Steve Petteway

Evaluation of virus and prion reduction in a new intravenous immunoglobulin manufacturing process.

Background and Objectives Minimizing the transmission risk of infectious diseases is of primary importance in the manufacture of products derived from human plasma. A novel chromatography‐based intravenous immunoglobulin (IGIV) manufacturing process was developed and the reduction of virus and transmissible spongiform encephalopathies (TSE) during the manufacturing process was assessed. Mechanistically distinct steps that could affect virus reduction were identified, and the robustness of virus reduction over the range of process conditions was determined.

Immunoglobulin Replacement Therapy in Primary Antibody Deficiency Diseases – Maximizing Success

Antibody or humoral immunodeficiencies comprise the largest group of primary immunodeficiency diseases. Since the first description of patients with low gammaglobulin levels more than four decades ago, a great wealth of information has been accumulated. Especially in the last several years, the application of molecular and genetic techniques has unraveled many of these disorders, identifying disorders of B cell development, failure of class switch recombination and abnormalities of specific antibody production. Regardless of the underlying defect, the mainstay of therapy has been and remains immunoglobulin (Ig) replacement therapy, currently by intravenous infusion or subcutaneous injection. With advances in manufacturing, a number of products are not only safe for intravenous administration but doses can be increased to provide even more effective infection prophylaxis. However, manufacturing processes, methods of viral inactivation and removal and final composition differ widely among the available preparations. How these variables impact clinical outcome is not clear, but they have the potential to do so. As a result, careful selection of an intravenous immunoglobulin (IVIG), matching patient needs and risks to those risks associated with a specific IVIG, is necessary to optimize outcomes and maximize the success of Ig replacement therapy.

Critical factors influencing prion inactivation by sodium hydroxide

Background and Objectives  Transmissible spongiform encephalopathies (TSEs) are fatal neurodegenerative diseases caused by aberrantly folded cellular proteins (PrPSc; prions) that are generally resistant to conventional pathogen‐inactivation techniques. To ensure effective decontamination and inactivation of prions that could be present in source material, we investigated critical factors that influence prion inactivation by NaOH.

Establishing a GLP compliance program for non‐toxicology safety studies

Abstract Good Laboratory Practices (GLP) were originally promulgated for regulating non‐clinical laboratory safety studies, specifically, toxicology studies. Since the introduction of GLPs, regulatory agencies worldwide have increasingly required additional types of safety studies, such as viral clearance studies for plasma‐derived and biotechnology products, to be performed in accordance with the principles of the GLP regulations. Establishment of a GLP compliance program for non‐toxicology safety studies, however, has many challenges. In a viral validation study, a bench‐scale model of a manufacturing step is developed and is used to evaluate virus clearance, and so, many GLP elements such as the definitions for test article and test system, are not directly applicable. In spite of these difficulties, GLP concepts can be implemented as much as possible to ensure the integrity of the study. A GLP compliance program, with application to a number of disciplines, including viral validation, was established at Bayer HealthCare Biological Products Division. Integral to the effort was a multi‐functional team comprised of members from the quality Assurance Unit (QAU) and different departments within Research and Development (R&D). The team is primarily responsible for preparing, reviewing, and harmonizing the Standard Operating Procedures (SOPs) used in all regulated non‐clinical laboratory studies. Through the effective interactions between R&D and QAU, study participants gain essential knowledge and experience in GLPs. In addition to performing audits, the QAU plays an important role in the implementation of strategies for GLP compliance. As a result, significant progress has been made toward meeting the challenges of establishing a GLP compliance program for non‐toxicology safety studies. Copyright

Incorporating robustness and an evaluation of independent mechanisms into studies evaluating virus reduction in a new IGIV product manufactured by a chromatography-based process

5 0 ~ Selective IgA Deficiency Associated With a Non-PR-3, Positive ~JIl~ C-ANCA Nancy Wasserbauer*, Robert W Hostoffer§ *Midwestern University, Highland Heights, OH §Case Western Reserve University, Highland Hts, OH Selective IgA deficiency is associated with multiple serologic autoantibodies and multiple autoimmune disorders such as hemolytic anemia, rheumatoid arthritis, and systemic lupus erythematosus. We report a patient with IgA deficiency, a positive C-ANCA, and a negative PR-3. RM is a 55year-old white female who presented for the evaluation of IgA deficiency, positive ANA, hemolytic anemia, and recurrent infections. The patient initially sought care for a bladder infection and submental lymphadenitis. She subsequently developed a Coombs positive hemolytic anemia. A C T scan revealed splenomegaly. Additional CT scans of the chest and sinuses were unremarkable except for a left maxillary sinus cyst. Lab studies revealed a positive C-ANCA, negative PR-3, positive mild proteinurea at 210 mg/L. Serum immunoglobulins revealed an absence of IgA, but an elevated IgG at 2681 mg/dl (620-1400 mg/dl). The IgM was normal. IgG subclasses revealed an increase in IgGl at 2038 mg/dl (450-1400 mg/dl). Serum immunoelectrophoresis showed an elevated gammaglobulin at 41.9 (0.012.5 mg/L) with no monoclonal spikes. Urine immunoelectrophoresis showed an increase in the alpha-1 at 36.7 mg/L (0.0-11.1 mg/L), alph-2 at 70.2 mg/L (0.9-14.1 mg/L), betaglobulin 28.6 mg/L (0.0-15.9 rag/L) and gammaglobulin at 41.9 mg/L (0.0-12.5 mg.L), suggestive of glomerular and tubular proteinuria. The ESR was high at 29 (0-20). CBC showed a depressed total leukocyte count due to a decreased lymphocyte count at 670 g/L (1200-4800 g/L). C3, C4 and CH50 were normal and her rheumatoid factor was normal. These urine results were transient and a subsequent nephrology consultation revealed an absence of renal involvement. A positive C-ANCA represents a family of cytoplasmic staining antibodies which includes anti-PR-3. We report the first case of IgA deficiency with a positive C-ANCA, a negative PR-3 and no evidence of vasculitis.