Industry perspective on regulatory authority (RA) quality reviews of biosimilar applications – an evaluation of RA guidance and expectations for chemical, manufacturing, and controls information through in-depth query analysis

Abstract

ABSTRACT Purpose Evaluate the type and quantity of quality information (i.e. Chemistry, Manufacturing, and Control) requested by the US FDA and EMA in queries pertaining to biosimilar applications. Methods Numbers/types of queries received following regulatory submissions (FDA/EMA, n = 7/n = 5) for seven biosimilars (PF-filgrastim [Nivestym], PF-rituximab [Ruxience®], PF-trastuzumab [Trazimera®], PF-bevacizumab [Zirabev®], PF-pegfilgrastim [Nyvepria®], PF-adalimumab [Abrilada™/Amsparity®], PF-infliximab [Ixifi]) from a single product portfolio were analyzed considering published regulatory authority (RA) guidance and in relation to sections/subsections of Module 3: Quality from the Common Technical Document regulatory dossier and topics based on keyword assignment. Results Queries were most frequently assigned (FDA/EMA %, range) to Drug Substance Manufacture (subsection 3.2.S.2; 21–35%/13–50%), Control of Drug Substance (3.2.S.4; 3–11%/5–17%), Drug Product Pharmaceutical Development (3.2.P.2; 1–12%/1–15%) and Manufacture (3.2.P.3; 17–41%/2–13%), and Analytical Similarity (3.2.R; 4–21%/4–20%). The proportion of Drug Substance and Drug Product queries was significantly different between RAs (n1 = 952, n2 = 468, p-value <0.001; two-sample proportion z-test). Topic assignments included: Control (12–27%/12–28%), Manufacturing (56–72%/34–66%), Stability (1–12%/2–24%), Biosimilarity (5–16%/5–25%), and Container Closure (0–3%/0–9%). Conclusion The focus of both RAs on topics related to manufacturing and controls is valuable in understanding expectations for scientific and technical content related to gaining biosimilar approval.