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Developing Robust Analytical Methods for Early-Stage Biologics

Biologics are a broad class of therapeutic agents, encompassing vaccines, monoclonal antibodies, therapeutic proteins, nucleic acid-based therapies, blood components, tissue therapies, and cellular therapies. Recently, the US Food and Drug Administration (FDA) revised the definition of the term “protein” to include peptides containing more than 40 amino acids, therefore categorising them as biologics.1 The search for new and effective treatments for serious and life-threatening diseases has led to a growing interest in biologics in the last two decades. Biologics have shown promising clinical outcomes compared to traditional small molecules due to their high specificity, profoundly transforming the treatment strategies for cancer and autoimmune disorders. The COVID-19 pandemic has also accelerated the adoption of biologics within the healthcare sector. It is estimated that by 2027, the biologics market will have significant growth to $666 billion from $474 billion in 2023.2 This remarkable shift can be attributed to several factors, including the rising prevalence of chronic diseases, approval of several Advanced Therapy Medicinal Products (ATMPs), the increasing availability of biosimilars to patients, and the growing recognition of the benefits of biologics over small molecules. Emerging biopharmaceutical companies1 have also contributed to the growth of the biologics market. Approximately 65% of molecules in the research and development pipeline, including biologics and small molecules, are from emerging biopharmaceutical companies without the involvement of larger biopharmaceutical organisations. This share has seen a steady growth from 34% in 2001 to 50% in 2016, due to increased funding and investments.3

Biologics, however, present unique challenges in the journey from discovery to commercialisation due to their inherent complexity, size and charge heterogeneity and susceptibility to changes that could potentially impact efficacy and patient safety. Therefore, the development and implementation of robust analytical methods to monitor critical quality attributes (CQAs) during early-stage is vital for successful biologic development. At an early stage, analytical methods play an important role in candidate screening, process development, formulation screening, stability determination and release testing for first-in-human (FIH) studies. However, developing sensitive and robust analytical methods is challenging in the early stages of biologics development as there is often insufficient product knowledge. The draft ICH Q14 guideline4 provides a comprehensive framework based on science and risk-based approaches to overcome some of these challenges and streamlines the post-approval change management of analytical methods. This article primarily focuses on developing analytical methods for release and stability testing of biologics, while developing methods required for characterisation is out-of-scope.