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Observations on Marketed Alpha-1-Proteinase Inhibitor Products Ewa Marszal, PhD FDA/CBER

Observations on Marketed Alpha-1-Proteinase Inhibitor Products Ewa Marszal, PhD FDA/CBER BPAC, November 2005. Presentation Contents Differences between a 1 -PI products Consistency of manufacturing. Differences between a 1 -PI products Contaminating plasma proteins

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Observations on Marketed Alpha-1-Proteinase Inhibitor Products Ewa Marszal, PhD FDA/CBER

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  1. Observations on Marketed Alpha-1-Proteinase Inhibitor Products Ewa Marszal, PhD FDA/CBER BPAC, November 2005

  2. Presentation Contents Differences between a1-PI products Consistency of manufacturing

  3. Differences between a1-PI products Contaminating plasma proteins Inactive a1-PI (e.g., polymer/latent form) Modifications of the primary structure

  4. Protein impurities (SDS-PAGE, reducing) Prolastin Aralast Zemaira albumin → a1-PI → Specific activity: ≥ 0.35 ≥ 0.55 ≥ 0.7 mg functional a1-PI/mg total protein

  5. Presence of high molecular weight species (SE-HPLC, absorbance@215 nm) M% 95.4 89.8 88.1 (a1-PI + albumin) Zemaira Aralast Prolastin M

  6. Isoelectric focusing (IEF) cathode (-) anode (+) higher pH lower pH zero net charge pH gradient

  7. Heterogeneity of a1-PI in plasma by IEF (charge heterogeneity) 3 polysaccharide chains (sialic acid) N-terminal pentapeptide EDPNG Polymorphism, e.g., E342K

  8. Dominant a1-PI isoforms in plasma (charge heterogeneity) M6 M4 M2 EDPNG N N N EDPNG N N N EDPNG N N N

  9. Heterogeneity of a1-PI products by IEF Plasma Aralast Zemaira Prolastin Plasma Aralast Zemaira Prolastin desialylated M6 → M4 → M2 →

  10. Consistency of manufacturing by IEF Analysis of patients’ plasma from Aralast pivotal clinical trial Analysis of current and historical lots of a1-PI products

  11. Conclusions a1-PI products contain: different levels of contaminating plasma proteins different amounts of inactive a1-PI species different levels of primary structure modifications a1-PI in each product differs somewhat from a1-PI in plasma (IEF, polymer) Manufacturing of each a1-PI product appears to be consistent over time by IEF

  12. Consistency of manufacturing Bayer Baxter Behring Desialylated Non-desialylated

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