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

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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.