IVIVC level

Fig. 1 IVIVC Level A for formulation X, each square represents a time point.

At both the evaluation and the application level of a point-to-point IVIVC, in vitro dissolution data sets need to be treated and/or compared with each other. Appropriate methods vary with the data collection procedure and whether or not a model is to be fitted to the data. 

Model-dependent comparison of two time profiles is best achieved in terms of the semi-invariants discussed earlier in the section on Characterization of Semi-invariants ( Moments ). This treatment is in accordance with the Level B definition of IVIVC, as proposed in several official guidelines. It makes full use of the underlying model that the data are presented by a distribution function, but no specific function is required. Although derived function parameters (e.g., Weibull, polyexponential, etc.) may be used, the computation may also be performed numerically on the observations as such. 

The modeling discussed here depends on being able to describe the entire concentration-time curve. This can only be done using a Level A IVIVC (i.e., a point-to-point relationship between in vitro release and in vivo release/absorption). In fact, the U.S. Food and Drug Administration (FDA) defines a Level A IVIVC as a predictive mathematical model for the relationship between the entire in vitro dissolution-release time course and the entire in vivo response time course. 

The FDA guidance on IVIVC development and validation defines a number of circumstances where an IVIVC can be used to justify a biowaiver request in support of (1) level 3 process changes, (2) complete removal or replacement of non-release-controlling excipients, (3) level 3 changes in release-controlling excipients, (4) approval of lower strengths, and (5) approval of new strengths. Additionally, use of the IVIVC to justify biorelevant dissolution specifications is cited as the optimal approach. 

In general, if an IVIVC method has been established, the requirement for additional dissolution test conditions is waived in favor of multi-point dissolution testing according to the in vitro method with which the IVIVC has been established. For level 3 changes, multi-point dissolution testing according to application-release test conditions is required in addition to in vivo BE. If IVIVC is available, this requirement is reduced to comparison of dissolution profiles of... 

Setting of specifications for IVIVC on Level B is more of a challenge. A procedure has been described requiring homomorphic dissolution profiles on the in vitro side and BA data for at least three formulation variables on the in vivo side using interpolation (24). Extrapolation of Level B IVIVC is considered to be very questionable, so one is limited to interpolation within the established limits of the IVIVC. For Level B or C correlations, additional BA/BE will be needed if the IVIVC is to be extended to different types of formulations and/or different brands. 

In addition, for level 2 change, no additional bioequivalence study is required if the proposed alteration matches with the situation for cases A, B, and C. However, if there is any deviation, then documentation containing the results and assessment of a new bioequivalence and/or bioavailability study [if proper in vitro/in vivo correlation (ivivc) has not been established] should be submitted as per the conditions mentioned in the level 3 alteration. 

A USP PF Stimuli Article in July 1988 established the classification of IVIVC into Levels A, B and C, which are currently in use. 

Whatever the method used to establish a Level A IVIVC, the model should predict the entire in vivo time course from the in vitro data. In this context, the... 

A Level B IVIVC uses the principles of statistical moment analysis. The mean in vitro dissolution time is compared either to the mean residence time or to the mean in vivo dissolution time. A Level B correlation, like a Level A, uses all of the in vitro and in vivo data, but is not considered to be a point-to-point correlalion. A Level B correlation does not uniquely reflect the actual in vivo plasma level curve, because a number of different in vivo curves will produce similar mean residence time values. 

A Level C IVIVC establishes a single point relationship between a dissolution parameter, for example, t5o%, percent dissolved in 4 hours and a pharmacokinetic parameter (e.g., AUC, C ax. I max)- A Level C correlation does not reflect the complete shape of the plasma concentration time curve, which is the critical factor that defines the performance of ER products. 

A Level A IVIVC is considered to be the most informative and is recommended, if possible. 

The most commonly seen process for developing a Level A IVIVC is to (1) develop formulations with different release rates, such as slow, medium, fast, or a... 

The simple reading of these definitions allows the distinction between two main types of correlations to be made. Level A correlations that use all the information of the dissolution and absorption curve (Table 1 and Fig. 1). For Level A, each regression line represents a set of information relation to one type or one formulation. For Levels B or C, the establishment of a relationship implies the use of many formulations, each of them giving one pair of data (vitro and vivo. Table 1, Fig. 2). The establishment of Level B and C needs more data and, as they do not use all the information related to vitro and vivo behavior of the formulation, they are less powerful. The FDA ranked the levels as follows A Level A IVIVC is considered to be the most informative and is recommended, if possible. Multiple Level C correlations can be as useful as Level A correlations. However, if a multiple Level C correlation is possible, then a Level A correlation is also likely and is preferred. Level C correlations can be useful in the early stages of formulation development when pilot formulations are being selected. Level B correlations are least... 

Table 1 Various parameters used in IVIVC depending on the level...

Success in establishing a Level A IVIVC is dependant on the quality of the in vivo data obtained. 

The purpose of Level A correlations is to define a direct relationship between in vitro and in vivo data so that measurement of the in vitro dissolution rate alone is sufficient to determine the biopharmaceutical fate of the dosage form. IVIVCs should be sought as early as possible during the dosage form development (a priori correlations). In some cases, formulation has been undertaken rapidly and correlations sought on the finished product from subsequent in vitro tests. The predictive power of these correlations (a posteriori correlations) is thus limited, and they require additional validation. 

Level C IVIVC presents anyway some interest as defined in the FDA note for guidance A single point Level C correlation allows a dissolution specification to be set at the specified time point. While the information may be useful in formulation development, waiver of an in vivo bioequivalence study (biowaiver)... 

Fig. 11 In vitro limits with a priori Level A IVIVC.

Most published examples of IVIVC concern oral administration and sustained release products. ° The following examples demonstrate the application to non-classical formulation and the use of a new in vitro approach for Level A, as well as a classical formulation for Levels B and C. 

The study was performed with a Class 1 member in the form of tablets. Changes in pH have no effects while changes in agitation intensity for USP apparatus II and IV have shown clear influences on the tablet erosion and subsequently on its release. Finally to simulate the fasted and fed state in vivo, fasted state stimulated intestinal fluid(Fassif) and fed state simulated intestinal fluid(Fessif) media were used. None of the USP traditional apparatus show a clear relationship with the in vivo results, especially in the fed conditions. In vitro data obtained by the ADS in the fasted state were consistent with those in vivo, as well as in the fed state after a slight time adjustment allowed in the FDA notes of guidance. A Level A of IVIVC was easily established with a good correlation coefficient in the fasted and fed states, respectively. The main results are presented in Fig. 13. 

The in vitro-in vivo correlation (IVIVC) is an extremely useful exercise at the preformulation level that determines how scale up and post approval changes or Biowaiver principles would be exploited. Conceptually, IVIVC describes a relationship between the in vitro dissolution/release versus the in vivo absorption. This relationship is an important item of research in the development of drug... 

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