Transcript Document 7260050

Designing quality in
Colin R Gardner,
Currently: CSO, Transform Pharmaceuticals Inc
Lexington, MA, 02421
Formerly: VP Global Pharmaceutical R&D
Merck & Co Inc.
Acknowledgement for useful discussions:
Dr. Scott Reynolds,
Executive Director, Pharmaceutical Development,
Merck and Co Inc.
Presentation to Manufacturing Subcommittee of the FDA
Advisory Committee for Pharmaceutical Science.
Sept 17 , 2003
www.transformpharma.com
Summary
• Continuum of process development activities from
NCE selection through manufacturing
• Fundamental NCE characterization and process
development leads to meaningful control points
• Success of the scale up exercise is judged by
rational comparison of meaningful process and
product parameters
• Fingerprint parameters are identified to monitor
process robustness and used to flag issues before
control is lost
Issues within the industry
Drug Discovery / Development /
Marketing
Discovery
Targets
Hits
Leads
Candidate
2-5 yrs
Market
Development
Preclinical
Development
0.5 - 2 yrs
Phase 1
1 - 2 yrs
Phase 2a/b
1.5 - 3.5 yrs
Phase 3
2.5 - 4 yrs
Submission&
Approval
Lifecycle
Management
0.5-2 yrs
10-20 yrs
R&D takes
6.5 - 13.5 years
Up to $800MM
Challenges: - Find safe and effective drugs
- Speed to market
Source: PRTM
Drug company products
•The API
•The marketed dosage form(s)
• Approved label claim used to position
product in the market
Drug company products
•The API
•The marketed dosage form(s)
• Approved label claim used to
position product in the market
Intra-company Consequences
• R&D heads focus on potency, selectivity, safety and clinical
response
• do not uniformly recognize the importance of
investment in process chemistry and formulation
development
• Inexperienced clinical staff often set timelines and targets
independent of product development capabilities
• The goals and rewards of Discovery, Development and
Manufacturing staffs are often not aligned
• CEO’s have not regarded manufacturing excellence as a
competitive advantage
Issues created by the
regulatory agencies
• Depth of understanding of process
engineering
•Timeframe to review and understand the
regulatory filing
•Training of compliance inspectors –
especially for PAI’s
PAI examples
Scaling up a suspension formulation
drug
excipients
drug
excipients
Batch size
Biobatch
10 liters
Commercial
batch 100 liters
Mixing
time
15 mins
45 mins
FDA inspector conclusion:
“The processes are different”
Suspension formulation preparation
and filling
Preparation
tank
Filling
tank
Re-circulating
filling line
Pump
Filling
points
Preservative
adsorption to tubing
FDA inspector conclusion:
“Any stoppage of the filing process > 15 mins should result
in destruction of the entire batch
What can we do about this situation?
Manufacturing processes start with
the choice of the NCE, its form and
formulation
We must link discovery, early
development, process scale-up and
manufacturing
Industry role
• Develop methodologies to improve:
• Candidate selection
• Form selection and Formulation design
• Process development and optimization
• Process control
• Scale-up and tech transfer
• Process validation
• Process monitoring and continuous improvement
• Demonstrate reduced risk to regulatory agencies
• Obtain regulatory relief
• Demonstrate value to company management
HOW?
1. Picking better development
candidates:
Building in “developability”
Pre-clinical Research &
Early Development Process
Early Discovery
Genomics
Libraries
HTS
Target
Hits to Leads
Discovery
Development
Synthetic
chemistry
Scale up
100-500mg
Lead optimization
Sample collection
in vitro selectivity
Animal model
Probe Tox,
PK, met
in vitro metabolism
Animal model
efficacy
in vitro Tox
Lead optimization
2-4 cmpds
F&
F
GLP
Tox
Ph I
Process
chemistry
Pharm.
Sci.
New R&D Challenges
Resource
constraints
Discovery
revolution
Pharmaceutical
Development
Drug
Discovery
Preclinical
development
Clinical
development
Time
constraints
Pre-clinical Research &
Early Development Process
Early Discovery
Genomics
Libraries
HTS
Target
Hits to Leads
Discovery
Development
Synthetic
chemistry
Scale up
100-500mg
Lead optimization
Sample collection
in vitro selectivity
Animal model
Probe Tox,
PK, met
in vitro metabolism
Animal model
efficacy
in vitro Tox
Lead optimization
2-4 cmpds
F&
F
GLP
Tox
Ph I
Process
chemistry
Pharm.
Sci.
Candidate selection:
Building in “Developability”
Lead
(active molecule)
Potency
Physical properties
Metabolism
Potency
Selectivity
Metabolism
Selectivity
Best leads
LO
(optimized molecule)
Physical / chemical
properties
Biopharmaceutics
2. Form and formulation selection
Product Development Timeline
Discovery
Non GLP
Probes
First
Supplies
Drug Substance
• Develop Process and Scale-up
• Establish Specifications
Transfer to
Manufacturing
Validation Launch
Quantities
PAI
Safety Assessment
IND/Phase
I/II Safety
• Extended Safety Studies
• Degradate Qualification
Carcinogenicity
• Preformulation Studies
Launch
Product Development
• Biopharm Evaluation
Quantities
• Formulation
Transfer to Validation
• Phase I/IIA • Composition • Process
Design
Formulations & Process
Development Manufacturing
PAI
• Analytical
Defined
and Scale Up
Methods
• Probe
• Biobatch
Stability
• Specifications
• MCSS
Launch
Develop
Synthetic
Route
Clinical Program
• Phase I/IIA
• Wide Dose
Range
• Multiple
Formulations
First in
Man
• Phase IIB
Dose
Range
Phase
IIB
$5-10MM
$250-800MM
3-10 years
4-8 years
crg development timeline
•Phase III
•Final process
•>1/10 scale
Phase
III
File
NDA
WMA
Approval
Exploration of solid forms
Traditional
High throughput
process impurity
or degradate
process impurity
or degradate
3
1
2
process (t,T)
solvent
5 4
solvent
process (t,T)
Weakly Crystalline Anhydrous Form
Solubility >100 mg/mL
Crystalline Trihydrate
Solubility ~0.73 mg/mL
Ritonavir: HIV protease inhibitor
H3C
CH3
O
H3 C
H
N
N
N
H3C
O
S
CH3
N
H
N
H
O
OH
Case history:
 ABT-538 discovered
 Launch of semi-solid capsule/polymorph I
 Polymorph II appears, <50% solubility
 Product pulled from the market
1998 - 1999  Massive effort to reformulate the product
1999
 Reformulated softgel capsule launched
1992
1996
1998
O
S
N
Summary of Ritonavir Crystal Forms
IV
mp 122 °C
mp 125 °C
mp 80 °C
mp 97 °C
mp 116 °C
Launch in 1996
Launch in 1996
Summer of 1998
Summer of 1998
Morissette et al. PNAS 100, (2003).
TransForm 2002 – 6 week effort
2002 5 forms found
Solubility
TPI 745: New salt form with
improved solubility
New TPI Form Has Faster Onset
2 10
30 mpk P.O.
4
TPI-745A
TPI-745B
Parent
1.5 10
4
1 10
4
Cmax
Tmax
Salt form with
“solubility
modifier”
AUC
TPI-A 23.2±6.2 1.3±1.0* 139±26
TPI-B 19.6±4.6 2.1±1.1 135±24
T-745 21.4±4.0 2.8±1.6 150±43
5000
0
0
2
4
time, hours
6
8
Faster Onset, Increased Bioavailability
and Linear Dose Response
New form & formulation combination significantly improves
dissolution, resulting in better onset and bioavailability
30
TPI-336
Marketed capsule
Neat chemical in capsule
Solution in 2:1 PEG/water
20
10
0
0
5
Dose, mg/kg
10
3. Process development
The current norm
The future
raw material properties
raw material properties
3
1
2
process
conditions
environmental
5 4
environmental
process
conditions
Pharmaceutical Process Development:
Objectives
• Provide a continuous link from early phase
characterization to final manufacturing process
• Define process based on unit operations
approach
• Provide a road map for tracking success of
scale up activities and technology transfer
• Enable effective process monitoring and
improvements
Pharmaceutical Process Development:
Initial Design
• Identify parts of process which are most
susceptible to failure upon scale-up
• Conceptual “scale down” of the final
manufacturing process into the pilot plant
and the lab
Process Understanding
• Determine fundamental process constraints
– Where appropriate, utilize unit operations
which are most forgiving – lower risk
• Identify underlying principles which control
process
– Avoid “black box” analysis
– Identify appropriate process parameters to
monitor and control - value of PAT
- provides confidence
about process robustness
Pharmaceutical Process Development:
Optimization
• Optimization Studies
– Find regions of process parameters where
raw material properties
raw material properties
performance
is most stable
– Design process to operate within this region.
3
process
conditions
environmental
2
5
environmental
1
4
process
conditions
Process optimization
Process most stable
Target values
Region where process is unstable
Pharmaceutical Process Development:
Optimization
• Optimization Studies
– Find regions of process parameters where
raw material properties
raw material properties
performance
is most stable
– Design process to operate within this region.
3
•Process Robustness
process
conditions
–Stress ranges of variables
environmental
environmental
–Include ranges in materials,
environmental conditions, process
parameters
1
2
5
4
process
conditions
Process optimization
Region where process
is robust
Region where process is unstable
Process most stable
Target values
Pharmaceutical Process Development:
Process Control
• Define process through measurable,
quantitative endpoints – PAT?
• Eliminate dependence upon qualitative
endpoints
• Evaluate how process can respond to
variations in process equipment performance
and/or raw materials characteristics
• Provide continuous fingerprint of process
performance – NOT regulatory specifications
Pharmaceutical Process Development:
Continuous Improvement
• “Hooks” for future process improvement.
– Plan into development program collection of
“fingerprint” data for future comparisons
– Design validation protocols to collect similar
“fingerprints”
– Use in manufacturing to continuously
monitor process operation and status
Process optimization
Region where process
is robust
Process most stable
Target values
Fingerprint region to
monitor process
robustness and
Region where process is unstable prospectively identify
drifts
Summary
• Continuum of process development activities from
NCE selection through manufacturing
• Fundamental NCE characterization and process
development leads to meaningful control points
• Success of the scale up exercise is judged by
rational comparison of meaningful process and
product parameters
• Fingerprint parameters are identified to monitor
process robustness and used to flag issues before
control is lost