Development and scale

W. J. Dawson and M. K. Han, "Development and Scale-Up of Hydrothermal Processes for Synthesis of High Performance Materials," Proceedings of the Milton E. Wadsworth IH International Symposium on Mydrometallurgy, Aug. 1—5,1993. 

A few excellent books are also available on reaction engineering in the widest sense and from a fundamental point of view. These books treat the subject with mathematical rigor, yet are too inclusive to have any space left for details on experimental procedures. Here, the reader can find more insight and practical examples on the development and scale-up of... 

Fluid bed processes have been subject to many problems and uncertainties in development and scale up from bench-scale reactors. The fluidization behavior of each process seems different and very often does not meet expectations based on experience with earlier plants. With hindsight fluid cat cracking seems to be an ideal system from the point of view of easy operation and straightforward scale up. 

Sie, S.T. and Krishna, R., 1998. Process development and scale-up 1. Process development strategy and methodology. Reviews in Chemical Engineering, 14, 46-87. 

Although the asymmetric hydrogenation route to 3,3-diphenylalanine via this modified substrate preparation was not developed further, Dowpharma had a requirement to rapidly develop and scale up the manufacture of a related 3,3-diarylalanine product. The work to 3,3-diphenylalanine centred around substrate preparation and removal of impurities leading to high activity associated with the PhanePhos catalyst system allowed for a facile transfer from laboratory scale experiments to the commercial manufacture of the related diphenylalanine derivative by a robust, reproducible and scaleable procedure. 

BPD is a contract research facility, which started operations in 1996. From the storage of frozen materials, the customized laboratory services to the consulting in process development and scaling up, BPD has been accumulating useful experiences in the biotechnological scenario. Very flexible set of fermenters are used to satisfy customer needs, through very small and fast adaptation and modifications. Bioreactors productivity varies from 100 mg to 1000 mg scale. 

Chemical development and scale-up synthesis of drug compound... 

A novel homogeneous process for the catalytic rearrangement of 3,4-epoxy-l-butene to 2,5-dihydrofuran has been successfully developed and scaled-up to production scale. A tri(n-alkyl)tin iodide and tetra-(n-alkyl)phosphonium iodide co-catalyst system was developed which met the many requirements for process operation. The production of a minor, non-volatile side product (oligomer) was the dominating factor in the design of catalysts. Liquid-liquid extraction provided the needed catalyst-oligomer separation process. 

The goal of this chapter is to provide a brief overview of standard engineering methods for process development and scale-up and discuss their applicability to the pharmaceutical industry. Model-based design methods and their impact on optimization, scale-up, and process control are discussed. The state of the art is contrasted to a realistic desirable state where these methods become part of a new standard of technological articulation. 

General Considerations in the Development and Scale-Up of Cell Culture Processes... 

The following paragraphs provide several examples for uses of a compaction simulator during development and scale-up. In these cases, the Presster was used as the compaction simulator. 

FDA inspectors are instructed to look for any differences between the process filed in the application and the process used to manufacturer the bio/clinical batch. Furthermore, one of the main requirements of a manufacturing process is that the process will yield a product that is equivalent to the substance on which the biostudy or pivotal clinical study was conducted. Validation of the process development and scale-up should include sufficient documentation so that a link between the bio/clinical batches and the commercial process can be established. If the process is different after scale-up, the company has to demonstrate that the product produced by a modified process will be equivalent, using data such as granulation studies, finished product test results, and dissolution profiles. 

Conhnued development and scale-up confirmed that the recovery, racemization, and quality criteria could all be met from the use of the MCC approach to radafaxine. 

Phoenix technologies have developed and scaled up to pilot scale a procedure using a variable-time reactor [12]. The procedure uses TEMPO, catalyst, bleach. 

The next example originates from our own laboratory Two potential intermediates for the angiotensin-converting enzyme inhibitor benazepril can be synthesized using cinchona modified noble metal catalysts (3). While the hydrogenation of the a-ketoester has been developed and scaled-up into a production process (10-200 kg scale, chemical yield >98%, ee 79-82%), the novel enantioselective hydrodechlorination reaction (see Section in) could be a potential alternative to the established synthesis where the racemic a-bromobenzazepinon is used [75]. At the moment both selectivity and productivity of the catalyst are too low and substitution reactions occur less readily with the chloro analog. 

Construction of the influence matrix assists in identifying those variables with the greatest influence on key process or product characteristics. These variables are potentially the most critical for maintaining process control and should be included in the earliest experiments. Some may continue to be investigated during development and scale-up. 

AN INTEGRATED METHOD FOR DEVELOPMENT AND SCALING UP OF EXTRACTION PROCESSES Baruch Grinbaum... 

In conclusion, the process development and scale up already achieved for several organocatalytic reactions have shown that organocatalysis can be a valuable tool... 

Schirrmeister, S., Markowz, G., Bulk chemicals in microreactors development and scale-up of a new synthesis route into the pilot plant scale, in Proceedings of the 27th International Exhibition-Congress on Chemical Engineering, Environmental Protection and Biotechnology, ACHEMA... 

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