NIR spectroscopy in a manufacturing plant

Near infrared spectroscopy is a well-accepted analytical technique in the pharma industry. Applications include raw material identity and moisture content analysis

Many near infrared spectroscopy (NIR) methods now have regulatory acceptance and as an analytical technique, NIR has a unique set of values for the potential user; it is rapid, non-destructive, easy to operate and capable of producing high quality analytical data outside of a laboratory environment.

Pioneering work in NIR applications began in the late 1980s and was generally carried out within major research-based pharmaceutical companies, notably Pfizer, Merck, GlaxoWellcome, SKB and Astra.

Such companies operated multiple production sites that could benefit from implementation of the technique and, equally importantly, also employed large numbers of analytical chemists who could carry out method development.

Thus it was these largest companies in the industry that first implemented NIR, and through them, its use spread from Western Europe and the US to other areas of the world where large-scale pharmaceutical manufacture takes place.

Over the past few years, however, structural changes in the pharmaceutical industry have led to new demands on suppliers of such technologies as NIR that require the linking of hardware, software and application development to produce a dedicated 'analyzer solution'.

Consolidation and globalisation has led to the creation of a few global pharmaceutical 'giants'. At the same time though, concentration by these global giants on their 'core competences' has led to their outsourcing many activities that they cannot, or do not wish to carry out in-house.

outsourcing strategies

Outsourcing can give a company the opportunity to grow its volume and profits faster, by sharing technical and financial risk, while maintaining a competitive cost base. Almost all of the largest pharmaceutical companies have outsourcing strategies, encompassing such activities as drug discovery, product development, drug delivery systems, contract manufacturing and packaging. This has created an opportunity for smaller companies whose size allows them to blend creativity, flexibility and responsiveness to create successful niche businesses in these areas.

It is in the area of contract manufacturing that many such opportunities are being realised, where smaller operations can offer advantages over those of larger plants for example in

In the former case, the larger company can free up manufacturing capacity, facilities and expertise so that they can be used more profitably. In the latter, they can benefit from specialised expertise available outside of their own company, without additional investment.

It is in contract manufacturing, too, that the merits of NIR are now being appreciated. However, unlike Pfizer, and other pioneers of NIR in the 1980s, the niche companies now carrying out work in this area have neither the scale of operation to justify putting extensive effort into method development, validation and registration, nor the staff to carry out the necessary work in a timely fashion.

Thus a typical contract manufacturer's requirement is for a dedicated 'plug and play' analyzer, rather than for a development instrument, that requires the user to develop his own applications.

analysis at RP Scherer

To highlight in more detail this requirement and how it can be met, it is instructive to look at the experience of such a niche contract manufacturing facility.

RP Scherer, which is part of the Cardinal Health Corp of the US, is the world's largest producer of soft gelatin capsules, and also provides other innovative drug delivery systems.

Basic softgel manufacturing technology has changed little since Robert Paul Scherer invented and patented the basic rotary die manufacturing process in 1933.

Gelatin mass is manufactured, from a mixture of gelatin, water, colourants, and other ingredients. Fill materials are typically natural oils such as cod liver oil, or botanical extracts suspended in edible oils, sometimes with a thickening agent. Gelatin capsules are formed in rotating dies, fill material is injected and the capsules are cleaned and dried.

Newer developments in die and wedge technology are improving product style and production rate, while the elimination of gelatin by shell materials based on non-animal products is a response to customer demand.

An exciting new growth area for Scherer is in their Zydis fast dissolving delivery technology which enables patients such as young people, elderly patients and others who can't swallow easily, to take medication through wafers that dissolve on the tongue.

As well as drug formulation and softgel manufacturing capability, RP Scherer's two facilities in Swindon, UK, provide comprehensive support services, including research, analytical and process development, stability testing, packaging, production of clinical trial materials and assistance with regulatory affairs. These support services have to be provided in a cost effective and responsive manner, commensurate with the needs of the customer, but within the constraints set by their own operational size.

Thus when rapid business growth put additional demands on RP Scherer's analytical capability, it was natural that they should invest in NIR technology.

In 1998, Scherer purchased its first two Foss NIR Systems units for raw material identification, both direct content analyzer (DCA) models were equipped with Foss's Vision software.

At the RP Scherer site in Swindon, one of the major challenges for the quality control unit is in the testing of the raw materials for the manufacture of Softgel capsules, as these number over 2,000, including many natural products such as extracts and oils. For solids, reflectance measurements were taken at the reading window in flat bottomed vials, while liquids were analysed, also by reflectance, after addition of titanium dioxide, which serves as a reflectance medium.

rapid identification

With the support of Foss technical specialists, a basic library of most of the common materials was established over a six month period. This period was needed to obtain a sufficient range of samples for the materials in question.

The instrument is now in use in the production units receiving area, and as new materials come in, they are qualified and added to the spectral library.

Because raw material identity by NIR is so rapid, there was time potentially available on the instruments to carry out additional tests. Thus during the last year, Scherer analysts have applied NIR to the measurement of moisture in capsules, with great success. So much so that factory production operators now use the NIR instrument for in-process control on a 24h/day basis.

The increased need for documentation in support of GMP places a disproportionate burden on smaller companies such as Scherer in many different ways. It is important that instrument suppliers respond by providing the tools to facilitate speedy implementation and thus ensure rapid payback of the investment made.

A good proportion of the Zydis products manufactured by RP Scherer are exported to the US. Thus, it needs to work to the highest standards of cGMP to meet the expectations of worldwide markets, including the regulations of the US FDA.

In some ways, this can be a difficult target to meet, and therefore RP Scherer will tend to seek instrument suppliers who can provide the right tools and infrastructure to ensure speedy and compliant implementation.

Encouraged by success with the Foss NIR Systems equipment at Swindon, technical staff at Swindon are investigating a number of other applications of NIR, mainly for in-process testing.

Firstly, in the softgel plant, there is an interest in measuring the potency of specific natural materials in viscous oily matrices that, if successful, could have benefits both economically, and in improved product monitoring.

Secondly, in Zydis production, the staff have already shown that NIR has potential to monitor the homogeneity of drug suspensions. Hence the RP Scherer scientists are now working on using NIR in a continuous loop to monitor and thus provide key control data for the dosing process.

Other areas of interest are the investigation of sedimentation, crystal morphology and polymorphism, and content uniformity of Zydis dosage forms.

The NIR System in use at RP Scherer

The DCA system is a rapid scanning near infrared monochromator, equipped with Vision software, which can analyse solid and liquid samples in around 25 sec. During this time, a sample spectrum is generated over the range 1100-2500nm, and this is compared with spectra of reference samples in a spectral library. The unknown sample is then identified by comparison with library spectra and the result presented. For solids, no sample pre-treatment is required, while for liquids, sample pre-treatment is minimal. Routine operation requires no specialist knowledge or training.