The PAT initiative: NIR technology helps to increase manufacturing efficiency

An Ask the Expert feature with Jörg-Peter Conzen, Bruker Optics

The production of pharmaceutical products is a chain of different engineering processes – from setting up the formulation to granulating, drying, mixing, tabletting, coating and packaging the finished product. Only a totally error-free progression through each of the single steps guarantees a product of sufficient quality. The analytical control of all inter­mediates is another major issue in the pharmaceutical industry.

The extent of utilisation of pharmaceutical production plants worldwide is far below what is technically feasible due to non-specification grade batches and the long idle time prior to product release. In addition, in most cases, laboratory quality control measurements permit no statement about the cause of a non-specification grade batch. The economic losses are accordingly high.

Quality control during the process

Ideally, quality control would be introduced not only after, but also during, the manufacturing process. With direct in-line control the effectiveness of pharmaceutical processes will be increased and the respective costs reduced. It is intended to control specific quality parameters during the process and to predict them for the final product before its release.

Classical process variables such as pressure, temperature, pH or other physical parameters are, however, not selective enough to make precise statements on relevant material properties. This can only be done with optical techniques like infrared, NIR or Raman spectroscopy.

Concentrating on NIR technology

The PAT initiative concentrates in particular on the NIR technology as the most important analytical procedure for the in-line control, as NIR is unrivalled in the sum of its possibilities. The use of probes or flow cells permits a direct investigation of most relevant processes. This measuring technique is generally suitable to analyse substances that contain CH-, NH-, OH-, SH- or -C=O groups in a concentration range of approximately 1% and above.

Both solid and liquid samples can be analysed and, with the development of modern probes and transmission cells, measurements can be accomplished even under extreme conditions. Sampling is no longer as necessary as the analysis by qualified technical personnel. All spectroscopic information can be transported via fibre optics over distances of more than 100m to the instrument.

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.
• Formulation and reaction control: as each molecule has a characteristic NIR spectrum, formulations can be directly examined. This also applies if the con­tents change with time, for example, during a syn­thesis or an extraction process. In this way it is possible to determine the optimum reaction end point.
• 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 surveilled with NIR technology.
• 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.
• Tabletting and packing: thickness, hardness 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.

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.

Dr. Jörg-Peter Conzen is VP of Bruker Optics and head of the NIR & Process Technology group. He studied chemistry at the University of Karlsruhe and received a doctorate for his thesis focussing on NIR spectroscopy and chemometrics. Since 1995 he has been working for Bruker Optics.