FDA 发布 7356.000 合规计划，规定 CDER 或 CDRH 主导组合产品的检查安排
Inspections of CDER-Led or CDRH-Led Combination Products (7356.000)
FDA 发布合规计划 7356.000，用于 CDER 或 CDRH 主导的单体式和共同包装组合产品生产场地的检查，文件签发与实施日期为 2020 年 6 月 4 日。该计划适用于上市前、上市后、监督、有因及其他基于风险的检查，重点说明基础 CGMP 加 21 CFR Part 4 指定条款的覆盖方式与报告要求。CBER 主导的组合产品不适用本计划，应参考 CBER 相应合规计划。
文件列出组合产品检查中基础 CGMP 与 21 CFR Part 4 指定条款的覆盖安排，可供核对检查类型与报告路径。
PDF 文字版；图形和原始排版请参阅官方 PDF。
第 1 页
FOOD AND DRUG ADMINISTRATION
COMPLIANCE PROGRAM PROGRAM 7356.000
SUBJECT: IMPLEMENTATION DATE:
Inspections of CDER-led or CDRH-led Combination Products June 4, 2020
DATA REPORTING
PRODUCT CODES PRODUCT/ASSIGNMENT CODES
Use Appropriate Product Code Use Product/Assignment Code(s) for the Base
Compliance Program (see PART III.1.A)
FIELD REPORTING REQUIREMENTS:
EIRs (Establishment Inspection Report) and FDA-483: A single EIR and, when applicable,
FDA-483 should be used to document all observations made during an inspection at a
combination product manufacturer1 (See PART III.2– Reporting). Follow the Office of
Regulatory Affairs (ORA) policies associated with the lead center, for example, regarding
whether to annotate the 483 and practices for inspections (see also Reference 12, Chapter 5).
Reporting Requirements: Document the inspection in accordance with the field reporting
requirements of the base compliance program for the combination product and with specific
expectations identified in this Compliance Program:
1. For pre-approval inspections of CDER-led combination products approved under an
Abbreviated New Drug Application (ANDA) or a New Drug Application (NDA),
document in accordance with the field reporting requirements of Compliance Program
7346.832. For pre-licensing inspections of CDER-led combination products approved
under a Biologics License Application (BLA), document in accordance with the field
reporting requirements of Compliance Program 7356.002M.
2. For pre-approval inspections of CDRH-led combination products (Premarket Approval
(PMA)), document in accordance with the field reporting requirements of Compliance
Program 7383.001.
3. For surveillance inspections of CDER-led NDA/ANDA combination products, document
in accordance with the field reporting requirements of Compliance Program 7356.002.
For surveillance inspections of CDER-led BLA combination products, document in
accordance with the field reporting requirements of Compliance Program 7356.002M.
4. For surveillance inspections of CDRH-led combination products, document in
accordance with the field reporting requirements of Compliance Program 7382.845.
5. See PART III.2 – Reporting, for additional, specific reporting expectations.
Coordination with the Lead Center: If a compliance action is contemplated following a
combination product inspection, ORA should coordinate with the lead center before such an
action is taken. The lead center should be contacted regardless of which Current Good
Manufacturing Practice (CGMP) regulations are cited (e.g., for a CDRH-led product, inspections
resulting solely in drug-CGMP (21 CFR Part 211) and, if applicable, 21 CFR Part 600
observations, the compliance action should still be coordinated through CDRH).
1
See Attachment C for discussion of “lead center” and other italicized terms used throughout this compliance
program.
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PROGRAM 7356.000
Investigators are encouraged to request pre-inspectional meetings through the lead center to
support alignment regarding instructions or approach. Communication between the lead center
and ORA should be conducted consistent with existing processes for ORA and that center.
Use of Profile Codes for CDER-led Combination Products: Inspections of CDER-led
combination product manufacturers as described in this program should include at least one drug
profile code and one device profile code (e.g., for an inspection of a facility manufacturing a
sterile-filled prefilled syringe, use profile codes SVS-Sterile-filled small volume parenteral drugs
and IDD-injectable delivery device (syringes, auto injectors/pens)). See also Reference 12,
Exhibit 5-14.
NOTE: CBER-led combination products are not covered by this Compliance Program. For
CBER-led combination products, refer to the CBER Compliance Programs, found at
https://www.fda.gov/vaccines-blood-biologics/enforcement-actions-cber/compliance-programs-
cber
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PROGRAM 7356.000
Contents
PART I – BACKGROUND ............................................................................................................ 4
Combination Products .......................................................................................................... 4
Combination Product CGMPs ............................................................................................. 5
PART II - IMPLEMENTATION.................................................................................................... 6
Scope .................................................................................................................................... 6
Objective .............................................................................................................................. 7
A. Approach ...................................................................................................................... 7
B. Inspectional Planning ................................................................................................... 7
C. Personnel ...................................................................................................................... 9
Program Management Instructions. ..................................................................................... 9
PART III - INSPECTIONAL ......................................................................................................... 9
Operations ............................................................................................................................ 9
A. Inspections .................................................................................................................... 9
Reporting............................................................................................................................ 19
PART IV – ANALYTICAL ......................................................................................................... 20
PART V - REGULATORY/ADMINISTRATIVE STRATEGY ................................................. 21
Pre-approval Inspections for Combination Products ......................................................... 21
Surveillance Inspections and Risk-Based Inspections for Combination Products ............ 22
Inspections for Pre-approval in Conjunction with Another Type of Inspection ................ 22
Significant Findings from the Called-out Provisions of 21 CFR Part 4 ............................ 22
PART VI REFERENCES, ATTACHMENTS, AND PROGRAM CONTACTS ........................ 24
References .......................................................................................................................... 24
Attachments ....................................................................................................................... 24
Program Contacts ............................................................................................................... 24
PART VII - CENTER RESPONSIBILITIES ............................................................................... 25
ATTACHMENT A – Combination Product Inspectional Considerations for Called-out
Provisions of 21 CFR Part 211 ..................................................................................................... 26
ATTACHMENT B – Combination product inspectional considerations for Called-out provisions
of 21 CFR Part 820 ....................................................................................................................... 38
ATTACHMENT C – Definitions and Acronyms ......................................................................... 45
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PROGRAM 7356.000
PART I – BACKGROUND
In January 2013, FDA published a Final Rule on Current Good Manufacturing Practice (CGMP)2
requirements for combination products (21 CFR Part 4, Subpart A). Before issuance of the final
rule, CGMP regulations were in place to establish requirements for drugs, devices, biological
products, and Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps).
However, there were no regulations to clarify and explain the application of these CGMP
requirements to combination products. The final rule was followed by an accompanying final
guidance document Current Good Manufacturing Practice Requirements for Combination
Products (Reference 9).
Combination Products
Definition of a Combination Product. A combination product is a product comprised of two or
more different types of medical products (i.e., drug and device, drug and biological product,
device and biological product, or all three together) (see 21 CFR 3.2(e)). A constituent part of a
combination product is a drug, device, or biological product that is part of a combination
product. This Compliance Program focuses on two types of combination products:3
• Single-entity combination product: The constituent parts are physically or chemically
combined (e.g., a prefilled syringe or drug-eluting stent). See 21 CFR 3.2(e)(1).
• Co-packaged combination product: The constituent parts are packaged together (e.g., a
surgical or first-aid kit containing devices and drugs, a delivery device packaged with a
container of drug product). See 21 CFR 3.2(e)(2).
Examples of combination products include (see also list of examples):
• Prefilled syringes, transdermal systems, autoinjectors containing or packaged with drugs
or biologics
• Drug-eluting stents
• Implants coated/impregnated with an antimicrobial drug
• Filled intravenous (IV) bags
• Antibody-drug conjugates
A combination product is assigned to an Agency center that will have primary jurisdiction (i.e.,
the lead center) for that combination product’s review and regulation. Assignment of a
combination product to a lead center is based on which constituent part provides the primary
mode of action of the combination product (21 U.S.C. 351(g)). Generally, the application type, if
any, for a combination product is aligned with the lead center (e.g., CDRH-led products would
be approved or cleared under PMAs/510(k)/De Novo, whereas CDER-led combination products
would be approved under ANDA/NDA/BLA). Generally, when needed, the lead center serves as
the primary point of contact for the field related to an inspection of a combination product
2
See 78 FR 4307.
3
There is a third type of combination product, cross-labeled, where the constituent parts are distributed separately
(e.g., as might be the case for a light-activated drug product and a separately distributed laser, drug-activating
device) (21 CFR 3.2(e)(3), (4)). Manufacturers of constituent parts of cross-labeled combination products need only
comply with the requirements otherwise applicable to that type of product (e.g., 21 CFR Parts 210 and 211 for a
drug constituent part or 21 CFR Part 820 for a device constituent part). See also footnote 8 regarding expectations
when constituent parts of a cross-labeled combination product are manufactured at the same facility.
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PROGRAM 7356.000
manufacturer. The lead center will engage other FDA organizational components, as appropriate
(see also Part VII – CENTER RESPONSIBILITIES).
Combination Product CGMPs
For single-entity combination products and co-packaged combination products, 21 CFR Part 4,
Subpart A identifies two ways to demonstrate compliance with CGMP requirements for the
combination product:
1. Compliance with all Applicable CGMPs. Demonstrate compliance with all CGMP
regulations applicable to each of the constituent parts included in the combination
product,
OR
2. Streamlined Approach. Implement a streamlined approach for combination products that
include both a drug and a device or a biological product and a device by demonstrating
compliance with (i) either the drug CGMPs (21 CFR Parts 210 and 211) or the device
Quality System (QS) regulation (21 CFR Part 820) (base CGMPs) and (ii) also with
specified provisions (called-out provisions) from the other of these two sets of CGMP
requirements. See below regarding additional requirements that apply to combination
products that include a biological product constituent part.
Specifically, the streamlined approach allows combination product manufacturers to
meet the requirements of both the drug CGMPs and device QS regulation by designing
and implementing a CGMP operating system that demonstrates compliance with either of
the following:
• The drug CGMPs and the following called-out provisions from the device QS
regulation in accordance with 21 CFR 4.4(b)(1) (drug CGMP-based streamlined
approach):
o 21 CFR 820.20 - Management responsibility
o 21 CFR 820.30 - Design controls (if applicable)
o 21 CFR 820.50 - Purchasing controls
o 21 CFR 820.100 - Corrective and preventive action
o 21 CFR 820.170 - Installation (if applicable)
o 21 CFR 820.200 - Servicing (if applicable)
OR
• The device QS regulation and the following called-out provisions from the drug
CGMPs in accordance with 21 CFR 4.4(b)(2) (device QS regulation-based
streamlined approach):
o 21 CFR 211.84 - Testing and approval or rejection of components, drug
product containers, and closures
o 21 CFR 211.103 - Calculation of yield
o 21 CFR 211.132 - Tamper-evident packaging requirements for over-the-
counter (OTC) human drug products
o 21 CFR 211.137 - Expiration dating
o 21 CFR 211.165 - Testing and release for distribution
o 21 CFR 211.166 - Stability testing
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PROGRAM 7356.000
o 21 CFR 211.167 - Special testing requirements
o 21 CFR 211.170 - Reserve samples
Regardless of whether a streamlined approach is used, in addition, for a combination product that
includes a biological product, the manufacturer must demonstrate compliance with all applicable
CGMP requirements for biological products (including standards) that are found within 21 CFR
Parts 600 through 680 (21 CFR 4.3(c)). For a combination product that includes any HCT/P, the
manufacturer must demonstrate compliance with all applicable regulations in 21 CFR Part 1271.
PART II - IMPLEMENTATION
Scope
This compliance program focuses on inspections of combination product manufacturers (see
definition in Attachment C) of CDER or CDRH-led4 single-entity and co-packaged finished
combination products that include both drug and device or biological product and device
constituent parts, with limited reference to inspectional considerations for combination products
that include a biological product or a human cell, tissue, or cellular or tissue-based product
(HCT/P) constituent part. This compliance program should be used for pre-approval, post-
approval, surveillance, for cause, and other risk-based inspections.5 This compliance program
does not cover inspection of combination products for which CBER is the lead center.6
This combination product compliance program should NOT be used for:
1. Facilities that manufacture7 only one type of constituent part of a combination product
(e.g., only the drug, device, or biological product). Such facilities should be inspected
according to the existing commodity-specific compliance program for that product (see
Attachment C and also footnote 3 regarding cross-labeled combination products). For
example, if a facility manufactures only a drug constituent part that is then sent to a
separate facility to be filled into a syringe, the facility manufacturing the drug constituent
part to ship to the filling facility would be inspected according to the appropriate drug
compliance program; whereas this combination product compliance program would be
used to inspect the facility that fills the syringe with the drug constituent part to produce
the single-entity combination product.8
4
The use of the term “CDRH-led” or “CDER-led” refers to which center is the lead center for the combination
product.
5
Third-party audit, appraisal or inspection programs (e.g., the Medical Device Single Audit Program (MDSAP))
may impact implementation of this compliance program. Contact the lead center if you have questions.
6
For CBER-regulated products, refer to the CBER Compliance Programs, found at https://www.fda.gov/vaccines-
blood-biologics/enforcement-actions-cber/compliance-programs-cber. CBER will consult with the other center(s), as
appropriate, to evaluate inspectional observations for combination products. See SMG 4101 Inter-Center Consult
Request Process.
7
Note that “manufacturing” includes activities related to the design of the combination product (21 CFR 4.2). Any
facility participating in design control, including recordkeeping, for the combination product is a combination
product manufacturer. See Section III.C of Reference 9 and Attachment C of this Compliance Program.
8
As discussed in the combination product CGMP guidance (Reference 9), for cross-labeled combination products
manufactured at the same facility, the Agency does not intend to object to the use of a streamlined CGMP operating
system for the manufacture of the combination product rather than distinct systems for the manufacture of each
constituent part that is occurring at that facility. Contact the lead center if such a situation is encountered during an
inspection. See also footnote 3.
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2. Facilities that manufacture only “components9.” 21 CFR Part 4 does not alter the CGMP
regulatory requirements for component manufacturers. Facilities that manufacture only
device components are not subject to the QS regulation (21 CFR 820.1(a)) and, similarly,
manufacturers of active pharmaceutical ingredients, other components (e.g., excipients),
or container/closures10 of a drug product are not subject to 21 CFR Part 211 (though such
manufacturers are subject to statutory CGMP requirements under Section 501 of the
FD&C Act (21 U.S.C. 351). However, a facility that assembles components into a
combination product is subject to combination product CGMPs and is within the scope of
this compliance program.
Objective
The objective of this compliance program is to provide a framework for conducting inspections
of single-entity and co-packaged combination product manufacturing facilities. This compliance
program relies on relevant inspectional processes for CGMPs from the compliance programs
specific to drugs, devices, and biological products, and addresses combination product-specific
considerations.
A. Approach
Generally, the inspectional and administrative practices of the lead center and base compliance
program will be the foundation of a combination product inspection. However, the approach
outlined in this compliance program also relies extensively on other commodity-specific
compliance programs associated with the constituent parts of a combination product (see PART
III – INSPECTIONAL), to guide the conduct of combination product inspections.
Because most combination product manufacturers use a streamlined approach, this compliance
program focuses on inspections of compliance with the base CGMPs plus the called-out
provisions specified in 21 CFR Part 4.
B. Inspectional Planning
For surveillance inspections, the Office of Medical Device and Radiological Health Operations
(OMDRHO), Office of Biological Products Operations (OBPO), and Office of Pharmaceutical
Quality Operations (OPQO), within the Office of Regulatory Affairs (ORA), will compare
workplan assignments for combination products and will utilize a risk-based evaluation of the
product and the complexity of the manufacturing to determine each program’s role.
For pre-approval inspections other than for BLAs, the ORA program aligned with the lead center
will be the lead on the inspection. For example, for preapproval inspections of CDER-led NDA
9
Under the drug CGMPs, “component” is defined as “any ingredient intended for use in the manufacture of a drug
product, including those that may not appear in such drug product.” (21 CFR 210.3). Under the device QS
regulation, the term “component” is defined as “any raw material, substance, piece, part, software, firmware,
labeling, or assembly which is intended to be included as part of the finished, packaged, and labeled device.” (21
CFR 820.3(c)).
10
If the container/closure is provided as a finished device, the facility that manufactured that device would be
subject to 21 CFR Part 820 requirements.
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products, OPQO will be the lead on the inspection. For pre-licensing inspections for CDER-led
BLAs, CDER will be the lead for the inspection.
Investigators are encouraged to request pre-inspectional meetings through the lead center to align
instructions or approach. These meetings can be requested via the inspectional assignment
contact, where available, or using the contacts in PART VI.3 – Program Contacts.11
If not already available, investigators should request the following information from the lead
center before the inspection and/or, when the inspection is pre-announced, from the firm. The
application holder for a combination product has and maintains overall responsibility for the
combination product CGMPs and should be able to describe how all applicable CGMPs are
being met for the combination product at each facility involved in the manufacturing of the
combination product. If the information below cannot be obtained prior to the inspection, the
information should be addressed early in the inspection.
• CGMP Operating System Approach. Determine the CGMP operating system chosen by
the combination product manufacturer. Most combination product manufacturers choose
to follow a streamlined approach that aligns with the lead center/application type (e.g.,
combination products approved under a PMA usually follow the QS regulation-based
streamlined approach complying with all 21 CFR Part 820 requirements and the
specified called-out provisions from the drug CGMPs). However, regardless of
application type, a combination product manufacturer can choose to follow either of the
streamlined approaches or full compliance.
• Relationship Between Entities. Request information about the facilities involved in the
manufacturing (including design activities, see also footnote 7) for the combination
product and about the scope of CGMP responsibilities of the facility to be inspected.
CGMP activities for a combination product may occur at multiple facilities. For example,
if another site is responsible for design controls for the combination product, (e.g., a
specification developer contracting with the combination product manufacturer with
documented responsibility for design), it may be more efficient or necessary to perform
an additional inspection at that other site. Additional information or clarification about
responsibilities determined during an inspection should be communicated back to the
lead center.
• Availability of Documentation. For pre-announced inspections, confirm that
documentation needed for review during the inspection will be available or accessible at
the site being inspected. Documentation should include materials to enable review of
compliance with called out provisions, including where to find content on considerations
relating to called out provisions within related, broader elements of the facility’s CGMP
operating system (See e.g., Attachment A, discussion of augmenting 21 CFR 820.80
acceptance activities to address 21 CFR 211.84 requirements).
11
If during preparation for an inspection or during an inspection an investigator believes a product may be a
combination product that has not been identified as such, the investigator may contact the Office of Combination
Products ([email protected]) for assistance.
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C. Personnel
Combination product inspections with coverage of both CGMP systems as described in this
compliance program may be conducted with dual-program staffing (e.g., both a drug and a
device investigator) or by an investigator with training and experience in combination product
CGMPs. Regardless of the staffing for a combination product inspection, the inspection will be
conducted consistent with the approach described in this compliance program.
Program Management Instructions.
Inspections for CDER-led and CDRH-led combination products should be conducted as
indicated in this compliance program using content from the commodity-specific compliance
programs (e.g., drug, biological product, and device) as described. This compliance program
describes inspection considerations specific to facilities involved in the manufacturing of
combination products. For example, PART III - INSPECTIONAL describes full and abbreviated
inspection options for combination product manufacturers that are different from the options for
drug-only or device-only facility inspections.
Where appropriate, the lead center will communicate any specific products for coverage or focus
for the inspection via the established mechanisms for communicating such information.
Any interactions between the field and the centers regarding a combination product inspection
should include the lead center. The lead center will engage expertise from other agency
components, including other center(s), as needed, including to support review of inspectional
findings (see Part VII – CENTER RESPONSIBILITIES).
PART III - INSPECTIONAL
Operations
A. Inspections
Combination Product CGMP Coverage During Inspections. As discussed below, coverage of
CGMPs during a combination product inspection depends upon the inspection type, base
CGMPs, scope of manufacturing activities at the facility, inspectional instructions provided by
the lead center, and the application type for the product being inspected. Investigators are
encouraged to request pre-inspectional meetings through the lead center and ORA supervisory
staff to discuss inspectional coverage, center instructions, or the approach described in this
compliance program. Communicate with the lead center via the contact provided in the
inspection request, if available, or using the contacts in PART VI.3 – Program Contacts.
Some facilities participate in a limited part of combination product CGMP activities (e.g., a
facility that manages only the design activities for the combination product, or a facility that only
sterilizes a combination product). Inspectional coverage should be of those CGMP activities
occurring at the facility. If there are questions regarding which facility is responsible for
particular CGMP requirements, contact the lead center for assistance.
Approach for Combination Product CGMP Inspections. The inspectional approach described
below involves (i) conduct of an inspection under the commodity-specific compliance program
relevant to the base CGMPs and type of inspection (i.e., inspection under the base compliance
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PROGRAM 7356.000
program) plus (ii) coverage of the relevant called-out provisions of 21 CFR Part 4 (see PART
II.2 - Objective above).
Base CGMPs. Use of inspectional elements from the base program should include
evaluation of CGMP considerations for the combination product as a whole. For
example, during coverage of the production system at a facility that uses a drug CGMP-
based streamlined approach, the investigator should evaluate production and process
controls as directed in the associated drug compliance program. This evaluation should
include evaluation of production and process controls for each constituent part and the
combination product. Any observations related to these types of controls would be
deficiencies in the 21 CFR Part 211 requirements (e.g., 21 CFR 211, Subpart F).
Conversely, for a facility that uses a device QS-based streamlined approach, the
investigator should evaluate production and process controls for the constituent parts and
the combination product as directed in the associated device compliance program. Any
observations related to these types of controls would be deficiencies in the 21 CFR Part
820 requirements (e.g., 21 CFR 820.70, 820.72, 820.75).
Called-out Provisions. Regarding called-out provisions (covered as described in Table 1
or Table 2 below), any observations related to these provisions would be deficiencies
against the associated 21 CFR Part 820 or 21 CFR Part 211 requirements. Additional
information on combination product inspectional considerations for called-out provisions
is contained in Attachment A and Attachment B.
Other Inspectional Considerations for Combination Products: When conducting inspections of a
combination product manufacturer, consider:
• The terminology (for example the definitions used in different quality system or
regulatory documents) used by combination product manufacturers may vary (e.g.,
because they otherwise manufacture drugs or devices). Terminology differences should
not be the basis of 483-observations as long as the combination product manufacturer
can explain how their practices meet the requirements of the CGMP regulations
applicable to the facility.
• FDA has signaled some flexibility in the CGMP approach for combination products in
areas including testing and release for distribution (21 CFR 211.165), stability testing (21
CFR 211.166), special testing requirements (21 CFR 211.167), reserve samples (21 CFR
211.170), and design controls (21 CFR 820.30). See Reference 9. If a combination
product manufacturer is using such approaches, appropriate evidence and an explanation
of the rationale to support the approach should be accessible for review during facility
inspections.
NOTE: If during an inspection an investigator identifies potential problems related to
registration and listing, the investigator should contact the lead center for assistance. The
investigator should contact ORA supervisory staff if there are any questions about combination
product District Use Codes (DUCs) for a facility.
(1) Pre-Approval Inspections
Pre-announcement will typically apply to pre-approval inspections for ANDA/NDA/PMA
combination products, consistent with the ORA inspectional process for the lead center (see also
Reference 12). Pre-licensing inspections for CDER-led BLAs are also typically preannounced.
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For combination product pre-approval inspections, the focus of the inspection should be on the
combination product for which marketing approval is sought. Follow any inspectional guidance
provided by the center(s), which will specify the coverage to be conducted during the pre-
approval inspection. When coverage of both the base CGMPs and called-out provisions is
specified, the base compliance program should be used to conduct the inspection, with
additional inspectional coverage of the called-out provisions as specified in Table 1. Process
validation coverage, including what process validation activities are expected to be complete at
the time of the pre-approval inspection, will be communicated from the lead center. If there are
questions on expectations for process validation, contact the lead center for assistance.
Generally, combination product manufacturers use a streamlined approach with base CGMPs
that align with the application type for which pre-approval is sought (e.g., a drug CGMP-based
streamlined approach for an NDA or ANDA, or a device QS regulation-based streamlined
approach for a PMA). Although this is the most common situation, it is also acceptable for a
combination product manufacturer to choose to operate under the other streamlined approach
(e.g., a manufacturer for a PMA combination product could choose to operate under a drug
CGMP-based streamlined approach). In these situations, the lead center will provide additional
information or instruction in pre-inspectional meetings as necessary, and the coverage may differ
from Table 1. If there are questions regarding coverage, the investigator should consult with
ORA supervisory staff and the lead center, as appropriate.
NOTE: If a facility indicates that their combination product CGMP operating system is
compliant with 21 CFR Part 820 and 21 CFR Part 211 in their entirety, conduct the inspection
consistent with the approach for the combination product’s application type as shown in Table 1.
For example, if the pre-approval inspection is for a PMA, follow the inspection approach
outlined for a PMA.
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Table 1. General Approach to Pre-Approval Inspection Coverage for Combination Product
Manufacturing Facilities
Application
Type for
Pre-Approval Base Base Compliance Additional Coverage of Called-out
Inspection CGMPs Program Provisions
NDA/BLA12/ Drug 7346.83213 Cover the following requirements in
ANDA CGMP (NDA/ANDA) accordance with Attachment B:
(21 CFR Management Controls (21 CFR 820.20)
Part 211) 7356.002M
7356.002A (BLA) Design Controls (21 CFR 820.30)
Purchasing Controls (21 CFR 820.50)
CAPA (21 CFR 820.100)
Installation (21 CFR 820.170) and/or
Servicing (21 CFR 820.200), if
appropriate14
NOTE: If the combination product includes a
CBER-regulated biological product or an
HCT/P,15 follow the relevant inspectional
instructions and compliance programs (see
Compliance Program 7345.848 and
Compliance Program 7341.002) or contact
ORA supervisory staff and the lead center for
assistance.
12
CDER-led combination products that include a biological product constituent part are subject to both the drug
CGMPs in 21 CFR Part 210 and 211 and the applicable CGMP requirements for biological products (including
standards) found in 21 CFR Parts 600 through 680. As such, a manufacturer using a drug CGMP-based streamlined
approach for such a combination product is subject to all of the requirements in 21 CFR Parts 210, 211, and 600
through 680 (as well as the called-out provisions of 21 CFR Part 820 if the combination product includes a device
constituent part). See also PART I.2 – Combination Products CGMPs.
13
Compliance Program 7346.832 is the general pre-approval inspection program for drugs. Other compliance
programs, such as Compliance Program 7356.002A for Sterile Drugs should also be used, as applicable.
14
Coverage of installation (21 CFR 820.170) and servicing (21 CFR 820.200) requirements and tamper-evident
packaging requirements (21 CFR 211.132) should be included only for those products for which the requirements
apply (i.e., combination products that require installation and servicing or OTC combination products, respectively).
15
Biological products and biologic-led combination products are assigned to either CBER or CDER, depending on
the type of biological product (see https://www.fda.gov/about-fda/about-center-biologics-evaluation-and-research-
cber/transfer-therapeutic-products-center-drug-evaluation-and-research-cder).
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PROGRAM 7356.000
Application
Type for
Pre-Approval Base Base Compliance Additional Coverage of Called-out
Inspection CGMPs Program Provisions
PMA Device 7383.001 Cover the following requirements in
QS accordance with Attachment A:
(21 CFR Testing and approval or rejection of
Part 820) components, drug product containers, and
closures (21 CFR 211.84)
Calculation of yield (21 CFR 211.103)
Tamper-evident packaging requirements
for over-the-counter (OTC) human drug
products (21 CFR 211.132)14
Expiration dating (21 CFR 211.137)
Testing and release for distribution
(21 CFR 211.165)
Stability testing (21 CFR 211.166)
Special testing requirements
(21 CFR 211.167)
Reserve samples (21 CFR 211.170)
NOTE: If the combination product includes a
biological product or an HCT/P,15 follow the
relevant inspectional instructions and
compliance programs (for CDER-led
biological products see Compliance Program
7356.002M, for CBER-led HCT/Ps see
Compliance Program 7341.002 and for CBER-
led biological products see Compliance
Program 7345.848) or contact ORA
supervisory staff and the lead center for
assistance.
(2) Surveillance Inspections
Pre-announcement will apply to surveillance inspections, as appropriate, consistent with the
process for the base compliance program. For surveillance inspections where combination
product coverage is conducted, investigators should prioritize combination products recently
approved, cleared, or significantly changed (in terms of design) or those that include complex
technology or manufacturing considerations. This applies unless there are indicators that there
are safety and effectiveness concerns with other products. In all cases, coverage should include
review of complaint trends to identify any potentially significant defects for inspectional
scrutiny.
Abbreviated Inspections. Abbreviated inspections are generally used when the facility has a
record of satisfactory CGMP compliance with no significant product defect incidents (including
Date of Issuance: June 4, 2020 Page 13 of 46
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PROGRAM 7356.000
significant Field Alert Reports (FARs), biological product deviation reports (BPDRs), medical
device reports (MDRs), safety alerts, or recalls). See also Compliance Program 7356.002 and
Compliance Program 7382.845.
Abbreviated inspections should typically not be used if:
• The facility has a history of non-compliance, recent product quality problems, complaint-
handling issues, or significant defect issues, recalls, quality related consumer complaints,
failure to meet specifications, potency failures, impurity failures and/or newly discovered
impurities
• There have been significant changes in management or organization procedures (e.g., a
change in ownership)
• New technologies or equipment requiring new expertise have been implemented since the
previous inspection
An abbreviated inspection for a combination product manufacturer may be conducted in one of
two ways, depending on whether the facility has previously been inspected against the called-out
provisions:
1) Abbreviated Base Plus Full Call-outs (Abbreviated coverage of ONLY the base CGMPs
plus FULL coverage of all the called-out provisions): The Abbreviated Base Plus All
Call-outs option is appropriate when the facility has a record of satisfactory CGMP
compliance and no significant product quality issues but has never been inspected against
the called-out provisions. The abbreviated coverage applies only to the base CGMPs and
the abbreviated coverage is consistent with the underlying compliance program for the
base CGMPs. See Table 2.
2) Abbreviated Base and Abbreviated Call-outs (Abbreviated coverage of the base CGMPs
AND abbreviated coverage of the called-out provisions): The Abbreviated Base and
Abbreviated Call-outs option is appropriate when the facility has a record of satisfactory
CGMP compliance, has been inspected against the called-out provisions, and has had no
significant product quality issues. The abbreviated coverage applies to the base CGMPs
and the called-out provisions. See Table 2.
During an abbreviated inspection, verification of overall quality system activities may warrant
additional coverage in other systems. For example, for CDRH-led combination products, when
the facility manufactures a sterile drug constituent part and/or combination product, coverage of
related critical production and process control elements should be considered (see also
Compliance Program 7356.002A).
An Abbreviated Inspection may change to a Comprehensive (Full) Inspection upon findings of
objectionable conditions (see PART V – REGULATORY/ADMINISTRATIVE STRATEGY)
with ORA division concurrence.
Comprehensive (Full)16 inspections. Comprehensive (Full) inspections will be performed as
resources permit, based on a risk-based determination:
• For the first inspection of a combination product manufacturer (e.g., an initial inspection)
16
The terms “Comprehensive” and “Full” for purposes of this compliance program are equivalent. Because the
underlying compliance programs for devices and drugs, respectively, use these terms, they are both included for
completeness.
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PROGRAM 7356.000
• For the initial coverage of called-out provisions after introduction of combination product
manufacturing operations to a facility that previously manufactured only a drug, device,
or biological product.
• When directed by the assignment
• For CDRH-led combination product foreign inspections
• When an inspection, started as an abbreviated inspection, reveals postmarket information
or objectionable conditions (see PART V – REGULATORY/ADMINISTRATIVE
STRATEGY) that cannot be adequately assessed in abbreviated inspectional coverage
Conduct abbreviated and full inspections consistent with the row of Table 2 for the base CGMPs
in use at the facility.
NOTE: If a facility indicates that the combination product CGMP operating system is compliant
with 21 CFR Part 820 and 21 CFR Part 211 in their entirety, conduct the inspection described in
Table 2 for the base CGMPs that align with the application type(s) of the combination product(s)
being covered during the inspection. For example, if the inspectional coverage is of NDA
approved combination products, follow the inspection approach outlined for “Drug CGMP-
Based.” If the inspectional coverage if for PMA approved or 510(k) cleared combination
products, follow the inspectional approach outlined for “Device QS-Based.”
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PROGRAM 7356.000
Table 2. General Approach to Surveillance Inspectional Coverage for Combination Product
Manufacturing Facilities
Base Compliance
Base CGMPs Program Additional Coverage of Called-out Provisions
Drug CGMP- 7356.00217 For Comprehensive (full) AND for Abbreviated Base
Based (NDA/ANDA) Plus Full Call-outs inspections, cover in accordance
(21 CFR 211) with Attachment B:
7356.002M18
• Management Controls (21 CFR 820.20)
7356.002A
• Design Controls (21 CFR 820.30), if applicable
(BLAs)
• Purchasing Controls (21 FR 820.50)
• CAPA (21 CFR 820.100)
• Installation (21 CFR 820.170) or Servicing (21
CFR 820.200), if applicable14
For Abbreviated Base and Abbreviated Call Outs
inspections, cover in accordance with Attachment B:
• Design Controls (21 CFR 820.30), if applicable
• CAPA (21 CFR 820.100)
• Purchasing Controls (21 CFR 820.50)
NOTE: If the combination product includes a CBER-
regulated biological product or an HCT/P15, follow the
relevant inspectional instructions and compliance programs
(see Compliance Program 7345.848 and Compliance
Program 7341.002) or contact ORA supervisory staff and the
lead center for assistance.
17
Compliance Program 7356.002 is the general inspection program for drugs. Other compliance programs, such as
Compliance Program 7356.002A for Sterile Drugs should also be used, as applicable.
18
Compliance Program 7356.002M for inspections of licensed therapeutic biological products does not distinguish
between full and abbreviated coverage. For surveillance inspections for combination products that contain a
therapeutic biological product either full or abbreviated coverage of the call-outs may be used based on the
inspectional history and other factors as discussed in the “Abbreviated Inspections” section above.
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PROGRAM 7356.000
Base Compliance
Base CGMPs Program Additional Coverage of Called-out Provisions
Device QS- 7382.84519 For Comprehensive (full) AND for Abbreviated Base
Based Plus Full Call-outs inspections, cover in accordance
(21 CFR Part with Attachment A:
820) Materials System:
• Testing and approval or rejection of
components, drug product containers, and
closures (21 CFR 211.84)
Laboratory Controls System:
• Testing and release for distribution (21 CFR
211.165)
• Stability testing (21 CFR 211.166)
• Special testing requirements (21 CFR 211.167),
if applicable
• Reserve samples (21 CFR 211.170)
Production System
• Calculation of yield (21 CFR 211.103)
Packaging and Labeling System
• Tamper-evident packaging requirements for
over-the-counter (OTC) human drug products
(21 CFR 211.132), if applicable14
• Expiration Dating (21 CFR 211.137)
For Abbreviated Base and Abbreviated Call Outs
inspections, cover in accordance with Attachment A:
Laboratory Controls System:
• Testing and release for distribution (21 CFR
211.165)
• Stability testing (21 CFR 211.166)
• Special testing requirements (21 CFR 211.167),
if applicable
• Reserve samples (21 CFR 211.170)
NOTE: If the combination product includes a biological
product or an HCT/P, follow the relevant inspectional
instructions and compliance programs (for CDER-led
biological products see Compliance Program 7356.002M,
for CBER-led HCT/Ps see Compliance Program 7341.002,
and for CBER-led biological products see Compliance
Program 7345.848) or contact ORA supervisory staff and the
lead center for assistance.15
19
See also Guidance for Industry Quality Systems Approach to Pharmaceutical Current Good Manufacturing
Practices Regulations.
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PROGRAM 7356.000
(3) For Cause and Risk-Based Inspections
These inspections are carried out in response to information that raises questions or concerns
about a combination product or a facility that manufactures a combination product. These
inspections are usually initiated at the request of the lead center for the combination product. The
inspectional assignment provided by the lead center will outline coverage. These assignments
are typically conducted to address specific issues (e.g., adequate implementation of corrective
actions to address observations from previous inspections, or in response to specific events such
as adverse events, complaints, FARs, BPDRs, or recalls).
For Cause inspections may require additional center expertise, especially for more complex
products or when investigating apparent defects that could pose a significant health hazard.
These inspections may not require coverage of all constituent parts and/or CGMP requirements
that apply to the combination product. When such inspections are related to called-out provisions
from 21 CFR Part 4, refer to Attachments A and Attachment B as resources for combination
product inspectional considerations.
(4) Post-approval / Postmarket Inspections
Post-approval/Postmarket 20 inspections may be conducted for combination products to confirm
continued compliance, including monitoring changes in the manufacturing processes that occur
after product approval.
For both CDER-led and CDRH-led combination product post-approval/postmarket inspections,
inspectional coverage should include assessment of the combination product and not just a
constituent part, as appropriate. For example, if process validation for the specific combination
product is covered during the inspection, process validation for any device, drug, or combination
product manufacturing processes occurring at the facility should be assessed. If necessary, based
on significant findings during a post-approval/postmarket inspection for a specific combination
product, the scope of the inspection may be expanded.
For CDER-led combination products, post-approval inspections will be conducted consistent
with Integration of FDA Facility Evaluation and Inspection Program for Human Drugs: A
Concept of Operations, an agreement established between CDER and ORA in 2017. Post-
approval inspections largely focus on the process validation lifecycle, change management,
changes submitted to the application, and the execution of supporting activities per application
commitments and CGMP requirements. Coverage of combination product CGMP requirements
will be described in the related inspectional assignment.
For CDRH-led combination products, PMA postmarket inspections will be conducted consistent
with Compliance Program 7383.001and coverage of combination product CGMP requirements
aligns with Table 1 above.
(5) Special Situations – Combination Product “Convenience Kit” Manufacturers
Some facilities may assemble combination product “convenience kits.”21 These are kits that
include only constituent parts that 1) are already legally marketed independently, and
20
The terms “Post-approval” and “Postmarket” are used consistent with the terminology in the underlying
compliance programs for drugs and devices, respectively.
21
The term “convenience kits” is used in other documents for other types of kits. The definition of convenience kits
in this Compliance Program is specific to combination product convenience kits (see also Reference 9, Section
VI.1).
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PROGRAM 7356.000
2) packaged in the kit consistent with how they are independently marketed (i.e., cannot include
a change to the intended use of any of the constituent parts). Combination product convenience
kit manufacturers only need to demonstrate compliance with applicable CGMP requirements
with respect to the assembly, packaging, labeling, sterilization, and further processing of the kit
itself, including purchasing controls.
If an investigator has questions about whether a combination product is a convenience kit and
what CGMP requirements apply, they should contact the lead center or Office of Combination
Products (OCP) for assistance (see PART VI.3 - Program Contacts). During review of Corrective
and Preventive Action (CAPA) and complaints for a purported convenience kit, if there are
1) indicators of safety issues or 2) other concerns that suggest a change in intended use for any
constituent part(s) as compared to the use(s) for which the constituent part(s) is legally marketed
independently, the investigator should collect supporting documents, including any instructions
for use, inserts, other product labeling, and evidence of interstate commerce for the combination
product and constituent parts. Document the content of the kit and contact the lead center for
assistance.
(6) Special Situations – Device Constituent Part Exempt from the device QS-
regulations
FDA has exempted some devices from all or certain provisions of the device QS regulations
(including Design Controls). This is not a consideration relevant to most types of devices that
may be used as constituent parts of combination products. However, if such an exemption
applies to a device type, it is also considered to apply to device constituent parts and, thereby, to
the combination products of which they are a part in cases where the device constituent part in
the combination product is of that same type (i.e., it does not have a new intended use and does
not otherwise raise different device performance-related safety and/or effectiveness questions). If
the exemptions for a device constituent part of a drug-device combination product cover all of the
21 CFR Part 820 provisions included in 21 CFR 4.4(b)(1), then the Agency will consider the
combination product manufacturer CGMP compliant so long as the CGMP operating system is
compliant with 21 CFR Part 211 (no demonstration of compliance with 21 CFR Part 820 will be
necessary). See also Reference 9.
Many devices commonly used in combination products such as syringes, autoinjectors, and
metered dose inhalers are NOT exempt. Examples of device types that may be exempt include
medicine cups and oral dosing devices such as droppers and oral syringes. If a combination
product manufacturer claims that the device constituent part and/or their combination product is
exempt from 21 CFR 820 requirements, any investigator with concerns should contact the lead
center.
Reporting
A single EIR and, when applicable, FDA 483 should be used to document all observations made
at a combination product manufacturer.
Compliance with base compliance program reporting requirements. Documentation of the
inspection should be in accordance with the reporting requirements of the base compliance
program for the combination product (see FIELD REPORTING REQUIREMENTS on the cover
page of this Compliance Program).
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Additional reporting requirements. In addition to complying with the base compliance program
reporting requirements, the EIR should include information on:
• The CGMP operating system in use at the facility for the combination product (e.g., Drug
CGMP-based streamlined approach, Device QS-based streamlined approach, or full
compliance with all drug CGMPs and device QS regulation requirements).
• A description of the manufacturing activities (including design activities, if applicable)
occurring at the facility inspected. Also describe the relationship between the facility
being inspected and other facilities that supply constituent parts or components thereof
and/or perform combination product manufacturing activities (see footnote 7). For
example, if the inspected facility is the contract manufacturer for the combination
product, but a separate facility maintains the Design History File (DHF) and handles
complaints, this should be documented in the EIR.
• Collect the evidence and samples necessary to support each observation including, where
necessary, both specific examples and related procedures. For example, if an observation
is made against the CAPA system, collect a copy of the overall CAPA procedure for the
facility in addition to collecting evidence regarding the example(s) of failure to establish
and/or maintain a CAPA system.
Citations. If a combination product manufacturer is operating under a streamlined approach,
citations should ONLY be to provisions of the base CGMPs and to the relevant called-out
provisions from the other CGMP system (e.g., for a drug-CGMP streamlined approach, citations
should be limited to 21 CFR Part 211 and the called-out provisions from 21 CFR Part 820.
Citations should not be made to other provisions of 21 CFR Part 820 that are not called-out).
Note: Observations on the FDA 483 should be limited to those related to the adequacy of, and
adherence to, the procedures and/or controls established by the firm. Do not place observations
on the FDA 483 that concern the adequacy, safety, or efficacy of a particular design. Any such
concerns should be noted in the EIR and flagged for review by the lead center. See also
Compliance Program 7382.845 “Special Instructions Concerning Design Controls.”
PART IV – ANALYTICAL
Refer to PART IV of the applicable compliance programs for discussion of sampling and
analytical testing:
• Compliance Program 7346.832 for pre-approval inspections for CDER-led combination
products
• Compliance Program 7356.002 for surveillance inspections of CDER-led combination
products
• Compliance Program 7382.845 for surveillance inspections of CDRH-led combination
products
• Compliance Program 7383.001 for pre-approval and postmarket inspections for CDRH-
led combination products
If there are questions on sampling or analytical testing, contact the lead center for assistance.
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PART V - REGULATORY/ADMINISTRATIVE STRATEGY
The risks and intended use of the combination product and the potential adverse effect of the
CGMP deviations on the finished combination product must be considered when determining the
appropriate action needed.
Official Action Indicated-OAI. The field (ORA division (OMPTO, OPQO or OMDRHO))
submits a recommendation for regulatory action (OAI) to the lead center when a judgment is
made that the combination product manufacturer is not operating in a state of control and
management is unwilling or unable to make adequate corrective actions in an appropriate
timeframe. See also PART V.2 and PART V.4 below.
Voluntary Action Indicated-VAI. If the nature of the CGMP deviations poses minimal risks
when considered in relation to the risks and intended use of the product and there is not a history
of repeat observation(s), the recommendation should normally be voluntary corrections by the
firm (VAI). When voluntary action to address observation(s) identified during a previous
inspection is not accomplished or when the deviations observed pose a serious risk to the
consumer, then regulatory and/or administrative action should be recommended.
The procedures for developing recommendations and determining the need for regulatory action
following an inspection are conducted consistent with the established process within and
between ORA and the lead center. The lead center process should be used regardless of the
types of observations (e.g., for a CDER-led product, even if the recommendation for regulatory
action is based on 21 CFR Part 820 observations, the recommendation should be managed
consistent with the CDER process). See also PART VII-CENTER RESPONSIBILITIES.
Pre-approval Inspections for Combination Products
FDA expects that a combination product manufacturer is compliant with the requirements in
21 CFR Part 4 at the time of a pre-approval inspection. After a pre-approval inspection for a
combination product manufacturer, the inspection team makes an initial recommendation to the
lead center through the Establishment Inspection Report (EIR) endorsement to approve or
withhold the application approval based on the outcome of the establishment inspection.
Significant observations from either the base CGMPs22 or called-out provisions (see PART V.4
below) should be equally considered when making a recommendation to approve or withhold.
The lead center classifies the inspection after consideration of recommendations from the
consulted center, as applicable (see PART V.3 below and also PART VII – CENTER
RESPONSIBILITIES).
22
As discussed in PART III.1.A – Inspections, inspectional elements from the base compliance program should
include evaluation of CGMP considerations for the combination product as a whole. As such, significant
observations from the base CGMPs may involve any type of constituent part or the combination product as a whole,
as appropriate. For example, under a drug-CGMP based streamlined approach, significant deficiencies related to
production and process controls for a device constituent part, drug constituent part, or the combination product as a
whole would be cited under the base CGMPs (21 CFR Part 211).
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PROGRAM 7356.000
Surveillance Inspections and Risk-Based Inspections for Combination Products
Inspection findings that demonstrate significant CGMP deficiencies or repetition of deficiencies
identified in previous inspections, in relation to either the base CGMPs22 or called-out
provisions (see PART V.4 below), are bases for an inspection being recommended as OAI.
Inspections for Pre-approval in Conjunction with Another Type of Inspection
Combination product pre-approval inspections may be conducted in conjunction with another
type of inspection that involves commercially-marketed product(s) (e.g., a pre-approval
inspection conducted in conjunction with a surveillance inspection). Separate recommendations
and associated actions may occur in these cases, as appropriate. For example, if significant
findings result in a withhold decision for the pre-approval inspection and the findings extend
beyond the pre-approval combination product, regulatory and/or administrative actions (such as
issuance of a Warning Letter) may also be taken after coordinating with the lead center.
Significant Findings from the Called-out Provisions of 21 CFR Part 4
For combination product inspections, significant findings relating to the called-out provisions
(in addition to the base CGMPs) should be considered when determining the division
recommendation as explained below.
General Considerations. Regardless of the CGMP operating system for a combination product
facility, non-correction of significant findings from previous inspections or repeat findings of
the same or similar type as those observed on previous inspections (repeat observations) are
significant findings.
Drug CGMP-Based Streamlined Approach. For a facility using a drug CGMP-based streamlined
approach, in addition to the significant findings identified in the base compliance program, the
following are examples of significant findings from the called-out provisions of the device QS
regulation that could warrant an ORA division recommendation23 to withhold approval or OAI
(the following is not intended to be an exhaustive list):
1. Existence of combination products that do not meet the manufacturer’s specifications
and/or the applicable CGMP requirements in the 21 CFR Part 4 regulation and were not
adequately addressed by the CAPA process.
2. Failure to adequately define, document, or implement Quality System Regulation
requirements that apply to combination product facilities under 21 CFR Part 4, Subpart
A. Consistent with Compliance Program 7382.845, examples include, where required:
a. No procedure(s) that address corrective and preventive action (21 CFR 820.100)
b. No procedure(s) on how quality data will be analyzed and used
(21 CFR 820.100(a)(1))
c. Where design controls are required, no design controls procedure(s) for the
combination product (21 CFR 820.30)
23
Note that for CDER-led pre-license BLA inspections, CDER is the lead for the inspection and the inspection team
submits this initial recommendation.
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PROGRAM 7356.000
d. Where design controls are required, no design change control procedure(s)
(21 CFR 820.30(i))
e. No purchasing control procedure(s) (21 CFR 820.50)
Device QS Regulation-Based Streamlined Approach. For a facility using a device QS
Regulation-based streamlined approach, in addition to significant findings identified in the base
compliance program, the following are examples of significant findings from the called-out
provisions from the drug CGMPs that could warrant an ORA division recommendation to
withhold approval or OAI (the following is not intended to be an exhaustive list):
1. Significant data integrity problems, including misrepresented data or other conditions as
related to the called-out provisions of 21 CFR Part 211. Issues related to data integrity
should typically be cited under the related 21 CFR Part 211 called-out provision with
associated discussion in the EIR narrative.
2. Incomplete or unsuccessful analytical method validation or verification for testing
methods used to comply with called-out provisions of 21 CFR Part 211 for the drug
constituent part and/or the combination product (e.g., testing methods used for stability
(21 CFR 211.166), sterility/final release testing (21 CFR 211.165, 21 CFR 211.167),
testing of reserve samples (21 CFR 211.170)).
3. Pattern of failure to follow approved analytical procedures and/or testing methods used
for called-out provisions of 21 CFR Part 211 for the drug constituent part and/or the
combination product (e.g., identity testing (21 CFR 211.84), testing methods used for
stability (21 CFR 211.166), sterility/final release testing (21 CFR 211.165, 21 CFR
211.167), testing of reserve samples (21 CFR 211.170)).
4. Significant stability concerns (21 CFR 211.166) that raise questions about the drug
constituent part such as:
a. Stability study failures under recommended storage conditions
b. Pattern of failure to follow stability programs
c. Pattern of failure to evaluate stability failures
5. Pattern of failure to conduct testing (21 CFR 211.84 - identity testing for components,
21 CFR 211.165 - testing and release for distribution), including with regard to device
constituent parts that also serve as a container/closure or part thereof.
6. An expiration date that is not supported by stability studies (21 CFR 211.137).
Particular attention should also be paid to the relationships between requirements, and to broader
implications of deficiencies in one element for other elements or the operating process. For
combination product manufacturer inspections, related deficiencies under different elements of
the CGMP and/or Quality System subsystems24 could warrant an ORA division recommendation
to withhold approval or for OAI (see PART V of Compliance Program 7382.845 and
Compliance Program 7383.001). In particular, deficiencies in requirements related to control of
supplied products and in investigation of product problems can indicate a significant problem.
For instance:
24
Subsystems refers to the 21 CFR Part 211 (drug CGMP) subsystems as described in Reference 10 and the 21 CFR
Part 820 (device Quality System) subsystems as described in Reference 9. See also Attachment C.
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PROGRAM 7356.000
• For a facility operating under a drug CGMP-based streamlined approach, deficiencies in
both purchasing controls (21 CFR 820.50) and testing and release for distribution
(21 CFR 211.165) can indicate a significant finding is warranted. Similarly, a mixture of
CAPA deficiencies (21 CFR 820.100) and complaint file (21 CFR 211.198) deficiencies
can indicate a significant finding related to the firm’s control over nonconforming
product.
• For a facility operating under a device QS-based streamlined approach, deficiencies in
both purchasing controls (21 CFR 820.50) and control of components, containers, and
closures (21 CFR 211.84) can indicate a significant finding.
PART VI REFERENCES, ATTACHMENTS, AND PROGRAM CONTACTS
References
1. Chapters II, III, V, and VII of Federal Food, Drug, and Cosmetic Act, as amended
2. Code of Federal Regulations, Title 21, Parts 4, 210, 211, and 820 as revised
3. Compliance Program 7346.832 - Pre-Approval Inspections [Drugs]
4. Compliance Program 7356.002 - Drug Manufacturing Inspections
5. Compliance Program 7356.002A - Sterile Drug Process Inspections
6. Compliance Program 7356.002M - Inspections of Licensed Biological Therapeutic Drug
Products
7. Compliance Program 7382.845 - Inspection of Medical Device Manufacturers
8. Compliance Program 7383.001 - Medical Device Premarket Approval and Postmarket
Inspections
9. Guidance for Industry and FDA Staff - Current Good Manufacturing Practice
Requirements for Combination Products
10. Guidance for Industry - Quality Systems Approach to Pharmaceutical CGMP
Regulations
11. Guide to Inspections of Quality Systems, Quality System Inspection Technique
12. Investigation Operations Manual – Chapter 5
Attachments
• Attachment A - Combination product inspectional considerations for the Called-out
provisions of 21 CFR Part 211 (see 21 CFR 4.4(b)(2))
• Attachment B - Combination product inspectional considerations for the Called-out
provisions of 21 CFR Part 820 (see 21 CFR 4.4(b)(1))
• Attachment C – Definitions and Acronyms
Program Contacts
Office of Regulatory Affairs
Questions regarding inspectional requirements and/or technical assistance:
• OMDRHO: [email protected]
• OPQO: [email protected]
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Center for Drug Evaluation and Research
For questions related to CDER-led combination products:
• Pre-approval inspections: [email protected]
• Surveillance Inspections: [email protected]
• For Cause Inspections: [email protected] or
[email protected] (depending on the issuing office for the For Cause
Inspection)
• If the product includes a CDER biologic, include:
[email protected]
Center for Devices and Radiological Health
For questions related to CDRH-led combination products:
[email protected]
Center for Biologics Evaluation and Research
For questions on CDER/CDRH-led products that include a CBER biologic:
[email protected]
Office of Combination Products
For questions related to the status of a product as a combination product or cross-cutting
combination product policy questions: [email protected]
PART VII - CENTER RESPONSIBILITIES
When ORA contacts the lead center during a combination product inspection as provided in this
program, the lead center will facilitate interaction between product reviewers in that and
secondary center(s) for the product.25 When center review before an inspection identifies
manufacturing concerns or issues that need to be addressed by the combination product
manufacturer, that information will be highlighted in the inspection request. In some cases,
expert(s) from the centers may accompany the ORA investigators during an inspection.
For CDER-led combination products, following a combination product inspection, findings will
be reviewed consistent with the existing process for center review.26 For CDRH-led combination
products, a combination product inspection with findings27 should be reviewed by CDRH. In
either case, the lead center will engage other center(s) and OCP, as applicable, to ensure
application of relevant expertise, appropriate consideration of cross-cutting implications of any
action that may be taken, and consistency of Agency actions to address similar issues.
25
The lead center will consult with the other center, as needed, to evaluate inspectional observations. See SMG
4101 Inter-Center Consult Request Process.
26
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/Manufacturing/ucm576307.htm.
27
CDRH review of NAI inspections for PMAs and Foreign Surveillance Inspections will occur as consistent with
existing practices.
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ATTACHMENT A – Combination Product Inspectional Considerations for Called-out
Provisions of 21 CFR Part 211
This attachment provides additional information regarding the called-out provisions of the drug-
CGMPs (21 CFR Part 211) for combination product manufacturers who utilize the device QS
regulation (21 CFR Part 820) as their base CGMPs.
In addition to covering the device QS requirements according to the applicable base compliance
program, evaluate the combination product manufacturer’s compliance with the called-out
provisions of 21 CFR Part 211 as described below.
21 CFR 211.84 Testing and approval or rejection of components, drug product containers,
and closures
Combination Product Considerations for 21 CFR 211.84:
For purposes of 21 CFR 211.84, component could include active pharmaceutical ingredients,
excipients, and water or process gases that contact the drug constituent part (see 21 CFR
210.3(a)(3)). A container closure is the sum of packaging components that together contain and
protect the drug constituent part. This includes primary packaging components that contact the
drug constituent part and will also include secondary packaging components if intended to
provide additional protection to the drug constituent part.
Combination product manufacturers do not need to comply with 21 CFR 211.84 for device
constituent parts or materials used in the manufacture of a device constituent part unless the
device constituent part is also the drug container or closure or a part thereof. For example,
syringe components that are prefilled with the drug constituent part would be subject to
21 CFR 211.84, whereas materials used solely for manufacture of a device constituent part that is
not part of the drug container or closure (e.g., a co-packaged syringe with a drug vial) would not
be subject to 21 CFR 211.84.
21 CFR 211.84 may be related to other supplier controls activities (see also discussion of 21
CFR 820.50, Purchasing Controls, in Attachment B).
Inspectional Approach to 21 CFR 211.84 for a Facility Operating under a Device QS-based
Streamlined Approach:
Evaluate the combination product manufacturer’s compliance with 21 CFR 211.84. For pre-
approval inspections, refer to Compliance Program 7346.832: 1) Objective 1(b), related to the
sampling, testing, and evaluation of drug constituent part components, containers, and closures,
2) Objective 2 elements related to the analytical methods for tests of drug constituent part
components, containers, and closures described in the application, and 3) Objective 3 elements
related to the authenticity and veracity of any incoming material testing results. For surveillance
inspections, refer to Compliance Program 7356.002 “Materials System” elements related to the
drug constituent part components, containers, and closures.
It is appropriate for facilities operating under a device QS-based streamlined approach to
comply with 21 CFR 211.84 requirements by augmenting acceptance activities under 21 CFR
820.80 to incorporate 21 CFR 211.84 compliant measures.
For any active pharmaceutical ingredient and/or drug product intended for further processing into
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the drug constituent part that is supplied to the combination product manufacturer, coverage of
21 CFR 211.84 should include confirming that at least one test is conducted to verify the identity
of incoming material. If the facility relies on the supplier’s report of analysis, the facility should
have established the reliability of the supplier’s analysis through appropriate validation of the
supplier’s test results at appropriate intervals and conduct additional testing (e.g., at least one
specific identity test on components and at least visual identification for containers/closures, as
appropriate. See 21 CFR 211.84(d)).
Reference/Resources:
• Compliance Program 7346.832 - Pre-Approval Inspections.
• Compliance Program 7356.002 - Drug Manufacturing Inspections.
• Section IV.B.1, FDA Guidance for Industry and FDA Staff - Current Good
Manufacturing Practice Requirements for Combination Products
• Guidance for Industry - Quality Systems Approach to Pharmaceutical CGMP
Regulations
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21 CFR 211.103 Calculation of Yield
Combination Product Considerations:
Yield calculation requirements apply to the drug constituent parts of combination products. For
single-entity combination products, calculation of yield must be performed on every batch of the
combination product. For co-packaged combination products, calculation of yield must be
performed on every batch of the drug constituent part(s).
Although data on the number of device constituent parts and components used and lost during
the manufacture of a combination product may be necessary to ensure appropriate control of the
manufacturing process in accordance with 21 CFR 820.70, yield calculation in accordance with
21 CFR 211.103 is not required for device constituent parts. However, problems with the device
constituent part during combination product manufacturing may affect drug yield. For example,
prefilled syringes that are rejected because of nonconformity of the syringe needle may result in
corresponding loss of drug. Any loss would be captured as part of the yield calculations for the
drug constituent part. Investigation into the cause of that loss should identify the manufacturing
problem that led to these device nonconformities.
Inspectional Approach to 21 CFR 211.103 for a Facility Operating Under a device QS-based
Streamlined Approach:
Evaluate the combination product manufacturer’s compliance with 21 CFR 211.103. Calculation
of yield should be determined at the conclusion of each appropriate phase of manufacturing,
processing, packaging, and holding for the drug constituent part(s) and for the combination
product as a whole. Accordingly, calculation of yield should be determined at each phase at
which drug component, in-process material, or product loss may occur, including during the
formulation of the drug, during incorporation of the drug into the combination product (e.g.,
filling or coating), and, where applicable, during the packaging process.
Reference/Resources
• Compliance Program 7346.832 - Pre-Approval Inspections
• Compliance Program 7356.002 - Drug Manufacturing Inspections
• Section IV.B.2, FDA Guidance for Industry and FDA Staff - Current Good
Manufacturing Practice Requirements for Combination Products
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21 CFR 211.132 Tamper-evident packaging requirements for over-the-counter (OTC)
human drug products
Combination Product Considerations for 21 CFR 211.132:
If a combination product is accessible to the public while it is for sale (i.e., non-prescription), it
should have tamper-evident packaging. If this packaging is breached or missing, the consumer
should be able to determine that tampering occurred. For single-entity combination products, the
requirement for tamper-evident packaging applies to the combination product. For co-packaged
combination products, the requirement for tamper-evident packaging applies to the drug
constituent part(s), but this requirement can be met if the entire combination product, including
the drug constituent part, has tamper-evident packaging.
Certain combination products may be exempt from over-the-counter (OTC) tamper-evident
packaging requirements, see 21 CFR 211.132(b)(1) (e.g., dentifrice products such as toothpaste
co-packaged with a toothbrush or dermatological products such as a dermatological drug pre-
filled into a delivery device, see 21 CFR 211.132(b)(1)). Certain combination products may be
exempt from bearing a statement of tamper-evident features on the package, see 21 CFR
211.132(c)(1) (e.g., propellant-based aerosols and saline nasal sprays).
Inspectional Approach to 21 CFR 211.132 for a Facility Operating Under a device QS-based
Streamlined Approach:
Evaluate the combination product manufacturer’s compliance with 21 CFR 211.132. Note that
21 CFR 211.132 is only applicable to OTC products and is, therefore, not applicable to many
types of CDRH-led combination products. If an investigator has questions on whether this
requirement applies, contact the lead center for assistance.
Reference/Resources
• Compliance Program 7346.832 - Pre-Approval Inspections
• Compliance Program 7356.002 - Drug Manufacturing Inspections
• Section IV.B.3, FDA Guidance for Industry and FDA Staff - Current Good
Manufacturing Practice Requirements for Combination Products
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21 CFR 211.137 Expiration dating
Combination Product Considerations for 21 CFR 211.137:
21 CFR 211.137 helps ensure that drug constituent parts of combination products meet applicable
standards of identity, strength, quality, and purity at the time of use, by requiring that the product
labeling bear an expiration date. Shelf-life28 expectations for device constituent parts generally
arise from design considerations (see 21 CFR 820.30). Generally, when constituent parts of a co-
packaged combination product can be used independently, expiration dating, when required,
should be listed separately for each constituent part. If a single expiration date is listed for a co-
packaged combination product, this date should be the earliest expiration date/shortest shelf-life
for any constituent part. In some cases, the drug constituent part might not have an expiration
date because current regulations exempt it from this requirement (e.g., homeopathic drug
products and investigational use products see 21 CFR 211.137(e) – (h)).
The expiration date for a combination product may be shorter than the expiration date or shelf-
life for its constituent part(s) if marketed independently. Reasons for a shorter expiration date
could include interactions between the constituent parts when combined, the effects of additional
manufacturing steps, or one constituent part having a shorter expiration date than the other(s).
Inspectional Approach to 21 CFR 211.137 for a Facility Operating under a Device QS-based
Streamlined Approach:
For pre-approval inspections, refer to Objective 2 elements of Compliance Program 7346.832
related to ensuring that the batches placed on stability for purposes of establishing expiration
date are representative of the proposed marketed product (see also discussion of stability in 21
CFR 211.166 section below). For surveillance inspections, refer to “Packaging and Labeling
System” elements of Compliance Program 7356.002 related to labeling the product with an
expiration date.
Any observations related to the shelf-life/expiration dating for only the device constituent part
should not be cited under 21 CFR 211.137. Such device constituent part considerations should
be evaluated and, when appropriate, cited under 21 CFR 820.30 and related provisions (see also
Attachment B for discussion of 21 CFR 820.30).
Reference/Resources:
• Compliance Program 7346.832 - Pre-Approval Inspections.
• Compliance Program 7356.002 - Drug Manufacturing Inspections.
• Section IV.B.4, FDA Guidance for Industry and FDA Staff - Current Good
Manufacturing Practice Requirements for Combination Products
• Guidance for Industry - Quality Systems Approach to Pharmaceutical CGMP
Regulations
28
Expiration dating is the more commonly used term for drug constituent parts, whereas shelf life is more
commonly used for device constituent parts.
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21 CFR 211.165 Testing and release for distribution
Combination Product Considerations for 21 CFR 211.165:
Testing must be conducted to confirm whether drug constituent parts meet final specifications
prior to releasing for distribution. For single-entity combination products, laboratory testing must
be performed on every batch of the combination product. For co-packaged combination
products, laboratory testing must be performed on every batch of the drug constituent part(s).
For single-entity combination products, instead of using units from a finished combination
product batch, manufacturers may wish to use samples that are not finished combination
products but are representative of the finished combination product with respect to the
characteristics and attributes relevant to testing the drug constituent part (see Section IV.B.5,
FDA Guidance for Industry and FDA Staff - Current Good Manufacturing Practice
Requirements for Combination Products).
Inspectional Approach to 21 CFR 211.165 for a Facility Operating under a Device QS-based
Streamlined Approach:
Evaluate the combination product manufacturer’s compliance with 21 CFR 211.165. For pre-
approval inspections, refer to Compliance Program 7346.832: 1) Objective 1(a) elements related
to out-of-specification (OOS) results during final product testing;29 2) Objective 1(b) elements
related to sampling, testing and evaluating finished products, 3) Objective 2 elements related to
analytical methods validation for testing of the finished combination product, and 4) Objective 3
elements related to the authenticity and veracity of analytical results. For Surveillance
Inspections, refer to Compliance Program 7356.002 “Materials System” elements related to
testing and release of products for distribution.
If a combination product manufacturer uses product samples that are not finished combination
products, appropriate evidence and an explanation of the rationale to support the approach should
be accessible at the manufacturing facility for review during the inspection. If samples are being
used for testing and release and there does not appear to be adequate data or justification for the
approach, contact the lead center for assistance.
Reference/Resources:
• Compliance Program 7346.832 - Pre-Approval Inspections.
• Compliance Program 7356.002 - Drug Manufacturing Inspections.
• Section IV.B.3 and IV.B.5, FDA Guidance for Industry and FDA Staff - Current Good
Manufacturing Practice Requirements for Combination Products
• Guidance for Industry - Quality Systems Approach to Pharmaceutical CGMP
Regulations
29
Quality data from OOS investigations and any related corrective actions should be addressed through the
combination product manufacturer’s quality system (see also 21 CFR 820.100 Corrective and Preventive Action
(CAPA) below)
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21 CFR 211.166 Stability testing
Combination Product Considerations for 21 CFR 211.166:
For both single-entity and co-packaged combination products, stability testing must be
performed on the drug constituent part as incorporated into the finished combination product.
For co-packaged combination products, if the drug product is purchased from another
manufacturer for inclusion in the combination product, the combination product manufacturer is
still responsible for ensuring the stability of the drug constituent part as marketed in the co-
packaged combination product through appropriate mechanisms, such as by implementing
purchasing controls to ensure the adequacy of the drug product manufacturer's stability testing or
by conducting additional stability testing (see 21 CFR 820.50). Documentation of such oversight
should be included in the CGMP records.
Combination product manufacturers may be able to use bracketing and matrixing approaches or
use stability data for a previously marketed product when a new combination product is a
modification of that already marketed product and the modification does not impact the stability
of the drug constituent part (see Section IV.B.6, FDA Guidance for Industry and FDA Staff -
Current Good Manufacturing Practice Requirements for Combination Products). Appropriate
evidence and an explanation of the rationale to support the approach should be accessible at the
manufacturing facility for review during the inspection.
Inspectional Approach to 21 CFR 211.166 for a Facility Operating under a Device QS-based
Streamlined Approach:
Evaluate the combination product manufacturer’s compliance with 21 CFR 211.166. For pre-
approval inspections, refer to Compliance Program 7346.832: 1) Objective 1(a) elements related
to out-of-specification (OOS) results during stability testing;30 2) Objective 1(b) elements related
to sampling, testing, release, 3) Objective 2 elements related to assurance that the batches placed
on stability for purposes of establishing expiration date will be representative of the marketed
product (see also discussion of expiration date in 21 CFR 211.137 section above), and 4)
Objective 3 elements related to assurance that the analytical results obtained are accurate. For
surveillance inspections, refer to Compliance Program 7356.002 “Laboratory Control System”
elements related to the stability program.
If the manufacturer is using stability data from a previously marketed product or bracketing or
matrixing approaches, and there does not appear to be adequate data or justification for the
approach, contact the lead center for assistance.
Reference/Resources:
• Compliance Program 7346.832 - Pre-Approval Inspections
• Compliance Program 7356.002 - Drug Manufacturing Inspections
• Compliance Program 7356.002B - Drug Repackagers/Relabelers
• Section IV.B.6, FDA Guidance for Industry and FDA Staff - Current Good
Manufacturing Practice Requirements for Combination Products
30
Quality data from OOS investigations and any related corrective actions should be addressed through the
combination product manufacturer’s quality system (see also 21 CFR 820.100 Corrective and Preventive Action
(CAPA) below).
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• Guidance for Industry - Quality Systems Approach to Pharmaceutical CGMP
Regulations
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21 CFR 211.167 Special testing requirements
Combination Product Considerations:
Special testing requirements to perform laboratory testing on each batch apply only if a
combination product or the drug constituent part thereof is: purported to be sterile and/or
pyrogen free,31 includes an ophthalmic ointment or is a controlled-release product.
Parametric release in lieu of these special testing requirements may be acceptable for some
terminally sterilized combination products and is common for some types of CDRH-led
combination products. Use of parametric release requires FDA approval for combination
products approved in an NDA, BLA, ANDA, or PMA. For some combination products (e.g.,
510(k) cleared products), it may be permissible for manufacturers to adopt parametric release
postmarket for a few well-established sterilization modalities (e.g., Ethylene Oxide Sterilization,
Gamma Irradiation Sterilization) and control such changes under their Quality System without
FDA review. If an investigator has concerns about whether a change to sterilization procedures
should have been reviewed by FDA, contact the lead center for assistance.
It may be acceptable for the combination product manufacturer to define “batch” based on the
drug constituent part rather than the finished combination product for purposes of special testing
requirements for pyrogens and endotoxins. For example, it may be acceptable to define a batch
as a subcomponent of the combination product that incorporates the drug constituent part (see
Section IV.B.7, FDA Guidance for Industry and FDA Staff - Current Good Manufacturing
Practice Requirements for Combination Products). Appropriate evidence and an explanation of
the rationale to support the approach should be accessible at the manufacturing facility for
review during the inspection.
Inspectional Approach to 21 CFR 211.167 for a Facility Operating under a Device QS-based
Streamlined Approach:
Evaluate the combination product manufacturer’s compliance with 21 CFR 211.167. For
products requiring sterility and endotoxin testing prior to batch release, refer to Compliance
Program 7356.002A, Section 3.10 “Laboratory Controls System.” For manufacturers using
parametric release for sterility and endotoxins see Quality System Inspection Technique (QSIT)
Product and Process Controls Subsystem and Sterilization Process Controls. If the manufacturer
is using a parametric release approach, and there does not appear to be adequate data or
justification for the approach, contact the lead center for assistance.
Generally, for terminally-sterilized CDRH-led combination products that are labeled as sterile,
the sterility assurance level (SAL) is expected to be 10-6 (see Guidance Submission and Review
of Sterility Information in Premarket Notification (510(k) Submissions for Devices Labeled as
Sterile below). If a CDRH-led combination product or constituent part thereof labeled as sterile
has another SAL value, you may contact the lead center for assistance, as needed.
If the combination product contains a sterile biological product constituent part, the combination
product manufacturer must also comply with the requirements of 21 CFR 610.12 (Reference
Compliance Program 7345.848, “Laboratory Controls System” “Availability for Distribution and
Testing for Release for Distribution,” Compliance Program 7356.002M “Aseptic/controlled
31
Note that the appropriate terminology on the label of products may vary based on the combination product (for
example, use of “non-pyrogenic,” “meets pyrogen limit specifications” or “pyrogen free”). If an investigator has
questions related to the labeling of a combination product, contact the lead center for assistance.
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processes,” and Compliance Program 7356.002A). Note that although 21 CFR 610.12 is
specifically referenced as related to sterile product requirements, if a combination product
contains a biological product all other requirements in 21 CFR 600 through 680 also apply (see
PART I.2 – Combination Product CGMPs)
If the manufacturer is defining batch based on the drug constituent part, and there does not
appear to be adequate data or justification for the approach, contact the lead center for
assistance, as needed.
Reference/Resources
• Compliance Program 7345.848 – Inspection of Biological Drug Products (CBER)
• Compliance Program 7356.002A - Sterile Drug Process Inspections
• Compliance Program 7356.002M - Inspections of Licensed Biological Therapeutic Drug
Products
• Guide to Inspections of Quality Systems, Quality System Inspection Technique
• Compliance Policy Guide Sec. 490.200 - Parametric Release of Parenteral Drug Products
Terminally Sterilized by Moist Heat
• Section IV.B.7, FDA Guidance for Industry and FDA Staff - Current Good
Manufacturing Practice Requirements for Combination Products
• Guidance for Industry - Quality Systems Approach to Pharmaceutical CGMP
Regulations
• FDA Guidance for Industry - Q4B Evaluation and Recommendation of Pharmacopoeial
Texts for Use in the ICH Regions: Annex 14 Bacterial Endotoxins Test General Chapter
• FDA Guidance for Industry - Submission of Documentation in Applications for
Parametric Release of Human and Veterinary Drug Products Terminally Sterilized by
Moist Heat Processes
• FDA Guidance for Industry - Sterile Drug Products Produced by Aseptic Processing -
Current Good Manufacturing Practice
• Guidance for Industry and Food and Drug Administration Staff - Submission and Review
of Sterility Information in Premarket Notification (510(k)) Submissions for Devices
Labeled as Sterile
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21 CFR 211.170 Reserve samples
Combination Product Considerations:
Single-entity and co-packaged combination product manufacturers must keep reserve samples of
each lot of the active ingredient, if any, that they receive, in whatever form it arrives at their
facility (e.g., as bulk active pharmaceutical ingredient or incorporated into an in-process
material) as well as reserve samples for the combination product.
For co-packaged combination products, the requirement to keep reserve samples for the
combination product can be met by maintaining samples of the drug constituent part in its
immediate container-closure system without retaining samples of the device constituent part
from the same package. For single-entity combination products, the combination product reserve
sample is generally the finished combination product, including the device constituent part or
components thereof that come into contact with the drug constituent part as packaged for
distribution. This may involve retaining the entire combination product (e.g., prefilled syringe) or
a separable portion (e.g., a cartridge).
It may be acceptable for combination product manufacturers to retain reserve samples that are
representative of, but not identical to, a finished drug constituent part or combination product, or
to maintain validated surrogates for some testing while retaining complete samples of the
combination product for other tests (see below). It may also be acceptable to retain samples that
are representative lots of a larger batch (e.g., representative samples of each size from within a
broadly defined batch that includes multiple sizes of the same family of coated combination
products such as drug eluting stents or drug coated catheters). (See Section IV.B.8, FDA
Guidance for Industry and FDA Staff - Current Good Manufacturing Practice Requirements for
Combination Products). Appropriate evidence and an explanation of the rationale to support the
approach should be accessible at the manufacturing facility for review during the inspection.
The combination product manufacturer must maintain twice the quantity of active ingredient and
combination product reserve samples necessary to perform required tests, except for sterility and
pyrogen testing (see 21 CFR 211.167 Special testing requirements above for additional
information regarding sterility and endotoxin testing). The quantity of product kept as reserve
samples should be aligned with the batch definitions in any related premarket submission for the
combination product. A sample of the device constituent part(s) may also need to be kept if, for
example, the device constituent part is needed to perform any required tests.
Inspectional Approach to 21 CFR 211.170 for a Facility Operating Under a device QS-based
Streamlined Approach:
Evaluate the combination product manufacturer’s compliance with 21 CFR 211.170. For pre-
approval inspections, refer to Compliance Program 7346.832 Objective 2 to assess whether the
reserve sampling practices at the facility are consistent with what was specified in the premarket
application and/or follow any instructions provided from the lead center regarding acceptable
reserve sample approach. For surveillance inspections, refer to Compliance Program 7356.002
“Laboratory Control System” elements related to the stability program.
If a combination product manufacturer is keeping reserve samples that are representative but not
identical to the marketed product or using samples from a representative lot (see above), and
there does not appear to be adequate data or justification for the approach contact the lead center
for assistance.
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Reference/Resources
• Compliance Program 7346.832 - Pre-Approval Inspections
• Compliance Program 7356.002 - Drug Manufacturing Inspections. Refer to “Laboratory
Control System” elements related to the stability program
• Section IV.B.8, FDA Guidance for Industry and FDA Staff - Current Good
Manufacturing Practice Requirements for Combination Products
• Guidance for Industry - Quality Systems Approach to Pharmaceutical CGMP Regulations
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ATTACHMENT B – Combination product inspectional considerations for
Called-out provisions of 21 CFR Part 820
This attachment provides additional information regarding the called-out provisions for the
streamlined approach under 21 CFR 4.4(b) and information on the inspectional approach for
these provisions for combination product manufacturers who use the drug CGMP-based
streamlined approach.
In addition to covering the drug requirements according to the applicable base compliance
program, evaluate the combination product manufacturer’s compliance with the called-out
provisions of 21 CFR Part 820 as described below.
NOTE: If the combination product is exempt from the device QS regulations, this attachment
does not apply. See PART III.1.A.(6) - Special Situations – Device Constituent Part Exempt from
the device QS-regulations. If a manufacturer claims that the device used in their combination
product is exempt from 21 CFR 820 requirements and the investigator has concerns, contact the
lead center.
NOTE: Installation (21 CFR 820.170) and Servicing (21 CFR 820.200) are called-out provisions
but are not described below. These requirements are not typically a focus of inspections and do
not apply to most CDER-led combination products. If an investigator has questions on these
requirements for a particular combination product or inspection, contact the lead center for
assistance.
21 CFR 820.20 Management responsibility
Combination Product Considerations:
Although companies that traditionally manufacture drug products are subject to statutory CGMP
provisions related to management responsibility and quality management systems,32 there are
specific requirements in 21 CFR 820.20 that are not explicitly addressed in drug CGMP
requirements (e.g., conducting management reviews to assess the suitability and effectiveness of
the quality system at defined intervals). Manufacturers of a combination product that includes a
device constituent part must satisfy all elements of 21 CFR 820.20.
Inspectional Approach to 21 CFR 820.20 for a Facility Operating Under a drug CGMP-based
Streamlined Approach:
Evaluate the combination product manufacturer’s compliance with 21 CFR 820.20. Refer to
QSIT section on Management Responsibility.
Reference/Resources
• Guide to Inspections of Quality Systems, Quality System Inspection Technique (QSIT).
Refer to QSIT section on Management Responsibility.
• Compliance Program 7382.845 - Inspection of Medical Device Manufacturers
32
See Section 501(a)(2)(B) of the FD&C Act [21 USC 351(a)(2)(B)].
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• Compliance Program 7383.001 - Medical Device PMA Preapproval and PMA
Postmarket Inspections
• Section IV.A.1, FDA Guidance for Industry and FDA Staff - Current Good
Manufacturing Practice Requirements for Combination Products
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21 CFR 820.30 Design controls
Combination Product Considerations:
Design controls requirements apply to the combination product as a whole, including design
considerations for each constituent part specific to its use in the combination products However,
it is appropriate for a combination product manufacturer to leverage design and development
information for any constituent part as part of the overall design controls for the combination
product. For example, design control activities for a combination product composed of a device
to be used with an already developed drug product, can leverage the drug properties as inputs for
design control activities that would focus on ensuring that the device appropriately delivers the
drug and that the drug quality is not adversely affected by its contact with the device.
Note that in some cases, design activities may occur at a separate facility from other
manufacturing activities for the combination product (see also “Special Instructions Concerning
Design Controls” in Compliance Program 7383.001 and Compliance Program 7382.845). These
facilities (often termed “specification developers”) may maintain the Design History File (DHF)
for the combination product. The combination product DHF may include cross-references to
relevant information rather than be a direct repository for all the information it needs to include.
Regardless of where DHF information is maintained, the combination product manufacturer
should be able to access necessary DHF information during the inspection to demonstrate
compliance with design control requirements. However, if another site is responsible for design
controls for the combination product, (e.g., a specification developer, see also PART II.2.B), it
may be more efficient or necessary to perform an additional inspection at that other site.
Inspectional Approach to 21 CFR 820.30 for a Facility Operating Under a drug CGMP-based
Streamlined Approach:
Evaluate the combination product manufacturer’s compliance with 21 CFR 820.30. Refer to the
QSIT section on Design Controls, which discusses comprehensive coverage of design controls.
Evaluation of design controls should start with the DHF for the combination product.
In cases where the combination product manufacturer is purchasing the device constituent part
(or its components to be assembled) from another entity (e.g., buying syringe components to be
combined and filled with the drug product), the combination product DHF may reference design
information from the supplier to support design of the device constituent part. However, the
DHF should demonstrate how the constituent part’s specifications are appropriate for its use in
the combination product, addressing any interaction of the constituent parts when combined.
Similarly, if the combination product manufacturer designed the entire product, previously
developed constituent part information can also be referenced in the DHF (e.g., using
development information on a previously approved drug product that is now being developed in
a pre-filled delivery device configuration).
Pharmaceutical development practices such as Quality by Design33 can be used and built upon to
demonstrate compliance with 21 CFR 820.30. However, the combination product manufacturer
should be able to communicate to the investigator how their design practices and terminology
align with design controls requirements. The manufacturer should also communicate how the
procedures in place align with all the requirements of 21 CFR 820.30. For example, the
33
See the Guidance for Industry on Q8(R2) Pharmaceutical Development.
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PROGRAM 7356.000
manufacturer should have procedures that describe the process for design verification and design
validation and should be able to explain the design verification and validation activities that were
conducted for the combination product.34
Reference/Resources
• Guide to Inspections of Quality Systems, Quality System Inspection Technique (QSIT).
Refer to QSIT section on Design Controls.
• Compliance Program 7382.845 - Inspection of Medical Device Manufacturers
• Compliance Program 7383.001 - Medical Device PMA Preapproval and PMA
Postmarket Inspections
• Section IV.A.2, FDA Guidance for Industry and FDA Staff - Current Good
Manufacturing Practice Requirements for Combination Products
• Design Control Guidance for Medical Device Manufacturers
• Guidance for Industry - Q8(R2) Pharmaceutical Development
• Guidance for Industry - Q9 Quality Risk Management
• ISO 14971 – Medical devices – Application of risk management to medical devices
34
Design validation provides objective evidence that product specifications conform with user needs and intended
uses. Design validation activities may include, for example, clinical evaluations or simulated use testing. Design
verification provides objective evidence that design outputs (e.g., diagrams, drawings, specifications and
procedures) meet design inputs (e.g., the physical and performance requirements). Design verification activities may
include, for example, tests, inspections, analyses, measurements, or demonstrations. See also Section IV.A.2, FDA
Guidance for Industry and FDA Staff Current good Manufacturing Practice Requirements for Combination
Products.
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21 CFR 820.50 Purchasing controls
Combination Product Considerations:
Purchasing controls are required for products received at the facility for use in the manufacture
of the combination product, for all suppliers of these products, and for suppliers of services
obtained (such as terminal sterilization conducted by an outside entity). Purchasing controls are
also related to acceptance activities performed to ensure that the supplied products and services
meet requirements. (Under a drug CGMP-based streamlined approach, acceptance activities are
evaluated under relevant 21 CFR Part 211 provisions including 21 CFR 211.82 and 21 CFR
211.84.)
Inspectional Approach to 21 CFR 820.50 for a Facility Operating Under a drug CGMP-based
Streamlined Approach:
Evaluate the combination product manufacturer’s compliance with 21 CFR 820.50. Evaluate the
following purchasing controls elements:
• Purchasing control and related incoming acceptance procedures.
• Purchasing data to evaluate the facility’s approach to accepting suppliers and
communicating specifications for purchased products and services.
• Actions taken in response to findings from supplier assessments.
• Relationship(s) and agreements between the combination product manufacturer and other
entities (e.g., the combination product sponsor (if not the manufacturer), constituent part
manufacturers, component suppliers). Determine how changes made by one of these
entities is communicated to the combination product manufacturer and, if applicable, to
other entities.
• How received products are tested, when needed, and controlled to ensure that
specifications are met.
Evaluation of purchasing controls should include suppliers of constituent parts and/or
components of constituent parts (note that components can include not only device components
but also drug components, as well as containers and closures, that are subject to the requirements
of 21 CFR 211.84 – see Attachment A discussion of 21 CFR 211.84). For example, if conducting
an evaluation of purchasing controls for a CDER-led combination product for which device
constituent parts (or their components) are purchased from a supplier, evaluate purchasing
controls over that supplier.
NOTE: Although constituent part suppliers may themselves be subject to premarket review and
to CGMP requirements, purchasing controls for these suppliers should still be a focus of
evaluation. For example, if supplied biological products or HCT/Ps are used in the combination
product, suppliers of the biological product and/or HCT/P should be evaluated during coverage
of purchasing controls even though the suppliers may themselves be subject to premarket review
and be subject to CGMP requirements applicable to biological products (see 21 CFR Parts 210,
211, 600 through 680) and/or current good tissue practice and donor eligibility requirements for
HCT/Ps (21 CFR Part 1271). As discussed in PART I.2, the combination product manufacturer
must also demonstrate compliance with applicable CGMP requirements under 21 CFR Parts
600 through 680 and/or 21 CFR Part 1271.
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Reference/Resources:
• Compliance Program 7382.845 - Inspection of Medical Device Manufacturers
• Compliance Program 7383.001 - Medical Device PMA Preapproval and PMA
Postmarket Inspections
• Section IV.A.3, FDA Guidance for Industry and FDA Staff - Current Good
Manufacturing Practice Requirements for Combination Products
• GHTF Final Document - Quality Management System – Medical Devices – Guidance on
the Control of Products and Services Obtained from Suppliers
• FDA Guidance - Contract Manufacturing Arrangements for Drugs: Quality Agreements
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21 CFR 820.100 Corrective and preventive action
Combination Product Considerations:
Although there is flexibility in coordinating CAPA across facilities, a combination product
manufacturer must ensure that applicable 21 CFR 820.100 requirements are met for their
facility.35 The manufacturer should have appropriate mechanisms in place to ensure that issues
are identified and action(s) needed to correct and prevent recurrence are taken. The combination
product manufacturer should take appropriate measures, which may include CAPAs, with regard
to all relevant manufacturing activities, including coordinating with other manufacturers, as
needed, to correct problems with the combination product and to prevent or mitigate them going
forward. The CAPA process should consider the impact of corrective and preventive actions on
the constituent parts and for the combination product as a whole.
Inspectional Approach to 21 CFR 820.100 for a Facility Operating Under a drug CGMP-based
Streamlined Approach:
Evaluate the combination product manufacturer’s responsibility for and compliance with
21 CFR 820.100. Refer to the QSIT section on Corrective and Preventive Action (but see also
NOTE below). Confirm that the CAPA process ensures a comprehensive review of activities is
undertaken to determine the cause of existing or potential problems, which could include
manufacturing problems, deviations (including issues with product yield), or nonconformities for
a constituent part or the combination product as a whole.
The combination product manufacturer’s CAPA process should consider implications of
corrective and preventive actions for each constituent part and for the combination product as a
whole. For example, review the CAPA documentation for implications of how changes may
impact constituent parts and the product as a whole, including adequate testing/evaluation of the
change. Effectiveness checks may need to consider the product as a whole even if the corrective
action is to a single constituent part.
NOTE: QSIT contains information in the CAPA section on coverage of Medical Device
Reporting (MDR), Corrections and Removals, and Medical Device Tracking. Compliance with
these requirements should NOT be evaluated in an inspection for a CDER-led combination
product unless such coverage is specifically requested in the inspectional assignment. If you
have questions, contact the lead center.
Reference/Resources:
• Guide to Inspections of Quality Systems, Quality System Inspection Technique (QSIT).
Refer to Refer to QSIT section on CAPA.
• Compliance Program 7382.845 - Inspection of Medical Device Manufacturers
• Compliance Program 7383.001 - Medical Device PMA Preapproval and PMA
Postmarket Inspections
• Section IV.A.4, FDA Guidance for Industry and FDA Staff - Current Good
Manufacturing Practice Requirements for Combination Products
35
Relevant requirements in the drug CGMPs include 21 CFR 211.192 and 21 CFR 211.180(e). Quality data from
OOS investigations and any related corrective actions should be addressed through the combination product
manufacturer’s quality system.
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ATTACHMENT C – Definitions and Acronyms
Definitions:
Base Compliance Program: The commodity-specific (e.g., drug, device, or biological product)
compliance program that aligns with the base CGMPs and the type of inspection being
performed at combination product manufacturing facility. For example, for an NDA preapproval
inspection of a combination product facility operating under a drug CGMP-based streamlined
approach, the base compliance program would be the compliance program for pre-approval
inspection of NDAs (Compliance Program 7346.832).
Base CGMPs: For combination product manufacturers using a streamlined approach, the base
CGMPs are the drug or device CGMPs that the manufacturer will follow in their entirety. The
base CGMPs can be either the drug CGMPs (21 CFR Parts 210 and 211) or the Quality System
Regulation (21 CFR Part 820).36
Called-out Provisions: Provisions from 21 CFR Part 4 that are specified for manufacturers of
combination products using a streamlined approach. The called-out provisions are those
provisions that the manufacturer is required to comply with from the non-base CGMPs. See
PART I.2 for the specific called-out provisions.
Commodity-specific Compliance Program: Compliance programs developed for the inspection
of drugs, devices, or biological products.
Constituent Part: A drug, device, or biological product that is part of a combination product.
Cross-labeled Combination Product: A combination product for which the constituent parts are
distributed separately (as may be the case for a light-activated drug product and a separately
distributed laser drug-activation device). See 21 CFR 3.2(e)(3), (4).
Co-packaged Combination Product: The constituent parts are packaged together (e.g., a surgical
or first-aid kit containing devices and drugs, a delivery device packaged with a container of drug
product). See 21 CFR 3.2(e)(2).
Current Good Manufacturing Practice (CGMP) Operating System: The operating system within
an establishment that is designed and implemented to address and meet the current good
manufacturing practice requirements for a combination product. (21 CFR 4.2).
Lead Center: The Agency medical product center (e.g., CBER, CDER, or CDRH) that has
primary jurisdiction for a specific combination product’s review and regulation.
Combination Product Manufacturer: A combination product manufacturer is an entity (facility)
engaged in activities for a combination product that are considered within the scope of
manufacturing for drugs, devices, biological products, and HCT/Ps. Such manufacturing
activities include, but are not limited to, designing, fabricating, assembling, filling, processing,
sterilizing, testing, labeling, packaging, repackaging, holding, and storage, including a contract
manufacturing facility (see also 21 CFR 4.2 and Reference 9).
36
Note that for combination products that include a biological product, the manufacturer must demonstrate
compliance with applicable CGMP requirements for biological products that are found within the standards in parts
600 through 680 (21 CFR Parts 600 through 680). For a combination product that includes any HCT/P, the
manufacturer must demonstrate compliance with applicable regulations in part 1271 (21 CFR Part 1271).
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Single-entity Combination Product: A combination product the constituent parts of which are
physically or chemically combined (e.g., a prefilled syringe or drug-eluting stent). See 21 CFR
3.2(e)(1).
Streamlined Approach: Demonstrating compliance with either the drug CGMPs (21 CFR Parts
210 and 211) or the device Quality System (QS) regulation (21 CFR Part 820) (base CGMPs)
and also demonstrating compliance with specified provisions identified in 21 CFR Part 4 (called-
out provisions) from the other of these two sets of CGMP requirements (see PART I.2). Using
21 CFR Parts 210 and 211 as the base CGMPs with the specified called-out provisions of
21 CFR Part 820 is a “drug CGMP-based streamlined approach.” Using 21 CFR Part 820 as the
base CGMPs with the specified called-out provisions of 21 CFR Part 211 is a “device QS
regulation-based streamlined approach.”
Subsystem: The elements which together comprise the CGMP Operating System for the base
CGMPs. For 21 CFR Part 211, these subsystems include Quality System, Production System,
Facilities and Equipment System, Laboratory Controls System, Materials System, and Packaging
and Labeling System (see Reference 10). For 21 CFR Part 820, these subsystems include
Management Controls, Design Controls, Corrective and Preventive Action, and Production and
Process Controls (see Reference 11).
Acronyms:
ANDA: Abbreviated New Drug Application
API: Active Pharmaceutical Ingredient
BLA: Biologic License Applications
BPDR: Biological Product Deviation Report
CAPA: Corrective Actions and Preventive Actions or Corrective and Preventive Actions
CGMP: Current Good Manufacturing Practice
DHF: Design History File
EIR: Establishment Inspection Report
FAR: Field Alert Report
HCT/P: Human Cells, Tissues, and Cellular and Tissue-Based Products
MDR: Medical Device Report
NDA: New Drug Application
OAI: Official Action Indicated
OOS: Out-of-Specification
OTC: Over-the-Counter
PMA: Premarket Approval
QS: Quality System
QSIT: Quality System Inspection Technique
Date of Issuance: June 4, 2020 Page 46 of 46
来源：FDA Pharmaceutical Quality Documents · fda.gov