Process-scale considerations safety

The principal considerations involved in design of a process-scale chromatographic purification include scalability, reproducibility, safety, and validatability. Cost factors, however, must by necessity enter into all industrial decisions. Due to the high value-added nature of most biopharmaceuticals, this cost factor is driven by throughput, rather than by capital investment cost. 

During the development of a chemical process, a choice must be made regarding the type of reactor to be used on a plant scale. Some theoretical considerations and their practical impact on reactor issues are presented here. Choosing the right type of reactor can indeed improve the safety of the process. The considerations are reflected as well in the mode of operation. Reactors are characterized by type of operation (i.e., batch, semi-batch, and continuous). 

The fine chemicals business is characterized by a small volume of products manufactured. Therefore, batch production predominates and small-scale reactors are used. The need to implement fine chemistry processes into existing multiproduct plants often forces the choice of batch reactors. However, safety considerations may lead to the choice of continuous processing in spite of the small scale of operation. The inventory of hazardous materials must be kept low and this is achieved only in smaller continuous reactors. Thermal mnaways are less probable in continuous equipment as proven by statistics of accidents in the chemical industries. For short reaction times, continuous or semicontinuous operation is preferred. 

At AWE, the Lewis acid-catalyzed bulk polymerization route has been the main synthesis route to poly(m-carborane-siloxane) elastomers. Our selection has been based on considerations of safety, availability of key reagents, and ease of scale-up operations. An understanding of the physical and chemical properties of these materials, and how these properties can be modified through the synthesis process, is essential in order to develop materials of controlled characteristics. 

The RC1 is an automated laboratory batch/semi-batch reactor for calorimetric studies which has proven precision. The calorimetric principle used and the physical design of the system are sound. The application of the RC1 extends from process safety assessments including calorimetric measurements, to chemical research, to process development, and to optimization. The ability of the RC1 to generate accurate and reproducible data under simulated plant scale operating conditions may result in considerably reduced testing time and fewer small scale pilot plant runs. 

Scale-up can also have a significant effect on the basic process control system and safety systems in a reactive process. In particular, a larger process will likely require more temperature sensors at different locations in the process to be able to rapidly detect the onset of out-of-control situations. Consideration should be given to the impact of higher-temperature gradients in plant-scale equipment compared to a laboratory or pilot plant reactor (Hendershot 2002). 

For a study of methods of assessment of thermal runaway risk from laboratory to industrial scales [2], A more detailed but eminently clear treatment of this and other needful safety considerations on scaling reactions up to production has since been published [3], So slight a scale-up as replacing two charcoal filters by one bigger one may cause a fire because heat loss was reduced [4], A journal largely devoted to scale-up of organic chemical processes has been launched [5]. 

But even a small-scale trial-and-error strategy has to be organised within society. As discussed in the previous section, iimovations are rather improbable and disadvantaged by stractural frameworks. Iimovations depend upon freedom for them to be developed. At the same time safety barriers have to be formulated within which the search process can move freely. For example, possible environmental effects must be anticipated, necessitating controlled release in small increments and retrievability must be ensured. (Quantitative and qualitative restrictions must be imposed so that retrieval and repair options can still be effective if a trial is aborted. This approach is more successful if the persistence and spatial range of a chemical is low than for persistent chemicals like CFCs and PCBs. This requires that limited Teaming spaces or experimentation spaces have to be created intentionally under technical and economic risk considerations. Small increments and a steady increase are to be preferred, accompanied by intensive monitoring of detectable consequences. 

All process development starts with chemistry. The selection criteria for the most suitable chemistry for a continuous process do not suffer from the same constraints as those for a large-scale batch process. For example, highly exothermic reactions are not only possible in a flow reactor, but are in fact preferred [47]. As operator exposure will be low and so will stock levels, different safety considerations come into play that may allow utilisation of otherwise intolerably toxic reagents. Process telescoping is a necessity to minimise the number of intermediate isolations. Examination of all these factors is facilitated by online analysis because of its speed and maintenance of experimental integrity (i.e. no requirement for sampling). 

To gain FDA approval or license for marketing, a pharmaceutical product must be shown to be safe and effective for its proposed or intended use. The drug company or sponsor must also provide evidence to show that the processes and control procedures used for synthesis, manufacture, and packaging are independently validated to ensure that the pharmaceutical product meets established standards of quality. The overall effort from the inception of a new molecular entity and the establishment of analytical, scale-up, and quality control procedures, to the collection of safety and efficacy data for consideration by the FDA as part of an NDA or BLA, is called the drug development process. 

These authors suggested that the process could be scaled up industrially and was attractive because, although the water-miscible solvents have potential for flammability, it was operated under carbon dioxide gas and at low temperatures which considerably improved the safety of the overall operation. 

As already mentioned, major industrial fluoroaromatics are manufactured by fluorodediazoniation (ca. 9000 tons were consumed in 1991).71 Due to the hazards inherent in the unstable diazonium compounds, safety considerations are very important in this technique which, in general, is not performed batchwise on a unit scale larger than 5 m3. In order to circumvent this limitation, continuous processes have been proposed. 

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