Manufacturing Science and the Pharmaceutical Inspectorate
Within FDA's Center for Drug Evaluation and Research (CDER) and the Office of Pharmaceutical Science's (OPS) Office of New
Drug Quality Assessment (ONDQA), a small, specialized review group has been assembled and established. This Manufacturing
Science Team is a group of reviewers drawn from various backgrounds who have hands-on manufacturing experience in the pharmaceutical
industry. All have had development, scale-up, or production experience in areas such as bulk raw materials and dosage form
production. The team's focus will be on the distinctly manufacturing sections of NDA submissions—a more specialized review
team approach. These efforts will be coupled with increased emphasis on integrating the review and inspection processes—i.e.,
facility inspections that involve both a field investigator (such as a member of the new Pharmaceutical Inspectorate cadre)
and a CDER CMC reviewer. In this manner, both the scientific soundness as well as the compliance aspects can be discussed
and agreed upon in a more complete fashion at the time of inspection and evaluation. Through efforts like these, the agency
hopes to achieve more balance between scientific review and compliance/field activities, with the aim of ensuring that drug
products are produced in a reliable and reproducible manner and that manufacturing methods can be improved over time with
more regulatory flexibility.
In the Fall of 2005, FDA announced a pilot program18 that sought volunteer firms to participate in submitting NDAs or postapproval change submissions that incorporate the principles
discussed here. In doing so, the agency is attempting to encourage companies to implement quality-by-design concepts, product
development submissions, product design space, risk-based product controls, process analytical technologies, and continuous
improvement planning in new applications. This pilot program is ongoing and will be evaluated for effectiveness at the end
of the pilot program period.
The FDA also has responded to the challenges outlined above by moving to streamline CMC review and promote drug quality. It
has proposed a more comprehensive team approach to product evaluation. Within OPS and ONDQA, staff are focused on bringing
together the appropriate skills and specialties to review a specific product. At the same time, the agency is encouraging
communication and discussion between headquarters reviewers and field investigators (e.g., Pharmaceutical Inspectorate or
PAT Team members) so that a product can be evaluated for scientific content as well as compliance in a more thoughtful and
coordinated manner. The long-term goals include regulatory flexibility and appropriate scientific product quality controls.
In the future, pharmaceutical firms, nonprofit institutions, and academic research centers would be well advised to take advantage
of the new globally developing paradigm. A carefully executed product development project will incorporate some or all of
the concepts mentioned above to achieve a deeper understanding of the drug and allow for postapproval improvements with more
regulatory flexibility. But the primary reason for adopting research and development approaches that are consistent with these
initiatives appears to be a higher comfort level that CMC development will proceed more smoothly, without delays caused by
inadequate knowledge or ad hoc experimentation.
JOHN E. SIMMONS, PhD, formerly a senior scientist at FDA's Center for Drug Evaluation and Research, OPS/Office of New Drug Chemistry, is currently
president of Simmons FDA CMC Consulting, LLC, 323 Night Harbor Dr., Chapin, SC 29036, tel. 240.888.5726, Simmonsfdacmc@aol.com
DAVID BERNSTEIN, PhD, is president and CEO of Bernstein CMC Regulatory Consulting, tel. 510.658.3334, firstname.lastname@example.org