Development of Scalable Production Processes

Premises Expression system defined Process scalability Primary definition of process No validation Refinement of operational control parameters Development of scale-down process models for validation Process out-of-limit definition Finalization of process control parameters Fixed and defined process and products Pivotal process validation and characterization studies Validated production process Well-characterized product Robust process ... 

In the development of new products, optimization of the fermentation medium for titer only often ignores the consequences of the medium properties on subsequent downstream processing steps such as filtration and chromatography. It is imperative, therefore, that there be effective communication and understanding between workers on the upstream and downstream phases of the product development if rational trade-offs are to be made to ensure overall optimality of the process. One example is to make the conscious decision, in collaboration with those responsible for the downstream operations, whether to produce a protein in an unfolded form or in its native folded form the purification of the aggregated unfolded proteins is simpler than that of the native protein, but the refolding process itself to obtain the product in its final form may lack scalability. 

To measure the scalability of a process it is necessary to understand the chemistry and reaction kinetics involved and then to determine their impact on well-defined critical quality attributes desired of the product in order to find the optimum processing window within which there is certainty that the product will be of acceptable quality. However, these data are not readily available for many pharmaceutical chemistry reactions, so a subjective measure of a the scalability, robustness, and greenness of many processes has been developed by Pfizer based on operator knowledge and experience to assist development teams both in the laboratory and in pilot plants to develop greener processes [28]. 

The demand for increasing control of physical attributes for final bulk pharmaceuticals has necessitated a shift in emphasis from control of nucleation to control of growth. This trend is also finding application for control of purity and improved downstream handling for both intermediates and final bulk products. The obvious critical factors then become seeding and control of supersaturation. Quantification of these factors for each growth process is essential for development of a scalable process. Much of the discussion to follow focuses on the growth process and methods to minimize nucleation. 

The hydrolytic kinetic resolution (HKR) of racemic terminal epoxides catalyzed by chiral (salen)-Co(III) complexes provides efficient access to epoxides and 1,2-diols, valuable chiral building blocks, in highly enantioenriched forms. While the original procedure has proved scalable for many substrates, several issues needed to be overcome for the process to be industrially practical for one of the most useful epoxides, epichlorohydrin. Combined with kinetic modelling of the HKR of epichlorohydrin, novel solutions were developed which resulted in linearly scalable processes that successfully addressed issues of catalyst activation, analysis and reactivity, control of exothermicity, product isolation, racemization, and side-product formation. 

Optimization of this synthetic route to LY414197 positioned it as a reasonable candidate as a production process, provided a scalable resolution methodology is developed. Much effort was thus expended in hnding an acceptable resolution process of the TH(3C. 

The naphthyl ligand provided more challenges in developing a scalable process, but this was achieved.This hgand is superior for the amination of racemic epoxybutene, by a DYKAT process. We have developed this reaction to work on a kilogram scale at an acceptable S/C ratio of 1000 1. The product from this reaction, phthalimidovinylglycinol... 

Dr. Mukund Chorghade then introduces readers to the field of process chemistry the quest for the elucidation of novel, cost-effective, and scalable routes for production of active pharmaceutical ingredients. The medicinal chemistry routes used in the past have often involved the use of cryogenic reactions, unstable intermediates, and hazardous or expensive reagents. A case smdy of the development of a process for an antiepileptic drug is presented readers will also see how problems in the isolation, structure elucidation, and synthesis of metabolites were circumvented. Described is an interesting application of the technology of metalloporphyrins assisted metabolite prediction, estimation, quantitation and synthesis. 

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