Designing quality in

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Designing quality in
Colin R Gardner, Currently CSO, Transform
Pharmaceuticals Inc Lexington, MA,
02421 Formerly VP Global Pharmaceutical RD
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
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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

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Issues within the industry
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Drug Discovery / Development / Marketing
Discovery
Market
Development
Lifecycle Management
Submission Approval
Phase 3
Phase 2a/b
Phase 1
Pre- clinical Development
Targets Hits Leads Candidate
0.5 - 2 yrs
1 - 2 yrs
1.5 - 3.5 yrs
2.5 - 4 yrs
0.5-2 yrs
2-5 yrs
10-20 yrs
RD takes 6.5 - 13.5 years Up to 800MM
Challenges - Find safe and effective drugs
- Speed to market
Source PRTM
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Drug company products

• The API

• The marketed dosage form(s)

• Approved label claim used to position product in
  the market

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Drug company products

• The API

• The marketed dosage form(s)

• Approved label claim used to position product in
  the market

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Intra-company Consequences

• RD 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
• CEOs have not regarded manufacturing excellence
  as a competitive advantage

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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 PAIs

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PAI examples
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Scaling up a suspension formulation
FDA inspector conclusion The processes are
different
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Suspension formulation preparation and filling
Preparation tank
Re-circulating filling line
Filling tank
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
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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
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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

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HOW?
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Building in developability
1. Picking better development candidates
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Pre-clinical Research Early Development
Process
Genomics
Libraries
Target
HTS
Sample collection
Early Discovery
Hits to Leads
Discovery
Development
Synthetic chemistry
Scale up 100-500mg
in vitro selectivity
GLP Tox
Animal model Probe Tox, PK, met
in vitro metabolism
Lead optimization
Ph I
2-4 cmpds
Animal model efficacy
Process chemistry
Pharm. Sci.
in vitro Tox
Lead optimization
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New RD Challenges
Resource constraints
Time constraints
Discovery revolution
Pharmaceutical Development
Clinical
development
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Pre-clinical Research Early Development
Process
Genomics
Libraries
Target
HTS
Sample collection
Early Discovery
Hits to Leads
Discovery
Development
Synthetic chemistry
Scale up 100-500mg
in vitro selectivity
GLP Tox
Animal model Probe Tox, PK, met
in vitro metabolism
Lead optimization
Ph I
2-4 cmpds
Animal model efficacy
Process chemistry
Pharm. Sci.
in vitro Tox
Lead optimization
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Candidate selectionBuilding in Developability
Lead (active molecule)
Metabolism
Potency
Potency
Selectivity
Metabolism
Selectivity
LO (optimized molecule)
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2. Form and formulation selection
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Product Development Timeline
Drug Substance
Develop Synthetic Route
Validation
First Supplies
Transfer to Manufacturing
Launch Quantities

• Develop Process and Scale-up
• Establish Specifications

PAI
Safety Assessment
Non GLP Probes
IND/Phase I/II Safety
Carcinogenicity

• Extended Safety Studies
• Degradate Qualification

• Preformulation Studies
• Biopharm Evaluation
• Formulation
• Design

Product Development
Launch Quantities
Validation
Transfer to Manufacturing

• Phase I/IIA
• Formulations
• Analytical
• Methods

• Composition
• Process
• Defined
• Probe
• Stability

• Process
• Development
• and Scale Up
• Biobatch
• Specifications
• MCSS

Discovery
PAI
Launch
Clinical Program

• Phase III
• Final process
• 1/10 scale

• Phase I/IIA
• Wide Dose
• Range
• Multiple
• Formulations

• Phase IIB
• Dose
• Range

File NDA WMA
Approval
First in Man
Phase III
Phase IIB
5-10MM
250-800MM
4-8 years
3-10 years
crg development timeline
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Exploration of solid forms
Traditional
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Weakly Crystalline Anhydrous Form Solubility 100
mg/mL
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Ritonavir HIV protease inhibitor
Case history

• ABT-538 discovered
• Launch of semi-solid capsule/polymorph I
• Polymorph II appears,
• Product pulled from the market
• Massive effort to reformulate the product
• Reformulated softgel capsule launched

1992 1996 1998 1998 - 1999 1999
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Summary of Ritonavir Crystal Forms
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
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TPI 745 New salt form with improved solubility
Solubility
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New TPI Form Has Faster Onset
Parent
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Faster Onset, Increased Bioavailability and
Linear Dose Response
New form formulation combination significantly
improves dissolution, resulting in better onset
and bioavailability
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3. Process development
The current norm
The future
raw material properties
raw material properties
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1
2
process conditions
process conditions
4
5
environmental
environmental
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Pharmaceutical Process DevelopmentObjectives

• 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

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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

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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
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Pharmaceutical Process Development Optimization

• Optimization Studies
• Find regions of process parameters where
  performance is most stable
• Design process to operate within this region.

2
5
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Process optimization
Process most stable Target values
Region where process is unstable
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Pharmaceutical Process Development Optimization

• Optimization Studies
• Find regions of process parameters where
  performance is most stable
• Design process to operate within this region.

raw material properties
raw material properties
3
1
2

• Process Robustness
• Stress ranges of variables
• Include ranges in materials, environmental
  conditions, process parameters

process conditions
process conditions
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4
environmental
environmental
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Process optimization
Process most stable Target values
Region where process is robust
Region where process is unstable
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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

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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

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Process optimization
Process most stable Target values
Region where process is robust
Fingerprint region to monitor process robustness
and prospectively identify drifts
Region where process is unstable
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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