FDA Exempts Most Investigational Drugs in Phase I Studies From CGMP Regulations, but not CGMP Statutory Requirements

On July 15, 2008, FDA issued a final rule exempting investigational drugs used in phase 1 studies (as described in 21 C.F.R. § 312.21 of FDA’s IND regulations) from the Current Good Manufacturing Practice (“CGMP”) requirements in 21 C.F.R. Part 211.  This exemption does not apply to an investigational drug for use in a phase 1 study once the investigational drug has been made available for use by or for the sponsor in a phase 2 or phase 3 study, or the drug has been lawfully marketed.  If the investigational drug has been made available in a phase 2 or phase 3 study or the drug has been lawfully marketed, the drug used in the phase 1 study must comply with part 211. 

FDA states that it believes this change is appropriate because many of the issues presented by the production of investigational drugs intended for use in the relatively small phase 1 trials are different from the issues presented by the production of drug products for use in larger phase 2 or 3 trials or for commercial marketing.  Additionally, many of the specific requirements in the regulations in part 211, such as those relating to stock rotation, repackaging, or relabeling, do not apply to the conditions under which many drugs for use in phase 1 are produced.

The exempt phase 1 drugs are, however, still required to meet the statutory (as opposed to regulatory) requirements for CGMP.  To help companies determine what is required to comply with these statutory requirements, FDA simultaneously issued a final guidance document discussing CGMP for phase 1 drugs. This guidance provides both specific, detailed information for complying with CGMP, as well as general guidance. With respect to general guidance, it notes that adherence to CGMP during manufacture of phase 1 investigational drugs occurs mostly through: (1) well-defined, written procedure; (2) adequately controlled equipment and manufacturing environment; and (3) accurately and consistently recorded data from manufacturing (including testing).  The guidance further notes it is the manufacturer’s responsibility to provide and use methods, facilities, and manufacturing controls to ensure that the phase 1 investigational drug meets appropriate standards of safety, identity, strength, quality, and purity and that manufacturers should consider carefully how to best ensure the implementation of standards, practices, and procedures that conform to CGMP for their specific product and manufacturing operation.   

By Gwendolyn M. McKee