ray scherzer fda acps october 26, 2005 breaking with tradition: the manufacturing challenges ahead!
TRANSCRIPT
Ray Scherzer
FDA ACPSOctober 26, 2005
Breaking with Tradition:
The Manufacturing Challenges Ahead!
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Setting the stage
• The Traditional Pharma Business Model … changes underway
• Our current technology
• The challenge ahead!
• A vision of the future
• What can you do??
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The 70s, 80s and 90s … the traditional model
Double Digit G
rowth
+
+
Profits, $$$$$
Challenging Regulators
4
Industry pressures today
Pharma Industry
Regulatory Scrutiny
Attrition
Payer resistance
PoliticsPricing
Generics&Re-importation
5
Fundamental change in regulatory framework
Past
• Avoid change
• Quality “tested in”
• Regulatory fear
• Silo organisations
• Empirical science
Future Opportunities
• Innovation
• Good science
• Collaboration
• Efficiency
• Quality by design
• Real time release
Regula
tory
hurdle
sR
egulatory
hurdles
PATCGMPsCritical
path
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Regulatory changes
• Major shift by FDA
• Dedicated Pharma inspectorate
• Approvals and inspections focused on scientific and engineering principles
• Hiring physicists, chem engineers, C&I engineers, statisticians ... Plus!
• Empirical methods are last resort
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Significant impacts
• Higher scrutiny of existing products
• Higher expectations for new products
“If you can’t explain how your manufacturing processes work in the first 25 pages of your submission … the approval process will become much more difficult!”
Moheb Nasr, FDA, Director Office of New Drug Chemistry …
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The changing pharma business model
DiscoverDevelop
TestLaunch
Market
80s: 7 -8 yrs
90s: 8 -10 yrs
00s: 10+? yrs
$500m
$800m
$1,700m
Launch costsLaunch time Avg. ROI, %
9 -10
5
> 10
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Today’s business is much different than yesterdays!
The Industry will and is changing!!
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CurrentTechnology
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DESCRIPTIVE KNOWLEDGE
CORRELATIVE KNOWLEDGE
CAUSAL KNOWLEDGE
MECHANISTICKNOWLEDGE
1st Principles
Control and release against process signature
Establish processEstablish processoutlineoutline
Prediction of performance (in-vivo)
Correlate process inputs and outputs
Relate critical process variables to quality attributes of finished product
2
1
3
5
4
Extent of knowledge
Manufacturing process knowledge
Industry
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V Blenders: lab and pilot plant scale
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Commercial scale
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“We’ve got a few problems going from lab scale to full scale commercial”
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The Challenge Ahead!!
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DESCRIPTIVE KNOWLEDGE
CORRELATIVE KNOWLEDGE
CAUSAL KNOWLEDGE
MECHANISTICKNOWLEDGE
1st Principles
Control and release against process signature
Establish processEstablish processoutlineoutline
Prediction of performance (in-vivo)
Correlate process inputs and outputs
Relate critical process variables to quality attributes of finished product
2
1
3
5
4
Extent of knowledge
Manufacturing process knowledge
Industry target
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Significant gaps exist:
• Manufacturing and scale up sciences
• Unit operation technology and control
• Academic training & skilled resources
• Industrial organization and structure
• Correlation to in vivo performance
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First steps: Unit operation science
• Reaction• Crystallization• Drying• Separation• Particle engineering
• Formulation• Dispensing• Blending• Granulation• Compression• Coating• Filling• Aseptic operations• Packaging
Material Handling, Analytical
Industry basic unit operations
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Unit operations goals
• Well understood platform technologies• Develop the science of all unit operations• Fully instrumented• Closed loop control … fully automated• Material interactions (formulation & devices)• Predictable scale effects• Design/use the right equipment
• Predict performance without extensive experimentation
• Math modeling to speed design• GOAL: Final testing to confirm operations
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Once UOs understood and platform technologies developed, then
Integrated Process Designs
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Integrated process design: Objectives
• Aligns with FDA’s Quality by Design Concept• Link “Platform Technologies” in an integrated process
design• 1ST step of API to primary pack and device performance• Identify CCPs that affect up and down stream ops • Control systems will manage variability within the process• Link CCPs to traditional release testing; i.e. dissolution,
assay, CU, ACI• Produce in spec product by monitoring and controlling
critical parameters … rather than end point testing• Obtain real time release
PROCESS FLOW DIAGRAM…….PANADOL CONTINUOUS PROCESS
BAG UNLOADING STATION
DISPENSING ROOM
IBC-01
IBC-01
HO-01A HO-01BHO-02
HO-05 HO-04 HO-03
IBC-02
F-01
F-02
F-04 F-03F-05
F-06
F-07
BL-03
BL-03
GR-01 GR-02
DR-01
M-01
BL-02
BL-01
SIFTED & PREWEIGHEDSTARCH MAIZEPOVIDONE
POT. SORBATE
PREGELATINIZED STARCH
CAFFEINE
PANADOL
GRANULATE
BASE
TABLET PRESS
SIFTED & PREWEIGHEDSTARCH MAIZESTEARIC ACIDMAG. STEARATETALCAVICILAC-DI-SOL
MOISTURE
PURIFIED WATER
METERING PUMP
1
2
6
7
7
89
33
5 5
4 4
2 2
TABLETS TO COATING
AHUAHU AHU
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HO-03
SODIUM BICARB
PARACETAMOL
DELUMPER
FRESH AIR
PARACETAMOLPREGELATIZENED STARCHSODIUM BICARBONATECAFFEINE
IBC-01
IBC-02
SIFTER
SIFTER
SIFTER
SIFTER
SIFTER
DISPENSING ROOM
BL-03
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DEDUSTER
METALDETECTOR
Integrated process design
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Engineering models would:
• Process design tool of preference• Rapid evaluation of excipients, DS, formulations,
equipment, environmental, devices, etc.• Narrow alternatives in silica• Reduce scale up trial and error … focus testing on high
probability results … time & money!! • After confirmation, use model to demonstrate full
process understanding … regulatory expectation• Would be the basis for continuous improvement studies
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The future manufacturing vision!
• Fundamental understanding of the science• Develop mfg scale processes … before registration• Small scale, contained, dedicated, automated, continuous
processes • Late stage customization• On line measurement and control• Real time release • Product plants … not component plants• Leverage relationships … internal, academia, industry,
regulatory agencies to develop the science
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Gaps in skills and facilities exist
• Manufacturing sciences
• Powder technology
• Chemical / Process engineers
• Rheologists (non Newtonian fluids)
• Physicists
• Spectromisists
• Chemometricians
• Process development pilot plants (not CT PPs)
• “Soft skills” & Business skills
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Some current activities
• Industry/Company Culture changes underway• Empirical to fundamental sciences• Industry pressures key driver• External work lays foundation (FDA, ASTM, CAMP,
ISPE, IFPATma)
• Develop the next level of manufacturing science• PAT and cGMPs for 21st century• Pharma professional of the future … engineering +• Universities need to develop and teach the science
• Capitalize on today’s situation to forge an even stronger future
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Your role in this:
• Support/create means for fundamental research in the Pharma manufacturing sciences
• Encourage students into science & engineering careers
• Encourage universities to create the programs• Be consistent and science based in your activities• Give this priority and attention
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Questions