The document discusses improving pharmaceutical process development by: 1) Selecting drug candidates based on their "developability". 2) Choosing optimal solid forms and formulations early. 3) Taking a unit operations approach to process development to enable effective scale up and monitoring of process robustness.

1. 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

2. 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

3. Issues within the industry

4. 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 takes
6.5 - 13.5 years
Up to $800MM
Discovery
Drug Discovery / Development /
Marketing
Market
2-5 yrs
Submission&
Approval
10-20 yrs
Source: PRTM
Phase 3Phase 2a/bPhase 1
Pre-
clinical
Development
Targets
Hits
Leads
Candidate
Challenges: - Find safe and effective drugs
- Speed to market

5. Drug company products
• Approved label claim used to position
product in the market
•The marketed dosage form(s)
•The API

6. Drug company products
• Approved label claim used to
position product in the market
•The marketed dosage form(s)
•The API

7. 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

8. 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

9. PAI examples

10. 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”

11. 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

12. 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

13. • 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

14. HOW?

15. Building in “developability”
1. Picking better development
candidates:

16. Discovery Development
Target HTS
Synthetic
chemistryScale up
100-500mg
Animal model
Probe Tox,
PK, met
Pre-clinical Research &
Early Development Process
2-4 cmpds
GLP
Tox
F &
F
Process
chemistry
Sample collection
in vitro selectivity
in vitro metabolism
in vitro Tox
Animal model
efficacy
EarlyDiscoveryLeadoptimization
Pharm.
Sci.
Ph I
Genomics Libraries
Hits to Leads
Lead optimization

17. New R&D Challenges
Drug
Discovery
Preclinical
development
Clinical
development
Resource
constraints
Time
constraints
Discovery
revolution
Pharmaceutical
Development

18. Discovery Development
Target HTS
Synthetic
chemistryScale up
100-500mg
Animal model
Probe Tox,
PK, met
2-4 cmpds
GLP
Tox
F &
F
Process
chemistry
Sample collection
in vitro selectivity
in vitro metabolism
in vitro Tox
Animal model
efficacy
EarlyDiscoveryLeadoptimization
Pharm.
Sci.
Ph I
Genomics Libraries
Hits to Leads
Lead optimization
Pre-clinical Research &
Early Development Process

19. Candidate selection:
Building in “Developability”
Lead
(active molecule)
Metabolism
Selectivity
Potency
LO
(optimized molecule)
Physical properties
Potency
Selectivity
Metabolism
Best leads
Physical / chemical
properties
Biopharmaceutics

20. 2. Form and formulation selection

21. Product Development Timeline
Develop
Synthetic
Route
First
Supplies
Non GLP
Probes
IND/Phase
I/II Safety
Drug Substance Transfer to
Manufacturing
Validation
Safety Assessment
• Extended Safety Studies
• Degradate Qualification
Carcinogenicity
PAI
Launch
Quantities
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 in
Man
Phase
IIB
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
Discovery
Launch
Validation
Launch
Quantities
Clinical Program
Phase
III
$250-800MM
3-10 years 4-8 years
File
NDA
WMA
crg development timeline

22. Exploration of solid forms
solvent
process impurity
or degradate
process (t,T)
Traditional
5
3 1
4
process (t,T)
process impurity
or degradate
solvent
High throughput
2

23. Crystalline Trihydrate
Solubility ~0.73 mg/mL
Weakly Crystalline Anhydrous Form
Solubility >100 mg/mL

24. Ritonavir: HIV protease inhibitor
ON
H
H
N
N
H
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:
1992
1996
1998
1998 - 1999
1999

25. 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

26. TPI 745: New salt form with
improved solubility
Solubility

27. New TPI Form Has Faster Onset
Salt form with
“solubility
modifier”
30 mpk P.O.
0
5000
1 10
4
1.5 10
4
2 10
4
0 2 4 6 8
TPI-745A
TPI-745B
time, hours
Cmax Tmax 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
Parent

28. 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

29. The current norm
5
3 1
4
The future
2
environmental
raw material properties
process
conditions
environmental
raw material properties
process
conditions
3. Process development

30. 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

31. 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

32. 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

33. 2
5
Pharmaceutical Process Development:
Optimization
environmental
raw material properties
process
conditions
3 1
4
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.

34. Process optimization
Region where process is unstable
Process most stable
Target values

35. 2
5
environmental
raw material properties
process
conditions
3 1
4
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

36. Region where process
is robust
Region where process is unstable
Process most stable
Target values
Process optimization

37. 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

38. 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

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

40. 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