Analytical considerations in the dissolution testing of oral modified release productsGraham ClarkeBristol-Myers SquibbMoreton, UKThe British Pharmaceutical Conference, 26th September 2005

Fit for purpose dissolution methods for testing oral modified release productsGraham ClarkeBristol-Myers SquibbMoreton, UKThe British Pharmaceutical Conference, 26th September 2005

Analytical considerations in the dissolution testing of oral modified release productsPresentation OutlinePurposePracticalities SpecificationsMethod ValidationUnusual case studiesFuture

Analytical considerations in the dissolution testing of oral modified release productsPurpose of dissolution testIV/IVC (next Speaker) Safety/Quality requirementsRelease profileIntegrity of action e.g. enteric coat

Analytical considerations in the dissolution testing of oral modified release productsSelection of test methodologyChoice of apparatusBaskets (1970, USP 18)PaddlesReciprocating CylinderFlow through cell OtherChoice of medium, deaerationMedia switchingAdequate samplingAnalytical finishUV, Fast LC, other?

Analytical considerations in the dissolution testing of oral modified release productsMaking it practical (avoiding late nights in the lab)

On-line (UV or on-line LC). Autosampling (off-line)

Analytical considerations in the dissolution testing of oral modified release productsIn-situ Fibre-optic (different probes)

Analytical considerations in the dissolution testing of oral modified release productsDeveloping SpecificationsRegulatory/Pharmacopoeial guidanceControl dose dumping or non-release3-phase specificationEarly avoid dose dumpingMiddle appropriate controlLate demonstrate full release (80% or plateau)FDA Guidance for IndustryER 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)

Analytical considerations in the dissolution testing of oral modified release productsUSP Extended Release Dosage Forms

LevelNumber TestedAcceptance CriteriaL16No individual value lies outside each of the stated ranges and no individual value is less than the stated amount at the final test time.L26The average value of the 12 units (L1 + L2) lies within each of the stated ranges and is not less than the stated amount at the final test time; none is more than 10% of labeled content outside each of the stated ranges; and none is more than 10% of labeled content below the stated amount at the final test time.L312The average value of the 24 units (L1 + L2 + L3) lies within each of the stated ranges, and is not less than the stated amount at the final test time; not more than 2 of the 24 units are more than 10% of labeled content outside each of the stated ranges; not more than 2 of the 24 units are more than 10% of labeled content below the stated amount at the final test time; and none of the units is more than 20% of labeled content outside each of the stated ranges or more than 20% of labeled content below the stated amount at the final test time.

Analytical considerations in the dissolution testing of oral modified release productsValidation of methods (fit for purpose)UV/HPLCICH Guidance Q2A and Q2B

Analytical considerations in the dissolution testing of oral modified release productsValidationSpecificityUV Interference from excipientsLC Demonstrate separation

Carryover or bindingTubing, syringes? Not necessary as concentration increasing.

Analytical considerations in the dissolution testing of oral modified release productsValidationLinearity (range)evaluate the linear range of the analytical procedurefor dissolution testing: +/- 20% over the specified rangeGeneral six points between 20 and 120%Correlation coefficientResidual sum of squaresStandard alone and also in presence of excipients.

Analytical considerations in the dissolution testing of oral modified release productsValidationAccuracyapplication of the analytical procedure to synthetic mixtures of the drug product components aka spikingOver the Range or Worst case scenarioUse a minimum of 9 determinations over a minimum of 3 concentration levels covering the specified range.Report % recovered and confidence intervals

Analytical considerations in the dissolution testing of oral modified release productsValidationPrecisionRepeatability9 determinations over the range (3 reps at 3 concs) or6 reps at 100% of the test concentrationIntermediate precisionEstablish the effect of random eventsDifferent days, analysts, equipment etc.

Analytical considerations in the dissolution testing of oral modified release productsRobustnessEffect of filtrationStability of solutionsAre samples collected/stored before analysis?Automated procedureDemonstrate equivalence to manualFDA Guidance for IndustryAnalytical Procedures and Methods Validation (Aug 2000)

Analytical considerations in the dissolution testing of oral modified release productsFloating or Sticking to surfacese.g. hydrophilic polymer matrixProblem results in reduced agitation in inadequate exposure to medium

SolutionObserve and invalidate testDeaerateBaskets vs paddles

Analytical considerations in the dissolution testing of oral modified release productsDegrading activee.g. ER enteric coated beadlets, meadia switch

Acid catalysed hydrolysis productLow dose drug degradant has different UV response factor.Required LC for sensitivityResponse factor and calculate

Analytical considerations in the dissolution testing of oral modified release productsAvoiding evaporationEvident as higher than theoretical values obtainedAccuracy demonstrated

Analytical considerations in the dissolution testing of oral modified release products

Analytical considerations in the dissolution testing of oral modified release productsAvoiding evaporationEvident as higher than theoretical values obtainedAccuracy demonstratedSolutionTightly fitting lidsParafilm seal

Analytical considerations in the dissolution testing of oral modified release productsEquipment issuesProblem 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.

Chart3

9.89.69.49

19.417.917.515.5

38.435.52826.9

56.650.941.337.8

79.674.160.853.3

95.490.38167.7

100.496.99581.5

10197.799.693.9

Initial

2 Month

3 Month

4 Month

Time (min)

% Dissolution

Stability Study Dissolution Rates

Sheet1

No Cu (II)3 ppm Ci (II)6 ppm Ci (II)

609.89.59.1

12019.415.514.1

24038.427.723.4

36056.641.333.6

54079.662.248.4

72095.481.760.1

900100.494.170.3

108010197.880.2

Sheet1

No Cu (II)

3 ppm Ci (II)

6 ppm Ci (II)

Time (min)

% Dissolution

Effect of Copper ions

Sheet2

Initial2 Month3 Month4 Month

609.89.69.49

12019.417.917.515.5

24038.435.52826.9

36056.650.941.337.8

54079.674.160.853.3

72095.490.38167.7

900100.496.99581.5

108010197.799.693.9

Sheet2

Initial

2 Month

3 Month

4 Month

Time (min)

% Dissolution

Stability Study Dissolution Rates

Sheet3

Chart2

9.89.59.1

19.415.514.1

38.427.723.4

56.641.333.6

79.662.248.4

95.481.760.1

100.494.170.3

10197.880.2

No Cu (II)

3 ppm Ci (II)

6 ppm Ci (II)

Time (min)

% Dissolution

Effect of Copper ions

Sheet1

No Cu (II)3 ppm Ci (II)6 ppm Ci (II)

609.89.59.1

12019.415.514.1

24038.427.723.4

36056.641.333.6

54079.662.248.4

72095.481.760.1

900100.494.170.3

108010197.880.2

Sheet1

No Cu (II)

3 ppm Ci (II)

6 ppm Ci (II)

Time (min)

% Dissolution

Effect of Copper ions

Sheet2

Sheet3

Analytical considerations in the dissolution testing of oral modified release productsThe FutureAlternate technologies ?More physiological media?

Choice of apparatusBaskets (1970, USP 18)PREFERREDPaddles PREFERREDReciprocating CylinderFlow through cell Choice of medium, acid, neutral, basic. Mimic in vivo physiology or constrained by solubility of the drug deaeration Warming, filtration, Helium sparge Media switching Change medium of swamp buffer.Adequate sampling SUPAC Guidance for industry..ER 1,2,4 evry 2 hours until 80% or plateau MR15, 30, 45, 60 and 120 until 80%....Analytical finishUV, Fast LC, other?Who likes being there in the middle of the night anyway!

Exapmles.

Non-chromophore.Without IV/IVC

Based on the performance of Clinical/Bioavailability lots

Recommended range is +/- 10% deviation from mean profile (exceptions but not exceed 25%)

Late at least 80% (if max is less than 80% then plateau must be reached)

USP stage 2 or 3 expected.Stages are L Allows for failure of individual units

OFFICIAL April 1 2006 Acid and Buffer stage also defined A B Controls early and late stages. NOT ACCEPTED IN JPWorst case would be lowest drug level with maximum excipientsEffect of filtrationStability of solutionsAre samples collected/stored before analysis?

Specifically identified in Dissolution section of the guidance given.

Any bias should be addressed

Only becomes evident with long dissolution runsInvestigation shows that Accuracy demonstrated

Only becomes evident with long dissolution runsInvestigation shows that Accuracy demonstrated

Two rate controlling polymers. HPMC and sodium alginate.