A.Atilla Hincal, Ph.D., Professor Emeritus, Hacettepe University, Ankara, Turkey;
İDE Drug Information, Consultancy, Education Ltd Sti, Ankara/Istanbul, Turkey


Examining how the process of pharmaceutical formulation development has progressed from past to present in pharmaceutical sciences enables us to be better equipped scientifically for the future. Beginning at early 1990s, approving pharmaceutical products according to international rules rose as a main topic of discussion. With the introduction of ICH, international rules were introduced for approving therapeutic pharmaceutical products based on scientific and regulatory guidelines to assure the same level of quality, efficacy and safety in products.

Magistral and officinal galenic and pharmaceutical products at pharmacies for medical use passed to the pharmaceutical industry from the late second quarter of the 20th century. Studies in pharmaceutical sciences over the past 50 years have shown us that therapeutic value of pharmaceutical products did not result solely from pharmacological characteristics of an active substance and/or the general physical, chemical and physicochemical properties of other ingredients used in a formulation. Nevertheless, the past 35 to 40 years have shown that all parameters involved in formulation development were extremely important for the effectiveness of a pharmaceutical form, which marked the beginning of a new approach that included new criteria involving bioavailability / bioequivalence /advanced dissolution studies, in contrast to the former approach where only disintegration, hardness and simple dissolution testing were deemed sufficient to assure product quality in pharmaceutical formulation development. Intensive studies since early 1960s have shown that the dosage form and composition of a pharmaceutical product significantly affected its therapeutic properties, as much as its in vivo behavior. These findings were associated with the impact of varying characteristics of excipients used in the pharmaceutical formulation, the differences in manufacturing methods of medicinal products, and the characteristics of the pharmaceutical dosage form, or the finished product, on the absorption rate and extent at the point of administration. An Australian manufacturer’s replacing an inactive excipient used in the formulation of a product containing phenylhydantoin with a different excipient, and similar type observations for different plasma levels occurring in patients using digoxin products from different European manufacturers had resulted in undertreatment in some patients, and toxicity in others. These events highlighted the importance of using BA/BE studies outcomes in formulation studies as part of product development for pharmaceutical products intended for therapeutic use, and led to the understanding that BA and BE, alongside preformulation and formulation studies, are highly important parameters for both novel – innovative – and generic product development. Thus, data from BA and pilot and pivotal BE studies have emerged as a crucial parameters for quality, safety and efficacy assessment in formulation studies for various pharmaceutical dosage forms. A generic product must demonstrate therapeutic equivalency and substitutability with the innovator product. Considering the phases of product development that an innovator product must go through, a product claiming the same therapeutic value with an innovator product must furnish evidence of this claim. Based on scientific advances and experience, BE began receiving regulatory consideration only from mid-1970s onward. These advances not only taught generic manufacturers the meaning and importance of formulation development, it helped enhance the quality of pharmaceutical research capabilities of these companies. This talk will be focusing on the value that bioequivalence studies have contributed to the pharmaceutical industry over the past 35 to 40 years, given the current point reached in formulation development.