achieving optimum levels of discrimination in dissolution testing

8/19/2019 Achieving Optimum Levels of Discrimination in Dissolution Testing

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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


– 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


• 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


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


• 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


• 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






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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


– 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


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


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


bioavailability ≠ in vivo dissolution


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Löbenberg (AAPS, April 2007)


Achieving opt imum levels ofdiscrimination in dissolutiontesting….but how?



• Biorelevant dissolution testing – apparatus – media






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In vitro – in vivorelationship?

in vitro in vivo


Full GI tract simulation

• -• simulation takes into account:

– dynamic conditions (sequentialpassage)

– mechanical stress (peristalticmovement)

– body temperature – body pH


– – 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


, 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


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


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


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


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


Turbulent flow

Laminar flow

flow characteristicsless predictable no beads

Any type of dissolutionapparatus preferred?

Differential dissolution profileumu a ve sso u on pro e


no!


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In vitro modeling of food effects?

s tandard b reak fas t - mixer - di ssolut ion t es t


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.


– 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


–

Achieving opt imum levels ofdiscrimination in dissolutiontesting….but how?




– media






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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.“


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


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


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)


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)


• 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?




– media






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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


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

[%]


Zeit [h]

Zeit [h]

in vivo-dissolution

Discriminatory power -a bioequivalence aproach

upper side batch

lower side batchtarget profile


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


0

1

0 2 4 6 8 10

vitro [h]

Thank


achieving optimum levels of discrimination in dissolution testing

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