Recently 30th October, 2025 the U.S. Food and Drug Administration (FDA) issued guidance titled "M13A: Bioequivalence for Immediate-Release Solid Oral Dosage Forms" to standardize and enhance bioequivalence (BE) studies globally. This guidance is part of the International Council for Harmonisation (ICH) M13 series, aimed at providing consistent approaches for conducting BE studies of immediate-release (IR) solid oral dosage forms—medications that release their active ingredients immediately after ingestion.
This guideline is intended to provide recommendations on conducting bioequivalence (BE) studies during both the development and post-approval phases for oral administration of immediate-release solid oral dosage forms, such as tablets, capsules, and powders for oral suspension, designed to deliver drugs to the systemic circulation.
Bioequivalence ensures that two products release their active ingredients at similar rates and extents, ensuring comparable safety and efficacy. A common BE standard reduces the need for redundant testing across jurisdictions, supporting ICH’s goal for global standardization.
General Principles in Establishing Bioequivalence
Study Design: BE studies primarily use pharmacokinetic (PK) endpoint studies, focusing on parameters such as Cmax (maximum concentration of drug in blood) and AUC (area under the concentration-time curve).
Study Population: Healthy adults are typically chosen to limit variability unless the drug's safety profile restricts this.
Sample Size: The number of participants should be statistically calculated to ensure study power, with a minimum of 12 subjects for crossover designs.
Study Conditions (Fasting/Fed): For IR dosage forms, studies under fasting conditions are standard. High-risk products may require both fasting and fed studies to ensure stability under different GI conditions.
The specific topics covered in this guidance are the comprehensive documentation that is required for submission, including data on PK parameters, subject sampling, protocol deviations, and certificates of analysis and in addition covers
Endogenous Compounds: If the drug is an endogenous compound, baseline correction of plasma levels before administration is required for accuracy.
Immediate Release Dosage Forms Variants: Specific recommendations exist for orally disintegrating tablets, chewable tablets, and oral suspensions, all of which must adhere to the conditions outlined in the comparator’s label.
Fixed-Dose Combinations: For combination products, BE must be demonstrated individually for each active ingredient.
pH-Dependency: For drugs sensitive to pH, additional BE testing in altered gastric pH conditions (e.g., with acid reducers) may be necessary.
The guidance emphasizes the need for robust study design and accurate data recording to ensure reliable BE assessment. Adherence to these standards is critical for consistency in therapeutic efficacy and regulatory compliance across markets.
For further details, the full guidance document can be accessed through the FDA's website. Also, check out these Questions and Answers on M13A Bioequivalence for Immediate-Release Solid Oral Dosage Forms that are frequently asked and addressed by the USFDA.
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