NIR enters the pharma arena

Adopting NIR spectroscopy for in-process analysis has enabled Abbott Laboratories to speed up drug development, reduce time to market and make significant cost savings

Today's pharmaceutical industry is being asked to provide ever more innovative medicines to satisfy rising patient expectations. Yet the costs involved in developing those drugs are significant and increasing. Therefore, in a highly competitive marketplace, there is tremendous pressure on companies to reduce manufacturing costs while maintaining operational quality and satisfying regulatory requirements.

Through the innovative adoption of novel technologies such as Near Infrared spectroscopy (NIR), Abbott Laboratories has been able to streamline its operations to improve the quality of its products and at the same time improve its position in terms of cost base and inventory management.

NIR spectroscopy measures the wavelength and intensity of the absorption or reflectance of near-infrared light within a sample and can be applied to compounds rich in organic functional groups, particularly carbon-hydrogen bonds, oxygen-hydrogen bonds and nitrogen-hydrogen bonds. Because NIR detects the near infrared band of the spectrum - between 1100nm and 2500nm - its absorptions and overtones are subsequently of lower intensity, contain less accessible structural information and are more convoluted than most other spectra such as UV and mid-IR. Historically, little information could be extracted from this broad spectrum. But with the advent of modern computers and statistical packages, sufficient information can be extracted to provide both qualitative and quantitative information.

process optimisation

Developed in the 1960s, NIR spectroscopy was initially used in the agricultural industry; its use within the pharmaceutical industry has been more recent. Most pharmaceutical companies use NIR for identification purposes; it can be used for in-process testing and quality control to help optimise processes such as blend uniformity. NIR testing offers significant advantages over other methods as it requires no sample preparation, solvents or reagents and is non-invasive and completely non-destructive to the samples analysed. Importantly, it also reduces the potential for analyst error.

Because NIR offers instantaneous results, Abbott uses the technology for in-process analyses within the manufacturing arena, e.g. bottle-by-bottle analyses of filling runs can readily determine whether there are any differences within runs.

Not only does this reduce the cycle time, 'it also means that we can perform more quality control checks during the process validation rather than stopping while the tests are performed,' explains Roger Draper, a QA director at Abbott's Queenborough manufacturing plant in Kent.

'So it improves the quality of the process validation and reduces the potential for batch problems and rejections.'

But uniquely among pharmaceutical companies, Abbott's main interest is in the quantitative aspects of NIR, specifically in multi-component quantitative analysis. As Mark Morton, Abbott's QA NIR specialist, explains: 'Because NIR relates to Beer's law it can give information about the concentration of materials. When you are dealing with a formulated product of more than one component, the spectra that you obtain are very complex.

'What the statistical package does is match data that you've generated from those compounds using a reference method, be it high pressure liquid chromatography or gas chromatography, with the actual spectral differences in concentration, extract a number of statistical factors and generate an equation that correlates absorbances with concentration in multi-dimensional space. So if it sees that pattern in the spectral material it will use the equation previously generated to predict the concentration.'

time to market

The success of NIR testing for raw materials in its nutritional plants led scientists within Abbott to look for uses for the technology in other areas of the business. Interest focused on the possibility of using it to reduce the time it takes to get products to market and in using it in product release.

Prior to the launch of Norvir, one of Abbott's anti-HIV drugs, the company realised that demand was likely to be very high. The product achieved rapid approval, and Abbott needed to be able to analyse batches quickly to supply the worldwide market.

inevitable bottleneck

Conventional HPLC analysis of a batch of Norvir Liquid would take up to a week, and for a company with a highly efficient manufacturing floor producing many batches of a product each week, there was bound to be a bottleneck - no matter how efficient the laboratories are. 'The only way to resolve that bottleneck in the laboratory was to come up with a better technique,' explains Morton.

NIR provided the solution as it fulfils all the parameters of the reference methods - accuracy, linearity and reproducibility - but in a fraction of the time. 'Typically, it takes only 2-3 minutes to determine what by the reference method would be 2-3 days' work,' adds Morton. Abbott decided to embark on a programme of work that would result in the multicomponent analysis of Norvir by NIR.

As QA pharmaceutical operations manager Peter Casey explains, using NIR to gain a licence for product release presented a challenge. Guidelines currently available from the International Council on Harmonization include parameters that need to be included in a method validation submission within the EU, Japan and the US. Since NIR represents a fundamentally different approach to analytical testing, many of these parameters do not apply to NIR methods, or if they do apply need to be proven with statistical methods.

cautious approach

Initially, the regulatory authorities were cautious because the technique had not been used for a submission for more than two component quantification testing of a final product. 'They had received few NIR applications previously so they were very interested in Abbott's approach. The company was also cautious because it was not sure what the authorities were expecting,' says Casey.

Abbott set up a team in early 2000, which took as its goal a submission to the European Medicines Evaluation Agency (EMEA). The team comprised two NIR team leaders, one in the UK, one in Canada: one with expertise in nutritional products, the other in pharmaceuticals. It spent most of 2000 generating protocols and investigations into the technique and developing a strategy for getting a submission made and accepted.

The strategy developed by the team meant that from a very early stage, Abbott worked with the EMEA, sharing test capabilities and developing a rapport with the regulatory body.

The work took about a year to complete and the submission was finally made in late November 2000. Norvir Liquid was accepted and approved for release in mid-2001 - the first product in the world to be accepted by the EMEA using NIR technology for more than two component quantification testing of a final product.

But it wasn't simply a case of using a new technology for its own sake. Implementing the NIR analytical methods allowed the project team to reduce final product testing from 2-3 days using traditional methods to around 15 minutes. But as well as dramatically improving throughput and supply to market, it also generated cost savings in the order of $456,000 through inventory and laboratory labour savings.

other uses

Following the success with Norvir Liquid, Abbott is now looking at ways of extending the use of NIR, says Draper. 'We have a team of people working selectively on high volume products that are time-consuming to analyse where there could be a significant impact on our European operations, either from an inventory or from an efficiency standpoint.

'We are working towards making regulatory submissions for these products. We see the use of NIR as a strategy for us to improve the overall efficiency within the European QA operations, specifically targeting the turnaround and reduction of cycle time more than the traditional labour efficiency.'

That team is also working on proving calibration transfer, an issue that many people have tackled but no regulatory authority has yet accepted. In addition, Abbott sees great potential for NIR in Active Pharmaceutical Ingredient production, and has a further project team working in this area at the moment.

'Within continuous chemical processes, there is a significant potential for in-line testing - analysing specific parameters within the process and feeding back to the control loops allowing instantaneous monitoring and control of processes using the results from the NIR probes.

'This is where we expect to see future benefits from the use of NIR within the API area,' adds Draper.