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1
Overview of Pharmaceutical Technology and Education
Areas:Industrialization
Pharmaceutical TechnologyManufacturing Science
Pharmaceutical EngineeringEducation
2
The Pipeline Problem
Despite the most sophisticated 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
5
Critical Path Initiative
Tools for increasing the number of drugs reaching the market
Tools for speeding drugs to market Modernize tools for product development Create new tools
7
Three Areas on the Critical Path (FDA)
Scenario 1: The Pharma Industry will Fragment into these three areas and Discovery
8
Critical Path
D ru gS u b s ta n c e
(A P I)s y n th e s is
P r o c es s D ev elo p m en tM an u f ac tu r e
lau n c hs u p p lies
P r o c es s
T r an s f er
E a r ly so lidst a t e c h e m ist r y
a n dp r e f o r m ula t io n
P r o c es s D es ig n , P r o c es sD ev elo p m en t
M an u f ac tu r eP h as e 3S u p p lies
M an u f ac tu r elau n c h
s u p p lies
I n it ia lT o x ic o lo g ic a l
S tu d ies
P r o c es s
T r an s f er
C o m p le teT o x ic o lo g ic a l S tu d ies
P h as e 1( F I M )
P h as e 2 P h as e 3
I N D U S T R I A L I Z A T I O N
S A F E T Y
M E D I C A L U T I L I T Y
T I M E (Y E A R S )
0 1 2 3 4 5 6 +
10
Amlodipine Industrialization
Initially the maleate salt was made Maleate salt had a biologically active degradation
product Switched to besylate salt late in development Amlodipine besylate (Norvasc is the most
successful heart drug ever developed)
11
Status of Pharmaceutical Technology
HISTORICAL DATA DERIVED FROMTRIAL-N-ERROR EXPERIMENTATION
HEURISTIC RULES“Rules of Thumb”
EMPIRICAL MODELS
MECHANISTICMODELS
Rules
Current Level of Knowledge
Desired Level of Knowledge
12
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
13
Critical Path Dimensions
Physical design
• Screening and Simplified Formulations► Toxicology► Clinical trials► Example – salt, disintegrant, lubricant
Characterization
• XRPD Specifications
• GMP Analytical methods
14
Critical Path Dimensions
Lack of trained personnel Few educational programs Very little fundamental research on
pharmaceutical materials
15
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
16
Educational Strategies
Pharmaceutical Engineering Molecules to Market educational strategy Allen Chao GMP Center Regulatory Programs
• National GMP Curriculum
19
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)
20
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
21
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
22
Status of Pharmaceutical Technology
HISTORICAL DATA DERIVED FROMTRIAL-N-ERROR EXPERIMENTATION
HEURISTIC RULES“Rules of Thumb”
EMPIRICAL MODELS
MECHANISTICMODELS
Rules
Current Level of Knowledge
Desired Level of Knowledge
23
Detector
Filter Whee
l
Optical filters
Sensors for Process Understanding and Control: Fixed-Wavelength (Filter) NIR Gauge
MM55
Beamspotsize
NDC-Infrared EngineeringIrwindale, CA
24
Heat and Mass Transfer Modeling of Drying: Two-Stage Drying In a UniGlatt
APAP Granulation at 60 °C
0 10 20 30Time (min)
25
50
75
100
125
150
175
NIR
KtoQQ
Linear Region (Evaporative Cooling)
)'exp('0 tkkQQQ
Exponential Region (Diffusion Limited)
P.L.D. Wildfong, A.-S. Samy, J. Corfa, G.E.Peck, and K.R. Morris J Pharm Sci 91 3 631–639 (2002).
25
Temperature vs Time for APAP Granulation: The Opportunity for Innovation
Critical moisture
Te
mp
era
ture
Mo
istu
re C
on
ten
t
40
60
80
100
120
140
160
180
Drying Time (min)
MM
55
Re
ad
ing
45
47
49
51
53
55
57
59
61
63
65
Te
mp
era
ture
(°C
)
T
MM55
0 30252015105
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).
26
Fast-Drying Trials of an Ibuprofen GranulationComparison of Average MM55 Values
Between Fast Drying and Traditional Drying
75
95
115
135
155
175
195
215
235
0 5 10 15 20 25
Time (min)
MM
55
Fast-DryingAverage MM55
Traditional-DryingAverage MM55
P.L.D. Wildfong, A.-S. Samy, J. Corfa, G.E.Peck, and K.R. Morris J Pharm Sci 91 3 631–639 (2002).
27
A National Center to Address these Issues
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
31
Science and Engineering Expertise at Purdue
Leading basic and applied science programs in • Engineering• Chemistry• Pharmacy• Materials science
Top Pharmacy School and Industrial Pharmacy Department
Leading Chemical Engineering Department Leading manufacturing program Top analytical chemistry program Ability and willingness to collaborate
32
Regulatory Expertise Purdue faculty participation in Pharmaceutical
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
33
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
34
Conclusion – StrategyNational Center for Pharmaceutical Technology
Establish a Center patterned after the National 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
35
Administration of National Center
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