[Federal Register Volume 74, Number 183 (Wednesday, September 23, 2009)]
[Proposed Rules]
[Pages 48423-48431]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: E9-22850]


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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:
    <bullet> Federal eRulemaking Portal: http://www.regulations.gov. 
Follow the instructions for submitting comments.
Written Submissions
    Submit written submissions in the following ways:
    <bullet> FAX: 301-827-6870.
    <bullet> 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-

[[Page 48424]]

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, 301-427-1934.

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

[[Page 48425]]

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

[[Page 48426]]

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.

[[Page 48427]]

    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:
    <bullet> 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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    <bullet> Either the drug cGMPs or the QS regulation; and
    <bullet> 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

[[Page 48428]]

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:
    <bullet> 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.
    <bullet> QS regulation for devices set forth at part 820.
    <bullet> 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

[[Page 48429]]

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.

[[Page 48430]]

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.

[[Page 48431]]

    (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]
BILLING CODE 4160-01-S