Quality by design (QbD) encourages the pharmaceutical industry to gain a better understanding of the sources of risk and variability
inherent in product manufacture. Effective process analytical technology (PAT) plays an important role in QbD because it enables
efficient information gathering at the development stage and offers opportunities for improved process control. An optimal
PAT solution provides reliable and timely measurement of a critical variable in a cost-effective manner.
The particle-size distribution of an active pharmaceutical ingredient (API) is often a critical quality attribute that can
impact not only drug-product performance, dissolution, and content uniformity, but also the manufacturability of drug product
by such issues as flowability and segregation. An integral part of new product development, therefore, is to determine the
appropriate range for API particle-size distribution based on drug-product performance. Typically, API particle size is controlled
within this range through the milling operation.
Batch API milling with off-line analysis
Batch milling is used widely during API manufacturing to reduce particle size to an acceptable range to meet the defined specification.
Figure 1 shows a comminutor mill setup, commonly used in API manufacturing for a milling application.
Figure 1: Image of a comminutor mill with the Insitec on-line particle-size analyzer installed. (FIGURES ARE COURTESY OF AUTHORS)
In this mill, material entering via the feed throat is broken up by the rotating blades, which apply a cutting and impacting action. Particles within a defined
size range exit via the screen, which retains oversized material in the mill for further comminution. Blade profile and screen specification both
influence the size of the exiting particles, but from an operational standpoint, rotor speed is the principal control variable.
With only off-line analysis in place, controlling the API particle size within an acceptable range is an iterative process.
Initially, a small quantity of material (1 to 5 kg, for example) is milled at a speed selected on the basis of historical
experience. Measuring the particle size of the resulting material in the laboratory determines acceptability. If the milled
powder meets the specification for the product, the remainder of the batch is processed under these conditions. If not, mill
speed is altered, and another small quantity of material is milled and tested. This process continues until acceptable conditions
are established. Because of batch-to-batch variability, this procedure is repeated for every batch in a campaign.
This iterative process is time consuming and wastes material. Equally important, the particle size of the milled powder can
be quite variable. The process is fixed rather than responsive to the properties of the feed, so, for example, if the feed
batch is segregated and/or the test sample is not truly representative, there is an impact on final-product particle-size
distribution. Final testing only verifies that the average properties of the batch are acceptable and reveals no information
about manufacturing consistency. It is therefore common to produce material with a relatively broad particle-size distribution,
which maybe detrimental to steady downstream operation.