FDA Updates Regulations for Establishment Registration and Drug Listing

By Susan Crane, Independent Advisor for OTC Drugs and Labeling, and David Clark, Independent Consultant

Ten years after issuing proposed rules to amend and update regulations regarding establishment registration and drug listing, FDA published the final rule on August 31, 2016. The amendments update and clarify existing regulations and implement most of those proposed in 2006, and which were subsequently mandated by legislative changes to the Food, Drug and Cosmetic Act (FD&C Act), particularly those requiring electronic submissions. The effective date for updated regulations is November 29, 2016.

Here are some of the key changes and clarifications:


  • Active pharmaceutical ingredient and Bulk drug substance are both included in the regulation to ensure conformity in terminology with the FD&C Act, but they have the same meaning.
  • Establishment registration number and Unique Facility Identifier (UFI) are two different numbers. The former is assigned by the FDA (upon a separate request) after an establishment is registered for the first time and is also referred to as the Facility Establishment Identifier (FEI). The UFI is the DUNS number that is included with the initial registration.
  • Content of labeling was added to describe what information needs to be included in that section of the drug listing submission for prescription, nonprescription, and animal drugs.
  • Private label distribution, Relabeler and Repacker were all added to the definitions as these functions have responsibilities that may have previously been unclear with regard to the registration and listing requirements.
  • Salvage/Salvager were added to the final rule to define activities surrounding segregation of products that may have been subject to adverse storage or handling conditions but for which a firm wishes to return them to the market.

Establishment Registration

  • Establishment registration is required for all foreign and domestic manufacturers, repackers, relabelers and salvagers (unless otherwise exempt as provided for in the regulation).
  • Private label distributors should not register any establishment (unless they also perform one of the functions above or are acting as an authorized agent on behalf of another establishment). They must, however, have their own labeler code.

Drug Listing

  • Registrants are responsible for listing each drug in commercial distribution, including those drug products that are marketed through a private label distributor.
  • While private label distributors are not responsible for listing their products, they may elect to do so if acting as an authorized agent on behalf of a registrant.
  • Drug listings must be submitted no later than three days after the initial registration of the establishment, although the FDA said that this time window relates to drugs for commercial distribution and will allow for situations where products that are held in storage for longer periods prior to launch do not require listing within that time limitation.
  • Registrants must review their drug listing information each June and December and either update it accordingly or certify that no changes have occurred. Registrants are additionally encouraged, but not required, to update drug listing information at the time changes are made, however these updates do not replace the June and December updates nor any “no change” certification.
  • Drug listing submissions must now include a complete listing of inactive ingredients and their corresponding Unique Ingredient Identifier (UNII) – this was previously optional. Registrants will need to ensure that their inactive ingredients are in FDA’s Substance Registration System so that the appropriate UNII can be submitted with the drug listing.


  • The regulation allows for FDA to assign 6-digit labeler codes in the future. The product code and package configurations otherwise remain the same.
  • NDC numbers can be reserved as part of a drug application.
  • Changes that trigger a revision to the product code portion (i.e., middle segment) of the NDC were clarified. Although the proposed rule had included a provision such that changes to inactive ingredients would necessitate a new product code, this was not adopted in the final rule.
  • The FDA clarified the restrictions for using NDC numbers on non-drug products (e.g., dietary supplements, medical foods). Such representations render the product misbranded.

There were two major changes proposed in 2006 that were NOT incorporated into the final rule:

  1. FDA did not assume responsibility for the assignment of the complete NDC to a product, but will continue to accept the product and packaging segments of the NDC that are assigned by the manufacturer in the drug listing submission.
  2. Product labeling will generally not be required to declare human readable NDC numbers on drug labels, although FDA will continue to request their inclusion. However, an intervening statutory amendment, the Drug Supply Chain Security Act (DSCSA), does require NDCs to appear as part of the product identifier on certain drug labels.

The information above is not all-inclusive with regard to the establishment registration and drug listing requirements. Companies should review the entire ruling to ensure that their procedures are compliant with FDA’s expectations.

FDA Invites Comment on Two Draft CGMP Guidances

FDA is inviting public comments by November 23 on two draft guidances — on current good manufacturing practices (CGMP) requirements for food for animals and on CGMPs for human food by-products for use as animal food.

The two guidances are essential reading if your company is required to implement CGMPs for animal foods, especially as FDA is allowing flexibility in compliance depending on the nature of the products and the facilities.

As with all FDA draft guidances, the contents are non-binding and some elements in the final versions may be amended based on stakeholder comments. Nonetheless, the drafts provide useful examples and offer insights into the agency’s latest thinking.

Human food by-products used for animal food must be generally recognized as safe (GRAS) or approved as a food additive. But a substance that is considered GRAS or approved as a food additive for human use “may not always be suitable for use in animal food,” the agency says. Propylene glycol, for example, is considered GRAS as an anti-caking agent for human food but is prohibited in or on cat food.

The agency says it will be reviewing the list of animal food ingredient definitions in the Official Publication of the Association of American Feed Control Officials (AAFCO). Until that review is completed, FDA will accept ingredients in the AAFCO list “provided there are no food safety concerns about the use or composition of the ingredient that would render the food adulterated.”

In guidance on the use of shipping containers and bulk vehicles, the agency says it would expect a facility to know the previous use of a shipping container and whether it needed to be cleaned prior to containing a human food by-product for use as animal food. However, “this does not mean that the shipping container must be cleaned prior to each use in all situations,” the agency adds. But it would be “good practice for the facility to examine the customer’s shipping container or bulk vehicle to confirm that the shipping container or bulk vehicle will not lead to contamination of the human food by-products for use as animal food,” the agency says.

The two guidance documents list exemptions from the CGMP requirements. Generally, if a facility is not required to register with FDA under the Food, Drug and Cosmetic Act (FDCA), it does not have to comply with the CGMP requirements. This includes: farms; facilities regulated exclusively by the U.S. Department of Agriculture (under the Federal Meat Inspection Act, the Poultry Products Inspection Act, or the Egg Products Inspection Act); retail food establishments; restaurants (including pet shelters, kennels and veterinary facilities that provide food to animals are considered restaurants); and foreign facilities – if the food undergoes further processing by another facility outside the United States.

In situations where a facility is required to follow both the human food CGMPs and the animal food CGMPs, FDA will allow them to choose either compliance with the CGMPs in CFR part 117 for its human and animal food or following the CGMPs in part 117 for the human food and the CGMPs in 21 CFR part 507 for the animal food.

Some facilities manufacture, process, pack, or hold food for both humans and animals, FDA notes. For example, a facility that manufactures salt may process some salt meeting certain specifications for human use and other salt meeting certain specifications for animal use.

To decide which CGMPs to follow, the agency suggests that facilities consider how they are manufacturing, processing, packing, or holding the human and animal food. For example, if they have separate employees, production lines, and holding areas for human food and animal food, they might follow 21 CFR part 117 for the human food and 21 CFR part 507 for the animal food. If not, they it might prefer to follow 21 CFR part 117 for both the human and animal food, the agency says.

“We recognize that in many instances animal food facilities will be using the same building, grounds, employees, supervisors, management, equipment, and utensils to perform operations under 21 CFR part 507, subpart B, and part 225. In instances where the facility is subject to both 21 CFR parts 225 and 507 and the CGMPs overlap, the facility must follow the more specific requirements found in 21 CFR part 507, the agency says.

The CGMPs in 21 CFR part 507 are “umbrella” CGMPs that apply broadly to animal foods, but some animal foods, such as low acid canned food and medicated feed, also require specialized CGMPs, FDA explains.

September 19, 2016 was the compliance deadline for larger animal food facilities to comply with new CGMP requirements under FSMA. Small businesses have until September 18, 2017 and very small businesses have an extra year to comply.

As FDA begins to implement the new FSMA rules, the agency is committed to outreach and education rather than enforcement. So I think it would be entirely appropriate to consult with your local FDA district office if you are not clear about anything in the guidance.