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Licensed Biological Products with Structural Heterogeneity

Licensed Biological Products with Structural Heterogeneity. Andrew C. Chang, Ph.D. Associate Director for Policy and Regulation Division of Hematology, CBER, FDA BPAC, Gaithersburg, MD November 4, 2005. TOPICS TO BE COVERED. Structural Heterogeneity of Biological Products: Case Studies

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Licensed Biological Products with Structural Heterogeneity

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  1. Licensed Biological Products with Structural Heterogeneity Andrew C. Chang, Ph.D. Associate Director for Policy and Regulation Division of Hematology, CBER, FDA BPAC, Gaithersburg, MD November 4, 2005

  2. TOPICS TO BE COVERED • Structural Heterogeneity of Biological Products: Case Studies • Plasma derived products - Andrew Chang, Ph.D. OBRR/CBER • Recombinant products and monoclonal antibodies - Kurt Brorson, Ph.D. OPS/CDER

  3. Structural Heterogeneity of Biological Products • Factors contributing to structural heterogeneity • Biosynthetic processes used by living organisms • Manufacture and/or storage of the drug substance and drug product • Control of structural heterogeneity • To demonstrate consistency of the heterogeneity pattern of commercial lots with that of the lots used in preclinical and clinical studies • To assure lot-to-lot consistency, the kind and extent of this heterogeneity should be characterized and controlled

  4. Acylation Amidation or deamidation Carbamylation Carboxylation Formylation Formation of gamma carboxyglutamic acid Methylation Succinimide forms Aspartate isomerization Disulfide linkage Oxidation Phosphorylation Sulphation Proteolysis (terminal or domain deletion) Glycosylation (N-linked, O-linked, site occupancy, terminal groups, fucosylation) Aggregation High order structural change (conformational change or denaturization) Structural Heterogeneity of Biological Products (Cont) Examples of potential structural modifications

  5. Case Study (I) • Charge analysis of N-linked Oligosaccharides from FVIII Standards, Recombinant and Plasma Derived FVIII Products

  6. XI IX VIII Ca, PL XII Intrinsic Pathway Hemostasis Contact Kallikrein XIIa + HMWK Extrinsic Pathway PK XIa + Ca Vascular Injury Thrombin X IXa or Xa VIIa VII + Tissue Factor IXa Ca TF VIIIa Ca Ca, PL Prothrombin Xa V Va Ca, PL Ca, PL Thrombin Fibrinogen Fibrin XL-Fibrin XIIIa

  7. 80 kDa 80 kDa 90 kDa 90 kDa 80 kDa • FVIII: • Multi-domain glycoprotein (Mr 264,763) • Potential 25 N-linked Oligosaccharides N A1 A2 B A3 C1 C2 C IC Protease 1648/1649 210 kDa Heavy Chain Light Chain FVIII 90-210 kDa 1689/1690 740/741 Thrombin vWF 372/373 Activated FVIII 50 kDa 43 kDa 72 kDa vWF 1689/1690 372/373 Light Chain Heavy Chain B-Domain Deleted FVIII Toole et al., PNAS 1986; 83: 5939-5942 N A1 A2 A3 C1 C2 C

  8. Charge Analysis of N-linked Oligosaccharides from FVIII Standards, Recombinant and Plasma Derived FVIII ProductsSchilow et al., Thromb Haemost 2004; 92:427-428

  9. Conclusion • The charge analysis demonstrated heterogeneity of the glycoforms of the tested FVIII products.

  10. Case Study (II) • Characterization of five von Willebrand Factor (VWF) concentrates produced by five different manufacturing processes

  11. von Willebrand Factor

  12. Variation of vWF MultimersAmong Five Different VWF Concentrates 1% Gel 2% Gel IS P C-1 C-2 C-3 C-4 C-5 IS P C-1 C-2 C-3 C-4 C-5 Chang et al., Blood 2000; 96:567a, 2434

  13. VWF Activities from 5 Different VWF Concentrates Chang et al., Blood 2000; 96:567a, 2434

  14. Conclusion • The characteristics (e.g., Multimeric pattern and specific activity) of von Willebrand factor concentrates depend on the manufacturing processes.

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