Guidance for Industry and 
FDA Staff: 
Current Good Manufacturing Practice 
Requirements for Combination Products
 
 
FINAL GUIDANCE 
 
 
 
The draft of this document was issued in January 2015. 
 
Additional copies are available from: 
Office of Combination Products 
 Food and Drug Administration  
WO32, Hub/Mail Room #5129  
10903 New Hampshire Avenue  
Silver Spring, MD 20993  
(Tel) 301-796-8930 
 (Fax) 301-847-8619 
http://www.fda.gov/oc/combination 
 
For questions regarding this document, contact the Office of Combination Products at 301-796-
8930 or combination@fda.gov. 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Office of Combination Products (OCP) in the Office of the Commissioner  
Center for Biologics Evaluation and Research (CBER) 
Center for Drug Evaluation and Research (CDER) 
Center for Devices and Radiological Health (CDRH) 
Office of Regulatory Affairs (ORA) 
 
 
January 2017 TABLE OF CONTENTS 
 
I.  Introduction ............................................................................................................................ 3 
II.  Background ............................................................................................................................ 4 
A.  Definition of a combination product ............................................................................................ 4 
B.  Quality and Current Good Manufacturing Practices................................................................. 5 
C.  Overview of the final rule .............................................................................................................. 5 
D.  The role of the lead center and other agency components ......................................................... 9 
III.  General Considerations for CGMP Compliance .............................................................. 9 
A.  Demonstrating compliance .......................................................................................................... 10 
B.  Investigational products .............................................................................................................. 11 
C.  Definitions and terminology. ....................................................................................................... 12 
D.  What CGMP requirements apply to a product or facility? ..................................................... 15 
E.  Control of changes to a combination product ........................................................................... 18 
IV.  What do I need to know about the CGMP requirements specified in 21 CFR 4.4(b)? . 19 
A.  Provisions from the device QS regulation specified in 21 CFR 4.4(b)(1) ................................ 19 
B.  Provisions from the drug CGMPs specified in 21 CFR 4.4(b)(2) ............................................ 28 
C.  Combination products that include biological products and HCT/Ps .................................... 38 
V.  Application of CGMP requirements to specific types of combination products ................ 40 
A.  Prefilled syringe ........................................................................................................................... 41 
B.  Drug-coated mesh ........................................................................................................................ 46 
C.  Drug Eluting Stent (DES) ............................................................................................................ 49 
VI.  Contact Us ........................................................................................................................ 53 
VII.  Glossary ............................................................................................................................ 54 
VIII.  References .................................................................................................................... 56  Contains Nonbinding Recommendations  
 
Guidance for Industry and FDA Staff: 
Current Good Manufacturing Practice Requirements for Combination 
1
Products  
 
This guidance represents the current thinking of the Food and Drug Administration (FDA or 
Agency) on this topic.  It does not establish any rights for any person and is not binding on FDA 
or the public.  You can use an alternative approach if the approach satisfies the requirements of 
the applicable statutes and regulations.  To discuss an alternative approach, contact the FDA 
office responsible for this guidance as listed on the title page of this guidance.  
 
I.  Introduction 
 
This guidance describes and explains the final rule on current good manufacturing 
practice (CGMP) requirements for combination products that FDA issued on January 22, 2013 
(final rule).2 (21 Code of Federal Regulations (CFR) part 4).  Prior to issuance of the final rule, 
although 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), there 
were no regulations to clarify and explain the application of these CGMP requirements to 
combination products.  The final rule did not establish any new requirements; it was intended to 
clarify which CGMP requirements apply when drugs, devices, and biological products are 
combined to create combination products, and to set forth a transparent and streamlined 
regulatory framework for firms to use when demonstrating compliance with applicable CGMP 
requirements.3   
 
Section II of this document provides the definition of combination product, an 
overview of the final rule, and describes the role of the lead center and other Agency 
components4 with respect to combination product CGMP issues.  Section III addresses certain 
general considerations for CGMP compliance for combination products.  Section IV presents the 
purpose and content of specific CGMP requirements addressed in the final rule.  Finally, Section 
V analyzes hypothetical scenarios that illustrate how to comply with certain CGMP requirements 
                                                 
1 This guidance was prepared by the Office of Combination Products in the Office of the Commissioner in 
conjunction with the Center for Biologics Evaluation and Research, Center for Drug Evaluation and Research, 
Center for Devices and Radiological Health, and the Office of Regulatory Affairs.   
2 See the Current Good Manufacturing Practice Requirements for Combination Products, 78 FR 4307 (January 22, 
2013). 
3 As stated in the preamble to the final rule, combination products were subject to CGMP requirements that apply to 
each constituent part of their combination product prior to promulgation of 21 CFR part 4.  Although products 
developed prior to promulgation of part 4 are frequently termed legacy combination products, FDA deliberately 
does not use this terminology in this guidance because it could be inappropriately interpreted to indicate that 
products developed prior to promulgation of part 4 are therefore subject to fewer CGMP obligations than products 
developed after promulgation of part 4. 
4 Agency component is defined at 21 CFR 3.2(b) as the Center for Biologics Evaluation and Research, the Center 
for Devices and Radiological Health, the Center for Drug Evaluation and Research, or alternative organizational 
component of the agency. 
  3  Contains Nonbinding Recommendations  
 
for specific types of combination products.  Throughout this guidance, the Agency also refers to 
existing guidance and additional resources that address CGMP requirements for drugs, devices, 
biological products, and HCT/Ps, to further inform combination product manufacturers on how 
to comply with CGMP requirements.  
 
FDAs guidance documents, including this guidance, do not establish legally enforceable 
responsibilities.  Instead, this guidance describes the Agencys current thinking on a topic that 
should be viewed only as recommendations, unless specific regulatory or statutory requirements 
are cited.  The use of the word should in Agency guidance means that something is suggested or 
recommended, but not required.  
 
II.  Background 
 
A. Definition of a combination product 
 
As set forth in part 3 (21 CFR part 3), a combination product is a product composed of 
two or more different types of medical products (i.e., a combination of a drug, device, and/or 
biological product with one another).5  The drugs, devices, and biological products included in 
combination products are referred to as constituent parts of the combination product. 
 
Under 21 CFR 3.2(e), a combination product includes: 
 
  A product comprised of two or more regulated components, i.e., drug/device, 
biologic/device, drug/biologic, or drug/device/biologic, that are physically, 
chemically, or otherwise combined or mixed and produced as a single entity (a 
single entity combination product, such as a prefilled syringe or drug-eluting 
stent);  
 
  Two or more separate products packaged together in a single package or as a unit 
and comprised of drug and device products, device and biological products, or 
biological and drug products (a co-packaged combination product, such as a 
surgical or first-aid kit); 
 
  A drug, device, or biological product packaged separately that according to its 
investigational plan or proposed labeling is intended for use only with an 
approved, individually specified drug, device, or biological product where both 
are required to achieve the intended use, indication, or effect and where upon 
approval of the proposed product the labeling of the approved product would need 
to be changed (e.g., to reflect a change in intended use, dosage form, strength, 
                                                 
5 Any reference in this guidance to CGMP requirements as applicable to a combination product that includes a drug 
constituent part should be understood to refer as well to any combination product that includes a biological product 
constituent part that is also subject to regulation under the Federal Food, Drug, and Cosmetic Act (FD&C Act) as a 
drug, and any reference to CGMP requirements as applicable to a combination product that includes a device 
constituent part should be understood to refer as well to combination products that include a biological product 
constituent part that is also subject to regulation as a device under the FD&C Act. 
  4  Contains Nonbinding Recommendations  
 
route of administration, or significant change in dose) (a cross-labeled 
combination product, as might be the case for a light-emitting device and a light-
activated drug); or 
 
  Any investigational drug, device, or biological product packaged separately that 
according to its proposed labeling is for use only with another individually 
specified investigational drug, device, or biological product where both are 
required to achieve the intended use, indication, or effect (another type of cross-
labeled combination product). 
 
B. Quality and Current Good Manufacturing Practice 
 
One of FDAs goals is to assure the availability of quality drugs, biologics, devices, and 
combination products that consistently meet applicable requirements and specifications.  The 
drug CGMP and device QS regulations, as well as the CGMPs for biologics and current good 
tissue practices for HCT/Ps, provide a framework of minimum requirements to help assure 
product quality.  The core requirements embedded in these regulations  provide for systems that 
assure proper design, monitoring, and control of manufacturing processes and facilities.  This 
includes establishing a strong quality management system, using appropriate quality raw 
materials, establishing robust manufacturing and control procedures based on sound design 
principles, and detecting and investigating product quality deviations.  In addition, these 
regulations call for ongoing assessment of systems and the implementation of corrective actions 
where appropriate.  
 
C. Overview of the final rule 
 
1.  Summary of the Final Rule 
 
The constituent parts of a combination product retain their regulatory status (as a drug or 
device, for example) after they are combined.  The final rule clarifies that the CGMP 
requirements that apply to each of the constituent parts apply to the combination product they 
constitute. This guidance refers to a CGMP operating system to mean the operating system 
within an establishment that is designed and implemented to address and meet the current good 
manufacturing practice requirements applicable to the manufacture of a combination product. 
 
  The final rule on CGMP requirements for combination products applies to all 
combination products.  The CGMP requirements for constituent parts of cross-labeled 
combination products that are entirely manufactured at separate facilities are the same as those 
that would apply if these constituent parts were not part of a combination product (e.g., for a 
drug/device combination product, only parts 210 and 211 (21 CFR parts 210 and 211) would 
apply to the manufacture of the drug constituent part(s) of the cross-labeled combination product, 
and only part 820 (21 CFR part 820) would apply to the device constituent part(s)).  With regard 
to cross-labeled combination products, part 4 was intended to clarify only that the CGMP 
obligations applicable to the drugs, devices, or biological products also apply to these types of 
articles when they are constituent parts of cross-labeled combination products.   
 
  5  Contains Nonbinding Recommendations  
 
Because constituent parts of cross-labeled combination products need only comply with 
the requirements otherwise applicable to that type of product (e.g, part 211 for a drug constituent 
part or part 820 for a device constituent part), the streamlined approach (discussed below) is 
generally not relevant or applicable to them.  However, to the extent that the constituent parts of 
a cross-labeled combination product are manufactured at the same facility, the manufacturing 
process would be akin to when the manufacture of the constituent parts of a co-packaged 
combination product occurs at the same facility.  Accordingly, for  cross-labeled combination 
products when 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.   
We believe this approach is consistent with the principles of part 4.   
 
For single-entity combination products and co-packaged combination products, part 4 
identifies two ways to demonstrate compliance with CGMP requirements.  Under the first 
option, manufacturers demonstrate compliance with all CGMP regulations applicable to each of 
the constituent parts included in the combination product.6  Under the second option, 
manufacturers implement a streamlined approach for combination products that include both a 
drug and a device by demonstrating compliance with either the drug CGMPs (21 CFR parts 210 
and 211) or the device Quality System (QS) regulation (21 CFR part 820) and also 
demonstrating compliance with specified provisions from the other of these two sets of CGMP 
requirements.7, 8  In addition, for a combination product that includes a biological product, the 
manufacturer must demonstrate compliance with the CGMP requirements specific to biological 
products 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 the regulations in 
part 1271 (21 CFR part 1271)including the current good tissue practice (CGTP) requirements 
and donor eligibility requirements.9, 10, 11  
 
Specifically, the streamlined approach under 21 CFR 4.4(b) provides that combination 
product manufacturers may 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: 
 
                                                 
6 See 21 CFR 4.4(a) 
7 See 21 CFR 4.4(b).   
8 While 21 CFR 211 requirements apply to all combination products because combination products always contain a 
drug and/or a biological product, 21 CFR 820 requirements apply only to combination products which include a 
device constituent part. 
9 See 21 CFR 4.4(a) and (b). 
10 As discussed later in section IV.C, an HCT/P may be a constituent part of a combination product when the 
HCT/P is not regulated solely under section 361 of the PHS Act because it fails to meet one or more of the criteria in 
21 CFR 1271.10, and is, therefore, regulated as a drug, device, and/or biological product. See also 21 CFR 1271.20. 
11 For the purposes of part 4, FDA uses the term CGMP requirements to include all such requirements found in 
the standards in parts 600 through 680 that may apply to biological products.  We note that biological products and 
combination products that include biological product constituent parts must comply with all applicable requirements 
in parts 600 through 680.  Because many of the requirements in parts 600 through 680 are not considered CGMP 
requirements, such requirements are not addressed in part 4 and are not a focus of this guidance.  
 
  6  Contains Nonbinding Recommendations  
 
  The drug CGMPs and the following provisions from the device QS regulation in 
accordance with 21 CFR 4.4(b)(1) (drug CGMP-based streamlined approach): 
 
(i) 21 CFR 820.20     Management responsibility  
(ii) 21 CFR 820.30     Design controls 
(iii) 21 CFR 820.50    Purchasing controls 
(iv) 21 CFR 820.100    Corrective and preventive action 
(v) 21 CFR 820.170     Installation 
(vi) 21 CFR 820.200    Servicing 
 
OR 
 
  The device QS regulation and the following provisions from the drug CGMPs in 
accordance with 21 CFR 4.4(b)(2) (device QS regulation-based streamlined approach): 
 
(i) 21 CFR 211.84   Testing and approval or rejection of components, drug 
product containers, and closures 
(ii) 21 CFR 211.103     Calculation of yield 
(iii) 21 CFR 211.132  Tamper-evident packaging requirements for over-the-
counter (OTC) human drug products 
(iv) 21 CFR 211.137    Expiration dating 
(v) 21 CFR 211.165    Testing and release for distribution 
(vi) 21 CFR 211.166    Stability testing 
(vii) 21 CFR 211.167   Special testing requirements  
(viii) 21 CFR 211.170   Reserve samples 
 
A manufacturer may prefer one approach over the other based, for example, on the details 
of the manufacturing process used at the facility or in light of other manufacturing activities 
undertaken at the facility.  The manufacturer is not required to choose a streamlined approach 
based on the CGMP regulations for the constituent part that provides the primary mode of action 
(PMOA) of the combination product (see II.D below).  For example, if the drug constituent part 
of a drug-device combination product provides the products PMOA, the manufacturer of that 
combination product may choose to adopt either the device QS regulation-based or drug CGMP-
based streamlined approach, or choose to develop a CGMP operating system that wholly 
complies with the specifics of applicable provisions of both the drug CGMPs and the device QS 
regulation. 
 
21 CFR 4.4(c) provides that if a facility manufactures only one type of constituent part 
(e.g., a drug or device constituent part) of a co-packaged or single-entity combination product, 
that facility is subject only to the CGMP regulations applicable to that constituent part (i.e., part 
211 for a drug or part 820 for a device, as well as those under parts 600 through 680 for a 
biological product and part 1271 for an HCT/P).  21 CFR 4.4(d) provides that when two or more 
types of constituent parts to be included in a single-entity or co-packaged combination product 
have arrived at the same facility, or the manufacture of these constituent parts is occurring at the 
same facility, that facility must comply with all CGMP requirements described in part 4 
  7  Contains Nonbinding Recommendations  
 
applicable to the manufacturing activities at that facility, and a streamlined approach under 21 
CFR 4.4(b) may be used to demonstrate compliance with these requirements.   
 
Similarly, if a facility manufactures a drug or device that is not a constituent part of a 
combination product and also manufactures a combination product, the CGMP requirements for 
the independently marketed drug or device do not change (compliance with parts 210/211 or part 
820, respectively).  Accordingly, if a facility manufactures an independently marketed device 
that is subject to part 820 and a combination product, it cannot manufacture the device under a 
drug CGMP-based streamlined operating system, even if it is used for the combination product, 
because this operating system only includes limited, specified provisions from the QS regulation.  
However, both the device and the combination product may be manufactured under a device QS 
regulation-based streamlined operating system, with the device that is not part of a combination 
product then being subject only to part 820. 
 
2.  Documentation of CGMP Approach 
 
Combination product manufacturers should be able to identify all documentation needed 
to demonstrate compliance with part 4, and make it readily accessible for an FDA inspection.  
The facilitys quality system documentation should identify the CGMP operating system for the 
combination product(s) manufactured at that facility, and the manufacturer should share this 
information with investigators at the initiation of an inspection.  For combination product 
manufacturers implementing a streamlined approach (See Section II.B.1 above), inspection of 
the base CGMP operating system (i.e., 21 CFR part 210/211 or 21 CFR part 820) will typically 
be consistent with existing compliance programs and policies associated with it.  For specified  
provisions from the non-base system, FDA intends to utilize the compliance program and policy 
elements specific to these provisions.12 
 
Prior to the promulgation of part 4, manufacturers of combination products already had to 
demonstrate compliance with the applicable CGMP requirements for each constituent part of 
their combination product.  Manufacturers should ensure that their CGMP procedures and 
processes are compliant with the regulatory framework provided in part 4.  If the operating 
system requires changes to come into compliance, manufacturers should document the steps they 
take to ensure ongoing product safety and effectiveness.  Manufacturers should be prepared to 
discuss their approach during inspections. 
 
Combination product manufacturers who are required to address CGMP issues as part of 
premarket review should identify in premarket submissions whether they are operating under a 
streamlined approach, and if so, whether it is a drug CGMP-based or device QS regulation-based 
streamlined approach.13  In premarket submissions, the CGMP approach should be identified for 
each relevant facility.  For NDAs, BLAs and ANDAs, the CGMP approach should be described 
                                                 
12 For a listing of existing Compliance Program Guidance Manuals (CPGMs) for drugs, devices, and biologics, see 
http://www.fda.gov/ICECI/ComplianceManuals/ComplianceProgramManual/ucm2005382.htm.   
13 Submission of CGMP information is not routinely required prior to clearance of 510(k)s.  As discussed, 
manufacturers of 510(k) combination products should identify their CGMP operating system in the quality system 
documentation at their facilities. 
  8  Contains Nonbinding Recommendations  
 
in the Common Technical Document.  For additional details on placement within the CTD, see 
eCTD Technical Conformance Guide, Section 3.3.2.14  For PMAs, the CGMP approach should 
be documented in the manufacturing section of the PMA (the manufacturing module for a 
modular PMA). 
 
D. The role of the lead center and other Agency components 
 
A combination product is assigned to an Agency center that will have primary 
jurisdiction (i.e., the lead) for that combination products premarket review and regulation.  
Under section 503(g)(1) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 
351(g)), assignment of a combination product to a lead center is based on a determination of 
which constituent part provides the PMOA of the combination product.15 
 
If the PMOA of a device-biological product combination product is attributable to the 
biological product, for example, the center responsible for premarket review of such a biological 
product would have primary jurisdiction for the regulation of the combination product.  The lead 
center for premarket review of the combination product also has the lead for ensuring 
compliance with CGMP regulatory requirements.  Regardless of the PMOA, Agency 
components will coordinate as appropriate to enable efficient, effective CGMP regulatory 
oversight, including appropriate CGMP inspections.   
 
The lead center is a manufacturers primary point of contact.   Manufacturers may also 
contact the Office of Combination Products (OCP) for assistance, as needed, in identifying 
appropriate contact points (including those in the lead center), resolving substantive issues, or 
otherwise facilitating interactions with the Agency and collaboration among Agency 
components, including centers and the Office of Regulatory Affairs (ORA). 
 
III.  General Considerations for CGMP Compliance 
 
This section addresses some general considerations for CGMP compliance for 
combination products.  Note that this guidance addresses only CGMP requirements.  Additional 
requirements may apply including the need for premarket submissions as a result of changes to 
product design, intended use, or manufacture.   
 
                                                 
14 Available at 
http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/ElectronicSub
missions/UCM465411.pdf.  
15 The primary mode of action of a combination product is the single mode of action (drug, device, or biological 
product) that provides the most important therapeutic action of the combination product.  The most important 
therapeutic action is the mode of action expected to make the greatest contribution to the overall intended 
therapeutic effects of the combination product.  See 21 CFR 3.2(k) (which defines mode of action and 
therapeutic) and (m) (which defines primary mode of action).  For more information on product classification, 
assignment, and PMOA, see the guidance for industry How to Write a Request for Designation (RFD)(April 2011). 
  9  Contains Nonbinding Recommendations  
 
A. Demonstrating compliance 
 
The final rule identifies two ways for co-packaged and single-entity combination product 
manufacturers to demonstrate compliance with applicable CGMP requirements.  The Agency 
intends for the term demonstrate to apply for part 4 as it would be for purposes of fulfilling the 
underlying CGMP regulations listed in 21 CFR 4.3.  Manufacturers must demonstrate 
compliance with each applicable CGMP requirement for constituent parts and combination 
products.16 
 
If a streamlined approach is used, the manufacturer must demonstrate compliance with all 
of the relevant provisions of either the drug CGMPs or device QS regulation, and the provisions 
specified in 21 CFR 4.4(b) for the other set(s) of CGMP requirements applicable to the product.   
Further guidance on how to demonstrate compliance with the regulations specified in 21 CFR 
4.4(b) is provided in section IV of this guidance.  A manufacturer who implements a streamlined 
approach is not expected to demonstrate compliance with the specific provisions of the non-base 
set of requirements other than those specified in 21 CFR 4.4(b) (e.g., for a drug CGMP-based 
streamlined approach, the manufacturer must demonstrate compliance with applicable drug 
CGMPs plus the six specified provisions from part 820, as applicable, but the manufacturer does 
not need to demonstrate compliance with the other specific provisions in part 820). 
 
As provided in 21 CFR 4.4(e), in the event of a conflict between regulations applicable 
under part 4, the regulations most specifically applicable to the constituent part in question  
supersede the more general.  The intent of this provision is to address any potential conflicts 
between regulations.  This provision does not provide a basis for the Agency to require 
manufacturers to demonstrate compliance with provisions not otherwise identified in part 4 as 
applicable to them.   
 
Some of the provisions specified in part 4 from the drug CGMPs and device QS 
regulation cross-reference other provisions of parts 211 and 820, respectively.  This raises the 
question of whether manufacturers must specifically demonstrate compliance with these cross-
referenced provisions.  FDA believes that manufacturers can adequately address the expectations 
of these cross-referenced provisions through implementation of either a drug CGMP-based or 
device QS regulation-based CGMP streamlined approach.   
 
For example, 21 CFR 211.170 (Reserve samples) references 21 CFR 211.192 (Production 
record review).  However, 21 CFR 211.192 is not a specified provision in 21 CFR 4.4(b)(2) 
because part 820 encompasses the requirements of that section.  In particular, under the CAPA 
requirements in 21 CFR 820.100, a manufacturer operating under a device QS-based streamlined 
approach should have the systems in place that would satisfy the requirements of 21 CFR 
211.192.  Similarly, 21 CFR 211.103 (Calculation of yield) references 21 CFR 211.68 
(Automatic, mechanical, and electronic equipment) in relation to using automated equipment for 
yield calculations and maintaining appropriate controls over such equipment.  Corresponding 
provisions in 21 CFR 820.70(i), applicable under a QS-regulation based streamlined approach, 
                                                 
16 21 CFR part 4. 
  10  Contains Nonbinding Recommendations  
 
require that automated data processing systems be validated for their intended uses.  To take 
another example, the definition of design output in 21 CFR 820.3 makes reference to device 
master record.  Both part 211 and part 820 have requirements for master records (21 CFR 
211.186, Master Production and Control Records and 21 CFR 820.181, Device Master Record).  
FDA believes the substantive expectations of these master record provisions are aligned and 
needed to control product development and manufacture. 
 
This guidance does not focus on how to demonstrate compliance with provisions of the 
drug CGMPs and device QS regulation other than those specified in 21 CFR 4.4(b).  Other 
provisions of these regulations address a variety of manufacturing considerations regarding, for 
example, in-process materials, facility and equipment, record-keeping, labeling, personnel, 
inputs, testing, and distribution. 
 
B. Investigational products 
 
Part 4 does not alter the scope of the underlying CGMP regulations for drugs, devices, 
biological products, and HCT/Ps.  In particular, part 4 does not alter the applicability of these 
CGMP regulations to investigational products.   
 
An investigational drug for use in a phase 1 study is subject to the statutory requirements 
set forth in 21 U.S.C. 351(a)(2)(B).  The production of such a drug is generally exempt from 
compliance with the regulations in parts 210 and 21117 and, therefore, so is an investigational 
combination product that includes a drug constituent part for use in a phase 1 study.  This 
exemption does not apply to an investigational combination product or drug constituent part, 
however, once it has been made available for use by or for the sponsor in phase 2 or phase 3 
studies, nor does the exemption apply to a drug product that has been lawfully marketed.  For 
additional information on study phases, see 21 CFR 312.21. 
 
Under 21 CFR 812.1, investigational devices are exempt from part 820 except for design 
control requirements under 21 CFR 820.30.  This exemption also applies to the manufacturing of 
investigational combination products that include device constituent parts.  Investigational 
combination products that include a device constituent part are subject to design controls (except 
when the device constituent part is exempt from design controls, see III.C.3 below), but not to 
the other provisions of part 820.  Design controls should start as early as possible, once a 
company has determined that a product appears to have clinical utility and management has 
committed to further development (see also IV.A.2 below).18   
 
The Agency considers these exemptions from requirements under parts 211 and 820 
applicable to combination products and constituent parts of combination products whether they 
                                                 
17 See 21 CFR 210.2(c). 
18 The preamble to the device QS regulation (61 FR 52602) provides additional detail on when design controls apply 
for products early in the design life-cycle:  The design control requirements are not intended to apply to the 
development of concepts and feasibility studies.  However, once it is decided that a design will be developed, a plan 
must be established to determine the adequacy of the design requirements and to ensure that the design that will 
eventually be released to production meets the approved requirements. (61 FR 52616, Comment 62) 
  11  Contains Nonbinding Recommendations  
 
are being studied under an investigational device exemption (IDE) or an investigational new 
drug application (IND).  Even when these exemptions apply, however, methods, facilities, and 
manufacturing controls that are appropriate for the investigational products should be used.  
When developing and applying appropriate manufacturing practices, the Agency recommends 
that the hazards and associated risks from the manufacturing environment that might adversely 
affect an investigational combination product be considered. 
 
For further information on the CGMP requirements for investigational products, see 21 
CFR 210.2(c), 21 CFR 820.1, 61 Federal Register (FR) 52,616-52,617, and the Guidance for 
Industry on CGMP for Phase 1 Investigational Drugs (July 2008).  Manufacturers who have 
questions about IDE or IND requirements for their combination product should contact the lead 
center or OCP, if needed, for assistance.  
 
C. Definitions and terminology 
 
Unless 21 CFR part 4 expressly states otherwise, terms used have the same meaning as 
when used in the underlying, referenced regulations.  This section addresses the meaning and 
significance for combination products of the terms manufacture and manufacturer, 
constituent part and component, device, and drug container and closure.  It also 
addresses the meaning of convenience kit as a type of co-packaged combination product.  
Other relevant definitions can be found in part 4 and the underlying CGMP regulations (see, e.g., 
21 CFR 210.3, 21 CFR 211.3, 21 CFR 600.3, 21 CFR 606.3, 21 CFR 820.3, and 21 CFR 1271.3) 
 
1.  Manufacture and manufacturer 
 
The definition of the term manufacture in part 4 is intended to include all of the 
activities considered within the scope of manufacturing for drugs, devices, biological products, 
and HCT/Ps.  Accordingly, the definition of manufacture in 21 CFR 4.2 includes, but is not 
limited to, designing, fabricating, assembling, filling, processing, testing, labeling, packaging, 
repackaging, holding, and storage.  For example, if a company designs a drug-device 
combination product, that activity constitutes manufacture of that product, and the facility at 
which the design work occurs is a manufacturing facility.  That company is a manufacturer 
subject to part 4 for the design activities it performs, even if all other aspects of the combination 
products manufacture (e.g., fabricating, labeling, or packaging) are performed by another entity.  
Similarly, a facility responsible for the holding and storage of a combination product would be 
subject to related CGMP requirements such as 21 CFR 211.142 (Warehousing procedures) 
and/or 21 CFR 820.150 (Storage), depending upon whether the facility applies a streamlined 
approach and if so, which approach it applies. 
 
2.  Constituent part versus component 
 
The term constituent part is used by the Agency as a succinct way to identify a drug, 
device, or biological product included in a combination product.  Under the drug CGMPs, 
component is defined as any ingredient intended for use in the manufacture of a drug product, 
  12  Contains Nonbinding Recommendations  
 
including those that may not appear in such drug product.19  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.20  Components can include sub-assemblies that are further processed to make a 
finished device.  In contrast, a finished device is suitable for use or capable of functioning, 
whether or not it is packaged, labeled, or sterilized,21 as would be the case for a device 
constituent part as incorporated into a combination product.22   
 
A facility that manufactures only device components, including device components used 
in a combination product, is not made subject to the device QS regulation by part 4.23  Similarly, 
a facility that manufactures solely active pharmaceutical ingredients (APIs) is not subject to part 
211, though it is subject to statutory CGMP requirements under Section 501 of the FD&C Act 
(21 U.S.C. 351).  Part 4 does not make such a drug component manufacturing facility subject to 
part 211 if those components are for use in a combination product.  However, a facility that 
manufacturers a drug-device combination product formed from components is subject to parts 
211 and 820, and must comply with these two sets of regulations as provided in part 4.24  
 
In short, the terms constituent part in part 4 and component in the CGMP regulations 
serve different regulatory purposes.  The use of the term constituent part in part 4 refers to 
drugs, devices, and biological products included in combination products and does not alter the 
meaning of the term component or alter whether the regulations listed in 21 CFR 4.3 apply to 
component manufacturers.   
 
3.  Drug containers and closures versus delivery devices  
 
The Agency draws a distinction between mere drug containers and closures and 
containers and closures that are also devices.  The essential difference is generally whether the 
article is designed to deliver the drug it contains or merely to hold it.  If the article merely holds 
the drug, it is only subject to drug CGMPs as a container or closure.  An article that holds or 
contains a drug, but also delivers it, may also be a device subject to the device QS regulation in 
addition to the requirements relating to drug containers and closures.   
 
A container closure system is the sum of packaging components that together contain and 
protect the drug product.  This includes primary and secondary packaging components if the 
latter are intended to provide additional protection to the drug product.25  Elements of container 
closure systems that are device constituent parts include piston syringes, metered dose inhalers 
(MDIs), and containers for intravenously-administered (IV) fluids (such as IV bags containing 
                                                 
19 21 CFR 210.3. 
20 21 CFR 820.3(c). 
21 21 CFR 820.3(l). 
22 21 CFR 4.2. 
23 See 21 CFR 820.1(a). 
24 See 78 FR 4313-4314, Comment 15. 
25 See the Guidance for Industry on Container Closure Systems for Packaging Human Drugs and Biologics: 
Chemistry, Manufacturing, and Controls Documentation (May 1999). 
  13  Contains Nonbinding Recommendations  
 
saline or anti-coagulants), which both hold and deliver the drugs or biological products they 
contain.26  In the case of an IV container, the drug is delivered to the patient via the IV line. 
 
The Agency has exempted some devices from all or certain provisions of the device QS 
regulations.  For example, 21 CFR 880.6430 exempts liquid medication dispensers (cups, 
droppers, etc.) from all provisions of the device QS regulation with the exception of 820.180 and 
820.198.  Such exemptions may extend to device constituent parts of combination products and 
to the combination products of which they are a part.  If the exemptions for a device constituent 
part of a drug-device combination product cover all of the 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 part 211 (no demonstration 
of compliance with part 820 will be necessary).  However, if a device that would ordinarily be 
exempt from all or certain provisions in part 820 is incorporated into a container closure system, 
for example if a dropper is incorporated into the cap of a bottle of a drug, this may be a new use 
of the device such that the exemptions from part 820 may not be applicable.27  In any event, 
when incorporated into a container closure system, the device must be addressed as part of the 
container closure system for purposes of part 211 (e.g., requirements under 21 CFR 211.84, 
211.165, and 211.166, discussed in section IV.B). 
 
Manufacturers should document their evaluation if they believe a container closure 
system that has delivery attributes is not a device, or if they believe a device constituent part is 
exempt from any or all provisions under the device QS regulation.  Manufacturers who have 
questions about whether their container closure system, or an element thereof, is regulated as a 
device, or whether exemptions from part 820 apply, are encouraged to discuss the issue with the 
lead center or OCP, as needed. 
 
4.  Convenience kits 
 
A kit that includes two or more different types of medical products (e.g., a device and a 
drug) is a co-packaged combination product and, therefore, part 4 applies to the manufacture of 
the kit.  The CGMP requirements applicable to a kit manufacturer depend on what products are 
included in the kit.   
 
If the kit includes only products that are 1) legally marketed independently and 2) 
packaged in the kit as they are when independently marketed (including any labeling used for 
                                                 
26 The Agency notes that other Agency guidance addresses syringes and other devices that contain a drug as 
container closures for the drug, and focuses on considerations related to their use as container closures, while 
addressing only in a summary manner other requirements applicable because these container closures are also 
regulated as devices.  See, e.g., Guidance for Industry Container Closure Systems for Packaging Human Drugs and 
Biologics[1999].  As reflected in this section and elsewhere in this guidance, such devices are subject to container 
closure requirements because they hold a drug. However, because they are also devices, they and the combination 
product of which they are a part are subject to additional requirements, including under part 820.    
27 Although outside the scope of this guidance, we note that changes to the intended use of constituent parts of a 
combination product may require premarket review by FDA.  
  14  Contains Nonbinding Recommendations  
 
independent marketing), it is a convenience kit,28 and the only manufacturing steps for the 
combination product would be the assembly, packaging, labeling, any sterilization, and further 
processing of the kit itself.  Accordingly, the kit manufacturer would only have to demonstrate 
compliance with CGMP requirements with respect to those manufacturing activities.   
 
Kit manufacturers should carefully analyze what CGMP requirements apply to a kit. 27   
If a kit includes any products that are repackaged, relabeled, or otherwise modified from the 
independently marketed product, then the kit is not a convenience kit.  Likewise, if the kit 
manufacturer includes labeling for the kit that modifies the intended use for a constituent part, 
then the kit is not a convenience kit.  In these cases, the manufacturer would have to demonstrate 
compliance with CGMP requirements for the constituent parts and the overall product.  Also, if a 
device constituent part would be considered exempt from the device QS regulation if marketed 
outside the kit, the kit manufacturer may not be able to claim this exemption from part 820 if the 
intended use of the device constituent part in the kit is new.   
 
Co-packaged combination product manufacturers, including manufacturers of 
convenience kits, should carefully consider the impact of any sterilization process on the items in 
the co-package.29  For example, a constituent part may be sensitive to further processing, as may 
be the case for surgical sutures.  Similarly, some sterilization methods suitable for devices, such 
as irradiation, are not suitable for many drugs.  Also, additional verification to confirm no 
degradation in safety and effectiveness after any re-sterilization may be necessary.  For example, 
manufacturers should consider whether re-sterilization affects stability, material properties, and 
expiration dating/shelf-life of any of the products within the kit.  Additional issues may need to 
be considered, including validation of the sterilization process to ensure sterility for each 
constituent part within the kit, as appropriate.30  
 
Manufacturers should document their evaluation if they believe a kit qualifies as a 
convenience kit or that a device constituent part (and, therefore, a kit) should not be subject to 
requirements under part 820.  Kit manufacturers who have questions about whether their kit is a 
convenience kit, or about the applicability of part 820 requirements, are encouraged to contact 
the lead center or OCP, as needed. 
 
D. What CGMP requirements apply to a product or facility?  
 
While combination product manufacturers must demonstrate compliance with all of the 
CGMP regulations applicable to their combination product under 21 CFR 4.3, they may, as 
discussed above, demonstrate compliance with the drug CGMPs and device QS regulation 
requirements through one of the streamlined approaches under 21 CFR 4.4(b).  Further, not all 
                                                 
28 The term convenience kit as used in this guidance embraces solely the definition presented in this section, 
initially provided in the preamble to the part 4 regulation (see 78 FR 4310).  The term convenience kit is used in 
other FDA regulations for different purposes.  See, for example, 21 CFR 801.3. 
29 See, e.g., 21 CFR 211.166. 
30 See, for example, the Guidance for Industry on Sterilized Convenience Kits for Clinical and Surgical Use (January 
2002). 
  15  Contains Nonbinding Recommendations  
 
the provisions of the CGMP regulations listed in 21 CFR 4.3 may be applicable to a specific 
combination product or constituent part. 
 
1.  Applicability of CGMP requirements to a product  
 
The preamble to the proposed rule addressed which CGMP requirements apply to which 
combination products (see 74 FR at 48426), noting, for example, that only an over-the-counter 
(OTC) combination product must comply with the tamper-evident packaging requirements in the 
drug CGMPs and only combination products that include a type of device constituent part that is 
installed or serviced must comply with installation and servicing requirements in the device QS 
regulation.  The preamble to the final rule addressed similar considerations for combination 
products that include a biological product constituent part, explaining that many of the 
requirements for biological products are applicable only to certain types of biological products.  
For example, blood and blood components are subject to the CGMP requirements for such 
products under part 606 (21 CFR part 606).  In addition, a vaccine manufactured using a spore-
forming microorganism would be subject to 21 CFR 600.11(e)(3).   
 
Similarly, not all CGMP requirements may apply at a facility that performs only certain 
aspects of the manufacture of a combination product.  As 21 CFR 210.2(b) and 820.1(a)(1) 
describe, an entity that engages in only some operations subject to the regulations in parts 210, 
211, 600 through 680, 820, and 1271, need only comply with the regulations applicable to those 
operations.  For example, a facility that manufactures a co-packaged combination product that 
includes a finished, already-packaged drug manufactured under the drug CGMPs and received 
from another facility need not calculate yield for that drug constituent part. 
 
2.  What is the meaning of where appropriate in the CGMP, QS, and CGTP 
regulations?   
 
Firms must demonstrate compliance with all regulations applicable to their product and 
facility under part 4.  However, the drug CGMPs, device QS regulation, and CGTPs for HCT/Ps 
use language such as  where appropriate or as necessary to acknowledge that certain 
measures may not be necessary or applicable under certain circumstances and that manufacturers 
must pursue such measures if they are needed.  Such language indicates that firms have the 
opportunity to document justifications for determining that such a measure or approach is not 
appropriate or necessary for a particular product or the specific manufacturing activity they are 
undertaking.31  Such justifications should generally be maintained within the quality system 
documentation and may warrant Agency review prior to implementation depending on the 
product type and relevant premarket submission obligations. 
 
                                                 
 
31 Under both 21 CFR 820.1(a)(3) and 1271.150(e), a requirement that is qualified by where appropriate, is 
appropriate if, for example, non-implementation of the requirement could reasonably be expected to result in the 
product not meeting its specified requirements.  In the case of an HCT/P, these may be requirements related to 
preventing introduction, transmission, or spread of communicable diseases, or a manufacturers inability to carry out 
any necessary corrective action. Under both provisions, a requirement is deemed to be appropriate unless the 
manufacturer can document justification that it is not. 
  16  Contains Nonbinding Recommendations  
 
For example, 21 CFR 820.30(i) stipulates that each manufacturer establish32 and maintain 
procedures for the identification, documentation, validation or where appropriate verification, 
review, and approval of design changes before their implementation (emphasis added).  
Changes to the design, such as changes to properties of the material or dimensional 
specifications, may not need to be validated if they can be verified through appropriate 
measurement and test methods.  However, changes that could impact user needs, such as changes 
to the user interface, may require validation.  Similarly, part 211 requires compliance with 
certain duties as appropriate (e.g., 21 CFR 211.84(a) addressing the sampling, testing, or 
examining of components, containers, and closures prior to release by the quality control unit).  
Containers may not need to be tested, for example, if visual examination is sufficient to evaluate 
critical attributes. 
   
3.  What CGMP responsibilities apply to specific manufacturers and facilities, and 
how should CGMP compliance be coordinated across facilities? 
 
A facility that manufacturers a constituent part of a combination product or a complete 
combination product must be compliant with the CGMP requirements applicable to each 
manufacturing process that occurs at that specific facility.  In addition, the combination product 
owner (the holder of the marketing authorization for the product) retains overall responsibility 
for the product, even if the owner is not directly engaged in its manufacture.  As outlined below, 
quality agreements and audits can be helpful in assuring compliance with applicable CGMP 
requirements. 
   
A facility that manufactures only a finished device intended to be a constituent part of a 
combination product (i.e., does not engage in any other manufacturing of the combination 
product) must comply only with the device QS regulation.  Similarly, a facility that manufactures 
only a drug intended to be a constituent part of a combination product (i.e., does not engage in 
any other manufacturing of the combination product), must comply only with the drug CGMPs.  
Even if a facility is manufacturing only one type of constituent part for a combination product, 
the CGMP operating system should take into account considerations for the combination product 
as a whole as appropriate.  Before changes are made to the manufacturing process of a 
constituent part, the CGMP operating system should ensure consideration of whether such 
changes could affect performance and/or interaction with the other constituent part(s) and, if so, 
whether the safety and effectiveness of the combination product could be impacted.  Quality 
agreements with constituent part manufacturer(s) are one way to ensure that changes to a 
constituent part are transparent to a combination product manufacturer or owner. 
 
Some CGMP requirements concern the product as a whole, such as design controls, and 
some concern overarching considerations for the manufacturing process as a whole, such as 
CAPA requirements.  Take, for example, a manufacturing facility collecting nonconformance 
data that are trended as an input to the CAPA system for a combination product.  If a problem is 
detected that requires a product or process design change, the change may require modification 
of manufacturing activities at another facility or the expertise to develop and implement the 
change may reside at a different facility.  Similarly, a facility that only handles customer calls 
                                                 
32 21 CFR 820.3(k) states that  Establish means define, document (in writing or electronically), and implement. 
  17  Contains Nonbinding Recommendations  
 
may provide relevant complaint data to another facility responsible for trending all quality data 
and managing the CAPA system.  A CAPA system that is shared between facilities, or facility-
specific CAPA systems with established links between them, may facilitate handling of issues 
requiring multi-facility collaboration.  Regardless of the approach, the CAPA system(s) should 
allow for adequate flow of information between facilities and manufacturers for the combination 
product and appropriate investigation and resolution of identified CAPA issues.   
 
Manufacturing activities that occur at multiple facilities and associated CGMP operating 
systems should be coordinated appropriately.  Each manufacturing facility for a combination 
product should have documentation specifying its respective responsibilities, and the 
manufacturer of the finished combination product should have access to this documentation.  For 
example, if the manufacturer of the finished combination product uses a specification developer 
to design the finished product, that manufacturer should have the design control records or have 
access to them if they are held by the specification developer.  In addition, the manufacturer 
should have assurances that the specification developer maintained an adequate design control 
system.  To give another example, if product testing occurs at a contract testing facility, the 
manufacturer of the finished combination product should have documentation of the testing 
conducted and controls applied at the contract facility or have access to the documentation if 
held at the contract facility.  Accordingly, manufacturers should address access to such records 
among other issues as part of supplier evaluation and oversight. 
 
Measures that might be taken to ensure CGMP compliance at all manufacturing facilities 
for the combination product include auditing and other oversight activities.  For example, when 
multiple facilities participate in the manufacturing process, the owner may facilitate CGMP 
compliance by coordinating interactions among the facilities, including by entering into 
comprehensive quality agreements with the various facilities and suppliers .  These quality 
agreements may, for instance, specify expectations as to which facility will perform what 
activities and develop and maintain what documentation needed to demonstrate compliance with 
particular CGMP requirements (based, for example, on which aspects of manufacture each 
facility conducts).  These agreements may also detail what measures a facility will take to ensure 
compliance with CGMP requirements and any other relevant duties established by the owner for 
that facility.  For example, an owner may contract for the manufacture of the final combination 
product with a contract manufacturing facility, and detail in the supplier agreements the CGMP 
responsibilities and approaches for that facility. 
 
E. Control of changes to a combination product 
 
While not an issue unique to combination products, coordination of changes among 
manufacturers participating in the manufacture of a combination product is an important CGMP 
issue.  Appropriate consideration should be given to any implications for the safety or 
effectiveness of the combination product that might arise from changes to the combination 
product or its constituent parts.   
 
Single-entity and co-packaged combination product manufacturers must establish 
arrangements with their suppliers, contractors, and consultants to receive notice of changes in the 
product or service, where possible, in accordance with 21 CFR 820.50.  This notice should 
  18  Contains Nonbinding Recommendations  
 
address changes the supplier makes to its process or productincluding to an API, other drug 
components, or a container-closure systemthat it manufactures, if the change might affect the 
downstream manufacturing process or the quality of the combination product itself.  These 
combination product manufacturers should also establish procedures for acceptance of 
components, containers/closures, and constituent parts to ensure both detection and evaluation of 
any changes that are critical to the safety or effectiveness of the combination product prior to 
incorporating them into the finished combination product.33   
 
Similarly, if one entity manufactures one constituent part of a cross-labeled combination 
product and another entity manufactures the other constituent part, both should have procedures 
in place to inform one another of changes that may affect the safety or effectiveness of the 
combination product, and to confirm that the specifications for the respective constituent parts 
remain appropriate or are updated as needed to ensure that the combination product remains safe 
and effective.  For example, a change to the drug constituent part of a cross-labeled combination 
product might require a design change to the device constituent part for the combination product 
to remain safe and effective.  Accordingly, awareness and assessment of drug changes to 
determine whether they require a change to the device constituent part(s) of such a combination 
product may be important to compliance with design control requirements for the device under 
21 CFR 820.30.  Similarly, a change to a device constituent part of a cross-labeled combination 
product may necessitate a change to a drug constituent part, which may require a change in its 
chemistry, manufacturing, and controls (CMC).34, 35  
 
IV.  What do I need to know about the CGMP requirements 
specified in 21 CFR 4.4(b)? 
 
A. Provisions from the device QS regulation specified in 21 CFR 
4.4(b)(1)  
 
This section provides summary descriptions of the provisions from the device QS 
regulation with which manufacturers of single-entity and co-packaged combination products that 
include a device constituent part must demonstrate compliance when using the drug CGMP-
based streamlined approach established under 21 CFR 4.4(b)(1), including considerations 
specific to applying these device QS regulation requirements to combination products.   This 
discussion is not meant to provide a comprehensive analysis, but rather to help manufacturers
particularly drug and biological product manufacturers who may be less familiar with the device 
QS regulationunderstand the purpose and basic elements of the device QS regulation 
                                                 
33 21 CFR 211.84 details how a manufacturer must sample, test, examine, and accept or reject drug product 
components, containers, and closures. 
34 For additional information on guidance related to CMC topics, see FDAs webpage:  
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm064979.htm. 
35 While beyond the scope of this guidance, it bears noting that product owners may be obligated to notify the 
Agency of changes or seek Agency approval prior to making them, depending upon the nature of the change.  See, 
for example, 21 CFR 314.70, 601.12, 807.81(a)(3) and 814.39.  Accordingly, controlling changes to combination 
products and the processes and facilities used for their manufacture can be important to ensure compliance with 
other regulatory requirements (in addition to CGMP requirements). 
  19  Contains Nonbinding Recommendations  
 
provisions specified in 21 CFR 4.4(b)(1). This section also includes references to additional 
guidance documents that may be helpful.36  Section V presents hypothetical examples offering 
additional guidance on how to address these provisions for a combination product. 
 
1.  Management responsibility (21 CFR 820.20) 
 
Requirements under 21 CFR 820.20 ensure that management with executive 
responsibility (i.e., senior employees of a manufacturer who have the authority to establish or 
make changes to the quality policy and quality system)37 are actively engaged in oversight of the 
quality system, and reflect the expectation that management with executive responsibility 
demonstrate an active, ongoing commitment to quality system development and 
implementation.38  Statutory CGMP provisions and regulations for drugs establish requirements 
related to management responsibility, and the Agency has also issued guidance on this topic.39  
However, there are specific requirements in 21 CFR 820.20 that are not explicitly addressed in 
drug CGMP requirements, and a manufacturer of a combination product that includes a device 
constituent part must ensure that the elements required under 21 CFR 820.20 are satisfied.   
 
A combination product manufacturer must establish and maintain an adequate 
organizational structure to ensure that the product is designed and produced in accordance with 
CGMP requirements.  This structure must: establish the appropriate responsibility, authority, and 
interrelation of all personnel who manage, perform, and assess work affecting quality; provide 
adequate resources for management, performance of work, and assessment activities; and include 
                                                 
36 This section does not address 21 CFR 4.4(b)(1)(v) and (vi), which require manufacturers to demonstrate 
compliance with installation and servicing requirements under 21 CFR 820.170 and 820.200, respectively.  These 
requirements are included in 21 CFR 4.4(b)(1) to ensure manufacturers comply with them when applicable to a 
single-entity or co-packaged combination product.  However, the Agency anticipates that installed and serviced 
devices will rarely be constituent parts of such combination products.  If they are constituent parts of a combination 
product, they are more likely to be separately manufactured and marketed as constituent parts of cross-labeled 
combination products.  In such cases, as discussed in Section II.C.1 II.B, each constituent part manufacturer would 
be subject to the CGMP requirements associated with the constituent part it manufactures.  Accordingly, the device 
constituent part of such a cross-labeled combination product would be subject to installation and servicing 
requirements. 
37 21 CFR 820.3(n). 
38
 As stated in the preamble to the device QS regulation, Management with executive responsibility is that level of 
management that has the authority to establish and make changes to the company quality policy.  The establishment 
of quality objectives, the translation of such objectives into actual methods and procedures, and the implementation 
of the quality system may be delegated.  The regulation does not prohibit the delegation.  However, it is the 
responsibility of the highest level of management to establish the quality policy and to ensure that it is followed ... It 
is without question managements responsibility to undertake appropriate actions to ensure that employees 
understand managements policies and objectives. Understanding is a learning process achieved through training 
and reinforcement.  Management reinforces understanding of policies and objectives by demonstrating a 
commitment to the quality system visibly and actively on a continuous basis.  Such commitment can be 
demonstrated by providing adequate resources and training to support quality system development and 
implementation. (61 FR 52602-52612) 
39 See Section 501 of the FD&C Act [21 USC 351], which requires oversight and controls to ensure product quality, 
including to manage risks and establish the safety of raw materials, in-process materials, and the finished drug 
product (establishing that current good manufacturing practice includes management oversight of manufacturing 
and controls to ensure quality and lifecycle risk management).  See also 21 CFR 211.22, 211.25, and 211.180; and 
the Guidance for Industry Q10 Pharmaceutical Quality System (April 2009). 
  20  Contains Nonbinding Recommendations  
 
an appointed management member who is responsible for ensuring that quality system 
requirements are effectively established and maintained, and for reporting on the performance of 
the quality system to management with executive responsibility.40  Management with executive 
responsibility must establish the policy and objectives for and commitment to quality.41  These 
policies and objectives are reflected in the quality plan and quality system procedures.42   
 
The quality plan must define the quality practices, resources, and activities relevant to the 
combination product that is being designed and manufactured and must establish how the quality 
requirements will be met.43  The plan can either be an independent document, or it can reference 
elements of the manufacturers quality system.   
 
The quality system procedures (21 CFR 820.20(e)) ensure compliance with each aspect 
of the CGMPs applicable to the combination product.44  The number, complexity, and structure 
of a combination product manufacturers procedures and instructions may vary depending on 
factors such as the manufacturers organizational structure and the complexity of the 
combination product being manufactured.  Drug manufacturers may already have some such 
procedures in place as part of the requirements for a quality control unit under 21 CFR 211.22 
and can reference these procedures and augment them as needed to meet the requirements of 21 
CFR 820.20. 
 
Management with executive responsibility must periodically review the suitability and 
effectiveness of the quality system, including to ensure that the quality system satisfies the 
established quality policy and objectives.45  These reviews must be conducted at defined 
intervals and with sufficient frequency.  Management review procedures should ensure that 
management has adequate access to relevant information from facilities contracted to perform 
manufacturing activities for the combination product. 
 
2.  Design controls (21 CFR 820.30) 
 
The preamble to the rule discusses design control requirements for combination products 
at some length.46  This section discusses the design controls that apply to single-entity or co-
packaged combination products that include a device constituent part that is subject to them.47  
Design control activities confirm that there are no negative interactions between constituent 
parts, and ensure that their combined use results in a combination product that is safe and 
effective and performs as expected.   
 
                                                 
40 21 CFR 820.20(b). 
41 21 CFR 820.20(a). 
42 See 21 CFR 820.20(d) and (e). 
43 21 CFR 820.20(d). 
44 21 CFR 820.20(e) 
45 21 CFR 820.20(c). 
46 See 78 FR 4314-4315. 
47 If a manufacturer claims that the device constituent part or combination product is exempt from 21 CFR 820.30, 
the manufacturer should document its evaluation to support this determination.  See sections III.C.3 and C.4 of this 
guidance; see also 21 CFR 820.30(a)(1). 
  21  Contains Nonbinding Recommendations  
 
The following is a description of design control requirements and the documentation that 
must be maintained for co-packaged and single-entity combination products.48  While 
pharmaceutical development focuses on drug considerations, if broadened to take into account 
the other constituent parts of combination products and how they interrelate, many 
pharmaceutical development practices (for example, Quality by Design principles49) can be 
leveraged and built upon when demonstrating compliance with design controls for a combination 
product.  The Agency recognizes that the terminology used in 21 CFR 820.30 can differ from 
that used for pharmaceutical development.  Manufacturers should be able to communicate to the 
Agency how the terminology they use relates to design control principles and requirements.   
 
Design control requirements apply to activities during product development as well as to 
postmarket changes to the design or manufacturing process.  Accordingly, the activities 
described below may be conducted as part of premarket development and reflected in 
documentation submitted as part of the marketing authorization process.  Regardless of when the 
activity occurs or where related records may reside, the CGMP operating system should include 
or reference appropriate documentation to ensure readily available access to this documentation 
for FDA inspection.50 
 
The extent and complexity of the design controls process and associated documentation 
will vary based on the product.  For example, consider a drug product that is already legally 
marketed independently that will have the same formulation, route of administration and 
intended use when marketed as part of a combination product that also incorporates a delivery 
device.  Design controls would begin when the delivery device configuration is judged to be 
feasible and appropriate to develop.  The drug properties would be 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.  Conversely, for a novel 
combination product with novel drug and device constituent parts, design controls ensure 
coordinated development of the drug and device resulting in a final combination product that 
meets user needs and achieves intended uses.  The extensiveness of design control activities and 
related documentation for products should also be commensurate with the phase of product 
development.    
 
  As part of the design controls, a design and development plan must be established to 
describe or reference the design and development activities and define responsibility for 
implementation. The plans must identify and describe the interfaces with different groups or 
activities that provide, or result in, input to the design and development process.51    
 
                                                 
48 While outside the scope of 21 CFR 4.4(b)(1), it bears noting that the design control process and design history file 
for the device constituent parts of cross-labeled combination products should address the suitability of the device for 
use as part of the combination product, including the interactions and interrelationships between it and other 
constituent parts of the combination product.   
49 See the Guidance for Industry on Q8(R2) Pharmaceutical Development (November 2009), 
http://www.fda.gov/downloads/Drugs/.../Guidances/ucm073507.pdf. 
50 See 21 CFR 820.30(j), 820.180, and 211.180. 
51 21 CFR 820.30(b). 
  22  Contains Nonbinding Recommendations  
 
Design input requirements for the combination product should include considerations 
such as performance characteristics, safety and reliability requirements, and expected needs of 
product users and patients.52  Design inputs should be considered early in product development 
to ensure that development efforts are consistent with the products intended use, including the 
needs of users, including patients.  Once the design inputs have been established, the design 
outputs (e.g., specifications and engineering drawings) must be developed based on those 
inputs.53  Once design outputs have been established for all design inputs, design verification and 
validation activities must be performed to ensure that the combination product design output 
meets design input requirements, including user needs and intended uses.  Design review is also 
required to ensure that formal and documented reviews of the design are planned and conducted 
at appropriate stages of the products design development,54 and all of these activities must be 
documented in the design history file.55  
 
Design inputs ensure that design requirements are appropriate to address the intended use 
of the product, and design outputs include documentation of the product specifications that can 
be evaluated against the design inputs as development progresses.  Similarly, Quality Target 
Product Profile (QTPP) in pharmaceutical development involves prospective consideration of the 
quality characteristics of a drug product to ensure desired quality taking into account safety and 
efficacy of the drug product.  A manufacturer may identify potential Critical Quality Attributes 
(CQAs) or properties of a drug product that should be within appropriate limits, ranges, or 
distributions to ensure product quality and refine these CQAs as product development continues.  
QTPP and CQA principles may be applied for combination products in a manner consistent with 
design input and output requirements.  In addition, when developing a combination product, the 
QTPP and CQA for the drug constituent part may be helpful in establishing design inputs and 
design outputs for the combination product. 
 
Verification means confirmation by examination and provision of objective evidence that 
specified requirements have been fulfilled.56  Design verification confirms that the product 
developed is consistent with the assumptions made by the design team when developing design 
inputs, but does not necessarily confirm that the product is safe and effective for its intended use.  
Design verification activities may include, for example, performance tests, safety tests, or visual 
inspections. 
 
Design validation means establishing by objective evidence that product specifications 
conform to user needs and intended use(s).57  Design validation ensures that the product is 
designed correctly to achieve its intended purpose(s), and includes testing of production units or 
their equivalents (with appropriate justification58) under actual or simulated use conditions.  
                                                 
52 See 21 CFR 820.30(c). 
53 See 21 CFR 820.30(d). 
54 See 21 CFR 820.30(e). 
55 See 21 CFR 820.30(j). 
56 See 21 CFR 820.30(f) and 21 CFR 820.3(aa). 
57 See 21 CFR 820.30(g) and 21 CFR 820.3(z)(2). 
58 The preamble to the device QS regulation (61 FR 52619) provides additional detail on use of equivalents: When 
equivalent devices are used in the final design validation, the manufacturer must document in detail how the device 
was manufactured and how the manufacturing is similar to and possibly different from initial production. Where 
 
  23  Contains Nonbinding Recommendations  
 
Design validation activities, for example, may include simulated use testing or 
clinical/nonclinical evaluation, including human factors59 and software validation.  Some design 
verification (e.g., bench and/or pre-clinical testing) and validation (e.g., human factors testing, 
when appropriate) will typically be completed prior to the initiation of clinical studies of safety 
and efficacy for the combination product, which are also part of design validation.  Clinical 
studies conducted to support safety and/or efficacy of the constituent parts of a combination 
product may be appropriate to be leveraged as part of the cumulative design validation efforts for 
the overall combination product.   
 
In addition, manufacturers must perform risk analysis where appropriate,60 which should 
begin early in the design process and continue throughout the lifecycle for the product.  Risk 
analysis should enable identification of unacceptable risks so that they can be mitigated.  It 
influences other aspects of design control and additional activities including purchasing controls 
(see section IV.A.3).  Although existing risk analysis for products used as constituent parts of the 
combination products may be relevant, risk analysis should include considerations for the 
combination product as a whole to identify risks associated with its design, manufacturing 
processes, and intended uses.  Some risks may be identifiable during initial design development 
and addressed in design inputs, while others may become apparent later in product development, 
during premarket review, or based on postmarket experience (including adverse event reporting) 
and used to determine whether any aspect of the design should be modified.  Standards and 
guidance addressing conduct of risk management activities such as risk assessment, risk control, 
risk reporting, and risk review for devices and drugs are appropriate references to inform these 
activities for a combination product.61  Also, risk assessment and management activities 
performed for a drug constituent part under pharmaceutical development practices may become 
elements of the overall risk analysis for a combination product. 
 
Manufacturers must establish and maintain design transfer procedures to ensure effective 
translation of design specifications into production methods and procedures.62  Design transfer is 
the bridge between the design of the product and the manufacturing process to make the 
commercial product. 
 
                                                                                                                                                             
there are differences, the manufacturer must justify why design validation results are valid for the production units, 
lots, or batches.  For a combination product, this documentation and justification must account for considerations 
arising from inclusion of a drug or biological product, including equivalence of the manufacturing process for the 
drug/biologic constituent part or the combination product as a whole.  The rationale for equivalence should be 
documented and may require bridging studies, completion of comparability protocols, or other test data to support 
that products used for design validation are representative of the combination product that the manufacturer intends 
to market. 
59 For more information on human factors for combination products, see Draft Guidance for Industry an FDA Staff 
Human Factors Studies and Related Clinical Study Considerations in Combination Product Design and 
Development (February 2016).  When finalized, this document will represent the Agencys current thinking on this 
topic. 
60 21 CFR 820.30(g). 
61 For more information on risk analysis and risk management see, e.g.,  ISO 14971 Risk Management  Medical 
Devices and FDA Guidance for Industry Q9 Quality Risk Management  (June 2006).   
62 21 CFR 820.30(h). 
  24  Contains Nonbinding Recommendations  
 
Manufacturers are required to have procedures to ensure that any changes to design 
requirements are identified, documented, validated or verified where appropriate, reviewed, and 
approved prior to implementation.63  Change controls apply once initial design inputs have been 
approved by the manufacturer.64  A change control process is essential to manage design changes 
both during the original design process for the combination product and after the design has been 
transferred to manufacturing. 65  The records of these changes must be maintained as part of the 
design history file (21 CFR 820.30(j)).  They create a history of the evolution of the design, 
which can be important when investigating failures or evaluating the appropriateness of 
proposed, additional changes to the product.  A manufacturer may choose to use different 
processes for premarket (as opposed to postmarket) changes to accommodate the rapid, iterative 
design process that is often present during investigational stages, so long as the design change 
and transfer process is compliant with 21 CFR 820.30.   
 
The Design History File (DHF) for a combination product captures all design issues 
relating to the combined use of the constituent parts.  The DHF may not need to document design 
and development planning for established characteristics of the individual constituent parts, for 
example the safety and effectiveness of a drug constituent part of a co-packaged combination 
product, if that drug constituent part was previously approved for the same indication.  If a 
finished device, drug, or biological product is purchased, the combination product manufacturer 
is not required to retrospectively design that constituent part with respect to such previously 
reviewed characteristics.  Rather, the combination product manufacturer should understand the 
constituent parts existing design specifications thoroughly in order to perform design controls 
properly for its use in the combination product.66  If a separately developed drug, device, or 
biological product constituent part needs to be modified to be used in the combination product, 
the manufacturer must assess what design control activities must be performed to ensure safety 
and effectiveness of the combination product (e.g., new formulation of a drug or new features of 
a device).67 
 
It is appropriate for a DHF for a combination product to leverage and cross-reference 
developmental data and data systems.  Manufacturers transitioning from drug development to 
combination product development should evaluate existing development documentation and 
systems and assess what, if any, changes may be needed to demonstrate compliance with 21 CFR 
820.30.  Manufacturers should be able to explain to FDA in premarket submissions and in 
inspections how their practices and terminology align with the requirements in 21 CFR 820.30, 
                                                 
63 21 CFR 820.30(i). 
64 61 FR 52621, Comment 87. 
65 21 CFR 820.30(h). 
66 Similarly, if a combination product manufacturer is purchasing device components for inclusion in a combination 
product, and the device component supplier is manufacturing a finished device from the same or similar components 
and is therefore subject to the device QS regulation, the combination product manufacturer may be able to leverage 
elements of that suppliers design controls in developing the overall design controls for the combination product.  
The information leveraged should typically be covered by a formal agreement between the combination product 
manufacturer and supplier defining maintenance and sharing of design information.  If the component supplier does 
not itself comply with the device QS regulation, the combination product manufacturers design control activities for 
the device constituent part will likely need to be more extensive.   
67 21 CFR 820.30(c). 
  25  Contains Nonbinding Recommendations  
 
and be able to identify and readily access for FDA inspection all documentation needed to 
demonstrate compliance with design control requirements.   
 
If a manufacturer is evaluating the adequacy of their design controls and documentation 
for a currently marketed combination product, it may be helpful to review premarket 
submissions, the product risk profile, and postmarket experience for the combination product.  
The results of this review can inform decisions on whether additional testing and documentation 
is required.  FDA encourages combination product manufacturers to direct specific questions on 
the adequacy of their design control measures and documentation to the lead center for their 
products, and OCP as needed, for assistance.  For further information on design controls, see the 
preamble to the final device QS regulation.68 
 
3.  Purchasing controls (21 CFR 820.50) 
 
Manufacturers of single-entity and co-packaged combination products that include a 
device constituent part must control purchased products69 and services as described in 21 CFR 
820.50.  They must establish such purchasing controls for products received at their 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) (21 
CFR 820.50(a)).  Facilities that have previously manufactured only drugs, rather than devices or 
combination products, will likely have relevant procedures in place in accordance with part 211, 
subpart E.  However, if these procedures do not demonstrate compliance with the specific 
requirements of 21 CFR 820.50, they must be augmented to do so. 
 
 Manufacturers must evaluate potential suppliers and define the type and extent of control 
to be exercised over them based on the evaluation results.70  Manufacturers may design and 
conduct such evaluations based on factors such as the risks associated with the supplied product 
or service and complexity of the specifications for it.  Manufacturers must establish and maintain 
records of acceptable suppliers for purchased products and services,71 and establish and maintain 
data that clearly describe or reference the specified requirements for products and services 
received (e.g., contracts with relevant terms).72  
 
One way to facilitate purchasing control is the careful structuring of purchasing 
agreements with suppliers.  Where possible, such agreements are used to ensure that the 
combination product manufacturer is notified of changes to the products, the manufacturing 
process, or the services being provided.73  Such notice of changes facilitates compliance not only 
with purchasing control duties, but also, potentially, with other regulatory requirements, 
including design control obligations to complete additional design verification testing to address 
                                                 
68 See Medical Devices; Current Good Manufacturing Practice (CGMP) Final Rule; Quality System Regulation, 61 
FR 52602-52662 (October 7, 1996). 
69 Under 21 CFR 820.3(r), the term product includes components and manufacturing materials, in addition to in-
process and finished articles.  
70 See 21 CFR 820.50(a)(2). 
71 See 21 CFR 820.50(a)(3). 
72 See 21 CFR 820.50(b). 
73 See 21 CFR 820.50(b). 
  26  Contains Nonbinding Recommendations  
 
the change (e.g., to ensure that the purity and stability of a drug constituent part is maintained 
when the materials change in a device constituent part that is also a container closure).  If it is not 
possible to obtain such notice, the combination product manufacturer should implement 
additional controls to ensure that changes are identified and appropriate measures are taken.  The 
combination product manufacturer should ensure agreements are appropriately structured, 
whether through direct agreements with suppliers and contract manufacturers or through 
confirmation that such parties have adequate agreements between themselves.  For example, a 
combination product manufacturer may choose to maintain a change agreement with a material 
supplier who provides material directly to a contract manufacturing facility. 
 
Note that regardless of the nature of purchasing controls, combination product 
manufacturers must comply with the testing requirements under 21 CFR 211.84 with respect to 
drug components, and product containers and closures (see IV.B.1 below).   
 
4.  Corrective and Preventive Actions (21 CFR 820.100) 
 
Manufacturers of co-packaged or single-entity combination products that have a device 
constituent part must establish and maintain procedures for implementing CAPA in accordance 
with 21 CFR 820.100.  Relevant requirements in the drug CGMPs include 21 CFR 211.192 and 
21 CFR 211.180(e).74  Manufacturers of the combination product must undertake CAPA 
measures, when required, for issues arising at their facilities.  All relevant manufacturers should 
participate in cross-facility efforts, as appropriate, to determine the root-cause of problems and 
the appropriate measures to correct such problems and prevent recurrence.  Manufacturers of 
combination products should document these activities.75  The CAPA process for combination 
products also should consider implications of corrective and preventive actions for all constituent 
parts and for the combination product as a whole.  
 
While combination product manufacturers have flexibility in coordinating CAPA systems 
across facilities, they maintain responsibility for ensuring that the 21 CFR 820.100 requirements 
are met. Manufacturers should ensure that an appropriately comprehensive review of activities is 
undertaken at relevant facilities to determine the cause of existing or potential problems, which 
could include manufacturing problems, deviations, or nonconformities for a constituent part or 
the combination product as a whole.  The manufacturer should have appropriate mechanisms in 
place to ensure that issues are identified, action(s) needed to correct and prevent recurrence are 
taken, and necessary changes are implemented.  The manufacturer should take appropriate 
measures, which may include CAPAs, with regard to all relevant manufacturing steps at all 
relevant facilities to correct problems and to prevent or mitigate them going forward.   
                                                 
74 See also FDA Guidance for Industry,  Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical 
Production (October 2006), which discusses appropriate identification, assessment, and investigation of OOS results 
for drug products, including results obtained under 21 CFR 211.165 (a provision specified in 21 CFR part 4).  
Quality data from OOS investigations and any related corrective actions should be addressed through the 
combination product manufacturers quality system. Also, FDA guidance for industry, ICH Q10 Pharmaceutical 
Quality System (April 2009), includes additional recommendations for preventive actions and, when failures or other 
issues occur, corrective actions. 
75 For further guidance, see the preamble to the device QS regulation at 61 Fed. Reg. at 52633-52635, Comments 
158-166. 
  27  Contains Nonbinding Recommendations  
 
 
B. Provisions from the drug CGMPs specified in 21 CFR 4.4(b)(2) 
 
This section provides a brief description of the provisions from the drug CGMPs with 
which single-entity and co-packaged combination product manufacturers must demonstrate 
compliance when using the device QS regulation-based streamlined approach established under 
21 CFR 4.4(b)(2), including considerations specific to applying these requirements to 
combination products.  This discussion is not meant to be a comprehensive analysis, but rather to 
help manufacturersparticularly device manufacturers, who may be less familiar with drug 
CGMPsunderstand the purpose and basic elements of the provisions of the drug CGMPs 
specified in 21 CFR 4.4(b)(2), as well as to direct such manufacturers to additional guidance. 
 
The specified provisions of the drug CGMPs include requirements for testing and other 
verification procedures for batches or lots, whether of drug components, drug containers and 
closures, drug constituent parts, or the whole combination product.  Combination product 
manufacturers should establish procedures defining a batch or lot in all phases of production 
and describe all batch and lot numbering systems used for incoming material, in-process 
material, and finished products.  These procedures allow manufacturers to connect specific 
batches or lots of constituent parts, components, and in-process material to the specific batches 
or lots of the combination product for which they are used.  These procedures enable traceability 
of sampling and testing, packaging, and labeling activities, and can be important when assessing 
and responding to issues including complaints and adverse events.  Master production and 
control records should be designed to enable this traceability.  An explanation of batch and lot 
definitions, controls, and tracking should be available for review on inspection.  
 
1.  Testing and approval or rejection of drug product components, containers, and 
closures (21 CFR 211.84) 
 
Drug product components, containers, and closures must be tested in accordance with 21 
CFR 211.84.  A drug component is any ingredient intended for use in the manufacture of a drug 
product, including those that may not appear in the drug product.76  A container closure system is 
the sum of packaging components that together contain and protect the drug product.  This 
includes primary packaging components and also secondary packaging components if the latter 
are intended to provide additional protection to the drug product.77  Examples of packaging 
components are ampules, vials, screw caps, stoppers, and stopper overseals.  As discussed in 
section III.C.3, container closure systems and elements of container closure systems may also be 
regulated as devices.     
 
Combination product manufacturers do not need to demonstrate compliance with this 
provision 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, for a CGMP operating system established in accordance with 21 CFR 4.4(b)(2) (device 
                                                 
76 See 21 CFR 210.3(b)(3). 
77 See the Guidance for Industry on Container Closure Systems for Packaging Human Drugs and Biologics: 
Chemistry, Manufacturing, and Controls Documentation (May 1999). 
  28  Contains Nonbinding Recommendations  
 
QS regulation-based streamlined approach), if materials are used solely for manufacture of a 
device constituent part that is not part of the drug container or closure (e.g., a co-packaged 
device), the manufacturer need only demonstrate compliance with applicable provisions of part 
820 to show appropriate control of such materials for that device constituent part (including 21 
CFR 820.30, 820.50, 820.80, and 820.86). 
 
21 CFR 211.84 details how to sample, test, examine, and accept or reject drug product 
components, containers, and closures.  In lieu of such testing, 21 CFR 211.84 allows for some 
reliance on a suppliers report of analysis, provided that certain identity testing is conducted and 
that the reliability of the suppliers analysis is established by the manufacturer through 
appropriate validation of the testing results at appropriate intervals.  These duties augment and 
elaborate upon acceptance activity requirements expressly established under 21 CFR 820.80.  
Accordingly, if a facility already has 21 CFR 820.80-based acceptance procedures, it would be 
appropriate to provide for compliance with 21 CFR 211.84 requirements by augmenting these 
existing procedures as needed to incorporate 21 CFR 211.84 compliant measures. 
 
Each lot of drug components, containers, and closures must be withheld from use until it 
has been sampled, tested, or examined, as appropriate, and released for use by the quality control 
unit.78,  The samples collected for each lot must be representative of the entire lot.79  These 
representative samples must be collected and tested or examined in accordance with the 
procedures specified in 21 CFR 211.84.  These procedures require, among other things, 
appropriate sampling technique to prevent contamination of the sampled component or of other 
materials.80  In addition, the number of containers to sample and the amount of material to be 
taken from each container must be based on appropriate criteria (e.g., component variability, 
confidence levels, degree of precision desired, past quality history of the supplier, and the 
quantity needed for analysis).81, 82 
 
2.  Calculation of Yield (21 CFR 211.103) 
 
Actual yields and percentages of theoretical yield for the drug constituent part(s) of a 
combination product must be determined as described in 21 CFR 211.103.  Excess or low yields 
may suggest problems in the production process, including equipment failure, that may affect 
product quality and that may not be discovered, or not be discovered as quickly, using sample-
based release testing alone.  Actual yield discrepancies outside of established and documented 
allowable variation from theoretical yield should be investigated.    
 
                                                 
78 See 21 CFR 211.84(a). 
79 See 21 CFR 211.84(b). 
80 See 21 CFR 211.84(c). 
81 See 21 CFR 211.84(b). 
82 Some references that may be useful for sampling by variables and sampling by attributes include American 
Standards for Testing and Materials (ASTM) Standard E2709, Standard Practice for Demonstrating Capability to 
Comply with an Acceptance Procedure and ASTM Standard E2334, Standard Practice for Setting an Upper 
Confidence Bound For a Fraction or Number of Non-conforming Items, or a Rate of Occurrence for Non-
conformities, Using Attribute Data, When there is a Zero Response in the Sample, respectively. 
  29  Contains Nonbinding Recommendations  
 
Yield calculation requirements under 21 CFR 211.103 apply to the drug constituent parts 
of combination products.  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 211.100 or 21 CFR 
820.70, but 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 and result in further investigation.  For example, 
prefilled syringes that are rejected due to nonconformity of the syringe needle may result in 
corresponding loss of drug from the batch/lot.  Any loss would be captured as part of the yield 
calculations for the drug constituent part, and investigation of the cause of that loss should 
identify the manufacturing problem that is leading to these device nonconformities.     
 
Yield determinations must be made 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.83  Accordingly, calculation of yield should be determined at 
each phase at which component, in-process material, or product loss may occur, including during 
the formulation of the drug prior to incorporation into the combination product, during 
incorporation into the combination product (e.g., filling or coating), and, possibly, during the 
packaging process.  These calculations must be performed by one person and independently 
verified by a second person, unless the yield is calculated by automated equipment in accordance 
with section 21 CFR 211.68, in which case it must be independently verified by one person.84    
 
For each appropriate phase of the manufacturing process performed, the formula used 
and the data generated for the yield calculation for the phase should be documented.  For 
manufacturers operating under a device QS regulation-based system, documentation of yield 
calculations may be incorporated into existing part 820 documentation (for example, as part of 
the device history record, 21 CFR 820.184).  These records should include actual yields, 
percentages of theoretical yields, and the maximum and minimum percentages of theoretical 
yield beyond which investigation is required for the drug constituent part, including as it is 
processed and combined with the other constituent part(s) of the combination product.   
 
If a third party is manufacturing the drug for the combination product, that manufacturer 
is responsible for complying with the calculation of yield requirement at the appropriate phases 
of the drug manufacturing process it performs, but the combination product manufacturer is 
responsible for ensuring that the supplier satisfies these requirements, as a part of the 
combination product manufacturers purchasing controls for its product in accordance with 21 
CFR 820.50.   
 
3.  Tamper-evident packaging requirements for over-the-counter human drug 
products (21 CFR 211.132)  
 
Manufacturers of OTC combination products must comply with the requirements of 21 
CFR 211.132.  The required controls include tamper-evident packaging and labeling alerting 
                                                 
83 See 21 CFR 211.103. 
84 See 21 CFR 211.103. 
  30  Contains Nonbinding Recommendations  
 
customers to these protective features of the products packaging.  These controls are important 
to help improve the security of OTC combination product packaging and help ensure the safety 
and effectiveness of OTC combination products.   
 
For single-entity combination products, tamper-evident packaging requirements apply to 
the packaging for the combination product as a whole.  For co-packaged combination products, 
these requirements can be met through appropriate packaging of the drug constituent part(s) 
within the larger co-package so long as such an approach is otherwise permissible under the 
packaging and labeling requirements applicable to that combination product. 
 
Certain combination products may be exempt from OTC tamper-evident packaging 
requirements85 (e.g., toothpaste co-packaged with a toothbrush) or from bearing a statement of 
tamper-evident features on the package86 (e.g., aerosol saline nasal spray). 
 
An exemption from tamper-evident packaging and labeling requirements for an OTC 
combination product may be requested in accordance with 21 CFR 211.132(d).  If the 
manufacturer makes changes to packaging and labeling of an approved OTC product to comply 
with the requirements of 21 CFR 211.132, it must notify the lead center for the combination 
product before distributing it.87  
   
4.  Expiration dating (21 CFR 211.137) 
 
21 CFR 211.137 helps ensure that drug products (drug constituent parts in the case 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.  This date must take 
into account any storage conditions stated in the labeling and be based on appropriate stability 
testing as described in 21 CFR 211.166 (See section IV.B.6).88  The expiration dating also 
should take into account any other applicable shelf-life considerations (e.g., for a product that is 
to be provided sterile, the length of time that its packaging material can be ensured to retain its 
integrity and, thereby, maintain a sterile barrier).  In some cases, the drug constituent part might 
not have an expiration date because current regulations exempt it from this requirement.89  
Similarly, some device constituent parts may not have expiration dates. 
 
When expiration dating is required, the constituent parts of combination products may 
have individual expiration dates or an expiration date for the entire combination product may be 
appropriate.  Generally, when constituent parts of a co-packaged combination product can be 
used independently, expiration dating should be addressed 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.  The expiration date for a 
combination product may be shorter than the expiration date or shelf life for its constituent 
                                                 
85 See 21 CFR 211.132(b)(1). 
86 See 21 CFR 211.132(c)(1). 
87 See 21 CFR 211.132(e).  
88 See 21 CFR 211.137(b).  
89 See 21 CFR 211.137. 
  31  Contains Nonbinding Recommendations  
 
part(s) if marketed independently.  Reasons for a shorter expiration period could include 
interactions between the constituent parts when combined, the effects of additional 
manufacturing steps, or other differences arising from the combination of the constituent parts. 
 
5.  Testing and release for distribution (21 CFR 211.165) 
 
Testing and release for distribution are critical in drug product manufacture and quality 
control.  21 CFR 211.165 requires that an appropriate laboratory determination of satisfactory 
conformance to final specifications (including the identity and strength of each active ingredient) 
is made for each batch of drug product prior to release.  21 CFR 211.165 also requires 
appropriate laboratory testing, as necessary, of each batch of a drug product required to be free of 
objectionable microorganisms.  In addition, sampling and testing plans must be described by 
written procedures.90 
 
Accordingly, manufacturers must test each batch of their combination product to 
determine satisfactory conformance to final written specifications for the drug constituent part.91  
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). 92  This testing ensures that all batches 
meet appropriate specifications for their approval and release.93  A detailed listing of all the tests 
performed and the acceptance criteria used should be maintained and be available for 
inspection.94   
 
In some cases, for single-entity combination products, in lieu of using actual units from a 
finished combination product batch for testing to determine whether the drug constituent part 
meets final specifications, manufacturers may wish to use samples that are not finished 
combination products (but that are representative of the finished combination product with 
respect to the characteristics and attributes being tested).  The Agency does not intend to object 
to such an approach where the manufacturer can establish, including where appropriate through 
bridging studies and other quantitative means, that any differences in the manufacturing process 
for the samples and the finished combination product do not affect the drug constituent part.  
Such approaches should be supported by appropriate justification and data and discussed with 
the lead Center, and OCP as needed. 
                                                 
90 See 21 CFR 211.165(c). 
91 See 21 CFR 211.165(a). 
92 See 21 CFR 211.165(a). 
93 See 21 CFR 211.165(a), (b). 
94 21 CFR 211.165 addresses testing and release for drug products; appropriate controls for intermediate stages 
(e.g., in-process materials) in the manufacture of combination products are addressed under separate provisions of 
the drug CGMPs and device QS regulation that are not specified in part 4.  If a manufacturer operates under a 
streamlined approach under 21 CFR 4.4(b), it should take into consideration the materials and manufacturing steps 
for the combination product as a whole in determining how to demonstrate compliance with obligations for in-
process materials, and may find it helpful to refer to the corresponding requirements under the other regulation (that 
it did not choose as the base for its CGMP operating system).  For example, if the facility operates under a device 
QS regulation-based streamlined approach, in determining how to comply with duties under 21 CFR 820.70, 820.80, 
and 820.86 for the combination product as a whole, reference to 21 CFR 211.110 and guidance relating to in-process 
materials for drug products may facilitate appropriate consideration of the controls for drug constituent parts.   
  32  Contains Nonbinding Recommendations  
 
     
If one facility is manufacturing a drug product as a constituent part to be supplied to 
another facility or manufacturer for inclusion in a co-packaged combination product, appropriate 
and adequate laboratory testing should be conducted by the drug product manufacturing facility 
prior to release of the drug constituent part(s) for distribution in accordance with 21 CFR 
211.165.  For combination products that include a device constituent part, the combination 
product manufacturer is responsible for ensuring through purchasing controls in accordance with 
21 CFR 820.50 that the drug constituent part conforms to specified requirements, including 
laboratory testing requirements.  Appropriate testing or examination (such as visual inspection) 
should also be conducted throughout the remaining manufacture of the finished co-packaged 
combination product to ensure that the drug constituent part(s) continues to conform to its final 
specifications. 
 
6.  Stability testing (21 CFR 211.166) 
 
21 CFR 211.166 requires a testing program designed to assess the stability characteristics 
of drug products.  Furthermore, 21 CFR 211.166 sets forth required elements of the testing 
program, including elements concerning sample size, storage conditions for samples retained for 
testing, and other elements related to testing methodology and frequency.95 
 
Stability testing is performed to determine appropriate storage conditions and expiration 
dates (see section IV.B.4).  Among other considerations, this testing must enable evaluation of 
any effects on the stability of the drug due to storage in its marketed container closure system, 
which may be a device constituent part (or component of a device constituent part).96  For a 
single-entity combination product, testing must be performed on the drug constituent part as 
incorporated into the finished combination product.97   
 
  The Agency does not intend to object to the use of bracketing and matrix approaches for 
stability studies where the approach has been adequately justified and, where applicable, 
reviewed by FDA.98  The Agency also does not intend to object to leveraging stability data for an 
already marketed combination product during new product development, with adequate 
justification and, where applicable, review by FDA.  In particular, for purposes of establishing an 
expiration date for a new combination product, such leveraging may be acceptable if the new 
product represents a modification to the existing marketed combination product that would not 
impact the stability of the drug constituent part (for example, a change to the catheter length for a 
                                                 
95 For further information on stability testing considerations, see, for example, the Guidance for Industry on 
Q1A(R2) Stability Testing of New Drug Substances and Products (November 2003). 
96 See 21 CFR 211.166(a)(4). 
97 See 21 CFR 4.3, 4.4, and 211.166.  In addition, while stability testing requirements under 21 CFR 211.166 do not 
apply to device constituent parts of a co-packaged combination product, under design control requirements, testing 
must be performed to demonstrate that device functionality (i.e., mechanical performance of the device constituent 
part) is maintained until the specified expiration date for the combination product. See 21 CFR 820.30.   
98 For further information on bracketing and matrixing considerations, see, for example, the Guidance for Industry 
on Q1D Bracketing and Matrixing Designs for Stability Testing of New Drug Substances and Products (January 
2003). 
  33  Contains Nonbinding Recommendations  
 
drug-coated balloon, where the balloon component remains unchanged) and is not otherwise 
material to the expiration date.99 
 
  If a new product has minor differences that present a low risk of affecting the stability of 
the drug (for example, a different size of a drug-coated balloon that is bracketed within the 
balloon size matrix previously used to establish the expiration date, and without other changes 
relevant to stability, for example, in the coating application process),100 the Agency does not 
intend to object, in appropriate cases, to: i) the use of previously generated stability data for the 
existing product (or family of products) to support reduced stability data requirements for the 
new product (for example, generation of only short-term accelerated data) or ii) to incorporating 
the product into the ongoing stability program for the existing marketed product(s), provided that 
stability data trends and stability history for the existing product or product family are 
sufficiently robust for this purpose.  Applicants should contact the lead center for their product, 
or OCP as needed, regarding such approaches.101 
 
The need for new stability studies should be evaluated when there are changes to any 
constituent part of a combination product.  For example, changes to the manufacturing process, 
including changes based on the size or shape of the device constituent part that holds the drug or 
that is coated with the drug, or changes in material of construction of such a device constituent 
part, may impact drug stability. 
 
Manufacturers are responsible for establishing and managing the stability program.  If a 
combination product manufacturer purchases a drug product from another manufacturer for 
inclusion in its co-packaged combination product, the combination product manufacturer is 
responsible for ensuring the stability of the drug product as marketed in the co-packaged 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. 
 
If a drug constituent part of a co-packaged combination product has an expiration date, 
the combination product manufacturer may be able to rely on that labeled expiration date in lieu 
of conducting new stability studies, if it can be documented that any additional manufacturing 
operations conducted on the co-packaged product would not be expected to impact the 
constituent part, including its container-closure system. 
 
                                                 
99 Note that shelf life testing to evaluate the impact of the modification to the device constituent part may still be 
appropriate. 
100 This might also be the case for a family of products that vary in shape from one another, provided, again, that 
these variations pose a low risk. 
101 Note that shelf life testing to evaluate the impact of a modification on the device constituent part may still be 
appropriate. 
  34  Contains Nonbinding Recommendations  
 
7.  Special testing requirements (21 CFR 211.167) 
 
21 CFR 211.167 establishes requirements for batch testing applicable to drug products 
having particular characteristics.  Specifically, 21 CFR 211.167(a) requires appropriate 
laboratory testing of drug products purporting to be sterile and/or pyrogen-free to determine 
conformance with such requirements; 21 CFR 211.167(b) requires appropriate testing of 
ophthalmic ointments to determine conformance to specifications regarding the presence of 
foreign particles and harsh or abrasive substances; and 21 CFR 211.167(c) requires appropriate 
laboratory testing of controlled-release dosage forms to determine conformance to the 
specifications for the rate of release of each active ingredient.   
 
A special testing requirement specified in 21 CFR 211.167 applies to a combination 
product only if the combination product or a drug constituent part of it falls into one or more of 
the three categories described above.  Special testing may be required for the drug constituent 
part, or the combination product as a whole, depending on the product.   
 
With respect to 21 CFR 211.167(a), batch testing requirements would apply both to the 
drug constituent part and to the finished combination product for a single-entity combination 
product (such as a prefilled syringe) to ensure the combination product is sterile and pyrogen-
free when distributed.  In contrast, if a vial of a vaccine were co-packaged with an empty 
syringe, the requirements in 21 CFR 211.167(a) would apply only to the vial of vaccine.102  A 
similar analysis would apply for compliance with 21 CFR 211.167(b) for a single-entity versus a 
co-packaged combination product that includes an ophthalmic ointment. 
 
For purposes of conducting pyrogen and endotoxin testing, it may be permissible in some 
circumstances to define a batch based on the finished drug product rather than the finished 
combination product.  For example, it may be acceptable to define a batch as a subcomponent of 
the combination product that incorporates the drug constituent part.  However, the viability of 
such an approach would depend on many factors including:  appropriate upstream controls to 
reduce/limit pyrogens and endotoxins; the chemical or materials-mediated pyrogenicity of the 
constituent parts, and the risks of pyrogen and endotoxin introduction to the combination product 
by manufacturing operations that occur after the step at which the batch is defined.  For instance, 
for some products, it may be possible to test material for endotoxin during an in-process 
manufacturing step and there may be no need to test for endotoxins in the single entity 
combination product. 
 
21 CFR 211.167(c) would apply both to a controlled-release drug constituent part of a co-
packaged combination product and also to a controlled release single-entity combination product, 
to confirm rate of release of the active ingredient. For example, a transdermal drug patch or drug-
                                                 
102 The requirements related to sterility and non-pyrogenicity of the empty syringe would be addressed through 
compliance with other provisions (for example, process controls requirements under 21 CFR 211 or 21 CFR 820, 
design controls requirements under 21 CFR 820.30, and purchasing controls requirements under 21 CFR 820.50).  
For additional information on pyrogen and endotoxin testing, see the Guidance for Industry on Pyrogen and 
Endotoxins Testing: Questions and Answers (June 2012)). 
  35  Contains Nonbinding Recommendations  
 
eluting disc or stent would be subject to 21 CFR 211.167(c).  
 
As with drugs and devices, parametric release may be acceptable for some combination 
products when supported by appropriate data.  Such approaches should be discussed with the 
lead Center, or OCP as needed, prior to implementation and included in premarket 
submissions.103 
 
8.  Reserve samples (21 CFR 211.170) 
 
Reserve samples are needed to help ensure the safety and effectiveness of combination 
products in distribution, as they are for drugs and biological products.  They are used, for 
example, to address certain product complaints, evaluate stability concerns, and assess the causes 
of adverse events.  The reserve sampling requirements of 21 CFR 211.170 must be met for the 
drug constituent parts of combination products.   
 
Under 21 CFR 211.170, reserve samples must be kept that are representative of both: 
 
  each lot of the active ingredient (21 CFR 211.170(a)), and  
  each lot or batch of the drug product (21 CFR 211.170(b)).   
 
All reserve samples must consist of at least twice the quantity necessary to perform all 
required tests, except those for sterility and pyrogenicity.104  Furthermore, reserve samples of 
drug products must be retained and stored under conditions consistent with product labeling and 
stored in the same immediate container-closure system in which the drug product is marketed or 
in one that has essentially the same characteristics.105    
 
Accordingly, single-entity and co-packaged combination product manufacturers alike 
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).   
 
For co-packaged combination products, the requirement to keep reserve samples of drug 
products can be met by maintaining samples of the drug constituent part in its immediate 
container-closure system, without the need to retain any samples of the device or portions of 
it.106  For single-entity combination products, the drug product reserve samples should be of the 
drug constituent part in or upon the device constituent part or components thereof that come into 
contact with the drug product as packaged for distribution. 
 
                                                 
103 See, for example, Guidance for Industry Submission of Documentation in Applications for Parametric Release of 
Human and Veterinary Drug Products Terminally Sterilized by Moist Heat Processes (February 2010) . 
104 21 CFR 211.170. Stability is not required to be assessed on every drug batch. See 21 CFR 211.166(b).   Drug 
product reserve samples must be visually examined at least once a year while in storage as an ongoing check on the 
quality of the material in distribution, unless a visual examination would affect the integrity of the reserve sample. 
21 CFR 211.170(b). 
105 21 CFR 211.170(b). 
106 See 21 CFR 211.170(b). 
  36  Contains Nonbinding Recommendations  
 
Manufacturers must examine drug product samples for deterioration, investigate evidence 
of deterioration, and record and maintain the results of such examination.107  Drug product 
reserve samples generally must be maintained for 1 year after the expiration date for the drug 
product; different time periods apply to certain radioactive and OTC products.108  Active 
ingredient samples generally must be kept for 1 year after the expiration date for the last lot of 
the combination product containing the active ingredient.109  Accordingly, manufacturers should 
retain samples from each lot of bulk drug substance for 1 year after the expiration date of the last 
lot of the combination product that uses that lot of the active ingredient.   
 
Combination product manufacturers may choose to have their reserve samples of the 
API, drug/biologic constituent part, or finished combination product at a location other than the 
combination product manufacturing facility.  In these cases, the combination product 
manufacturer should have appropriate controls in place to ensure that requirements under 21 
CFR 211.170 continue to be met.  Such controls could include agreements with the facilities 
holding the reserve samples to ensure appropriate storage conditions, access to the samples by 
the combination product manufacturer, ability to analyze the reserve samples, if needed, and 
maintenance of adequate numbers of samples for each lot. 
 
For combination products, it is generally sufficient to maintain the appropriate number of 
reserve samples from each lot of the active ingredient and from each lot or batch of the drug 
constituent part in the immediate container/closure in which it is marketed.  For single-entity 
combination products, the device constituent part may be the drugs container/closure or a part of 
it, or the container/closure may be distinct from the device constituent part.  For a drug-eluting 
stent or disc, or a prefilled syringe, for example, reserve samples should generally be kept of the 
entire combination product.  In contrast, if, for example, the combination product consists of an 
injector system (device constituent part) into which the user inserts a prefilled cartridge 
containing the drug, reserve samples of the prefilled cartridge alone would generally suffice to 
comply with the drug product sample retention requirements.  An injector may need to be 
available, however, to enable testing of reserve samples.    
 
Manufacturers that want to retain and store reserve samples that are representative of, but 
not identical to, a finished drug constituent part or combination product, as appropriate, should 
include adequate justification and data to support that:  
 
  Any differences in the manufacturing process for the reserve sample and the 
finished combination product do not affect the drug constituent part (see 
discussion in IV.B.5 above);  
  The immediate container/closure has essentially the same characteristics as the 
immediate container/closure for the drug as packaged in the combination product 
for distribution (if the actual immediate container closure is not being used), and  
  The proposed representative samples are suitable for all required testing of the 
drug constituent part for which those reserve samples are being kept.   
                                                 
107 See 21 CFR 211.170(b). 
108 See 21 CFR 211.170(b).  
109 See 21 CFR 211.170(a). 
  37  Contains Nonbinding Recommendations  
 
 
It may be possible to keep properly defined and validated surrogates for some testing 
while retaining complete samples of the combination product for other tests as an alternative to 
retaining complete samples for all testing.  Bracketing and matrixing approaches also may be 
acceptable, as may use of samples from representative lots of a larger batch (for example, 
representative samples of each size from within a broadly defined batch that includes multiple 
sizes from the same family of coated combination products).110 
 
Manufacturers considering use of novel approaches to comply with reserve sampling 
requirements are advised to discuss them with the lead center for their combination product, or 
OCP, as needed.   
 
C. Combination products that include biological products and HCT/Ps  
 
In addition to complying with drug CGMP and device QS regulation requirements as 
applicable in accordance with part 4, a manufacturer of a combination product that contains a 
biological product or an HCT/P must comply with the requirements that would apply to the 
biological product or HCT/P if it were not part of a combination product. 
 
1.  Complying with CGMP requirements for biological products 
 
It is important to remember that a biological product regulated under section 351 of the 
PHS Act is also, by definition, a drug or a device.  Accordingly, in addition to the requirements 
in parts 600 through 680, a biological product is always either subject to the drug CGMPs or 
subject to the device QS regulation, regardless of whether the biological product is a constituent 
part of a combination product.  The CGMP requirements for biological products in parts 600 
through 680 augment the drug CGMPs and device QS regulation to ensure adequate 
consideration of issues for biological products.  The CGMP requirements for biological products 
in parts 600 through 680 address the particular challenges biological products pose, including 
challenges arising from their relative complexity.  For biological products, consistency of 
manufacturing procedures can, in fact, be a primary means by which to ensure the safety, purity, 
and potency of the product. 
 
The CGMP requirements for biological products in parts 600 through 680 must be 
satisfied if a combination product includes a biological product constituent part.  However, many 
requirements in parts 600 through 680 are applicable only to certain types of biological products.  
For example, while part 600 facially addresses biological products in general, only products 
manufactured using a spore-forming microorganism would be subject to 21 CFR 600.11(e)(3) 
(work with spore-forming microorganisms).  Similarly, only blood and blood components are 
subject to the CGMP requirements for such products under part 606.  In addition, the CGMP 
requirements for biological products applicable to a given product can vary based on 
considerations specific to the particular biological product. 
                                                 
110 FDA notes that approaches that depend upon retaining samples against more broadly defined batches may 
increase the number of distributed products implicated when corrective actions are necessary to address postmarket 
issues. 
  38  Contains Nonbinding Recommendations  
 
 
In short, the specific requirements in parts 600 through 680 that must be met to comply 
with 21 CFR 4.3 and 4.4(c) for a particular combination product that includes a biological 
product constituent part will depend on the type of biological product it includes.  The Agency 
welcomes the opportunity to discuss these requirements with manufacturers to ensure sound, 
effective CGMP operating systems.  If manufacturers have questions regarding these 
requirements, they may contact the lead center for the combination product or OCP, as needed, 
for assistance.   
 
2.  Complying with CGMPs for HCT/Ps 
 
An HCT/P that is not regulated solely under section 361 of the PHS Act and Part 1271 is 
also regulated as a drug, device, or biological product. 111  The drug CGMPs, device QS 
regulation, and the requirements in parts 600 through 680 may apply to an HCT/P depending on 
whether the product is regulated as a drug, device, or biological product.112  CGMPs and the 
CGTPs for HCT/Ps supplement one another and do not supersede each other unless the 
regulation specifically provides otherwise.  In the event that a regulation in part 1271 is in 
conflict with a requirement in parts 210, 211, 600 through 680, or 820, the regulations more 
specifically applicable to the product in question will supersede the more general.113 
 
The CGTPs, including donor eligibility requirements for the manufacture of HCT/Ps 
under part 1271, are designed to prevent the introduction, transmission, and spread of 
communicable diseases, and thereby are essential to protecting the public health.  Accordingly, 
the current CGTPs apply to combination products that include an HCT/P.  However, 
requirements under some sections of part 1271 overlap with the requirements under the drug 
CGMPs and the device QS regulation.  These overlaps are addressed in part 1271 and in the 
Guidance for Industry on Current Good Tissue Practice (CGTP) and Additional Requirements 
for Manufacturers of Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps) 
(CGTP Guidance).   
 
                                                 
111 The HCT/P regulations at part 1271 distinguish between HCT/Ps regulated solely under section 361 of the PHS 
Act (42 U.S.C. 264) and part 1271 and those that are also regulated as drugs, devices, and/or biological products.  
Section 1271.10 provides that an HCT/P is regulated solely under section 361 of the PHS Act if it meets all of the 
following criteria:  (1) it is minimally manipulated; (2) it is in intended for homologous use only, as reflected by the 
labeling, advertising, or other indications of the manufacturer's objective intent; (3) manufacturer of the HCT/P does 
not involve the combination of the cells or tissues with another article (other than water, crystalloids, or a sterilizing, 
preserving, or storage agent) provided that the addition of water, crystalloids, or the sterilizing, preserving, or 
storage agent does not raise new clinical safety concerns with respect to the HCT/P; and (4) Either: (i) The HCT/P 
does not have a systemic effect and is not dependent upon the metabolic activity of living cells for its primary 
function; or (ii) The HCT/P has a systemic effect or is dependent upon the metabolic activity of living cells for its 
primary function, and is for autologous use, is for allogeneic use in a first-degree or second-degree blood relative; or 
is for reproductive use.  Refer to 21 CFR 3.2(e), 1271.10, 1271.15, and 1271.20, to determine whether an HCT/P is 
regulated as a drug, device, or biological product constituent part of a combination product.  
112 See 78 FR 4317. 
113 See 21 CFR 1271.150(d).  Also see the Guidance for Industry on Current Good Tissue Practice (CGTP) and 
Additional Requirements for Manufacturers of Human Cells, Tissues, and Cellular and Tissue-Based Products 
(HCT/Ps) (December 2011). 
  39  Contains Nonbinding Recommendations  
 
21 CFR 1271.150(d) explains that for HCT/Ps regulated as biological products, drugs or 
devices, the procedures contained in subpart D and in subpart C of part 1271 and the procedures 
contained in parts 210, 211, and 820, supplement one another.  As a consequence, compliance 
with certain provisions of part 211 or 820 may also constitute partial or complete compliance 
with certain provisions of part 1271.  However, for certain issues, the CGTP requirements would 
require additional manufacturing practices.  The adjustments that might need to be made to an 
existing CGMP operating system to be fully compliant with the part 1271 CGTP requirements 
for a combination product that includes an HCT/P may differ if the system being augmented is a 
drug manufacturing system under 21 CFR 211, a device manufacturing system under part 820, or 
a combination product manufacturing system that demonstrates compliance with 21 CFR 211 
and 21 CFR part 820 in accordance with 21 CFR 4.4(a)(1), 4.4(b)(1), or 4.4(b)(2). 
 
For further information, see the CGTP Guidance.  FDA understands the complexity of 
manufacturing considerations and duties for combination products that contain an HCT/P.  
Accordingly, the Agency encourage manufacturers to contact the lead center for their product or 
OCP, as needed, with questions about how to comply with CGMP requirements for their 
particular product. 
 
V.  Application of CGMP requirements to specific types of 
combination products 
 
The hypothetical scenarios addressed in this section focus on three types of combination 
products.  While each of these types of combination products is subject both to the drug CGMPs 
and to the device QS regulation, each example is used to focus on particular CGMP 
considerations relating to CGMP provisions specified in 21 CFR 4.4(b).  Specifically: 
 
  Section A, a prefilled syringe example, focuses on how to comply with the device QS 
regulation provisions specified in 21 CFR 4.4(b)(1) if a manufacturer adopts a drug 
CGMP-based streamlined approach for its CGMP operating system. 
   
  Section B, a drug-coated mesh example, focuses on considerations for complying with 
certain device QS regulations after a drug constituent part is combined with a device.   
 
  Section C, a drug-eluting stent (DES) example, focuses on how to comply with the drug 
CGMP provisions specified in 21 CFR 4.4(b)(2) if a manufacturer adopts a device QS 
regulation-based streamlined approach for its CGMP operating system.  
 
This discussion is intended to highlight only certain issues that a combination product 
might raise relating to the CGMP provisions specified in 21 CFR 4.4(b), and considerations for 
addressing these issues.  The discussion may be helpful to inform understanding of the CGMP 
provisions that are addressed here not only in regard to the types of combination products in the 
scenarios, but for other types of combination products as well.  However, this discussion is not 
intended to reflect a complete analysis of the CGMP issues that need to be addressed for the 
types of products discussed in the scenarios or other types of combination products.  In addition, 
specific products may raise distinct issues that are not taken into account in the hypothetical 
scenarios presented below.  If manufacturers have specific questions relating to their particular 
  40  Contains Nonbinding Recommendations  
 
products, the Agency recommends that they contact the lead center for the product or OCP, as 
needed, for assistance. 
 
A. Prefilled syringe 
 
1.  Scenario Description 
 
A drug manufacturer (Manufacturer A) plans to sell a drug in a prefilled syringe  
presentation.114  Manufacturer A already has marketing approval for the drug product and 
intends to apply for marketing approval for the prefilled syringe presentation.  No changes to the 
drug formulation will be made.  Manufacturer A will buy off-the-shelf syringe components from 
a supplier (Manufacturer B) who also manufactures finished syringes using the same 
components.  Manufacturer A will assemble the syringe components, prefill the syringe at a 
facility it operates, and then package, label, and distribute the prefilled syringe from this facility.   
 
Manufacturer As facility has an existing drug CGMP operating system.  As the prefilled 
syringe is a single-entity combination product under 21 CFR 3.2(e)(1), Manufacturer A must 
demonstrate compliance with both the drug CGMPs and device QS regulation.115  To do so, 
Manufacturer A opts to establish a CGMP operating system using the drug CGMP-based 
streamlined approach in accordance with 21 CFR 4.4(b)(1).  While Manufacturer A must ensure 
that its operating system fully complies with the drug CGMPs for this product, taking into 
account all of the issues raised by inclusion of the device constituent part, this example focuses 
on considerations for demonstrating compliance with the provisions from the device QS 
regulation specified in 21 CFR 4.4(b)(1).  
 
2.  Compliance with device QS regulation requirements 
 
Having chosen to use the drug CGMP-based streamlined approach under 21 CFR 
4.4(b)(1), in addition to demonstrating compliance with the drug CGMPs, Manufacturer A must 
comply with the provisions of the device Quality System (QS) regulation specified in 21 CFR 
4.4(b)(1).  For each such provision, this discussion offers exemplary considerations and activities 
for the combination product manufacturer seeking to meet the device QS regulation 
requirements. 
 
a)  21 CFR 820.20, Management Responsibility   
 
  While section 501 of the FD&C Act (21 U.S.C. 351) and 21 CFR 211.22, 211.25, and 
211.180 establish requirements relevant to management responsibility, Manufacturer A must 
ensure that its CGMP operating system demonstrates compliance with the specific requirements 
in 21 CFR 820.20 (discussed in greater detail in section IV.A.1). 116 
                                                 
114 The design control considerations for a prefilled syringe with a biological product are largely similar to those 
covered in the example, although some additional issues may be more common such as the interaction of the 
biological product with the syringe materials and the effect of product viscosity on delivery. 
115 See 21 CFR part 4. 
116 See 21 CFR 4.4(b)(1). 
  41  Contains Nonbinding Recommendations  
 
 
  Manufacturer A should, for example, review its existing CGMP operating system to 
assess whether changes are needed to comply with this provision.  As part of this review, 
management with executive responsibility for Manufacturer A should review the facilitys 
quality policy and develop and implement appropriate oversight procedures, if such procedures 
are not already in place, to ensure that both the policy and oversight are adequate.  The oversight 
procedures should include clear delineation of the personnel to whom management with 
executive responsibility is delegating responsibility for implementing the quality policy 
(including translation into methods and procedures) and the CGMP operating system for this 
product at the facility. 
 
b)  21 CFR 820.30, Design Controls   
 
Manufacturer A is responsible for establishing and maintaining procedures for design 
control activities for the combination product.  In this scenario, Manufacturer A is the owner and 
is manufacturing the prefilled syringe.  Accordingly, Manufacturer A is responsible for the 
design control activities for the syringe as part of the combination product, as well as having 
overall responsibility for the combination product.  However, Manufacturer A is buying the 
syringe components from Manufacturer B, another manufacturer, which uses the same 
components to manufacture finished syringes.  As a result, Manufacturer A may be able to 
leverage syringe-specific design control documentation from the design controls Manufacturer B 
uses for its finished syringes.117  Because no changes are to be made to the drug other than being 
put into the syringe, the drug comes into the design control process as an input to the design of 
the syringe to ensure that the syringes design reflects adequate consideration of the drugs 
characteristics, as indicated below.   
 
An appropriate first step for Manufacturer A would be to review Manufacturer Bs design 
control data to determine what new questions are raised by the use of the syringe with the drug, 
and to assess what additional design control activities may be needed as a consequence.  It may 
be the case, for example, that Manufacturer A can demonstrate that the only new design 
questions that are raised concern the performance of the syringe as a container/closure to store 
the drug and the extent to which the contact between the syringe and the drug may affect its 
performance as a delivery system.  Regardless, Manufacturer A must ensure that all design 
considerations for the combination product are addressed in accordance with 21 CFR 820.30. 
 
                                                 
117 If the supplier of the device components did not have design control information, Manufacturer A would likely 
need to undertake more extensive design control activities for the syringe.  For example, Manufacturer A would 
need to perform device-specific verification testing to confirm that the syringe meets necessary specifications for 
plunger force or other parameters if the syringe component supplier has not conducted such testing suitable to enable 
leveraging. 
  42  Contains Nonbinding Recommendations  
 
i.  Design inputs and outputs 
 
The table below includes illustrative examples of design inputs and user needs and 
related design outputs for this prefilled syringe. 
 
Design Input/User Needs  Design Output 
Required minimum/maximum dose delivery  Drawing/specification for syringe dimensions, 
for drug  markings, etc. 
Drug viscosity and desired/required delivery  Drawing/specification for needle bore, glide 
rate  force, etc. 
Expected use condition (e.g., expected user  Content and reading level for the prefilled 
experience/education level)  syringes labeling 
Maximum and minimum allowable  Packaging/labeling specifications for the 
temperature for prefilled syringe  prefilled syringe 
No degradation of drug or syringe over the  Specifications for drug-contacting syringe 
expected shelf-life as a result of contact with  materials 
one another 
Expected shipping method and appropriate  Design drawings/specifications for primary 
storage conditions  and secondary packaging, labeling for 
acceptable storage conditions 
Drug delivery method (e.g., needle or  Drawing/specification for needle and/or other 
needleless delivery)  associated syringe components 
 
ii.  Design verification and validation 
 
Once Manufacturer A has established design outputs for all design inputs, it must 
perform design verification and validation activities to ensure that the combination product meets 
design input requirements, including user needs and intended uses.118  Examples of appropriate 
testing of the prefilled syringe include:  bench testing of the delivery of the drug from the syringe 
to ensure repeatable and accurate drug delivery; shock and vibration testing of the packaged 
prefilled syringe to ensure no damage or loss of integrity in shipping; validation that expected 
users can adequately follow the instructions for use; other human factors studies; 
biocompatibility testing; 119 drug and syringe compatibility studies; leachables and extractables 
testing; and verification that the prefilled syringe works with all expected delivery methods (i.e., 
needle, needleless).  These activities would be documented in the DHF pursuant to 21 CFR 
820.30(j) and would be subject to design change and review requirements pursuant to 21 CFR 
820.30(e) and (i). 
 
                                                 
118 See 21 CFR 820.30(f) and (g). 
119 For additional information on biocompatibility, see Guidance for Industry and FDA Staff:  Use of International 
Standard ISO 10993-1, "Biological evaluation of medical devices - Part 1: Evaluation and testing within a risk 
management process" (June 2016).   
 See also, USP Chapter <87> Biological Reactivity, In Vitro and USP <88> Biological Reactivity Tests, In Vivo. 
  43  Contains Nonbinding Recommendations  
 
iii.  Risk Analysis 
 
Manufacturer A should identify risks associated with the prefilled syringe design, its 
manufacturing processes, and intended uses, and also reduce or mitigate any unacceptable 
risk(s).120  The table below lists some potential risks associated with prefilled syringes and 
potential mitigations for these risks. 
 
Risk  Mitigation 
Syringe filled with incorrect drug dose  In-process acceptance testing, process validation 
Loss of sterility   Container-closure integrity testing, packaging 
validation/testing 
Drug contamination from materials of  Purchasing controls (including receiving 
syringe construction  acceptance activities for components received from 
syringe component manufacturer), in-process and 
finished product testing to ensure no introduction of 
contaminants during manufacture and over the 
product shelf-life  
Syringe failure during use  Design verification testing on syringe, purchasing 
controls over syringe component manufacturer(s) 
 
iv.  Design changes  
 
Manufacturer A must also have procedures in place to ensure that any changes to design 
requirements are identified, documented, validated and/or verified, reviewed, and approved prior 
to implementation.121  Activities should include review of the original risk analysis, review and 
approval of the revised design inputs and outputs, and review and approval of the design change.  
For example, before changing a material used in the syringe that comes into contact with the 
drug, Manufacturer A should conduct verification activities to ensure that no degradation of 
performance characteristics will occur before the expiration date for the combination product as 
a result of the change of materials.122  Likewise, any change to the formulation of the drug 
should include design control activities such as verification to confirm that the new formulation 
does not degrade performance of the syringe.  All of this information would need to become a 
part of the DHF.123   
 
v.  Design history file  
 
The DHF may include references or point to information residing elsewhere so long as 
the reference or pointer is precise enough to allow the necessary information to be readily 
                                                 
120 See 21 CFR 820.30(g). 
121 See 21 CFR 820.30(i). 
122 Changes to materials that contact the drug may raise drug CGMP considerations, for example, under stability 
testing and expiration dating requirements (21 CFR 211.137 and 21 CFR 211.167).  When possible, manufacturers 
may leverage data collected in meeting these 21 CFR 211 requirements when determining what verification 
activities are required under 21 CFR 820.30.   
123 See 21 CFR 820.30(j).  
  44  Contains Nonbinding Recommendations  
 
accessed as needed, including for inspections.  For example, elements of the syringe component 
manufacturers design documentation may be relied upon to support the combination product 
DHF.  Such information on the syringe may reside at Manufacturer Bs (syringe component 
manufacturer) facility, so long as the necessary documentation can be accessed in a reasonable 
time during inspection of Manufacturer A.  Manufacturer A should ensure access to such 
documentation through supplier agreements with Manufacturer B under its purchasing controls 
(21 CFR 820.50).  Documentation of development of the drug product that preceded the design 
effort to incorporate the drug product into a prefilled syringe may be referenced in the DHF and 
become an input to the combination product design effort (though such drug-only development is 
not itself subject to design controls). 
 
c)  21 CFR 820.50, Purchasing Controls   
 
Manufacturer A is required to control its purchasing activities, including for the syringe 
components, in accordance with 21 CFR 820.50.124  For example, if the syringe barrel and 
plunger material is critical to ensuring that there is no adverse reaction with the drug, 
Manufacturer A should structure purchasing agreements with Manufacturer B to ensure that 
Manufacturer A is notified of any changes to this material prior to implementation of the change.  
Similarly, if Manufacturer A uses an outside facility for terminal sterilization of the prefilled 
syringe, Manufacturer A must also have appropriate controls over that sterilization service 
provider.125   
 
d)  21 CFR 820.100, Corrective and Preventive Actions   
 
Manufacturer A is required to establish and maintain CAPA procedures for the 
combination product.  Following are two examples of issues that might arise and exemplary 
steps for addressing them: 
 
Example 1:  Manufacturer A has implemented in-process manufacturing verification 
procedures to confirm that the syringe is being filled with the correct amount of the drug, and the 
data from this verification are analyzed for potential nonconformities.  Manufacturer A notes an 
increase in nonconformities relating to the volume of drug being put in the syringe and in turn 
opens a CAPA to investigate the problem.  Upon investigation of the cause of the improper fill 
volume, Manufacturer A determines that maintenance procedures on the filling equipment are 
the cause of the incorrect fill volume.  Manufacturer A updates the maintenance procedures and 
performs verification/validation testing to confirm that the changes correct the problem and do 
not cause new ones.   
 
Example 2:  Manufacturer A begins receiving an increased number of customer 
complaints related to holes or other damage to the syringes sterile package and opens a CAPA 
to investigate the issue.  The CAPA reveals that Manufacturer B has made changes to a syringe 
component such that there are sharp edges that can damage the sterile pouch during shipping.  
                                                 
124 In addition, because the device constituent part (syringe) is also a container/closure for the drug, Manufacturer A 
must perform acceptance testing of the syringe components in accordance with 21 CFR 211.84. 
125 See 21 CFR 820.50. 
  45  Contains Nonbinding Recommendations  
 
Manufacturer A works with Manufacturer B to eliminate the sharp edge or finds a new supplier.  
Manufacturer A also augments purchasing specifications and acceptance test steps to perform 
visual inspection of the syringe components.  Manufacturer A repeats related design verification 
testing to ensure that the new syringe meets all design requirements and does not result in pouch 
damage during shipping.   
 
e)  21 CFR 820.170, Installation and 820.200, Servicing 
 
Installation and servicing requirements would not apply to the prefilled syringe because 
the product does not require installation or servicing activities. 
 
B. Drug-coated mesh 
 
1.  Scenario Description 
 
Manufacturer A plans to sell a synthetic surgical mesh coated with a drug.  Manufacturer 
A has a marketing authorization to sell the uncoated mesh.  Manufacturer A wants to coat the 
mesh with a drug to treat infection at the site of the products implantation.  Manufacturer B has 
an approval to market a drug for local administration to treat infection at the site of implantation 
of this class of device, but not in a formulation suitable for coating onto the mesh.  Manufacturer 
A has established a business relationship with Manufacturer B to use the drug and develop the 
data needed to support Manufacturer As marketing authorization for the coated mesh.  
Manufacturer B will manufacture the drug formulation for spraying onto the mesh, and 
Manufacturer A will manufacture the finished drug-coated mesh combination product. 
 
2.  Compliance with QS regulation requirements 
 
The coated mesh product is a single-entity combination product under 21 CFR 3.2(e)(1).  
Therefore, Manufacturer A is subject both to the drug CGMPs and the device QS regulation for 
this combination product.  Accordingly, Manufacturer A must ensure that its CGMP operating 
system complies with both the device QS regulation and drug CGMPs, in accordance with one of 
the approaches permitted under 21 CFR 4.4.  Because Manufacturer A is already marketing the 
uncoated mesh, it has an existing device QS regulation-based operating system, and chooses to 
operate under a device QS regulation-based streamlined approach for the combination product.  
This discussion focuses on design control and purchasing control considerations arising from 
inclusion of the drug constituent part in the combination product. 
 
a)  21 CFR 820.30, Design Controls 
 
A focus of the design control process for the drug constituent part of the combination 
product is to ensure that the drug-coated mesh will be safe and effective for treating infection at 
the site of implantation.  Accordingly, if the necessary dose of the drug for effective treatment  of 
infection, for example, is already known, it would be an input (if the precise dose is not yet 
known, then an input would be that the product elute a safe and effective dose); design outputs 
  46  Contains Nonbinding Recommendations  
 
and validation and verification would need to be established to ensure that the required dose is 
provided when the drug elutes from the mesh.126  In addition, risk analysis must be conducted to 
identify any risks associated with the design, manufacturing, and use of the mesh.127  Mitigation 
measures should then be identified and performed to address any identified risks.  Design 
reviews should cover these and other related design considerations for the product, and personnel 
with expertise in both the drug- and device-specific issues (as well as an individual independent 
from the design stage being reviewed) should be included in these reviews.  The transfer of the 
product design into production specifications should address all important aspects of the drug 
constituent part for use in the combination product.128 
 
i.  Design inputs and outputs 
 
The table below includes illustrative examples of design inputs, including user needs, and 
corresponding design outputs relating to the inclusion of the drug constituent part. 
 
Design Input/User Needs  Design Output 
Required delivery dose and delivery rate for  Drug formulation and concentration, coating 
the drug  thickness, uniformity of coating, manufacturing 
process requirements, allowable storage 
conditions 
Expected use condition (e.g., anatomical  Labeling (instructions for use), material/drug 
location of use, surgical technique)  composition to ensure no damage to mesh or 
coating during surgical placement 
Maximum allowable temperature during  Packaging/labeling specifications for the 
transportation, handling, and storage for the  combination product 
combination product 
No unacceptable degradation of the drug  Specifications for the drug formulation drug-
over the expected shelf-life   contacting materials and packaging, shelf-life 
labeling 
No degradation of the surgical mesh over  Specifications for mesh material, drug 
the expected shelf-life  formulation and packaging, shelf-life labeling  
 
ii.  Design verification and validation 
 
Several examples of design verification and validation activities are described below: 
 
-  One intended use is that the drug-coated mesh will treat infections.  Manufacturer A 
must develop adequate clinical data (design validation) to ensure that the drug, when 
combined with the mesh, is effective in treating infection and does not raise safety 
concerns.129  Design outputs from this study would include the drug concentration in 
the coating formulation (to be specified in purchasing controls over Manufacturer B) 
                                                 
126 See 21 CFR 820.30(d), (f), and (g). 
127 See 21 CFR 820.30(g). 
128 See 21 CFR 820.30(h). 
129 See 21 CFR 820.30(g). 
  47  Contains Nonbinding Recommendations  
 
and the coating thickness (specified in process controls over the application of the 
coating by Manufacturer A). 
 
  A user need is that a physician be able to use the mesh product as labeled without 
damaging the drug coating or the mesh material.  Manufacturer A would have to 
verify that the mechanical properties of the coated mesh are such that the product can 
withstand the stresses anticipated during the surgical procedure and still perform as 
intended.130  The results would be used to define and develop design outputs for the 
combination product, including in-process acceptance testing criteria during 
manufacturing, appropriate product specifications for the drug coated mesh, and 
instructions for use. 
 
  Another input to the design process is that the product have a shelf-life consistent 
with the stability of the drug formulation and the mesh.  Manufacturer A would 
perform design verification testing such as bench testing after aging to confirm that 
the critical performance properties of the mesh material are not degraded during 
storage or as a result of contact with the drug coating, as well as stability studies131 to 
ensure that the properties of the drug are not degraded over the expected shelf life.  
The design outputs arising from this process would include the labeled expiration date 
and storage conditions for the combination product and packaging design 
specifications.   
 
iii.  Risk analysis and mitigation 
 
The table below lists some potential risks associated with a surgical mesh coated with a 
drug, and potential mitigations for these risks. 
 
Risk  Mitigation 
Drug concentration in coating not  Clinical testing of the combination product, in-
sufficient to treat infection (e.g., due to  process acceptance testing, manufacturing process 
insufficient drug coating per surface area  validation 
of the mesh or non-uniformity of   
coating),  inappropriate delivery rate 
Mesh erodes or drug degrades during use  Design verification testing (bench), clinical 
or storage  testing, labeling (instructions for use, expiration 
dating), purchasing controls over drug supplier, 
specifications and other process controls 
 
iv.  Design history file 
 
All of the design control activities required by 21 CFR 820.30 (summarized in IV.A.2 
above) must be addressed in the DHF for the drug-coated mesh.  The information developed as a 
                                                 
130 See 21 CFR 820.30(f). 
131 See the Guidance for Industry on Q1A(R2) Stability Testing of New Drug Substances and Products (November 
2003). 
  48  Contains Nonbinding Recommendations  
 
result of design control activities will be assessed as part of premarket review of this 
combination product (e.g., the suitability of the drug formulation and the compatibility of the 
mesh with the drug).  Accordingly, much of the information included in the DHF would be 
submitted as part of the premarket review process.  Manufacturer A may opt to incorporate such 
information into the DHF by cross-reference to such premarket documentation.  Whatever 
approach Manufacturer A selects must ensure that all required design history information is 
readily available to FDA for review. 
 
The DHF for the surgical mesh must include design input, output, verification and 
validation data, and the results of design reviews for the combination product.  In developing the 
design controls related to the drug constituent part, Manufacturer A may rely on the safety, 
efficacy, quality and in situ dose data for the drug as independently marketed.  These existing 
data that supported approval of the drug would be available as a reference for the combination 
product DHF to enable development of design inputs for the drug constituent part and the 
combination product as a whole, and thus facilitate its development process. 
 
b)  21 CFR 820.50, Purchasing Controls 
 
Manufacturer A already has established procedures for controlling purchasing/supplier 
activities pursuant to 21 CFR 820.50.  Under this provision, Manufacturer A must ensure that 
appropriate purchasing controls for Manufacturer B are established and maintained.  In 
particular, based on risk associated with the drug and supplier, Manufacturer A must evaluate 
Manufacturer B as a potential supplier of the drug and establish the type and extent of control to 
be exercised over Manufacturer B as a selected supplier.132 
 
Purchasing controls (and acceptance activities under 21 CFR 211.84) with respect to the 
drug constituent part should focus on ensuring that Manufacturer B can supply the drug that 
meets the specifications that Manufacturer A has established during the design control process.  
Manufacturer A should establish purchasing agreements with Manufacturer B to ensure that 
Manufacturer A is notified of any changes that may affect the performance of the combination 
product prior to Manufacturer Bs implementation of the changes.  The notifications should 
address issues including changes in the drug specification, its components, composition of drug 
coating materials, or the drug manufacturing process or facility.  Such proposed changes may 
require that Manufacturer A complete additional design verification and/or validation.  For 
example, verification testing may be necessary to confirm that the purity and stability of the drug 
is maintained, pursuant to the requirements of 21 CFR 820.30(i).  
 
C. Drug Eluting Stent (DES)   
 
1.  Scenario Description 
 
In this scenario, Manufacturer A is the owner for a drug-eluting stent (DES) composed of 
a stent coated with a drug.  Manufacturer B manufactures the active pharmaceutical ingredient 
                                                 
132 See 21 CFR 820.50(a)(2). 
  49  Contains Nonbinding Recommendations  
 
(API or bulk drug substance), Manufacturer C manufactures a polymer with which the bulk drug 
substance will be combined for coating onto the stent, and Manufacturer D manufactures the 
materials used for the products primary packaging.  Manufacturer A purchases the bulk drug 
substance from Manufacturer B and the polymer from Manufacturer C, then formulates the drug 
coating solution and uses it to coat the stent in its own facility.  At the same facility, 
Manufacturer A packages the DES using the primary packaging materials it purchases from 
Manufacturer D.   
 
2.  Compliance with drug CGMP requirements 
 
The DES is a single-entity combination product as defined in 21 CFR 3.2(e)(1) and, 
therefore, is subject to both the drug CGMPs and device QS regulation.  As a device 
manufacturer, Manufacturer A already has a CGMP operating system designed to comply with 
the device QS regulation and has elected to establish a device QS regulation-based streamlined 
approach for the DES in accordance with 21 CFR 4.4(b)(2).  While Manufacturer A must ensure 
that this operating system complies with the device QS regulation, taking into account all of the 
issues raised by inclusion of the drug constituent part, this example focuses on considerations for 
complying with the drug CGMP provisions specified in 21 CFR 4.4(b)(2). 
 
a)  21 CFR 211.84, Testing and approval or rejection of drug components, product 
containers, and closures 
 
Manufacturer A has controls in place to evaluate suppliers, contractors, and consultants 
based on their ability to meet quality and other specified requirements and to control incoming 
materials in accordance with 21 CFR 820.50 and 21 CFR 820.80.  Under 21 CFR 4.4(b)(2), 
Manufacturer A must augment its existing CGMP operating system as needed to satisfy the 
requirements of 21 CFR 211.84 for the DES. 
 
Manufacturer As purchasing controls for the DES must include evaluation of 
Manufacturer B as the supplier of the bulk drug substance,  Manufacturer C as the supplier of the 
polymer for the coating, and Manufacturer D as the supplier of the primary packaging materials, 
in conformance with 21 CFR 820.50(a)(1).  In addition, under its CGMP operating system for 
the facility, Manufacturer A has controls to identify the acceptance status of manufactured 
products.  Manufacturer As responsibilities under 21 CFR 211.84 relate to these various 
obligations and controls arising from the device QS regulation.   
 
   In accordance with 21 CFR 211.84, the bulk drug substance, polymer, and primary 
packaging materials supplied by manufacturers B, C, and D must be sampled, tested, or 
examined, as appropriate, by Manufacturer A to determine whether they should be approved or 
rejected for use.  The primary packaging materials should be visually inspected to ensure that the 
correct, specified materials are received from Manufacturer D.  Each lot of bulk drug substance 
and polymer must be tested to verify conformity with written specifications for purity, quality, 
and strength.133  Due to the nature and intended use of sterile drug eluting stents, testing must 
include microbiological testing of the bulk drug substance and polymer.   
                                                 
133 See 21 CFR 211.84(d)(2). 
  50  Contains Nonbinding Recommendations  
 
 
Under certain circumstances, Manufacturer A may rely on a report of analysis from a 
supplier in lieu of conducting some of its own testing.  If, for example, Manufacturer B performs 
conformity testing for the bulk drug substance (testing to ensure that the material meets 
appropriate purity, strength, and quality specifications) just prior to the shipment of material to 
Manufacturer A, then a report of analysis may be accepted by Manufacturer A in lieu of testing 
for these characteristics by Manufacturer A, if the following conditions are met.134 
 
Manufacturer A is still responsible for the performance of at least one specific identity 
test upon receipt of each lot of the bulk drug substance, even when a report of analysis 
accompanies the lot.135  Reliance on reports of analyses is also contingent on Manufacturer A 
establishing the reliability of the suppliers analyses through appropriate validation of the test 
results at appropriate intervals.136  The supplier can be evaluated through initial purchasing 
controls and subsequently at suitable intervals.  A similar analysis would apply if Manufacturer 
C were to conduct conformity testing for the polymer it supplies to Manufacturer A.  Incoming 
examination or testing by Manufacturer A and receipt of any reports of analysis must occur prior 
to use of the material in the manufacture of the DES. 
 
b)  21 CFR 211.103, Calculation of yield 
 
Calculation of yield should be conducted during all appropriate steps in the 
manufacturing process prior to and after application of the coating to the stent, including the 
formulation of the coating.137  Manufacturer A is responsible for the calculation of yield at 
appropriate phases of manufacture at its facility, including application of the coating to the DES, 
and the packaging of the DES.  The formula used and the data generated for the calculation 
should be maintained in Manufacturer As batch production and control record.   
 
c)  21 CFR 211.132, Tamper-evident packaging requirements for over-the-counter 
(OTC) human drug products 
 
This regulatory requirement is not applicable to drug-eluting stents, as they are not OTC 
products. 
 
d)  21 CFR 211.137, Expiration dating 
 
As the manufacturer of the combination product, Manufacturer A is responsible for 
establishing the expiration date on the labeling of the finished combination product.  The 
expiration date must be established based on the data from the stability studies for the finished 
packaged DES and should also take into account other shelf-life considerations as required under 
                                                 
134 See 21 CFR 211.84(d)(2). 
135 21 CFR 211.84(d)(2). 
136 See 21 CFR 211.84(d)(2). 
137 Drug-coated stents that are rejected due only to defects in the device constituent part (stent) will result in 
corresponding loss of drug constituent part from the batch/lot.  This loss should be captured as part of the yield 
calculations for the drug constituent part and investigation of the cause of that loss should identify the manufacturing 
problem that is leading to these device constituent part nonconformities. 
  51  Contains Nonbinding Recommendations  
 
design control.  These considerations include the functionality of the stent and polymer and the 
integrity of the coating and the packaging.138 
 
e)  21 CFR 211.165, Testing and release for distribution 
 
Manufacturer A must test each batch of the finished combination product to determine 
conformance with the final written specifications for the product.139  A detailed listing of all the 
tests performed on the DES and the acceptance criteria should be incorporated into the 
documentation for the manufacturing, production, and laboratory systems.  A description of each 
analytical test should be prepared and documented in standard operating procedures.  A general 
list of tests for drug-eluting stents is provided below:   
 
  Appearance 
  Identification 
  Assay 
  Impurities and Degradation Products 
  Content Uniformity 
  Drug Release Rate (immediate and/or extended release rates) 
  Package Integrity and Sterility Assurance 
  Endotoxins 
  Particulate Matter 
  Additional Testing, when applicable (including testing for polymer molecular weight, 
residual monomers, catalysts, and other additives) 
 
f)  21 CFR 211.166, Stability testing 
 
Stability testing for the final DES product should address the following considerations: 
appearance, assay/drug content, impurities/degradation products, rate of drug release, particulate 
matter, sterility, and package integrity.  Methods used for batch release under 21 CFR 211.165 
may also be suitable for stability testing.  Analytical procedures for stability testing should be 
fully validated as suitable to demonstrate stability.140  
 
g)  21 CFR 211.167, Special testing requirements 
 
Manufacturer A must conduct or contract to conduct testing of the DES in accordance 
with 21 CFR 211.167(a) because this class of product is purported to be sterile and non-
pyrogenic.  In addition, testing in accordance with 21 CFR 211.167(c) must be conducted 
because the DES constitutes a controlled-release dosage form. 
                                                 
138 See 21 CFR 211.137(a) and (b). 
139 See 21 CFR 211.165(a). 
140 If Manufacturer A decides to develop a family of drug-eluting stents over time, differing from one another in the 
size of the stent, the Agency does not intend to object to the manufacturers leveraging previously generated stability 
data for the existing versions to establish expiration dating for later versions, or newer products being incorporated 
into the ongoing stability program for the existing marketed drug-eluting stents, so long as the manufacturer can 
provide adequate justification and such approaches have been reviewed by FDA, where applicable. 
  52  Contains Nonbinding Recommendations  
 
 
h)  21 CFR 211.170, Reserve samples   
 
Manufacturer A must maintain reserve samples representative of each lot of the active 
ingredient used in the combination product and of each lot or batch of the finished, packaged 
DES.141  Reserve samples must consist of at least twice the quantity necessary to perform all 
tests required for the active ingredient and the finished DES, excluding sterility and pyrogen 
testing.142  The reserve samples must be kept for the time periods required by 21 CFR 211.170.  
The samples of the active ingredient must be kept for 1 year past the expiration date of the last 
lot of finished drug-eluting stents to use that lot of the active ingredient.143 The samples for each 
lot or batch of the finished DES must be kept for 1 year after the expiration date for the 
combination product.144  If Manufacturer A maintains reserve samples in a third-party storage 
facility, Manufacturer A should ensure, via purchasing controls (21 CFR 820.50), that the facility 
can meet applicable CGMP requirements.145 
 
VI.  Contact Us 
 
If you have questions regarding compliance with CGMP requirements for combination 
products after reviewing this guidance and the materials cited in this document, we encourage 
you to contact us.  We recommend you contact the lead center for your product in the first 
instance.  However, you may also contact OCP for assistance.  Below are contact points for each 
center and OCP.  You may follow existing processes for your lead center when requesting 
feedback on combination product issues (e.g., meeting requests to CBER/CDER,146 pre-
submissions to CDRH147). 
 
1.  CBER   
 
Mail:    Office of Communication, Outreach and Development (OCOD) 
10903 New Hampshire Avenue 
     Building 71, Room 3128 
Silver Spring, MD  20993   
Phone:   1-800-835-4709 or 240-402-8010  
Email:    ocod@fda.hhs.gov 
 
                                                 
141 See 21 CFR 211.170(a) and (b). 
142 See 21 CFR 211.170(a) and (b). 
143 See 21 CFR 211.170(a)(1). 
144 See 21 CFR 211.170(b)(1). 
145 Additional information on drug-eluting stents is provided in the draft Guidance for Industry on Coronary Drug-
Eluting StentsNonclinical and Clinical Studies (March 2008). When finalized, this guidance will represent FDAs 
current thinking on this topic.   
146 See Guidance for Industry: Formal Meetings Between the FDA and Sponsors or Applicants (May 2009). 
147 See Guidance for Industry and FDA Staff: Requests for Feedback on Medical Device Submissions: 
The Pre-Submission Program and Meetings with Food and Drug Administration Staff  (February 2014). 
  53  Contains Nonbinding Recommendations  
 
2.  CDER     
 
Mail:  Division of Drug Information (DDI) 
        Hillandale Building 
       10001 New Hampshire Avenue 
      Silver Spring, MD  20993 
Phone:  1-855-543-3784 or 301-796-3400 
Email:  druginfo@fda.hhs.gov 
 
3.  CDRH     
 
Mail:   Division of Industry and Consumer Education (DICE) 
     10903 New Hampshire Avenue 
     Building 66, Room 4621 
      Silver Spring, MD  20993 
Phone:    1-800-638-2041 or 301-796-7100 
Email:    DICE@fda.hhs.gov 
 
4.  OCP 
 
Mail:    Office of Combination Products 
Food and Drug Administration  
10903 New Hampshire Avenue 
Building 32, Hub/Mail Room #5129 
Silver Spring, MD  20993 
Phone:  301-796-8930 
Fax:       301-847-8619 
Email:    combination@fda.gov 
 
VII.  Glossary 
 
Note: this glossary is for use exclusively with this guidance document.  Definitions that have 
been taken from federal regulations include the relevant citation. 
 
Constituent part:  A drug, device, or biological product that is part of a combination product. 
(21 CFR 4.2) 
 
Co-packaged combination product:  Two or more separate products packaged together in a 
single package or as a unit and comprised of drug and device products, device and biological 
products, or biological and drug products.  (21 CFR 3.2(e)(2)) 
 
Cross-labeled combination product:  (i) A drug, device, or biological product packaged 
separately that according to its investigational plan or proposed labeling is intended for use only 
with an approved individually specified drug, device, or biological product where both are 
required to achieve the intended use, indication, or effect and where upon approval of the 
proposed product the labeling of the approved product would need to be changed, e.g., to reflect 
  54  Contains Nonbinding Recommendations  
 
a change in intended use, dosage form, strength, route of administration, or significant change in 
dose; or (ii) any investigational drug, device, or biological product packaged separately that 
according to its proposed labeling is for use only with another individually specified 
investigational drug, device, or biological product where both are required to achieve the 
intended use, indication, or effect. (21 CFR 3.2(e)(3) and 21 CFR 3.2(e)(4)) 
 
Device QS regulation-based streamlined approach:  A CGMP operating system that is 
intended to demonstrate compliance with all of the provisions of the device QS regulation and 
the following provisions from the drug CGMPs in accordance with 21 CFR 4.4(b)(2): 
 
(i) 21 CFR 211.84   Testing and approval or rejection of components, drug 
product containers, and closures 
(ii) 21 CFR 211.103     Calculation of yield 
(iii) 21 CFR 211.132  Tamper-evident packaging requirements for over-the-
counter (OTC) human drug products 
(iv) 21 CFR 211.137    Expiration dating 
(v) 21 CFR 211.165    Testing and release for distribution 
(vi) 21 CFR 211.166    Stability testing 
(vii) 21 CFR 211.167   Special testing requirements  
(viii) 21 CFR 211.170   Reserve samples 
 
Drug CGMPs:  The current good manufacturing practice regulations set forth in 21 CFR 210 
and 21 CFR part 211. (21 CFR 4.2) 
 
Drug CGMP-based streamlined approach:  A CGMP operating system that is intended to 
demonstrate compliance with all of the provisions from the drug CGMPs and the following 
provisions from the device QS regulation in accordance with 21 CFR 4.4(b)(1): 
 
(i) 21 CFR 820.20     Management responsibility  
(ii) 21 CFR 820.30     Design controls 
(iii) 21 CFR 820.50    Purchasing controls 
(iv) 21 CFR 820.100    Corrective and preventive action 
(v) 21 CFR 820.170     Installation 
(vi) 21 CFR 820.200    Servicing 
 
Lead center:  The FDA center (CBER, CDER, or CDRH) that has primary jurisdiction for 
premarket review and regulation of a combination product. 
 
Manufacture:  Includes, but is not limited to, designing, fabricating, assembling, filling, 
processing, testing, labeling, packaging, repackaging, holding, and storage. (21 CFR 4.2) 
 
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) 
 
  55  Contains Nonbinding Recommendations  
 
Owner:  For purposes of this guidance, the entity that holds the marketing authorization for a 
combination product (regardless of whether that entity is directly engaged in the manufacture of 
the product).   
 
Device QS regulation:  The quality system regulation in 21 CFR part 820. (21 CFR 4.2) 
 
Single-entity combination product:  A product comprised of two or more regulated 
components, i.e., drug/device, biologic/device, drug/biologic, or drug/device/biologic, that are 
physically, chemically, or otherwise combined or mixed and produced as a single entity. (21 
CFR 3.2(e)(1)) 
 
Streamlined approach:  Either of the two approaches permitted under 21 CFR part 4, which 
allows combination product manufacturers to demonstrate compliance with both the drug 
CGMPs and device QS regulation by designing and implementing a CGMP operating system 
that demonstrates compliance with part 211 or part 820 in its entirety plus specified provisions of 
the other set of regulations. 
 
VIII. References 
Device 
 
1.  Applying Human Factors and Usability Engineering to Medical Devices 
(http://www.fda.gov/downloads/MedicalDevices/.../UCM259760.pdf) (February 2016) 
 
2.  Design Control Guidance for Medical Device Manufacturers, Guidance for Industry 
(March 1997) 
(http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/Guidanc
eDocuments/ucm070642.pdf)  
 
3.  Glass Syringes for Delivering Drug and Biological Products: Technical Information to 
Supplement International Organization for Standardization (ISO) Standard 11040-4 - 
Draft Guidance for Industry and FDA Staff (April 2013) 
(http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM346181.pdf) 
 
4.  Quality System Information for Certain Premarket Application Reviews, Guidance for 
Industry and FDA Staff (Feb. 3, 2003) 
(http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/Guidanc
eDocuments/ucm070899.pdf) 
 
5.  Requests for Feedback on Medical Device Submissions: The Pre-Submission Program 
and Meetings with Food and Drug Administration Staff, Guidance for Industry (February 
2014) 
(http://www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidanced
ocuments/ucm311176.pdf) 
 
6.  Sterilized Convenience Kits for Clinical and Surgical Use, Guidance for Industry (Jan. 
2002) 
  56  Contains Nonbinding Recommendations  
 
(http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/Guidanc
eDocuments/ucm071029.pdf) 
 
7.  Use of International Standard ISO- 1 10993, "Biological Evaluation of 2 Medical Devices 
Part 1: Evaluation 3 and Testing", DRAFT Guidance for Industry 
(http://www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidanced
ocuments/ucm348890.pdf) 
 
Drugs 
 
8.  CGMP for Phase 1 Investigational Drugs, Guidance for Industry (July 2008) 
(http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM070273.pdf) 
 
9.  Container Closure Systems for Packaging Human Drugs and Biologics:  Chemistry, 
Manufacturing, and Controls Documentation, Guidance for Industry, (May 1999) 
(http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM070551.pdf) 
 
10. Contract Manufacturing Arrangement for Drugs: Quality Agreements, Guidance for 
Industry (November 2016)  
(http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidan
ces/ucm353925.pdf) 
 
11. Formal Meetings Between the FDA and Sponsor or Applicants, Guidance for Industry 
(March 2015) 
(http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidan
ces/ucm437431.pdf) 
 
12. Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production, 
Guidance for Industry (Oct. 2006) 
(http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM070287.pdf) 
 
13. Process Validation:  General Principles and Practices, Guidance for Industry (Jan. 2011) 
(http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM070336.pdf) 
 
14. Q1A(R2) Stability Testing of New Drug Substances and Products, Guidance for Industry 
(Nov. 2003) 
(http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM073369.pdf) 
 
15. Q1B Photostability Testing of Drug Substances and Products, Guidance for Industry 
(November 1996) 
  57  Contains Nonbinding Recommendations  
 
(http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidan
ces/ucm073373.pdf) 
 
16. Q1C Stability Testing for New Dosage Forms, Guidance for Industry (November 1996) 
(http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidan
ces/ucm073374.pdf) 
 
17. Q1D Bracketing and Matrixing Designs for Stability Testing of New Drug Substances 
and Products, Guidance for Industry (January 2003) 
(http://www.fda.gov/downloads/Drugs/.../Guidances/ucm073379.pdf) 
 
18. Q1E Evaluation of Stability Data, Guidance for Industry (June 2004) 
(http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidan
ces/ucm073380.pdf) 
 
19. Q7A Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients, 
Guidance for Industry (Aug 2001) 
(http://www.fda.gov/ICECI/ComplianceManuals/CompliancePolicyGuidanceManual/uc
m200364.htm) 
 
20. Q8(R2) Pharmaceutical Development, Guidance for Industry (November 2009) 
(http://www.fda.gov/downloads/Drugs/.../Guidances/ucm073507.pdf) 
 
21. Q9 Quality Risk Management, Guidance for Industry (June 2006) 
(http://www.fda.gov/downloads/Drugs/.../Guidances/ucm073511.pdf) 
 
22. Q10 Pharmaceutical Quality System, Guidance for Industry (April 2009) 
(http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM073517.pdf) 
 
23. Sterile Drug Products Produced by Aseptic Processing  Current Good Manufacturing 
Practice, Guidance for Industry (Sept. 2004) 
(http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM070342.pdf)  
 
24. Submission of Documentation in Applications for Parametric Release of Human and 
Veterinary Drug Products Terminally Sterilized by Moist Heat Process, Guidance for 
Industry (February 2010) 
(http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidan
ces/ucm437431.pdf) 
 
Biological Products 
 
25. Cooperative Manufacturing Arrangements for Licensed Biologics, Guidance for Industry 
(Nov. 2008) 
(http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulator
  58  Contains Nonbinding Recommendations  
 
yInformation/Guidances/General/UCM069908.pdf) 
 
HCT/Ps 
 
26. Current Good Tissue Practice (CGTP) and Additional Requirements for Manufacturers of 
Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps), Guidance for 
Industry (Dec 2011) 
(http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulator
yInformation/Guidances/Tissue/UCM285223.pdf) 
 
Combination Products 
 
27. Coronary Drug-Eluting Stents  Nonclinical and Clinical Studies, Draft Guidance for 
Industry (March 2008) 
(http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM228704.pdf) 
 
28. How to Write a Request for Designation (RFD), Guidance for Industry (April 2011) 
(http://www.fda.gov/RegulatoryInformation/Guidances/ucm126053.htm) 
 
29. Human Factors Studies and Related Clinical Study Considerations in Combination 
Product Design and Development, Draft Guidance for Industry and FDA Staff  (February 
2016) (http://www.fda.gov/ucm/groups/fdagov-public/@fdagov-
afdagen/documents/document/ucm484345.pdf) 
 
30. Technical Considerations for Pen, Jet, and Related Injectors Intended for Use with Drugs 
and Biological Products, Guidance for Industry and FDA Staff (June 2013) 
(http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM147095.pdf) 
 
General 
 
31. Pyrogen and Endotoxins Testing:  Questions and Answers, Guidance for Industry (June 
2012) 
(http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM310098.pdf) 
  59