accelerating pharmaceutical development pharmaceutical development when there are challenges:...
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Accelerating pharmaceutical development part of 2015 AAPS session on: Fast to FIH versus Fast to Commercial: Paradigms, Trade-offs, and counter-balances
Rahul Rajan
Why accelerate process development? The patient is waiting…
• Development times are very long – typically 12-15 years
• Costs of drug development are high: e.g. $13-19M just to have drug for first in human
• Pressures exist on healthcare system and payers demand unambiguous value
• Need to accelerate process development, especially to test effect of drug on human biology (First in human introduction)
Aspects of pharmaceutical development covered in this presentation
Molecule
Selection
Drug
Substance
(API) process
development
Drug Product
Development
Manufacturing,
testing,
release,
stability
Pharmaceutical development has several inter-dependent workstreams…
CMC Activities for Development of MAbs By Susan Dana Jones, Patricia Seymour and Howard L. Levine
| April 5, 2010 Critical steps to reach IND with a therapeutic antibody - See more at:
http://www.contractpharma.com/issues/2010-04/view_features/cmc-activities-for-development-of-
mabs#sthash.SO9aprO8.dpuf
Example
Large molecule
Process development
timeline
Smart from the start: finding the right drug candidate for pharmaceutical development using predictive approaches • Traditional approach: detect
stability differences under accelerated conditions e.g. 40C
• Covalent modifications typically follow trends at higher temperatures
• Cases exist for inverse in aggregation trends for mAbs
• “pH jump” experiment can be used as a predictive tool to assess molecule behavior under physiological conditions (parenteral delivery)
Expose to pH 7, 37C
Candidate 1, 4C
Candidate 2, 4C
Candidate 2, 40C
Candidate 1, 40C
Accelerating pharmaceutical development when there are challenges: modeling approaches
• Arginine found to prevent protein aggregation
• Molecular dynamics simulations reveal
arginine cluster formation by head-to-tail
hydrogen bonding
• Interaction of arginine with aromatic and
charged side chains
• Arginine behaves as a “chemical chaperone”
Shukla D and Trout BL J.Phys.Chem. 2010, 114 (42), pp
13426–13438
Rajan RS, Tsumoto K, Tokunaga M, Tokunaga H, Kita Y,
Arakawa T.
Curr Med Chem. 2011;18(1):1-15
• Predicting the efficiency of human
intenstinal absorption using a “unity
model”
• Measure aqueous solubility (log Sw) and
octanol-water partition coefficient (log Kow)
• Using this calculate “maximum absorption
potential” values
• Correlation between MAP value and drugs
that are absorbed well (FA≥0.5) or poorly
absorbed (FA<0.5)
Patel, RB, Admire B, Yalkowsky SH Curr Drug Deliv.
2015;12(2):238-43.
Accelerating pharmaceutical development by means of technology investments
Clinical
New Clinical
Capabilities
Global Support
& Expansion
Technologies
The Drug Product Continuum: A transformational Network Solution to Product Commercialization and Life Cycle Management
Commercial
Formulation Dev
DP Commercial
Process Dev
Clinical DP
Manufacturing
Commercial DP
Manufacturing
Continuum of capabilities, data sharing, knowledge management and coordinated investments
ensures robust drug product commercialization and life cycle management
Drug Product
Pilot Facility
Engineering
Technology
Advancement &
Experimentation
Development / Engineering
New
Commercial
Capability
Improved
Current
Processes &
Global
Expansion
Capability
Commercial
Creating an end-to-end Drug Product facility to address pharmaceutical development challenges
9
How such a facility may be used to capture manufacturing stresses for formulation & DP process development
UF/DF Bulk Drug
Processing
Storage Filler Transportation Analytics
Small & medium
scale semi-
automated units
Process multiple
formulations
through “worst
case”
manufacturing
stresses
Increase
capacity
Introduce
representative
filler stress e.g.
time/pressure
filler
Subject product to
representative
transportation stress
High throughput
analytics especially
to analyze particles;
Higher
temperature to
enable high
concentration
formulations
Unit
operation/process
development
Facility will meet large
increase in demand for
this type of testing
Introduce new high-
throughput
capabilities; layer in
complexity in
automation
10
Accelerating formulation development: leverage miniaturization and automation
Buffer and Excipient Stock Solutions
Automated Formulation Preparation Systems
+
Stability storage, stresses
Analytical tests to evaluate
compatibility and stability
Accelerate development and reduce resources to identify stable formulations
through implementation of automated technologies
Statistical Design
of Experiments
Enhanced Data
Processing Capabilities
Automated Analytics
Accelerating process development: example of time savings by automation
• These are newly designed automated capabilities at Amgen
• They are designed to significantly expedite drug product development
Automated Capability
FTE hours to
test 1000
samples manually
FTE hours to
test 1000
samples w/ automation
Aliquotting 5 2.5
Sample prep for CE-SDS
42 21
Viscosity 300 8
Subvisible detection (HIAC)
50 3
pH 50 8
Absorption (UV-Vis)
80 5
Syringe to vial/plate transfer
8 2
Labeler 8 1.5
Machine vision 17 2
Subvisible detection (MFI)
400 30
Plate-based buffer exchange
400 48
For Internal Use Only. Amgen Confidential. 13
New commercial formulation development
paradigm
Rapidly screen formulation landscape
Directly integrate into pilot facility: in-depth
formulation and processability study
• High throughput capabilities
• Increased capacity to
process formulations
20 Formulation
Screening
3–5 Formulation Processability
CFR OLD
~1.5–2yrs ~10mo
≥ 9
6 F
orm
ula
tio
n
HT
Scre
enin
g
5–20 Formulation
Processability CFR NEW
Shortened timeline to CFR
Earlier, longer stability data
~3mo ~12mo
Accelerating pharmaceutical development: using automated workflows
• Automation was used to synthesize co-crystals in a 96-well plate
• Ability to sample a greater design space and more effectively do so
• Other examples include automating solid-phase synthesis
V. Luu et al, International Journal of
Pharmaceutics 441 (2013) 356– 364
Tan, Het al 2008. An integrated highthroughput screening approach for purification of solid organic compounds by titration and
crystallization in solvents. Org. Process Res. Dev. 12, 58–65.
Accelerating process development: use of platforms
• Platform: a collective body of knowledge translated into a consistent set of practices
• suit certain kinds of modalities e.g. mAbs
• Example of drug product process is shown here
• Platforms are not static but evolve with increasing knowledge
• Utilizing platforms = speed by avoiding redevelopment for each “similar” molecule
• Require integrated drug product design
• Formulation, process, container, device and related attribute control
Current Perspectives on Stability of Protein Drug Products during Formulation, Fill and Finish Operations
Nitin Rathore and Rahul Rajan, Biotechnology Prog. (2008) 24, 3, 504-514
Accelerating process development: change the paradigm (using pools instead of clones)
TIM
E
Accelerating pharmaceutical development: change the paradigm (continuous manufacturing)
Synthesis Crystallization Blending Granulation
&
Sizing
Tablet press
& coating
Test & Storage Test & Storage Test & Storage
Transport
Test & Tablets
Test & Storage
Region 1 Region 2 (Months)
Batch
Adapted from Lee, S.L et al J.Pharm.Innovation (2015) 10(3), 191-199
Synthesis Crystallization Blending Granulation
&
Sizing Tablets
Tablet press
& coating
PAT & Active process control systems (Days) Continuous
Paradigms for clinical and commercial pharmaceutical development
Discovery Preclinical Phase 1 Phase 2 Phase 3
Molecule
selection
Clinical
Pharmaceutical
development
Commercial
Pharmaceutical
development
Discovery Preclinical Phase 1 Phase 2
Molecule
selection
Clinical & commercial
Pharmaceutical
development
Discovery Preclinical Phase 1 Phase 2
Molecule
selection
Clinical & commercial
Pharmaceutical
development
Phase 3
Fast to Patient
Front Loading:
Single cycle
Front Loading:
reduced clinical development
In summary: approaches to accelerate process development
Modeling &
Predictive
Approaches
Automation
Platforms
Better
information
management
Acknowledgements
• Ping Yeh
• Arwinder Nagi
• Darren Reid
• Paco Alvarez
• Nitin Rathore
• Ranjini Ramachander
• Karthik Nagapudi
• Jason Tedrow
• Rohini Deshpande
• Dave Pecosky
• Vishal Nashine
• Ajit Narang
• Rajesh Gandhi
• Earl Dye
• David Le
• Judy Purtell
• Kim Westland
• Jeff Yeary
• Kevin Melford
• Cindy Ren