Preface

An active pharmaceutical ingredient (API) is seldom administered alone to a subject (human or an animal) for evaluation of its biological efficacy, i.e., bioefficacy. It is invariably combined with excipients and processed into a formulation that is ultimately administered as a dosage form (pharmaceutical product) that meets the required attributes of quality with respect to performance, both in vitro and in vivo. Without regard to the type of the dosage form - solid (powders, tablet, capsule, etc.,), liquids (suspensions, creams, etc.,), and semisolids (ointments, creams, lotions, etc.,) - administered to a subject (human and/or animal) for determination of its resultant systemic availability (in vivo absorption, i.e., bioavailability [BA]), if the API exists in its solid state, it has to dissolve out of the formulation into the biological medium - in vivo dissolution. The dissolved drug is subsequently absorbed across the biological absorption surface (in vivo absorption). It results in the appearance of the drug in the systemic circulation, thus effecting BA. Such a process, comprehensively, is commonly referred to as the overall bioefficacy of the administered dosage form. Thus, it has been realized that in vivo dissolution is a prerequisite to in vivo absorption and thereby the resulting bioefficacy of the administered formulation (drug product/dosage form).

Pharmaceutical product design and development is still considered more of an art than science! Nonetheless, a clear and comprehensive understanding of the multitude of factors influencing formulation design and development including evaluation, both in vitro and in vivo, is pivotal to succeed in the development of a pharmaceutical formulation. The constant quest of a pharmaceutical scientist and formulation scientist, in particular, is to implement appropriate steps during the development process such that the resultant formulation (product) meets the preset criteria for bioefficacy and ultimately clinical efficacy.

The development of pharmaceutical dosage forms often requires a multidisciplinary approach taking advantage of sound science and the technical skills required to combine these approaches. While the primary target of formulation development is to meet the preset and/or expected requirements of BA (bioefficacy), each and every formulation cannot be evaluated for BA for obvious reasons of cost, time, and availability of limited resources. Hence, there are numerous prospective tests, such as in vitro dissolution tests, presumably biophysiologically relevant (biorelevant), employed to screen the formulations during the various stages of drug development process. In so doing, the potential for success of the various formulations designed, developed, and evaluated can be substantially enhanced if such surrogate tests are appropriately used. As a result, a bioefficacy-centered pharmaceutical product design, development, and evaluation especially focusing on the role of dissolution testing in drug product development is of paramount significance.

Generic drug development, in particular, leading to the successful demonstration of bioequivalence (BE) relies heavily on in vitro dissolution test, right from screening of formulations to deciding which formulation proceeds to evaluation of BE. Additionally, the in vitro dissolution test is employed to demonstrate compliance with the criteria for biowaivers for dose-proportionate formulations and various levels of changes employed in the manufacturing process of the product post approval. Furthermore, in vitro dissolution test is often employed to respond and satisfy regulatory queries about the quality performance, both in vitro dissolution and in vivo efficacy, of the product.

Two pharmaceutical formulations are considered BE when their respective rate and extent of BA following administration of a unit dose under standard clinical conditions are substantially similar. Statements regarding bioavailability and bioequivalence appear to be simple and straightforward but have given rise to considerable controversy in pharmaceutical and clinical circles for many years that are compounded by economic factors associated with establishing bio- and therapeutic equivalence. Numerous rules and global regulations have been issued, and equal, if not more, number of interpretations and opinions have been reported primarily due to our insufficient understanding of the scope and depth of fundamental considerations associated with pharmaceutical bioequivalence.

Challenges, more than often, surface while designing bioequivalence investigations for complex generic formulations. While generic bioequivalence that is strictly based on similar bioefficacy between two formulations and their respective clinical and therapeutic equivalence is more desirable, thus, designing a bioequivalence investigation with clinical endpoint assessment seems to be emerging as an assessment tool for generic equivalence between two products. Despite complying with the regulatory requirements, various regulatory agencies seek further clarifications in the submissions in the data of a "successful" bioequivalence investigation. To address such challenges, one has to adopt an "out-of-the-box" approaches that are scientifically sound yet are convincing and compelling.

Global perspectives - regulatory and technical - addressing the various challenges in designing, conducting, and presenting successful BA/BE investigations including providing satisfactory and convincing rationale for queries from various regulatory agencies pose submission of results/data through a judicial blend of technical information and case studies. Special attention is warranted to stand the intricacies associated with BE of complex generics!

Dissolution testing, of course, is a regular quality control procedure in good manufacturing practice. However, the dissolution test can be employed prospectively - while developing a formulation with appropriate drug release characteristics and retrospectively - to assess whether a dosage form is releasing the drug at prescribed/predetermined rate and extent. The common principal assumption underlying these two uses of this test is that the dissolution test is able to adequately represent, if not predict, the biological performance, i.e., BA, of the drug.

As of date, in vitro dissolution tests seem to be the most reliable predictors of in vivo availability. Although official tests have great practical value, the fact that there is still a need for test more directly related to bioavailability has been recognized. Numerous attempts have been made to understand, develop, and potentially quantify the correlation between dissolution and bioavailability. Additionally, several compendial descriptions and regulatory guidelines are available that provide assistance and direction in establishing and demonstrating such correlations. However, accomplishing an in vitro-in vivo correlation (IVIVC) still appears to be elusive and potentially comprehensible only in a handful of circumstances. As a result, a concerted focus on how to overcome such challenges, both in the conceptual and the practical understanding of IVIVC and its applications in drug development and approval through case studies, yet ensuring that such an attempt results in its simplified workable approach, is not only essential but also overdue.

Biologics Price Competition and Innovation () Act creates an abbreviated licensure pathway for biological products shown to be biosimilar to or interchangeable with an Food and Drug Administration (FDA)-licensed (approved) reference product (Section 351(k) of Public Health Service [PHS]). The biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive components, and there are no clinically meaningful differences between the biological product and the reference product in terms of safety, purity, and potency of the product. As a consequence, biosimilarity is judged on demonstrated "Totality of Evidence" that is expected to integrate various types of information - scope and extent of development plan and, ultimately, an overall assessment that a biological product is (or is not) biosimilar to an approved reference product. One of the primary criteria is the structural and functional characterization of the proposed biosimilar product. The role of dissolution in this context can play a critical role in the functional characterization, among others, of the proposed biosimilar product. Hence, biosimilars, which is considered as the emerging frontier for generics, and the role of dissolution testing in their development and evaluation should be explored.

Over the past decade, the dissolution test in drug development has matured from a simple convenient test for routine testing to assure batch-to-batch quality of the product to extremely complex application to predict bioefficacy of the product through demonstration of IVIVC. This test has now forayed into the discipline of intellectual property (IP) wherein the novel and innovative considerations of the invention have been secured. Often these inventions are worth "multimillion dollars," and their ratification through (in)validity and/or (non)infringement focuses on convincing and compelling rationale based on...