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Q: What factors should we consider when microdosing APIs and excipients?
Four factors determine the best solutions for microdosing:
The active pharmaceutical ingredients (APIs) and/or excipients you're handling;
The intended use of the process—for R&D only or for R&D that will lead to production;
The required levels of accuracy and repeatability; and
Area constraints for both the R&D and the production processes.
APIs and excipients
Material costs are always key when microdosing pharmaceutical ingredients:
How many ingredients does the tablet or capsule require? Each dosing unit may require a special design to accommodate the material's specific characteristics and throughput requirements.
What are the limitations of the dosing systems? Some low-percentage ingredients may require preblending to reduce costs and improve content accuracy. You will typically need to test individual or preblended materials to design the dosing unit specifically for the application. If you can't use the actual pharmaceutical ingredients for testing, you'll need to use placebos. Your feeder supplier can help you understand these limitations.
What type of transfer system will refill the dosing units, and what are the material discharge requirements? Transfer can be challenging because some materials require special handling to prevent contamination or because the mechanical or vacuum transfer-system design may be large and difficult to use in connection with low-rate dosing equipment. Material discharge is important due to the need to contain some materials. Very fine particles can remain airborne for extended periods of time after discharge, and some materials can build up static over time when discharged at low rates.
R&D applications require numerous changeovers, short runs, and easy feeder removal and cleaning. For applications that are strictly R&D, dosing units must be very flexible and capable of feeding as many different pharmaceutical ingredients as possible. However, differences between ingredients can influence feeding performance, from throughput to material flow.
When moving from R&D to production scale, you will typically need larger dosing units, and the units may require control changes. Additional material testing may be necessary to accommodate your process needs, and some materials may not be suitable for feeding because of their flowability.
Consult your feeder supplier for assistance in material testing and designing a feeder capable of achieving the entire feed-rate range your application requires.
Accuracy and repeatability
Once you have developed your APIs and excipients and determined the percentage of each that your product requires, identify the necessary accuracy and repeatability for each dosing unit. For batch-weighing processes, this can provide the information needed to allow the dosing unit to operate in a coarse-dribble manner, in which the unit feeds most of the ingredient for the batch quickly in coarse mode and then slows to dribble mode to accurately feed the final amount. This can help maintain the tight tolerances required for certain materials.
With the introduction of continuous pharmaceutical manufacturing and the new technology being developed around this concept, feeding your ingredients becomes more critical. You must establish time-based variations, which are defined as changes in material weight over an acceptable timetable that you establish through volumetric or gravimetric testing. You can consider performance of the dosing unit on a minute-to-minute basis over a 30-minute period, but based on your material's characteristics, you may want to consider more frequent intervals, such as every 15 or 30 seconds, over a 30-minute period. Prior material testing with your feeder supplier can help you decide the time consideration. During R&D, you may be able to use only volumetric feeding due to the low feed rates, but when you move to the higher feed rates required for continuous production, you must determine whether to use volumetric or gravimetric feeding technology.
For continuous processes, accuracy at low feed rates is very dependent on the material's flowability. You must determine not only each ingredient's accuracy requirements to ensure the drug product's effectiveness but also the feed rate at which you need to achieve that accuracy.
Achieving 1 percent accuracy at 10 g/h is different from achieving 1 percent accuracy at 100 g/h. You should understand your dosing unit's capabilities and limitations before specifying an ingredient's accuracy requirements. If you can't achieve sufficient accuracy feeding low-percentage ingredients individually, you may need to preblend 2 or 3 low-percentage ingredients and feed them together.
Space limitations in the lab and production plant can present challenges when designing a manufacturing process, and equipment suppliers have been working to reduce the size of their feeding devices. Microdosing units the size of a coffee cup are now available that can help you feed multiple ingredients into a process while using a smaller production frame. When designing a system, review your available operating area with your feeder supplier to determine the best configuration for your feeding equipment.
Roger Hultquist is president and co-owner at Orbetron, Cumberland, RI. The company supplies technology that ensures consistent and repeatable feeding of dry bulk solid and liquid materials.