DAY 1, WEDNESDAY, JUNE 13, 2012
7:30 am Registration and Morning Coffee
8:30 Chairperson’s Opening Remarks
Neal Anderson, Ph.D., President, Anderson’s Process Solutions
8:40 Identification of a Process for the Large Scale Preparation of APD916, a Potent Histamine H3 Receptor Antagonist
Antonio Montalban, Ph.D., Director, Chemical R&D,
A chemical reaction sequence for the large scale preparation of APD916, a potent histamine H3 receptor antagonist, based on a biphenylethanol starting point was identified. This chemical route was found to be adequate to produce a suitable salt form of the API under cGMP conditions. The successful preparation of over 10 kg of high quality APD916 with this process allowed it to be selected for further development.
9:10 Route Redesign for Scale-Up: Catalysis Applied to a Complex Drug Candidate
Roman Davis, Ph.D., Manager, Early Product Development, GlaxoSmithKline
Catalytic methods were employed and scaled to a drug candidate, where previous syntheses were insufficiently safe to scale. Transition metal catalysis by Cu (“CF3Cu”), Ir (C-H activation), and Ru (ring-closing metathesis) were applied to prepare a complicated tetra substituted pyrazolopyridine drug candidate at GlaxoSmithKline. The synthesis is presented in three parts: CF3 installation in a complicated heterocycle; C-H activation at a remote site; enantioselective cyclopropanation and aminoketone reduction.
9:40 Process Development and Strategic Considerations for the Synthesis of a Tetrazole-Containing API
Neil F. Langille, Ph.D., Scientist, Chemistry Process R&D, Amgen
A case study is presented in which a preliminary synthesis of a structurally complex API included conversion of an unactivated nitrile to a tetrazole as a late-stage GMP step. An alternate convergent approach was devised where a metalated tetrazole could be added to an advanced fragment, thereby removing the potentially high-energy tetrazole formation from the GMP sequence. The resulting strategy provided access to the target molecule with decreased overall cost, eliminated specialized reagents from the synthetic route, and avoided transfer of GMP steps to a specialized vendor.
10:10 Coffee Break with Poster Viewing
10:40 Route Selection and Process Development of Bosutinib, A SRC Kinase Inhibitor
Shengquan Duan, Ph.D., Senior Principal Scientist, Chemical Research and Development, Pfizer
Bosutinib is currently being developed as an orally active Src and Abl kinase inhibitor. I will present the different criteria, such as robustness, greenness, cost-efficiency and potential genotoxic impurities, that played a role in selecting the manufacture route for Bosutinib. Five bond forming strategies to make Bosutinib API will be presented and each approach will be critically evaluated.
11:10 Route Scouting and Scale-Up Synthesis of a TRPV1 Antagonist
Jing Liu, Ph.D., Senior Scientist, Scale-Up Synthesis, Janssen Research & Development
An efficient and practical synthesis of a TRPV1 inhibitor bearing a thiazolo[5,4-d]pyrimidine core was developed. The initial synthesis was modified to facilitate acylation of 5-aminopyrimidine and subsequent thiazole formation. The synthesis features a two-pot, five-step process for the construction of the thiazolo[5,4-d]pyrimidine ring. The new route is concise, chromatography-free, and amenable to large-scale preparation.
11:40 Buffet Lunch Provided in the Homestate Cafe (Please Bring Your Ticket)
1:00 Chairperson’s Remarks
Ambarish Singh, Ph.D., Associate Director, CMC, Bristol-Myers Squibb
1:05 Applying Impurity-Specific Limits to Guide Process Controls
Michelle Kenyon, DSRD, Genetic Toxicology, Pfizer Global Research and Development
It is widely accepted that diligence is required to limit human exposure to impurities from pharmaceutical products. Several regulatory documents, including ICH Q3A, Q3B and Q3C, an EMEA guideline on the limits of genotoxic impurities and a draft FDA guideline regarding genotoxic and carcinogenic impurities, recommend some default control thresholds (e.g. identification, reporting, and qualification thresholds and the Threshold of Toxicological Concern). Similar to the permissible daily exposure limits established by ICH Q3C for some solvents, when appropriate safety data exists for an impurity, it is important to consider compound-specific limits as lower levels may be important to ensure patient safety or higher levels may be justified. Therefore, it is important for process chemists to engage with toxicologists when establishing process control limits for impurities. This talk will focus on the application of compound-specific impurity limits and will use case examples to demonstrate methods that can be used to establish limits for different types of impurities.
1:35 Biocatalysts: Removal and Tracking during API Production
Jacob Janey, Ph.D., Senior Research Chemist, Chemical Development, Bristol Myers Squibb
One of the major challenges with the use of biocatalysts during GMP production is the removal and subsequent fate of a complex mixture of components present in most commercial enzyme preparations. This talk with focus on efficient, scalable strategies for biocatalyst removal along with subsequent tracking and detection.
2:05 Refreshment Break with Poster Viewing
2:30 Expanding Flow Chemistry: On-Demand Gas Addition, Organic Synthesis and Organometallic Chemistry
Nicholas Leadbeater, Ph.D., Associate Professor, Chemistry, University of Connecticut
The use of an on-demand gas delivery flow reactor in a range of synthetic transformations involving reactive gases will be presented, attention being focused on hydrogenation and carbonylation chemistry. Alongside this, we will also report other developments in organic and inorganic flow chemistry from our research group.
3:00 Preparative Synthesis via Continuous Flow of a Propargyl Boronate: A General Propargylation Reagent
Daniel Fandrick, Ph.D., Principal Scientist, Chemical Development, Boehringer-Ingelheim Pharmaceuticals, Inc.
This talk will discuss the limitation encountered with a batch process, a mechanistic hypothesis, development of a continuous flow process and application to produce ~300 kg of the key reagent.
3:30 ROUNDTABLE BREAKOUT DISCUSSIONS
In this interactive session, audience members choose one of the breakout topics listed below and join the moderated discussion at hand. Participants are encouraged to share examples from their work, vet ideas with peers and ask questions of one another. This discussion is a relaxed, informal exchange amongst scientists and is not meant to be, in any way, a corporate or specific product discussion.
Topic: Process Control Justifications
Co-Moderators: Matthew Ravn, Ph.D., Senior Scientist III, GPRD Process R&D, Abbott
Robert Hughes, Ph.D., Chemical Development, Vertex Pharmaceuticals Inc.
- Success or failures in experimental models – pathway to file and do they provide regulatory flexibility?
- How does interpretation of QbD impact execution of Process Control Justficiations (PCJ)?
- PCJ experimental approaches - forward (process), backward (risk assessment) or somewhere in between?
- Success or failures on incorporation of PAT into PCJ and process validation.
Topic: Impurities and the Regulatory Environment
Moderator: Michelle Kenyon, DSRD, Genetic Toxicology, Pfizer Global Research and Development
- What type of impurity information (safety/quality) is being disclosed in regulatory submissions?
- How do we deal with differing regulatory views regarding impurities for global submissions?
- Are compound-specific PDEs being used/accepted to justify levels of impurities above the TTC?
- How is ICH S9 being applied for oncology products and is it generally accepted by regulators?
Topic: Control of Final Form
Moderator: Neal Anderson, Ph.D., President, Anderson’s Process Solutions
- Advanced technologies for detecting crystal polymorphs
- How much of a crystal polymorph is too much?
- What are the most relevant critical quality attributes?
- What/when to report about crystal polymorphs
4:30-5:30 Welcome Reception in the Exhibit Hall with Poster Viewing
*Separate Registration Required