designing quality in colin r gardner, currently: cso, transform pharmaceuticals inc lexington, ma,...
TRANSCRIPT
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.
www.transformpharma.com
Presentation to Manufacturing Subcommittee of the FDA Advisory Committee for Pharmaceutical Science.
Sept 17 , 2003
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
Lifecycle Management
Development
0.5 - 2 yrs 1 - 2 yrs 1.5 - 3.5 yrs 2.5 - 4 yrs 0.5-2 yrs
R&D takes6.5 - 13.5 yearsUp to $800MM
Discovery
Drug Discovery / Development / Marketing
Market
2-5 yrs
Submission&Approval
10-20 yrs
Source: PRTM
Phase 3 Phase 2a/bPhase 1Pre-
clinicalDevelopment
TargetsHits
LeadsCandidate
Challenges: - Find safe and effective drugs - Speed to market
Drug company products
• Approved label claim used to position product in the market
•The marketed dosage form(s)
•The API
Drug company products
• Approved label claim used to position product in the market
•The marketed dosage form(s)
•The API
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
Batch size Biobatch 10 liters
Commercial batch 100 liters
Mixing time
15 mins 45 mins
drug excipients drug excipients
FDA inspector conclusion: “The processes are different”
Preparation tank
Filling tank
Filling points
Re-circulating filling line
Pump
Suspension formulation preparation and filling
FDA inspector conclusion:
“Any stoppage of the filing process > 15 mins should result in destruction of the entire batch
Preservative adsorption to tubing
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
• 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
Industry role
HOW?
Building in “developability”
1. Picking better development candidates:
Discovery Development
Target
HTS
SyntheticchemistryScale up
100-500mg
Animal modelProbe Tox,
PK, met
Pre-clinical Research & Early Development Process
2-4 cmpds
GLPTox
F & F
Process chemistry
Sample collection
in vitro selectivity
in vitro metabolism
in vitro Tox
Animal modelefficacy
Earl
y D
iscovery
Lead
op
tim
izati
on
Pharm. Sci.
Ph I
Genomics Libraries
Hits to Leads
Lead optimization
New R&D Challenges
DrugDiscovery
Preclinicaldevelopment
Clinical development
Resourceconstraints
Timeconstraints
Discoveryrevolution
Pharmaceutical Development
Discovery Development
Target
HTS
SyntheticchemistryScale up
100-500mg
Animal modelProbe Tox,
PK, met
2-4 cmpds
GLPTox
F & F
Process chemistry
Sample collection
in vitro selectivity
in vitro metabolism
in vitro Tox
Animal modelefficacy
Earl
y D
iscovery
Lead
op
tim
izati
on
Pharm. Sci.
Ph I
Genomics Libraries
Hits to Leads
Lead optimization
Pre-clinical Research & Early Development Process
Candidate selection:Building in “Developability”
Lead (active molecule)
MetabolismSelectivity
Potency
LO (optimized molecule)
Physical properties
Potency
Selectivity
Metabolism
Best leadsPhysical / chemical
propertiesBiopharmaceutics
2. Form and formulation selection
Product Development Timeline
DevelopSynthetic
Route
FirstSupplies
Non GLPProbes
IND/PhaseI/II Safety
Drug Substance Transfer toManufacturing
Validation
Safety Assessment
• Extended Safety Studies• Degradate Qualification
Carcinogenicity
PAI
LaunchQuantities
Product Development• Preformulation Studies• Biopharm Evaluation
• Formulation Design
• Phase I/IIA Formulations• Analytical Methods
• Composition & Process Defined• Probe Stability
$5-10MM
• Process Development and Scale Up• Biobatch• Specifications• MCSS
Transfer to Manufacturing
First inMan
PhaseIIB
Approval
• Develop Process and Scale-up• Establish Specifications
• Phase I/IIA• Wide Dose Range• Multiple Formulations
• Phase IIB Dose Range
•Phase III•Final process•>1/10 scale
PAI
Dis
cove
ry
Lau
nchValidation
LaunchQuantities
Clinical Program
PhaseIII
$250-800MM
3-10 years 4-8 years
FileNDAWMA
crg development timeline
Exploration of solid forms
solvent
process impurityor degradate
process (t,T)
Traditional
process (t,T)
process impurityor degradate
solvent
High throughput
Crystalline TrihydrateSolubility ~0.73 mg/mL
Weakly Crystalline Anhydrous FormSolubility >100 mg/mL
Ritonavir: HIV protease inhibitor
ONH
HN
NH
N
CH3
O
OHO
CH3H3C
O
N
SS
NH3C
H3C
ABT-538 discovered Launch of semi-solid capsule/polymorph I Polymorph II appears, <50% solubility
Product pulled from the market Massive effort to reformulate the product Reformulated softgel capsule launched
Case history:
199219961998
1998 - 19991999
Summary of Ritonavir Crystal Forms
IV
mp 122 °C mp 125 °C mp 80 °C mp 97 °C mp 116 °C
Launch in 1996
Summer of 1998
TransForm 2002 – 6 week effort
Launch in 1996
Summer of 1998 Morissette et al. PNAS 100, (2003).
2002 5 forms found
TPI 745: New salt form with improved solubility
So
lub
ility
New TPI Form Has Faster Onset
Salt form with “solubility modifier”
30 mpk P.O.
0
5000
1 104
1.5 104
2 104
0 2 4 6 8
TPI-745A
TPI-745B
time, hours
Cmax Tmax AUCTPI-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
Parent
0
10
20
30
0 5 10
TPI-336
Marketed capsule
Neat chemical in capsule
Solution in 2:1 PEG/water
Dose, mg/kg
Faster Onset, Increased Bioavailability and Linear Dose Response
New form & formulation combination significantly improves dissolution, resulting in better onset and bioavailability
The current norm
The future
environmental
raw material properties
process conditions
environmental
raw material properties
process conditions
3. Process development
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
environmental
raw material properties
process conditions
environmental
raw material properties
process conditions
• Optimization Studies– Find regions of process parameters where
performance is most stable– Design process to operate within this region.
Process optimization
Region where process is unstable
Process most stableTarget values
environmental
raw material properties
process conditions
Pharmaceutical Process Development: Optimization
environmental
raw material properties
process conditions
• Optimization Studies– Find regions of process parameters where
performance is most stable– Design process to operate within this region.
•Process Robustness–Stress ranges of variables–Include ranges in materials, environmental conditions, process parameters
Region where process is robust
Region where process is unstable
Process most stableTarget values
Process optimization
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 unstable
Process most stableTarget values
Region where process is robust
Fingerprint region to monitor process robustness and 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