Case Study: Milling Optimization for Pilot Drug Trials

A pharmaceutical manufacturer experienced difficulties in optimizing milling systems for pilot drug trials. The challenges arose from dealing with changes in particle size specifications and differences between products.

The typical cost of the high value products being processed was in the region of US $0.5-1.0M / kg. The micronizing system in use was fitted with a pharmaceutical grade filter to prevent active pharmaceutical ingredients (API) being released into the atmosphere. Batches were processed in lots of 500g.

There was a poor understanding of the influence of different process parameters on the particle size distribution of the final product, including the effects of:

• air flow rate
• air pressure
• feed flow rate
• mill speed

These parameters would be stepped through, each requiring a sample to be taken and measured using an off-line particle size analyzer. Process validation was therefore hard work, with long periods of stopping and starting the milling process. Typically, when using off-line analyses, the milling optimization study would take about one week.

Yields were generally poor, with wastage represented by large amounts of superfines in the filter - the result of overgrinding. Consequently the filter would block quickly and require frequent cleaning.

An Insitec on-line particle sizer was installed in its in-line configuration at the mill exit, and was used to monitor the entire product as it left the mill. Instantly, instead of measuring small samples of 3-5g infrequently with off-line techniques, the entire batch was being characterized. Milling could be adjusted by the operator in real-time to the correct particle size specification, without the need to stop the mill. This more "active" role of the operator was seen as a more valued task than simply collecting samples for measurement.

Using the Insitec, a more complete study using a greater number of steps in the parameters was now completed in under four hours- a saving of 4.5 work days!

Other advantages noted by the pharmaceutical company were:

• automatic mill control is now a possibility currently which under investigation the team are investigating
• other parameters usually deemed to difficult to study are now being actively pursued
• lot size is now being increased
• alarms on the powder loading are used to prevent the blocking of the mill, increasing the process reliability
• visualization of "hot spots" i.e. (small amounts numbers of large particles which that have short-circuited the mill), can be detected achieved in real-time
• through high control of the milling process, the amount volume of of superfines wastage of super-fines has been dramatically reduced - yields of 98-99% are now commonplace!
• manpower required for mill optimization has been reduced from 5 days to 0.5 days