ABSTRACT
Polyvalent human normal immunoglobulins for intravenous use (IVIg), indicated for rare and often severe diseases, are complex plasma-derived protein preparations. A quality by design approach has been used to develop the Laboratoire Français du Fractionnement et des Biotechnologies new-generation IVIg, targeting a high level of purity to generate an enhanced safety profile while maintaining a high level of efficacy. A modular approach of quality by design was implemented consisting of five consecutive steps to cover all the stages from the product design to the final product control strategy.A well-defined target product profile was translated into 27 product quality attributes that formed the basis of the process design. In parallel, a product risk analysis was conducted and identified 19 critical quality attributes among the product quality attributes. Process risk analysis was carried out to establish the links between process parameters and critical quality attributes. Twelve critical steps were identified, and for each of these steps a risk mitigation plan was established.Among the different process risk mitigation exercises, five process robustness studies were conducted at qualified small scale with a design of experiment approach. For each process step, critical process parameters were identified and, for each critical process parameter, proven acceptable ranges were established. The quality risk management and risk mitigation outputs, including verification of proven acceptable ranges, were used to design the process verification exercise at industrial scale.Finally, the control strategy was established using a mix, or hybrid, of the traditional approach plus elements of the quality by design enhanced approach, as illustrated, to more robustly assign material and process controls and in order to securely meet product specifications.The advantages of this quality by design approach were improved process knowledge for industrial design and process validation and a clear justification of the process and product specifications as a basis for control strategy and future comparability exercises.
Subject(s)
Immunoglobulins, Intravenous/standards , Technology, Pharmaceutical/standards , Administration, Intravenous , Drug Compounding , Drug Contamination , Humans , Immunoglobulins, Intravenous/administration & dosage , Immunoglobulins, Intravenous/chemistry , Patient Safety , Quality Control , Risk Management , Technology, Pharmaceutical/methods , WorkflowABSTRACT
BACKGROUND: A highly purified 10% liquid intravenous immunoglobulin, IQYMUNE®, has been developed using an innovative manufacturing process including an affinity chromatography step for the removal of anti-A and anti-B hemagglutinins. OBJECTIVES: The pathogen (viruses and prions) clearance efficacy of the manufacturing process and its robustness for critical steps were investigated. METHODS: The manufacturing process of IQYMUNE® includes two dedicated complementary virus reduction steps: solvent/detergent (S/D) treatment and 20 nm nanofiltration as well as two contributing steps, namely caprylic acid fractionation and anion-exchange chromatography. The clearance capacity and robustness of these steps were evaluated with a wide range of viruses (enveloped and non-enveloped) and with a model of human transmissible spongiform encephalopathies (TSEs). RESULTS: The IQYMUNE® manufacturing process demonstrated a high and robust virus removal capacity with global reduction factors (RFs) of relevant and model viruses: ≥14.8 log10 for human immunodeficiency virus type 1 (HIV-1), ≥16.9 log10 for bovine viral diarrhoea virus (BVDV)/Sindbis virus, ≥15.7 log10 for pseudorabies virus (PRV), ≥12.8 log10 for encephalomyocarditis virus (EMCV) and 11.0 log10 for porcine parvovirus (PPV). The process also exhibited a high removal capacity for the TSE agent with an overall RF of ≥12.9 log10 due to the complementary actions of the caprylic acid fractionation, anion-exchange chromatography and nanofiltration steps. CONCLUSION: Data from virus and prion clearance studies fully support the high safety profile of IQYMUNE®, with a minimal reduction of 11 log10 for the smallest and most resistant non-enveloped virus, PPV, and more than 12 log10 for the TSE agent.
