Section 21 of the Code of Federal Regulations (CFR) stipulates that generics and their reference drugs have the same active ingredient(s), strength, dosage form, route of administration and condition of use (21 CFR 314.92 [a] [1]). The regulations allow for formulation differences, i.e. changes in inactive ingredients (excipients), impurities and residual solvents, if applicants provide information demonstrating that these differences do not affect the safety or efficacy of the proposed drug product (21 CFR 314.94 [a] [9] [ii]). However, differences in drug formulations can exert a physiological effect, depending upon the concentration, target population, route of administration and duration of drug use.

Examples of such effects include bicarbonates used in paracetamol drug products, which may accelerate gastric emptying, or polyoxyethylene polymers, which have been shown to affect the bioavailability of ranitidine in males, but not in females.

In answer to how FDA deals with these issues, author Sree Rayavarapu and co-authors describe a scientific, evidence-based methodology for the evaluation of generics and provide specific insights into the generics review process from a pharmacology–toxicology perspective. In the following three articles, these are discussed in light of the excipients, impurities and residual solvents found in generics.

Conflict of interest
The authors of the research paper [1] did not provide any conflict of interest statement.

Disclaimer: The ideas and views provided in the research paper [1] are the opinions of the authors and do not reflect any official policy of the FDA.

Related articles
FDA evaluation of residual solvents in generics

FDA evaluation of impurities in generics

FDA evaluation of excipients in generics

Reference
1.   Rayavarapu S, et al. Comparative risk assessment of formulation changes in generic drug products: a pharmacology/toxicology perspective. Toxicol Sci. 2015;146(1):2-10.

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