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Challenging the Bioequivalence Hurdles for OINDPs: Achieving Q3 Structural Equivalence

Price R, Farias G, Ganley W, Shur J.

RDD Asia 2018. Volume , 2018: 1-14.

Abstract:

The 2003 Federal Drug and Cosmetic Act, Section 505(j)(8)(C), states that a drug that is not intended to be absorbed systemically can be assessed for bioequivalence (BE) by alternative scientifically valid measurements that can establish and detect a significant difference between the generic and the reference listed drug (RLD) in terms of safety and therapeutic effect. While pharmacokinetic (PK) studies in combination with in vitro based measurements have provided useful insight relating to the systemic exposure of inhaled compounds, these analyses do not provide the evidence to support therapeutic equivalence at the local site of action. In the abbreviated new drug application (ANDA) pathway for orally inhaled and nasal drug products (OINDPs), the US Food and Drug Administration (FDA) has introduced the concept of microstructural equivalence (Q3) for local acting products that are qualitatively (Q1) and quantitatively (Q2) the same as the reference listed drug products in terms of their active and inactive pharmaceutical materials. The microstructural differences in the arrangement of matter and state of aggregation within formulated and aerosolized forms of OINDPs will be dependent on the physicochemical properties of active and inactive materials, device characteristics, and processing history. Differences in Q3 at both a microscopic and macroscopic scale can manifest itself as a difference in properties that could be characterized using a combination of orthogonal in vitro- or ex vivo-based techniques. Some of the techniques currently under assessment for characterizing Q3 of OINDPs include the use of morphologically directed and surface mapping Raman spectroscopy and an integrated measurement of structure using in vitro dissolution and permeability kinetics. For OINDPs, the ongoing discussion will be how to investigate and characterize Q3 for the individual dosage forms and to demonstrate the validity of Q3 measurements for BE determinations.