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Use of in-process particle size analysis has enabled pharmaceutical scientists and process engineers to track the progress of a granulation process and detect its endpoint.
Alon Vaisman. Applications Development Manager, Pharmaceuticals, at Malvern Instruments Ltd.Use of in-process particle size analysis has enabled pharmaceutical scientists and process engineers to track the progress of a granulation process and detect its endpoint. In both fluid bed and high shear granulation processes, particle size is typically one of the most critical quality attributes that impact the performance of the finished product. For example, granule size affects the flow properties of the powder and its performance during compression in the tablet press. For coated, controlled release products, granule size is also an indication of the coating thickness.
Without in-process particle size analysis, controlling the granulation process is more art than science. Traditional quality control tests are typically performed after a drying cycle and provide only limited insight into the granulation step. In‑line particle size analysis enables the user to track the process trajectory in real time, vary the process parameters to keep it in specification, and stop the process when the desired endpoint is reached. As a result, batch-to-batch variations are reduced and production is more consistent.
The benefits of having particle size information while the process is running are fairly obvious. The challenge is in the details. Is the information produced by the measurement system reliable and robust? Could the installation of an analyser adversely impact my process? And, of course, validation!
To answer the first question, a feasibility study must be performed and the data thoroughly evaluated and compared to reference methods; measurement systems should be challenged to determine performance limits; and the scalability of the method must be tested. Secondly, a risk assessment should be conducted to evaluate the analyser’s potential impact on the process. Could it cause clumping? Could moving components cause contamination, etc? Finally, the method and system must pass validation requirements. As these can differ between users, vendor experience tends to play a significant role in this area.
The most significant improvements in particle size analysis are in the area of the process interface and the ability of the measurement systems to maintain data integrity in rapidly changing process conditions. Analyser vendors have developed various ways of dealing with optics fouling and granule dispersion, while software platforms have advanced significantly to simplify integration with control systems and use of data.
However, there is still room for improvement, particularly in continuous manufacturing with on-line quality assurance and real-time release. It is a lofty goal, but many manufacturers are making great progress in this area and the first commercial systems are already beginning to appear on the market.
As with any new technology or application, there are early adopters, mainstream users and then those who lag behind! Specifically in the pharma industry, there is an ingrained reluctance to try new things because of strict regulations. Without the approval of a regulatory agency, PAT adoption would not have been possible or, at least, would have progressed at a much slower pace. Cost and lack of internal expertise to make use of the technology can also be deterring. However, regulating authorities are no longer satisfied by limited process characterisation and expect manufacturers to demonstrate adequate process controls. The need for higher product quality and faster time to market is bound to drive the industry towards on-line analytical techniques and QbD methodology.
Today, most big and medium pharma companies are actively working with PAT applications, and many generic and contract manufacturers are also following their lead.
This article is part of a special feature on granulation that was published in the March issue of PTE Digital, available at www.pharmtech.com/ptedigital0311