CDP - Comparative Dissolution Profiles

Basic Concept of Comparative Dissolution Profiles (CDP)

Introduction

CDP is among the common quality control tools in pharmaceutical industries. To prove effect of manufacturing process related changes on formulation in the preapproval or post-approval space, most regulatory agencies recommend dissolution profile comparison be conducted with a specified number of reference (prechange) and test (postchange) drug product lots. Various regulatory guidelines are available on this subject such as EMA, TGA, USFDA etc. This post tries to summarise some basic concepts of CDP refering regulatory guidelines.

What is CDP?

Dissolution profiles of reference and test products are performed with a validated dissolution method using the medium described in the regulatory application as well as two additional media, for example:

·         0.1 N HCl or simulated gastric fluid without enzymes

·         pH 4.5 acetate buffer

·         pH 6.8 phosphate buffer or simulated intestinal fluid without enzyme

The purpose of testing the product in these three media is to assess its dissolution performance across the physiologically relevant pH range. In cases where multiple time points and multiple media testing are required, special consideration should be given to media selection.

Why and when it should be performed?

Until recently, Single-point dissolution tests and specifications have been employed in evaluating scale-up and postapproval changes, such as (1) scale-up, (2) manufacturing site changes, (3) component and composition changes, and (4) equipment and process changes. A changed product may also be a lower strength of a previously approved drug product. In the presence of certain minor changes, the single-point dissolution test may be adequate to ensure unchanged product quality and performance. For more major changes, a dissolution profile comparison performed under identical conditions for the product before and after the change(s) is recommended.

How it should be tested?

·         At least 12 dosage units (e.g. tablets, capsules) of each batch must be tested individually,             and mean and individual results reported.
·         The percentage of nominal content released are measured at a minimum of three (3)                    suitably spaced time points (excluding zero time point) to provide a profile for each batch         (e.g. at 5, 15, 30 and 45 minutes, or as appropriate to achieve virtually complete                             dissolution).
·         The batches are tested using the same apparatus and, if possible, on the same day.
·         The stirrer used is normally a paddle at 50 rpm for tablets and a basket at 100 rpm for                capsules. However, other systems or speeds may be used if adequately justified and                     validated.

Test conditions are those used in routine quality control or, if dissolution is not part of routine quality control, any reasonable, validated method.

How to compare dissolution profiles?

The dissolution profile comparison can be conducted using model-independent or model-dependent statistical methods.

In this comparison of global dissolution requirements study, the following aspects associated with the similarity factor approach are compared:

·         f ₂ criteria for demonstrating similarity

·         Criteria for exemptions from f ₂ comparisons

·         Minimum number of time points required for  f ₂ calculation

·         Determination of the last time point for  f ₂ calculation

·         Coefficient of variation criteria

Model independent Methods

A.     Similarity factor f2 and difference factor f1 calculation

·         The f ₁ factor calculates the percent difference between the two dissolution profiles at each time point and is a measurement of the relative error between the two profiles:

 

where,

n is the number of time points, 

R _t is the mean dissolution value for the reference product at time t,

T _t is the mean dissolution value for the test product at that same time point.

The f ₁ value is equal to zero when the test and reference profiles are identical and increases as the two profiles become less similar.

·         The f ₂ factor is a logarithmic reciprocal square root transformation of the sum of squared error and is a measurement of the similarity in the percent dissolution between the two profiles:

B.     Multivariate Confidence Region Procedure

In instances where within batch variation is more than 15% CV, a multivariate model independent procedure is more suitable for dissolution profile comparison.

The following steps are suggested:

·      Determine the similarity limits in terms of multivariate statistical distance (MSD) based on interbatch differences in dissolution from reference (standard approved) batches.

·          Estimate the MSD between the test and reference mean dissolutions.

·          Estimate 90% confidence interval of true MSD between test and reference batches.

·         Compare the upper limit of the confidence interval with the similarity limit. The test batch is considered similar to the reference batch if the upper limit of the confidence interval is less than or equal to the similarity limit.

Model dependent methods

Model Dependent Approaches Several mathematical models have been described in the literature to fit dissolution profiles. To allow application of these models to comparison of dissolution profiles, the following procedures are suggested:

·  Select the most appropriate model for the dissolution profiles from the standard, prechange, approved batches. A model with no more than three parameters (such as linear, quadratic, logistic, probit, and Weibull models) is recommended.

·    Using data for the profile generated for each unit, fit the data to the most appropriate model.

·     A similarity region is set based on variation of parameters of the fitted model for test units (e.g., capsules or tablets) from the standard approved batches.

·         Calculate the MSD in model parameters between test and reference batches.

·         Estimate the 90% confidence region of the true difference between the two batches.

·         Compare the limits of the confidence region with the similarity region. If the confidence region is within the limits of the similarity region, the test batch is considered to have a similar dissolution profile to the reference batch.

Bootstrapping and TOST are other statistical methods which are used in comparison of dissolution profiles. Bootstrapping is the practice of estimating properties of an estimator (such as its variance) by measuring those properties when randomly sampling from an approximating distribution.  A two one-sided t test (TOST) approach at each dissolution time point requires defining a criterion for similarity with respect to the maximum acceptable difference between the two mean dissolution profiles.

Acceptance Criteria used to compare dissolution profiles :

Number of units for test and reference	12 unless otherwise justified
f 1 difference factor	0-15
f 2 similarity factor	50–100
Criteria for f 2exemption	Where more than 85% of the drug is dissolved for both test and reference products within 15 min, dissolution profiles may be accepted as similar without further mathematical evaluation.
Early time points	For immediate-release products, early time points are those that are less than or equal to 15 min. For modified-release products, early time points should be based on the shape of the profile (e.g., on the mean dissolution results).
Coefficient of variation	The percent coefficient of variation at the earlier time points should not be more than 20%, and at other time points should not be more than 10%

 

Conclusion :

The similarity factor approach is widely used criteria for comparing in vitro dissolution profiles. There are various methods available for determination of equivalence in dissolution profiles. Some of the links of regulatory guidelines are given below

https://www.tga.gov.au/book-page/152-comparative-dissolution-profiles-biopharmaceutic-studies

https://www.who.int/medicines/areas/quality_safety/quality_assurance/Annex7-TRS992.pdf

https://www.fda.gov/media/70936/download#:~:text=Dissolution

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