Module 9 2024

03/09/2024

Biologics vs Small Molecules (NBEs vs NCEs)

The Organisation for Professionals in Regulatory Affairs

Preclinical Testing of Biologicals – Sept 2024

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Nonclinical Safety of Biologics : Important → NBEs are not just “large” small molecules

Characteristics

Biologics

Small Molecules

Molecular Weight

Greater than 1 kilodalton (kDa) (monoclonal antibody = 150 kDa)

Less than 0.5 kDa

Toxicity

Primarily on-target = Exaggerated pharmacology On and/or off-target

Species specificity

Pharmacology often only in one species → MUST demonstrate pharmacological relevance of species used; Often primate

Pharmacology and any off-target toxicity are often species independent → One species should express the target but can be either rodent or non-rodent

Route of Admin

Typically intravenous or sub-cutaneous

Typically Oral

Absorption, Distribution, Metabolism, Excretion

Long half-life in blood (~18-22 days) Not metabolized - usually catabolized in a similar manner to other proteins/peptides Immunogenicity often observed → monitored in nonclinical/clinical studies Immunotoxicity often exaggerated pharmacology

Short half-life (<24hr) May have one or more metabolites which may be active and/or have safety issues

Immunogenicity (anti drug antibodies) and immunotoxicity

Rare

Drug product

Simpler formulations, usually a solution

Complex formulation (tablet, nanoparticle, suspension)

The Organisation for Professionals in Regulatory Affairs

Preclinical Testing of Biologicals – Sept 2024

6

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