Drug product performance,1in vivo, may be defined as the release of the drug substance from the drug product leading to bioavailability of the drug substance. The assessment of drug product performance is important since bioavailability is related to the pharmacodynamic response and related adverse events. Thus, performance tests relate the quality of a drug product to clinical safety and efficacy. Bioavailability studies are drug product performance studies used to define the effect of changes in the physicochemical properties of the drug substance, the formulation of the drug, and the manufacture process of the drug product (dosage form). Bioavailability is one aspect of drug product quality that links the in vivo performance of a new drug product to the original formulation that was used in clinical safety and efficacy studies. Bioequivalence studies are drug product performance tests that compare the bioavailability of the same active pharmaceutical ingredient from one drug product (test) to a second drug product (reference). Bioavailability and bioequivalence can be considered as measures of the drug product performance in vivo.
Drug product performance studies are used in the development of new and generic drug products. The initial safety and efficacy clinical studies during new drug development may use a simple formulation such as a hard gelatin capsule containing only the active ingredient diluted with lactose. If the new drug demonstrates appropriate human efficacy and safety, a to-be-marketed drug product (eg, compressed tablet) may be developed. Since the initial safety and efficacy studies were performed using a different formulation (ie, hard gelatin capsule), the pharmaceutical manufacturer must demonstrate that the to-be-marketed drug product demonstrates equivalent drug product performance to the original formulation (Fig. 15-1). Equivalent drug product performance is generally demonstrated by an in vivo bioequivalence study in normal healthy volunteers. Under certain conditions, equivalent drug product performance may be demonstrated in vitro using comparative dissolution profiles (see Chapter 14).
Drug product performance and new drug product development. Drug product performance may be determined in vivo by bioequivalence studies or in vitro by comparative drug/dissolution studies. BA = bioavailability.
As stated above, the marketed drug product that is approved by the FDA may not be the same formulation that was used in the original safety and efficacy clinical studies. After the drug product is approved by the FDA and marketed, the manufacturer may perform changes to the formulation. These changes to the marketed drug product are known as postapproval changes (see also Chapter 16). These postapproval changes, often termed SUPAC (scale-up and postapproval change), could include a change in the supplier of the active ingredient, a change in the formulation, a change in the manufacturing process and/or a change in the manufacturing site.2,3 In each case, the manufacturer must demonstrate that drug product performance did not change and is the same for ...