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. 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