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Achieving optimum levels of discrimination indissolution testing
AAPS: DISSOLUTION WORKSHOPRhodes University, Grahamstown
December 09-10, 2009
Dr. Johannes Krämer
Achieving opt imum levels ofdiscrimination in dissolutiontesting….but how?• Goals of dissolution testing
• Bioperformance of drugs
• Biorelevant dissolution testing – apparatus
– media
• Rank order for predictive power of dissolution testing – the BCS – a look at GI physiology – dosage form properties
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• Discriminative power – patient vs. manufacturer risk – a qualitative issue – the attempt for a quantitative approach
• Biorelevant dissolution testing
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Goals of dissolution testingearly phase
• dissolution testing
– to evaluate the in vitro performance of drug products
– products for systemic and/or local administration and action
– in early development: to model in vivo findings with the goal to identify
the best delivery concept
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– results always relative
Dissolution methodology
• determining drug release – in closed systems – in open systems – with apparatus – and dissolution m edia that act
as» solvents» carriers of mechanical energy» absorbers of dissolved drug
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• no ye o mo e - r ans o – dosage forms – disintegrated particles – solutions alone or ……with
chyme
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GI transfer modelpredictive?
• Disintegratio n in SGFsp pH 2.0• Transfer to FeSSIF or FaSSIF (immediate or w ith tr ansfer rate)
– Monitor dissolution & precipitation
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Goals of dissolution testinglater phase
• dissolution testin – in product lifecycle:
• to predict differences in bi operformances• to ascertain constant quality
– within a meaningful range
– optimum: to evaluate the impact of critical quality parameters on thein vivo performance of drugs
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• prerequisite – standardized equipment and “reagents” for
• precise testing to measure quality differences• link to relevant in vivo p arameters
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Concept of mapping
• Critical manufacturing variables
critical processing variables
• variables:those materials and methods
used in the manufacturingprocess that can significantlyaffect drug release from theproduct
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• to develop productspecifications withbioavailability implications
Achieving optimum levels ofdiscrimination in dissolutiontesting….but how?
• Goals of dissolution testing
• Bioperformance of drugs• Biorelevant dissolution testing
– apparatus – media
• Rank order for predictive power of dissolution testing – the BCS – a look at GI physiology – dosage form properties
© PHAST GmbH, www.phast .de 8
• Discriminative power – patient vs. manufacturer risk – a qualitative issue – the attempt for a quantitative approach
• Biorelevant dissolution testing
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Bioperformance of drugs
• For locall and s stemicall actin dru s – Delivery of drug substance
• at given pattern – prompt – immediate – modified…
• complete dose for orals• at given rate for i mplants and transdermals
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– i.e. in vivo drug release
– not per se accessible
In vivo-dissolut ion vs.BA as the sur rogate parameter
drugproduct stomach small Int.
blood
feces /urine
residual content
kaka
ke
k r
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feces/urinein dosage form Classical BA
kr not directlyaccessible
kr derived fromcomposite [kr, ka]
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Apparent in vivo dissolution
system function
time [h]
response function
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time [h]
deconvoluted fct.
Bioperformance of drugs
• – the surrogate parameter of therapeutic efficacy is the
bioavailability of the drug product
Bioavailability – the rate and extent to which the activeingredient or active moiety is absorbed from a drugproduct and becomes available at the site of action
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bioavailability ≠ in vivo dissolution
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Löbenberg (AAPS, April 2007)
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Achieving opt imum levels ofdiscrimination in dissolutiontesting….but how?
• Goals of dissolution testing
• Bioperformance of drugs
• Biorelevant dissolution testing – apparatus – media
• Rank order for predictive power of dissolution testing – the BCS – a look at GI physiology – dosage form properties
© PHAST GmbH, www.phast .de 14
• Discriminative power – patient vs. manufacturer risk – a qualitative issue – the attempt for a quantitative approach
• Biorelevant dissolution testing
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In vitro – in vivorelationship?
in vitro in vivo
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Full GI tract simulation
• -• simulation takes into account:
– dynamic conditions (sequentialpassage)
– mechanical stress (peristalticmovement)
– body temperature – body pH
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– – enzymes – concentration of bile salts – removal of water / solubilized molecules
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Standardized equipmentwanted
• USP FIP Position Paper on Qualification of Paddle and Basket Dissolution Apparatus – harmonized via ICH Q4B – more or less standardized – qualification procedures for GMP available
Cynthia K. Brown [1] , Lucinda Buhse [2] , Horst-Dieter Friedel [3] , Susanne Keitel [4] , Johannes Kraemer [5] , J.Michael Morris [6] , Mary Stickelmeyer [7] , Chikako Yomota [8] and Vinod P. Shah [9]Members of FIP Special Interest Group, Dissolution / Drug ReleasePaddle/Basket Dissolution Apparatus Qualification
[1] Eli Lilly and Company[2] Food and Drug Administration[3] Bayer Schering Pharma AG, Germany[4] European Directorate for the Quality of Medicines and Healthcare, France
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, ermany[6] Irish Medicines Board, Ireland [7] Eli Lilly and Company, Indianapolis, IN, USA[8] National Institute of Health Sciences, Japan[9] FIP Scientific Secretary, The Hague, Netherlands
Any preference w it h regard to biorelevance?
Dissolution methodology:closed systems
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3 5
. 8
1 9
74.5
42
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Compendial apparatus-Basket(apparatus )
adopted in 1970 by the USP
standard basket
40 mesh stainless steele.g. 900 mL at 37 °Ce.g. 100 rpm
Basket
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Vessel
Compendial apparatus-Paddle(apparatus )
Standard paddle
shaft paddle made of inert material(coated)/stainless steel (uncoated)e.g. 900 mL at 37 °C
50
Shaft
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e.g. 50 rpmsinkers optional for floating
dosage formsPaddle
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Compendial apparatus-reciprocating cylinder(apparatus )
Apparatus developed by Beckett &
evaporation cap
upper mesh screeninner cylinder
co-workers
Adopted by the USP in 1991
e.g. 200 mL volume
e.g. 5-30 dips/min
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differences to
pH profiling
outer cylinder
lower mesh screen
dosage form
Dissolution methodology:open systems
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Flow-through cellapparatus
glass beads
linear flow
dampened pump pulsation
Turbulent flow
fl h t i ti
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Turbulent flow
Laminar flow
flow characteristicsless predictable no beads
Any type of dissolutionapparatus preferred?
Differential dissolution profileumu a ve sso u on pro e
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no!
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In vitro modeling of food effects?
s tandard b reak fas t - mixer - di ssolut ion t es t
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Biorelevant media byJenny Dressman
• Biorelevant Media:
– stomach• FaSSGF (250 mL): Fasted State Simulated Gastric Fluid
– pH 2.0, 0.01 N HCl, 0.1 mg/ml pepsin, 80 µM Na-taurocholate, 20 µM lecithin, 34 mMNaCl.
– small intestine• FeSSIF (900 mL): Fed State Simulated Intestinal Fluid
– pH 5.0, 15 mM NaTC, 3.75 mM Lecithin, 670 mosmol/kg.
• FaSSIF (500 mL): Fasted State Simulated Intestinal Fluid – pH 6.5, 3 mM NaTC, 0.75 mM Lecithin, 270 mosmol/kg.
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– food / co-medication• Milk• Bio-relevant medium + mixed food• Bio-relevant medium + co-medication
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Biorelevant media in QC
• yes• but as qu alified reagents• with regard to
– pH – osmolality – ional composition – volume – temperature
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–
Achieving opt imum levels ofdiscrimination in dissolutiontesting….but how?
• Goals of dissolution testing
• Bioperformance of drugs
• Biorelevant dissolution testing – apparatus
– media
• Rank order for predictive power of dissolution testing – the BCS – a look at GI physiology – dosage form properties
© PHAST GmbH, www.phast .de 28
• Discriminative power – patient vs. manufacturer risk – a qualitative issue – the attempt for a quantitative approach
• Biorelevant dissolution testing
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Correlation of in-vitro- andin-vivo-data
NF XIV (1975) 941: ...“ in many cases i t i spossib le to correlate dissolution r ates withbiological availability of t he activeingredient.“
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Relationship between BCSand IVIVC for IR dosage forms
Class Absorption ratecontrol
when predicting in vivoerformance from
diss. data
I Gastric emptying Diss.rate < gastric emptying Yes
II Dissolution In vitro diss.rate similar toin vivo diss.rate
Yes
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III Permeabili ty absorpti on is ratedetermining and limited orno correlation
No
IV Case by case Limited or no IVIVCcorrelation
No
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Gastroin testinal transit
PYLORUS continues grinding of food -
antral mill
emptying controlled bypylorus
exclusion size 5-7 mmlarge particles only with
housekeeper wave
2. GRINDING1. Propulsion
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small particles (2mm)together with grindedchyme3. Retropulsion
Gastric transit
n e as e s a e n er ges ve
phase I: 40 - 60 min, no to small activityphase II: 30 - 45 min some occasional activity
phase III: 5 - 15 stron g contracti ons, housekeeper wavephase IV: leads to next cycl e
MMC in the fed state (postprandial)
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one phase with constant peristaltic activitystrong antral activitiespylorus is generally closed but opens to release chyme
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Impact of drug productproperties
• MR dosage forms designed to be robust againstphysiological variables
• gastrointestinal transit highly relevant – multiparticulates – monoparticulates (size matters)
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• pre c a y grea er or an or• FASSIF/FESSIF and others of greater significance
for IR
Achieving optimum levels ofdiscrimination in dissolutiontesting….but how?
• Goals of dissolution testing
• Bioperformance of drugs
• Biorelevant dissolution testing – apparatus
– media
• Rank order for predictive power of dissolution testing – the BCS – a look at GI physiology – dosage form properties
© PHAST GmbH, www.phast .de 36
• Discriminative power – patient vs. manufacturer risk – a qualitative issue – the attempt for a quantitative approach
• Biorelevant dissolution testing
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Discriminatory power BA-study
i.e. detection of biorelevant differences
vivo
Charge C
Charge A
Charge B
[mg/ml]
theophylline ER
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bio study
Zeit [h]Zeit [h]
in vivo-dissolution
IVIVC: the “ Swiss ArmyKnife” in biopharmacy?
•IVIVC is a stochasti calrelationship! An existing correlation
includes the proof ofthe discriminatory power…
but in the correct order
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Disriminatory Power Cont'd
in vitropH 6.8
150 r m
in vitropH 4.5
100 rpm rank order
vivo
Charge C
Charge A
Charge B
[%]ChargeC
ChargeA
ChargeB
[%]
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Zeit [h]
Zeit [h]
in vivo-dissolution
Discriminatory power -a bioequivalence aproach
upper side batch
lower side batchtarget profile
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bio-study, n=18 relative bioavailabilities
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Summary
8
9
10
3
4
5
6
7
v i v
o [
h ] manufacturer risk
shared risk
patient risk
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0
1
0 2 4 6 8 10
vitro [h]
Thank
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