We got a late but very generous response to our questions about formulations/analysis from Dr. Li Shi (senior director of bioanalytics and formulation technology development at Genzyme). Dr. Shi presented a keynote titled "The Use of Biophysical Analysis to Determine the Optimal Formulation" at the BPI European Conference and Exhibition on Wednesday 19 May 2010 in Vienna, Austria. But considering the latest news about the company's consent decree, I believe this is still a timely discussion.

—Cheryl Scott, senior technical editor

BPI: Protein aggregates seem to be the most prevalent visible/subvisible particles that plague biopharmaceutical drugs (especially highly concentrated liquid formulations). What are some other contaminants that fall into this category? Will different methods work for detecting both, or do they require different analytical approaches? Is this becoming a bigger problem with highly concentrated formulations — or do certain types of products seem to be plagued more than others?

Shi: Sources of subvisible and visible particles other than protein aggregates include silicone oil, piston pump particles, erosion iron and tungsten metals, silicones (grease, rubber, and resin), glass resins, Teflon and other polymer particles, tubing coating materials, as well as dust and particles in WFI (water for injection). Those foreign particles can be detected using same technologies that are used for protein particles. And they're not new issues. However, the amount and type of such particles varies product to product and vial to vial. So it is case-by-case issue that can be controlled by filtration and monitoring.

BPI: Can you explain a little bit about biophysical analysis in biopharmaceutical development? What exactly is it, and what does it in entail? Is it newly elevated to importance in formulations (and why), or has it always been a priority? What analytical methods are most often involved?

Shi: Biophysical analysis focuses on physical properties of biopharmaceutical products. Specifically for protein-based products, biophysical analysis mainly focuses on protein structural unfolding and aggregation behaviours. New attention has paid to subvisible protein aggregate particles due to hypotheses that they are potentially important to immunogenicity. Methods involved are mainly particle counting and imaging technologies developed recently.

BPI: Certain speakers at BPI-Europe will discuss high-throughput (HTP) approaches to forced degradation studies and preformulation product characterization work. In what other formulations/analytical laboratory work are such assays making a difference?

Shi: The HTP in formulation development is different from that in drug discovery and screening. The former is in much smaller in scale, and it is mainly used to test multiple factors in a single study or test a relatively large number (one to two hundreds) of samples using automated assays. Such practice can increase the efficiency of sample analysis of formulation stability study but does make much difference in cutting the overall stability study time.

BPI: Is design of experiements (DoE) new to formulators, or have they been using it longer than other folks in biopharmaceutical development?

Shi: The use of DoE concept has been seen in some formulation development work recently, but it is still new the field. However, similar methods have been long used in formulation experiment design. Most formulation development works are not necessary to be on the high-cost or time-determining on the path of product development; therefore, using DoE in formulation development focuses on reducing the total number of experiments for formulation factor screening. Different from this, the use of DoE in engineering and manufacturing process development is driven by both time and cost savings.