Swiss-medic developement and validation of dissol methods ...• Case study #3: Development of a dissolution method for lipid formulation • General consideration for a QC Dissolution

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E.Scheubel, PTDF-A, Hoffmann-La Roche AG, Basel (CH) SAQ 25.01.2006

The use of different dissolution methods in the development of new drug product:

Development and Validation

E. Scheubel

Global Technical Operation

Formulation Management, Analytical Development

Hoffmann La Roche AG, Basel

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Outline

• Purpose of the Dissolution Method

• Case study #1: Dissolution methods as Guiding Tool for Dissolution methods as Guiding Tool for Process Development & Understanding & OptimizationProcess Development & Understanding & Optimization

• Case study #2: Methods in Methods in biorelevantbiorelevant media as Guiding Tool for media as Guiding Tool for formulation selection.formulation selection.

• Case study #3: Development of a dissolution method for lipid formulationDevelopment of a dissolution method for lipid formulation

• General consideration for a QC Dissolution Method development: “Decision TreeDecision Tree”” for Immediate Release formulationfor Immediate Release formulation

• Validation of the Dissolution Method

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GalenicalProduction

Phase 0/1

QC Analytics

Phase II Phase III Phase IVLaunch

Development Analytics

Clinical trials

EIH Full development

Pre-clinical

Process developmentScale up

Analytical research

Marketedproducts

r&d

Galenical research

Development of a Dissolution MethodDrug Product Life Cycle

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Development of a Dissolution MethodPurpose of the method (s)

•• Quality ControlQuality Controlbatch release and control of batch to batch variability for a definedformulation and a defined process

The method should be able to detect change :

• in manufacturing process • on stability• on excipient quality etc….

The dissolution testing is well defined in the Pharmacopeias, CDER, EMEA, ICH….

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•• Formulation ScreeningFormulation Screening : : evaluate the impact of composition and manufacturing on drug product release performance

•• Process MonitoringProcess Monitoring:: understand, evaluate and control the manufacturing process by reflecting the CMV (scale up..)

•• BiorelevantBiorelevant dissolution testing: dissolution testing: evaluate drug product performanceunder physiological conditions identify rate-limiting steps in oral drugabsorption

•• IVIVIVIV --C / C / --RR : : quantitative / / qualitative relationship with in vivo performance by reflecting the critical key parameters (if dissolution is the rate limiting step).

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• Not always possible to reflect all criteria (key parameters) witha single method

• Need of a set of methods for the development as tool to measure, understand & control release mechanism

• need of simulationsimulation softwaresoftware to better predict impact of changes and better reflect in vivo key parameter


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Outline


• Case study #1: Dissolution methods as Guiding Tool forDissolution methods as Guiding Tool forProcessProcess Development & Understanding & OptimizationDevelopment & Understanding & Optimization

• Case study #2: Methods in Methods in biorelevantbiorelevant media as Guiding Tool media as Guiding Tool formulation selection.formulation selection.

•• Case study #3: Development of a dissolution method for lipid forCase study #3: Development of a dissolution method for lipid formulationmulation



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Case study # 1 Dissolution methods asGuiding Tool for Process Development & Optimization

Standard QC Method

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PT9547 D 01 PT9547 D 02

PT9547 D 03 PT9547 D 04

PT9547 D 05 PT9547 D 06

PT9547 D 07 PT9547 D 08

PT9547 D 09

Question: Which process parameters does reflect the alternative method ?

supported by a „non Sink“ method

all others < 7 min

Development batches0

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D01 D02 D03 D04 D05 D06

D07 D08 D09

10:21 min

10:33 min

7:10 min

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21.5 1.5 11 162-168 03:47 04:2823.0 3.4 10 148-151 05:00 05:1821.5 3.5 11 130-135 05:24 05:5023.0 2.7 10.5 163-166 06:13 06:3723.0 3.5 10.2 111-119 05:51 06:3123.0 2.7 11 158-167 06:43 06:5623.7 3.0 12 148-157 07:00 07:1023.7 4.1 14 132-138 09:58 10:3323.7 4.2 14 120-123 08:51 10:21

hard-ness

120-180 [N]

min.Disintegr.

[min]

max.Disintegr.

[min]

DisintegrationCompaction parametersGranulation parameters% water per schedules quantity

Power consumption (kW)

main compr. force[kN]

Case study # 1 Guiding Tool for Process Development:

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PT9547 D 01 PT9547 D 02PT9547 D 03 PT9547 D 04PT9547 D 05 PT9547 D 06PT9547 D 07 PT9547 D 08PT9547 D 09 C206132 (300mg in 900ml)

79.473.370.269.866.965.455.846.8

The differences in dissolution areallocated to :- differences in the tablet properties (desint.)- granule properties (final blend particle size)- process parameters

Conclusion:- correlation between dissolution rate and granule size is evident- granule size is linked with process parameters “quantity of granulation liquid” and

“power consumption”- compression forces also impact dissolution rate

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Outline



• Case study #2: Methods in Methods in biorelevantbiorelevant media as Guiding Tool media as Guiding Tool for formulation selection.for formulation selection.


• General consideration for a QC Dissolution Method development: “Decision TreeDecision Tree”” for Immediate Release formulation for Immediate Release formulation

•• VValidation of the Dissolution Method

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Marques, M., Dissolution Technologies, 2004. 11(2): p. 16.

Case study # 2 Methods in biorelevant media asGuiding Tool for formulation selection

FaSSIFFaSSIF:: FastedFasted State State SimulatedSimulated IntestinalIntestinal FluidFluid• simulates the conditions in the fasted jejunum• pH 6.5, 3mM sodium taurocholate, 0.75mM lecithin

FeSSIFFeSSIF: : FedFed State State SimulatedSimulated IntestinalIntestinal FluidFluid• simulates the conditions in the postprandial jejunum• pH 5.0 , 15mM sodium taurocholate, 3.75mM lecithin

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SolubilitySolubility FeSSiFFeSSiF > > FaSSIFFaSSIF ((15mM vs 3 mM Na-taurocholate)

Hydrolyse at Hydrolyse at pHpH 6.56.5 ((FaSSiFFaSSiF)) >> >> pHpH 5.05.0 ((FeSSiFFeSSiF),),

HydrolysatHydrolysat notnot absorbedabsorbed ; ; TmaxTmax ap. 2 ap. 2 hourshours

Ester Pro Ester Pro drugdrug BCSBCS classclass IV, IV, WeakWeak basebasesolubilitysolubility pHpH dependingdependingStrongStrong hydrolysishydrolysis at high at high pHpH

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2 IR 2 IR TabletsTablets FormulationsFormulations testedtested in in clinicclinic ..

Desintegrating tabletstablets

Eroding tabletstablets ((LutrolLutrol))

Ester Pro Ester Pro drugdrug BCSBCS classclass IV, IV, WeakWeak basebasesolubilitysolubility pHpH dependingdependingStrongStrong hydrolysishydrolysis at high at high pHpH

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Overlay in Biorelevant Media

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Lutrol T max (h) AUCP-P 0% 3.7 3700

(30%)4-h 0% 1.9 2800

(27%)

Case study # 2 Methods in biorelevant media asGuiding Tool for formulation selectiondesintegrating tablets - impact of difference in FaSSIF vs FeSSIF

PP = Postprandial 4-h = fasted state :


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case#2 - P 50 rpm in FeSSIF case#2 - P 50 rpm in FaSSIF

⇨ assumption: positive food effect due to hydrolysis in the fasted state⇨ no dissolution limitation of oral BA anticipated (DR > 70% in 30’)

+42 %

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Food effect17% Lutrol

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Mean 17% Fasted Mean 17 % fed

Lutrol T max (h) AUCP-P 17% 2.5 4140

(29%)4-h 17% 1.75 5610

(34%)

Case study # 2 Methods in biorelevant media asGuiding Tool for formulation selectionEroding tablets (Lutrol) - impact of difference in FaSSIF vs FeSSIF

⇨ Assumption: negative food effect (release FeSSIF < release FaSSIF)

PP = Postprandial 4-h = fasted state :


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case#2 - P 50 rpm in FaSSIF case#2 - P 50 rpm in FeSSIF

⇨ erosion mechanism impaired by the bile salt ? Protection from hydrolyse

- 36 %

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Outline



• Case study #2: Methods in Methods in biorelevantbiorelevant media as Guiding Tool for media as Guiding Tool for formulation selection. formulation selection.

•• Case study #3Case study #3: : Development of a dissolution method for lipid formulation



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in in vitrovitro::

capsule shell disintegration

⇩

release of oily solution

(no digestion of oil)

⇩

drug release: partitioning out of oil into dissolution media

oil dropletsfloating on

mediumsurfaceChallenge: adequate dissolution within appropriate time frame

Case study # 3: Development of a dissolution method for lipid formulation with USP2

Pro Pro drugdrug BCSBCS classclass IV, IV, WeakWeak basebase, , VeryVery lowlow solubilitysolubilitylogP > 7.0 ⇨ high affinity to the lipid carrier

(10 000 000 parts oil : 1 part water)

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Dissolution Overlay

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50mg - P 100rpm 1000ml - 0.1N HCl (2.5% Crem/2.5%Soft) 50mg - P 100rpm 1000ml - 0.1N HCl (2.5% Crem/2.5%Labr)

Dissolution Overlay

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50 mg - P 150rpm 500ml - 0.1N HCl (0.5% Crem./2%CTAB)

UnusualUnusual conditionsconditions neededneeded withwith USP2USP2 appartusappartus::

• High amount of surfactant (> 8 %) or surfactant plus co-surfactant

• high agitation needed (150 rpm !)

• maximum 80 – 85% dissolution after 3 hours (due to partitioning)

100 100 rpmrpm:: 150 150 rpmrpm::

Recovery Issue

Case study # 3: Development of a dissolution method for lipid formulation with USP2

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Mov00415.mpg Flow direction

Ph.Eur. 5.3 2.9.42.:Dissolution test forlipophilic solid dosage forms

alternative hydrodynamic

Dedicated cell (two chambers) for lipid formulation

Open system

The method is a continuous dissolution method (indefinite amount of solvent possible) vs. the staticUSP 1&2 methods (defined solvent volume 500 ml to 1000 ml)

The test sample is located in a small-volume cell through which fresh solvent passes at 37°C (facilitate drug partitioning).

Case study # 3: Development of a dissolution method

for lipid formulation with USP4

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Dissolution Overlay

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50mg - supp. cell 10 ml/min - 0.1N HCl (0.5%Crem/2%CTAB) 50mg - supp. cell 20 ml/min - 0.1N HCl (0.5%Crem/2%CTAB)

50mg - supp. cell 35 ml/min - 0.1N HCl (0.5%Crem/2%CTAB)

USP4USP4: drug release as function of flow rate: drug release as function of flow rate

Case study # 3: Development of a dissolution method

for lipid formulation with USP4

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• unusual conditions needed for the lipid formulation with USP2

⇨ surfactant plus co-surfactant⇨ strong hydrodynamics

• USP4 with the dedicated cell for lipid formulations enables quantitative drug release

Case study # 3: Development of a dissolution method for lipid formulation

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Outline







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Development of a Dissolution MethodQC Decision Tree for IR

• Medium

• Apparatus screening

• Fine tuning & discrimination

• Change

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QC Decision Tree Media screening

ffi

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QC Decision Tree Media screening

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QC Decision Tree Apparatus Screening

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Dissolution Profiles : non recommended shapes

IR Dissolution profiles : Theoretical exemples

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too slow


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too slow precipitation


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too slow precipitation plateau at 80 %


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too slow precipitation plateau at 80 % too quick

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Dissolution Profiles : filter type impact

Dissolution Overlay

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Filter 1 µm Filter Premium 1 µm

Profile Shape

Recovery Issue

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QC Decision Tree Apparatus Screening

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Dissolution Profiles : Sampling points optimization


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sampling point inadequate


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sampling point inadequate sampling point best1


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sampling point inadequate sampling point best1 sampling point best2


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sampling point inadequate sampling point best1 sampling point best2 sampling point best3

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Change :Wet granulation versus dry compaction(IR; BCS class 1)

Dissolution Overlay

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dry compaction wet granulation

Suitability of the method, sampling ect..

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QC Decision Tree Fine Tuning

SUPACor

Changes

?

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Overlay

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initial Alu-Alu 3 Mo 25°C + 60% r.h Alu-Alu 3 Mo 30°C + 60% r.h Alu-Alu 3 Mo 40°C + 75% r.h Alu-Alu 1 Mo 40°C + 75% r.h

Stability and Packaging effectblister Alu-Alu after 3 months at different temperatures

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initial Blister 1Mo +40°C + 75% r.h. Blister 3 Mo 25°C + 60% r.h Blister 3 Mo 30°C + 60% r.h Blister 3 Mo 40°C + 75% r.h

Stability and packaging effectblister PVC-PVDC after 3 months at different temperatures

40°C+75% r.h.

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Overlay Tarceva in HCl 0.1N

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PT 9498 T12 mean FCT - Basket 100 rpm in HCl 0.1N + SDS 1 % P 425801 mean FCT - Basket 100 rpm in HCl 0.1N + SDS 1 %

Choice of Working condition(IR; BCS class 2)Same tablet 2 batches with different dissolution methods

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Batch 2 FCT - Paddle 75 rpm in HCl 0.1N + SDS 1 % Batch 1 FCT - Paddle 75 rpm in HCl 0.1N + SDS 1 %

method 1: similar ProfilePaddle @75 rpm, HCL + 1% SDS

Is the difference of in vitro drug performance a quality issue ? Overdiscrimination ? ?

method 2: non comparable profileBasket @75 rpm, HCL + 1% SDS

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Development of a Dissolution methodA living process

• The purpose of the dissolution test evolves through the variousstages in drug development. Therefore the test method shouldbe re evaluate and optimized (if needed) after bioavaibility databecome available from clinical trials.

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Outline







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Validation of Dissolution Methods

• Reference : ICH, USP <711> + <724> + <1092> etc..

data Assay

Selectivity/Specificity +

Linearity +

Accuracy +

Precision +

by Repeatability +

by Intermediate Precision +

Limit of Detection

Limit of Quantitation

Range +

Robustness +

must cover entire profile range; 20% -130%

R > 0.99 98 % to 102 % 2 %2 %2 %

Specifical criteria are needed

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Validation : Robustness

• Filter recovery (± 2%)

• Stability of the API in the medium at 37°C (± 1%)

• Stability of the pH up to test completion (± 0.05 unit)

• Stability of the collected samples (± 2%)

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Caliper Multidose

Sotax AT70 smart

Automation Fully automated system‘s

• Method comparison (n=3 Batches; ± 5% at Q or f2 )

• Carry over (max. 1%)

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Summary

• for QC release

• to support formulation selection

• for Process Development & Optimization & Understanding

• to evaluate ageing impact & packaging

• …..

Dissolution Testing as a tool :

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Thank You for your attention

Documents

Swiss-medic developement and validation of dissol methods ...• Case study #3: Development of a dissolution method for lipid formulation • General consideration for a QC Dissolution