A Risk-Based Approach to Product and Process Quality in Spray Drying - Pharmaceutical Technology

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A Risk-Based Approach to Product and Process Quality in Spray Drying
Process designs and control strategies can be improved by adopting a risk-based approach to product quality. The author describes how this approach can be applied to spray-drying operations.


Pharmaceutical Technology


Applying control strategy

Process measurements and control loops. The process measurements and control loops are effective and reliable. A real-time heat and mass-balance calculation based on the process measurements is used to detect instruments that need calibration or certain liquid-feed abnormalities.

Spray-drying applications with an inadequate correlation between product-quality attributes and the basic process measurements require careful reevaluation of the process design space. The lack of correlation is frequently explained by the choice of a marginal or unsustainable operating point.


Figure 4
For example, an operation close to the limits for drying often results in particle agglomeration in the drying chamber and a high risk of deposits or irregular powder discharge (see Figure 4). Furthermore, single particles rarely have the same performance as agglomerates of the same size. The result is a poor correlation between atomization conditions and particle size because the drying conditions are marginalized typically by lowering the outlet drying-gas temperature.

Fine powders and fragile particles may change size dramatically when they are collected in a cyclone. Cyclones have a limited efficiency in collecting fine powders. As a result, a reduced particle size may appear as a reduction in cyclone yield and not as the expected reduction in particle size. On the other hand, fragile particles may break when collected in a cyclone. In extreme cases, attempts to increase the particle size through changes in atomization conditions make the particles even more fragile. Again, the result is a poor correlation between atomization conditions and particle size. The lack of correlation appears to stem from the drying-gas flow rate. The real cause, however, is a poor choice of the cyclone for the application.

Product may change after discharge if the conditions in the product container are not compatible with the product. When the product changes, it reflects the process conditions in the container, not in the spray dryer. Some product characteristics to monitor are particle size (some products are likely to form lumps or agglomerate), residual moisture (reabsorption of solvent vapor because of the increase in relative humidity as the surrounding gas cools down), amorphousness (crystal growth in products kept at temperatures above glass-transition temperature), and activity or impurities (product is kept at an excessively high temperature for too long).

Variation in feed characteristics. The process impact of long-term variations in feed characteristics can be evaluated using PAT. In line or on line liquid-feed and final-product monitoring are ideal for establishing a correlation between feed properties and final-product properties. Unfortunately, it is time consuming to set up the monitoring system and analyze the collected data.

A fully developed liquid-feed and product-monitoring system can be used as an advanced feed-forward or feedback system to adjust operating parameters. Such a system can reduce the consistency requirements for the liquid feed and, at the same time, improve the consistency of the final product.

A system with only in line or on line final-product monitoring still requires a liquid feed with a high level of consistency. Even though, in most cases, variability is best controlled at its source, such a system still provides benefits in processes with a tight design space or in a development environment where real-time data allow the process to be adjusted quickly. The danger in such a system is when the cause of the disturbance is not known.


Figure 5
The choice of measurement type and location is naturally application-dependent. An in line or on line measuring device is generally able to provide substantially more detailed information than traditional sampling. For example, an on line particle-size measurement shows the effect of the automated hammers on the drying chamber (see Figure 5).

Mechanical errors. Mechanical failures frequently are not part of a process-control strategy but are one of the most common reasons for process deviations. A pressure nozzle, for example, must be clean and without leaks to work as intended. Pressure nozzles, however, often start to leak because they have been damaged, worn out, or assembled with insufficient care. The leak causes the nozzle to foul, disturb the spray, change the particle size, create deposits, and ultimately cause a premature shutdown. Monitoring and recording nozzles with a camera provide early warnings and facilitate fault identification.

Summary

A risk-based approach to process design provides valuable insight to the areas where process design and control strategy are most likely to fail. Interestingly enough, it is frequently not the high-risk areas that personnel devote most of their attention to before making a risk assessment. In many cases, the most effective process monitoring is achieved though a blend of technologies.

Subprocesses such as cleaning can and should be evaluated in the same way as the main process and can be improved by means similar to those described above.

Henrik Schwartzbach is a senior process technologist at Niro A/S GEA Pharma Systems, Gladsaxevej 305, 2860 Soeborg, Denmark, tel. +45 39 54 54 54,


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