An alternative approach to assessing bioequivalence
Given the assumption of constant clearance, which is generally true within each individual across different formulations of
the same drug substance, it has been recognized that bioequivalence should be assessed by focusing on the comparison of absorption
pattern rather than distribution, metabolism, or elimination process of the drug. This recommendation is preferred because
the absorptive process is more sensitive to a difference between formulations as compared with other biological events occurring
subsequent to drug absorption. It follows that because absorption is mainly controlled by when, where, and how a drug is released
from a formulation, an alternative approach for the assessment of bioequivalence may be directed to the comparison of in vivo drug delivery profiles (iDDPs) before the drug is absorbed (8). In doing so, equivalence in the rate and extent of drug absorption
may be established by showing the similarity of iDDPs between products in comparison.
Schematically, from the entry of a formulation into the body to the point at which the drug reaches systemic circulation or
the site of action, an iDDP may consist of some or all of the following steps: deposition, transit, retention, release, and
transport. In this setting, the relative contribution of each step to an iDDP may depend on the dosage form, drug product,
route of administration, or clinical indication under consideration. For example, various dosage forms are made with distinct
objectives that can be manifested in their iDDPs. Where the drug is deposited will be an important point for nasal sprays
and aerosols, as well as locally acting GI products and dermatological medications. In contrast, maneuvering drug transit
through the GI tract is the primary goal in the design of orally administered extended-release products. Although control
of retention time in the stomach is essential for floating systems, the location of drug release in the intestine is the focus
for delayed-release dosage forms (e.g., enteric-coated tablets). On the other hand, consideration of transport process is
crucial for achieving bioequivalence of liposomal products and other similar lipid-based formulations, given the unique characteristics
of these dosage forms.
Equivalence by design
From product design and manufacturing perspectives, bioequivalence can be advanced by matching the iDDP of the reference product
during test-product development, which is particularly important for complex pharmaceutical dosage forms and delivery systems.
Technically, this objective can be achieved using an approach analogous to the quality-by-design (QbD) paradigm that the ICH
and FDA are currently promoting for pharmaceutical development (9). As illustrated in the FDA Q8(R1) guidance, the application
of a QbD approach must begin with predefined objectives; namely, a quality target product profile as related to quality, safety,
and efficacy (9). After the quality target product profile is defined, one will identify critical quality attributes of the
product and use these attributes as the benchmark to design formulation and manufacturing process. In parallel with the QbD
concept, an equivalence-by-design (EbD) approach can start with determining the target (or reference) product profile based
on the critical steps of its iDDP as related to bioequivalence. Once the target (reference) iDDP is defined, one may identify
biomarkers or in vitro markers to characterize critical steps of the target (reference) iDDP. The test formulation and manufacturing process can
then be designed with the use of these markers to match the target iDDP.