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Advisory Committee for Pharmaceutical Science

Advisory Committee for Pharmaceutical Science. Process Analytical Technology and Biotechnology Products Keith O. Webber, Ph.D. Office of Biotechnology Products OPS/CDER April 13, 2004. Which Products?. Biological Products include:. Blood and Blood Products Vaccines Allergenic Products

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Advisory Committee for Pharmaceutical Science

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  1. Advisory Committeefor Pharmaceutical Science Process Analytical Technology and Biotechnology Products Keith O. Webber, Ph.D. Office of Biotechnology Products OPS/CDER April 13, 2004

  2. Which Products? Biological Products include: Blood and Blood Products Vaccines Allergenic Products Cell Therapies Gene Therapies Recombinant DNA-derived Protein Products

  3. Which Products? Biological Products include: Blood and Blood Products Vaccines Allergenic Products Cell Therapies Gene Therapies Recombinant DNA-derived Protein Products

  4. Two Aspects of PAT • Monitoring product characteristics or surrogates. • Monitoring and modulating critical process parameters to guide the product characteristics during processing.

  5. Process Analytical Technology Process Monitor Adjust Decision Data Evaluate

  6. Biotechnology Processes Concentration Harvesting Product Capture Fermentation Chromatography Formulation Filtration Lyophilization

  7. Biotech API Characteristics Primary structure (amino acid sequence) Secondary structure (local interactions)

  8. Biotech API Characteristics Tertiary structure (domain interactions) Quaternary structure (subunit interactions)

  9. Biotech API Characteristics Post-translational modifications: • Glycosylation • Proteolysis • Acylation • Sulfation • many others

  10. Biotech Product Characteristics Impurity profile: Process-related impurities • Media components • Host cell proteins • Leachates Product-related impurities • Truncations • mis-foldings • aggregates

  11. Analytical MethodsPrimary Structure Methods: • amino acid analysis • protein sequencing • peptide mapping • mass spectrometry • immunoassay

  12. Analytical MethodsSecondary Structure Methods: • circular dichroism • NMR

  13. Analytical MethodsTertiary & Quaternary Structure Methods: • Functional assay • Immunoassay • Peptide mapping (for mapping disulfides) • Size-exclusion chromatography • Hydrophobic-interaction chromatography

  14. Analytical MethodsPost-translational Modifications • Enzymatic cleavage & analysis • Mass spectroscopy • NMR • Immunoassay • Peptide mapping • Functional assay

  15. Inherent Challenges Biotech products are large, complex, plieotropic molecules - mixture of post-translational modifications - multiple active sites - homologous - heterologous - activities are dependent on complex, folded conformations - susceptible to multiple degradative events - proteolysis, aggregation, mis-folding, oxidation, deamidation, etc.

  16. Factors to Consider Purity Potency Strength Pharmacokinetics Pharmacodynamics Immunogenicity

  17. Fermentation Processes Control: Agitation pH Ionic strength Temperature Dissolved O2 & CO2 Media components Growth rate Expression rate Monitor: Agitation pH Ionic strength Temperature Dissolved O2 & CO2 Media components Biomass Bioburden (sterility, mycoplasma) Light absorbance (e.g., A280)

  18. Chromatographic Processes Control: pH Ionic strength Flow rate Temperature Volume Monitor: pH Ionic strength Flow rate Temperature Volume Bioburden Light absorbance

  19. Filtration Processes Control: Temperature Flow rate Back-pressure Volume Monitor: Temperature Flow rate Back-pressure Volume Bioburden Light absorbance

  20. Lyophilization Control: Shelf temperature Product temperature Chamber Pressure Condenser temperature Condenser pressure Time Freezing rate Drying rate Product moisture content Monitor: Shelf temperature Product temperature Chamber Pressure Condenser temperature Condenser pressure Time

  21. Questions • What technologies are available now to evaluate the characteristics of protein products in real time during manufacturing? • What tools would allow us to understand the manufacturing process better? • What processes in biological drug manufacturing would benefit the most from implementation of PAT? • For processes or products that do not currently allow direct product quality monitoring, what other strategies do you recommend for product quality control in addition to control of in-process parameters? • What additional elements should be incorporated in a training and certification program for reviewers and inspectors of biotechnology PAT applications?

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