play. Gathering expertise from a cross functional team during
the risk assessment process, and properly documenting the
analysis, is important in developing this knowledge base.
With the advent of new technology, PAT is becoming highly
important in the QbD approach. For example, endpoint determination has evolved from being a qualitative test based on
material appearance and feel into a quantified scientific correlation. Mixer power and torque profiles, as well as PAT tools
to measure particle size of the granules on-line, have increased
control and lead to less processing risk. The implementation of
PAT allows for a granulation endpoint to be determined in real
time rather than relying on operator experience.
In conclusion, wet milling and extended spraying times are
two parameters that can and should be evaluated during product development for wet high shear granulating processes.
Additionally, new process analytical technologies are adding increased process understanding and control bringing high shear
wet granulation from an art to a science.
ABOUT THE AUTHORS:
Raja Krishnan is a Senior Process Development Engineer at
URL PharmPro. He has over 15 years industry experience in
oral solid dosage and is a six sigma black belt.
Michael Buzecky is the Process Development Manager at
URL PhamroPro. He has 10 years pharmaceutical industry
experience in oral solid dosage including roles in quality
assurance and process engineering. ■
extended liquid addition times of approximately 30 – 60 minutes,
which is consistently achievable using spray nozzle technology.
The longer liquid addition time produces a more uniform distribution of granulating liquid. This is an obvious advantage for a
granulating liquid that contains an active ingredient, especially if
the active ingredient is in low concentration in the final product.
Also, the longer granulating liquid addition rate allows for a
slower, controlled granulation growth resulting in a tighter particle size distribution. Fine particles are well incorporated into the
granulation and larger particles are hampered from forming.
Finally, the extended spray times allow a slower approach
to a granulation endpoint. This slower approach can provide
a more robust granulating process with less variability.
The disadvantages of using an extended spray time include longer processing times. In addition, heat accumulation due to the mechanical forces imparted during mixing
can cause elevated temperatures. Temperature rise can be
combatted by using jacketed equipment.
THE FUTURE: RISK MANAGEMENT AND QBD
Even though the foundation technologies in the pharmaceutical industry have not changed significantly over the past
several decades, process knowledge and risk management
expectations have. Regulators and industry alike are moving in
the direction of increased process understanding and robust
control strategies. This is where the risk management process
and the knowledge base of the product and process comes into