running complex operations under the determined containment.
Figure 2- Proposed OEB strategy Note- For ease of interpretation, chemical substances are grouped into a simplified system of OEBs, rated 1-5 from the least hazardous( Band 1) to the most hazardous( Band 5)
risk management, design space and control strategies to ensure product quality and safety. 2, 3
This approach will limit the overall amount of hazardous compounds. Potential critical quality attributes( CQAs) are identified early in the process to establish the design space and determine the safest and most efficient synthesis. Building a solid understanding of the operational parameter ranges supports the process optimisation, scale-up, robustness, quality consistency and safety of the synthesis.
Continuous flow chemistry offers advantages such as reduced risk of exposure during the manufacturing process in addition to improved control over reaction conditions and enhanced yield. Including the concept of automating a continuous manufacturing line, encompassing API synthesis and downstream processing( e. g., crystallisation, filtering and drying), can be implemented. They may be planned modularly, giving flexibility to accommodate various combinations of unit operations.
Integrating process analytical technology( PAT) tools are of primary importance for HPAPI process to a much greater extent than API does, by identifying critical process parameters( CPPs) and measuring in real-time, using the most appropriate in automation, sampling, multivariate data acquisition and data storage systems, among others, so as to control CQAs.
The use of PAT reduces unnecessary sampling, thereby reducing the risk of contamination. Also, since PAT uses mostly non-destructive methods, there is reduced sampling and testing that would otherwise lead to production waste.
Using simulation approaches, such as kinetic modelling, helps to implement and test the developed control strategy, making it possible to reduce the number of in-process controls( IPCs). Based on virtual reaction conditions, smart selection of optimised conditions can be tested directly in the wet lab environment, minimising the work to be performed in the state-ofthe-art dedicated containment lab. Typically, the necessary equipment includes a glovebox, walk-in fume hoods offering flexible spaces for
Case study 1
In the following two case studies, the selected route design highlights the importance of convergent synthesis in potent compounds production. A strategic approach for route design is to bring convergence to the synthesis so that the potency is built into the molecule late in the process and the upstream stages can be handled in a conventional plant.
Bortezomib( BTZ) is a dipeptide boronic acid proteasome inhibitor that is used in the treatment of multiple myeloma( MM). The synthesis of BTZ( Figure 3) involves the assembly of key intermediates, pyrazine-Lphenylalanine( 3) and dioxaborol( 4). 4 Intermediate 5 was synthesised from the condensation of 3 with 4 under DCC and dichloromethane at 20-30 ° C for three hours.
Without further purification, 5 is converted to final target product( 6) by trans esterification in the presence of isobutyl boronic acid and methanol at 25-30 ° C for one to two hours. The use of DCC and methanol gave excellent yields of BTZ compound.
Compared to other reported methods, this alternative and convergent synthesis approach was obtained in a reduced number of steps, mild conditions and higher yields( 30-35 %).
Figure 3- Overall synthesis route to Bortezomib
24 SPECIALITY CHEMICALS MAGAZINE ESTABLISHED 1981