About biologics

A biologic is an active pharmaceutical ingredient derived from a living organism that cannot be synthesized by chemical means.¹

Through better understanding of pathologic pathways, recombinant proteins such as glycosylated monoclonal antibodies (mAbs) and fusion proteins have emerged as therapeutic candidates to treat many diseases because of their specificity and stability in binding to molecular, pharmacological targets (Examples).²

These therapies have greatly advanced treatment paradigms and improved outcomes of many diseases since their first introduction in the 1990s. However, they are, in the vast majority of cases, more expensive than conventional small-molecule medications and broad use can significantly impact healthcare budgets. As a result, access to these therapies is frequently limited through the application of reimbursement criteria that are often stricter than treatment guidelines potentially leading to sub-optimal treatment of eligible patients.^2,3

Biologics have large and complex structures compared to small-molecule drugs. Unlike small-molecule drugs, which are chemically defined molecular entities, biologics such as recombinant monoclonal antibodies and fusion proteins have greater structural complexity, including primary, secondary, tertiary and quaternary structures. They can be more than 1000-fold larger than small-molecule drugs.^9,10

Adapted from Kozlowski S, et al. N Engl J1 Med 2011;365(5):385–388.

Recombinant proteins are engineered by introducing manipulated DNA into a living organism (cell lines) such as bacteria (E. coli), yeast (ex. S. cerevisiae), mammalian (ex. CHO, Chinese Hamster Ovary), or human cells (ex. HEK293, HT-1080). The DNA instructs the living organism to produce large quantities of the recombinant protein.¹¹

DNA, deoxyribonucleic acid.
Icons designed by Freepik from Flaticon (https://www.flaticon.com/).

The biologic activity of recombinant proteins is defined by their complex structure but also by the cell-line involved in the manufacturing process to produce them.^10-12 For instance, post-translational modifications such as glycosylation pattern but also charge profile are very dependent on the cell line used for manufacturing and can be defined as critical or non-critical quality attributes (CQA) for the biological activity of a recombinant protein. This is also called the “biochemical fingerprint” of a protein. It defines its pharmacological activity and ultimately its efficacy, safety profile and immunogenicity.¹²

Images shown are for illustrative purposes only, and are adapted from the below mentioned references.

1. Berkowitz S, et al. Nat Rev Drug Discov 2012;11(7):527–540; 2. Lee C, et al. MAbs 2017;9(6):968–977;3. Turner A & Schiel JE. Anal Bioanal Chem 2018;410(8):2079–2093; 4. Cho IH, et al. MAbs 2016;8(6):1136–1155.

Adapted from Kozlowski S & Swann P. Adv Drug Deliv Rev 2006;58(5-6):707–722.

Hence, no two lots are the same even when the manufacturing process is “unchanged”, which makes them impossible to be replicated exactly.^12,15,16

Further, there are numerous post-approval manufacturing changes observed in monoclonal antibodies (see Figure below).¹⁷

Figure 1. The biologics manufacturing process and the manufacturing steps that affect final characteristics of biologics. Adapted from Vezér B, et al. Curr Med Res Opin 2016;32(5):829-834.¹⁷

By the International Council for Harmonisation (ICH) of Technical Requirements for Pharmaceuticals for Human Use, product changes introduced through manufacturing changes should have no adverse impact on critical quality attributes (“biological fingerprint”). If there are changes, additional data and studies are required for risk minimization.²⁴

Learn through a series of animated videos the essential facts about biosimilars.