Wednesday, October 26
8:00 Registration and Morning Coffee
8:20 Chairperson's Remarks
8:30 Some Emerging Approaches to Separation and Purification in the Pharmaceutical Industry
Dr. Berkeley W. Cue, Jr., Consultant (former VP Pharmaceutical Science, Pfizer Global R&D)
|
Supercritical Fluid Chromatography
(SFC) for Chiral Separation
|
9:00 Addressing Purity and Enantiopurity Concerns in Pharmaceutical Process
Dr. Peter Sajonz, Research Fellow, MRL, Process Research, Merck & Co., Inc.
A variety of options are available for solving purity and enantiopurity problems in pharmaceutical process research. We present here an integrated family of approaches used for solving the most frequently encountered purity concerns, including chiral resolution, enantiopurity upgrade, removal of minor impurities, removal of color, and removal of undesired metal impurities.
9:30 Rapid and High-Throughput Separation Technologies - Steady State Recycling (SSR) and Supercritical Fluid Chromatography (SFC) for Chiral Resolution of Pharmaceutical Intermediates
Dr. Tony Yan, Separation Chemist, Process R&D, Amgen Inc.
This presentation will cover the separation conditions, results, productivity and solvent cost of SSR and SFC techniques for the enantiomeric resolution of two pharmaceutical intermediates at kg scale. A productivity of 720 g racemate/kg stationary phase/day was achieved using the SSR separation technique. The solvent usage is only ~220 liters of solvent per kg racemate. This method's development and process optimization of the SSR is discussed. A few examples of SFC separations will also be presented.
10:00 SFC at Pfizer
Joe Collins, Manager, Chiral Chromatography Lab, Pfizer Inc
| 10:30 Automating the Purification Process for Activated Carbon with Significant ROI
|
Sponsored by: |
Dr. Michael Lally, Vice President of Marketing, Biotage Discovery Chemistry Group
This presentation reviews a pharmaceutical case study with a process change in an existing cGMP facility for a $500M per year API. The traditional process used a deep-bed powered activated carbon (PAC) approach. Working closely with Biotage on lab- and pilot-scale trials, the pharmaceutical company installed a Flash 400 pre-packed cartridge system. This case study will explain how the new process reduced solvent consumption by 36%, cut process time by 40%, and increased product yield by 0.3%. Return on investment was realized with the first batch and the new process was quickly validated by the client's corporate QA and QC team. |
|
|
|
11:00 Coffee Break, Poster and Exhibit Viewing
|
Simulated Moving Bed (SMB) for Chiral Separation
|
11:30 The Optimization of SMB Processes for Large Scale Enantiomer Separations
Dr. Geoffrey Cox, VP & General Manager, Separation Solutions, Chiral Technologies Inc
Simulated moving bed chromatography is of growing importance in the production of pure enantiomer intermediates and drug molecules. As with any unit operation, the process requires optimization to ensure the lowest cost per kg of finished product. Optimisation processes, the impact of operating parameters and material properties on the cost of production and case studies will be discussed.
12:00 Unexpected Partial Racemization of Substituted Benzodiazepinone Enantiomers
Dr. Teri Hochdorfer, Scientist, Separation Science Group, Pfizer Global R&D Groton Labs
A request was made to the Pfizer Separation Science group to resolve a significantly functionalized, racemic benzodiazepinone. Numerous chiral stationary phases were evaluated and S,S Whelk-O1 was eventually determined to be the most advantageous. Solubility of the racemate was very poor in all solvents but tetrahydrofuran. Trial separations were performed on the above chiral phase in mixtures of methyl tert-butyl ether and tetrahydrofuran in which the latter solvent was the major component. A clean enantiomeric separation was effected and a facile scale-up in the pilot plant was anticipated. However, re-analysis of the desired cuts after storage indicated the re-appearance of a small proportion (~3%) of the undesired enantiomer. Surprisingly, the ratio of forms in the resulting scalemic mixture then remained completely stable. It did not appear that the diminution in chiral purity was dependent on solvent, temperature, or the presence of a contaminant. Subsequent studies eventually showed that partial racemization was linked to restricted rotation (atropisomerism) of the benzodiazepinone ring and an unfortunate ability of the high energy form of the undesired enantiomer to co-elute with the low energy form of the desired. The talk will delineate the analytical methods we used to unravel the conundrum of (apparent) partial racemization. It will also describe the successful large-scale separation of the racemate that recently occurred in our pilot plant.
|
Chiral Separation Technology Watch Session
|
Technology Watch One
12:30 Automated Method Development and Purification of Chiral Compounds
Mr. Gary Yanik, President, Contract Manufacturing, PDR-Chiral Inc.
As pharmaceutical companies transition to prodominantly enantiopure formulations, the need to rapidly develop and optimize methods for chiral separations is growing and becoming more difficult to achieve quickly. Chemists in preparative and process environments are increasingly under pressure to find chromatographic conditions that are simpler and more appropriate for their needs. For example, the preparative chemist may inherit a method with additives that are difficult to remove or he may receive a method with limited loading.
Technology Watch Two
12:45 New and Novel Continuous Separation Method and Media
TBA
Prime Separations, Inc (PSI) has developed a novel concept in separation and purification mechanisms, when compared to current practices. This new purification technology has application in the following industries: Chemical/ Pharmaceutical, Biotechnology, Bio-Mass and Environmental Remediation. PSI technologies are focused on Process Development and Scale–Up utilizing thin film functionalized coatings on various support materials. The Selective Capture Web System can be applied in a continuous capture, release and discrimination mode, uniquely configured to an industry, or customer specific target molecule. The continuous mode method and target specificity clearly differentiates PSI technology from current separation and purification methods and will contribute directly to significant cost savings by eliminating multi-step purification processes, reducing overall purification time and increasing process throughput. PSI will present laboratory data demonstrating a high-throughput system and will contrast the Belt Web Chromatographic Film System with conventional preparative column chromatography.
1:00 Lunch on Your Own
2:25 Chairperson's Remarks
2:30 HPLC-Based Calculation Method for the Determination of the Product Recovery During Selective Crystallization of Diastereomeric Salts and Other Preparative Separations
Dr. Michael Breslav, Principal Scientist Johnson & Johnson Pharmaceutical Research and Development
Selective crystallization of diastereomeric derivatives is a common method for enantiomeric separations. Investigation, comparison and optimization of the selective crystallization parameters (resolving reagents and conditions) require knowledge of the recovery of single enantiomers in the precipitate. In this work correlation between ratios of enantiomers found chromatographically in
racemate, precipitate and mother liquor, and subsequent recovery of precipitated enantiomers were recognized, established, and expressed mathematically. Consequently a simple way of getting the recovery measurements was applied and validated for the selective crystallization of synthetic dipeptides and diastereomeric salts. |
|
|
Dealing with Impurities and Trace Compounds:
Challenges for Synthesis and Purification
|
3:00 Development of a Sensitive GC-MS Method for the Determination of Trace Level Impurities in Active Pharmaceutical Ingredients
Dr. Hanlin Li, Principle Research Scientist, Analytical Research, Pfizer Inc.
A sensitive and selective GC-MS method with ppm level of LOQ was developed to determine a process related impurity (PRI) in an active pharmaceutical ingredient. A variety of analytical techniques including LC-MS, GC-FID, GC-ECD and GC-MS were evaluated during the method development. The method was used to analyze more than 60 pilot samples in support of process optimization. The same methodology was later applied to determine PRIs in other pharmaceutical drug substances with slight modifications.
3:30 Refreshment Break, Poster and Exhibit Viewing
4:00 Automated Peak Tracking for Comprehensive Impurity Profiling
Dr. Gang Xue, Principal Scientist, Analytical R&D, Pfizer Inc.
Comprehensive Orthogonal Method Evaluation Technology (COMET) provides a systematic and comprehensive drug impurity profiling strategy. It includes automated MS peak tracking by program-based mass spectral interpretation. The program first utilizes component data analysis to filter out most of the background ion signal, which dramatically reduces the noise. Then it passes the cleaned-up electro-spray ionization mass spectra (ESI-MS) through four sequential decision-making mass ion tests and determines molecular weights for every peak. The COMET system reduces the time required to obtain a comprehensive impurity profile from weeks to days, while the automated MS peak tracking takes only minutes to interpret all MS spectral data of interest.
4:30 Chairperson's Closing Comments
4:40 Close of Conference
