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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 on theme: "Advisory Committee for Pharmaceutical Science Process Analytical Technology and Biotechnology Products Keith O. Webber, Ph.D. Office of Biotechnology Products."— Presentation transcript:

1 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

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

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

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

5 Process Analytical Technology Data Process Decision Monitor Adjust Evaluate

6 Biotechnology Processes Fermentation Concentration Harvesting Product Capture Chromatography Filtration Formulation 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: GlycosylationGlycosylation ProteolysisProteolysis AcylationAcylation SulfationSulfation many othersmany 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 Methods Primary Structure Methods: amino acid analysisamino acid analysis protein sequencingprotein sequencing peptide mappingpeptide mapping mass spectrometrymass spectrometry immunoassayimmunoassay

12 Analytical Methods Secondary Structure Methods: circular dichroismcircular dichroism NMRNMR

13 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

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

17 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

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

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

20 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

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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