Alpha1-antitrypsin Deficiency


Virus and Prion Safety of a New Preparation of Human Alpha1-proteinase Inhibitor, Prolastin®-C


Nathan J Roth, PhD, Michael D Burdick, PhD, Kang Cai, PhD, Hilton Renfrow, DVM, Greg Buczynski, PhD, Wendy P Osheroff, PhD, JoAnn Hotta, PhD and Douglas C Lee, PhD


Pathogen Safety, Talecris Biotherapeutics Inc., Research Triangle Park, North Carolina


Abstract


The manufacture of Prolastin®-C (alpha1-proteinase inhibitor [human]) uses a modified process for Prolastin® that incorporates two new dedicated virus reduction steps: a unique solvent/detergent treatment and a small pore nanofiltration. The Prolastin-C manufacturing process was


investigated for its capacity to remove or inactivate relevant viruses or models of relevant viruses by evaluating individual process steps across production ranges for key operating parameters. To address the theoretical risk of prion transmission, the Prolastin-C process was also investigated for its capacity to decrease the infectivity of an experimental agent of transmissible spongiform encephalopathy, considered as a model for the variant Creutzfeldt–Jakob disease and Creutzfeldt–Jakob disease agents. These studies demonstrate that the manufacturing process for Prolastin-C maintains a high safety margin from the risk of transmission of infectious viruses with a wide range of physicochemical properties and maintains the capacity to effectively remove prions, if present in the starting material.


Keywords


Alpha1-antitrypsin, alpha1-proteinase inhibitor, Prolastin, Prolastin-C, pathogen reduction, prion, protein, purity, virus, transmissible spongiform encephalopathy


Disclosure: All authors are full-time employees of Talecris Biotherapeutics Inc. Acknowledgments: The following reagents were obtained through the National Institutes of Health (NIH) AIDS Research and Reference Reagent Program, Division of AIDS, NIAID, NIH: C8166-45 cell line from Dr Robert Gallo; H9 cell line from Dr Robert Gallo. Received: October 5, 2010 Accepted: December 9, 2010 Citation: US Respiratory Disease, 2010;6:31–9 Correspondence: Nathan J Roth, PhD, Pathogen Safety, Talecris Biotherapeutics Inc., PO Box 110526, 85 TW Alexander Drive, Research Triangle Park, NC 27709. E: nathan.roth@talecris.com


Support: This study was sponsored by Talecris Biotherapeutics, Inc. (Research Triangle Park, NC 27709, US). Editorial assistance was provided under the direction of the authors by Anne-Marie Manwaring, BSc, and Martin Kenig, DPhil, of PAREXEL and was supported by Talecris Biotherapeutics, Inc.


Prolastin® (alpha1-proteinase inhibitor [human]) has been used since 1988 in patients with alpha1-antitrypsin deficiency. Observational and placebo-controlled studies have shown that Prolastin attenuates the decline in lung function.1–5 profile6–9


Prolastin also has an excellent tolerability and record of pathogen safety.10


A new preparation of purified human alpha1-proteinase inhibitor (tradename Prolastin®-C, alpha1-proteinase inhibitor [human]) is produced from large pools of human plasma using a modification of the


Prolastin manufacturing process. Additional purification steps incorporated into the modified manufacturing process result in a more concentrated final product with a higher functional activity relative to Prolastin and also excellent purity.11


As with all plasma-derived products, there is a potential risk for pathogen transmission if the plasma manufacturing pool contains plasma units from infected donors.12


reduction strategies are employed during manufacture to minimize © TOUCH BRIEFINGS 2010


this risk (see Figure 1). Overall, the pathogen safety of plasma-derived protein therapies relies on an integrated approach that includes careful screening and management of donors; testing of plasma donations and manufacturing pools for bloodborne pathogens using both serological and/or nucleic acid amplification technology assays; and integrating process steps into the manufacturing process that have the capability to reduce potential pathogen burdens using independent mechanisms of action.


Virus reduction for biological therapies encompasses both virus removal and virus inactivation strategies. Virus removal is the physical separation of the virus from the product, while virus inactivation is designed to render the virus (by physical or chemical means) incapable of causing an infection.13


The manufacturing process for Prolastin-C Multiple complementary pathogen


incorporates two new dedicated virus reduction steps: a novel solvent/detergent treatment step for enveloped virus inactivation and small pore nanofiltration for removal of viruses as small as approximately 20nm. These steps replace the pasteurization step used


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