Spectroscopy - Lean work for Bruker

Today quality control is the major issue in pharmaceutical manufacturing. With the PAT initiative, the FDA is striving for greater efficiency and cost reduction.

Manufacturing pharmaceutical products is a very complex task – from controlling the raw materials to the release analysis of finished products, there are a numerous sources of error. The FDA has laid the cornerstone for an intense discussion as part of its PAT (Process Analytical Technology) initiative for a better understanding of the process and increased product and security at lower cost. The FDA sees process analysis technology as a key to monitor the Critical Quality Attributes (CQAs) and Critical Process Parameters (CPPs) of pharmaceutical manufacturing processes.

The aim is to increase the robustness of the processes by defining the CPPs and their timely control – preferably in-line or on-line. This can improve product quality, reduce reject and rework rates and minimise the number of release analyses. Even an on-line release of the products is possible. The implementation of other initiatives such as QbD (Quality by Design) and RTRT (Real Time Release Testing) in the course of the control strategy are useful particularly for continuous manufacturing. The automatic interpretation of reliable on-line analysis values for use in control loops plays a crucial role. Only an error-free flow of the individual production steps, as well as their understanding guarantee a product of the desired quality. Classic process variables such as pressure, temperature, pH or other physical parameters are often not specific enough to adequately characterize the processes and the relevant properties of the product. In addition to other analytical methods the optical spectroscopy (UV, VIS, IR, NIR, Raman) is here of particular interest.

These methods are

• non-destructive

• free of sample preparation and

• process-suited for on-line or in-line applications.

Bruker’s Matrix-F FT-NIR spectrometer allows the direct measurement in process reactors and pipelines, leading to a better understanding and control of the process.

Conventional spectrometers can only be installed close to the process that they are monitoring, which exposes the analyser to a hostile environment, like drastic temperature changes and exposure to dust and dirt. Furthermore, the instrument needs to be positioned in hard-to-access and often ex-protected area. By using fibre optics technology, the difficult-to-reach measurement points can be accessed by industry hardened fibre optic probes, while the Matrix-F is positioned, eg in an analysis house. Bruker Optics offers complete solutions for various on-line analysis tasks.

Manifold applications

Since the NIR technology permits a quantitative analysis of organic molecules in small concentrations, a monitoring of most pharmaceutical production processes is possible. In many areas, even the direct control of processes as demanded by the PAT initiative.

Applications include:

• Quality control of incoming goods: During the goods­ in control the identity of the raw materials is checked. Only if they are within the specified qual­ity, is the consignment accepted and forwarded to the process. Hierarchical identification libraries based on NIR spectra allow real identification of all substances and not only checks of similarity.

• Formulation and reaction control: As each molecule has a characteristic NIR spectrum, formulations can be directly examined in-line. This also applies if the contents change with time, for example, during a synthesis, fermentation or an extraction process. In this way it is possible to determine the optimum reaction end point and to document the process has succeeded in the defined design space.

• Mixing: Producing homogeneous mixtures that are suitable for the tabletting is usually difficult. The homogeneity of pharmaceutical mixtures can be measured with the NIR technology, if a probe records spectra continuously during the mixing process or the complete spectrometer is rotating with the blend container. At the beginning of the blend process large differences between the spectra will be measured, since the individual materials are not yet homoge­neously distributed. With increasing homogenisation the spectra become more similar. Since NIR probes can have very small measurement spots, the homogeneity of smallest volumes can be supervised.

• Granulation and drying process: More than 60% of all pharmaceuticals are solids. The individual powder substances are in most cases granu­lated and dried before tabletting. Both processes can be monitored with NIR technology. Here the exact end point determination of the time consuming drying process in fluid bed dryers is of special interest, since suitable in-line measurements can reduce the drying times considerably.

• Tablet coating: Coating procedures in a drum coater or a vertical centrifugal coater can be monitored by means of NIR spectroscopy. The correlation of NIR spectra to eg spray rate and coating thickness helps to produce in specification.

• Tabletting and packing: Thickness, hardness, dimensions, and active ingredient content are relevant quality param­eters of tablets. Their automatic measurement directly off the machine offers large advantages compared to the classical laboratory analysis. Especially when producing tablets, which do not cor­respond to the specifications, it must be recognised immediately. Otherwise thousands of tablets must be rejected and disposed of, leading to high eco­nomical damage.

Final product testing and release analytics

There is no doubt that the cardinal task of the PAT initiative is to avoid time-consuming release analytics in the laboratory. Nevertheless: If in-line monitoring does not seem suitable, NIR technology can still be beneficial. In the QA/QC laboratory NIR can be used for release analytics, because the advantages of a fast and non-destructive measurement are also available off-line. With the FT-NIR laboratory spectrometer MPA all kind of samples (liquids, solids, pastes, foils) can be analysed quickly and reliably.

The NIR spectroscopy allows in many areas the direct control of processes as demanded by the PAT initiative. Shorter cycle times, higher product quality and the avoidance of non-specification grade batches are the result. Furthermore, with real-time analysis, many system parameters can be monitored and their meaning better understood. Today, many users say that the PAT initiative represents a paradigm shift in pharmaceutical analytics, meaning that the current ‘testing to document quality’ paradigm is shifted to a ‘continuous quality assurance’ paradigm. So the analytics get a complete new relevance: it does not only serve for the examination, but it is tool for the control. And in this context the NIR technology represents the most valuable tool at present.