United States of drugs they manufacture, repack, relabel, or salvage
that is known to the establishment as well as each person who imports
or offers for import such drugs to the United States. This comment
stated that contract manufactures may not have this information.
    (Response) This requirement is retained in the final rule, in Sec.
207.25(h). The provision implements a statutory requirement (section
510(i)(1) of the FD&C Act). This requirement pertains only to foreign
establishments, and it requires them to identify ``importers'' known to
the establishment and ``persons who import or offer for import,'' as
these terms are defined in Sec.  207.1. Both of these definitions have
been refined and narrowed in this final rule. A foreign contract
manufacturer exporting drugs to the United States should be able to
identify such persons.
4. What are the requirements for reviewing and updating registration
information? (Sec.  207.29)
    Section 207.29 describes the requirements for: (1) Expedited
updating of certain changes to establishment registration information
and (2) annual reviewing and updating of establishment registration.
This section is retained in the final rule with very minor revisions.
Fax numbers are no longer mentioned in Sec.  207.29(a) because they are
no longer required for establishment registration. Additionally, the
dates during which the annual review and update of registration
information must take place have been adjusted to match section
510(b)(2) of the FD&C Act, added by FDAAA.
    (Comment 30) Some comments opposed the requirement that if no
changes have occurred since the last registration, registrants certify
that no changes have occurred.
    (Response) The annual review and updating of establishment
registration information is critical to the integrity of FDA's
database. The requirement that registrants certify that no changes have
occurred when that is true provides important assurance that
registrants have reviewed the establishment registration information
they previously submitted. Otherwise, FDA would need to interpret
silence from a registrant as indicating either that the information
remains up to date or that the registrant may have neglected to review
and update the information. We further note that section 510(b)(1) of
the FD&C Act now requires annual registration of establishments between
October 1 and December 31, and the option to certify that no changes
have occurred since the last registration is a minimally burdensome
implementation of this statutory requirement.
    Please see our response to Comment 74, which addresses this issue
in the context of drug listing updates.

D. National Drug Code (Part 207, Subpart C)

1. What is the national drug code (NDC), how is it assigned, and what
are its requirements? (Sec.  207.33)
    The NDC provisions in this final rule have been revised in response
to comments received on the proposed rule. Most significantly, new
Sec.  207.33:
     Allows for 11 digits in the NDC (when 10-digit
combinations are exhausted).
     Reflects that registrants will propose their own NDCs for
drugs they

list. Under the proposed rule, FDA would have assigned NDCs in response
to submissions from registrants. Under this final rule, each registrant
must propose its own NDC for each drug the registrant lists. FDA will
assign the proposed NDCs to the listed drugs unless they are improperly
formatted, previously assigned to a listed drug, or reserved.
     Includes new NDC formatting requirements for registrants
to observe when proposing NDCs.
     Transfers some information that would have been required
under proposed Sec.  207.33(c) (What information must a manufacturer
submit before we will assign an NDC number to a drug?) to information
that must be included in a drug listing submission.
     Allows certain drug products to be assigned alternatively
formatted NDCs if approved by the Center Director. This applies to the
HCT/Ps specified in new Sec.  207.33(b)(4) if they are minimally
manipulated.
     Includes a new Sec.  207.33(c) that explains who must
obtain an NDC labeler code and how labeler codes are assigned and
updated.
     Includes new provisions in Sec.  207.33(d) that explain
how a proposed NDC can be voluntarily reserved.
    Comments on the NDC provisions of the proposed rule and FDA's
responses are summarized in this document. This does not include some
comments that have been made moot by the revisions summarized
previously.
    (Comment 31) FDA received many comments opposing the proposed
rule's requirement that FDA, rather than registrants, generate and
assign the complete NDC for drugs that are subject to listing. Some
comments were concerned about possible delays associated with NDC
request submissions. Others were concerned about losing control over
numbering conventions that individual registrants may apply to their
own product codes and package codes. One comment expressed concern that
subjecting OTC monograph products to an NDC assignment process could
begin to resemble an FDA approval process for such products.
    (Response) The objective behind FDA's proposal to generate and
assign NDCs was to assure they are assigned appropriately. Although we
did not intend FDA's issuance of NDCs to be time consuming or to
operate as an approval process, we recognize that FDA's objectives can
be met in a way that is more flexible and less burdensome for
registrants. Accordingly, the proposed requirement that FDA generate
the complete NDC for each listed drug is not included in this final
rule.
    Under new Sec.  207.33(d), registrants, not FDA, will generate NDCs
for assignment to their listed drugs. An NDC is considered to be
``proposed for assignment'' when a registrant submits it for the first
time with drug listing information in accordance with Sec.  207.49 or
Sec.  207.53. If the proposed NDC conforms to the formatting
requirements of Sec.  207.33, is not reserved for a different drug, and
was not previously assigned to a different listed drug, FDA will assign
the proposed NDC when it receives all required listing information for
the drug.
    (Comment 32) Some comments asked how far in advance of marketing a
drug for the first time an NDC may be requested. Comments also pointed
out that manufacturers need to know the NDC for a drug in development
prior to the time of drug listing.
    (Response) As explained in response to Comment 31, this final rule
requires registrants to propose their own NDCs for drugs they list. FDA
will assign a proposed NDC to the drug identified by the registrant if
the proposed NDC conforms to the formatting requirements of Sec.
207.33, is not reserved for a different drug, and was not previously
assigned to a different listed drug.
    We recognize that a mechanism for reserving a specific NDC may be
helpful, as this would provide greater certainty that a proposed NDC
will be accepted by FDA when it is included with a listing submission
at the time of marketing. Accordingly, this final rule includes a new
Sec.  207.33(d)(3) that allows a person to voluntarily reserve a
proposed NDC for a period of 2 years prior to its inclusion in a drug
listing submission for the first time. Note that an NDC reserved under
Sec.  207.33(d)(3) would need to include most importantly a labeler
code and a product code. At the discretion of the person submitting the
reservation request, a single package code could be included, or not,
with one or more package codes included later in NDC(s) submitted with
complete drug listing information.
    Certain minimal information must be submitted to reserve a proposed
NDC, as specified in new Sec.  207.33(d)(3). This information does not
include identification of the drug's inactive ingredients. Many
comments opposed the inclusion of such detailed information in the
proposed rule's provision governing NDC requests.
    NDCs reserved under Sec.  207.33(d)(3) would be reserved for 2
years unless the person whose labeler code is included in the NDC asks
FDA to cancel the reservation earlier. If a reserved NDC is not used
during the 2-year reservation period (i.e., is not submitted to FDA
with complete listing information for the drug matching the
reservation), the NDC will be available for assignment to another drug.
Anyone wishing to extend an NDC reservation beyond 2 years may submit
another reservation request.
    In addition to the procedure established under Sec.  207.33(d)(3),
a registrant wishing to reserve an NDC also has the option of
submitting complete listing information for a drug that is under
development and specifying a future ``start marketing date'' in the
listing submission. That listing submission could then be updated, as
needed, when the actual marketing date arrives.
    (Comment 33) One comment questioned how, when listing a drug for
the first time, a registrant can supply a drug's labeling if the
labeling must include the drug's NDC, and if the NDC is not assigned
until the drug is listed.
    (Response) As explained in response to Comment 1, unlike the
proposed rule, this final rule does not require NDCs to appear in
human-readable form on drug labels (but an intervening statutory
amendment, the DSCSA, does require NDCs to appear as part of the
product identifier on certain drug labels). After the effective date of
this final rule, our regulations will continue to encourage, but not
require, the appearance of human-readable NDCs on drug labels (Sec.
201.2) and continue to require that NDCs appear in bar codes on drug
labels (Sec.  201.25(c)).
    Under this final rule, unlike the proposed rule, registrants are
able to develop and propose their own NDCs to FDA. Upon receipt of a
first-time listing submission, FDA will assign the NDC proposed by the
registrant to the drug being listed unless the NDC is improperly
formatted, reserved for a different drug, or was previously assigned to
a different listed drug. Registrants are also able to reserve an NDC
for a drug under development under Sec.  207.33(d)(3) of this final
rule. Accordingly, registrants should not have difficulty determining,
with adequate certainty, the NDC for a drug under development.
    (Comment 34) Some comments supported the proposed rule's revocation
of then-current Sec.  207.35(b)(4)(ii), which stated that the product
code of a discontinued product could 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. Commenters generally agreed that the reuse of old
NDCs for a different

product in the future can be confusing. One comment, however, urged FDA
to allow for the reuse of NDCs.
    (Response) FDA is retaining this general prohibition against the
reuse of NDCs in the final rule. As indicated in new Sec.
207.33(d)(2), an NDC will not be assigned to a drug if it was
previously assigned to a different drug. The prohibition against reuse
of NDCs applies to listings submitted on or after the effective date of
this final rule. Drugs that are currently listed under NDCs that have
been reused in accordance with previous Sec.  207.35(b)(4)(ii) may
continue to be listed under such NDCs.
    Conversely, if a registrant reintroduces a drug it listed and
discontinued in the past, that registrant must list the drug using the
same NDC under which it was listed in the past. See Sec.  207.37(b) of
this final rule. However, if the reintroduced drug includes changes,
compared to the discontinued drug, that would warrant a new NDC under
new Sec.  207.35, then it should be listed under a new NDC.
    As discussed in response to Comment 19, under new Sec.  207.49, if
a private label distributor uses a contract manufacturer to produce a
human drug, the contract manufacturer has an obligation to list the
drug under two NDCs, one that includes the labeler code of the contract
manufacturer and one that includes the labeler code of the private
label distributor. If the private label distributor switches to a new
contract manufacturer in the future, that new contract manufacturer
would also have an obligation to list the drug under two NDCs, one that
includes its own labeler code and one that includes the labeler code of
the private label distributor. The NDC that includes the new contract
manufacturer's labeler code will obviously differ from the NDC under
which the previous contract manufacturer listed the drug (because the
labeler codes will differ). The NDC that includes the private label
distributor's labeler code may be the same as that under which the
previous contract manufacturer listed the drug provided: (1) There have
been no changes to the drug that warrant a new NDC under Sec.  207.35
and (2) the previous contract manufacturer updates its listing
information to indicate it no longer manufactures the drug (as it is
required to do under Sec.  207.57 at the time of its next June or
December listing update, or sooner at its discretion). If those two
conditions do not exist, FDA would accept a listing from the new
contract manufacturer under a new NDC that includes the private label
distributor's labeler code.
    (Comment 35) We received several comments concerning the format of
the NDC. Many comments expressed concern about the impact of any
changes in the NDC format on various systems that track and use NDCs.
Some comments urged FDA to retain the 10-digit NDC format. Others
encouraged the adoption of a standard 11-digit NDC. Some comments
opposed the possible introduction of alphanumeric NDCs, preferring all
numeric NDCs. Others were concerned about the possible coexistence of
10- and 11-digit NDCs.
    (Response) FDA is sensitive to these concerns. Section 207.33(b) of
this final rule specifies the format of an NDC recognized by FDA. The
final rule necessarily includes more specifications than did the
proposed rule concerning NDC formatting because under the final rule,
registrants, not FDA, develop their own proposed NDCs, and they must
all meet certain formatting parameters. The final rule states, for
example, that the NDC is 10 or 11 digits to preclude the submission of
longer NDCs.
    Our regulations have long stated that FDA will expand the labeler
code from five to six numeric characters when the available five-
character code combinations are exhausted (previous Sec.
207.35(b)(2)(i)). This occurrence is mathematically inevitable and is
reflected in new Sec.  207.33(b)(1), which states that the NDC must
consist of 10 or 11 digits. FDA will begin issuing 6-digit labeler
codes, leading to 11-digit NDCs, only when the available 5-digit
labeler codes are exhausted. FDA will not assign 11-digit NDCs until we
begin to issue 6-digit labeler codes.
    FDA recognizes the desirability of a single, standard format for
NDCs, having three segments of consistent lengths, as we eventually
transition to six-digit labeler codes. We intend to initiate a public
discussion of future formatting options in the near future. In the
meantime, the provisions included in this final rule are intended to
accommodate the range of existing NDC formats, leaving room for
necessary expansion to 11 digits.
    This final rule refers to the NDC as a numeric code, not an
alphanumeric code. This takes into account comments that objected to
the inclusion of alpha characters in NDCs as disruptive of current
systems and practices.
    (Comment 36) Some comments urged FDA not to require NDCs for HCT/
Ps, citing the International Society of Blood Transfusion (ISBT) number
as a better means of identifying these products.
    (Response) In response to these comments, Sec.  207.33(b)(4) of
this final rule states that an alternatively formatted NDC may be used
for certain identified HCT/Ps if they are minimally manipulated and if
the alternatively formatted NDC is approved by the Center Director
(CDER or CBER, as appropriate). Such approval may be indicated in
Guidance for Industry issued by one or both Centers or in this
preamble, for example. Accordingly, FDA identifies ISBT-128 as a
currently approved alternatively formatted NDC to identify HCT/Ps
within the scope of Sec.  207.33(b)(4). ISBT-128 is an international
standard for the identification of medical products of human origin.
Please note that an alternatively formatted NDC approved under Sec.
207.33(b)(4) qualifies as an NDC. HCT/Ps that are not within the scope
of Sec.  207.33(b)(4) require traditionally formatted NDCs.
    (Comment 37) One comment encouraged FDA to allow a single NDC, with
a single package code, to be assigned to an API, which may be
commercially distributed in various quantities.
    (Response) This comment refers to APIs, but the question applies to
any bulk product supplied in variable quantities. We would like to
accept non-numeric characters, such as one or more asterisks, in the
package code segment of an NDC to indicate a bulk product supplied in
various quantities (as was previously done in paper submissions).
However, the SPL format, currently specified in the electronic
registration and listing guidance, does not accommodate non-numeric
characters. Manufacturers in this situation may adopt a variety of
practices. They may submit multiple NDCs with package codes
corresponding to a variety of commonly ordered package sizes. They may
submit an NDC package code corresponding to 1 kilogram (kg), for
example, and then treat a shipment of 10 kg as being comprised of 10
units. In some cases, they may submit an NDC with a package code
corresponding to a 55-gallon drum, for example, and use that packaging
to ship 55-gallon orders as well as orders that are slightly less than
55 gallons in volume.
    (Comment 38) One comment recommended that the NDC for a drug that
was repacked or relabeled include the product code of the source drug.
    (Response) Section 207.53 of this final rule requires repackers and
relabelers to list drugs they repack or relabel and requires them to
submit an appropriate NDC for each such drug that includes the
repacker's/relabeler's labeler code. It would not be feasible to
require the NDC for a repacked or relabled drug to include the labeler
code of the repacker or relabeler combined with the product code of the
source drug. Such a

requirement might produce an NDC that was previously assigned to a
different drug. Because registrants will continue to propose their own
NDCs under this final rule, a repacker or relabeler may generally adopt
the convention proposed in the comment, but may not list a drug under
an NDC that was previously assigned to a different listed drug.
    Listing submissions for repacked or relabeled drugs must also
include the complete NDC assigned to each finished drug received by the
registrant for repacking or relabeling (i.e., the source drug), so this
link will exist in the drug's listing information.
    (Comment 39) Two comments asked whether FDA will assign NDCs to
products that do not have application numbers, i.e., products that are
not the subject of an approved application.
    (Response) This question was posed in the context of the proposed
requirement that registrants request an NDC from FDA by submitting
information specified in proposed Sec.  207.33(c) prior to a listing
submission. In the case of finished drugs, proposed Sec.  207.33(c)
would have allowed registrants to submit an approved U.S. application
number in place of certain information. As discussed in response to
Comment 31, this final rule allows registrants to propose their own
NDCs with listing submissions, and FDA will accept those proposed NDCs
unless they are formatted incorrectly, reserved for a different drug,
or previously assigned to a different drug. Under this final rule, NDCs
are still ``assigned'' only by FDA, after all required listing
information is received. We affirm that NDCs will be assigned in this
manner to all drugs subject to the listing requirement, including drugs
that do not have application numbers. As we have stated in the past
(e.g., previous Sec.  207.39 and in the preamble to the proposed rule
(71 FR 51276 at 51305)), FDA's assignment of an NDC does not in any way
denote FDA approval of a product. Section 207.37 of this final rule
states that a product may be deemed misbranded if an NDC is used to
denote or imply FDA approval.
    (Comment 40) Some comments asked how NDCs will be assigned to
multidrug kits. Here we are addressing kits that do not contain medical
devices. (See related discussion of drug/device combination products in
response to Comment 22.)
    (Response) If a product contains more than one finished drug
product, co-packaged as a kit, and that kit is commercially
distributed, the kit itself must be listed in accordance with Sec.
207.41, under Sec.  207.49 or Sec.  207.53, as appropriate. A
registrant submitting the listing should propose an NDC for the kit
itself, distinct from any NDCs assigned to individual drug constituents
contained in the kit. The NDC proposed for the kit should include the
labeler code of the registrant obligated to submit the listing. If the
kit is packaged for private label distribution, it should be listed
under an additional NDC that includes the labeler code of the private
label distributor.
    (Comment 41) A comment asked whether a finished drug product,
manufactured under one approved application at two different
manufacturing sites under the same ownership and control could be
listed under a single NDC. In this example, the finished product from
each manufacturing site would have the same composition and physical
appearance. The comment also asked whether the answer would change if
the manufacturing sites are located in two different countries.
    (Response) Each manufacturing site would need its own establishment
registration under Sec.  207.17 unless exempt under section 510(g) of
the FD&C Act or under Sec.  207.13. (Foreign establishments must
register only if they manufacture, repack, relabel, or salvage drugs
that are imported or offered for import into the United States.) With
respect to the drug listing requirement, the proposed rule and the
final rule specify in Sec.  207.41(a) that when operations are
conducted at more than one establishment, and common ownership and
control exists among all the establishments, the parent, subsidiary, or
affiliate company may submit listing information for any drug
manufactured, repacked, relabeled, or salvaged at any such
establishment. This language allows a registrant that manufactures a
drug at more than one of its own establishments to submit a single
listing for that product, while identifying all establishments where
the registrant manufactures the drug under Sec.  207.49(a)(12). The
listed drug would have a single NDC in this scenario. The answer does
not change if one or more manufacturing sites are located outside the
United States.
    Note, however, that FDA would also accept multiple listings if a
manufacturer in this situation wished for any reason to submit separate
listings and NDCs for the same drug manufactured at multiple
establishments.
    This analysis does not apply to an entity that uses one or more
contract manufacturers to manufacture, repack, relabel, or salvage a
drug. In that case, each contract manufacturing site must be registered
under Sec.  207.17, unless exempt under section 510(g) of the FD&C Act
or under Sec.  207.13. If more than one contract manufacturing site is
used, and those sites are under common ownership and control, the
contract manufacturer could submit a single listing for this drug
covering its activities at multiple sites (also listing other drugs it
is required to list under Sec.  207.49 or Sec.  207.53). Furthermore,
as discussed in our response to comment 19, contract manufacturers must
generally list a drug under two NDCs, one that includes the contract
manufacturer's labeler code and one that includes the private label
distributor's labeler code. In this scenario, a single NDC that
includes the private label distributor's labeler code could be used
with a drug manufactured at multiple contractor sites along with a
single NDC that includes the contract manufacturer's labeler code,
provided there are no differences in the product produced at the
various sites that would warrant a new NDC under Sec.  207.35.
    (Comment 42) One comment asked how registrants should assess
whether their existing NDCs comply with this rule. Some comments noted
a statement in the preamble to the proposed rule that FDA intends to
validate that current NDCs comply with the new regulations when the
rule is finalized (71 FR 51276 at 51280) and requested more information
about this process.
    (Response) This final rule is not intended to require extensive
changes to NDCs themselves. The NDC formatting provisions of new Sec.
207.33(b) are intended to accommodate NDC formats currently in use. The
10-digit NDC formats provided for under Sec.  207.33(b) of this final
rule include (in terms of numbers of digits in the labeler code,
product code, and package code respectively) 4-4-2, 5-3-2, and 5-4-1.
Any NDC in one of those formats that is not assigned to multiple drug
products and is not assigned to a non-drug product should comply with
this final rule. When five-digit labeler codes are exhausted, FDA will
begin issuing six-digit labeler codes, allowing for additional formats
of 6-3-2 and 6-4-1.
    (Comment 43) Some comments encouraged FDA to permit one registrant
or business to maintain more than one labeler code. These comments
pointed out that mergers and acquisitions in the pharmaceutical
industry result in corporate entities responsible for drugs listed
under multiple NDC labeler codes. Consolidation of such NDCs to a
single labeler code would be burdensome and may not be possible in some
cases if, for

example, one product code has been used with two different labeler
codes.
    (Response) FDA agrees with this comment. We encourage registrants
and private label distributors to maintain a single labeler code
wherever possible. But FDA will not require each registrant and private
label distributor to maintain only one labeler code. This flexible
approach accommodates mergers and acquisitions. It departs from a
statement in the preamble to the proposed rule that only one labeler
code would be used for new NDC numbers that FDA would have assigned
prospectively for any given manufacturer, repacker, or relabeler (71 FR
51276 at 51299). It also accommodates situations in which any
registrant wishes to maintain different labeler codes for different
product lines or situations in which a registrant risks exhausting all
available labeler code and product code combinations if the registrant
operates with a single labeler code. Importantly, new Sec.
207.33(c)(2) requires each person who is assigned a labeler code to
update the information required under Sec.  207.33(c)(1). This will
allow FDA to reliably associate every labeler code with the person to
whom it is assigned and the person's contact information.
    Registrants and private label distributors who currently have NDC
labeler codes but for whom FDA does not have up-to-date information
described in Sec.  207.33(c)(2) on the effective date of this rule are
required to update their information. FDA may refuse to accept new drug
listings that include an NDC labeler code for which the information
required by Sec.  207.33(c)(2) is not current in our system.
    (Comment 44) One comment asked FDA to confirm that a business
owning many registered establishments may maintain only one labeler
code, so that all of its NDCs include a single labeler code.
    (Response) FDA prefers that such a business maintain only one
labeler code, and that it use this single labeler code when proposing
NDCs for drugs it manufactures, repacks, relabels, or salvages at
establishments under common ownership and control. However, as
explained in our response to Comment 43, FDA will not require any
business to maintain only one labeler code.
    (Comment 45) One comment interpreted the proposed rule as
preventing an entity that does not distribute its own products from
maintaining its own labeler code. The comment recommended that such an
entity not be required to assume distribution responsibilities to
retain its labeler code.
    (Response) FDA is not certain whether this comment is concerned
with which NDC would have been required to appear on product labels had
we finalized the proposed amendments to Sec.  201.2, or more generally
concerned with the NDCs under which private label distributor products
are listed. Under Sec.  207.33(c) of this final rule, a labeler code
must be requested and maintained by any person who engages in
manufacturing, repacking, relabeling, or private label distribution of
drug products. The term ``private label distribution'' is defined in
Sec.  207.1 of this final rule to mean commercial distribution of a
drug under the label or trade name of a person who did not manufacture,
repack, relabel, or salvage that drug. A private label distributor does
not need to physically engage in drug distribution to qualify as a
private label distributor under this definition and maintain a labeler
code under Sec.  207.33(c).
    (Comment 46) One comment gave an example of two establishments
``located in the same geographical location within two cities located
five miles apart'' and asked whether those establishments would need
separate NDC labeler codes and registration numbers.
    (Response) Under the final rule's definition of ``establishment,''
two establishments located 5 miles apart would not qualify as being at
``one general physical location'' and would therefore require two
separate registrations. Each establishment would be associated with its
own UFI and establishment registration number. As stated in Sec.
207.17 of this final rule, when operations are conducted at more than
one establishment and common ownership and control among all the
establishments exists, the parent, subsidiary, or affiliate company may
submit registration information for all establishments. Likewise, with
respect to drug listing information, Sec.  207.41 states that when
operations are conducted at more than one establishment, and common
ownership and control exists among all the establishments, the parent,
subsidiary, or affiliate company may submit listing information for any
drug manufactured, repacked, relabeled, or salvaged at any such
establishment. A single labeler code may be used in the NDCs for all
drugs proposed by such a parent, subsidiary, or affiliate company.
    (Comment 47) A comment asked FDA to confirm that the NDC assignment
requirement for APIs applies to all APIs, whether they are supplied by
domestic or foreign establishments.
    (Response) Any drug, including an API, manufactured at a domestic
establishment for commercial distribution in the United States must be
listed under Sec.  207.49 unless exempt under Sec.  207.13. As proposed
and under this final rule, the registration and listing requirements
apply to foreign establishments whose drugs, including APIs, are
imported or offered for import into the United States. See Sec. Sec.
207.13(j), 207.49, and 207.53.
    (Comment 48) Some comments urged FDA to exempt allergenic extract
products from the NDC requirement or from drug establishment
registration and listing generally. These comments argued that the
proposed rule would require manufacturers of allergenic extracts to
manage a large number of NDCs without obvious benefits.
    (Response) Allergenic extracts are used in the diagnosis and
treatment of allergies. As such, they are appropriately regulated as
drugs under the FD&C Act and FDA's regulations. Section 510 of the FD&C
Act authorizes FDA to exempt certain persons from establishment
registration (and hence listing) if registration ``is not necessary for
the protection of the public health.'' We decline to make this finding
for allergenic extracts. Such an exemption would diminish FDA's ability
to inspect establishments at which allergenic extracts are manufactured
and track marketed products.
    Both before and after this final rule, our regulations in part 207
have required that each listed drug product have an NDC. We understand
that this requires manufacturers of allergenic extracts to associate a
unique NDC with each product they manufacture for commercial
distribution, and this may result in a large number of NDCs. We believe
the public health benefits associated with drug registration and
listing outweigh the burden this places on manufacturers to manage a
large number of NDCs.
    (Comment 49) One comment asked whether drug samples are subject to
the NDC requirement.
    (Response) Under this final rule, registrants must list drugs they
manufacture, repack, relabel, or salvage for commercial distribution.
The term ``commercial distribution'' is defined in a way that
encompasses free samples. Because any listed drug requires an NDC,
drugs packaged for distribution as promotional samples are expected to
have NDCs.
    (Comment 50) Some comments recommended that pharmacy compounded
drugs be eligible for NDC

assignment. These comments noted that hospital pharmacies use the NDC
to reduce medication errors.
    (Response) Drug products compounded by a licensed pharmacist or a
licensed physician in conformance with section 503A of the FD&C Act are
generally exempt from drug establishment registration and listing under
part 207 before and after this final rule, consistent with the
exemptions for pharmacies and practitioners in section 510(g) of the
FD&C Act. The DQSA added section 503B to the FD&C Act. Under section
503B, a compounder can register with FDA as an ``outsourcing
facility.'' Because the FD&C Act now establishes a separate
registration and drug product reporting process for such outsourcing
facilities, this final rule exempts outsourcing facilities from the
registration and listing requirements of part 207. (See new Sec.
207.13(k).)
    Compounders that meet the conditions for exemption from
registration and listing requirements under part 207 may elect to
voluntarily register and list their products under part 207 and obtain
NDCs.
2. What changes require a new NDC? (Sec.  207.35)
    Section 207.33(f) of the proposed rule identified the types of
changes to a drug that require a new NDC. This final rule includes new
Sec.  207.35 that states with greater clarity the types of changes to a
drug that require a new NDC. Substantively, new Sec.  207.35 is similar
to the corresponding requirements in the proposed rule, but the
provision does not require a new NDC when changes are made to inactive
ingredients or when the Drug Master File number or Veterinary Master
File number, if any, assigned to an API changes.
    (Comment 51) Some comments were concerned about the types of
changes to a drug that would require a new NDC in the proposed rule. In
particular, many comments opposed the proposed requirement that changes
in a drug's inactive ingredients would necessitate a new NDC.
    (Response) This proposed requirement--that a change in a drug's
inactive ingredients would necessitate a new NDC--has not been retained
in the final rule. Under both the proposed rule and the final rule, any
change in information submitted with a drug listing must be reflected
in an updated listing under Sec.  207.57. Certain more significant
changes also require a new NDC, as specified in new Sec.  207.35. Upon
careful consideration, we agree with those comments that stated it
would be unreasonably burdensome to require registrants to submit a new
NDC each time they change the inactive ingredient composition of a
product.
    Some comments questioned the scope of the proposed requirement:
Would it apply to changes from one inactive ingredient supplier to
another? Would it apply to changes in the quantity at which an inactive
ingredient is used? Would it apply to changes in the compositional
specifications of an inactive ingredient?
    The justification for this requirement suggested in the proposed
rule was that some patients may be sensitive to certain inactive
ingredients, and a change in NDC would flag for those patients and
their pharmacists and health care providers that a drug's composition
may have changed (or that some other characteristic identified in Sec.
207.35 changed).
    Upon careful consideration, we agree with those comments that
challenged this justification. Paying attention to changes in NDCs
would be an inexact way for patients, pharmacists, and health care
providers to discover changes in inactive ingredients. As proposed and
under this final rule, updates to drug listing information (including a
new NDC) will be submitted each June and December, or sooner at the
registrant's discretion. Thus, manufacturers will not be obligated to
change an NDC immediately upon changing an inactive ingredient and
update the NDC on their labels on a batch specific basis.
    Comments pointed out that, particularly in the case of OTC
monograph products, manufacturers currently have the flexibility to use
certain inactive ingredients interchangeably. FDA's current guidance
regarding the labeling of OTC drug products acknowledges this practice
and includes formatting recommendations to accommodate the practice.\2\
The proposed rule did not explain, for example, how the new NDC
requirement would apply in a situation where the manufacturer of an OTC
monograph product may have switched inactive ingredients in several
different batches in the 6 months leading up to a semiannual listing
update submission.
---------------------------------------------------------------------------

    \2\ See the guidance for industry ``Labeling OTC Human Drug
Products--Questions and Answers,'' December 2008, pp. 10-11,
available on the Internet at http://www.fda.gov/Drugs under
Guidances (Drugs).
---------------------------------------------------------------------------

    Rather than impose this burden on some manufacturers, and
recognizing that ingredient labeling and reference to batch numbers are
more useful and exact ways to ascertain a drug's composition, this
final rule does not require a new NDC when a drug's inactive
ingredients change.
    (Comment 52) One group of comments expressed concern about the many
situations in which a new NDC would be needed under the proposed rule.
In addition to mentioning changes in inactive ingredients, the comments
cited any addition to a drug's label or labeling, including the
addition of stickers with delivery and handling instructions and ``any
material change to a drug's labeling or packaging insert'' as things
that should not warrant a new NDC. The comments emphasized the burden
associated with changes to a drug's NDC.
    (Response) Several changes in this final rule will reduce the
number of occasions when a drug requires a new or additional NDC,
compared to the proposed rule. See the response to comment 51 regarding
changes to inactive ingredients. See our response to Comment 17
regarding the revised definition of ``relabel'' in the final rule to
exclude the addition or modification of information affixed solely for
purposes of delivery to a customer, customer identification, or
inventory management. Under this final rule, changes or additions to a
label that do not qualify as relabeling do not necessitate a drug
listing submission and NDC under Sec.  207.53. Section 207.35 of this
final rule does not include ``any material change'' to a drug's
labeling or package insert among the changes that necessitate a new
NDC. Labeling changes are generally not included in new Sec.  207.35.
Some labeling changes will be incidental to the changes included in new
Sec.  207.35 (e.g., a change to a drug's established or proprietary
name), but labeling changes themselves do not trigger the need for a
new NDC under this final rule. FDA has also determined that changes in
Drug Master File numbers or Veterinary Master File numbers describing
APIs, alone, should not necessitate new NDCs. Changes in APIs
themselves, i.e., a change in the identity of an API, will continue to
necessitate new NDCs under new Sec.  207.35.
    (Comment 53) The Animal Health Institute noted that Animal Drug
User Fee Act (ADUFA) fees are assessed for each animal drug NDC. This
comment pointed out that manufacturers of animal drug products will be
potentially charged twice for a single drug product due to a change in
the NDC during a fiscal year or due to multiple listings for a single
product required under this final rule. The comment urged FDA to exempt
animal drug manufacturers from paying such extra product fees imposed
by this final rule.
    (Response) As noted in our response to Comment 52, several changes
in this

final rule will reduce the number of occasions when a drug requires a
new or additional NDC, compared to the proposed rule. Under ADUFA, the
term ``animal drug product'' means each specific strength or potency of
a particular active ingredient or ingredients in final dosage form
marketed by a particular manufacturer or distributor, which is uniquely
identified by the labeler code and product code portions of the NDC,
and for which an animal drug application or a supplemental animal drug
application has been approved. See section 739(3) of the FD&C Act.
Because product fees are assessed under ADUFA for animal drug products
meeting this definition, fees are not assessed for unfinished animal
drugs or animal drugs that are not marketed. However, there may be
instances where a change is made to a marketed animal drug product that
necessitates a new NDC for that product during a single fiscal year,
resulting in a new ADUFA product fee. This is an issue that has existed
prior to this final rule.
    (Comment 54) One comment asked whether a new NDC will be required
when a manufacturer changes to a new supplier of an API or, relatedly,
whether multiple NDCs would be needed if multiple suppliers of an API
are indicated in an approval application for a finished drug product.
    (Response) Section 207.35 of this final rule requires a new NDC
when there is a change to any API. This provision includes changes from
one API to another (e.g., a change from acetaminophen to ibuprofen) and
changes in the strength of an API. The provision does not encompass
changes in suppliers and does not require multiple NDC product codes
corresponding to multiple API suppliers.
    (Comment 55) One comment requested clarification regarding when a
change in drug product strength will require a new NDC (or when
multiple strengths will require multiple NDCs). This comment
distinguished between concentration and strength.
    (Response) Section 207.35 of this final rule requires a new NDC if
the strength of any API changes. The term ``strength'' is generally
used to refer to the absolute quantity of API in a single unit dose
(e.g., 250 milligrams (mg) per tablet). Concentration, on the other
hand, refers to the amount of an ingredient per defined weight or
volume of product (e.g., 1 mg/1 milliliter (mL)). Examples of multiple
strengths requiring separate NDCs include 100 mg/tablet, 250 mg/tablet,
1 mg/1 mL, and 2 mg/2 mL. Each of these would require its own NDC if
each is supplied as a unit dose. This is true even though the last two
concentrations are equivalent.
    (Comment 56) Some comments questioned whether two digits are
sufficient for the package code segment of the NDC. Relatedly, some
comments requested clarification regarding the need for a new NDC when
changes are made to a drug's package size or type. For example, would a
change from one type of plastic bottle to another necessitate a new
NDC? Another comment argued that changes in medical gas packaging
should not necessitate many new NDCs.
    (Response) A 2-digit package code segment accommodates 100
different packaging configurations, counting ``00'' as one possibility.
    There should be a separate package code for each package size.
Therefore, if a package is enlarged to hold more of a drug product, it
would need a new NDC.
    A change in package configuration, such as a change from a bottle
to a blister pack, would also require a new NDC.
    Under new Sec.  207.35(c), a new NDC (specifically a new package
code segment) is needed for changes in the composition of packaging
material that are significant enough so that the packaging type
description previously submitted is no longer accurate. When submitting
drug listing information electronically, registrants are currently
prompted to identify the package type by selecting a choice from a drop
down list. For example, ``Bottle, Plastic'' is currently one available
selection in the drop down list. If a registrant originally described
its packaging material using this term and later switched from one type
of plastic bottle to another, there would be no need for a new NDC. But
if a change in packaging material is more significant, from plastic
bottle to glass bottle, for example, so that a new package type should
be selected from the drop down list, FDA would require a new NDC with a
new package code segment to accompany the revised listing under Sec.
207.35(c). (This discussion pertains only to drug listing obligations.
Please see the FDA guidance for industry on ``Container Closure Systems
for Packaging Human Drugs and Biologics'' (May 1999, available on the
Internet at http://www.fda.gov/Drugs under Guidances (Drugs)) regarding
filing requirements for changes to container closure systems in the
case of drug products that are the subject of an approved application
(NDA, abbreviated new drug application (ANDA), or BLA)).
    Medical gases are generally packaged in tanks, canisters, or
cylinders. A registrant listing a medical gas would choose the
appropriate packaging type from the drop down list, populated with such
terms, in our electronic drug establishment registration and listing
system. We do not currently require more detail about the composition
of a tank, canister, or cylinder in which a medical gas is packaged and
would not require a listing update or a new NDC if the composition of a
tank, canister, or cylinder changes. Therefore, we do not anticipate an
unreasonable proliferation of NDCs associated with medical gas
packaging under this final rule.
    If a registrant exhausts all 100 package codes for a single
product, that registrant may add a second product code, effectively
making 100 more package codes available. This provision is reflected in
Sec.  207.35(c) of this final rule.
    (Comment 57) One comment stated that many minor changes are made to
a drug's packaging, such as resin composition and size optimization.
This comment stated that these minor changes are already the subject of
submissions to FDA, for example, as an annual report (submitted under
Sec.  314.81(b)(2)), a prior approval supplement to an NDA, or a
changes-being-effected supplement. This comment implicitly questioned
the need for new NDC package codes triggered by these changes.
    (Response) Section 207.35(c) of this final rule requires new NDCs,
specifically new package codes, when changes are made to a drug's
package size or type. See our response to comment 56 regarding our
interpretation of this requirement. We acknowledge that certain
postapproval packaging changes are reported to an NDA, BLA, or ANDA
consistent with current Sec.  314.70 and FDA http://www.fda.gov/Drugss
guidance for industry ``Container Closure Systems for Packaging Human
Drugs and Biologics; Chemistry Manufacturing, and Controls
Documentation'' (May 1999, available on the Internet at http://www.fda.gov/Drugs under Guidances (Drugs)) and to a new animal drug
application (NADA) or an abbreviated new animal drug application
(ANADA) consistent with current Sec.  514.8 and FDA's guidance for
industry ``Chemistry, Manufacturing, and Controls Changes to an
Approved NADA or ANDA'' (May 2007, available on the Internet at http://www.fda.gov/Drugs under Guidances (Drugs)). These submissions, however,
do not duplicate or satisfy the Agency's objectives behind drug listing
and the use of the NDC to identify individual marketed drug products.
These submissions also are

not made for drugs that are not subject to the new drug approval
requirements.
3. What restrictions pertain to the use of the NDC? (Sec.  207.37)
    Proposed Sec.  207.37 set forth restrictions pertaining to the use
of NDCs. These provisions are retained in the final rule with minor
revisions. New Sec.  207.37 clarifies that a product improperly bearing
an NDC may be deemed to be misbranded. Additionally, new Sec.  207.37
is not addressed only to ``manufacturers, repackers, and relabelers.''
Persons who are not subject to part 207 are cautioned against
concluding that the restrictions stated in Sec.  207.37 do not apply to
them. Improper use of an NDC, as described in Sec.  207.37, may result
in a misbranding charge under the FD&C Act, whether or not the
responsible party is generally subject to part 207.
    (Comment 58) One comment agreed that NDCs should not appear in the
labeling of dietary supplements, foods, and medical devices, but
encouraged FDA to exercise enforcement discretion in this area. Other
comments urged FDA to permit the use of NDCs on medical devices and
medical foods. Others asked FDA to implement an alternative
identification system for medical devices before finalizing this rule.
    (Response) Section 207.37 of this final rule states that a product
may be deemed to be misbranded if an NDC is used on the product but it
is not subject to part 207. Since publication of the proposed rule, FDA
has issued a final rule requiring UDIs on medical devices (78 FR 58786,
September 24, 2013). Section 801.57 of that rule (21 CFR 801.57)
generally prohibits the use of an NDC on the label of a medical device
after the date on which it must bear a UDI.
    The use of an NDC on the label of a product that is not regulated
as a drug may confuse and mislead consumers and health care providers
into believing FDA regulates the product as a drug. Any enforcement
actions in this area will be subject to a determination that a product
violates Sec.  801.57 or is misbranded, or otherwise violates the FD&C
Act.
    (Comment 59) One comment argued against the proposed rule's
prohibition against the use of NDCs on non-drug products and asked, if
this prohibition is retained in the final rule, how long manufacturers
of such products would have to remove NDCs from their labels.
    (Response) Please see our response to comment 58 regarding the
nature of Sec.  207.37, specifically our clarification that the use of
NDCs in the labeling of non-drug products may be handled as misbranding
violations or as violations of Sec.  801.57 as appropriate. See FDA's
Unique Device Identifier rule (78 FR 58786) and any guidance FDA may
issue regarding the compliance deadline for Sec.  801.57. When an NDC
in the labeling of a non-drug product creates the misleading impression
that FDA regulates the product as a drug, that product may be subject
to enforcement action.

E. Listing (Part 207, Subpart D)

1. Who must list drugs and what drugs must they list? (Sec.  207.41)
    Proposed Sec.  207.41 specified who must list drugs, and the
provision is retained in this final rule. Section 207.41(c) now
includes more detail about the manner in which drugs manufactured for
private label distribution are listed.
    (Comment 60) Some comments urged FDA to allow private label
distributors to list drugs that are distributed under their names.
    (Response) Please see our response to comment 16 regarding the
definitions of ``private label distributor'' and ``private label
distribution'' in Sec.  207.1 for a discussion of the responsibilities
of private label distributors in this final rule. Private label
distributors are not obligated--by their status as private label
distributors--to register an establishment or list drugs. They may,
however, submit drug listing information or establishment registration
information if acting as the authorized agent of a registrant on whose
behalf the information is submitted.
2. When, after initial registration of an establishment, must drug
listing information be submitted? (Sec.  207.45)
    Proposed Sec.  207.45 described an establishment's drug listing
obligation at the time of initial registration. It stated that an
establishment must, at the time of initial registration, list any drug
then being manufactured, repacked, relabeled, or salvaged for
commercial distribution at the establishment. Section 207.45 is revised
in this final rule to state that such drugs must be listed no later
than 3 calendar days after initial registration of the establishment.
    (Comment 61) One comment encouraged FDA to provide flexibility in
the timing of new drug listing submissions. The comment stated that it
supported the current requirement of 5 calendar days from the start of
manufacturing.
    (Response) Several provisions of this final rule relate to the time
periods within which establishment registrations, drug listings, and
drug listing updates must be submitted. Section 207.21 states that
domestic establishments must register for the first time no later than
5 calendar days after beginning to manufacture, repack, relabel, or
salvage a drug or an animal feed bearing or containing a new animal
drug (whether or not commercially distributed). This 5-day window for
initial establishment registration starts at the beginning of
manufacture, not the beginning of commercial distribution. Section
207.45 states that each drug being manufactured, repacked, relabeled,
or salvaged for commercial distribution at the time of initial
registration must be listed no later than 3 calendar days after initial
registration. Thus, the 3-day window established in Sec.  207.45
relates to those drugs being manufactured at the establishment for
commercial distribution at the time of initial registration. We will
interpret the phrase ``for commercial distribution'' in Sec.  207.45
flexibly as meaning immediate or near-term commercial distribution, not
for storage prior to an initial product launch.
    FDA recognizes that because it has made findings that nondisclosure
of most drug listing information would be inconsistent with the
protection of the public health (see Sec.  207.81), registrants may be
reluctant to list drugs that have not yet been commercially launched.
FDA intends to interpret the timing requirements in a way that
accommodates this concern. FDA also encourages and expects registrants
to list drugs promptly upon commercial launch (following Sec.  207.45
or Sec.  207.57 as appropriate), recognizing that manufacturers have an
incentive to list drugs promptly and have their proposed NDCs assigned
by FDA. After a drug is listed, it should appear in our public NDC
database within approximately 1 business day and in our internal
database almost immediately.
3. What listing information must a registrant submit for a drug it
manufactures? (Sec.  207.49)
    Proposed Sec.  207.49 identified the information that a registrant
must provide with a drug listing submission for a drug it manufactures.
Section 207.49 is retained and reorganized in this final rule. Some
information included in proposed Sec.  207.33(c) (what information must
a manufacturer submit before we will assign an NDC number to a drug?)
has been incorporated into new Sec.  207.49 as drug listing information
because it is not necessary under this final rule for manufacturers to
request an NDC from FDA.
    (Comment 62) One comment noted that an approved U.S. application

number is included with drug listing information identified in Sec.
207.49 and asked FDA to clarify whether an application must be approved
before drug listing information is submitted.
    (Response) Section 207.49(a)(7) of this final rule requires
registrants to provide the approved U.S. application number with
listing information for a drug if one exists. Thus, Sec.  207.49
requires that an approved U.S. application number be provided with drug
listing information only if it exists. Unapproved drugs can and must be
listed without an application number.
    Drugs that are the subject of an application need not be listed
until they are manufactured for commercial distribution. Registrants
who are awaiting approval of an application may voluntarily reserve an
NDC for the drug that is the subject of the application prior to its
approval under new Sec.  207.33(d)(3). These registrants are also
permitted, but not required, to list a drug before it is marketed,
while providing a future start marketing date.
    (Comment 63) Many comments opposed the submission of production
volume information with drug listing information.
    (Response) In the preamble to the proposed rule, FDA stated that it
was considering whether to require establishments to provide the number
of batches and batch size for each drug subject to the listing
requirement that they manufactured, repacked, or relabeled since the
establishment last provided listing information (71 FR 51276 at 51312).
We have decided not to include such a requirement in this final rule.
    (Comment 64) One comment urged FDA to eliminate the requirement
that registrants submit representative samples of any other labeling
for OTC drug products.
    (Response) Section 207.49(a)(14)(ii)(b) of this final rule requires
that for each human nonprescription drug not subject to section 505 of
the FD&C Act or section 351 of the PHS Act (i.e., not subject to
premarket approval), drug listing information include the current
label, the package insert (if any), and a representative sampling of
any other labeling. The submission of ``any other labeling'' for such
drugs is a requirement of section 510(j)(1)(B)(ii) of the FD&C Act.
    (Comment 65) One comment questioned the proposed requirement that
the ``drug facts'' labeling for OTC drug products be included in drug
listing information, arguing that required labeling for OTC products is
set forth in OTC monographs and in FDA's regulations in Sec.  201.66.
    (Response) We disagree with this comment. Section
207.49(a)(14)(ii)(B) of this final rule requires that labeling
submitted with drug listing information for human nonprescription drugs
not subject to section 505 of the FD&C Act or section 351 of the PHS
Act include the ``content of labeling.'' This term is defined in Sec.
207.1(b) to include, for these drugs, the drug facts labeling required
by Sec.  201.66. The submission of drug listing information is the only
mechanism by which FDA has quick access to the labeling that is
currently in use for marketed OTC drug products. Furthermore, section
510(j)(1)(B)(ii) of the FD&C Act requires that the label, package
insert, and a representative sampling of any other labeling be provided
with listing information for all such drugs, thus encompassing the drug
facts labeling.
    (Comment 66) One comment urged FDA to require that drug listing
information for human OTC drugs include the current product label, but
not other labeling. This comment also urged FDA to accept such labels
in portable document format (PDF) files rather than structured product
labeling (SPL).
    (Response) As explained in response to Comments 64 and 65, the FD&C
Act requires that drug listing information for OTC human drugs not
subject to section 505 of the FD&C Act or section 351 of the PHS Act
include the label, package insert, and a representative sampling of
``any other labeling.'' Therefore, this comment's recommendation that
only the current product label (i.e., the container label) be submitted
for such products is contrary to the FD&C Act, and we decline to adopt
it. Drug listing information is the only mechanism by which FDA
collects labeling for such products, and it is important that we have
it readily available.
    This final rule does not specify a file format for the submission
of drug listing information, but it does require electronic submission
in a format FDA can ``process, review, and archive.'' (See Sec.
207.61(a) of this final rule.) As explained in our electronic
registration and listing guidance, to facilitate the submission of drug
establishment registration and drug listing information (including the
content of labeling), FDA has adopted the use of extensible markup
language (XML) files in a standard SPL format. The automated submission
process functions most efficiently and effectively when this
information is provided in a standardized format with defined code sets
and codes. Information in a properly created and complete SPL file can
facilitate processing and allows for greater precision and accuracy
through the use of coded data fields rather than merely electronic
text. For these reasons, we will continue to expect drug listing
information in SPL format.
    In the case of unfinished drugs, Sec.  207.49(a)(15)(iv) requires
submission of the label (if any) but does not require registrants to
submit the content of labeling. Because FDA does not currently
electronically process the labels submitted for unfinished drugs, we
have accepted and will continue to accept electronic submission
unfinished drug labels in JPEG (Joint Photographic Experts Group) file
format.
    (Comment 67) One comment questioned the proposed requirement that
drug listing information include the name of each inactive ingredient
in a listed drug. Another comment argued that drug listing submissions
for animal drug products in particular should not be required to
identify inactive ingredients.
    (Response) This requirement is retained in the final rule,
specifically in new Sec.  207.49(a)(5), applicable to both human and
animal drugs. FDA finds it important to maintain up-to-date inactive
ingredient information for all marketed drug products. This allows FDA,
for example, to determine the extent to which a particular inactive
ingredient is currently in use and identify drug products that contain
it. FDA does not have access to this information in the form of a
searchable database outside of our drug registration and listing
information.
    (Comment 68) We received several comments pertaining to the drug
listing obligations of contract manufacturers, contract packagers, and
contract laboratories. One requested clarification regarding the manner
in which a contract manufacturer or packager would submit listing
information for an investigational drug manufactured or packaged for
use in a clinical trial.
    (Response) Contract manufacturers, packagers, and laboratories--
unless they are exempt under section 510(g) of the FD&C Act or Sec.
207.13--will generally qualify as manufacturers under this final rule
and will be required to register their establishments. Under Sec.
207.41 of this final rule, registrants must list drugs they
manufacture, repack, relabel or salvage for commercial distribution.
The definition of ``commercial distribution in new Sec.  207.1 excludes
drugs distributed for investigational use under part 312 (21 CFR part
312) or part 511 (21 CFR part 511). The drugs referred to in this
comment may be exempt from listing under this analysis.
    (Comment 69) Another comment asked how a contract manufacturer or

packager should be expected to submit twice annual drug listing
updates, attesting for example that there have been no changes to a
drug's labeling, when the contract manufacturer or packager is not
responsible for or aware of labeling changes in the ordinary course of
its business.
    (Response) This comment relates to a wide variety of situations. We
recognize that contractors play an important role in drug manufacture.
Some perform specialized operations for another manufacturer (e.g.,
blister packaging), and others perform all manufacturing operations for
a virtual drug company. Some contract manufacturers handle drugs that
are the subject of an approved application and are sold under the name
of the application holder. Others manufacture OTC drugs for multiple
private label distributors. Each situation will require its own
analysis under this final rule, and there may be more than one way to
satisfy the rule's requirements.
    If a contract manufacturer is performing one or more steps in a
larger manufacturing operation, it may be shipping an unfinished drug
to another contracting party. In that case, the contract manufacturer
would submit listing information under Sec.  207.49 for the unfinished
drug it distributes commercially, i.e., the unfinished drug that leaves
its registered establishment(s). This would include labeling
information required under Sec.  207.49(a)(15)(iv), meaning the label
applied to the unfinished drug. In this scenario, the contract
manufacturer would not be responsible for listing updates that describe
labeling changes for the finished drug product, if the contract
manufacturer does not commercially distribute the finished drug
product.
    If a contractor is performing all steps or just the final steps in
a drug manufacturing process, the contractor should describe the
finished drug product in its listing submission. In some cases, a
contract manufacturer may be responsible for formulating the product
and developing its labeling. This might be true in the case of an OTC
store brand, private label distribution product, for example. In that
situation, the contracting parties would likely agree that the contract
manufacturer is in the best position to submit drug listing information
and updates (as it is required to do under this final rule), and this
would include the submission of any labeling changes with twice annual
listing updates. In other cases, a contractor might play a much smaller
role. It might only place a product manufactured and developed by
someone else into its final packaging. In that case, the contractor
would be required by this final rule to submit listing information
pertaining to the finished drug product, including the twice annual
updates. The contractor might satisfy this obligation by consulting
with the drug's developer about any changes in drug listing information
or by letting the drug's developer act as its authorized agent for the
submission of drug listing information and updates. At all times,
however, the actual manufacturer of a drug (or repacker, relabeler, or
salvager) is legally responsible for ensuring that the requirements of
this final rule are satisfied.
    (Comment 70) One comment stated that ``the proposed requirement for
finished product contract testing laboratories to list all of the
products they test should be eliminated.'' The comment pointed out that
testing laboratories only handle representative samples of products
that do not enter the supply chain.
    (Response) This comment addresses an issue that arises under the
FD&C Act and the drug registration and listing regulations as they have
long existed. (See the definition of ``manufacturing or processing''
that has existed in Sec.  207.3 prior to this final rule.) Testing
laboratories, whether they test finished drug products or in-process
materials, may have important roles in drug manufacturing and are
appropriately treated as manufacturers under part 207 if they engage in
testing or control procedures necessary for manufacture under current
good manufacturing practices. Any testing laboratory that qualifies as
a ``manufacturer'' under this final rule must register its
establishment(s) where drugs are tested. The listing obligation,
however, applies only to drugs that a registrant places into commercial
distribution. Therefore, if a laboratory tests in-process materials or
finished product and then commercially distributes the tested product,
e.g., for further processing or for distribution as finished product,
that laboratory would have an obligation to list the drugs it
commercially distributes. More likely, however, if the laboratory
merely tests product samples and reports the test results to another
party without further distributing the tested samples, it has no
listing obligation.
    (Comment 71) One comment expressed concern that importers would
have to identify manufacturers for their drug components and provide a
chain of custody description for each handler from manufacturer to
importer.
    (Response) This comment reflects a misunderstanding of a statement
in the proposed rule describing section 801(d)(3) of the FD&C Act. To
clarify, Sec.  207.49(a)(12) of this final rule requires a registrant
listing a drug it manufacturers to provide: (1) The name and UFI of the
establishment where the registrant manufactures the drug and (2) the
name and UFI of every other establishment where manufacturing is
performed for the drug. With respect to this second category of
information, if the registrant provides a properly assigned and listed
NDC for unfinished drug(s) it uses to produce the listed drug
(sometimes referred to as ``immediate source NDCs''), the registrant
does not need to provide names and UFIs of the upstream establishments.
    (Comment 72) One comment asked FDA to clarify a statement in the
preamble of the proposed rule regarding certificates of analysis for
imported articles.
    (Response) This comment reflects a misunderstanding of the proposed
rule. The passage it refers to quotes section 801(d)(3) of the FD&C Act
(71 FR 51276 at 51284). Section 801(d)(3) of the FD&C Act applies only
to certain imported products, and this final rule does not implement
it.
4. What listing information must a registrant submit for a drug it
repacks or relabels? (Sec.  207.53)
    Proposed Sec.  207.53 identified the information that a registrant
must provide with a listing submission for a drug it repacks or
relabels. Section 207.53 is retained and reorganized in this final
rule. Some information included in proposed Sec.  207.33(d) (What
information must a repacker or relabeler submit before we will assign
an NDC number to a drug?) has been incorporated into new Sec.  207.53
as drug listing information because it is not necessary under this
final rule for manufacturers to request an NDC from FDA.
    (Comment 73) A comment from the medical gas industry expressed
concern about the proposed rule's requirement that repackers identify,
in drug listing information, the NDC associated with a drug immediately
before it is received by the repacker for repackaging. This comment
argued that the complexity of medical gas distribution makes this
requirement difficult to satisfy.
    (Response) We agree that medical gas repackers would need to
significantly change the way they currently do business to identify
immediate source NDCs as specified in the proposed rule. In response to
this comment, we have included an exception in Sec.  207.53 of

this final rule so that repackers and relabelers of medical gases are
not required to include with drug listing submissions the NDC assigned
to each medical gas they receive for repacking or relabeling.
5. What are the requirements for reviewing and updating listing
information? (Sec.  207.57)
    Proposed Sec.  207.57 described the requirements for reviewing and
updating drug listing information. The provision is retained in this
final rule with editorial revisions intended to improve clarity.
Additionally, the section now says registrants are encouraged to submit
listing updates at the time of any change affecting previously
submitted information. We have also deleted a reference to Sec.
207.55. Under Sec.  207.55, FDA may ask a registrant to explain the
basis for its belief that a drug is not subject to approval. We do not
expect registrants to routinely update information provided to us under
Sec.  207.55.
    (Comment 74) Some comments opposed the requirement that to satisfy
the June and December listing update obligation, registrants must
certify that no changes have occurred if no changes have occurred since
the last review and update of listing information.
    (Response) The preamble to the proposed rule specifically requested
comments regarding the burden that may result from the no changes
certification requirement in the context of drug listing updates (71 FR
51276 at 51314). We have retained in this final rule the requirement in
Sec.  207.57(b) that registrants update their submitted drug listing
information each June and December. The review and updating of drug
listing information is critical to the integrity of FDA's database. We
recognize, however, that requiring registrants to submit a twice-annual
``no changes'' certification, on a product-by-product basis, for each
of their listings would impose a substantial burden on registrants,
particularly those that maintain hundreds or thousands of drug
listings. Therefore, Sec.  207.57 of this final rule requires
registrants to report changes to drug listing information either at the
time of any change affecting information previously reported or during
the next June or December listing update following the change. At the
time of the annual registration update under Sec.  207.29(b), a
registrant may submit a blanket ``no changes'' certification covering
all of its listed drug products for which no changes affecting
previously reported listing information were made since the last annual
registration update or listing submission. This blanket, ``no changes''
certification applies only to drug listing information that has been
submitted electronically, as it would be too burdensome for FDA to
maintain certifications for information that has not been submitted
electronically. Therefore, it cannot be used to report that drug
listing information submitted on paper in the past remains current.
This limitation is intended to ease FDA's administrative burden and
allow FDA to consider drug listing information to be fully migrated
from paper submissions to our electronic drug registration and listing
system.
    Please see our response to Comment 30, which addresses this issue
in the context of establishment registration updates.
    (Comment 75) One comment stated that the obligation to provide
updates on individual drug listings within 30 days will demand a great
deal of resources from manufacturers.
    (Response) This comment did not cite the specific provision of the
proposed rule at issue. The preamble to the proposed rule acknowledged
that proposed Sec.  207.57(b) would require that drug listing
information be reviewed and updated only every June and December, but
also stated that FDA would request updates to listing information
within 30 calendar days of a change, to maintain the accuracy of our
drug listing database (71 FR 51276 at 51314). Under Sec.  207.57 of
this final rule, registrants are encouraged to submit updated drug
listing information at the time of any change affecting information
previously submitted, but they are required to submit such information
only every June and December.
    (Comment 76) Two comments asked FDA to clarify whether a registrant
may report all changes to drug listing information when they occur,
i.e., on a rolling basis, instead of conducting a review and update
each June and December.
    (Response) Under Sec.  207.57 of this final rule, registrants must
review and update their drug listing information each June and
December. This is a requirement of section 510(j)(2) of the FD&C Act.
Registrants are additionally encouraged, but not required, to update
drug listing information at the time when changes are made to
previously reported information. These updates do not, however, take
the place of the June and December updates, which may be satisfied by a
no changes certification if no changes have occurred since the last
review and update. We will read ``since the last review and update'' in
Sec.  207.57(b)(2) as referring to the registrant's most recent listing
update for a given drug, whether submitted in June, December, or at any
other time.
    (Comment 77) One comment encouraged FDA to codify a registrant's
ability to submit updated listing information at the time a change is
made, rather than waiting for the next June or December review and
update. This comment referred to a statement in the preamble to the
proposed rule stating that registrants are requested to submit listing
information within 30 days of a change.
    (Response) We agree with this comment and have revised Sec.  207.57
accordingly. New Sec.  207.57 states that registrants are encouraged to
submit listing updates at the time of any change affecting information
previously submitted. This provision of the final rule does not refer
to a 30-day window for such listing updates. We intend to read ``at the
time of any change'' flexibly, encouraging registrants to submit
listing updates as soon as possible, but allowing such updates at any
time before they are due at the next June or December review and
update.
    (Comment 78) One comment expressed concern regarding the manner in
which a drug's discontinuation is to be reported under Sec.  207.57.
This comment noted that historically, many registrants have waited to
report that a drug has been discontinued until they no longer have to
report the drug under applicable agreements with the Centers for
Medicare and Medicaid Services. According to this comment, if an NDC is
identified as discontinued while the drug is still in distribution up
until expiration, there may be problems related to reimbursement and
other matters.
    (Response) The FD&C Act and Sec.  207.57 of this final rule require
listing updates, including information that a drug has been
discontinued, at the latest, at the time of the next June or December
review and update following the discontinuation. In the case of drugs
that are subject to part 314, Sec.  314.81(b)(3)(iv) also requires that
their withdrawal from sale be reported to FDA. The reporting deadline
under Sec.  314.81(b)(3)(iv) is within 15 working days of the
withdrawal from sale before the effective date of this final rule and
within 30 calendar days of the withdrawal from sale after the effective
date of this final rule. It is important that FDA receive this
information soon after discontinuation for the integrity of our
database.
    In this final rule, as in the proposed rule, Sec.  207.57 requires
registrants, when reporting that a listed drug has been discontinued,
to provide the expiration

date of the last lot manufactured, repacked, relabeled, or salvaged.
FDA regards this date as the ``end marketing date'' and includes it in
the public NDC database when a drug is reported to be discontinued.
    Please note that, in addition to the requirements just discussed,
section 506C of the FD&C Act, as amended by FDASIA, requires
manufacturers of certain drugs that are life-supporting, life-
sustaining, or intended for use in the prevention or treatment of a
debilitating disease or condition, to notify FDA of a permanent
discontinuance or certain interruptions in manufacture at least 6
months prior to the date of discontinuance or interruption or as soon
as practicable if 6-month's prior notice is not possible.
    (Comment 79) Two comments opposed the requirement in Sec.  207.57
that registrants provide, for a discontinued drug, the expiration date
of the last lot manufactured, repacked, relabeled, or salvaged, arguing
that the expiration date of the last lot provides no assurance that the
drug product will be available to consumers until that date is reached.
    (Response) As explained in response to Comment 78, our use of the
expiration date of the last lot as an ``end marketing date''
facilitates reimbursement while remaining stock of a discontinued drug
works its way through distribution.
    (Comment 80) Two comments requested clarification regarding how the
inclusion of an approved application number in a drug listing
submission can take the place of the content of labeling in SPL format,
specifically how updated labeling would be provided at the time of a
listing update if only the application number is referenced.
    (Response) The proposed rule indicated that if ``a manufacturer
provides a drug's approved U.S. application number as part of a drug's
listing information, the labeling required under proposed Sec.
207.49(g)(1) and . . . 207.49(g)(2) would be deemed to accompany the
listing information'' (71 FR 51276 at 51309). This was written prior to
FDA's adoption of SPL as the submission standard and is not an accurate
reflection of how the process operates today. However, FDA has
considered how our electronic system can avoid unnecessary duplication
of effort between the submission of labeling updates to applications
and the submission of drug listing information.
    Under this final rule, a drug listing submission, whether it
includes an approved application number or not, must include content of
labeling as specified in Sec.  207.49. An advantage of the SPL format
is that it allows the holder of a newly approved application to submit
the content of labeling once, satisfying its obligations under parts
314 and 207 in a single submission. Upon initial approval, an applicant
is required to submit a copy of final approved labeling. An electronic
drug listing submission that includes the content of labeling in SPL
format can satisfy this obligation. Even if the drug product is not yet
ready for commercial distribution upon approval, SPL allows for a
future start marketing date in the listing information so that a second
submission is not necessary when the product is commercially launched.
    As discussed in response to Comment 15, most drug labeling changes
necessitate a listing update under Sec.  207.57 of this final rule.
Registrants who submit drug listing information through FDA's CDER
Direct electronic submission portal (as well as those using some
commercial software) will be able to recall a previous submission,
including the content of labeling, and make appropriate changes when a
listing update is due. But reference to an application number alone
will not satisfy the requirement that updated content of labeling be
submitted under Sec.  207.57 in this final rule.

F. Electronic Format for Registration and Listing (Part 207, Subpart E)

    Proposed Sec.  207.61 stated that establishment registration and
listing information must be submitted to FDA electronically. As
proposed, Sec.  207.61 would have allowed advertisements and some
labeling to be submitted to FDA either in paper or electronic format.
In this final rule, Sec.  207.61 is revised for clarity. Additionally,
the final version of Sec.  207.61 requires electronic submission of all
establishment registration and listing information, consistent with
FDAAA (no longer allowing for the submission of advertising on paper),
unless a waiver is granted, and states that FDA may issue guidance from
time to time on how to provide information in electronic format.
Because the SPL format currently used for electronic submission of
registration and listing information does not accommodate the
submission of drug advertising, taking into account various types of
advertising media currently in use, FDA is not currently collecting
advertisements as part of drug listing information. If this technical
limitation is resolved, we will explain in future guidance how and what
registrants should transmit electronically as a representative sampling
of advertisements. In the meantime, we may ask individual registrants
to submit a representative sampling of advertisements for specific
prescription human drug products not subject to section 505 of the FD&C
Act, relying on our authority under section 510(j)(1)(B)(i) of the FD&C
Act and Sec.  207.49(a)(14) of this final rule.
    The final version of Sec.  207.61 also clarifies that, while drug
registration and listing information must generally be submitted in the
English language, in some cases the content of labeling may be
submitted in a foreign language along with an accurate English
translation.
    (Comment 81) One comment stated that information should be included
in the final rule to address whether FDA intends to develop a separate
database for animal health products or incorporate animal drugs into
the proposed electronic drug registration and listing database. The
comment recommended that if a separate database is planned, information
on whether the same data elements will be required to obtain an NDC
number and list products would be helpful.
    (Response) At issue in this rulemaking are changes to FDA's
regulations governing drug establishment registration and listing,
i.e., changes to the codified language presented in the proposed rule
and in this final rule. These regulations do not describe the
electronic drug registration and listing systems developed by FDA,
which may change from time to time. Currently, FDA maintains separate
electronic systems for establishment registration and listing for human
drugs and for animal drugs. The information that must be submitted with
a drug listing submission, for both human drugs and animal drugs, is
described in the regulations codified in part 207 as amended by this
final rule.
    (Comment 82) One comment noted that at the time of the proposed
rule and the comment period, FDA's electronic drug registration and
listing system had yet to be developed. Accordingly, stakeholders were
unable to comment on an electronic system that had yet to be developed.
    (Response) We understand stakeholder interest in the development of
our electronic system for drug registration and listing. As noted in
response to Comment 81, however, the amended regulations adopted in
this rulemaking do not describe the electronic drug registration and
listing systems developed by FDA. They generally describe information
that must be submitted to FDA, and they require that it be submitted
electronically. Therefore, the proposed rule did not solicit comments
on the electronic drug

registration and listing system then under development.
    After the proposed rule was published, Congress amended the FD&C
Act to require electronic submission of drug establishment registration
and listing information. To implement this statutory change, FDA
published draft guidance in 2008 and final guidance in 2009 concerning
electronic submission of drug establishment registration and listing
information. Stakeholders had an opportunity to comment on the
electronic system described in our draft guidance and, as with all FDA
guidance, have an ongoing opportunity to comment at any time.
    FDA currently accepts drug establishment registration and drug
listing information submitted electronically. We expect registrants to
find electronic submission less burdensome than the use of paper forms,
and we accept comments and suggestions from stakeholders regarding
improvements to our electronic submission systems.
    (Comment 83) One comment recommended that to facilitate the annual
review and updating of both establishment registration and drug listing
information, FDA provide registrants with a report of their current
registration and listing information.
    (Response) This comment does not relate to language that would be
included in the codified portion of this final rule, but it does raise
an important issue we would like to address. At all times, registrants
are responsible for keeping track of registration and listing
information they have submitted to FDA and should ensure the
information is securely stored and can be retrieved.
    Registrants who use an agent to submit establishment registration
and drug listing information to FDA are encouraged to maintain their
own records of the submitted information or obtain assurances that the
agent will do so and will make the information available to the
registrant on request, including if their business relationship is
terminated.
    FDA currently maintains publicly searchable databases that can be
used to confirm an establishment is registered. Information about
registered blood establishments is available through FDA's electronic
Blood Establishment Registration (eBER) public query application.
Information about registered HCT/P establishments is available through
the Human Cell and Tissue Establishment Registration (HCTERS) public
query application. Information about registered drug establishments can
be obtained through FDA's Drug Establishments Current Registration Site
(DECRS). Additionally, FDA's NDC Directory currently includes listed
finished drug products, but not unfinished drug products. It may be
expanded in the future to include all listed drugs. Registrants can
check these sources and may also request a report of their own
registration and listing information from CDER's Drug Registration and
Listing staff.
    (Comment 84) Comments noted that changes to part 11 (21 CFR part
11) are being considered by the Agency and recommended that electronic
submission of drug registration and listing information be delayed or
exempt from compliance with part 11 until these changes have been
decided.
    (Response) Because of changes to section 510(p) of the FD&C Act
adopted in FDAAA, registration and listing information is currently
submitted electronically. Exceptions from the electronic submission
requirement will be handled in accordance with the waiver provisions in
this final rule (Sec. Sec.  207.65, 607.22, and 1271.23).
    Part 11 sets forth criteria under which FDA considers electronic
records and signatures to be trustworthy and reliable. Part 11 applies
to electronic records that are created, modified, maintained, archived,
retrieved, or transmitted under statutory and regulatory requirements.
In 2003, FDA published guidance for industry titled ``Part 11,
Electronic Records; Electronic Signatures--Scope and Application''
(2003 Part 11 Guidance, available on the Internet at http://www.fda.gov/Drugs under Guidances (Drugs)) and announced its
availability in the Federal Register (68 FR 52779, September 5, 2003).
This guidance announced a reexamination of part 11, a narrow
interpretation of its scope, and a policy of enforcement discretion
with respect to certain of its requirements. Part 11 currently remains
in effect, and FDA's policy of enforcement discretion applies as
described in the guidance.
    Against this backdrop, the proposed rule included a discussion of
how FDA intended to apply part 11 to electronic drug registration and
listing. (See 71 FR 51276 at 51317.) Proposed Sec. Sec.  207.61,
607.22, and 1271.22 specified that certain requirements of part 11
would not apply to information submitted to FDA under parts 207, 607,
and 1271. In Sec.  207.61 of this final rule, the applicability of part
11 is stated as follows: The submission of advertisements and labeling
is exempt from the requirements of Sec.  11.10(a), (c) through (h), and
(k) and the corresponding requirements of Sec.  11.30. Other
information submitted under part 207, as well as information submitted
under parts 607 and 1271, is exempt from the requirements of Sec.
11.10(b), (c), and (e) and the corresponding requirements of Sec.
11.30. These statements in the codified portion of this final rule are
intended to be read together with any current FDA guidance concerning
our enforcement of part 11. For example, FDA's 2003 Part 11 Guidance
states that we do not intend to take action to enforce compliance with
the validation and audit trail requirements of part 11. This includes
requirements described in Sec.  11.10(a) and (e). Until our 2003 Part
11 Guidance is withdrawn or modified, these statements regarding
enforcement discretion remain current. Therefore, any person submitting
information electronically to FDA under this final rule may rely on the
exemptions from part 11 written into parts 207, 607, and 1271, in
addition to statements regarding part 11 enforcement discretion in
current FDA guidance.
    (Comment 85) One comment noted that a citizen petition is currently
pending before FDA requesting that part 11 be revoked in its entirety
(Docket No. FDA-2004-P-0036, formerly Docket No. 2004P-0429/CP1). This
comment asked FDA to respond to the citizen petition before it
completes this rulemaking.
    (Response) The referenced citizen petition remains under review,
and the part 11 regulations are currently being implemented as
explained in FDA's 2003 Part 11 Guidance. FDA's publication of this
final rule should not be interpreted as providing any indication of the
manner in which the citizen petition will be resolved.

G. Miscellaneous (Part 207, Subpart F)

    Section 207.81 of the proposed rule identified establishment
registration and listing information that will be available or not
available for public disclosure after it is submitted to FDA. Section
510(f) of the FD&C Act states that establishment registration
information is available for inspection and drug listing information is
generally not available for inspection unless the Secretary (by
delegation FDA) finds that an exemption from disclosure would be
inconsistent with protection of the public health. Consistent with this
statutory provision, proposed Sec.  207.81 stated that establishment
registration information would be generally available for disclosure
and that most, but not all, drug listing information would be available
for disclosure, as its nondisclosure would be inconsistent with
protection of the public health. Generally categorized as not available
for disclosure in the proposed rule was information obtained under:

     Proposed Sec.  207.33(d)(1)(ii)--Source NDCs for repacked
or relabeled drugs submitted in the context of an NDC request for such
drugs,
     Proposed Sec.  207.54(b)(1)--Source NDCs for salvaged
drugs, and
     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 FD&C Act, the premarket approval requirement for new
drugs and new animal drugs.
    In this final rule, Sec.  207.81 has been revised in several ways.
The section has been reorganized so that registration and listing
information that will be available for public disclosure is identified
in paragraph (a), and exceptions are identified in paragraphs (b) and
(c). Cited section numbers have been revised, consistent with the
renumbering of sections in this final rule (and the shifting of some
information required in the proposed rule as supporting an NDC request
to information required in the final rule as drug listing information).
Substantively, Sec.  207.81 of this final rule identifies an expanded
set of information obtained under the following sections as information
that will not be available for public disclosure:
     Sec.  207.53(b)--Immediate source NDCs for repacked or
relabeled drugs;
     Sec.  207.54(a)--Immediate source NDCs for salvaged drugs;
     Sec.  207.54(c)--The name or UFI of an establishment where
a specific drug is salvaged;
     Sec.  207.55--Information submitted as the basis upon
which it has been determined that a particular drug is not subject to
section 505 or 512 of the Federal Food, Drug, and Cosmetic Act or
section 351 of the Public Health Service Act;
     Sec.  207.33(d)(3)--Information submitted to reserve an
NDC;
     Sec.  207.49(a)(9)--For unfinished drugs, the number
assigned to the Drug Master File or Veterinary Master File, if any;
     Sec.  207.49(a)(12)--The names and UFIs of establishments
where manufacturing is performed for listed drugs and/or immediate
source NDCs;
     Sec.  207.53(c)--The names and UFIs of establishments
where repacking or relabeling is performed for listed drugs; and
     Sec.  207.49(a)(5)--The names of any inactive ingredients
submitted with drug listing information for which the registrant makes
a valid assertion of confidentiality.
    In this final rule, establishment registration information will be
available for disclosure, consistent with section 510(f) of the FD&C
Act, except in limited circumstances as described in Sec.  207.81(c).
FDA has found that nondisclosure of most drug listing information for
marketed drugs would be inconsistent with the protection of the public
health. In most cases, drug listing information is obvious or is
disclosed elsewhere (e.g., a drug's established and proprietary names,
its dosage form and route of administration, its active ingredient(s)).
Specifically, FDA has made a finding that nondisclosure of the listing
information identified in the following bulleted list would be
inconsistent with protection of the public health, except in limited
circumstances as described in Sec.  207.81(c):
     Information obtained under Sec.  207.33 will be available
for public disclosure, but only after a drug is marketed. This
information that will be available for public disclosure includes
information a registrant or private label distributor submits or
updates under Sec.  207.33(c) to obtain an NDC labeler code but does
not include information submitted under Sec.  207.33(d)(3) to reserve
an NDC. Information submitted under Sec.  207.33(c) to obtain a labeler
code (and updates to the information) includes basic contact
information for the registrant or private label distributor to whom the
labeler code is assigned, the types of activities (e.g., manufacture,
repackaging, or private label distribution) in which the person
requesting the labeler code engages with respect to drugs, and the
types of drugs to which the labeler code will be applied. This is not
necessarily, but is arguably, classified as drug listing information
because it relates to NDCs and labeler code segments of NDCs. FDA makes
the finding referred to in section 510(f) of the FD&C Act that
nondisclosure of this information, in the case of marketed drugs, would
be inconsistent with protection of the public health. The contact
information described in Sec.  207.33(c)(1)(i) allows consumers to
verify in some cases that they do not have a counterfeit product. It
also provides additional contact information for the consumer's
reference. Disclosure of the types of activities reported under Sec.
207.33(c)(1)(ii) may provide additional clarity as to a labeler's role
in producing or marketing a drug. Information on the types of drugs to
which a labeler code will be applied, described in Sec.
207.33(c)(1)(iii), is largely available to the public, but centralizing
it promotes the free flow of information to interested consumers.
     Most information obtained under Sec.  207.49 (listing
information a registrant must submit for a drug it manufactures) will
be available for public disclosure after a drug is marketed. This
information includes the drug's NDC; its established and proprietary
name; the name and quantity of each active pharmaceutical ingredient in
the drug; the name of each inactive ingredient (unless a valid
assertion of confidentiality is made); the dosage form; the drug's
approved U.S. application number if any; the drug type (finished vs.
unfinished, human vs. animal, prescription vs. nonprescription); for
drugs subject to the imprinting requirements of 21 CFR part 206, the
drug's size, shape, color, scoring, and code imprint (if any); the
route or routes of administration of the drug; the schedule of the drug
under the Controlled Substances Act; advertisements; labeling; contact
information for private label distributors; OTC monograph references if
any; and the date on which a drug was introduced into commercial
distribution. FDA makes the finding referred to in section 510(f) of
the FD&C Act that nondisclosure of the foregoing information, in the
case of marketed drugs, would be inconsistent with protection of the
public health. The drug information described in Sec. Sec.
207.49(a)(1), (3), (10), (15), and 207.49(b)(1) and (2) will enable
individuals with concerns about counterfeiting to compare information
about a product in their possession with information provided to FDA.
The ingredient information described in Sec. Sec.  207.49(a)(4) and (5)
will in some cases allow individuals to verify ingredient information
provided in labeling against FDA's records. The information described
in Sec. Sec.  207.49(a)(6), (8), and (11) relates to proper physical
form and use of a drug. The application number described in Sec.
207.49(a)(7) allows individuals to access disclosable FDA records about
a drug's approval. Whether and how a drug is scheduled under the
Controlled Substances Act (Sec.  207.49(a)(13)) relates to safe use of
the drug. The advertisements and labeling described in Sec. Sec.
207.49(a)(14) and (15) may include information individuals have not
seen elsewhere describing the risks and benefits of a drug.
Furthermore, FDA's disclosure of labeling information obtained under
Sec.  207.49(a)(15) will allow for the availability of current drug
labeling information through DailyMed, a computerized repository of
drug information maintained by the National Library of Medicine. The
contact information described in Sec.  207.49(a)(16)(ii) may provide
additional contact information for an

individual's reference. All of this information is largely available to
the public, but centralizing it promotes the free flow of information
to interested consumers, health care providers, and others. Note that
two types of information obtained under Sec.  207.49 will not be
available for public disclosure: (1) The names of inactive ingredients
in a listed drug if the registrant listing the drug makes a valid
assertion of confidentiality for them at the time of drug listing and
(2) the number assigned to the Drug Master File or Veterinary Master
File, if any, that describes the manufacture of an unfinished drug.
     Most information obtained under Sec.  207.53 (listing
information a registrant must submit for a drug that it repacks or
relabels) will be available for public disclosure after a drug is
marketed. This information includes the repacked or relabeled drug's
NDC, labeling, advertisements, and contact information for private
label distributors. FDA makes the finding referred to in section 510(f)
of the FD&C Act that nondisclosure of the foregoing information, in the
case of marketed drugs, would be inconsistent with protection of the
public health. The NDC described in Sec.  207.53(a) helps identify who
repacked or relabeled a drug. Labeling and advertising information
described in Sec. Sec.  207.53(d) and 207.53(e) may include information
individuals have not seen elsewhere describing the risks and benefits
of a drug. Furthermore, FDA's disclosure of labeling information
obtained under Sec.  207.53(d) will allow for the availability of
current drug labeling information through DailyMed, a computerized
repository of drug information maintained by the National Library of
Medicine. The contact information for private label distributors
described in Sec.  207.53(f)(2) may provide additional contact
information for an individual's reference. All of this information is
largely available to the public, but centralizing it will promote the
free flow of information. Note that two types of information obtained
under Sec.  207.53 are not available for disclosure: (1) The NDC
assigned to a finished drug received by a registrant for repacking or
relabeling and (2) the name and UFI of establishments where repacking
or relabeling is performed.
     Some information obtained under Sec.  207.54 (listing
information a registrant must submit for a drug it salvages) will be
available for public disclosure after a drug is marketed. This
information includes the salvaged drug's lot number and expiration
date. FDA makes the finding referred to in section 510(f) of the FD&C
Act that nondisclosure of the foregoing information, in the case of
marketed drugs, would be inconsistent with protection of the public
health. Disclosure of the lot number and expiration date information
described in Sec.  207.54(b) may help address any concerns about a
salvaged product's quality, potency, and shelf life.
     Most information obtained under Sec.  207.57 (information
registrants must submit when updating listing information) will be
available for public disclosure. In most cases, information submitted
under Sec.  207.57 updates information previously submitted under
Sec. Sec.  207.49, 207.53, or 207.54. The same disclosure rules will
apply whether information is submitted in an original drug listing
submission or in an updated listing. Our findings under section 510(f)
of the FD&C Act, described previously, that nondisclosure of certain
listing information obtained under Sec. Sec.  207.49, 207.53, and
207.54 would be inconsistent with protection of the public health apply
whether the information is obtained in an original listing submission
or an updated listing submission. Accordingly, the reasons supporting
this finding discussed previously apply to updates submitted under
Sec.  207.57. Some information obtained under Sec.  207.57 will not
have been received previously under Sec. Sec.  207.49, 207.53, or
207.54. This information includes: (1) The date a registrant
discontinues the manufacture, repacking, relabeling, or salvaging for
commercial distribution of a listed drug and the expiration date of the
last lot manufactured, repacked, relabeled, or salvaged, (2) the date a
registrant resumes the manufacture, repacking, or relabeling, for
commercial distribution or a drug previously discontinued, and (3)
certifications that no changes have occurred since the last listing
review and update. FDA makes the finding referred to in section 510(f)
of the FD&C Act that nondisclosure of the foregoing information, in the
case of marketed or discontinued drugs, would be inconsistent with
protection of the public health. The date a business discontinues or
resumes manufacturing a drug, submitted under Sec.  207.57(b)(1)(ii) or
(iii), may help address concerns some individuals may have about
whether a drug in their possession is counterfeit. The certification
that no changes have occurred described in Sec.  207.57(b)(2) will
inform individuals that drug listing information previously submitted
to FDA is up to date as of the no changes certification date.
    (Comment 86) One comment requested that FDA not disclose the names
of inactive ingredients in animal drugs submitted with drug listing
information. This comment stated that inactive ingredients in animal
drugs are generally not listed on labels. Another comment urged FDA not
to place the burden on registrants to proactively request that the
names of inactive ingredients in human drugs be treated as trade
secrets.
    (Response) The proposed rule included a discussion about disclosure
of inactive ingredients reported in drug listing submissions and stated
that FDA will disclose this information unless it is subject to trade
secret protection. See 71 FR 51276 at 51321. In this final rule, we are
codifying that approach by making it clear in Sec.  207.81 that we will
not disclose the names of any inactive ingredients submitted with drug
listing information for which the registrant makes a valid assertion of
confidentiality under Sec.  20.61 or other applicable provision of law.
    This approach will apply to both human and animal drugs in an
ingredient-specific way. In other words, in the absence of a well-
supported assertion of confidentiality for any given inactive
ingredient reported under Sec.  207.49, the name of that inactive
ingredient will be available for public disclosure. The inactive
ingredient composition of a drug product is of interest to consumers
and in most cases is already disclosed on drug labels. We find that
categorical nondisclosure of inactive ingredient information would be
inconsistent with protection of the public health. It is therefore
appropriate that FDA consider this information disclosable in the
absence of a valid assertion of confidentiality that supports
nondisclosure.
    (Comment 87) One comment urged FDA not to disclose the relationship
between customs brokers and their clients. This comment noted that the
proposed rule would have required foreign establishments to identify in
their establishment registrations each person who imports or offers for
import their drugs into the United States. The proposed rule would have
defined the term ``person who imports or offers for import'' broadly to
include agents and brokers. As with establishment registration
information generally, this information would have been available for
disclosure under Sec.  207.81 of the proposed rule.
    (Response) As explained in our response to comment 11, in this
final rule, we define the term ``person who imports or offers for
import'' more narrowly than it was defined in the proposed rule. The
new definition is not intended to include persons operating

merely as customs brokers. Therefore, a person operating merely as a
customs broker will not be identified in a foreign establishment's
registration information and hence will not have its relationship with
the foreign establishment disclosed under Sec.  207.81.
    (Comment 88) One comment asked FDA to clarify the confidentiality
of information submitted to obtain an NDC. Several comments stated that
disclosure of listing information is inappropriate for a yet-to-be
approved product.
    (Response) As discussed in response to comment 31, under this final
rule, registrants will propose their own NDCs with drug listing
submissions. It is not necessary under this final rule to request an
NDC from FDA and support that request with the information specified in
Sec.  207.33(c) of the proposed rule. Some of the information specified
in proposed Sec.  207.33(c) (e.g., the drug's proprietary name and
established name) has been added to drug listing information required
under Sec. Sec.  207.49, 207.53, and 207.54 of this final rule. The
foregoing discussion explains which drug listing information will be
available for disclosure and that it will not be available for
disclosure until after the drug is marketed.
    Section 207.33(d)(3) of this final rule allows anyone with a
labeler code to voluntarily reserve an NDC for a drug product under
development before it is listed. Information submitted under Sec.
207.33(d)(3) to reserve an NDC is identified in Sec.  207.81(b)(3) as
generally exempt from disclosure. Because information submitted to FDA
under Sec.  207.33(d)(3) will relate to drug products under
development, this exemption from disclosure prior to marketing is not
inconsistent with protection of the public health.
    (Comment 89) Two comments stated that under the proposed rule, drug
listing information would be exempt from public disclosure unless the
Secretary deemed its release to be necessary. These comments asked FDA
to clarify the circumstances under which disclosure of drug listing
information would be considered necessary.
    (Response) These comments reflect a misunderstanding of the
proposed rule. In the proposed rule, Sec.  207.81 stated unambiguously
that ``[a]fter a drug is listed, all information obtained for that drug
under Sec. Sec.  207.33, 207.49, 207.53, and 207.54,'' except for
stated exceptions, would be made available for public disclosure upon
request or at FDA's discretion (71 FR 51276 at 51353). We have
determined, under section 510(f) of the FD&C Act and as explained in
the foregoing discussion, that most drug listing information relating
to marketed products will be categorically presumed to be available for
public disclosure because an exemption from disclosure would be
inconsistent with protection of the public health. In the foregoing
discussion, we have explained that Sec.  207.81 of this final rule
identifies a set of drug listing information that will generally not be
available for public disclosure.
    (Comment 90) One comment urged FDA not to disclose registration and
listing information that reveals business relationships among trading
partners, such as those between a drug's manufacturer and a private
label distributor or between a manufacturer and a retail service
repackager.
    (Response) We have carefully considered this comment, along with
section 510(f) of the FD&C Act and our longstanding rules and policies
regarding disclosure of registration and listing information. As a
statutory matter, establishment registration information is generally
disclosable. (See section 510(f) of the FD&C Act.) Thus, information
required for establishment registration under Sec.  207.25 of this
final rule is disclosable.
    This final rule requires that foreign establishments report the
name of each importer known to the establishment and the name of each
person who imports or offers to import its drugs into the United
States. This information is treated as establishment registration
information under section 510(i) of the FD&C Act and under Sec.  207.25
of this final rule, rather than as drug listing information. Because
the information is establishment registration information, both the
FD&C Act and this final rule require that it be available for public
disclosure. FDA's intention to make this information available for
disclosure was highlighted in the proposed rule (71 FR 51276 at 51321).
    Drug listing information will not be available for public
disclosure under this final rule unless its nondisclosure would be
inconsistent with protection of the public health, as set forth in
section 510(f) of the FD&C Act. Most drug listing information is
obvious or is disclosed elsewhere such as in labeling (e.g., size,
shape, color, scoring, route of administration, approved application
number, active ingredient(s)) and its nondisclosure would be
inconsistent with protection of the public health. However, we
recognize that, as emphasized in this comment, some drug listing
information may reveal confidential business relationships. This final
rule exempts from public disclosure drug listing information obtained
under Sec.  207.49(a)(12) (name and UFI of the establishments where a
drug is manufactured and/or immediate source NDCs), Sec.  207.53(c)
(name and UFI of establishments where repacking or relabeling is
performed), or Sec.  207.54(c) (name and UFI of establishments where
salvaging is performed).
    (Comment 91) One comment urged FDA to treat all registration and
listing information as categorically exempt from disclosure.
    (Response) We decline to take this approach. As explained in the
foregoing discussion, the disclosure provisions in this final rule are
consistent with section 510(f) of the FD&C Act, notably its requirement
that establishment registration information be made publicly available
and that drug listing information be disclosed only to the extent that
its nondisclosure would be inconsistent with protection of the public
health.

H. Human Cells, Tissues, and Cellular and Tissue-Based Products (Part
1271)

    The proposed rule included relatively minor amendments to part 1271
to require electronic submission of establishment registration and
listing information for HCT/Ps. These amendments are retained in this
final rule with some revisions. Under this final rule, manufacturers of
HCT/Ps that are regulated solely under section 361 of the PHS Act are
subject to establishment registration and listing under part 1271.
Manufacturers of HCT/Ps that are regulated under section 351 of the PHS
Act or as drugs under section 505 of the FD&C Act are subject to
establishment registration and listing under part 207. (HCT/Ps that are
regulated as medical devices under the FD&C Act are subject to
establishment registration and listing under part 807.)
    (Comment 92) One comment was concerned about the breadth of the
definition of ``importer'' in proposed Sec.  1271.3(mm). This comment
noted that the proposed rule's definition of ``importer'' appeared to
include domestic transplant centers (hospitals) housing patients
awaiting hematopoietic stem cell (HSC) transplant and argued that
requiring foreign establishments to identify such hospitals as
``importers'' would be unreasonably burdensome.
    (Response) Please see our response to Comment 9 regarding the
definition of ``importer'' in Sec.  207.1. We agree with those comments
that challenged the proposed definition as too broad, particularly as
it would have captured downstream recipients of imported products. In
parts 207, 607, and 1271,

we have narrowed the new definitions of ``importer'' by adding the
words ``at the time of entry.'' Therefore, these definitions no longer
capture downstream recipients such as hospitals.

IV. Compliance Dates

    This final rule is effective November 29, 2016.
    The proposed rule included proposed compliance dates by which
registrants and other affected persons would be required to comply with
different aspects of a final rule. For example, we proposed that
manufacturers, repackers, and relabelers be given 3 years from the
effective date of a final rule to ensure that the appropriate NDC
appear on their labels. Proposed compliance deadlines were set forth in
the preamble to the proposed rule but were not reflected in proposed
codified regulatory language. (See 71 FR 51276 at 51345.)
    The compliance dates are adjusted in this final rule to account for
changes we have made in the final rule and to account for our 2009
implementation of electronic registration and listing under part 207 in
accordance with revisions to the FD&C Act. Compliance dates associated
with this final rule are presented in table 2.
    Registrants are encouraged to comply with this final rule as soon
as possible after its effective date. In many cases, the final rule
will not necessitate changes in a registrant's current registration and
listing practices because electronic submission of registration and
listing information already takes place, and the information currently
collected generally comports with this final rule. We recognize,
however, that this final rule introduces new requirements, and some
registrants will need to adjust their registration and listing
activities. Table 2 should be read as a statement that FDA intends to
exercise enforcement discretion between the effective date of this
final rule and the compliance deadlines set forth in the table with
respect to changes introduced in this final rule. At all times,
however, persons subject to registration and listing must fulfill their
statutory obligations and the relevant regulatory provisions set forth
in parts 207, 607, and 1271, either before or after the effective date
of this final rule.

                      Table 2--Compliance Deadlines
------------------------------------------------------------------------
                                           Effective date or compliance
              Requirement                            deadline
------------------------------------------------------------------------
Effective date of the final rule.......  90 days after publication.
Electronic submission of establishment   For products currently subject
 registration and listing information     to part 207, the electronic
 under amended part 207.                  submission requirement in
                                          section 510(p) of the FD&C Act
                                          was largely implemented
                                          through FDA's 2009 electronic
                                          registration and listing
                                          guidance (74 FR 26248). Upon
                                          the effective date of this
                                          final rule, FDA expects
                                          continued electronic
                                          submission of registration and
                                          listing information in
                                          accordance with our electronic
                                          registration and listing
                                          guidance and with new Sec.
                                          207.61. This applies to newly
                                          submitted registration and
                                          listing information as well as
                                          updates to information
                                          previously submitted. FDA will
                                          accept waiver requests in
                                          accordance with Sec.   207.65
                                          of this final rule upon its
                                          effective date.
                                         Two years after the effective
                                          date of this final rule, FDA
                                          intends to remove from our
                                          current electronic database
                                          establishment registration and
                                          listing information submitted
                                          in the past on paper and not
                                          updated with a more recent
                                          electronic submission. The
                                          purpose of this removal is to
                                          purge outdated information
                                          from our database, such as
                                          information registrants failed
                                          to update after discontinuing
                                          a drug product or closing an
                                          establishment. Therefore,
                                          registrants must migrate their
                                          establishment registration and
                                          listing information to our
                                          electronic system (or obtain a
                                          waiver from the electronic
                                          submission requirement) before
                                          that time if they have not
                                          already done so. Registrants
                                          may not rely on a ``no
                                          changes'' certification to
                                          migrate information submitted
                                          in the past on paper to our
                                          electronic system. They must
                                          enter and transmit current
                                          registration and listing
                                          information to FDA
                                          electronically.
Electronic submission of blood           Owners or operators of human
 establishment registration and listing   blood product establishments
 information under amended part 607.      currently register and list
                                          either electronically or by
                                          submitting Form FDA 2830 by
                                          mail. FDA will stop accepting
                                          paper submissions and require
                                          electronic submission of
                                          establishment registration and
                                          product listing information
                                          under amended part 607, unless
                                          individual waivers are
                                          granted, 1 year after the
                                          effective date of this final
                                          rule.
Electronic submission of HCT/P           Owners or operators of HCT/P
 establishment registration and listing   establishments currently
 information under part 1271.             register and list either
                                          electronically or by
                                          submitting Form FDA 3356 by
                                          mail. FDA will stop accepting
                                          paper submissions and require
                                          electronic submission of
                                          establishment registration and
                                          product listing information
                                          under amended part 1271,
                                          unless individual waivers are
                                          granted, 1 year after the
                                          effective date of this final
                                          rule.
Part 207, Subpart B--Registration        Registrants are required to
 (timing of establishment registration    submit and update
 and update submissions and substance     establishment registration
 of the information submitted).           information in accordance with
                                          amended subpart B of part 207
                                          no later than the time when
                                          registration information is
                                          due after the first
                                          anniversary of the effective
                                          date of this final rule. If
                                          the effective date falls
                                          between October 1 and December
                                          31, registrants must submit
                                          information required by
                                          amended subpart B no later
                                          than the next October through
                                          December annual review and
                                          update period.
                                         However, registrants must