Transition to commercial
The development of a continuous step is still centered on the chemistry . It is key to have a set of tools to develop and understand the chemistry , access the kinetic data at different temperatures and screen multiple conditions rapidly .
This work can be performed in batch reactors with some limitations ( pressure and temperature ) or with microreactors to access higher pressure and temperature ranges to measure the corresponding reaction kinetics without heat and mass transfer limitations ( Figure 1 ). High ( up to 100 bar ) pressures and high ( 200 ° C ) temperatures are not uncommon in continuous processes . This makes it possible to increase the speed of reaction and achieve manageable (< 1 hour ) residence times .
Assuming that the chemistry is well developed for continuous processing , the process kinetics , mass transfer and heat transfer can then be modelled using engineering tools ( Aspen , Dynochem or others ). Then the process needs to be demonstrated at a larger bench scale to assess and confirm the modelling . This is still performed under R & D supervision ( Figure 2 ), using lab equipment and with minimum automation .
The reactor may be equipped with a variety of detector devices to gain more information on the process ( PAT ). The stoichiometry of the reaction is controlled by the pumps ( typically a syringe , HPLC or peristaltic pump ) and the various flow rates can be measured periodically using a scale or a graduated cylinder and a stopwatch .
The process temperature will be set by a typical bench-scale temperature control unit and will be recorded periodically from a gauge or a digital display . The pressure will be set manually with a back-pressure regulator and will also be recorded in the lab notebook from a gauge or digital display .
At this scale , the expected flow rates are below 10 ml / min and therefore the process will consume a few litres of raw material solutions in a 10-12 hour run , enough to reach steady state and to show typicality and stability . This can easily be handled with carboys or small vessels . The expected throughput for this scale is a few hundred grams , usually sufficient to supply material for further development work ( formulation , tox study , downstream chemistry ).
Next is addressing the commercial scale where the demand could be in the tonnes range . Typically , flow rates are significantly larger ( 1-100 L / min ) and the manufacturing equipment is fully automated with built-in recycling strategies to mitigate the solvent and
waste costs . Process monitoring is driven by the knowledge gained during the manufacturing of clinical material .
A risk assessment should be performed based on a FMEA analysis to identify all the possible causes of variability and failures . A ranking system is typically used to assess the likelihood of an event , its severity and its detectability to provide a score to each process parameter . The score is then used to make process improvements or control decisions to minimise the processing risks .
It is very likely that this equipment will be designed specifically for the drug since a multi-year production is expected and will be able to bear the required capex to build the capacity . However , this expense is only triggered when the clinical phases are nearing completion and the risks of drug supply outweigh the financial cost of installing a new manufacturing line .
In between these two scales , there is a requirement to produce material for clinical trials using the process that will be used for commercial scale . This is within the realm of cGMP but not yet full commercial-scale . Therefore , the process needs to be scaled in qualified equipment with some automation to ensure robustness and quality . Typically , the demand remains relatively small , 10-100 kg of product .
Throughput |
0.5 kg / day |
5 kg / day |
> 50 kg / day |
Flow rate 10 ml / min 100 ml / min
> 1 l / min
Safety PR & D monitoring Control system Enhanced control system
Quality Non-GMP IQ / PQ / OQ Validated system
Storage 1 gal 50 gal > 1,000 gal
Change to continuous duty equipment Increased size of equipment and field devices
Figure 2 - Scale-up consideration for continuous process from lab to commercial scale
36 SPECIALITY CHEMICALS MAGAZINE ESTABLISHED 1981