[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]]
-----------------------------------------------------------------------
Part II
Department of Health and Human Services
-----------------------------------------------------------------------
Food and Drug Administration
-----------------------------------------------------------------------
21 CFR Parts 20, 201, 207, et al.
Requirements for Foreign and Domestic Establishment Registration and
Listing for Human Drugs, Including Drugs that are Regulated Under a
Biologics License Application, and Animal Drugs; Proposed Rule
[[Page 51276]]
-----------------------------------------------------------------------
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.
-----------------------------------------------------------------------
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\
---------------------------------------------------------------------------
\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).
---------------------------------------------------------------------------
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.
---------------------------------------------------------------------------
\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).
---------------------------------------------------------------------------
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.
---------------------------------------------------------------------------
\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\
---------------------------------------------------------------------------
\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
[[Page 51290]]
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.
[[Page 51291]]
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
[[Page 51292]]
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 those drugs they
manufacture, repack, relabel, or salvage for commercial distribution
for a private label distributor.
2. When Would Initial Registration Information Be Provided?
Under proposed Sec. 207.21, a domestic manufacturer, domestic
repacker, domestic relabeler, and domestic drug product salvager must
register each establishment no later than 5 calendar days after
beginning to manufacture, repack, relabel, or salvage a drug. The
proposed timeframe ``no later than 5 calendar days'' is consistent with
current Sec. 207.21(a) in that the current registration requirement
also provides for a 5-day registration timeframe for owners or
operators of establishments entering into the ``manufacturing or
processing'' of a drug (as defined in current Sec. 207.3(a)(8)). The
proposed timeframe is also consistent with the requirement in section
510(c) of the act to register each establishment ``immediately'' and
``upon first engaging in the manufacture, preparation, propagation,
compounding, or processing'' of a drug.
Under proposed Sec. 207.21, a foreign manufacturer, foreign
repacker, foreign relabeler, and foreign drug product salvager must
register each establishment before a drug manufactured, repacked,
relabeled, or salvaged at the establishment is imported or offered for
import into the United States. This is consistent with current Sec.
207.40(b), which states that no drug may be imported or offered for
import into the United States unless it is listed and manufactured,
prepared, propagated, compounded, or processed at a registered foreign
drug establishment. In addition, section 510(i) of the act states that
any establishment within any foreign country engaged in the
manufacture, preparation, propagation, compounding, or processing of a
drug or device that is imported or offered for import into the United
States shall register with the Secretary.
Proposed Sec. 207.21 uses the term ``each establishment'' to
emphasize that the requirement to register would apply even if the
manufacturer, repacker, relabeler, or drug product salvager has
previously registered one or more other establishments. This proposed
requirement is consistent with two provisions of section 510 of the
act. Section 510(d) of the act requires registration of any additional
establishment immediately upon beginning the manufacture, preparation,
propagation, compounding, or processing of a drug at that
establishment. Section 510(i)(1) of the act states that any
establishment within any foreign country engaged in the manufacture,
preparation, propagation, compounding, or processing of a drug or a
device that is imported or offered for import into the United States
must register with the Secretary.
We are proposing to specify ``calendar'' days to be consistent with
the terminology and timeframes used in the international pharmaceutical
regulatory guidances of the International Conference on the
Harmonisation of Technical Requirements for Registration of
Pharmaceuticals for Human Use (ICH) (http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.ich.org) and the World
Health Organization's Council for International Organizations of
Medical Sciences (CIOMS) (http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.cioms.ch).
We are proposing to revoke the requirement in current Sec.
207.21(a) to register within 5 days after submitting certain marketing
applications if the owner or operator has not previously entered into
the manufacture or processing of a drug (as defined in current Sec.
207.3(a)(8)). We are also proposing to revoke the requirement in
current Sec. 207.20(c) that, before beginning the manufacture or
processing of a drug subject to certain marketing applications, an
owner or operator of an establishment must register before the
application is approved. We are proposing to revoke these requirements
because, under proposed Sec. 207.21 and consistent with section 510(c)
and (d) of the act, registration of each establishment must occur no
later than 5 calendar days after beginning to manufacture, repack,
relabel, or salvage a drug at the establishment. This provision would
govern when to register an establishment rather than the date a
marketing application is submitted or approved. We believe that this
proposed requirement would provide us with sufficient notice as to who
is manufacturing, repacking, relabeling, or salvaging drugs and where
those activities are taking place. In addition, marketing application
approval is linked to registration elsewhere in our regulations. Under
current Sec. 314.125(b)(11) (21 CFR 314.125(b)(11)), we may refuse to
approve an application if the drug will be manufactured or processed in
an establishment that is not registered. For consistency with current
Sec. 314.125(b)(11), we are proposing to revise Sec. 514.111(a)(12)
(21 CFR 514.111(a)(12)) for NADAs to state that we will refuse to
approve an application if ``the drug will be manufactured in whole or
in part in an establishment that is not registered and not exempt from
registration under section 510 of the act and part 207.'' For licensed
human biological products, current 21 CFR 601.4(b) includes a provision
that we must deny a BLA if the establishment or product does not meet
``requirements established in Title 21, Chapter I'' (this would include
the registration and listing provisions).
3. What Information Would Be Required for Registration?
Under proposed Sec. 207.25, all manufacturers, repackers,
relabelers,
[[Page 51293]]
and drug product salvagers must provide the following information to
register each of their establishments:
Name of the owner or operator of each establishment; if a
partnership, the name of each partner would be submitted; if a
corporation, the name of each corporate officer and director and the
place of incorporation would be submitted (proposed Sec. 207.25(a)).
This provision is consistent with section 510(a)(2) of the act, which
states that ``the term 'name' shall include in the case of a
partnership the name of each partner and, in the case of a corporation,
the name of each corporate officer and director, and the State of
incorporation.'' The proposal would replace ``State of incorporation''
with ``place of incorporation'' to include foreign corporations.
Proposed Sec. 207.25(a) is also consistent with section 510(c) of the
act, which states that ``Every person * * * shall immediately register
with the Secretary his name, place of business, and such
establishment.'' The proposal would use ``owner or operator'' for
consistency with current Sec. 207.25(a), which provides that the
information required for registration includes the name of the owner or
operator of the establishment. Current Sec. 207.25(a) provides that
the term ``name of the owner or operator'' includes, in the case of a
partnership, the name of each partner and, in the case of a
corporation, the name and title of each corporate officer and director
and the name of the State of incorporation. The proposal would revoke
the requirement to include the title of each corporate officer and
director because we have determined that it is not necessary for
registration purposes. Current Sec. 207.25(a) also requires the
submission of the ``kind of ownership or operation (that is,
individually owned, partnership, or corporation).'' The proposal would
replace this requirement because the kind of ownership or operation
would be captured under the requirement to provide, if applicable, the
name of each partner, and corporate officer and director, and the place
of incorporation in proposed Sec. 207.25(a).
Name, trade name(s), and address of each establishment
(proposed Sec. 207.25(b), (c), and (d)). This provision is consistent
with section 510(c) of the act and current Sec. 207.25(a). The
proposal would continue the requirement in current Sec. 207.25(a) to
submit all trade names used by the establishment, but rephrase current
Sec. 207.25(a) to clarify that, for purposes of this subsection, we
want the trade name(s) of the establishment, names under which the
establishment conducts business, and additional names by which the
establishment is known. We are not seeking under this section the trade
name(s) of the drugs of the establishment. Although we are interested
in the trade names of the drugs, we can obtain that information through
the drug listing requirements.
Registration number of each establishment, if previously
assigned to the establishment by us (proposed Sec. 207.25(e)). If not
previously assigned by us, we would assign a registration number after
we receive the registration information (proposed Sec. 207.25(e)).
Under section 510(e) of the act, we may assign a registration number to
any person or establishment registered and, under current Sec.
207.35(a), we will assign a permanent registration number to each
establishment that registers. The ``establishment registration number''
is defined in proposed Sec. 207.1 to mean the number assigned by FDA
to the establishment during the establishment registration process.
(Currently, the FEI will be the number we assign as the establishment
registration number.) We are proposing to require the submission of the
registration number because each establishment is identified by its
registration number for registration and inspection purposes and to
enable us to identify all registered establishments. The registration
number is currently submitted on Form FDA 2656.
Type of operations(s) performed at each establishment--for
example, manufacturing, repacking, relabeling, or salvaging (proposed
Sec. 207.25(f)). We are proposing to require this information because
it is important for identifying, prior to an inspection, which
operation the establishment engages in so that our investigators can be
better prepared before inspection. Currently, the ``business type''
(for example, manufacturer, repacker, relabeler) must be submitted on
Form FDA 2656.
Name, address, telephone and fax numbers, and e-mail
address of the official contact, as provided in proposed Sec.
207.69(a), for each establishment (proposed Sec. 207.25(g)). We are
proposing to require this information because we need a contact person
to facilitate discussion with the manufacturer, repacker, relabeler,
and drug product salvager. This information needs to be current and,
under proposed Sec. 207.29(a)(3), any change in this information must
be provided to us within 30 calendar days. This information is not
required under current part 207. The requirements for the official
contact are discussed in section IV.F.1 of this document.
Information for foreign establishments only (proposed
Sec. 207.25(h)). With respect to foreign establishments only, for
drugs manufactured, repacked, relabeled, or salvaged at the
establishment, the name, address, telephone and fax numbers, and e-mail
address must also be provided for: (1) The United States agent, as
provided in proposed Sec. 207.69(b), (2) each importer of such drug in
the United States that is known to the establishment, and (3) each
person who imports or offers for import such drug to the United States.
The requirements for the United States agent are discussed in section
IV.F.1 of this document. The name, address, and phone number of the
United States agent is required to be submitted under current Sec.
207.40(c). The information on importers and persons who import is not
required to be submitted under current part 207. We are proposing to
require the submission of the information on importers and persons who
import because the Bioterrorism Act requires foreign establishments to
submit, among other things, the name of each importer of each drug that
is known to the manufacturer, repacker, relabeler, and drug product
salvager and the name of each person who imports or offers for import
each drug to the United States for purposes of importation. We want to
make clear that the term ``known to'' would include any importer that
is known to the foreign establishment as well as any importer that the
foreign establishment has reason to know of. We therefore expect that
the person responsible for completing the required registration forms
on behalf of the foreign establishment would undertake appropriate due
diligence in completing those forms, including to find out and report
importers that others in his or her establishment know of or have
reason to know of. In addition to the name, the proposal would require
that the address, telephone and fax numbers, and e-mail address of each
importer and of each person who imports or offers for import be
provided to enable us to contact these persons.
All information required under proposed Sec. 207.25 must be
submitted for the establishment to be considered registered. As
explained in section IV.B.l of this document, establishment
registration 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 for protecting the public
health. Among other things, registration information would enable us to
become aware of and take action to stop manufacturers,
[[Page 51294]]
repackers, relabelers, and drug product salvagers who do not follow the
requirements set forth in the act and in our regulations.
4. What Are the Proposed Requirements for Reviewing and Updating
Registration Information?
The proposal would modify and streamline the requirements
associated with updating registration information. Currently,
manufacturers, repackers, relabelers, and drug product salvagers must
enter new or revised registration information on Form FDA 2656 and
return the form to us annually. Under the proposal, manufacturers,
repackers, relabelers, and drug product salvagers would access the
electronic drug registration and listing system and review their
current registration information online, making any changes where
needed. Updating registration information would be less time consuming
under the proposal because the manufacturer's, repacker's, relabeler's,
and drug product salvager's information would be easily accessible at
any time and only changes to the information already in the system
would need to be entered in the fields provided.
The following sections provide a description of the proposed
requirements for reviewing and updating registration information and
how they modify or reduce the burden of the current requirements.
a. Expedited updates of registration information. Manufacturers,
repackers, relabelers, and drug product salvagers would report, under
proposed Sec. 207.29(a), the following changes as expedited updates no
later than 30 calendar days after the change:
The close or sale of an establishment;
Any change in the name or address of an establishment; and
Any change in the name, address, telephone and fax
numbers, or e-mail address of the official contact or the United States
agent.
We are proposing to require that these changes be reported as
expedited updates because we need to know as soon as possible when a
business has closed or has been sold and when the establishment's name
or address has changed. This information is especially important for
scheduling inspections. We also need current information for contacting
the official contact or United States agent. As previously mentioned,
it is increasingly important for us to be able to identify where drugs
are being made and when drugs are no longer available. The expedited
receipt of this information will help promote the efficient enforcement
of the act.
Manufacturers, repackers, relabelers, and drug product salvagers
are encouraged to provide expedited updates as soon as possible but no
later than 30 calendar days after the change occurs. Our electronic
drug registration and listing system will be easily accessible all the
time to make changes.
The close or sale of an establishment, and a change in the name or
address of an establishment, are currently reported annually on Form
FDA 2656.
Proposed Sec. 207.29(a) would revise current Sec. Sec. 207.26 and
207.40(c)(3). Current Sec. 207.26 requires the submission of certain
amendments to registration information within 5 days of the change, and
as noted previously, Sec. 207.40(c)(3) requires the submission of any
changes to the United States agent's name, address, or phone number
within 10 business days of the change. As explained below, the proposal
would lengthen the time period for reporting the changes in current
Sec. 207.40(c)(3). The proposal also would lengthen the time period
for reporting some of the changes in current Sec. 207.26 and revoke
some of the reporting requirements in current Sec. 207.26:
A change in location would no longer be submitted as an
amendment to registration within 5 days of the change, but would be
reported under proposed Sec. 207.29(a)(2) as an expedited update no
later than 30 calendar days after the change (``address'' of an
establishment is used in the proposal instead of location). We have
determined that notification no later than 30 calendar days would be
sufficient and would be consistent with the proposed timeframe for the
other expedited updates.
A change in ``drug-handling activity'' would no longer be
submitted as an amendment to registration within 5 days of the change.
A change in this information would only be reported during the annual
review and update under proposed Sec. 207.29(b). (The term ``type of
operations'' is used in proposed Sec. 207.25(f) instead of ``drug-
handling activity.'') We have determined that annual notification of
this change would be sufficient.
Changes in ``individual ownership'' and ``corporate or
partnership structure,'' in current Sec. 207.26, would no longer be
reported as amendments to registration because the proposal would
revoke the corresponding provision for registration in current Sec.
207.25(a) (the ``kind of ownership or operation (that is, individually
owned, partnership or corporation)''). As explained in section IV.B.3
of this document, the kind of ownership or operation would no longer be
submitted for registration because the information would be captured
under the requirement to provide, if applicable, the name of the
partner, corporate officer and director, and the place of incorporation
in proposed Sec. 207.25(a). This information would be reviewed and
updated annually under proposed Sec. 207.29(b). This proposed
requirement is consistent with current Sec. 207.26, which specifies
that changes in the names of officers and directors of the corporation
do not require an amendment and must be submitted at the time of annual
registration.
Under current Sec. 207.26, a change in a registered
establishment's firm name within 6 months of the registration of the
establishment must be supported by a signed statement of the
establishment's owner or operator that the change was not made for the
purpose of changing the name of the manufacturer of a drug product
under current Sec. 201.1. This verification would no longer be
required to be submitted as an amendment to registration. A change in
the name of an establishment would be reported under proposed Sec.
207.29(a)(2) no later than 30 calendar days after the change.
Proposed Sec. 207.29(a)(3) would revise current Sec.
207.40(c)(3), which provides that a foreign drug establishment or
United States agent must report to us, within 10 business days, any
changes to the United States agent's name, address, or phone number.
The proposal would make the following revisions:
The changes to the information about the United States
agent would be revised to include not only the name, address, and
telephone number, but also the fax number and e-mail address. This
provision would be consistent with the information required to be
submitted for the United States agent for registration under proposed
Sec. 207.25(h).
The time period for reporting the changes would be
lengthened to no later than 30 calendar days for consistency with the
time period for the other expedited reports in proposed Sec.
207.29(a).
Changes in the name, address, telephone and fax numbers,
and e-mail address of the official contact would also be reported under
proposed Sec. 207.29(a)(3) within 30 calendar days. This provision
would be consistent with the information required to be submitted for
the official contact for registration under proposed Sec. 207.25(g).
Under proposed Sec. 207.29(a)(3), the manufacturer,
repacker, relabeler, and drug product salvager, official contact, or
United States agent may notify us about a change of information for the
designated official contact or United
[[Page 51295]]
States agent. This provision would make the updates easier than the
requirement in current Sec. 207.40(c)(3) because it would enable the
official contact and the United States agent (in addition to the
manufacturer, repacker, relabeler, and drug product salvager) to update
their own or each other's registration information.
Under proposed Sec. 207.29(a)(3), only a manufacturer,
repacker, relabeler, or drug product salvager may designate a new
official contact or United States agent. This proposed requirement is
necessary because the manufacturer, repacker, relabeler, and drug
product salvager is ultimately responsible for the actions of the
official contact and the United States agent.
The requirements for the official contact and the United States
agent are discussed in section IV.F.1 of this document.
b. Annual review and update of registration information. Proposed
Sec. 207.29(b) would require that the registration information
provided under proposed Sec. 207.25 be reviewed and updated annually.
This timeframe is consistent with the requirement in section 510(b) of
the act that owners or operators register on or before December 31 of
each year and with the requirement in current Sec. 207.21(a) that
owners or operators renew their registration information annually.
Proposed Sec. 207.29(b) uses the term ``review and update'' to stress
the importance of first reviewing all registration information to
determine if any changes have occurred and then updating the
information where needed. Proposed Sec. 207.29(b)(1) specifies that
the first review and update must occur no later than 1 year after the
date of the initial registration of each establishment and that
subsequent reviews and updates must occur no later than annually
thereafter from the date of initial registration. Proposed Sec.
207.29(b)(2) provides that the updates must reflect all changes that
have occurred since the last annual review and update.
The proposal would add a new requirement for updating registration
information. Under proposed Sec. 207.29(b)(3), if none of the
registration information has changed since the last annual registration
(accomplished through the review and update of registration
information), manufacturers, repackers, relabelers, and drug product
salvagers must certify electronically that no changes have occurred.
This is consistent with section 510(b) of the act, which requires
manufacturers to register on or before December 31 of each year. If
manufacturers, repackers, relabelers, and drug product salvagers
certify that no changes have occurred, this certification would be the
equivalent of resubmitting registration information, thereby satisfying
the annual registration requirement. We are proposing to require that
manufacturers, repackers, relabelers, and drug product salvagers
certify annually that no changes have occurred because many
manufacturers, repackers, relabelers, and drug product salvagers have
not reviewed or updated this information on a regular basis. It has
been difficult for us to determine whether failure to register annually
is the result of no changes in information or noncompliance. The
proposed requirement is intended to reduce these instances and improve
the accuracy of our registration database. To increase the nation's
ability to prepare for and respond effectively to bioterrorism and
other public health emergencies, it is increasingly important for
manufacturers, repackers, relabelers, and drug product salvagers to
comply with registration requirements. With accurate information, we
can identify where drugs are being made and better ensure that drugs
are promptly available when needed. Furthermore, taking steps to
increase compliance is consistent with section 301(p) of the act (21
U.S.C 331(p)), which makes it a prohibited act to fail to register
under section 510 of act.
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?
The NDC number is a widely used identifier for drugs. It is a
unique 10-digit number consisting of 3 segments: The labeler code, the
product code, and the package code. Currently, the labeler code
consists of four or five digits, the product code consists of either
three or four digits, and the package code consists of either one or
two digits. We assign the labeler code to the manufacturer, repacker,
or relabeler after it has registered with us. For private label
distributors, currently we provide a labeler code to the private label
distributor if the private label distributor submits the required
information to us. Alternatively, we provide a labeler code for a
private label distributor to the manufacturer, repacker, or relabeler
who is manufacturing, repacking, or relabeling the drug for the private
label distributor after the manufacturer, repacker, or relabeler
provides the required registration information pertaining to the
private label distributor. The manufacturer, repacker, relabeler, or
private label distributor then assigns the product code and package
code to each drug within certain parameters that we have established.
2. How Did NDC Numbers Originate? How Are They Used?
Created in 1969, NDC numbers were originally intended to ``provide
an identification system in computer language to permit automated
processing of drug data by Government agencies, drug manufacturers and
distributors, hospitals, and insurance companies'' (see 34 FR 11157,
July 2, 1969). Participation in the NDC system was voluntary initially,
and the program covered ``firms which manufacture and label or which
repackage and label drugs'' (id.). In 1971, the NDC system expanded to
include ``distributors who are marketing drug products in interstate
commerce, under their own name (label), and through multiple wholesale
outlets and/or five or more retail outlets'' (see 36 FR 27, January 1,
1971).
The enactment of the Drug Listing Act of 1972 (Public Law 92-387,
86 Stat. 559) changed the NDC number system even further. The Drug
Listing Act required registered establishments to list all drugs that
the establishment manufactures, prepares, propagates, compounds, or
processes for commercial distribution and authorized us to assign a
``listing number'' to each drug or class of drugs that was listed. The
Drug Listing Act declared that, ``Any number assigned * * * shall be
the same as that assigned pursuant to the National Drug Code.'' Thus,
by linking drug listings to the NDC numbers, the Drug Listing Act, in
essence, authorized us to make participation in the NDC number system
mandatory. In addition, by referring to the word, ``drug,'' the Drug
Listing Act extended the NDC number system to over-the-counter drugs
and animal drugs (because both are ``drugs'' under the act and are
listed under section 510(j) of the act).
Today, NDC numbers continue to be an important, standardized,
identification system for drug products used in data or claims
processing, as well as in applications other than data or claims
processing. For example, consumers may use NDC numbers to identify
drugs that are the subject of a recall. Health care professionals
submitting MedWatch reports (concerning possible adverse drug events)
use NDC numbers to identify the drug at issue. Our investigators
sometimes use NDC numbers to
[[Page 51296]]
determine a drug's compliance status by linking the NDC number to our
registration and listing database to verify whether the manufacturer
has registered and listed a particular drug. We compile the NDC numbers
in the National Drug Code Directory, and the directory is accessible
online at http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/cder/ndc/database.
In addition, several new or future public health programs or
initiatives rely or will rely on NDC numbers. For example:
On February 26, 2004 (69 FR 9120), we published in the
Federal Register a final rule to require certain human drug and
biological products to have bar codes (see 69 FR 9120). The bar code
must contain, at a minimum, the drug's NDC number. This rule is
designed to reduce the number of medication errors in hospitals and
other health care settings by allowing health care professionals to use
bar code scanning equipment to verify that the right drug (in the right
dose and right route of administration) is being administered to the
right patient at the right time.
The electronic prescription drug program established by
the Medicare Modernization Act promotes uniform standards that permit
(among other things) electronic exchange of drug labeling and drug
listing information maintained by us and by the National Library of
Medicine (see 42 U.S.C. 1860D-4(e)(3)(C)(iii)). The goal behind the
program is to reduce transcription and dispensing errors (which, in
turn, lead to medication errors) and to prevent adverse drug
interactions. As we stated previously in this document, drug listing
numbers are, under the Drug Listing Act of 1972, to be the same as NDC
numbers.
The Health Insurance Portability and Accountability Act
(Public Law 104-191) required, among other things, adoption of code set
standards to facilitate electronic transactions. The standard code set
for drugs is the NDC (see final rule on ``Health Insurance Reform:
Standards for Electronic Transactions'' (65 FR 50312, August 17, 2000),
45 CFR 162.1002(c); amended February 20, 2003: ``Health Insurance
Reform: Modifications to Electronic Data Transaction Standards and Code
Sets'' (68 FR 8381), 45 CFR 162.1002(a)(3) and (b)(2)).
We are working with the National Library of Medicine,
manufacturers, repackers, relabelers, and health care information
suppliers to improve patient safety by better access to medication
information through the DailyMed initiative. The DailyMed is an up-to-
date, computerized repository of medication information including
product labeling. The changes we are proposing to the NDC number would
complement the DailyMed initiative by providing a link to product
labeling made available through the DailyMed. The product labeling in
this repository would be in the form of SPL. SPL is a standardized
computer readable product labeling that links the NDC number to the
product information.
To illustrate how this would work, someone could simply scan a bar
code encoded with the NDC number or type into the DailyMed search
program the NDC number on the carton label to access the most current
information in the product labeling available from the DailyMed. This
capability would enable DailyMed users to have the most up-to-date
information for a drug, which could be an important public health
benefit for consumers and health care professionals. For example,
assume that a manufacturer modified its labeling to reflect a new
adverse drug experience. If a consumer, pharmacist, or health care
provider received a drug whose labeling had been printed earlier, the
consumer, pharmacist, or health care provider would not be alerted to
the new adverse drug experience. By using the DailyMed, the consumer,
pharmacist, or health care provider would be able to access the new
drug labeling and would, therefore, learn about the new adverse drug
experience and possibly be able to avoid it. The consumer, pharmacist,
or health care provider would also be better able to assess the risks
and benefits of the drug and, therefore, would be able to make more
informed decisions about using the drug. The DailyMed would be a
publicly accessible repository of drug information that could be used
in many ways by various parties, such as by those who could add value
to the information, such as pricing information, and make it available
to other parties.
Unfortunately, despite the widespread and growing use and reliance
on NDC numbers, the existing NDC number system has several
shortcomings. For example, manufacturers, repackers, and relabelers can
assign NDC numbers, and the current regulations at Sec.
207.35(b)(4)(ii) permit them to re-use the product codes under certain
circumstances (such as taking the NDC number assigned to drug X and
then, after drug X has been discontinued, later assign the same NDC
number to drug Z). Also, under current regulations, it is difficult for
FDA to control the practice of a manufacturer, repacker, or relabeler
making changes to a drug but continuing to use the same NDC number
despite those changes.
The manufacturer, repacker, and relabeler's ability to assign the
product code and package code themselves has also resulted in problems
that affect the National Drug Code Directory and its reliability.
Product and package codes are not always assigned appropriately, and
industry practices for assigning codes are inconsistent. In addition,
manufacturers, repackers, and relabelers currently do not tell us what
codes they have assigned until they list drugs with us; this means that
the National Drug Code Directory is not always complete or
comprehensive. Moreover, manufacturers, repackers, and relabelers may
never list a product or may sometimes omit information or submit
incorrect information to us; this often prevents us from including the
correct information in the National Drug Code Directory and forces us
to devote resources to obtaining, sometimes unsuccessfully, the correct
information.
Furthermore, because NDC code segments can vary in length (such as
a NDC having a four-digit labeler code, a four-digit product code, and
a two-digit package code while another NDC has a five-digit labeler
code, a three-digit product code, and a two-digit package code),
electronic systems that view the NDC as a single number might interpret
two different NDC numbers as being the same number. For example, one
manufacturer, repacker, or relabeler's drug might have a NDC number
that reads as 12345-678-90 while another could have a drug whose NDC
number reads as 1234-5678-90. If a database omits the hyphens, the
result would be a misleading impression that both drugs have identical
NDC numbers (i.e., 1234567890), although they are made by different
manufacturers and may be entirely different products.
We have also found that some manufacturers, repackers, and
relabelers have assigned NDC numbers to products that are not drugs,
such as dietary supplements and medical devices; such actions can
confuse drug databases or lead to inappropriate reimbursements.
Consequently, to address these shortcomings and to create an
accurate, up-to-date NDC number system, we propose to revise the NDC
number system. In brief, we believe that to ensure that the numbers are
unique and unambiguous, we need to take on the responsibility of
assigning the NDC numbers prospectively to drugs that have not
previously been assigned NDC numbers by a manufacturer, repacker, or
relabeler. 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
[[Page 51297]]
regulations as finalized. FDA intends to validate that current NDC
numbers comply with the new regulations as finalized. We believe that
the NDC number structure can remain very similar to what exists today,
as we describe below, and still allow for unique and unambiguous NDC
numbers if we assign the NDC numbers.
The proposal would also delete obsolete or unnecessary
requirements. For example, current Sec. 207.35 refers to the National
Health Related Items Code (NHRIC) system as another code system; the
proposal would omit references to the NHRIC system because we no longer
maintain the NHRIC database (see 42 FR 52808 at 52810, September 30,
1977)).
We describe the proposed changes in more detail in the next
section.
3. What Changes Are We Proposing?
a. Proposed Sec. 201.2--Drugs; National Drug Code (NDC) Number.
Currently, Sec. 201.2 states that NDC numbers are requested, but not
required, to appear on all drug labels and in all drug labeling,
``including the label of any prescription drug container furnished to a
consumer.'' Section 201.2 also states that if the NDC number appears on
the drug label, it must be displayed as required by current Sec.
207.35(b)(3).
The proposal would revise Sec. 201.2 to explain:
What drugs must have an NDC number, in human-readable
form, on the label;
What an appropriate NDC number is;
Whether any other NDC number may appear on a label;
What prefix must be used to identify the NDC number on the
label; and
Where the NDC number goes on the label.
Specifically, proposed Sec. 201.2(a) would require the appropriate
NDC number, in human-readable form, to appear on the labels of drugs
subject to the drug listing requirements. In this case, the word
``drugs'' should be interpreted in light of proposed Sec. 207.1 and
encompasses human drugs, including the drugs regulated under a BLA, as
described in proposed Sec. 207.9(c), and animal drugs, including Type
A medicated articles. These drugs may be active pharmaceutical
ingredients or finished dosage forms, whether prescription or OTC. The
drugs regulated under a BLA, as described in proposed Sec. 207.9(c)
include, but are 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.
We propose to require human-readable NDC numbers to appear on drug
labels because various individuals and databases use and rely on NDC
numbers, and those individuals or databases might not have the
technology or means to read an automatic identification technology such
as a bar code that is required under Sec. 201.25. In addition, for
those who are able to read bar codes, a human-readable NDC number may
serve as a ``backup'' in case the bar code is damaged, cannot be read,
or is otherwise illegible.
Proposed Sec. 201.2(b) would explain that an ``appropriate NDC
number'' is the NDC number that we have assigned (under proposed
Sec. Sec. 207.33 or 207.37, which we discuss later in this part) to
the last manufacturer, repacker or relabeler (including a drug product
salvager who repacks or relabels the drug), or private label
distributor responsible for the drug immediately before it is received
by the wholesaler or retailer. For example, assume that a manufacturer
makes a drug and sells that drug to a wholesaler or retailer. Under
proposed Sec. 201.2(b), the manufacturer is the last person
responsible for the drug immediately before it reached the wholesaler
or retailer, so the appropriate NDC number would be the manufacturer's
NDC number that we have assigned to that drug. If, however, the
manufacturer sold the drug to a repacker, who then repackages the drug
and sells the repackaged drug to a retailer, the repacker is the last
person responsible for the drug immediately before it reached the
retailer, so the appropriate NDC number would be the repacker's NDC
number that we have assigned and not the manufacturer's NDC number.
Identifying the last person responsible for a drug may be important
in situations where the drug's quality, purity, labeling, or packaging
may be at issue; for example, if a drug appeared to be contaminated,
knowing who the last person was who manufactured, repacked, or
relabeled the drug could help focus an investigation to determine how
the contamination occurred. It also allows linking to the correct
product information in the DailyMed. In addition, requiring the NDC
number of the last manufacturer, repacker, relabeler, or private label
distributor responsible for the drug immediately before it is received
by the wholesaler or retailer would enable us to accurately and quickly
identify the original manufacturer by connecting the NDC number on the
label to the information in the electronic drug registration and
listing system.
The proposed approach of assigning NDC numbers would mean that
repackers, for example, would have to use their own NDC number, rather
than using the manufacturer's NDC number on drug labels. We recognize
that some, but not all, repackers have been using the manufacturer's
NDC number rather than their own on drug labels. We are aware that some
repackers' practice of using the manufacturers' NDC numbers has led to
some confusion among FDA, the Centers for Medicare & Medicaid Services
(CMS), other Federal agencies, State agencies, and private insurance
organizations that rely on NDC numbers for many purposes, including to
identify a drug and a drug's source and for purposes of reimbursement
and dispensing systems. It also has led to some confusion by
practitioners and patients. There may be other reasons that this
practice has posed difficulties or is cause for concern.
We are aware that the use of manufacturer's NDC numbers by some
repackers may lead to inaccurate or improper reimbursement by Medicaid,
Medicare, and private insurers. It also may result in misunderstanding
as to which rebate agreement a particular drug is covered by or whether
a particular drug is covered by any rebate agreement at all.
We are also aware that the use of manufacturer's NDC numbers by
repackers may not always be accurate or consistent. For example, a
repacker might use a manufacturer's NDC number for a particular drug
and then continue to use that manufacturer's NDC number for generic
equivalents to that drug. This may lead to confusion for caregivers and
patients who may be dispensed medication based on the original
manufacturer's NDC number, but receive a drug that is different in
size, shape and/or color than the drug they are accustomed to using.
Additionally, there could be reimbursement differences between one
firm's product and another firm's product. Further, the NDC number of
the wrong manufacturer on the drug's label (even if the drugs of both
manufacturers are generic equivalents) may also be a problem when
pharmacies rely on verification systems that include exact color images
of drugs based on NDC numbers.
Recently, the National Association of Chain Drug Stores (NACDS) and
the Healthcare Distribution Management Association (HDMA) asked us to
exercise enforcement discretion concerning our recent bar code rule
(see
[[Page 51298]]
21 CFR 201.25 (69 FR 9170, February 26, 2004)) so that repackers could
continue using manufacturers' NDC numbers on retail-based repackaged
drug products (Ref. 1). In brief, NACDS and HDMA assert that FDA has
``historically allowed the use of original manufacturer NDC numbers by
repackagers on the product labels of retail-based repackaged drug
products'' and that this practice is standard among repackers (Ref. 1,
p. 2). NACDS and HDMA also stated that use of the repackers' NDC
numbers ``is not necessary or desirable'' because repackers identify
themselves on the drug labels and that procedures exist to allow recall
of particular lots of repacked drugs (rather than all drugs made by a
manufacturer). They also stated that mandatory use of the repackers'
NDC numbers might affect patient safety adversely and create
additional, excessive costs to patients, health care providers, and
payers because databases use the manufacturers' NDC numbers and cannot
be modified to accommodate repackers' NDC numbers (Ref. 1, pp. 4
through 9). For example, NACDS and HDMA said that requiring repackers
to use their own NDC numbers could ``greatly increase the potential for
medication errors'' because pharmacists would: ``be required to
inefficiently and manually choose between multiple options of the same
product, e.g., Motrin 800mg by [one manufacturer] or Motrin 800mg
repackaged by 5 different repackagers. The more NDC numbers in use for
the same product across the country, the greater the chance that data
entry errors will occur across the many pharmacies that use repackaged
products.'' (Ref. 1, p. 7.) In addition, NACDS and HDMA said that
requiring repackers to use their own NDC numbers would oblige them to
pay substantial rebate fees under Medicaid when Congress intended drug
manufacturers, not repackers, to pay those rebates and would complicate
Medicaid billing; they further stated that requiring repackers to use
their own NDC numbers would lead to a ``sharp reduction or elimination
of this type of repackaging'' (Ref. 1, p. 8).
On March 28, 2005, we issued a response to the letter from NACDS
and HDMA. The response stated, among other things, that we intend to
temporarily exercise our enforcement discretion and permit repackers to
use manufacturers' NDC numbers in bar codes placed on their products.
We said that there will be an opportunity to directly consider this
issue when we issue our proposed rule on establishment registration and
drug listing. The response stated that we will consider all information
provided that documents the impact on repackers.
We lack sufficient information to assess whether requiring
repackers to use their own NDC numbers would be as problematic and
expensive as NACDS and HDMA suggest. We also do not know the extent to
which databases that use NDC numbers cannot be modified to accommodate
repackers' NDC numbers or to associate more than one NDC number with
drugs made by the same manufacturer. Moreover, although repackers
currently assign their own NDC numbers and report those numbers to us,
we do not know whether databases ignore or omit repackers' NDC numbers
that we make available through the National Drug Code Directory.
We believe that allowing repackers to use the manufacturers' NDC
numbers would be contrary to the proposal's goal of making the NDC
number unique and the system more accurate and reliable.
We are requesting additional information on this issue. We
specifically invite comments on the proposed approach of requiring on
the drug's label the NDC number of the last manufacturer, repacker or
relabeler (including the drug product salvager who repacks or relabels
the drug), or private label distributor responsible for the drug
immediately before it is received by the wholesaler or retailer, which
would result in prohibiting the use of manufacturer's NDC numbers by
repackers. We are especially interested in: (1) Examples and
discussions of dispensing errors or difficulties, confusion,
reimbursement problems, or other difficulties that may have been caused
or contributed to by the practice of some repackers using the
manufacturer's NDC number; (2) The magnitude of the problems that may
be attributed to the use of manufacturer's NDC numbers by repackers and
of the problems that NACDS and HDMA have articulated that may result
from mandating the use of repacker's NDC numbers by repackers; (3) the
extent to which such problems do or are likely to occur; and (4)
whether there are technological (that is, software) solutions or
alternatives that could address the issues presented in the NACDS and
HDMA letter, other issues identified in this preamble, or those raised
in comments to this proposed rule.
By inviting comment, we are specifically giving NACDS and HDMA, and
any other interested parties, the opportunity to comment on whether
repackers should be able to use the manufacturers' NDC numbers on the
repacked drugs' label.
Proposed Sec. 201.2(c) states that only the appropriate NDC number
required by proposed Sec. 201.2(b) may appear on the label. This
provision would complement proposed Sec. 201.2(b) by requiring the
drug's label to bear the appropriate NDC number.
Proposed Sec. 201.2(d) would require the human-readable NDC number
to be immediately preceded by the letters ``NDC.'' This provision would
modify the current requirement at Sec. 207.35(b)(3)(ii), which states
that the NDC number must be preceded by the prefix ``NDC'' or ``N''
when used on a label or labeling. We decided to limit the prefix to
``NDC'' because, when compared to ``N'' alone, ``NDC'' is a clearer
signal that the number following ``NDC'' is the NDC number.
Proposed Sec. 201.2(e) would require that the appropriate NDC
number appear clearly on the drug's label as defined by section 201(k)
of the act. Section 201(k) of the act defines ``label'' as ``a display
of written, printed, or graphic matter upon the immediate container of
any article.'' Section 201(k) also states that ``a requirement made by
or under authority of this Act that any word, statement, or other
information appear on the label shall not be considered to be complied
with unless such word, statement, or other information also appears on
the outside container or wrapper, if any there be, of the retail
package of such article, or is easily legible through the outside
container or wrapper.'' This proposed requirement would be a change
from current Sec. 207.35(b)(3)(i), which requires the NDC number to
appear ``prominently in the top third of the principal display panel.''
We decided to remove the restriction on the NDC number's location
because our bar code rule, which requires the bar code to encode the
drug's NDC number, allows the bar code to appear anywhere on the drug's
label. Consequently, some establishments may wish to place the human-
readable NDC number next to the bar code, so we have decided against
specifying the location of the human-readable NDC number.
We are also proposing to revise current Sec. 201.25 because, as
discussed in section IV.A.5 of this document (definition of
``drug(s)'') and in the February 26, 2004, bar code final rule, certain
drugs that would be subject to proposed part 207 are not subject to
current Sec. 201.25. Under proposed Sec. 201.25(e), a drug product
that is subject to the drug listing requirements of proposed part 207
but is not subject to current Sec. 201.25 may display a bar
[[Page 51299]]
code on the label only if the bar code meets the requirements of Sec.
201.25(c). We are proposing this revision to help ensure consistency in
the appearance, content, and placement of bar codes on drug labels. We
are also proposing to revise current Sec. 201.25 to further clarify
what ``appropriate'' NDC number must appear in the bar code. Current
Sec. 201.25(c)(1) states that each drug product subject to current
Sec. 201.25 must have a bar code that contains, at a minimum, the
appropriate NDC number. To clarify this requirement, we are proposing
to amend current Sec. 201.25(c)(1) to state that the ``appropriate NDC
number,'' as used in current Sec. 201.25(c)(1), is described in
proposed Sec. 201.2(b).
We note that when there is a change in the NDC number on a drug
product label, or when an NDC number is added to a label, application
holders must submit revised labeling to us with their annual reports
under Sec. 314.81(b)(2) for human drugs, Sec. 514.80(b)(4) for animal
drugs (``periodic reports'' are required instead of ``annual
reports''), and Sec. 601.12(f)(3) for biological drugs.
b. Proposed Sec. 207.33--What is the National Drug Code Number,
who must obtain it, and what information must be submitted? Proposed
Sec. 207.33 would describe the NDC number and the process for
obtaining NDC numbers. The proposal would differ from the pre-existing
NDC number system by having us assign the NDC number for newly listed
drugs, by describing the changes that would require a manufacturer,
repacker, or relabeler to obtain a new NDC number, and by describing
when information must be submitted to us to obtain an NDC number. Under
the proposal, all three sections of the NDC number would be assigned
prospectively by us to drugs that have not previously been assigned NDC
numbers by a manufacturer, repacker, or relabeler. 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.
Currently, Sec. 207.35(a) states that we will provide a validated
copy of an establishment's registration form and assign a permanent
registration number to each drug establishment in accordance with our
regulations. Current Sec. 207.35(b)(1) and (b)(2) state that we will
assign a drug listing number to each drug or class of drugs and that
the number of characters in that number may differ depending on whether
the drug is already listed in the NDC system or the NHRIC system. For
example, current Sec. 207.35(b)(1) states that if a drug is already
listed in the NDC system or NHRIC system, the drug listing number is
the same as that assigned under those codes and that we will add a lead
zero to the first three characters to create a four-character labeler
code. Current Sec. 207.35(b)(1) also states that manufacturers or
distributors may retain alphanumeric characters that they already use
in the product and package code segments and must inform us if they
convert those code segments into numeric digits. Current Sec.
207.35(b)(2) also explains how many characters may be in a labeler
code, product code, and package code.
Given that this proposal would designate the responsibility of
assigning the NDC number to FDA, the proposal would eliminate many of
the provisions in current Sec. 207.35, such as our need to provide to
sponsors validated copies of registration forms as well as information
on how to assign the product code and package code. Proposed Sec.
207.33(a) explains that the NDC number is a unique 10-digit number
composed of a labeler code, product code, and package code. Proposed
Sec. 207.33(a) also states that we would assign the complete NDC
number (that would include the existing labeler code, if any) to each
drug that is subject to the listing requirements in part 207. We would
use the same configuration when assigning each segment of the NDC
number: The labeler code would be either five or four digits, the
product code would be either four or three digits, and the package code
would be either two digits or one digit. When we assign a NDC number to
a drug, we intend to leave a space between the segments of the NDC
number so that the separate codes are distinguishable. Manufacturers,
repackers, and relabelers may add symbols, such as hyphens or
asterisks, between the segments of the human-readable NDC number if
they want to visually distinguish the codes in such a manner. Under the
proposal, manufacturers, repackers, and relabelers would keep the same
labeler code that they use for currently marketed drugs. However, if
more than one labeler code is currently used by a manufacturer,
repacker, or relabeler, only one labeler code would be used for any new
NDC numbers that we would assign under this rule prospectively. Also,
as described below, the proposal would allow currently marketed drugs
to keep the same NDC numbers in most cases.
Proposed Sec. 207.33(b)(1) and (b)(2) would require that
manufacturers, repackers, relabelers, and, in certain circumstances,
drug product salvagers, obtain NDC numbers from us for each drug that
is subject to the drug listing requirements. In the case of drug
product salvagers, they would obtain an NDC number for each drug that
is subject to the drug listing requirements only if they repack or
relabel the salvaged drug. For private label distributors, proposed
Sec. 207.33(b)(3) states that the manufacturer, repacker, or relabeler
who manufactures, repacks, or relabels the drug for the private label
distributor is responsible for obtaining the NDC number from us for
each drug that is subject to the drug listing requirements.
Proposed Sec. 207.33(b) is intended to clarify who must obtain NDC
numbers. For example, drug product salvagers ordinarily would not need
to obtain NDC numbers because they merely salvage drugs. If a drug
product salvager simply recovers the drug and sells it without
repacking or relabeling the product, the drug product salvager would
not need to obtain an NDC number for the salvaged drug. However, if the
drug product salvager repacks or relabels the salvaged drug, then the
drug product salvager is similar to a repacker or relabeler, and
proposed Sec. 207.33(b) would require the drug product salvager to
obtain an NDC number from us for the repacked or relabeled drug. As
another example, under the proposal, private label distributors would
not be permitted to register or list and, consequently, they would not
obtain NDC numbers for the drugs they distribute. Instead, the
manufacturer, repacker, or relabeler who manufactures, repacks, or
relabels the drug for the private label distributor would be
responsible for obtaining the NDC number, including a labeler code
appropriate for the private label distributor. This change ensures that
more accurate information is provided to FDA about the drug distributed
by the private label distributor because the manufacturer supplies the
necessary drug information to FDA.
Under current Sec. 207.35, manufacturers, repackers, and
relabelers assign NDC numbers to the drugs they manufacture, repack, or
relabel, and private label distributors assign NDC numbers to the drugs
they distribute if they opt to list the drugs themselves. Drug product
salvagers currently do not receive NDC numbers for the drugs they
salvage, and under current Sec. 207.20(a), they are not required to
list the drugs they salvage.
As noted previously, even though we would assign NDC numbers under
the proposal, an establishment's labeler code would remain the same in
most
[[Page 51300]]
cases. For example, if a manufacturer's labeler code were 12345, we
would assign NDC numbers for the manufacturer's drugs and still use
12345 as the manufacturer's labeler code. However, under the proposal,
if a manufacturer, repacker, or relabeler uses more than one labeler
code, we would prospectively assign NDC numbers that use only one
labeler code for that manufacturer, repacker, or relabeler.
Note, too, that other components in an NDC number may remain
unchanged under the proposal. For example, assume that a drug is
already listed in the National Drug Code Directory and its manufacturer
later decides to change its package size. In this situation, the
labeler code and the product code would ordinarily remain the same,
and, generally, we would assign a new package code for the changed
drug.
Furthermore, if a drug already has an NDC number at the time of the
effective date of a final rule, the drug would retain that NDC number
provided that the manufacturer, repacker, or relabeler, within 9 months
after the effective date of a final rule, reviews and updates, in
accordance with proposed Sec. Sec. 201.2, 207.33, 207.37, 610.60, and
610.61, the information in our database for the NDC number (see
sections IV.C.4, IX, and X of this document for information on the
proposed implementation and effective and compliance dates of this
rulemaking). We also will work with manufacturers, repackers, and
relabelers to address any problems with existing NDC numbers (such as
duplicate or potentially duplicate NDC numbers) that might arise after
a final rule becomes effective.
Using a 5-digit labeler code, we estimate that we have the capacity
for NDC numbers for up to 100,000 registered establishments, each
having a capacity for up to 100,000 product/package size combinations
(using the 5 remaining digits). If a registered establishment requires
more than 100,000 product/package size codes, we could issue that
establishment an additional labeler code. We currently have about
25,000 active establishments in our registration database, utilizing
less than half of the 5-digit labeler code capacity. We currently issue
about 1,000 new labeler codes annually. If we reach NDC number capacity
(possibly in 30 to 50 years), we could propose to either add
alphanumeric capability or expand the number of numeric digits to 11 or
12 (current Sec. 207.35(b)(2)(i) states that FDA will go from a 5- to
6-digit labeler code if needed). This change in NDC numbers will
necessitate advances in current UPC technology (due to the need for bar
code reading), which we anticipate will likely occur prior to our
reaching the 10-digit NDC numeric capacity.
The proposal would also omit the references to Form FDA-2656 in
current Sec. 207.35(a) and (b)(2) because the proposal's electronic
submission of registration and listing information would make it
unnecessary for us to provide validated copies of forms. In addition,
because we would assign NDC numbers, the proposal would eliminate the
provision in current Sec. 207.35(b)(1) that allows manufacturers and
distributors to convert alphanumeric product codes and package codes
they may have and report such changes to us. (If any establishment
still has alphanumeric product or package codes for a drug, we will
work with them to assign new NDC numbers.) The proposal would also omit
references in current Sec. 207.35(b)(1) and (b)(2) to the NHRIC system
because we do not maintain a NHRIC database (see 42 FR 52808 at 52810).
Proposed Sec. 207.33(c) and (d) describes the information that a
manufacturer, repacker, or relabeler would be required to submit before
we assign an NDC number to a drug. As discussed earlier in this
section, if a drug product salvager simply recovers the drug and sells
it without repacking or relabeling the drug, the drug product salvager
would not need to obtain an NDC number for the salvaged drug. However,
if the drug product salvager repacks or relabels the salvaged drug,
then the drug product salvager is similar to a repacker or relabeler,
and proposed Sec. 207.33(b) would require the drug product salvager to
obtain an NDC number from us for the repacked or relabeled drug. The
following table illustrates the proposed requirements.
Table 1.--Information to be Submitted to Obtain an NDC Number, Arranged by Manufacturer, Repacker, or Relabeler
and Drug
----------------------------------------------------------------------------------------------------------------
Proposed Section Type of Drug Information to be Submitted
----------------------------------------------------------------------------------------------------------------
Sec. 207.33(c)(1) Active pharmaceutical Manufacturer's name, address, telephone number, fax
(Manufacturer) ingredient number, e-mail address, and labeler code
Drug's established name and proprietary name (if
any)
Package size and type
Drug Master File number or Veterinary Master File
number, if any, assigned to the active pharmaceutical
ingredient
----------------------------------------------------------------------------------------------------------------
Sec. 207.33(c)(2) Drug other than an active Manufacturer's name, address, telephone number, fax
(Manufacturer) pharmaceutical ingredient number, e-mail address, and labeler code
Drug's established name and proprietary name (if
any)
Name and quantity of each active pharmaceutical
ingredient or the approved U.S. application number
Name of each inactive ingredient (or approved U.S.
application number) for certain drugs, and whether you
consider the name of the inactive ingredient to fall under
Sec. 20.61 (21 CFR 20.61) of this chapter or to be
otherwise prohibited from disclosure and, if so, why
Dosage form
Package size and type, including immediate unit-of-
use container
Marketing status (e.g., prescription or OTC)
Drug or drug product type (human drug or animal
drug)
Imprinting information
----------------------------------------------------------------------------------------------------------------
[[Page 51301]]
Sec. 207.33(c)(3) Active pharmaceutical Manufacturer's name, address, telephone number, fax
(Manufacturer) ingredient for a private number, e-mail address, and labeler code
label distributor Drug's established name and proprietary name (if
any)
Package size and type
Drug Master File number or Veterinary Master File
number, if any, assigned to the active pharmaceutical
ingredient
Private label distributor's name, address, telephone
number, fax number, e-mail address, labeler code
Drug's proprietary name (if any) as assigned by the
private label distributor
----------------------------------------------------------------------------------------------------------------
Sec. 207.33(c)(3) Drug other than an active Manufacturer's name, address, telephone number, fax
(Manufacturer) pharmaceutical ingredient number, e-mail address, and labeler code
for a private label Drug's established name and proprietary name (if
distributor any)
Name and quantity of each active pharmaceutical
ingredient or the approved U.S. application number
Name of each inactive ingredient (or approved U.S.
application number) for certain drugs, and whether you
consider the name of the inactive ingredient to fall under
Sec. 20.61 of this chapter or to be otherwise prohibited
from disclosure and, if so, why
Dosage form
Package size and type, including immediate unit-of-
use container
Marketing status (e.g., prescription or OTC)
Drug or drug product type (human drug or animal
drug)
Imprinting information
Private label distributor's name, address, telephone
number, fax number, e-mail address, and labeler code
Drug's proprietary name (if any) as assigned by the
private label distributor
----------------------------------------------------------------------------------------------------------------
Sec. 207.33(d)(1) Drug that is repacked or Repacker's or relabeler's name, address, telephone
(Repacker or relabeled number, fax number, e-mail address, and labeler code
relabeler) NDC number assigned to the drug immediately before
its receipt by the repacker or relabeler
Type of operation performed for the drug (repacking
or relabeling)
Drug's established name and proprietary name (if
any)
Package size and type, including immediate unit-of-
use container, if any (required for repackers only)
----------------------------------------------------------------------------------------------------------------
Sec. 207.33(d)(2) Drug that is repacked or Repacker's or relabeler's name, address, telephone
(Repacker or relabeled for a private number, fax number, e-mail address, and labeler code
relabeler) label distributor NDC number assigned to the drug immediately before
its receipt by the repacker or relabeler
Type of operation performed for the drug (repacking
or relabeling)
Drug's established name and proprietary name (if
any)
Package size and type, including immediate unit-of-
use container, if any (required for repackers only)
Private label distributor's name, address, telephone
number, fax number, e-mail address, and labeler code
Drug's proprietary name (if any) assigned by the
private label distributor
----------------------------------------------------------------------------------------------------------------
Proposed Sec. 207.33(c) and (d) are intended to accomplish several
goals:
1. The proposal would reduce redundant data submission and improve
the accuracy of information that we receive. For example, under the
current system, a manufacturer and a repacker may submit the same drug
listing information for the same type of drug. However, the repacker
might not have adequate information from the manufacturer or might
describe the drug differently than the manufacturer; this would lead to
data discrepancies and omissions. So, by requiring only manufacturers
to provide descriptive information about the drugs they make, we would
eliminate potential duplicate submissions, data discrepancies, and data
omissions. Instead, the repacker, under the proposal, would simply tell
us the NDC number of the drug that the repacker receives, and we could
use the NDC number to link the drug back to its manufacturer.
2. By having manufacturers, repackers, relabelers, and drug product
salvagers submit information on behalf of private label distributors,
the proposal would eliminate the potential for redundant, incomplete,
or inconsistent submissions by private label distributors. For example,
under the current system, some manufacturers have submitted information
for drugs that they manufactured for private label distributors, and
the private label distributors also submitted information for the same
drugs; if the manufacturers and private label distributors described
the drugs differently to us, we then had different information for the
same drugs.
3. By linking a repacker's or relabeler's drug to an NDC number,
the proposal would eliminate a problem that some repackers and
relabelers have encountered in the past. Under the current listing
system, repackers and relabelers have sometimes found it difficult to
obtain necessary information from manufacturers. This difficulty has
[[Page 51302]]
resulted in data errors and omissions and an incomplete or inaccurate
National Drug Code Directory.
4. By separating the NDC number process from drug listing and
creating an electronic drug registration and listing system, the
proposal should make it easier for manufacturers, repackers, and
relabelers (and drug product salvagers who obtain NDC numbers for
private label distributors) to obtain their NDC numbers quickly and, as
a result, prepare product labels and marketing plans earlier.
5. Under the proposal, the information submitted about the drug to
obtain an NDC number would be retained in the electronic drug
registration and listing system. Thus, when the manufacturer, repacker,
or relabeler later lists the drug, they would need to provide only the
additional information required for listing.
6. By assigning a unique NDC number to each drug, the proposal
would ensure that the drug has an accurate identifier, allowing us to
support the implementation of the electronic prescribing provisions of
the Medicare Modernization Act. We would link the accurate NDC number
to the product labeling that would be made available through the
DailyMed initiative.
i. Information to be submitted to receive an NDC number. We
describe the information that proposed Sec. 207.33(c) and (d) would
require and our reasons for proposing to require the information, as
follows:
Name, address, telephone and fax numbers, e-mail address,
and labeler code. Proposed Sec. 207.33(c) and (d) would require
manufacturers, repackers, and relabelers to provide this information to
enable us to identify and contact (if necessary) the appropriate
manufacturer, repacker, or relabeler and identify their labeler code.
In situations where a manufacturer, repacker, or relabeler
manufactures, repacks, or relabels a drug for a private label
distributor, the proposal would also require the manufacturer,
repacker, or relabeler to provide comparable information for the
private label distributor. This information would enable us to
associate the manufacturer's, repacker's, or relabeler's drugs with a
particular private label distributor and to contact that private label
distributor if necessary.
The drug's or active pharmaceutical ingredient's
established name and proprietary name (if any). The established name
(sometimes referred to as generic name) is ordinarily either the drug's
compendial name or, if there is no compendial name, the drug's common
or usual name. The proprietary name (sometimes referred to as trade
name) is generally the drug's marketed or advertised name as designated
by the manufacturer, repacker, relabeler, or private label distributor.
Most consumers recognize a drug by its proprietary name rather than its
established name. Proposed Sec. 207.33(c) and (d) would require
submission of these names because knowing a drug's established name
would let us determine, for example, which companies market identical
drugs and which drugs can be substituted in the event of drug shortages
or recalls. Knowing a drug's proprietary name would enable us to
identify a drug to the public during a recall or consumer alert. This
information is currently required under Sec. 207.25(b)(1) and is
submitted on Form FDA 2657.
The Drug Master File (DMF) number or Veterinary Master
File (VMF) number, if any, assigned to the active pharmaceutical
ingredient. Under proposed Sec. 207.33(c)(1)(iv) (and, if applicable,
proposed Sec. 207.33(c)(3)), if a DMF number or VMF number is assigned
to the active pharmaceutical ingredient, the manufacturer would
identify for us the DMF number or the VMF number. The DMF or VMF may
contain additional information about the active pharmaceutical
ingredient that our electronic drug registration and listing system
could associate with the active pharmaceutical ingredient at other
points in the registration and listing process. This could reduce the
burden on the manufacturer of submitting to us the information already
contained in the DMF or VMF. This information is not currently provided
to us under current part 207 or Form FDA 2657 or Form FDA 2658.
Name and quantity of each active pharmaceutical ingredient
in a drug. Proposed Sec. 207.33(c)(2) and, if applicable, proposed
Sec. 207.33(c)(3), would require manufacturers to submit this
information to us (unless the approved U.S. application number is
provided). Knowing the name and quantity of a drug's active
pharmaceutical ingredients would help us assign unique product codes
and help ensure that the assigned NDC numbers are unique to different
products. For example, assume that a manufacturer makes a drug in two
different strengths, 100 milligrams (mg) and 500 mg. If we only
required the manufacturer to identify the active pharmaceutical
ingredient, we might assume, incorrectly, that the manufacturer made
two versions of the same drug in the same strength and then assign the
same product code to both drugs. Instead, by proposing to require
information about the quantity of the drug's active pharmaceutical
ingredient, we would be able to assign one product code to the 100 mg
product and a different product code to the 500 mg product. As an
alternative to providing the name and quantity of the drug's active
pharmaceutical ingredient, proposed Sec. 207.33(c)(2) would allow a
manufacturer to give us the drug's approved U.S. application number;
the approved U.S. application number would allow us to link the drug to
a particular application and determine the name and quantity of the
active pharmaceutical ingredients in that drug.
The proposed requirement is similar to the requirement regarding
quantitative listing of active ingredients in current Sec. 207.25(b).
Current Sec. 207.25(b)(6) requires a quantitative listing of a drug's
active ingredient(s) for drugs that a registrant regards as not being
subject to sections 505 or 512 of the act or section 351 of the PHS
Act. Current 207.25(b)(2) requires, for each drug listed that the
registrant regards as subject to section 505 or 512 of the act, the
application number. The act, for purposes of certain drug listing
requirements, appears to treat drugs differently depending on whether
those drugs are subject to sections 505 or 512 of the act or not.
Section 510(j)(1)(A) of the act mandates that the drug list be prepared
in the form and manner prescribed by us. That drug list, for drugs
subject to sections 505 or 512 of the act, must be accompanied by ``the
authority for the marketing of such drug''. In contrast, section
510(j)(1)(C) of the act states that the drug list, for drugs that are
not subject to either section 505 or 512 of the act, must be
accompanied by a ``quantitative listing'' of the drug's active
ingredient or ingredients and that we may require a quantitative
listing of all ingredients with respect to a particular product if we
find such submission is necessary to carry out the act's purposes.
We believe that these provisions, and others, give us sufficient
authority to require the submission of active ingredient information
for all drugs as part of the NDC number assignment process. We already
have such information for drugs approved under sections 505 and 512 of
the act because information concerning active ingredients is an
essential part of the drug's marketing application. Thus, when a
manufacturer gives us the approved U.S. application number (as proposed
Sec. 207.33(c)(2)(i) would require and as current Sec. 207.25(b)(2)
(pertaining to required drug listing information) requires), the
manufacturer is, in essence, giving us a link to information
[[Page 51303]]
about the drug's active ingredients. As noted previously, section
510(j)(1)(A) of the act, for drugs subject to sections 505 or 512 of
the act, requires the ``reference to the authority for the marketing of
such drug.'' This reference would be the approved U.S. application
number. The act, for drugs not subject to section 505 or 512,
explicitly requires a quantitative listing of active ingredients.
Proposed Sec. 207.33(c)(2)(i) would, therefore, enable us to input the
active ingredient information into an electronic database. This would
enable us to link to certain information in the application, and would
be more efficient than having to review individual marketing
applications, identify each drug's active ingredients, and then enter
that data into the database ourselves.
Name of the inactive ingredient(s). Proposed Sec.
207.33(c)(2), and, if applicable, (c)(3) would require manufacturers to
give us the drug's approved U.S. application number or, in the
alternative, the name of each inactive ingredient for each human and
animal drug that the manufacturer regards as subject to section 505 or
section 512 of the act or section 351 of the PHS Act, and for each
human OTC drug that the manufacturer regards as not subject to section
505 of the act, and whether the name of an inactive ingredient falls
under Sec. 20.61 or is otherwise prohibited from disclosure and, if
so, why. Proposed Sec. 207.33(c)(3) describes the requirements of the
manufacturer who is manufacturing a drug for a private label
distributor. Such manufacturers would be required to give us the name
of each inactive ingredient for certain drugs, as described previously,
or the drug's U.S. approved application number for the drug it
manufactures for a private label distributor. Proposed Sec.
207.33(c)(2) and (c)(3) are authorized under section 510 of the act as
well as other provisions. We are considering whether to require the
name of each inactive ingredient to be submitted for other categories
of drugs as well.
Dosage form. Proposed Sec. 207.33(c)(2) and (c)(3) would
require manufacturers to identify a drug's dosage form. This
information will also help us distinguish between drug products that
contain the same active ingredient and, consequently, assign unique
product codes to such drugs. For example, assume that a manufacturer
makes drug X, in a 100 mg strength, in a tablet form and also in a
gelatin capsule. If we did not know there were two dosage forms of drug
X, we might mistakenly assign the same product code to the tablet and
gelatin capsule. Thus, information about dosage forms will help us
create an NDC system that ties unique NDC numbers to unique products.
The drug's dosage form is currently submitted on Form FDA 2657.
Package size and type. Proposed Sec. 207.33(c)(1),
(c)(2), (c)(3) (if applicable), (d)(1), and (d)(2) would require
manufacturers and repackers respectively to provide information about
package size and type. This information would obviously be relevant in
helping us assign package codes to a particular drug. For example, a
drug packaged in a glass container would have a different NDC number
from the same drug packaged in a plastic container. The proposal would
require that information about the drug's package size and type be
provided for each package, including the immediate unit-of-use
container. For example, a drug packaged in a box containing a card of
12 unit-of-use blisters would have a different NDC number than each
individual blister (unit-of-use). In the latter example, the different
NDC numbers would have a practical impact with respect to our bar code
requirements. A database system computer reading the bar code for the
individual unit-of-use blister would see that the health care
professional is administering a single dose of a particular drug to a
patient; if the NDC number for the box were the same as that used for
each unit-of-use blister, then the computer might mistakenly believe
that the health care professional was administering 12 doses to the
patient. In these scenarios, distinct NDC numbers for each package
level would enhance the bar code's accuracy and value. The drug's
package size and type is currently submitted on Form FDA 2657.
Marketing status. Proposed Sec. 207.33(c)(2) and, if
applicable, (c)(3), would require manufacturers to tell us whether the
drug is available only by prescription or is available OTC. Having such
information in our electronic database would enable us to determine
quickly which drugs are available by prescription and which are OTC. In
addition, some entities that rely on NDC numbers, such as CMS and
health care insurance companies, might treat prescription drugs
differently from OTC drugs. For example, an insurer might reimburse
consumers for prescription drug expenses, but not for OTC drug
expenses. The drug's marketing status--whether prescription or OTC--is
currently submitted on Form FDA 2657.
Drug or drug product type. Under proposed Sec.
207.33(c)(2) and, if applicable, (c)(3), manufacturers would identify
whether a drug is a human drug or animal drug. This information would
enable us to refine our databases to distinguish quickly between human
and animal drugs. Having such information readily available could help
us determine the regulatory obligations for a particular drug. For
example, the bar code requirement applies to human drugs only. Thus, if
we could differentiate quickly between human and animal drugs based on
NDC numbers alone and we received a report that a particular drug
failed to have a bar code on its label, we would be able to determine,
based on the NDC number alone, whether that drug was subject to the bar
code requirement. This information is currently submitted under
``product type'' on Form FDA 2657.
Imprinting information. For each drug product subject to
the listing requirements and covered under Sec. 206.1, including
products that are exempted under Sec. 206.7(b), manufacturers must
provide the size, shape, color, and code imprint (if any) (proposed
Sec. 207.33(c)(2)(vii) and, if applicable, proposed Sec.
207.33(c)(3)). This provision is similar to current Sec. 207.25(c),
except the current provision also requires that the name of the drug
product, its active ingredient(s), dosage strength, NDC number, and the
name of its manufacturer or distributor be submitted. Under the
proposal, the name of the drug product, its active ingredient(s)
(proposed Sec. 207.33(c)(2) uses the term ``active pharmaceutical
ingredient''), and dosage strength (proposed Sec. 207.33(c)(2) uses
the term ``dosage form'') would be submitted to us under proposed Sec.
207.33(c) along with the imprinting information. The NDC number would
be submitted under proposed Sec. 207.49 for listing, the name of the
private label distributor would be submitted under proposed Sec. Sec.
207.33 and 207.49 for listing, and the name of the manufacturer would
be submitted under proposed Sec. 207.25 for registration. All of this
information would be accessible via our electronic drug registration
and listing system. The proposal would also delete the requirement in
current Sec. 207.25(c) that ``any other characteristic that identifies
the drug product as unique'' must be submitted. We need to know the
drug's size, shape, color, and code imprint, as well as the other
information required under proposed Sec. 207.33(c), to assign an NDC
number to the manufacturer's drug. Imprinting information would enable
us to investigate reports of medication errors and counterfeiting and
to assist poison control centers in identifying drugs in overdose and
accidental poisoning situations.
[[Page 51304]]
NDC number assigned to the drug immediately before the
repacker or relabeler received that drug. Proposed Sec. 207.33(d)
would require repackers and relabelers to give us the NDC number of the
drug that they receive. This information would enable us to link that
drug to a particular source and, as we said earlier in this part,
eliminate the need for repackers and relabelers to obtain certain drug
information from those sources to obtain an NDC number. For example,
assume that relabeler Alpha received drug X from manufacturer Beta. If
Alpha gives us the NDC number for drug X, we will then be able to link
Alpha's relabeled drug to Beta. We would also eliminate any need for
Alpha to ask Beta for information about drug X for purposes of getting
an NDC number and eliminate the possibility that Alpha might report
incorrect or contradictory information about drug X compared to the
information given to us by Beta.
Type of operation. Proposed Sec. 207.33(d) would require
repackers and relabelers to report the type of operation (that is,
repacking or relabeling) performed for a drug. This information is
comparable to the information we currently receive about an
establishment's ``type of business'' on Form FDA 2657, except that
proposed Sec. 207.33(d) is limited to repackers and relabelers.
Information regarding private label distributors. Proposed
Sec. 207.33(c)(3) and 207.33(d)(2) would require manufacturers,
repackers, and relabelers who manufacture, repack, or relabel drugs for
a private label distributor to tell us the private label distributor's
name, address, telephone number, fax number, e-mail address, labeler
code, and any proprietary name assigned by the private label
distributor to the drug. This information will help us link the
manufacturer's, repacker's, or relabeler's drug to a particular private
label distributor and, as we stated earlier in this part, eliminate
potential data duplication, omissions, and inaccuracies that would
otherwise result if private label distributors were able to seek NDC
numbers from us. Manufacturers, repackers, and relabelers should be
able to obtain the necessary information from private label
distributors. Listing information for private label distributors is
currently submitted on Form FDA 2658.
ii. How the information would be submitted. Proposed Sec.
207.33(e) would require manufacturers, repackers, and relabelers to
submit information to us electronically, in accordance with proposed
Sec. 207.61 unless we grant a waiver under proposed Sec. 207.65. We
discuss proposed Sec. Sec. 207.61 and 207.65 later in this document.
iii. Types of changes that would require a new NDC number. Proposed
Sec. 207.33(f) would describe the types of changes in information that
would require a new NDC number. In brief, proposed Sec. 207.33(f)(1)
would require a new NDC number for any change of information that would
be required under proposed Sec. 207.33(c) and (d), except for the
following contact information: Name; address; telephone and fax
numbers; and e-mail address for the manufacturer, repacker, relabeler,
or private label distributor. In addition, Sec. 207.33(f)(2) requires
manufacturers to obtain a new NDC number when there is a change in an
inactive ingredient for each human prescription drug that the
manufacturer regards as not subject to section 505 of the act and for
each animal drug that the manufacturer regards as not subject to
section 512 of the act. Although we are not proposing to require, at
this time, that manufacturers submit the name of each inactive
ingredient to us when they obtain an NDC number for these drugs, we are
proposing to require that manufacturers notify us only of the fact that
there has been a change in an inactive ingredient for these drugs. This
would ensure that a unique NDC number is assigned to these drugs when
the drug's inactive ingredient(s) has changed. It is important that
marketed drugs have unique NDC numbers that are accurate because, as
discussed in section IV.C.2 of this document, NDC numbers are an
important, standardized, identification system for drug products and
are used for many purposes. In addition, identifying marketed drugs in
our electronic database for which inactive ingredients have changed
would help us investigate, as discussed in section IV.C.3 of this
document, incidents of allergic reactions in patients as well as
possible drug contamination, counterfeiting, or adulteration. Although
we are not proposing it at this time, we are considering requiring in
the future that manufacturers submit the name of each inactive
ingredient to obtain an NDC number for categories of drugs beyond those
referenced in proposed Sec. 207.33(c)(2)(ii) and 207.33(c)(3). We are
specifically requesting comments on the feasibility of submitting these
inactive ingredients. The proposed rule would be similar to current
Sec. 207.35(b)(4)(i), which requires a registrant to assign a new NDC
number if any change occurs in a product's characteristics that clearly
distinguishes one drug product version from another. However, proposed
Sec. 207.33(f) would differ from the current requirement in several
important respects. First, proposed Sec. 207.33(f) would require
changes to be reported to us in accordance with proposed Sec.
207.33(e) (which would require electronic submission of information)
and Sec. 207.33(g) (which describes timing requirements discussed
later in this part). The current regulation has no comparable
electronic reporting requirement. Second, proposed Sec. 207.33(f)
would not require us to publish a notice in the Federal Register
announcing our determination as to whether a change requires assignment
of a new product code. Because the proposed rule would create an
electronic drug registration and listing system and have us assign NDC
numbers quickly that would be accessible in the registration and
listing database, we find it unnecessary and impractical to publish
Federal Register notices regarding product code changes. Third,
although current Sec. 207.35(b)(4)(i) allows registrants to assign
their own package codes for changes involving trade packages, proposed
Sec. 207.33(f) would eliminate this provision because we would assign
the new NDC number ourselves to ensure that the NDC number is unique
and that our NDC number database is accurate and up-to-date. Fourth,
proposed Sec. 207.33(f), in conjunction with proposed Sec. 207.33(c)
and (d), gives a more complete description of which changes would
require a new NDC number, compared with current Sec. 207.25(b)(4)(i)
(which currently lists examples of changes). Because manufacturers,
repackers, and relabelers currently have different practices with
respect to assigning NDC numbers, this change would eliminate
inconsistency and would introduce an element of certainty with respect
to the assignment of new NDC numbers.
iv. When the information would be provided. Proposed Sec.
207.33(g) would explain when a manufacturer, repacker, or relabeler
must provide the information to obtain an NDC number. In brief, the
proposal would require a manufacturer, repacker, or relabeler to
provide the information described in proposed Sec. 207.33(c), (d), and
(f) either before or at the time drug listing information is required
under proposed Sec. Sec. 207.45 or 207.57. (We discuss proposed
Sec. Sec. 207.45 and 207.57 later in this document.) The proposed
requirement differs slightly from current Sec. Sec. 207.21(b),
207.22(b), and 207.25(b)(8), which allows manufacturers, repackers, and
relabelers to give us NDC numbers as part of their
[[Page 51305]]
drug listing information, because the proposal would allow companies to
give us information earlier than the drug listing process would be
completed. This ability to seek NDC numbers throughout the year should
help us keep the National Drug Code Directory current and, as a result,
provide more accurate and useful NDC number information to entities
that rely on or use NDC numbers. In addition, the proposed scheme would
give manufacturers, repackers, and relabelers more flexibility to
obtain an NDC number earlier for their own planning purposes.
Furthermore, we will know which NDC number corresponds to a drug
immediately because we will assign it, rather than the current system
where manufacturers, repackers, and relabelers assign their own NDC
numbers and only report those numbers to us as part of their drug
listing information.
We considered assigning the NDC number as part of the drug listing
process, but believe that allowing for earlier assignment would provide
optimal flexibility for manufacturers, repackers, and relabelers. We
note that the information submitted to have an NDC number assigned is a
subset of the information submitted to list a drug. Therefore, if a
manufacturer, repacker, or relabeler provides us the information early
to get an NDC number, they will only need to provide the additional
information needed when they later list the drug.
c. Proposed Sec. 207.37--What restrictions pertain to the use of
NDC numbers? Proposed Sec. 207.37 would establish four restrictions on
the use of NDC numbers insofar as FDA-regulated products or activities
are concerned. The proposed restrictions reflect practical problems or
difficulties that we have encountered when manufacturers, repackers, or
relabelers assign their own NDC numbers.
Proposed Sec. 207.37(a) would state that an NDC number must not be
used to represent a different drug than the drug to which it was
assigned. This restriction would prevent manufacturers, for example,
from using the same NDC number for different drugs and thus prevent
potential discrepancies among databases that rely on or use NDC numbers
to distinguish between drugs. The restriction would prevent two
different drugs from having the same NDC number and avoid medication
errors that could result if the NDC number encoded in a bar code
represented more than one drug. Use of an NDC number not assigned to a
drug would also cause a drug to be misbranded under section 502(a) of
the act because the drug's label would be misleading.
Proposed Sec. 207.37(b) would state that a different NDC number
must not be used if marketing is resumed for a drug that was
discontinued earlier. If marketing is resumed for a drug, and no
changes have been made to the drug that would require a new NDC number
under Sec. 207.33(f), the drug must have the same NDC number that was
assigned to it earlier before marketing was discontinued. This would
prevent two NDC numbers from being assigned to or used for the same
drug. Consistent with this rationale, proposed Sec. 207.37(b) would
revoke current Sec. 207.35(b)(4)(ii), which states that the product
code of a discontinued product may be reassigned to another product 5
years after the expiration date of the discontinued product or, if
there is no expiration date, 5 years after the last shipment of the
discontinued product into commercial distribution.
Proposed Sec. 207.37(c) would state that NDC numbers must not be
used to denote FDA approval. This is similar to current Sec. 207.39,
which states, in part, that assignment of an NDC number does not in any
way denote approval of a product. For drugs subject to sections 505 or
512 of the act, those drugs must be shown to be safe and effective for
their intended uses to obtain FDA approval. Mere assignment of an NDC
number by us is not equivalent to our determining whether a drug is
safe and effective for its intended uses.
Proposed Sec. 207.37(d) would state that NDC numbers must not be
used on products that are not subject to the drug listing requirements
of part 207, such as dietary supplements and medical devices. We are
proposing this requirement because the fundamental purpose behind NDC
numbers was to establish an identification system to help in the
automated processing of drug data and claims. Use of NDC numbers on
non-drug products could introduce misleading information in databases,
lead to inappropriate claims processing, and undermine the accuracy and
reliability of an NDC system. For example, some human dietary
supplements bear an NDC number on their labels. FDA considers a human
dietary supplement that bears an NDC number misbranded under 21 U.S.C.
343(a)(1), which provides that a food is misbranded if its labeling is
false or misleading in any particular. A product labeled and marketed
as a human dietary supplement is not a drug listed with FDA; thus, the
presence of an NDC number on the label is a false representation about
the nature of the product.
d. Proposed Sec. Sec. 610.60(a)(2) and 610.61(b)--Where would the
NDC number be required for biological products? Under proposed Sec.
201.2(a), all drugs, including human biological drugs, subject to the
drug listing requirements of part 207 must have labels that bear the
appropriate NDC number in human-readable form, in accordance with the
provisions in proposed Sec. 201.2. Current Sec. 610.60(a) (21 CFR
610.60(a)) specifies which items must appear on the label affixed to
each container of a biological product capable of bearing a full label
and current Sec. 610.61 specifies which items must appear on the label
affixed to each package containing a biological product. We are
proposing to amend Sec. Sec. 610.60(a)(2) and 610.61(b) (21 CFR
610.60(b)) to require that the NDC number appear, in accordance with
proposed part 207, on these biological product labels. Many individuals
and companies use NDC numbers and they may not have the technology or
ability to read an automatic identification technology such as a bar
code that is required under current Sec. 207.25 or Sec. 610.67. In
addition, a human-readable NDC number may serve as a ``backup'' in case
the bar code is damaged, cannot be read, or is otherwise illegible.
4. How Do We Intend to Implement the NDC Number Changes?
a. When would we expect compliance with the NDC number
requirements? We are proposing that our electronic drug registration
and listing system be used to enter and update all NDC number
information, as well as all registration and listing information, no
later than 9 months after the effective date of a final rule. If a drug
already has an NDC number at the time of the effective date of a final
rule, the drug would retain that NDC number provided that the
manufacturer, repacker, or relabeler, within 9 months after the
effective date of a final rule, reviews and updates, in accordance with
proposed Sec. Sec. 201.2, 207.33, 207.37, 610.60, and 610.61, the
information in our database for the NDC number. To retain the NDC
number, new information about the drug's characteristics may need to be
provided to us. We will, if necessary, assign a new product code and/or
package code, creating a new NDC number for the drug. If a
manufacturer, repacker, or relabeler does not review or update its
information within 9 months after a final rule's effective date, we may
assign a new NDC number to the drug or take other appropriate steps.
As discussed in section IV.E.6 of this document, we intend to make
available guidance on how to provide to us in
[[Page 51306]]
electronic format information required to receive an NDC number, as
well as registration and listing information. We can assist
manufacturers, repackers, and relabelers in determining whether their
NDC numbers are accurate and address any problems with existing NDC
numbers (such as duplicate or potentially duplicate NDC numbers). We
are available to work with manufacturers, repackers, and relabelers to
resolve issues that might arise after a final rule becomes effective.
Information on how to contact us for assistance will be specified in
the guidance.
b. When would we expect NDC numbers to appear on drug labels?
Although current regulations do not require NDC numbers on drug labels
(other than NDC numbers encoded in a bar code, where such bar codes are
required under current Sec. 201.25), almost all human and animal
prescription drugs already have NDC numbers on their labels because
government agencies and third-party payers rely on NDC numbers for
reimbursement and other purposes. Thus, when we issue a final rule
requiring NDC numbers to appear on drug labels, such a requirement
should have little impact on human and animal prescription drug labels.
We intend to phase-in the requirements for NDC number placement and
appearance on human and animal prescription drug labels over a 3-year
period, starting from the effective date of a final rule. This
implementation scheme should lessen the impact on prescription drug
labels (which might stem from changing the NDC number on the label or
adding an NDC number, for example, for unit-of-use blisters).
As for human and animal OTC drugs, we estimate that approximately
30 percent of these drug labels currently have NDC numbers. (We discuss
this issue further in section VI of this document.) We intend to phase-
in the requirements for NDC number placement and appearance on OTC drug
labels over a 7-year period, starting from the effective date of a
final rule.
We are considering shortening the compliance dates by which the
appropriate NDC number must appear on drug labels to 2 years after the
effective date of a final rule for prescription drugs and 5 years after
the effective date of a final rule for OTC drugs. We discuss this issue
further in section VI of this document. We invite comment on whether a
shorter implementation period would be preferable.
These implementation periods would permit manufacturers, repackers,
and relabelers to incorporate the appropriate NDC number at minimal
additional cost when redesigning their labels in the course of the
normal relabeling cycle. We should note, however, that manufacturers,
repackers, relabelers, and private label distributors who are subject
to the bar code requirements at current Sec. 201.25 might find it
easier to put human-readable NDC numbers on their labels when they
revise those labels to accommodate the bar code. We remind readers that
the bar code requirement became effective on April 26, 2004, and the
compliance dates varied depending on when we approved a drug relative
to the April 26, 2004, date. For example, for drugs approved on or
after April 26, 2004, we expected compliance within 60 days of the
drug's approval date. For drugs approved before April 26, 2004, we
expect compliance within 2 years. So, for example, a manufacturer whose
prescription drug is subject to the bar code requirement might find it
easier to redesign its label once to add a human-readable NDC number
and a bar code, rather than redesign its label twice.
We invite comments on the implementation scheme described here.
D. Listing
1. Who Would Be Required To List Drugs?
Proposed Sec. 207.41(a) would require manufacturers, repackers,
relabelers, and drug product salvagers who are subject to the
registration requirements under proposed Sec. 207.17 (and not exempt
under proposed Sec. 207.13) to list drugs being manufactured,
repacked, relabeled, or salvaged by them for commercial distribution.
Proposed Sec. 207.41(a) is consistent with current Sec. 207.20(a),
which states that owners or operators of all drug establishments, not
exempt under section 510(g) of the act or current Sec. 207.10, that
engage in the manufacture, preparation, propagation, compounding, or
processing of a drug submit a list of every drug in commercial
distribution. Section 510(j)(1) of the act requires, among other
things, that every person who registers with the Secretary must list
drugs that are being manufactured, prepared, propagated, compounded, or
processed for commercial distribution.
Under current Sec. 207.20(a), such drugs must be listed whether or
not they enter interstate commerce. This is consistent with Congress's
intention for section 510 of the act to apply to drugs both in
interstate and intrastate commerce as 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.''
Proposed Sec. 207.41(a) also provides that when operations are
conducted at more than one establishment and there exists joint
ownership and control among all the establishments, listing information
may be submitted by the parent, subsidiary, and/or affiliate company
for drugs at all establishments. This provision would also apply when
operations are 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).
Under proposed Sec. 207.41(a), drug product salvagers would be
required to list. As discussed in sections IV.A.5 and IV.B.1 of this
document, and consistent with current Sec. 207.20(a), drug product
salvagers would continue to be required to register because their
activities include applying manufacturing controls to drug products and
segregating drug products. This activity would be covered under the
scope of manufacturing, preparing, propagating, compounding, or
processing, and would trigger the requirement to register under the
act. Because drug product salvagers are conducting one of these
activities with respect to a given drug for the purpose of commercial
distribution, this activity would also trigger the requirement to list
under the act (section 510(j)(1) of the act). (Drug product salvagers
sometimes repack/relabel drug products and would also have to register
because of those activities.) Under current Sec. 207.20(a), drug
product salvagers are not required to list. Because drug product
salvagers place the salvaged drug in commercial distribution, we are
proposing to require that drug product salvagers submit listing
information to us. We specifically invite comments on the scope of
activities of drug product salvagers, that is, whether drug product
salvagers salvage drug products for commercial distribution and whether
these activities should trigger listing under the act.
Under proposed Sec. 207.41(b), manufacturers, repackers,
relabelers, and drug product salvagers who engage
[[Page 51307]]
in more than one activity for drugs would list each drug in accordance
with the requirements for the activity engaged in for that drug. An
example of a company that engages in more than one activity for drugs
would be a company that manufactures Drug X and relabels Drug Y. The
company would provide the listing information described in proposed
Sec. 207.49 for Drug X and the listing information described in
proposed Sec. 207.53 for Drug Y. We are proposing this requirement to
clarify which listing information would be provided by manufacturers,
repackers, relabelers, and drug product salvagers who engage in more
than one activity for drugs. As discussed below, manufacturers,
repackers and relabelers, and drug product salvagers would provide
similar listing information to us (although some information would be
provided by reference).
Under proposed Sec. 207.41(c), manufacturers, repackers,
relabelers, and drug product salvagers would, in addition to listing
their own drugs, provide all listing information to us for drugs they
manufacture, repack, relabel, or salvage for private label
distributors. In general, private label distributors would not list
drugs with us. However, private label distributors would be required to
list a drug with us if they manufacture, repack, relabel, or salvage
the drug for commercial distribution. Proposed Sec. 207.41(c) would
revise current Sec. 207.20(b), which states that owners or operators
of establishments, not otherwise required to register, 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 submit listing information directly to us and obtain a
labeler code. Under current part 207, if a private label distributor
does not elect to submit drug listing information to us, the registered
establishment must submit the drug listing information. Currently,
private label distributors that elect to submit listing information
must include the registration number of the establishment that
manufactured or processed (as defined in current Sec. 207.3(a)(8))
each drug listed and must assume full responsibility for compliance
with all the requirements of part 207. Private label distributors must
currently certify to the registered establishment that the submission
has been made by providing a signed copy of Form FDA 2656 to the
registered establishment. Private label distributors must submit to us
the original Form FDA 2656 showing this certification. A list showing
the NDC number assigned to each drug must accompany the certification.
We are proposing to alter the arrangement permitted under current
Sec. 207.20(b). Although we recognize that this proposed shift in
responsibility may alter current business practices, we believe that
proposed Sec. 207.41(c) will help to ensure that listing information
is more accurate and complete. The current scheme has caused confusion
and resulted in inaccurate and incomplete listing information. Some
private label distributors that have elected to list their drugs have
not had access to all the information needed to list the drugs
accurately. Some private label distributors have claimed that
manufacturers, repackers, and relabelers have been reluctant to provide
certain information to them. In addition, in some instances, the
parties have been uncertain about who is responsible for listing.
As discussed in section IV.B.1 of this document and previously,
manufacturers, repackers, relabelers, and drug product salvagers would
be required to register and list the drugs they manufacture, repack,
relabel, or salvage. They would be required to do so even if they
conduct such activities on behalf of private label distributors. This
proposed requirement would be consistent with section 510(j)(1) of the
act which requires every person who registers to submit listing
information for drugs ``which are being manufactured, prepared,
propagated, compounded, or processed by him for commercial
distribution'' (emphasis added). In addition, private label
distributors would not be required (nor permitted) to register because
their activities are not covered under the scope of manufacturing,
preparing, propagating, compounding, or processing. Nor do private
label distributors conduct one of these activities with respect to a
given drug for the purpose of commercial distribution and, thus, would
not be required (nor permitted) to list. Private label distributors
only commercially distribute drugs under their own label or trade name.
Manufacturers, repackers, relabelers, and drug product salvagers often
manufacture, repack, relabel, or salvage drugs that are distributed by
a private label distributor, and they have all the information about
the drug that is necessary to list the drug distributed by the private
label distributor. Under the proposal, to list a drug that is
manufactured, repacked, relabeled, or salvaged for a private label
distributor, manufacturers, repackers, relabelers, and drug product
salvagers would have to obtain any existing NDC number from the private
label distributor or would have to obtain the NDC number from FDA for a
drug distributed by a private label distributor. Manufacturers,
repackers, relabelers, and drug product salvagers would have to place
the NDC number assigned to the private label distributor's drug on the
label. We specifically invite comments on this proposed change in the
listing responsibilities of manufacturers, repackers, relabelers, drug
product salvagers, and private label distributors and its potential
effect on business practices.
2. When Would Initial Listing Information Be Provided?
Under proposed Sec. 207.45, manufacturers, repackers, relabelers,
and drug product salvagers would list, at the time of initial
registration of an establishment, any drug being manufactured,
repacked, relabeled, or salvaged for commercial distribution at that
establishment. This provision is consistent with section 510(j)(1) of
the act, which requires, among other things, that every person who
registers with the Secretary under sections 510(b), (c), (d), or (i) of
the act must list drugs that are being manufactured, prepared,
propagated, compounded, or processed for commercial distribution.
Proposed Sec. 207.45 pertains to the submission of listing information
for drugs at the time of the initial registration of an establishment.
Reviewing and updating information for drugs already listed and
providing listing information for drugs not previously listed are
covered under proposed Sec. 207.57. Proposed Sec. 207.57 is discussed
in section IV.D.8 of this document.
3. What Listing Information Would Be Required?
To list a drug, manufacturers would be required to provide the
information in proposed Sec. 207.49, repackers and relabelers would be
required to provide the information in proposed Sec. 207.53, and drug
product salvagers who are not repackers or relabelers would be required
to provide the information in proposed Sec. 207.54. We are proposing
different listing requirements for manufacturers, repackers and
relabelers, and drug product salvagers because much of the information
about a drug is submitted to us by the manufacturer to obtain an NDC
number and to list the drug. When the repacker, relabeler, and drug
product salvager provide, during listing, the required NDC number for
the drug, we can incorporate by reference the information already
submitted about the drug by the manufacturer. The information required
to obtain an NDC
[[Page 51308]]
number is explained in section IV.C of this document, and the
requirements for providing the NDC number during listing are explained
in section IV.D.4.a of this document.
The following paragraphs summarize the information that would be
required for listing from manufacturers, repackers, relabelers, and
drug product salvagers. These summaries are followed by descriptions of
each of the listing requirements (see section IV.D.4 of this document).
a. Summary of proposed listing information for manufacturers.
Manufacturers would be required to submit to us the following listing
information (if applicable to the drug being listed) under proposed
Sec. 207.49:
NDC number;
Route of administration;
Approved U.S. application number or approved U.S. BLA
number, if any;
Registration number of each establishment where the
manufacturing is performed for the drug;
Schedule of the drug under section 202 of the Controlled
Substances Act (21 U.S.C. 812);
With respect to foreign establishments only, the name and
contact information of each importer of the drug and of each person who
imports or offers for import the drug;
Labeling;
Advertisements; and
Information about the private label distributor, if any.
b. Summary of proposed listing information for repackers and
relabelers. Repackers and relabelers would be required to submit to us
the following listing information (if applicable to the drug being
listed) under proposed Sec. 207.53:
NDC number;
Registration number of each establishment where the
repacking or relabeling is performed for the drug;
With respect to foreign establishments only, the name and
contact information of each importer of the drug and of each person who
imports or offers for import the drug;
Labeling;
Advertisements; and
Information about the private label distributor, if any.
c. Summary of proposed listing information for drug product
salvagers who are not repackers or relabelers. Drug product salvagers
who do not otherwise repack or relabel the drugs they salvage would be
required to submit to us the following listing information (if
applicable to the drug being listed) under proposed Sec. 207.54:
NDC number assigned to the drug immediately before the
drug is received by the drug product salvager;
Lot number and expiration date of the salvaged drug;
Registration number of each establishment where the drug
product salvager salvages the drug;
With respect to foreign establishments only, the name and
contact information of each importer and of each person who imports or
offers for import the drug; and
Information about the private label distributor, if any.
4. What Listing Information Would Be Required for Manufacturers?
Under proposed Sec. 207.49, manufacturers would be required to
provide to us the following listing information for each drug they
list, including a drug manufactured for a private label distributor.
a. NDC number. For a drug to be considered listed, manufacturers
and, as discussed below, repackers, relabelers, and drug product
salvagers, must submit the NDC number for the drug as part of the
drug's listing information.\7\ The NDC number, including the
information that would be submitted to us to obtain an NDC number, is
explained under proposed Sec. 207.33. Knowing the NDC number of the
drug would enable us to incorporate by reference information about the
drug submitted by the manufacturer, repacker, or relabeler to obtain an
NDC number under proposed Sec. 207.33(c) and (d), as well as
information submitted by the manufacturer, repacker, or relabeler to
list the drug. This would reduce the amount of information that must be
provided to us by manufacturers, repackers, relabelers, and drug
product salvagers for listing. Current Sec. 207.25(b)(8) requires the
submission of the NDC number for each drug listed, and this information
is currently submitted on Form FDA 2657.
---------------------------------------------------------------------------
\7\The drug product salvager (that does not repack or relabel)
would submit the NDC number assigned to the drug immediately before
the drug is received by the drug product salvager; the manufacturer,
repacker, and relabeler (and the drug product salvager that repacks
or relabels) would submit the NDC number assigned to their drug
under proposed Sec. 207.33(c) and (d).
---------------------------------------------------------------------------
b. Route of administration. The route of administration would
enable us to identify a specific formulation of a drug. For example,
drugs having the same active ingredient may have different routes of
administration. The route of administration is currently submitted on
Form FDA 2657.
c. Approved U.S. application number. The approved U.S. application
number or the approved U.S. BLA number,\8\ if any, would enable us to
link to the information about the drug that was already submitted to us
for marketing approval. Section 510(j)(1)(A) of the act requires the
submission of a reference to the authority for marketing a drug subject
to section 505 or 512 of the act. In addition, current Sec.
207.25(b)(2) requires the submission of the application number for each
drug listed that the registrant regards as subject to section 505 or
512 of the act. The drug's application number is currently submitted on
Form FDA 2657. As discussed in section IV.D.4.g of this document, if
the approved U.S. application number is provided to us when a human
prescription or OTC drug is listed, the manufacturer would not be
required to re-submit the labeling for the approved drug. The
application number would incorporate by reference the labeling for
approved drugs. This would eliminate unnecessary duplication of effort
and cost to industry. The application number may have already been
provided under Sec. 207.33(c)(2)(i) and (c)(2)(ii) instead of
providing the names of the active pharmaceutical ingredient and the
inactive ingredient. If so, it will already be in our database and
would not need to be resubmitted.
---------------------------------------------------------------------------
\8\Human drugs are approved by FDA under an NDA, ANDA, or a BLA.
Part 314 (21 CFR part 314) for human drugs and part 601 (21 CFR part
601) for biologics set forth the approval requirements.
---------------------------------------------------------------------------
d. Registration number of each establishment. The registration
number of each establishment where the manufacturing is performed for
the drug would enable us to identify the establishment where the drug
is manufactured. This would help our investigators better prepare for
inspections and collect postmarketing surveillance samples. Although
this information would already be submitted for registration under
proposed Sec. 207.25(e), submitting it at listing would enable us to
link this information to the drug being listed. Current Sec.
207.25(b)(7) requires, for each drug listed, the submission of the
registration number of each drug establishment at which the drug is
manufactured or processed (within the meaning of current Sec.
207.3(a)(8)). Current Sec. 207.25(b)(3) requires the submission of the
license number of the manufacturer of drugs subject to section 351 of
the PHS Act. The ``establishment registration number'' is defined in
proposed Sec. 207.1 to mean the number assigned by FDA to the
establishment during the establishment registration process. Currently,
we plan to assign the FEI number as the establishment registration
number. In the future, however, we may use a different
[[Page 51309]]
number as the establishment registration number. The establishment
registration number is currently submitted on Form FDA 2657.
e. Schedule of the drug. The schedule of the drug under section 202
of the Controlled Substances Act would enable us to provide yearly
estimates of medical, scientific, and reserve stock needs for Schedule
I and II substances (21 CFR part 1303, 21 U.S.C. 826). Under section
302(a) of the PHS Act (42 U.S.C. 242(a)), the Secretary is responsible
for providing to the Drug Enforcement Administration estimates of the
quantities of controlled substances for which production quotas must be
established that will be required to meet the legitimate medical,
scientific, and reserve stock needs of the United States for the
following calendar year. The schedule of the drug is currently
submitted on Form FDA 2657.
f. Information about each importer of the drug and each person who
imports or offers for import the drug to the United States. Foreign
establishments only must provide the name, address, telephone and fax
numbers, and e-mail address of each importer of such drug in the United
States that is known to the establishment, and of each person who
imports or offers for import such drug to the United States. As
discussed under section IV.B.3 of this document, the term ``known to''
would mean any importer that is known to the foreign establishment as
well as any importer that the foreign establishment has reason to know
of. We therefore expect that the person responsible for completing the
required registration forms on behalf of the foreign establishment
would undertake appropriate due diligence in completing those forms,
including to find out and report importers that others in his or her
establishment know of or have reason to know of. Foreign establishments
would provide this information for listing unless previously provided
under proposed Sec. 207.25(h) for registration. The Bioterrorism Act
requires foreign establishments to submit, among other things, the name
of each importer of each drug that is known to the establishment, and
the name of each person who imports or offers for import each drug to
the United States for purposes of importation. The Bioterrorism Act
requires submission of such information as part of registration
information and also specifically requires listing information to be
submitted for each drug being manufactured for commercial distribution
(see section IV.A.4.d of this document). We are proposing, under this
part, to make the submission of information concerning importers of
drugs and persons who import or offer for import drugs to the United
States both a registration and a listing requirement. However, if the
information has been previously provided by the foreign establishment
at registration, the foreign establishment would not be required to re-
enter that information into the database at listing. Our listing
database will be populated automatically with the required information.
This would reduce the amount of information that must be provided to us
by the foreign establishment at listing. The information about each
importer of the establishment's drug that is known to the establishment
and each person who imports or offers for import the drug to the United
States is not currently required to be submitted under current part 207
or on Form FDA 2656 or Form FDA 2657.
g. Labeling. Under proposed Sec. 207.49(g), the following labeling
would be provided to us for each drug listed:
Human prescription drugs. If the manufacturer has not
provided the drug's approved U.S. application number as part of the
listing information under proposed Sec. 207.49(c), the manufacturer
would submit a copy of all current labeling, including the content of
labeling, for each human prescription drug (proposed Sec.
207.49(g)(1)).
Under proposed Sec. 207.49(g)(1) and, as discussed below under
proposed Sec. Sec. 207.49(g)(2) and 207.49(g)(3), only one
representative container or carton label would be submitted where
differences exist only in the quantity of contents statement or the bar
code. This proposed provision is consistent with current Sec.
207.25(b)(2), although the proposal would add differences in the bar
code to the provision. This provision would reduce the number of labels
that must be submitted to us by the manufacturer.
If the manufacturer provides the drug's approved U.S. application
number as part of the drug's listing information, the labeling required
under proposed Sec. 207.49(g)(1) and, as discussed below under
proposed Sec. 207.49(g)(2), would be deemed to accompany the listing
information. Incorporating the labeling, including the content of
labeling, by reference to the application number would eliminate
unnecessary duplication of effort and cost to industry. This proposed
exception would not apply to animal drugs approved under section 512 of
the act because currently these application holders are not required to
provide the content of labeling electronically with the application for
those drugs.
The ``content of labeling'' would be provided to FDA under proposed
Sec. 207.49(g)(1) and, as discussed below, under proposed Sec.
207.49(g)(2) and (g)(3). The ``content of labeling'' is defined in
proposed Sec. 207.1 and discussed in sections IV.A.5 and IV.E.4 of
this document and would mean, for human prescription drugs that the
manufacturer regards as subject to section 505 of the act or section
351 of the PHS Act, the content of the prescription drug labeling,
including all text, tables, and figures. For human prescription drugs
that the manufacturer regards as not subject to section 505 of the act
or section 351 of the PHS Act, the ``content of labeling'' would mean
the labeling equivalent to the content of the prescription drug
labeling, including all text, tables, and figures. For human OTC drugs,
the ``content of labeling'' would mean the content of the drug facts
labeling required by Sec. 201.66, including all text, tables, and
figures. For animal drugs, the ``content of labeling'' would mean the
content of the labeling that accompanies the drug that is necessary to
enable the safe and proper administration of the drug, including all
text, tables, and figures.
The labeling submission requirements in proposed Sec. 207.49(g)
are almost identical in substance to the labeling submission
requirements of current Sec. 207.25(b)(2) through (b)(5), except that
manufacturers would also be required, as discussed previously, to
submit electronically the ``content of labeling.'' In addition, the
labeling submission requirements in proposed Sec. 207.49(g) conform to
the statutory requirements of section 510(j) of the act. The proposed
requirement to submit labeling, including the content of labeling, for
human prescription drugs and, as discussed below, for human OTC drugs
and animal drugs, whether or not the drugs are subject to the pre-
approval provisions of the act or the PHS Act, is consistent with the
statutory requirements of section 510(j)(1)(A), 510(j)(1)(B)(i), and
510(j)(1)(B)(ii) of the act. Section 510(j)(1)(A) of the act requires,
among other things, the submission of a copy of all labeling for drugs
subject to section 505 or 512 of the act. Section 510(j)(1)(B)(i)
requires, among other things, the submission of a copy of all labeling
for prescription drugs not subject to section 505 or 512 of the act,
and section 510(j)(1)(B)(ii) requires, among other things, the
submission of the label, package insert, and representative sampling of
any other labeling for OTC drugs not subject to section 505 or 512 of
the act. We also
[[Page 51310]]
have the authority to require that labeling be submitted in this format
under other sections of the act (e.g., sections 201, 301, 501, 502,
503, 505, 506, 506A, 506B, 506C, 513-516, 518-520, 701, 704, 721, 801
of the act) and the PHS Act.
Human OTC drugs that manufacturers regard as subject to
section 505 of the act or section 351 of the PHS Act. If the
manufacturer has not provided the drug's approved U.S. application
number as part of the listing information under proposed Sec.
207.49(c), the manufacturer would submit a copy of all current
labeling, including the content of labeling, for each human OTC drug
that the manufacturer regards as subject to section 505 of the act or
section 351 of the PHS Act (proposed Sec. 207.49(g)(2)(i)).
Drugs subject to section 505 of the act or section 351 of the PHS
Act must be approved by FDA under an NDA, ANDA, or a BLA. Part 314 for
human drugs and part 601 for biological products set forth the approval
requirements.
Human OTC drugs that manufacturers regard as not subject
to section 505 of the act or section 351 of the PHS Act. The
manufacturer would submit a copy of the current label, the content of
labeling, the package insert (if any), and a representative sampling of
any other labeling for each human OTC drug that the manufacturer
regards as not subject to section 505 of the act or section 351 of the
PHS Act (proposed Sec. 207.49(g)(2)(ii)).
The term ``label'' means the container label as defined at section
201(k) of the act. ``Content of labeling'' is defined at proposed Sec.
207.1 (as discussed in section IV.A.5 of this document) and for OTC
drugs refers to the content of the drug facts labeling as specified at
Sec. 201.66. Most OTC drugs do not have a package insert. However, for
those that do, it is currently required to be submitted for drug
listing under section 510(j)(1)(A) and (j)(1)(B)(ii) of the act and
current Sec. 207.25(b)(4) and (b)(5). We are proposing to retain that
requirement in proposed Sec. 207.49(g)(2)(i) and (g)(2)(ii). For OTC
drugs marketed pursuant to an approved application, any package insert
would be included within the requirement to submit ``all current
labeling.'' The term ``representative sampling of any other labeling,''
as used in proposed Sec. 207.49(g)(2)(ii) and, as discussed below, in
proposed Sec. 207.49(g)(3)(ii), is defined in proposed Sec. 207.1 and
discussed in section IV.A.5 of this document. Examples of OTC drugs
that a manufacturer may regard as not subject to section 505 of the act
or section 351 of the PHS Act would include human OTC drugs marketed
under an OTC monograph and deemed generally recognized as safe and
effective (see part 330 (21 CFR part 330)).
Animal drugs that manufacturers regard as subject to
section 512 of the act. The manufacturer would submit a copy of all
current labeling, including the content of labeling, for each animal
drug that the manufacturer regards as subject to section 512 of the act
(proposed Sec. 207.49(g)(3)(i)).
Animal drugs that manufacturers regard as not subject to
section 512 of the act. For all other animal drugs, the manufacturer
would submit a copy of the current label, the package insert, the
content of labeling, and a representative sampling of any other
labeling, for each animal drug that the manufacturer regards as not
subject to section 512 of the act (proposed Sec. 207.49(g)(3)(ii)).
h. Advertisements. Under proposed Sec. 207.49(h), and in
accordance with section 505(j)(1)(B)(i) of the act, the following
advertisements would be provided by the manufacturer for each drug
listed:
A representative sampling of advertisements for human
prescription drugs that the manufacturer regards as not subject to
section 505 of the act or section 351 of the PHS Act. Proposed Sec.
207.49(h)(1) is consistent with section 510(j)(1)(B)(i) of the act and
current Sec. 207.25(b)(4). The term ``representative sampling of
advertisements'' is defined in proposed Sec. 207.1 and discussed in
section IV.A.5 of this document.
If we request it, for good cause, a copy of all
advertisements for human prescription drugs that the manufacturer
regards as not subject to section 505 of the act or section 351 of the
PHS Act, including those advertisements described in Sec. 202.1(l)(1),
would be required to be submitted to FDA within 30 calendar days after
our request. Proposed Sec. 207.49(h)(2) is consistent with section
510(j)(1)(B)(i) of the act and current Sec. 207.31(a)(1). Section
510(j)(1)(B)(i) of the act requires, among other things, the submission
of a representative sampling of advertisements and, upon request for
good cause, a copy of all advertisements for prescription drugs not
subject to section 505 of the act. Current Sec. 207.31(a)(1) requires,
upon request, the submission of a copy of all advertisements for
prescription drugs that the manufacturer regards as not subject to
section 505 of the act.
i. Private label distributor. If the drug is manufactured for a
private label distributor, the manufacturer would submit the name,
address, labeler code, telephone and fax numbers, and e-mail address of
the private label distributor. The manufacturer may obtain this
information from the private label distributor or other sources. This
information would indicate whose drug (the manufacturer's or the
private label distributor's) is being listed and would identify and
enable us, if needed, to contact the private label distributor. The
information for a private label distributor is currently submitted on
Form FDA 2658.
5. What Listing Information Would Be Required for Repackers and
Relabelers?
Under proposed Sec. 207.53, repackers and relabelers would be
required to provide to us all of the following listing information for
each drug they list, including a drug repacked or relabeled for a
private label distributor.
a. NDC number. For a drug to be considered listed, repackers and
relabelers would submit the NDC number for the drug being repacked or
relabeled as part of the drug's listing information. This requirement
is explained in section IV.D.4.a of this document.
b. Registration number of each establishment. The registration
number of each establishment where the repacking or relabeling is
performed for the drug would enable us to identify the establishment
where the drug is repacked or relabeled. This requirement is explained
in section IV.D.4.d of this document.
c. Information about each importer of the drug and each person who
imports, or offers for import, the drug to the United States. This
requirement is explained in section IV.D.4.f of this document.
d. Labeling. Under proposed Sec. 207.53(d), the following labeling
must be provided for each drug listed:
Human prescription drugs. If the repacker or relabeler
makes any change in the labeling of the drug repacked or relabeled, the
repacker or relabeler would submit a copy of all changed labeling for
each human prescription drug that is repacked or relabeled (proposed
Sec. 207.53(d)(1)). We would already have, as required under proposed
Sec. 207.49(g), the labeling for the drug provided by the manufacturer
during listing, and the repacker or relabeler would not need to
resubmit it to us unless they make changes to the labeling. Proposed
Sec. 207.53(d)(1) is consistent with section 510(j)(1)(A) and
(j)(1)(B)(i) of the act and current Sec. 207.25(b)(2) and (b)(4),
except that repackers and relabelers would not need to resubmit
labeling when no changes have been made.
[[Page 51311]]
Human OTC drugs that manufacturers regard as subject to
section 505 of the act or section 351 of the PHS Act. If the repacker
or relabeler makes any changes, in accordance with the act and FDA
regulations, in the labeling of the drug repacked or relabeled, the
repacker or relabeler would submit a copy of all changed labeling for
each human OTC drug that the manufacturer of the drug regards as
subject to section 505 of the act or section 351 of the PHS Act
(proposed Sec. 207.53(d)(2)(i)). As stated previously, we would not
need a copy of the unchanged labeling because we would already have the
labeling for the drug provided by the manufacturer during listing.
Proposed Sec. 207.53(d)(2)(i) is consistent with section
510(j)(1)(B)(i) of the act and current Sec. 207.25(b)(2), except that
some of the information required under current Sec. 207.25(b)(2) would
not need to be provided by the repacker or relabeler under proposed
Sec. 207.53(d)(2)(i) if the repacker or relabeler provides the
manufacturer's NDC number. The NDC number would provide a link to that
information.
Human OTC drugs that manufacturers regard as not subject
to section 505 of the act or section 351 of the PHS Act. The repacker
or relabeler would submit a copy of the current label, a copy of any
changes made to the package insert, if there is one, and a
representative sampling of any other labeling for each human OTC drug
that the manufacturer of the drug regards as not subject to section 505
of the act or section 351 of the PHS Act (proposed Sec.
207.53(d)(2)(ii)). The term ``representative sampling of any other
labeling,'' as used in proposed Sec. 207.53(d)(2)(ii) and, as
discussed below, in Sec. 207.53(d)(3), is defined in proposed Sec.
207.1 and discussed in section IV.A.5 of this document. Examples of OTC
drugs that a manufacturer may regard as not subject to section 505 of
the act or section 351 of the PHS Act would include human OTC drugs
marketed under an OTC monograph and deemed generally recognized as safe
and effective (see part 330). Proposed Sec. 207.53(d)(2)(ii) is
consistent with section 510(j)(1)(B)(ii) of the act and current Sec.
207.25(b)(5), except redundant information would not be submitted.
Animal drugs. The repacker or relabeler would submit a
copy of the current label, a copy of any changes made to each animal
drug labeling, and a representative sampling of any other labeling for
each animal drug (proposed Sec. Sec. 207.53(d)(3)). Proposed Sec.
207.53(d)(3) is consistent with section 510(j)(1)(B)(ii) of the act and
current Sec. 207.25(b)(2) and (b)(5), except redundant information
would not be submitted.
e. Advertisements. Under proposed Sec. 207.53(e), and in
accordance with section 505(j)(1)(B)(i) of the act, the following
advertisements would be provided by the repacker or relabeler for each
drug listed:
A representative sampling of advertisements for human
prescription drugs that the repacker or relabeler regards as not
subject to section 505 of the act or section 351 of the PHS Act.
Proposed Sec. 207.53(e)(1) is consistent with section 510(j)(1)(B)(i)
of the act and current Sec. 207.25(b)(4).
If we request it, for good cause, a copy of all
advertisements for human prescription drugs that the repacker or
relabeler regards as not subject to section 505 of the act or section
351 of the PHS Act, including those advertisements described in Sec.
202.1(l)(1), would be required within 30 calendar days after our
request. Proposed Sec. 207.53(e)(2) is consistent with section
510(j)(1)(B)(i) of the act and current Sec. 207.31(a)(1).
f. Private label distributor. If the drug is repacked or relabeled
for a private label distributor, the repacker or relabeler would submit
the name, address, labeler code, telephone and fax numbers, and e-mail
address of the private label distributor. The repacker or relabeler may
obtain this information from the private label distributor or other
sources. This information would indicate whose drug (the repacker's,
relabeler's, or private label distributor's) is being listed and would
identify and enable us, if needed, to contact the private label
distributor. The information for a private label distributor is
currently submitted on Form FDA 2658.
6. What Listing Information Would Be Required for Drug Product
Salvagers Who Are Not Repackers or Relabelers?
Drug product salvagers who do not otherwise repack or relabel the
drugs they salvage would be required to provide all of the following
listing information to us for each drug they list, including a drug
salvaged for a private label distributor. Drug product salvagers who
also repack and relabel the drugs they salvage must list those drugs as
a repacker or relabeler in accordance with Sec. 207.53.
a. NDC number. For a drug to be considered listed, the drug product
salvager would be required to provide the NDC number assigned to the
drug immediately before the drug is received by the drug product
salvager. Under the proposal, we would assign an NDC number to a
manufacturer's, repacker's, or relabeler's drug (or to a drug
manufactured, repacked, or relabeled for a private label distributor)
after the information required under proposed Sec. 207.33(c) or (d) is
provided (see discussion in section IV.D.4.a of this document). The
drug product salvager who is not also a repacker or a relabeler for the
drug would provide to us the NDC number that is already on the salvaged
drug's label (that is, the NDC number of the manufacturer, repacker,
relabeler, or private label distributor). Knowing the NDC number of the
drug would enable us to incorporate by reference information about the
drug submitted by the manufacturer, repacker, or relabeler to obtain an
NDC number under proposed Sec. 207.33(c) and (d), as well as
information submitted by the manufacturer, repacker, or relabeler to
list the drug.
b. Lot number and expiration date. We need to know the lot number
and expiration date to properly identify the drug because the drug
product salvager who is not a repacker or relabeler for the drug would
not be assigned an NDC number for the drug. The salvaged drug's lot
number would enable us to specifically identify the salvaged drug and
determine which batch of a manufacturer's drug has been processed by
the drug product salvager. Lot number (or control number or batch
number) is defined at current Sec. 210.3(b)(11) as any distinctive
combination of letters, numbers, or symbols, or any combination of
them, from which the complete history of the manufacture, processing,
packing, holding, and distribution of a batch or lot of drug product or
other material can be determined. Knowing the drug's expiration date
would indicate approximately how long the salvaged drug may be
available for use by consumers. The expiration date would also allow us
to identify the approximate date that the salvaged drug would no longer
be marketed.
c. Registration number of each establishment. The registration
number of each establishment where the drug product salvager salvages
the drug would enable us to connect the salvaging activity to a
particular drug and identify the specific location where the drug
product salvaging is performed for the drug. This information would
also be used in conducting our establishment inspections and for
collecting postmarketing surveillance samples. Current Sec.
207.25(b)(7) requires, for each drug listed, the submission of the
registration number of each drug establishment at which the drug is
manufactured or processed (within the meaning of current Sec.
207.3(a)(8)), and
[[Page 51312]]
current Sec. 207.25(b)(3) requires the submission of the license
number of the manufacturer of drugs subject to section 351 of the PHS
Act. The establishment registration number is currently submitted on
Form FDA 2657.
d. Information about each importer of the drug and each person who
imports, or offers for import, the drug to the United States. This
requirement is explained under section IV.D.4.f of this document.
e. Private label distributor. If the drug is salvaged for a private
label distributor, the drug product salvager would be required to
submit the name, address, labeler code, telephone and fax numbers, and
e-mail address of the private label distributor. The drug product
salvager may obtain this information from the private label distributor
or other sources. This information would identify the private label
distributor and enable us, if needed, to contact the private label
distributor. The information for a private label distributor is
currently submitted on Form FDA 2658.
7. What Additional Drug Listing Information May Be Required?
Under proposed Sec. 207.55, if we request it, the manufacturer,
repacker, relabeler, or drug product salvager would be required to
briefly state the basis for its belief that a particular drug product
is not subject to section 505 or 512 of the act or section 351 of the
PHS Act. This proposed provision, which is consistent with section
510(j)(1)(D) of the act and current Sec. 207.31(a)(3), is needed
because some manufacturers, repackers, and relabelers have mistakenly
considered a drug not to be subject to section 505 or 512 of the act or
section 351 of the PHS Act. Although in some cases manufacturers,
repackers, and relabelers have correctly concluded that a drug is not
subject to section 505 or 512 of the act or section 351 of the PHS Act,
in other cases we may consider the drug to be subject to section 505 or
512 despite that conclusion.
The brief statement that would be requested under proposed Sec.
207.55 may include, for example, the Federal Register citation for the
applicable OTC monograph. We anticipate that our electronic drug
registration and listing system will provide some options for brief
statements, including Federal Register citations as described in the
example above, from which manufacturers, repackers, relabelers, and
drug product salvagers may select as the basis for their belief that a
particular drug product is not subject to section 505 or 512 of the act
or section 351 of the PHS Act.
We are also considering whether to require establishments to
provide the number of batches and batch size for each drug subject to
the listing requirements that they manufactured, repacked, or relabeled
since the establishment last provided listing information. Typically,
this information would be provided every 6 months, based on the
obligation to review and update listing information in June and
December of each year. We would consider ``batch size'' to mean, as a
general matter, the batch size included in the master production and
control records for each drug, as required by the regulations governing
current good manufacturing practice for finished pharmaceuticals in
part 211, including Sec. 211.186(a) (master production and control
records). Typically, ``batch size'' would be the number of unit dosage
forms (such as for tablets) or, if the unit dosage form is not defined
before primary packaging (such as for liquids), the total batch weight
or volume before primary packaging.
We are considering this requirement because it would provide us
with important data regarding a product's volume in the U.S.
marketplace to assess the potential impact the product has on the
public health, which, in turn, will enable us to use our limited
resources more efficiently, particularly with regard to inspectional
oversight. For example, we currently use data collected as a surrogate
for production volume, among many other factors, in our risk-based
model to prioritize routine inspections. This model is a systematic,
objective, data-driven method to prioritize inspections. (See ``Risk-
Based Method for Prioritizing CGMP Inspections of Pharmaceutical
Manufacturing Sites--A Pilot Risk Ranking Model'' at http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/cder/gmp/gmp2004/risk_based_method.htm.
) However, better
estimates of manufacturing volume would improve our ability to
implement a more risk-based approach to manufacturing quality oversight
activities. By requiring establishments to provide the number of
batches and batch size for each drug subject to the listing
requirements, we would have objective data regarding production volume
and be better able to find and address CGMP violations that may have
the most impact on public health. Actual production data would also
give us the ability to more efficiently allocate our resources in other
areas.
We specifically invite comments on whether we should require
manufacturers, repackers, relabelers, and drug product salvagers to
provide the number of batches and batch size for each drug subject to
the listing requirements.
8. What Are the Proposed Requirements for Reviewing and Updating
Listing Information?
Currently, manufacturers, repackers, and relabelers must enter new
or revised listing information on Form FDA 2657 (Form FDA 2658 is used
when manufacturers, repackers, and relabelers enter new or revised
information for a private label distributor's drug) and return the form
to FDA. Under the proposal, manufacturers, repackers, relabelers, and
drug product salvagers would access our electronic drug registration
and listing system and review their current listing information online,
making any changes where needed. Updating listing information would be
less time consuming under the proposal because the manufacturer,
repacker, relabeler, and drug product salvager would be able to easily
access their information at any time, and only changes to the
information already in the system would need to be entered in the
fields provided.
Under proposed Sec. 207.57, manufacturers who are required to list
under proposed Sec. 207.41 would review and update all listing
information provided under proposed Sec. Sec. 207.49, 207.55, and
207.57; repackers and relabelers (including drug product salvagers who
repack and/or relabel) who are required to list under proposed Sec.
207.41 would review and update all listing information provided under
proposed Sec. Sec. 207.53, 207.55, and 207.57; and drug product
salvagers (who are not repackers and/or relabelers) who are required to
list under proposed Sec. 207.41 would review and update all listing
information provided under proposed Sec. Sec. 207.54, 207.55, and
207.57. Proposed Sec. 207.57 uses the term ``review and update'' to
stress the importance of first reviewing all listing information to
determine if any changes have occurred and then updating the
information.
Under proposed Sec. 207.57(a), during the annual review and update
of registration information, manufacturers, repackers, relabelers, and
drug product salvagers would provide listing information for any drug
that has not been previously listed. Proposed Sec. 207.57(a) is
consistent with section 510(j)(1) of the act, which requires, among
other things, that a list of all drugs must be provided at the time of
annual registration.
Under proposed Sec. 207.57(b), manufacturers, repackers,
relabelers, and drug product salvagers would
[[Page 51313]]
review and update their listing information each June and December of
every year. Proposed Sec. 207.57(b) is consistent with the timeframes
set forth in section 510(j)(2) of the act, which requires, among other
things, that each person who registers must report certain listing
information ``once during the month of June of each year and once
during the month of December of each year.'' Under current Sec.
207.21(b), an update of listing information must occur each June and
December.
Under proposed Sec. 207.57(b)(1) through (b)(5), manufacturers,
repackers, relabelers, and drug product salvagers would, during the
review and update, submit the following information:
Listing information would be provided for any drug
manufactured, repacked, relabeled, or salvaged for commercial
distribution that has not been previously listed (proposed Sec.
207.57(b)(1)). The information would be provided in accordance with
proposed Sec. Sec. 207.49, 207.53, 207.54, and 207.55. This
information is currently required under section 510(j)(2)(A) of the act
and current Sec. 207.30(a)(1).
The date that the manufacture, repacking, relabeling, or
salvaging for commercial distribution of a listed drug has been
discontinued would be provided (proposed Sec. 207.57(b)(2)). The date
of discontinuation is currently required under section 510(j)(2)(B) of
the act and current Sec. 207.30(a)(2). Section 510(j)(2)(B) of the act
requires submission of a ``notice of discontinuance.'' We are proposing
to also require that the expiration date of the last lot manufactured,
repacked, relabeled, or salvaged be part of proposed Sec.
207.57(b)(2). This information would enable us to know when a drug is
no longer marketed and approximately how long the discontinued drug may
be available for use by consumers.
We recognize that because of their business practices, drug product
salvagers may discontinue commercial distribution of a listed drug
almost immediately after they salvage the drug. Drug product salvagers
may salvage a drug, put the drug into commercial distribution by
selling it to a retailer or other party, and then discontinue salvaging
the drug. In that case, we intend to minimize the reporting burden on
drug product salvagers by allowing the drug product salvager to provide
notice of discontinuation of the drug at the same time the drug product
salvager lists the drug. We would not expect under proposed Sec.
207.57(b)(2) that the drug product salvager inform us again, during the
review and update of listing information in either June or December of
the year, that the salvaged drug is discontinued. Under this proposal,
we expect that our electronic drug registration and listing system
would provide the opportunity for drug product salvagers to first list
a drug, as required by proposed Sec. 207.54, and then indicate that
they are discontinuing the drug, as required by proposed Sec.
207.57(b)(2). Because the drug product salvager would have provided the
lot number and expiration date for the drug under proposed Sec.
207.54(b)(2), we would not require that same information be submitted
again under proposed Sec. 207.57(b)(2).
The date that the manufacture, repacking, or relabeling
for commercial distribution of a previously discontinued drug has
resumed and any other listing information not previously required or
submitted for the drug would be provided (proposed Sec. 207.57(b)(3)).
This proposed provision is consistent with section 510(j)(2)(C) of the
act, which requires, among other things, that if a registrant has
resumed the manufacture, preparation, propagation, compounding, or
processing of a discontinued drug for commercial distribution, the
registrant must provide notice and the date of such resumption, the
established name and proprietary name of the drug, and other listing
information required under section 510(j)(1) of the act not previously
provided. The established name and proprietary name would have
previously been submitted at the time of listing. Because we would be
able to reference that information in our listing database,
manufacturers, repackers, and relabelers would not need to resubmit the
established name and proprietary name. Current Sec. 207.30(a)(3)
requires, in addition to the date of resumption of commercial
distribution, that the NDC number, the established name and proprietary
name, and any other listing information not previously submitted must
be provided. Under the proposal, this information would not need to be
provided at this time because we would have access to it from the
listing database.
We anticipate that drug product salvagers would not report
information under proposed Sec. 207.57(b)(3) because we are unaware of
instances when drug product salvagers resume salvaging a drug that they
have already salvaged and returned to the marketplace. Drug product
salvagers salvage a drug and then put the drug into commercial
distribution by selling it to a retailer or other party. This activity
ends the drug product salvager's association with that drug. In
contrast, manufacturers, repackers, and relabelers may resume the
manufacture, repacking, or relabeling of a drug (usually a different
lot of the drug) that they had previously listed but are currently not
manufacturing, repacking, or relabeling. Thus, we anticipate that
proposed Sec. 207.57(b)(3) would not be applicable to drug product
salvagers. We invite comment on whether drug product salvagers resume
salvaging a drug that they have already salvaged and returned to the
marketplace.
The June and December review and update of listing
information would include the submission of all material changes in any
information previously submitted under Sec. 207.49, Sec. 207.53,
Sec. 207.54, Sec. 207.55, or Sec. 207.57 (proposed Sec.
207.57(b)(4)). Current Sec. 207.30(a)(4) requires that any material
change in any information previously submitted must be reported every
June and December or, at the discretion of the registrant, when the
change occurs. Material changes are listed in the definition of ``any
material change'' in current Sec. 207.3(a)(3). As discussed in section
IV.A.5 of this document, we are proposing to broaden this definition to
mean any change in any listing information provided under proposed
Sec. Sec. 207.49, 207.53, 207.54, 207.55, and 207.57 (except for
labeling changes in arrangement or printing or of an editorial nature,
or the inclusion of a bar code or NDC number on the label). Under the
proposed definition of ``material change,'' the number of changes in
listing information that are considered ``material'' would include more
than the five types of changes considered ``material'' in the current
definition. We are proposing a broader definition of material change
because, for the reasons explained in section IV.D of this document,
the accuracy of all listing information is essential for us to maintain
a reliable and current drug listing database. Proposed Sec.
207.57(b)(4) is consistent with section 510(j)(2)(D) of the act, which
requires that each person who registers shall report once during the
month of June of each year and once during the month of December of
each year any material change in any information previously submitted
pursuant to section 510(j)(1) or section 510(j)(2) of the act. Section
510 of the act does not define ``material change.''
If no changes have occurred since the last review and
update of listing information, manufacturers, repackers, relabelers,
and drug product salvagers would certify that no changes have occurred
(proposed Sec. 207.57(b)(5)). Proposed Sec. 207.57(b)(5) also
provides that if a drug is discontinued and we have received the
information required under proposed Sec. 207.57(b)(2)
[[Page 51314]]
concerning the discontinuation of a listed drug, no further
certifications would be necessary for the discontinued drug. We are
proposing to revoke current Sec. 207.30(b), which states that no
report is required when no changes have occurred since the previously
submitted list.
FDA is proposing this certification to ensure that manufacturers,
repackers, relabelers, and drug product salvagers have reviewed their
listing information and have determined that there have been no
changes. There have been many instances where manufacturers, repackers,
and relabelers have not updated their listing information on a regular
basis. It has been difficult for us to determine whether failure to
update listing information is the result of no changes in information
or noncompliance. The proposed requirement is intended to reduce these
instances and improve the accuracy of our drug listing database.
Furthermore, under section 301(p) of the act, it is a prohibited act to
fail to submit drug listing information under section 510(j) of the
act. Failure to submit drug listing information would also render a
drug misbranded under section 502(o) of the act. In addition, the
proposed requirement to certify is supported by the statutory provision
in section 701(a) of the act (21 U.S.C. 371(a)) that the Secretary has
the authority to promulgate regulations for the efficient enforcement
of the act.
We specifically request comment on any burden that may result from
this proposed requirement that manufacturers, repackers, relabelers,
and drug product salvagers certify that no changes have occurred.
Current Sec. 207.30(a) provides that the updates to listing
information must be submitted during each June and December or, at the
discretion of the registrant, when the change occurs. Although proposed
Sec. 207.57(b) would require that listing information be reviewed and
updated only every June and December, we are requesting that
manufacturers, repackers, relabelers, and drug product salvagers
provide all updates to listing information within 30 calendar days of a
change. We are requesting that this information be provided on an
expedited basis because our listing database will be more accurate if
listing information is submitted sooner.
E. Electronic Format
1. How Would Registration and Listing Information Be Provided To FDA?
Under proposed Sec. 207.61(a)(1), the following information
required under proposed part 207 would be provided to us using our
electronic drug registration and listing system:
Establishment registration information required in
proposed Sec. Sec. 207.25 and 207.29 (proposed Sec. 207.61(a)(1)(i));
Information required for an NDC number in proposed Sec.
207.33 (proposed Sec. 207.61(a)(1)(ii)); and
Drug listing information required in proposed Sec. 207.49
(except for labeling and advertising information in proposed Sec.
207.49(g) and (h)), 207.53 (except proposed Sec. Sec. 207.53(d) and
(e)), 207.54, 207.55, and 207.57 (proposed Sec. 207.61(a)(1)(iii)). As
explained in section IV.E.7 of this document, the submission of
establishment registration and drug listing information and information
required for an NDC number would be made in accordance with 21 CFR part
11, except for the requirements under Sec. 11.10(b), (c), and (e), and
the corresponding requirements in Sec. 11.30.
Proposed Sec. 207.61(a)(2) would require that the content of
labeling defined in proposed Sec. 207.1 and required under proposed
Sec. 207.49(g)(1) through (g)(3) be provided to us in electronic
format. The NDC number would also be provided with\9\ the content of
labeling for each drug. As explained in section IV.E.7 of this
document, the submission of the content of labeling would be made in
accordance with 21 CFR part 11, except for the requirements under Sec.
11.10(a), (c) through (h), and (k), and the corresponding requirements
under Sec. 11.30. As explained in section IV.E.4 of this document and
stated in proposed Sec. 207.49(g), the labeling, including the content
of labeling, would not be required if the approved U.S. application
number is provided by the manufacturer when the drug is listed.
---------------------------------------------------------------------------
\9\ As explained in section IV.E.4 of this document, the NDC
number may accompany the content of labeling; it does not need to be
in the content of labeling.
---------------------------------------------------------------------------
In addition to the electronic submission of information under
proposed Sec. 207.61(a)(1)(i), (a)(1)(ii), (a)(1)(iii), and (a)(2)),
advertisements and labeling (other than the content of labeling)
required under Sec. Sec. 207.49(g) and (h) and 207.53(d) and (e) would
be provided to us in either paper or electronic format (proposed Sec.
207.61(a)(3)). The NDC number would also be provided with\10\ the
advertisements and labeling. As explained in section IV.E.7 of this
document, the electronic submission of advertisements and labeling,
other than the content of labeling, would be made in accordance with
part 11 (21 CFR part 11), except for the requirements under Sec.
11.10(a), (c) through (h), and (k), and the corresponding requirements
under Sec. 11.30.
---------------------------------------------------------------------------
\10\ See footnote 9.
---------------------------------------------------------------------------
Under proposed Sec. 207.61(a)(4), electronic format submissions
must be in a form that we can process, review, and archive. As
explained in section IV.E.6 of this document, we may periodically issue
guidance on how to provide registration and listing information in
electronic format (for example, method of transmission, media, file
formats, preparation and organization of files).
The electronic submission of the information covered under proposed
Sec. 207.61(a) would provide a number of advantages over the current
submission of FDA paper forms:
We would receive a greater quantity of accurate
information in less time than it takes to receive information from
paper submissions. The information received would also be more accurate
because our electronic drug registration and listing system would
eliminate errors associated with inputting paper-based data into an
electronic system.
The electronic transmission of the information would be
easier and more efficient for both industry and us than the current use
of paper forms. For example, you would receive on-screen feedback if
the information submitted was not complete, reducing errors and the
time and cost of communicating with us. Similarly, electronic
transmission of the information would reduce significantly the time and
cost associated with our processing paper forms and communicating with
industry concerning errors on those forms.
Information search and retrieval time would be reduced,
allowing quicker access to the information in the database.
The requirement to provide listing information to us electronically
is consistent with the requirement to list in section 510(j)(1) of the
act: ``Every person who registers with the Secretary * * * shall * * *
file with the Secretary a list of all drugs * * *. Such list shall be
prepared in such form and manner as the Secretary may prescribe * *
*.'' The requirement to provide registration information to us
electronically is consistent with section 510(p) of the act:
``Registrations * * * (including the submission of updated information)
shall be submitted to the Secretary by electronic means, upon a finding
by the Secretary that the electronic receipt of such registrations is
feasible * * *.'' Persons who register are also required to list drugs
which are being manufactured, prepared,
[[Page 51315]]
propagated, compounded, or processed for commercial distribution (21
U.S.C. 510(j)(1)).
2. What Was the Electronic Submission Pilot Project?
In the Federal Register of January 9, 2001 (66 FR 1684), we
requested volunteers to participate in a pilot project involving the
electronic submission of registration and listing information. In a
September 2001 meeting/teleconference with the pilot project
volunteers, we provided information on the major functions of the
electronic drug registration and listing system, including instructions
on the installation, setup, and testing of the systems. The pilot test
was held from October 19, 2001, through November 9, 2001, and
approximately 28 industry representatives voluntarily participated.
As mentioned previously, our electronic drug registration and
listing system is expected to be a Web-enabled, integrated system that
provides controlled database access for you to register establishments
and list drugs. A separate capability--an extranet--could be used that
authenticates external users and controls their access to the our
online registration and listing database. This system would allow you
to create user accounts and manage additional users.
Industry representatives accessed the pilot test through our
extranet to perform the following functions: (l) Initial company setup
and establishment registration; (2) registration of additional
establishments; (3) drug listing; (4) updates; and (5) system access,
logoff, and exit. The pilot test included installation, setup, and
operational testing of our electronic drug registration and listing
system.
The pilot test was intended to get direct input from the pilot
participants about the usability and functionality of the system. The
pilot test provided feedback to us on:
The pilot participants' experience in submitting and
preparing registration and listing data.
Web browsers used.
Acceptability of proposed normal operating hours.
Page layout and design.
Ease of navigation within pages and between functions.
Whether error messages provide sufficient information to
resolve the error.
The appropriateness of the style, content, and depth of
detail of the onpage help.
The comments we received on our electronic drug registration and
listing system were generally positive. Those who volunteered to
participate in the pilot test were able to successfully access the
system, set up a company account within the system, register
establishments, and list drugs. Pilot participants encountered a few
one-time difficulties that we will address, including minor password
problems and difficulties completing the initial company setup and
establishment registration process.
We are using information from the pilot program to develop our
electronic system.
3. How Would the Electronic Drug Registration and Listing System Work?
Electronic format submissions of registration and listing
information, as well as information required for an NDC number, would
consist of the electronic transmission via the Internet of the required
information from manufacturers, repackers, relabelers, and drug product
salvagers into our electronic drug registration and listing system.
Our electronic drug registration and listing system would be made
available using an Internet-based data collection system accessed
through our FDA Internet site.
To use the Web site, you would need access to the Internet
using a browser.
You could arrange for Internet access through one of many
available Internet Service Providers (ISPs).
You would need an e-mail address so we can send you
confirmation of submissions and other related information.
This e-mail service could be provided by the ISP or by
other sources.
Prior to accepting registration and listing information from this
online system, we would authenticate the source (that is, the
manufacturer, repacker, relabeler, or drug product salvager) providing
the data.
We could, for example, authenticate entry into the
electronic drug registration and listing system by establishing user
accounts based on current registration information.
We anticipate that we may contact manufacturers,
repackers, relabelers, and drug product salvagers to obtain contact
information to establish an administration account.
To register and list electronically, to provide updated
registration and listing information, and to provide information to
obtain an NDC number, you would go to our Web site and follow the
prompts.
You could sign onto the system by entering the account
number, user name, and password obtained by following the procedures in
the guidance we intend to issue on our electronic drug registration and
listing system, as discussed in section IV.E.6 of this document.
You would then be prompted to provide general information
about your company and then specific information about each
establishment and drug as required in proposed part 207.
When all of the required information is provided, your
official contact would receive confirmation electronically that the
information has been received by us.
If you provide information to obtain an NDC number, the
number could be issued electronically.
4. What Are the Proposed Requirements for the Submission of Content of
Labeling in Electronic Format?
Under proposed Sec. 207.61(a)(2), the content of labeling would be
provided to us in an electronic format. The electronic submission of
the content of labeling would permit us to electronically review,
compare, and extract data from the labeling.
The content of labeling would be submitted in electronic format for
the following drugs:
Human prescription drugs;
Human OTC drugs, including those that the manufacturer
regards as subject to section 505 of the act or section 351 of the
Public Health Service Act as well as those regarded as not subject to
sections 505 or 351; and
Animal drugs, including those that the manufacturer
regards as subject to section 512 of the act as well as those regarded
as not subject to section 512.
The ``content of labeling'' is defined in proposed Sec. 207.1 (and
discussed in section IV.A.5 of this document) to mean:
For human prescription drugs that the manufacturer regards
as subject to section 505 of the act or section 351 of the Public
Health Service Act: The content of the prescription drug labeling (as
specified in Sec. Sec. 201.56, 201.57, and 201.80 of this chapter),
including all text, tables, and figures.
For human prescription drugs that the manufacturer regards
as not subject to section 505 of the act or section 351 of the Public
Health Service Act: The labeling equivalent to the content of the
prescription drug labeling (as specified in Sec. Sec. 201.56, 201.57,
and 201.80 of this chapter), including all text, tables, and figures.
For human OTC drugs: The content of the drug facts
labeling required by Sec. 201.66 of this chapter, including all text,
tables, and figures.
[[Page 51316]]
For animal drugs (including, but not limited to, drugs
that the manufacturer regards as subject to section 512 of the act):
The content of the labeling that accompanies the drug that is necessary
to enable the safe and proper administration of the drug (e.g., the
labeling specified in Sec. Sec. 201.1 and 201.5 of this chapter),
including all text, tables, and figures.
The proposed requirement to provide the content of labeling
electronically is consistent with (among other things) that part of the
listing requirement in section 510(j)(1) of the act which states that
``Such list shall be prepared in such form and manner as the Secretary
may prescribe.'' The proposed requirement to submit the content of
labeling for human prescription drugs, human OTC drugs, and animal
drugs is consistent with the statutory requirements of section
510(j)(1)(A), (j)(1)(B)(i), and (j)(1)(B)(ii) of the act. Section
510(j)(1)(A) of the act requires, among other things, the submission of
a copy of all labeling for drugs subject to sections 505 or 512 of the
act. Section 510(j)(1)(B)(i) requires, among other things, the
submission of a copy of all labeling for prescription drugs not subject
to section 505 or 512 of the act. Section 510(j)(1)(B)(ii) requires,
among other things, the submission of the label, package insert, and
representative sampling of any other labeling for OTC drugs not subject
to section 505 or 512 of the act.
We are proposing that manufacturers provide the NDC number
electronically with the content of labeling during listing so that we
can more easily link the content of labeling to the listed drug and,
thus, expedite the listing process. The NDC number may accompany the
content of labeling by being referenced, for example, in the
transmittal message to us that contains the content of labeling. The
NDC number does not need to be on the content of labeling.
As discussed in greater detail in section IV.D.4 of this document,
we are proposing that you need not submit the content of labeling for
human prescription or OTC drugs approved under section 505 of the act
or section 351 of the PHS Act if you provide the application number
when listing the drug or requesting an NDC number for the drug.
Incorporating the content of labeling by reference to the application
number would eliminate unnecessary duplication of effort and cost to
industry.
The submission of the content of labeling in an electronic format
would assist us in several ways:
The use of computer technology to identify changes in
different versions of the labeling would greatly enhance our accuracy
and efficiency in updating our listing database.
Our ability to protect the public health would be enhanced
because electronic review and comparison of labeling files would
provide a higher degree of certainty that all portions of the labeling
are consistent and up to date.
Our ability to protect the public health would be enhanced
because we could provide and make easily accessible up-to-date product
labeling through the DailyMed initiative, as described in section
IV.C.2 of this document.
Our ability to protect the public health would be enhanced
by supporting the implementation of the electronic prescribing
provisions of the Medicare Modernization Act. The product labeling
information we would make available through DailyMed would be
associated with the unique NDC number for each drug, supporting
electronic prescribing.
In the future, the electronic submission of the content of
labeling would enable us to receive much of the drug listing
information through the labeling, thus improving efficiency in the drug
registration and listing system. Industry would be able to satisfy many
drug listing requirements through the submission of the content of
labeling.
The proposed requirement to provide the content of labeling would
not significantly burden industry because labeling is maintained in
electronic format by most manufacturers. In addition, our proposal
seeks to limit industry costs by avoiding unnecessary duplication of
effort--for example, as mentioned previously, if the content of
labeling has already been submitted in an approved application,
supplement, or annual report, the manufacturer would only have to
reference the application number to comply with this listing
requirement. In addition, only the manufacturer would be required to
submit the content of labeling.
We would require, under proposed 207.61(a)(4), that the information
in electronic format be submitted in a form we can process, review, and
archive. We are prepared at this time to receive the content of
labeling as a portable document format (PDF) file that is searchable.
Using commercially available software, an electronic source document
created by any number of programs (for example, word processors and
desktop publishing programs) can be converted to a PDF file, preserving
the fonts, formatting, and graphics of the source document, regardless
of the application and platform used to create it. The PDF file can be
copied onto a disk or CD-ROM and shared with other users who can use
PDF reading software to view, navigate through, and print the document,
as well as view, search, and print the file, and copy text, tables, and
figures from the file.
However, to be responsive to technological advances, we may
recommend in the future that new file formats such as extensible markup
language and software applications be used to submit labeling
electronically. The language in proposed Sec. 207.61(a)(4), that
electronic format submissions must be in a form that we can process,
review, and archive, will provide us with the flexibility to recommend
file formats or software other than PDF, if appropriate, such as SPL
(described earlier in sections III.B and IV.C.2 of this document). We
will provide advance notice, in accordance with FDA's good guidance
practice regulations under Sec. 10.115 (21 CFR 10.115), so that
affected parties will have adequate time to convert to any new format
or software. In addition, we expect that such format or software will
be widely available before we switch to a new technology. Changes in
format and/or software will be identified in public docket number 92S-
0251.\11\ During any such transition, we will accept submissions using
either file format or software.
---------------------------------------------------------------------------
\11\ This docket may be accessed on the Internet at http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/ohrms/dockets
.
---------------------------------------------------------------------------
5. Would the Proposal Require Electronic Submission of Advertisements
and Other Labeling?
Under proposed Sec. 207.61(a)(3), advertisements and labeling,
other than the content of labeling, required under proposed Sec. Sec.
207.49(g) and (h) and 207.53(d) and (e) would be provided to us in
paper or electronic format. Information on how and where to send
labeling and advertisements that are not provided electronically will
be described in the guidance document we intend to develop, as
discussed in section IV.E.6 of this document. Although we are proposing
to require that only registration and listing information, information
submitted to receive an NDC number, and the content of labeling need be
submitted in electronic format, we expect to identify in public docket
number 92S-0251 copies and samples of labeling and advertisements as
types of documents we accept in electronic format. Under the proposal,
you would have the option of submitting advertisements and labeling
either electronically or in paper.
[[Page 51317]]
The proposed requirement to submit advertisements is consistent
with section 510(j)(1)(B)(i) of the act, which requires, among other
things, the submission of a representative sampling of advertisements
and, upon request, a copy of all advertisements for prescription drugs
not subject to section 505 of the act. The proposed requirement to
submit labeling is, as explained previously, consistent with the
statutory requirements of section 510(j)(1)(A), (j)(1)(B)(i), and
(j)(1)(B)(ii) of the act.
6. What Guidance Documents Do We Intend To Issue on Providing
Registration and Listing Information Electronically?
We plan to publish draft guidance and technical specifications on
the electronic submission of registration and listing information
through our electronic drug registration and listing system (the draft
guidance). The draft guidance and technical specifications will explain
the electronic process for providing registration and listing
information and for providing the information that would be required to
obtain an NDC number, including step-by-step instructions on entering
information required under proposed part 207. We are also planning to
issue guidance on providing registration and listing information in
electronic format (concerning the method of transmission, media, file
formats, and preparation and organization of files), and this guidance
will be updated regularly to reflect the evolving nature of the
technology.
In addition to the draft guidance and the guidance on providing
registration and listing information in electronic format under
development, we have issued other guidances that explain the process
for submitting information to us in electronic format. These guidance
documents are available at FDA's Web site http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/cder/guidance/index.htm
under the heading ``Electronic Submissions.''
7. How Would Part 11 Apply to the Electronic Submission of Registration
and Listing Information?
Under proposed Sec. 207.61(a)(1), the submission of registration
and listing information (except for the content of labeling and
advertisements and labeling) and the information required to receive an
NDC number would be made in accordance with part 11, except for the
requirements under Sec. 11.10(b), (c), and (e) and the corresponding
requirements under Sec. 11.30. Under proposed Sec. 207.61(a)(2) and
(a)(3), the submission of the content of labeling, and advertisements
and other labeling in electronic format, would be made in accordance
with part 11, except for the requirements under Sec. 11.10(a), (c)
through (h), and (k), and the corresponding requirements under Sec.
11.30. In the Federal Register of March 20, 1997 (62 FR 13430), we
published regulations on electronic records and electronic signatures
(part 11). Part 11 regulations, among other things, set forth the
criteria under which records submitted to us may be submitted in
electronic format in lieu of paper records. Section 11.2(b) states
that, for records submitted to us, persons may use electronic records
in lieu of paper records, in whole or part, provided the requirements
of part 11 are met and the documents or parts of documents to be
submitted have been identified by us in public docket number 92S-0251
as being the type of submission we are prepared to accept in electronic
format.
Part 11 permits the widest possible use of electronic technology,
compatible with our responsibility to promote and protect the public
health (62 FR 13430). Part 11 helps to ensure the authenticity,
integrity, and, when appropriate, the confidentiality of electronic
records. Part 11 also helps to safeguard against the possible
repudiation of those records. The controls in subpart B of part 11 are
intended to further this purpose.
We recently announced in the Federal Register our current thinking
on part 11. In the Federal Register of September 5, 2003 (68 FR 52779),
we announced the availability of a guidance for industry entitled
``Part 11, Electronic Records; Electronic Signatures--Scope and
Application'' (the part 11 guidance). The part 11 guidance explains our
current thinking regarding the requirements and application of part 11
and states that we intend to exercise enforcement discretion in the
manner specified in the guidance with respect to the validation (Sec.
11.10 (a)), audit trail (Sec. Sec. 11.10(e) and (k)(2)), record
retention (Sec. 11.10(c)), and copies of records (Sec. 11.10(b))
requirements of part 11, and any corresponding requirements in Sec.
11.30. In addition, we announced that we intend to exercise enforcement
discretion and do not intend to take (or recommend) action to enforce
any part 11 requirements with regard to systems that were operational
before August 20, 1997, the effective date of part 11 (commonly known
as legacy systems) under the circumstances described in section III.C.3
of the part 11 guidance. Although we explain the relationship between
the part 11 guidance and this proposal, as discussed below, you should
refer to the guidance we intend to issue on electronic registration and
listing for information on complying with part 11 when providing
registration and listing information electronically. The part 11
requirements from which we propose exemptions in this proposal differ
from the part 11 requirements for which we intend to exercise
enforcement discretion, as described in the part 11 guidance. They
differ because the proposed exemptions in this rule are specific to the
electronic submission of registration and listing information,
including information that must be submitted to receive an NDC number
and the content of labeling, for drugs that would be covered under
proposed part 207, whereas the part 11 draft guidance applies to the
maintenance of all electronic records and to all electronic submissions
subject to part 11.
With respect to the electronic submission of registration and
listing information, including the information required to receive an
NDC number but not including the content of labeling and advertisements
and other labeling, as previously noted, we believe, as provided in
proposed Sec. 207.61(a)(1), that several of the requirements in
subpart B of part 11 are not necessary to further the goals of part 11.
Because we control the electronic drug registration and listing system,
certain controls for systems would not apply to the submission of
registration and listing information, such as:
The ability to generate accurate and complete copies of
records in both human readable and electronic form suitable for
inspection, review, and copying by the agency (Sec. 11.10(b));
The protection of records to enable their accurate and
ready retrieval throughout the records retention period (Sec.
11.10(c));
The use of secure, computer-generated, time-stamped audit
trails to independently record the date and time of operator entries
and actions that create, modify, or delete electronic records (Sec.
11.10(e)); and
The corresponding controls of Sec. 11.30.
You would be exempt from these subpart B controls because our
registration and listing database is designed to ensure the
authenticity, integrity, and confidentiality of this information in
several ways. For example, we would control the database, and you would
only be able to enter and/or revise information in your own account. In
addition, the database would contain records of registration and
listing information, and we could generate accurate and complete copies
of records.
[[Page 51318]]
With respect to the electronic submission of the content of
labeling and advertisements and other labeling, as previously noted, we
believe, as provided in proposed Sec. 207.61(a)(2) and (a)(3), that
several of the requirements in subpart B of part 11 are not necessary
to further the goals of part 11. For the reasons described below,
certain controls for systems would not apply to the submission of the
content of labeling and advertisements and other labeling, such as:
The validation of systems to ensure accuracy, reliability,
consistent intended performance, and the ability to discern invalid or
altered records (Sec. 11.10(a));
The protection of records to enable their accurate and
ready retrieval throughout the records retention period (Sec.
11.10(c));
Limiting system access to authorized individuals(Sec.
11.10(d));
The use of secure, computer-generated, time-stamped audit
trails to independently record the date and time of operator entries
and actions that create, modify, or delete electronic records (Sec.
11.10(e));
The use of operational system checks to enforce permitted
sequencing of steps and events, as appropriate (Sec. 11.10(f));
The use of authority checks to ensure that only authorized
individuals can use the system, electronically sign a record, access
the operation or computer system input or output device, alter a
record, or perform the operation at hand (Sec. 11.10(g));
The use of device checks to determine, as appropriate, the
validity of the source of data input or operational instruction (Sec.
11.10(h));
The use of appropriate controls over certain systems
documentation (Sec. 11.10(k));and
The corresponding controls of Sec. 11.30.
We are proposing to exempt the submission of electronic content of
labeling from certain part 11 requirements because we believe these
part 11 requirements are not critical to ensure the quality of the
content of labeling that would be submitted under this proposed rule
and we do not think it is necessary for industry to expend resources on
controls that are not necessary to further the goals of part 11. For
example, validation for the system used to generate the labeling record
is not necessary because the manufacturer's verification that the
information in the labeling record is accurate serves the same
objective. Our review of the content of labeling is based on the
version of the labeling record submitted to us. Earlier versions of the
record, as well as changes made to the earlier versions, are not
relevant to our analysis. In addition, our registration and listing
database is designed to ensure the authenticity, integrity, and
confidentiality of this information. As mentioned, we would control the
database, you would only be able to enter and/or revise information in
your own account, and the database would contain records of the
information from which we could generate accurate and complete copies.
Thus, controls related to the creation, modification, and maintenance
of the content of labeling are not needed.
For the content of labeling and advertisements and other labeling,
we recognize that there are some differences with respect to the
exemptions from part 11 requirements provided in this proposal (that
is, Sec. 11.10(a), (c) through (h), and (k), and the corresponding
requirements of Sec. 11.30), and the part 11 requirements set forth in
the part 11 guidance for which we intend to exercise enforcement
discretion (that is, Sec. 11.10(a) through (c), (e), and (k)(2), and
any other corresponding requirements in Sec. 11.30)). Although the
proposal does not provide an exemption from Sec. 11.10(b) for the
content of labeling and advertisements and other labeling, the part 11
guidance announces that we intend to exercise enforcement discretion
with respect to that section in the manner described in the guidance.
If this proposed rule is finalized, we intend to identify in docket
number 92S-0251 the registration and listing information and the
content of labeling specified previously as the types of records that
we are prepared to accept in electronic format.
8. What Language Would Be Used to Provide Registration and Listing
Information?
Under proposed Sec. 207.61(b), we would require that all
registration and listing information be submitted in the English
language. We are also proposing that labeling be submitted in the
English language except, as provided under current 21 CFR 201.15(c),
when drugs are distributed solely in the Commonwealth of Puerto Rico or
in a Territory where the predominant language is one other than
English. In those instances, the predominant language may be
substituted for English. We are proposing Sec. 207.61(b) because
providing information in languages other than English would lead to
problems using the registration and listing computerized database and
problems with our review of registration and listing information and
the content of labeling. Foreign establishments are currently required
to submit all registration and listing information in the English
language under current Sec. 207.40(b). Because all domestic
manufacturers, repackers, relabelers, and drug product salvagers
currently submit this information in English, and because foreign
establishments are already subject to this requirement, we do not
believe the proposed requirement would increase the burden on industry.
9. Could the Electronic Format Requirements Be Waived?
Under proposed Sec. 207.65, manufacturers, repackers, relabelers,
and drug product salvagers may request a waiver from the proposed
requirement in Sec. 207.61(a) that information be provided to us in
electronic format. This proposed waiver provision is consistent with
the Medical Device User Fee and Modernization Act of 2002 (Public Law
107-250) which amended section 510 of the act to add section 510(p) to
explicitly give 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 because the use of electronic
means is not reasonable for the person requesting the waiver. Under
proposed Sec. 207.65, we may grant a waiver request if the
manufacturer, repacker, relabeler, or drug product salvager does not
have an e-mail address and access to a computer and an ISP that can
access our Web-based registration and listing database and communicate
with us. The request must include a telephone number and/or mailing
address where we can contact the person making the request. We intend
to provide the mailing address for submitting a waiver request in the
draft guidance and technical specifications on the electronic
submission of registration and listing information.
We do not anticipate many waiver requests because the expenses
associated with owning a personal computer, obtaining an e-mail
address, and subscribing to Internet access are low. If owning a
computer is not possible, however, only access to a computer and an ISP
as well as having an e-mail address would be needed to input
information electronically in accordance with the registration and
listing requirements under this part, including the requirements for
obtaining an NDC number. There would be no need for you to maintain
data files on disks or other formats; all data would be
[[Page 51319]]
maintained in our database and accessed electronically via the
Internet. We would control the database and the information contained
in it, and you would only enter new information and/or revise your own
previously submitted information.
In those instances when we grant a request for a waiver, we would
provide information on how to submit registration and/or listing
information. One option may be to make available a paper form for
submitting the required registration and listing information (including
the information required to obtain an NDC number).
F. Miscellaneous
1. What Are the Proposed Requirements for an Official Contact and a
United States agent?
Under proposed Sec. 207.69(a), manufacturers, repackers,
relabelers, and drug product salvagers that are subject to the
registration requirements in proposed part 207 would designate an
official contact for each establishment. The official contact would be
responsible for:
Ensuring the accuracy of registration and listing
information; and
Reviewing, disseminating, routing, and responding to
communications from us.
We are proposing to require an official contact to facilitate
communications between you and us and to help ensure compliance with
the registration and listing requirements. On numerous occasions, we
have found it difficult to contact certain manufacturers, repackers,
relabelers, and drug product salvagers to discuss registration and
listing issues.
In addition to the proposed requirement to designate an official
contact, each foreign manufacturer, foreign repacker, foreign
relabeler, and foreign drug product salvager would be required, under
proposed Sec. 207.69(b), to designate a single United States agent.
The United States agent would be responsible for:
Helping us communicate with the foreign manufacturer,
foreign repacker, foreign relabeler, and foreign drug product salvager;
Responding to questions concerning those drugs that are
imported or offered for import to the United States; and
Helping us schedule inspections.
We would not object if the same individual serves as both the
United States agent and the official contact for a foreign
manufacturer, foreign repacker, foreign relabeler, or foreign drug
product salvager, or if the same individual serves as the United States
agent for more than one foreign manufacturer, foreign repacker, foreign
relabeler, or foreign drug product salvager.
We are proposing that each foreign manufacturer, foreign repacker,
foreign relabeler, and foreign drug product salvager designate a single
United States agent. (We note, however, the United States agent may be
a company comprised of more than one person). As we explained in the
final rule entitled ``Foreign Establishment Registration and Listing''
(66 FR 59138 at 59140), we interpret section 510(i) of the act as
allowing only one United States agent for each foreign establishment
because section 510(i) of the act refers to the United States agent in
singular, rather than plural, terms. We also explained in that final
rule (66 FR 59138 at 59141) that we interpret section 510(i) of the act
as requiring that the United States agent must be in the United States.
These proposed provisions are also consistent with the use of ``U.S.
agent'' in the interim final rule entitled ``Registration of Food
Facilities Under the Public Health Security and Bioterrorism
Preparedness Act of 2002'' (68 FR 58894 at 58915, October 10, 2003).
Currently, the provisions concerning a United States agent, as well
as other requirements for foreign manufacturers, foreign repackers,
foreign relabelers, or foreign drug product salvagers, are set forth
under Sec. 207.40. In addition, current Sec. 207.3(a)(11) defines
United States agent as a person residing or maintaining a place of
business in the United States whom a foreign establishment designates
as its agent. The definition states that ``United States agent''
excludes mailboxes, answering machines or services, or other places
where an individual acting as the foreign establishment's agent is not
physically present. We are proposing to revoke current Sec. Sec.
207.3(a)(11) and 207.40 and include these requirements (as revised),
for example, under proposed Sec. Sec. 207.1, 207.9, 207.13, 207.17,
207.33, 207.41, 207.61, and 207.69.
Under proposed Sec. 207.69(b)(2) through (b)(4), the United States
agent would be required to reside or maintain a place of business in
the United States. A United States agent may not be a mailbox,
answering machine or service, or other place where a person acting as
the United States agent is not physically present. If we are unable to
contact the foreign manufacturer, foreign repacker, foreign relabeler,
or foreign drug product salvager directly or expeditiously, we may
provide information or documents to the United States agent, which we
would consider equivalent to providing the same information or
documents to the foreign manufacturer, foreign repacker, foreign
relabeler, or foreign drug product salvager.
We are proposing the requirements for a United States agent to
facilitate communications between you and us and to help ensure
compliance with the registration and listing requirements. On numerous
occasions, we have found it difficult to contact certain foreign
manufacturers, foreign repackers, foreign relabelers, and foreign drug
product salvagers, resulting in their drugs being detained because
certain registration and/or listing issues have not been resolved.
2. What Legal Status Is Conferred by Registration and Listing?
Under proposed Sec. 207.77(a), registration of an establishment or
listing of a drug does not denote approval of the establishment, the
drug, or other drugs of the establishment, nor does it mean that a
product may be legally marketed. Any representation that creates an
impression of official approval or that a drug is approved or is
legally marketable because of registration or listing would be
misleading and would constitute misbranding under section 502 of the
act. To clarify and consolidate current regulations, we are proposing
to revise and move a similar provision in current Sec. 207.39 to
proposed Sec. Sec. 207.77(a) and 207.37. Current Sec. 207.39 states
that registration of a drug establishment or drug wholesaler,
assignment of a registration number, or assignment of an NDC number
does not in any way denote approval of the firm or its products. Any
representation that creates an impression of official approval because
of registration or possession of a registration number or NDC number is
misleading and constitutes misbranding. The registration provisions in
current Sec. 207.39 would be included in proposed Sec. 207.77(a), and
the NDC number provisions in current Sec. 207.39 would be included in
proposed Sec. 207.37. Proposed Sec. 207.37(c) states that the NDC
number must not be used to denote FDA approval of that drug. We are
proposing to include in proposed Sec. 207.77(a) that listing a drug
would not denote approval of the drug and that any such representation
would be misleading and constitute misbranding.
Under proposed Sec. 207.77(b), assignment of an establishment
registration number, inclusion of a drug in our database of drugs, or
assignment of an NDC number does not denote approval of the
establishment or the
[[Page 51320]]
drug or any other drugs of the establishment, nor does it mean that the
drug may be legally marketed. Any representation that creates an
impression that a drug is approved or is legally marketable because it
appears in our database of drugs, has been assigned a NDC number, or
the establishment has been assigned an establishment registration
number, is misleading and constitutes misbranding. Failure to comply
with proposed Sec. 207.37 also constitutes misbranding. We are
proposing to add this provision to clarify that a drug's marketing
approval status is determined, for example, under section 505 or 512 of
the act, section 351 of the PHS Act, and parts 314, 514 (21 CFR part
514), and 601 of the regulations, and not under section 510 of the act
or part 207 of the regulations.
Under proposed Sec. 207.77(c), neither registration nor listing
constitutes a determination by FDA that a product is a drug as defined
by section 201(g)(1) of the act. This provision reflects a revision and
relocation of current Sec. 207.20(e) to proposed Sec. 207.77(c).
Current Sec. 207.20(e) states that registration and listing do not
constitute an admission, agreement, or determination that a product is
a drug as defined under section 201(g) of the act. Proposed Sec.
207.77(c) also states that registration and listing may be evidence
that a facility is manufacturing, repacking, relabeling, or salvaging
drugs or that a product is a drug. Thus, the proposed rule revises
current Sec. 207.20(e) such that, while neither registration nor
listing constitutes a determination by FDA that a product is a drug as
defined by the act, registration and listing may be evidence that a
facility is manufacturing, repacking, relabeling, or salvaging drugs or
that a product is a drug.
FDA is proposing to delete the statement in current Sec. 207.35(c)
that validation of registration and the assignment of a drug listing
number do not, in themselves, establish that the holder of the
registration is legally qualified to deal in such drugs. As explained
in sections IV.B and IV.C of this document, FDA is proposing to
discontinue the validation of registration. As explained previously in
this document, the provision on the legal status of registration and
listing is included in proposed Sec. 207.77, and proposed Sec.
207.37(c) sets forth restrictions pertaining to the use of the NDC
number (e.g., the NDC number must not be used to denote FDA approval of
the drug).
3. What Registration and Listing Information Would Be Made Available
for Public Disclosure?
Current Sec. 207.37 pertains to the public availability of
registration and listing information. Proposed Sec. 207.81 would
revoke, in part, and revise current Sec. 207.37. The heading
``Inspection of registrations and drug listings'' in current Sec.
207.37 would be changed to ``What registration and listing information
will we make available for public disclosure?'' This heading would more
accurately describe the scope of the provision in that the provision
relates to the type of registration and listing information that we
intend to make available for public disclosure.
The proposal would revoke the introductory text of current Sec.
207.37(a), which includes a description of the types of forms available
for inspection, the addresses at which such forms can be inspected, and
the addresses that requests for verification of registration numbers
and requests for locations of registered establishments can be
directed. We are proposing to revoke this introductory text because
these forms would no longer be used under the proposed scheme. Instead,
we intend to make most information that is available for public
disclosure accessible via the Internet. This initiative would be
consistent with the GPEA and would also help to reduce the number of
Freedom of Information Act (5 U.S.C. 552) requests we receive for
registration and listing information. Accordingly, we are also
proposing to revoke current Sec. 207.37(b), which sets forth the
address to which requests for information about drug registration and
listing can be directed. We note that persons may still submit Freedom
of Information Act requests to the agency for drug registration and
listing information that is not available on the Internet.
Current Sec. 207.37(a)(1) sets forth 11 categories of information
that, when compiled, will be available for public disclosure. Proposed
Sec. 207.81(a) would simplify this section to reference the following
information as generally available for public disclosure: All
registration information and, after a drug is listed, all information
obtained for that drug under proposed Sec. Sec. 207.33, 207.49,
207.53, and 207.54, except for that information obtained under proposed
Sec. Sec. 207.33(d)(1)(ii) and 207.54(b)(1) or the information that
would otherwise be exempt from disclosure under proposed Sec.
207.81(b) or (c).
Proposed Sec. 207.81(a) would add registration information to the
list of the types of information that would generally be considered to
be publicly available. Registration information is currently available
for public inspection as referenced in Sec. 207.37(a).
For various reasons, proposed Sec. 207.81(a) would not include
certain specific categories of information that are listed in current
Sec. 207.37. The provision relating to a list of all drug products
arranged by labeled indications or pharmacological category would not
be included in the proposal because we currently do not compile or
index drug registration and listing information by labeled indication.
The provisions related to a list of drug products newly marketed or for
which marketing is resumed, a list of drug products discontinued, and
information that has become a matter of public knowledge would be
deleted because these categories of information would also be
disclosable under the general provision of proposed Sec. 207.81(a).
We are proposing to exempt proposed Sec. Sec. 207.33(d)(1)(ii) and
207.54(b)(1) from proposed Sec. 207.81(a) because this information may
disclose a business relationship between the manufacturer, repacker,
relabeler, or drug product salvager and the business from which they
obtained the drug, and may constitute commercial or financial
information that is exempt from public disclosure under Sec. 20.61(c).
We are proposing to exempt from public disclosure the information
collected under proposed Sec. 207.33(d)(1)(ii), which would require
that repackers or relabelers, to obtain an NDC number, must provide,
among other things, the NDC number assigned to the drug immediately
before the drug is received by the repacker or relabeler. We also are
proposing to exempt from public disclosure the information collected
under proposed Sec. 207.54(b)(1), which would require that drug
product salvagers, to list a drug, must provide, among other things,
the NDC number assigned to the drug immediately before the drug is
received by the drug product salvager.
In addition to these changes, the proposal would make some
fundamental changes to the disclosure provision in current Sec.
207.37. We are proposing to add one category of listing information to
the list of information that would generally be regarded as publicly
available information. Specifically, proposed Sec. 207.81 generally
would make available for public disclosure a drug product's inactive
ingredients when provided under Sec. 207.33(c)(2)(ii) and (c)(3). When
the firm provides the approved application number, we can link to the
[[Page 51321]]
application and retrieve the names of the inactive ingredients included
in the approved application. We will then make the names of the
inactive ingredients available to consumers unless they are subject to
trade secret protection, as discussed below. Proposed Sec. 207.81
would change the current provision in Sec. 207.37(a)(2). Current Sec.
207.37(a)(2)(ii) and (a)(2)(iii) provide that information on inactive
ingredients will not be available for public disclosure (except that
any of the information will be available for public disclosure if it
has become a matter of public knowledge or if we find that it would be
inconsistent with the protection of the public health).
We are proposing, under Sec. 207.33(c)(2)(ii), to give
manufacturers the opportunity at the time of listing to identify
inactive ingredients that they consider trade secret. Information
identified by the applicant as trade secret would not be routinely
posted on the Internet. Public disclosure of inactive ingredients not
designated as trade secret at the time of listing would be authorized
by the proposed regulations. We would evaluate claims of trade secret
protection based on the definition of a trade secret in Sec. 20.61(a)
when making disclosure decisions in response to requests made under the
Freedom of Information Act for this information and would withhold the
information from public disclosure, when appropriate, under Sec.
207.81(c). This evaluation is consistent with how FDA evaluates
requests asking for inactive ingredient information that is included in
approved U.S. applications. When manufacturers submit the approved
application number instead of listing inactive ingredients under
proposed Sec. 207.33(c)(2)(ii), they similarly would need to identify
any inactive ingredients they considered to be trade secret. Proposed
Sec. Sec. 207.33(c)(2)(ii), 207.81(a), and 207.81(c) would strike a
balance between manufacturers' commercial interests and the fact that
it would generally be inconsistent with protection of the public health
to withhold inactive ingredient information. We expect that
manufacturers would only avail themselves of the opportunity to claim
trade secret protection in extremely limited circumstances. We note
that information in a drug's labeling, including the names of inactive
ingredients, is not trade secret information.
The proposal to add information about inactive ingredients to the
list of categories considered to be public information is also
consistent with section 510(f) of the act. Section 510(f) of the act
generally provides that listing information shall be exempt from
inspection unless the Secretary finds that such an exemption would be
inconsistent with protection of the public health. We find that
exempting, among other things, a list of inactive ingredients from
public disclosure would be inconsistent with the protection of the
public health. It is important for consumers to know the inactive
ingredients of the drugs they might be taking because such information
can be important in certain situations. For example, some inactive
ingredients can trigger allergic reactions in patients. If a particular
inactive ingredient appeared to trigger such reactions in an
individual, and the name of the inactive ingredient was available to
the public, individuals and their caregivers would be able to access
such information to prevent potentially serious reactions.
Additionally, some inactive ingredients may be particularly toxic to
individuals with certain medical conditions and some may exacerbate a
person's medical condition. If inactive ingredient information is
available for drugs, individuals and their caregivers could get this
information and avoid adverse reactions. We could also use inactive
ingredients information to help us investigate possible drug
contamination, counterfeiting, or adulteration. For example, if a drug
appeared to be linked to an unexpected number of adverse drug events or
seemed less effective than expected, an analysis of the drug showing
the presence of unidentified (i.e., not previously listed) inactive
ingredients in that drug could suggest that the drug was adulterated or
counterfeit, or that the unidentified inactive ingredient may interfere
with the drug's mode of action. Additionally, the presence of an
unidentified inactive ingredient in a drug product may suggest
contamination or that the drug was not manufactured by the legitimate
manufacturer. Generally, we believe that knowing about a drug's
inactive ingredients and having such information readily available in
an electronic database is consistent with protection of the public
health.
We recognize that because we may make a large amount of
registration and listing information publicly available under proposed
Sec. 207.81, there may be instances where some of the information
authorized by this proposed rule for public disclosure could identify
business relationships. We believe that many of these business
relationships could be identified currently, but that the electronic
registration and listing system may make it somewhat easier to do so.
For example, a contractual relationship that might not otherwise be
publicly disclosed may be revealed when a manufacturer of a sole source
material provides the drug's established name under proposed Sec.
207.33(c)(1)(ii) or when a manufacturer provides registration numbers
of each establishment where manufacturing is performed under proposed
Sec. 207.49(d). Also, for example, business relationships between
private label distributors and manufacturers, repackers, relabelers may
be revealed when providing information under Sec. 207.33(c) or (d)(2).
However, we believe this would be a rare event and that exemption of
the information required by these regulatory provisions from public
disclosure would be inconsistent with protection of the public health.
For example, we believe that we should not exempt from public
disclosure the names of inactive ingredients that would be submitted
under proposed Sec. 207.33(c)(2)(ii) because of the remote possibility
that the names, along with other information that may be disclosed
under this proposal, could reveal a business relationship. We believe
that the potential public health benefits of releasing the names of the
inactive ingredients justify our decision not to exempt them from
public disclosure because they outweigh the remote possibility that a
business relationship could be revealed. Therefore we have concluded
that the public interest in disclosure of most registration and listing
information supports the proposals in the rulemaking.
We also note that, for foreign manufacturers, foreign repackers,
foreign relabelers, and foreign drug product salvagers, the name of
each importer and the names of persons who import a drug or offer a
drug for import would be required for registration and we are proposing
that this information would be available for public disclosure.
Disclosure of this information would be consistent with section 510(f)
of the act, which requires that any registration filed be made
available for inspection.
We invite comments on which specific registration and listing
information should be available for public disclosure. We request that
you identify the specific registration and listing information on which
you are commenting and explain why you believe the information should
or should not be publicly disclosed.
Proposed Sec. 207.81(b) would make one other conforming change to
the current
[[Page 51322]]
disclosure provision. Current Sec. 207.37(a)(2) sets forth three
categories of information that will not be available for public
disclosure (except that any of the information will be available for
public disclosure if it has become a matter of public knowledge or if
we find that confidentiality would be inconsistent with protection of
the public health). Proposed Sec. 207.81(b) would retain the category
treating as nondisclosable any information submitted as the basis upon
which it has been determined that a particular drug product is not
subject to section 505 or 512 of the act. As explained previously in
this document, we are moving two previously nondisclosable categories
(now disclosable) regarding information on inactive ingredients to
proposed Sec. 207.81(a) that relate to information generally regarded
as publicly available. Those categories, in current Sec.
207.37(a)(2)(ii) and (a)(2)(iii), would be disclosable under proposed
Sec. 207.81(a). Proposed Sec. 207.81(c) would allow FDA to determine,
in limited circumstances and on a case-by-case basis, that it would be
consistent with protection of the public health and the Freedom of
Information Act to exempt from public disclosure specific information
in paragraph (a) of this section. As explained previously in this
document, we are proposing, under Sec. 207.33(c)(2)(ii), to give
manufacturers the opportunity at the time of listing to identify
inactive ingredients that they consider trade secret and therefore,
prohibited from disclosure under Sec. 20.61. There may be other
appropriate reasons for exempting certain drug listing and registration
information from public disclosure. For example, FDA may decide for
security reasons, and consistent with the Freedom of Information Act,
not to publicly disclose the manufacturing site location for certain
drugs.
G. Conforming Actions
1. Withdrawal from Sale of Drugs with Approved Marketing Applications
We are proposing to revise our human drug regulations on
applications for approval to market a new drug to make them consistent
with proposed part 207. Under current Sec. 314.81(b)(3)(iii)(a),
holders of new drug applications must report to us the withdrawal from
sale of a drug product. Under this provision, the information must be
submitted on Form FDA 2657 within 15 working days of the drug product's
withdrawal from sale. The following information must be submitted: The
NDC number; the identity of the drug by established name and by
proprietary name; the new drug application number or abbreviated
application number; and the date of withdrawal from sale. The reason
for withdrawal of the drug from sale is requested but not required to
be submitted. Section 314.81(b)(3)(iii)(b) provides the address for
submitting the completed form, and Sec. 314.81(b)(3)(iii)(c) states
that reporting under Sec. 314.81(b)(3)(iii) constitutes compliance
with the requirements under current Sec. 207.30(a) to report ``at the
discretion of the registrant when the change occurs.''
We are proposing to revise this requirement to be consistent with
the requirements in proposed Sec. Sec. 207.57 and 207.61. Proposed
Sec. 314.81(b)(3)(iii)(a) would provide that within 30 calendar days
of the withdrawal of an approved drug from sale, applicants who are
manufacturers, repackers, or relabelers subject to proposed part 207
would be required to submit certain information about the withdrawn
drug in electronic format, in accordance with the applicable
requirements described in Sec. 207.61(a).
Under proposed Sec. 314.81(b)(3)(iii)(b), applicants who are not
subject to proposed part 207 would submit the information specified
under proposed Sec. 314.81(b)(3)(iii)(a) on the appropriate form,
which would be submitted to the Drug Listing Branch, Food and Drug
Administration, CDER Central Document Room, 5901B Ammendale Rd.,
Beltsville, MD 20705-1266. We are proposing to require applicants who
are subject to proposed part 207 to submit the information specified
under proposed Sec. 314.81(b)(3)(iii)(a) in electronic format, in
accordance with the applicable requirements described in proposed Sec.
207.61(a). Consistent with the proposed requirements in Sec. 207.61,
and discussed in section IV.E.3 of this document, these applicants
would be required to obtain an account number, user name, and password
to sign onto the electronic drug registration and listing system. We
are considering this requirement because we believe the electronic
submission of this information would be more efficient for applicants
than the preparation and mailing of paper forms. Electronic submission
would also make our review and processing of this information more
efficient. We request comments on requiring applicants who are not
subject to proposed part 207 to submit electronically the information
specified in proposed Sec. 314.81(b)(3)(iii)(a).
Currently, we do not have a provision in our regulations for
reporting withdrawals from sale of biological products. We are
proposing to revise our regulations to include such a provision. Under
proposed Sec. 601.2(f), holders of BLAs must report to us,
electronically in accordance with part 207, the withdrawal from sale of
licensed biological products. The information must be submitted to us
within 30 working days of the biological product's withdrawal from
sale. The following information would be submitted: The holder's name;
product name; BLA number; the NDC number, if applicable; and the date
of withdrawal from sale. The reason for the withdrawal of the
biological product would be requested but not required.
2. Proposed Revisions to Other Regulations
In addition to the revisions of regulations discussed previously in
this document, we are also proposing revisions to other FDA regulations
as a result of this proposed rule. The proposed revisions are as
follows:
Section 20.100(c)(9): The reference to Sec. 207.37 would
be changed to Sec. 207.81 to correspond to the proposed provision on
disclosure of registration and listing information.
Section 20.116: The reference to Sec. 207.37 would be
changed to Sec. 207.81 to correspond to the proposed provision on
disclosure of registration and listing information.
Section 201.1(f): The reference to Sec. 207.3(b) would be
changed to Sec. 207.1 to correspond to the proposed definitions
section.
Section 330.1(b): As explained in section IV.C.5 of this
document, the NDC number would be required to appear on OTC drug
labels.
Section 514.111(a)(12): As explained in section IV.B.2 of
this document, we would refuse to approve an NADA if the drug is
manufactured in an establishment that is not registered.
Section 515.10(b)(8): The reference to ``Sec. Sec. 207.20
and 207.21'' would be changed to ``part 207'' as a result of the
proposed reorganization and revision of part 207.
Section 607.3(b): Current Sec. 607.3(b) defines ``blood
and blood product'' to mean a drug which consists of human whole blood,
plasma, or serum or any product derived from human whole blood, plasma,
or serum, hereinafter referred to as ``blood product.'' The current
definition also states that ``blood and blood product'' also means
those products that meet the definition of a device under the act and
that are licensed under section 351 of the PHS Act. We are proposing to
amend this definition to add the phrase ``as well as licensed biologic
components used in the manufacture of a licensed device.'' This
proposed revision is intended to
[[Page 51323]]
clarify that licensed biologic components used in the manufacture of a
licensed device are covered under the definition of ``blood and blood
product'' and that manufacturers of licensed biologic components used
in the manufacture of a licensed device are required to register and
list under part 607. It is important that manufacturers of licensed
biologic components used in the manufacture of a licensed device
register and list because licensed devices are used to ensure the
safety of blood and blood products.
Section 607.3(k): We are proposing to define ``importer''
as a company or individual in the United States that is the owner,
consignee, or recipient of the foreign establishment's blood product
that is imported into the United States.
Section 607.7: Current Sec. 607.7(a) states that all
owners or operators of establishments that engage in the manufacturing
of blood and blood products are required to register, and that
registration and listing of blood and blood products must comply with
part 607. Current Sec. 607.7(a) also states that registration does not
permit blood banks or similar establishments to ship blood products in
interstate commerce. Current Sec. 607.7(b) and (c) explain how the
registration form for these establishments may be obtained from CBER
and where the completed form should be mailed to.
We are proposing to delete current Sec. 607.7(b) and (c) and
explain where to obtain establishment registration forms and where to
send completed forms in proposed Sec. 607.22(b) (discussed below in
this document). We are deleting these provisions from current Sec.
607.7 to eliminate redundancy in part 607. We are proposing to
redesignate paragraph (a) in Sec. 607.7 as the introductory paragraph.
Section 607.22: For clarity, we are proposing to revise
the title of current Sec. 607.22--``How and where to register
establishments and list blood products''--to read ``How to register
blood product establishments and list blood products.''
Current Sec. 607.22(a) requires the first registration of an
establishment to be on Form FDA 2830 (Blood Establishment Registration
and Product Listing), provides the mailing address where the Form FDA
2830 may be obtained and submitted, states that FDA will furnish a Form
FDA 2830 before November 15 of each year to establishments whose
registration for that year was validated under Sec. 607.35, and states
that the completed form must be mailed to us before December 31 of that
year. Current Sec. 607.22(b) states that the first and subsequent
blood product listing updates shall be on Form FDA 2830.
We are proposing to reorganize and update current Sec. 607.22 as
follows: Initial and subsequent registrations and product listings by a
blood product establishment for blood products would be on Form FDA
2830 (Blood Establishment Registration and Product Listing).
Manufacturers may obtain, complete, and submit the form in the
following ways:
Complete the form online and submit electronically at
http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/cber/blood/bldreg.htm; this information must be
submitted in accordance with part 11 of this chapter, except for the
requirements in Sec. 11.10(b), (c), and (e) and the corresponding
requirements in Sec. 11.30 (as discussed in section IV.E.7 of this
document); or
Download the form from the Internet at http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/cber/blood/bldreg.htm
, and mail the completed form to the address in
Sec. 607.22(e); or
Request the form by mail using the address in Sec.
607.22(e), or by e-mail at bloodregis@cber.fda.gov, and mail the
completed form to the address in Sec. 607.22(e).
For subsequent annual registration renewals, we will
furnish the establishment's most recent Form FDA 2830 before November
15 of each year. The updated Form FDA 2830 would be submitted to us
before December 31 of that year.
Forms may be requested from and mailed to: Center for
Biologics Evaluation and Research (HFM-370), 1401 Rockville Pike, suite
200N, Rockville, MD 20852-1448.
We are proposing these revisions to current Sec. 607.22 to make
the registration and blood product listing process for blood product
establishments more efficient by utilizing the latest technology for
completing and submitting registration and listing forms.
Section 607.25(b)(1): Current Sec. 607.25(b) lists the
information required for blood product listing. Currently, blood
establishments that manufacture bulk product substances and finished
dosage forms must list their products under part 607 and also under
part 207 to receive a NDC number. We are proposing to revise current
Sec. 607.25(b)(1) to delete the phrase ``including bulk product
substances as well as finished dosage forms'' because we are proposing
to require these manufacturers to list only under part 207 to reduce
their reporting burden. In addition, we are proposing to add the phrase
``if any'' after ``by proprietary name'' because not all of these
products have a proprietary name. We are also proposing to delete the
reference to Form FDA 2250 (National Drug Code Directory Input) because
this form is no longer being used by CDER or CBER.
Section 607.35: For clarity, we are proposing to revise
the title of current Sec. 607.35--``Notification of registrant; blood
product establishment registration number and NDC Labeler Code''--to
read ``Blood product establishment registration number.''
Current Sec. 607.35(a) states that FDA will send a validated copy
of Form FDA 2830 as evidence of registration to the registering
establishment, and that FDA will assign a permanent registration number
to each establishment. We are proposing to revoke the provision that we
will send a validated copy of Form FDA 2830 to blood establishments.
All registration information will be available to registered blood
establishments on the Internet; therefore, to increase efficiency we
will discontinue sending the validated copy of Form FDA 2830. Proposed
Sec. 607.35 would state only that we will assign a permanent
registration number to each blood product establishment registered in
accordance with part 607.
Current Sec. 607.35(b) states that if a registered blood product
establishment has not previously participated in the NDC system or in
the National Health Related Items Code system, the NDC numbering system
must be used. We are proposing to revoke this section because blood
product manufacturers that obtain a NDC number for their products will
register under proposed part 207 and not under part 607. We are also
proposing to delete reference to the National Health Related Items Code
system because it is a voluntary system for medical device
manufacturers that is managed by CDRH.
Current Sec. 607.35(c) states that although establishment
registration and blood product listing are required, validation of
registration and the assignment of a NDC Labeler Code do not, in
themselves, establish that the holder of the registration is legally
qualified to deal in such products. We are proposing to incorporate
into proposed Sec. 607.39 the provision that validation of
registration does not establish that the holder of the registration is
legally qualified to deal in such products. We are proposing to revoke
the provision concerning the assignment of a Labeler Code because the
NDC number requirements would be covered under proposed part 207 and
not proposed part 607.
[[Page 51324]]
Section 607.37(a): Current Sec. 607.37(a) states that a
copy of Form FDA 2830 will be available for inspection under section
510(f) of the act at FDA headquarters and at each of the FDA district
offices. In addition, current Sec. 607.37(a) states that FDA will
provide by mail verification of registration number and location of a
registered establishment. Current Sec. 607.37(a) also gives examples
of the blood product listing information that will be available for
public disclosure.
Under proposed Sec. 607.37(a), information submitted on Form FDA
2830 would be available for inspection at http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/cber/blood/bldregdata.htm
and at the Department of Health and Human
Services, Food and Drug Administration, Office of Communication,
Training, and Manufacturers Assistance (HFM-40), Center for Biologics
Evaluation and Research, 1401 Rockville Pike, suite 200N, Rockville, MD
20852-1448.
Section 607.39: Current Sec. 607.39 states that
registration of an establishment or assignment of a registration number
or assignment of a NDC number does not in any way denote approval of
the firm or its products, and that any representation that creates an
impression of official approval because of registration is misleading
and constitutes misbranding.
We are proposing to revise current Sec. 607.39 to delete the
reference to the NDC number, to incorporate the provision from current
Sec. 607.35(c) that validation of registration does not establish that
the holder of registration is legally qualified to deal in blood
products, and to revise the title accordingly. Manufacturers of blood
products that obtain a NDC number would not register under proposed
part 607; therefore, it is not necessary to reference NDC numbers under
this part. Proposed Sec. 607.39 would state that registration of an
establishment, validating registration, or obtaining a registration
number does not in any way denote approval of the firm or its products
nor does it establish legal authority for the holder of the
registration number to market such products.