Dr R. Williams, USA

Potency relates conceptually to bioavailability (BA) and comparative bioequivalence (BE) to indicate the degree to which the active ingredient is released from the drug product and becomes available at one or more sites of action. At these sites of action, the drug substance and/or its metabolites produce the safety and efficacy outcomes reflected in product labelling.

Focusing on BA/BE, pharmacokinetic (PK), pharmacodynamic, comparative clinical, and/or in vitro studies are used to benchmark the performance of a pioneer product (BA) and to understand that this performance is unchanged (BE) in the presence of some kind of change in components/composition and/or method of manufacture. From a benchmarking perspective, BA may require formal comparisons, although BA information from other formulations and/ or routes of administration may amplify understanding of the biopharmaceutical properties of a drug substance and product.

While measuring product quality BA as a benchmarking effort, establishing BE can be a more formal comparative test that uses specified criteria for comparisons and predetermined BE limits (goalposts). In the USA, BA/BE failures have been documented for phenytoin capsules, digoxin tablets, warfarin tablets, and levothyroxine tablets. Where pharmaceutical manufacturers have followed FDA procedures, to include manufacture according to application commitments, compendial standards, and strict adherence to GMP, bioequivalence failures have not occurred.

Multi-source products

Many nations throughout the world have come to rely on low-cost, good-quality multi-source (generic) pharmaceutical products as means of providing lower healthcare costs without sacrificing important public health goals. In the USA, prescriptions for multi-source products now account for approximately 50% of all prescriptions that are written and save consumers about US$10 billion per year.

Available guidelines

Following generally accepted scientific principles for BA/BE and based on ICDRA recommendations, the World Health Organization has created a set of approaches and recommendations for manufacturers and Member State regulatory authorities to assure good quality multi-source products that are interchangeable with a pioneer product with defined safety, efficacy, and quality attributes. WHO documents include 1) Multisource Pharmaceutical Products: WHO Guidelines on Registration Requirements to Establish Interchangeability; 2) WHO List of Essential Drugs and Examples of Bioequivalence Requirements in Japan, USA, and Zimbabwe; 3) Selection of International Comparator Pharmaceutical Products; 4) Model Application Form for Marketing Authorization of Pharmaceutical Products: Content of Registration Dossier (Abridged Application); 5) Marketing Authorization of Multi-source (Generic) Pharmaceutical Products: A Manual for Drug Regulatory Authorities.