TUESDAY, OCTOBER 16

8:40 am Interactive Roundtable Discussions: Threats and Opportunities for Process Development
Note: Roundtables will run concurrently; attendees to select one to participate in.

#1: Converting Process Development Difficulties (Threat) to Opportunities for Process Optimization
Moderator: Neal G. Anderson, Ph.D., Anderson’s Process Solutions

Some process development difficulties can threaten to delay the development of a drug candidate. Re-examination of such difficulties may reveal opportunities for process optimization. Informal discussion on the topics below may help develop directions for future research.

Threat / Opportunity

• Difficult control of semi-batch operations / Continuous processing
• Meeting specifications for low-level impurities (e.g., genotoxins) in the API / Consistent production of safe, high-quality API
• Extended operations can degrade products with labile stereocenters / Crystallization-induced asymmetric transformation (CIAT) processes can improve yields of thermodynamic products
• Non-specific reactions / Developing selective processes, perhaps using scavenging substrates

#2: Meeting the Challenges of Outsourcing Difficult Chemistries
Moderator: Roger P. Bakale, Ph.D., Executive Director, Process R&D, Sepracor, Inc.

Threats and opportunities for process development:
Customer perspectives on CRO/CMO selection strategies (pros & cons)

·         Innovative and technology-rich strategies vs. traditional well-established methodologies

o        Supply vendor technology/process vs. develop technology at CRO/CMO

·         ROI time horizon for process selection: Early vs. late (commercial success vs. supply deliverable) and factoring in risk of candidate failure?

o        Short term vs. long term (single product needs vs. multiple product & project applications)

·         Green processing 

o        Environmentally friendly

o        Renewable feedstocks

o        Low operational energy consumption and waste

o        Catalytic approaches & recycling

·         PAT / improving process performance, opportunities to streamline validation

o        Success/failure ratios, risks, rewards

·         Regulatory and logistics (challenges & strategies)

o        DMF driven vs. customer-data driven (data storage/retrieval reporting)

o        Product specifications & quality expectations (realistic?)

o        Quality systems and documentation

o        Warehousing/storage/shipping

o        Infrastructure and personnel

o        Local/regional political stability

·         Proprietary technology (easily IP protectable) or established approaches (narrow IP, trade secret approaches) or both

o        Supply agreement costs/risks

o        Life cycle management challenges & opportunities

o        Who pays maintenance cost: “Knowledge Basis”

#3: The Need to Introduce Superior New Synthetic Technologies (Opportunity) vs. Project Dynamics that Suggest Waiting (Until It Is Too Late?) (Threat)
Moderator: Quirinus B. Broxterman, Ph.D., Corporate Scientist – Route Scouting & Selection, DSM Pharmaceutical Products – Advanced Synthesis, Catalysis & Development (DPP-ASC&D)

CMO perspectives on introduction of new synthetic technologies vs. scaling and running existing chemistry:

Pros

• Potentially lowered fixed and variable costs of processes
• Compliance with modern society's demand for cleaner and more sustainable processes and chemistries
• Defense line against Low Cost Countries?

Cons

• Attrition rate of (early) clinical trial projects
• Division of IP on application of new technologies in project at hand
• Who is going to pay for it?
• Requires more time, whereas direct delivery is needed 

#4: Green Chemistry: Threat or Opportunity?
Moderator: Chris Davis, D.Phil., Codexis, Inc.

Among the questions we will consider:

• Is any well-designed process inherently green?
• Is a bio-process a green process?
• How much should analysis of the full life cycle of raw materials be included in process development?
• How will carbon credit trading affect process development?

9:40 Chairperson’s Remarks

9:45 Title to Be Announced 
Joseph D'Antuono, Ph.D., Vice President, Process Chemistry Solutions, ROW2 Technologies, Inc.

10:15 Cost-Efficient Deprotection of PMP: Toward an Industrially Viable Asymmetric Mannich Protocol
Quirinus B. Broxterman, Ph.D., Corporate Scientist – Route Scouting & Selection, DSM Pharmaceutical Products – Advanced Synthesis, Catalysis & Development (DPP-ASC&D)
A number of conceptually very useful asymmetric synthesis technologies, such as asymmetric Mannich reactions, proceed through imine intermediates. In many of these, use of the para-methoxyphenyl (PMP) protecting group is essential. State-of-the-art deprotection technology such as use of ceric ammonium nitrate, however, is not cost effective from an industrial perspective. This slows down the large-scale use of asymmetric Mannich technology for the production of chiral intermediates for the pharmaceutical industry. Therefore, we developed cost-efficient removal technologies: the use of TCCA (trichloroisocyanuric acid) and other oxidants lead to deprotection in high yield. Moreover, laccases (EC 1.10.3.2), especially in the presence of mediators, also proved to be an efficient enzymatic removal method.

10:45 Networking Coffee Break, Poster and Exhibit Viewing

11:30 Case Study of Outsourcing Process Chemistry 
David Mitchell, Ph.D., Research Advisor, Chemical Process R&D, Eli Lilly and Co.
The goal of this presentation is to discuss the process chemistry of a potential pharmaceutical target. As a case study, outsourcing strategies, enabling greener chemistry along with improved synthesis efficiency, will be presented. This talk discloses current trends along with challenges faced in process R&D. Using a central molecule as a theme, several current tools that are available for process development will be demonstrated for solving process chemistry problems.

12:00 pm Process Validation from the Standpoint of an Organic Chemist
Neal G. Anderson, Ph.D., Anderson’s Process Solutions
The benefits of validating processes will be discussed. Proactive validation requires laboratory scouting to determine suitable ranges of parameters for rugged processing. For successful process introduction fail-safe operations must be considered. Organic chemists can provide practical guidelines to validate processes on the manufacturing scale. Points will be illustrated by brief case studies.

12:30 Lunch on Your Own or Luncheon Technology Workshops
(Sponsorships Available)

2:00 Chairperson's Remarks

2:05 Spotlight on Biologics Process Development: Challenges in mAb Production and Application of PAT
Amit Banerjee, Ph.D., Research Fellow, Global Biologics Worldwide Pharmaceutical Sciences, Pfizer, Inc.
Application of Process Analytical Technology (PAT) to monitor and control the key parameters of the cell cultivation bioreactor used for the manufacture of monoclonal antibody (mAb) will be discussed.

2:50  An Overview of Micro-technology in Process Analytics 
Mel Koch, Ph.D., Director, Center for Process Analytical Chemistry (CPAC), University of Washington
There has been advancement in measurement tools that support efforts in improving process monitoring and control. These advances have been driven by the use of Quality by Design (QbD) approaches to achieve process understanding. A key part of these advances has been in miniaturization technology, where the development and application of micro-analytical tools in laboratory-based high-throughput experimentation, process optimization, and subsequent process monitoring will have a large impact. These micro-analytical tools, combined with advances in process sampling and sensor platforms, will be described as a valuable approach for implementing Process Analytical Technology (PAT) for process development. The possibility to obtain a competitive edge and yet demonstrate green chemistry is achievable. 

3:35 Networking Refreshment Break, Poster and Exhibit Viewing
(Last Chance for Viewing)

4:05 Isolation of the Drug Substance Impurities at 0.05–0.1% Level Using At-Column Dilution, Mass-Driven Collection, and Comprehensive Automation of the Entire Process
Michael Breslav, Ph.D., Research Fellow, US EC [East Coast] Early Development, Johnson & Johnson Pharmaceutical Research and Development
ICH guidelines suggest identification of the process impurities and/or degradation products present at or over certain levels in new drug substances. For example, if the maximum daily dose is less than or equal to 2g/day, impurities present at > 0.05% should be reported, and impurities present at > 0.1% should be identified. However, if the daily dose exceeds 2g/day, impurities present at > 0.03% should be reported, and impurities present at > 0.05% should be identified. Identified impurity is defined as an impurity for which a structural characterization has been achieved. Identification usually requires isolation of these impurities for structure elucidation by NMR. Our goal was to develop new methods, techniques, and processes in preparative chromatography in order to achieve isolation of the low-level impurities in a short time frame. At-column dilution, mass-driven collection, and extensive automation allowed for the efficient isolation of the impurities in various drug substances, followed by the structure elucidation and subsequent reporting and registration of the impurities and standards within J&J. 

4:35 Anticipation of Scale-Up Issues in Process Development: Scale Up Risk Evaluation (SURE)
Dr. Ir. Frans L. Muller, Associate Principal Scientist, Process Research & Development, AstraZeneca
Scale Up Risk Evaluation (SURE) is a tool developed to anticipate scale-up issues early on in the development of a new compound. The principle of SURE is based on that of a hazard and operability study (HazOp). For each operation in a process recipe, various scale-up/down scenarios are identified. A scenario represents an unplanned change in conditions from those specified in the recipe. The potential impact of a scenario on the process is qualitatively assessed and identified as a "threat" or an "opportunity." The scale-up scenario is then scored on: (i) The likelihood process conditions change with scale; (ii) The likelihood the operation affects the product quality or process operability. A number of examples from SURE studies will illustrate the use of the tool. The output of a SURE study is risk matrix, and a prioritized list of the threats and opportunities that provide development drivers for the development team. We conclude with an analysis of the data generated by SURE studies in AstraZeneca that demonstrates how risk changes as processes move through the stages of development. 

5:05 Close of Day Two