In-Vitro-In-Vivo Correlation Definitions and Regulatory Guidance

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 in the 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 will allow for dissolution testing for subsequent formulation changes which take place as a function of product optimization without the need for additional bioavailability / bioequivalency studies. INTRODUCTION Formulation 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 requirement delayed 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 on scientifically sound research.(1) http://www.locumusa.com International Journal of Generic Drugs e-* journal@locumusa.com http://www.locumusa.com International Journal of Generic Drugs e-* journal@locumusa.com ISSN 0793 758X US/ Canada ISSN 0793 7776 Euro ISSN 0793 7849 Pacific Rim 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 of In Vitro-In-Vivo Correlations 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”. Generally, the in-vitro property is the rate or extent of drug dissolution or release while the in-vivo response is the plasma drug concentration 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 physicochemical property is the in vitro dissolution profile. A linear relationship with slope of unity, if possible, is preferred, as the dissolution profile is a representative of the absorption profile.(1,3) Figure 2 presents a linear correlation between Cmax and the percent dissolved in 15 minutes for an immediate release dosage form. Since, IVIVCs are basically mathematical relationships, non-linear correlations may also be appropriate. IVIVC plays an important role in product development in that it:first, serves as a surrogate of in vivo and assists in supporting biowaivers; second, supports and / or validates the use of dissolution methods and specifications; and Thirdly, assists in quality control during manufacturing and selecting appropriate formulations (1,4). The first and main role of establishing IVIVC is to use dissolution test as a surrogate for human studies. The benefit of this is to minimize the number of bioequivalence studies performed during the initial approval process and during the scaling-up and post-approval changes (1). Additional advantages of an IVIVC is to assist in validating or setting dissolution specifications. This is because the IVIVC includes in-vivo relevance to invitro dissolution specification. In other words, dissolution specifications are set based on the performance of the biobatch in-vivo. The general dissolution time point specification is ± 10% deviation from the mean dissolution profile obtained from the biobatch (1). Bioequivalency between formulations would be expected if the formulation(s) fall within the upper and lower limits of the specification. Dissolution specification setting based on an IVIVC can also be used as a quality control for product performance. However, this quality control may sometimes be more rigorous than the usual control standard since it depends on the product bioavailability. The use of IVIVC, however, is limited to a certain drug product. It can be used only on that particular formulation. http://www.locumusa.com International Journal of Generic Drugs e-* journal@locumusa.com http://www.locumusa.com International Journal of Generic Drugs e-* journal@locumusa.com ISSN 0793 758X US/ Canada ISSN 0793 7776 Euro ISSN 0793 7849 Pacific Rim The IVIVC cannot be used across the products, especially drug product with different release mechanisms (1,5). This premise has been recently investigated in our laboratory. In this work, two major types of oral extended release dosage forms were compared: coated pellets filled in a gelatin capsule and a hydrophilic matrix tablet. The tablet formulation was manufactured under separate investigations using fluid bed granulation. The active compound, metoprolol tartrate, was blended with the release rate-controlling polymer (hydroxypropyl methylcellulose) and with other excipients, such as a filler (lactose and dicalcium phosphate), a binder (hydroxypropylmethylcellulose) and a lubricant (magnesium stearate). The granules were then compressed into a tablet. A correlation developed with the hydroxypropyl methylcellulose system and was applied to predicting the in vivo behavior of the multiparticulate gelatin capsule. The IVIVC was predictive of the extent of absorption. Prediction errors associated with AUC were found to be less than 10 percent. However, the IVIVC was unable to accurately estimate the rate of drug absorption, Cmax. Prediction errors were found to be greater than 20 %. These results support the contention that IVIVCs are product specific. IVIVC is usually developed when drug dissolution is a rate-limiting step for the in vivo absorption. The absorption and consequently the bioavailability of an oral solid dosage form depends on two main processes, drug dissolution and permeation. Drug dissolution is the process in which the drug is released and available in solution and ready to be absorbed. Physicochemical properties of a drug such as solubility as well as the gastrointestinal environment are the crucial parameters affecting dissolution. Drug permeability is the second process beginning after the solid drug is converted into a solution form. Permeability is the ability of the drug to penetrate across a membrane into the systemic circulation. The extent of permeation and ultimately absorption also depends upon the physicochemical properties of the drug and blood perfusion (6). The complete penetration of a highly permeable drug occurs in a short time. Thus, the only factor governing drug absorption is drug release and/or dissolution from the dosage form. In-vitro drug dissolution then can be used as a surrogate for the in-vivo absorption. On the contrary side, the dissolution rate of immediate release drug products is relatively very rapid. The rate of absorption then is likely to be a function of the gastric emptying rate or the intestinal permeability. In this case, the IVIVC may not be obtained (5). In Vitro In Vivo Correlations Examples Previous IVIVC studies have been reported for various drugs (7-18). The studies were conducted both in animal, such as rat, rabbit, and dog and human. Most of the studies focused on the development of a level B and level C correlations. The level B is a correlation in which it compares the mean in-vivo http://www.locumusa.com International Journal of Generic Drugs e-* journal@locumusa.com http://www.locumusa.com International Journal of Generic Drugs e-* journal@locumusa.com ISSN 0793 758X US/ Canada ISSN 0793 7776 Euro ISSN 0793 7849 Pacific Rim dissolution to the mean in-vitro dissolution as outlined in Figure 3. Whereas the level C correlation describes a relationship between the amount of drug dissolved at one time point and one pharmacokinetic parameter. The level C is also considered the lowest level of correlation. Figure 4 displays a typical level C correlation between Cmax and percent dissolved at 15 minutes. Level B and C IVIVCs have been developed for several purposes in formulation development, for example, for selecting the appropriate excipients and optimizing manufacturing processes, for quality control purposes, and for characterizing the release patterns of a newly formulated immediate release (IR) and modified release (MR) products relative to the reference (7-18). However, current IVIVC studies have focused on the development and validation of a level A correlation. It is a point-to-point relationship between drug release in-vitro and invivo. Although, a concern of non-linear correlation has been addressed, no formal guidance on t