Tim Kelly, Ph.D., vp of biopharmaceutical development at KBI Biopharma , will discuss a variety of approaches for evaluating protein drug stability during the early stages of formulation development. The goal of formulation development, at KBI and elsewhere, is to determine a final dosage form that results in a safe, efficacious product that remains stable over the course of its intended use. The stability of candidate formulations is evaluated during development via a combination of real-time and accelerated studies. Among drug companies, there are diverging opinions about the accelerated stability data deemed appropriate to support formulation development during preclinical and Phase I clinical development.
At the meeting, Dr. Kelly will present a case study that compares conservative and aggressive approaches used on different proteins to evaluate stability of candidate protein formulations. Therapeutic antibodies are the largest class of protein therapeutics today, but this group also includes enzymes, cytokines, hormones, and other proteins.
The analyses used to evaluate real-time and accelerated stability typically include purity assays such as SEC-HPLC, IEX-HPLC, RP-HPLC, SDS-PAGE, IEF, SDS-CGE, and cIEF to quantify product and process-related impurities such as deamidation, oxidation, aggregates, clipped species, and host-cell proteins. In addition, such studies often include assays to monitor the activity of the product, which may include ligand-binding ELISA methods or cell-based assays to measure proliferation, cell death, or cytokine release.
A conservative approach for evaluating formulation stability may involve placing 10 or more candidate formulations in a long-term stability study under real-time (e.g., 5°C) and accelerated (e.g., 30°C/65% relative humidity conditions. The duration for such a study may range from six months to two years, with samples from each of the candidate formulations analyzed in one- to three-month intervals over the study duration.
At the conclusion of the study, the candidate formulation that exhibits the best overall conservation of native purity and activity is chosen and utilized for manufacturing of clinical trial material. This conservative approach is most commonly utilized by large pharma companies that have the time and resources to permit this approach.
The main advantage of this approach is that the formulation decision is based on real-time stability data at the intended product storage temperature. Therefore, drug developers may have a high degree of confidence that the product will remain stable throughout the duration of its intended use in clinical studies.
Smaller pharma and biotech companies, especially those that do not yet have revenue streams from commercial products, often can’t afford to devote the time and resources required to execute a 1–2 year real-time stability study during formulation development. Such companies may take a more aggressive approach, with a greater emphasis on accelerated stability over a shorter duration.
KBI Biopharma frequently employs an approach where a large number (30–40) of candidate formulations are evaluated via statistical design of experiments including short term stability under real-time and accelerated conditions for 1–2 months.
The accelerated stability conditions used in such studies may range from 40–55°C to increase the rates of degradation and enhance the likelihood of observing significant differences among the candidate formulations over the short duration of the study. A long-term stability study is then performed on the actual clinical trial material prepared in the final selected formulation, in accordance with the ICH guidelines.
The main advantage of this approach over the more conservative approach is the acceleration of development timelines. The quantity of API available for such studies during pre-clinical development also impacts the duration of formulation stability studies.
A potential disadvantage of this approach is the challenge of assigning predictive value to accelerated stability data for protein therapeutics. The translation of accelerated stability data into a real-time storage shelf life is problematic as protein degradation processes are quite complex and often do not follow Arrhenius kinetics.
“We have used both approaches successfully to develop stable formulations for different therapeutic proteins” says Dr. Kelly. “I would love the opportunity to evaluate both approaches in parallel on the same protein to see if the more aggressive approach consistently and accurately predicts formulation shelf life. I expect our client partners will continue to request each approach in order to best meet their Phase I clinical trial timelines.”