Guidance for Industry and FDA Staff:
Current Good Manufacturing Practice Requirements for Combination
Products
FINAL GUIDANCEThe 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
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
II. Background
A. Definition of a combination product
B. Quality and Current Good Manufacturing Practices
C. Overview of the final rule
D. The role of the lead center and other agency components
III. General Considerations for CGMP Compliance
A. Demonstrating compliance
B. Investigational products
C. Definitions and terminology
D. What CGMP requirements apply to a product or facility?
E. Control of changes to a combination product
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)
B. Provisions from the drug CGMPs specified in 21 CFR 4.4(b)(2)
C. Combination products that include biological products and HCT/Ps
V. Application of CGMP requirements to specific types of combination products
A. Prefilled syringe
B. Drug-coated mesh
C. Drug Eluting Stent (DES)
VI. Contact Us
VII. Glossary
VIII. References
Guidance for Industry and FDA Staff:
Current Good Manufacturing Practice Requirements for Combination Products 1
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
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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.”
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 investigation 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,
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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.
route of administration, or significant change in
dose) (a “cross-labeled” combination
product, as might be the case for a light-emitting device and a light-
activated drug); or
·
Any investigational drug, device, or biological product packaged
separately that according to its proposed labeling is for use only with another
individually specified investigational drug, device, or biological product
where both are required to achieve the intended use, indication, or effect (another type of cross- labeled combination product).
B. Quality and Current Good Manufacturing Practice
One of 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.
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:
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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.
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.
·
The drug CGMPs and the following provisions from the device QS
regulation in accordance with 21 CFR 4.4(b)(1) (drug CGMP-based streamlined approach):
(i)
21 CFR 820.20 Management responsibility
(ii)
21 CFR 820.30 Design
controls
(iii)
21 CFR 820.50 Purchasing controls
(iv)
21 CFR 820.100 Corrective
and preventive action
(v)
21 CFR 820.170 Installation
(vi)
21 CFR 820.200 Servicing
OR
·
The device QS regulation and the following provisions from the drug
CGMPs in accordance with 21 CFR 4.4(b)(2) (device QS regulation-based
streamlined approach):
(i)
21 CFR 211.84 Testing
and approval or rejection of components, drug
product containers, and closures
(ii)
21 CFR 211.103 Calculation
of yield
(iii)
21 CFR 211.132 Tamper-evident
packaging requirements for over-the-
counter (OTC) human drug
products
(iv)
21 CFR 211.137 Expiration
dating
(v)
21 CFR 211.165 Testing
and release for distribution
(vi)
21 CFR 211.166 Stability testing
(vii)
21 CFR 211.167 Special
testing requirements
(viii)
21 CFR 211.170 Reserve
samples
A manufacturer
may prefer one approach over the other based, for example, on the details of the manufacturing process used
at the facility or in light of other manufacturing activities undertaken at the
facility. The manufacturer is not required to choose a streamlined approach
based on the CGMP regulations for the constituent part that provides the
primary mode of action (PMOA) of the combination product (see II.D below). For
example, if the drug constituent part of a drug-device combination product
provides the product’s PMOA, the manufacturer of that combination product may
choose to adopt either the device QS regulation-based or drug CGMP- based
streamlined approach, or choose to develop a CGMP operating system that wholly
complies with the specifics of applicable provisions of both the drug CGMPs and
the device QS regulation.
21 CFR 4.4(c)
provides that if a facility manufactures only one type of constituent part
(e.g., a drug or device constituent part) of a co-packaged or single-entity
combination product, that facility is subject only to the CGMP regulations
applicable to that constituent part (i.e., part 211 for a drug or part 820 for
a device, as well as those under parts 600 through 680 for a biological product
and part 1271 for an HCT/P). 21 CFR 4.4(d) provides that when two or more types
of constituent parts to be included in a single-entity or co-packaged
combination product have arrived at the same facility, or the manufacture of
these constituent parts is occurring at the same facility, that facility must
comply with all CGMP requirements described in part 4
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
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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.
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.
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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).
A. Demonstrating compliance
The final rule
identifies two ways for co-packaged and single-entity combination product
manufacturers to demonstrate compliance with applicable CGMP requirements. The
Agency intends for the term “demonstrate” to apply for part 4 as it would be
for purposes of fulfilling the underlying CGMP regulations listed in 21 CFR
4.3. Manufacturers must demonstrate compliance with each applicable CGMP
requirement for constituent parts and combination products.16
If a
streamlined approach is used, the manufacturer must demonstrate compliance with
all of the relevant provisions of either the drug CGMPs or device QS
regulation, and the provisions specified in 21 CFR 4.4(b) for the other set(s)
of CGMP requirements applicable to the product. Further guidance on how to
demonstrate compliance with the regulations specified in 21 CFR 4.4(b) is
provided in section IV of this guidance. A
manufacturer who implements a streamlined approach is not expected to
demonstrate compliance with the specific provisions of the non-base set of
requirements other than those specified in 21 CFR 4.4(b) (e.g., for a drug
CGMP-based streamlined approach, the manufacturer must demonstrate compliance
with applicable drug CGMPs plus the six specified provisions from part 820, as
applicable, but the manufacturer does not need to demonstrate compliance with
the other specific provisions in part 820).
As provided in
21 CFR 4.4(e), in the event of a conflict between regulations applicable under
part 4, the regulations most specifically applicable to the constituent part in
question supersede the more general. The intent of this provision is to address
any potential conflicts between regulations. This provision does not provide a
basis for the Agency to require manufacturers to demonstrate compliance with
provisions not otherwise identified in part 4 as applicable to them.
Some of the
provisions specified in part 4 from the drug CGMPs and device QS regulation
cross-reference other provisions of parts 211 and 820, respectively. This
raises the question of whether manufacturers must specifically demonstrate
compliance with these cross- referenced provisions. FDA believes that
manufacturers can adequately address the expectations of these cross-referenced
provisions through implementation of either a drug CGMP-based or device QS
regulation-based CGMP streamlined approach.
For example, 21
CFR 211.170 (Reserve samples) references 21 CFR 211.192 (Production record
review). However, 21 CFR 211.192 is not a specified provision in 21 CFR
4.4(b)(2) because part 820 encompasses the requirements of that section. In
particular, under the CAPA requirements in 21 CFR 820.100, a manufacturer
operating under a device QS-based streamlined approach should have the systems
in place that would satisfy the requirements of 21 CFR
211.192. Similarly, 21 CFR
211.103 (Calculation of yield) references 21 CFR 211.68 (Automatic, mechanical,
and electronic equipment) in relation to using automated equipment for yield
calculations and maintaining appropriate controls over such equipment.
Corresponding provisions in 21 CFR 820.70(i), applicable under a QS-regulation
based streamlined approach,
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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
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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)
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,
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
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23 See 21 CFR 820.1(a).
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
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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.
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
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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.
the provisions of the CGMP
regulations listed in 21 CFR 4.3 may be applicable to a specific combination
product or constituent part.
1. Applicability of CGMP requirements to a product
The preamble to
the proposed rule addressed which CGMP requirements apply to which combination
products (see 74 FR at 48426), noting, for example, that only an
over-the-counter (OTC) combination product must comply with the tamper-evident
packaging requirements in the drug CGMPs and only combination products that
include a type of device constituent part that is installed or serviced must
comply with installation and servicing requirements in the device QS
regulation. The preamble to the final rule addressed similar considerations for
combination products that include a biological product constituent part,
explaining that many of the requirements for biological products are applicable
only to certain types of biological products. For example, blood and blood
components are subject to the CGMP requirements for such products under part
606 (21 CFR part 606). In addition, a vaccine manufactured using a spore-
forming microorganism would be subject to 21 CFR 600.11(e)(3).
Similarly, not
all CGMP requirements may apply at a facility that performs only certain
aspects of the manufacture of a combination product. As 21 CFR 210.2(b) and
820.1(a)(1) describe, an entity that engages in only some operations subject to
the regulations in parts 210, 211, 600 through 680, 820, and 1271, need only
comply with the regulations applicable to those operations. For example, a
facility that manufactures a co-packaged combination product that includes a
finished, already-packaged drug manufactured under the drug CGMPs and received
from another facility need not calculate yield for that drug constituent part.
2. What is the meaning of “where appropriate” in the CGMP, QS, and CGTP regulations?
Firms must
demonstrate compliance with all regulations applicable to their product and
facility under part 4. However, the drug CGMPs, device QS regulation, and CGTPs
for HCT/Ps use language such as “where appropriate” or “as necessary” to
acknowledge that certain measures may not be necessary or applicable under
certain circumstances and that manufacturers must pursue such measures if they
are needed. Such language indicates that firms have the opportunity to document
justifications for determining that such a measure or approach is not
appropriate or necessary for a particular product or the specific manufacturing
activity they are undertaking.31
Such justifications should generally be maintained within the quality system
documentation and may warrant Agency review prior to implementation depending
on the product type and relevant premarket submission obligations.
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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.
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
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may provide relevant complaint
data to another facility responsible for trending all quality data and managing
the CAPA system. A CAPA system that is shared between facilities, or facility-
specific CAPA systems with established links between them, may facilitate
handling of issues requiring multi-facility collaboration. Regardless of the
approach, the CAPA system(s) should allow for adequate flow of information
between facilities and manufacturers for the combination product and
appropriate investigation and resolution of identified CAPA issues.
Manufacturing
activities that occur at multiple facilities and associated CGMP operating
systems should be coordinated appropriately. Each manufacturing facility for a
combination product should have documentation specifying its respective
responsibilities, and the manufacturer of the finished combination product
should have access to this documentation. For
example, if the manufacturer of the finished combination product uses a
specification developer to design the finished product, that manufacturer
should have the design control records or have access to them if they are held
by the specification developer. In addition, the manufacturer should have
assurances that the specification developer maintained an adequate design
control system. To give another example, if product testing occurs at a
contract testing facility, the manufacturer of the finished combination product
should have documentation of the testing conducted and controls applied at the
contract facility or have access to the documentation if held at the contract
facility. Accordingly, manufacturers should address access to such records
among other issues as part of supplier evaluation and oversight.
Measures that
might be taken to ensure CGMP compliance at all manufacturing facilities for
the combination product include auditing and other oversight activities. For
example, when multiple facilities participate in the manufacturing process, the
owner may facilitate CGMP compliance by coordinating interactions among the
facilities, including by entering into comprehensive quality agreements with
the various facilities and suppliers . These quality agreements may, for
instance, specify expectations as to which facility will perform what
activities and develop and maintain what documentation needed to demonstrate
compliance with particular CGMP requirements (based, for example, on which
aspects of manufacture each facility conducts). These agreements may also
detail what measures a facility will take to ensure compliance with CGMP
requirements and any other relevant duties established by the owner for that
facility. For example, an owner may contract for the manufacture of the final
combination product with a contract manufacturing facility, and detail in the supplier
agreements the CGMP responsibilities and approaches for that facility.
E. Control of changes to a combination product
While not an
issue unique to combination products, coordination of changes among
manufacturers participating in the manufacture of a combination product is an
important CGMP issue. Appropriate consideration should be given to any
implications for the safety or effectiveness of the combination product that
might arise from changes to the combination product or its constituent parts.
Single-entity
and co-packaged combination product manufacturers must establish arrangements
with their suppliers, contractors, and consultants to receive notice of changes
in the product or service, where possible, in accordance with 21 CFR 820.50.
This notice should
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 CGMP- based streamlined approach established under 21 CFR 4.4(b)(1),
including considerations specific to applying these device QS regulation
requirements to combination products. This discussion is not meant to provide a
comprehensive analysis, but rather to help manufacturers— particularly drug and
biological product manufacturers who may be less familiar with the device QS
regulation—understand the purpose and basic elements of the device QS
regulation
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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).
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
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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).
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 co- packaged combination products that
include a device constituent part that is subject to them.47
Design control activities confirm that there are no negative interactions
between constituent parts, and ensure that their combined use results in a
combination product that is safe and effective and performs as expected.
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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).
The following
is a description of design control requirements and the documentation that must
be maintained for co-packaged and single-entity combination products.48 While pharmaceutical development
focuses on drug considerations, if broadened to take into account the other
constituent parts of combination products and how they interrelate, many
pharmaceutical development practices (for example, Quality by Design principles49) can be leveraged and built upon when
demonstrating compliance with design controls for a combination product. The
Agency recognizes that the terminology used in 21 CFR 820.30 can differ from
that used for pharmaceutical development. Manufacturers should be able to
communicate to the Agency how the terminology they use relates to design
control principles and requirements.
Design control requirements
apply to activities during product development as well as to postmarket changes
to the design or manufacturing process. Accordingly, the activities described
below may be conducted as part of premarket development and reflected in
documentation submitted as part of the marketing authorization process.
Regardless of when the activity occurs or where related records may reside, the
CGMP operating system should include or reference appropriate documentation to
ensure readily available access to this documentation for FDA inspection.50
The extent and
complexity of the design controls process and associated documentation will
vary based on the product. For example, consider a drug product that is already
legally marketed independently that will have the same formulation, route of
administration and intended use when marketed as part of a combination product
that also incorporates a delivery device. Design controls would begin when the
delivery device configuration is judged to be feasible and appropriate to
develop. The drug properties would be inputs for design control activities that
would focus on ensuring that the device appropriately delivers the drug and
that the drug quality is not adversely affected by its contact with the device.
Conversely, for a novel combination product with novel drug and device
constituent parts, design controls ensure coordinated development of the drug
and device resulting in a final combination product that meets user needs and
achieves intended uses. The extensiveness of design control activities and related
documentation for products should also be commensurate with the phase of
product development.
As part of the
design controls, a design and development plan must be established to describe
or reference the design and development activities and define responsibility
for implementation. The plans must identify and describe the interfaces with
different groups or activities that provide, or result in, input to the design
and development process.51
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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.
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.
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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
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.
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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).
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,
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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.
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
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68 See Medical Devices; Current
Good Manufacturing Practice (CGMP) Final Rule; Quality System Regulation, 61 FR
52602-52662 (October 7, 1996).
69 Under 21 CFR 820.3(r), the term “product” includes components and
manufacturing materials, in addition to in- process
and finished articles.
70 See 21 CFR 820.50(a)(2).
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.
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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.
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
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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
sample- based release testing alone. Actual yield discrepancies outside of
established and documented allowable variation from theoretical yield should be investigated.
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82 Some references that may be
useful for sampling by variables and sampling by attributes include “American
Standards for Testing and Materials (ASTM) Standard E2709, Standard Practice
for Demonstrating Capability to
Comply with an Acceptance Procedure” and “ASTM
Standard E2334, Standard Practice for Setting an Upper Confidence Bound For a
Fraction or Number of Non-conforming Items, or a Rate of Occurrence for Non-
conformities, Using Attribute Data, When there is a Zero Response in the
Sample,” respectively.
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
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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
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86 See 21 CFR 211.132(c)(1).
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.
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94 21 CFR 211.165 addresses
testing and release for “drug products”; appropriate controls for intermediate
stages (e.g., in-process materials) in the manufacture of combination products
are addressed under separate provisions of
the drug CGMPs and device QS regulation that are not
specified in part 4. If a manufacturer operates under a streamlined approach
under 21 CFR 4.4(b), it should take into consideration the materials and
manufacturing steps for the combination product as a whole in determining how
to demonstrate compliance with obligations for in- process materials, and may
find it helpful to refer to the corresponding requirements under the other
regulation (that it did not choose as the base for its CGMP operating system). For example, if the facility operates under a
device QS regulation-based streamlined approach, in determining how to comply
with duties under 21 CFR 820.70, 820.80, and
820.86 for the combination product
as a whole, reference to 21 CFR 211.110 and guidance relating
to in-process materials for drug products may facilitate appropriate
consideration of the controls for drug constituent parts.
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
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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).
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).
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.
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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.
7. Special testing requirements (21 CFR 211.167)
21 CFR 211.167
establishes requirements for batch testing applicable to drug products having
particular characteristics. Specifically, 21 CFR 211.167(a) requires
appropriate laboratory testing of drug products purporting to be sterile and/or
pyrogen-free to determine conformance with such requirements; 21 CFR 211.167(b)
requires appropriate testing of ophthalmic ointments to determine conformance
to specifications regarding the presence of foreign particles and harsh or
abrasive substances; and 21 CFR 211.167(c) requires appropriate laboratory
testing of controlled-release dosage forms to determine conformance to the
specifications for the rate of release of each active ingredient.
A special
testing requirement specified in 21 CFR 211.167 applies to a combination
product only if the combination product or a drug constituent part of it falls
into one or more of the three categories described above. Special testing may
be required for the drug constituent part, or the combination product as a
whole, depending on the product.
With respect to
21 CFR 211.167(a), batch testing requirements would apply both to the drug
constituent part and to the finished combination product for a single-entity
combination product (such as a prefilled syringe) to ensure the combination
product is sterile and pyrogen- free when distributed. In contrast, if a vial
of a vaccine were co-packaged with an empty syringe, the requirements in 21 CFR
211.167(a) would apply only to the vial of vaccine.102
A similar analysis would apply for compliance with 21 CFR 211.167(b) for a
single-entity versus a co-packaged combination product that includes an
ophthalmic ointment.
For purposes of
conducting pyrogen and endotoxin testing, it may be permissible in some circumstances
to define a “batch” based on the finished drug product rather than the finished
combination product. For example, it may be acceptable to define a batch as a
subcomponent of the combination product that incorporates the drug constituent
part. However, the viability of such an approach would depend on many factors
including: appropriate upstream controls to reduce/limit pyrogens and
endotoxins; the chemical or materials-mediated pyrogenicity of the constituent
parts, and the risks of pyrogen and endotoxin introduction to the combination
product by manufacturing operations that occur after the step at which the
batch is defined. For instance, for some products, it may be possible to test
material for endotoxin during an in-process manufacturing step and there may be
no need to test for endotoxins in the single entity combination product.
21 CFR 211.167(c) would apply both to a controlled-release drug
constituent part of a co- packaged combination product and also to a controlled
release single-entity combination product, to confirm rate of release of the
active ingredient. For example, a transdermal drug patch or drug-
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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)).
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.
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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).
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.
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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.
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).
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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).
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
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.
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
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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.
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.
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.
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).
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.
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
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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.
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).
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
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.
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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.
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 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
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
drug- contacting 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)
|
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, in- process 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
|
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.
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
|
(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.
|
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.
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.
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
|
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.
design control. These
considerations include the functionality of the stent and polymer and the
integrity of the coating and the packaging.138
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)
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
Manufacturer A
must conduct or contract to conduct testing of the DES in accordance with 21
CFR 211.167(a) because this class of product is purported to be sterile and
non- pyrogenic. In addition, testing in accordance with 21 CFR 211.167(c) must
be conducted because the DES constitutes a controlled-release dosage form.
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.
Manufacturer A
must maintain reserve samples representative of each lot of the active
ingredient used in the combination product and of each lot or batch of the
finished, packaged DES.141 Reserve samples must consist of at least
twice the quantity necessary to perform all tests required for the active
ingredient and the finished DES, excluding sterility and pyrogen testing.142 The reserve samples must be kept for
the time periods required by 21 CFR 211.170. The samples of the active
ingredient must be kept for 1 year past the expiration date of the last lot of
finished drug-eluting stents to use that lot of the active ingredient.143 The samples for each lot or batch of the
finished DES must be kept for 1 year after the expiration date for the
combination product.144 If Manufacturer
A maintains reserve samples in a third-party storage facility, Manufacturer A
should ensure, via purchasing controls (21 CFR 820.50), that the facility can
meet applicable CGMP requirements.145
VI. Contact Us
If you have
questions regarding compliance with CGMP requirements for combination products
after reviewing this guidance and the materials cited in this document, we
encourage you to contact us. We recommend you contact the lead center for your
product in the first instance. However, you may also contact OCP for
assistance. Below are contact points for each center and OCP. You may follow
existing processes for your lead center when requesting feedback on combination
product issues (e.g., meeting requests to CBER/CDER,146 pre-
submissions to CDRH147).
1.
CBER
Mail: Office of
Communication, Outreach and Development (OCOD) 10903 New Hampshire Avenue
Building 71, Room 3128 Silver
Spring, MD 20993
Phone: 1-800-835-4709 or 240-402-8010
Email: ocod@fda.hhs.gov
|
145 Additional information on
drug-eluting stents is provided in the draft Guidance for Industry on Coronary
Drug-
Eluting Stents–Nonclinical
and Clinical Studies –(March 2008). When finalized, this guidance will
represent FDA’s current thinking on this topic.
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
a change in intended use, dosage
form, strength, route of administration, or significant change in dose; or (ii)
any investigational drug, device, or biological product packaged separately
that according to its proposed labeling is for use only with another
individually specified investigational drug, device, or biological product
where both are required to achieve the intended use, indication, or effect. (21
CFR 3.2(e)(3) and 21 CFR 3.2(e)(4))
Device QS regulation-based streamlined approach: A CGMP operating
system that is intended to demonstrate compliance with all of the provisions of
the device QS regulation and the following provisions from the drug CGMPs in
accordance with 21 CFR 4.4(b)(2):
(i)
21 CFR 211.84 Testing
and approval or rejection of components, drug
product containers, and closures
(ii)
21 CFR 211.103 Calculation
of yield
(iii)
21 CFR 211.132 Tamper-evident
packaging requirements for over-the-
counter (OTC) human drug
products
(iv)
21 CFR 211.137 Expiration
dating
(v)
21 CFR 211.165 Testing
and release for distribution
(vi)
21 CFR 211.166 Stability testing
(vii)
21 CFR 211.167 Special
testing requirements
(viii)
21 CFR 211.170 Reserve
samples
Drug CGMPs: The current good manufacturing practice regulations set
forth in 21 CFR 210 and 21 CFR part 211. (21 CFR 4.2)
Drug CGMP-based streamlined approach: A CGMP operating system that
is intended to demonstrate compliance with all of the provisions from the drug
CGMPs and the following provisions from the device QS regulation in accordance
with 21 CFR 4.4(b)(1):
(i)
21 CFR 820.20 Management responsibility
(ii)
21 CFR 820.30 Design
controls
(iii)
21 CFR 820.50 Purchasing controls
(iv)
21 CFR 820.100 Corrective
and preventive action
(v)
21 CFR 820.170 Installation
(vi)
21 CFR 820.200 Servicing
Lead center: The FDA center (CBER, CDER, or CDRH) that has primary
jurisdiction for premarket review and regulation of a combination product.
Manufacture: Includes, but is not limited to, designing,
fabricating, assembling, filling, processing, testing, labeling, packaging,
repackaging, holding, and storage. (21 CFR 4.2)
CGMP operating system: The operating system within an establishment
that is designed and implemented to address and meet the current good
manufacturing practice requirements for a combination product. (21 CFR 4.2)
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)
(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)
(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
HCT/Ps
26.
Current Good Tissue Practice (CGTP) and Additional Requirements for
Manufacturers of Human Cells, Tissues, and Cellular and Tissue-Based Products
(HCT/Ps), Guidance for Industry (Dec 2011) (http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulator
yInformation/Guidances/Tissue/UCM285223.pdf)
Combination Products
27.
Coronary Drug-Eluting Stents – Nonclinical and Clinical Studies, Draft
Guidance for Industry (March 2008) (http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid ances/UCM228704.pdf)
28.
How to Write a Request for Designation (RFD), Guidance for Industry
(April 2011) (http://www.fda.gov/RegulatoryInformation/Guidances/ucm126053.htm)
29.
Human Factors Studies and Related Clinical Study Considerations in
Combination Product Design and Development, Draft Guidance for Industry and FDA
Staff (February 2016) (http://www.fda.gov/ucm/groups/fdagov-public/@fdagov-
afdagen/documents/document/ucm484345.pdf)
30.
Technical Considerations for Pen, Jet, and Related Injectors Intended
for Use with Drugs and Biological Products, Guidance for Industry and FDA Staff
(June 2013) (http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM147095.pdf)
General
31.
Pyrogen and Endotoxins Testing: Questions and Answers, Guidance for
Industry (June 2012) (http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid ances/UCM310098.pdf)
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