Highly potent APIs :
Assessing the manufacturing risks
Conrad Roten , group leader of API development services , and Lisa Wiesner , occupational toxicologist , at Lonza , look at the toxicological challenges in HPAPI development *
A
careful risk assessment that evaluates all of the potential hazards is critical to ensuring safety when working with HPAPIs . Some key characteristics that must be included in the risk assessment are related to potential genotoxicity and carcinogenicity in humans , and whether there is pharmaceutical activity at low doses . More stringent occupational exposure limits ( OELs ) are likely to be applied in the early stages of development , when less data are available . HPAPIs pose additional manufacturing challenges , as much more stringent protections are required for the personnel .
Toxicology is key
It is essential to develop a good understanding of an HPAPI ’ s toxicological properties early on . Several critical questions need to be answered at this stage . What risks might it pose to operators ? Is acute exposure likely to lead to respiratory difficulties ? Or are the toxicological hazards related to genotoxicity or carcinogenicity ? Could long-term exposure lead to severe organ toxicity or pharmacological effects ? And could it have reproductive or developmental effects ? The toxicological aspects of a compound are extrapolated in order to protect a worker who may be exposed to a compound over a protracted period ( 40 years work-time ). For quality reasons , to comply with cGMP and to prevent cross-contamination in a multipurpose facility , permitted daily exposure ( PDE ) or acceptable daily intake ( ADE ) are calculated for a manufacturing carry-over scenario . PDE takes a similar approach to the OEL , but also includes specific considerations relating to the drug ’ s route of administration . These values underpin the choice of facility and equipment . Before operators begin work on a project , they must have a clear picture of how to handle the materials involved . This includes starting materials , intermediates , reagents , samples , solvents , any side products , byproducts or waste streams that might be generated , and the HPAPI itself . The starting point for a CDMO in determining OEL and PDE values will always be data from the customer . At the outset , there should be a process
Figure 1 – HPAPI challenges & Lonza strategy step when occupational toxicologists consider the hazards of the properties of the target molecule , and then determine the acceptable OEL and PDE . Risk assessment helps to determine the correct procedures . The PDE informs the level of carryover permissible and therefore the cleaning procedures required once a project moves from the lab to GMP production . The regulatory authorities also check OEL and PDE values when reviewing the control measures for highly potent compounds . In the early stages of a product ’ s development , very little data will probably be available . Conservative default OEL values can be assigned during the drug discovery stage . Predictions of the potential toxicological effects can often be made from analogous molecules for which data are already available ( read-across ) or through quantitative structureactivity relationship ( QSAR ) modelling .
24 SPECIALITY CHEMICALS MAGAZINE ESTABLISHED 1981