What is a biologic drug and how does it differ from a traditional small molecule drug?
Biologic drugs have increasingly provided for broader therapeutic use over the last few decades and this trend is accelerating. As the first part of a multi-part series, this article provides a discussion of the key differences between biologic and small molecule drugs below:
Source
Traditional small molecule drugs are typically chemically synthesized, although may be produced via fermentation or through extraction from plant sources, with or without subsequent synthetic modifications. Biologic drugs are derived from or produced by living sources, such as animals, humans, or other organisms, and range from larger peptides (>40 amino acids1) to monoclonal antibodies to cell and gene therapies. Due to the source of biologics, variability in the molecule and risk of potential adventitious agents dramatically increases.
Size
A cardinal characteristic of a biologic drug is the molecule’s high molecular weight, many-fold higher than a small molecule, with magnitudes over 900 Daltons. This larger size alone leads to complexities with respect to structure, homogeneity, and molecular characteristics.
Structure
Small molecule drugs are less complex, well characterized, and homogenous with known structure and degradation pathways and are assessed through established analytical techniques from wet chemistry to spectroscopic methods. Biologic drug substances are heterogeneous due to biological variation in starting materials including cell culture medium, cell line instability, post-translational modifications, and physical and chemical effects of the manufacturing process itself. Molecule variants include differences in carbohydrate structure, missed or additional sequences, or modification of amino acids, leading to variant species making a heterogenous drug substance. Additionally, a large molecule’s nature to fold into secondary and tertiary structures adds to the complexity of analytical method characterization. These conformational attributes challenge established analytical techniques and required complex and orthogonal methods to fully characterize the drug substance, including the requirement for a potency assay demonstrating the mechanism of action and indicative of the therapeutic activity. The requirements can be more complex for demonstrating equivalence for manufacturing changes during development and post-marketing including extended comparability and characterization.
Stability
With noted exceptions, small molecule drugs are stable to the routine stresses of manufacturing processes and environmental conditions. These drugs are administered by various routes, including orally, as they are stable in and absorbed from the intestinal tract. In contrast, biologics are more sensitive to physio-chemical effects which affect decisions for drug product formulation, manufacturing, filling, storage, shipping, and administration. Biologics are typically administered parenterally due to ease of degradation in the intestinal tract.
Immunogenicity
Development of an immune response against these large molecules is seen with biologic drugs. Immunogenicity can lead to allergic responses and development of neutralizing antibodies in contrast to traditional small molecules where immunogenicity is not typically seen. Biologic drug immunogenicity arises from exposure to molecular aggregates, degradants, or process impurities such as host cell proteins resulting in formation of anti-drug antibodies (ADA). The ADAs not only can reduce the therapeutic effects of the drug, but more critically ADAs can neutralize native proteins in-vivo. Therefore, monitoring molecular attributes is critical for a biologic drug program.
Stay tuned for future blogs in the series including discussions of the historical events that prompted the development of the BLA regulatory pathway and the unique considerations for advanced therapies including cell and gene therapy biologics.
Syner-G Biopharma Group
Syner-G Biopharma Group is a leading solution provider specializing in Chemistry, Manufacturing, and Controls (CMC) services for the life sciences industry. Here is how we can assist you:
- Technical Development: Syner-G can support or lead your product development efforts. Whether you need assistance with biologics, small molecules, or combination products, our expertise covers a wide range of therapeutic areas.
- Regulatory Strategy and Execution: Syner-G offers regulatory services to guide your regulatory strategy. They can help you prepare for agency meetings, navigate global regulatory requirements, and ensure compliance throughout the development process.
- Quality and GxP Compliance: Syner-G emphasizes quality and compliance. Their comprehensive approach ensures that your CMC activities meet the highest standards, from manufacturing to post-marketing.
1 Food and Drug Administration, Docket No. FDA-2018-N-2732, Definition of the Term ‘Biological’ Product
