dissolution testing in drug product development
TRANSCRIPT
Avivia
DISSOLUTION TESTING IN DRUG PRODUCT
DEVELOPMENT
Menno Wiltink 16/17-02-2016
CONTENT
Avivia company
Dissolution Platform
USP IV
USP III BioDis
Case studies
Excipient characterization
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AVIVIA
Bridge between idea and market
Project Management
Consultancy
IP Strategies
Contract Research and Development
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EXPERIENCE
20 years of experience in field of
Innovator drugs
Generics
Excipients
Veterinary
Small molecules
Solids, liquids
Oral and parenteral medications
MR/CR, DR, IR, ODT, sub-lingual, depot, etc.
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CRO SERVICES
Laboratory facilities
Pharmaceutical R&D
Analytical R&D
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DRUG PRODUCT DEVELOPMENT
Formulation and Process Development,
Improvement and Troubleshooting
Technical Feasibility and Concept Development
Patent evaluation
API assessment
Formulation selection and development
Process implementation and optimization
Scale-up and manufacturing
Clinical studies
Close cooperation with analytical department
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ANALTICAL RESEARCH
Non-GMP Highly flexible, fast and efficient
Cooperative direct support API and Formulation development
Stability indicating method development Troubleshooting, optimization and transfer
Excipient characterization platform Physico-chemical characterization, QbD support
Dissolution platform Bio-relevant, Preclinical Evaluation and Equivalence selection
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DISSOLUTION PLATFORM
Experience
Apparatus I, II, III, IV
Release vs R&D methods
GENERAL SCHEME IN VIVO
Drug
ProductFree API
Dissolved
API
Absorbed
Drug
Release Dissolution Absorption
In vivo dissolution
Can be simulated in vitro
J.M.Cardot 2010
BIO-RELEVANT DISSOLUTION METHODS
Translate knowledge into predictive dissolution methods
API
Process
Excipients
(Biorelevant) Dissolution Methods
PK information / Pilot Study / DesignGIT
Formulation
Clinical Study
OPTIMAL EXCHANGE OF INFORMATION
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Input for optimization API, excipients,
formulation, processes, manufacturing
OBSERVATIONS
APPARATUS 4 FLOW THROUGH CELL
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USP4 FLOW CELL TYPES
For tablets, powders and granulates, implants,
suppositories and soft gelatin capsules
APPARATUS 3 BIODIS
APPARATUS 3 BIODIS
DISSOLUTION METHOD VARIABLES
Apparatus 3 BioDis
• Volume: 100/300 mL up to 700/2100 mL
• Sample points per rows
• Dipping speed: 5 – 30 (60) dips per minute
• pH/dip/time step gradient
• mesh screens and material
DISSOLUTION APPARATUS PROPERTIES
Apparatus 3 BioDis
• MR, CR, ER
• pH gradient, up to six pH per run
• Various dipping rates per run
• “Turbulent” flow increase erosion rate
• Sink conditions
• Hydrogel matrix tablets
• Mechanical stability
• comparable profiles to apparatus 2 possible
• avoiding cone formation
APPARATUS 3 BIODIS
Cons
• Not for IR or fast eroding products
• Variable movement product (size, shape, stickiness)
• Variable flow (clogging screens, viscosity)
• Sediment on the bottom
• Limited simulation of the physiological conditions
• Sink conditions?
• Requires extensive method development
• Low throughput
• Labor intensive, half automated
• Not the preferred QC tool
Development 24 hours CR tablet
Approach: Fast, Target and Slow formulation
Initial method: Basket USP I
CASE 1 DEVELOPMENT GENERIC CONTROLLED RELEASE
Development of a multiple particulate dosage form
FDA/EMA recommended dissolution method for Delayed Release;
Gastric Challenge:
2 hours pH 1.0 0.1M HCl followed by 1 hour pH 6.8 phosphate buffer
CASE 2 DELAYED RELEASE AND BIODIS
TYPICAL RELEASE TEST
0,0
10,0
20,0
30,0
40,0
50,0
60,0
70,0
80,0
90,0
100,0
0 20 40 60 80 100 120 140 160 180 200
Dis
solv
ed a
mo
un
t (%
)
Sampling timepoints (hrs)
dissolution (n=6) 2hrs in 0.1M HCl pH1 and after full media-change 1hr in
phosphate buffer pH6.8
Gastric challenge pH 1.0 pH 6.8
CASE 3 MODIFIED RELEASE AND BIODIS :
• Generic CR polymer matrix tablet, 24 hours release
• Dissolution tests performed apparatus I Basket and II Paddle :
• FDA method
• pH
• Media compositions
• Rpm
• Combinations
• Disintegration tests
All tests: f2 > 58 Bioequivalency failed…………
EXCIPIENT CHARACTERIZATION PLATFORM
Stability issues
Incompatibility
Supplier variability
Batch tot batch variation
Physico chemical characterization
MW, PSD, surface area, water sorption, composition,
homogeneity, etc.
Reactive impurities
Compatibility studies
DEFORMULATION
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Avivia: Bridge between idea and market
Technical Feasibility and Concept Development
Formulation and Process Development, Improvement and Troubleshooting
Patent evaluation and strategy
Project management
Predictive Dissolution Testing, Preclinical Evaluation and Equivalence selection
Analytical Research and Support
QbD Excipient Characterization and Troubleshooting
Novio Tech Campus NijmegenTransistorweg 5 6534 AT Nijmegen
Netherlands
www.avivia.nl
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Thank you
For more information, please contact:
Menno Wiltink
Avivia
Transistorweg 5
6534 AT Nijmegen
The Netherlands
E-mail: [email protected]
www.avivia.nl