Yesterday, the U.S. Food and Drug Administration (FDA) issued a final rule amending its regulations governing drug establishment registration and listing requirements for U.S. and foreign firms. Also noteworthy is that the final rule expands FDA’s regulations governing National Drug Codes (NDCs). The final rule is available at 81 Fed. Reg. 60170 (Aug. 31, 2016) (to be codified at 21 CFR Parts 20, 201, 207, et al.). The final rule comes a decade after the agency published the proposed rule. 71 Fed. Reg. 51276 (Aug. 29, 2006).
Drug manufacturers are required to register their establishments with FDA annually to identify establishments for FDA inspection and to provide the agency with a list of drugs manufactured at the establishment. The final rule reorganizes, modifies, and clarifies current regulations regarding who must register and list drug products. The rule also provides more details on how and when owners or operators of establishments must register their establishments with FDA and list the drugs they manufacture or process. The changes apply to finished drug products and active pharmaceutical ingredients (APIs) manufactured at both U.S. and foreign establishments.
Some key points from the final rule include:
- A requirement for electronic submission of registration and listing information, unless waived in certain circumstances.
- Clarification that the establishment registration and listing obligations rest with the person(s) who manufacture, repack, relabel, or salvage drug products. In particular, the rule revised 21 CFR 207.41 to clarify who must list drugs and what drugs must be listed. In response to comments, FDA stated when operations are conducted at more than one establishment, and common ownership and control exist among all the establishments, the parent, subsidiary, or affiliate company, may submit a single listing information for any drug manufactured, repacked, relabeled, or salvaged at any such establishment. But, FDA would also accept multiple listings if a manufacturer submits separate listings and NDC for the same drug product.
- Acknowledgment that contact manufacturers play an important role in drug manufacturing. Some perform specialized operations for another manufacturer and others perform all manufacturing operations for a virtual drug company. If a contract manufacturer is performing one or more steps in a manufacturing operation, it may be shipping an unfinished drug to another contracting party. In such case, the contract manufacturer should submit listing information for the unfinished drug but it may not be responsible for listing updates if it does not commercially distribute the finished product. If a contract manufacturer is performing all steps or just the final steps in a drug manufacturing process, it should describe the finished drug product in its listing submission. FDA also noted that the implementation of the final rule may depend on the facts because “[e]ach situation will require its own analysis under the final rule and there may be more than one way to satisfy the rule’s requirements.”
- Explanation that private label distributors (PLD) are not required to register establishments or list drugs arising from their activities. But, FDA stated that it will accept establishment registration or listing information submitted by a PLD if it is properly authorized to act as an agent for the establishment.
- Clarification regarding the terms ‘‘finished drug product,’’ ‘‘unfinished drug product,’’ ‘‘bulk drug substance,’’ ‘‘private label distribution,’’ ‘‘registrant,’’ and ‘‘outsourcing facility’’ not included in the proposed rule.
- Direction that a facility at which drugs are stored, such as a warehouse, does not need to be registered provided drugs are not manufactured, repacked, relabeled, or salvaged (as those terms are defined in 21 CFR 207.1) at the facility. But, that the definition of ‘‘manufacture’’ includes sampling, testing, or control procedures applied to the final product or to any part of the process. Thus, for example, if a warehouse includes a temperature controlled storage area where drug samples are stored for stability testing to satisfy current good manufacturing practice (cGMP) requirements, that activity would qualify as a manufacturing operation and require registration of the warehouse as a drug establishment. Other state or federal requirements may apply to such facilities.
With regard to NDCs, FDA did retreat from proposed NDC format changes based on concerns raised about the impact on various systems that track and use NDCs. But, the final rule does revise 21 CFR 207.49 to reflect more specifications concerning NDC formatting. Another noteworthy addition is 21 CFR 207.33, which provides clarification on what is an NDC, how is it assigned, and what are its requirements. The rule also introduces revised 21 CFR 207.35 to more clearly explain what changes to drugs require a new NDC, and revises 21 CFR 207.37 to state that a product may be deemed to be misbranded if an NDC is used improperly. As a consequence, the final rule may have implications for government price reporting and government contract obligations.
FDA stated that the new rule is intended to improve management of drug establishment registration and listing requirements, and to make processes more efficient and effective for industry and the agency. The action is intended to support the availability of up-to-date drug labeling information through DailyMed, a computerized repository of drug information, and the implementation of the electronic prescribing requirements under the Medicare Prescription Drug, Improvement, and Modernization Act of 2003 (MMA). The final rule is expected to become effective in 90 days.