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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:

Definitions

  • 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.

NDCs

  • 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.

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