BioPharm

www.biopharminternational.com October 2018 BioPharm International eBook 19 forms for drug substance and drug product development. Karan Shah, a principal development associ- ate, analytical CMC and formu- lation, Immunogen, uses various biophysical techniques for higher order structure (HOS) analysis and characterization of antibodies and ADCs, along with stability testing for formulations, and analytical support. In a contract services environ- ment, Brent Kendrick, vice-pres- ident R&D for K BI Biophar ma, conducts biochemical and biophys- ical product characterization and analytical method development for large-molecule ADCs, peptides, and pegylated conjugates. Gorm Yoder, scientific director of analytical small molecule at Janssen, identifies analytical innovations for both small and large molecules at Janssen. Large-molecule drug devel- opment focus is on monoclonal antibodies (mAbs), ADCs, peptides, and oligonucleotides. C h r i s Rob e r t s h a s mu lt iple roles as a professor in chem i- cal and biolog ical eng ineer ing at t he Universit y of Delawa re, a s s o c i a t e I n s t i t u t e D i r e c t o r at t he Nat ion a l I n s t it ute for Innovation in Manufacturing of Biopharmaceuticals, and director of the Biomolecular Interaction Technolog ies Center. Resea rch goals are to develop better mecha- nistic understanding and predic- tive models for protein stability, physical interactions of proteins with their environments, critical drug formulation properties such as v iscosit y, v isual appearance, and particle formation, "essentially anything in the space of physi- cal characterization and physical behavior of the protein in solution and sometimes in solid state," he says. Information is used to build better predictive approaches, some are qualitative, and some are more quantitative, which are used in computer modeling. CHARACTERIZATION IS PARAMOUNT Protein characterization is a cru- cial part of the overall quality con- trol strategy for biopharmaceutical drugs including an understanding of the product attributes. "When proteins are produced by a bio- logical system, they create a lot of impurities and product-related substances that need a number of tools to characterize the primary structure, the higher-order struc- tures, and the biological activity," says Kendrick. Types of analysis depend on the product and can include various glycoforms; protein aggregates; covalent changes like oxidation, deamidation, and mis- incorporation; and product-related impurities that need characterizing and understanding to form a con- trol strategy to control the purity and content of a drug to ensure safety and efficacy, he explains. KBI Biopharma works on a vari- ety of biologics including antibod- ies, cytokines, proteins, pegylated peptides, cell-based therapies, and viruses. In addition to manufac- turing and process development, the company characterizes prod- uct structures, purity, stability and degradation profiles, develops and runs analytical methods for qual- ity control, performs formulation development, and consults on reg- ulatory filings from pre-investiga- tional new drug application (IND) to commercial manufacturing. Immunogen is developing ADCs for the treatment of various types of cancer. The conjugation process can be dependent on the type of linker you are using and the type of drug, but, the process of doing the conjugation itself can disrupt the structure of the protein and alter its physical and biophysical properties and its stability, says F lem ing. "We a re heav ily reli- ant on protein characterization to look at issues that come from t he n at u r e of t he A D C , how hydrophobic they become once you do the conjugation, how that impacts the stability, whether the HOS is modified in some way that affects the stability, and whether it affects the solubility during the conjugation process." I m m u n o g e n s c i e n t i s t s u s e analytical techniques to look at stabi l it y a nd to help w it h t he development of the formulation of the ADC. "Eventually, we take that forward into developing the d r ug pro duc t pro cesses whe re we—in a lot of cases—use a lyoph- ilization procedure to help stabi- lize the drug product," Fleming says. T he s e me t ho d s a r e ap pl ie d t h roug hout t he d r ug develop - ment process. "We use protein characterization and analytics to advance programs through dif- ferent phases in clinical develop- ment and eventually commercial development," says Shah. "Once the I N D is filed and promising clinical data are obta ined, the scale of these processes signifi- cantly changes to support clinical demand and commercial projec- tions. Going from one CMO (con- tract manufacturing organization) to another, these tools become rea l ly i mp or t a nt i n e st abl i sh- ing comparability—making sure the processes are transferred for effective scale-up and the product manufactured has similar or bet- ter quality and impurity profile." KEY TECHNIQUES FOR CRUCIAL MEASUREMENTS Aggregation is the most complex degradation pathway to charac- terize, says Kendrick. "Aggregates ca n for m u n folded agg regates; they can form native aggregates; Biopharma Laboratory Best Practices Protein Characterization

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