swiss-medic developement and validation of dissol methods ...• case study #3: development of a...
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Pharm
aceuticals
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
Pharm
aceuticals
E.Scheubel, PTDF-A, Hoffmann-La Roche AG, Basel (CH) SAQ 25.01.2006
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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Pharm
aceuticals
E.Scheubel, PTDF-A, Hoffmann-La Roche AG, Basel (CH) SAQ 25.01.2006
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
Pharm
aceuticals
E.Scheubel, PTDF-A, Hoffmann-La Roche AG, Basel (CH) SAQ 25.01.2006
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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Pharm
aceuticals
E.Scheubel, PTDF-A, Hoffmann-La Roche AG, Basel (CH) SAQ 25.01.2006
Development of a Dissolution MethodPurpose of the method (s)
•• 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).
Pharm
aceuticals
E.Scheubel, PTDF-A, Hoffmann-La Roche AG, Basel (CH) SAQ 25.01.2006
• 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
Development of a Dissolution MethodPurpose of the method (s)
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Pharm
aceuticals
E.Scheubel, PTDF-A, Hoffmann-La Roche AG, Basel (CH) SAQ 25.01.2006
Outline
• Purpose of the Dissolution Method
• 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
• General consideration for a QC Dissolution Method development: “Decision TreeDecision Tree”” for Immediate Release formulationfor Immediate Release formulation
• Validation of the Dissolution Method
Pharm
aceuticals
E.Scheubel, PTDF-A, Hoffmann-La Roche AG, Basel (CH) SAQ 25.01.2006
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
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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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Pharm
aceuticals
E.Scheubel, PTDF-A, Hoffmann-La Roche AG, Basel (CH) SAQ 25.01.2006
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
Pharm
aceuticals
E.Scheubel, PTDF-A, Hoffmann-La Roche AG, Basel (CH) SAQ 25.01.2006
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 media as Guiding Tool for formulation selection.for formulation selection.
•• Case study #3: Development of a dissolution method for lipid forCase study #3: Development of a dissolution method for lipid formulationmulation
• 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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Pharm
aceuticals
E.Scheubel, PTDF-A, Hoffmann-La Roche AG, Basel (CH) SAQ 25.01.2006
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
Pharm
aceuticals
E.Scheubel, PTDF-A, Hoffmann-La Roche AG, Basel (CH) SAQ 25.01.2006
Case study # 2 Methods in biorelevant media asGuiding Tool for formulation selection
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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Pharm
aceuticals
E.Scheubel, PTDF-A, Hoffmann-La Roche AG, Basel (CH) SAQ 25.01.2006
Case study # 2 Methods in biorelevant media asGuiding Tool for formulation selection
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
Pharm
aceuticals
E.Scheubel, PTDF-A, Hoffmann-La Roche AG, Basel (CH) SAQ 25.01.2006
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 :
Overlay in Biorelevant Media
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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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Pharm
aceuticals
E.Scheubel, PTDF-A, Hoffmann-La Roche AG, Basel (CH) SAQ 25.01.2006
Food effect17% Lutrol
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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 :
Overlay in Biorelevant Media
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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 %
Pharm
aceuticals
E.Scheubel, PTDF-A, Hoffmann-La Roche AG, Basel (CH) SAQ 25.01.2006
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 #3Case study #3: : Development 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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Pharm
aceuticals
E.Scheubel, PTDF-A, Hoffmann-La Roche AG, Basel (CH) SAQ 25.01.2006
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)
Pharm
aceuticals
E.Scheubel, PTDF-A, Hoffmann-La Roche AG, Basel (CH) SAQ 25.01.2006
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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Pharm
aceuticals
E.Scheubel, PTDF-A, Hoffmann-La Roche AG, Basel (CH) SAQ 25.01.2006
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
Pharm
aceuticals
E.Scheubel, PTDF-A, Hoffmann-La Roche AG, Basel (CH) SAQ 25.01.2006
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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Pharm
aceuticals
E.Scheubel, PTDF-A, Hoffmann-La Roche AG, Basel (CH) SAQ 25.01.2006
• 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
Pharm
aceuticals
E.Scheubel, PTDF-A, Hoffmann-La Roche AG, Basel (CH) SAQ 25.01.2006
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 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
• 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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Pharm
aceuticals
E.Scheubel, PTDF-A, Hoffmann-La Roche AG, Basel (CH) SAQ 25.01.2006
Development of a Dissolution MethodQC Decision Tree for IR
• Medium
• Apparatus screening
• Fine tuning & discrimination
• Change
Pharm
aceuticals
E.Scheubel, PTDF-A, Hoffmann-La Roche AG, Basel (CH) SAQ 25.01.2006
QC Decision Tree Media screening
ffi
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Pharm
aceuticals
E.Scheubel, PTDF-A, Hoffmann-La Roche AG, Basel (CH) SAQ 25.01.2006
QC Decision Tree Media screening
Pharm
aceuticals
E.Scheubel, PTDF-A, Hoffmann-La Roche AG, Basel (CH) SAQ 25.01.2006
QC Decision Tree Apparatus Screening
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Pharm
aceuticals
E.Scheubel, PTDF-A, Hoffmann-La Roche AG, Basel (CH) SAQ 25.01.2006
Dissolution Profiles : non recommended shapes
IR Dissolution profiles : Theoretical exemples
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too slow
IR Dissolution profiles : Theoretical exemples
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too slow precipitation
IR Dissolution profiles : Theoretical exemples
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too slow precipitation plateau at 80 %
IR Dissolution profiles : Theoretical exemples
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too slow precipitation plateau at 80 % too quick
Pharm
aceuticals
E.Scheubel, PTDF-A, Hoffmann-La Roche AG, Basel (CH) SAQ 25.01.2006
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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Pharm
aceuticals
E.Scheubel, PTDF-A, Hoffmann-La Roche AG, Basel (CH) SAQ 25.01.2006
QC Decision Tree Apparatus Screening
Pharm
aceuticals
E.Scheubel, PTDF-A, Hoffmann-La Roche AG, Basel (CH) SAQ 25.01.2006
Dissolution Profiles : Sampling points optimization
IR Dissolution profiles : Theoretical exemples
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sampling point inadequate
IR Dissolution profiles : Theoretical exemples
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sampling point inadequate sampling point best1
IR Dissolution profiles : Theoretical exemples
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sampling point inadequate sampling point best1 sampling point best2
IR Dissolution profiles : Theoretical exemples
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sampling point inadequate sampling point best1 sampling point best2 sampling point best3
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Pharm
aceuticals
E.Scheubel, PTDF-A, Hoffmann-La Roche AG, Basel (CH) SAQ 25.01.2006
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..
Pharm
aceuticals
E.Scheubel, PTDF-A, Hoffmann-La Roche AG, Basel (CH) SAQ 25.01.2006
QC Decision Tree Fine Tuning
SUPACor
Changes
?
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Pharm
aceuticals
E.Scheubel, PTDF-A, Hoffmann-La Roche AG, Basel (CH) SAQ 25.01.2006
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
Pharm
aceuticals
E.Scheubel, PTDF-A, Hoffmann-La Roche AG, Basel (CH) SAQ 25.01.2006
Overlay
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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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Pharm
aceuticals
E.Scheubel, PTDF-A, Hoffmann-La Roche AG, Basel (CH) SAQ 25.01.2006
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
Pharm
aceuticals
E.Scheubel, PTDF-A, Hoffmann-La Roche AG, Basel (CH) SAQ 25.01.2006
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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Pharm
aceuticals
E.Scheubel, PTDF-A, Hoffmann-La Roche AG, Basel (CH) SAQ 25.01.2006
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 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
• General consideration for a QC Dissolution Method development: “Decision TreeDecision Tree”” for Immediate Release formulationfor Immediate Release formulation
• Validation of the Dissolution Method
Pharm
aceuticals
E.Scheubel, PTDF-A, Hoffmann-La Roche AG, Basel (CH) SAQ 25.01.2006
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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Pharm
aceuticals
E.Scheubel, PTDF-A, Hoffmann-La Roche AG, Basel (CH) SAQ 25.01.2006
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%)
Pharm
aceuticals
E.Scheubel, PTDF-A, Hoffmann-La Roche AG, Basel (CH) SAQ 25.01.2006
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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Pharm
aceuticals
E.Scheubel, PTDF-A, Hoffmann-La Roche AG, Basel (CH) SAQ 25.01.2006
Summary
• for QC release
• to support formulation selection
• for Process Development & Optimization & Understanding
• to evaluate ageing impact & packaging
• …..
Dissolution Testing as a tool :
Pharm
aceuticals
E.Scheubel, PTDF-A, Hoffmann-La Roche AG, Basel (CH) SAQ 25.01.2006
Thank You for your attention