The Relevance of Continuous Solid Oral Dosage Processing and NIR Spectroscopy In Meeting the Needs of QbD and PAT - Pharmaceutical Technology

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The Relevance of Continuous Solid Oral Dosage Processing and NIR Spectroscopy In Meeting the Needs of QbD and PAT
The author discusses control strategies via near infrared instrumentation for continuous mixing, granulation, drying, and extrusion with a more focused detail on mixing.

Pharmaceutical Technology
Volume 33, Issue 10, pp. 112-120

Continuous mixing

A representative unit operation in solid oral dosage processing relates to the mixing of direct compression formulations before delivery at the tablet press. In batch mode, the formulation ingredients would be placed in a vessel and undergo some energy input to achieve uniformity. There are a variety of vessel shapes suitable to the task including round, square, and rectangular bins as well as modifications of the common V-shaped design. Depending on the formulation, additional, more energetic mixing devices within the vessel may be needed. For example, a binary formulation of good-flowing, similarly sized particles may mix quite well while gently tumbling through their angle of repose. In contrast, a formulation with a minor active component and additional functional excipients may need an agitator bar to aid in the march toward uniformity. Various characterizations of classical mixing mechanisms related to diffusive, convective, and shear modes may be studied for deeper knowledge about the processes journey toward uniformity. These issues may be studied with current analytical methods but efficiency suffers with methods that have slow turnaround and destroy the sample.

A secondary mixing step is often necessary for lubricant addition. This formulation component is not amenable to an aggressive mixing environment. A less aggressive mixing environment may also be necessary for lubricating a granulated product that is susceptible to particle-size degradation. In either case, the secondary mixing step may require transfer to another vessel with the potential loss of some drug product, as well as the costs associated with material handling.

Sampling for uniformity, whether of the primary mix or the subsequently lubricated formulation, is often done by thief sampling. Thief sampling is rife with bias points. There is the inevitable drawing down of surface material upon thief entry into the powder bed. The potential also exists for preferentially filling the thief cavity with better-flowing formulation constituents as well as the possibility of smaller particle size components being lost in the annular space of the tubular design. Ultimately, the samples are taken back to the analytical lab for assessment of uniformity. Final release, in turn, depends on the analytical-lab schedule.

Figure 1: Thermo Scientific Antaris Target near-infrared analyzer situated on a bin for real-time spectral acquisition. (FIGURE 1 IS COURTESY THERMO FISHER SCIENTIFIC.)
The analysis may be done more efficiently by placing an NIR spectrometer on the rotating vessel (see Figure 1) and making the assessment in real time. This method has substantial economic benefits because it is nondestructive and saves quarantine time, but the constraint of this process being in the batch mode limits the potential because of the necessity of adhering to rigid standard opearting procedures. The crucial assessment that one batch is uniform in 15 min versus a 12-min uniformity for a second batch under the same operating procedures is available quickly and nondestructively with NIR, but the ability to quickly use this information to adjust a prior process is impossible within the batch-mode processing regimen.

In continuous mode, mixers with highly adaptable throughputs can function quite reliably as pilot-laboratory devices, as well as production devices, using throughput rates between 10 and 100 kg/h. The adaptability is important because, in effect, the same device can be used for development at the pilot-laboratory scale as well as full-scale production. For example, eight hours of processing at 10 kg/h yields the same approximate product mass as a 250-L batch mixer and at 100 kg/h, the yield would be similar to a 2500-L batch vessel.

In the development stage, well-designed factorial experimentation can readily assess the influence of raw-material variations such as particle size and density as they relate to response variables like content uniformity of the effluent process stream. Within the same scope of experimentation, details of variance- reduction ratios and resident time distributions can elucidate mechanistic principles with regard to the feeders and the mixer. The key is that rapid assessment by NIR spectroscopy ensures immediate feedback on content uniformity through nondestructive methods and minimal waste to expensive and limited drug substances. If the continuous mixing device can operate in intermittent mode, as many are capable of doing, there is virtually no low throughput value. In practical terms, continuous throughput rates as low as 5 kg/h are feasible.

Figure 2: Low-throughput continuous mixer processing binary solid oral dosage formulation at 20 kg/h. (FIGURE 2 IS COURTESY HARSCO INDUSTRIALS, PATTERSON KELLEY.)
A final point is that many continuous mixing devices can be characterized by different mixing regimes within a single device. For example, selection of different flight profiles on the mixing screw can allow the lubricant to be placed in a less energetic section of the device after the mass formulation components have been mixed in a more energetic section. Other mixers have substantial recycling sections allowing the lubricant to be fed into the effluent end of the device through a precise screw feeder, and thus be mixed with other components after the high intensity section (see Figure 2).

Figure 3: Thermo Fisher Scientific MX FT-NIR Process Analyzer capable of acquiring spectral information on-line and at up to four process points. (FIGURES 3 IS COURTESY THERMO FISHER SCIENTIFIC.)
In production mode, the higher throughput can be engaged under the confirmed process principles determined in development. This abrogates the need to rely on arcane scale-up rules associated with batch mixing. For example, one tries to maintain similarity relationships among vessel sizes based on criteria like geometric, kinematic, and dynamic similarity. The process is amenable to real-time characterization by NIR at several points in the process stream using multichanneled instrumentation (see Figure 3). Fiberoptic probes (see Figure 4) within the feeder hoppers can qualitatively confirm raw-material identification and immediately sense a problem. A secondary confirmation by analytical means within the travel screw can be further related to possible degradation of physical characteristics such as particle size and density. Additional probes along the mixer axis can evaluate content uniformity at several points in the travel through the residence time in the mixer. Ultimately, effluent uniformity for both active pharmaceutical ingredient (API) and lubricant is assured at the mixer exit.

Figure 4: Diffuse reflectance probe with purge option for analysis of powders. (FIGURES 4 IS COURTESY THERMO FISHER SCIENTIFIC.)
Any of the attributes that have been sensed can be fed forward and back to effect real time change to other continuous processes. Also, at any point in time, the at-risk portion of the production material is limited to material contained in the hold-up volume of the continuous vessel. Contrast this amount with the at-risk amount in a 2500-L batch mixer.


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