HIGH POTENCY APIS involving a comprehensive review of safety, preclinical and physicochemical properties.
This approach starts by classifying the product into an occupational exposure banding( OEB). OEBs and OEBs set the acceptable exposure levels for personnel, guiding the containment strategy.
OEB classification systems may vary between companies. The initial risk assessment ensures efficient precautionary measures during synthesis. The OEB does not replace the OEL and should only be taken as an easy way for a company to raise its employees’ awareness of hazard levels.
Risk assessment should consider not only the OEL but also the physical nature of the API, manufacturing steps and employee exposure. There is no one-size-fits-all approach to containment.
Using appropriate levels of controls is crucial to avoid risks and unnecessary costs. When considering the risk equation( hazard x exposure = risk), hazard is defined by the health effect of the product. Exposure is defined by the type of equipment, the physical properties of the product, the unit operation performed including the quantity handled and the duration of the operation.
For example, a solid OEB 4 with inhalation hazards will lead to exposure if there is a dust potential. If the solid is used as a granulate, exposure will be much lower. If the solid is in solution, there is almost no exposure. In this case, there is no need to manage the product in a closed system.
Always keep in mind that exposure is linked to the quantity of chemical handled and the duration of the activity. The risk-based approach will be continuously updated as more clinical and safety relevant data become available during the course of the project.
Drug synthesis: Process development & design
Once the operative OEB for the compound and its intermediates during synthesis have been determined, potential synthetic routes are evaluated. The selection of the synthesis will be guided by the principles of efficiency, low exposure risk and scalability.
Alongside the synthetic process, appropriate qualitative and quantitative analytical methods for the intermediates, the impurities and the product must be developed and qualified. Analytics are also essential for safety and cleaning monitoring
Figure 1- Number of reported R & D projects classified by typology of product families through the analysis of 1,098 companies
Source- Inpart Data as well as process monitoring, even within a contained chemical manufacturing process.
Producing high-potency drugs at gram scale presents several challenges, including safe handling, contamination prevention and ensuring lab personnel safety. This requires proper process design and welltrained staff. Containment devices, like glove boxes, help with sampling, product discharge and pack-off, while protecting personnel and preventing contamination. Isolators, installed on filter-dryers, vary in design based on the required degree of containment.
Processes may be modified to work safely and practically in containment. Chemists try to simplify and telescope synthetic routes as much as possible. Minimising the number of solid-product transfers should be considered, since these steps present the greatest risk for exposure. In contrast, handling liquids and slurries presents fewer concerns because they are less prone to dispersing in the air than powders.
Overcoming challenges
Like many candidates in the pharmaceutical pipeline, HPAPIs often suffer from poor solubility and permeability, leading to low bioavailability. Various technologies can enhance HPAPI absorption, even at low doses due to their high potency.
Amorphous solid dispersions( ASDs), especially spray drying, can deliver poorly soluble HPAPIs by diluting them in excipients. Lipid-based formulations can also improve bioavailability through better solubility, permeability and reduced metabolic loss. Early-stage understanding of API properties is essential for successful formulation, with pre-formulation studies being foundational for selecting appropriate techniques.
Boosting operational efficiency
Based on experience and know-how, a miniaturised screening synthesis approach is applied to accelerate the development according to Quality by Design( QbD) principles, focusing on
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