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?
· 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.
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
Hope this post will be useful for
readers. We will try to post next article related to pharmaceutical industries
as early as possible. Please share your valuable comments after reading.
Comments
Post a Comment