PAT: A New Dawn for Drug Product Quality - Pharmaceutical Technology

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PAT: A New Dawn for Drug Product Quality
Leading experts share insight on the current and future direction of process analytical technology.


Pharmaceutical Technology
Volume 34, Issue 2

Mattes (NIR spectroscopy): The FOSS MasterLab includes a transmission NIR option designed specifically for solid dosage form analysis. It has been adopted by major pharmaceutical manufacturers because it can be used at-line to measure content uniformity of active ingredients in capsules and tablets. The MasterLab can be placed next to the tablet press to ensure the quality of the cores and/or the finished product. Process NIR instruments are designed to be used in-line to measure residual granulating liquid in fluid-bed dryers or single-pot granulators. Mean particle size and polymorph conversion can be monitored at the same time.

Dubois (NIRCI): Industry and regulators alike recognized very soon after the PAT initiative began that NIRCI was a unique laboratory technique that could help determine which product parameters should be monitored on-line and at what stage of the manufacturing process. Indeed, analyses of blends, intermediates, and finished tablets have provided pharmaceutical manufacturers with information about the critical quality attributes that affect quality and performance.


On the horizon...
Similarly, the correlation between size, shape, and chemistry in granules has been shown to be important in understanding product performance. Interestingly, however, this correlation has led many to conclude that, in most cases, online monitoring of size only is required once the size-chemistry relationship is understood. While not in itself a PAT sensor, NIRCI can be used to deploy PAT sensors where it matters in the process. It can also be used as a risk-assessment tool for factors such as ingredient sourcing and process modifications.

Dobbs (UPLC): Throughout a therapeutic compound's life cycle, liquid chromatography (LC) is routinely used in discovery, research, development, manufacturing, quality control and release, and post-shipment stability monitoring. It is imperative that such LC analytical data be secured, easily archived and searchable, quickly cross-referenced, overlayed, and instantaneously available. The concept of a long-term historical database focused specifically on full characterization of a therapeutic molecule is at the core of FDA's quality-by-design (QbD) initiative. LC permits disparate analytical data from different process stages to be compared.

The manufacture of an API is invariably a solution-phase-based process, which is the ideal sample matrix for LC analysis. Whether the sample matrix is aqueous, organic, or a mixture, analytical LC testing of in-process material (IPM) is routinely performed today in an off-line manufacturing quality-control (QC) laboratory to monitor reaction progress or to specifically measure individual parameters such as IPM purity or concentration. During a single in-process LC analysis, a breadth of information can be extracted: raw-material consumption, IPM purity, IPM concentration, and low-level or trace concentrations of impurities as low as 0.01%

What has kept LC from being adopted directly onto the manufacturing floor is that LC analysis simply takes too long to generate a result. LC may produce data with breadth, specificity, sensitivity, and accuracy, but off-line QC laboratory sample-to-answer times are typically in excess of 4 to 6 hours. That reality is rapidly changing. With new at-line and on-line analytical LC tools, manufacturers can make a measurement, generate information, and make a decision in real-time, or under 5 minutes. Waters introduced UPLC technology (Acquity UPLC System) in 2004 to provide real-time LC capability. The technology is available for automated direct on-line and at-line IPM analysis on the manufacturing floor with a process analyzer (Patrol UPLC, Waters).

Vaisman (particle-size analysis): To provide the maximum return on investment, a PAT tool should provide the user with accurate and precise results in an automated fashion without compromising process performance or quality. These results must be available in timeframes that allow the user to make process decisions and facilitate real-time release (RTR). The results must be available in a standardized format to allow integration into plant-control systems. And finally, the PAT tool must be designed to comply with current good manufacturing practice (GMP) guidelines and be robust enough to last.

Compared with various imaging and chord-length measuring techniques, laser diffraction, a well-understood method throughout industry, offers the user precision as well as high statistical significance of an ensemble technique. Instruments such as Malvern Instruments' Insitec On-line Particle Size Analyzer are capable of producing up to 4 complete results per second while analyzing a large fraction (several kg/h) of the product. Compliance with the OPC data access specification enables this analyzer to communicate with most commercial plant-control systems and devices. Because the analyzer can produce results in real time, it is an efficient tool for pharmaceutical milling, spray-drying, and roller compaction applications. By producing absolute-size information rather than trend monitoring alone, Insitec enables closed-loop process control and on-line quality control. For example, when installed on a discharge of a hammer mill, the analyzer can be used to control the speed of the milling rotor by reporting particle-size parameters to a mill programmable logic controller (PLC). The PLC will adjust the rotor speed to maintain constant size, which results in stronger product consistency. At the same time, the analyzer data can help produce cumulative batch results.

Freeman (powder-flow techniques): For formulators of solid oral-dosage forms, or tablets, it is essential that the properties of the [powder] blend be such that they can be manufactured in an efficient way. For example, a certain number of fines may be an advantage when it comes to expediting dissolution. These fines, however, may cause the blend to behave in a more cohesive manner, which could result in flow problems during manufacture. It goes without saying, if a formulation can't be processed into a final product, its suitability for optimum final-product properties is irrelevant because it can't be manufactured in the first place.

Although powder-flow measurements are not taken in-line, they provide new and valuable at-line information about the powder and its suitability for processing. For example, at-line powder-flow measurement tools can help verify the 'end-point'" of a wet granulation process, identify batch to batch variability of raw materials or intermediate product, or ensure that the final blend powder characteristics are suitable for processing through the hopper, feedframe, and into the die, before final compression in a rotary tablet press.

Traditionally, techniques such as particle-size distribution and tapped density have been measured to try to correlate these parameters with powder behavior in process. Today, with the introduction of techniques that can simulate the conditions imposed in the process environment and measure the powder's response, performance can be measured rather than inferred. This new information enables [a formulator] to establish a database of flow properties for each product and provides a platform on which new products can be introduced with greater confidence. The formulator will know

which powders will work well in the planned process, and which powders may be problematic. Armed with this information, formulators can engineer new products to have characteristics that are similar to those of powders that have previously demonstrated desirable process behavior, and avoid powders with properties that have been shown to cause trouble during manufacture. This, of course, is the essence of quality by design.


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