Acceptance Criteria

Setting specifications
for dissolution testing

of modified-release
formulations
Dr. Alexander Pontius
EUFEPS, Revision of BE Requirements
for Modified Release Products - Dissolution Testing
Barcelona, February 23-24, 2011
Dr. Alexander Pontius EUFEBS, Dissolution Testing, Barcelona, 23-24 February 2011 Page 2
Contents
Introduction
Characterization of modified-release products
Prerequisites for dissolution testing
Selection of dissolution method parameters
Automated dissolution testing
Setting guideline-compliant and appropriate specifications
Conclusion
Official requirements
Physiology: Gastrointestinal tract
stomach: 1-5 h
small intestine: 2-4 h
colon: 7-70 h
[Figure taken from http://www.vitaltree.com]
[Principals of Biology II, Biol 102 (Vogt)]
Modified-release products
Complex pharmaceutical dosage forms with controlled release
mechanism (e.g. matrix-based or coating-based, osmotic pumps)
Increase of efficacy and safety:
reduced administration interval
reduced plasma peak-through and fluctuations
increase of compliance
Oral dosage forms: coated tablets or capsules, pellets, Multiple
Pellet Systems (MUPS), OROS (Osmotic-controlled Release Oral
delivery System) etc.
Others: transdermal patches, intrauterine device etc.
OROS technology
Once-daily formulation
Constant drug release over 24 hours
Pharmacological reliability
Improved tolerability and compliance
osmotic process of an Adalat
GITS
Aim of a suitable dissolution method
Robust dissolution method generating reliable data!
Discriminatory but no over-discriminatory potency
Quality indication concerning
influence on stability
inadequate manufacturing process
change in composition
In vivo predictive
Prerequisites for dissolution method
development
Gathering information on new drug substance (solubility data,
stability effects, polymorphism, particle sizes, if existing intrinsic
dissolution rates)
Formulation type and composition (tablets, capsules, pellets,
suspensions, suppositories etc.)
Drug release characteristics: immediate-release, modified-release,
delayed-release
Solubility data at different pH values at 37C (32C) covering
physiological range (pH 1-2 to pH 7 or pH 8)
development
Reflecting already available in vivo data (bioavailability and clinical
data, t
max
value, prodrug characteristics etc.)
Establish a validated analytical method (UV spectroscopy or HPLC)
The formulation determines drug release with regard to time and
place within gastro-intestinal tract.
Significant for selection of medium and specification!
development
Apparatus selection
Aqueous media (biorelevant media?)
Surfactant concentration
Agitation speed (for MR: may reflect the mechanical stress exposed
to the formulation in the GIT)
Temperature (route/site of administration)
Multi point determination (profiles!) recommended in development
stage of a new product
Use of automated techniques (e.g. for MR formulations)
Apparatus selection
Paddle type (USP II) more advantageous than Basket type (USP I):
Providing generally robust and reliable data and enable adequate
product characterization
Well-established equipments: simple, experienced, standardized
Basket: air bubbles may disturb the test over the testing time and
ingredients of he matrix or coatings may clog the mesh screen
Automation easier to realize
Using sinkers is possible
Using sinkers for USP II apparatus
Mandatory for special dosage forms (capsules, OROS, pessaries)
Sinkers according to Pharm. Jap. recommended; other types can be
used if validated (e.g. different types of helix sinkers)
Sinkers prevent the interference of the product with the vessel wall
Positioning of the formulation at the bottom centre of the vessel
Automatisation easier to realize
Fully automated dissolution system: Robodis
in particular suitable for MR products

Completely automated dissolution process including tablet

placement, medium preparation and cleaning
Online monitoring of rotation speed, temperature and sampling time
High sample throughput
2 dissolution tests can be performed simultaneously!
n=12 tablets per run and up to 20 runs per start (up to 2 weeks)
Monitoring of dissolution profiles from 1 h up to 24 h
Standardization of analytical technique (e.g. filtration (10 m),
sampling procedure, cleaning)
HPLC or UV quantification
Equipped with 12 online cameras for time lapse videos
Automatisation mandatory regarding:

high through-put of samples
standardized and homogenous analytical technique
24 hours analyses
saving human resources
no external technological capacities (mostly no sourcing possible)
Automation leads to an increase of efficiency and
precision and is time saving !
Media selection
Use of water unfavorable as pH and composition can vary
Avoid strongly alkaline media and the use of very high amounts of
surfactant (> 1 %)
Surfactant: solubilizer, wetting agent (SDS, polysorbates, bile salts)
FaSSIF: Fasted State Simulated Intestinal Fluid
FeSSIF: Fed State Simulated Intestinal Fluid
(Phosphate buffer pH 8.0)
Phosphate buffer pH 6.8
Modified Release Acetate buffer pH 4.5 Immediate Release
(0.01 M HCl pH 2)
0.1 M HCl pH 1
not for routine
solubility [mg/900 mL]
after 24 h
0.1 M HCl 0 31
pH ~1 0.1 52
0.2 171
acetate buffer 0 23
pH 4.5 0.1 107
0.2 333
phosphate buffer 0 22
pH 6.8 0.1 153
0.2 365
medium SDS conc. [%]
Media selection
Providing sink conditions:
are defined as the volume of medium at least greater than three
times that is required to form a saturated solution of the drug
substance
Monitoring dissolution behavior out of the drug product and not
solubility characteristics of drug substance
Dissolution medium should reflect physiological conditions at
lower parts of the GIT
medium of first choice
example: 5 mg of a modified
release formulation
0,00
20,00
40,00
60,00
80,00
100,00
120,00
0 100 200 300 400 500 600
time [ min ]
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Dissolution characteristics or even critical release kinetics can be
detected, in particular visually
Supportive information available in case of official requests
Formulation characteristics are better reflected
by dissolution profiles
Recording dissolution profiles
single value curves, n=6
lag time
proof of no dose dumping
proof of complete
drug release
profile shape
At least at the 3 specified time points, better more at early stages of
drug product development
Until quantitative drug release is reached
0,00
20,00
40,00
60,00
80,00
100,00
120,00
0 5 10 15 20
time [ h ]
d
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4 h
(0-20 %)
12 h
(50-70 %)
24 h
(> 85 %)
4 h
(0-20 %)
12 h
(50-70 %)
24 h
(> 85 %)
Recording dissolution profiles
single value curves
Setting specifications for MR formulations
Prolonged-release dosage form (EP)
Extended-release dosage form (USP, JP)
According to level testing based on pharmacopoeias:
level testing (harmonized)
Ph. Eur. 7th edition (7.0):
MR formulations are specified (at least) by 3 time points:
1
st
time point: approx. 20 to 30 % of API is dissolved
range 10 %* to be defined
proof of no dose dumping
2
nd
time point: approx. 50 % of API is dissolved
range 10 %* to be defined
description of profile
3
rd
time point: generally more than 80 % of API is dissolved
lower range to be defined
proof of complete drug release
*Note: The range of 10% is not being specified in the pharmacopeia but
taken from the EMEA guideline Note for Guidance on the Quality of
Modified Release Products, A: Oral Dosage Forms,
B: Transdermal Dosage Forms, 1999
ICH Q6A: Decision Tree #7: Setting Acceptance Criteria for Drug
Product Dissolution - Part 3: Extended Release Formulations
ICH Q6A: Decision Tree #7: Setting Acceptance Criteria for Drug
Product Dissolution - Part 3: Extended Release Formulations
ranges > 10% are accepted if: IVIVC (in vitro in vivo
correlation) is established => limits of IVIVC can be applied
> 20% will be accepted if verified by clinical data (e.g. obtained
from a bioavailability study)
comparable plasma profiles
of different MR products
data obtained from a bioavailability study
Example: MR formulation
specifications: 3 h L
low
: 10 % L
up
: 30 %
5 h L
low
: 40 % L
up
: 60 %
17 h L
low
: 85 % L
up
: -
0
20
40
60
80
100
120
0 120 240 360 480 600 720 840 960 1080 1200 1320 1440
time [min]
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3 h L
low
: 10 % L
up
: 30 %
5 h L
low
: 40 % L
up
: 60 %
17 h L
low
: 85 % L
up
: -
0
20
40
60
80
100
120
0 120 240 360 480 600 720 840 960 1080 1200 1320 1440
time [min]
d
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spec. time
point
acceptance
criteria [%]
level 1: 6 samples
L
1
average 10-30
10-30
level 2: 12 samples
L
2
average 10-30
0-40
level 3: 24 samples
L
3
average 10-30
0-40
0-50
level 1: 6 samples
L
1
average 40-60
40-60
level 2: 12 samples
L
2
average 40-60
30-70
level 3: 24 samples
L
3
average 40-60
30-70
20-80
level 1: 6 samples
L
1
average 85
85
level 2: 12 samples
L
2
average 85
75
level 3: 24 samples
L
3
average 85
75
65
3 h
5 h
17 h
and not more than 2 single values min-max
and single values min
22 single values min
and not more than 2 single values min
and single values min
and not more than 2 single values min-max
and single values min-max
22 single values min-max
dissolution testing - requirments
22 single values min-max
Stability effects of a new formulation within 3 month storage
only dissolution is affected (assay and degradation in spec)
clear influence of temperature and humidity
in vivo relevance very likely
Evaluating stability effects on the formulation
0
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time [ h ]
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start
1 month
3 months
accelerated test
conditions: 40C/75 rh
HDPE bottles
mean value curves
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60
80
100
120
0 5 10 15 20
time [ h ]
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Stability effects of a new formulation within 3 month storage
selecting a suitable packing material based on dissolution tests
alu/alu blister provide an appropriate protection of the product
Evaluating stability effects on the formulation
start
1 month
3 months
accelerated test
conditions: 40C/75 rh
alu/alu blister
mean value curves
0
20
40
60
80
100
120
0 5 10 15 20
time [ h ]
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Thickness of semi-permeable membrane of an OROS
clear influence of manufacturing process on dissolution behavior
setting appropriate specification ranges to qualify the product
in vivo relevance
Evaluating manufacturing process
increase of
coating
mean value curves
Conclusion
Relevance of dissolution testing for MR products:
in terms of formulation development and quality control
to monitor batch to batch consistency
for scale-up and post-approval changes (SUPAC)
Standardized methods applicable in combination with automated
techniques cost/time saving
In vivo performance may be predicted
Dissolution testing for MR products is a critical regulatory aspect for
submission be well prepared, in particular in terms of
setting the specifications
Official regulations
Pharmacopeias:
USP 33 (NF 28) chapters <711>, <1092>, <1088>, <1225>
Ph. Jap. 15
th
edition
Ph. Eur. 7
th
edition (7.0)
Guidance for Industry (edited by FDA/USA):
Dissolution Testing of Immediate Release Solid Oral Dosage Forms,
1997
Extended-Release Oral Dosage Forms: Development, Evaluation
and Application of In Vitro/In Vivo Correlations, 1997
Waiver of In Vivo Bioavailability and Bioequivalence Studies for
Immediate-Release Solid Oral Dosage Forms based on a
Biopharmaceutics Classification System, 2000
Bioavailability and Bioequivalence, Studies for Orally Administered
Drug Products General Considerations, 2002
SUPAC-IR: Immediate Release Solid Oral Dosage Forms, Scale-up
and Postapproval Changes: Chemistry, Manufacturing, and
Controls, In Vitro Dissolution Testing, and In Vivo Bioequivalence
Documentation, 1995
SUPAC-MR: Modified Release Solid Oral Dosage Forms, Scale-up
and Postapproval Changes: Chemistry, Manufacturing, and
Controls; In Vitro Dissolution Testing and In Vivo Bioequivalence
Documentation, 1997
ICH, guidelines harmonized among EU, USA and Japan:
ICH Q6A: Specifications: Test Procedures And Acceptance Criteria
For New Drug Substances and New Drug Products: Chemical
Substances
Note for Guidance (edited by EMEA/Europe):
Note for Guidance on the Investigation of Bioavailability and
Bioequivalence, 2001
Note for Guidance on the Quality of Modified Release Products, A:
Oral Dosage Forms; B: Transdermal Dosage Forms, 1999
FIP Guidelines (edited by FIP/France):
FIP: Guidelines for Dissolution Testing of Solid Oral Dosage
Products, 1997
FIP/AAPS Guideline for Dissolution/In Vitro Release Testing of
Novel/Special Dosage Forms, 2003; updated 2011
In addition to JP following documents need to be considered:
Guidelines for Bioequivalence Studies of Generic Products
Guidelines for Bioequivalence Studies for Different Strength of Oral
Solid Dosage Forms
Guidelines for Bioequivalence Studies for Formulation Changes of
Oral Solid Dosage Forms
Database
FDA homepage provides information about dissolution methods of
approved drug products:
Thank you for your attention!
Apparatus
selection
Franz Cell Diffusion System Topicals - Semisolids
Modified Flow Through Cell Implants
Modified Flow Through Cell Microparticulate Formulations
Paddle, modified Basket or Dual Chamber Flow
Through Cell
Suppositories
Aerodynamic Particle Size Distribution (ASPD) Aerosols
Paddle Over Disk Transdermals - Patches
Special apparatus (Ph.Eur.) Chewing Gum
Flow Through Cell (powder/granule sample cell) Powders and Granules
Basket, Paddle or Reciprocating Cylinder with glass
beads
Chewable Tablets
Basket and a disintegration method Dissolving films/Wafers
Paddle and a disintegration method Oral disintegrating Tablets
Paddle Oral Suspensions
Basket, Paddle, Reciprocating Cylinder or Flow
Through Cell
Solid Oral Dosage Forms
(conventional)
Apparatus/Method Drug product
recommended by FIP, 2010/2011
Dissolution/In Vitro Release Testing of Novel/Special Dosage Forms

Acceptance Criteria

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Acceptance Criteria

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Setting specifications

for dissolution testing

in particular suitable for MR products

Completely automated dissolution process including tablet

Automatisation mandatory regarding:

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