A biopharmaceutical drug can go into development before anyone knows much about how it works. The protein may be identified
through genomics or proteomics activities or through more traditional medical research. It may initially be associated with
a particular disease process or a certain metabolic event. In any case, its mechanism of action — as well as many of its structural
characteristics and biochemical properties — may be unknown. One of the more challenging aspects of developing protein pharmaceuticals
is dealing with and overcoming the inherent physical and chemical instabilities of proteins. This inherent instability has
the potential to alter the state of the protein from the desired (native) form to an undesirable form (upon storage), compromising
patient safety and drug efficacy. The set of activities related to overcoming the inherent instability of the drug is referred
to as formulation development.
A successful formulation process has four stages: preformulation, stabilization of the active substance in bulk form, formulation
in the designated dosage forms (drug delivery), and fill and finish of aseptic manufacturing activities.
Preformulation is an exploratory activity that begins early in biopharmaceutical development. Preformulation studies are designed
to determine the compatibility of initial excipients with the active substance for a biopharmaceutical, physicochemical, and
analytical investigation in support of promising experimental formulations. Data from preformulation studies provide the necessary
groundwork for formulation attempts. Successful formulations take into account a drug's interactions with the physicochemical
properties of other ingredients (and their interactions with each other) to produce a safe, stable, beneficial, and marketable
Corporate concerns. Some companies have a preformulation/formulation team specifically devoted to these tasks. In other (usually smaller) companies,
formulation development may be the responsibility of the fermentation, process chemistry, or quality control group. Industry
experts claim that preformulation teams are often understaffed, underresourced, and not well understood by company management.
Formulation is sometimes considered a sort of "black art" in drug development. This is because in the history of protein formulation,
development began as an empirical science due to the unique nature of each protein. However, a better understanding of protein
behavior and an increased awareness of the adverse effects of an improperly formulated protein product on clinical trials
and on the marketed product have highlighted the need for a more rational approach to formulation development. Such an approach
has been developing over the past decade. A dedicated formulation development group that is adequately staffed and resourced
has thus become necessary in order to successfully incorporate protein formulation development in the overall drug development
strategy. Bio-pharmaceutical companies should consider their formulation teams to be just as essential to their survival as
process development and finance. Doing things right the first time is always preferable to going back to the drawing board
and starting over — and it's also the faster way to market.
Formulation and delivery issues must be considered early in development. An initial formulation is needed for preclinical
studies, and a better formulation will be needed for clinical trials. The formulation may be critical to the safety and efficacy
of a therapeutic protein, and, as development progresses, it will become harder and harder to make changes.
Marketing concerns come up earlier than you might think. Route of administration is determined by the target product profile:
Will our product treat a chronic or acute disorder? Will it need specific targeting — a broad or narrow therapeutic window?
Will it be administered at home or in the clinic or hospital? What is the competitive landscape; are other drugs already treating
the same indication? What will give our project the advantage over existing treatments and those that may emerge?
For example, marketing considerations arise early in product development for monoclonal antibodies (MAbs). Typically, MAbs
are needed at high doses (hundreds of milligrams per dose) and are normally delivered intravenously. The drive to reduce healthcare
costs has created a need to administer MAb therapeutics more conveniently, at home, subcutaneously. Thus, MAbs must be available
at high concentrations (~200 mg/mL) in the vial. At these high concentrations, MAb-containing solutions are viscous, making
them difficult to administer conveniently. Hence, a preformulation activity that needs to be considered is a concentration
study investigating solubility behavior, effect of concentration on viscosity, and increased potential for aggregation. These
studies have the potential to strongly influence the target product profile as well as the design of the clinical trial.