David Edwards is Director of Pharmaceutical Technology at Capsugel.

David Edwards

Direct dosing APIs during research and development studies can reduce the overall testing time of a drug candidate by allowing for a greater throughput of compounds through the research and development department. According to our data, dosing of pure API into a capsule may reduce time to first-in-Human Phase 1 studies by as much as 13 weeks because of the potential elimination of stability and formulation development studies, compared with traditional methods. Reducing the formulation bottleneck is an important goal in many pharma companies because trial deadlines, if missed, can incur financial penalties. Direct dosing can also assist research and development by helping to weed out chemical entities with less potential thanks to the increased throughput mentioned above, thereby increasing project throughput and focusing resources on the candidates most likely to succeed.

The drug doses required for early clinical studies are often as low as a fraction of a milligram. Testing these doses directly is difficult because these small doses are hard to dispense accurately. Usually, the drug active must either be filled by hand (a slow, boring, costly and inaccurate process!) or blended with excipients to dilute the drug, which also involves stability and homogeneity testing of the drug–excipient blend. Most companies will not attempt to fill weights of less than about 10 mg by hand, so for weights below this, blending is the preferred option.

Another method, however, is to use automated microdosing— the use of automated equipment to accurately and precisely dose very small amounts of powder into capsules or other small dose containers and automatically record the weight of each dispense. Micro-dosing technologies facilitate the filling of very small quantities of drug powder into capsules or other small containers with speed, accuracy and precision unattainable by manual dosing by hand. Systems are also available that can run repeatedly with minimal operator input and yield unlimited batches of material, while also providing batch reports for regulatory submissions. 

In particular, microdosing is highly beneficial when working with HPAPIs. Using such small amounts of these compounds significantly reduces the risk of operator exposure and makes containment solutions less onerous. As more potent APIs are developed to meet medical requirements, a technology that allows safe doses to be tested is essential and microdosing could have much to offer in this application. 

Most companies treat New Chemical Entities as a minimum default of occupational exposure band 4 (OEB4) until toxicity is better understood. If working with HPAPIs is a regular activity for the company, suitable reusable containment solutions are required. These must provide the correct level of protection, and give operators the necessary equipment access to conduct normal working tasks, while also being easy to clean at the end of a batch. Examples of the types of solutions often used include process-specific flow hoods, restricted access barrier systems and isolators.

Employee safety is a primary concern for companies when working with hazardous ingredients. Containment technologies can involve high costs, but HPAPIs often have unknown properties, so it is important that manufacturers invest in the necessary safety controls. In this scenario, the real issue is: can manufacturers afford not to invest in these technologies? In particular, using microdosing equipment in contained environments can reduce or eliminate the hazards involved with directly handling potent compounds.

Articles

Direct dosing APIs during R&D studies can reduce the overall testing time of a drug candidate by allowing for a greater throughput of compounds through the R&D department.