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Manufacture of Phase 1 clinical trial material

Recently one of our clients asked whether it would be acceptable to use bulk drug produced during a scale-up or engineering run in a Phase 1 clinical trial. In the past, non-GMP engineering runs were used to confirm a manufacturing process and material produced during these runs could not be used in human clinical trials but could be used for preclinical GLP studies to support an IND.

However, under the guidance on cGMP for Phase 1 investigational drugs issued by FDA in July 2008, we believe that under certain circumstances the use of such material should be acceptable for Phase 1 clinical trials.

The Phase 1 guidance explicitly states that sponsors are exempt from complying with the regulatory cGMP requirements, but not from statutory cGMP review. What this means is that while not relaxing the stringent standards for sterility and safety of investigational products, the application of GMP regulations to investigational products will be on a sliding scale with less stringently controlled manufacturing conditions permitted for early stage clinical products. The guidance specifically acknowledges the acceptability of using pilot manufacturing facilities and processes that are not yet validated or shown to be fully reproducible provided that written procedures are used during manufacturing and testing of Phase 1 clinical supplies and that a written record of the manufacturing and control of these materials is maintained. This means that Sponsors have a wider range of approaches to meet the expectations of cGMP and, provided that the engineering run was performed using adequate batch records and SOPs and that it was tested and released using appropriate test methods with written acceptance criteria, it is reasonable that bulk material so produced should be acceptable for use in a Phase 1 clinical trial. Rather than referring to such engineering runs as “non-GMP” it may be more appropriate to refer to them as being produced under “Phase 1 GMPs,” especially if the final aseptic processing of the bulk material for preparation of the final sterile parenteral product was done under full GMP. Despite the relaxing of the GMP regulations for Phase 1 materials, the Sponsor must still demonstrate a thorough understanding of the scientific principles supporting the manufacture and testing of the new drug and ensure patient safety through rigorous QA and QC. The IND filing for a new drug should still include a description of the development of the manufacturing process as well as clear documentation of manufacturing activities, acceptance criteria for impurities (which may be higher than would be acceptable in a later stage product) and control of impurities with known safety implications (bioburden, sterility, and endotoxin) in the intermediates, drug substance, and final product.


Blog article by: Howard Levine and Susan Dana Jones