[Federal Register Volume 78, Number 14 (Tuesday, January 22, 2013)]
[Rules and Regulations]
[Pages 4307-4323]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 2013-01068]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 4

[Docket No. FDA-2009-N-0435]


Current Good Manufacturing Practice Requirements for Combination 
Products

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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SUMMARY: The Food and Drug Administration (FDA or Agency) is issuing 
this regulation on the current good manufacturing practice (CGMP) 
requirements applicable to combination products. This rule is intended 
to promote the public health by clarifying which CGMP requirements 
apply when drugs, devices, and biological products are combined to 
create combination products. In addition, the rule sets forth a 
transparent and streamlined regulatory framework for firms to use when 
demonstrating compliance with CGMP requirements for ``single-entity'' 
and ``co-packaged'' combination products.

DATES: This rule is effective July 22, 2013.

FOR FURTHER INFORMATION CONTACT: John Barlow Weiner, Office of 
Combination Products, Food and Drug Administration, 10903 New Hampshire 
Ave., Bldg. 32, Rm. 5130, Silver Spring, MD 20993, 301-796-8930.

SUPPLEMENTARY INFORMATION:

Table of Contents

I. Background
    A. Rationale for the Rulemaking
    B. The Proposed Rule
    C. The Final Rule
II. Comments on the Proposed Rule
    A. General
    B. What is the scope of this subpart? (Sec.  4.1)
    C. How does FDA define key terms and phrases in this subpart? 
(Sec.  4.2)
    D. What current good manufacturing practice requirements apply 
to my combination product? (Sec.  4.3)
    E. How can I comply with these current good manufacturing 
practice requirements for a co-packaged or single-entity combination 
product? (Sec.  4.4)
    E.1. How To Comply With QS Regulation Requirements Under Sec.  
4.4(b)(1)
    E.2. How To Comply With Drug CGMP Requirements Under Sec.  
4.4(b)(2)
    E.3. How To Comply With Biological Product and HCT/P 
Requirements Under Sec.  4.4(b)(3)
    F. Enforcement and Effective Date
    G. Alternate Approaches
    H. Guidance
    I. Other
III. Legal Authority
IV. Analysis of Economic Impacts
    A. Introduction
    B. Rationale for Final Rule
    C. Response to Comments
    D. Impact of Final Rule
V. Environmental Impact
VI. Paperwork Reduction Act of 1995
VII. Executive Order 13132: Federalism

I. Background

A. Rationale for the Rulemaking

    As set forth in part 3 (21 CFR part 3), a combination product is a 
product comprised of any combination of a drug and a device; a device 
and a biological product; a biological product and a drug; or a drug, a 
device, and a biological product.\1\ Under Sec.  3.2(e), a combination 
product includes:
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    \1\ For purposes of part 3 and this rule, a ``biological 
product''' means a biological product subject to regulation under 
section 351 of the Public Health Service Act (the PHS Act) (42 
U.S.C. 262). All biological products regulated under the PHS Act 
meet the definitions of drug or device in section 201 of the Federal 
Food, Drug, and Cosmetic Act (the FD&C Act) (21 U.S.C. 321).
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    1. 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 (single-entity combination products);
    2. 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 (co-packaged 
combination products);
    3. 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 (a type of cross-labeled 
combination product); or
    4. 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).
    The constituent parts of a combination product retain their 
regulatory status (as a drug or device, for example) after they are 
combined. Accordingly, the CGMP requirements that apply to each of the 
constituent parts continue to apply when they are combined to make 
combination products.\2\ To date, however, the Agency has not issued 
specific regulations clarifying the applicability of the CGMP 
requirements to combination products. While CGMP regulations are in 
place that establish requirements for drugs, devices, and biological 
products, there are currently no regulations that clarify and explain 
the application of these CGMP requirements when these drugs, devices, 
and biological products are constituent parts of a combination product. 
FDA believes that the absence of clear CGMP requirements for 
combination products could result in inconsistent or differing 
application of the various CGMP requirements applicable to the 
constituent parts, which could affect product safety and the public 
health. In addition, the absence of clear requirements could lead some 
manufacturers to develop and document manufacturing practices that are 
redundant and overly burdensome.
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    \2\ Section 501 of the FD&C Act (21 U.S.C. 351) states 
circumstances under which drugs and devices (including biological 
products, which also meet the definition of either drug or device) 
are deemed adulterated. Adulteration includes the failure to 
manufacture a product in accordance with applicable CGMP 
requirements, regardless of whether the product appears to meet its 
final specifications. See, generally, 21 U.S.C. 351(a)(2)(B) and 
(h).
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    In the Federal Register of October 4, 2004 (69 FR 59239), the 
Agency announced the availability of a Draft Guidance for Industry and 
FDA entitled ``Current Good Manufacturing Practices for Combination 
Products.'' The Agency received 15 comments, which were largely 
supportive of the regulatory approach described in the draft guidance. 
A common theme that emerged from these comments was the need to develop 
a clear regulatory framework that takes account of the fact that 
combination products are made up of drug, device, and biological 
product constituent parts. At the same time, commenters wanted to 
ensure that the framework would not lead to unnecessary redundancy in 
the operating systems used to meet CGMP

[[Page 4308]]

requirements (CGMP operating systems).
    After careful consideration of the comments, and of how best to 
ensure that CGMPs for combination products are consistent and 
appropriate, FDA determined that rulemaking was warranted. We concluded 
that rulemaking would best facilitate the manufacture of safe and 
effective combination products by providing a clear and transparent 
regulatory roadmap for the application of CGMP requirements to these 
products. Accordingly, the Agency published a proposed rule in the 
Federal Register of September 23, 2009 (74 FR 48423), as part of FDA's 
ongoing effort to improve the consistency and aid implementation of the 
regulatory requirements for combination products.

B. The Proposed Rule

    The proposed rule addressed CGMP requirements for all combination 
products. However, for certain types of combination products, the 
application of CGMP requirements is fairly straightforward. 
Specifically, the constituent parts of a combination product are each 
subject only to the CGMP regulations applicable to that type of 
constituent part (e.g., drug or device) if the constituent parts are 
manufactured and marketed separately, as may be the case for 
constituent parts of cross-labeled combination products. Because these 
constituent parts, while part of a combination product, are separately 
manufactured and marketed, they remain separate for purposes of 
applying the CGMP regulations. Therefore, the proposed rule merely 
provided that all such constituent parts must be manufactured in 
accordance with the CGMP requirements that would apply to them if they 
were not part of a combination product.
    The application of CGMP requirements to single-entity and co-
packaged combination products is less straightforward. Consequently, 
the proposed rule expressly addressed the practical application of CGMP 
requirements to these two categories of combination products. The 
proposed rule reflected Agency recognition that, in most instances, for 
single-entity and co-packaged combination products, a CGMP operating 
system that satisfies the CGMP regulations applicable to one 
constituent part will also satisfy most of the CGMP requirements 
applicable to the other constituent part. In particular, we explained 
that compliance with either the CGMP regulations for drugs at parts 210 
and 211 (21 CFR parts 210 and 211) (drug CGMPs) or the quality system 
(QS) regulation for devices at part 820 (21 CFR part 820) will satisfy 
many, though not all, of the CGMP requirements applicable to both drug 
and device constituent parts.
    In developing the proposed rule, the Agency reviewed the drug CGMPs 
and QS regulation. We identified specific provisions from the drug 
CGMPs and QS regulation that a firm would need to satisfy in addition 
to complying with the other of these two sets of CGMP requirements to 
demonstrate compliance with both of these sets of requirements. Based 
on this assessment, the proposed rule offered two options for 
demonstrating compliance with the CGMP requirements applicable to a co-
packaged or single-entity combination product. These options were 
either: (1) To demonstrate compliance with the specifics of all CGMP 
regulations applicable to each of the constituent parts included in the 
combination product or (2) to demonstrate compliance with the specifics 
of either the drug CGMPs or the QS regulation, rather than both, when 
the combination contains both a drug and a device, under certain 
conditions. These conditions included demonstrating compliance with 
specified provisions from the other of these two sets of CGMP 
requirements. In addition, for a combination product that included a 
biological product, the CGMPs requirements for biological products in 
parts 600 through 680 (21 CFR parts 600 through 680) would apply, and, 
for a combination product that included any human cell, tissue, and 
cellular and tissue-based products (HCT/Ps), the regulations in part 
1271 (21 CFR part 1271) would apply.\3\
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    \3\ For the purposes of this rule, 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. FDA notes that biological products, including biological 
product constituent parts of combination products, must comply with 
all applicable requirements in parts 600 through 680, but many of 
the requirements in parts 600 through 680 are not considered CGMP 
requirements and are therefore not covered by this rule.
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    We intended for the proposed rule to help ensure that CGMP 
requirements that apply to single-entity and co-packaged combination 
products are clear and consistent, regardless of which Agency component 
has lead jurisdiction for the combination product, or which type of 
application is submitted for marketing authorization. The proposed rule 
was also intended to streamline demonstrating compliance with CGMP 
requirements for these types of combination products and to help ensure 
appropriate implementation of these requirements while avoiding 
unnecessary redundancy in CGMP operating systems for these products.
    After publication of the proposed rule, to facilitate development 
of comments on the rule, FDA co-sponsored a workshop in January 2010. 
At this workshop, the Agency provided a summary of the proposed rule 
and stakeholders then worked in groups to identify issues on which it 
might be helpful to develop comments.

C. The Final Rule

    The final rule is largely identical to the proposed rule. It is 
organized in the same four sections addressing scope (Sec.  4.1), 
definitions (Sec.  4.2), the CGMPs that apply to combination products 
(Sec.  4.3), and how to comply with these CGMP requirements for a 
single-entity or co-packaged combination product (Sec.  4.4).
    Section 4.1. Section 4.1 states that the rule establishes which 
CGMP requirements apply to combination products, clarifies the 
application of these requirements, and provides a regulatory framework 
for designing and implementing CGMP operating systems at facilities 
that manufacture copackaged or single-entity combination products.
    Section 4.2. Section 4.2 provides definitions for terms used in the 
regulation. Some of these definitions are included for convenience, for 
example, cross-referencing an existing definition (such as for 
``combination product'') or to establish the meaning for a reference 
term (such as ``drug CGMP''). Other definitions include content 
specific to the rule. In addition to cross-referencing the definition 
for ``device'' in Sec.  3.2(f), the rule states that a device that is a 
constituent part of a combination product is considered a finished 
device within the meaning of the QS regulation; and the definition for 
``drug'' cross-references Sec.  3.2(g) and also states that a drug that 
is a constituent part of a combination product is a drug product within 
the meaning of the drug CGMPs. The definition for ``current good 
manufacturing practice operating system'' states that such a system is 
the operating system within an establishment that is designed and 
implemented to address and meet the CGMP requirements for a combination 
product.
    Section 4.3. Section 4.3 lists all of the requirements that may 
apply to a combination product under this rule, depending on the types 
of constituent parts the combination product includes. The CGMP 
requirements listed are those found in parts 210 and 211 for drugs, 
part 820 for devices, and parts 600 through 680 for biological 
products, and

[[Page 4309]]

the current good tissue practices found in part 1271 for HCT/Ps. We 
have removed the specific reference to part 606 because it is already 
reflected in the reference to parts 600 through 680.
    Section 4.4. Section 4.4 addresses how to comply with these CGMP 
requirements for co-packaged and single-entity combination products, as 
summarized in the subsections that follow.
    Section 4.4(a). This subsection states that the CGMP requirements 
applicable to a combination product can be satisfied in one of two 
ways. Under Sec.  4.4(a)(1), a manufacturer can demonstrate compliance 
with each applicable regulation in its entirety (e.g., with all of the 
drug CGMPs and the QS regulation, for a drug-device combination 
product). Alternatively, under Sec.  4.4(a)(2), if the combination 
product is subject to the drug CGMPs and QS regulation, these two sets 
of requirements can be met by demonstrating compliance with: (1) Either 
the drug CGMPs or QS regulation and (2) those provisions specified in 
Sec.  4.4(b) from the other of these two sets of regulations.
    Section 4.4(b)(1). This subsection states that if a manufacturer 
chooses to demonstrate compliance with the drug CGMPs per Sec.  
4.4(a)(2), that manufacture must also demonstrate compliance with the 
following provisions of the QS regulation to demonstrate compliance 
with both sets of regulations:
     Sec.  820.20. Management responsibility.
     Sec.  820.30. Design controls.
     Sec.  820.50. Purchasing controls.
     Sec.  820.100. Corrective and preventive action.
     Sec.  820.170. Installation.
     Sec.  820.200. Servicing.
    Section 4.4(b)(2). This subsection states that if a manufacturer 
chooses to demonstrate compliance with the QS regulation per Sec.  
4.4(a)(2), that manufacturer must also demonstrate compliance with the 
following provisions of the drug CGMPs to demonstrate compliance with 
both sets of regulations:
     Sec.  211.84. Testing and approval or rejection of 
components, drug product containers, and closures.
     Sec.  211.103. Calculation of yield.
     Sec.  211.132. Tamper-evident packaging requirements for 
over the-counter (OTC) human drug products.
     Sec.  211.137. Expiration dating.
     Sec.  211.165. Testing and release for distribution.
     Sec.  211.166. Stability testing.
     Sec.  211.167. Special testing requirements.
     Sec.  211.170. Reserve samples.
    Section 4.4(b)(3). This subsection states that manufacturers must 
also demonstrate compliance with the CGMPs among the requirements 
(including standards) for biological products listed in Sec.  4.3(c) if 
the combination product includes a biological product, and with the 
requirements for HCT/Ps listed in Sec.  4.3(d) if the combination 
product includes an HCT/P.
    Section 4.4(c). This subsection states that a facility at which a 
single type of constituent part is manufactured must demonstrate 
compliance with the CGMP requirements applicable to that type of 
constituent part.
    Section 4.4(d). This subsection states that a facility at which two 
or more types of constituent parts have arrived or continue to be 
manufactured may apply a CGMP system that complies with Sec.  4.4(b).
    Section 4.4(e). This subsection states that, in the event of a 
conflict between CGMP requirements applicable to a combination product, 
the regulations most specifically applicable to the constituent part at 
issue shall prevail.

II. Comments on the Proposed Rule

    FDA received 25 sets of comments from regulated entities, trade 
associations, and individuals. To make it easier to identify comments 
and our responses, the word ``Comment'' appears before the comment's 
description, and the word ``Response'' appears before our response. We 
have also numbered the comments to help distinguish among them. The 
number assigned to each comment is purely for organizational purposes 
and does not signify the comment's value or importance or the order in 
which it was received. Certain comments were grouped together under a 
single number because the subject matter of the comments was similar.

A. General

    (Comment 1) Some commenters sought clarification of what 
manufacturers must do to ``demonstrate'' compliance for purposes of 
this rule. Commenters proposed that the Agency confirm that 
``demonstrate'' is used in this rule as ``it always has been with 
respect to GMPs.'' Specifically, commenters stated that the 
requirements for firms to demonstrate compliance are set forth in the 
rules and include, for example, the implementation of written 
procedures, internal auditing and other requirements. Commenters noted 
that '' 'demonstrate' also encompasses demonstrating and justifying 
that specific provisions are inapplicable to a facility.''
    (Response) We confirm that the term ``demonstrate'' is not intended 
to have a new meaning for purposes of this rule. The Agency intends for 
it to be interpreted in the same manner as it would be for purposes of 
the CGMP regulations listed in Sec.  4.3. As the commenters state, 
depending on the circumstances and requirements at issue, appropriate 
means by which to demonstrate compliance with these CGMP requirements 
may include development of written procedures and maintenance of 
records documenting use and verification of CGMPs.

B. What is the scope of this subpart? (Sec.  4.1)

    (Comment 2) Some comments stated that the rule is unclear as to 
whether it applies only to commercial production or also during product 
development and to investigational products. One commenter proposed 
including information on the stages of a product's life cycle during 
which the rule applies. Another requested further guidance on this 
issue.
    (Response) Section 4.3 lists all of the CGMP regulations that apply 
to a combination product under the rule. The rule does not modify these 
regulations; rather it addresses how to comply with them for a 
combination product.
    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 exempt from compliance with the 
regulations in part 211. This exemption does not apply to an 
investigational combination product or constituent part of a 
combination product for use by or for the sponsor in phase 2 or phase 3 
studies, or when the drug has been lawfully marketed.\4\ Similarly, 
while device sponsors must ensure that investigational devices are 
manufactured under a state of control, 21 CFR 812.1 provides that 
investigational devices are exempt from part 820 except for design 
control requirements under Sec.  820.30. (See 21 CFR 812.30(b)(5)(ii)). 
The Agency considers both these exemptions, from parts 211 and 820 
obligations, to apply to combination products and constituent parts of 
combination products, whether being studied under an approved 
investigational device exemption (IDE) or an approved investigational 
new drug application (IND).
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    \4\ See Sec.  210.2(c).

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    (Comment 3) One comment noted that the rule does not address 
products that produce another product on site at the point of care, 
which the commenter notes are typically devices that produce a drug. 
The commenter requests that the final rule clarify that the 
manufacturer is subject only to the CGMP requirements applicable to the 
product that makes the other product on site.
    (Response) This rule applies to combination products. Accordingly, 
questions regarding CGMPs for non-combination products are beyond its 
scope. However, this comment raises the question of whether medical 
products that make other medical products at the point of care are 
regulated as combination products and, therefore, subject to this rule.
    There are two potential scenarios to consider. The first is where a 
single medical product (e.g., a device) makes another medical product 
(e.g., a drug) at the point of care. In this case, the medical product 
that makes the other medical product at the point of care and the 
medical product manufactured at the point of care would not be 
regulated as a combination product. Rather, the medical product that 
makes the other medical product would be regulated in accordance with 
its own classification and, therefore, subject to the CGMP requirements 
applicable to that type of article. For example, if the product that 
makes the other product is a device, it would be subject to the QS 
regulation.
    The second scenario is where two or more different types of medical 
products (e.g., a device and a biological product) are used together at 
the point of care to make another medical product. The medical products 
used to make the other medical product might comprise a combination 
product. In such cases, the CGMP requirements applicable under this 
rule to the type of combination product that they constitute (e.g., 
cross-labeled or co-packaged) may apply. See Sec. Sec.  4.3 and 4.4. 
The Agency has not published general guidance on the issue of when two 
medical products used at the point of care to make another product 
constitute a combination product. Accordingly, product sponsors are 
encouraged to contact the Office of Combination Products (OCP) with any 
questions on this topic.
    (Comment 4) One commenter asked for Agency guidance on whether 
products on the market prior to the establishment of OCP are considered 
combination products by the Agency and, therefore, subject to the rule. 
Several commenters stated that the proposed rule did not clearly 
address its applicability to approved products already being marketed. 
Commenters requested that the Agency limit application of the rule to 
new products and to existing products only when a design change, or 
significant design change, is made to the product, and not be applied 
retroactively to existing products. One commenter stated that existing 
manufacturers should be exempt from pre-manufacturing design control 
requirements. One commenter stated there was a need for guidance 
regarding how the rule would affect CGMP requirements for products 
addressed in master files. One stated that the Agency should identify 
which currently marketed products are subject to this rule.
    (Response) This rule does not create new CGMP requirements, but 
rather attempts to clarify how to apply them to combination products. 
Compliance with all applicable CGMP requirements is required for all 
products and appropriate to ensure consistent manufacture of products 
that meet the safety and effectiveness and quality standards that form 
the basis for product marketing authorization, regardless of when a 
product was first marketed or approved.
    As noted elsewhere in this document, we intend to provide further 
information in related guidance, on how to comply with this rule and 
the underlying regulations to which it refers, including with respect 
to coming into compliance with pre-manufacturing design control 
requirements for products currently being marketed.
    Regarding the issue of master files, we note that, as discussed 
throughout this preamble, this rule is not intended to change existing 
CGMP requirements established under the regulations listed in Sec.  
4.3. Rather, this rule is intended to clarify how to comply with those 
requirements for a combination product. Accordingly, if the manufacture 
of an item addressed in a master file would be subject to CGMP 
requirements under a rule listed in Sec.  4.3, those CGMP requirements 
must be met under this rule, including as provided in Sec.  4.4. If the 
manufacture of the item would not be subject to CGMP requirements under 
a rule listed in Sec.  4.3, then no CGMP requirements apply to the 
manufacture of that item under this rule. For example, if the item is a 
component of a device and its manufacture, therefore, would not be 
subject to the QS regulation, the manufacture of that item is not made 
subject to the QS regulation by this rule. However, the CGMP 
requirements for manufacturers of combination products and constituent 
parts of combination products that include items addressed in master 
files may include duties with respect to such items (e.g., purchasing 
control requirements under the QS regulation for a combination product 
that includes a device).
    (Comment 5) Some commenters raised concerns regarding application 
of the rule to co-packaged combination products, arguing that the rule 
as written would be overly burdensome for these products. One commenter 
proposed that ``Convenience kits that contain device(s) and drugs or 
biologics would be governed under 21 CFR 4 only if the device(s) 
included in the kit are Class II or III.'' The commenter offered as a 
rationale for this change that application of the approach in the 
proposed rule to such products would represent ``an unnecessarily 
burdensome approach to the industry and in most instances will not 
provide greater protection of the public health.'' Other commenters 
asked for guidance on the application of CGMP requirements to a drug 
manufacturer who purchases a finished, ``off-the-shelf'' medical device 
to include in a kit. A commenter stated that the control, packaging and 
release of kits can be adequately handled by current parts 210, 211, 
and 600 CGMP regulations, and that existing guidance and supplement 
approval requirements (design verification testing for container 
closure) are adequate to address any additional considerations 
necessitated by the packaging and labeling of a kit.
    (Response) We do not agree that the rule represents an 
unnecessarily burdensome approach to CGMP compliance for ``convenience 
kits'' or other kits and do not find it necessary to alter the 
application of the rule to ``convenience kits.''
    This rule is not intended to create new CGMP requirements, and 
instead seeks to clarify how to apply them to combination products. A 
kit that includes two or more types of medical products (e.g., a device 
and a drug), is a combination product and subject to this rule. 
Accordingly, the manufacture of the products in the kit would also be 
subject to this rule.
    An important question, however, in responding to this comment is 
how to define the term ``convenience kit.'' For purposes of this rule, 
we define the term to include only kits that solely include products 
that are: (1) Also legally marketed independently and (2) included in 
the kit as already packaged for independent marketing and with the same 
labeling as for independent marketing. This is an important question 
because no additional CGMP requirements generally would apply to the 
products in such a ``convenience

[[Page 4311]]

kit'' simply because they have been included in the kit. The only 
additional CGMP requirements that would generally apply to such a 
convenience kit would be those applicable to the assembly, packaging, 
labeling, any sterilization, or further processing of the kit itself. 
In contrast, if any products to be included in a kit are repackaged, 
relabeled or otherwise modified for purposes of their inclusion in the 
kit, the kit is not a ``convenience kit'' for purposes of this rule and 
all the CGMP requirements applicable under this rule based on any 
changes made to the constituent parts would apply.
    Accordingly, no additional CGMP requirements would apply to an 
``off-the-shelf'' device that is packaged and labeled in accordance 
with its existing marketing authorization for the independent sale 
solely because of its inclusion in a convenience kit. However, if an 
off-the-shelf device is included in a co-packaged combination product 
for an intended use that differs from the intended use for which that 
device is marketed separately, additional CGMP requirements may apply, 
including design controls to ensure that the device is appropriate for 
the specific use to which it is put in the combination product.

C. How does FDA define key terms and phrases in this subpart? (Sec.  
4.2)

    (Comment 6) One commenter asked whether a device combined with a 
medical device accessory would be considered a combination product.
    (Response) A combination product must include two or more different 
types of constituent parts (e.g., a drug and device, or biological 
product and a drug). The definition of device at section 201(h) of the 
FD&C Act (21 U.S.C. 321(h)) includes devices that are an ``accessory'' 
to another device. A device and such an accessory to it are, therefore, 
both devices and when combined would not constitute a combination 
product.
    (Comment 7) One commenter requested clarification relating to the 
definition of the term ``manufacture.'' This commenter sought 
confirmation that the rule is intended to encompass the types of 
activities included in the definition of manufacture under drug CGMPs 
and the QS regulation, and to cover the entities undertaking these 
activities. This commenter also sought clarification of what parties 
must do to comply with CGMPs, for example, if the manufacture of a 
combination product involves a specification developer, contract 
manufacturer, and component manufacturer. This commenter proposed that 
the responsibility for ensuring that all requirements are met should 
fall to the manufacturer who holds the marketing application.
    (Response) The term ``manufacture'' for purposes of the rule is 
intended to encompass all activities defined as manufacturing under the 
drug CGMPs and QS regulation and also under the biological product and 
HCT/P regulations listed in Sec.  4.3. Both specification developers 
and contract manufacturers ``manufacture'' and are considered 
manufacturers for purposes of these underlying CGMP regulations and 
are, therefore, subject to this rule if they manufacture combination 
products or constituent parts of combination products However, an 
entity that is not considered a manufacturer for purposes of the QS 
regulation, which manufactures a device component, is not subject to 
this rule even if that component will be incorporated into a 
combination product or constituent part of a combination product at 
some other facility. See Quality System (QS) Regulation/Medical Device 
Good Manufacturing Practices (http://www.fda.gov/medicaldevices/deviceregulationandguidance/postmarketrequirements/qualitysystemsregulations/default.htm).
    As discussed in response to Comments 13 and 14 of this document, 
the CGMP requirements applicable to a particular manufacturer for the 
work done at its facility may vary based upon the type or types of 
constituent parts being manufactured and the aspects of their 
manufacture that are being performed. Where multiple facilities bear 
responsibility for various aspects of the manufacturing process, only 
the holder of the application or clearance for the product (hereafter 
referred to as the applicant for purposes of the preamble to this rule) 
is responsible for compliance with all aspects of the CGMP requirements 
applicable to the entire manufacturing process and across all 
facilities.
    (Comment 8) Some commenters sought confirmation that containers and 
closures, which they asserted are currently treated as drug components, 
would continue to be treated as such. Some commenters sought guidance 
on whether a prefilled syringe would be considered a combination 
product.
    (Response) The suggestion that containers and closures are treated 
as drug components for purposes of CGMPs is incorrect. Components are 
defined under Sec.  210.3 as ``any ingredient intended for use in the 
manufacture of a drug product, including those that may not appear in 
such drug product.'' It is true that containers and closures are 
subject to the drug CGMPs rather than the device QS regulation. While 
some CGMP requirements apply to both drug components and containers/
closures, containers/closures are separately addressed in the drug 
CGMPs, and distinct CGMP requirements apply to them (see Sec.  211.84).
    The Agency will continue to regulate drug containers and closures 
in accordance with parts 210 and 211. A syringe, however, is not a mere 
container/closure. A syringe is a device used to deliver another 
medical product (e.g., a drug) (see, e.g., 21 CFR 880.5860). 
Accordingly, a prefilled syringe is a combination product and subject 
to this rule. See also response to Comment 15 of this document 
distinguishing complete syringe constituent parts from components of 
syringes. We plan to address distinctions between devices and 
containers/closures in further detail in later guidance.
    (Comment 9) Several commenters asked that the Agency revise and 
clarify the term ``constituent part,'' arguing that its interpretation 
is important to understanding the scope of the rule. Some commenters 
proposed inclusion of a definition for component or language in the 
codified regarding how manufacturers should address components in their 
CGMP systems. These and other commenters sought clarification of how 
the rule might apply to components of devices and ingredients for drugs 
and biological products. Some commenters also sought clarification of 
how the definition of constituent part might relate to whether an 
article should be considered a drug component as opposed to a device, 
citing container closures as an example. Some commenters also asked 
that the Agency provide guidance, including examples, of articles the 
Agency considers constituent parts and articles that we consider 
components.
    (Response) We have declined to revise the definition of constituent 
part, or to include a definition of component, in the rule. The current 
definition of constituent part found in Sec.  4.2 provides a succinct 
way to identify a drug, device, or biological product as included in a 
combination product. Such a term of reference is needed not only for 
this rule but in relation to virtually all regulatory activity for 
combination products.
    The rule does not change the scope of the regulations listed in 
Sec.  4.3. Rather, it expressly codifies the applicability of these 
requirements to combination products and clarifies how to comply with 
these regulations for combination products. Accordingly, articles not

[[Page 4312]]

otherwise subject to the regulations listed in Sec.  4.3 are not made 
subject to those regulations by this rule. Therefore, for example, if 
an article would be considered a device component, and it would not be 
subject to the QS regulations in the absence of this rule, that device 
component does not become subject to the QS regulations because of this 
rule.
    In addition, we note that the term component is defined for a drug 
at Sec.  210.3(b)(3) and for a device at Sec.  820.3(c). The existing 
definitions appropriately characterize the components of drugs and 
devices, respectively, and we see no need to develop a distinct 
definition in relation to combination products.
    The Agency appreciates the value of guidance to ensure 
understanding of this rule by both industry and FDA staff. The Agency 
is developing guidance on the application of the rule, including 
examples to illustrate these and other concepts addressed.
    (Comment 10) One commenter sought clarification of the definitions 
for ``co-packaged'' and ``single-entity'' combination products. This 
commenter also requested a list of examples to clarify these 
definitions.
    (Response) The definitions for co-packaged and single-entity 
combination product are quoted in part I.A. of this preamble and are 
found in Sec.  3.2(e). This rule merely cross-references those existing 
definitions. We note, however, that the term ``component'' as used in 
the definition for single-entity combination product in Sec.  3.2(e) 
and this rule, is synonymous with ``constituent part'' under this rule. 
We recommend visiting the Web page for OCP on the Agency's Web site at 
http://www.fda.gov/CombinationProducts/default.htm, for further 
information relating to these definitions and examples of combination 
products.
    (Comment 11) One commenter urged the Agency to take care to ensure 
that stakeholders understand the terminology being used in the rule and 
its preamble.
    (Response) We have been mindful of this consideration in attempting 
to make the rule and this preamble as clear as possible, including in 
the selection and manner of defining key terms in Sec.  4.2.

D. What current good manufacturing practice requirements apply to my 
combination product? (Sec.  4.3)

    (Comment 12) One commenter sought clarification of the CGMP 
requirements applicable to combination products comprised of 
constituent parts that are manufactured and marketed separately. This 
commenter proposed revising Sec.  4.3 to address this issue by 
replacing ``The current good manufacturing practice requirements in 
parts 210 and 211 of this chapter apply to a combination product that 
includes a drug constituent part * * * '' with ``The current good 
manufacturing practice requirements in parts 210 and 211 of this 
chapter apply to the drug constituent part of a combination product'' 
and parallel changes with respect to device and biologic constituent 
parts.
    (Response) The preamble to the proposed rule discussed in some 
detail the issue of what CGMP requirements apply to the manufacture of 
constituent parts that are manufactured and marketed separately from 
one another (see 74 FR 48423 at 48424 to 48425). We do not see a need 
to revise Sec.  4.3 to provide further clarity as requested by the 
commenter. Section 4.3 lists the CGMP regulations applicable to 
combination products. This rule does not change the requirements of 
these listed regulations. In Sec.  4.4, this rule addresses how to 
comply with these requirements for single-entity and co-packaged 
combination products because of the complexity of applying these 
requirements to these types of combination products. The rule does not 
expressly address how to comply with these requirements for separately 
manufactured and marketed constituent parts of combination products 
because each of these separately manufactured constituent parts is 
subject only to the regulations listed in Sec.  4.3 that are applicable 
to that type of constituent part. We note that we have modified Sec.  
4.3(c) for clarity.

E. How can I comply with these current good manufacturing practice 
requirements for a co-packaged or single-entity combination product? 
(Sec.  4.4)

    (Comment 13) Some commenters noted that not all requirements of the 
CGMP regulations applicable to combination products may be relevant to 
a particular product or to when and where particular aspects of the 
manufacturing process are undertaken. Commenters offered 
recommendations for addressing this variation in guidance or through 
revision of the rule.
    (Response) This rule does not alter the regulations listed in Sec.  
4.3. All of the CGMP requirements applicable to a combination product 
or constituent part must be met where and when required.
    We agree that not all the provisions of the CGMP regulations listed 
in Sec.  4.3 as applicable to a class of combination product (e.g., 
drug-device or biological product-drug combination product) or 
constituent part (drug, device, or biological product) may be relevant 
to a specific type of combination product or constituent part. The 
preamble to the proposed rule addressed this point (see 74 FR 48423 at 
48426). For example, only combination products that include an OTC drug 
must comply with tamper-evident packaging requirements, and only 
combination products that include a type of device that is installed or 
serviced must comply with installation and servicing requirements.
    Similarly, we agree that not all CGMP requirements may apply at a 
facility that is performing only certain aspects of the manufacture of 
a combination product. As Sec. Sec.  210.2(b) and 820.1(a)(1) reflect, 
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. In 
addition, manufacturers retain the ability to demonstrate that a 
departure from stipulated CGMP requirements is appropriate, to the 
extent that the CGMP regulations for drugs, devices, biological 
products, and HCT/Ps permit such showings (see, for example, Sec.  
820.1(a)(3), providing manufacturers an opportunity to document 
justifications for determining that requirements qualified by ``where 
appropriate'' in part 820 are not appropriate for the particular 
product).
    Many, but not all, CGMP requirements are facility specific. 
Examples of such requirements include requirements for testing of the 
product by a facility or controls over the supplies brought into the 
facility. Other requirements, however, are not facility-specific. For 
example, some concern the product as a whole, such as design controls, 
and some concern overarching duties for the manufacturing process as a 
whole, such as Corrective and Preventive Action (CAPA) and management 
responsibility. Duties associated with such cross-cutting CGMP 
requirements may be shared by several facilities.
    All manufacturers are responsible for ensuring compliance with all 
CGMP requirements applicable to the manufacturing activities at their 
facilities. In addition, the applicant is responsible for ensuring 
compliance with all of the CGMP requirements applicable to the product, 
taking into account all of the activities occurring at all facilities 
involved with the manufacturing process.
    Section 4.3 of the rule lists all of the CGMP requirements that may 
apply to a combination product and its constituent parts. Section 4.4 
addresses how manufacturers may comply with these requirements for 
single-entity and

[[Page 4313]]

co-packaged combination products. Section 4.4 states that manufacturers 
may comply with these requirements through the design and 
implementation of a CGMP operating system that meets all applicable 
CGMP requirements. Section 4.2 defines CGMP operating system as the 
operating system within an establishment that is designed and 
implemented to address and meet the CGMP requirements for a combination 
product. Accordingly, if the combination product is manufactured at 
multiple facilities, each facility would need such an operating system, 
including the facility from which the applicant oversees all of the 
manufacturing activities and compliance with all CGMP requirements 
related to the product.
    The issues raised in these comments are not peculiar to combination 
products or their constituent parts, though addressing them may present 
some added complexity because of the number of sets of regulations that 
may apply to a combination product, the relatively complex nature of 
these products, and the multiple Agency components that may have an 
interest in ensuring compliance with CGMP requirements for these 
products. Examples and clarification to aid compliance will be provided 
in subsequent guidance.
    (Comment 14) Some commenters sought clarification of Sec.  
4.4(b)(1) and (b)(2) and confirmation of whether the rule requires 
compliance with both the drug CGMPs and with the QS regulation 
throughout the entire manufacturing process for combination products 
and their constituent parts, or only at facilities where constituent 
parts subject to both of these two sets of requirements are being made. 
Commenters asserted that applying both sets of requirements throughout 
the entire manufacturing process of a combination product would result 
in a more demanding and complex CGMP system than currently expected for 
non-combination medical products. Other commenters proposed that the 
rule should be revised to have a ``product-based'' rather than a 
``facility-based'' approach.
    (Response) As discussed in response to Comment 13 of this document, 
the applicability of some CGMP requirements will vary depending on the 
circumstances, including what aspect of a product's manufacture takes 
place at a facility and whether multiple facilities are involved in the 
manufacture of a combination product. Accordingly, we do not agree that 
the rule should be either ``product-based'' or ``facility-based.'' A 
manufacturer must comply with the requirements applicable to the 
activities undertaken at its facility, including applicable aspects of 
requirements that apply to multiple facilities or the overall 
manufacturing process for the product, and a product applicant must 
ensure compliance with all CGMP requirements for its product.
    The rule provides that a facility that is manufacturing only one 
type of constituent part of a co-packaged or single-entity combination 
product need only comply with the CGMP requirements applicable to that 
constituent part type (Sec.  4.4(c)). Facilities that perform 
manufacturing activities for more than one type of constituent part of 
such a combination product must comply with the CGMP requirements 
applicable to each type of constituent part being manufactured at that 
facility (Sec.  4.4(d)). The rule permits the use of the streamlined 
approach to demonstrate compliance with the drug CGMP and device QS 
regulation requirements when both are applicable to a facility's 
manufacturing activities for a single-entity or co-packaged combination 
product (Sec.  4.4(a) and (b)).
    With regard to CAPA requirements and the parallel requirements of 
the drug CGMPs, for example, the applicant and any other 
manufacturer(s) for a single-entity or co-packaged combination product 
must ensure that an appropriately comprehensive review of activities is 
undertaken at whatever facilities may be relevant to determine the root 
cause of manufacturing problems, deviations, or nonconformities. These 
requirements also call for corrective actions and preventive measures 
to be taken with regard to all relevant manufacturing steps at all 
relevant facilities, so that the problem is corrected and potential 
problems will be prevented or mitigated going forward. In the case of 
the product applicant these duties are comprehensive, applying to all 
relevant facilities and all appropriate measures for the product. For 
products with multiple manufacturers, the scope of the duties for each 
manufacturer parallels and depends upon the scope of the activity 
undertaken at that manufacturer's facility. The related guidance for 
this rule will address these issues further.
    (Comment 15) Some commenters sought clarification of the language 
of Sec.  4.4(d) that states that a facility where two or more different 
types of constituent parts have arrived or at which their manufacture 
is proceeding may apply the streamlined approach provided for under 
Sec.  4.4(a)(2) and (b). One commenter proposed that this streamlined 
system should only have to be met once two or more types of constituent 
parts have been assembled. Some commenters proposed that once 
initiated, the system should apply on a ``forward-looking'' basis and 
should not reach back to manufacturing operations that occurred prior 
to when the constituent parts begin being manufactured together at the 
same facility.
    (Response) As discussed previously in response to Comment 13 of 
this document, there are various types of CGMP requirements, some of 
which are facility-specific, and some that apply to multiple facilities 
or the overall manufacturing process for the product. All of these 
requirements must be met for a combination product. As these comments 
suggest, the requirements applicable to a particular manufacturer 
depend on the activities undertaken at the facility or facilities that 
manufacturer operates, with the applicant having responsibilities for 
compliance with all CGMP requirements for its product.
    Section 4.4(d) concerns the CGMP operating system for a specific 
facility participating in the manufacture of a single-entity or co-
packaged combination product. If a facility manufactures only one type 
of constituent part of such a combination product, it must comply with 
the CGMPs for that type of product (e.g., the QS regulation if the 
constituent part is a device). In contrast, when two or more 
constituent parts of a combination product are being manufactured at 
the same facility, the manufacturer must comply with the CGMPs 
applicable to each type of constituent part (e.g., the drug CGMPs and 
device QS regulation if the facility is combining or otherwise 
manufacturing both drug and device constituent parts). Accordingly, 
Sec.  4.4(d) states that a facility may initiate a CGMP operating 
system that complies with Sec.  4.4(b) when the manufacture of two or 
more different types of constituent parts is being conducted at that 
facility. Section 4.4(d) is intended to clarify that when a facility 
must comply with the CGMP requirements for more than one type of 
constituent part, a Sec.  4.4(b)-compliant CGMP operating system is 
available as a means of demonstrating compliance.
    We reject the proposal that the CGMP requirements applicable to a 
constituent part come into effect only after that constituent part has 
been formed. Such an approach would be inconsistent with the 
application of the underlying CGMP regulations listed in Sec.  4.3. The 
trigger is whether the facility is conducting manufacturing operations 
that would be subject to the underlying CGMP

[[Page 4314]]

requirements. For example, if a facility is manufacturing only device 
components, it might not be subject to CGMP requirements under the QS 
regulation. However, a facility that is manufacturing a finished device 
from such components is subject to the QS regulation. Therefore, for 
example, if a facility is manufacturing a finished combination product, 
a prefilled syringe for instance, from device components and drug 
components, that facility is subject to both the QS regulation and drug 
CGMPs.
    (Comment 16) One commenter asserted that due to ambiguities 
associated with an out-of-specification (OOS) investigation, excessive 
work may be involved if there is a need to perform a device component 
review.
    (Response) FDA disagrees with this comment. Medical device In Vitro 
Diagnostic (IVD) product manufacturers routinely perform OOS 
investigations successfully. OOS investigation is conducted under Sec.  
211.192 for drugs and under Sec. Sec.  820.80(d) and 820.90 for 
devices. In some cases, as for IVD devices, OOS for a device may be 
similar to OOS for a drug. In others, the approach may differ. This 
rule is not intended to alter the scope of such investigations for 
drugs or devices. Accordingly, whether a combination product 
manufacturer opts to institute a CGMP operating system that implements 
the QS regulation plus the called-out provisions from part 211, or one 
that implements the drug CGMPs plus the specified provisions of the QS 
regulation, OOS for the combination product should be appropriate to 
address the considerations articulated in Sec.  211.192 for the drug 
constituent part and in Sec. Sec.  820.80(d) and 820.90 for the device 
constituent part. For example, unexplained discrepancies (or the 
failure of a batch or any components to meet any specifications) shall 
be thoroughly investigated as appropriate.
    (Comment 17) Some commenters requested that the Agency clarify 
selection criteria for whether to adopt the approach under Sec.  
4.4(b)(1) that calls for implementation of the drug CGMPs plus 
specified provisions of the QS regulation or the approach under Sec.  
4.4(b)(2) that calls for implementation of the QS regulation plus 
specified provisions of the drug CGMPs. One commenter suggested the 
primary mode of action of the combination product as one possible basis 
for selection.
    (Response) We do not see a need to limit under what circumstances a 
manufacturer may or should select the approach under Sec.  4.4(b)(1) or 
(b)(2). It is appropriate to leave the decision of whether to implement 
a system in accordance with Sec.  4.4(b)(1) or (b)(2) to the discretion 
of the manufacturer. Some facilities, for example, may already operate 
under either the drug CGMPs or QS regulation in manufacturing other 
products, and may prefer to demonstrate compliance with both sets of 
regulations by taking the steps necessary to demonstrate compliance 
with the called out provisions of the regulation under which they do 
not otherwise operate. Other facilities may have no pre-existing 
manufacturing approach, for example, and select an option on other 
grounds. Both the approaches permitted in Sec.  4.4(b) are permissible 
under the rule, and neither is considered preferable by the Agency.
    (Comment 18) One commenter sought guidance on how to implement a 
CGMP system in accordance with Sec.  4.4(a)(1), which permits 
establishment of a system that fully implements all of the CGMP 
regulations applicable to the combination product under Sec.  4.3. 
Specifically, this commenter sought guidance on how to resolve 
conflicts among requirements of the regulations applicable to a 
combination product if implemented in accordance with Sec.  4.4(a)(1).
    (Response) As discussed previously in this document, the 
requirements of the drug CGMP and QS regulation are similar in many 
respects. Further, the various regulations listed in Sec.  4.3 are 
generally compatible with one another. Nonetheless, we appreciate that 
questions as to how to reconcile them and actual conflicts may arise. 
Accordingly, regulations listed in Sec.  4.3 and this regulation 
include provisions addressing how to resolve any conflicts among them. 
These provisions essentially call for following whichever requirement 
is more specifically applicable. See Sec. Sec.  211.1(b), 820.1(b), and 
4.4(e) of this rule. This determination may be based on such factors 
such as which regulation addresses a manufacturing issue most precisely 
and which requirement arises from the regulation most specifically 
applicable to the constituent part. Should we become aware of potential 
conflicts with respect to combination products in general or classes of 
combination products, we intend to address them in guidance. However, 
we are not aware of any such potential conflicts at this time.
    (Comment 19) One commenter requested that the following language be 
added to Sec.  4.4(c): ``Device components and constituent parts are 
governed under QSR. The drug components and constituent parts are 
governed under CGMPs. The components of constituent parts would be 
governed under the quality system in which they are specified.'' A 
second commenter proposed a similar change to Sec.  4.3(a) to state 
that drug CGMPs ``apply to the drug constituent part of a combination 
product,'' and corresponding changes to Sec.  4.3(b) through (d).
    (Response) We have not made either proposed revision because we do 
not agree that they would clarify the rule, and also because they could 
cause confusion. Section 4.4(c) provides that all CGMP requirements 
applicable to a constituent part of a single-entity or co-packaged 
combination product must be satisfied during any period in which that 
constituent part is manufactured at a separate facility. In some cases, 
the CGMPs applicable to that constituent part may arise from only one 
of the regulations listed in Sec.  4.3. In other cases, the applicable 
CGMPs may arise from several of these listed regulations. Similarly, as 
explained in sections E.1 and E.2 of this document, the CGMP 
requirements listed in Sec.  4.3 apply to the combination product, and 
compliance with them may involve policies, procedures, and practices 
applicable to the combination product as a whole or to multiple 
constituent parts.
E.1. How To Comply With QS Regulation Requirements Under Sec.  
4.4(b)(1)
    (Comment 20) As discussed previously in this document, some 
commenters sought guidance concerning the applicability of the 
requirements specified in Sec.  4.4(b) as a general matter. The great 
majority of comments addressing in particular the application of the QS 
regulation requirements specified under Sec.  4.4(b)(1) focused on 
Sec.  820.30 (design controls). Some commenters asked for clarification 
of how to apply design controls to combination products. Some 
questioned whether design controls should apply other than to the 
device constituent part of a combination product. Some asked for 
guidance regarding how to apply design controls to non-device 
constituent parts of a combination product, noting that the decision to 
incorporate such an article into a combination product may occur after 
that article has already been developed.
    (Response) Design controls apply when a device constituent part is 
used in a combination product. Design controls require the manufacturer 
of a combination product which includes a device constituent part to 
establish and maintain procedures to ensure that the design 
requirements for the combination product are appropriate and address 
the

[[Page 4315]]

intended use of the combination product, including the needs of the 
user and patient. The design control process may rely on existing 
information for the constituent parts, such as information provided in 
support of the combination product's marketing authorization.
    The design history file for a combination product with device and 
drug or biological product constituent part must address all design 
issues resulting from the combination of the constituent parts, 
regardless of whether the manufacturer chooses to apply a CGMP 
operating system that implements part 820 plus the provisions of part 
211 specified in Sec.  4.4(b)(2) of this rule or implements part 211 
plus the provisions of part 820 specified in Sec.  4.4(b)(1) of this 
rule. For example, with regard to a drug or biologic product 
constituent part in a combination product, the design history file 
would document and provide objective evidence that the drug or biologic 
is appropriate for use with the device (e.g., why the formulation of 
the drug constituent part is appropriate for use in a drug-eluting 
stent given the need to ensure controlled elution, resistance to 
flaking, etc.). Similarly, with regard to a device constituent part in 
a combination product, the design history file would document and 
provide objective evidence that the device constituent part is 
appropriate for use with the drug or biological product (e.g., that a 
syringe is appropriate for use as a delivery device for a drug by 
providing assurance that there is no interaction with the drug, that 
the syringe will deliver the drug properly, and that container closure 
integrity and shelf life can be maintained, etc.).
    The combination product manufacturer is responsible for design and 
development planning, including the design of processes for the 
manufacture of the combination product. For products manufactured by 
multiple manufacturers, the finished combination product manufacturer 
and the application holder (if they are not the same entity), each are 
responsible for these duties. The design inputs must ensure that the 
design requirements are appropriate and address the intended use of the 
combination product, including the needs of the patient and the user of 
that combination product. Design output procedures must ensure that 
those design outputs that are essential for the proper functioning of 
the combination product are identified. The total finished design 
output consists of the combination product, its packaging, and its 
labeling. In addition, design control requirements for review, 
verification, validation, design changes and design history file apply. 
If a sponsor wishes to use an existing or off-the-shelf product as a 
constituent part of a combination product, the design controls must 
ensure that the existing product meets appropriate design requirements 
for the combination product to be safe and effective, which may require 
modification of the existing product for use as part of the combination 
product. See Sec.  820.30. Further explanation will be provided in the 
related guidance.
E.2. How To Comply With Drug CGMP Requirements Under Sec.  4.4(b)(2)
    (Comment 21) Some commenters proposed adding the requirements from 
Sec. Sec.  211.160 (general requirements) and 211.194 (laboratory 
records) of the drug CGMP requirements to the list of requirements with 
which manufacturers must demonstrate compliance under Sec.  4.4(b)(2).
    (Response) We do not find that it is necessary to add Sec. Sec.  
211.160 and 211.194 to Sec.  4.4(b)(2). The topics addressed in these 
sections are adequately addressed in part 820, including, for example, 
in Sec. Sec.  820.70 (production and process controls), 820.72 
(calibration), 820.80 (acceptance activities), 820.180 (general 
requirements), and 820.250 (statistical techniques).
    Section 211.160 is primarily concerned with the ``establishment of 
* * * specifications, standards, sampling plans, test procedures, or 
other * * * control mechanisms'' with respect to the laboratory. This 
section also states that these control mechanisms and changes to them 
shall be drafted by the appropriate organizational unit and reviewed by 
the quality control unit. These requirements shall be followed and 
documented, and any deviation shall be recorded and justified. Also, 
appropriate ``instruments, apparatus, gauges, and recording devices'' 
shall be calibrated. While we recognize that pharmaceutical laboratory 
control is critical to the quality of drug components, in-process 
materials, and the final product, this section's requirements are broad 
enough to be comparable to requirements specified in Sec. Sec.  
820.70(a) and (b) (general requirements and changes to production and 
process controls), 820.80(c) (in-process acceptance activities), 
820.250 (statistical techniques), 820.20(a)(1) (responsibility and 
authority), and 820.72(b) (calibration).
    Section 211.194 is primarily concerned with the management and 
maintenance of official records with respect to the laboratory. This 
section's requirements are comparable to requirements specified in 
Sec.  820.180 (general requirements for official records). While Sec.  
211.194 specifies some requirements for testing of laboratory samples, 
``complete records'' of all data generated within a laboratory is 
comparable to ``all records'' as described in Sec.  820.180. Section 
211.194 can be used as a source of information for specific 
pharmaceutical laboratory testing records needing to be managed and 
maintained, as well as relevant CGMP guidance with respect to 
pharmaceutical and microbiological laboratories.
    (Comment 22) Some commenters sought clarification of circumstances 
under which Sec.  211.103 (calculation of yield) should be satisfied 
and questioned whether determining yield would provide meaningful 
information beyond what the QS regulation requires regarding whether 
processes are under control. One sought clarification of whether the 
requirement applies only to drug constituent parts.
    (Response) Section 211.103 states that calculation of yield ``shall 
be determined at the conclusion of each appropriate phase of 
manufacturing, processing, packaging, or holding'' for a drug product. 
This may provide valuable information and insight to the status of a 
manufacturing process at significant evaluation points, not just for 
the final product. In addition, Sec.  211.103 provides an important 
quality check both for a pharmaceutical production process as a whole 
and for individual unit operations of the process. It is important to 
account for any increase or decrease in expected yield of materials 
during the manufacturing process. When either occurs, it is important 
to conduct a prompt and thorough investigation. Appropriate 
manufacturing controls can help prevent deviations from expected 
process yield, which can be important to the success of manufacturing 
steps and to ensuring that the final product meets specifications. Any 
phase of the pharmaceutical process that is subject to potential 
component, in-process material, or product loss, due to physical or 
chemical means, should be evaluated with respect to actual and 
theoretical yield of these materials. Section 211.103 does not apply to 
device constituent parts of combination products.
    (Comment 23) Some commenters sought clarification of the 
application of Sec.  211.170 (reserve samples). Some argued that 
reserve sample requirements should apply only to drug constituent parts 
of combination products and not to device constituent parts or the 
entire combination product, asserting that keeping samples of devices 
or complete

[[Page 4316]]

combination products would be cost prohibitive. Others sought guidance 
regarding how to comply with reserve sampling requirements for ``small 
lot'' products with less than 100 products in a lot, or products that 
come in multiple sizes and shapes.
    (Response) Reserve samples are needed to help ensure the postmarket 
safety and effectiveness of combination products, 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. Under Sec.  211.170, reserve samples must be 
maintained for each lot of a drug (or biological product) ``under 
conditions consistent with product labeling,'' ``stored in the same 
immediate container-closure system in which the drug product is 
marketed or in one that has essentially the same characteristics,'' and 
must consist of ``at least twice the quantity necessary to perform all 
the required tests, except those for sterility and pyrogens.''
    For a single-entity combination product, such as a prefilled 
syringe or a drug-eluting disc or stent, it would be appropriate to 
retain samples of the complete product from each lot and, in any event, 
the samples should include the drug and all device components that come 
into direct contact with the drug. For co-packaged and cross-labeled 
combination products, it generally should be sufficient to maintain 
samples of each lot of the drug or biological product in the immediate 
container/closure in which it is marketed. Specific questions or 
concerns about reserve samples should be discussed with the lead review 
center for the combination product. We will provide further information 
regarding how to comply with sample retention requirements for 
combination products in related guidance for this rule.
    (Comment 24) Some commenters sought guidance on compliance with 
batch release testing requirements under Sec.  211.165. One asserted 
that such ``testing-in'' requirements are in conflict with ``design-
in'' requirements of the QS regulation. Some sought clarification of 
who is responsible for batch release for drug constituent parts, and 
whether the release is under a Certificate of Analysis or based on 
actual approval of the batch records. One asked how ``batch'' would be 
defined, specifically whether the batching of the device constituent 
part or the drug would prevail in determining what is a ``batch.'' One 
noted that a different approach might be appropriate for smaller 
production batches (for example, of less than 100) as opposed to 
batches that might contain 100,000 units. One asked if the Agency 
agreed that flexibility in applying the requirements would be 
appropriate if the combination product has a device primary mode of 
action. One asked if the Agency would consider testing of selected 
batches appropriate for small batch, high-cost combination products. 
One asked whether the Agency would permit combining sub-batches or 
testing of representative samples of the finished product. One asked, 
with regard to devices that contain antimicrobials, whether testing of 
antimicrobial activity could be considered a suitable surrogate 
endpoint for the determination of strength of the active ingredient.
    (Response) Section 4.4 applies to single-entity and co-packaged 
combination products. Testing and release for distribution of finished 
pharmaceuticals is a critical step in drug product manufacture and 
quality control. This applies to all single entity and co-packaged 
combination products that contain a drug constituent part. Such testing 
requirements do not conflict with design-based controls. Rather, the 
two work hand-in-hand to ensure appropriate manufacture and product 
performance.
    Each combination product manufacturer should establish procedures 
defining ``a batch'' in all phases of production, and describe all 
batch numbering systems used for incoming material, in-process 
material, and finished products. These procedures allow the 
manufacturer to connect specific lots of constituent parts, components 
and in-process material to the specific lot of combination product in 
which they were used as well as provide traceability of sampling and 
testing, packaging and labeling activities. Master production and 
control records should be designed to enable this traceability. Batch 
definition, control, and tracking procedures should be explained in 
product applications and available for review on inspection.
    All proposed testing and sampling plans of drug constituent parts 
should be conducted in accordance with Sec. Sec.  211.160 and 211.165. 
Sampling plans should be designed to assure appropriate statistical 
quality control criteria are met as a condition for the drug 
constituent part's approval and release. The acceptance criteria for 
all sampling and testing of a drug constituent part for product release 
should be reviewed and approved by the firm's quality unit.
    ``Release'' of pharmaceutical ingredients, excipients, and/or 
products may mean different things depending on where in the 
manufacturing process the materials are being tested. Incoming 
ingredients, excipients, and supplies from suppliers must be tested, 
controlled, and documented in accordance with Sec.  211.84. Reliance on 
reports of analysis and certificates of testing may be permitted under 
certain circumstances as provided at Sec.  211.84(d) so long as at 
least one specific identity test is conducted for each component of a 
drug constituent part. Acceptable materials can be ``released'' into 
the drug constituent part or combination product production system. 
Finished drug constituent parts or combination products must also be 
tested, controlled, and documented before they can be ``released'' for 
distribution to other clients or the market.
    Regarding the issue of whether verification and testing of 
antimicrobial activity could be a suitable surrogate for the 
determination of strength, we note that it would not be appropriate to 
use a qualitative activity determination (such as a determination of 
general antimicrobial activity) in place of a quantitative 
determination of biological activity (such as a determination of 
microbial inhibitory concentration (MIC)). Further, what type of test 
to conduct can depend on the purpose of the antimicrobial. For example, 
if a device is coated with an antimicrobial drug, and the intended use 
of the combination product involves dissemination of the drug to 
produce a pharmacologic effect, then ``strength'' could be determined 
by chemical analysis (reflecting chemical content) or by MIC 
(reflecting biological activity). However, if the antimicrobial coating 
serves only to inhibit or prevent microbial colonization of the device, 
then an antimicrobial preservative effectiveness test might be more 
appropriate.
    We plan to discuss batch release testing further in the related 
guidance for this rule.
    (Comment 25) Some commenters sought clarification of how to comply 
with Sec. Sec.  211.166 (stability testing) and 211.137 (expiration 
dating) requirements. Two comments sought clarification of stability 
testing and expiration testing for kits, and one questioned the 
practicality of annual stability testing for each ``size and shape'' of 
a combination product.
    (Response) Combination products that include drug constituent parts 
must comply with Sec.  211.166. A written testing program must be 
established to verify the stability of the drug constituent part. These 
stability testing programs are critical in determining appropriate 
storage conditions and

[[Page 4317]]

expiration dating. Any drug product manufactured for commercial 
distribution should be subjected to stability testing, including each 
type of drug constituent part included in a kit. Among other 
considerations, this testing must enable evaluation of any effects of 
storage in a container closure system, which may be a device 
constituent part, on the stability of the drug. See Sec.  
211.166(a)(4). As stated in Sec.  211.137, expiration dating must 
comply with 21 CFR 201.17. We plan to provide additional information on 
how to comply with the requirements of Sec. Sec.  211.166 and 211.137 
in the related guidance for this rule.
E.3. How To Comply With Biological Product and HCT/P Requirements Under 
Sec.  4.4(b)(3)
    (Comment 26) Some commenters sought clarification of which CGMP 
requirements for biological products and HCT/Ps might apply to a 
combination product. Some noted that the proposed rule provided that 
manufacturers of drug-device combination products could demonstrate 
compliance with both the drug CGMPs and device QS regulation by 
demonstrating compliance with one of these regulations in its entirety 
and with specified provisions of the other regulation. In contrast, 
they noted, the proposed rule stated that manufacturers of combination 
products that include a biological product or HCT/P must demonstrate 
compliance with all of the CGMP requirements applicable to a biological 
product or HCT/P, respectively. Commenters asked whether the Agency 
could specify biological product and HCT/P CGMP requirements with which 
compliance must be demonstrated if a manufacturer has demonstrated 
compliance with the drug CGMPs or device QS regulation.
    (Response) As noted previously in this document, and stated in the 
definition for biological product at Sec.  4.2, a biological product is 
also by definition a drug or a device. Accordingly, a biological 
product is always either subject to the drug CGMP regulations described 
in parts 210 and 211, or to the QS regulation described in part 820, as 
appropriate, regardless of whether the biological product is a 
constituent part of a combination product. Furthermore, biological 
products, including those that are constituent parts of combination 
products, must comply with all applicable requirements in parts 600 
through 680. To the extent that requirements in parts 600 through 680 
pertain to manufacturing for biological products, these requirements 
apply in conjunction with the CGMP regulations in parts 210, 211, and 
820 and do not create a separate CGMP operating system. Therefore, the 
additional requirements that pertain to manufacturing for biological 
products in parts 600 through 680 that would otherwise apply to a 
biological product if it were not part of a combination product must 
still be met when that biological product is a constituent part of a 
combination product.
    As noted in the preamble to the proposed rule, many requirements in 
parts 600 through 680 are not considered CGMP requirements. Moreover, 
many requirements in parts 600 through 680 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. Additionally, a vaccine manufactured using a spore-forming 
microorganism would be subject to Sec.  600.11(e)(3) (work with Spore-
forming microorganisms). As a result, the specific requirements in 
parts 600 through 680 that apply will depend on the type of biological 
product.
    An HCT/P that is not regulated solely under section 361 of the PHS 
Act (42 U.S.C. 264) is regulated as a drug, device, and/or biological 
product (see Sec. Sec.  1271.10 and 1271.20).\5\ The requirements for 
HCT/Ps under part 1271 are designed to prevent the introduction, 
transmission, and spread of communicable diseases. These requirements 
must be met for HCT/Ps, and are essential to protecting the public 
health. However, the Agency recognizes that there are some sections of 
part 1271 that overlap with the requirements under the drug CGMPs and 
the QS regulation, and has addressed these overlaps in draft guidance. 
See ``Guidance for Industry; Current Good Tissue Practice (CGTP) and 
Additional Requirements for Manufacturers of Human Cells, Tissues, and 
Cellular and Tissue-Based Products (HCT/Ps)'' (http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Tissue/UCM285223.pdf).
---------------------------------------------------------------------------

    \5\ The HCT/P regulation at part 1271 distinguishes between HCT/
Ps regulated solely under section 361 of the PHS Act (42 U.S.C. 264) 
and those that are regulated as drugs, devices and/or biological 
products under the PHS Act. The HCT/P regulation provides that an 
HCT/P that is combined with another article (other than water, 
crytalloids, or a sterilizing, preserving or storage agent) does not 
meet the criteria for regulation solely under section 361 of the PHS 
Act, but would be regulated as a drug, device and/or biological 
product. Refer to Sec. Sec.  1271.10 and 1271.20 when considering 
what regulations apply to a combination product with an HCT/P 
constituent part.
---------------------------------------------------------------------------

    (Comment 27) One commenter sought clarification of how to reconcile 
conflicts between HCT/P manufacturing requirements and drug CGMP and QS 
regulation requirements. This commenter stated that some HCT/Ps are 
also considered xenotransplantation products due to their exposure to 
animal materials (mouse, insects) during manufacturing and that FDA 
should consider addressing this topic in the final rule and/or 
associated guidance.
    (Response) Based on experience to date, the Agency believes that 
conflicts are unlikely to occur between the HCT/Ps manufacturing 
requirements listed in Sec.  4.3(d) and the drug CGMPs or device QS 
regulation. Further, as discussed in response to Comment 18 of this 
document, the rule includes a provision at Sec.  4.4(e) on how to 
resolve conflicts between CGMP requirements. Accordingly, we do not see 
a need to revise the rule in respect to this issue or to address it in 
guidance at this time. Regarding the issue of xenotransplantation 
products, we note that the Agency has already addressed this topic in 
guidance (see ``Guidance for Industry: Source Animal, Product, 
Preclinical, and Clinical Issues Concerning the Use of 
Xenotransplantation Products in Humans,'' (http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Xenotransplantation/ucm074354.htm).

F. Enforcement and Effective Date

    (Comment 28) Several commenters recommended delaying the effective 
date, in most cases to 1 year after publication of this rule. Some 
noted a need to coordinate various functions and conduct extensive 
communications and analyses in developing a compliant system. Others 
noted the time the Agency provided for implementation of aspects of 
other rules, such as the design control requirements of the QS 
regulation. Some addressed the time and financial costs of making such 
changes, arguing that the Agency has substantially underestimated the 
costs of implementing this rule, and should extend the effective date 
in light of the greater costs they believe will be incurred.
    (Response) This final rule serves to clarify options for 
manufacturers to comply with the sets of CGMPS applicable to their 
combination product. As stated in the preamble to the proposed rule, 
manufacturers are responsible for compliance with the CGMP requirements 
that apply to each constituent part of their combination

[[Page 4318]]

products (74 FR 48423 at 48424). This rule does not establish any new 
requirements. Accordingly, we see no reason to delay its effective 
date, and consistent with the plan described in the proposed rule, we 
are issuing this rule to be effective in 180 days. The Agency wants to 
move forward in providing greater assurance that the streamlined 
approach outlined in the 2004 draft guidance and codified in Sec.  
4.4(b) of this rule may be used to demonstrate compliance with CGMPs 
for combination products. As noted throughout this notice, we are 
preparing companion guidance to provide further, general information 
regarding our expectations for compliance with CGMPs for combination 
products, and we remain available to work with manufacturers to resolve 
product-specific questions. We intend to continue to apply a risk-based 
approach to facility inspection and, consistent with ensuring 
protection of the public health and in light of the specific 
circumstances, to offer manufacturers a reasonable opportunity to 
correct deficiencies before taking further compliance or enforcement 
actions.

G. Alternate Approaches

    (Comment 29) Some commenters proposed alternate approaches, 
suggesting a more ``unified'' approach would be preferable or arguing 
that the drug CGMPs and device QS regulation are not well-suited for 
application to products including devices and drugs, respectively. Some 
encouraged reliance on guidance instead.
    (Response) As discussed in the preamble to the proposed rule and 
summarized in section I.A of this document, the Agency undertook an 
extensive evaluation of the drug CGMPs, device QS regulation, and 
biological product and HCT/P requirements in developing this rule. This 
process included consideration of comments received on the draft 
guidance that proposed an approach much the same as the approach 
offered in the proposed rule and adopted in this final rule. The 
comments received on that draft guidance and on the proposed rule were 
largely supportive of this approach, and the Agency believes that this 
approach offers an efficient and effective means to ensure that 
combination products are manufactured in accordance with all 
appropriate CGMP requirements.
    We see no reason to develop an entirely new regime for combination 
products, but rather find that it is appropriate to utilize the well-
established and understood CGMP requirements that already exist for the 
constituent parts of which combination products are comprised. At the 
same time, it is important to establish with clarity and certainty the 
CGMP requirements that apply to combination products, to ensure 
effective compliance and consistent, appropriate regulation. 
Accordingly, we determined that a rulemaking rather than reliance on 
guidance alone is appropriate to achieve these goals. As discussed 
throughout this preamble and in the preamble to the proposed rule, we 
understand that guidance is important to the effective implementation 
of this rule, and are issuing companion guidance for this reason.

H. Guidance

    (Comment 30) Several commenters requested that FDA issue companion 
guidance for this rule. Some requested that such guidance include 
relevant case studies or descriptions of what would constitute a 
demonstration of compliance with requirements for examples of 
combination products and manufacturing activities. One proposed that 
the guidance address the application of provisions of the drug CGMPs 
and QS regulation that are not specified in the rule and their 
compatibility with those provisions that are specified in Sec.  4.4(b) 
from the other of these two regulations. One commenter proposed 
guidance on the application of CGMP requirements for combination 
products in relation to master files. One commenter proposed a need for 
a table of key CGMP considerations for developing a streamlined system 
and for audit instructions and inspection check lists. Some emphasized 
the need to address what actions existing facilities should take to 
come into compliance. One encouraged harmonization with international 
efforts where possible. One stated that FDA should provide additional 
guidance on how the rule will affect Agency policy on CGMP requirements 
for investigational device constituent parts in combination products 
for which the Center for Biologics Evaluation and Research or the 
Center for Drug Evaluation and Research has the lead. One requested 
that guidance provide for the opportunity to discuss CGMP issues with 
the Agency. Some requested that such guidance issue prior to the final 
rule. One commenter advised that we review existing guidance to ensure 
its consistency with this rule.
    (Response) As noted in the proposed rulemaking, FDA recognizes that 
timely, comprehensive guidance is important to help ensure consistent 
and appropriate implementation of this rule. FDA intends to issue such 
guidance to industry and staff, focusing on the implementation of the 
regulatory requirements for use of a streamlined CGMP operating system 
for single-entity and co-packaged combination products. We welcome the 
comments received on this issue and look forward to further feedback in 
response to the guidance we issue. With regard to the requests that we 
issue draft guidance prior to issuance of this final rule, we did not 
believe it would be appropriate to anticipate the content of this rule 
by publishing guidance concerning its content prior to its 
finalization.
    We remain committed to international harmonization efforts, 
including those related to CGMP requirements for combination products. 
A practical challenge for combination products in particular is that 
international collaboration and harmonization efforts are at an early 
stage for these products. At the same time, there is a current need to 
clarify and rationalize our domestic CGMP requirements for this rapidly 
growing class of products. We have taken an approach that integrates 
underlying CGMP approaches for drugs, devices, and biological products, 
which have each benefited in various respects from substantial 
international harmonization efforts. The approach adopted in this rule 
will facilitate implementation of streamlined CGMP operating systems 
for combination products that will integrate as readily as possible 
with these existing and ongoing harmonization efforts. We are committed 
to continuing to work with our foreign counterparts on CGMPs and other 
issues for combination products, and to pursuing domestic regulatory 
approaches in the United States that will enable such efforts to the 
extent practicable and appropriate consistent with meeting our domestic 
regulatory needs.
    With regard to the comment concerning review of existing guidance 
for consistency with this rule, we note that any prior guidance must be 
read in light of subsequent changes to legal requirements, whether 
through new statutory law or issuance of new regulations. The Agency 
will continue to review all guidance to ensure its continued utility 
and accuracy.

I. Other

    (Comment 31) Some commenters recommended using the term ``hybrid'' 
rather than ``streamlined'' in reference to the compliance option under 
Sec.  4.4(b) for single-entity and co-packaged combination products. 
One commenter suggested that the rule does not reduce the burden of 
compliance with both the drug CGMPs and QS regulation. Some

[[Page 4319]]

commenters argued that the term streamlined might suggest a relaxation 
of requirements when Sec.  4.4(b), in fact, does not relax CGMP 
requirements for such products.
    (Response) We appreciate the concerns raised by these commenters. 
However, we disagree with the conclusion that Sec.  4.4(b) does not 
provide a means to streamline compliance with the drug CGMPs and device 
QS regulations for single-entity and co-packaged combination products. 
The alternative to the approach permitted under Sec.  4.4(b) is that of 
Sec.  4.4(a), under which a facility would need to demonstrate 
compliance with all applicable requirements under both of these 
regulations. Section 4.4(b), in contrast, reflects the Agency's 
judgment that many provisions of these two regulations are similar to 
one another and that demonstrating compliance with most requirements of 
one of these sets of regulations suffices to demonstrate compliance 
with similar provisions of the other set.
    We also disagree that use of the term ``streamlined,'' which is 
consistent with the rule's removal of redundant requirements for 
compliance with similar provisions of the drug CGMPs and QS regulation, 
implies a relaxation of CGMP requirements. Rather, it reflects the 
provision of a more efficient means to satisfy them.
    (Comment 32) Some commenters raised issues concerning training of 
compliance staff, inspection standards, coordination and allocation of 
responsibilities among Agency staff, and tracking and oversight for 
compliance activities within the Agency.
    (Response) The Agency recognizes the importance of effective and 
appropriate training, oversight, and standards for CGMP inspection, and 
for efficient, effective coordination among staff. We intend to address 
such matters through appropriate inspectional standards, training, and 
other mechanisms used in relation to other CGMP inspectional 
activities. However, these issues are matters of internal Agency 
operation outside the scope of this rulemaking and we do not address 
them further here.
    (Comment 33) Some commenters stated that the Agency should address 
how to ensure appropriate change controls for combination products, 
with one comment highlighting the issue with respect to cross-labeled 
combination products. Some commenters proposed that the Agency consider 
requiring constituent part manufacturers to notify one another before 
making changes to the constituent part. Some commenters also addressed 
the question of which post-approval change requirements should apply 
under what circumstances, proposing that the submission requirements 
for the change be those applicable to the constituent part being 
changed, or the most stringent requirement applicable to any of the 
constituent parts being changed if a change is being made to more than 
one.
    (Response) We agree that coordination with regard to changes among 
manufacturers participating in the manufacture of a combination product 
is an important CGMP issue. It is not unique to combination products 
however, and we do not see a need to establish additional requirements 
specifically for combination products. Where constituent parts of 
single-entity or co-packaged combination products are being made by one 
entity and supplied to another's facility where the finished 
combination product is made, compliance with purchasing control 
requirements, for example, would necessitate tracking of changes and 
confirmation that the change will not prevent the combination product 
from meeting its specifications.
    Similarly, the manufacturers of separately manufactured and 
marketed constituent parts of cross-labeled combination products are 
subject to the CGMP requirements applicable to the type of constituent 
part they are manufacturing. They must ensure that the manufacture of 
their constituent part complies with the specifications established to 
ensure the safe and effective use of that constituent part in 
combination with the other constituent parts for the combination 
product's intended use(s). Appropriate coordination among manufacturers 
with respect to CGMP compliance for changes to constituent parts of 
combination products will be further addressed in later guidance.
    The requirements for reporting post-marketing changes to the Agency 
or for obtaining Agency review of post-marketing changes, when making a 
post-market change to a combination product or a constituent part of a 
cross-labeled combination product, are beyond the scope of this rule. 
The issue of what type of submission to make to the Agency for a post-
approval change to a combination product is also beyond the scope of 
this rule. However, we note that we intend to issue guidance addressing 
post-marketing change submission requirements.
    (Comment 34) One commenter raised an issue regarding reporting of 
adverse events for ``cross-labeled'' combination products. One 
commenter asked for guidance on labeling requirements for combination 
products. Another proposed that the Agency develop a new master file 
category for combination product constituent parts and components to 
address application and quality requirements for these parts of 
combination products. Another requested that planned guidance for the 
rule address establishment registration and product listing for 
manufacturers and importers of combination products. Another commenter 
proposed development of a new export certificate program for 
combination product CGMP compliance. Another sought guidance on needle 
registration, labeling, and testing.
    (Response) We appreciate these comments, which raise issues that we 
may address in other contexts. However, these issues are beyond the 
scope of this rule and, therefore, we are not offering substantive 
responses to them here.

III. Legal Authority

    The Agency derives its authority to issue the regulations in 21 CFR 
part 4, subpart A, from 21 U.S.C. 321, 331, 351, 352, 353, 355, 360, 
360b-360f, 360h-360j, 360l, 360hh-360ss, 360aaa-360bbb, 371(a), 372-
374, 379e, 381, 383, and 394, Federal Food, Drug, and Cosmetic Act, and 
42 U.S.C. 216, 262, 263a, 264, and 271, Public Health Service Act.
    Most importantly, the provisions at sections 501(a)(2)(B) and (h) 
of the FD&C Act (21 U.S.C. 351(a)(2)(B) and (h)) require drugs and 
devices to be manufactured in accordance with CGMPs. Section 520(f) of 
the FD&C Act (21 U.S.C. 360j(f)) specifically authorizes the issuance 
of CGMP regulations for devices. Section 501 of the FD&C Act states 
that a drug or device is deemed adulterated if it is not manufactured 
in accordance with CGMPs. This provision applies to biological products 
including those that are constituent parts of combination products 
because these products meet the definition of drug or device under 
section 201 of the FD&C Act. This provision also applies to HCT/Ps that 
do not meet the criteria for regulation solely as HCT/Ps under section 
361 of the PHS Act, because they meet the definition of a drug, or 
device under section 201 of the FD&C Act. In addition, section 351 of 
the PHS Act (42 U.S.C. 262) authorizes FDA to issue manufacturing 
standards for biological products. Section 361 of the PHS Act 
authorizes the issuance of regulations to prevent the introduction, 
transmission, or spread of communicable diseases.
    Under applicable statutory provisions, the following CGMP 
regulations were previously issued for drugs, devices, biological 
products, and HCT/Ps that

[[Page 4320]]

may be included in combination products:
     Drug CGMP regulations for finished pharmaceuticals or drug 
products set forth at parts 210 and 211). Drug products not subject to 
these regulations (e.g., bulk drugs or active pharmaceutical 
ingredients) must still meet the current good manufacturing practice 
general standard required by the statute.
     QS regulation for devices set forth at part 820.
     Requirements that pertain to manufacturing within the 
requirements (including standards) for biological products in parts 600 
through 680.
     Current good tissue practices for HCT/Ps set forth in part 
1271.
    There is considerable overlap in the drug CGMPs and QS regulation, 
and for the most part the overlap is clear. For example, both establish 
requirements for management, organization, and personnel; both require 
documentation and recordkeeping; and both allow flexibility in their 
application to the manufacture of a particular product. FDA considers 
the drug CGMPs and the QS regulation to be similar, and they are meant 
to achieve the same general goals.
    Nevertheless, these two sets of regulations differ somewhat because 
each is tailored to the characteristics of the types of products for 
which it was designed. Each set of regulations contains certain 
specific requirements for various CGMP concepts that are only more 
generally addressed in the other regulation. For example, the QS 
regulation has detailed CAPA requirements (Sec.  820.100) while CAPA 
principles are currently more generally addressed in the drug CGMP 
regulation as part of Subpart J, Records and Reports, specifically at 
Sec. Sec.  211.180(e) and 211.192).
    This rule clarifies the applicability of these two regulations to 
combination products and provides a streamlined option for practical 
implementation for co-packaged and single-entity combination products. 
Because the drug and device CGMP requirements are so similar, when 
using this streamlined approach, demonstrating compliance with the 
requirements of one of these two set of regulations (e.g., drug CGMPs), 
along with demonstrating compliance with the requirements of the 
specified provisions from the other set (e.g., QS regulation), would be 
considered to be demonstrating compliance with all requirements from 
both.
    The CGMP requirements specific to each constituent part of a 
combination product also apply to the combination product itself 
because, by definition, combination products consist of drugs, devices, 
and/or biological products. (See Sec.  3.2(e)). These articles do not 
lose their discrete regulatory identity when they become constituent 
parts of a combination product. Therefore, all combination products are 
subject to at least two sets of CGMP requirements. For example, in the 
case of a drug-device combination product, the QS regulation in part 
820 and the drug CGMP regulations in parts 210 and 211 would apply to 
the combination product.
    Although combination products retain the regulatory identities of 
their constituent parts, the FD&C Act also recognizes combination 
products as a category of products that are distinct from products that 
are solely drugs, devices, or biological products. For example, section 
503(g)(4)(A) of the FD&C Act (21 U.S.C. 353(g)(4)(A)) requires OCP to 
``designate'' a product as a combination product as well as to ensure 
``consistent and appropriate postmarket regulation of like products 
subject to the same statutory requirements.'' Further, section 563(a) 
of the FD&C Act, (21 U.S.C. 360bbb-2(a)), governs the 
``classification'' of products as ``drug, biological product, device, 
or a combination product subject to section 503(g)'' (emphasis added). 
In this respect, the FD&C Act identifies a combination product as a 
distinct type of product that could be subject to specialized 
regulatory controls.
    Under the preceding authorities and section 701(a) of the FD&C Act 
(21 U.S.C. 371), which authorizes FDA to issue regulations for the 
efficient enforcement of the FD&C Act, FDA has the authority to issue 
regulations clarifying the applicability of CGMP requirements to 
combination products. The Agency is also authorized under these 
authorities to issue regulations specifying how compliance with CGMP 
requirements for combination products may be demonstrated.

IV. Analysis of Economic Impacts

A. Introduction

    FDA has examined the impacts of the final rule under Executive 
Order 12866, Executive Order 13563, the Regulatory Flexibility Act (5 
U.S.C. 601-612), and the Unfunded Mandates Reform Act of 1995 (Pub. L. 
104-4). Executive Orders 12866 and 13563 direct Agencies to assess all 
costs and benefits of available regulatory alternatives and, when 
regulation is necessary, to select regulatory approaches that maximize 
net benefits (including potential economic, environmental, public 
health and safety, and other advantages; distributive impacts; and 
equity). FDA believes that this final rule is not a significant 
regulatory action under Executive Order 12866.
    The Regulatory Flexibility Act requires Agencies to analyze 
regulatory options that would minimize any significant impact of a rule 
on small entities. Because the final rule codifies what is currently in 
effect, the Agency certifies that the final rule will not have a 
significant economic impact on a substantial number of small entities.
    Section 202(a) of the Unfunded Mandates Reform Act of 1995 requires 
that Agencies prepare a written statement, which includes an assessment 
of anticipated costs and benefits, before proposing ``any rule that 
includes any Federal mandate that may result in the expenditure by 
State, local, and tribal governments, in the aggregate, or by the 
private sector, of $100,000,000 or more (adjusted annually for 
inflation) in any one year.'' The current threshold after adjustment 
for inflation is $139 million, using the most current (2011) Implicit 
Price Deflator for the Gross Domestic Product. FDA does not expect this 
final rule to result in any 1-year expenditure that would meet or 
exceed this amount.

B. Rationale for Final Rule

    The final rule has two related purposes. The first is to clarify 
the CGMP requirements that apply to combination products, and the 
second is to help ensure the consistent and appropriate application and 
enforcement of these requirements. Constituent parts and manufacturing 
practices vary among combination products; different CGMP requirements 
apply depending upon the constituent parts in the combination product 
and what manufacturing practices are used. The final rule attempts to 
streamline the practical implementation of CGMP requirements for co-
packaged and single-entity combination products.

C. Response to Comments

    A number of comments suggested that the regulatory impact analysis 
of the proposed rule underestimated the incremental cost to comply with 
this rule; however they did not suggest alternative estimates or 
methodologies. There were divergent views as to whether the burden of 
compliance would be greater for legacy products or for small firms and 
those new to manufacturing combination products. One comment suggested 
the rule, as proposed, would inhibit innovation.
    FDA disagrees with these comments. The Agency has made its views 
clear

[[Page 4321]]

that all manufacturers are already responsible for compliance with the 
CGMP requirements that apply to each constituent part of their 
combination products. This final rule clarifies and codifies this view. 
The CGMPs for drugs, devices, and biological products all require 
periodic review and update to the systems to ensure they remain current 
with advances in technology and regulatory practice. Those 
manufacturers who choose to streamline their systems for legacy 
products that are in compliance with current practice, do so 
voluntarily, and it is assumed would only do so if the private benefits 
of doing it out-weigh the private costs. Because the final rule 
clarifies and codifies Agency practice on the application of existing 
CGMP regulations to combination products, it will make it simpler and 
less burdensome for all manufacturers to apply the regulations when 
developing new products. It could even shorten approval times for some 
products by reducing delays caused by lack of systems in place to 
comply with all applicable CGMP requirements.

D. Impact of Final Rule

    FDA estimates that approximately 300 manufacturers of combination 
products will be affected by the final rule. These manufacturers of 
combination products should benefit from the greater clarity provided 
regarding what regulatory provisions apply to their products and how 
they may comply with them. For both existing and future products, the 
streamlined approach set forth in the final rule will help ensure that 
CGMP requirements for co-packaged and single-entity combination 
products are consistent and appropriate, without duplicative or 
otherwise unnecessary aspects. This codification of CGMP requirements 
for combination products will also help ensure predictability and 
consistency in the application and enforcement of these regulatory 
requirements with regard to all combination products across FDA.
    Firms must already comply with the CGMP regulations for drugs, 
devices, and biological products, including the current good tissue 
practice regulations for HCT/Ps, found at parts 211, 820, 600 through 
680, and 1271, that are applicable to the constituent parts of their 
combination products. The cost of this final rule would be the 
incremental costs to modify or streamline existing standard operating 
systems. Because this final rule is codifying our current practice, any 
firms that choose to streamline or modify existing SOPs are doing so 
because the private benefits are greater than the private costs. If 
some firms choose to modify their SOPs as a result of this final rule, 
the net benefits of the rule will be greater than the costs.
    Some firms may incur one-time incremental costs reassessing 
compliance with the final rule. Because this final rule codifies Agency 
practice that is described in current guidance documents and because no 
new CGMP requirements are proposed, we believe the time required would 
be small and estimate it to be about 25 hours per product. The amount 
of these compliance assessment costs for an individual firm, and the 
impact of any such costs, will depend on the number and nature of the 
products the firm produces and how the firm has applied current 
regulations. Nonetheless, because the time required would be limited, 
the Agency believes the impact will not be significant on entities 
considered small based on the Small Business Administration's 
definition of a small entity (500 employees for device and biological 
product firms and 750 employees for drug firms).

V. Environmental Impact

    FDA has determined under 21 CFR 25.30(a), 25.30(h), 25.30(j), 
25.31(a), (c), (h), and (j), and 25.34(a) and (d) that this action is 
of a type that does not individually or cumulatively have a significant 
effect on the human environment. Therefore, neither an environmental 
assessment nor an environmental impact statement is required.

VI. Paperwork Reduction Act of 1995

    We note that the information collected under the underlying CGMP 
regulations for drugs, devices, and biological products, including 
current good tissue practices for HCT/Ps, found at parts 211, 820, 600 
through 680, and 1271, have already been approved and are in effect. 
The provisions of part 211 are approved under the Office of Management 
and Budget (OMB) control number 0910-0139. The provisions of part 820 
are approved under OMB control number 0910-0073. The provisions of 
parts 606, 640, and 660 are approved under OMB control number 0910-
0116. The provisions of part 610 are approved under OMB control number 
0910-0116 and OMB control number 0910-0338 (also for part 680). The 
provisions of part 1271, subparts C and D, are approved under OMB 
control number 0910-0543. This final rule contains no new collections 
of information. Therefore, clearance by OMB under the Paperwork 
Reduction Act of 1995 is not required.

VII. Executive Order 13132: Federalism

    FDA has analyzed this final rule in accordance with the principles 
set forth in Executive Order 13132. FDA has determined that the rule 
does not contain policies that have substantial direct effects on the 
States, on the relationship between the National Government and the 
States, or on the distribution of power and responsibilities among the 
various levels of government. Accordingly, the Agency has concluded 
that the rule does not contain policies that have federalism 
implications as defined in the Executive order and, consequently, a 
federalism summary impact statement is not required. The sole statutory 
provision giving preemptive effect to this rule is section 751 of the 
FD&C Act (21 U.S.C. 379r), which would apply only with respect to OTC 
drug constituent parts of combination products.

List of Subjects in 21 CFR Part 4

    Combination products, Biological products, Devices, Drugs, and 
Human cell, Tissue, and cellular and tissue based products, Regulation 
of combination products.

    Therefore, under the Federal Food, Drug, and Cosmetic Act, the 
Public Health Service Act, and under authority delegated to the 
Commissioner of Food and Drugs, 21 CFR part 4 is added to read as 
follows:

PART 4--REGULATION OF COMBINATION PRODUCTS

Subpart A--Current Good Manufacturing Practice Requirements for 
Combination Products
Sec.
4.1 What is the scope of this subpart?
4.2 How does FDA define key terms and phrases in this subpart?
4.3 What current good manufacturing practice requirements apply to 
my combination product?
4.4 How can I comply with these current good manufacturing practice 
requirements for a co-packaged or single-entity combination product?
Subpart B [Reserved]

    Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 360, 360b-
360f, 360h-360j, 360l, 360hh-360ss, 360aaa-360bbb, 371(a), 372-374, 
379e, 381, 383, 394; 42 U.S.C. 216, 262, 263a, 264, 271.

Subpart A--Current Good Manufacturing Practice Requirements for 
Combination Products


Sec.  4.1  What is the scope of this subpart?

    This subpart applies to combination products. It establishes which 
current good manufacturing practice

[[Page 4322]]

requirements apply to these products. This subpart clarifies the 
application of current good manufacturing practice regulations to 
combination products, and provides a regulatory framework for designing 
and implementing the current good manufacturing practice operating 
system at facilities that manufacture co-packaged or single-entity 
combination products.


Sec.  4.2  How does FDA define key terms and phrases in this subpart?

    The terms listed in this section have the following meanings for 
purposes of this subpart:
    Biological product has the meaning set forth in Sec.  3.2(d) of 
this chapter. A biological product also meets the definitions of either 
a drug or device as these terms are defined under this section.
    Combination product has the meaning set forth in Sec.  3.2(e) of 
this chapter.
    Constituent part is a drug, device, or biological product that is 
part of a combination product.
    Co-packaged combination product has the meaning set forth in Sec.  
3.2(e)(2) of this chapter.
    Current good manufacturing practice operating system means 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.
    Current good manufacturing practice requirements means the 
requirements set forth under Sec.  4.3(a) through (d).
    Device has the meaning set forth in Sec.  3.2(f) of this chapter. A 
device that is a constituent part of a combination product is 
considered a finished device within the meaning of the QS regulation.
    Drug has the meaning set forth in Sec.  3.2(g) of this chapter. A 
drug that is a constituent part of a combination product is considered 
a drug product within the meaning of the drug CGMPs.
    Drug CGMPs refers to the current good manufacturing practice 
regulations set forth in parts 210 and 211 of this chapter.
    HCT/Ps refers to human cell, tissue, and cellular and tissue-based 
products, as defined in Sec.  1271.3(d) of this chapter. An HCT/P that 
is not solely regulated under section 361 of the Public Health Service 
Act may be a constituent part of a combination product. Such an HCT/P 
is subject to part 1271 of this chapter and is also regulated as a 
drug, device, and/or biological product.
    Manufacture includes, but is not limited to, designing, 
fabricating, assembling, filling, processing, testing, labeling, 
packaging, repackaging, holding, and storage.
    QS regulation refers to the quality system regulation in part 820 
of this chapter.
    Single-entity combination product has the meaning set forth in 
Sec.  3.2(e)(1) of this chapter.
    Type of constituent part refers to the category of the constituent 
part, which can be either a biological product, a device, or a drug, as 
these terms are defined under this section.


Sec.  4.3  What current good manufacturing practice requirements apply 
to my combination product?

    If you manufacture a combination product, the requirements listed 
in this section apply as follows:
    (a) The current good manufacturing practice requirements in parts 
210 and 211 of this chapter apply to a combination product that 
includes a drug constituent part;
    (b) The current good manufacturing practice requirements in part 
820 of this chapter apply to a combination product that includes a 
device constituent part;
    (c) The current good manufacturing practice requirements among the 
requirements (including standards) for biological products in parts 600 
through 680 of this chapter apply to a combination product that 
includes a biological product constituent part to which those 
requirements would apply if that constituent part were not part of a 
combination product; and
    (d) The current good tissue practice requirements including donor 
eligibility requirements for HCT/Ps in part 1271 of this chapter apply 
to a combination product that includes an HCT/P.


Sec.  4.4  How can I comply with these current good manufacturing 
practice requirements for a co-packaged or single-entity combination 
product?

    (a) Under this subpart, for single entity or co-packaged 
combination products, compliance with all applicable current good 
manufacturing practice requirements for the combination product shall 
be achieved through the design and implementation of a current good 
manufacturing practice operating system that is demonstrated to comply 
with:
    (1) The specifics of each set of current good manufacturing 
practice regulations listed under Sec.  4.3 as they apply to each 
constituent part included in the combination product; or
    (2) Paragraph (b) of this section.
    (b) If you elect to establish a current good manufacturing practice 
operating system in accordance with paragraph (b) of this section, the 
following requirements apply:
    (1) If the combination product includes a device constituent part 
and a drug constituent part, and the current good manufacturing 
practice operating system has been shown to comply with the drug CGMPs, 
the following provisions of the QS regulation must also be shown to 
have been satisfied; upon demonstration that these requirements have 
been satisfied, no additional showing of compliance with respect to the 
QS regulation need be made:
    (i) Section 820.20 of this chapter. Management responsibility.
    (ii) Section 820.30 of this chapter. Design controls.
    (iii) Section 820.50 of this chapter. Purchasing controls.
    (iv) Section 820.100 of this chapter. Corrective and preventive 
action.
    (v) Section 820.170 of this chapter. Installation.
    (vi) Section 820.200 of this chapter. Servicing.
    (2) If the combination product includes a device constituent part 
and a drug constituent part, and the current good manufacturing 
practice operating system has been shown to comply with the QS 
regulation, the following provisions of the drug CGMPs must also be 
shown to have been satisfied; upon demonstration that these 
requirements have been satisfied, no additional showing of compliance 
with respect to the drug CGMPs need be made:
    (i) Section 211.84 of this chapter. Testing and approval or 
rejection of components, drug product containers, and closures.
    (ii) Section 211.103 of this chapter. Calculation of yield.
    (iii) Section 211.132 of this chapter. Tamper-evident packaging 
requirements for over-the-counter (OTC) human drug products.
    (iv) Section 211.137 of this chapter. Expiration dating.
    (v) Section 211.165 of this chapter. Testing and release for 
distribution.
    (vi) Section 211.166 of this chapter. Stability testing.
    (vii) Section 211.167 of this chapter. Special testing 
requirements.
    (viii) Section 211.170 of this chapter. Reserve samples.
    (3) In addition to being shown to comply with the other applicable 
manufacturing requirements listed under Sec.  4.3, if the combination 
product includes a biological product constituent part, the current 
good manufacturing practice operating system must also be shown to 
implement and comply with all manufacturing requirements identified 
under Sec.  4.3(c) that would apply to that biological product if that 
constituent part were not part of a combination product.

[[Page 4323]]

    (4) In addition to being shown to comply with the other applicable 
current good manufacturing practice requirements listed under Sec.  
4.3, if the combination product includes an HCT/P, the current good 
manufacturing practice operating system must also be shown to implement 
and comply with all current good tissue practice requirements 
identified under Sec.  4.3(d) that would apply to that HCT/P if it were 
not part of a combination product.
    (c) During any period in which the manufacture of a constituent 
part to be included in a co-packaged or single entity combination 
product occurs at a separate facility from the other constituent 
part(s) to be included in that single-entity or co-packaged combination 
product, the current good manufacturing practice operating system for 
that constituent part at that facility must be demonstrated to comply 
with all current good manufacturing practice requirements applicable to 
that type of constituent part.
    (d) 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 
proceeding at the same facility, application of a current good 
manufacturing process operating system that complies with paragraph (b) 
of this section may begin.
    (e) The requirements set forth in this subpart and in parts 210, 
211, 820, 600 through 680, and 1271 of this chapter listed in Sec.  
4.3, supplement, and do not supersede, each other unless the 
regulations explicitly provide otherwise. In the event of a conflict 
between regulations applicable under this subpart to combination 
products, including their constituent parts, the regulations most 
specifically applicable to the constituent part in question shall 
supersede the more general.

Subpart B [Reserved]

    Dated: January 15, 2013.
Leslie Kux,
Assistant Commissioner for Policy.
[FR Doc. 2013-01068 Filed 1-18-13; 8:45 am]
BILLING CODE 4160-01-P