Transcript Gibb`s Free Energy - Purdue University

Overview of Pharmaceutical
Technology and Education
Areas:
Industrialization
Pharmaceutical Technology
Manufacturing Science
Pharmaceutical Engineering
Education
1
The Pipeline Problem
 Despite the most sophisticated
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drug discovery methods and
the largest expenditures ever,
fewer new drugs are reaching
the market
Last year only 20 (not 50) New
Molecular Entities reached the
market
This is termed “the pipeline
problem”
New technologies for bringing
Molecules to Market are
needed
Pharmaceutical Technology will
achieve this goal
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The Pipeline Problem
3
Critical Path Concepts
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Critical Path Initiative
 Tools for increasing the number of drugs reaching
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the market
Tools for speeding drugs to market
Modernize tools for product development
Create new tools
5
Critical Path
Critical Path Research and Translational Research are related
6
Three Areas on the Critical Path
(FDA)
Scenario 1: The Pharma Industry will Fragment into these three areas and Discovery
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INDUSTRIALIZATION
Drug
Substance
(API)
synthesis
Process
Process Development
Early solid
state chemistry
and
preformulation
Critical
Path
Transfer
Manufacture
Phase 3
Supplies
Process Design, Process
Development
Process
Transfer
Manufacture
launch
supplies
Manufacture
launch
supplies
SAFETY
Initial
Toxicological
Studies
CompleteToxicological Studies
MEDICAL UTILITY
Phase 1
(FIM)
Phase 3
Phase 2
TIME (YEARS)
0
1
2
3
4
5
6+8
The Amlodipine Story
H 3C
H
N
H3CO
CH3
OCH3
O
O
NO2
Nifedipine
H3C
H
N
O
O
H3CO
O
Cl
NH2
CH3
O
Amlodipine
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Amlodipine Industrialization
 Initially the maleate salt was made
 Maleate salt had a biologically active degradation
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product
Switched to besylate salt late in development
Amlodipine besylate (Norvasc is the most
successful heart drug ever developed)
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Status of Pharmaceutical
Technology
Rules
MECHANISTIC
MODELS
Desired Level
of Knowledge
EMPIRICAL
MODELS
Current Level
of Knowledge
HEURISTIC RULES
“Rules of Thumb”
HISTORICAL DATA DERIVED FROM
TRIAL-N-ERROR EXPERIMENTATION
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Tools and Strategies
 Approaches to dealing with problem compounds
 Product design concept and quality by design
 Predictive capabilities
• Solubility
• Bioavailability
• Stability
 FDA – predictive capabilities could save $100
million per drug
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Critical Path Dimensions
 Physical design
• Screening and Simplified Formulations
Toxicology
► Clinical trials
► Example – salt, disintegrant, lubricant
Characterization
• XRPD
Specifications
• GMP Analytical methods
►
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Critical Path Dimensions
 Lack of trained personnel
 Few educational programs
 Very little fundamental research on
pharmaceutical materials
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Key Concepts
•
Improve quality
1. Know what you have
2. Make the same thing every time (within the
design space)
•
Reduce costs
•
Cost of goods sold is up to $80 billion dollars
•
A 20% reduction leaves $16 billion to discover
new drugs or reduce costs
15
Educational Strategies
 Pharmaceutical Engineering
 Molecules to Market educational strategy
 Allen Chao GMP Center
 Regulatory Programs
• National GMP Curriculum
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Outcomes
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More drugs on market
Reduced time to market
Improved quality
Reduced costs of drugs
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Extras
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Dimensions of the Pipeline Problem
 Patient deaths and unfavorable
outcomes because of delays in
marketing new drugs
 At least $100,000,000 per drug under
development ($2-4 billion per year)
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Pipeline Problem - Related Issues
 Higher risk manufacturing processes
(variability is two sigma not six sigma)
 Reduced flexibility in manufacturing
 Major manufacturing problems and
issues
• Disastrous CMC inspections by the
FDA
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Pipeline Problem - Related Issues
 Significance /Insignificance of Validation
• Is validation just a well rehearsed
demonstration lacking any significant
value?
 Difficulty in scaling up
• Numerous bridging bioequivalence
studies
 Insufficient size and personnel in existing
centers and programs to address these
issues
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Status of Pharmaceutical Technology
Rules
MECHANISTIC
MODELS
Desired Level
of Knowledge
EMPIRICAL
MODELS
Current Level
of Knowledge
HEURISTIC RULES
“Rules of Thumb”
HISTORICAL DATA DERIVED FROM
TRIAL-N-ERROR EXPERIMENTATION
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Sensors for Process Understanding and Control:
Fixed-Wavelength (Filter) NIR Gauge
Detector
Filter
Wheel
Beam
spot
size
Optical filters
NDC-Infrared Engineering
Irwindale, CA
MM55
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Heat and Mass Transfer Modeling of
Drying: Two-Stage Drying In a UniGlatt
APAP Granulation at 60 °C
175
150
NIR
125
Exponential Region
(Diffusion Limited)
100
Linear Region
(Evaporative Cooling)
Q  Q  Q0' k  exp( k ' t )
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Q  Qo  Kt
50
25
0
10
Time (min)
20
30
P.L.D. Wildfong, A.-S. Samy, J. Corfa, G.E.Peck, and K.R. Morris J Pharm Sci 91 3 631–639 (2002).
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Temperature vs Time for APAP Granulation: The
Opportunity for Innovation
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61
Critical
moisture
140
MM55 Reading
63
59
57
T
120
55
100
Temperature (°C)
160
Temperature
Moisture Content
180
53
51
80
MM55
49
60
47
40
45
0
5
10
15
20
25
30
Drying Time (min)
K.R. Morris, S.L. Nail, G.E. Peck, S.R. Byrn, U.J. Griesser, J.G. Stowell,
S.-J. Hwang, K. Park Pharm Sci Tech Today 1 6 235–245 (1998).
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Fast-Drying Trials of an Ibuprofen Granulation
Comparison of Average MM55 Values
Between Fast Drying and Traditional Drying
235
215
Fast-Drying
Average MM55
MM55
195
Traditional-Drying
Average MM55
175
155
135
115
95
75
0
5
10
15
20
25
Time (min)
P.L.D. Wildfong, A.-S. Samy, J. Corfa, G.E.Peck, and K.R. Morris J Pharm Sci 91 3 631–639 (2002).
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A National Center to Address these Issues
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Materials science – fundamental understanding
Pharmaceutical engineering
Process understanding and control
Design for six sigma
Informatics
Industrialization
• Physical design
• Characterization
• Scale-up & small scale production
• Specifications
Build on success of current centers/consortia
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National Center
Current Consortia
& Programs
New Programs
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Current
Consortia
& Programs
CAMP
NSF
CPPR
PTCC
21st
Century
GMP
Regulatory
Education
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New
Programs
ERC
Mater.
Sci.
Informatics
Anal.
Chem.
Six
Sigma
Prediction
Pharm.
Engr.
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Science and Engineering Expertise
at Purdue
 Leading basic and applied science programs in
• Engineering
• Chemistry
• Pharmacy
• Materials science
 Top Pharmacy School and Industrial Pharmacy
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Department
Leading Chemical Engineering Department
Leading manufacturing program
Top analytical chemistry program
Ability and willingness to collaborate
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Regulatory Expertise
 Purdue faculty participation in Pharmaceutical
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Sciences Advisory Committee of the FDA
• Garnet Peck
• Steve Byrn (former Chair)
• Ken Morris
Training FDA “Patriot Team” in process analytical
technology (PAT), receiving international kudos
Teaching courses to FDA and the only academics
advising major CMC revisions (Ken Morris)
Purdue IPPH faculty are members of United
States Pharmacopoeia Committee of Experts
(Byrn and Peck)
Harvey Wiley a Purdue Professor was the first
commissioner of the FDA
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Multi-university Programs
 Collaborator via CAMP – MIT
 Collaborator via PTCC – IIT
 Collaborators via NSF CPPR – Univ.
of Puerto Rico, U. Conn., Minnesota,
Rutgers
 Collaborators via ERC and National
Center (Proposed) - Rutgers
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Conclusion – Strategy
National Center for Pharmaceutical Technology
 Establish a Center patterned after the National
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Center for Food Safety and Technology and/or
Argonne Laboratory
Establish facilities and infrastructure
Obtain programmatic support from FDA (for FDA
employees) and a consortium of companies
Investigate scientific issues of mutual interest to
the FDA, companies and academia
Establish educational programs
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Administration of National
Center
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Not for profit
Administered by Purdue
MOU with several universities in process
Run by full time professional project manager
Board integrated by academics, industrialists,
government rep.
Funding in the $20 M per year range
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Extra
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Hierarchy of Projects
1.
2.
3.
4.
5.
Materials Science
PAT – Process understanding
Informatics
Prediction
Low Variability – 6 Sigma
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