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International Journal of Generic Drugs

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In-Vitro-In-Vivo Correlation Definitions and Regulatory Guidance
Nattee Sirisuth and Natalie D. Eddington1,2* Pharmacokinetics Biopharmaceutics Laboratory 2 Department of Pharmaceutical Sciences School of Pharmacy, University of Maryland at Baltimore 100 Penn Street, AHB Baltimore, MD 21201-6808(410) (Fax) 706-6710 (410) 7066580 neddingt@rx.umaryland.edu
1

INTRODUCTION
development and optimization is an ongoing process in the design, manufacturer and marketing of any therapeutic agent. Depending on the design and delivery goals of a particular dosage form, this process of formulation development and optimization may require a significant amount of time as well as financial investment.Formulation optimization may require altering formulation composition, manufacturing, equipment and batch sizes. In the past when these types of changes are applied to a formulation, bioavailability studies would also have to be performed in many instances to ensure that the “new” formulation displayed statistically similar in-vivo behavior as the “old” formulation. Of course this requirementdelayed the marketing of the new formulation and added time and cost to the process of formulation optimization. Recently a regulatory guidance was developed to minimize the need for additional bioavailability studies as part of the formulation design. This guidance referred to as the, In Vitro/In Vivo Correlation Guidance was developed by the Food and Drug Administration and was based onscientifically sound research.(1)

Formulation

ABSTRACT

The purpose of this report is to present
definitions of the various levels of in vitro in vivo correlations (IVIVCs) and to provide a regulatory perspective on its utility in product development and optimization. The importance of a representative dissolution testing method that accurately describes the in vivo release rate is discussed inthe context of developing a predictive IVIVC. The role of the dissolution testing method in IVIVC development and validation is to serve as a surrogate measure of the rate and extent of oral absorption. In addition, the Biopharmaceutical Classification System provides a science-based guidance on solubility and permeability drug issues, which are indicators of predictive IVIVCs. A valid IVIVC willallow for dissolution testing for subsequent formulation changes which take place as a function of product optimization without the need for additional bioavailability / bioequivalency studies.

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It states that the main objective of
developing and evaluating an IVIVC is to enable the dissolution test to serve as a surrogate for in vivo bioavailability studies (Figure 1). This may reduce the number of bioequivalence studies required for approval as well as during scale-up and post-approval changes. (2)

Definition ofCorrelations

In

Vitro-In-Vivo

An In-vitro in-vivo correlation (IVIVC) has been defined by the Food and Drug Administration (FDA) as “a predictive mathematical model describing the relationship between an in-vitro property of a dosage form and an in-vivo response”.1 Generally, the in-vitro property is the rate or extent of drug dissolution or release while the in-vivo response is the plasma drugconcentration or amount of drug absorbed. The United States Pharmacopoeia (USP) also defines IVIVC as “the establishment of a relationship between a biological property, or a parameter derived from a biological property produced from a dosage form, and a physicochemical property of the same dosage form”.(3) Typically, the parameter derived from the biological property is AUC or Cmax, while the...