Day 2

Tuesday, October 25

8:00 Morning Coffee

8:25 Chairperson’s Remarks

8:30 Investigation of Several Routes to CP-724,714 Utilizing Palladium-Catalyzed Cross-Coupling Reactions and Their Application on Kilogram Scale
Dr. David Ripin, Senior Principal Scientist, Chemical Research and Development, Pfizer Inc.
The synthesis of the anti-cancer compound 2-Methoxy-N-(3-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quin azolin-6-yl}-E-allyl)-acetamide (CP-724,714) (1) on multi-kilogram scale using several different synthetic routes is described. Application of the Sonogashira, Suzuki, and Heck couplings to this synthesis was investigated to identify a safe, environmentally friendly, and robust process for the production of this drug candidate. A convergent and selective synthesis of the candidate was identified which utilizes a Heck coupling of a protected allylamine to install the critical olefin.

9:00 Rapid Discovery and Optimization of Catalytic Reactions in the Catalysis Lab at Merck
Dr. J. Chris McWilliams, Senior Research Fellow, Process Research, Merck & Co., Inc.
Critical to the implementation of the most efficient processes for API synthesis is the ability to screen and optimize catalytic reactions. The technology and strategy used to accomplish this goal at Merck will be presented, highlighted with case studies applied to asymmetric hydrogenations and cross-coupling.

9:30 Process Development for a Pharmaceutical Intermediate
Dr. Jeff Song, Principal Scientist, Boehringer Ingelheim GmbH

10:00 Coffee Break, Poster and Exhibit Viewing

 

Impact of Technology on Process Development

Featured Speaker

10:30 Enhancing Efficiency in Process R&D Dr. Ambarish Singh, Associate Director, Process Development, Bristol-Myers Squibb Co. The generation of process knowledge on reactions and separations prior to scale-up is key to enhancing efficiency in Process R&D. Solutions afforded by implementation of disciplined approaches ("bottom-up approach," parallel experimentation) and tools (automation, PAT) in the lab need to be incorporated into the overall process design to make scale-up predictable. An overview of this approach will be presented and illustrated with appropriate examples.

11:15 Optimization in the Drug Substance Development Factory Drs. Robert Roginski, Principal Research Scientist and Mark LaPack (co-author), Eli Lilly & Co. Over the past few years, the growth of data-rich experimentation in drug substance development under the umbrella of the FDA's PAT initiative has been substantial. The arguments for the use of process analytics - improved understanding and control of manufacturing processes, greater efficiency in resource constrained environments, and shortened timelines - are further strengthened when the potential impacts of price controls and adoption of targeted models are considered. We present case studies of the use of process analytical tools in drug substance development which resulted in greater robustness in shorter times than could be achieved by traditional means.

11:45 Lunch on Your Own (Technology Workshop, Sponsorship Available)

12:55 Chairperson's Remarks
Sharon Deram, SBI Analytical

2:30 Process Development in Parallel with Lead Optimization
Dr. Jeffrey Marra, Principle Investigator, Process Development, Purdue Pharma L.P.
A state-dependent sodium channel blocker, V112054, was designed and synthesized using current research technologies, including combinatorial chemistry and high-throughput screening. This compound was subsequently selected as a candidate for development (DC) based primarily on its effectiveness in animal models of neuropathic, post-surgical, and inflammatory pain following oral administration. The initial attempts to scale-up the compound for IND-enabling studies began with minimal communication between discovery chemists and the pilot plant / manufacturing chemists. This case study will illustrate our lessons learned along the way, as well as the corrective actions implemented to improve the technology transfer between discovery and process research. A main conclusion is that scaleable process chemistry should be considered in parallel with pharmacology and pharmaceutical profile during the lead optimization phase of their programs.

3:00 Refreshment Break, Poster and Exhibit Viewing

Under increasing pressure to reduce the development time of new molecular entities as well as improve their survival rate, many of the classical pharmaceutical discovery and development paradigms are being re-evaluated. Among these is the relationship between Lead Optimization and Process Development. Historically, new drug candidates were sought totally without process chemistry considerations. Once the best molecule was chosen, it was “tossed over the wall” to chemical development with little information and no room for negotiation. This panel will discuss breaking down that wall and the evolution of process development and lead optimization from two distinct linear timelines to a parallel continuum.

Key Topics to be Addressed:
• Communication Between Medicinal and Process Chemists 
• Where Does Process Development Fit in the Lead Optimization Screening Tree? 
• Technology Transfer: Cold vs. Warm Handoff 
Chairperson
Dr. Jeffrey M. Marra, Purdue Pharma L.P.
Panelist
Dr. Bhaskar Venepalli, CiVentiChem
Dr. Peter Newsome, PharmAgra Inc.
Dr. Peter Bonk, Principal Scientist, R&D, Rhodes Technologies

 

Outsourcing

4:00 Adding Value Through Outsourcing of Process R&D Activities
Dr. Alan R. Harris, Associate Director of Business Development, Global Process R&D, AstraZeneca
It is easy to be negative about outsourcing, it is often seen as something that is a necessity rather than something which is desirable for a specific project. This presentation will explore the five “W”s of outsourcing will be explored. Why outsource – reasons to do or not do outsource project activities. When to do it – and the dependence on What to outsource on the phase of development. Whether or not to outsource or retain in-house. Where to outsource – finding and developing relationships with partners for outsourcing. Through the presentation the emphasis will be on the positive reasons to outsource, and some examples will be provided of cases where outsourcing has added value to development projects.

4:30 Compliance Concerns in Outsourced Chemistry
Dr. Cara Weyker, Director of Quality Assurance, deCODE
The mandate for compliance in pharmaceutical process chemistry has become increasingly more important as recalled drug products and problematic clinical trials wreak havoc on the revenues of pharmaceutical companies and, more importantly, on the health of the patients being exposed to such drugs. The drive for profitability in the volatile pharmaceutical marketplace is motivating companies to outsource work on their most promising drug compounds to get them into clinical trials and out to market faster. However, if certain factors related to quality and compliance are not addressed in the vendor selection process, an outside service provider can seriously delay or impede progress of a drug compound towards reaching clinical trials. Our presentation will review the key components of a quality system and the attributes that a company should address when choosing a chemistry service provider. We will discuss the major variables to look for to ensure a technical "fit" and increase the likelihood of a successful collaboration.

4:45 Designing Novel Routes Faster: A New Outsourcing Model
Dr. Joseph D'Antuono, Vice President, Process Chemistry Solutions, ROW2 Technologies, Inc.
Design of new, efficient, safe and scalable synthetic routes to a target compound is an integral part of the drug development cycle that has recently come under extreme scrutiny and pressure. Since this process is primarily an intellectual/intuitive process and much of the data available stems from academic efforts - not commercial applications - companies are finding it increasingly difficult to elucidate appropriate routes given tighter deadlines and tougher regulations. Through a recent non-published study, we have collected information on how companies are currently operating and factors that influence their decisions. This talk will present these data, discuss the importance of route design and selection on drug development and illustrate effective methods for tackling the hurdles of developing commercial syntheses faster. It will also describe a new model for outsourcing "route design," which is being utilized by several large and small pharmaceutical companies worldwide.

5:00 Close of Conference