Approaches to Quality Risk Management When Using Single-Use Systems in the Manufacture of Biologics

Abstract

Biologics manufacturing technology has made great progress in the last decade. One of the most promising new technologies is the single-use system, which has improved the efficiency of biologics manufacturing processes. To ensure safety of biologics when employing such single-use systems in the manufacturing process, various issues need to be considered including possible extractables/leachables and particles arising from the components used in single-use systems. Japanese pharmaceutical manufacturers, together with single-use suppliers, members of the academia and regulatory authorities have discussed the risks of using single-use systems and established control strategies for the quality assurance of biologics. In this study, we describe approaches for quality risk management when employing single-use systems in the manufacturing of biologics. We consider the potential impact of impurities related to single-use components on drug safety and the potential impact of the single-use system on other critical quality attributes as well as the stable supply of biologics. We also suggest a risk-mitigating strategy combining multiple control methods which includes the selection of appropriate single-use components, their inspections upon receipt and before releasing for use and qualification of single-use systems. Communication between suppliers of single-use systems and the users, as well as change controls in the facilities both of suppliers and users, are also important in risk-mitigating strategies. Implementing these control strategies can mitigate the risks attributed to the use of single-use systems. This study will be useful in promoting the development of biologics as well as in ensuring their safety, quality and stable supply.

Visible particles in parenteral drug products: A review of current safety assessment practice

“…For SVPs ranging in size from 10 µm to the visible threshold, the limits are harmonized in the USP, EP, and JP at 6,000 and 600 per container for ≥10 µm and ≥25 µm particles, respectively, in 100 mL containers. For containers larger than 100 mL, limits are 25 per mL and 3 per mL for particles of ≥10 µm and ≥25 µm, respectively ( Ishii-Watabe et al, 2015 , Perez et al, 2016 ). For particles <10 µm, no compendial limits would be applicable, presumably this correlates to the approximate size of a human erythrocyte suggesting that particles smaller than an erythrocyte are of less concern because they are unlikely to embolize.…”

Large-Scale Assessment of Extractables and Leachables in Single-Use Bags for Biomanufacturing

“…Extractables are defined as compounds that migrate from any product-contact material when exposed to an appropriate solvent under exaggerated conditions of time and temperature, while leachables may represent a subset of extractables that are found after the interaction between product and contact material under standard operating conditions . E&Ls may include a variety of chemicals or their derivatives used in the manufacturing of SUBs, including catalysts, initiators, additives (e.g., lubricants, antioxidants, antitack, and antistatic agents), oligomers with a low degree of polymerization, adhesives, anchoring agents, adhesive resins, and irradiation-induced degradation products and oxides …”

“…5 E&Ls may include a variety of chemicals or their derivatives used in the manufacturing of SUBs, including catalysts, initiators, additives (e.g., lubricants, antioxidants, antitack, and antistatic agents), oligomers with a low degree of polymerization, adhesives, anchoring agents, adhesive resins, and irradiation-induced degradation products and oxides. 6 Extractables screening is crucial to provide a profile of potential substances that may also leach into the bioprocess to ensure no detrimental effect on the process such as those previously reported. 7−12 Regulatory bodies require that any production equipment used in biopharmaceutical manufacturing must not present any hazards to the final drug product.…”