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 

3

Guidance for Industry and FDA Staff:

Current Good Manufacturing Practice Requirements for Combination 

Products1

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.”
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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. 

FDA’s guidance documents, including this guidance, do not establish legally enforceable 

responsibilities. Instead, this guidance describes the Agency’s 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.
Contains Nonbinding Recommendations 

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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 lightactivated 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 crosslabeled combination product). 

B. Quality and Current Good Manufacturing Practice

One of FDA’s 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. 
Contains Nonbinding Recommendations 

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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.
Contains Nonbinding Recommendations 

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• 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-thecounter (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 product’s PMOA, the manufacturer of that 

combination product may choose to adopt either the device QS regulation-based or drug CGMPbased 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 
Contains Nonbinding Recommendations 

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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 facility’s 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.
Contains Nonbinding Recommendations 

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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 product’s 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 manufacturer’s 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).
Contains Nonbinding Recommendations 

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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 crossreferenced 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.
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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)
Contains Nonbinding Recommendations 

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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 

product’s 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, 
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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).
Contains Nonbinding Recommendations 

14

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. 
Contains Nonbinding Recommendations 

15

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).
Contains Nonbinding Recommendations 

16

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 sporeforming 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 manufacturer’s 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.
Contains Nonbinding Recommendations 

17

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.”
Contains Nonbinding Recommendations 

18

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 facilityspecific 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 
Contains Nonbinding Recommendations 

19

address changes the supplier makes to its process or product—including to an API, other drug 

components, or a container-closure system—that 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 CGMPbased 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 regulation—understand 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 FDA’s 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).
Contains Nonbinding Recommendations 

20

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 management’s responsibility to undertake appropriate actions to ensure that employees 

understand management’s 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).
Contains Nonbinding Recommendations 

21

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 manufacturer’s 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 manufacturer’s procedures and instructions may vary depending on 

factors such as the manufacturer’s 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 copackaged 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).
Contains Nonbinding Recommendations 

22

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 principles

49) 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).
Contains Nonbinding Recommendations 

23

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 product’s 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 product’s 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 
Contains Nonbinding Recommendations 

24

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 Agency’s 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). 
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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 part’s 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 supplier’s 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 manufacturer’s design control activities for 

the device constituent part will likely need to be more extensive. 

67 21 CFR 820.30(c).
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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 inprocess 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). 
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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 manufacturer’s 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.
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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 manufacturers—particularly device manufacturers, who may be less familiar with drug 

CGMPs—understand 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).
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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 supplier’s report of analysis, provided that certain identity testing is conducted and 

that the reliability of the supplier’s 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 samplebased 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 Nonconformities, Using Attribute Data, When there is a Zero Response in the Sample,” respectively.
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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 manufacturer’s 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.
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customers to these protective features of the product’s 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.
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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 inprocess 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. 
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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).
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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.
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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 pyrogenfree 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 copackaged 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)).
Contains Nonbinding Recommendations 

36

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).
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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 drug’s 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).
Contains Nonbinding Recommendations 

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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.
Contains Nonbinding Recommendations 

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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).
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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 
Contains Nonbinding Recommendations 

41

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 A’s 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).
Contains Nonbinding Recommendations 

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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 facility’s 

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 syringe’s design reflects adequate consideration of the drug’s 

characteristics, as indicated below. 

An appropriate first step for Manufacturer A would be to review Manufacturer B’s 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.
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43

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 

for drug

Drawing/specification for syringe dimensions, 

markings, etc.

Drug viscosity and desired/required delivery 

rate

Drawing/specification for needle bore, glide 

force, etc.

Expected use condition (e.g., expected user 

experience/education level)

Content and reading level for the prefilled 

syringe’s labeling

Maximum and minimum allowable 

temperature for prefilled syringe

Packaging/labeling specifications for the 

prefilled syringe

No degradation of drug or syringe over the 

expected shelf-life as a result of contact with 

one another

Specifications for drug-contacting syringe 

materials

Expected shipping method and appropriate 

storage conditions

Design drawings/specifications for primary 

and secondary packaging, labeling for 

acceptable storage conditions

Drug delivery method (e.g., needle or 

needleless delivery)

Drawing/specification for needle and/or other 

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.
Contains Nonbinding Recommendations 

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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 

syringe construction

Purchasing controls (including receiving 

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). 
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accessed as needed, including for inspections. For example, elements of the syringe component 

manufacturer’s design documentation may be relied upon to support the combination product 

DHF. Such information on the syringe may reside at Manufacturer B’s (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 syringe’s 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.
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46

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 product’s 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 A’s 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 
Contains Nonbinding Recommendations 

47

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 

the drug 

Drug formulation and concentration, coating 

thickness, uniformity of coating, manufacturing 

process requirements, allowable storage 

conditions

Expected use condition (e.g., anatomical 

location of use, surgical technique) 

Labeling (instructions for use), material/drug 

composition to ensure no damage to mesh or 

coating during surgical placement

Maximum allowable temperature during 

transportation, handling, and storage for the 

combination product

Packaging/labeling specifications for the 

combination product 

No unacceptable degradation of the drug 

over the expected shelf-life 

Specifications for the drug formulation drugcontacting materials and packaging, shelf-life 

labeling

No degradation of the surgical mesh over 

the expected shelf-life

Specifications for mesh material, drug 

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). 
Contains Nonbinding Recommendations 

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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 

sufficient to treat infection (e.g., due to 

insufficient drug coating per surface area 

of the mesh or non-uniformity of 

coating), inappropriate delivery rate

Clinical testing of the combination product, inprocess acceptance testing, manufacturing process 

validation

Mesh erodes or drug degrades during use 

or storage 

Design verification testing (bench), clinical 

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).
Contains Nonbinding Recommendations 

49

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 B’s 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).
Contains Nonbinding Recommendations 

50

(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 product’s 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 A’s 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 A’s 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).
Contains Nonbinding Recommendations 

51

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 supplier’s 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 A’s 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.
Contains Nonbinding Recommendations 

52

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 nonpyrogenic. 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 manufacturer’s 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.
Contains Nonbinding Recommendations 

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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 presubmissions 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 DrugEluting Stents–Nonclinical and Clinical Studies –(March 2008). When finalized, this guidance will represent FDA’s 

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).
Contains Nonbinding Recommendations 

54

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 
Contains Nonbinding Recommendations 

55

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-thecounter (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) 
Contains Nonbinding Recommendations 

56

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) 
Contains Nonbinding Recommendations 

57

(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) 
Contains Nonbinding Recommendations 

58

(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
Contains Nonbinding Recommendations 

59

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/@fdagovafdagen/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)