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Why are Biologics Drugs Different

Why are Biologics Drugs Different

01 Jul 2024

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:



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.



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.



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.



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.



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

About The Authors

Roland Buhler, R.Ph.

RAC Senior Director, CMC Regulatory Affairs

Roland Buhler, R.Ph., RAC, has over 30 years in the pharmaceutical industry. As a CMC Regulatory Affairs professional and a licensed pharmacist, he brings an exceptional blend of technical knowledge and regulatory acumen. His qualifications have positioned him adeptly for overseeing intricate and varied initiatives, from the preliminary stages of Investigational New Drug (IND) applications to post-market authorization. He has lead teams through complicated regulatory processes to ensure compliance with global regulatory standards.

Before joining Syner-G, Roland has provided strategic guidance and operational support for developing and commercializing biologic and small molecule compounds for various therapeutic areas. He has successfully led teams through agency meetings, submissions, and inquiries, ensuring compliance with global standards and regulations, and has contributed to due diligence activities for in-licensing and acquisitions.

Prior to regulatory, he held several positions in quality assurance managing internal and external audit programming, compliance projects, and acquisition integrations. In this capacity, he directed high-level, risk-based assessments to determine strategy and remediation prioritization, managed consultants to develop a site master validation plan and organize inspectional history for upcoming agency inspections, and developed and maintained programs to identify and prioritize compliance risks that might result in business interruptions to existing commercial products or NDA approval delays.

Roland has managed various pharmaceutical dosage forms supporting biological and small molecules for investigational and marketed products within oncology, neuroscience, immunology, renal, and pain therapeutic areas.

As a team leader, he has managed personnel supporting anti-infective, cardiovascular, renal, and inhaled anesthetic products and was responsible for monitoring supplements, amendments, and variations for changes to manufacturing processes, test methods, manufacturing sites, or specifications.

Roland received his Bachelor of Science, Pharmacy, from the University of Wisconsin, Madison, WI. He also attended the University of Wisconsin, Milwaukee, WI, studying Computer Science, Mathematics, and Physics. He has been a member of the Regulatory Affairs Professional Society, Rockville, MD, since 2005.