What is the difference between biotechnological drugs and traditional drugs?

The term biotechnological (or biological) drug refers to a macromolecule, typically a recombinant protein, approved for therapeutic use and produced through biotechnological processes using living organisms.

This definition, which takes up that of the European Medicines regulatory agency:

European Medicines Agency (EMA) denotes recombinant therapeutic proteins obtained with the use of recombinant DNA techniques, and includes monoclonal antibodies and their derivatives. Recombinant DNA technology allows human proteins to be formulated as therapeutic agents, allowing not only to faithfully reproduce them for substitution therapy (such as human recombinant insulin) but also to optimize them through rational design to achieve new drugs with better pharmacological properties.

In contrast, the term “traditional” drug denotes a “small molecule” drug, usually with lower structural complexity, typically obtained by “traditional” chemical synthesis. As with a traditional drug, the biotechnological product must pass clinical trials and demonstrate safety and efficacy to obtain marketing authorization. If the clinical studies are successful, the manufacturer will submit a license application for the biological product providing information that takes into account the peculiar methods of production of biological drugs.

To summarize, the many differences between biological medicines and small molecule drugs can be described in terms of:

1. Manufacturing processes:

• biological drugs are biosynthesized by and through living cells, making their manufacturing process very complex
• small molecule drugs are typically synthesized through standardized chemical processes resulting in well-defined structures

2. Structural complexities:

• biological drugs are large, structurally complex macromolecules produced in living cells
• traditional chemical drugs are small molecules created through chemical synthesis

3. Analytical characterization:

• analysis of biological drugs to achieve a full characterization of both the final product and the possible impurities/contaminants is complex and highly challenging
• traditional drugs are more easily characterized due to their simpler structures and standardized manufacturing

4. Regulatory pathways for approval:

• biological drugs are approved under a “Biological License Application” (BLA) pathway by regulatory agencies
• synthetic traditional drugs are approved under standard new drug application (NDA) pathways

5. Definitions of “follow-on” products (biosimilar vs generic)

• biosimilars of biological drugs are not considered identical to the reference medicine due to the inherent micro-heterogeneity of the biological product
• generic versions of chemical drugs are identical to the original drug and are considered bioequivalents.

Suggested readings:

• Rader RA. (Re)defining biopharmaceutical. Nat Biotechnol. 2008 Jul;26(7):743-51. doi: 10.1038/nbt0708-743. PMID: 18612293.
• Quality of biotechnological products: analysis of the expression construct in cells used for production of r-DNA derived protein products, ICH Q5B. Available at: www.ich.org/page/quality-guidelines (accessed on Feb.28, 2024)
• Biosimilars in the EU: Information guide for healthcare professional. Available at: www.ema.europa.eu/en/documents/leaflet/biosimilars-eu-information-guide-healthcare-professionals_en.pdf (accessed on Feb.28, 2024)