Ten years and two days after FDA issued the proposed rule, the Agency published the final rule - Requirements for Foreign and Domestic Establishment Registration and Listing for Human Drugs, Including Drugs That Are Regulated Under a Biologics License Application, and Animal Drugs - on August 31, 2016.
The rule codifies the requirement to electronically submit drug establishment registration and listing information, (unless waived under certain circumstances), a functional requirement since June 2009 when FDA implemented the electronic system to comply with the statutory provisions of the Food and Drug Administration Amendments Act (FDAAA).
The final rule has few surprises for those that have been involved with drug establishment registration and drug listing over the past 7 years. Of note, two significant proposals were ultimately not included in the final rule: “(1) [a] requirement that FDA, not registrants, develop national drug codes (NDCs) for assignment to listed drugs, and (2) a requirement that the NDC appear in human-readable form on the label of each listed drug and provisions that would have defined the appropriate NDC for that purpose.”
While the rule applies to persons who manufacture, repack, relabel, or salvage human drugs, drugs that are also biological products, and animal drugs, it also applies, to a degree, to private label distributors (PLDs). Private label distribution, which is defined in the final rule, “means, with respect to a particular drug, a person who did not manufacture, repack, relabel, or salvage the drug but under whose label or trade name the drug is commercially distributed.” The final rule clarifies that PLDs are required to obtain labeler codes. This is significant as it codifies FDA’s current practice, which has been somewhat controversial. More on that in a bit.
In addition to the requirements for PLDs, FDA has also codified the requirement that each drug distributed by a PLD have two NDCs. This has also been an area of controversy in that, when the electronic system was rolled out in 2009, a Final Guidance, Providing Regulatory Submissions in Electronic Format – Drug Establishment Registration and Drug Listing, indicated this was not how drugs should be listed. The Guidance provided that, “If a drug product is listed by the PLD, it should not also be listed by the owner(s) of the registered establishment(s) that manufactured, prepared, propagated, compounded or processed (which includes, among other things, repackaging and relabeling) the listed drug(s).” This provision in the Guidance created the most confusion surrounding products that were proposed for import. Typically, FDA detained products that had not been listed by the foreign manufacturer, despite their listing with the PLD’s labeler code. New 21 C.F.R. § 207.41(c)(1) and (2) clarify that FDA now requires two listings.
Other notable provisions include as follows:
National Drug Codes. New 21 C.F.R. § 207.33 allows for an 11 digit NDC number to accommodate an anticipated increase in the number of digits used to identify labelers. FDA anticipates that 5-digit labeler codes will be exhausted, and the agency will need to move to 6-digit labeler codes. The new provision allows for configurations of labeler codes, drug product codes, and package codes of 5-4-1 or 6-4-1, or 5-3-2 or 6-3-2. If a labeler code is 4 digits, it may only be combined with a 4 digit product code and 2 digit package code (4-4-2). The rule requires that once a product-package configuration is assigned by a company in association with a particular labeler code, all NDCs that include the given labeler code must include the same product-package configuration. For example, if the first drug listed by a company is assigned the NDC 12345-678-90, all subsequent drugs listed with labeler code 12345 will need to have a 3 digit drug product code and 2 digit package code.
The rule allows registrants to reserve an NDC for a drug under development. This is a significant benefit to registrants that previously may have printed packaging/labeling “at risk” with an NDC number that may ultimately be rejected by FDA at the time of listing.
New 21 C.F.R. § 207.35 provides greater clarity on the changes that may require a new NDC – including a new name, a new API or strength of API, change to dosage form, a change in drug’s status between Rx and OTC, change in use between human and animal, or any distinguishing characteristics (e.g., size, shape, color, code imprint, flavor, and scoring). Specifically, the provision does not require a new NDC when changes are made to inactive ingredients or there is a new supplier of API. Further, the final rule does not include the proposal that “any material change” to a drug’s labeling or package insert necessitates a new NDC. The preamble to the final rule clarifies that “labeling [content] changes themselves do not trigger the need for a new NDC under this final rule.”
Bar Codes. The final rule revises the bar code provisions in 21 C.F.R. § 201.25 to allow for alternatively formatted NDCs in bar codes if approved by the relevant FDA Center Director.
Importers, Persons Who Import or Offer for Import, and Imported Drugs. The final rule requires foreign establishments, when registering, to provide names and contact information for each importer in the United States of drugs manufactured, repacked, relabeled, or salvaged at the establishment that is known to the establishment. Further, the rule also requires that these registrants provide the names and contact information for each person who imports or offers for import these drugs. FDA considers “person who imports or offers for import” in this context to mean the owner or exporter of a drug who consigns and ships a drug from a foreign country to the United States.
In addition, the final rule clarifies that the provisions included in the rule apply to foreign establishments unless the drugs that they manufacture, repack, relabel or salvage are only brought into a U.S. foreign trade zone or are otherwise subject to the import for export provisions of the Federal Food, Drug, and Cosmetic Act section 801(d)(3).
Establishment Registration Number and Unique Facility Identifier. Establishment registration numbers were historically assigned by FDA and known as FDA Establishment Identifiers (FEIs). Following implementation of the electronic system, FDA required utilization of the Data Universal Numbering System (DUNS) numbers (business identifiers assigned and managed by Dun & Bradstreet) for entities submitting registration information or requesting a labeler code but continued to assign FEIs. The final rule requires registrants to use a Unique Facility Identifier (UFI), which FDA prefers to be the DUNS number. The UFI and FEI number are distinct numbers. In the preamble, FDA states that , “[f]or now, FDA will continue to assign an FEI as the establishment registration number after an establishment is registered for the first time.” In the future, we expect that FDA will eliminate use of FEIs, and transition to solely using UFIs.
Use of NDCs on Non-Drug Products. New 21 C.F.R. § 207.37 provides that the use of an NDC on the labeling of a product that is not a drug, such as a dietary supplement, may render the product misbranded. Despite this, we note that “dietary supplement” as well as other non-drug descriptors including “cosmetic” and “medical food” are included as “marketing category” options when listing products with FDA.
Private Label Distributors. As stated above, under the final rule, PLDs are required to obtain labeler codes and are otherwise not required to register and list (unless they are also engaged in activities that qualify as those that require registration). That said, PLDs may be subject to additional requirements pertaining to maintaining NDC numbers and responding to FDA inquiries.
PLDs of over-the-counter (OTC) drugs likely are the group that has been impacted the most by the implementation of the electronic listing system in 2009, as it created a requirement that was not otherwise articulated in the Federal Food, Drug, and Cosmetic Act or the regulations pertaining to drug establishment registration and listing. When the electronic system was rolled out, it required PLDs to obtain labeler codes and maintain NDCs for products despite regulatory language to the contrary. 21 C.F.R. § 207.20(b) was clear that obtaining a labeler code would be voluntary, in that PLDs “that distribute under their own label or trade name a drug manufactured or processed by a registered establishment may elect to submit listing information directly to FDA and to obtain a Labeler Code . . . If a distributor does not elect to submit drug listing information directly to FDA and to obtain a Labeler Code, the registered establishment shall submit the drug listing information.”
Prior to 2009 and the implementation of the electronic system, PLDs relied on manufacturers to list the drugs they manufactured for the PLDs and include a list of distributors to FDA. With the implementation of the electronic system, PLDs now needed to obtain their own labeler codes, and manufacturers were expected to list drugs for PLDs using those PLD labeler codes.
The problems with this system came quickly and, apparently, will continue, given the requirement in the final rule. Although FDA has been reluctant to admit to creating additional requirements for PLDs beyond obtaining labeler codes, PLDs are functionally required to manage assignments of NDCs and ensure listing accuracy. A PLD that utilizes multiple contract manufacturers for its branded OTC products cannot, as a practical matter, rely on those contract manufacturers to generate unique codes. Although the electronic drug listing system, in theory, should catch duplicative assignments of NDCs, it does not always do so. And, when FDA has questions about issues with drug listings (including duplicative NDCs), it has been our experience that FDA contacts the PLD for resolution – not the actual manufacturer that may have submitted the listing. The failure to codify the proposal that FDA assign NDCs to listed drugs continues to effectively place the requirement with the PLDs, not the manufacturers, and leaves open this opportunity for confusion and error.
Compliance Dates. FDA has stated that two years after the effective date of the final rule, FDA intends to remove from the current electronic database any establishment registration and listing information that had previously been submitted in paper and not updated with a more recent electronic submission. There are also additional compliance deadlines for blood establishments and products as well as Human Cell and Tissue Products establishment and products.
The effective date of the rule is November 29, 2016.