Process Development and Scale Up

The scale-up to industrial size was based on data gathered from the two pilot plants, which were then elaborated for the design of the commercial unit. The above data were also used for the contemporaneous development of an in-house proprietary reactor simulator for training purposes. 

Conversely, a wider range of superficial gas velocities than that of the pilot plant was chosen to increase the flexibility of the riser-downcomer hold-up ratio. Notably, the industrial-scale plant operates with superficial velocities that are generally higher than those used in the pilot plants, but within the original design range. Further room for maneuver was added by increasing the head of the recirculation compressor relative to that in use at the pilot plants. 

Lastly, the riser-downcomer coimection was also studied during the scale-up. 

The thermal stresses due to the temperature increase along the downcomer, and the consequent different elongations of riser and downcomer, were not negligible. To address that issue, the polymer transfer line from the riser into the downcomer was shaped as a 270° bend, to act as an elastic (compensation) element. 

The Brindisi Spherizone unit was started up in August 2002 - seven years after research began. The plant has been producing commercially since early 2003 with a high operability. It has proven its competitive operating costs, ease of start-up, shutdown and recovery from operating setbacks as well as short transition times. It 

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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. 

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. 

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. 

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. 

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

The (ft)-4-phenyl-2-oxazolidinonc auxiliary was used in the process development and scale up of Novartis purine nucleoside phosphorylase inhibitor PNP405 (16) (Scheme 23.2).43 Asymmetric alkylation of 17 with bromoacetonitrile provided a 7 1 diastereoisomeric ratio of crude 18. Recrystallization afforded 18 in 80% yield and >99% de. Simple addition of sodium borohydride in tetrahydrofuran (THF)-water at room temperature44 resulted in the desired y-cyano alcohol 19 and recovery of the auxiliary. 

By the beginning of 1990, the reactions in Scheme 10 had mostly reached the Method stage of development (see Chapter 8 for the definition of Method). In short, considerable process development and scale-up work, in collaboration with manufacturing and others, was still needed to create a process. 

Sie ST. Process development and scale up IV. Case history of the development of a Fischer-Tropsch synthesis process. Rev Chem Eng. 1998 14(2) 109—57. 

In multiple impeller systems, it appears that conditions in the region around the impeller nearest to the point of gas injection have the greatest influence on system performance. In view of the work of Tereshkevitz, which showed a large influence of bubble size (as compared with liquid shear) on mass transfer, a tentative conclusion is that the average bubble size is determined mostly by the conditions near the gassed impeller. It follows that primary emphasis in process development and scale-up should be placed upon selection of the impeller and the gas-inlet conditions variations in the over-all system geometry, with the possible exception of liquid depth, may be of secondary importance. 

R. Kirkendahl, Good Manufacturing Pracitcc Compliance through Product/Process Development and Scale Up Phase, PREP 99. Sunday. May 23. San Francisco, CA. 1999. 

The pilot plant and its staff play a critical role in technology evaluation, scale-up, and transfer activities of new products. These activities begin early in the development cycle and include technical aspects of process development and scale-up, organization and responsibilities of technology-transfer teams, documentation of the transfer process, and often preparation for an FDA pre-approval inspection (PAI). A properly designed and operated pilot plant can enhance the collection of scientific data necessary to support internal transfer activities, as well as regulatory submissions and FDA PAIs.P ... 

The process development and scale-up of APIs require a multidisciplinary cooperation be-... 

In reality, product and process development and scale-up will be progressing concurrently in order to meet the demands of Phase I and II clinical and long-term safety supplies. The process used for initial clinical supply manufacture will probably be relatively small scale (laboratory scale). As more drug substance becomes available, and the clinical requirements increase, the product batch size will increase to pilot scale, and the process may have to be modified during scale-up. If drug substance is available and very large Phase III studies are anticipated, it may be essential to scale-up to production scale and transfer the process to the commercial production site. 

It is much more difficult to carry out small-scale tests for most of the pressure agglomeration methods and obtain results that are meaningful and can be used for process development and scale-up. 

Carta, G. and Jungbauer, A. (2010) Protein Chromatography Process Development and Scale-Up, Wiley-VCH Verlag GmbH, Weinheim. 

MEETING THE CHALLENGES OF PROCESS DEVELOPMENT AND SCALE-UP OF ACTIVE PHARMACEUTICAL INGREDIENTS... 

Repeatability and reproducibility are two key factors in determining the success of process development and scale-up work. Failing to get the desired yield and quality consistently at a commercial scale is a humbling experience for any process development chemist. There... 

There is a distinction that some people recommend be made between process development and scale-up see, for example, Basu, P.K. et al.. Consider a new approach to pharmaceutical process development, CEP, August 1999, p. 82. 

In several investigations the feasibility of development of a sustained-release form for diclofenac sodium was studied. Matrix-type formulation was designed, which appears to be a very attractive approach from process development and scale up points of view. HPMC is the most important hydrophilic polymer used for the preparation of oral controlled-release drug-delivery systems. - One of the most important characteristics of HPMC is the high swellability, which has a considerable effect on the release kinetics of the incorporated drug. 

Sie ST, Krishna R. Process development and scale-up HI. Scale-up and scale-down of trickle bed processes. Rev. Chem. Eng. 1998 14 203. 

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