Speciality Chemicals Magazine SEP / OCT 2021 | Page 26

HIGH POTENCY APIS

‣ or in process design – perhaps by avoiding the isolation of intermediates that have increased safety risks . Toxicologists and chemists need to work together to consider all the steps in the synthetic route and assess every intermediate that might be isolated . An experienced medicinal or process chemist should be able to spot any obvious structural alerts from the chemical structure , with toxicology assessments providing further insight into issues that are not immediately evident . It is a different story for impurities . In terms of pure volume , the risk will be lower for a compound that is only present at a very low level . If it is highly potent , that risk might not be negligible . While it is unusual , an impurity can be more potent than the API . This risk cannot be discounted without careful consideration . A good example is the withdrawal of ranitidine-containing drugs because of the presence of low levels of nitrosamines . As a result , nitrosamines are now considered impurities of high concern , with new substance-specific limits ranging from 25.5 to 96.0 ng / day . ² This is even lower than the limits for potentially mutagenic impurities at 1.5 µ g / day , according to the ICH M7 . ³ Additionally , if side products are highly potent , this will also have an impact on the way that waste streams must be handled and disposed of . Safety measures for APIs and intermediates will often be the same . However , in some cases , the potency can vary from one synthesis step to the next , and this needs to be accounted for to ensure that everything is handled within the correct equipment and with appropriate containment .

Changing the synthesis route

In extreme cases , it might be necessary to change the synthesis route to avoid a problematic intermediate completely . This would be very unusual and costly because time is of the essence in clinical supply and changing the route may introduce excessive delays . The move from lab or pilot equipment into full-blown GMP production can exacerbate problems , and cleaning requirements and validation procedures take on added importance . Scale is the key . It might be straightforward to make a few kg of an HPAPI via a complex synthesis , with chromatographic purification steps . At 100 kg , chromatography is impractical and a switch to crystallisation is required . This involves handling large amounts of a highly potent substance in a more hazardous solid form , which triggers the need to use appropriate isolation equipment and a containment setup . A view to GMP production should always be employed at the outset in case the initial route is not readily scalable for an HPAPI .

Risk assessment & safe handling

The occupational risk from HPAPIs depends both on the toxicological properties of the substances and on the likelihood of an operator coming into contact with the compound . Indeed , to choose the appropriate containment , the risk assessment considers the quantities being handled , as well as the API ’ s physical properties . Particularly for HPAPIs , a detailed risk assessment is critical . An electrostatic compound , for example , will be far more challenging to contain than one that physically resembles table salt . In this case , it might be better to telescope two steps to avoid the need for isolation and purification . If a compound is handled at any point in a solid or powder form , the risk will necessarily be higher than if it were in a solution , due to the potential for dust particles to become airborne , creating a significant handling challenge . In solution , handling is generally much easier and more predictable , whether the compound in question is an intermediate or the API itself . Fundamentally , safe handling relies on the trained operators working safely , with systems in place that allow them to do so . At the core of the process is a thorough , realistic risk assessment , which is used to inform the manufacturing strategy . While a big pharmaceutical company is likely to have more knowledge and experience in-house , a small biopharmaceutical company is more likely to rely on consultant experts and the toxicology team at the CDMO . In both cases , timely expertise in all aspects of HPAPI development and manufacturing is invaluable in safely and successfully advancing these molecules to market . •

* Also contributing to this article was Selene Araya , managing toxicologist

26 SPECIALITY CHEMICALS MAGAZINE ESTABLISHED 1981