[Federal Register Volume 78, Number 14 (Tuesday, January 22, 2013)]
[Rules and Regulations]
[Pages 4307-4323]
[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,<PHONE_NUMBER>.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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.

    (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