Why Measure Particle or Droplet Distribution in Process or Development?

After last week’s introduction to liquid dosage formulations, I wanted to follow-up with: why measure the particle or droplet distribution in process or in development?Particle or Droplet Distribution in Process Development
A set of unit operations for a liquid formulations process could be in development in the laboratory or manufacturing.  It could be almost any type of liquid formulation process where you have a suspension or an emulsion being created.  The active ingredients could be mixed with a buffer, such as an oil and water emulsion.  Or the Active Pharmaceutical Ingredients (APIs) could be a metered dose inhaler homogenized and mixed with a buffer perhaps an alcohol or a propellant and then mixed in a large mixing tank and re-circulated on to a filling line and then onto the product.  In development, there are many concerns where particles could potentially play a role.  In manufacturing, there are concerns in which particles and droplets may play a role in these unit operations.

As we look at this process and Quality by Design (QbD), we often use Process Analytical Technology (PAT) to develop an understanding of where the risk is in the unit operations.  By designing experiments and using Process Analytical Technology (PAT) and statistics, we can understand the impact of particles and droplets along each process.  If we look at the beginning of this, we may understand the active ingredients.  There could be risk in the particle or droplet systems – if there is inconsistent dispersion of those particles or an agglomeration of those particles in the early stages.  This could be in the development stages or in the early homogenization stage.  One of the problems could cause problems downstream, whether it is onto the encapsulating of the product into a canister in the MDI situation or in the bottling of a lotion.  Downstream, past homogenization, there could be a system being missed in a large tank, and there could be issues with agglomeration, settling, breakage, segregation, or crystal growth even.  Also, there could be coalescence taking place in that large tank and each one of these problems could cause problems with the downstream bioavailability or batch consistency of the product.

In the filling line, there can be and often are inconsistencies due to upstream problems.  If there is agglomeration upstream, that can cause inconsistent filling.  If there is coalescence or the emulsion is breaking or separating, that could cause inconsistencies in the concentration or in the distribution of droplets or particles in the filling line.  All of these could cause problems at the product stage which would be content uniformity, stability issues, shelf life issues or bioavailability issues.

Considering all of the risks in this series of unit operations, whether developing a process in the laboratory or already in manufacturing, there is impetus to monitor the particle system inline as I discuss further here.