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In Vitro and In Vivo Correlations and BiorelevantDissolution Using Computers
Simulations in a QbDEnvironment
November 14, 2016
Raimar Löbenberg
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Outline
• Fundamentals in QbD
• Fundamentals of the BCS
• API vs. Formulation controlled dissolution
• How to identify clinically relevant product specifications
–Example lysosomal trapping
–Permeability vs dissolution controlled absorption
• Conclusions
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Quality by DesignProduct Quality Implementation Lifecycle Initiative (PQLI)
• Quality by Design is a systematic approach to development that begins with predefined objectives and emphasizes product and process understanding based on sound science and quality risk management.
– ICH Q8 Pharmaceutical Development
– ICH Q9 Quality Risk Management
– ICH Q10 Quality Systems
– FDA Pharmaceutical cGMPs for the 21st Century - A Risk-Based Approach. Final Report
16-07-06 7
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IVIVC 1997
16-07-06
9
BCS Classification Lifecycle Management
BCS Biowaiver 2000
QbD
SUPAC 1995/ 1997 Level 1/2/3 Changes
Level A CorrelationBio-
waiver
BSC Class waiver
Design Space
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How things started…
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Fundamental 1
Only what is dissolved can be absorbed
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Fundamental 2Only what is absorbed can be studied in
vivo
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Solubility directly influences the dissolution behavior of oral dosage forms in gastrointestinal tract
Biopharmaceutical Drug Classification System (BCS)
8
Class Solubility Permeability
I High High
II Low High
III High Low
IV Low Low
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When to use Dissolution/Disintegration?
ICH Guideline Q6A “Specifications: Test procedures and acceptance criteria for new drug substances and new drug products” outlines acceptance criteria for different dosage forms and routes of administration. The guidance document contains decision tree #7.1, which allows disintegration testing to be used as a performance/quality control test if a relationship between dissolution and disintegration has been establishedU.S. Department of Health and Human Services, 1999
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FDA Study 2009
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FDA Study 2009
However, no direct correlation was observed between the
disintegration and the dissolution
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For certain Formulations Disintegration and Dissolution are Sequential ProcessesNo correlation other than the Sequence should be found if API controls Dissolution
≈≈≈ ≈
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≈
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? ≈≈
≈
≈
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≈
≈
≈≈
≈≈
≈
≈
≈≈
dlAPI
Cs
≈≈
≈
≈
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≈
≈
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≈ ≈≈
≈
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≈
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≈
≈
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F=kKP*tn
Drug release mechanism
KorsmeyerPeppas equation:
Exponent n of the power law and drug release mechanism from polymeric controlled delivery systems of different geometry
n values Drug release mechanism
Thin Film Cylinder Sphere
0.5 0.45 0.43 Fickian Diffusion
0.5 <n<1.0 0.45<n<0.89 0.43<n<0.85 Anomalous Transport
1 0.89 0.85 Case-II Transport
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Fast Disintegrating slow eroding Tablet
0
20
40
60
80
100
120
0 20 40 60
% D
isso
luti
on
Time
25 rpm observed50 rpm observed75 rpm observed
0
20
40
60
80
100
120
0 20 40 60
% D
isso
luti
on
Time
25 rpm observed50 rpm observed75 rpm observed
Korsmeyer-Peppas n values75 0.11150 0.29325 0.413
Korsmeyer-Peppas n values75 1.1150 0.93825 0.924
Sphere<0.43
0.43<n<0.85>0.85
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Sequential EventsTablet Disintegration
• After you pull the handle the valve opens fully
• Water will flush down the pipe
• The rate depends only on the hydrostatic pressure and diameter of the pipe
• The extend is 100%• If you only pull a little and do
not trigger the valve to open you can control the amount and rate of water
Flushing a Toilet
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Dissolution TestDisintegration Test
Direct compression
Dry granulation
Powder blend
Wet granulation
Fluid bed granulation
Sinter granulation
Melt extrusion
Dissolution Test
API controls
dissolution
excipients
have no
significant
impact
Capsule
Tablet or ODT/FDT
Formulation
significantly
controls
dissolution
Dosage form
Manufacturing process
R&DDevelopment
QC Method
PHASE 1/2 R&D DEVELOPMENT
Proposed New Formulation
Classification:
API vs.Formulation
Controlled Dissolution
Release mechanism Modeling
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In vitro: Dissolution Testand Clinical relevance?
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Prediction Software
• DDDPlus
• MembranePlus
• GastroPlus
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Computer Simulations
Using ACAT and PK models
• In vitro data can be used as input function into Gastro Plus™ to simulate the absorption profiles of the drugs
• Gastro Plus™ uses a mathematical model called Advanced Compartmental, Absorption and Transit (ACAT), model which is based on the principles of the BCS
• The 3 major data input tabs are:– Compound tab
– Physiology tab
– Pharmacokinetics tab
SmallIntestine
Portalvein
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GastroPlus Sodware
• Physicochemical Data as Input
• Dissolution Data as Input
• Permeability
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GastroPlus Software
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GastroPlus Software
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How you get it wrong doing the right thing
“NO STRAIT LINE PLEASE”• Lysosomal trapping of
weak bases with high pKa
• Example Dextromethorphane
• Pharmacokinetic differences EM/PM
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Metabolism of dextromethorphan by CYP2D6 and CYP3A4 (P450 enzyme system)
CYP3A4 CYP3A4
CYP2D6
CYP2D6
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GastroPlus Software
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In Vivo Amount in SystemicCirculation
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Dissolution simulation DDDPlus
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pH 7.8App 4 Closed loop 20hrs
Dissolution simulation DDDPlus
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Desired profile which
matches the in vivo
observed fraction
dose absorbed!
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0
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0 5 10 15 20 25 30
Systemic Circulation
0
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0 5 10 15 20 25 30
Dextromethorphan Dissolution
R² = 0.9959
0
20
40
60
80
100
120
0 50 100 150
% dissolved vs.% absorbed
Classical IVIVC
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Let Snoopy tell you…
I have heard you are writing
a book on theology
I hope you have a good title for it
I have the perfecttitle
“has it ever occured to you that you might be wrong?”
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What really happens
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Lysosomal-Trapping of weak bases pKa >7
Gut: pH 5.5 -7.0
Cytoplasm
Lysosome pH 4.5 -5.5
Cytoplasm
Blood 7.4
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Membrane Plus
apical chamber
basolateral chamber
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PBPK ModelTeorell (1937)Provide a clear physiologicaldescription of determinants of drug disposition.Over the years so-called compartmental PK analysis wasdeveloped to examinepharmacokinetic behavior. These simplified models give equations that have exact solutions and have provided many useful insights despite their very much simplified depiction of physiology.
(lung, liver, heart, brain, kidney, spleen, skin, reproductive organs, muscle, adipose, red/ yellow marrow and rest of body)
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PO 30mg EM Gorski
2
3
4
1
5
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F (not Fa!)Fa
D PV
FDp(not Fa!)Absorption
Metabolism
A
ACAT model PK models/PBPK
SC
Metabolism
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Dextromethorphan in Extensive metabolizers
%Drug in SC
Drug Dissolved
Drug Absorbed%Drug in PV
Observed Drug in Plasma
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Dextromethorphan in Extensive metabolizers
Drug Dissolved
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Dextromethorphan in Extensive metabolizers
Drug Absorbed
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F (not Fa!)
Dosage form interface
Biological System
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Dextromethorphan in Extensive metabolizers
Drug in Portal vein
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Dextromethorphan in Extensive metabolizers
Ca
Drug in Systemic circulation
Concentration
% of dose
SC
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0
20
40
60
80
100
120
0 5 10 15 20 25 30
Systemic Circulation
0
20
40
60
80
100
120
0 5 10 15 20 25 30
Dextromethorphan Dissolution
R² = 0.9959
0
20
40
60
80
100
120
0 50 100 150
% dissolved vs.% absorbed
Classical IVIVC
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Classical PK model
Classical IVIVC
Wagner Nelson: D0 = D body + D urine + D not Abs
% D Abs = D body + D urine
=SC
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Dosage form impact is limited to the gut lumen / enterocyte interface!!!
Drug Dissolved & Absorbed
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Product Dissolution Specification
%Drug in SC
Drug Dissolved
Drug Absorbed%Drug in PV
Observed Drug in Plasma
Q80 @ 2 hrs
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Dissolution Specification
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Summary of IVIVC• IVIVC - It works but you better knw what
you are doing!
• Software can assist the formulation scientist to identify critical formulation variables
• If Permeability controls absorption dissolution criteria might not be important.
• Lysosomal trapping can impact the appearance of the drug in the systemic circulation
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Conclusions
• BCS allows us to ask the right questions to find the solutions in drugdevelopment and dissolution method development
• The BCS has changed the way we look at drugs and the drug development process
• Software can assist to establish IVIVIC• You must know what you are doing
16-07-06 62
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YES, the generic is cheaper. But for
real savings take the placebo
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Questions
https://www.ualberta.ca/pharmacy/about-us/contact-us-and-people/people/raimar-loebenberg
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Acknowledgments
• Abbvie
• Simulations Plus
• DDIC
• University of Alberta
• Muhammad Sarfaz
• Gregory Webster, PhD
• Michael Bolger