Validation of Dissolution Methods

1
Validation of Dissolution Methods

• In Vitro Release and Dissolution Testing, Groton
  CT
• Diane Worrell
• April 29, 2005

2
Validation Parameters and Criteria
ICH Topic Q2B Validation of Analytical
Procedures Methodology

• Specificity
• less than 2 interference at the 100 working
  standard solution level using the highest
  concentration of excipents
• Linearity, Include at least 5 points across the
  range ( 20 of specification)
• r 0.995 and the y-intercept should be NMT 3 of
  the 100 spiked solution response
• Accuracy
• 3 to 5 of expected recovery
• Precision Repeatability minimum of 9
  determinations covering the specified range for
  the procedure (e.g. 3 concentrations/3
  replicates)
• 5.0 RSD
• Precision Intermediate Precision
• 5 to 10 RSD between days, analysts, equipment
  at
• specification timepoints
• Precision Reproducibility
• 5 to 10 RSD between laboratories

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Robustness/Ruggedness

• Dissolution Parameters
• Paddle Height ( 2.0 mm)
• Vessel Temperature ( 0.5C)
• RPM ( 4)
• Medium preparation (salt concentration, pH)
• Degassing Technique (induced air vs. standard
  degassing technique)

• HPLC Conditions
• Mobile Phase preparation (salt concentration, pH,
  composition)
• Wavelength ( 2 nm)
• Flow rate ( 5-10)
• Auto-sampler Temperature ( 2C)
• Column Temperature ( 2ºC)

An absolute difference between the dissolved at
the specification timepoint with variation should
not be more than 5 from the result without
variation.
4
Recommended Additional Validation Parameters

• Filtration
• Less than 2-3 interference
• Sample and Standard Stability
• Between 100 2-3 (recovery) stability for up
  to 3 days (recommendation)
• Real Sample Precision
• Compare results for the final formulation with
  multiple analysts
• Critical examination of dosage form performance
  throughout the test

5
Example Validation Procedure
6
Helpful Hints

• Evaluate filtration early in the process for both
  sample and standard and across all timepoints.
• Evaluate any automated sampling procedures across
  all timepoints.
• Test the highest and lowest dose of drug product
  prior to validation.
• Write a validation protocol and have it approved
  by all interested parties.
• Have a well-defined and predictable method prior
  to validation.
• Sink/solubility
• Medium
• Analytical finish
• Suitability of deaeration procedure

7
Helpful Hints

• Pre-validation (i.e. an abbreviated linearity,
  accuracy, specificity) is an important activity
  to identify unanticipated problems. Evaluate the
  proposed validation acceptance criteria against
  these findings.
• Document investigations of any failures during
  validation.
• Conduct the investigation in a logical and
  step-wise manner. Multiple causes maybe present
  that are resulting in the failure. These may
  cancel each other out unless studied
  individually.

8
Acknowledgements

• Jonathan Kretz
• Jack Zynger
• Cindy Brown
• Elizabeth Gooch
• Michael Keeton