAC: product/assignment code
Manual
PAM: preapproval program manager
MRA: mutual recognition agreement
PET: positron emission tomography
NAI: No Action Indicated
PLCM: product lifecycle management
NDA: new drug application
pOAI: potential Official Action
OAI: Official Action Indicated Indicated
OC: Office of Compliance PQS: pharmaceutical quality system
OMPTSLO: Office of Medical Products, RRA: remote regulatory assessments
Tobacco, and Specialty
Laboratory Operations RIE: remote interactive evaluation
OMQ: Office of Manufacturing SOP: standard operating procedure
Quality USP: United States Pharmacopeia
OOS: out-of-specification VAI: Voluntary Action Indicated
OPMA: Office of Pharmaceutical
Manufacturing Assessment
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PROGRAM 7356.002
PART VII—CDER AND ORA RESPONSIBILITIES OVERVIEW
CDER and ORA redefined their roles and responsibilities with regard to application review and
inspections of human drugs facilities under the concept of operations Integration of FDA Facility
Evaluation and Inspection Program for Human Drugs: A Concept Of Operations (ConOps). 28
This ConOps operating model applies to preapproval, postapproval, surveillance, and for-cause
inspections. The roles and responsibilities for surveillance and for-cause inspections subject to
this compliance program are summarized below.
1. Surveillance Inspection Responsibilities
OQS uses a risk-based site selection model to identify establishments for inspection and prepares
an up-to-date site dossier for each of the identified establishments in advance of a scheduled
surveillance inspection. ORA schedules surveillance inspections for individual sites. ORA leads
surveillance establishment inspections with CDER participation, when requested by ORA. ORA
then conducts an on-site inspection based on this compliance program and compliance program
7356.002M, as appropriate, and quality information summarized in the site dossier.
If the initial classification is OAI, the responsible ORA division provides a written classification
analysis, including the electronic documents, to OMQ within 45 calendar days of closing the
inspection. OMQ makes a final classification with input from the Office of the Chief Counsel, if
needed, and issues a decisional letter in the following 45 calendar days (90 calendar days
following the inspection closing). If an inspection is classified as final OAI, OMQ, solely or in
collaboration with ORA, takes an appropriate action within 90 calendar days of the decisional
letter. If OMQ determines that an advisory or enforcement action is not warranted, ORA is
notified of the change in classification. OMQ will then issue an FMD 145 decisional letter no
later than 90 calendar days following the inspection closing.
If the establishment inspection results in an ORA recommendation for a No Action Indicated
(NAI) or Voluntary Action Indicated (VAI) classification and no further action is recommended,
ORA issues an FMD 145 decisional letter within 90 calendar days following the inspection
closing.
2. For-Cause Inspection Responsibilities
Requests for for-cause inspections can be initiated by ORA, OPMA, OQS, or OC. Once the
initiating office determines a for-cause inspection is warranted, the office prepares an assignment
that sets forth the areas of required coverage, which may or may not include surveillance
program coverage. If required, ORA approves the assignment per ORA internal procedures and
schedules the inspection. ORA leads the inspection, and CDER participates when appropriate.
28
See
https://www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofGlobalRegulatoryOperationsandPolicy/ORA/UC
M574362.pdf.
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ORA or CDER will not issue an FMD 145 decisional letter without the concurrence of the
initiating office. For-cause inspections that result in surveillance program coverage and are
initially classified OAI will receive final classification from OMQ 90 days after the close of the
inspection; OMQ involves other offices (e.g., ORA, OPMA, OQS) as appropriate, based on the
inspection findings. In addition, the office that initiates the for-cause inspection assignment
completes the final assessment 90 days after the close of the inspection, involving other offices
(e.g., ORA, OPMA, OQS, OC) as appropriate. Any follow-up actions are completed by CDER
within 6 months after the inspection.
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ATTACHMENT A: REMOTE REGULATORY ASSESSMENTS
In addition to its inspectional authority, FDA may conduct remote regulatory assessments
(RRAs), under certain circumstances, to support oversight of FDA-regulated products and
establishments. 1 An RRA is an examination of an FDA-regulated establishment and/or its
records, conducted entirely remotely, to evaluate compliance with applicable FDA requirements.
RRAs assist in protecting human health, informing regulatory decisions, and verifying certain
information submitted to the Agency.
RRAs used in lieu of or in advance of inspections have allowed FDA to remotely evaluate drug
manufacturing establishments to mitigate risks. However, RRAs are not the same as an
inspection as described in section 704(a)(1) of the Federal Food, Drug, and Cosmetic Act
(FD&C Act), and FDA does not consider them to satisfy the statutory requirement for an
inspection under section 510(h) of the FD&C Act.
The following RRAs, along with applicable FDA policies, may be used to help meet the
objectives of this compliance program to determine whether the establishment meets CGMP
requirements.
1. FDA Records and Other Information Requests Under Section 704(a)(4) of the FD&C
Act (Statutorily Authorized RRA)
In 2012, with the passage of the Food and Drug Administration Safety and Innovation Act to
amend the FD&C Act, Congress gave FDA the authority to request “any records or other
information” in advance of or in lieu of an inspection related to human or animal drugs,
including human biological drug products. Section 704(a)(4) of the FD&C Act requires “a
person that owns or operates an establishment that is engaged in the manufacture, preparation,
propagation, compounding, or processing of a drug” to provide FDA, upon request, records or
other information that FDA may inspect under section 704(a)(1).
With regards to this compliance program, the use of this authority helps strengthen FDA’s
surveillance program and improve the overall effectiveness of the drug inspection program. The
records received from an establishment can be used to help assess an establishment’s compliance
with current good manufacturing practice, support regulatory decisions, inform inspection
planning (e.g., a risk-based inspection schedule), and prepare for a scheduled inspection (e.g.,
inspection coverage). The use of 704(a)(4) authority does not prevent an FDA investigator from
requesting records or other information on inspection. During an inspection, FDA may collect
copies of previously received documents and other documents not previously requested.
1
See the draft guidance for industry Conducting Remote Regulatory Assessments: Questions and Answers (July
2022). When final, this guidance will represent FDA’s current thinking on this topic. Also see FDA’s An Update to
the Resiliency Roadmap for FDA Inspectional Oversight and section 704 of the Federal Food, Drug, and Cosmetic
Act.
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2. Remote Interactive Evaluation (Voluntary RRA)
A remote interactive evaluation (RIE) is an evaluation of a firm’s compliance with regulations
that a firm participates in voluntarily. 2 RIEs are defined as FDA’s use of any combination of
remote interactive tools (e.g., remote livestreaming video of operations, teleconferences, screen
sharing) to evaluate establishments where drugs are manufactured, processed, packaged, or held.
FDA may request to conduct an RIE whenever a program office determines it is appropriate
based on mission needs.
With regards to this compliance program, the use of RIEs helps strengthen FDA’s surveillance
program and improve the overall effectiveness of the drug inspection program. Information
evaluated from an RIE may be used to help assess an establishment’s compliance with current
good manufacturing practice, support regulatory decisions, inform inspection planning (e.g., a
risk-based inspection schedule), and prepare for a scheduled inspection (e.g., inspection
coverage).
2
See the guidance for industry Remote Interactive Evaluations of Drug Manufacturing and Bioresearch Monitoring
Facilities During the COVID-19 Public Health Emergency.
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ATTACHMENT B: EXAMPLES OF INDICATORS OF AN ADVANCED QUALITY
SYSTEM
Manufacturers can demonstrate practices that are indicative of mature quality practices that, if
effectively implemented, provide the foundation for exceeding current good manufacturing
practice (CGMP) requirements. Examples may include a steadfast focus on implementing
continual improvements, using the latest innovations to enhance control, 1 and creating a culture
of quality where leadership demonstrates a commitment to quality and promotes employee
engagement and empowerment. For manufacturers with a more advanced quality system, FDA
may exercise a more flexible regulatory approach, leading toward the goal of producing high-
quality drug products without extensive regulatory oversight. 2
During an inspection, investigators may assess quality management practices to gain insight into
an establishment’s processes and continual system improvements. The areas below are examples
of indicators of an advanced quality system, some of which may be evaluated during an
inspection.
• Management Responsibility
o Communication and reward system for employees to bring quality issues to the
attention of management
o Monitoring of external regulatory and business environments to identify unexpected
risks to quality
o Increased levels of personnel understanding, ownership, and engagement that create
company-wide quality commitment
o All personnel trained on the impact of poor quality on the patient
• Investigations
o Effective use of standardized tools (e.g., FMEA, DOE, 5 Whys, fishbone diagram) 3 to
determine a potential root cause
• Corrective Actions and Preventive Actions
o Routine production and laboratory “shop floor” meetings (e.g., weekly) to collect
employee feedback, reduce operational risks, and ensure initiation of corrective
actions and preventive actions
1
The term innovation is defined as the introduction of new technologies or methodologies. See ICH Q10.
2
See the International Council for Harmonisation guidances for industry Q10 Pharmaceutical Quality System and
Q12 Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management and the Office of
Pharmaceutical Quality’s white paper Quality Management Maturity: Essential for Stable U.S. Supply Chains of
Quality Pharmaceuticals.
3
FMEA=failure mode and effects analysis; DOE=design of experiments.
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• Supply Chain and Contracted Service Management
o Consistently meeting planned time frames for product delivery to the customer or
internal stock because of high manufacturing robustness (i.e., avoiding delays caused
by manufacturing quality problems)
o Active solicitation and analysis of customer feedback (beyond solely complaints)
related to quality and delivery
• Training Program
o Extensive staff training on Six Sigma and/or other advanced quality assurance tools to
improve process capability
• Quality Oversight
o Electronic systems that use analytics to optimize implementation of knowledge
management related to products, processes, and components
o Continual improvement program to optimize quality indicator metrics
• Process Parameters, Product Quality Monitoring, and Annual Product Review
o Programs to improve manufacturing processes by adopting the latest beneficial
innovations and technologies
o Use of visuals throughout the establishment to indicate quality performance status
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来源：FDA Pharmaceutical Quality Documents · fda.gov