Figure 2 - Key step of the optimised synthetic route to Tesirine
Then , to limit the handling of highly potent compound , the number of unit operations should be reduced as much as possible . Therefore , each unit operation ( extraction , distillation , isolation , etc .) will be challenged to confirm its needs . The process should be adapted to the facility to ensure that all unit operations can be run within full containment . This is true for unit operations related to the process itself , such as reagent loading , IPC sampling or salt filtration , but also for the cleaning operation , which is sometimes very challenging with the highly potent compounds associated with small batch sizes . Finally , as for any process , the yield and the production scale should be increased to reduce as much as possible the number of batches and consequently the handling of highly potent compounds .
Risk mitigation in process industralisation
Risk mitigation continues with the industrialisation of the process . Precautions in terms of exposure must be taken at three different levels to secure the operations : process equipment , protective equipment and the facility . When selecting your process equipment , you will have several objectives : first , to make sure the equipment train is fully sealed from the main vessel to the piping and especially the connections ; next , to minimise the number of connections and invest in high quality drip-proof fittings . To limit the risk of breakage , metal is a better option than glass as the material of construction , but such solutions are not always readily available at the small production scale of HPAPIs . Cleanability is a well-known requirement for GMP . In this case , the high toxicity level makes it an even bigger challenge , especially when health-based data take your MACO below the classic 10 ppm rule . Cleanability can be optimised in the equipment design phase using computer modelling . Regarding protective equipment , two principles should drive your decisions : having physical barriers between the product and the workers , and giving priority to collective protection . At facility level , the safe transfer of samples and bulk product between departments ( production , QC and R & D ) is essential . At Novasep ’ s Le Mans site in France , we have equipped the ADC payload and bioconjugation units with the same high double-door technology . Even more important , production and QC are adjacent , and an air-lock cabinet is available for the transfer of the samples . The bulk product leaving the plant may be tested before use at the formulation site . One of our practices consists of preparing a satellite sample to avoid one sampling operation . Anticipation always helps to reduce the risk .
Exposure control & communication
Once measures are implemented to mitigate the risk of exposure to highly potent products , the actual exposure level must be controlled . Physical barriers are not 100 % leakproof and the human variability factor is critical especially in the absence of a physical barrier . Keep in mind that the OELs of HPAPIs are so low that the hazard is invisible . To proceed with the control of the collective protective equipment itself , the best is to apply in safety and occupational health the same principles as in quality for cGMP production : check the design , the
16 SPECIALITY CHEMICALS MAGAZINE ESTABLISHED 1981