ACCELERATING BIOTHERAPEUTIC DEVELOPMENT STREAMLINING CONCEPT TO MARKET

Accelerating Biotherapeutic Development - Streamlining concept to market SOLUTIONS TO SUPPORT DEVELOPMENT AND MANUFACTURE As market interest and investment in biopharmaceuticals surges and the requirement for novel biological drugs continues to grow, the industry is under increasing pressure to ensure delivery of therapies rapidly yet safely. Biopharmaceutical development and manufacture, focusing on molecules such as monoclonal antibodies (mAbs), recombinant proteins, vaccines and oligonucleotides, are lengthy and complex processes with very specific analytical challenges. We know that in order...

DEVELOP COST-EFFECTIVE, NOVEL PRODUCTS FASTER DEVELOPMENT STAGES CANDIDATE VALIDATION • Indication of developability/ manufacturability DEVELOPMENT COSTS • Label-free samples • Easy-to-interpret data • Large sample numbers • Stability prediction • Stability indicators PIPELINE SUPPORT EARLY FORMULATION DEVELOPMENT • Manufacturability • Optimization of bioactivity • Excipient/formulation screening • Subvisible particles • Absolute viscosity profiling, with shear rate and temperature • Pilot scale/scale-up PROCESS DEVELOPMENT LATE FORMULATION DEVELOPMENT • Stability indicators • Aggregation characterization...

Accelerating Biotherapeutic Development - Streamlining concept to market SOLUTIONS TO SUPPORT DEVELOPMENT CANDIDATE VALIDATION EARLY FORMULATION DEVELOPMENT • Measure of bioefficacy • Indication of developability/ manufacturability • Label-free samples • Easy-to-interpret data • Large sample numbers • Advanced binding affinity characterization • Protein size screening • Protein viscosity screening • Automation • Stability prediction • Stability indicators • Manufacturability • Optimization of bioactivity • Excipient/formulation screening LATE FORMULATION DEVELOPMENT • Subvisible particles • Aggregation...

AND MANUFACTURE PROCESS DEVELOPMENT • QbD • Biocomparability • Product quality • Container/closure stability • Pilot scale/scale-up • Shelf life stability • Particle characterization MANUFACTURING SUPPORT • Biocomparability • Particle characterization • Product quality/ consistency • Orthogonal methodology • Process understanding • Root cause analysis • Stability • Sizing/qualification of subvisible particles • Advanced particle characterization • Chemical identification of particles • Advanced protein aggregate characterization • Detection and quantification of aggregates over full range • Multiple,...

Accelerating Biotherapeutic Development - Streamlining concept to market PIPELINE SUPPORT Pipeline support activities run parallel to those of the core development pipeline, providing additional physicochemical analysis and screening. As potential candidates progress, they are subjected to a battery of tests to ensure only the most suitable molecules move on to the next stage. Candidates and formulations that fail to satisfy the predetermined criteria are removed from the main product pipeline and placed in the pipeline support area. More in-depth characterization testing is then performed to...

CANDIDATE VALIDATION • • • Bioactivity Hydrodynamic size (DH) Viscosity (η) Candidate validation studies aim to quickly identify and validate the most suitable candidates, screening for attributes such as biological activity and developability. Early removal of potentially problematic molecules reduces time and costs. MicroCal Isothermal Titration Calorimeters (ITC) allow direct, label-free measurement of binding affinity and thermodynamics in a single experiment, enabling the accurate determination of binding constants (K D), reaction stoichiometry (n), enthalpy (ΔH) and entropy (ΔS). These...

Accelerating Biotherapeutic Development - Streamlining concept to market EARLY STAGE FORMULATION DEVELOPMENT – I DEVELOPING STABLE FORMULATIONS • • • Zeta potential (ZP) Second virial coefficient (B22) DLS interaction parameter (KD) The ability to predict product stability early in the development pipeline, with the use of low concentration formulations, can streamline early formulation development. ICH stability testing guidelines (Q5C) are written with the understanding that the only way to measure the stability of biopharmaceuticals is to perform long-term stability studies under true-to-life...

EARLY STAGE FORMULATION DEVELOPMENT – II DETECTION AND CHARACTERIZATION OF PROTEIN AGGREGATES • • • Hydrodynamic size (DH) Molecular weight (MW) Intrinsic viscosity (IV) Protein aggregation in biopharmaceuticals is of particular concern for the industry, reducing product efficacy and stability and increasing immunogenic risk. Malvern’s highly sensitive protein aggregation characterization tools allow complete evaluation of therapeutic proteins and early identification of potential stability concerns. The Zetasizer determines a protein’s hydrodynamic size as well as detecting the presence of larger...

Accelerating Biotherapeutic Development - Streamlining concept to market EARLY STAGE FORMULATION DEVELOPMENT – III UNDERSTANDING AND CONTROLLING FORMULATION VISCOSITY • The production of high concentration yet low viscosity biotherapeutic formulations is one of the key challenges faced by the biopharmaceutical industry. Viscosity issues often accompany the desired high concentration/low frequency doses of parenteral administration. High viscosities can be unsuitable for injection and cause challenges during bioprocessing. Discovering too late that a particular formulation has a high viscosity...

EARLY STAGE FORMULATION DEVELOPMENT – IV CHARACTERIZING STRUCTURAL STABILITY TO AID PREFORMULATION DEVELOPMENT • • Melting temperature (TM) Aggregation temperature (Tagg) Thermal stability is a widely used parameter for measuring protein stability, enabling screening of different formulations and comparisons of different candidates. Malvern Instruments provides two technologies which offer complementary data to evaluate the thermal stability of selected candidates and formulations. MicroCal differential scanning microcalorimeters (DSC) provide fast and accurate determination of melting transition...