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Pharmaceutical Quality Standards
Dr. Johannes Krämer
Bioavailability and Bioequivalence
IKEV / APV ConferenceIstanbul April 15-16, 2004
Dissolution Testing as a Surrogate for Bio-Studies
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State of the Art of Dissolution Testing
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Relevant Questions:• What are the dissolution testing devices used in the realm
governed by ICH?• What are the principal differences between the apparati?• Are there alternatives to pharmacopeial instruments?• Which one mimics best the physiological conditions?• What are the critical points in the qualification of the
equipment and the laboratory?• How to compare results / profiles?
State of the Art
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The Concept of Dissolution Testing
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release absorptionfirst-pass-effect
elimination
dosage-form kr
GI-tract ka
bloodke
feces /urine
feces tissue
Scheme of Kinetic Steps After Application of Oral Dosage Forms
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Scheme of In Vivo Dissolution
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Goals of Dissolution Testing
prediction of bioavailability, the surrogate-parameter of therapeutic efficacy
evaluation of robustness as a parameter of drug product- related safety
critical manufacturing variables
in QC (quality control) for investigations on uniformity of product quality within the technological range of manufacturing processes
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Influences on Intra-Lot Homogeneity and Lot-To-Lot Conformity – of Great Relevance for CTM
• small size experimental lots • poor experience in manufacturing process • "critical manufacturing variables"
drug substance modificationexcipients particle sizeprocess grinding
mixing granulation tablettingcoating...
but within spec's tolerated by GMP!
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Lack of Lot-To-Lot Conformity – Example: Marketed Batches
basket 120 rpm, 400 ml deionized water / ethanol
50 100 150 2000
20
40
60
80
100 lot UM 1 lot UM 2 lot UM 3
perc
enta
ge re
lease
d
time [min]
10 mg-nifedipine sugarcoated tabletssame manufacturing plant
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One Method Throughout the Entire Products Lifecycle
development: to find the best candidate to fit to medical/kinetic requirements
scale-up: to ascertain conformity of “glass and steel products”stability: to define shelf life
post approval changes: to prove similarity of pre- and post-change quality
in QC (quality control): for investigations on uniformity of product quality within the technological range ofmanufacturing processes
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Dissolution Testing Uses Conventional Methods
•dissolution-tests are conventionalpharmacopeial methods
•one dissolution-method is primarily suitable to characterize one formulation
•apparati do not reflect the physiology nor the anatomy of human gastrointestinal tract
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The Instruments Used for Dissolution Testing
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Devices for Dissolution Testing of Oral Dosage Forms
small differences of apparati of European, Japanese, and USprovenance still exist!
JP, Ph. Eur. basketpaddleflow-through cellchewing machine
USP basketpaddleflow-through cellreciprocating cylinder
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Preferably Closed Systems
• these are:• paddle
• basket
• (reciprocating cylinder)
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in-vitro-/ in-vivo-comparison
R1.2
35.8
19
74.5
R41.5
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principle: closed (stirred) system
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Basket Apparatus
EUROPEJAPAN
USA
Preferably Closed Systems
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example: the 40-mesh basket
wire dia. mesh size
Ph. Eur. USP 0.254 mm 0.381 mm0.01 Inch 0.015 Inch
EU industry standard
0.250 mm 0.375 mm
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Reciprocating Cylinder Apparatus
USA
Preferably Closed Systems
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Flow-Through Cell Apparatus
Open Systems
EUROPEJAPAN
USA
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Flow-Through Cell Apparatus22.6 mm-Cell
Open Systems
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Low Solubility Drug in Open System
Dissolution dependency from flow rateFlow-throughcell apparatus, 12 mm-cell, artif. gastric fluid USP0.5 % SLS
Total Medium Volume24-96 l
0 1 2 3 4 5 6 7 8 90
20
40
60
80
100
8 ml/min; 16 ml/min; 32 ml/min;
freig
eset
zter
Arz
neist
off [
% d
er D
ekla
ratio
n]
Zeit [h]
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Apparatus for the Determination of Drug Release
chewing chamber
operational volume up to 20 mL
horizontal piston
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The Need for Qualification and Validation
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Specifications: Dissolution
• US– general chapter <711> and <724>
» apparatus suitability tests» acceptance tables
– more than 600 monographs in USP 27» specifications
• Europe– general chapter
» no apparatus suitability test» no indiv. monographs on formulations
• Japan– general chapter
» no apparatus suitability test» no indiv. monographs on formulations
• FIP dissolution guideline– 1 st version, 1981 [Pharm. Ind. 43, 334-343]– 2nd version. 1997– special dosage forms 2003
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Qualification, Validation, and Calibrationof Dissolution Equipment
general test: "Apparatus Suitability Test" of USP
individual tests: part of method Validation
• use of sinkers• use of special sampling probes • automation
– additional valves– use of filters– cover of vessels (e.g.
Reciprocating Cylinder)...Valuable source of information
USP Chapter <1092>PF, 30(1), Jan-Feb 2004
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Major Source of Error: the Vessels
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2004: Vessels Still Handmade
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2004: Vessels Still Handmade cont’d
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2004: Vessels Still Handmade cont’d
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(Re-)Qualification: Dissolution Testing Apparati
Only supplier: USP via ditributors:Turkey: Dr. Murat Citiroglu www.ekinkimya.comGermany: www.phast.de
in PreparationFlow-through cell
Chlorpheniramine MaleateBio Dis III Apparatus
Prednisone, Salicylic AcidPaddle Apparatus
Prednisone, Salicylic Acid Basket Apparatus
USP CalibratorEquipment
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Basket Quality / USP Salicylic Acid Calibrators
Passed according to USP
0
10
20
30
40
50 rpm 100 rpm
EU-Standard EU Special USP-Specifications
mean (n=6), range
perc
enta
ge re
leas
ed
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Basket Quality / USP Prednisone Calibrators
Failed
0
20
40
60
80
50 rpm 100 rpm
EU-Standard Baskets EU-Special Baskets USP-Specifications
mean (n=6), range
perc
enta
ge re
lease
d
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Complex Qualification of Dissolution Testing Systems
1. dissolution bath2. sampling devices3. sample transfer4. analytical unit5. data evaluation
1
2
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5
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Identification Type of Analytical ProcedureTesting for Impurities
Assay
Quantitative Limits DissolutionMeasurement OnlyContent/Potency
AccuracyPrecision Repeatability Intermediate PrecisionSpecificity **Detection LimitQuant. LimitLinearityRange
-
+----
+
++ *+
- ***+++
-
--++---
+
++ *+--++
- signifies that this characteristic is not normally evaluated+ signifies that this characteristic is normally evaluated* in cases where reproducability has been performed, intermediate precision is not needed** the lack of specificity of one analytical procedure could be compensated by another supporting analytical procedure(s)*** may be needed in some cases
Analytical Method Validation
CPMP/ICH/381/95"Validation of Analytical Methods: Definitions and Terminology"
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Method Development – but How?
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Method Development
a stepwise procedure• superimposability • discriminatory power
+ test of robustness of dosage form
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Method Development
robustness of dosage form
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Experimental Variations
• apparatus • agitation • medium • sampling• temperature?
use of pharmacopeial monographs on formulations?
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Development of Suitable Methods
Situation in Europe: no monographs on formulationstherefore: development of individual methods necessaryproperties of dosage form
geometry monoparticulatemultiparticulate
technology conventionalmodified
properties of drug substance solubility
wettability
stability...
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Choice of a suitable Apparatus
BIO DIS III (recip. cylinder): Influence of mesh size on apparent dissolution rate
50 mg diclofenac enteric coated tablet
time [h]
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Pharmacopeial Monograph: Sampling
Generic IR Verapamil 80 mgQC according to USP monograph: one-point sampling after 30 min
[%]
time [min]
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Pharmacopeial Monograph: Sampling Cont´d
paddle 50 rpm, 900 ml artific. gastric fluid without e. pH 1.2
[%]
time [min]
Generic IR Verapamil 80 mg ………profiling
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How Similar is Similar?How to Compare Results?
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SUPAC was first guidance to define sameness of in vitro dissolution profiles (n=12)
Rt reference formulation dissolved at time t [%]Tt test formulation dissolved at time t [%]
with: CVt15min < 20 % and CVtlater < 10 %
profiles are considered to be similar, if 50 < f2 < 100
f2 = 50 log {[1+(1/n) Σ t=1n(Rt-Tt)2]-0,5*100}
taken over in EU in CPMP/QWP/1401/98
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SUPAC defines sameness of in vitro dissolution profiles (n=12)
0 15 30 45 60 75 90 105 1200
20
40
60
80
100
Referenz Test1: f2 = 63,5
Freis
etzu
ng [%
]
Zeit [min]0 15 30 45 60 75 90 105 120
0
20
40
60
80
100
Referenz Test2: f2 = 50,6
Freis
etzu
ng [%
]
Zeit [min]0 15 30 45 60 75 90 105 120
0
20
40
60
80
100
Referenz Test3: f2 = 43,3
Freis
etzu
ng [%
]
Zeit [min]
f2 = 63,5 f2 = 50,6 f2 = 43,3
profiles are considered to be similar, if 50 < f2 < 100
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SUPAC provides help for decisionson the base of BCS
BCS
class
solubility permeability requirements
for in vitro testing
IVIVC
1 high high multi-point profiles unlikely
2 low high multi-point profiles in
different media
possible under certain
circumstances
3 high low multi-point profiles unlikely
4 low low multi-point profiles in
different media
possible under certain
circumstances
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Method Development – a StepwiseApproach?
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Influence on In Vivo-Dissolution Stepwise Adjustment of In Vitro-Methods
1* consideration of known factors – pH-value– concentration of salts– temperature– addition of bile salts– addition of enzymes
2* optimisation of other factors– agitation– influence of food
3* use of analogous in vitro-/in vivo-data
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Influence of Solubility on Dissolution Rate
Nernst and Brunner:
A surface area t timeD coefficient of diffusion C concentrationV volume of solutionx thickness of diffusion layer
dCdt
=⋅⋅
−D Ax V
Cs Ct( )
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Consideration of pH-Values of Human GI-tract
e.g. pH dependent solubility of verapamil pKa 8.6
• solubility dissolution rate
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Influence of pH-value
e.g. 240 mg verapamil ER formulations
Diffusion controlledmultiple-units
Erosion controlled single-units
Swelling controlled single-units
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Influence of Solubility of API
Phenprocoumon• important factor qualityof purified water:according to USP pH 5-7
4 5 6 7 80
200
400
600
800
Lösl
ichk
eit [
mg/
l]
pH - Wert
0 2 4 6 8 10 120
2000
4000
6000
8000
10000
12000
Lösl
ichk
eit [
mg/
l]
pH - Wert
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In-vitro-Dissolution Testing / Influence of Solubility
pH-dependant solubility of phenprocoumon (pKa 5,12)...
...the cause for pH-dependantdissolution rate?
4 5 6 7 8pH-Wert
0
100
200
300
400
500
600
700
800
900
Lösli
chke
it [m
g/l]
0 10 20 30 40 50 600
20
40
60
80
100
Fre
iset
zung
[% d
. Dek
l.]
A Marcumar, Hoffmann-La Roche AG B Falithrom, SALUTAS FAHLBERG-LIST Pharma GmbH C Phenpro.-ratiopharm, ratiopharm GmbH & Co. D Marcoumar, EMRA-MED Arzneimittel GmbH E Marcoumar, Pharma Westen GmbH F Marcoumar, Opti-Arznei GmbH (LPC) G Marcoumar, kohl-pharma GmbH H Marcoumar, Eurim-Pharm Arzneimittel GmbH I Marcoumar, IPEXA-PHARMA (Repa) J Marcoumar, MTK-PHARMA Vertriebs GmbH K Marcoumar, Opti-Arznei GmbH L Marcoumar, Pharma Gerke GmbH
Zeit [min]
pH 6,8
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4 5 6 7 8pH-Wert
0
100
200
300
400
500
600
700
800
900
Lösli
chke
it [m
g/l]
pH 5,20 10 20 30 40 50 60
0
20
40
60
80
100
Fre
iset
zung
[% d
. Dek
l.]
A Marcumar, Hoffmann-La Roche AG B Falithrom, SALUTAS FAHLBERG-LIST Pharma GmbH C Phenpro.-ratiopharm, ratiopharm GmbH & Co. D Marcoumar, EMRA-MED Arzneimittel GmbH E Marcoumar, Pharma Westen GmbH F Marcoumar, Opti-Arznei GmbH (LPC) G Marcoumar, kohl-pharma GmbH H Marcoumar, Eurim-Pharm Arzneimittel GmbH I Marcoumar, IPEXA-PHARMA (Repa) J Marcoumar, MTK-PHARMA Vertriebs GmbH K Marcoumar, Opti-Arznei GmbH L Marcoumar, Pharma Gerke GmbH Anforderung nach USP XXII
Zeit [min]
In-vitro-Dissolution Testing / Influence of Solubility
pH-dependant solubility of phenprocoumon (pKa 5,12)...
...the cause for pH-dependantdissolution rate?
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Influence on In Vivo-Dissolution Stepwise Adjustment of In Vitro-Methods
1* consideration of known factors – pH-value– concentration of salts– temperature– addition of bile salts– addition of enzymes
2* optimisation of unknown factors– agitation– influence of food?
3* use of analogous in vitro-/in vivo-data
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Unknown Agitation The Proximal Gastrointestinal Tract
what is "physiological" agitation?
• paddle 50 rpm?• basket 100 rpm?
reasonable results also from dissolution tests at much higher revolution speed!
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Factor of influence agitation
manometric pressure inantral part of stomach highly variable
the "antral mill"a challenge for the
robustness of controlled release dosage forms
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in vivo-dissolutionbio-studies
paddle-apparatuspH 6.8, 150 rpm
Levy-Plots
time [h]
[%]
time [h]
[%]
dissolution time
In Vitro- / In Vivo-Correlation of Theophylline Extended-Release Dosage Forms: Fasted
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Summary and Conclusions:•dissolution testing is performed with well defined equipment throughout the parts of the world governed by ICH?
•the conventional equipment needs to be qualified according to the apparatus suitability test
•this is part of the general qualification of non-product relatedparts of a system like the UV-spectrophotometer used in chem. analysis
•in addition product related validation concerns sampling and transfer as well as chemical analysis
•in vivo verification is highly desirable for full “validation” of a method. It is a sound basis for setting specifications
...an Overview
