[Federal Register: September 23, 2009 (Volume 74, Number 183)]
[Proposed Rules]
[Page 48423-48431]
[DOCID:fr23se09-17]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 4

[Docket No. FDA-2008-D-0409]

Current Good Manufacturing Practice Requirements for Combination
Products

AGENCY: Food and Drug Administration, HHS.

ACTION:  Proposed rule.

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SUMMARY:  The Food and Drug Administration (FDA or agency) proposes to
codify the current good manufacturing practice (cGMP) requirements
applicable to combination products. This proposed rule is intended to
promote the public health by clarifying which cGMP requirements apply
when drugs, devices, and biological products are combined to create a
combination product. In addition, the proposed 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:  Submit written or electronic comments on this proposed rule by
December 22, 2009. See section IX of this document for the proposed
effective date of a final rule based on this document.

ADDRESSES:  You may submit comments, identified by Docket No. FDA-2008-
D-0409 (formerly Docket No. 2004D-0431), by any of the following
methods:
Electronic Submissions
    Submit electronic comments in the following way:
     Federal eRulemaking Portal: http://www.regulations.gov.
Follow the instructions for submitting comments.
Written Submissions
    Submit written submissions in the following ways:
     FAX:<PHONE_NUMBER>.
     Mail/Hand delivery/Courier (for paper, disk, or CD-ROM
submissions): Division of Dockets Management (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.
    To ensure more timely processing of comments, FDA is no longer
accepting comments submitted to the agency by e-

mail. FDA encourages you to continue to submit electronic comments by
using the Federal eRulemaking Portal, as described previously, in the
ADDRESSES portion of this document under Electronic Submissions.
    Instructions: All submissions received must include the agency name
and docket number for this rulemaking. All comments received may be
posted without change to http://www.regulations.gov, including any
personal information provided. For additional information on submitting
comments, see the ``Comments'' heading of the SUPPLEMENTARY INFORMATION
section of this document.
    Docket: For access to the docket to read background documents or
comments received, go to http://www.regulations.gov and insert the
docket number, found in brackets in the heading of this document, into
the ``Search'' box and follow the prompts and/or go to the Division of
Dockets Management, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT:  John Weiner, Office of Combination
Products (HFG-3), Food and Drug Administration, 15800 Crabbs Branch
Way, suite 200, Rockville, MD 20855,<PHONE_NUMBER>.

SUPPLEMENTARY INFORMATION:

I. Introduction

    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 proposed 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 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; 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.
    The Medical Device User Fee and Modernization Act of 2002 (MDUFMA)
modified section 503(g) of the act) (21 U.S.C. 353(g)) to require the
establishment of an Office (Office of Combination Products (OCP))
within the Office of the Commissioner of FDA. The responsibilities of
OCP include ensuring the prompt assignment of combination products to
agency components, the timely and effective premarket review of such
products, and the consistent and appropriate postmarket regulation of
like products subject to the same statutory requirements to the extent
permitted by law (21 U.S.C. 353(g)(4)).
    Section 501 of the act (21 U.S.C. 351) states circumstances under
which drugs and devices (including biological products, which by
definition are also drugs or devices, and including human cellular and
tissue-based products (HCT[sol]Ps) that are regulated as drugs,
devices, and/or biological products) are deemed adulterated.\2\
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.\3\
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    \2\ See also 21 U.S.C. 360j(f)(1).
    \3\ See, generally, 21 U.S.C. 351(a)(2)(B) and (h).
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    The constituent parts of a combination product retain their
regulatory status (as a drug or device, for example) even 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. 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, biological
products, and HCT[sol]Ps, there are currently no regulations that
clarify and explain the application of these cGMP requirements when
these drugs, devices, biological products, and HCT[sol]Ps 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 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 Practice for Combination
Products.'' The agency received 15 comments, which were largely
supportive of the regulatory approach described in the draft guidance.
The agency has carefully reviewed these comments and has addressed many
of them in the proposed rule. 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 demand
unnecessary redundancy in the operating systems 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 has determined that rulemaking is warranted. FDA
believes that rulemaking will best help ensure 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. The rule is being proposed as part of FDA's ongoing
effort to improve the consistency and appropriateness of the regulatory
requirements for combination products.
    For certain types of combination products, the application of
current good manufacturing practice 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 combination
product consists of constituent parts that are packaged separately and
intended for use only with another approved or investigational,
individually specified drug, device, or biological product, as defined
in

Sec.  3.2(e)(3) and (e)(4). This is because these constituent parts,
while part of a combination product, are separately manufactured and
packaged. Accordingly, they remain separate for purposes of applying
the cGMP regulations.
    Thus, for example, if a combination product were to include a
separately manufactured and packaged drug constituent part, the
manufacture of that constituent part would be subject to the cGMP
regulations for drugs at parts 210 and 211 (21 CFR parts 210 and 211)
(drug cGMPs). Similarly, if a combination product were to include a
separately manufactured and packaged device constituent part, the
manufacture of that constituent part would be subject to the quality
system (QS) regulation for devices at part 820 (21 CFR part 820).
Likewise, a drug, device, or biological constituent part of a
combination product that is separately packaged for investigational use
as defined in Sec.  3.2(e)(4) is subject to the cGMP requirements that
apply to either an investigational drug, device, or biological product,
respectively. For example, an investigational drug that was labeled for
use with a separately marketed device would be subject to the cGMP
requirements that apply to investigational drugs under section
501(a)(2)(B) of the act and part 211.
    Section 4.3 of the proposed rule would identify the cGMP
regulations that apply to the constituent parts of a combination
product, regardless of whether the product is a combination product
under Sec.  3.2(e)(1), (e)(2), (e)(3), or (e)(4). Since each
constituent part of a combination product as defined in Sec.  3.2(e)(3)
and (e)(4) is subject only to the cGMP requirements that would
otherwise apply to that constituent part, the agency sees no need to
elaborate upon the practical application of cGMP requirements for these
two types of combination products. The proposed rule would expressly
address, however, the practical application of cGMP requirements to
single-entity and co-packaged combination products as defined at Sec.
3.2(e)(1) and (e)(2).
    The proposed rule recognizes 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, the agency believes that compliance
with either the drug cGMPs or the QS regulation will satisfy most of
the cGMP requirements applicable to either a drug or a device
constituent part. The agency has reviewed the drug cGMPs and QS
regulation and identified those specific provisions from each that a
firm would need to satisfy in addition to complying with the other of
these two sets of cGMP regulations.
    Accordingly, the proposed rule at Sec.  4.4(b) would offer two
options for demonstrating compliance with the cGMP requirements
applicable to each of the constituent parts in a co-packaged or single-
entity combination product. These options would be either: (1) To
demonstrate compliance with the specifics of all cGMP regulations
applicable to each of the constituent parts included in the combination
product containing, 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 include demonstrating compliance with
specified provisions for the other of these two sets of requirements,
and with all other cGMP requirements applicable to the constituent
parts (i.e., in parts 600 through 680 (21 CFR parts 600 through 680)
for biological products or in part 1271 (21 CFR part 1271) for
HCT[sol]Ps).
    The proposed rule would 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 would
permit practical streamlining by providing options for demonstrating
compliance with cGMP requirements for these types of combination
products. This proposed approach would help ensure appropriate
implementation of these requirements while avoiding unnecessary
redundancy in cGMP operating systems for these products. The proposed
rule would also help ensure that the cGMP operating systems for these
types of combination products are appropriately tailored both to the
specific constituent parts included in the combination product and to
the specific manufacturing processes being used.
    FDA recognizes that timely, comprehensive guidance and training is
important to help ensure consistent and appropriate implementation of
any final rule that may issue based upon this proposed rule. FDA
intends to issue such guidance to industry on the implementation of the
regulatory requirements for use of a streamlined cGMP operating system
for single-entity and co-packaged combination products. FDA invites
comments on particular areas of guidance that would be most helpful in
designing and implementing a cGMP operating system in accordance with
the proposed rule.

II. Description of the Proposed Rule

    FDA proposes to create 21 CFR part 4, subpart A, to codify the cGMP
requirements that apply to combination products.\4\
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    \4\ As described in the Department of Health and Human Services
(DHHS) Unified Agenda, 72 FR 22490 (April 30, 2007), FDA also plans
to propose regulations on postmarketing safety reporting for
combination products. FDA proposes to codify those requirements in
21 CFR part 4, subpart B.
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A. General Principles

    A combination product is comprised of constituent parts, i.e.,
drug(s), device(s), and/or biological product(s) (21 U.S.C. 353(g)(1);
see also Sec.  3.2(e)). These drug, device, and/or biological product
constituent parts retain their regulatory identity as a drug, device
and/or biological product when they are combined to create a
combination product. Accordingly, when combined to create a combination
product, each of the constituent parts remains subject to its
respective cGMP requirements.
    Under proposed Sec.  4.3, the cGMP requirements in parts 210 and
211 would apply to combination products that include a drug, and those
in part 820 would apply to combination products that include a device.
All biological constituent parts of combination products meet the
definition for device or drug in the act, and all HCT[sol]Ps included
as constituent parts of combination products are regulated as drugs,
devices, and/or biological products (see section C below). Accordingly,
all constituent parts of a combination product would be subject either
to the drug cGMPs or QS regulation. In addition, if a constituent part
of a combination product is also a biological product, the cGMP
requirements in part 606 for blood and blood components, and among the
requirements (standards) for biological products in other sections of
parts 600 through 680 would be applicable.\5\ Similarly, if a
constituent part is also an HCT[sol]P, the current good

tissue practice requirements in part 1271 would be applicable.
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    \5\ See Sec. Sec.  210.1(c), 820.1(a), and 1271.45(a). For the
purposes of this proposed rule, FDA uses the term ``current good
manufacturing practice requirements'' to include all such
requirements found in the standards in parts 600 through 680 that
may apply to combination products. See Sec.  211.1(b). FDA notes
that many of the requirements in parts 600 through 680 are not
considered cGMP requirements and are not covered by this proposed
rule. In addition, FDA notes that biological products must comply
with all applicable requirements in parts 600 through 680.
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B. CGMP Requirements for Single-Entity and Co-Packaged Combination
Products

    For single-entity and co-packaged combination products, the
proposed rule would allow firms to demonstrate compliance with cGMP
requirements by implementing and complying with either the drug cGMPs
or the QS regulation, rather than both, under certain conditions. These
conditions include demonstrating that the cGMP operating system
complies with specified provisions from the other of these two sets of
regulations. In addition, this operating system would have to be shown
to comply with all other cGMP regulations applicable to the constituent
parts (i.e., in parts 600 through 680 for biological products or in
part 1271 for HCT[sol]Ps).
    More specifically, if a single-entity or co-packaged combination
product includes both a drug and a device and the cGMP operating system
is shown to comply with the drug cGMP regulations at 21 CFR parts 210
and 211, the system would also have to be shown to comply with the
following specific provisions of the QS regulation, as described in
proposed Sec.  4.4(b)(1):
    1. Sec.  820.20. Management responsibility.
    2. Sec.  820.30. Design controls.
    3. Sec.  820.50. Purchasing controls.
    4. Sec.  820.100. Corrective and preventive action.
    5. Sec.  820.170. Installation.
    6. Sec.  820.200. Servicing.
    In this instance, if a firm demonstrates compliance with the drug
cGMP regulations at parts 210 and 211 and the specific QS regulation
provisions listed above, it would also be considered to be in
compliance with all other provisions of the QS regulation. The firm
would not have to demonstrate compliance with the other provisions of
the QS regulation.
    If a single-entity or co-packaged combination product includes both
a drug and a device and the cGMP operating system is shown to comply
with the QS regulation requirements at part 820, the system would also
have to be shown to comply with the following specific provisions of
the drug cGMP regulations, as described in proposed Sec.  4.4(b)(2):
    1. Sec.  211.84. Testing and approval or rejection of components,
drug product containers, and closures.
    2. Sec.  211.103. Calculation of yield.
    3. Sec.  211.132. Tamper-evident packaging for over-the-counter
(OTC) human drug products.
    4. Sec.  211.137. Expiration dating.
    5. Sec.  211.165. Testing and release for distribution.
    6. Sec.  211.166. Stability testing.
    7. Sec.  211.167. Special testing requirements.
    8. Sec.  211.170. Reserve samples.
    In this instance, if a firm demonstrates compliance with the QS
regulation at part 820 and the specific drug cGMP regulation provisions
listed above, it would also be considered to be in compliance with all
other provisions of the drug cGMP regulations. The firm would not have
to demonstrate compliance with the other provisions of the drug cGMPs.
    Furthermore, if the combination product includes a biological
product constituent part, in addition to demonstrating compliance with
either the drug cGMPs or the device QS regulation, along with the
specified provisions of the other of these two sets of regulations if
applicable, the cGMP operating system would also have to be shown to
comply with all additional cGMP requirements that apply to that
constituent part as a biological product (see parts 600 through 680).
Similarly, if the combination product includes an HCT[sol]P constituent
part, it would also have to be shown to comply with the requirements of
part 1271. For those combination products that contain biological
products and/or HCT[sol]Ps, the proposed rule would impose no
additional burdens and, in many cases, would offer the option of
streamlining related to the drug cGMPs and the device QS regulation.
    The applicability of the specific provisions identified in proposed
Sec.  4.4(b) would, as is the case with all cGMP regulations, depend
upon the characteristics of the constituent part and the type of
manufacturing activity performed. For example, if a manufacturer makes
an OTC combination product that includes a drug constituent part, it
would need to comply with the specific tamper-evident packaging
requirements of Sec.  211.132. A manufacturer who makes a prescription
combination product would not need to comply with that provision. To
take another example, if a manufacturer makes a product that has
hardware requiring installation and/or servicing, it would need to
comply with the installation and/or servicing provisions at Sec. Sec.
820.170 and 820.200, respectively. Similarly, the scope, specificity,
and complexity of the requirements will vary depending on the type of
activity performed. For example, the cGMP requirements for firms that
repackage articles into certain ``convenience'' kits or package a drug
with a disposable delivery device will generally be less demanding than
the more extensive requirements associated with the manufacture of some
other combination products, such as drug-coated devices.
    The streamlined option provides for the potential to incorporate
specific requirements from the drug cGMPs into the framework of a QS
operating system, and vice versa. These additional, specific
requirements should be incorporated where most appropriate into the
operating system.
    Both the QS and drug cGMP regulations require that procedures be
written to assure that the products being manufactured, processed, and
held meet cGMP requirements. Accordingly, the written procedures for a
streamlined system would have to assure that the firm could demonstrate
compliance with the cGMP requirements specified in the proposed rule.
    In addition to reducing duplicative documentation that would
otherwise be required if multiple sets of cGMP regulations were
implemented independently, this approach to documentation of the
procedures would help facilitate cGMP inspections, by setting forth how
the cGMP requirements for combination products are being met and how
this is being demonstrated in accordance with the streamlined approach.

C. Requirements for a Combination Product That Includes an HCT[sol]P

    Questions have been raised by stakeholders concerning the
application of cGMP requirements to HCT[sol]Ps that are constituent
parts of combination products. The HCT[sol]P regulation at part 1271
distinguishes between HCT[sol]Ps regulated solely under section 361 of
the PHS Act (42 U.S.C. 264), and those that are regulated as drugs,
devices, and biological products under the PHS Act and/or the act. The
HCT[sol]P regulation provides, among other things, that an HCT[sol]P
that is combined with another article (other than water, crystalloids,
or a sterilizing, preserving, or storage agent) does not meet the
criteria for regulation solely under section 361 of the PHS Act, but
rather would be regulated under the PHS Act and/or the act as a drug,
device, and/or biological product. (See Sec. Sec.  1271.10 and
1271.20). Thus, by operation of the HCT[sol]P regulation, an HCT[sol]P
that is a constituent part of a combination product will be regulated
as a drug, device, and/or biological product. Further, because all
biological product constituent parts meet the definition of drug or
device, all HCT[sol]P constituent parts of a combination product
regulated as a biological product also meet the definition of drug or
device.

    Therefore, if a combination product includes an HCT[sol]P
constituent part, in addition to whatever other cGMP requirements may
apply due to the other constituent parts of the combination product,
these cGMP requirements would apply:
     Part 1271;\6\
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    \6\ See Sec. Sec.  210.1(c), 210.2, 211.1(b), 820.1(a), and
1271.1(b)(2).
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     Either the drug cGMPs or the QS regulation; and
     If the HCT[sol]P is regulated as a biological product,
whichever biological product cGMP requirements apply, as specified in
parts 600 through 680.
    As indicated in section II.B of this document, a firm could choose
the streamlining option in proposed Sec.  4.4(b), as applicable, with
respect to the drug and device cGMP requirements for combination
products containing HCT[sol]Ps.

D. What Requirements Apply to the Constituent Parts of a Combination
Product Before They Are Combined, or Packaged Together?

    FDA recognizes that the manufacture of a single-entity or co-
packaged combination product is a complex process. The firm or firms
participating in the production process may manufacture, receive,
store, or otherwise handle the constituent parts of the combination
product at various facilities, including the facility at which the
constituent parts are combined to make the single-entity or co-packaged
combination product. The fact that many firms and/or facilities may be
involved raises questions about whether and when the proposed
streamlined approach to cGMP operating systems could be used. Proposed
Sec.  4.4(c) would make clear that when manufacturing of a constituent
part does not occur at the same facility as another type of constituent
part, the operating system must be shown to comply with all of the cGMP
regulations applicable to that constituent part. Proposed Sec.  4.4(d)
would provide that when two or more types of constituent parts are in
the same facility, the streamlined approach may be used. However,
proposed Sec.  4.4(d) also clarifies that whenever manufacture of a
constituent part occurs at a separate facility from all other types of
constituent parts, the manufacture of that part must occur under the
regulations applicable to that part.
    Following are some examples to illustrate the situations in which
the proposed streamlined approach could or could not be used.
    Example 1: Drug and device constituent parts are manufactured at
two different facilities. Then a third facility combines the
constituent parts into a single-entity or co-packaged combination
product. Before the constituent parts of a single-entity or co-packaged
combination product are in the same facility for incorporation into the
combination product, the manufacturing processes for the constituent
parts at their separate facilities are distinct. Accordingly, under
proposed Sec.  4.4(c), each of these separate facilities must maintain
a separate cGMP operating system and demonstrate compliance with the
cGMP regulations applicable to that type of constituent part (for
example, drug cGMPs if the constituent part is a drug). Once the
constituent parts are brought to the third facility, the streamlined
approach could be used.
    Example 2: The constituent parts are manufactured in the same
facility, and are then sent to another facility to be combined into a
single-entity or co-packaged combination product.
    The streamlined approach could be used for the manufacture in both
facilities. Proposed Sec.  4.4(d) addresses this situation.
    Example 3: Facility 1 manufactures a drug constituent part.
Facility 2 manufactures a device constituent part. The drug constituent
part is shipped to facility 2. Then both the drug constituent part and
the device constituent part are shipped from facility 2 to facility 3.
Facility 3 combines the constituent parts into a single-entity or co-
packaged combination product.
    In this situation, manufacture of the drug constituent part at
facility 1 must be shown to comply with the drug cGMP regulations.
Manufacture of the device at facility 2 must be shown to comply with
the device QS regulation. Proposed Sec.  4.4(c) would make this clear.
    For the drug constituent part while it is at facility 2, the
streamlined approach could be used. That is, the QS operating system at
facility 2 could be supplemented by the applicable, additional drug
cGMP provisions specified in proposed Sec.  4.4(b). Proposed Sec.
4.4(d) addresses this situation. Facility 3 could use the streamlined
approach by demonstrating compliance with either the drug cGMPs or the
QS regulation as the cGMP operating system, supplemented by the
particular provisions from the other (drug or device) regulations
specified in proposed Sec.  4.4(b). Proposed Sec.  4.4(d) also
addresses this situation.

E. Inspection and Enforcement

    For purposes of enforcing the act, section 704 of the act provides
that FDA can enter any factory, warehouse, or establishment in which
drugs and devices are manufactured, processed, packed, or held, for
introduction into interstate commerce or after such introduction, to
enter any vehicle being used to transport or hold drugs or devices in
interstate commerce, and to inspect such factory, warehouse,
establishment, or vehicle and all pertinent equipment, finished and
unfinished materials, containers, and labeling therein. This inspection
extends to all records and all things bearing on whether the drugs or
devices are adulterated.
    In the case of combination products, if a firm chooses to use the
streamlined approach outlined in the proposed rule at Sec.  4.4(b) by
implementing the drug cGMPs supplemented by compliance with the
provisions of the QS regulation specified in proposed Sec.  4.4(b)(1),
the FDA inspection would focus on compliance with the drug cGMPs and
the specified QS provisions. If the firm complies with the drug cGMPs
and the specified QS provisions, the firm would be considered to be in
compliance with the other provisions of the QS regulation. Likewise, if
the operating system satisfies the QS regulation and the drug cGMP
provisions proposed at Sec.  4.4(b)(2) are also satisfied, a firm would
be considered to be in compliance with all other drug cGMP provisions.

III. Legal Authority

    The agency derives its authority to issue the regulations in
proposed 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 501(h) of the act (21 U.S.C. 351(a)(2)(B) and 351(h)) require drugs
and devices to be manufactured in accordance with cGMPs. Section 520(f)
of the act (21 U.S.C. 360j(f)) specifically authorizes the issuance of
cGMP regulations for devices.
    Section 501 of the act (21 U.S.C. 351) states that a drug or device
is deemed adulterated if it is not manufactured in accordance with
cGMPs. This provision also applies to biological products that are
constituent parts of combination products because these products meet
the definition of drug or device under section 201 of the act (21
U.S.C. 321). This provision also applies to HCT[sol]Ps that are
constituent parts of combination products because the HCT[sol]P
regulation

provides, among other things, that an HCT[sol]P that is combined with
another article (other than water, crystalloids, or a sterilizing,
preserving, or storage agent) is regulated under the PHS Act and/or the
act as a drug, device, and/or biological product (see Sec. Sec.
1271.10 and 1271.20). 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 (42 U.S.C. 264)
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, and biological
products that may be included as constituent parts of 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.
     cGMP regulations specific to certain types of biological
products and/or HCT[sol]Ps set forth at parts 600 through 680 and 1271.
    There is considerable overlap in the drug cGMPs and QS regulation,
and for the most part the overlap is apparent. For example, both
establish requirements for management, organization, and personnel;
both require documentation and record keeping; 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. For instance, 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 corrective and preventive action (CAPA)
requirements (Sec.  820.100) while CAPA principles are more generally
addressed in the cGMP regulation as part of Production Record Review
(Sec.  211.192).
    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. 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. This proposed rule is intended to clarify the applicability of
these requirements to combination products and to provide 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 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
the other set (e.g., QS regulation).
    Although combination products retain the regulatory identities of
their constituent parts, the 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 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 of
the 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 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 act (21
U.S.C. 371), which authorizes FDA to issue regulations for the
efficient enforcement of the 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. 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.

V. Paperwork Reduction Act of 1995

    We note that the information collected under the underlying cGMP
regulations for drugs, devices, and biological products, including
HCT[sol]Ps, found at parts 211, 820, 600 through 680, and 1271 have
already been approved and are in effect. The currently approved burden
estimates are available in the following links. The provisions of part
211 are approved under OMB control number 0910-0139, which expires
November 30, 2011 (http://www.reginfo.gov/public/do/PRAViewICR?ref_
nbr=200809-0910-008). The provisions of part 820 are approved under OMB
control number 0910-0073, which expires on November 30, 2010 (http://
www.reginfo.gov/public/do/PRAViewICR?ref_nbr=200709-0910-006). The
provisions of parts 606, 640, and 660 are approved under OMB control
number 0910-0116, which expires February 29, 2012 (http://
www.reginfo.gov/public/do/PRAViewICR?ref_nbr=200811-0910-006). The
provisions of part 610 are approved under OMB control number 0910-0116,
which expires February 29, 2012, (link already provided in this
paragraph) and OMB control number 0910-0338, which expires on June 10,
2010 (also for part 680) (http://www.reginfo.gov/public/do/
PRAViewICR?ref_nbr=200703-0910-017). The provisions of part 1271,
subparts C and D, are approved under OMB control number 0910-0543,
which expires on May 31, 2010 (http://www.reginfo.gov/public/do/
PRAViewICR?ref_nbr=200705-0910-001). To obtain more detailed, itemized
estimates of the burden associated with particular regulatory
provisions, please click on the link called ``View Supporting Statement
and Other Documents'' from any of the Reginfo.gov links provided in
this paragraph. (FDA has verified the Web site addresses, but FDA is
not responsible for any subsequent changes to the Web sites after this
document publishes in the Federal Register.)
    We do not believe that this proposal would constitute an additional
paperwork burden because firms must currently comply with the cGMP
regulations addressed by this proposed

rule: In fact, our intent is to minimize burden on respondents by
providing a more streamlined approach. Therefore, burden associated
with complying with these cGMP regulations represents the maximum
burden for compliance with this proposed rule. We invite comment on how
many firms might avail themselves of the streamlined approach presented
in this proposed rule for co-packaged and single-entity combination
products and on what the reduction in paperwork burden would be.

VI. Federalism

    FDA has analyzed this proposed rule in accordance with the
principles set forth in Executive Order 13132. Section 4(a) of the
Executive order requires agencies to ``construe * * * a Federal statute
to preempt State law only where the statute contains an express
preemption provision or there is some other clear evidence that the
Congress intended preemption of State law, or where the exercise of
State authority conflicts with the exercise of Federal authority under
the Federal statute.'' The sole statutory provision giving preemptive
effect to the proposed rule is section 751 of the act (21 U.S.C. 379r),
which would apply only with respect to OTC drug components of
combination.\7\
---------------------------------------------------------------------------

    \7\ The proposed rule seeks to clarify which cGMP requirements
apply when drugs, devices, and biological products are used to
create combination products. The agency notes that there are no
express preemption provisions of the act applicable to prescription
drugs or biological products. Section 521 of the act (21 U.S.C.
360k) contains an express preemption provision that applies to
devices; nonetheless, the Supreme Court concluded in Medtronic, Inc.
v. Lohr, 581 U.S. 470, 500-01 (1996), that requirements not
applicable to a particular device (such as the device good
manufacturing practice requirements at issue in this proposed rule)
do not preempt State law under section 521 of the act.
---------------------------------------------------------------------------

VII. Analysis of Impacts

A. Introduction

    FDA has examined the impacts of the proposed rule under Executive
Order 12866 and the Regulatory Flexibility Act (5 U.S.C. 601-612), and
the Unfunded Mandates Reform Act of 1995 (Public Law 104-4). Executive
Order 12866 directs 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). The agency believes that
this proposed rule is not a significant regulatory action as defined by
the Executive order.
    The Regulatory Flexibility Act requires agencies to analyze
regulatory options that would minimize any significant impact of a rule
on small entities. Because this proposed rule explains how requirements
that are currently in effect apply to combination products, the agency
does not believe that this proposed rule would have a significant
economic impact on a substantial number of small entities. FDA requests
comment on this issue.
    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 $130 million, using the most current (2007) Implicit
Price Deflator for the Gross Domestic Product. FDA does not expect this
proposed rule to result in any 1-year expenditure that would meet or
exceed this amount.

B. The Rationale Behind the Proposed Rule

    The proposed 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. Second, the proposed rule
attempts to streamline the practical implementation of cGMP
requirements for co-packaged and single-entity combination products.

C. Impact of Proposed Rule

    FDA estimates that approximately 300 manufacturers of combination
products will be affected by the proposed rule. These manufacturers of
combination products should benefit from the greater clarity provided
regarding which regulatory provisions apply to their products. For both
existing and future products, the streamlined approach set forth in the
proposed rule would help ensure that cGMPs 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 would 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 HCT[sol]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
proposed rule would be the incremental costs to modify or streamline
existing SOPs. We do not know how many firms may choose to use the
proposed streamlined approach for single-entity and co-packaged
combination products, or for how many products; nor do we know how many
firms are already using such an approach in light of the draft
guidance.
    Some firms may incur one-time incremental costs assessing
compliance with the proposed rule and perhaps altering some standard
operating procedures. Because this proposed 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. This
estimate is based on numbers we have used in previous rules with
similar requirements. 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). The
agency requests comment on the incremental burden estimate associated
with this rule.

VIII. Request for Comments

    Interested persons may submit to the Division of Dockets Management
(see ADDRESSES) written or electronic comments regarding this proposed
rule. Submit a single copy of electronic comments or two paper copies
of any mailed comments, except that individuals may submit one paper
copy. Comments are to be identified with the docket number found in
brackets in the heading of this document. Received comments may be seen
in the Division of Dockets Management between 9 a.m. and 4 p.m., Monday
through Friday.

IX. Proposed Effective Date

    The agency is proposing that any final rule that may issue based
upon this proposed rule become effective 180 days after its date of
publication in the Federal Register.

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, it is proposed that 21 CFR part 4 be
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 product.

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.
    Act means the Federal Food, Drug, and Cosmetic Act.
    Agency means the Food and Drug Administration.
    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 Sec.  4.2.
    Combination product has the meaning set forth in Sec.  3.2(e) of
this chapter.
    Constituent part is a drug, device, or biological product,
including an HCT[sol]P, that is part of a combination product as
defined in Sec.  3.2(e) of this chapter.
    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 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.
    FDA means the Food and Drug Administration.
    HCT[sol]Ps refers to human cell, tissue, and cellular and tissue-
based products, as defined in Sec.  1271.3(d) of this chapter.
    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, a drug, or an
HCT[sol]P, as these terms are defined under this Sec.  4.2.

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

    If you manufacture a combination product, the current good
manufacturing practice 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 in part
606 of this chapter for blood and blood components and among the
requirements (standards) for biological products in other sections of
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 and donor eligibility
requirements for HCT[sol]Ps in part 1271 of this chapter apply to a
combination product that includes an HCT[sol]P constituent part to
which those requirements would apply if that constituent part were not
part of a combination product.

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) Sec.  820.20 of this chapter. Management responsibility.

    (ii) Sec.  820.30 of this chapter. Design controls.
    (iii) Sec.  820.50 of this chapter. Purchasing controls.
    (iv) Sec.  820.100 of this chapter. Corrective and preventive
action.
    (v) Sec.  820.170 of this chapter. Installation.
    (vi) Sec.  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) Sec.  211.84 of this chapter. Testing and approval or rejection
of components, drug product containers, and closures.
    (ii) Sec.  211.103 of this chapter. Calculation of yield.
    (iii) Sec.  211.132 of this chapter. Tamper-evident packaging
requirements for over-the-counter (OTC) human drug products.
    (iv) Sec.  211.137 of this chapter. Expiration dating.
    (v) Sec.  211.165 of this chapter. Testing and release for
distribution.
    (vi) Sec.  211.166. of this chapter. Stability testing.
    (vii) Sec.  211.167 of this chapter. Special testing requirements.
    (viii) Sec.  211.170 of this chapter. Reserve samples.
    (3) 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 a biological product
constituent part, the current good manufacturing practice operation
system must also be shown to implement and comply with all current good
manufacturing practice 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[sol]P, the current good
manufacturing practice operation system must also be shown to implement
and comply with all current good manufacturing practice requirements
identified under Sec.  4.3(d) that would apply to that HCT[sol]P
constituent part if that constituent part 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 type(s) of
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 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 Sec.  4.4(b)
may begin, except with respect to any constituent part that remains or
becomes subject to Sec.  4.4(c).
    (e) The current good manufacturing practice requirements set forth
in this subpart and in parts 210, 211, 600 through 680, 820, and 1271
of this chapter, 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: September 17, 2009.
David Horowitz,
Assistant Commissioner for Policy.
[FR Doc. E9-22850 Filed 9-22-09; 8:45 am]

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