FDA advocates building quality into a product through PAT.¹ One of the ways this can be achieved is by in-, at- and on-line measurements of critical product and process attributes with various PAT-enabled equipment. In-line PAT involves mounting the instrument directly onto the process line without any sample extraction. For at-line PAT, the instrument is physically separate from the process line, but is located within the production floor, and periodic samples are taken and tested. On-line measurements require an eductor system to extract a portion of the product from the bulk flow for testing, after which it is returned to the main line. Both at-line and on-line applications allow for additional sample manipulation such as dispersion, whereas in-line application samples are evaluated in the path of product flow.

The focus on the concept of Quality by Design instead of relying on end-product testing and release, has resulted in manufacturing industries investing considerable resources on systems that enable continuous monitoring of critical processes and product parameters. Concurrently, attention is on the design of analytical tools to meet PAT requirements.

The function of PAT is to monitor critical quality attributes of a product or intermediate material. For a particulate system, particle size and particle size distribution are major considerations. From the production of toner and cement to raw drugs and final dosage forms, the particle size distribution of the product is an important, defining characteristic and has a huge impact on quality. PAT allows the manufacturer to achieve and maintain a high level of process understanding and control. While particle sizing by PAT has been reported for the measurement of primary particles undergoing milling and crystallization processes,^2,3 little information is available on utilizing PAT for sizing products that have been created with processes such as spray drying and microencapsulation.

Spray drying is common in the pharmaceutical and food industries, and can be used for the microencapsulation of a solid or an oily liquid. Spray-dried microspheres can control release and protect core materials against oxidation and degradation, as their walls form a physical and permeability barrier against the effects of the external environment. Other useful applications include taste masking and solubility enhancement.

Controlling microsphere size is a must as it is an important process variable that can affect product performance. The conventional method of sizing involves periodic sampling and subsequent analysis using off-line techniques, but these have limitations associated with late feedback response times and sampling errors. More importantly, the information lacks the sensitivity required for it to be used in the detection of fluctuations that indicate changing process trends. If left unchecked, these could affect overall product quality.

Utilizing PAT as an in-process monitor during spray drying could offer better process control, improve product quality and, ultimately, result in products of greater value, thus increasing cost-effectiveness.

This article discusses the use of an in-line particle sizer, Insitec (Malvern Instruments; UK), with a pilot-scale spray dryer for the production of microspheres. Both the in-line and at-line use of the instrument are explored and evaluated.

Method of microsphere sizing

Figure 1: Layout of spray dryer with in-line and at-line Insitec.

The Insitec system comprises several parts: the optical head, an interface box, and computer and data analysis software. The optical head functions as a standard laser diffraction system. For the in-line set-up, the optical head is directly connected to the process stream (Figure 1). Unlike the on-line systems more commonly used in the industry (which are designed for bigger product throughput), there is no eductor that extracts part of the product flow for measurement before returning it to the main product line. In the smaller spray dryer, the entire product flow is monitored. This is only possible if the product flow stream is not too large. In the at-line set up, the laser module is not connected to the product flow stream and is positioned instead adjacent to the spray dryer, where it works as a separate system. Sampling is conducted when necessary.