Regulatory Education
for Industry (REdI):
GENERIC DRUGS FORUM
Sheraton | Silver Spring, MD | April 22-23, 2015
Dissolution Method Development
for Generic Drug Products
Banu Sizanli Zolnik, Ph.D.
Division of Biopharmaceutics, Office of New Drug Products,
Office of Pharmaceutical Quality -
CDER, FDA
This presentation reflects the views of the presenter and should not be construed to represent
FDAs views of policies
Outline
Role of dissolution method development
Current approaches for dissolution method
development for generic drugs
Product specific dissolution method
Common deficiencies identified in the applications
Summary
Dissolution testing as a tool
A quality control
Batch-to-batch consistency
Provide quality assurance
Important for formulation development
Biowaiver purposes
In vitro BE studies
Alcohol-induced dose dumping
Post-approval manufacturing changes
Role of Dissolution Method
Development
Material Formulation
Process Attributes variables
Parameters
Dissolution
Current Approaches for Dissolution
Method Development
ANDA
USP method available
Yes No
FDA recommended
Follow USP method
method available
Yes No
New dissolution method
Follow FDA
development report
recommended method
FDA Dissolution Method
http://www.accessdata.fda.gov/scripts/cder/dissolution/dsp_SearchResults_Dissolutions.cfm?P
rintAll=1
Product Specific Method Development
Three Components:
1. Evaluation of the method
2. Discriminating ability
3. The acceptance criterion
1. Evaluation of the method
Solubility profile
Selection of the apparatus
In vitro dissolution/release media
Rotation/Agitation speed
Sink conditions
Data to support selection of surfactant
2. Discriminating Dissolution Method
Differentiates drug products
manufactured under target conditions
vs. formulations with meaningful
variations for the most relevant
manufacturing variables
Different Particle Size Ranges
Batch D failed f2 testing (<50)
100 Lower bound
Drug Dissolved (%)
80
Discriminating
Dissolution spec:
60 Q= 80% at 15 min.
Upper bound
Batch A
40 Clinical Batch
Batch B
Batch C
Batch D
20
Non-discriminating
0.0 dissolution spec:
Q= 80% at 20 min.
0 5 10 15 20 25
Time (minutes)
Ref: 2012 AAPS presentation by Dr. Sandra Suarez Sharp
Based on bioequivalence batches
Manufacture product variants with different release
characteristics
Select optimal dissolution method Determine bioavailability for
with adequate discriminating power product variants
Determine dissolution rates resulting in
similar in vivo performance
Dissolution specifications chosen to ensure similar (BE)
product performance
Illustration of the dissolution profiles
based on BE batches
Batches A, B, C, D, and Clinical were BE
100 Lower bound
Drug Dissolved (%)
80
Approach 1:
60 Q= 80% at 15 min.
Upper bound
Batch A
40 Clinical Batch
Batch B
Batch C
Batch D
20
Approach 2:
0.0 Q= 80% at 20 min.
0 5 10 15 20 25
Time (minutes)
Ref: 2012 AAPS presentation by Dr. Sandra Suarez Sharp
3. Acceptance Criterion
Bioequivalence batches
At least 85% of the drug is dissolved
or
Where plateau of drug dissolved is
reached
The selection of time point should be
where Q=80% of drug dissolved.
Applications: Common deficiencies
Dissolution method development is not included
in the application
Fails to demonstrate that dissolution method is
discriminating
No information on critical material attributes and
process parameters
Data do not support the proposed acceptance
criterion
There is no dissolution data for lower strength
waivers, alcohol dose dumping studies, multi-
media testing for MR products.
Applications: Common deficiencies
There is no method transfer report when
method validation is conducted at a
different site
Dissolution data collected on aged lots
Individual dissolution data is not
submitted.
Ref: Common Deficiencies with BE submissions in ANDAs Assessed by FDA. AAPS Journal, Volume 14. No. 1, March 2012
Summary
Dissolution method is product specific
Three Components
1. Evaluation of the method
2. Discriminating ability
3. The acceptance criterion
Acknowledgments
Om Anand, Ph.D.
Elsbeth Chikhale, Ph.D.
Angelica Dorantes, Ph.D.
Kelly Kitchens, Ph.D.
Jing Li, Ph.D.
Haritha Mandula, Ph.D.
Mei Ou, Ph.D.
Paul Seo, Ph.D.
Sandra Suarez Sharp, Ph.D.
Questions?
Evaluation: surveymonkey.com/s/GDF-D2S8
