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[Federal Register: August 29, 2006 (Volume 71, Number 167)]
[Proposed Rules]
[Page 51275-51357]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr29au06-21]
[[Page 51275]]
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Part II
Department of Health and Human Services
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Food and Drug Administration
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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; Proposed Rule
[[Page 51276]]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Parts 20, 201, 207, 314, 330, 514, 515, 601, 607, 610, and
1271
[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: Proposed rule.
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SUMMARY: The Food and Drug Administration (FDA) is proposing to amend
its regulations governing drug establishment registration and drug
listing. The proposed revisions would reorganize, consolidate, clarify,
and modify current regulations concerning who must register
establishments and list human drugs, human drugs that are also
biological products (including vaccines and allergenic products), and/
or human cells, tissues, and cellular and tissue-based products (HCT/
Ps), and animal drugs. The proposal describes when and how to register
and list and what information must be submitted for registration and
listing. In addition, the proposal would make certain changes to the
National Drug Code (NDC) system and would require the appropriate NDC
number to appear on the labels for drugs subject to the listing
requirements. The proposed regulations generally would require the
electronic submission of all registration and most listing information.
We (FDA) rely on establishment registration and drug listing
information for administering many of our programs, such as
postmarketing surveillance (including FDA inspections), bioterrorism,
drug shortages and availability, and user fee assessments. We are
taking this action to use the latest technology to improve our
registration and listing system, which would further our goal of
protecting the public health. We also believe that the conversion to an
electronic system would make the registration and listing processes
more efficient and effective for industry and us. We are also taking
this action to support the implementation of, for example, the
electronic prescribing provisions of the Medicare Prescription Drug,
Improvement, and Modernization Act, our rulemaking requiring a bar code
on certain drug products, and the DailyMed initiative.
DATES: Submit written or electronic comments by November 27, 2006.
Submit written comments on the information collection requirements by
September 28, 2006 to OMB (see ADDRESSES). See section IX of this
document for the proposed effective date and section X for the proposed
compliance dates of a final rule based on this document.
ADDRESSES: You may submit comments, identified by Docket No. 2005N-0403
and/RIN 0910-AA49, by any of the following methods:
Electronic Submissions
Submit electronic comments in the following ways:
Federal eRulemaking Portal: http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.regulations.gov.
Follow the instructions for submitting comments.
Agency Web site: http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/dockets/ecomments.
Follow the instructions for submitting comments on the agency Web site.
Written Submissions
Submit written submissions in the following ways:
FAX: 301-827-6870.
Mail/Hand delivery/Courier [For paper, disk, or CD-ROM
submissions]: Division of Dockets Management (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.
To ensure more timely processing of comments, FDA is no longer
accepting comments submitted to the agency by e-mail. FDA encourages
you to continue to submit electronic comments by using the Federal
eRulemaking Portal or the agency Web site, as described in the
Electronic Submissions portion of this paragraph.
Instructions: All submissions received must include the agency name
and Docket No(s). and Regulatory Information Number (RIN) (if a RIN
number has been assigned) for this rulemaking. All comments received
may be posted without change to http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/ohrms/dockets/default.htm
, including any personal information provided. For
additional information on submitting comments, see the ``Comments''
heading of the SUPPLEMENTARY INFORMATION section of this document.
Docket: For access to the docket to read background documents or
comments received, go to http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/ohrms/dockets/default.htm
and insert the docket number(s), found in brackets in the heading of
this document, into the ``Search'' box and follow the prompts and/or go
to the Division of Dockets Management, 5630 Fishers Lane, rm. 1061,
Rockville, MD 20852.
Information Collection Provisions: Submit written comments on the
information collection provisions to the Office of Information and
Regulatory Affairs, Office of Management and Budget (OMB).To ensure
that comments on the information collection are received, OMB
recommends that written comments be faxed to the Office of Information
and Regulatory Affairs, OMB, Attn: FDA Desk Officer, FAX: 202-395-6974.
FOR FURTHER INFORMATION CONTACT: For information concerning drugs
regulated by the Center for Drug Evaluation and Research (CDER):
Herbert Gerstenzang or John W. Gardner, Center for Drug Evaluation and
Research (HFD-330), Food and Drug Administration, 5600 Fishers Lane,
Rockville, MD 20857, 301-827-8920, herbert.gerstenzang@fda.hhs.gov or
john.gardner@fda.hhs.gov.
For information concerning products regulated by the Center for
Biologics Evaluation and Research (CBER): Valerie A. Butler, Center for
Biologics Evaluation and Research (HFM-17), Food and Drug
Administration, 1401 Rockville Pike, Rockville, MD 20852-1448, 301-827-
6210, valerie.butler@fda.hhs.gov.
For information concerning animal drugs: Lowell Fried (HFV-212) or
Isabel W. Pocurull (HFV-226), Center for Veterinary Medicine (CVM),
Food and Drug Administration, 7519 Standish Pl., Rockville, MD 20855,
301-827-7820 or 240-453-6853, lowell.fried@fda.hhs.gov or
isabel.pocurull@fda.hhs.gov.
SUPPLEMENTARY INFORMATION:
Table of Contents
I. Background
II. Summary of Current Registration and Listing Requirements
A. Summary of Section 510 of the Act
B. Summary of Current Registration and Listing Regulations
1. Who Must Register and List Under Current Regulations?
2. What Are the Current Registration Requirements?
3. What Are the Current Listing Requirements?
4. What Are the Current Requirements Associated With the Use of
the NDC Number?
5. Who Is Exempt from Registration and Listing Under Current
Regulations and Who Is Not Covered by the Current Registration and
Listing Requirements in 21 CFR part 207?
6. Do Current Regulations Permit the Disclosure of Registration
and Listing Information?
III. Highlights of the Proposed Rule
A. Proposed Changes to the Current Registration and Listing
Requirements
[[Page 51277]]
B. Promotion of Department of Health and Human Services Federal
Health Information Technology Initiatives
IV. Description of the Proposed Rule
A. General
1. What Is the Purpose of Proposed Part 207?
2. Who Would Part 207 Cover?
3. Who Would Not Be Subject to Part 207?
4. Who Would Be Exempt from Registration and Listing?
5. What Definitions and Interpretations of Terms Would Apply to
Part 207?
B. Registration
1. Who Would Be Required to Register?
2. When Would Initial Registration Information Be Provided?
3. What Information Would Be Required for Registration?
4. What Are the Proposed Requirements for Reviewing and Updating
Registration Information?
C. The National Drug Code (NDC) Number: What is It? How is It
Used? What Changes Are We Proposing?
1. What Is the NDC Number?
2. How Did NDC Numbers Originate? How Are They Used?
3. What Changes Are We Proposing?
4. How Do We Intend to Implement the NDC Number Changes?
D. Listing
1. Who Would Be Required to List Drugs?
2. When Would Initial Listing Information Be Provided?
3. What Listing Information Would Be Required?
4. What Listing Information Would Be Required for Manufacturers?
5. What Listing Information Would Be Required for Repackers and
Relabelers?
6. What Listing Information Would Be Required for Drug Product
Salvagers Who are Not Repackers or Relabelers?
7. What Additional Drug Listing Information May Be Required?
8. What Are the Proposed Requirements for Reviewing and Updating
Listing Information?
E. Electronic Format
1. How Would Registration and Listing Information Be Provided to
FDA?
2. What Was the Electronic Submission Pilot Project?
3. How Would the Electronic Registration and Listing System
Work?
4. What Are the Proposed Requirements for the Submission of
Content of Labeling in Electronic Format?
5. Would the Proposal Require Electronic Submission of
Advertisements and Other Labeling?
6. What Guidance Documents Do We Intend To Issue on Providing
Registration and Listing Information Electronically?
7. How Would 21 CFR Part 11 Apply to the Electronic Submission
of Registration and Listing Information?
8. What Language Would Be Used to Provide Registration and
Listing Information?
9. Could the Electronic Format Requirements Be Waived?
F. Miscellaneous
1. What Are the Proposed Requirements for an Official Contact
and a United States Agent?
2. What Legal Status Is Conferred by Registration and Listing?
3. What Registration and Listing Information Would Be Made
Available for Public Disclosure?
G. Conforming Actions
1. Withdrawal from Sale of Drugs with Approved Marketing
Applications
2. Proposed Revisions to Other Regulations
3. Compliance Verification Reports
V. Legal Authority
VI. Analysis of Economic Impacts
VII. Paperwork Reduction Act of 1995
VIII. Environmental Impact
IX. Proposed Effective Date
X. Proposed Compliance Dates
XI. Federalism
XII. Request for Comments
XIII. References
I. Background
We originally published establishment registration regulations for
human drugs, certain biological products, and animal drugs in the
Federal Register of February 14, 1963 (28 FR 1457) (proposed rule) and
April 3, 1963 (28 FR 3195) (final rule), and listing regulations for
these drugs in the Federal Register of December 12, 1972 (37 FR 26431)
(proposed rule) and March 7, 1973 (38 FR 6258) (final rule).
We currently maintain a database containing the establishment
registration and drug listing information submitted on paper to us. We
rely on complete and accurate registration and listing information to
accomplish a number of our statutory and regulatory objectives. For
example, we use registration and listing information to:
Identify the manufacturers, repackers, relabelers, and
drug product salvagers of marketed drugs;\1\
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\1\ ``Drug'' or ``drugs'' refers to human drugs, including drugs
that are regulated under a biologics license application, and animal
drugs (including Type A medicated articles), unless otherwise
specifically stated. ``Drugs'' is defined in proposed Sec. 207.1
and discussed in section IV.A.5 of this document. Biological
products subject to proposed part 207 are described in proposed
Sec. 207.9(c).
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Identify the manufacturers, repackers, or relabelers of a
specific drug or ingredient when that drug or ingredient is in short
supply or is needed for a national emergency. This information helps us
facilitate prompt drug shipment to the place where it is needed. For
example, during a bioterrorism incident, we could use drug listing
information to identify manufacturers, repackers, and relabelers of
drugs that would be helpful in preventing or counteracting the deadly
effects of biological weapons. With this information, we could
facilitate prompt shipment of the drugs as needed;
Facilitate the recall of drugs marketed by manufacturers,
repackers, and relabelers;
Identify and catalogue marketed drugs;
Administer our postmarketing surveillance programs for
drugs, including the drug surveillance sampling program that monitors
the quality of the national drug supply;
Identify drugs marketed in violation of the law;
Schedule and plan inspections of registered establishments
pursuant to section 704 of the Federal Food, Drug, and Cosmetic Act
(the act) (21 U.S.C. 374); and
Determine which marketed drugs are identical, related, or
similar to drugs reviewed for effectiveness under the Drug Efficacy
Study Implementation (DESI) program.
We also rely on registration and listing information to help us
comply with several other statutory provisions. We use the information
to:
Determine which entities are subject to establishment and
product user fees under the prescription drug user fee program and the
animal drug user fee program (21 U.S.C.379h and 379).
Generate accurate estimates of the number of
manufacturers, repackers, relabelers, and drug product salvagers and
drugs that are affected by our rulemaking. These estimates help us
assess the impact of our regulations on the regulated industry, which
we are required to do under the Regulatory Flexibility Act (5 U.S.C.
601-612), as amended by the Small Business Regulatory Enforcement
Fairness Act (Public Law 104-121), the Unfunded Mandates Reform Act of
1995 (2 U.S.C. 1501 et seq.), the Paperwork Reduction Act of 1995 (44
U.S.C. 3501-3520), Executive Order 12866 (September 30, 1993), and the
Congressional Review Act (section 251 of Public Law 104-121).
Registration and listing information will continue to be used for
all of the important public health purposes outlined above. Moreover,
recent technological advances would allow us to enhance the usefulness
of registration and listing information. Specifically, we are proposing
that registration and listing information be submitted to us by using
the electronic drug registration and listing system that we intend to
develop. In addition to making the registration and listing process
more efficient for industry, the electronic submission of registration
and listing information would allow us to review and use such
information more quickly and effectively in carrying out all of the
[[Page 51278]]
activities described above. Electronic submission of this information
would also allow us to fully support the implementation of the
provisions of the Medicare Prescription Drug, Improvement, and
Modernization Act (Public Law 108-173) (Medicare Modernization Act),
specifically the electronic prescribing provisions. In addition,
electronic submission of registration and listing information would
further the purpose of several statutes:
The Public Health Security and Bioterrorism Preparedness
and Response Act of 2002 (Public Law 107-188) (Bioterrorism Act)
amended section 510(i) of the act (21 U.S.C. 360(i)) to require that
foreign establishments submit, among other things, registration
information electronically.
The Medical Device User Fee and Modernization Act of 2002
(Public Law 107-250) also amended section 510 of the act (at section
510(p)) to explicitly give the Secretary of Health and Human Services
(the Secretary) discretion to require the electronic submission of
registration information, upon a finding that electronic receipt of
such registration information is feasible, unless the Secretary grants
a request for a waiver.
The Government Paperwork Elimination Act of 1998 (Public
Law 105-277, Title XVII) (GPEA) requires Federal agencies to give
persons who are required to maintain, submit, or disclose information
the option of doing so electronically when practicable as a substitute
for paper, and to use electronic authentication (electronic signature)
methods to verify the identity of the sender and the integrity of the
electronic content.
We believe that conversion to the electronic submission of
registration and listing information will further the purpose of these
laws and make the registration and listing processes more efficient and
effective for industry and us.
II. Summary of Current Registration and Listing Requirements
A. Summary of Section 510 of the Act
Section 510(c) of the act requires every person upon first engaging
in the ``manufacture, preparation, propagation, compounding, or
processing'' of a drug in any establishment that he owns or operates in
any State to immediately register his name and place of business and
such establishment. Under section 510(a)(1) of the act, the term
``manufacture, preparation, propagation, compounding, or processing''
must include ``repackaging or otherwise changing the container,
wrapper, or labeling of any drug package * * * in furtherance of the
distribution of the drug * * * from the original place of manufacture
to the person who makes final delivery or sale to the ultimate consumer
or user.'' Section 510(a)(2) of the act mandates that the term ``name''
include, among other things, the name of each partner of a partnership,
and the name of each corporate officer and director of a corporation.
An owner or operator of a registered establishment must also
immediately register any additional establishment that he owns or
operates in any State and in which he begins the ``manufacture,
preparation, propagation, compounding, or processing'' of a drug
(section 510(d) of the act). An owner or operator of any establishment
that engages in these activities must register its establishment on or
before December 31 of each year (section 510(b) of the act). Section
510(i) of the act contains certain registration requirements pertaining
to foreign establishments (e.g., submission of the name of each
importer of a drug in the United States that is known to the
establishment, submission of the name of each person who imports or
offers for import a drug into the United States for purposes of
importation). Section 510(g) of the act provides for certain exemptions
from the registration requirements. In addition, section 510(p) of the
act gives the Secretary discretion to require the electronic submission
of registration information, upon a finding that electronic receipt of
such registration information is feasible, unless the Secretary grants
a request for a waiver.
Section 510(j)(1) of the act requires that every person, at the
time of registration, submit a list of all drugs that are being
manufactured, prepared, propagated, compounded, or processed by him for
commercial distribution and that have not been previously listed by
him. This information must be submitted in the form and manner
prescribed by the Secretary (section 510(j)(1) of the act). This
listing information must be accompanied by, among other things, a copy
of certain labeling and, in some cases, advertising for certain
categories of drugs. Section 510(j)(2) of the act requires certain
changes in listing information to be reported every June and December,
including any material changes in information previously submitted
under the listing provisions.
Section 510(e) of the act permits the Secretary to assign a
registration number to any person or any establishments registered
under section 510 and a listing number to each drug or class of drugs
listed under section 510(j) as long as the listing number is the same
as that assigned pursuant to the National Drug Code. The disclosure
provision in section 510(f) of the act requires the Secretary to make
available for inspection any registration filed under section 510.
Section 510(f) also provides that certain listing information must be
exempt from disclosure unless the Secretary finds that such exemption
would be inconsistent with protection of the public health.
B. Summary of Current Registration and Listing Regulations
1. Who Must Register and List Under Current Regulations?
Under current part 207 (21 CFR part 207), with certain exceptions,
owners or operators of establishments that engage in the manufacturing
or processing of a drug or drugs must, in addition to other
requirements, register their establishments and submit listing
information for each of their drugs in commercial distribution.\2\
Notwithstanding certain exceptions, foreign drug establishments that
manufacture, repack, or relabel a drug that is imported or offered for
import into the United States must also comply with the registration
and listing requirements. As explained in section IV.E of this
document, all registration and listing information must currently be
submitted to us using paper forms specified by us.
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\2\``Drug or drugs'' includes drugs regulated under a BLA. For a
description of biological products covered under proposed part 207,
see proposed Sec. 207.9(c).
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2. What Are the Current Registration Requirements?
Current requirements for registration include, among other things,
the following provisions:
Owners or operators of establishments entering into the
manufacturing or processing of a drug or drugs must register their
establishments within 5 days after beginning the manufacturing or
processing of drugs at the establishments (Sec. 207.21(a)).
If owners or operators of the establishments have not
previously entered into such operations, then those owners or operators
must register within 5 days after the submission of a new drug
application (NDA), abbreviated new drug application (ANDA), new animal
drug application (NADA), abbreviated new animal drug application
(ANADA), medicated feed mill license application, or biologics license
application (BLA) (Sec. 207.21(a)).
[[Page 51279]]
Owners or operators of establishments that are required to
register must renew their registration annually in accordance with the
specified schedule (Sec. 207.21(a)). Changes in individual ownership,
corporate or partnership structure, location, or drug-handling activity
must be submitted as amendments to registration within 5 days of such
changes (Sec. 207.26).
We assign a permanent registration number to each
registered establishment (Sec. 207.35).
Private label distributors that do not otherwise
manufacture or process drugs are not required to register; however,
they must submit specified information to us to obtain a labeler code
(Sec. 207.20(b)). Private label distributors are owners or operators
of establishments not otherwise required to register under section 510
of the act that distribute under their own label or trade name a drug
manufactured or processed by a registered establishment.
3. What Are the Current Listing Requirements?
Current requirements for listing include, among other things, the
following provisions:
Owners or operators of establishments must, at the time of
registration, submit a list of every drug being manufactured or
processed in commercial distribution at that time (Sec. 207.21(a)).
Private label distributors that do not otherwise
manufacture or process drugs are not required to list, but may elect to
submit listing information directly to us (Sec. 207.20(b)). Currently,
private label distributors that elect to submit listing information
directly to us assume full responsibility for compliance with the
requirements of part 207 (Sec. 207.20(b)). Owners or operators of
establishments that are required to register and list must submit
listing information to us on behalf of private label distributors that
do not elect to submit listing information directly to us (Sec.
207.20(b)).
Drugs that may be subject to current listing requirements
include bulk drug substances; finished dosage forms, whether
prescription or over-the-counter (OTC) drugs; and Type A medicated
articles (Sec. 207.25(b)).
The required listing information submitted to us includes,
but is not limited to:
--The application number, if applicable,
--Copies of current labeling as specified in current Sec.
207.25(b) and, in some cases, a representative sampling of
advertisements,
--A quantitative listing of the active ingredient(s) (in some
cases),
--The NDC number, and
--Any imprinting information (Sec. 207.25(b)).
Owners or operators of establishments that are required to
register must update their listing information every June and December
or, at the discretion of the owner or operator, when the change occurs.
Updated information must include, but is not limited to:
--A list of each drug introduced by the registrant for commercial
distribution that has not been included in any previously submitted
list,
--A list of all previously listed drugs for which commercial
distribution has been discontinued,
--A list of all drugs for which a notice of discontinuance was
submitted and for which commercial distribution has resumed, and
--Any material change, as defined under current Sec. 207.3(a)(3),
in any information previously submitted (Sec. 207.30(a)).
4. What Are the Current Requirements Associated With the Use of the NDC
Number?
The NDC system is used, among other things, to assign a drug
listing number to each drug or class of drugs.
The NDC number currently consists of the labeler code,
product code, and package code. We assign the labeler code, and, as
stated in current regulations, ``establishments'' assign the product
code and package code within certain parameters specified by us (Sec.
207.35).
Currently, we request, but not require, that the NDC
number appear on all drug labels and labeling (Sec. 201.2 (21 CFR
201.2), Sec. 207.35(b)(3)). However, drug products described in
current Sec. 201.25(b) (21 CFR 201.25(b)) must have on the label a bar
code that contains, at a minimum, the appropriate NDC number in a
linear bar code that meets specified standards (Sec. 201.25).
The current regulations specify both format and placement
of the NDC number if the NDC number is included on drug labels and
labeling (Sec. 207.35(b)(3)).
5. Who Is Exempt From Registration and Listing Under Current
Regulations and Who Is Not Covered by the Current Registration and
Listing Requirements in 21 CFR Part 207?
Under current regulations, certain establishments are exempt from
the registration and listing requirements. For example, practitioners
who are licensed by law to prescribe or administer drugs and who
manufacture or process drugs solely for use in their professional
practice, and persons who manufacture or process drugs not for sale but
solely for use in research, teaching, or chemical analysis are exempt
from registration and listing requirements. Many of the exemptions in
current Sec. 207.10 are also listed in section 510(g) of the act.
The current regulations also describe those establishments that are
not covered under part 207. Owners and operators of human blood and
blood product establishments must register and list their products in
accordance with part 607 (21 CFR part 607). However, such owners and
operators who also manufacture or process other drug products at the
same establishment must also register and list those drugs in
accordance with part 207 (Sec. 207.7). Owners and operators of
establishments that solely engage in the manufacture or processing of
medical devices are not covered under part 207. However, such owners
and operators must register and list their products in accordance with
part 807.
6. Do Current Regulations Permit the Disclosure of Registration and
Listing Information?
The current regulations specify the registration and listing
information submitted to us that is available for public disclosure
(Sec. 207.37).
III. Highlights of the Proposed Rule
This proposal would reorganize, consolidate, and modify the current
registration and listing requirements. It would also assist us in
promoting other important electronic health initiatives.
A. Proposed Changes to the Current Registration and Listing
Requirements
We are proposing many changes to the current registration and
listing requirements. In section IV of this document, we discuss in
detail these changes and the reasons for the changes. The most
significant proposed changes to the current requirements are as
follows:
All registration information and most listing information
would be provided to us electronically using the electronic drug
registration and listing system that we intend to develop. (Currently,
the information is submitted to us on paper forms.)
The appropriate NDC number would be required, with certain
exceptions, to appear on drug labels. The appropriate NDC number is the
NDC number belonging to the manufacturer, repacker, or relabeler, that
corresponds to the particular drug;
[[Page 51280]]
a repacker or relabeler would not be permitted to place an NDC number
that corresponds to an original manufacturer on a repackaged or
relabeled drug. Although the NDC number would not be required to appear
on other drug labeling (that is, the prescription drug labeling or the
package insert), the NDC number would need to accompany the submission
of the other drug labeling. (Currently, we only request that the NDC
number appear on drug labels and labeling. However, certain drug
products must have on the label a bar code that contains, at a minimum,
the appropriate NDC number (see Sec. 201.25).)
All three sections of the NDC number--that is, the labeler
code, product code, and package code--would be assigned prospectively
by us to drugs that have not previously been assigned NDC numbers by a
manufacturer, repacker, or relabeler. (Currently, we assign the labeler
code, and the registered establishment or private label distributor
assigns the product code and package code within certain parameters
specified by us.) The labeler code assigned prospectively by us would
be the same as the labeler code (or one of the labeler codes) used by
the manufacturer, repacker, or relabeler on its currently marketed
drugs.
The NDC numbers currently assigned to drugs prior to the
effective date of the rule would remain unchanged, provided those NDC
numbers comply with the new regulations as finalized. FDA intends to
validate that current NDC numbers comply with the new regulations as
finalized. Manufacturers, repackers, and relabelers should review the
information that they submitted to our registration and listing
database to obtain an NDC number and update the information if
necessary. They should complete their reviews and updates within 9
months after a final rule's effective date. If, after the effective
date of the final rule, there is a change in a drug (in accordance with
proposed Sec. 207.33(f)), we would assign a new product code and
package code to the newly changed drug, but the drug would keep the
labeler code. If, after the effective date of the final rule, there is
a change in a drug's packaging, we would assign a new package code to
the drug, but the drug would keep the labeler code and the product
code. (Currently, the registered establishment or private label
distributor may assign the product and package codes within certain
parameters specified by us.)
Private label distributors would not be permitted to
register or list under the proposed rule. (Currently, private label
distributors submit certain information to request a labeler code and
may list drugs. If the private label distributor elects not to submit
drug listing information directly to us and to obtain a labeler code,
the registered establishment must submit the drug listing information.)
Manufacturers, repackers, relabelers, or drug product salvagers must
submit drug listing information for those drugs they manufacture,
repack, relabel, or salvage for a private label distributor.
Drug product salvagers would, in addition to registering,
be required to list the drugs they salvage, even if they do not repack
or relabel the drugs. (Currently, drug product salvagers are required
to register but not list.)
The ``content of labeling'' as defined in proposed Sec.
207.1 would be electronically submitted at the time of listing in a
format that we can process, review, and archive. (Currently, all
labeling required for listing is submitted in paper form.)
B. Promotion of the Department of Health and Human Services (DHHS)
Federal Health Information Technology Initiatives
The proposal would allow us to provide important support for the
full implementation of the electronic prescription provisions of the
Medicare Modernization Act. The proposal would also support other
initiatives, described in section IV.C.2 of this document, including
DHHS Federal Health Information Technology initiatives. The proposal
would result in an up-to-date NDC number system, in which we assign the
NDC number, providing for accurate, unique, and unambiguous NDC numbers
for each drug. This would allow electronic systems to reliably and
consistently link the NDC number to the appropriate drug labeling
through another DHHS health information technology initiative,
Structured Product Labeling (SPL). The drug labeling would supply the
drug ingredient and other information necessary to support the
development of the standards for medication terminology necessary for
electronic prescribing. Other initiatives supported by this proposal,
including bar coding for drugs, are discussed in section IV.C.2 of this
document.
IV. Description of the Proposed Rule
We are proposing to reorganize, consolidate, clarify, and modify
the regulations in part 207. As a result, we have revised and
recodified some provisions, added new provisions, and eliminated
others. The following description of the proposed rule describes both
new provisions and changes to existing regulations.
A. General
1. What Is the Purpose of Proposed Part 207?
We are proposing to add new Sec. 207.5 to explicitly state the
purpose of part 207, as set forth in the legislative history of the
Drug Amendments of 1962 and the Drug Listing Act of 1972.
Establishment registration information helps us to
identify who is manufacturing, repacking, relabeling, or salvaging
drugs and where those operations are being performed. As explained in
Senate Report No. 1744, ``drugs should not be on the market unless
[FDA] knows who is making them, and where they are being made. This
will help stop illicit and substandard manufacturers who do not follow
the methods or establish the controls called for by good manufacturing
practice'' (1962 U.S.C.C.A.N. 2884, 2889). Knowing where drugs are
being made is even more important today because it would increase the
Nation's ability to prepare for and respond effectively to bioterrorism
and other public health emergencies.
Drug listing information gives us a current inventory of
marketed drugs. As stated in Senate Report No. 92-924, ``[t]he
effective enforcement of the drug provisions of the [a]ct requires the
ready availability of a current inventory of all marketed drugs'' (1972
U.S.C.C.A.N. 2963, 2964). Moreover, the intent of drug listing is to
provide us ``with an effective means of surveillance'' (Id. at 2965).
Both establishment registration and drug listing information facilitate
our implementation and enforcement of the act and are used for many
important public health purposes. In addition, this information will
help us better respond to emergencies (for example, we will be in a
better position to effectively facilitate recalls should there be such
a need).
2. Who Would Part 207 Cover?
We are proposing to add new Sec. 207.9 to explain that part 207
would apply to the following.
Domestic manufacturers, domestic repackers, domestic
relabelers, and domestic drug product salvagers, unless they are exempt
under section 510(g) of the act or proposed Sec. 207.13. The terms
``domestic manufacturers,'' ``domestic repackers,'' ``domestic
relabelers,'' and ``domestic drug product salvagers'' are defined in
proposed Sec. 207.1 and are explained in section IV.A.5 of this
document. Proposed Sec. 207.9 does not
[[Page 51281]]
change the scope of current part 207. Domestic manufacturers, domestic
repackers, domestic relabelers, and domestic drug product salvagers
would be covered under proposed part 207 whether or not the drugs they
manufacture, repack, relabel, or salvage enter interstate commerce.
Section 510(b) and (c) of the act refer to an establishment ``in any
State.'' Congress's intention for section 510 of the act to apply to
drugs both in interstate and intrastate commerce is stated in section
301 of Public Law 82-781, in part, as follows: ``[T]he products of all
[establishments in which drugs are manufactured, prepared, propagated,
compounded, or processed] are likely to enter the channels of
interstate commerce and directly affect such commerce; and * * * the
regulation of interstate commerce in drugs without provision for
registration and inspection of establishments that may be engaged only
in intrastate commerce in such drugs would discriminate against and
depress interstate commerce in such drugs, and adversely burden,
obstruct, and affect such interstate commerce.''\3\ Accordingly, we are
proposing to add to proposed Sec. 207.9 the clause ``regardless of
whether their drugs enter interstate commerce'' to reflect this
congressional finding. The phrase ``Drug products * * * must be listed
whether or not the output of such establishments or any particular drug
so listed enters interstate commerce'' is already included in current
Sec. 207.20(a).
---------------------------------------------------------------------------
\3\See footnote 1 of section 510 of the act.
---------------------------------------------------------------------------
Foreign manufacturers, foreign repackers, foreign
relabelers, and foreign drug product salvagers, unless they are exempt
under proposed Sec. 207.13(c) through (h). Foreign manufacturers,
foreign repackers, foreign relabelers, and foreign drug product
salvagers are currently required to register, and foreign
manufacturers, foreign repackers, and foreign relabelers are currently
required to submit listing information in accordance with section 510
of the act and Sec. 207.40. The terms ``foreign manufacturers,''
``foreign repackers,'' ``foreign relabelers,'' and ``foreign drug
product salvagers'' are defined in proposed Sec. 207.1 and explained
in section IV.A.5 of this document.
An increased number of foreign manufacturers, foreign repackers,
foreign relabelers, and foreign drug product salvagers may be required
to comply with registration and/or listing requirements because we are
proposing, as explained in section IV.A.4 of this document, to revoke
certain provisions of current Sec. 207.40(a) and (b). We are proposing
to revoke the exemption in current Sec. 207.40(a) relating to foreign
establishments whose drugs enter a foreign trade zone and are re-
exported from the foreign trade zone without having entered U.S.
commerce. We are also proposing to revoke, in part, current Sec.
207.40(b), which allows for a component of a drug imported under
section 801(d)(3) of the act (21 U.S.C. 381(d)(3)) to be imported or
offered for import into the United States even if the component is not
listed and manufactured, prepared, propagated, compounded, or processed
at a registered foreign establishment. We are proposing to eliminate
these two exemptions in current Sec. 207.40(a) and (b) from the
registration and listing requirements in light of certain statutory
changes that have occurred since the publication of the final rule on
foreign establishment registration and listing. Those changes include
enactment of the Bioterrorism Act, which reflects Congress' desire to
increase the Nation's ability to prepare for and respond effectively to
bioterrorism and other public health emergencies.
Manufacturers of drugs regulated under a BLA, as follows:
Manufacturers of drugs regulated under a BLA including, but not
limited to: (1) Plasma derivatives such as albumin, Immune Globulin,
Factor VIII and Factor IX, and recombinant versions of plasma
derivatives or animal derived plasma derivatives; (2) vaccines; (3)
allergenic products; (4) bulk product substances such as fractionation
intermediates or pastes; and (5) therapeutic biological products.
Establishments solely engaged in the manufacture, as defined in
Sec. 1271.3(e) (21 CFR 1271.3(e)), of HCT/Ps, as defined in Sec.
1271.3(d), that, under Sec. 1271.20, are also drugs regulated under
section 351 of the Public Health Service Act (PHS Act) or section 505
of the act. Proposed Sec. 207.9(c)(2) would direct these
establishments to register and list those HCT/Ps with CBER by following
the procedures described in subpart B of part 1271 (21 CFR part 1271)
instead of the procedures for registration and listing described in
part 207. Proposed Sec. 207.9(c)(2) is similar to current Sec.
207.20(f), which we propose to revoke and replace with proposed Sec.
207.9(c)(2).
We are also explaining the relationship between the requirements
for HCT/Ps in part 207 and part 1271 of this chapter. We have
implemented, in part 1271, a comprehensive, risk-based regulatory
approach for HCT/Ps. Under this approach, some HCT/Ps are regulated
solely under section 361 of the PHS Act (42 U.S.C. 264) and the
regulations in part 1271; other HCT/Ps are also subject to regulation
as drugs or devices under the act and to premarket application or
notification requirements (submissions may include BLAs, NDAs, or
device PMAs, product development protocols, or 510(k) applications).
Current Sec. 207.20(f) also states that the additional listing
information requirements in current Sec. 207.31 are applicable to HCT/
Ps registered in accordance with the procedures in part 1271, subpart B
if they are also drugs regulated under a BLA and/or the act. We are
proposing to revoke current Sec. 207.31 and move several of its
requirements to other sections of the proposed rule (see discussion in
sections IV.C and IV.D of this document). Consistent with the
provisions in current Sec. 207.20(f), the requirements will continue
to apply to HCT/Ps that, under Sec. 1271.20, are also drugs regulated
under a BLA or section 505 of the act.
In addition, proposed Sec. 207.9(c)(2) would require the
submission of information not currently required for HCT/Ps under part
207, although the submission of such information has been required for
drug products that are not HCT/Ps. For example, proposed Sec.
207.9(c)(2) would require establishments to submit the NDC number, as
described in proposed Sec. Sec. 207.49(a), 207.53(a), and
207.54(b)(1), and the route of administration, as described in proposed
Sec. 207.49(b). Under these provisions, such HCT/P establishments
would not be required to register and list with both CBER and CDER.
Rather, we envision that establishments will register with CBER, and
then will be asked to provide additional information as required under
part 207. We will manage our databases so that both CBER and CDER have
use of the registration and listing information provided. The concept
is that there will be a link in place when the establishment
electronically accesses the electronic registration and listing system
at http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/cber/tissue/tisreg.htm for tissue registration.
This will allow access to the drug database fields to fill in the
additional information such as the NDC number. If the establishment
enters that it manufactures a licensed biologic, this will trigger the
link. At the current time, there is only one such product.
3. Who Would Not Be Subject to Part 207?
Proposed Sec. 207.9 also describes two categories of
establishments that would not be subject to part 207:
Owners and operators of human blood and blood product
[[Page 51282]]
establishments. This proposed rule does not apply to owners and
operators of human blood and blood product establishments unless they
manufacture any of the products listed in proposed Sec. 207.9(c)(1)(i)
and (c)(1)(iv). If the owners and operators of human blood and blood
product establishments manufacture any of those products, then they
must register and list under part 207. Establishments that collect or
process whole blood and blood products as well as establishments
involved in the testing of whole blood and blood products would
register and list under part 607. For purposes of this proposal, blood
and blood products consist of human whole blood, plasma, or serum or
any product derived from human whole blood, plasma, or serum, and the
term includes biological products regulated as licensed devices.
Manufacturers of licensed devices and manufacturers of licensed
biological components used in a licensed device would register and list
under part 607. This exclusion is consistent with current Sec.
207.7(a) and would not apply to owners and operators of human blood and
blood product establishments who also manufacture other drugs.
Establishments that solely manufacture, prepare,
propagate, compound, assemble, or process medical devices.
Establishment registration and device listing regulations for such
establishments and initial importers of devices, including in vitro
diagnostic products, are codified in part 807. Establishments that
manufacture, prepare, propagate, compound, assemble, or process medical
devices, and also manufacture, prepare, propagate, compound, or process
drugs, are subject to part 207 for drugs and part 807 for devices.
As a result of these proposed revisions clarifying the scope of
part 207, proposed Sec. 207.9 includes the provisions in current Sec.
207.7 that explain the applicability of part 207 to human blood and
blood products and medical devices. We are also proposing to revoke
related provisions that set forth addresses in the Center for Devices
and Radiological Health (CDRH) and CBER for submitting registration and
listing information, and provisions that specify the appropriate forms
for submitting such information.
4. Who Would Be Exempt From Registration and Listing?
Section 510(g) of the act and current Sec. 207.10 provide for
exemptions from registration and drug listing requirements. Proposed
Sec. 207.13 contains certain changes to some of the exemptions in
current Sec. 207.10, as discussed in the first part of this section.
Proposed Sec. 207.13 also incorporates without change some exemptions
from current Sec. 207.10, as discussed at the end of this section.
The introductory paragraph of proposed Sec. 207.13, largely
consistent with current Sec. 207.10, states that, except as provided
in proposed Sec. 207.13(i), the classes of persons listed in proposed
Sec. 207.13 are exempt from registration and drug listing under
section 510(g) of the act, or because we have found, under section
510(g)(5) of the act, that their registration is not necessary for the
protection of the public health. We are proposing to add the phrase
``except as provided in proposed Sec. 207.13(i)'' to indicate that
even though the classes of persons identified in paragraphs (a) through
(h) are exempt from registration and drug listing, if such persons
engage in activities as set forth in paragraph (i), the exemption does
not apply and they are required nonetheless to register and list. We
are also proposing to include in the introductory paragraph a sentence
clarifying that the exemption under proposed Sec. 207.13 would not
provide exemptions from other provisions of the act or regulations. For
example, persons that do not have to register establishments and list
drugs are still subject to the adulteration and misbranding provisions
under sections 501 and 502 of the act (21 U.S.C. 351 and 352) and also
may be subject to the new drug approval requirements under section 505
of the act (21 U.S.C. 355) or new animal drug approval requirements
under section 512 of the act (21 U.S.C. 360b). We may inspect their
establishments in accordance with section 704 of the act and the
current good manufacturing practice requirements. We are proposing to
add the clarifying sentence because in the past some manufacturers,
repackers, relabelers, and drug product salvagers that were exempt from
registration and listing requirements incorrectly believed these
provisions provided exemptions from other provisions of the act and
regulations. Accordingly, we are proposing to add this sentence to
remedy any confusion on this point.
a. Pharmacies--The current exemption for pharmacies is codified at
Sec. 207.10(a). The proposed rule would revise and clarify the
exemption, and would move it to Sec. 207.13(a). Except as noted in the
discussion below, proposed Sec. 207.13(a) is generally consistent with
current Sec. 207.10(a).
Under proposed Sec. 207.13(a), pharmacies would be exempt from the
registration and listing requirements if they: Operate in conformance
with all applicable local laws regulating the practice of pharmacy,
including all applicable local laws regulating the dispensing of
prescription drugs; regularly engage in dispensing prescription drugs
upon prescription of practitioners licensed by law to administer these
drugs to patients under their professional care; and do not manufacture
(as defined in proposed Sec. 207.1), repack, or relabel drugs for sale
other than in the regular course of the practice of pharmacy, including
dispensing and selling drugs at retail.
Additional language has been added to proposed Sec.
207.13(a)(1)(i) and (a)(1)(ii) to more closely track the language in
section 510(g)(1) of the act. In addition, proposed Sec. 207.13(a)
does not include language that is in current Sec. 207.10(a) that
provides that the supplying of prescription drugs to a practitioner
licensed to administer the drugs for use in the course of the
practitioner's professional practice or to other pharmacies to meet
temporary inventory shortages are not acts that require pharmacies to
register. We are deleting this language because it is not necessary.
Pharmacies that engage in such activities would be exempt from
registration if they fulfill the following requirements: Operate in
conformance with all applicable local laws regulating the practice of
pharmacy, including all applicable local laws regulating dispensing of
prescription drugs (proposed Sec. 207.13(a)(1)(i)); regularly engage
in dispensing prescription drugs upon prescription of practitioners
licensed by law to administer these drugs to patients under their
professional care (proposed Sec. 207.13(a)(1)(ii)); and do not
manufacture (as defined in Sec. 207.1), repack, or relabel drugs for
sale other than in the regular course of the practice of pharmacy,
including dispensing and selling drugs at retail (proposed Sec.
207.13(a)(1)(iii)).
Proposed Sec. 207.13(a)(2) clarifies that pharmacies may
potentially qualify for the exemption in proposed Sec. 207.13(a) only
if they are located in any State as defined in section 201(a)(l) of the
act (21 U.S.C. 321) (that is, any State or Territory of the United
States, the District of Columbia, and the Commonwealth of Puerto Rico).
This proposed provision is currently located in the introductory
paragraph in current Sec. 207.10. We believe it would be more clear to
place this provision in proposed Sec. 207.13(a)(2). This aspect of the
proposed provision is consistent with current Sec. Sec. 207.10 and
207.40.
b. Hospitals, clinics, other health care entities, and public
health agencies--The current exemption for hospitals, clinics, and
public health agencies is
[[Page 51283]]
codified at Sec. 207.10(b). The proposed exemption is generally
consistent with current Sec. 207.10(b), except for the addition of
``other health care entities'' and other mostly minor revisions and
clarifications, as described below. The proposed exemption would move
to Sec. 207.13(b).
Hospitals, clinics, other health care entities, and public health
agencies are exempt, under proposed Sec. 207.13(b), from the
registration and listing requirements if they: Operate establishments
in conformance with all applicable local laws regulating the practice
of pharmacy and medicine, including all applicable local laws
regulating the dispensing of prescription drugs; regularly engage in
dispensing prescription drugs, other than human blood or blood
products, upon prescription of practitioners licensed by law to
administer these drugs to patients under their professional care; and
do not manufacture (as defined in proposed Sec. 207.1), repack, or
relabel drugs other than in the regular course of the practice of
pharmacy, including dispensing.
The exemption in proposed Sec. 207.13(b) would be limited to
hospitals, clinics, other health care entities, and public health
agencies located in any State as defined in section 201(a)(1) of the
act. The proposed provision requiring that such facilities be located
in any State is currently located in the introductory paragraph in
current Sec. 207.10. We believe it would be more clear to place this
provision in proposed Sec. 207.13(b)(2). This proposed provision
(except with respect to BLA holders and the clarification with respect
to positron emission tomography (PET) drugs) is generally consistent
with current Sec. Sec. 207.10 and 207.40.
We are proposing to add ``other health care entities'' to this
exemption because we are aware that other health care entities besides
hospitals, clinics, and public health agencies (such as skilled nursing
facilities) lawfully provide medical care and dispense drugs and
logically are similarly situated to hospitals, clinics, and public
health agencies for purposes of exempting them from registration and
listing, if they meet the statutory and regulatory requirements.
We are also proposing to add language to proposed Sec. 207.13(b)
to make the exemption more consistent with the pharmacy exemption in
proposed Sec. 207.13(a). For example, we are proposing to add language
to proposed Sec. 207.13(b)(1)(i) so that this exemption also
specifically requires compliance with all applicable laws regulating
dispensing of prescription drugs, as is required by proposed Sec.
207.13(a)(1)(i). We are similarly proposing to add Sec.
207.13(b)(1)(iii) to be consistent with proposed Sec.
207.13(a)(1)(iii), although in proposed Sec. 207.13(b)(1)(iii) we have
not included the terms ``for sale'' or ``selling drugs at retail''
since this language is appropriate for retail pharmacies relying on the
exemption provided by proposed Sec. 207.13(a), but not for hospitals,
clinics, other health care entities, and public health agencies relying
on the exemption provided by proposed Sec. 207.13(b).
We believe that the exemption for hospitals, clinics, other health
care entities, and public health agencies provided in proposed Sec.
207.13(b)(2) should be relied upon by pharmacies within these health
care entities that dispense drugs to patients receiving care in the
health care entities and that meet the requirements of the exemption,
but should not be relied upon by retail pharmacies located within these
health care entities. Retail pharmacies should rely upon the exemption
in proposed Sec. 207.13(a) if they meet the requirements of that
proposed provision.
c. Persons who manufacture, repack, relabel, or salvage certain
medicated feeds--Although we are proposing to reorganize and clarify
the exemption for persons who manufacture, repack, relabel, or salvage
certain medicated feeds, we are not proposing to change the substance
of the exemption. Under proposed Sec. 207.13(f), persons who
manufacture, repack, relabel, or salvage Type B or Type C medicated
feeds, except for manufacturers, repackers, relabelers, or drug product
salvagers of Type B or Type C medicated feeds made from Category II,
Type A medicated articles, are exempt from registration. This exemption
would not apply to persons who would otherwise be required to register
(such as manufacturers, repackers, relabelers, or drug product
salvagers of certain free-choice feeds, as defined in 21 CFR 510.455,
or certain liquid feeds, as defined in 21 CFR 558.5, where the
specifications and/or formulas are not published and a feed mill
license is required). Proposed Sec. 207.13(f) also clarifies that all
manufacturers, repackers, relabelers, or drug product salvagers of Type
B or Type C medicated feeds would be exempt from listing.
d. The current exemptions for foreign trade zones and drugs
imported under section 801(d)(3) of the act would be revoked--In 2001,
we issued a final rule on foreign establishment registration and
listing (66 FR 59138, November 27, 2001). The regulation created two
exemptions in Sec. 207.40:
Under current Sec. 207.40(a), a foreign establishment is
not required to comply with the registration and listing requirements
if its drug enters a foreign trade zone and is re-exported from that
foreign trade zone without having entered U.S. commerce. We created
this exemption as part of the final rule on foreign establishment
registration and listing because registering such foreign
establishments or listing drugs that were confined to a foreign trade
zone--and were therefore not introduced into domestic commerce--was not
considered necessary for the protection of the public health (see 66 FR
59138 at 59139 and 59140).
Current Sec. 207.40(b), which states 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, also states that this
prohibition does not apply to components of drugs imported under
section 801(d)(3) of the act. Section 801(d)(3) of the act, as it
existed before June 2002, allowed persons to import unapproved or
otherwise noncompliant articles (such as drug components) provided that
the imported articles were further processed or incorporated into
products and exported or, if not used, the imported articles were
destroyed or exported. The provision in Sec. 207.40(b) reflected the
fact that, at the time, section 801(d)(3) of the act imposed very few
restrictions on the admission of drug components that are imported into
the United States for further processing or incorporation into a
product that will be exported from the United States (66 FR 59138 at
59148).
Given the additional level of import restrictions imposed by the
Bioterrorism Act, and the underlying security concerns that led to the
Bioterrorism Act's adoption, we are proposing to eliminate these two
exemptions in current Sec. 207.40(a) and (b) from the registration and
listing requirements. In particular, sections 321 and 322 of the
Bioterrorism Act, which affected foreign establishment registration by
amending sections 510 and 801 (among other provisions) of the act,
suggest that Congress intended the information requirements for foreign
establishments and imported products to be comprehensive, and that
Congress regarded the information it was requiring to be important to
its goal in increasing the Nation's ability to prepare for and respond
effectively to bioterrorism and other public health emergencies. This,
in turn, suggests to
[[Page 51284]]
FDA that the exceptions from the registration and listing requirements
are therefore no longer appropriate.
The Bioterrorism Act affected foreign establishment registration,
in relevant part, by amending sections 510(i) and 801 of the act:
To require, as part of an establishment's registration,
the name of each importer of the drug that is known to the
establishment and the name of each person who imports or offers to
import the drug into the United States; and
To provide that we may refuse admission of a product and,
if the product is refused admission, that the product shall be held at
the port of entry until a statement regarding the foreign
establishment's registration is submitted to us.
The amendment to section 510(i) of the act reflects a determination
on the part of Congress that a foreign establishment shipping drugs to
the United States should provide additional information in its
registration (that is, information about importers and persons who
import or offer for import). FDA is concerned that if a foreign
establishment is not subject to this establishment registration
requirement--either by virtue of importing into a foreign trade zone or
by importing components under section 801(d)(3) of the act--it would
allow some importers and persons who import or offer for import to go
undetected, thereby creating an unnecessary vulnerability in Congress'
system of requiring this information.
The amendment to section 801(o) of the act reflects a determination
that establishment registration and drug listing information is
important enough that, if it is lacking at the time the article is
offered for import, the article may be refused admission (and, if
refused, shall be held at the port of entry). FDA is concerned that if
a foreign establishment is exempt from the registration and listing
requirements--either by virtue of importing into a foreign trade zone
or by importing components under section 801(d)(3) of the act--FDA
would be unable to rely on amended sections 510(i) and 801 of the act
to require that imported products be held at the port of entry to the
United States or to prevent such product's delivery to the importer or
consignee. This situation would stand in the way of implementing
Congress' apparent intent that this information be a prerequisite for
entry of the imported product into the United States.
We believe that removing the exception to the registration and
listing requirements for products entering foreign trade zones and for
products imported under section 801(d)(3) of the act is consistent with
Congress' desire to increase the Nation's ability to prepare for and
respond effectively to bioterrorism and other public health emergencies
by requiring foreign establishments to provide more, rather than less,
information for imported products.
The Bioterrorism Act also revised section 801(d)(3) of the act, in
part, by:
Requiring importers to identify the manufacturers of the
imported drug component, and each processor, packer, distributor, or
other entity that had possession of the article from the manufacturer
to the importer;
Requiring certificates of analysis to accompany most
imported articles; and
Giving us the ability to refuse admission to the United
States if we determine there is credible evidence or information
indicating that the article is not intended to be further processed by
the initial owner or consignee, or incorporated by the initial owner or
consignee into a drug, biological product, or other product specified
in section 801(d)(3) of the act that will be exported from the United
States.
These statutory changes also indicate a congressional desire to
know more, rather than less, about the articles entering the United
States under section 801(d)(3) of the act and to prevent potentially
dangerous articles from entering the United States. The legislative
history supports this belief, as the conference report for the
Bioterrorism Act explained: ``Refusal of entry should not involve
shipments between known shippers and known recipients unless the
Secretary has received credible evidence or information that suggests
such shipments may not be legitimate. The Managers intend to permit the
Secretary to refuse admission of articles if the Secretary determines
there is credible evidence or information that the articles may be used
as instruments of terror. Such evidence might include highly toxic or
otherwise exceptionally dangerous products going to recipients unknown
to the Secretary or to recipients believed to lack the capability to
further process such dangerous articles * * *.'' (See H. Rept. 107-481,
l07th Cong. (2002), ``Joint Explanatory Statement of the Committee of
Conference,'' ``Subtitle B--Protection of Drug Supply'' (discussing
section 322).) The legislative history's references to ``known''
shippers, ``known'' recipients, and recipients who may lack the ability
to further process an article, combined with the new statutory
provision on refusing admission even if the article is imported under
section 801(d)(3) of the act, strongly support our proposal to require
that all drugs imported or offered for import into the United States be
listed and manufactured at a registered foreign establishment. Failure
to register such foreign establishments could compromise our ability to
refuse admission of a dangerous article.
Therefore, the proposed rule would eliminate the exemption from the
establishment registration and drug listing requirements for foreign
establishments whose drugs enter a foreign trade zone and are re-
exported from that foreign trade zone without having entered U.S.
commerce. In addition, the proposal would require that all drugs
imported or offered for import into the United States be listed and
manufactured at a registered foreign drug establishment, even if the
drug is imported under section 801(d)(3) of the act.
e. Other exemptions--As described in current Sec. 207.10, the
following remain exempt from registration and drug listing (proposed
Sec. 207.13):
Practitioners who are licensed by law to prescribe or
administer drugs and who manufacture, repack, relabel, or salvage drugs
solely for use in their professional practice (current Sec. 207.10(c);
proposed Sec. 207.13(c)).
Manufacturers, repackers, relabelers, or drug product
salvagers of drugs solely for use in research, teaching, or chemical
analysis and not for sale (current Sec. 207.10(d); proposed Sec.
207.13(d)). Under proposed Sec. 207.13(d), manufacturers, repackers,
relabelers, or drug product salvagers who manufacture, repack, relabel,
or salvage drugs solely for use in research, teaching, or chemical
analysis and not for sale are exempt from registration requirements.
Proposed Sec. 207.13(d) would be consistent with the exemption in
section 510(g)(3) of the act, except the language would be modified to
take into account the proposed rule's uses of the terms
``manufacturer,'' ``repacker,'' ``relabeler,'' ``drug product
salvager,'' ``manufacture,'' ``repack,'' ``relabel,'' and ``salvage.''
We want to take the opportunity to remind interested persons that while
the exemption from registration would apply to a sponsor that
manufactures its own drug for use in its clinical trial of the drug,
the exemption would not apply, for example, to a firm that manufactures
a drug with the purpose of selling the drug to a sponsor for use in a
clinical trial. In the latter situation, the manufacturer of the drug
would be required to register.
Manufacturers, repackers, relabelers, and drug product
salvagers of
[[Page 51285]]
harmless inactive ingredients (current Sec. 207.10(e); proposed Sec.
207.13(e)). We considered proposing to revoke this exemption because of
concerns related to potential contamination of those inactive
ingredients. However, we concluded that submitting and maintaining in
the database all excipients, colorings, flavorings, emulsifiers,
lubricants, preservatives, or solvents that become components of drugs
could be burdensome for industry. In proposing to maintain this
exemption, we note that current regulations governing the manufacture
of finished drug products require all manufacturers to perform quality
control testing to ensure that components meet established
specifications (see generally, part 211 (21 CFR part 211)).
Manufacturers, repackers, relabelers, and drug product
salvagers of animal viruses, serums, toxins, or analogous products
(current Sec. 207.10(g); proposed Sec. 207.13(g)).
Carriers (current Sec. 207.10(h); proposed Sec.
207.13(h)).
f. Limits on exemptions--Proposed Sec. 207.13(i) would clarify
that any of the persons who otherwise would qualify for an exemption
under Sec. 207.13(a) through (h) are not exempt from registration or
listing if they: (1) Manufacture (as defined in proposed Sec.
207.1),\4\ repack, relabel, or salvage compounded positron emission
tomography (PET) drugs as defined in section 201(ii) of the act; (2)
manufacture (as defined in Sec. 600.3(u)) a biological product subject
to licensing under section 351 of the Public Health Service (PHS) Act;
(3) manufacture (as defined in Sec. 1271.3(e)) an HCT/P that, under
Sec. 1271.20, are also drugs regulated under section 351 of the PHS
Act or section 505 of the act; or (4) engage in activities that would
otherwise require them to register under this part.
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\4\The term ``manufacture'' is defined in proposed Sec. 207.1
and is used here for brevity to refer to the activities that trigger
registration requirements (that is, ``manufacture, preparation,
propagation, compounding, or processing'' of drugs). Although many
PET facilities do not consider themselves to be ``manufacturing''
drugs, but rather preparing or compounding drugs, we are nonetheless
using the term ``manufacture'' for brevity.
---------------------------------------------------------------------------
Thus, any person identified in proposed Sec. 207.13(a) through
(h), such as pharmacies, hospitals, clinics, other health care
entities, public health agencies, or practitioners, if they
manufacture, repack, relabel, or salvage compounded PET drugs, as
defined in section 201(ii) of the act (21 U.S.C. 321(ii)), would fall
outside the scope of the exemptions provided in proposed Sec.
207.13(a) through (h). Manufacturers, repackers, relabelers, or drug
product salvagers of compounded PET drugs are not included among the
persons that are exempt from registration under proposed Sec. 207.13
because exempting manufacturers of compounded PET drugs from
registration would be inconsistent with section 121 of the Food and
Drug Administration Modernization Act of 1997 (the Modernization Act)
(Public Law 105-115), which addresses the regulation of PET drug
products. Section 121 of the Modernization Act directs us to develop
appropriate procedures for the approval of PET drugs under section 505
of the act and appropriate CGMP requirements for such drugs. It also
requires the submission of NDAs or ANDAs for PET drugs either 4 years
after the date of enactment or 2 years after the date on which we
establish approval procedures and CGMPs, whichever is longer. We
published proposed CGMPs for PET drugs on September 20, 2005 (70 FR
55038). If Congress had intended to exempt manufacturers, repackers,
relabelers, or drug product salvagers of PET drugs from registration
requirements, it would have done so. Given that PET manufacturers will
be expected to comply with CGMP requirements and FDA will need to
inspect them to determine compliance, it is reasonable to require PET
manufacturers, repackers, relabelers, or drug product salvagers to
register so we can identify PET manufacturers, repackers, relabelers,
or drug product salvagers and the drugs they manufacture, repack,
relabel, or salvage for inspection purposes. Therefore, the proposed
rule would require compounded PET drug manufacturers, repackers,
relabelers, or drug product salvagers to register with us and list
their drugs in accordance with section 510(j) of the act and proposed
part 207.
Likewise, any person identified in Sec. 207.13(a) through (h) who
would otherwise qualify for an exemption would not qualify for an
exemption if it manufactures (as defined in Sec. 600.3(u)) a
biological product subject to licensing under section 351 of the PHS
Act.
We note that to the extent a person manufactures, repacks,
relabels, or salvages PET drugs as set forth in proposed Sec.
207.13(i)(1) or manufactures a biological product subject to licensing
as set forth in proposed Sec. 207.13(i)(2), the obligation to register
and list would only apply to the extent that that person engages in the
activities identified in proposed Sec. 207.13(i)(1) or (i)(2). For
example, a hospital dispensing and administering drugs and that also
manufactures compounded PET drugs would list only the PET drugs it
manufactures, assuming none of its other activities would subject it to
registration or listing requirements. Likewise, a public health agency
dispensing and administering drugs that holds a biologics license
application would list only the biological drugs it manufactures,
assuming none of its other activities would subject it to registration
or listing requirements.
Proposed paragraph (i) also states that the exemptions provided in
proposed Sec. 207.13(a) through (h) do not apply to such persons if
they engage in activities that would otherwise require them to
register. This concept appeared in current Sec. 207.10(e). We are
proposing to apply this concept to all the exemptions in proposed Sec.
207.13 to reiterate that if a person qualifies for an exemption from
the activities stated in proposed Sec. 207.13(a) through (h), that
person may still need to register if that person engaged in activities
that would otherwise require registration.
5. What Definitions and Interpretations of Terms Would Apply to Part
207?
In proposed Sec. 207.1, we set forth new definitions and
interpretations of terms for part 207 and revise or revoke certain
definitions in current Sec. 207.3(a).
Current Sec. 207.3(b) states that the definitions and
interpretations of terms in sections 201, 502(e), and 510 of the act
apply to the terms used in part 207. We are proposing to revoke this
sentence because it is unnecessary and has caused confusion in the
past. For purposes of proposed part 207, the following definitions and
interpretations of terms would apply to proposed part 207:
Act. This term, as used in proposed Sec. 207.1, remains the same
as current Sec. 207.3(a)(1). ``Act'' means the Federal Food, Drug, and
Cosmetic Act (52 Stat. 1040 et seq., as amended (21 U.S.C. 301 et
seq.)), except as otherwise provided.
Active pharmaceutical ingredient. We are proposing to replace the
term ``bulk drug substance,'' as defined in current Sec. 207.3(a)(4),
with the term ``active pharmaceutical ingredient.'' We believe that the
term ``bulk drug substance'' may be confused with the term ``bulk
drug.'' The term ``bulk drug,'' as commonly used in the pharmaceutical
industry, means an active ingredient, inactive ingredient, or finished
dosage form, packaged in a large container (for example, a drum). To
prevent confusion, we are proposing to replace the term ``bulk drug
substance'' with the more descriptive term ``active pharmaceutical
ingredient.''
We are also proposing to revise the definition of the current term
``bulk
[[Page 51286]]
drug substance'' (changed to ``active pharmaceutical ingredient'' in
the proposal) to make it consistent with the definition of ``drug
substance'' in current Sec. 314.3 (21 CFR 314.3). Current Sec.
207.3(a)(4) states, in part, that a ``bulk drug substance * * * becomes
an active ingredient,'' but does not explain what it means for an
ingredient to be ``active.'' We believe that the definition of ``drug
substance'' in current Sec. 314.3 is more descriptive; that definition
explains, in part, that ``drug substance means an active ingredient
that is intended to furnish pharmacological activity or other direct
effect in the diagnosis, cure, mitigation, treatment, or prevention of
disease or to affect the structure or any function of the * * * body.''
Consistent with the language of current Sec. 314.3, we are proposing
to define ``active pharmaceutical ingredient'' in proposed Sec. 207.1
as any substance that is intended to furnish pharmacological activity
or other direct effect in the diagnosis, cure, mitigation, treatment,
or prevention of disease, or to affect the structure or any function of
the body. Consistent with both current Sec. 314.3 and current Sec.
207.3(a)(4), the term would not include intermediates used in the
synthesis of the substance. As proposed, the term would include both an
active pharmaceutical ingredient marketed alone and as part of a
finished dosage form.
Advertising and labeling. We are proposing to delete current Sec.
207.3(a)(2), which explains that the terms ``advertising'' and
``labeling,'' as used in current part 207, include the promotional
material described in current Sec. 202.1(l)(1) and (l)(2) (21 CFR
202.1(l)(1) and (l)(2)), respectively. We believe that this information
is more appropriately included in the definitions of ``representative
sampling of advertisements'' and ``representative sampling of any other
labeling.'' As a result, we are proposing to revise the definitions of
those terms accordingly and delete current Sec. 207.3(a)(2).
Commercial distribution. We are not proposing to substantively
change the definition of ``commercial distribution'' from that set
forth in current Sec. 207.3(a)(5). The term would still mean any
distribution of a human drug, except for investigational use under 21
CFR part 312, and any distribution of an animal drug or an animal feed
bearing or containing an animal drug for non-investigational uses. The
term would not include internal or interplant transfer of an active
pharmaceutical ingredient between registered establishments within the
same parent, subsidiary, and/or affiliate company. For foreign
manufacturers, foreign repackers, foreign relabelers, foreign drug
product salvagers, foreign private label distributors, and foreign
establishments, the term ``commercial distribution'' would have the
same meaning except that it does not include distribution of any drug
that is neither imported nor offered for import by it into the United
States. We are proposing to change the term ``bulk drug substance'' in
the current definition to ``active pharmaceutical ingredient'' because
the proposal replaces the definition of ``bulk drug substance'' with
the definition of ``active pharmaceutical ingredient.'' Defining
``commercial distribution'' is important because, under proposed part
207, listing information must be provided to us for any drug that is
being manufactured, repacked, relabeled, or salvaged for commercial
distribution.
Content of labeling. We are proposing to add a new term, ``content
of labeling,'' to part 207. The proposed definition of the term
describes the labeling material that would be required to be
electronically submitted at the time of listing under proposed
Sec. Sec. 207.49(g) and 207.61(a)(2). The proposed requirement to
electronically submit the ``content of labeling'' would be in addition
to the current listing requirement that formatted copies of certain
labeling be submitted. We are proposing to define ``content of
labeling'' because, as explained in section IV.E.4 of this document,
the electronic submission of the ``content of labeling'' would be
required for drug listing to permit us to electronically review,
compare, and extract data from the labeling.
For human prescription drugs that the manufacturer regards
as subject to section 505 of the act or section 351 of the PHS Act, we
are proposing to define ``content of labeling'' as the content of the
prescription drug labeling, as specified in Sec. Sec. 201.56, 201.57,
and 201.80 (21 CFR 201.56, 201.57, and 201.80), including all text,
tables, and figures.\5\
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\5\The use of the language ``that the manufacturer regards as
subject to section 505 of the act or section 351 of the PHS Act,''
is explained in detail in section IV.D.7 of this document.
---------------------------------------------------------------------------
This proposed definition is consistent with how the term ``content
of labeling'' is used in the final rule entitled ``Requirements for
Submission of Labeling for Human Prescription Drugs and Biologics in
Electronic Format,'' (electronic labeling final rule), which published
in the Federal Register of December 11, 2003 (68 FR 69009). Under the
electronic labeling final rule, applicants are required to
electronically submit, in a format that we can process, review, and
archive, the ``content of labeling'' for human prescription drugs in
NDAs, certain BLAs, ANDAs, supplements, and annual reports.\6\ The
electronic labeling final rule, including the use of the term ``content
of labeling,'' only applies to this subset of drugs. Under the
proposal, however, as set forth in proposed Sec. 207.49(g), the
``content of labeling'' would be provided for drugs subject to the
listing requirements of proposed part 207.
---------------------------------------------------------------------------
\6\For additional information, also see the guidance ``Providing
Regulatory Submissions in Electronic Format--Content of Labeling''
(April 2005) (available at http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/cder/guidance/index.htm
), which discusses issues related to the submission of the
content of labeling in electronic format in marketing applications
for human drug and biological products. This guidance reflects our
current thinking on providing in electronic format the content of
labeling required in 21 CFR parts 314 and 601.
---------------------------------------------------------------------------
Proposed part 207 would also differ in one other respect from the
way ``content of labeling'' is used in the electronic labeling final
rule. The electronic labeling final rule states that the ``content of
labeling'' that must be submitted electronically is commonly referred
to as the content of the package insert or professional labeling. We
are proposing to use the term ``prescription drug labeling'' instead of
the term package insert or professional labeling. ``Prescription drug
labeling'' is used in the final rule entitled ``Requirements on Content
and Format of Labeling for Human Prescription Drug and Biological
Products,'' published in the Federal Register of January 24, 2006 (71
FR 3922). In that final rule, ``prescription drug labeling'' is used to
mean labeling for approved prescription drug products described in
Sec. Sec. 201.56, 201.57, and 201.80, which is commonly described
using a variety of terms including ``professional labeling,'' ``package
insert,'' ``direction circular,'' or ``package circular.'' We are
proposing that the term ``content of labeling'' for human prescription
drugs, as defined in proposed Sec. 207.1 and required under proposed
Sec. 207.49(g), would be the content of the ``prescription drug
labeling.''
For human prescription drugs that the manufacturer regards
as not subject to section 505 of the act or section 351 of the PHS Act,
we are proposing to define ``content of labeling'' as the labeling
equivalent to the content of the prescription drug labeling, as
specified in Sec. Sec. 201.56, 201.57, and 201.80, including all text,
tables, and figures.
For human OTC drugs, we are proposing to define ``content
of labeling'' as the content of the drug facts labeling required by
Sec. 201.66 (21 CFR
[[Page 51287]]
201.66) (format and content requirements for OTC drug product
labeling), including all text, tables, and figures. Under Sec.
201.66(b)(10), drug facts labeling means the title, headings,
subheadings, and information required under or described in Sec.
201.66(c) (content requirements).
For animal drugs (including, but not limited to, drugs
that the manufacturer regards as subject to section 512 of the act), we
are proposing to define ``content of labeling'' as the content of the
labeling that accompanies the drug that is necessary to enable safe and
proper administration of the drug (for example, the labeling specified
in Sec. Sec. 201.1 and 201.5 (21 CFR 201.1 and 201.5)), including all
text, tables, and figures.
Domestic. For the purposes of registration and listing under this
proposal, and when used to modify the term ``manufacturer,''
``repacker,'' ``relabeler,'' ``drug product salvager,'' ``private label
distributor,'' or ``establishment,'' we are proposing to use the term
``domestic'' to refer to a manufacturer, repacker, relabeler, drug
product salvager, private label distributor, or establishment within
any State or Territory of the United States, the District of Columbia,
or the Commonwealth of Puerto Rico. The terms ``manufacturer,''
``repacker,'' ``relabeler,'' ``drug product salvager,'' ``private label
distributor,'' and ``establishment'' are defined in proposed Sec.
207.1, and these definitions are discussed elsewhere in this section of
the preamble. We are proposing to define the term ``domestic''
separately rather than repeat the meaning of the term under separate
definitions for domestic manufacturer, domestic repacker, domestic
relabeler, domestic drug product salvager, domestic private label
distributor, and domestic establishment. The definition of ``foreign,''
as it would modify manufacturer, repacker, relabeler, drug product
salvager, private label distributor, and establishment, is discussed
elsewhere in this section of the preamble.
Drug(s). We are proposing to use the term ``drug(s),'' for purposes
of proposed part 207, to mean the same as the definition of ``drug'' in
section 201(g)(1) of the act. Section 201(g)(1) of the act defines
``drug'' to include, among other things, articles intended for use in
the diagnosis, cure, mitigation, treatment, or prevention of disease in
man or other animals, and articles (other than food) intended to affect
the structure or any function of the body of man or other animals.
``Drug(s)'' under proposed Sec. 207.1 would include drugs intended for
use in humans, including the biologics described in proposed Sec.
207.9(c), and animal drugs, including Type A medicated articles, and
also includes articles ``intended for use as a component'' of any drug.
The proposed term includes active pharmaceutical ingredients and
finished dosage forms (prescription and OTC).
Drug product salvager, drug product salvaging. We are proposing to
use the term ``drug product salvaging'' to mean applying manufacturing
controls such as those required by current good manufacturing practice
in parts 210 (21 CFR part 210) and part 211 to drug products and
segregating out those 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. We note, however, that drug product
salvaging, like all manufacturing, must be conducted in accordance with
current good manufacturing practice. We are proposing to use the term
``drug product salvager'' to mean a person who owns or operates an
establishment that engages in drug product salvaging. When not modified
by ``domestic'' or ``foreign,'' as defined in proposed Sec. 207.1 and
discussed in section IV.A.5 of this document, the term would include
both domestic drug product salvagers and foreign drug product
salvagers.
Under current Sec. 207.3(a)(6), drug product salvaging means the
act of segregating 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
some or all of the products to the marketplace. We are proposing to
revise the current definition of drug product salvaging to include
``applying manufacturing controls such as those required by current
good manufacturing practice in part 210 and part 211 to drug
products.'' We are not proposing to change the meaning of drug product
salvaging but to clarify the current definition by explaining that the
term also includes applying manufacturing controls to drug products.
Drug product salvagers apply manufacturing controls to drug products so
that they can determine whether the drug products may have been
subjected to improper storage conditions. As discussed further in
sections IV.B.1 and IV.D.1 of this document, ``applying manufacturing
controls to drug products and segregating drug products'' would be
covered under the scope of manufacturing, preparing, propagating,
compounding, or processing, and repackaging or otherwise changing the
container, wrapper, or labeling of any drug package in furtherance of
the distribution of the drug from the original place of manufacture to
the person who makes the final delivery or sale to the ultimate
consumer or user (section 510(a)(1) of the act). This activity would
trigger the requirement to register under the act. In addition, under
the proposal, drug product salvagers would also be subject to the drug
listing requirements in section 510(j)(1) of the act because their
activities involve conducting one of the aforementioned activities with
respect to a given drug for the purpose of commercial distribution. As
discussed in section IV.D.1 of this document, we are requesting
comments specifically on whether drug product salvagers should be
subject to the drug listing requirements because the drug products are
being salvaged for commercial distribution.
Establishment. We are proposing to revise the definition of
``establishment'' at current Sec. 207.3(a)(7) to mean, for purposes of
registration and drug listing, a place of business under one management
at one geographic location. Under the proposed definition, 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. When not
modified by ``domestic'' or ``foreign,'' as defined in proposed Sec.
207.1 and discussed in section IV.A.5 of this document, the term would
include both domestic establishments and foreign establishments. We are
proposing to define the term ``establishment'' because, under proposed
part 207, manufacturers, repackers, relabelers, and drug product
salvagers must register each establishment, providing to us such
information as the name and address of the establishment and type of
operation performed at the establishment.
The proposed definition of ``establishment'' would clarify the
phrase ``at one general physical location'' in the current definition
by revising the phrase to read ``one geographic location'' and stating
that this 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.
The proposed definition of ``establishment'' is intended to
simplify the current definition. The current definition defines
establishment as a
[[Page 51288]]
place of business under one management at one general physical
location, and includes, among others, independent laboratories that
engage in control activities for a registered drug establishment (for
example, consulting laboratories), manufacturers of medicated feeds and
vitamin products that are drugs in accordance with section 201(g) of
the act, human blood donor centers, animal facilities used for the
production or control testing of licensed biologics, and establishments
engaged in drug product salvaging. For brevity, the proposed definition
of establishment does not restate the examples of establishments stated
in the current definition. Some of these establishments would be
covered under other definitions set forth in proposed Sec. 207.1 and
explained in section IV.A.5 of this document. For example,
``independent laboratories that engage in control activities for a
registered drug establishment'' would be covered under the proposed
definition of ``manufacturer.'' ``Establishments engaged in drug
product salvaging'' would be covered under the proposed definition of
``drug product salvager.''
Establishment registration number. We are proposing to define
``establishment registration number'' as the number assigned by FDA to
the establishment during the establishment registration process
required in this part. The establishment registration number is
assigned to each establishment of each manufacturer, repacker,
relabeler, or drug product salvager inspected by our district office.
The establishment registration number is assigned when the
manufacturer, repacker, relabeler, or drug product salvager begins
manufacturing, repacking, relabeling, or salvaging drugs subject to
part 207. The establishment registration number would identify, among
other things, where the drug is manufactured, repacked, relabeled, or
salvaged. Currently, 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.
Foreign. For the purposes of registration and listing under this
proposal, and when used to modify the term ``manufacturer,''
``repacker,'' ``relabeler,'' ``drug product salvager,'' or ``private
label distributor,'' we are proposing 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 the term ``establishment,'' we are proposing to use the term
``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. The terms ``manufacturer,'' ``repacker,''
``relabeler,'' ``drug product salvager,'' ``private label
distributor,'' and ``establishment'' are defined in proposed Sec.
207.1, and these definitions are discussed elsewhere in this section of
the preamble. We are proposing to define the term ``foreign''
separately rather than repeat the meaning of the term under separate
definitions for foreign manufacturer, foreign repacker, foreign
relabeler, foreign drug product salvager, foreign private label
distributor, and foreign establishment. The definition of ``domestic,''
as it would modify manufacturer, repacker, relabeler, drug product
salvager, private label distributor, and establishment, is discussed
elsewhere in this section of the preamble.
Importer. We are proposing to define ``importer'' to mean 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. We recognize that a foreign establishment may have more
than one ``importer'' and we are proposing 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. Under this proposal, the recipient of
the drug would not include the consumer or patient who ultimately
purchases, receives, or is administered the drug, unless the foreign
establishment ships the drug directly to the consumer or patient. As
described in section IV.B.3 of this document, this proposal would
require foreign establishments to provide, for drugs manufactured,
repacked, relabeled, or salvaged at the establishment, the name of each
importer known to the establishment of such drug into the United
States. Therefore, the establishment would need to provide the name of
each owner, consignee, or recipient of the foreign establishment's drug
imported into the United States that was known to the establishment. We
describe more fully what we mean by ``known to the establishment'' in
section IV.B.3 of this document. We invite comments on our definition
of importer, including the scope of the entities included in the
definition.
Manufacture, manufacturer. We are proposing to use the term
``manufacture'' for purposes of this part to mean each step in the
manufacture, preparation, propagation, compounding, or processing of a
drug. Manufacture includes the making by chemical, physical,
biological, or other procedures or manipulations of a drug, including
control procedures applied to the final product or to any part of the
process. Manufacture includes manipulation, sampling, testing, or
control procedures applied to the final product or to any part of the
process, including, for example, analytical testing of drugs, for
another registered establishment's drug.
We are proposing to use the term ``manufacturer'' for purposes of
this part to mean a person who owns or operates an establishment that
manufactures a drug. When not modified by ``domestic'' or ``foreign,''
as defined in proposed Sec. 207.1 and discussed in section IV.A.5 of
this document, ``manufacturer'' would include both domestic
manufacturers and foreign manufacturers.
Under section 510(a)(1) of the act, the term ``manufacture,
preparation, propagation, compounding, or processing'' includes
repackaging or otherwise changing the container, wrapper, or labeling
of any drug package in furtherance of the distribution of the drug from
the original place of manufacture to the person who makes final
delivery or sale to the ultimate consumer or user. Accordingly, section
510(a)(1) of the act sets up a shorthand way of referring to all the
activities that trigger registration requirements by using the
specified phrase ``manufacture, preparation, propagation, compounding,
or processing'' throughout section 510 of the act. However, for
purposes of proposed part 207, the term ``manufacture'' would refer to
the manufacture, preparation, propagation, compounding, or processing
of a drug, as set forth in the proposed definition.
The term ``manufacturer'' would include, among others, control
laboratories, contract laboratories, contract manufacturers, contract
packers, contract labelers, and other entities that manufacture a drug,
as defined in proposed Sec. 207.1 and discussed in section IV.A.5 of
this document. A ``control laboratory'' and a ``contract laboratory''
include independent establishments that manipulate, sample, test, or
perform other quality control functions for another registered
establishment's drug, including, for example, analytical
[[Page 51289]]
testing of drugs. A ``contract manufacturer'' is sometimes employed by
other manufacturers to manufacture the drug. Similarly, a manufacturer
may sometimes subcontract part of the manufacturing process such as
packing or labeling to a ``contract packer'' or a ``contract labeler.''
The term ``manufacturer'' would include control laboratories, contract
laboratories, contract manufacturers, and other entities that
manufacture a drug because their activities include the making of drugs
by chemical, physical, biological, or other procedures, including the
manipulation, sampling, testing, or control procedures applied to the
final drug product or to a part of the process. Such activities would
fall under the scope of activities (that is, manufacture, prepare,
propagate, compound, or process) in section 510(a)(1) of the act that
trigger registration requirements.
The proposed definition of ``manufacture'' also explains that, for
purposes of proposed part 207, the term manufacture is defined and used
separately from the terms relabel, repack, and drug product salvage.
Although we explain that repacking, relabeling, and drug product
salvaging are activities that trigger registration (because the term
``manufacture, preparation, propagation, compounding, or processing,''
under section 510 of the act includes repackaging or otherwise changing
the container, wrapper, or labeling of any drug package in furtherance
of the distribution of the drug from the original place of manufacture
to the person who makes the final delivery or sale to the ultimate
consumer or user), we believe that it is clearer to use four separate
terms for the different activities for purposes of proposed part 207.
We use separate terms so that we can clarify and differentiate the
responsibilities of the four types of parties engaged in the separate
activities of: ((1) Manufacturing that does not include repacking,
relabeling, or drug product salvaging; (2) repacking; (3) relabeling;
and (4) drug product salvaging).
Similarly, the proposed definition of ``manufacturer'' explains
that the term manufacturer is defined and used separately from the
terms relabeler, repacker, and drug product salvager. We explain that
repackers, relabelers, and drug product salvagers are ``manufacturers''
(as that entity is contemplated in section 510 of the act), but we
believe that, for purposes of proposed part 207, it is clearer to use
four separate terms for the different entities: (1) Manufacturers (that
are not also repackers, relabelers, or drug product salvagers); (2)
repackers; (3) relabelers; and (4) drug product salvagers. Repackers,
relabelers, and drug product salvagers would be subject to the
provisions of part 207 that are applicable to repackers, relabelers,
and drug product salvagers, respectively, but would not be subject to
the provisions of part 207 that are applicable to ``manufacturers,'' as
that term is defined in this proposal. For example, if a repacker,
relabeler, or a drug product salvager supplies us with the
manufacturer's NDC number, we would not require the repacker,
relabeler, or drug product salvager to provide all of the information
that the manufacturer provides to list a drug or, for the repacker or
relabeler, to obtain an NDC number. We would already have much of the
information in the database linked to the manufacturer's NDC number,
and it would be an unnecessary burden to require that the information
be provided again.
We are proposing to delete the definition of ``manufacturing or
processing'' at current Sec. 207.3(a)(8) and incorporate parts of the
definition elsewhere in the proposed definitions. For example, the
phrase ``control procedures applied to the final product or to any part
of the process'' in the proposed definition of ``manufacture'' is part
of the current definition of ``manufacturing or processing.''
Material change. We are proposing to revise the definition of ``any
material change'' in current Sec. 207.3(a)(3). The current definition
includes, but is not limited to: (1) Any change in the name of the
drug; (2) any change in the identity or quantity of the active
ingredient(s); (3) any change in the identity or quantity of the
inactive ingredient(s) where quantitative listing of all ingredients is
required by current Sec. 207.31(a)(2); (4) any significant change in
the labeling of a prescription drug; and (5) any significant change in
the label or package insert of an OTC drug. Changes that are not
significant currently include changes in arrangement or printing or
changes of an editorial nature. The proposed definition would continue
to exclude labeling changes in arrangement or printing or labeling
changes of an editorial nature. The inclusion of a bar code or NDC
number on the label would not be considered a material change because
it would be too burdensome to require the resubmission of labeling if
the only change was to include a bar code or an NDC number. We are,
however, proposing to rename the term ``material change'' and to more
precisely identify all of the changes that would be considered
``material'' in the current definition. With respect to manufacturers,
repackers, and relabelers, and drug product salvagers, a change in any
information provided under proposed Sec. Sec. 207.49, 207.53, 207.54,
207.55, or 207.57 would be considered a material change.
All listing information required under the proposal is needed to
identify the drug. Under the broader definition of material change, as
proposed, we would be better informed of changes to marketed drugs.
This would result in more accurate and up-to-date drug listing
information. Under proposed Sec. 207.57 and section 510(j)(2)(D) of
the act, the June and December updates of listing information must
include reports of ``material changes'' in listing information
previously submitted. The proposed definition of ``material change''
has been revised to more precisely identify which changes must be
reported under proposed Sec. 207.57.
Person who imports or offers for import. We are proposing to define
a ``person who imports or offers for import'' as an agent, broker, or
other entity that the foreign establishment uses to facilitate the
import of its drug into the United States. As described in section
IV.B.3 of this document, this proposal would require foreign
establishments to provide, for drugs manufactured, repacked, relabeled,
or salvaged at the establishment, the name of each person known to the
establishment who imports or offers for import such drug into the
United States. Therefore, the establishment would need to provide the
name of each agent, broker, or other entity that the foreign registrant
uses to facilitate the import of its drug into the United States. We
describe more fully what we mean by ``known to the establishment'' in
section IV.B.3 of this document. The term ``person who imports or
offers to import'' would not include carriers, consistent with the
legislative history of the Bioterrorism Act. The legislative history
shows that although the House provision originally would have required
registration information for importers and carriers, the conference
substitute changed the language. The conference substitute deleted the
term ``carriers,'' replacing it with ``persons who import or offer for
import,'' clarifying that foreign manufacturers are not required to
include information on carriers with annual registration. (See H. Rept.
107-481, 107th Cong., 2d sess., p. 140, 2002, Conf. Rept. to accompany
H.R. 3448) We invite comments on our proposed definition of ``persons
who import or offer for import.''
We also invite comment on our use of the word ``facilitate'' in the
proposed definition. We recognize that the term
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could be interpreted to include middlemen or other entities that may be
viewed as assisting with or promoting the importation of a drug into
the United States. For example, we are aware that ``buyer's clubs''
could be captured in the definition if ``facilitate'' were to be
interpreted broadly. Buyer's clubs are groups that consolidate orders
for drugs purchased from foreign establishments and then, once those
drugs are imported into the United States, send them to the individuals
or other entities who ordered the drugs through the clubs. It is also
possible that ``facilitate'' could be interpreted to include
organizations that may promote the awareness and sale of products
through advertisements on the internet, for example. We recognize that,
under this proposal, foreign establishments would only be required to
give us information for persons who import or offer for import that are
known to the establishments. Although the knowledge requirement in this
proposed rule would include information that the foreign establishment,
and persons in the foreign establishment, has reason to know of, we
believe it is likely that foreign establishments generally would not
know about most of the ``middlemen'' described previously. Therefore,
even though the term ``facilitate'' in the proposed definition would be
interpreted broadly to include middlemen, if the foreign establishment
did not know of, or have reason to know of, the middlemen, the foreign
establishment would not be required to report information about the
middlemen under this proposal.
We also note that the terms ``broker'' or ``agent'' include
``customhouse brokers'' who facilitate importation by filing documents
with the U.S. Customs Service, as well as FDA and other Federal
agencies responsible for the regulation of imported products. We
specifically invite comment on our use of the term ``facilitate'' in
this proposal. We invite comment on whether we should interpret the
term ``facilitate'' broadly to include middlemen as described
previously. We also invite comment on whether foreign establishments
would know about such middlemen and, if so, what effect a requirement
to report information about those middlemen would have on foreign
establishments. We also invite comment on whether there are benefits
associated with such a reporting requirement, and, if so, what they
are.
Private label distributor. We are proposing 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. When not modified by ``domestic'' or
``foreign,'' as defined in proposed Sec. 207.1 and discussed in
section IV.A.5 of this document, the term would include both domestic
private label distributors and foreign private label distributors.
Private label distributors are not considered to be manufacturers,
repackers, relabelers, or drug product salvagers because they do not
conduct any of the activities covered in section 510(a)(1) of the act
with respect to the products they commercially distribute. Private
label distributors only distribute drugs under their own label or trade
name. The proposed definition is consistent with current Sec.
207.20(b) and the description of private label distributors set forth
in the 1973 final rule on drug listing requirements (38 FR 6258 at
6259). We are proposing to define this term to clarify its meaning and
to distinguish private label distributors from manufacturers,
repackers, relabelers, and drug product salvagers. Under the proposed
definition, a private label distributor does not engage in any
activities performed by a manufacturer, repacker, relabeler, or drug
product salvager for the drug it distributes. As discussed in section
IV.D.1 of this document, private label distributors currently may elect
to submit listing information to us for the drugs they distribute.
Under the proposal, private label distributors would not be permitted
to list, and manufacturers, repackers, relabelers, and drug product
salvagers would be required to provide listing information to us for
drugs being manufactured, repacked, relabeled, or salvaged for private
label distributors. However, if a private label distributor is a
manufacturer with respect to a particular drug or drugs, for example,
the private label distributor is subject to the registration and
listing requirements for manufacturers in proposed part 207 with
respect to that drug or drugs.
Relabel, relabeler. We are proposing to use the term ``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 remind interested persons that those activities
must be conducted in accordance with the act and FDA regulations. We
are proposing to use the term ``relabeler'' to mean a person who owns
or operates an establishment that relabels a drug. When not modified by
``domestic'' or ``foreign,'' as defined in proposed Sec. 207.1 and
discussed in section IV.A.5 of this document, the term would include
both domestic relabelers and foreign relabelers.
Under the proposal, relabelers must provide registration and
listing information. Under section 510(a)(1) of the act, the term
``manufacture, preparation, propagation, compounding, or processing''
includes repackaging or otherwise changing the container, wrapper, or
labeling of any drug package in furtherance of the distribution of the
drug from the original place of manufacture to the person who makes
final delivery or sale to the ultimate consumer or user. As discussed
previously, we use the term ``relabeler'' separately from the term
``manufacturer'' because, although the relabeler's registration and
listing responsibilities in general are the same as those for
manufacturers under the act, the proposal would modify some of these
requirements. For example, as described under the definition of
``manufacturer'' in section IV.A.5 of this document, if a relabeler
supplies us with the manufacturer's NDC number, we would not require
the relabeler to provide all of the information that the manufacturer
provides to obtain an NDC number and to list a drug. We would already
have much of the information in the database linked to the
manufacturer's NDC number, and it would be an unnecessary burden to
require that the information be provided again. Under the proposed
definition, a relabeler does not engage in any other activity performed
by a manufacturer for the drugs they relabel.
Repack, repacker. We are proposing to use the term ``repack'' to
mean repack or repackage or otherwise change the container or wrapper
of a drug or drug package. We are proposing to use both the terms
``repack'' and ``repackage'' in the definition because these terms are
often used interchangeably with respect to drugs and, whether such
activities are characterized as repacking or repackaging, they are
subject to the requirements of this part. Although the term
``repackaging'' is used in section 510(a)(1) of the act, the terms
``repacking,'' ``repack,'' and ``repacker'' are more commonly used by
industry when referring to this activity, and, therefore, we are using
these terms throughout the proposal. We are proposing to use the term
``repacker'' to mean a person who owns or operates an establishment
that repacks a drug or drug package. When not modified by ``domestic''
or ``foreign,'' as defined in proposed Sec. 207.1 and discussed in
section IV.A.5 of this document, the term would include both domestic
repackers and foreign repackers.
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Under the proposal, repackers must provide registration and listing
information. Under section 510(a)(1) of the act, the term
``manufacture, preparation, propagation, compounding, or processing''
includes repackaging or otherwise changing the container, wrapper, or
labeling of any drug package in furtherance of the distribution of the
drug from the original place of manufacture to the person who makes
final delivery or sale to the ultimate consumer or user. We use the
term ``repacker'' separately from the term ``manufacturer'' because,
although the repacker's registration and listing responsibilities in
general are the same as those for manufacturers under the act, the
proposal would modify some of these requirements. For example, as
described under the definition of ``manufacturer'' in section IV.A.5 of
this document, if a repacker supplies us with the manufacturer's NDC
number, we would not require the repacker to provide all of the
information that the manufacturer provides to obtain an NDC number and
to list a drug. We would already have much of the information in the
database linked to the manufacturer's NDC number, and it would be an
unnecessary burden to require that the information be provided again.
Under the proposed definition, a repacker does not engage in any other
activity performed by a manufacturer for the drugs they repack.
Representative sampling of advertisements. We are proposing to
revise the definition of ``representative sampling of advertisements.''
Currently, Sec. 207.3(a)(2) explains that the term ``advertising'' as
used in part 207 includes the promotional material described in Sec.
202.1(l). However, current Sec. 207.3(a)(9) expressly excludes such
material from the definition of ``representative sampling of
advertisements.'' We believe that the inconsistency between the two
provisions was an unintended result of certain editorial amendments
made to part 207. We are proposing to revise the definition of
``representative sampling of advertisements'' to resolve the
inconsistency. Specifically, we believe that the content of current
Sec. 207.3(a)(2) should be incorporated into the definition of
``representative sampling of advertisements'' to clarify that the term
includes the promotional material described in Sec. 202.1(l)(1).
We are proposing to define ``representative sampling of
advertisements'' as typical advertising material (including the
promotional material described in Sec. 202.1(l)(1), but excluding
labeling as determined in Sec. 202.1(l)(2)), that gives a balanced
picture of the promotional claims used for the drug. In addition to
resolving the inconsistency described previously, the proposed
definition would delete the example currently provided in Sec.
207.3(a)(9) (that is, if more than one medical journal advertisement is
used but the promotional content is essentially identical, only one
needs to be submitted). We believe that this example is unnecessary and
are proposing to simplify the definition by deleting it.
Representative sampling of any other labeling. We are proposing to
revise the definition of ``representative sampling of any other
labeling.'' We are proposing to delete current Sec. 207.3(a)(2), which
explains that the term ``labeling'' as used in part 207 includes the
promotional material described in Sec. 202.1(l)(2). We believe that
this information would be more appropriately included in the definition
of ``representative sampling of any other labeling.''
We are proposing to define ``representative sampling of any other
labeling'' as typical labeling material (including the promotional
material described in Sec. 202.1(l)(2), but excluding labels and
package inserts) that gives a balanced picture of the promotional
claims used for the drug. In addition to incorporating the relevant
content of current Sec. 207.3(a)(2), the proposed definition would
delete the example currently provided in current Sec. 207.3(a)(10)
(that is, if more than one brochure is used but the promotional content
is essentially identical, only one needs to be submitted). We believe
that this example is unnecessary and are proposing to simplify the
definition by deleting it.
United States agent. We are proposing to remove the definition of
``United States agent'' in current Sec. 207.3(a)(11). Proposed Sec.
207.69 would incorporate many of the provisions of the current
definition of United States agent and current Sec. 207.40
(registration and listing requirements for foreign establishments). The
same requirements in the current definition appear at proposed Sec.
207.69(b)(1), (b)(2), and (b)(3).
B. Registration
1. Who Would Be Required to Register?
Proposed Sec. 207.17(a) would require manufacturers, repackers,
relabelers, and drug product salvagers to register each establishment.
This provision would replace the requirement at current Sec. 207.20(a)
that owners or operators of all drug establishments that engage in the
manufacture, preparation, propagation, compounding, or processing of a
drug must register. The terms ``manufacturer,'' ``repacker,''
``relabeler,'' and ``drug product salvager,'' as defined in proposed
Sec. 207.1 and discussed in section IV.A.5 of this document, more
clearly indicate who must register.
Manufacturers, repackers, relabelers, and drug product salvagers
would be required to register because the activities they perform fall
within the scope of activities that trigger registration requirements
in section 510(a)(1) of the act. Section 510(a)(1) states that the
phrase ``manufacture, preparation, propagation, compounding, or
processing'' includes repacking or otherwise changing the container,
wrapper, or labeling of any drug package in furtherance of the
distribution of the drug from the original place of manufacture to the
person who makes final delivery or sale to the ultimate consumer or
user.
We are proposing to use the terms ``repacker,'' ``relabeler,'' and
``drug product salvager'' separately from the term ``manufacturer'' in
the proposal because, although the repacker, relabeler, and drug
product salvager's listing responsibilities in general are similar to
those for manufacturers under the act, the proposal would modify some
of these requirements. In particular, if a repacker, relabeler, or drug
product salvager supplies us with the manufacturer's NDC number, we
would not require the repacker, relabeler, or drug product salvager to
provide all of the information that the manufacturer provides to list a
drug. Similarly, we would not require repackers and relabelers to
submit all of the information that the manufacturer submits to obtain
an NDC number.
Proposed Sec. 207.17(a) would enable us to identify who is making
drugs and where they are being made. Being able to accurately identify
who makes drugs and where they are made is very important. Certain
marketed drugs may need to be quickly identified and used to help
counteract the effects of a bioterrorism attack. Registration
information also assists us in scheduling and planning inspections of
registered establishments pursuant to section 704 of the act.
Proposed Sec. 207.17(a) also provides that registration
information may be submitted by the parent, subsidiary, and/or
affiliate company for all establishments when operations are conducted
at more than one establishment and there exists joint ownership and
control among all the establishments. This provision would also apply
when operations are
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conducted at both domestic and foreign establishments and there exists
joint ownership and control among all the establishments. This
provision is consistent with current Sec. 207.20(a).
We are proposing to revoke the requirement in current Sec.
207.20(a) that no owner or operator may register an establishment if
any part of that establishment is registered by another owner or
operator. The requirement has caused uncertainty about who must
register and which establishment must be registered. Under proposed
Sec. 207.17(a), manufacturers, repackers, relabelers, and drug product
salvagers must register each establishment unless they are otherwise
exempt under section 510(g) of the act or proposed Sec. 207.13.
Under proposed Sec. 207.17(b), private label distributors would
not register with us unless they also manufacture, repack, relabel, or
salvage drugs and are required to register under the act or proposed
Sec. 207.17(a). Private label distributors are not considered to be
manufacturers, repackers, relabelers, or drug product salvagers because
they do not conduct any of the activities covered under section
510(a)(1) of the act with respect to the drugs they commercially
distribute. Private label distributors only distribute drugs under
their own label or trade name. Proposed Sec. 207.17(b) would revise
the provision in current Sec. 207.20(b) that owners or operators of
establishments that distribute under their own label or trade name a
drug manufactured or processed (as defined in current Sec.
207.3(a)(8)) by a registered establishment may elect to obtain a
labeler code from us and submit listing information directly to us.
Under current regulations, if a private label distributor does not
elect to submit drug listing information to us, the registered
establishment must submit the drug listing information. As explained in
section IV.D.1 of this document, we are proposing to revise current
Sec. 207.20(b) and not permit private label distributors to register
or list. Manufacturers, repackers, relabelers, and drug product
salvagers must submit drug listing information for thos