Advisory Committee for Pharmaceutical Science Process Analytical Technology and Biotechnology Products Keith O. Webber, Ph.D. Office of Biotechnology Products.

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Presentation transcript:

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

Which Products? Recombinant DNA-derived Protein Products Biological Products include:

Two Aspects of PAT 1.Monitoring product characteristics or surrogates. 2.Monitoring and modulating critical process parameters to guide the product characteristics during processing.

Process Analytical Technology Data Process Decision Monitor Adjust Evaluate

Biotechnology Processes Fermentation Concentration Harvesting Product Capture Chromatography Filtration Formulation Lyophilization

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

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

Biotech API Characteristics Post-translational modifications: GlycosylationGlycosylation ProteolysisProteolysis AcylationAcylation SulfationSulfation many othersmany others

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

Analytical Methods Primary Structure Methods: amino acid analysisamino acid analysis protein sequencingprotein sequencing peptide mappingpeptide mapping mass spectrometrymass spectrometry immunoassayimmunoassay

Analytical Methods Secondary Structure Methods: circular dichroismcircular dichroism NMRNMR

Analytical Methods Tertiary & Quaternary Structure Methods: Functional assayFunctional assay ImmunoassayImmunoassay Peptide mapping (for mapping disulfides)Peptide mapping (for mapping disulfides) Size-exclusion chromatographySize-exclusion chromatography Hydrophobic-interaction chromatographyHydrophobic-interaction chromatography

Analytical Methods Post-translational Modifications Enzymatic cleavage & analysisEnzymatic cleavage & analysis Mass spectroscopyMass spectroscopy NMRNMR ImmunoassayImmunoassay Peptide mappingPeptide mapping Functional assayFunctional assay

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.

Factors to Consider PurityPotencyStrengthPharmacokineticsPharmacodynamicsImmunogenicity

Fermentation Processes Monitor:AgitationpH Ionic strength Temperature Dissolved O 2 & CO 2 Media components Biomass Bioburden (sterility, mycoplasma) Light absorbance (e.g., A280) Control:AgitationpH Ionic strength Temperature Dissolved O 2 & CO 2 Media components Growth rate Expression rate

Chromatographic Processes Monitor:pH Ionic strength Flow rate TemperatureVolumeBioburden Light absorbance Control:pH Ionic strength Flow rate TemperatureVolume

Filtration Processes Monitor:Temperature Flow rate Back-pressureVolumeBioburden Light absorbance Control:Temperature Flow rate Back-pressureVolume

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

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?