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

Other continuous-processing operations

Other operations are adaptable to continuous processing and may reap similar benefits if implemented within the QbD and PAT frameworks. The major wet-granulation technologies include fluid-bed granulators, high-shear granulators, and low-shear granulators. Within these product lines, all the technologies offer continuous processing. Opportunities for feed-forward and feed-back optimization with NIR analysis can be related to several steps within the processes. To achieve acceptable wet granulation, some liquid must be added to the dry powder to initiate the growth sequence. The liquid may serve as a binder, activate a dry binder that is part of the granulation formulation, or, in most cases, contain a binder in solution. Fine control of the levels of aqueous or organic liquid addition is possible through NIR analysis because vibrational modes for water and organics are prominent features in NIR spectroscopy, allowing an operator to gauge the amount of solvent in the granulator at any time.

A second control point during the growth phase may be related to gross granule size. NIR is known to correlate to particle size and methods (5) can be constructed to engage a feedback loop for modifying the binder flow rate to maintain a selected particle size range (i.e., 500 to 700 μ). Control strategies related to particle size in a drum granulator have been associated with steady state spray rates of 0.005 kg/s and lower (6). These control strategies are particularly important as they influence yield for start-up and shut-down conditions. Precise definition of binder levels by NIR will minimize waste during these periods.

Continuous drying modes represented by fluidized beds and rotary drying technology may be used as part of the control scheme following wet granulation. Continuous drying can relate to fine control, primarily by using the inherent ability of NIR to sense water. Process-control techniques that allow assessment of the state of drying with regard to the classification of constant, falling, and diffusional periods of drying may finetune the process to minimize unwanted characteristics such as static charge build-up and particle attrition. Spectroscopic differentiation between chemical and free water offers the ability to maintain a multihydrated molecular form of the chemical that is crucial to a subsequent process. Reducing hydration levels often has a detrimental effect on the functionality of a chemical entity.


Figure 5: Hot-melt extruder with fiber optic probe analyzing active component in extrudate output. (FIGURE 5 IS COURTESY THERMO FISHER SCIENTIFIC.)
Continuous extruders are also amenable to control schemes. The extruders have ample process flexibility characterized by the ability to perform multiple operations along the length of the vessel (see Figure 5). Formulation attributes such as improved solubility, reduced dusting, characterization of the API mixing process (dispersive versus distributive), and degrees of crystallinity may be related to constant monitoring of extruder attributes like screw speed, torque, and temperature profile.

Economic benefits

Ultimately, the decision to consider continuous processing is economic, tied intimately to well-designed QbD protocols and PAT implementation as well as meeting the goals defined by lean manufacturing and six sigma quality standards. Waste reduction, reduced analytical expenditures, and faster time to market are prime benefits of a QbD program. Continuous machines can be stopped quite precisely at the end of a run, whereas batch processes are constrained to available batch equipment and thus susceptible to overproduction. Transportation and secondary processing characterized by discharging and charging to several unit operations are mitigated in continuous processing. Analytical results from NIR are available in real time, as opposed to a lengthy wait from analytical laboratories. Finally, a shortened cycle to market and a longer patent life are achievable when the pilot-lab and full-scale production are performed in the same vessel.

A proposed scenario for a hypothetical company that implements lean manufacturing and PAT techniques quantifies the potential (7). The authors show that in the improvements gained, a $450-million company could conservatively expect resulting cost savings of just under $30 million.

Thomas S. Chirkot Ph.D, P.E., is a near-infrared sales specialist at ThermoFisher Scientific, 4410 Lottsford Vista Road, Lanham, MD 20706, tel. 570.909.7657,


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