Document ID: FDA-2019-N-2374-0001
Agency: fda
Document Type: Notice
Title: Drugs Intended for Human Use That Are Improperly Listed Due to Lack of
Annual Certification or Identification of a Manufacturing Establishment Not Duly Registered With the Food and Drug Administration; Action Dates
Posted Date: 2019-08-14T04:00Z

[Federal Register Volume 84, Number 157 (Wednesday, August 14, 2019)]
[Notices]
[Pages 40417-40419]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2019-17436]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2019-N-2374]

Drugs Intended for Human Use That Are Improperly Listed Due to 
Lack of Annual Certification or Identification of a Manufacturing 
Establishment Not Duly Registered With the Food and Drug 
Administration; Action Dates

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice of intent.

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SUMMARY: The Food and Drug Administration (FDA or Agency) is announcing 
its intention to begin inactivating drug listing records that are 
improperly listed in accordance with FDA requirements because these 
drug listings are not certified as being active and up to date or are 
associated with a manufacturing establishment that is not currently 
registered with FDA. FDA's regulations governing drug establishment 
registration and drug listing require registrants to notify FDA if 
commercial distribution of a listed drug is discontinued. They also 
require firms to submit drug listing updates if any material changes 
are made to information previously submitted, including a change in 
manufacturing establishment(s). FDA has found that listings for many 
drug products do not comply with these regulations because they have 
not been updated in over a year, they have not been certified as being 
up to date, or they identify within the listing information at least 
one manufacturing establishment that is not currently registered with 
FDA. Many of the drugs that are the subject of these listings appear to 
no longer be in commercial distribution. The purpose of this notice is 
to remind registrants of their legal obligations and announce that, if 
drug listings are not appropriately updated, certified, or associated 
with a registered establishment, they will be marked by FDA as 
``inactive,'' and the date of inactivation will be added to the listing 
record. This process will result in the closure of drug records in all 
public drug listing databases maintained by FDA, including the National 
Drug Code (NDC) Directory and the NDC SPL Data Elements (NSDE) file, 
until corrections to the relevant listings are made.

DATES: This notice is applicable September 13, 2019.

FOR FURTHER INFORMATION CONTACT: Paul Loebach, Center for Drug 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 51, Rm. 2262, Silver Spring, MD 20993-0002, 301-
796-2173, Paul.loebach@fda.hhs.gov.

SUPPLEMENTARY INFORMATION:

I. Background

    Section 510 of the Federal Food, Drug, and Cosmetic Act (FD&C Act) 
(21 U.S.C. 360) and part 207 (21 CFR part 207) of FDA's regulations 
have long required owners or operators of drug manufacturing 
establishments to register their establishments with FDA. In this 
notice, the term ``manufacture'' refers to all activities that trigger 
the drug establishment registration obligation under part 207, 
including repacking, relabeling, and salvaging as defined in part 207. 
Registrants are also required by section 510 and part 207 to ``list'' 
each drug manufactured at their establishments for commercial 
distribution and submit updated drug listing information to FDA twice 
yearly, in June and December, notifying FDA if this information has 
changed. Specifically, section 510(i)(2) and (j) of the FD&C Act 
require registered establishments to report and periodically update, 
among other information, listing information for each drug 
manufactured, prepared, propagated, compounded, or processed by them 
for commercial distribution in the United States. Under 21 CFR 207.49, 
207.53, and 207.54, registrants must provide listing information that 
corresponds to the activity or activities they engage in for that drug.
    As part of the drug listing information they submit to FDA, 
registrants must identify all establishments where a ``listed drug'' 
(as the term used in the context of section 510 of the FD&C Act and 
part 207) is manufactured or provide a source NDC that enables FDA to 
identify such establishments. Registered establishments must also 
report to FDA the discontinuation of commercial distribution of a 
listed drug (section 510(j)(2)(B) of the FD&C Act) and any material 
change in drug listing information previously submitted, which includes 
any changes in the establishment(s) where the drug is manufactured 
(section 510(j)(2)(D) of the FD&C Act and 21 CFR 207.1). On August 31, 
2016, FDA amended part 207 to require drug manufacturers and other 
registrants, at the time of registration renewal, to certify that no 
changes have occurred to their listings that were not submitted or 
updated during the current calendar year (81 FR 60170 and Sec.  207.57 
(21 CFR 207.57)). The first certifications under this new requirement 
were due during the registration renewal period from October 1 to 
December 31, 2017 (81 FR 60170 at 60201 and Sec.  207.57). 
Establishments and labeler code holders are also required to update 
contact information (name, telephone number, and email) submitted to 
FDA within 30 calendar days of any changes (21 CFR 207.25(g), 
207.29(a)(3), and 207.33(c)(2)).
    Complete, accurate, and up-to-date establishment registration and 
drug listing information is essential to FDA's mission. FDA relies on 
establishment registration and drug listing information in 
administering several key programs, including drug establishment 
inspections, postmarketing surveillance, counterterrorism, recalls, 
drug quality reports, adverse event reports, monitoring of drug 
shortages and availability, supply chain security, and identification 
of products that are marketed without an approved application. If 
registration and listing information is outdated or otherwise 
unreliable (such as inaccurate, superfluous, incomplete, or missing), 
the integrity of the drug establishment registration and listing 
database--and FDA's ability to rely on the reported information for 
these programs--is compromised. Drug registration and listing 
information is also widely used outside FDA for several purposes, 
including electronic drug prescribing, prescription drug reimbursement, 
and patient education. A review of our data shows that the types of 
errors discussed in this notice affect tens of thousands of records. 
Therefore, the inclusion of such incorrect or outdated information in 
FDA's NDC Directory, the NSDE file, or other public drug listing 
databases can negatively affect public health.

II. Circumstances Under Which Certain Drug Listing Information Becomes 
Inaccurate

    Each registrant must list all drugs it manufactures for commercial 
distribution within 3 days of initial

[[Page 40418]]

registration (21 CFR 207.45). Establishment registration must be 
renewed annually between October 1 and December 31 (21 CFR 207.29). 
Each registrant must in June and December each year: (1) Update its 
drug listing information to provide FDA with information about any 
drugs introduced for U.S. commercial distribution not previously 
listed, (2) report the discontinuation of any listed drug, and (3) 
report any material changes in drug listing information submitted 
previously (including any updates in the manufacturing establishments) 
(Sec.  207.57). If there are no changes to listing information to 
report in June or December, then the registrant must certify that there 
have been no changes to the listing information previously submitted, 
during the October 1 and December 31 registration renewal and listing 
certification period (Sec.  207.57). By December 31 of each calendar 
year, registrants should review their current files of listed human 
drugs to determine whether any data elements in their drug listing 
records are no longer accurate and submit updated listing files or 
listing certifications.
    While a new drug listing submission transmitted to FDA 
electronically will not be accepted if the listing information 
identifies a manufacturing establishment that is not registered in 
accordance with FDA's requirements, previously submitted establishment 
and listing information may become outdated for a variety of reasons. 
In some cases, establishments that have discontinued manufacturing let 
their registration expire by not renewing their annual establishment 
registration at the end of the year but fail to update their drug 
listing information to report discontinuation of their listed drug(s). 
The result is that listing information for certain drugs may be 
certified to be current but potentially identifies one or more 
establishments that are not currently registered with FDA in accordance 
with FDA's requirements.
    In other cases, registrants may incorrectly include additional 
establishments in their drug listing submissions (for example, in 
anticipation of a future business relationship with a contract 
manufacturer). Consistent with the applicable regulatory requirements 
in part 207, FDA expects all establishments identified in a drug 
listing submission to reflect current manufacturing facilities for the 
listed drug at the time of the listing submission or at the time of the 
update so that the Agency can rely on the information when submitted as 
an accurate picture of the supply chain. There are also cases in which 
a registrant fails to review and update its previously reported drug 
listing information as required in June and December of each year. 
Similarly, a registrant may neglect to certify to FDA that its listings 
are still up to date and accurate. (See section IV of this document for 
links to FDA's NDC Directory and other resources that may help 
registrants determine whether any data elements in their drug listing 
records are no longer accurate and correct inaccurate drug listings.)

III. FDA's Intended Response

    To address the above registration and listing problems, FDA is 
encouraging firms that are required to register drug establishments and 
list human drugs under part 207 to review their currently listed human 
drugs and determine whether any information in their drug listings, 
including drug establishments identified, is no longer accurate. Any 
active drug listing submissions that are inaccurate should be updated 
as soon as possible.
    Thirty days after publication of this notice, and every January 
thereafter, FDA will begin to inactivate human drug listings that 
remain uncertified from the previous renewal period of October 1 to 
December 31. In addition, every July thereafter, FDA will begin to 
inactivate human drug listings that remain active and certified after 
the June listing update, but still contain at least one establishment 
that is not currently registered in accordance with FDA's requirements. 
This action taken by FDA will include listings for finished drug 
products, as well as for active pharmaceutical ingredients and other 
unfinished drugs. These listing records, including their NDCs, will be 
inactivated and subject to immediate removal from FDA's NDC Directory 
and notification of each NDC's inactivation date will be included in 
FDA's NSDE file. NDCs that are inactivated by FDA may be reactivated 
with an updated and compliant drug listing submission as soon as the 
next business day. If activated again, the listing will again be 
included in the NDC Directory and the reactivation date will be 
included in the NSDE file. If a drug remains in commercial distribution 
after it has been inactivated and removed from the NDC Directory, the 
drug may be deemed misbranded for failure to fulfill registration or 
listing obligations under section 502(o) of the FD&C Act (21 U.S.C. 
352(o)), and persons marketing the drug in the United States or 
offering it for import into the United States may be subject to 
enforcement.
    Manufacturers and repackagers of products subject to the new 
product identification requirement (see section 582(b)(2) and (e)(2) of 
the FD&C Act, respectively (21 U.S.C. 360eee-1(b)(2) and (e)(2))), and 
who have incorporated the new product identifier (serialization) into 
their labeling, must submit such updated labeling with listing updates 
(Sec.  207.57) and not merely certify that affected listings are up to 
date via ``no changes'' certifications during the registration renewal 
period. Such a change requires that a new and representative sample of 
labeling incorporating the new product identifier requirements be 
submitted as an update to listing (Sec.  207.57). Note that such an 
update would satisfy the annual certification requirement for the drug 
listing and not require an additional ``blanket no changes'' submission 
to maintain the listing's active status.
    Firms are required by law to update their drug listings when they 
discontinue marketing their listed drugs (Sec.  207.57). To properly 
discontinue a listed drug, the listing record must be updated to 
include an accurate marketing end date that corresponds with the last 
lot expiration date of the drug (Sec.  207.57(b)(ii)). If the listing 
record expires without an update, certification, or discontinuance 
submitted, the process described above will assign an inactivation date 
that is different from the actual date of discontinuance and may have 
unintended consequences for dispensing and reimbursement. Rather than 
explicitly discontinuing certain listings, some firms have notified FDA 
that they do not intend to certify or update those listings. However, 
listing certification is a separate requirement and should not be 
treated as a mechanism to discontinue the drug listing record.

IV. Resources Available To Assist With Updating or Certifying Drug 
Listings

    The NDC Directory (available at: https://www.fda.gov/Drugs/InformationOnDrugs/ucm142438.htm) currently identifies all active, but 
uncertified, listings. The online search marks uncertified listings 
with a ``(U)'' in red font. The online search also marks active but 
otherwise deficient or erroneous listing records with an ``(E)''. 
Listing records marked with an ``(E)'' have been identified by FDA as 
having an error or deficiency associated with the submission. These 
include, but are not limited to, records with at least one 
establishment that is not registered in accordance with FDA's 
requirements. All listing records should be reviewed for accuracy at 
least biannually,

[[Page 40419]]

regardless of whether they have been marked as deficient or not. Within 
the download files for the NDC Directory, uncertified listings may be 
identified using the LISTING CERTIFIED THROUGH DATE column. Any value 
that appears in this date field occurring in the past identifies a 
product listing that has not been certified. Erroneous or deficient 
listings are identified by a value of ``E'' in the EXCLUDE FLAG column.
    Updates and certifications to listing information must be provided 
electronically in Structured Product Labeling (SPL) format. Anyone 
seeking information on how to update listing information may visit 
www.fda.gov/edrls or contact edrls@fda.hhs.gov. Additionally, FDA 
offers two SPL authoring tools for use in the creation and submission 
of SPL: Xforms and CDER Direct. Xforms is available from FDA's SPL web 
page at: https://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm. CDER Direct is available at: 
https://direct.fda.gov.

    Dated: August 8, 2019.
Lowell J. Schiller,
Principal Associate Commissioner for Policy.
[FR Doc. 2019-17436 Filed 8-13-19; 8:45 am]
 BILLING CODE 4164-01-P