Optimizing Biologics Formulation Development
Candidate Screening, Profiling, Developability Assessment, and Optimization
January 21-22, 2013
Day 1| Day 2 | Download Pipeline 1 Brochure
TUESDAY, JANUARY 22
7:15 am Breakfast Presentation (Sponsorship Opportunity Available) or Morning Coffee
8:15 Chairperson’s Remarks
Mohan Srinivasan, Ph.D., Director, Protein Chemistry, Bristol-Myers Squibb
8:20 Optimization of a Manufacturing Process for an Oxidation-Sensitive Therapeutic mAb
Sylvain Raimondi, Head of Analytical Unit, Manufacturing, NovImmune
A fully human mAb formulated at 5 mg/mL in histidine buffer showed a tendency towards sub-visible particle formation which was addressed by the addition of polysorbate 80 during drug product (DP) manufacturing. However, when formulated with polysorbate 80, DP revealed an increase in aggregates (from 2.0% to 6.0%) coupled with a decrease in potency (about 50% Relative Potency compared to reference). Investigational studies revealed oxidation of tryptophan (about 30%) in the CDRH3 and oxidation of methionine (about 15%) in the CH2 of the heavy chain. The combination of polysorbate 80 (peroxide and alkylperoxide degradation products), the presence of trace heavy metal ions (iron, copper, nickel) and exposure to mechanical stress was hypothesised to cause oxidization during the manufacturing process. Forced degradation studies using the free radical scavenger 2,2'-azobis(2-aminopropane) dihydrochloride (AAPH) confirmed the susceptibility of tryptophan and methionine residues in the CDRH3 and CH2 region, respectively, to oxidation. In order to exploit the benefits of polysorbate 80 in controlling particle formation while eliminating unwanted effects, various antioxidants were investigated and introduced as excipients to find an optimized formulation for stability of the mAb following long term storage. In parallel, a newly generated “double mutant” antibody targeting the oxidation-susceptible tryptophan and methionine residues, was found to be resistant to oxidizing conditions. Thus, taken together, the two alternative strategies explored during these studies both paved the way to determine robust manufacturing/storage conditions and have enabled continued development of this therapeutic mAb.
8:50 Manufacturability Assessment of a Bispecific Antibody
Sharon Gao, Ph.D., Head, Analytical Chemistry, Alere
Bispecific antibodies (BsAbs) are a promising class of biologics with unique ability to target two antigens or two epitopes of the same antigen simultaneously. A stability engineered IgG-like bispecific antibody (BsAb) dual-targeting EGFR and IGF-1R was developed for its improved anti-tumor activity in preclinical models. Manufacturability assessment of this BsAb has shown that it displayed comparable product quality and stability attributes as a monoclonal antibody. These findings illustrated that the stability engineered BsAb has overcome instability issues that historically hindered the clinical advancement of BsAbs.
9:20 Manufacturability and Safety Issues in Biotherapeutics: A Role for Biopharmaceutical Informatics
Sandeep Kumar, Ph.D., Principal Scientist, Biotherapeutics Pharmaceutical Sciences R&D, Pfizer, Inc.
9:50 Selected Poster Presentation: Role of Electrostatic and Hydrophobic Forces in Governing the Protein Aggregation Kinetics at High Concentrations: A Case of Mono- and Bi-Specific Immunoglobulins
Nitin Dixit, Graduate Student, Pharmaceutical Sciences, University of Connecticut
Determining the nature of forces governing the kinetics of protein aggregation is important in the protein formulation development, especially at high concentrations. Using the examples of a monoclonal antibody (IgG1, mono-specific) and a dual variable domain-Ig (DVD-Ig, bi-specific), it will be shown that the molecular forces governing the aggregation kinetics of proteins are different in nature and magnitude. Results from biophysical characterization and stress studies on the aggregation and physical stability of the proteins will be discussed.
10:05 Coffee Break in the Exhibit Hall with Poster Viewing
» FEATURED PRESENTATION:
10:45 Cavitation-Induced Protein Aggregation
Theodore Randolph, Ph.D., Professor, Chemical and Biological Engineering, University of Colorado, Boulder; Co-Director of the University of Colorado’s Center for Pharmaceutical Biotechnology
During fill-finish operations or as a result of handling in vials, liquid formulations of proteins can cavitate. Collapse of cavitation bubbles leads to production of free radicals, protein aggregation, and particle formation. This talk will offer insight into the potential role of cavitation in process-induced protein aggregation and discuss new mechanism for protein instability during processing.
11:15 Composition Dependent Observations during a Platform Development of a Highly Concentrated mAb
Jonas Fast, Ph.D., Senior Scientist, Early Stage Pharmaceutical Development, F. Hoffmann-La Roche
During a platform development of a monoclonal antibody formulation significant composition-dependent physical bulk properties and chemical degradations were observed. The driving forces of these observations were investigated.
11:45 Formulation and Primary Packaging Development for Biosimilars: Concepts and Case Studies
Jennifer Kronthaler, Ph.D., Researcher, Pharmaceutical Development, Sandoz Biopharmaceuticals
The development of a biosimilar drug product, especially when intended for subcutaneous application, provides specific challenges and at the same time opportunities. Formulation development requires specific screening and analytical techniques in order to identify a formulation delivering not only protein quality and stability, but also the desired clinical effect within a tight biosimilarity window. Additionally, certain attributes of the pre-filled syringe or vial, quality of excipients, process-related impurities from drug substance and drug product process, among others need to be considered to achieve a biosimilar drug product. Case studies and lessons learned will be linked to our QbD based development concept. Opportunities for the biosimilar product to gain competitive advantage will be discussed, considering regulatory aspects.
12:15 pm Close of Morning Session
12:30 Luncheon Presentation (Sponsorship Opportunity Available) or Lunch on Your Own
2:00 BuzZ Session A (Please visit our website for a listing of topics.)
2:45 Refreshment Break in the Exhibit Hall with Poster Awards
3:30 BuzZ Session B (Please visit our website for a listing of topics.)
4:15 End of Conference
Day 1| Day 2 | Download Pipeline 1 Brochure