Beruflich Dokumente
Kultur Dokumente
Mitä on tuotekehitys?
A definition
Product development?
Tuotekehityksen vaiheet Drug development?
Technical development?
Luennot helmikuu 2006 Helsingin Pharmaceutical development?
Yliopisto, Farmasian tiedekunta, Drug delivery technology?
teknologia, lääkevalmisteblokki.
FaT Marja Ritala Chemistry and manufacturing?
M. Ritala 2006
Tuotekehityksen vaiheet
Contents (2)
Biostudies
Trends in the Pharmaceutical
New chemical entities Industry
Life cycle management of products
Generic drug substances and products
Marketing authorisation applications
Case studies of formulation and life cycle
management
Skilled people needed
Pharmaceutical development in the future
M. Ritala 2006
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DISCOVERY PRE-CLINICAL
DISCOVERY PRE-CLINICAL
PHASE I P II PHASE III PHASE IV
PHASE I P II PHASE III PHASE IV
LIFE CYCLE
Pharmceutical development
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Main Processes in
Pharmaceutical Development
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Preformulation
Solubility (aqueous, pKa, log P, log D)
Molecular optimization (salt, hydrate, solvate, new
Formulation
analogs,…)
Crystal Engineering (polymorph, habit, size, surface
characteristics…)
Crystal structure determination
Biopharmaceutical classification (BCS) (solubility,
dissolution, absorption)
Drug stability evaluation (physical, chemical, solution
phase, solid phase, …)
Compatibility analyses (drug substance, excipient,
packaging materials)
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Characteristics of a sound
Formulation innovation
Composition + process = formulation
Product design
Formulation determines how the drug is delivered Underpinning science must be sound
A good composition Uniqueness
is simple, but innovativeness may be needed it solves a problem
utilises standard compendial excipients
can be patented
easy to manufacture
good stability creates cost advantage
facilitates straightforward analytics can be used as an asset when
protects the product against generic competition
forming exclusive partnerships
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Analytical development
HPLC, TLC, IR, NIR, UV, GC, MS, CE... are the
methods to analyse
Assay of drug substance Specifications and quality
Degradation profile
Identification
Content uniformity
Dissolution
Organic volatile impurities
The methods are validated in regard to
accuracy, sensitivity, robustness, selectivity...
according to ICH
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Choise of manufacture
Make, byu or outsource?
Choice of manufacture Europe, U.S., China or India?
Investment on new buildings, new
machinery?
Calculations on volumes and costs
batch sizes?
cost of goods?
sourcing strategy?
M. Ritala 2006
Manufacturing process
Process development/Deliverables
development in different scales
•Screening studies for •Update of CCPs
identification of critical
control parameters
• Optimisation study Quality targets and metrics specified for the product and
(CCPs) • Update of FMEA manufacturing process
• FMEA • Use of database
Process Limits set for critical process control parameters
Risk analyses (FMEA, statistical predictions)
• Use of database •Quality team meetings Validation
•Quality team meetings &
Laboratory Pre-pilot Pilot Production Commercial Process database system established to be used during
scale scale scale scale manufacture commercial manufacture
Finalised master formula
Product Product Product Product Product Fine tuning of product specifications
eval. mtg eval. mtg eval. mtg eval. mtg eval. mtg
1 2 3 4 5
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Shelf-life of a product
Shelf-life is the period during which drug product conforms to a
given set of specifications
Based on the results of stability studies
Proposed and justified in regulatory documentation
Biostudies
12 month data from three batches required at the time of
submission (NCE’s)
6 month data from two batches required for generic products
Storage conditions to be studied:
25˚C, 60% RH
40˚C, 75% RH
30˚C, 60% RH
Usually enough data gathered at the time of approval for a
shelf-life of 24 months
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dosage form selection and design
0.25 mg/kg/day
Concentration, µg/ml
selection of strengths 1
in vivo-in vitro correlation ADME: 0,1
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DISCOVERY PRE-CLINICAL
Pharmceutical development
DRUG SUBSTANCE
INDUSTRI- PRODUCT
MFR PROCESS DEVELOPMENT
ALISATION MAINTENANCE
ANALYTICAL DEVELOPMENT
PRIMARY FOLLOW-
STABILITY
STABILITY UP STAB.
M. Ritala 2006
how long from discovery to market? High quality basic and biomedical research
Sufficient R&D funding
what does it cost? Who is financing it?
Tuotekehityksen vaiheet
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Marketing authorisation
applications
Marketing authorisation FDA: NDA and ANDA
applications EU: centralised and mutual regocnition
procedures
JAPAN
Applications are written in CTD-formats
M. Ritala 2006
Maize starch
Gelatin
exchengeable, because of different Magnesium stearate Citric acid
Stability 3 years Mannitol
dosage form
Peppermint aroma
Stability 2y, after
opening the foil:
6 months
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Pharmaceutical development
Skilled people are needed... relies heavily
on individual expertise!
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responsibilities Feedback
do not spend too much time trying to find concensus
Co-operation kill a few comittees and meetings
Control and reporting
Commitment escape unnecessary regulations
Empowerment open, honest, professionel relationship with the authorities
Communication do not overdevelop
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phase I and II a can give invaluable information
use miniaturisation and micro dosing where ever you can
in the future
maximise the molecule
do life cycle management early enough
remember the dosage forms patiens –consumers- like:
-transdermal, eye, oromucosal
use the opportunities to develop polymorphs, enantiomers
and controlled release formulations
watch the NIH syndrome!
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Improved macromolecules
sustained release injectable
Global strategies
Virtually integrated companies
Increasing R&D expenses and timelines
poor productivity?
true value creation?
Expanding number of technologies
challenging the traditional approaches
Increasing need to deliver return to
investors,
partners and
customers
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