Progress in all of the areas of biologics production has always been incremental and not marked by sweeping breakthroughs. The fine points of the latest hard-won advances in bioprocessing technology and operations were presented and debated at IBC’s “Early to Late Stage Bioprocessing Conference,” which took place in Boston.
Biologic drugs are a special category with regard to their patentability and resistance to patent infringement, according to Joan Shankle, managing director of Aurum Group. They are often complex mixtures, there are limits to the ability to characterize and identify their structures, the active components of the molecule may not be fully identified, and they are difficult to manufacture consistently.
For these reasons regulatory guidelines need to address product comparability rather than identity, as is the case with small molecule drugs. The latter are covered by the Hatch-Waxman Act, since small molecules can be chemically synthesized and identical versions produced.
“Historically, there was a fork in the regulatory road that occurred around 1993 between biologics and well-characterized biotechnology products. At this time the latter moved from CBER (Center for Biologics Evaluation and Research) to CDER (Center for Drug Evaluation and Research), and in 1996 the comparability guidance was issued,” Shankle continued.
“The basis for the differentiation was the well-characterized designation resulting from improved manufacturing (more consistent and better control) and also improved analytical techniques that facilitated a detailed description of protein structure, composition and function,” she added.
According to Shankle, the 1996 FDA Comparability Guidance ruling addressed the issue, taking into account improvements in technology for the characterization of macromolecules. This allowed more flexibility in manufacturing facilities and processes. “The most important assessment factor for FDA is whether manufacturing changes translate into significant differences in safety or efficacy,” she said.
Comparability testing demands that manufacturers should carefully assess modifications and evaluate the resulting molecule for similarity to the preexisting product through a side-by-side analysis. Shankle advised that manufacturers should take advantage of the benefits and flexibility provided by current comparability regulations, investing in the analytical tools necessary to identify critical attributes of the molecule early in the process, thus allowing the monitoring of product quality through all phases of development.
Shankle’s comments on biosimilar products call to mind ongoing discussions and proposed legislation regarding biogenerics. As the technology for characterization has developed, and as the patents for a number of biologic drugs are running out, the question has become more pressing. The EU has moved ahead of the U.S. by establishing a new system for evaluation of biological medicinal products that assumes that bioequivalence is not sufficient for approval but rather additional studies will be required.
In the EU legislation, substantial nonclinical and clinical data are now mandatory. Marketing authorization applications are submitted to The European Medicines Agency and reviewed by the Committee for Medicinal Products for Human Use. Canada has also fallen into line with similar legislation.
Currently in the U.S. Congress, the Waxman-Clinton-Schumer bill is under consideration, and while stalled for some time, it is expected to move ahead as the new administration puts forth a comprehensive healthcare overhaul. BIO has voiced concern over the legislation, which will, no doubt, be a contentious issue in the upcoming congressional session. Nonetheless, considering the staggering cost of biopharmaceuticals, there is a pressing need to develop a coherent regulatory process to allow biogenerics to obtain approval in the U.S.
For many companies, bioprocessing of a product may involve outsourcing one or more steps. Paul Mehelic, Ph.D., principal scientist and group leader at Pfizer, discussed solutions to challenges that arise in the course of an antibody-production project. These include failure of the scale-up phase to meet expectations, disagreements between client and contract manufacturer organization (CMO), changes in personnel midway through the project, and platform changes or modifications during the campaign.