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NIR Spectroscopy – The Key to Measurement and Control of the Solid Dosage Form Manufacturing Process
By Brian Davies, Director Process Analytical Technology, Scot Ellis, NIR Product
Manager, Thermo Electron Corporation
Introduction
Solid dosage form manufacturing is one of the key pharmaceutical processes, and although the basic process has been around for generations it is often not fully understood or controlled enough to yield highly reliable product quality batch after batch.
Consequently, this process is often top of the priority list for process understanding, measurement and control activities by Pharma companies, usually as part of their Process Analytical Technology (PAT) initiatives in both R&D and the manufacturing parts of the business.
This article will discuss, in overview, the integrated application of a single measurement tool, near infrared spectroscopy (NIR), across the breadth of the process and highlight the commercial and quality benefits that can be realized by exercising control.
Near Infrared Spectroscopy
The measurement technology of choice for the solid dosage form manufacturing process is NIR spectroscopy. The technique allows solid materials, in pure or mixture form, to be analyzed and characterized for chemical and physical content and the results used for both quality assurance purposes and active process control intervention, it is the PAT tool for the tablet process.
The Process
Figure 1: Basic Tablet Dosage Form Process with NIR Monitoring and Control points |
The basic process for manufacturing a solid dosage form is shown in Figure 1 along
with the typical applications of NIR for measurement and control.
Raw Materials Monitoring and Control
The basic application of NIR is at the beginning of the process; identifying and qualifying the raw materials of the product. Generally located in the warehouse of ‘Goods-In’ area of a factory these NIR systems use simplified user and sample measurement interfaces to allow non-laboratory staff to carry out the analysis of incoming materials. Integration of the system into the factory Enterprise Resource Planning (ERP) and Laboratory Information Management System (LIMS) with wireless technology allows rapid and easy material disposition and swift release to manufacturing of materials without tying an instrument to a laboratory. These systems have revolutionized the workflow of material qualification. Now they are often playing the first step in a PAT implementation that qualifies a raw material as suitable for a specific manufacturing process or product.
Dispensary Control
Ensuring that only the correct materials are dispensed at the beginning of the formulation process step is vital. Again, NIR can be used here to positively identify each ingredient of a product before it is weighed out as a production lot. Integration of the NIR spectrometer to the ERP is done to download the expected ingredient list to the measurement system. After a positive identification of each material the dispensary weighing systems can be electronically ‘un-locked’ for use through a simple communication interface with the NIR system.
A failure to positively identify any of the ingredients would lock out the weighing system to the operator and produce a warning that the wrong material is present.
Blender Monitoring and Control
Once the correct ingredients have been weighed out they need to be mixed together in a blending process. Without adequate and optimized mixing of the ingredients the finished product will not have the necessary dose uniformity to be safe and efficacious so this is a critical phase of the manufacturing.
Ensuring the homogeneity of a blend is not trivial. Traditionally this part of the process is not actively controlled. Blending is carried out by running the blender for a period of time, usually defined during product development and validation, and then blending is stopped, opened and the material sampled using ‘sample thief’ following a stratified sampling regime.
The samples are then transported to a QA/QC laboratory and measured by traditional techniques such as HPLC or UV. The results are analyzed to ensure they meet the acceptance criteria for homogeneity. If they do, the blend can be moved further along the manufacturing process. This is a time consuming and costly exercise. The blended material may need further blending or remedial processing and re-analysis before an optimum blend is obtained.
Sometimes a mixture of ingredients is over blended and materials re-segregate. Ideally a technique for monitoring the blending in real-time while the blending is operating is required. Thus, when an optimum blend point is reached the blender can be stopped.
The latest generation of NIR spectrometers can do this. They can be mounted on a blender and measure the blending operation while the blender is moving, giving a real-time measurement of the blend homogeneity. Once an optimum blend point has been reached the instrument can provide a signal to stop the blender.
The NIR system needs to be able to operate attached to a moving blender. This
is made possible using battery operation with built-in motion and
Figure 2 shows a typical on-blender NIR control instrument in place on a bin blender.
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orientation detection couples with wireless communication to the blender control
system. These are brought together in very small form factors that mount easily
onto a variety of blenders.
Drier Monitoring and Control
Some solid dosage forms use a wet granulation step to modify the physical characteristics of the material before compression or filling. This requires the material to be dried to a set moisture level before further processing.
Typically this phase is monitored by sampling material during the drying cycle, removing the samples to a laboratory and carrying out time-consuming loss on drying or chemical measurements to calculate the residual moisture level. NIR can easily be used as an in-process measurement and control tool for this process. Fiber optic probes can be mounted directly into a dryer and fully integrated into an NIR analysis to give real-time moisture analysis and if necessary switch off the dryer once a pre-determined moisture end point is reached. Modern industrial fiber-optic probes with automated self-cleaning cycles, and communication linkage, the latest generation of NIR spectrometers combined with internal spectral validation and background correction schemes make it possible for probes to be mounted in the dryer for long multi-batch runs without any maintenance.
Finished Product Monitoring
The finished product, whether a tablet or capsule can be monitored post compression
or filling to ensure uniformity of dose and consistency. Typically
Figure 3 shows a control scheme for a
fluid bed dryer using NIR and an industrial fiber probe. |
this is another laboratory based measurement requiring HPLC or UV analysis with
a long lag time before results can confirm uniformity and the product released
for final packing.
Although no longer in powder form, the NIR can easily carry out a transmittance and reflectance measurement of a tablet or capsule without any sample preparation or the need for a trained analytical scientist. Simultaneous transmittance and reflectance measurements now mean that this measurement step is extremely quick, allowing much more than the basic compliance testing to be carried out in far less time and a quicker release to packaging for a batch of product.
Enterprise Integration
While it is practical and often pragmatic to operate NIR measurement systems as stand-alone tools along the solid dosage form process the most business benefits are realized by integrating the measurement device directly, in real-time to the operating environment of the factory.
MRP integration links scheduling and formulation information to the NIR. LIMS integration allows for material disposition to be automated, linking the NIR system to a process weighing system which allows for a fail safe dispensary environments and most importantly integration with control systems which allows the NIR to move from a monitor to a process control tool for optimization.
Summary
The solid dosage manufacturing process is ideally suited to be monitored and actively controlled through the use of NIR spectroscopy.
Application of the technique can be scaled, from deployment at single high value or high risk critical control points in the process up to an integrated system approach across the width of the process.
This has made NIR the single most important process monitoring and control technology
for the solid dosage form process and given it a place in most companies Process
Analytical Technology strategies and implementation paths.
Pharmaceutical Processing
Advantage Business Media
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