[Federal Register Volume 81, Number 169 (Wednesday, August 31, 2016)]
[Rules and Regulations]
[Pages 60169-60224]
[FR Doc No: 2016-20471]

Vol. 81

Wednesday,

No. 169

August 31, 2016

Part III

Department of Health and Human Services

-----------------------------------------------------------------------

Food and Drug Administration

-----------------------------------------------------------------------

21 CFR Parts 20, 201, 207, et al.

Requirements for Foreign and Domestic Establishment Registration and
Listing for Human Drugs, Including Drugs That Are Regulated Under a
Biologics License Application, and Animal Drugs; Final Rule

Federal Register / Vol. 81 , No. 169 / Wednesday, August 31, 2016 /
Rules and Regulations

-----------------------------------------------------------------------

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 20, 201, 207, 314, 514, 515, 601, 607, and 1271

[Docket No. FDA-2005-N-0464 (formerly Docket No. 2005N-0403)]
RIN 0910-AA49

Requirements for Foreign and Domestic Establishment Registration
and Listing for Human Drugs, Including Drugs That Are Regulated Under a
Biologics License Application, and Animal Drugs

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

-----------------------------------------------------------------------

SUMMARY: The Food and Drug Administration (FDA) is amending its
regulations governing drug establishment registration and drug listing.
These amendments reorganize, modify, and clarify current regulations
concerning who must register establishments and list human drugs, human
drugs that are also biological products, and animal drugs. The final
rule requires electronic submission, unless waived in certain
circumstances, of registration and listing information. This rulemaking
pertains to finished drug products and to active pharmaceutical
ingredients (APIs) alone or together with one or more other
ingredients. The final rule describes how and when owners or operators
of establishments at which drugs are manufactured or processed must
register their establishments with FDA and list the drugs they
manufacture or process. In addition, the rule makes certain changes to
the National Drug Code (NDC) system. We are taking this action to
improve management of drug establishment registration and drug listing
requirements and make these processes more efficient and effective for
industry and for us. This action also supports implementation of the
electronic prescribing provisions of the Medicare Prescription Drug,
Improvement, and Modernization Act of 2003 (MMA) and the availability
of current drug labeling information through DailyMed, a computerized
repository of drug information maintained by the National Library of
Medicine.

DATES: This rule is effective on November 29, 2016. See section IV for
compliance dates.

FOR FURTHER INFORMATION CONTACT:
    For information pertaining to human drug products: Paul Loebach,
Center for Drug Evaluation and Research, Food and Drug Administration,
10903 New Hampshire Ave., Bldg. 51, Rm. 2262, Silver Spring, MD 20993,
301-796-2173.
    For information pertaining to human biological drug products or
human cells, tissue, and cellular and tissue-based products (HCT/Ps)
regulated solely under section 361 of the Public Health Service Act:
Stephen Ripley, Center for Biologics Evaluation and Research, Food and
Drug Administration, 10903 New Hampshire Ave., Bldg. 71, Rm. 7301,
Silver Spring, MD 20993,<PHONE_NUMBER>.
    For information pertaining to animal drug products: Charise Kasser,
Center for Veterinary Medicine (HFV-212), Food and Drug Administration,
7519 Standish Pl., Rm. 2626, Rockville, MD 20855,<PHONE_NUMBER>; or
Isabel Pocurull, Center for Veterinary Medicine (HFV-226), Food and
Drug Administration, 7519 Standish Pl., Rm. 2636, Rockville, MD 20855,
240-402-5877.

SUPPLEMENTARY INFORMATION:

Table of Contents

Executive Summary
    Purpose of the Regulatory Action
    Summary of the Major Provisions of the Regulatory Action
    Benefits and Costs
I. Background
II. Overview of the Final Rule Including Changes to the Proposed
Rule
    A. Overview
    B. Changes to the Proposed Rule
III. Comments on the Proposed Rule
    A. Labeling (Sec. Sec.  201.2 and 201.25)
    B. General Information (Part 207, Subpart A)
    C. Registration (Part 207, Subpart B)
    D. National Drug Code (Part 207, Subpart C)
    E. Listing (Part 207, Subpart D)
    F. Electronic Format for Registration and Listing (Part 207,
Subpart E)
    G. Miscellaneous (Part 207, Subpart F)
    H. Human Cells, Tissues, and Cellular and Tissue-Based Products
(Part 1271)
IV. Compliance Dates
V. Legal Authority
VI. Analysis of Environmental Impact
VII. Economic Analysis of Impacts
    A. Introduction
    B. Summary of Benefits and Costs
    C. Response to Comments on the Preliminary Impact Analysis of
the Proposed Rule
VIII. Paperwork Reduction Act of 1995
    A. Registration Information Collection Under Part 207
    B. Listing Information Collection Under Part 207
    C. Registration and Listing Information Collection Under Part
607
    D. Registration and Listing Information Collection Under Part
1271
    E. Waiver Request Information
    F. Public Disclosure Exemption Requests
    G. Standard Operating Procedure for Electronic Submission
    H. Capital Costs
IX. Federalism
X. References

Executive Summary

Purpose of the Regulatory Action

    This final rule amends FDA's longstanding regulations governing
drug establishment registration and drug listing. The amendments are
aimed at modernizing these regulations and improving efficiency and
reliability for FDA and drug manufacturers. These amendments also bring
FDA's regulations governing drug establishment registration and listing
into conformance with section 510 of the Federal Food, Drug, and
Cosmetic Act (the FD&C Act) (21 U.S.C. 360) as amended by the Food and
Drug Administration Amendments Act (FDAAA) (Pub. L. 110-85) and the
Food and Drug Administration Safety and Innovation Act (FDASIA) (Pub.
L. 112-144).
    Since the 1962 Kefauver Harris amendments to the FD&C Act (Pub. L.
87-781), drug manufacturers have been required to register their
establishments with FDA annually. Among other things, drug
establishment registration identifies establishments for inspection by
FDA. In 1973, the FD&C Act was further amended to require each
registered establishment to submit a list of drugs it manufactures.
FDA's regulations implementing these requirements are found in part 207
(21 CFR part 207) (pertaining to drugs and biological products
generally) and part 607 (21 CFR part 607) (pertaining to blood and
blood products). Manufacturers of HCT/Ps register and list either under
part 207, part 807 (21 CFR 807), or under part 1271 (21 CFR part 1271),
issued under authority of the Public Health Service Act (PHS Act),
depending on the type of HCT/P product they manufacture.
    The amendments to parts 207 and 607 adopted by this final rule
modernize those regulations and bring them into conformance with
section 510 of the FD&C Act following recent amendments.

Summary of the Major Provisions of the Regulatory Action

    This final rule requires electronic submission, unless waived in
certain circumstances, of drug establishment registration and listing
information. The electronic submission requirement is consistent with
FDAAA and with current practice.

    The rule makes clear that the establishment registration and
listing obligation rests with persons who manufacture, repack, relabel,
or salvage drug products. The rule does not require persons who act
only as private label distributors of drug products to register
establishments or list drugs, but allows them to submit drug listing
information as agents acting on behalf of persons who manufacture,
repack, relabel, or salvage drug products. The amendments make several
adjustments to the timing and substance of the submission of
information to register a drug establishment and list drugs
manufactured, repacked, relabeled, or salvaged at the establishment.
The amendments also update longstanding regulatory provisions governing
FDA disclosure of drug registration and listing information, stating
that with certain exceptions, establishment registration and drug
listing information is generally available for public disclosure.
    This final rule does not include certain aspects of the proposed
rule that were opposed by many who submitted comments. Features of the
proposed rule that have not been finalized include most significantly:
(1) A requirement that FDA, not registrants, develop national drug
codes (NDCs) for assignment to listed drugs and (2) a requirement that
the NDC appear in human-readable form on the label of each listed drug
and provisions that would have defined the appropriate NDC for that
purpose. As discussed in section III, revisions to the FD&C Act require
human-readable NDCs on certain drug labels.

Benefits and Costs

    All incremental costs from the final rule are one-time costs,
except for registrants' annually recurring costs of certifying no
change to listings upon annual registration for part 207 registrants.
We estimate one-time total costs of $59.7 million and recurring costs
of $0.5 million. These costs represent total annualized costs of $9
million when calculated at a 7-percent discount rate over 10 years, and
$7.5 million when calculated using a 3-percent discount rate. The
largest cost elements will be for registrants reading and understanding
the final rule and making changes to their standard operating
procedures.

                               Summary of Total Incremental Cost of the Final Rule
                                                  [$ millions]
----------------------------------------------------------------------------------------------------------------
                                                                     Recurring      Total costs     Total costs
                 Affected firms                   One-time costs       costs       annualized at   annualized at
                                                                     (annual)           7%              3%
----------------------------------------------------------------------------------------------------------------
Drugs and biological products (part 207)........           $48.9            $0.5            $7.5            $6.2
Human blood products (part 607).................             5.1             N/A             0.7             0.6
Human cell and tissue products (part 1271)......             5.7             N/A             0.8             0.7
                                                 ---------------------------------------------------------------
    Total \1\...................................            59.7             0.5             9.0             7.5
----------------------------------------------------------------------------------------------------------------
\1\ Total costs are annualized over a 10-year period. Recurring costs include only annual time costs of
  certifying that there are no changes to listings; these costs are unique to part 207. All estimates reflect
  rounded 2014 dollars.

    By codifying the statutory requirements of FDAAA and FDASIA, the
final rule clarifies and completes the modernization of our electronic
registration and listing systems. Thus, the final rule will improve
management of the establishment registration and drug listing
requirements and make these processes more efficient and effective for
industry and for us. The final rule also supports implementation of the
electronic prescribing provisions of the MMA and the availability of
current drug labeling information through DailyMed, a computerized
repository of drug information maintained by the National Library of
Medicine.

I. Background

    In the Federal Register of August 29, 2006 (71 FR 51276), FDA
proposed to amend its regulations governing drug establishment
registration and drug listing in part 207 (proposed rule). The proposed
rule included ancillary amendments to parts 20, 201, 314, 514, 515,
601, 607, and 1271 (21 CFR parts 20, 201, 314, 514, 515, 601, 607, and
1271). These amendments reorganize, modify, and clarify current
regulations concerning who must register establishments and list human
drugs, human drugs that are also biological products, and animal drugs.
The proposed rule and the final rule both specify that drug
establishment registration and drug listing information generally must
be submitted to FDA electronically.
    After the proposed rule was published, FDAAA was adopted into law.
FDAAA amended section 510(p) of the FD&C Act to require electronic
submission of drug establishment registration and listing information,
unless FDA waives the electronic submission requirement in individual
cases. In June 2009, FDA announced publication of a guidance for
industry on ``Providing Regulatory Submissions in Electronic Format--
Drug Establishment Registration and Drug Listing'' consistent with
FDAAA (74 FR 26248, June 1, 2009, available on the Internet at http://www.fda.gov/Drugs under Guidances (Drugs)) (the electronic registration
and listing guidance). This guidance applied to establishment
registration and listing required under part 207. It did not apply to
information required solely under part 607 (blood and blood products),
part 807 (devices), or part 1271 (human cells, tissues, and cellular
and tissue-based products). FDA generally stopped receiving drug
establishment registration and listing information required under part
207 submitted on paper in June 2009, allowing paper submissions only if
supported by a waiver from the electronic submission requirement in
individual cases. This final rule is consistent with the electronic
submission provisions of FDAAA.
    FDASIA made further amendments to section 510 of the FD&C Act in
2012 to specify that:
     Annual registration of establishments takes place during
the period beginning on October 1 and ending on December 31.
     The information registrants supply for annual registration
includes a Unique Facility Identifier (UFI) for the establishment and
includes a point-of-contact email address.
    This final rule includes changes to the proposed rule consistent
with these statutory provisions. The electronic registration and
listing guidance stated that FDA intended to use the Data Universal
Numbering System (DUNS) number, assigned and managed by Dun

& Bradstreet, as a registration number. In 2014, FDA announced
publication of a guidance for industry on ``Specifications of the
Unique Facility Identifier (UFI) System for Drug Establishment
Registration,'' (79 FR 65977, November 6, 2014, available on the
Internet at http://www.fda.gov/Drugs under Guidances (Drugs)), in which
FDA specified the DUNS number as the preferred UFI.

II. Overview of the Final Rule Including Changes to the Proposed Rule

A. Overview

    The final rule adopts significant amendments to FDA's regulations
governing drug registration and listing. It modernizes these
regulations to require electronic submission of drug establishment
registration and listing information and to otherwise match current
statutory requirements and FDA's information needs.
    The final rule:
     Makes minor technical amendments to Sec. Sec.  20.100,
20.116, and 201.1 (updating citations to regulations in part 207).
     Removes from Sec.  201.2 a statement about the manner in
which NDCs are displayed on drug labels.
     Amends Sec.  201.25 to allow an FDA Center Director to
approve an additional bar code standard or format.
     Revises part 207 significantly.
     Amends Sec.  314.81(b)(3)(iv) (requiring holders of
approved new drug applications (NDAs) to report the withdrawal of
approved drug products from sale) to make it consistent with part 207.
     Makes a minor conforming amendment to Sec.  314.125(b)(11)
(stating FDA may refuse to approve a new drug application if the drug
will be manufactured in whole or in part in an establishment that is
not registered and not exempt from registration under section 510 of
the FD&C Act and part 207).
     Adds new Sec.  514.111(a)(12) stating FDA will refuse to
approve a new animal drug application if the drug will be produced in
whole or in part in an establishment that is not registered and is not
exempt from registration under section 510 of the FD&C Act and part
207.
     Makes a minor technical amendment to Sec.  515.10(b)(8),
updating a reference to the regulations in part 207.
     Adds new Sec.  601.2(f) requiring holders of biologics
license applications (BLAs) to report to FDA electronically in
accordance with part 207 the withdrawal from sale of licensed
biological products.
     Amends part 607 (ESTABLISHMENT REGISTRATION AND PRODUCT
LISTING FOR MANUFACTURERS OF HUMAN BLOOD AND BLOOD PRODUCTS) consistent
with the amendments to part 207, to require electronic submission of
establishment registration and listing information.
     Amends part 1271 (HUMAN CELLS, TISSUES, AND CELLULAR AND
TISSUE-BASED PRODUCTS) to require electronic submission of
establishment registration and listing information, to state that
manufacturers of HCT/Ps that are regulated as drugs, devices, and/or
biological products under section 351 of the PHS Act (42 U.S.C. 262) or
under the FD&C Act are subject to registration and listing under part
207 or part 807, and to make other revisions consistent with the
amendments to part 207.

B. Changes to the Proposed Rule

    The final rule has been revised in response to comments received on
the proposed rule. Our responses are discussed in section III. The
final rule also includes several minor editorial revisions. The final
rule makes the changes summarized in table 1.

  Table 1--Substantive Changes From the Proposed Rule to the Final Rule
------------------------------------------------------------------------
 21 CFR Section in final
           rule               Description of change from proposed rule
------------------------------------------------------------------------
201.2....................  Labeling.
                               Does not include proposed
                               revisions to Sec.   201.2 requiring human-
                               readable NDCs on labels.
201.25...................  Bar code label requirements.
                               Revises Sec.   201.25(c)(1) to
                               accommodate alternatively formatted NDCs
                               in bar codes.
                               Does not include other proposed
                               amendments to Sec.   201.25.
207.1....................  Definitions.
                               Includes definitions for the
                               terms ``finished drug product,''
                               ``unfinished drug product,'' ``bulk drug
                               substance,'' ``private label
                               distribution,'' ``registrant,'' and
                               ``outsourcing facility'' not included in
                               the proposed rule.
                               States that the definitions and
                               interpretations of terms in sections 201
                               (21 U.S.C. 321) and 510 of the FD&C Act
                               apply to the terms used in part 207, if
                               not otherwise defined in Sec.   207.1.
                               Includes revised definitions of
                               the terms ``active pharmaceutical
                               ingredient,'' ``commercial
                               distribution,'' ``content of labeling,''
                               ``importer,'' ``manufacture,'' ``private
                               label distributor,'' ``relabel,''
                               ``repack,'' and ``representative sampling
                               of any other labeling''.
207.9....................  Who does this part cover?
                            Clarifies that private label
                            distributors are subject to part 207
                            (because they must have labeler codes).
                               States that all drugs regulated
                               under a BLA, except human blood or blood
                               products regulated under part 607, are
                               subject to part 207 and clarifies that
                               for this purpose certain products are not
                               included in the phrase ``human whole
                               blood and blood products''.
                               States that HCT/Ps regulated as
                               drugs under section 505 of the FD&C Act
                               (21 U.S.C. 355) or section 351 of the PHS
                               Act are subject to part 207.
207.13...................  Who is exempt from the registration and
                            listing requirements?
                               Generally exempts from
                               registration and listing individuals or
                               establishments engaged solely in
                               recovering cells or tissues to become
                               components of a biological product at a
                               registered establishment.
                               Eliminates a reference to
                               salvagers of inactive ingredients because
                               salvaging, as defined, is performed only
                               on finished drug products.
                               Revises Sec.   207.13 to clarify
                               the applicability of part 207 to
                               medicated feeds.
                               Revises Sec.   207.13 to remove a
                               reference to HCT/Ps made unnecessary by
                               revisions to Sec.   207.9.
                               Adds an exemption for outsourcing
                               facilities registered under section 503B
                               of the FD&C Act (21 U.S.C. 353b) so as to
                               avoid duplicative registration for those
                               entities.
                               Retains the previous
                               establishment registration exemptions for
                               certain drugs entering foreign trade
                               zones and certain drugs imported for
                               export.
207.17...................  Who must register?

                               Revises Sec.   207.17(b) to state
                               that FDA will accept establishment
                               registration or listing information
                               submitted by a private label distributor
                               if it is acting as an authorized agent
                               for an establishment that manufactures,
                               repacks, relabels, or salvages drugs.
207.25...................  What information is required for
                            registration?
                               Revises proposed Sec.   207.25 to
                               include the UFI required as part of
                               establishment registration under FDASIA.
207.29...................  What are the requirements for reviewing and
                            updating registration information?
                               Revises Sec.   207.29 to specify
                               that registrants must review and update
                               registration information between October
                               1 and December 31 each year, consistent
                               with FDASIA.
207.33...................  What is the National Drug Code (NDC), how is
                            it assigned, and what are its requirements?
                               Allows for 10- or 11-digit NDCs,
                               consistent with a longstanding statement
                               in Sec.   207.35(b)(2)(i), as it read
                               prior to this final rule, that FDA will
                               expand the NDC labeler code from 5 to 6
                               numeric characters when the available 5-
                               character code combinations are
                               exhausted.
                               States that registrants will
                               propose NDCs for assignment by FDA.
                               Includes formatting requirements
                               for registrants to follow when
                               formulating their own proposed NDCs.
                               Allows for alternatively
                               formatted NDCs for certain HCT/Ps.
                               Explains how a labeler code can
                               be obtained.
                               Allows registrants to reserve an
                               NDC for a drug product under development.
                               Eliminates proposed Sec.
                               207.33(c). (What information must a
                               manufacturer submit before we will assign
                               an NDC number to a drug?)
                               Adds some information elements
                               described in proposed Sec.   207.33(c) to
                               the drug listing information now
                               described in Sec.   207.49 (Added to the
                               listing information required under Sec.
                               207.49 are the names of inactive
                               ingredients in the listed drug and in the
                               case of an unfinished drug, the number
                               assigned to the Drug Master File or
                               Veterinary Master File, if any, that
                               describes the manufacture of the drug).
                               The option to submit an approved
                               U.S. application number instead of a list
                               of inactive ingredients for a finished
                               drug product (as proposed in Sec.
                               207.33(c)) is not retained in Sec.
                               207.49 of this final rule.
207.35...................  What changes require a new NDC?
                               Introduces new Sec.   207.35 to
                               more clearly explain what changes to
                               drugs require a new NDC and does not
                               include inactive ingredient changes in
                               this section.
207.37...................  What restrictions pertain to the use of the
                            NDC?
                               Revises Sec.   207.37 to state
                               that a product may be deemed to be
                               misbranded if an NDC is used improperly.
207.41...................  Who must list drugs and what drugs must they
                            list?
                               Revises Sec.   207.41 to clarify
                               the manner in which human drugs that are
                               manufactured, repacked, or relabeled for
                               private label distribution are listed.
207.45...................  When, after initial registration of an
                            establishment, must drug listing information
                            be submitted?
                               Revises Sec.   207.45 to state
                               that drug listing must take place no
                               later than 3 calendar days after initial
                               registration of an establishment, rather
                               than ``at the time of'' initial
                               registration.
207.49...................  What listing information must a registrant
                            submit for a drug it manufactures?
                               Revises Sec.   207.49 to reflect
                               that registrants will propose their own
                               NDCs under the final rule.
                               Eliminates the requirement of
                               proposed Sec.  Sec.   207.49(f),
                               207.53(c), and 207.54(b)(4) (which would
                               have required foreign establishments to
                               identify importers when listing drugs
                               they manufacture, repack, relabel, or
                               salvage). (This is now reported only as
                               establishment registration information
                               for foreign establishments.).
                               Expands the language of proposed
                               Sec.   207.49(d) (now Sec.
                               207.49(a)(11)) to make clear that a
                               registrant's own establishment(s) must be
                               identified in drug listing information as
                               well as other establishments involved in
                               the production of unfinished drugs
                               received by the registrant and to require
                               identification of all such establishments
                               using their UFIs.
                               Removes from proposed Sec.
                               207.49 the option to provide an approved
                               U.S. application number instead of
                               labeling.
                               Revises Sec.   207.49 (also Sec.
                               Sec.   207.1 and 207.53) to categorize
                               certain drug products according to
                               whether they are subject to sections 505
                               or 512 of the FD&C Act (21 U.S.C. 355 or
                               360b) or section 351 of the PHS Act,
                               rather than whether registrants regard
                               them as subject to those provisions.
                               Adds Sec.  Sec.
                               207.49(a)(15)(iv) and 207.53(d)(4) to
                               require the submission of labels for
                               listed drugs not elsewhere described in
                               Sec.  Sec.   207.49(a)(14) and 207.53(d).
                               Clarifies in new Sec.  Sec.
                               207.49(a)(15) and 207.53(f) the
                               information a registrant must submit when
                               listing a human drug manufactured for
                               private label distribution.
                               Adds Sec.   207.49(b) to describe
                               drug listing information that is
                               requested of registrants but not
                               required.
                               Adds Sec.   207.49(a)(2) so that
                               drug listing information includes package
                               size and type.
207.53...................  What listing information must a registrant
                            submit for a drug that it repacks or
                            relabels?
                               Shifts from proposed Sec.
                               207.33(d)(1)(iii) to new Sec.   207.53(b)
                               the requirement that for a repacked or
                               relabeled drug, registrants identify the
                               NDC assigned to the finished drug
                               received by the registrant for repacking
                               or relabeling and exempts repackaged
                               medical gases from this requirement.
                               Requires identification of
                               establishments where repacking, or
                               relabeling is performed based on their
                               UFIs rather than by their registration
                               numbers.
                               Clarifies that all current
                               labeling (new labeling) for a repacked or
                               relabeled drug must be submitted, not
                               only the changed labeling.
                               Specifies that for animal drugs
                               subject to section 512 of the FD&C Act,
                               all current labeling is submitted,
                               whereas a copy of the current label, and
                               other information, is submitted for other
                               animal drugs.
207.54...................  What listing information must a registrant
                            submit for a drug that it salvages?
                               Requires identification of
                               establishments where salvaging is
                               performed by their UFIs rather than by
                               their registration numbers.
                               Deletes references to salvaged
                               drugs distributed by private label
                               distributors.
207.57...................  What information must registrants submit when
                            updating listing information and when?
                               Revises proposed Sec.   207.57 to
                               improve clarity and to delete the
                               proposed requirement that registrants
                               routinely update information provided
                               under Sec.   207.55.

                               Allows registrants to submit a
                               blanket ``no changes'' certification
                               applicable to listing information they
                               have previously submitted electronically,
                               rather than making product-by-product
                               ``no changes'' certifications for
                               individual listed drugs.
207.61...................  How is registration and listing information
                            provided to FDA?
                               Revises Sec.   207.61 to improve
                               clarity, to state that we may
                               periodically issue guidance on electronic
                               registration and listing, and to clarify
                               that when foreign language labeling is
                               used under Sec.   201.15(c), the content
                               of labeling must be submitted in that
                               foreign language along with an accurate
                               English translation.
                               Removes the option to submit
                               advertisements and certain labeling in
                               paper format, consistent with the
                               electronic submission requirement of
                               section 510(p) of the FD&C Act, as
                               amended by FDAAA.
207.65...................  How can a waiver of the electronic submission
                            requirement be obtained?
                               Clarifies that requests for
                               waivers of the electronic submission
                               requirement cannot be relied upon until
                               FDA grants them.
                               States more broadly the
                               conditions under which FDA will grant
                               waiver requests.
                               Specifies that waiver requests
                               must be submitted in writing and must
                               state reasons why electronic submission
                               is not reasonable for the registrant.
                               States that FDA will specify
                               terms of waivers and may limit their
                               duration.
207.69...................  What are the requirements for an official
                            contact and a United States agent?
                               Revises proposed Sec.   207.69 to
                               state that designated official contacts
                               and United States agents are both
                               responsible for reviewing, disseminating,
                               routing, and responding to all
                               communications from FDA, including
                               emergency communications.
207.77...................  What legal status is conferred by
                            registration and listing?
                               Includes minor revisions to
                               improve clarity and mentions the UFI that
                               will be used to identify establishments.
207.81...................  What registration and listing information
                            will FDA make available for public
                            disclosure?
                               Reorganizes Sec.   207.81 so that
                               registration and listing information that
                               will be disclosed is described in
                               paragraph (a), and exceptions are
                               described in paragraphs (b) and (c).
                               Categorizes updated drug listing
                               information submitted under Sec.   207.57
                               as generally disclosable.
                               Adds Sec.   207.81(b)(2) to make
                               explicit that FDA will generally not
                               disclose the names of inactive
                               ingredients in listed drug products if
                               the registrant makes a valid assertion of
                               confidentiality.
                               Categorizes the information
                               submitted to reserve an NDC under new
                               Sec.   207.33(d)(3) as generally not
                               disclosable.
                               Categorizes the identities of the
                               establishments involved in manufacturing,
                               repacking, relabeling, or salvaging
                               listed drugs as generally not
                               disclosable.
                               Categorizes as generally not
                               disclosable the NDC assigned to an
                               unfinished drug received by a registrant
                               for use in the manufacture of a listed
                               drug reported under Sec.   207.49(a)(12)
                               (i.e., the association between the
                               unfinished drug and the listed drug is
                               generally not disclosable).
                               No longer categorizes the NDC
                               assigned to a drug immediately before it
                               is received by a registrant for salvaging
                               as generally not disclosable (because the
                               NDC assigned to a drug does not change
                               when a drug is merely salvaged and not
                               also repackaged or relabeled).
314.81...................  Other postmarketing reports (reporting the
                            discontinuation of a drug that is the
                            subject of an approved NDA).
 .                             Renumbers proposed Sec.
                               314.81(b)(3)(iii) as Sec.
                               314.81(b)(3)(iv) and revises this section
                               to provide for electronic or written
                               submissions in certain circumstances,
                               under both paragraphs (a) and (b).
601.2(f).................  Applications for biologics licenses
                            (reporting the discontinuation of a drug
                            that is licensed under a BLA).
                               Revises proposed Sec.   601.2(f)
                               to reference the electronic submission
                               requirement of Sec.   207.61 and the
                               waiver provision of Sec.   207.65 and to
                               clarify that the date on which the
                               product is expected to be no longer in
                               commercial distribution must be reported
                               rather than the ``date of withdrawal from
                               sale''.
607.1....................  Scope (Establishment registration and product
                            listing for manufacturers of human blood and
                            blood products.)
                               Adds a new scope provision (Sec.
                                607.1) to part 607 for clarity.
607.3....................  Definitions (Establishment registration and
                            listing for blood and blood products).
                               Adds a definition of ``foreign''.
                               Revises the proposed definition
                               of ``importer''.
607.22...................  How to register blood product establishments
                            and list blood products.
                               Revises proposed Sec.   607.22 to
                               remove references to Form FDA 2830 and to
                               state that blood product establishment
                               registration and blood product listing
                               must be transmitted to FDA electronically
                               through the Blood Establishment
                               Registration and Product Listing system,
                               unless FDA waives the electronic
                               submission requirement in individual
                               cases.
607.25...................  Information required for establishment
                            registration and blood product listing.
                               Removes references to Form FDA
                               2830.
                               Requires submission of a UFI when
                               registering blood and blood product
                               establishments along with a registration
                               number if previously assigned by FDA.
                               Adds the UFI of the parent
                               establishment to blood product listing
                               information required under Sec.
                               607.25(b)(3).
607.26...................  Amendments to establishment registration.
                               Revises Sec.   607.26 regarding
                               amendments to establishment registration
                               to reference the Blood Establishment
                               Registration and Listing System in place
                               of Form FDA 2830.
                               Clarifies that 5 days refers to 5
                               calendar days in this section.

607.30...................  Updating blood product listing information.
                               Revises Sec.   607.30 regarding
                               updates to blood product listing
                               information to reference the Blood
                               Establishment Registration and Listing
                               System in place of Form FDA 2830.
607.37...................  Public disclosure of establishment
                            registration and blood product listing
                            information.
                               Revises Sec.   607.37 to remove
                               references to Form FDA 2830.
                               Structures Sec.   607.37 in a way
                               that matches Sec.   207.81 (public
                               disclosure of drug registration and
                               listing information).
607.40...................  Establishment registration and blood product
                            listing requirements for foreign blood
                            product establishments.
                               Retains the exemptions applicable
                               to foreign trade zones and products
                               imported under section 801(d)(4) of the
                               FD&C Act (21 U.S.C. 381(d)(4)).

                               Revises proposed Sec.   607.40 to
                               state more broadly the circumstances
                               under which FDA will waive the electronic
                               submission requirement for foreign blood
                               product establishments.
607.80...................  Applicability of part 607 to licensed
                            devices.
                               Adds a new Sec.   607.80
                               clarifying the applicability of part 607
                               to certain licensed devices.
1271.1...................  What are the purpose and scope of this part?
                            (HCT/Ps)
                               Adds the word ``electronic'' in
                               place of ``unified'' in Sec.   1271.1.
1271.3...................  How does FDA define important terms in this
                            part?
                               Revises the definition of
                               ``importer'' in proposed Sec.
                               1271.3(mm) to include ``at the time of
                               entry''.
1271.20..................  If my HCT/Ps do not meet the criteria in Sec.
                              1271.10, and I do not qualify for any of
                            the exceptions, what regulations apply?
                               Adds a further amendment to Sec.
                                1271.20 to indicate that subpart B of
                               part 1271 (procedures for registration
                               and listing) does not apply to HCT/Ps
                               that do not meet the criteria set out in
                               Sec.   1271.10(a). (In other words, HCT/
                               Ps not regulated solely under section 361
                               of the PHS Act are subject to
                               registration and listing under part 207
                               or part 807 rather than part 1271.)
1271.25..................  What information is required for
                            establishment registration and HCT/P
                            listing?
                               Removes from proposed Sec.
                               1271.25(a)(6) the requirement that each
                               foreign HCT/P establishment designate
                               only one United States agent.
                               Removes a reference to Form FDA
                               3356 in proposed Sec.   1271.25(c)(4).
                               Revises proposed Sec.
                               1271.25(d) to clarify that it pertains to
                               HCT/Ps regulated under BLAs and to state
                               that establishment registration and
                               listing information for such products
                               must be submitted in accordance with the
                               electronic submission requirements of
                               part 207, subpart E.
------------------------------------------------------------------------

    This final rule does not include the proposed amendments to
Sec. Sec.  330.1, 610.60, and 610.61, all of which dealt with NDCs on
labels. This final rule also does not include the proposed minor
amendment to Sec.  1271.37 (regarding public disclosure of HCT/P
establishment registration and listing information) in light of the
technical amendments adopted on April 3, 2015 (80 FR 18087).
    Some changes from the proposed rule not addressed in section III
(Comments on the Proposed Rule) are addressed in the following
paragraphs.
    Active pharmaceutical ingredient: To prevent confusion, we proposed
to replace the term ``bulk drug substance'' with the more descriptive
term ``active pharmaceutical ingredient.'' This change is retained in
the final rule. Sections 503A(b)(1)(A) and 503B(a)(2) of the FD&C Act
(21 U.S.C. 353a(b)(1)(A) and 353b(a)(2)), however, refer specifically
to the definition of ``bulk drug substance'' within part 207. To ensure
conformity with the FD&C Act, both ``bulk drug substance'' and ``active
pharmaceutical ingredient'' are defined in Sec.  207.1 of the final
rule. As intended by the proposed rule, ``active pharmaceutical
ingredient'' will have the same meaning as ``bulk drug substance.''
    Salvage: In this final rule, the term ``salvage'' is defined to
mean the act of segregating out those finished drug products that may
have been subjected to improper storage conditions (such as extremes in
temperature, humidity, smoke, fumes, pressure, age, or radiation) for
the purpose of returning the products to the marketplace and includes
applying manufacturing controls such as those required by current good
manufacturing practice in parts 210 and 211 (21 CFR parts 210 and 211).
Substantively, this matches the definition of ``drug product
salvaging'' included in the proposed rule, but the words have been
rearranged for greater clarity. This final rule also includes a
definition for the term ``salvager.''
    Establishment registration number and Unique Facility Identifier:
We proposed to define the term ``establishment registration number'' in
Sec.  207.1 to mean ``the number assigned by FDA to the establishment
during the establishment registration process required in this part.''
The final rule changes the definition of ``establishment registration
number'' slightly to state that the number is assigned ``after'' the
registration process, rather than ``during.''
    The establishment registration number identifies establishments for
inspection by FDA. Historically, an establishment registration number
is assigned to each establishment of each manufacturer, repacker,
relabeler, or salvager after the initial registration, when such
activities begin. In the preamble to the proposed rule, we explained
that ``[c]urrently, the FDA Establishment Identifier (FEI) will be the
number we assign as the establishment registration number. In the
future, however, we may use a different number as the establishment
registration number'' (71 FR 51276 at 51288).
    After the proposed rule was published, FDASIA amended section 510
of the FD&C Act to require persons subject to the drug establishment
registration requirement to submit a UFI. In the electronic
registration and listing guidance, FDA stated that it intended to use
the DUNS number, assigned and managed by Dun & Bradstreet, as a
registration number. To implement the UFI provision of FDASIA, FDA also
issued guidance in 2014 that specified the DUNS number as the preferred
UFI.\1\
---------------------------------------------------------------------------

    \1\ See the guidance for industry ``Specification of the Unique
Facility Identifier (UFI) System for Drug Establishment
Registration,'' November 2014, available on the Internet at http://www.fda.gov/Drugs under Guidances (Drugs).
---------------------------------------------------------------------------

    Under the final rule, the establishment registration number and the
UFI are two distinct numbers. For now, FDA will continue to assign an
FEI as the establishment registration number after an establishment is
registered for the first time. The final rule requires registrants to
submit the establishment registration number (currently the FEI), ``if
previously assigned by FDA,'' under Sec.  207.25. Someone registering
an establishment for the first time is not expected to have a
registration number for the establishment. Such a registrant is
required to submit its registration number at the time of the first
annual review and update of registration information under Sec.
207.29(b) of this final rule and is encouraged to submit the
registration number sooner, as soon as it is received from FDA. The
establishment registration number does not need to be submitted at the
time of each annual registration update under Sec.  207.29 unless the
establishment registration number has changed. Likewise, the UFI,
currently specified as

the DUNS number, must be submitted when registering an establishment
for the first time under Sec.  207.25. The UFI does not need to be
submitted at the time of each annual registration update under Sec.
207.29 unless the UFI has changed.
    Bar code label requirements (Sec.  201.25): As explained in section
III, this final rule does not include two proposed amendments to Sec.
201.25. It does, however, include a minor new amendment to Sec.
201.25. To accommodate the possibility of alternatively formatted NDCs
in bar codes, Sec.  201.25 is amended in this final rule to allow FDA's
Center Directors to approve additional standards or formats for bar
codes.
    Submission of approved U.S. application number instead of inactive
ingredients (Sec.  207.33(c)(2)): Information registrants would have
submitted under Sec.  207.33(c) of the proposed rule to obtain an NDC
has been shifted to drug listing information required under Sec.
207.49 of this final rule. Under Sec.  207.49(a)(5) of this final rule,
a registrant must provide the name of each inactive ingredient in a
listed drug it manufactures. The option to submit an approved
application number instead of a list of inactive ingredients is not
retained in the final rule because FDA is not currently able to pull
inactive ingredient information from approved applications to our drug
listing systems.

III. Comments on the Proposed Rule

    In the Federal Register of October 31, 2006 (71 FR 63726), FDA
announced an extension of the comment period for this rulemaking and a
public meeting to discuss the proposed changes to the NDC system
presented in the proposed rule. The public meeting was held on December
11, 2006. In the Federal Register of February 8, 2007 (72 FR 5944), FDA
announced a reopening of the comment period because technical problems
prevented some persons from submitting comments electronically on the
last day of the previous comment period. The Agency received numerous
comments, including oral presentations made at the December 2006 public
meeting and approximately 200 written comments placed in the docket.
Comments were received from prescription and nonprescription drug
manufacturers and related companies, trade associations representing
drug manufacturers and other interested parties, academic institutions,
and professional associations.
    The docket for this rulemaking, Docket No. FDA-2005-N-0464, was
also used to collect comments on FDA's draft guidance for industry
entitled ``Providing Regulatory Submissions in Electronic Format--Drug
Establishment Registration and Drug Listing'' (74 FR 26248). In this
final rule, we are responding to comments that pertain to the
rulemaking, i.e., comments that relate to the changes in regulations
proposed on August 29, 2006.
    To make it easier to identify comments and our responses, the word
``Comment,'' in parentheses, appears before the comment's description,
and the word ``Response,'' in parentheses, appears before our response.
We have numbered each comment to help distinguish between different
comments. Similar comments are grouped together under the same number.
The number assigned to each comment is purely for organizational
purposes and does not signify the comment's value or importance or the
order in which comments were received.

A. Labeling (Sec. Sec.  201.2 and 201.25)

    The proposed rule included amendments to Sec.  201.2 that would
have required drugs subject to the listing requirement of part 207 to
have labels that bear the appropriate NDC in human-readable form. As
discussed in this document, this final rule does not include the
proposed amendments that would have made human-readable NDCs mandatory
on drug labels.
    Section 201.2 currently states that NDCs are ``requested but not
required'' to appear on all drug labels. Section 201.25 currently
requires bar codes on prescription human drug labels with certain
exceptions and on certain nonprescription human drug labels. Section
201.25(c) currently specifies that each bar code must contain, at a
minimum, the appropriate NDC.
    Sections 201.2 and 201.25 currently do not specify which NDC should
appear on labels and in bar codes apart from referring to it as ``the
appropriate'' NDC (Sec.  201.25(c)). This implies that the NDC
appearing on a drug's label match an NDC under which the drug is
appropriately listed under part 207.
1. NDC Numbers (Sec.  201.2)
    Pharmacists and health care providers use NDCs currently appearing
on drug labels in a variety of ways, including to help prevent
medication errors and to process prescription drug reimbursement
claims. We believe there is currently a high level of cooperation with
FDA's request in Sec.  201.2 that NDCs appear in human-readable form on
labels, as drug manufacturers recognize the importance of this
information.
    In addition to making human-readable NDCs on drug labels mandatory,
the proposed rule would have specified which NDC must appear on labels.
Specifically, proposed Sec.  201.2(b) sought to define the appropriate
NDC for this purpose as being that of the last manufacturer, repacker,
relabeler, or private label distributor responsible for the drug
immediately before it is received by the wholesaler or retailer.
    (Comment 1) Several comments recognized the importance of having
NDCs in human-readable form on labels, but many objected to FDA's
proposed provisions defining the appropriate NDC in proposed Sec.
201.2(b). In particular, certain repackers objected to the proposed
requirement that a repacker's NDC, rather than that of the original
manufacturer, appear on the labels of repackaged drug products.
    (Response) This final rule does not include the proposed amendments
to Sec.  201.2 that would have made human-readable NDCs mandatory on
drug labels. It includes only a conforming amendment to that section
(replacing the reference to Sec.  207.3(b)(3) with an updated reference
to new Sec.  207.1).
    The Drug Quality and Security Act (DQSA) (Pub. L. 113-54) of 2013
includes as Title II the Drug Supply Chain Security Act (DSCSA). The
DSCSA requires drug manufacturers and repackagers (as defined in
sections 581(10) and 581(16) of the FD&C Act, respectively) to affix or
imprint a product identifier on packages for certain prescription drugs
for human use. Under section 581(14) of the FD&C Act, a ``product
identifier'' is a standardized graphic that includes, in both human-
readable form and on a machine-readable data carrier, the
``standardized numerical identifier,'' lot number, and expiration date
of the product. The NDC is one component of the standardized numerical
identifier. FDA has determined that because the DSCSA requires the
inclusion of NDCs on certain prescription drug labels (as part of a
product identifier), it is unnecessary to include the proposed
amendments to Sec.  201.2 in this final rule.
    Our determination that the proposed amendments to Sec.  201.2
should not be finalized renders moot many comments concerning
identification of the appropriate NDC for labeling purposes, along with
placement and formatting issues. Therefore, we do not respond to those
comments.
    The DSCSA does not require manufacturers or repackagers to affix or
imprint product identifiers on nonprescription human drug products or
on animal drugs. Therefore, we will maintain the status quo for those
drug products, meaning FDA will continue to request that NDCs in human-
readable

form appear on all drug labels and in all drug labeling, as indicated
in Sec.  201.2. We may revisit a regulatory requirement that human-
readable NDCs appear on the labels of nonprescription human drug
products and animal drugs in the future.
2. Bar Code Label Requirements (Sec.  201.25)
    Section 201.25 currently requires that a human drug product's NDC
be included in its bar code. We proposed to amend Sec.  201.25 in two
minor ways: (1) To add a cross-reference to proposed new Sec.
201.2(b), which would have described the ``appropriate NDC'' for
labeling purposes and (2) to add new Sec.  201.25(e) stating that a bar
code may be displayed on certain drug product labels voluntarily but
only if it meets the requirements of Sec.  201.25(c). Neither proposed
amendment to Sec.  201.25 is retained in the final rule.
    (Comment 2) The Animal Health Institute expressed concern that
proposed Sec.  201.25(e) would unreasonably burden its members who,
although they are not currently required by Sec.  201.25 to place bar
codes on animal drug labels (because it applies to human drugs), may do
so for logistical reasons. They asked that the animal health industry
be exempt from the requirement to include an NDC in any bar codes
appearing on animal drug labels. Similar comments were received from
manufacturers of allergenic extracts. Allergenic extracts are currently
exempt from the bar code requirement (see Sec.  201.25(b)(1)(i)(B)).
Commenters explained that manufacturers of allergenic extracts may
place bar codes on their labels for inventory, warehousing, and other
logistical purposes. They objected to proposed Sec.  201.25(e) to the
extent that it would require such bar codes to include NDCs.
    (Response) FDA has not retained proposed Sec.  201.25(e) in this
final rule.
    (Comment 3) A group of comments asserted that 11-digit NDCs cannot
be encoded into a bar code that meets European Article Number/Uniform
Code Council or Health Industry Business Communications Council
standards, as required by current Sec.  201.25(c). Another comment
urged FDA to remove the NDC from bar codes.
    (Response) This final rule acknowledges that 10-digit NDCs will be
exhausted at some point in the future as a mathematical inevitability.
As discussed in our response to Comment 52, this final rule reduces the
number of occasions when a change to a drug requires a new NDC under
Sec.  207.35. This final rule also amends Sec.  201.25 to allow FDA's
Center Directors to approve additional bar code standards and formats.
    As discussed in response to Comment 1, the DSCSA requires the
inclusion of product identifiers on prescription human drug labels and
defines ``product identifier'' to mean a standardized graphic that
includes, in both human-readable form and on a machine-readable data
carrier the standardized numerical identifier, lot number, and
expiration date of the product. The standardized numerical identifier,
a component of the product identifier, is comprised of the NDC and a
serial number.
    FDA continues to recognize the importance of NDCs on drug labels in
both machine-readable and human-readable form. We remind manufacturers
of the current requirement in Sec.  201.25 that bar codes on human drug
labels include the appropriate NDC, and we encourage manufacturers to
continue to provide the NDC in human-readable form on drug labels where
not required by the DSCSA.

B. General Information (Part 207, Subpart A)

1. What definitions and interpretations of terms apply to this part?
(Sec.  207.1)
    The proposed rule included a set of terms and definitions in
Sec. Sec.  207.1, 607.3, and 1271.3. These definitions are retained in
the final rule with several modifications. Additionally, the final rule
includes definitions for the terms ``finished drug product,''
``unfinished drug product,'' ``bulk drug substance,'' ``outsourcing
facility,'' ``private label distribution,'' and ``registrant'' in Sec.
207.1 and a definition of ``foreign'' in Sec.  607.3.
    a. Commercial distribution. In the proposed rule, the definition of
``commercial distribution'' excluded ``the internal or interplant
transfer of an active pharmaceutical ingredient between registered
establishments within the same parent, subsidiary, and/or affiliate
company.''
    In the final rule, the definition does not include the phrase ``an
active pharmaceutical ingredient'' so that internal or interplant
transfers between such registered establishments are not treated as
commercial distribution under part 207, whether the transfer involves
active pharmaceutical ingredients, other unfinished drug products, or
finished drug products.
    (Comment 4) A comment suggested that the definition of ``commercial
distribution'' be revised to exclude transfers between a registered
establishment and a marketing authorization holder when the two are in
a contractual relationship. Otherwise, this comment argued, products
marketed by private label distributors who employ contract
manufacturers are held to a higher burden of documentation than
products manufactured and distributed by the same entity.
    (Response) We disagree with the suggestion that a transfer of drugs
from a contract manufacturer to another contracting party should not
qualify as commercial distribution. Such an exemption would interfere
with FDA's ability to track drugs and establishments for inspection.
However, by revising the definition of ``commercial distribution'' to
exclude internal or interplant transfers of drugs, including active
pharmaceutical ingredients, other unfinished drugs, and finished drug
products, between registered establishments under common ownership and
control, we have reduced the drug listing burden generally. This
exclusion accommodates the common practices of specialized
manufacturing at different registered establishments under common
ownership and control. This practice often results in multiple internal
and interplant transfers of these materials prior to marketing, which
we do not consider commercial distribution for registration and listing
purposes.
    b. Content of labeling. The proposed rule included a multipart
definition for the term ``content of labeling'' with separate
provisions applicable to:
     Human prescription drugs that the manufacturer regards as
subject to section 505 of the FD&C Act or section 351 of the PHS Act,
i.e., subject to premarket approval from FDA;
     Human prescription drugs that the manufacturer regards as
not subject to section 505 of the FD&C Act or section 351 of the PHS
Act;
     Human nonprescription drugs; and
     Animal drugs.
    The term ``content of labeling'' was used in the proposed rule to
describe some, but not all, labeling that must be submitted with drug
listing information. For example, proposed Sec.  207.49(g)(2)(i) stated
that listing information for certain human over-the-counter (OTC) drugs
must include ``all current labeling . . . including the content of
labeling.'' Content of labeling is defined in a very similar way in the
final rule with deletion of the phrase ``that the manufacturer regards
as'' and the addition of a reference to the labeling requirements for
veterinary drugs in 21 CFR part 201.

    We removed the language ``that the manufacturer regards as subject
to section 505 [or 512] of the FD&C Act or section 351 of the PHS Act''
and added in its place language that refers to drugs as being either
subject or not subject to those provisions. We made this change after
determining that the manner in which content of labeling is defined
should not depend on a manufacturer's subjective understanding or
intent with respect to sections 505 or 512 of the FD&C Act or section
351 of the PHS Act.
    The revised definition includes, among others, the category ``human
prescription drugs that are not subject to section 505 of the FD&C Act
or section 351 of the PHS Act.'' We have retained this construction
even though FDA considers it unlikely that any currently marketed human
prescription drug product is grandfathered or is otherwise not a new
drug subject to those provisions. However, the Agency recognizes that
the existence of such drugs is at least theoretically possible. No part
of this final rule is a finding as to the legal status of any
particular drug product.
    Regarding animal drugs, in part four of the definition of ``content
of labeling'' and in other places throughout this final rule, the
phrase ``subject to section 512'' means, for purposes of this final
rule, drugs meeting the definition of ``new animal drug'' as that term
is defined in section 201(v) of the FD&C Act, and which therefore are
subject to some or all of the provisions relating to new animal drugs
found in section 512 of the FD&C Act. This term includes not only new
animal drugs that are approved under section 512 but also new animal
drugs that are conditionally approved under section 571 of the FD&C Act
(21 U.S.C. 360ccc) or indexed under section 572 of the FD&C Act (21
U.S.C. 360ccc-1). The phrase ``all other animal drugs'' as used in
provisions of this final rule at Sec. Sec.  207.49(a)(15)(iii) and
207.53(d)(3) describing the labeling registrants must provide as part
of the listing for an animal drug, refers to animal drugs that do not
meet the definition of new animal drug found in section 201(v) of the
FD&C Act (e.g., grandfathered animal drugs). Although the Agency
recognizes that the existence of such animal drugs is theoretically
possible, we believe it is unlikely that any currently marketed animal
drug product is grandfathered or otherwise not a ``new animal drug''
subject to section 512 of the FD&C Act.
    (Comment 5) Commenters asked FDA to clarify how content of labeling
differs from package inserts and final printed labeling.
    (Response) A prescription human drug product's FDA-approved
labeling is sometimes referred to as a ``package insert'' or as
``professional labeling.'' In defining the term ``content of
labeling,'' for human drugs, we use the phrase ``prescription drug
labeling'' (instead of ``package insert'' or ``professional labeling'')
to mean FDA-approved labeling for prescription drug products described
in Sec. Sec.  201.56, 201.57, and 201.80. For human prescription drugs
that are subject to section 505 of the FD&C Act or section 351 of the
PHS Act, content of labeling is defined as the content of the
prescription drug labeling. For human OTC drugs, content of labeling is
not defined in these terms; it includes ``all text, tables, and figures
including the drug facts labeling required by Sec.  201.66.'' For
animal drugs, ``content of labeling'' is defined to mean labeling that
accompanies the drug that is necessary to enable safe and proper
administration of the drug. This would generally include package
inserts and final printed labeling. Sections 207.49 and 207.53 require
submission of labeling with drug listing information. In most cases,
all current labeling must be submitted, including the content of
labeling.
    (Comment 6) A comment stated that FDA should more clearly delineate
between the terms ``label'' and ``labeling'' throughout the rulemaking,
rather than using the term ``labeling'' to refer to both. This comment
pointed out that the proposed rule's definition of content of labeling
for human OTC drugs referred to ``labeling required by Sec.  201.66,''
but Sec.  201.66 pertains to information appearing on the ``outside
container or wrapper of the retail package, or the immediate container
label if there is no outside container or wrapper'' (Sec.  201.66(c)).
    (Response) We have clarified in Sec.  207.1(a) of the final rule
that the definitions and interpretations of terms in sections 201 and
510 of the FD&C Act apply to the terms used in part 207 unless
otherwise defined. Accordingly, the term ``label'' means a display of
written, printed, or graphic matter upon the immediate container of any
article consistent with section 201(k) of the FD&C Act. The term
``labeling'' more broadly includes both immediate container labels and
other written, printed, or graphic matter accompanying such article
consistent with section 201(m) of the FD&C Act. When we intend to refer
only to immediate container or package labels, we use the term
``label.'' More often, we use the broader term ``labeling'' in this
final rule to encompass both immediate container labels and/or other
written, printed, or graphic matter accompanying the drug, as the
labeling definition in section 201(m) of the FD&C Act has been
interpreted. The term ``content of labeling'' is defined slightly
differently for human prescription drugs, human OTC drugs, and animal
drugs, and the term is intended to encompass both labels and labeling.
    The proposed rule (proposed Sec.  207.1) referred only to
definitions in section 510 of the FD&C Act, and the preamble to the
proposed rule suggested that reference to the definitions in section
201 of the FD&C Act was intentionally omitted (71 FR 51276 at 51285).
Consistent with 21 CFR 1.1(b), this final rule clarifies that the
definitions in section 201 of the FD&C Act apply to the terms used in
part 207.
    c. Establishment. We proposed to define ``establishment'' in Sec.
207.1 as ``a place of business under one management at one geographic
location.'' The definition in proposed Sec.  207.1 also stated ``one
geographic location may include separate buildings within the same city
if their activities are closely related to the same business enterprise
and are under the supervision of the same local management.''
    Rather than adopt this proposed definition, the final rule retains
the definition of the term ``establishment'' that has appeared in the
part 207 regulations since 1980. This definition states that an
establishment is ``at one general physical location.''
    (Comment 7) One comment suggested that the phrase ``within the same
city'' used in the proposed definition of ``establishment'' was too
specific. This comment argued that a manufacturing facility located in
a city with a warehouse located just outside that city should together
be treated as a single establishment for registration purposes.
    (Response) In reviewing this comment and considering it in light of
the longstanding definition of ``establishment'' and the objectives
behind the establishment registration requirement, we determined that
the existing definition in part 207 is clearer and better serves our
objectives than would the proposed amended definition. The longstanding
language, ``one general physical location,'' generally restricts a
single establishment to one street address or one or more contiguous
plots of land. We do not agree with the comment that a second facility
located in a different city should be covered by the first facility's
establishment registration.
    We note, however, that a facility operated only as a warehouse may
not require registration. Section 510 of the FD&C Act and Sec.  207.17
of this final rule

require registration of establishments where drugs are manufactured,
repacked, relabeled, or salvaged. A facility at which drugs are merely
stored may not require registration under this final rule, unless the
facility includes, for example, controlled storage for stability
testing as an element of good manufacturing practices. Other Federal
and State requirements may apply to such facilities.
    Likewise, the corporate headquarters of a drug establishment should
not register under this rule if drugs are not manufactured, repacked,
relabeled, or salvaged at that location.
    d. Foreign. We proposed to use the term ``foreign'' to refer to a
manufacturer, repacker, relabeler, drug product salvager, or private
label distributor who is located in a foreign country and who
manufactures, repacks, relabels, salvages, or distributes a drug that
is imported or offered for import into the United States. When used to
modify ``establishment,'' we proposed to use ``foreign'' to refer to an
establishment that is located in a foreign country and is the site
where a drug that is imported or offered for import into the United
States was manufactured, repacked, relabeled, salvaged or distributed.
    We have omitted the words ``or distributed'' from this definition
because only establishments at which drugs are manufactured, repacked,
relabeled, or salvaged are required to be registered.
    (Comment 8) One comment urged us to revise the definition of
``foreign'' to mean ``located in a foreign country'' while stating in
Sec.  207.9 that part 207 applies to foreign entities who import or
offer for import products into the United States.
    (Response) We do not agree that the proposed rule was confusing or
difficult to understand in this respect and have decided against making
this change.
    e. Importer. Section 207.25 of this final rule and section 510(i)
of the FD&C Act require foreign establishments, when registering, to
provide names and contact information for each importer in the United
States of drugs manufactured, repacked, relabeled, or salvaged at the
establishment that is known to the establishment. We proposed to define
``importer'' to mean, in part, ``a company or individual in the United
States that is an owner, consignee, or recipient of the foreign
establishment's drug that is imported into the United States.'' In
proposing this language, we recognized that a foreign establishment may
have more than one importer, and we proposed to include in this term
any owner, consignee, or recipient, even if not the initial owner,
consignee, or recipient, of the foreign establishment's drug that is
imported into the United States.
    (Comment 9) Some comments stated that our proposed definition of
the term ``importer'' was too broad and would increase the burden on
manufacturers to provide unnecessary information concerning a wide
variety of entities that are not responsible for the drug. One comment
noted that the inclusion of downstream recipients in our definition of
``importer'' would impose a significant reporting burden on foreign
establishments that is not required of domestic establishments.
    (Response) We agree that we should clarify and narrow the proposed
definition of ``importer.'' As proposed, the definition included every
U.S. recipient of a foreign-produced drug, excepting only the final
consumer or patient. Of this large group, foreign establishments would
be required to identify in their establishment registration submissions
only those importers that are known to the establishment. To make this
information element more useful to FDA and to reduce the burden on
registered establishments, we have determined that in this context the
term ``importer'' should include a U.S. owner, consignee, or recipient
at the time of the drug's entry into the United States and should not
include additional subsequent owners, consignees, or recipients of the
drug. We have revised the definition of importer in Sec.  207.1 of the
final rule accordingly.
    (Comment 10) One comment recommended that we change ``company or
individual'' to ``person,'' in the rule's definition of ``importer,''
consistent with the definition of the term ``person'' in section 201(e)
of the FD&C Act.
    (Response) We agree that the term ``person,'' as defined in the
FD&C Act, is an improvement over ``company or individual'' in this
definition. We have made this change in Sec. Sec.  207.1 and 607.3 of
the final rule, and as discussed in our response to comment 6, we have
also added a statement in Sec. Sec.  207.1(a) and 607.3(a) that the
definitions and interpretations of terms in sections 201 and 510 of the
FD&C Act apply if not otherwise defined.
    f. Person who imports or offers for import. Section 207.25 of this
final rule and section 510(i) of the FD&C Act also require foreign
establishments, when registering, to supply names and contact
information for each person who imports or offers for import drugs
manufactured, repacked, relabeled, or salvaged at the establishment.
The proposed rule's definition of ``person who imports or offers for
import'' included ``an agent, broker, or other entity, other than a
carrier, that the foreign establishment uses to facilitate the import
of its drug into the United States.'' We invited comments on the use
and interpretation of the term ``facilitate.''
    (Comment 11) Some comments expressed concern regarding the
potential breadth of this definition, noting in particular that the
word ``facilitate'' could, in theory, encompass entities such as
foreign insurance adjusters, underwriters, and international banks.
Commenters pointed out the significant burden associated with the
identification of such entities in foreign establishment registrations
and updates to registrations, noting that international supply chains
and business relationships are not static. One comment urged FDA to
exclude customs brokers from the rule's definition of ``person who
imports or offers for import.'' Another comment encouraged FDA to
exclude middlemen from this definition, as their identities would
change frequently.
    (Response) Although we did not intend for the word ``facilitate''
to be read as broadly as some comments suggested, FDA agrees that the
definition of ``person who imports or offers for import'' should be
made more precise, narrow, and useful.
    We note, as a matter of clarification, that in section 510(i) of
the FD&C Act and in Sec.  207.25 of the final rule, the requirement
that foreign establishments identify each person who imports or offers
for import is not said to be limited to persons known to the
establishment (unlike the requirement that they identify
``importers''). The preamble to the proposed rule included statements
that were inconsistent with the FD&C Act in this regard, suggesting
that foreign establishments would be required to report the name of
each person known to the establishment who imports or offers for import
its drug(s) into the United States. See, e.g., 71 FR 51276 at 51289. In
fact, the proposed rule (proposed Sec.  207.25), the final rule, and
the FD&C Act all require foreign establishments to report, when
registering, the name of each person who imports or offers for import
its drug(s) into the United States without regard to whether such
persons are known to the establishment. Therefore, it is important that
we define ``person who imports or offers for import'' in a way that is
practical, useful, and consistent with this understanding.

    Our intention in defining this term is to include foreign persons
who are primarily responsible for sending a drug to the United States.
Foreign establishments are reasonably expected to know the identities
of such persons. In many cases, the establishment itself will be a
person who imports or offers for import its drugs into the United
States. In other cases, it will be a person the foreign establishment
engages to send one or more drugs to the United States. It will
generally be the foreign person who owns the drug and sells or enters
into a contractual obligation to supply the drug to a person in the
United States.
    In light of the comments received and FDA's objectives, the final
rule defines ``person who imports or offers for import'' to mean the
owner or exporter of a drug who consigns and ships a drug from a
foreign country to the United States. This definition includes persons
who send a drug to the United States by international mail or other
private delivery service, but does not include carriers who merely
transport the drug. This definition is not intended to include persons
operating merely as customs brokers.
    g. Manufacture, manufacturer. The definitions of ``manufacture''
and ``manufacturer'' in Sec.  207.1 of this final rule include minor
editorial revisions for clarity and new references to animal feed
bearing or containing a new animal drug.
    (Comment 12) Some comments stated that the definition of
``manufacturer'' should specify that it applies only to entities
manufacturing drugs for commercial distribution.
    (Response) We disagree with the recommendation that the definition
of ``manufacturer'' be limited to drugs manufactured ``for commercial
distribution.'' The underlying statutory provisions require
registration of establishments where drugs are manufactured, without
regard to commercial distribution (section 510(c) of the FD&C Act), but
require listing of drugs that are manufactured for commercial
distribution (section 510(j) of the FD&C Act). Accordingly, under Sec.
207.17 of this final rule, each domestic establishment where a drug is
manufactured (or repacked, relabeled, or salvaged) must be registered
unless exempt from registration under section 510(g) of the FD&C Act or
under Sec.  207.13, regardless of whether the drug is commercially
distributed. The drug listing obligation, as described in Sec.  207.41,
applies to drugs that are manufactured, repacked, relabeled, or
salvaged for commercial distribution. (See separate definition of
``commercial distribution.'')
    (Comment 13) One comment asked that drug sponsors be included in
the definition of manufacturer. Other comments suggested that FDA add
``product formulator'' to the definition of ``manufacturer'' or provide
definitions for terms such as ``drug sponsor.'' These comments pointed
out that the holder of an approved application, such as an NDA, or the
formulator of a nonprescription monograph product may use a contract
manufacturer to produce the product for distribution under the name of
the application holder or the product formulator. Some comments
recommended that the final rule treat such application holders or
product formulators as manufacturers so they would register their
establishments and list such products and that it exempt contract
manufacturers from the drug listing requirement.
    (Response) We decline to add the application holder or ``product
formulator'' concepts to the definition of ``manufacturer.'' Under
section 510(c) of the FD&C Act, the obligation to register drug
establishments rests on owners or operators of establishments engaged
in the manufacture (including repacking, relabeling, and salvaging) of
drugs, and the listing obligation applies to ``every person who
registers.'' FDA recognizes that this language could be read broadly to
encompass entities that develop or formulate drug products without
performing manufacturing operations. However, considering the
objectives behind drug registration and listing, we are currently
interested in the registration of establishments where manufacturing
operations (including repacking, relabeling, and salvaging) take place
and the listing of drugs handled at those establishments.
    We recognize, however, that an application holder or a product
formulator using a contract manufacturer to manufacture a drug may wish
to submit drug listing information for that product directly to FDA.
Although the actual manufacturer of the drug has the legal obligation
to list it, FDA would accept listing information for the drug submitted
by its formulator or any other person acting as an authorized agent for
the manufacturer. When we use the term ``authorized agent'' in this
final rule, we mean a person who is authorized to act on behalf of
another. The term ``authorized agent'' should not be confused with the
United States agent referred to in Sec.  207.69(b).
    (Comment 14) Several comments asked for clarification on how the
terms ``manufacture,'' ``repackage,'' ``relabel'' and ``private label
distributor'' would apply to the medical gas industry and pointed out
that certain medical gas operations, such as the transfilling of gas
from one container to another, have long been treated as drug
manufacturing by FDA but, under the proposed rule, would seem to
qualify as ``repacking.'' These comments asked FDA to classify medical
gas refillers as ``manufacturers'' rather than ``repackers'' in the
final rule.
    (Response) FDA agrees that these important points require
clarification. Nothing in this final rule is intended to alter the
definitions applicable to FDA's regulations governing current good
manufacturing practices for drug products, parts 210 and 211.
Therefore, the definition of ``manufacture, processing, packing, or
holding of a drug product'' currently appearing in Sec.  210.3(b)(12)
will continue to apply to medical gases as that definition has always
applied.
    For purposes of part 207, we will interpret the definition of
``manufacture'' in Sec.  207.1 as including the initial manufacturing
process that produces or purifies a medical gas, whether by air
separation, chemical reaction, or other process. Additionally, the
mixing of two or more medical gases to produce a combination would also
qualify as ``manufacture'' under Sec.  207.1. The impact of this
interpretation is that a person who thus qualifies as a manufacturer of
a medical gas will be required to submit the drug listing information
required under Sec.  207.49 of this final rule (``What listing
information must a registrant submit for a drug it manufactures?'') in
addition to registering the establishment(s) at which manufacturing is
conducted.
    All subsequent transfillings of a medical gas from one container to
another (i.e., from tanker trucks into standing tanks and from standing
tanks into smaller containers, etc.) would fall within the definition
of ``repack or repackage'' in Sec.  207.1 of this final rule. The
impact of this interpretation is that a person who thus qualifies as a
repacker of a medical gas will be required to submit the drug listing
information required under Sec.  207.53 of this final rule (``What
information must a registrant submit for a drug that it repacks or
relabels?'') in addition to registering the establishment(s) at which
repackaging is conducted. Comments opposing this classification
expressed concern that under the proposed rule, repackers would be
required to identify the NDC assigned to a drug immediately before it
is received by the repacker as information that must be submitted to
obtain an NDC for a repackaged drug

under proposed Sec.  207.33(d)(1)(ii). See our response to Comment 73
regarding an exemption for medical gases from the requirement that
registrants submit such source NDCs for drugs they repackage or
relabel.
    The definition of ``relabel'' in Sec.  207.1 of this final rule
applies to medical gases. It refers to changing or altering the
existing label on a drug or drug package, without repacking the drug or
drug package. A person who places a label on a repackaged drug (e.g., a
medical gas recently filled into a canister) for the first time
qualifies as a ``repackager'' as that term is defined in this final
rule.
    The term ``private label distributor'' is defined in Sec.  207.1 of
this final rule to mean, with respect to a particular drug, a person
who did not manufacture, repack, relabel, or salvage the drug but under
whose label or trade name the drug is commercially distributed. This
definition applies equally to private label distributors of medical
gases and other drugs. A medical gas transfiller is a repackager, and
not a private label distributor, under this final rule. As discussed in
our response to comment 16, private label distributors do not--by
reason of their status as private label distributors--have an
obligation to register establishments or list drugs. They must have
labeler codes, obtained under new Sec.  207.33(c), and they may submit
drug listing information or establishment registration information if
acting as the authorized agent of a registrant on whose behalf the
information is submitted.
    h. Material change. In the proposed rule, ``material change'' was
defined as any change in any drug listing information, excluding
labeling changes in arrangement or printing or labeling changes of an
editorial nature. This definition is retained in the final rule with
minor revisions to clarify that material change also does not include
changes in the format of labeling, or the inclusion of a bar code or
the initial inclusion of an NDC on a label.
    (Comment 15) One comment asked FDA to clarify the types of labeling
changes that would qualify as a material change and, hence, require
reporting as an update to drug listing information under Sec.  207.57.
This comment specifically suggested examples of labeling changes that
would qualify as significant changes in the labeling of a prescription
drug product or significant changes in the label or package insert of
an OTC drug product.
    (Response) In referring to ``significant'' labeling changes, this
comment seems to relate to the longstanding definition of ``material
change'' in Sec.  207.3(a)(3), prior to this final rule, which
encompassed labeling changes described as ``significant.'' Today's
final rule revises that definition so that material change includes any
labeling change other than changes in the format of labeling, changes
of an editorial nature, inclusion of a bar code, or initial inclusion
of an NDC. In this context, changes of an editorial nature would not
include any changes that add or revise meaning.
    Thus, the new definition of ``material change'' adopted as part of
this final rule is broader than the previous definition and is not
limited to ``significant'' changes. The definition includes--with very
few exceptions--any change in previously reported drug listing
information. FDA intends to rely primarily on new Sec.  207.57 to
maintain an up-to-date database of current drug labeling. Registrants
should submit current labeling (and a resubmission of all listing
information) each time they submit a drug listing update to report
changed information under Sec.  207.57.
    i. Private label distributor. We proposed to define ``private label
distributor'' to mean a person who owns or operates an establishment
that commercially distributes, under its own label or trade name, any
drug manufactured, repacked, relabeled, or salvaged by a registered
establishment. In the preamble to the proposed rule we explained that
the private label distributor does not engage in any activities
performed by a manufacturer, repacker, relabeler, or salvager for the
drug it distributes (71 FR 51276 at 51290).
    In the final rule, private label distributor is defined to mean,
with respect to a particular drug, a person who did not manufacture,
repack, relabel, or salvage the drug but under whose label or trade
name the drug is commercially distributed. We have also defined
``private label distribution'' in this final rule to mean commercial
distribution of a drug under the label or trade name of a person who
did not manufacture, repack, relabel, or salvage that drug.
    (Comment 16) Some comments requested clarification regarding the
distinction between private label distributors, manufacturers, and
wholesale distributors. Others urged FDA to allow private label
distributors to list the drugs they distribute. One comment requested
clarification regarding the responsibilities of private label
distributors under part 207.
    (Response) We agree that more clarity is needed regarding these
terms and the registration and listing obligations associated with
private label distribution of drug products. We have eliminated the
mention of establishment ownership in the proposed rule's definition of
``private label distributor'' because private label distributors do not
necessarily own establishments that require registration under section
510 of the FD&C Act. We have also clarified that an entity may act as a
private label distributor with respect to a particular drug. For
example, if a drug manufacturer distributes, under its own name or
trade name, a drug manufactured entirely by a contract manufacturer, it
is acting as a private label distributor with respect to that drug. The
difference between private label distributors and wholesale
distributors or others involved in drug distribution is that a private
label distributor's name, trade name, or label appears on the product.
A common example of private label distribution is the sale of aspirin
under a retail pharmacy's brand name when the retail pharmacy did not
manufacture the product. As defined in this final rule, private label
distribution encompasses the use of any brand name or business name on
a drug product where the named business or the owner of the brand name
did not manufacture the drug. Thus, as we are defining the term in part
207, a private label distributor may, but does not necessarily, operate
retail stores or play a role in the physical distribution of the drug
product. Even without using a brand name, if an entity is identified as
the distributor or marketer of a drug under Sec.  201.1 of the drug
labeling regulations, without having manufactured the drug, that person
will qualify as a private label distributor as the term is defined in
this final rule.
    Under this final rule, private label distributors do not have
registration or listing obligations with respect to drugs for which
they merely act as private label distributors. Only manufacturers,
repackers, relabelers, and salvagers have an obligation to register and
list. Private label distributors are subject to this final rule only in
that they must apply for an NDC labeler code as described in Sec.
207.33(c) and update the information submitted under that section when
the information changes. Private label distributors are in the best
position to obtain their own labeler codes and update information
associated with those codes, thereby preventing potential submissions
of inconsistent or inaccurate information by multiple contract
manufacturers.
    A person who is a private label distributor with respect to a
particular drug does not for that reason incur an establishment
registration or listing

obligation. The FD&C Act and the regulations in part 207 both place the
registration and listing obligation on persons who manufacture, repack,
relabel, or salvage drugs. The registration and listing obligation thus
rests with the actual manufacturer, repacker, relabeler, or salvager
whether or not a product is intended for private label distribution.
For this reason, the final rule does not include provisions regarding
establishment registrations or drug listings submitted by private label
distributors.
    We recognize, however, that some private label distributors are in
a position to supply listing information, including NDCs, for drugs
distributed under their names and may prefer to do so. FDA will accept
registration and listing information submitted by any authorized agent
acting on behalf of a manufacturer, repacker, relabeler, or salvager,
and this includes a private label distributor authorized by a
manufacturer, repacker, relabeler, or salvager, to submit drug listing
information on its behalf. In these cases, the manufacturer, repacker,
relabeler, or salvager remains responsible for compliance with all
registration and listing requirements and the accuracy of the
information submitted by its agent.
    A person who acts merely as a wholesale distributor of a drug
product (i.e, a person who did not manufacture, repack, relabel, or
salvage the drug product and whose name, trade name, or label does not
appear on the drug product) does not incur obligations under this rule.
    j. Relabel, relabeler, repack, repacker. We proposed to define
``relabel'' to mean changing the label or labels on a drug or drug
package, or adding to the labeling for a drug or drug package, without
repacking the drug or drug package. We also proposed to define
``relabeler'' to mean a person who owns or operates an establishment
that relabels a drug.
    We proposed to define ``repack'' to mean repack or repackage or
otherwise change the container or wrapper of a drug or drug package.
Similarly, we proposed to define ``repacker'' to mean a person who owns
or operates an establishment that repacks a drug or drug package.
    In the final rule, these definitions are clarified and revised in
response to comments.
    (Comment 17) Some comments noted that the definition of relabel
could include wholesale drug distributors who add information to outer
container labels for purposes of delivery to a customer, customer
identification, inventory management, special handling instructions, or
to aid in compliance with Federal and State pedigree requirements.
Commenters urged us not to require establishments (e.g., distribution
facilities) where such relabeling occurs to register and list.
    (Response) We agree generally with these comments and have revised
the definition of ``relabel'' in the final rule to exclude the addition
or modification of information affixed solely for purposes of delivery
to a customer, customer identification, or inventory management.
However, we did not exclude the addition of special handling
instructions from the definition of ``relabel,'' as recommended in
these comments. Such an exclusion might be misinterpreted as
accommodating revised storage instructions in drug labeling. However,
FDA would not object to the addition of storage information to an outer
label if such information is not inconsistent in any way with storage
instructions appearing elsewhere in the drug's labeling. In that case,
FDA would not regard the addition of such storage information to an
outer container label as relabeling that would subject a person to
registration and listing.
    k. Representative sampling of advertisements and Representative
sampling of any other labeling. The definitions of these terms included
in the proposed rule appear in this final rule with one minor revision.
    (Comment 18) The preamble to the proposed rule included a brief
discussion of these definitions. That discussion pointed out a
confusing aspect of the previous definitions of these terms and the
previous definition of the term ``advertising and labeling'' in part
207. See 71 FR 51276 at 51291. One comment argued that there was no
conflict in these definitions and urged FDA to retain our previous
definitions of ``representative sampling of advertisements'' and
``representative sampling of any other labeling.'' This comment pointed
out that the examples given in those previous definitions were helpful.
    (Response) We disagree with this comment. The revised definitions
are intended to eliminate some confusion associated with the previous
definitions as explained in the preamble to the proposed rule. The
examples appearing in the previous definitions read as follows: ``If
more than one medical journal advertisement is used but the promotional
content is essentially identical, only one need be submitted'' and ``if
more than one brochure is used but the promotional content is
essentially identical, only one need be submitted.'' The quoted
language served as common sense guidance regarding the application of
the definitions without being a central part of the definitions.
Although omitting that language from the definitions included in the
proposed rule and this final rule, FDA is not disavowing the examples
or suggesting that registrants should take a different approach.
2. Who does this part cover? (Sec.  207.9)
    The Agency proposed new Sec.  207.9 to clarify the types of
businesses that are subject to drug establishment registration and
listing under part 207. Section 207.9 is retained in this final rule
with certain revisions and clarifications.
    Section 207.9(a)(3) of this final rule clarifies that private label
distributors are subject to part 207. As discussed previously in this
document, private label distributors do not have an obligation to
register an establishment or list any drugs arising from their
activities as private label distributors. They are, however, expected
to obtain NDC labeler codes under Sec.  207.33(c) of this final rule
and update the information reported to FDA under Sec.  207.33(c) as
required by Sec.  207.33(c)(2).
    Section 207.9(a)(4) of this final rule is revised to state more
clearly its applicability to establishments engaged in the manufacture,
repacking, relabeling, or salvaging of drugs regulated under a BLA.
These establishments are subject to part 207 unless they are required
to register and list under part 607 (ESTABLISHMENT REGISTRATION AND
PRODUCT LISTING FOR MANUFACTURERS OF HUMAN BLOOD AND BLOOD PRODUCTS).
    Section 207.9(a)(5) of this final rule is revised to state that
HCT/Ps, as defined in Sec.  1271.3(d), are subject to registration and
listing under part 207 if they are drugs regulated under section 505 of
the FD&C Act or under section 351 of the PHS Act. A conforming
amendment is made to Sec.  1271.1. Manufacturers of HCT/Ps that are
regulated under section 361 of the PHS Act (42 U.S.C. 264) and not
under section 351 will remain subject to registration and listing under
part 1271.
    (Comment 19) Comments requested clarification on the applicability
of this rule to contract manufacturers and private label distributors
of drug products, saying it was not clear in the proposed rule how
contract manufacturers are to handle establishment registration and
labeler code assignment.
    (Response) Manufacturers of drug products are obligated by the FD&C
Act and by this final rule--whether or not

they are contract manufacturers--to register their establishments and
list the drugs they manufacture for commercial distribution (as the
term ``commercial distribution'' is defined in new Sec.  207.1).
Sections 207.49 and 207.53 of this final rule require manufacturers,
repackers, and relabelers to provide their own NDC (an NDC that
includes the registrant's own labeler code) for each drug they list.
(Salvagers are not required to provide new NDCs when listing drugs they
salvage because a drug's NDC does not change when it is merely
salvaged, and not repacked or relabeled. A person who salvages and then
repacks or relabels a drug is a repacker or relabeler, as those terms
are defined in Sec.  207.1, and must register and list as a repacker or
relabeler.) This provision requires manufacturers, repackers, and
relabelers responsible for listing drugs, including contract
manufacturers, to obtain an NDC labeler code in accordance with new
Sec.  207.33(c).
    When listing a human drug manufactured for private label
distribution (distribution under the name or trade name of someone
other than the drug's manufacturer, as defined in new Sec.  207.1),
Sec. Sec.  207.49 and 207.53 require registrants to provide two NDCs,
one that includes the registrant's own NDC labeler code and one that
includes the NDC labeler code of the private label distributor. As
stated in response to comment 16, FDA will accept drug listing
information submitted by a private label distributor (or anyone else)
if properly authorized to act as an agent for the actual manufacturer.
The use of an agent to handle establishment registration or drug
listing submissions does not, however, transfer legal responsibility
for complying with this final rule from a manufacturer, repacker,
relabeler, or salvager to its agent. Animal drugs manufactured for
private label distribution should be listed under a single NDC that
includes the labeler code of the private label distributor.
    Note that the term ``private label distributor'' is defined in new
Sec.  207.1 to mean, with respect to a particular drug, a person who
did not manufacture, repack, relabel, or salvage the drug but under
whose label or trade name the drug is commercially distributed. FDA's
statements in this document that private label distributors are not
obligated to register their establishments or list the drugs they
distribute are premised on this definition. If someone who would
otherwise qualify as a private label distributor carries out testing or
control procedures applied to the final product, e.g., systematic batch
release testing required under current good manufacturing practices,
that person may qualify as a manufacturer (see the definition of
``manufacture'' in new Sec.  207.1) and need to register its
establishment where the testing or control procedures are carried out.
(But if a private label distributor uses a contract laboratory to carry
out the testing or control procedures, the contract laboratory, not the
private label distributor, may qualify as a manufacturer and need to
register its establishment.) Likewise, if someone qualifies as a
private label distributor with respect to one or more drugs, but also
qualifies as a manufacturer, repacker, or relabeler with respect to
other drugs, that person would need to register the establishment where
manufacturing, repacking, or relabeling is conducted and list the drugs
that are manufactured, repacked, or relabeled for commercial
distribution at the registered establishment.
    Entities that qualify as private label distributors under this
final rule and do not also manufacture, repack, relabel, or salvage any
drugs may already have effective establishment registrations and drug
listings submitted in the past. We do not expect these entities to
renew their registrations after the effective date of this final rule.
They may either cancel their registrations or allow their registrations
to lapse by not making any further submissions. Any drug listings
submitted in the past by entities that qualify as private label
distributors under this final rule for drugs they do not manufacture,
repack, relabel, or salvage should be transferred to the actual
manufacturers, repackers, relabelers, or salvagers of the listed drugs.
    (Comment 20) One comment asked FDA to clarify whether radiologic
products are subject to this rule.
    (Response) This comment did not elaborate on the types of products
encompassed by the question so we are unable to respond specifically.
There is not an exemption from the establishment registration and drug
listing requirements for manufacturers of radioactive drugs, also known
as radiopharmaceutical products. Anyone with questions about the
applicability of part 207, either before or after this final rule, to
radioactive drug products should contact the electronic Drug
Registration and Listing System staff in the Office of Compliance at
FDA's Center for Drug Evaluation and Research (CDER). For diagnostic
device products that include a radioactive drug constituent part, see
our response to comment 22 in this document regarding drug/device
combination products. Also see part 807 regarding establishment
registration and listing for radiologic device products. Positron
emission tomography (PET) drugs are subject to part 207, as stated in
Sec.  207.13(l)(1) and as discussed in the proposed rule (71 FR 51276
at 51285).
    (Comment 21) One comment requested guidance regarding the
information needed for ``active drug substance manufacturers'' to
register and list.
    (Response) In this final rule, the term ``active pharmaceutical
ingredient'' (API) is defined in Sec.  207.1. The registration
obligation applies to each domestic establishment that manufacturers,
repacks, relabels, or salvages a drug or an animal feed bearing or
containing a new animal drug (whether or not that product is
commercially distributed). It also applies to each foreign
establishment that manufacturers, repacks, relabels, or salvages a drug
or an animal feed bearing or containing a new animal drug that is
imported or offered for import into the United States. In each case,
the term ``drug'' includes: (1) An API by itself, (2) an API that has
been combined with one or more other APIs or inactive ingredients (see
definition of ``unfinished drug'' in Sec.  207.1), and (3) finished
drug products (see definition of ``finished drug product'' in Sec.
207.1).
    The information that must be submitted for establishment
registration is set forth in new Sec.  207.25. These information
elements do not differ depending on whether the registrant handles
APIs, other unfinished drugs, or finished drugs.
    The information that must be submitted with a drug listing is set
forth in new Sec.  207.49 for a drug the registrant manufactures, Sec.
207.53 for a drug the registrant repacks or relabels, and in Sec.
207.54 for a drug the registrant salvages. As specified in Sec.
207.41, the drug listing obligation applies only to drugs that are
manufactured, repacked, relabeled, or salvaged for commercial
distribution. Sections 207.49, 207.53, and 207.54 indicate some minor
differences in the information that must be submitted depending on
whether the drug is finished or unfinished. For example, Sec.
207.49(a)(15)(iv) describes the labeling that must be submitted for an
unfinished drug.
    (Comment 22) One comment asked, in the context of the proposed
rule's requirement that NDCs appear on drug labels, how the rule would
apply to drug/device combination products. Other comments asked how
registration and listing should be handled for drug/device combination
product kits. (See the definition of ``combination product'' in Sec.
3.2(e) (21 CFR 3.2(e)), unaffected by this rulemaking.)

    (Response) We acknowledge that the proposed rule did not include an
explanation of its applicability to drug/device combination products,
including how manufacturers of such products should register their
establishments, list their combination products, and provide related
information on the labels of their combination products. The codified
of this final rule likewise does not contain specific provisions
regarding drug/device combination products. FDA expects to further
address drug/device combination product registration and listing in the
future. As stated previously in this document, we also are not
finalizing the proposed amendment to Sec.  201.2 that would have
required human-readable NDCs on the labels of all drugs subject to the
listing requirement.
3. Who is exempt from registration and listing requirements? (Sec.
207.13)
    The proposed rule included a new Sec.  207.13 aimed at clarifying
the types of businesses that are exempt from drug establishment
registration and listing under part 207. Section 207.13 is retained in
this final rule with certain revisions and clarifications. Some
exemptions described in Sec.  207.13 are derived directly from section
510(g) of the FD&C Act. Other exemptions are established under section
510(g)(5) of the FD&C Act supported by our finding that registration by
such classes of persons is not necessary for the protection of the
public health.
    (Comment 23) Several comments argued against the elimination of two
existing exemptions from registration and listing that the proposed
rule would have revoked. These two exemptions encompass: (1) Drugs
imported under section 801(d)(3) of the FD&C Act (often referred to as
``import for export'') and (2) drugs that enter a foreign trade zone
and are re-exported from that foreign trade zone without having entered
U.S. commerce.
    (Response) Previous Sec.  207.40(b) stated that no drug may be
imported or offered for import into the United States unless the drug
is listed and manufactured, prepared, propagated, compounded, or
processed at a registered foreign establishment. The section also
stated that this prohibition did not apply to, among other things,
components of drugs imported under section 801(d)(3) of the FD&C Act.
Section 801(d)(3) allows persons to import certain articles, including
components of drugs, if specified conditions are met, provided that the
imported articles are further processed or incorporated into products
and exported or, if not used, the imported articles are destroyed or
exported. Thus, previous Sec.  207.40(b) exempted certain foreign
establishments from the establishment registration and listing
requirement.
    Previous Sec.  207.40(a) stated that a foreign establishment was
not required to comply with the registration and listing requirements
if its drug entered a foreign trade zone and was re-exported from that
foreign trade zone without having entered U.S. commerce.
    Upon careful consideration of the comments received, we have
decided to retain both exemptions in this final rule. Therefore, under
Sec.  207.13(j) of this final rule, if all the conditions of section
801(d)(3) of the FD&C Act are satisfied, a component of a drug will not
be excluded from importation into the United States by reason that it
is unlisted or was manufactured at an unregistered foreign
establishment. Additionally, under Sec.  207.13(j) of this final rule,
a foreign establishment does not incur a registration and listing
obligation if its drug enters a foreign trade zone and is re-exported
from that foreign trade zone without having entered U.S. commerce.
These exemptions pertain only to drugs that are re-exported or
components of drugs that are processed or incorporated into products
and then exported, and these exemptions pertain only to foreign
establishments. If an establishment located within a foreign trade zone
manufactures, repacks, relabels, or salvages a drug for commercial
distribution in the United States, that establishment would need to
register and list those drugs it handles for U.S. commercial
distribution. Additionally, if a foreign establishment exports drugs to
the United States relying on either of these exemptions, but also
exports other drugs for commercial distribution in the United States,
it must comply with the registration and listing requirements for those
drugs that are commercially distributed in the United States.
    The corresponding exemptions for blood product establishments are
also retained in Sec.  607.40 under this final rule.
    (Comment 24) One comment asked FDA to confirm that animal
biological products are not subject to this rule.
    (Response) Some biological drugs intended for administration to
animals are regulated by the U.S. Department of Agriculture (USDA)
under the Virus, Serum, and Toxins Act of 1913. Section 510.4 (21 CFR
510.4) states that animal drugs produced and distributed in full
conformance with the Virus, Serum, and Toxins Act and any regulations
issued thereunder shall not be deemed to be subject to section 512 of
the FD&C Act (includes premarket approval and other requirements for
new animal drugs regulated by FDA). As proposed in Sec.  207.13(g), the
final rule includes an exemption applicable to these products in Sec.
207.13(h).
    (Comment 25) Comments from the medical gas industry expressed
concern about the ability of entities such as pharmacies, hospitals,
clinics, and emergency responders to refill medical gas cylinders if
the repackaging would require the repacker's NDC to appear on the label
of the repackaged product. The comment stated that if these entities
are exempt from part 207, they cannot obtain an NDC.
    (Response) Our decision not to include the proposed amendments to
Sec.  201.2 that would have required human-readable NDCs on drug labels
renders the concern expressed in this comment moot. We would like to
confirm that pharmacies, hospitals, clinics, other health care
entities, and public health agencies that qualify as exempt from the
registration and listing requirements under Sec.  207.13 of this final
rule do not lose their exemptions by dispensing medical gases or
filling medical gas containers in the normal course of their
activities.

C. Registration (Part 207, Subpart B)

1. Who must register? (Sec.  207.17)
    Section 207.17 describes who is required to register an
establishment under part 207. This section is reworded in the final
rule: (1) To distinguish between domestic and foreign manufacturers,
repackers, relabelers, and salvagers and (2) to clarify that FDA will
accept registration information submitted by a private label
distributor only if it is acting as an authorized agent for and
submitting information pertaining to an entity that has an
establishment registration obligation.
    (Comment 26) One comment asked FDA to clarify whether a storage
facility that does not repack or relabel drugs is required to register
under part 207.
    (Response) A facility at which drugs are stored, such as a
warehouse, does not need to be registered provided drugs are not
manufactured, repacked, relabeled, or salvaged (as those terms are
defined in Sec.  207.1) at the facility. Note that the definition of
``manufacture'' includes sampling, testing, or control procedures
applied to the final product or to any part of the process. Thus, for
example, if a warehouse includes a temperature-controlled storage area
where drug samples are stored for stability testing to satisfy current
good manufacturing practice requirements, that activity would qualify
as a manufacturing

operation and require registration of the warehouse as a drug
establishment. Other State or Federal requirements may apply to such
facilities.
    As explained in response to Comment 17, we have revised the
definitions of ``relabel'' and ``relabeler'' so they do not include the
addition or modification of information affixed to drug packaging
solely for purposes of delivery to a customer, customer identification,
or inventory management. Therefore, the addition or modification of
such information at a warehouse does not trigger the need to register
it as an establishment.

2. When must initial registration information be provided? (Sec.
207.21)

    Proposed Sec.  207.21 described when initial registration
information must be submitted for an establishment newly required to
register under part 207. The provision is retained in this final rule
and reorganized into paragraphs (a) and (b) for improved clarity.
    (Comment 27) One comment suggested that the words ``for commercial
distribution'' be added to Sec.  207.21, suggesting that establishment
registration is required only for establishments at which drugs
intended for commercial distribution are manufactured, repacked,
relabeled, or salvaged.
    (Response) The absence of these words--``for commercial
distribution''--from Sec.  207.21 is intentional and comports with
section 510 of the FD&C Act. Any establishment at which drugs are
manufactured, repacked, relabeled, or salvaged must be registered under
part 207, unless exempt from registration under section 510(g) of the
FD&C Act or under the relevant regulations (Sec. Sec.  207.13, 607.65,
or 1271.15, as applicable) whether or not the drugs are commercially
distributed. Accordingly, an establishment at which an investigational
drug is manufactured is subject to the establishment registration
requirement. The listing obligation, on the other hand, applies to
drugs that are for commercial distribution.
3. What information is required for registration? (Sec.  207.25)
    Proposed Sec.  207.25 described the information that must be
submitted to register an establishment. The provision is retained in
the final rule with minor substantive and editorial revisions.
Substantively, new Sec.  207.25 no longer requires the submission of
fax numbers to register establishments and now includes the new
statutory requirement that registrants provide a UFI for each
establishment. (See our discussion of establishment registration
numbers and UFIs in section II.B, Changes to the Proposed Rule.) New
Sec.  207.25 also clarifies that the physical address of each
establishment is required (rather than a post office box, for example),
and a mailing address is required for the establishment's official
contact.
    (Comment 28) One comment asked FDA to clarify what format should be
used when a foreign establishment submits contact information for each
importer. This comment also asked FDA to explain who should submit
establishment registration information when a business has both foreign
and U.S. establishments.
    (Response) According to new Sec.  207.61, all information
transmitted to FDA under part 207, including establishment registration
information, must be transmitted to FDA in electronic format unless a
waiver is granted. FDA's systems for electronic registration include
fields for information elements such as the required contact
information for U.S. importers of drugs manufactured, repacked,
relabeled, or salvaged at a foreign establishment.
    Section 207.17 addresses this comment's second question, who should
submit establishment registration information when a business has both
foreign and U.S. establishments? This section states that when
operations are conducted at more than one establishment, and common
ownership and control among all the establishments exists, the parent,
subsidiary, or affiliate company may submit registration information
for all establishments. This applies whether the establishments are
domestic, foreign, or both.
    (Comment 29) One comment asked FDA to exempt contract manufacturers
from the requirement that establishments identify each importer in the