Author: Mohammad Dulal, Industrial Pharmacist licensed in MOH/Dubai, Senior Scientist, Product Development Lab, Julphar Gulf Pharmaceutical Ltd, Ras Al Khaimah, United Arab Emirates.

 1.0 Introduction

Generic pharmaceutical products are clone of innovator products in the term of actives, strengths, dosage forms, dosage regimens and administrations. Actual fact is that innovator companies are very less in numbers in the world due to requirement of huge investment. Innovator companies are also not in good numbers enough to serve their medicines to all the worldwide patients. Reasonably, generic companies are established to serve their local patients with medicines at a manageable price. Generic companies cannot change strengths, dosage forms, dosage regimens, administration of a drug substance which are already researched and proved safe & effective via clinical trial by Innovator Company, rather generic company can play with excipients and physical attributes (appearance, shape, size, color, etc) of dosage form only.

2.0 Generic Products VS Innovator Products/Reference product

Innovator products have been approved as a new drug, or a drug that corresponds to one. Innovator products itself are considered as a reference product, besides reference product for Bio-equivalence study may be from other brand companies. Actually other brand product which BE study carried out with respect to innovator product will act as reference product. Innovator products itself is a reference product. Generic Products are the products of which active ingredients, strengths, dosage forms, and dosage regimens are the same as those of innovator products. Generic Products and Innovator Products differ in drug particle size, excipients, manufacturing process, equipment, site of manufacturing, batch size, but generic product should be equivalent with Innovator product in term of bioavailability. Bioavailability means the rate and extent of absorption of active ingredients or active metabolites from a drug product into the systemic circulation. When bioavailability of generic product and reference product are almost similar for same group of people, that case generic product is bioequivalent to that reference product which is already recognized as a reference product in the regulatory authority. Bio-equivalent study of generic product, known as ‘test product’ will be carried out with respect to brand product, known as reference product. Reference product will be from innovator company or other brand company. Regulatory authority will decide which one will be considered as a ‘Reference product’. One can find list of reference product in Orangebook (http://www.accessdata.fda.gov/scripts/cder/ob/ default.cfm).  

3.0 Bioequivalence: why required

Bioequivalence ensures a generic product how much it is as close as reference product in term of bioavailability. Excipients used as well as physical attributes (particle size, process, physical parameters such as hardness for tablet) are release rate limiting factor for active ingredient from dosageform. In order to be bioequivalent (BE) with reference product, generic product should have in-vitro release rate of active ingredient from its dosageform as much closely as reference product. International drug regulatory authority urges to conduct Bioequivalence for ensuring to get better therapeutic activity from generic drug products.

4.0 Category of Active Ingredients which require BE Study

The Biopharmaceutics Classification System is a guide for predicting the intestinal drug absorption provided by the U.S. Food and Drug Administration. This system restricts the prediction using the parameters solubility and intestinal permeability. The solubility classification is based on a United States Pharmacopoeia (USP) aperture. The intestinal permeability classification is based on a comparison to the intravenous injection. All those factors are highly important because 85% of the most sold drugs in the United States and Europe are orally administered. According to the Biopharmaceutics Classification System, drug substances are classified as follows: Class I – high permeability, high solubility (Eample: Metoprolol, the compounds of Class I are well absorbed and their absorption rate is usually higher than excretion). Class II – high permeability, low solubility (Example: Glibenclamide, the bioavailability of those products is limited by their solvation rate. A correlation between the in vivo bioavailability and the in vitro solvation can be found). Class III – low permeability, high solubility (Example: Cimetidine, the absorption is limited by the permeation rate but the drug is solvated very fast. If the formulation does not change the permeability or gastro-intestinal duration time, then class I criteria can be applied). Class IV – low permeability, low solubility (Example: Hydrochlorothiazide, the compounds of Class IV have a poor bioavailability. Usually they are not well absorbed over the intestinal mucosa and a high variability is expected).