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                                                    Proposed Rules                                                                                                Federal Register
                                                                                                                                                                  Vol. 74, No. 183

                                                                                                                                                                  Wednesday, September 23, 2009

                                                    This section of the FEDERAL REGISTER                    Branch, Fruit and Vegetable Programs,                 DEPARTMENT OF HEALTH AND
                                                    contains notices to the public of the proposed          Northwest Marketing Field Office, AMS,                HUMAN SERVICES
                                                    issuance of rules and regulations. The                  USDA, 1220 SW. Third Avenue, Room
                                                    purpose of these notices is to give interested                                                                Food and Drug Administration
                                                                                                            385, Portland, OR 97204; Telephone:
                                                    persons an opportunity to participate in the
                                                    rule making prior to the adoption of the final          (503) 326–2724, Fax: (503) 326–7440, or
                                                                                                            e-mail: Melissa.Schmaedick                            21 CFR Part 4
                                                                                                                                          [Docket No. FDA–2008–D–0409]

                                                    DEPARTMENT OF AGRICULTURE                               SUPPLEMENTARY INFORMATION:                            Current Good Manufacturing Practice
                                                                                                              Prior documents in this proceeding:                 Requirements for Combination
                                                    Agricultural Marketing Service                          Notice of Hearing issued August 31,                   Products
                                                                                                            2009; published September 3, 2009 (74                 AGENCY:    Food and Drug Administration,
                                                    7 CFR Part 970                                          FR 45565).                                            HHS.
                                                    [Docket No. AO–FV–09–0138; AMS–FV–09–                     Notice is hereby given that the                     ACTION:   Proposed rule.
                                                    0029; FV09–970–1E]
                                                                                                            scheduled hearing date for the
                                                                                                            Monterey, California session of a public              SUMMARY: The Food and Drug
                                                    Leafy Green Vegetables Handled in the
                                                                                                            hearing to consider a proposed                        Administration (FDA or agency)
                                                    United States; Extension of Time for
                                                                                                            marketing agreement for the handling of               proposes to codify the current good
                                                    First Session of Hearing on Proposed
                                                                                                            leafy green vegetables in the United                  manufacturing practice (cGMP)
                                                    Marketing Agreement No. 970
                                                                                                            States may be extended by one day, if                 requirements applicable to combination
                                                    AGENCY: Agricultural Marketing Service,                 deemed necessary by the presiding                     products. This proposed rule is
                                                    USDA.                                                   administrative law judge.                             intended to promote the public health
                                                    ACTION: Proposed rule; notice of                                                                              by clarifying which cGMP requirements
                                                                                                              The Department of Agriculture                       apply when drugs, devices, and
                                                    additional time for public hearing on
                                                    proposed national marketing agreement                   (USDA) previously announced a hearing                 biological products are combined to
                                                    for leafy green vegetables.                             to consider a proposed marketing                      create a combination product. In
                                                                                                            agreement for the handling of leafy                   addition, the proposed rule sets forth a
                                                    SUMMARY: This notice announces that                     green produce in the United States.                   transparent and streamlined regulatory
                                                    the scheduled hearing date for the                      Hearing dates have been scheduled for                 framework for firms to use when
                                                    Monterey, California session of a public                various locations throughout the United               demonstrating compliance with cGMP
                                                    hearing to consider a proposed                          States, including Monterey, California.               requirements for ‘‘single-entity’’ and
                                                    marketing agreement for the handling of                 However, an additional day may be                     ‘‘co-packaged’’ combination products.
                                                    leafy green vegetables in the United                    required to receive testimony and                     DATES: Submit written or electronic
                                                    States may be extended by one day, if                   evidence in Monterey. This notice                     comments on this proposed rule by
                                                    deemed necessary by the presiding                       announces the addition of September                   December 22, 2009. See section IX of
                                                    administrative law judge.                               25, 2009 to the first session, if deemed              this document for the proposed effective
                                                    DATES: The Monterey, California session                 necessary by the presiding                            date of a final rule based on this
                                                    for the public hearing is currently                     administrative law judge.                             document.
                                                    scheduled for September 22 through 24,
                                                                                                              Information regarding the hearing and               ADDRESSES: You may submit comments,
                                                    2009. This hearing session may be
                                                                                                            the proposed marketing agreement is                   identified by Docket No. FDA–2008–D–
                                                    extended by an additional day,
                                                                                                            contained in the Notice of Hearing,                   0409 (formerly Docket No. 2004D–
                                                    September 25, 2009, if deemed
                                                                                                            which may be viewed at: http://                       0431), by any of the following methods:
                                                    necessary. As with the other scheduled
                                                                                                                        Electronic Submissions
                                                    sessions, this session would begin at                                                                           Submit electronic comments in the
                                                    8:30 a.m. and conclude at 5 p.m., or any                home.html#documentDetail?R=
                                                                                                            0900006480a1c313.                                     following way:
                                                    other time as determined by the                                                                                 • Federal eRulemaking Portal: http://
                                                    presiding administrative law judge.                     List of Subjects in 7 CFR Part 970           Follow the
                                                    ADDRESSES: The hearing location in                                                                            instructions for submitting comments.
                                                    Monterey is: Hyatt Regency Monterey, 1                    Marketing agreements, Reporting and                 Written Submissions
                                                    Old Golf Course Road, Monterey,                         recordkeeping requirements, Vegetables.                 Submit written submissions in the
                                                    California, (831) 372–1234.                               Authority: U.S.C. 601–674.                          following ways:
                                                    FOR FURTHER INFORMATION CONTACT:                                                                                • FAX: 301–827–6870.
                                                                                                              Dated: September 18, 2009.
                                                    Antoinette Carter, Marketing Order                                                                              • Mail/Hand delivery/Courier (for
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                                                    Administration Branch, Fruit and                        Rayne Pegg,                                           paper, disk, or CD–ROM submissions):
                                                    Vegetable Programs, AMS, USDA, 1400                     Administrator, Agricultural Marketing                 Division of Dockets Management (HFA–
                                                    Independence Avenue, SW., Stop 0237,                    Service.                                              305), Food and Drug Administration,
                                                    Washington, DC 20250–0237;                              [FR Doc. E9–22992 Filed 9–21–09; 11:15 am]            5630 Fishers Lane, rm. 1061, Rockville,
                                                    Telephone: (202) 720–2491, Fax: (202)                   BILLING CODE 3410–02–P                                MD 20852.
                                                    720–8938, or e-mail: Antoinette.Carter                                                                          To ensure more timely processing of
                                          ; or Melissa Schmaedick,                                                                         comments, FDA is no longer accepting
                                                    Marketing Order Administration                                                                                comments submitted to the agency by e-

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                                                    48424             Federal Register / Vol. 74, No. 183 / Wednesday, September 23, 2009 / Proposed Rules

                                                    mail. FDA encourages you to continue                    according to its investigational plan or                HCT/Ps, there are currently no
                                                    to submit electronic comments by using                  proposed labeling is intended for use                   regulations that clarify and explain the
                                                    the Federal eRulemaking Portal, as                      only with an approved individually                      application of these cGMP requirements
                                                    described previously, in the ADDRESSES                  specified drug, device, or biological                   when these drugs, devices, biological
                                                    portion of this document under                          product where both are required to                      products, and HCT/Ps are constituent
                                                    Electronic Submissions.                                 achieve the intended use, indication, or                parts of a combination product.
                                                       Instructions: All submissions received               effect and where upon approval of the                      FDA believes that the absence of clear
                                                    must include the agency name and                        proposed product the labeling of the                    cGMP requirements for combination
                                                    docket number for this rulemaking. All                  approved product would need to be                       products could result in inconsistent or
                                                    comments received may be posted                         changed, e.g., to reflect a change in                   differing application of the various
                                                    without change to http://                               intended use, dosage form, strength,                    cGMP requirements applicable to the
                                          , including any                      route of administration, or significant                 constituent parts, which could affect
                                                    personal information provided. For                      change in dose; or                                      product safety and the public health.
                                                    additional information on submitting                       4. Any investigational drug, device, or                 In the Federal Register of October 4,
                                                    comments, see the ‘‘Comments’’ heading                  biological product packaged separately                  2004 (69 FR 59239), the agency
                                                    of the SUPPLEMENTARY INFORMATION                        that according to its proposed labeling                 announced the availability of a Draft
                                                    section of this document.                               is for use only with another individually               Guidance for Industry and FDA entitled
                                                       Docket: For access to the docket to                  specified investigational drug, device, or              ‘‘Current Good Manufacturing Practice
                                                    read background documents or                            biological product where both are                       for Combination Products.’’ The agency
                                                    comments received, go to http://                        required to achieve the intended use,                   received 15 comments, which were
                                           and insert the                      indication, or effect.                                  largely supportive of the regulatory
                                                    docket number, found in brackets in the                    The Medical Device User Fee and                      approach described in the draft
                                                    heading of this document, into the                      Modernization Act of 2002 (MDUFMA)                      guidance. The agency has carefully
                                                    ‘‘Search’’ box and follow the prompts                   modified section 503(g) of the act) (21                 reviewed these comments and has
                                                    and/or go to the Division of Dockets                    U.S.C. 353(g)) to require the                           addressed many of them in the
                                                    Management, 5630 Fishers Lane, rm.                      establishment of an Office (Office of                   proposed rule. A common theme that
                                                    1061, Rockville, MD 20852.                              Combination Products (OCP)) within the                  emerged from these comments was the
                                                    FOR FURTHER INFORMATION CONTACT: John                   Office of the Commissioner of FDA. The                  need to develop a clear regulatory
                                                    Weiner, Office of Combination Products                  responsibilities of OCP include ensuring                framework that takes account of the fact
                                                    (HFG–3), Food and Drug                                  the prompt assignment of combination                    that combination products are made up
                                                    Administration, 15800 Crabbs Branch                     products to agency components, the                      of drug, device, and biological product
                                                    Way, suite 200, Rockville, MD 20855,                    timely and effective premarket review of                constituent parts. At the same time,
                                                    301–427–1934.                                           such products, and the consistent and                   commenters wanted to ensure that the
                                                                                                            appropriate postmarket regulation of                    framework would not demand
                                                    SUPPLEMENTARY INFORMATION:
                                                                                                            like products subject to the same                       unnecessary redundancy in the
                                                    I. Introduction                                         statutory requirements to the extent                    operating systems to meet cGMP
                                                       As set forth in part 3 (21 CFR Part 3),              permitted by law (21 U.S.C. 353(g)(4)).                 requirements (cGMP operating systems).
                                                                                                               Section 501 of the act (21 U.S.C. 351)                  After careful consideration of the
                                                    a combination product is a product
                                                                                                            states circumstances under which drugs                  comments, and of how best to ensure
                                                    comprised of any combination of a drug
                                                                                                            and devices (including biological                       that cGMPs for combination products
                                                    and a device; a device and a biological
                                                                                                            products, which by definition are also                  are consistent and appropriate, FDA has
                                                    product; a biological product and a
                                                                                                            drugs or devices, and including human                   determined that rulemaking is
                                                    drug; or a drug, a device, and a
                                                                                                            cellular and tissue-based products                      warranted. FDA believes that
                                                    biological product.1 Under § 3.2(e), a
                                                                                                            (HCT/Ps) that are regulated as drugs,                   rulemaking will best help ensure the
                                                    combination product includes:
                                                                                                            devices, and/or biological products) are                manufacture of safe and effective
                                                       1. A product comprised of two or
                                                                                                            deemed adulterated.2 Adulteration                       combination products, by providing a
                                                    more regulated components, i.e., drug/
                                                                                                            includes the failure to manufacture a                   clear and transparent regulatory
                                                    device, biologic/device, drug/biologic,
                                                                                                            product in accordance with applicable                   roadmap for the application of cGMP
                                                    or drug/device/biologic, that are
                                                                                                            cGMP requirements, regardless of                        requirements to these products. The rule
                                                    physically, chemically, or otherwise
                                                                                                            whether the product appears to meet its                 is being proposed as part of FDA’s
                                                    combined or mixed and produced as a
                                                                                                            final specifications.3                                  ongoing effort to improve the
                                                    single entity (single-entity combination
                                                                                                               The constituent parts of a                           consistency and appropriateness of the
                                                                                                            combination product retain their                        regulatory requirements for combination
                                                       2. Two or more separate products
                                                                                                            regulatory status (as a drug or device, for             products.
                                                    packaged together in a single package or
                                                                                                            example) even after they are combined.                     For certain types of combination
                                                    as a unit and comprised of drug and
                                                                                                            Accordingly, the cGMP requirements                      products, the application of current
                                                    device products, device and biological
                                                                                                            that apply to each of the constituent                   good manufacturing practice
                                                    products, or biological and drug
                                                                                                            parts continue to apply when they are                   requirements is fairly straightforward.
                                                    products (co-packaged combination
                                                                                                            combined to make combination                            Specifically, the constituent parts of a
                                                                                                            products. To date, however, the agency                  combination product are each subject
                                                       3. A drug, device, or biological
                                                                                                                                                                    only to the cGMP regulations applicable
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                                                    product packaged separately that                        has not issued specific regulations
                                                                                                            clarifying the applicability of the cGMP                to that type of constituent part (e.g.,
                                                       1 For purposes of part 3 and this proposed rule,     requirements to combination products.                   drug or device) if the combination
                                                    a ‘‘biological product’’ means a biological product     While cGMP regulations are in place                     product consists of constituent parts
                                                    subject to regulation under section 351 of the Public   that establish requirements for drugs,                  that are packaged separately and
                                                    Health Service Act (the PHS Act) (42 U.S.C. 262).                                                               intended for use only with another
                                                    All biological products regulated under the PHS Act
                                                                                                            devices, biological products, and
                                                    meet the definitions of drug or device in section 201
                                                                                                                                                                    approved or investigational,
                                                    of the Federal Food, Drug, and Cosmetic Act (the          2 See   also 21 U.S.C. 360j(f)(1).                    individually specified drug, device, or
                                                    act) (21 U.S.C. 321).                                     3 See,   generally, 21 U.S.C. 351(a)(2)(B) and (h).   biological product, as defined in

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                                                                      Federal Register / Vol. 74, No. 183 / Wednesday, September 23, 2009 / Proposed Rules                                                     48425

                                                    § 3.2(e)(3) and (e)(4). This is because                 regulation and identified those specific              areas of guidance that would be most
                                                    these constituent parts, while part of a                provisions from each that a firm would                helpful in designing and implementing
                                                    combination product, are separately                     need to satisfy in addition to complying              a cGMP operating system in accordance
                                                    manufactured and packaged.                              with the other of these two sets of cGMP              with the proposed rule.
                                                    Accordingly, they remain separate for                   regulations.
                                                    purposes of applying the cGMP                             Accordingly, the proposed rule at                   II. Description of the Proposed Rule
                                                    regulations.                                            § 4.4(b) would offer two options for
                                                                                                                                                                     FDA proposes to create 21 CFR part
                                                      Thus, for example, if a combination                   demonstrating compliance with the
                                                                                                                                                                  4, subpart A, to codify the cGMP
                                                    product were to include a separately                    cGMP requirements applicable to each
                                                    manufactured and packaged drug                          of the constituent parts in a co-packaged             requirements that apply to combination
                                                    constituent part, the manufacture of that               or single-entity combination product.                 products.4
                                                    constituent part would be subject to the                These options would be either: (1) To                 A. General Principles
                                                    cGMP regulations for drugs at parts 210                 demonstrate compliance with the
                                                    and 211 (21 CFR parts 210 and 211)                      specifics of all cGMP regulations                        A combination product is comprised
                                                    (drug cGMPs). Similarly, if a                           applicable to each of the constituent                 of constituent parts, i.e., drug(s),
                                                    combination product were to include a                   parts included in the combination                     device(s), and/or biological product(s)
                                                    separately manufactured and packaged                    product containing, or (2) to                         (21 U.S.C. 353(g)(1); see also § 3.2(e)).
                                                    device constituent part, the manufacture                demonstrate compliance with the                       These drug, device, and/or biological
                                                    of that constituent part would be subject               specifics of either the drug cGMPs or the             product constituent parts retain their
                                                    to the quality system (QS) regulation for               QS regulation, rather than both, when                 regulatory identity as a drug, device
                                                    devices at part 820 (21 CFR part 820).                  the combination contains both a drug                  and/or biological product when they are
                                                    Likewise, a drug, device, or biological                 and a device, under certain conditions.               combined to create a combination
                                                    constituent part of a combination                       These conditions include demonstrating                product. Accordingly, when combined
                                                    product that is separately packaged for                 compliance with specified provisions                  to create a combination product, each of
                                                    investigational use as defined in                       for the other of these two sets of                    the constituent parts remains subject to
                                                    § 3.2(e)(4) is subject to the cGMP                      requirements, and with all other cGMP                 its respective cGMP requirements.
                                                    requirements that apply to either an                    requirements applicable to the
                                                                                                                                                                     Under proposed § 4.3, the cGMP
                                                    investigational drug, device, or                        constituent parts (i.e., in parts 600
                                                                                                                                                                  requirements in parts 210 and 211
                                                    biological product, respectively. For                   through 680 (21 CFR parts 600 through
                                                                                                                                                                  would apply to combination products
                                                    example, an investigational drug that                   680) for biological products or in part
                                                                                                                                                                  that include a drug, and those in part
                                                    was labeled for use with a separately                   1271 (21 CFR part 1271) for HCT/Ps).
                                                    marketed device would be subject to the                   The proposed rule would help ensure                 820 would apply to combination
                                                    cGMP requirements that apply to                         that cGMP requirements that apply to                  products that include a device. All
                                                    investigational drugs under section                     single-entity and co-packaged                         biological constituent parts of
                                                    501(a)(2)(B) of the act and part 211.                   combination products are clear and                    combination products meet the
                                                      Section 4.3 of the proposed rule                      consistent, regardless of which agency                definition for device or drug in the act,
                                                    would identify the cGMP regulations                     component has lead jurisdiction for the               and all HCT/Ps included as constituent
                                                    that apply to the constituent parts of a                combination product, or which type of                 parts of combination products are
                                                    combination product, regardless of                      application is submitted for marketing                regulated as drugs, devices, and/or
                                                    whether the product is a combination                    authorization. The proposed rule would                biological products (see section C
                                                    product under § 3.2(e)(1), (e)(2), (e)(3),              permit practical streamlining by                      below). Accordingly, all constituent
                                                    or (e)(4). Since each constituent part of               providing options for demonstrating                   parts of a combination product would
                                                    a combination product as defined in                     compliance with cGMP requirements for                 be subject either to the drug cGMPs or
                                                    § 3.2(e)(3) and (e)(4) is subject only to               these types of combination products.                  QS regulation. In addition, if a
                                                    the cGMP requirements that would                        This proposed approach would help                     constituent part of a combination
                                                    otherwise apply to that constituent part,               ensure appropriate implementation of                  product is also a biological product, the
                                                    the agency sees no need to elaborate                    these requirements while avoiding                     cGMP requirements in part 606 for
                                                    upon the practical application of cGMP                  unnecessary redundancy in cGMP                        blood and blood components, and
                                                    requirements for these two types of                     operating systems for these products.                 among the requirements (standards) for
                                                    combination products. The proposed                      The proposed rule would also help                     biological products in other sections of
                                                    rule would expressly address, however,                  ensure that the cGMP operating systems                parts 600 through 680 would be
                                                    the practical application of cGMP                       for these types of combination products               applicable.5 Similarly, if a constituent
                                                    requirements to single-entity and co-                   are appropriately tailored both to the                part is also an HCT/P, the current good
                                                    packaged combination products as                        specific constituent parts included in
                                                    defined at § 3.2(e)(1) and (e)(2).                      the combination product and to the                       4 As described in the Department of Health and

                                                      The proposed rule recognizes that, in                 specific manufacturing processes being                Human Services (DHHS) Unified Agenda, 72 FR
                                                    most instances, for single-entity and co-               used.                                                 22490 (April 30, 2007), FDA also plans to propose
                                                    packaged combination products, a                          FDA recognizes that timely,                         regulations on postmarketing safety reporting for
                                                                                                                                                                  combination products. FDA proposes to codify
                                                    cGMP operating system that satisfies the                comprehensive guidance and training is                those requirements in 21 CFR part 4, subpart B.
                                                    cGMP regulations applicable to one                      important to help ensure consistent and                  5 See §§ 210.1(c), 820.1(a), and 1271.45(a). For the

                                                    constituent part will also satisfy most of              appropriate implementation of any final
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                                                                                                                                                                  purposes of this proposed rule, FDA uses the term
                                                    the cGMP requirements applicable to                     rule that may issue based upon this                   ‘‘current good manufacturing practice
                                                                                                                                                                  requirements’’ to include all such requirements
                                                    the other constituent part. In particular,              proposed rule. FDA intends to issue                   found in the standards in parts 600 through 680 that
                                                    the agency believes that compliance                     such guidance to industry on the                      may apply to combination products. See § 211.1(b).
                                                    with either the drug cGMPs or the QS                    implementation of the regulatory                      FDA notes that many of the requirements in parts
                                                    regulation will satisfy most of the cGMP                requirements for use of a streamlined                 600 through 680 are not considered cGMP
                                                                                                                                                                  requirements and are not covered by this proposed
                                                    requirements applicable to either a drug                cGMP operating system for single-entity               rule. In addition, FDA notes that biological
                                                    or a device constituent part. The agency                and co-packaged combination products.                 products must comply with all applicable
                                                    has reviewed the drug cGMPs and QS                      FDA invites comments on particular                    requirements in parts 600 through 680.

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                                                    48426             Federal Register / Vol. 74, No. 183 / Wednesday, September 23, 2009 / Proposed Rules

                                                    tissue practice requirements in part                       5. § 211.165. Testing and release for              demanding than the more extensive
                                                    1271 would be applicable.                               distribution.                                         requirements associated with the
                                                                                                               6. § 211.166. Stability testing.                   manufacture of some other combination
                                                    B. CGMP Requirements for Single-Entity                     7. § 211.167. Special testing                      products, such as drug-coated devices.
                                                    and Co-Packaged Combination Products                    requirements.                                            The streamlined option provides for
                                                       For single-entity and co-packaged                       8. § 211.170. Reserve samples.                     the potential to incorporate specific
                                                    combination products, the proposed                         In this instance, if a firm demonstrates           requirements from the drug cGMPs into
                                                    rule would allow firms to demonstrate                   compliance with the QS regulation at                  the framework of a QS operating system,
                                                    compliance with cGMP requirements by                    part 820 and the specific drug cGMP                   and vice versa. These additional,
                                                    implementing and complying with                         regulation provisions listed above, it                specific requirements should be
                                                    either the drug cGMPs or the QS                         would also be considered to be in                     incorporated where most appropriate
                                                    regulation, rather than both, under                     compliance with all other provisions of               into the operating system.
                                                    certain conditions. These conditions                    the drug cGMP regulations. The firm                      Both the QS and drug cGMP
                                                    include demonstrating that the cGMP                     would not have to demonstrate                         regulations require that procedures be
                                                    operating system complies with                          compliance with the other provisions of               written to assure that the products being
                                                    specified provisions from the other of                  the drug cGMPs.                                       manufactured, processed, and held meet
                                                    these two sets of regulations. In                          Furthermore, if the combination                    cGMP requirements. Accordingly, the
                                                    addition, this operating system would                   product includes a biological product                 written procedures for a streamlined
                                                    have to be shown to comply with all                     constituent part, in addition to                      system would have to assure that the
                                                    other cGMP regulations applicable to                    demonstrating compliance with either                  firm could demonstrate compliance
                                                    the constituent parts (i.e., in parts 600               the drug cGMPs or the device QS                       with the cGMP requirements specified
                                                    through 680 for biological products or in               regulation, along with the specified                  in the proposed rule.
                                                    part 1271 for HCT/Ps).                                  provisions of the other of these two sets                In addition to reducing duplicative
                                                       More specifically, if a single-entity or             of regulations if applicable, the cGMP                documentation that would otherwise be
                                                    co-packaged combination product                         operating system would also have to be                required if multiple sets of cGMP
                                                    includes both a drug and a device and                   shown to comply with all additional                   regulations were implemented
                                                    the cGMP operating system is shown to                   cGMP requirements that apply to that                  independently, this approach to
                                                    comply with the drug cGMP regulations                   constituent part as a biological product              documentation of the procedures would
                                                    at 21 CFR parts 210 and 211, the system                 (see parts 600 through 680). Similarly, if            help facilitate cGMP inspections, by
                                                    would also have to be shown to comply                   the combination product includes an                   setting forth how the cGMP
                                                    with the following specific provisions of               HCT/P constituent part, it would also                 requirements for combination products
                                                                                                            have to be shown to comply with the                   are being met and how this is being
                                                    the QS regulation, as described in
                                                                                                            requirements of part 1271. For those                  demonstrated in accordance with the
                                                    proposed § 4.4(b)(1):
                                                       1. § 820.20. Management                              combination products that contain                     streamlined approach.
                                                    responsibility.                                         biological products and/or HCT/Ps, the
                                                                                                            proposed rule would impose no                         C. Requirements for a Combination
                                                       2. § 820.30. Design controls.                                                                              Product That Includes an HCT/P
                                                       3. § 820.50. Purchasing controls.                    additional burdens and, in many cases,
                                                       4. § 820.100. Corrective and                         would offer the option of streamlining                   Questions have been raised by
                                                    preventive action.                                      related to the drug cGMPs and the                     stakeholders concerning the application
                                                       5. § 820.170. Installation.                          device QS regulation.                                 of cGMP requirements to HCT/Ps that
                                                       6. § 820.200. Servicing.                                The applicability of the specific                  are constituent parts of combination
                                                       In this instance, if a firm demonstrates             provisions identified in proposed                     products. The HCT/P regulation at part
                                                    compliance with the drug cGMP                           § 4.4(b) would, as is the case with all               1271 distinguishes between HCT/Ps
                                                    regulations at parts 210 and 211 and the                cGMP regulations, depend upon the                     regulated solely under section 361 of the
                                                    specific QS regulation provisions listed                characteristics of the constituent part               PHS Act (42 U.S.C. 264), and those that
                                                    above, it would also be considered to be                and the type of manufacturing activity                are regulated as drugs, devices, and
                                                    in compliance with all other provisions                 performed. For example, if a                          biological products under the PHS Act
                                                    of the QS regulation. The firm would                    manufacturer makes an OTC                             and/or the act. The HCT/P regulation
                                                    not have to demonstrate compliance                      combination product that includes a                   provides, among other things, that an
                                                    with the other provisions of the QS                     drug constituent part, it would need to               HCT/P that is combined with another
                                                    regulation.                                             comply with the specific tamper-evident               article (other than water, crystalloids, or
                                                       If a single-entity or co-packaged                    packaging requirements of § 211.132. A                a sterilizing, preserving, or storage
                                                    combination product includes both a                     manufacturer who makes a prescription                 agent) does not meet the criteria for
                                                    drug and a device and the cGMP                          combination product would not need to                 regulation solely under section 361 of
                                                    operating system is shown to comply                     comply with that provision. To take                   the PHS Act, but rather would be
                                                    with the QS regulation requirements at                  another example, if a manufacturer                    regulated under the PHS Act and/or the
                                                    part 820, the system would also have to                 makes a product that has hardware                     act as a drug, device, and/or biological
                                                    be shown to comply with the following                   requiring installation and/or servicing,              product. (See §§ 1271.10 and 1271.20).
                                                    specific provisions of the drug cGMP                    it would need to comply with the                      Thus, by operation of the HCT/P
                                                    regulations, as described in proposed                   installation and/or servicing provisions              regulation, an HCT/P that is a
                                                                                                            at §§ 820.170 and 820.200, respectively.              constituent part of a combination
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                                                    § 4.4(b)(2):
                                                       1. § 211.84. Testing and approval or                 Similarly, the scope, specificity, and                product will be regulated as a drug,
                                                    rejection of components, drug product                   complexity of the requirements will                   device, and/or biological product.
                                                    containers, and closures.                               vary depending on the type of activity                Further, because all biological product
                                                       2. § 211.103. Calculation of yield.                  performed. For example, the cGMP                      constituent parts meet the definition of
                                                       3. § 211.132. Tamper-evident                         requirements for firms that repackage                 drug or device, all HCT/P constituent
                                                    packaging for over-the-counter (OTC)                    articles into certain ‘‘convenience’’ kits            parts of a combination product
                                                    human drug products.                                    or package a drug with a disposable                   regulated as a biological product also
                                                       4. § 211.137. Expiration dating.                     delivery device will generally be less                meet the definition of drug or device.

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                                                                       Federal Register / Vol. 74, No. 183 / Wednesday, September 23, 2009 / Proposed Rules                                           48427

                                                       Therefore, if a combination product                     two different facilities. Then a third                can enter any factory, warehouse, or
                                                    includes an HCT/P constituent part, in                     facility combines the constituent parts               establishment in which drugs and
                                                    addition to whatever other cGMP                            into a single-entity or co-packaged                   devices are manufactured, processed,
                                                    requirements may apply due to the                          combination product. Before the                       packed, or held, for introduction into
                                                    other constituent parts of the                             constituent parts of a single-entity or co-           interstate commerce or after such
                                                    combination product, these cGMP                            packaged combination product are in                   introduction, to enter any vehicle being
                                                    requirements would apply:                                  the same facility for incorporation into              used to transport or hold drugs or
                                                       • Part 1271;6                                           the combination product, the                          devices in interstate commerce, and to
                                                       • Either the drug cGMPs or the QS                       manufacturing processes for the                       inspect such factory, warehouse,
                                                    regulation; and                                            constituent parts at their separate                   establishment, or vehicle and all
                                                       • If the HCT/P is regulated as a                        facilities are distinct. Accordingly,                 pertinent equipment, finished and
                                                    biological product, whichever biological                   under proposed § 4.4(c), each of these                unfinished materials, containers, and
                                                    product cGMP requirements apply, as                        separate facilities must maintain a                   labeling therein. This inspection
                                                    specified in parts 600 through 680.                        separate cGMP operating system and                    extends to all records and all things
                                                       As indicated in section II.B of this                    demonstrate compliance with the cGMP                  bearing on whether the drugs or devices
                                                    document, a firm could choose the                          regulations applicable to that type of                are adulterated.
                                                    streamlining option in proposed                            constituent part (for example, drug                      In the case of combination products,
                                                    § 4.4(b), as applicable, with respect to                   cGMPs if the constituent part is a drug).             if a firm chooses to use the streamlined
                                                    the drug and device cGMP requirements                      Once the constituent parts are brought                approach outlined in the proposed rule
                                                    for combination products containing                        to the third facility, the streamlined                at § 4.4(b) by implementing the drug
                                                    HCT/Ps.                                                    approach could be used.                               cGMPs supplemented by compliance
                                                                                                                  Example 2: The constituent parts are               with the provisions of the QS regulation
                                                    D. What Requirements Apply to the
                                                                                                               manufactured in the same facility, and                specified in proposed § 4.4(b)(1), the
                                                    Constituent Parts of a Combination
                                                                                                               are then sent to another facility to be               FDA inspection would focus on
                                                    Product Before They Are Combined, or
                                                                                                               combined into a single-entity or co-                  compliance with the drug cGMPs and
                                                    Packaged Together?                                                                                               the specified QS provisions. If the firm
                                                                                                               packaged combination product.
                                                       FDA recognizes that the manufacture                        The streamlined approach could be                  complies with the drug cGMPs and the
                                                    of a single-entity or co-packaged                          used for the manufacture in both                      specified QS provisions, the firm would
                                                    combination product is a complex                           facilities. Proposed § 4.4(d) addresses               be considered to be in compliance with
                                                    process. The firm or firms participating                   this situation.                                       the other provisions of the QS
                                                    in the production process may                                 Example 3: Facility 1 manufactures a               regulation. Likewise, if the operating
                                                    manufacture, receive, store, or otherwise                  drug constituent part. Facility 2                     system satisfies the QS regulation and
                                                    handle the constituent parts of the                        manufactures a device constituent part.               the drug cGMP provisions proposed at
                                                    combination product at various                             The drug constituent part is shipped to               § 4.4(b)(2) are also satisfied, a firm
                                                    facilities, including the facility at which                facility 2. Then both the drug                        would be considered to be in
                                                    the constituent parts are combined to                      constituent part and the device                       compliance with all other drug cGMP
                                                    make the single-entity or co-packaged                      constituent part are shipped from                     provisions.
                                                    combination product. The fact that                         facility 2 to facility 3. Facility 3
                                                                                                                                                                     III. Legal Authority
                                                    many firms and/or facilities may be                        combines the constituent parts into a
                                                    involved raises questions about whether                    single-entity or co-packaged                             The agency derives its authority to
                                                    and when the proposed streamlined                          combination product.                                  issue the regulations in proposed 21
                                                    approach to cGMP operating systems                            In this situation, manufacture of the              CFR part 4, subpart A, from 21 U.S.C.
                                                    could be used. Proposed § 4.4(c) would                     drug constituent part at facility 1 must              321, 331, 351, 352, 353, 355, 360, 360b–
                                                    make clear that when manufacturing of                      be shown to comply with the drug                      360f, 360h–360j, 360l, 360hh–360ss,
                                                    a constituent part does not occur at the                   cGMP regulations. Manufacture of the                  360aaa–360bbb, 371(a), 372–374, 379e,
                                                    same facility as another type of                           device at facility 2 must be shown to                 381, 383, and 394, Federal Food, Drug,
                                                    constituent part, the operating system                     comply with the device QS regulation.                 and Cosmetic Act, and 42 U.S.C. 216,
                                                    must be shown to comply with all of the                    Proposed § 4.4(c) would make this clear.              262, 263a, 264, and 271, Public Health
                                                    cGMP regulations applicable to that                           For the drug constituent part while it             Service Act. Most importantly, the
                                                    constituent part. Proposed § 4.4(d)                        is at facility 2, the streamlined approach            provisions at sections 501(a)(2)(B) and
                                                    would provide that when two or more                        could be used. That is, the QS operating              501(h) of the act (21 U.S.C. 351(a)(2)(B)
                                                    types of constituent parts are in the                      system at facility 2 could be                         and 351(h)) require drugs and devices to
                                                    same facility, the streamlined approach                    supplemented by the applicable,                       be manufactured in accordance with
                                                    may be used. However, proposed                             additional drug cGMP provisions                       cGMPs. Section 520(f) of the act (21
                                                    § 4.4(d) also clarifies that whenever                      specified in proposed § 4.4(b). Proposed              U.S.C. 360j(f)) specifically authorizes
                                                    manufacture of a constituent part occurs                   § 4.4(d) addresses this situation. Facility           the issuance of cGMP regulations for
                                                    at a separate facility from all other types                3 could use the streamlined approach by               devices.
                                                    of constituent parts, the manufacture of                   demonstrating compliance with either                     Section 501 of the act (21 U.S.C. 351)
                                                    that part must occur under the                             the drug cGMPs or the QS regulation as                states that a drug or device is deemed
                                                    regulations applicable to that part.                       the cGMP operating system,                            adulterated if it is not manufactured in
                                                                                                                                                                     accordance with cGMPs. This provision
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                                                       Following are some examples to                          supplemented by the particular
                                                    illustrate the situations in which the                     provisions from the other (drug or                    also applies to biological products that
                                                    proposed streamlined approach could or                     device) regulations specified in                      are constituent parts of combination
                                                    could not be used.                                         proposed § 4.4(b). Proposed § 4.4(d) also             products because these products meet
                                                       Example 1: Drug and device                              addresses this situation.                             the definition of drug or device under
                                                    constituent parts are manufactured at                                                                            section 201 of the act (21 U.S.C. 321).
                                                                                                               E. Inspection and Enforcement                         This provision also applies to HCT/Ps
                                                      6 See §§ 210.1(c), 210.2, 211.1(b), 820.1(a), and          For purposes of enforcing the act,                  that are constituent parts of combination
                                                    1271.1(b)(2).                                              section 704 of the act provides that FDA              products because the HCT/P regulation

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                                                    48428             Federal Register / Vol. 74, No. 183 / Wednesday, September 23, 2009 / Proposed Rules

                                                    provides, among other things, that an                   devices, and/or biological products.                  IV. Environmental Impact
                                                    HCT/P that is combined with another                     These articles do not lose their discrete               FDA has determined under 21 CFR
                                                    article (other than water, crystalloids, or             regulatory identity when they become                  25.30(a), 25.30(h), 25.30(j), 25.31(a), (c),
                                                    a sterilizing, preserving, or storage                   constituent parts of a combination                    (h), and (j), and 25.34(a) and (d) that this
                                                    agent) is regulated under the PHS Act                   product. Therefore, all combination                   action is of a type that does not
                                                    and/or the act as a drug, device, and/or                products are subject to at least two sets             individually or cumulatively have a
                                                    biological product (see §§ 1271.10 and                  of cGMP requirements. For example, in                 significant effect on the human
                                                    1271.20). In addition, section 351 of the               the case of a drug-device combination                 environment. Therefore, neither an
                                                    PHS Act (42 U.S.C. 262) authorizes FDA                  product, the QS regulation in part 820                environmental assessment nor an
                                                    to issue manufacturing standards for                    and the drug cGMP regulations in parts                environmental impact statement is
                                                    biological products. Section 361 of the                 210 and 211 would apply to the                        required.
                                                    PHS Act (42 U.S.C. 264) authorizes the                  combination product. This proposed
                                                    issuance of regulations to prevent the                  rule is intended to clarify the                       V. Paperwork Reduction Act of 1995
                                                    introduction, transmission, or spread of                applicability of these requirements to                  We note that the information
                                                    communicable diseases.                                  combination products and to provide a                 collected under the underlying cGMP
                                                       Under applicable statutory provisions,               streamlined option for practical                      regulations for drugs, devices, and
                                                    the following cGMP regulations were                     implementation for co-packaged and                    biological products, including HCT/Ps,
                                                    previously issued for drugs, devices,                   single-entity combination products.                   found at parts 211, 820, 600 through
                                                    and biological products that may be                        Because the drug and device cGMP                   680, and 1271 have already been
                                                    included as constituent parts of                        requirements are so similar, when using               approved and are in effect. The
                                                    combination products:                                   this streamlined approach,                            currently approved burden estimates are
                                                       • Drug cGMP regulations for finished                 demonstrating compliance with the                     available in the following links. The
                                                    pharmaceuticals or drug products set                    requirements of one set of regulations                provisions of part 211 are approved
                                                    forth at parts 210 and 211).                            (e.g., drug cGMPs), along with
                                                       Drug products not subject to these                                                                         under OMB control number 0910–0139,
                                                                                                            demonstrating compliance with the                     which expires November 30, 2011
                                                    regulations (e.g., bulk drugs or active
                                                                                                            requirements of the specified provisions              (
                                                    pharmaceutical ingredients) must still
                                                                                                            from the other set (e.g., QS regulation),             PRAViewICR?ref_nbr=200809-0910-
                                                    meet the current good manufacturing
                                                                                                            would be considered to be                             008). The provisions of part 820 are
                                                    practice general standard required by
                                                                                                            demonstrating compliance with all                     approved under OMB control number
                                                    the statute.
                                                                                                            requirements from the other set (e.g., QS             0910–0073, which expires on November
                                                       • QS regulation for devices set forth
                                                                                                            regulation).                                          30, 2010 (
                                                    at part 820.
                                                       • cGMP regulations specific to certain                  Although combination products retain               public/do/PRAViewICR?ref_nbr=
                                                    types of biological products and/or                     the regulatory identities of their                    200709-0910-006). The provisions of
                                                    HCT/Ps set forth at parts 600 through                   constituent parts, the act also recognizes            parts 606, 640, and 660 are approved
                                                    680 and 1271.                                           combination products as a category of                 under OMB control number 0910–0116,
                                                       There is considerable overlap in the                 products that are distinct from products              which expires February 29, 2012 (http://
                                                    drug cGMPs and QS regulation, and for                   that are solely drugs, devices, or          
                                                    the most part the overlap is apparent.                  biological products. For example,                     ICR?ref_nbr=200811-0910-006). The
                                                    For example, both establish                             section 503(g)(4)(A) of the act (21 U.S.C.            provisions of part 610 are approved
                                                    requirements for management,                            353(g)(4)(A)) requires OCP to                         under OMB control number 0910–0116,
                                                    organization, and personnel; both                       ‘‘designate’’ a product as a combination              which expires February 29, 2012, (link
                                                    require documentation and record                        product as well as to ensure ‘‘consistent             already provided in this paragraph) and
                                                    keeping; and both allow flexibility in                  and appropriate postmarket regulation                 OMB control number 0910–0338, which
                                                    their application to the manufacture of                 of like products subject to the same                  expires on June 10, 2010 (also for part
                                                    a particular product. FDA considers the                 statutory requirements.’’ Further,                    680) (
                                                    drug cGMPs and the QS regulation to be                  section 563 of the act, (21 U.S.C.                    PRAViewICR?ref_nbr=200703-0910-
                                                    similar, and they are meant to achieve                  360bbb–2(a)), governs the                             017). The provisions of part 1271,
                                                    the same general goals.                                 ‘‘classification’’ of products as ‘‘drug,             subparts C and D, are approved under
                                                       Nevertheless, these two sets of                      biological product, device, or a                      OMB control number 0910–0543, which
                                                    regulations differ somewhat because                     combination product subject to section                expires on May 31, 2010 (http://
                                                    each is tailored to the characteristics of              503(g)’’ (emphasis added). In this          
                                                    the types of products for which it was                  respect, the act identifies a combination             ICR?ref_nbr=200705-0910-001). To
                                                    designed. For instance, each set of                     product as a distinct type of product                 obtain more detailed, itemized estimates
                                                    regulations contains certain specific                   that could be subject to specialized                  of the burden associated with particular
                                                    requirements for various cGMP concepts                  regulatory controls.                                  regulatory provisions, please click on
                                                    that are only more generally addressed                     Under the preceding authorities and                the link called ‘‘View Supporting
                                                    in the other regulation. For example, the               section 701(a) of the act (21 U.S.C. 371),            Statement and Other Documents’’ from
                                                    QS regulation has detailed corrective                   which authorizes FDA to issue                         any of the links provided in
                                                    and preventive action (CAPA)                            regulations for the efficient enforcement             this paragraph. (FDA has verified the
                                                    requirements (§ 820.100) while CAPA                     of the act, FDA has the authority to                  Web site addresses, but FDA is not
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                                                    principles are more generally addressed                 issue regulations clarifying the                      responsible for any subsequent changes
                                                    in the cGMP regulation as part of                       applicability of cGMP requirements to                 to the Web sites after this document
                                                    Production Record Review (§ 211.192).                   combination products. The agency is                   publishes in the Federal Register.)
                                                       The cGMP requirements specific to                    also authorized under these authorities                 We do not believe that this proposal
                                                    each constituent part of a combination                  to issue regulations specifying how                   would constitute an additional
                                                    product also apply to the combination                   compliance with cGMP requirements for                 paperwork burden because firms must
                                                    product itself because, by definition,                  combination products may be                           currently comply with the cGMP
                                                    combination products consist of drugs,                  demonstrated.                                         regulations addressed by this proposed

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                                                                      Federal Register / Vol. 74, No. 183 / Wednesday, September 23, 2009 / Proposed Rules                                        48429

                                                    rule: In fact, our intent is to minimize                   The Regulatory Flexibility Act                     would also help ensure predictability
                                                    burden on respondents by providing a                    requires agencies to analyze regulatory               and consistency in the application and
                                                    more streamlined approach. Therefore,                   options that would minimize any                       enforcement of these regulatory
                                                    burden associated with complying with                   significant impact of a rule on small                 requirements with regard to all
                                                    these cGMP regulations represents the                   entities. Because this proposed rule                  combination products across FDA.
                                                    maximum burden for compliance with                      explains how requirements that are                       Firms must already comply with the
                                                    this proposed rule. We invite comment                   currently in effect apply to combination              cGMP regulations for drugs, devices,
                                                    on how many firms might avail                           products, the agency does not believe                 and biological products, including
                                                    themselves of the streamlined approach                  that this proposed rule would have a                  HCT/Ps, found at parts 211, 820, 600
                                                    presented in this proposed rule for co-                 significant economic impact on a                      through 680, and 1271, that are
                                                    packaged and single-entity combination                  substantial number of small entities.                 applicable to the constituent parts of
                                                    products and on what the reduction in                   FDA requests comment on this issue.                   their combination products. The cost of
                                                    paperwork burden would be.                                 Section 202(a) of the Unfunded                     this proposed rule would be the
                                                                                                            Mandates Reform Act of 1995 requires                  incremental costs to modify or
                                                    VI. Federalism                                          that agencies prepare a written                       streamline existing SOPs. We do not
                                                      FDA has analyzed this proposed rule                   statement, which includes an                          know how many firms may choose to
                                                    in accordance with the principles set                   assessment of anticipated costs and                   use the proposed streamlined approach
                                                    forth in Executive Order 13132. Section                 benefits, before proposing ‘‘any rule that            for single-entity and co-packaged
                                                    4(a) of the Executive order requires                    includes any Federal mandate that may                 combination products, or for how many
                                                                                                            result in the expenditure by State, local,            products; nor do we know how many
                                                    agencies to ‘‘construe * * * a Federal
                                                                                                            and tribal governments, in the aggregate,             firms are already using such an
                                                    statute to preempt State law only where
                                                                                                            or by the private sector, of $100,000,000             approach in light of the draft guidance.
                                                    the statute contains an express                                                                                  Some firms may incur one-time
                                                                                                            or more (adjusted annually for inflation)
                                                    preemption provision or there is some                                                                         incremental costs assessing compliance
                                                                                                            in any one year.’’ The current threshold
                                                    other clear evidence that the Congress                                                                        with the proposed rule and perhaps
                                                                                                            after adjustment for inflation is $130
                                                    intended preemption of State law, or                                                                          altering some standard operating
                                                                                                            million, using the most current (2007)
                                                    where the exercise of State authority                                                                         procedures. Because this proposed rule
                                                                                                            Implicit Price Deflator for the Gross
                                                    conflicts with the exercise of Federal                                                                        codifies agency practice that is
                                                                                                            Domestic Product. FDA does not expect
                                                    authority under the Federal statute.’’                                                                        described in current guidance
                                                                                                            this proposed rule to result in any 1-
                                                    The sole statutory provision giving                     year expenditure that would meet or                   documents and because no new cGMP
                                                    preemptive effect to the proposed rule is               exceed this amount.                                   requirements are proposed, we believe
                                                    section 751 of the act (21 U.S.C. 379r),                                                                      the time required would be small and
                                                    which would apply only with respect to                  B. The Rationale Behind the Proposed                  estimate it to be about 25 hours per
                                                    OTC drug components of combination.7                    Rule                                                  product. This estimate is based on
                                                    VII. Analysis of Impacts                                   The proposed rule has two related                  numbers we have used in previous rules
                                                                                                            purposes. The first is to clarify the                 with similar requirements. The amount
                                                    A. Introduction                                         cGMP requirements that apply to                       of these compliance assessment costs for
                                                                                                            combination products, and the second is               an individual firm, and the impact of
                                                       FDA has examined the impacts of the
                                                                                                            to help ensure the consistent and                     any such costs, will depend on the
                                                    proposed rule under Executive Order
                                                                                                            appropriate application and                           number and nature of the products the
                                                    12866 and the Regulatory Flexibility Act
                                                                                                            enforcement of these requirements.                    firm produces and how the firm has
                                                    (5 U.S.C. 601–612), and the Unfunded
                                                                                                            Constituent parts and manufacturing                   applied current regulations.
                                                    Mandates Reform Act of 1995 (Public
                                                                                                            practices vary among combination                      Nonetheless, because the time required
                                                    Law 104–4). Executive Order 12866
                                                                                                            products; different cGMP requirements                 would be limited, the agency believes
                                                    directs agencies to assess all costs and
                                                                                                            apply depending upon the constituent                  the impact will not be significant on
                                                    benefits of available regulatory
                                                                                                            parts in the combination product and                  entities considered small based on the
                                                    alternatives and, when regulation is
                                                                                                            what manufacturing practices are used.                Small Business Administration’s
                                                    necessary, to select regulatory
                                                                                                            Second, the proposed rule attempts to                 definition of a small entity (500
                                                    approaches that maximize net benefits
                                                                                                            streamline the practical implementation               employees for device and biological
                                                    (including potential economic,
                                                                                                            of cGMP requirements for co-packaged                  product firms and 750 employees for
                                                    environmental, public health and safety,
                                                                                                            and single-entity combination products.               drug firms). The agency requests
                                                    and other advantages; distributive
                                                                                                                                                                  comment on the incremental burden
                                                    impacts; and equity). The agency                        C. Impact of Proposed Rule
                                                                                                                                                                  estimate associated with this rule.
                                                    believes that this proposed rule is not a                 FDA estimates that approximately 300
                                                    significant regulatory action as defined                manufacturers of combination products                 VIII. Request for Comments
                                                    by the Executive order.                                 will be affected by the proposed rule.                  Interested persons may submit to the
                                                                                                            These manufacturers of combination                    Division of Dockets Management (see
                                                      7 The proposed rule seeks to clarify which cGMP
                                                                                                            products should benefit from the greater              ADDRESSES) written or electronic
                                                    requirements apply when drugs, devices, and
                                                    biological products are used to create combination
                                                                                                            clarity provided regarding which                      comments regarding this proposed rule.
                                                    products. The agency notes that there are no            regulatory provisions apply to their                  Submit a single copy of electronic
                                                                                                            products. For both existing and future                comments or two paper copies of any
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                                                    express preemption provisions of the act applicable
                                                    to prescription drugs or biological products. Section   products, the streamlined approach set                mailed comments, except that
                                                    521 of the act (21 U.S.C. 360k) contains an express
                                                    preemption provision that applies to devices;
                                                                                                            forth in the proposed rule would help                 individuals may submit one paper copy.
                                                    nonetheless, the Supreme Court concluded in             ensure that cGMPs for co-packaged and                 Comments are to be identified with the
                                                    Medtronic, Inc. v. Lohr, 581 U.S. 470, 500–01           single-entity combination products are                docket number found in brackets in the
                                                    (1996), that requirements not applicable to a           consistent and appropriate, without                   heading of this document. Received
                                                    particular device (such as the device good
                                                    manufacturing practice requirements at issue in this
                                                                                                            duplicative or otherwise unnecessary                  comments may be seen in the Division
                                                    proposed rule) do not preempt State law under           aspects. This codification of cGMP                    of Dockets Management between 9 a.m.
                                                    section 521 of the act.                                 requirements for combination products                 and 4 p.m., Monday through Friday.

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                                                    48430             Federal Register / Vol. 74, No. 183 / Wednesday, September 23, 2009 / Proposed Rules

                                                    IX. Proposed Effective Date                               Agency means the Food and Drug                         (a) The current good manufacturing
                                                       The agency is proposing that any final               Administration.                                       practice requirements in parts 210 and
                                                    rule that may issue based upon this                       Biological product has the meaning                  211 of this chapter apply to a
                                                    proposed rule become effective 180 days                 set forth in § 3.2(d) of this chapter. A              combination product that includes a
                                                    after its date of publication in the                    biological product also meets the                     drug constituent part;
                                                                                                            definitions of either a drug or device as                (b) The current good manufacturing
                                                    Federal Register.
                                                                                                            these terms are defined under § 4.2.                  practice requirements in part 820 of this
                                                    List of Subjects in 21 CFR Part 4                         Combination product has the meaning                 chapter apply to a combination product
                                                      Combination products, Biological                      set forth in § 3.2(e) of this chapter.                that includes a device constituent part;
                                                                                                              Constituent part is a drug, device, or                 (c) The current good manufacturing
                                                    products, Devices, Drugs, and Human
                                                                                                            biological product, including an HCT/P,               practice requirements in part 606 of this
                                                    cell, Tissue, and cellular and tissue-
                                                                                                            that is part of a combination product as              chapter for blood and blood components
                                                    based products, Regulation of
                                                                                                            defined in § 3.2(e) of this chapter.                  and among the requirements (standards)
                                                    combination products.                                     Co-packaged combination product
                                                      Therefore, under the Federal Food,                                                                          for biological products in other sections
                                                                                                            has the meaning set forth in § 3.2(e)(2)              of parts 600 through 680 of this chapter
                                                    Drug, and Cosmetic Act, the Public
                                                                                                            of this chapter.                                      apply to a combination product that
                                                    Health Service Act, and under authority                   Current good manufacturing practice
                                                    delegated to the Commissioner of Food                                                                         includes a biological product
                                                                                                            operating system means the operating                  constituent part to which those
                                                    and Drugs, it is proposed that 21 CFR                   system within an establishment that is
                                                    part 4 be added to read as follows:                                                                           requirements would apply if that
                                                                                                            designed and implemented to address                   constituent part were not part of a
                                                    PART 4—REGULATION OF                                    and meet the current good                             combination product; and
                                                    COMBINATION PRODUCTS                                    manufacturing practice requirements for                  (d) The current good tissue practice
                                                                                                            a combination product.                                and donor eligibility requirements for
                                                    Subpart A—Current Good Manufacturing                      Current good manufacturing practice                 HCT/Ps in part 1271 of this chapter
                                                    Practice Requirements for Combination                   requirements means the requirements                   apply to a combination product that
                                                    Products                                                set forth under § 4.3(a) through (d).                 includes an HCT/P constituent part to
                                                    Sec.                                                      Device has the meaning set forth in                 which those requirements would apply
                                                    4.1 What is the scope of this subpart?                  3.2(f) of this chapter. A device that is a            if that constituent part were not part of
                                                    4.2 How does FDA define key terms and                   constituent part of a combination                     a combination product.
                                                         phrases in this subpart?                           product is considered a finished device
                                                    4.3 What current good manufacturing                     within the meaning of the QS                          § 4.4 How can I comply with these current
                                                         practice requirements apply to my                  regulation.                                           good manufacturing practice requirements
                                                         combination product?                                 Drug has the meaning set forth in                   for a co-packaged or single-entity
                                                    4.4 How can I comply with these current                                                                       combination product?
                                                         good manufacturing practice
                                                                                                            § 3.2(g) of this chapter. A drug that is a
                                                                                                            constituent part of a combination                        (a) Under this subpart, for single-
                                                         requirements for a co-packaged or single-                                                                entity or co-packaged combination
                                                         entity combination product?                        product is considered a drug product
                                                                                                            within the meaning of the drug cGMPs.                 products, compliance with all
                                                    Subpart B [Reserved]                                      Drug cGMPs refers to the current good               applicable current good manufacturing
                                                                                                            manufacturing practice regulations set                practice requirements for the
                                                      Authority: 21 U.S.C. 321, 331, 351, 352,                                                                    combination product shall be achieved
                                                    353, 355, 360, 360b–360f, 360h–360j, 360l,              forth in parts 210 and 211 of this
                                                                                                            chapter.                                              through the design and implementation
                                                    360hh–360ss, 360aaa–360bbb, 371(a), 372–
                                                    374, 379e, 381, 383, 394; 42 U.S.C. 216, 262,             FDA means the Food and Drug                         of a current good manufacturing
                                                    263a, 264, 271.                                         Administration.                                       practice operating system that is
                                                                                                              HCT/Ps refers to human cell, tissue,                demonstrated to comply with:
                                                    Subpart A—Current Good                                  and cellular and tissue-based products,                  (1) The specifics of each set of current
                                                    Manufacturing Practice Requirements                     as defined in § 1271.3(d) of this chapter.            good manufacturing practice regulations
                                                    for Combination Products                                  Manufacture includes, but is not                    listed under § 4.3 as they apply to each
                                                                                                            limited to, designing, fabricating,                   constituent part included in the
                                                    § 4.1   What is the scope of this subpart?                                                                    combination product; or
                                                                                                            assembling, filling, processing, testing,
                                                      This subpart applies to combination                   labeling, packaging, repackaging,                        (2) Paragraph (b) of this section.
                                                    products. It establishes which current                  holding, and storage.                                    (b) If you elect to establish a current
                                                    good manufacturing practice                               QS regulation refers to the quality                 good manufacturing practice operating
                                                    requirements apply to these products.                   system regulation in part 820 of this                 system in accordance with paragraph (b)
                                                    This subpart clarifies the application of               chapter.                                              of this section, the following
                                                    current good manufacturing practice                       Single-entity combination product has               requirements apply:
                                                    regulations to combination products,                    the meaning set forth in § 3.2(e)(1) of                  (1) If the combination product
                                                    and provides a regulatory framework for                 this chapter.                                         includes a device constituent part and a
                                                    designing and implementing the current                    Type of constituent part refers to the              drug constituent part, and the current
                                                    good manufacturing practice operating                   category of the constituent part, which               good manufacturing practice operating
                                                    system at facilities that manufacture co-               can be either a biological product, a                 system has been shown to comply with
                                                    packaged or single-entity combination                   device, a drug, or an HCT/P, as these                 the drug cGMPs, the following
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                                                    product.                                                terms are defined under this § 4.2.                   provisions of the QS regulation must
                                                                                                                                                                  also be shown to have been satisfied;
                                                    § 4.2 How does FDA define key terms and                 § 4.3 What current good manufacturing                 upon demonstration that these
                                                    phrases in this subpart?                                practice requirements apply to my                     requirements have been satisfied, no
                                                      The terms listed in this section have                 combination product?                                  additional showing of compliance with
                                                    the following meanings for purposes of                     If you manufacture a combination                   respect to the QS regulation need be
                                                    this subpart.                                           product, the current good                             made:
                                                      Act means the Federal Food, Drug,                     manufacturing practice requirements                      (i) § 820.20 of this chapter.
                                                    and Cosmetic Act.                                       listed in this section apply as follows:              Management responsibility.

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                                                                      Federal Register / Vol. 74, No. 183 / Wednesday, September 23, 2009 / Proposed Rules                                           48431

                                                       (ii) § 820.30 of this chapter. Design                  (c) During any period in which the                  Act (ADA) regulations and
                                                    controls.                                               manufacture of a constituent part to be               accompanying interpretive guidance in
                                                       (iii) § 820.50 of this chapter.                      included in a co-packaged or single-                  order to implement the ADA
                                                    Purchasing controls.                                    entity combination product occurs at a                Amendments Act of 2008. The
                                                       (iv) § 820.100 of this chapter.                      separate facility from the other type(s) of           Commission is responsible for
                                                    Corrective and preventive action.                       constituent part(s) to be included in that            enforcement of title I of the ADA, as
                                                       (v) § 820.170 of this chapter.                       single-entity or co-packaged                          amended, which prohibits employment
                                                    Installation.                                           combination product, the current good                 discrimination on the basis of disability.
                                                       (vi) § 820.200 of this chapter.                      manufacturing practice operating                      Pursuant to the ADA Amendments Act
                                                    Servicing.                                              system for that constituent part must be              of 2008, EEOC is expressly granted the
                                                       (2) If the combination product                       demonstrated to comply with all current               authority to amend these regulations,
                                                    includes a device constituent part and a                good manufacturing practice                           and is expected to do so, in order to
                                                    drug constituent part, and the current                  requirements applicable to that type of               conform certain provisions contained in
                                                    good manufacturing practice operating                   constituent part.                                     the regulations to the Amendments Act.
                                                    system has been shown to comply with                      (d) When two or more types of                       DATES: Written comments on this
                                                    the QS regulation, the following                        constituent parts to be included in a                 rulemaking must be submitted on or
                                                    provisions of the drug cGMPs must also                  single-entity or co-packaged                          before November 23, 2009.
                                                    be shown to have been satisfied; upon                   combination product have arrived at the               ADDRESSES: Written comments should
                                                    demonstration that these requirements                   same facility, or the manufacture of                  be submitted to Stephen Llewellyn,
                                                    have been satisfied, no additional                      these constituent parts is proceeding at              Executive Officer, Executive Secretariat,
                                                    showing of compliance with respect to                   the same facility, application of a                   Equal Employment Opportunity
                                                    the drug cGMPs need be made:                            current good manufacturing process                    Commission, 131 M Street, NE., Suite
                                                       (i) § 211.84 of this chapter. Testing                operating system that complies with                   4NW08R, Room 6NE03F, Washington,
                                                    and approval or rejection of                            § 4.4(b) may begin, except with respect               DC 20507. As a convenience to
                                                    components, drug product containers,                    to any constituent part that remains or               commenters, the Executive Secretariat
                                                    and closures.                                           becomes subject to § 4.4(c).                          will accept comments transmitted by
                                                       (ii) § 211.103 of this chapter.                        (e) The current good manufacturing                  facsimile (‘‘FAX’’) machine. The
                                                    Calculation of yield.                                   practice requirements set forth in this               telephone number of the FAX receiver
                                                       (iii) § 211.132 of this chapter. Tamper-             subpart and in parts 210, 211, 600                    is (202) 663–4114. (This is not a toll-free
                                                    evident packaging requirements for                      through 680, 820, and 1271 of this                    number.) Only comments of six or fewer
                                                    over-the-counter (OTC) human drug                       chapter, supplement, and do not                       pages will be accepted via FAX
                                                    products.                                               supersede, each other unless the                      transmittal to ensure access to the
                                                       (iv) § 211.137 of this chapter.                      regulations explicitly provide otherwise.             equipment. Receipt of FAX transmittals
                                                    Expiration dating.                                      In the event of a conflict between                    will not be acknowledged, except that
                                                       (v) § 211.165 of this chapter. Testing               regulations applicable under this                     the sender may request confirmation of
                                                    and release for distribution.                           subpart to combination products,                      receipt by calling the Executive
                                                       (vi) § 211.166. of this chapter.                     including their constituent parts, the                Secretariat staff at (202) 663–4070
                                                    Stability testing.                                      regulations most specifically applicable              (voice) or (202) 663–4074 (TTY). (These
                                                       (vii) § 211.167 of this chapter. Special             to the constituent part in question shall             are not toll-free telephone numbers.)
                                                    testing requirements.                                   supersede the more general.
                                                       (viii) § 211.170 of this chapter.                                                                          You may also submit comments and
                                                    Reserve samples.                                                                                              attachments electronically at http://
                                                                                                            Subpart B [Reserved]                        , which is the
                                                       (3) In addition to being shown to
                                                    comply with the other applicable                                                                              Federal eRulemaking Portal. Follow the
                                                                                                              Dated: September 17, 2009.                          instructions online for submitting
                                                    current good manufacturing practice                     David Horowitz,
                                                    requirements listed under § 4.3, if the                                                                       comments. Copies of comments
                                                                                                            Assistant Commissioner for Policy.                    submitted by the public will be
                                                    combination product includes a
                                                                                                            [FR Doc. E9–22850 Filed 9–22–09; 8:45 am]             available for review at the Commission’s
                                                    biological product constituent part, the
                                                    current good manufacturing practice                     BILLING CODE 4160–01–S                                library, 131 M Street, NE., Suite
                                                    operation system must also be shown to                                                                        4NW08R, Washington, DC 20507,
                                                    implement and comply with all current                                                                         between the hours of 9:30 a.m. and 5
                                                    good manufacturing practice                             EQUAL EMPLOYMENT OPPORTUNITY                          p.m. or can be reviewed at http://
                                                    requirements identified under § 4.3(c)                  COMMISSION                                  
                                                    that would apply to that biological                                                                           FOR FURTHER INFORMATION CONTACT:
                                                                                                            29 CFR Part 1630
                                                    product if that constituent part were not                                                                     Christopher Kuczynski, Assistant Legal
                                                    part of a combination product.                          RIN 3046–AA85                                         Counsel, or Jeanne Goldberg, Senior
                                                       (4) In addition to being shown to                                                                          Attorney Advisor, Office of Legal
                                                    comply with the other applicable                        Regulations To Implement the Equal                    Counsel, U.S. Equal Employment
                                                    current good manufacturing practice                     Employment Provisions of the                          Opportunity Commission at (202) 663–
                                                    requirements listed under § 4.3, if the                 Americans With Disabilities Act, as                   4638 (voice) or (202) 663–7026 (TTY).
                                                    combination product includes an                         Amended                                               These are not toll-free-telephone
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                                                    HCT/P, the current good manufacturing                   AGENCY: Equal Employment                              numbers. This document is also
                                                    practice operation system must also be                  Opportunity Commission (EEOC).                        available in the following formats: large
                                                    shown to implement and comply with                      ACTION: Notice of proposed rulemaking.                print, Braille, audio tape, and electronic
                                                    all current good manufacturing practice                                                                       file on computer disk. Requests for this
                                                    requirements identified under § 4.3(d)                  SUMMARY: The Equal Employment                         document in an alternative format
                                                    that would apply to that HCT/P                          Opportunity Commission (the                           should be made to the Office of
                                                    constituent part if that constituent part               Commission or EEOC) proposes to                       Communications and Legislative Affairs
                                                    were not part of a combination product.                 revise its Americans with Disabilities                at (202) 663–4191 (voice) or (202) 663–

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