Analytical considerations in the dissolution testing of oral modified release products

1
Analytical considerations in the dissolution
testing of oral modified release products

• Graham Clarke
• Bristol-Myers Squibb
• Moreton, UK

The British Pharmaceutical Conference, 26th
September 2005
2
Fit for purpose dissolution methods for testing
oral modified release products

• Graham Clarke
• Bristol-Myers Squibb
• Moreton, UK

The British Pharmaceutical Conference, 26th
September 2005
3
Analytical considerations in the dissolution
testing of oral modified release products

• Presentation Outline
• Purpose
• Practicalities
• Specifications
• Method Validation
• Unusual case studies
• Future

4
Analytical considerations in the dissolution
testing of oral modified release products

• Purpose of dissolution test
• IV/IVC (next Speaker)
• Safety/Quality requirements
• Release profile
• Integrity of action e.g. enteric coat

5
Analytical considerations in the dissolution
testing of oral modified release products

• Selection of test methodology
• Choice of apparatus
• Baskets (1970, USP 18)
• Paddles
• Reciprocating Cylinder
• Flow through cell
• Other
• Choice of medium, deaeration
• Media switching
• Adequate sampling
• Analytical finish
• UV, Fast LC, other?

6
Analytical considerations in the dissolution
testing of oral modified release products

• Making it practical (avoiding late nights in the
  lab)
• On-line (UV or on-line LC).
• Autosampling (off-line)

7
Analytical considerations in the dissolution
testing of oral modified release products

• In-situ
• Fibre-optic (different probes)

8
Analytical considerations in the dissolution
testing of oral modified release products

• Developing Specifications
• Regulatory/Pharmacopoeial guidance
• Control dose dumping or non-release
• 3-phase specification
• Early avoid dose dumping
• Middle appropriate control
• Late demonstrate full release (80 or plateau)

• FDA Guidance for Industry
• ER oral Dosage Forms Development, Evaluation and
  Application of In Vitro/In Vivo Correlations
  (Sept 1997)
• SUPAC- MR Modified Release Solid Oral Dosage
  Forms (Sept 1997)

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Analytical considerations in the dissolution
testing of oral modified release products

• USP Extended Release Dosage Forms

10
Analytical considerations in the dissolution
testing of oral modified release products

• Validation of methods (fit for purpose)
• UV/HPLC
• ICH Guidance Q2A and Q2B

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Analytical considerations in the dissolution
testing of oral modified release products

• Validation
• Specificity
• UV Interference from excipients
• LC Demonstrate separation
• Carryover or binding
• Tubing, syringes? Not necessary as concentration
  increasing.

12
Analytical considerations in the dissolution
testing of oral modified release products

• Validation
• Linearity (range)
• evaluate the linear range of the analytical
  procedure
• for dissolution testing /- 20 over the
  specified range
• General six points between 20 and 120
• Correlation coefficient
• Residual sum of squares
• Standard alone and also in presence of excipients.

13
Analytical considerations in the dissolution
testing of oral modified release products

• Validation
• Accuracy
• application of the analytical procedure to
  synthetic mixtures of the drug product
  components
• aka spiking
• Over the Range or Worst case scenario
• Use a minimum of 9 determinations over a minimum
  of 3 concentration levels covering the specified
  range.
• Report recovered and confidence intervals

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Analytical considerations in the dissolution
testing of oral modified release products

• Validation
• Precision
• Repeatability
• 9 determinations over the range
• (3 reps at 3 concs) or
• 6 reps at 100 of the test concentration
• Intermediate precision
• Establish the effect of random events
• Different days, analysts, equipment etc.

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Analytical considerations in the dissolution
testing of oral modified release products

• Robustness
• Effect of filtration
• Stability of solutions
• Are samples collected/stored before analysis?
• Automated procedure
• Demonstrate equivalence to manual

FDA Guidance for Industry Analytical Procedures
and Methods Validation (Aug 2000)
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Analytical considerations in the dissolution
testing of oral modified release products

• Floating or Sticking to surfaces
• e.g. hydrophilic polymer matrix
• Problem results in
• reduced agitation
• in inadequate exposure
• to medium
• Solution
• Observe and invalidate
• test
• Deaerate
• Baskets vs paddles

17
Analytical considerations in the dissolution
testing of oral modified release products

• Degrading active
• e.g. ER enteric coated beadlets, meadia switch
• Acid catalysed hydrolysis product
• Low dose drug degradant has different UV
  response factor.

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Analytical considerations in the dissolution
testing of oral modified release products

• Avoiding evaporation
• Evident as higher than theoretical values
  obtained
• Accuracy demonstrated

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Analytical considerations in the dissolution
testing of oral modified release products
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Analytical considerations in the dissolution
testing of oral modified release products

• Avoiding evaporation
• Evident as higher than theoretical values
  obtained
• Accuracy demonstrated
• Solution
• Tightly fitting lids
• Parafilm seal

21
Analytical considerations in the dissolution
testing of oral modified release products

• Equipment issues
• Problem Extended release product using cross
  linked alginates give inconsistent dissolution
  profiles.
• Solution Copper ions increase the degree of
  cross linking in alginates. De-aerator had brass
  fitting.

22
Analytical considerations in the dissolution
testing of oral modified release products

• The Future
• Alternate technologies ?
• More physiological media?