Approved drug products may be subject to change(s) for a variety of reasons. The changes may include, but are not limited to, increase in batch size, alteration of the drug product constituent(s), improvement in the manufacturing process, and shift in manufacturing sites. The extent of pharmaceutical testing and the regulatory pathway for timely implementation of any change in the approved product and/or process depends upon the nature and extent of change. The U.S. Food and Drug Administration (FDA) has published guidelines that outline its expectations for the Scale-Up and Postapproval Changes (SUPAC) in the solid oral immediate and modified release (MR) products, and semisolid formulations. However, to date, no such guidelines have been issued to address SUPAC in the orally inhaled drug products (OIDPs), and this article represents a seminal contribution in this direction. It is hoped that it will inspire contributions from the relevant multidisciplinary experts from the pharmaceutical industry and the agency in accomplishing formal regulatory guidelines relevant to the OIDP SUPAC. The OIDPs are complex drug-device combination products. Therefore, a conceptualization of SUPAC guidelines for these products warrants consideration of contributions of effect of change(s) in individual components (drug substance, formulation, device) as well as a compound effect that a single or multiple changes may have on product performance, and its safety and efficacy. This article provides a discussion of scientific aspects and regulatory bases relevant to the development of SUPAC for OIDPs, and it attempts to outline considerations that may be applicable in addressing issues related to the OIDP SUPAC in the context of human drugs. The authors' statements should not be viewed as recommendations from any regulatory agency, as the applicable guidelines would be determined on case-by-case evaluation by the relevant authorities.