Equivalence by Design for Advanced Dosage Forms and Drug Products

FDA has been encouraging drug sponsors to use a systematic approach such as quality-by-design principles for pharmaceutical development.
Oct 02, 2009
Volume 33, Issue 10

In the United States, drug products are deemed therapeutically equivalent if they meet the regulatory criteria of pharmaceutical equivalence and bioequivalence (1). Designation of therapeutic equivalence dictates interchangeability between a generic drug and its reference-listed drug (pioneer) product. As defined in Approved Drug Products with Therapeutic Equivalence Evaluation (i.e., the Orange Book):

Pharmaceutically equivalent drug products are formulated to contain the same amount of active ingredient in the same dosage form and to meet the same or compendial or other applicable standards (i.e., strength, quality, purity, and identity).

Hence, the regulatory concept of therapeutic equivalence only applies to drug products containing the same active ingredient(s) and does not encompass a comparison of different therapeutic agents used for the same clinical indication(s).

According to US regulations, bioequivalence means

the absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study (2).

Based on this definition, theoretically several methods can be used to demonstrate bioequivalence. However, the US Food and Drug Administration further recommends that drug sponsors use the following in vivo and in vitro approaches, in descending order of accuracy, sensitivity, and reproducibility, to demonstrate bioavailability and bioequivalence:

  • Pharmacokinetic studies (e.g., blood, plasma, serum) in humans
  • Pharmacokinetic studies (e.g., urine) in humans
  • Pharmacological or pharmacodynamic studies in humans
  • Well-controlled clinical trials
  • In vitro tests acceptable to FDA
  • Any other approach deemed adequate by FDA (2).

Therefore, pharmacokinetic studies using blood-level measurement have generally been used to demonstrate bioequivalence. This approach is especially applicable for systemically absorbed drugs found in many orally administered dosage forms and transdermal delivery systems because for such products, drug concentrations in the blood or plasma reflect drug availability at the site of action. The pharmacokinetic approach, however, cannot be applied to locally acting drug products because their blood/plasma concentrations may not reflect drug availability at the site of action. Another limitation in using pharmacokinetic studies lies in the fact that blood/plasma concentrations may be too low to be measured for these products. Consequently, bioequivalence methods recommended by FDA for locally acting drugs are tailored to individual dosage forms and drug products using various approaches (3). For example, to establish bioequivalence of orally inhaled products, FDA has required in vitro tests for comparison of device performance, pharmacodynamic studies for comparison of local delivery between products, and pharmacokinetic studies to ensure that systemic exposure to the drug is minimal. Likewise, depending on individual drugs or drug products, bioequivalence of gastrointestinal (GI) acting products is currently evaluated using one or more of the following methods: in vitro binding assay, in vitro dissolution studies, pharmacokinetic studies, and clinical trials.

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