REGULATORY ASPECTS OF MODIFICATIONS TO INNOVATOR BRONCHODILATOR METERED-DOSE INHALERS AND DEVELOPMENT OF GENERIC SUBSTITUTES

Regulatory requirements for modifications to an approved innovator metered dose inhaler (pressurized MDI; USP nomenclature: inhalation aerosol) and for development of a new generic product are discussed. Although many of the requirements apply generally to MDI's, they are discussed with specific reference to albuterol. Changes to the container and closure system may impact on the dosimetry of the redesigned product, as well as upon toxicologic and chemistry, manufacturing and controls (CMC) concerns. Changes to the formulation, including the use of alternate propellants, may raise issues requiring both clinical and in vitro performance evaluation. In view of the level of interest of a number of firms in approval requirements for generic Albuterol Inhalation Aerosol products, the article discusses in considerable detail the CMC and bioequivalence requirements for a generic product. Similarities in the CMC. requirements for innovator and generic products are evident. Three comparative in vitro bioequivalence tests, particle size distribution, spray pattern and plume geometry, and unit spray content, established by the Division of Bioequivalence are discussed. Similarities and differences in the in vivo requirements' for innovator and generic products are evident. Differences are the result of U.S. statute, which requires safety and efficacy testing for a product approved under a new drug application (NDA), but documentation of bioequivalence for a product approved under an abbreviated new drug application (ANDA). The advantages and disadvantages of three pharmacodynamic study designs which have potential usefulness for documentation of in vivo bioequivalence are discussed.