Good Manufacturing Processes
in Early Development
June 3, 2011
CNY Biotechnology Symposium
Speaker: Dr. Charlie Montgomery
Section Head of Chemical Development
What Exactly Does PR&D Do?
$
Value Chain Analysis for Chemical Development
$
NPV Drivers
Margin ($/Kg API cost)
Speed to Market
Maintaining exclusivity
Reduce
development
costs
Reduce
Time to
launch
Reduce COG
& increase
robustness
Defend
Patent
life
Revenue stream of
new product
Launch
Time
Key Messages
•
Need to always think of the bigger picture
• Can act tactically but always try and think long term
•
Small amounts of up front Chemical Development investment early on can
pay huge dividends later on even if the candidate drug (CD) doesn‟t make it
all the way to market
•
Losing even 1-2 years of exclusivity can reduce NPV of a product by 30%
•
So speed to market or key decision point needs to be considered from day
one, not once you‟ve got to Proof on Concept
Components of Speed
•
Efficient Chemistry
•
Excellent Communication
•
Dynamic Planning (keeping on top of the critical path)
Key Factors that Impact Speed
•
Process
•
Complexity (No of Steps)
•
Yields
•
Dilution / throughput
•
Scalability
•
Convergent vs. divergent route
of synthesis
•
Material Supply for
experimentation
•
Purification strategy
• Chromatography vs.
crystallisation
• Physical form issues
•
Plant
•
„hurdle‟
•
Capacity
•
working hours
•
planning / scheduling / other
projects
•
Project
•
Quantity
•
Specification target
•
Material supply from suppliers
• Selection of tactical vs.
catalogue
•
Phasing of CDs
• Resource bulging
•
Risk taking
At least 1 of the above is going to impact your project
The Development Process
Key points
• Critical path will vary from CD to CD
•
The faster the development plan and/or the more complex the molecule,
the longer API supply will be on the critical path
CD Complexity
•
What is Chemical Developments‟ unit of capacity?
•
•
It‟s number of chemical stages, not numbers of Drug Candidates
What is the most time-consuming aspect of Chemical Development?
•
Experimental lab and plant scale up, due to the fact that we are still
very poor at making predictions (is this likely to change in the next
10 years?)
CD Complexity
F
HO
HN
N
F
N
O
N
N
N
S
Cl
HO
O
Brilinta
24 steps
SO2 Me
Cl
N
Compound A
6 Steps
OH
N
O
Consequences of Step Count
1.
Delivery
•
For Compound A (5kg) delivered at candidate nomination
•
For Brilinta, (0.85kg) delivered 6 months after candidate nomination
2.
Synthesis Freeze:
•
Final Route in place in time for 28 day dog tox for Compound A
•
For Brilinta, Final Route in place 22 months after candidate nomination
3.
Synthesis Freeze:
•
2 Chemistry FTEs needed for Compound A to reach synthesis freeze
•
24 Chemistry FTEs needed for Brilinta (12X increase in resource)
You have to select the best molecule you have, but Step Count and API Amounts will have a big
impact on speed
.The relationship between steps and FTEs isn‟t linear
However, Route Development can often alter the delivery situation quickly and dramatically
Inefficient Chemistry
Cl
NH
N
Cl
O
1. NaH, DME,
80°C, >24h
Cl
2. chromatography
Cl
NH
61%
HO
N
N
MsCl, DCM
O
N
85%
S
O
O
Piperidine ether
LHMDS,
MeOAc,
THF
KCN, (NH4)2CO3,
EtOH/H2O,
pressure
O
Cl
98%, crude
S
N
N
O
O
Cl
N
O
O
50-70%
N
O
(racemate)
O
chiral
chromatography
20%
Cl
N
N
H
N
S
O
O
O
O
N
H
(S)-Piperidine hydantoin
5% overall yield
12
H
N
S
O
O
O
N
H
Efficient Chemistry
KCN,
(NH4)2CO3,
EtOH/H2O
pressure
O
S
N
H
chiral
chromatography
S
NH
O
90%
O
45%
Cl
H
N
S
N
H
N
O
88%
Cl
NH
O
S
O
HO
Cl
KOtBu, THF,
rt
90%
O
Cl
O
N
H
O
Cl2,
AcOH/H2O
NH
+
N
H
N
1. DIPEA,
THF, -15°C
2. EtOH/H2O
recryst.
Piperidine ether
75% (including recryst)
H
N
O
Cl
N
N
O
S
O
O
O
O
13
N
H
27% overall
What Creates most Value?
Which is Cheaper?
•
Route
Steps
Manufacture of 5kg in LSL.
Med. Chem. Route
7
18 wks
New Route
4
6 wks
Medicinal Chemistry Route
Develop
•
Scale
New Route
Discover
Develop
Scale
Outcome
•
Initial lab work to demonstrate efficient chemistry took less than 2
weeks!
•
Because of route improvement:
•
Discovery rapidly delivered 40g of API for initial tox
•
Chemical Development delivered 297g of API delivered in 4
week (cf 18 weeks predicted with original process)
•
Savings on 1st GMP manufacture over $700K
15
Advantages of Efficient Chemistry
•
Cost reduction
• Lower $/Kg price
• Campaign avoidance
•
Faster to NDA
• As development times speed up, API is on the critical
path for less time
• More activities can be done in parallel
•
Overall, you have more flexibility
•
This also holds true for discovery
Iterative Loops for Compound Design
Extend into Development
Make
Test
Speedier LO could mean a greater number of CDs
produced in absence of new knowledge unless we can
speed up the API delivery. This won’t reduce attrition
Hypothesis
CD Selected
External data
200-300g
prep
7 day rat &
dog tox
1 month tox
Rat and dog
FTIM
(SAD)
MAD
CMC development 1st GMP prep
1-3 Months
12-24 months
24-36 months
Customer Perceptions
•
Some seem happy for heroic efforts in the plant but scared of
commissioning lab work (value for money?)
•
Chemists just want to play around in the lab and will never get done
•
There is often little much value attributed to the process description, yet that
is probably the most valuable deliverable
•
We can always pile in effort and catch up later…to a point true, but there
are limits and adopting this approach as a general strategy can be a lost
opportunity
CROs make money whatever the process.. Not true. Inefficient process
often = unpredictable process which is bad for everyone
•
Extending this Back into Discovery
•
The faster we can go around the loops, the more likely CD 2 will be
invented with new knowledge
•
This will improve CD quality or stop programs earlier
•
Ease of synthesis represents the biggest stumbling block to doing this
routinely
Joining up the Dots:
Potential Benefits of Integration
•
Gives supplier a little more time to innovate (with minimal impact on time)
•
Can lower overall cost
•
Less handovers
•
Better preparation for subsequent campaigns
•
Savings increase dramatically as campaign size increases
About AMRI: An Accomplished Partner
Integrated Discovery Services
A broad spectrum of lead discovery services backed by decades of experience
Located in 400,000 ft2 of facilities across the globe
•
•
•
•
175 discovery projects in last 10 yrs, resulting in >80 clinical and preclinical lead
candidates (45% success rate)
> 90 issued US patents (dozens of foreign) on behalf of customer projects
> 300 peer reviewed publications
> 400 verbal presentations or posters
About AMRI: An Accomplished Partner
API Development/Manufacturing
A suite of drug development services to bring a clinical candidate from
laboratory scale to commercialization
270,000 L capacity across the globe
Supporting Customers Annually through
•
•
•
•
>750 R&D programs
60 programs in Phase I and II
22 programs in Phase III
35 Commercial APIs
Summary
•
Big savings doesn‟t always require big investments.
•
Discussions are always helpful.
“It‟s the planning, not the plan.”
•
The earlier we can get „efficient chemistry‟ into the program, the more
choices we can offer and the more value we can create.
Questions?