Every year, from October 1st to December 31st , sponsors are required to renew their Establishment Registrations with FDA, as well as their Drug Product Listings. Earlier this year, FDA announced a major “clean up” effort, warning sponsors that Drug Product Listings will be periodically inactivated if they fail to meet necessary registration renewal requirements. As we are currently in the reporting period for 2019, we will use this article to give a quick refresh on these two listing types, highlight what needs to be submitted in the renewal period, and how to avoid inactivation.
Establishment Registrations
Who Needs to Register?
Any establishment engaged in the manufacture, preparation, propagation, compounding, or processing (including, among other things, repackaging and relabeling) of a drug must submit an Establishment Registration to the FDA.
When to Register?
Domestic establishments must register within 5 days after beginning any manufacturing activities on a drug.
Foreign establishments must register before the drug is imported or offered to import to the US.
Information to be Included
The following information must be submitted for each establishment being registered, and, where applicable, should match exactly to the format used in its DUNS record:
Name and full address
All trade names used
Type of ownership or operation (ex: individually owned, partnership, corporation)
Name of the owner or operator
For partnerships, include name of each partner
For corporations, the name and title of each corporate officer, director, and the State of incorporation
Official contact’s name, mailing address, telephone number(s), and email address
Type of operation(s) performed at each establishment
For foreign establishments only:
Name address, and phone number of the foreign registrant’s United States agent
Name of each company or individual in the United States that is an owner, consignee, or recipient of the foreign establishment’s imported drug
Name of each each agent, broker, or other entity that the foreign drug establishment uses to facilitate the import of their drug into the United States (other than a carrier)
Format and Submission of Registration
Establishment Registrations must be submitted electronically in Structured Product Label (SPL) format.
Establishment Registrations SPL files can be created and directly submitted to the agency using the CDER Direct Portal, or created through external software, and submitted through the FDA ESG.
Multiple establishments can be included on a single SPL file.
If an establishment is not properly registered, but is referenced in a new drug product listing, it will cause that drug product listing to fail validation.
Updates and Annual Renewal Requirements
Throughout the year, Establishment Registrations should be updated within 30 days of a change such as a change in establishment name or address, change in agent contact information, or closing/selling of an establishment.
Per 21 CFR 207.29, sponsors are required, every year, to review and renew their Establishment Registrations between Oct. 1 and Dec. 31. Updates fall into 4 major categories:
New/Updated Establishment Registration
Uses the standard SPL structure for ERs
De-Registration SPL
Unique SPL structure – used when an establishment is no longer manufacturing drug product for commercial distribution
Out of business SPL
Unique SPL structure – used when company is out of business
No Changes Notification
Unique SPL structure – confirms there are no changes to previously submitted registration
The first 3 types can be submitted any time of year, but No Changes Notifications may ONLY be submitted during the annual update period.
Any updates received before Sep 30th are valid until the end of the current calendar year, whereas updates received within the Oct 1 to Dec 31 period are valid until the end of the following year. Therefore, it is crucial to get your updates in to ensure compliance.
Sponsors can check the status of their Establishment Registrations at the Drug Establishments Current Registration Site (DECRS) page.
Drug Product Listings
Who needs to register and when?
Drug Products in commercial distribution must be listed at the time that their initial establishments are registered, per 21 CFR 207.41. Drugs must be listed regardless of whether it enters interstate commerce.
Format and submission of registration
Similar to Establishment Registrations, Drug Product Listings are to be submitted electronically in SPL format, either through CDER Direct or the ESG. However, this is a separate file from the Establishment Registration, with its own unique SPL format .
There will be one Drug Product Listing SPL per product – multiple products cannot be included on a single file.
Information to be Included
The following information should be included in ALL types of Drug Product Listing SPL files:
Type of operation(s) performed
DEA schedule
Route(s) of administration
Inactive ingredients
Marketing information (e.g., category, start/stop date)
Information related to the application (e.g., type and year of approval)
OTC monograph citation number (if applicable)
Package size and type
NDC Product Code for a Source Drug Repacked or Relabeled
Unique Ingredient Identifiers (UNII) and other code sets
Confidentiality Flag
Distinctive Characteristics of Certain Listed Drugs (Flavor, Color, Image)
The following sections of 21 CFR 207 spell out the specific requirements for listing depending on the registrant’s involvement
21 CFR 207.49 – Listing information to submit for a drug the registrant manufactures
21 CFR 207.53 – Listing information to submit for a drug the registrant repacks or relabels
21 CFR 207.54 – Listing information to submit for a drug the registrant salvages
21 CFR 207.55 – Other Listing info the agency may request
Updates and Annual Renewal Requirements
Sections 510(j)(2)(B) and 510(j)(2)(D) of the FD&C Act required that registrants submit any listing updates or de-list any discontinued product twice a year: in June and December.
Establishment Registrations and Drug Product listings are tied very closely together. Whenever Establishments are updated, associated Drug Product Listings should also be updated.
Previously, if no updates were submitted, the information was assumed to be up to date. However, in 2016, an updated 21 CFR 207 was released, mandating an annual requirement similar to Establishment Registrations – listings either need to be updated, or the sponsor must certify that no changes have occurred.
Similar to Establishment Registrations, the annual reporting period is October 1st-December 31st. Sponsors have two main options:
Re-submit each individual Drug Product Listing SPL with changes, or re-submit with no changes
Submit a “Blanket No Changes” SPL – this allows a sponsor to include all drug product listings and certify that no changes have occurred. These are specially useful when sponsors have several drug products to keep track of.
Unlike Establishment Registrations, if the Drug Product Listing has been updated in the current calendar year, before the start of the Oct-Dec 31 reporting period, they are not obligated to submit something during the reporting period, they will be up to date until the end of the following year . However, Blanket No Change certifications are only permitted to be submitted in the Oct 1-Dec 31 reporting period.
Sponsors can check the status of their drug listings at the National Drug Code (NDC) Directory.
The updates to 21 CFR 207 did not override the need for sponsors to update their Drug Product Listings in June and December each year. While it is only mandatory to update once per year, sponsors should still review that their listings are up to date in the months of June and December, due to a new initiative set forth by the FDA to inactivate outdated listings.
Drug Product Listing Inactivation
As discussed at the start of this article, in August 2019, FDA announced a major effort to clean up their records by inactivating drug product listings that do not meet certain requirements.
The listings targeted for inactivation fall into two main categories: listings that have not been updated or certified in several years, and listings with associated establishments that are inactive or out of date.
In January of each year, starting in 2020, Drug Product listings that did not have their annual certification submitted by the December 31 deadline will be inactivated
In July of each year, starting in 2020, Drug Product listings with unregistered establishments associated will be inactivated.
Drug Products with an inactive status cannot be legally marketed in the US. In the event of an inactivation, listings can be reactivated, but it can take a few business days to reinstate, so it is critical to have your records in order. Feel free to contact WAYS if you are in need of any assistance in this process.
Additional Resources
https://sbiaevents.com/edrls2019/ – Slides/Recordings from FDA’s 2019 Webinar on Establishment Registrations and Drug Product Listings