Grasping the challenges of total testing

As the push for 100% testing of raw materials continues for the pharmaceutical industry we look at a way of making this a reality, and find the answer could be well within grasp - literally

AS THE pharmaceutical industry moves towards 100% inspection of incoming raw materials it will not be cost effective to sub-sample all containers of raw materials and send them for analysis to the lab. With the development of a handheld near infrared spectrometer capable of confirming identity in seconds – often through the original packaging – analysis can be carried out as the containers are received, in the warehouse.

To meet the stringent standards required for raw materials analysis in pharmaceutical manufacturing, all untested material should be kept quarantined until qualified and only then released into production. Given the increased demand for 100% inspection, the most efficient production facilities could simply grind to a halt waiting on the backlog of quarantined materials if every container required sub-sampling and then individual analysis in the laboratory. Near Infrared (NIR) spectroscopy has long been promoted as the technique of choice to replace more labour intensive methods for identity testing; single or combined wet chemical, UV-Visible, IR or chromatographic analyses. The PHAZIR Rx – a handheld NIR analyser – can be used by non-technical staff to provide unambiguous pass/fail identity confirmation in the warehouse itself, greatly increasing operational efficiency and ultimately ensuring product quality.

There are a number of spectroscopic techniques offering rapid analysis of a large number of excipient and active materials. All are well accepted and work exceptionally well in the laboratory controlled environment, however there are special considerations for instrumentation when used in a warehouse, often by non-technical staff:

• Accurate, fast and reliable
• Robust and easy to operate
• Ergonomic, lightweight, simple sampling
• Unambiguous; a clear Pass/Fail result reported
• Standalone; no external PC required for data collection, battery powered
• Routine system suitability testing
• Useable through material packaging - no need for sub-sampling or containment during analysis, aseptic, material stability uncompromised, avoids operator exposure, eliminates waste, reduces errors and risk of cross contamination.

The advent of MEMS (Micro-electromechanical systems) has enabled the construction of inexpensive, rugged, high precision, low power miniaturised NIR devices such as the PHAZIR Rx. Using MEMS, a diffraction grating can be created with electrically movable elements to filter light in specific spectral regions on the fly. A MEMS based spectrometer schematic is shown in figure 1, the spectrum collected from a sample is dispersed across the diffractive MEMS chip, the chip is then controlled to block light in specific regions of the spectrum while reflecting others and maintaining high throughput. The reflected light is then collected and recombined (using a regular fixed grating) onto a single photo-detector. A full spectrum measurement is possible via an encoding scheme for the chip, replacing an array of detectors with a single detector. By utilising MEMS based technology portable instrumentation can now provide the performance of bench top systems and meet the analyser requirements above.

Having no moving parts, the devices are extremely reliable under even the harshest conditions, and are tolerant to shock and vibration. Real time adjustment to ambient light conditions and simultaneous modulation of all wavelengths results in high quality data.
Novel fabrication techniques yield high device-to-device reproducibility, digital tuning provides direct methods transfer and single element detectors avoid calibration transference problems common in multi-element array based analysers.

Instruments based on IR, Raman and NIR have great potential to increase efficiency and reduce waste and re-work in pharmaceutical manufacture when used appropriately. Table 1 shows a comparison of the techniques as applied to raw materials testing. NIR spectroscopy has gained wide acceptance in the pharmaceutical industry, and the interest is continuing to grow as a result of its major advantages over other analytical techniques, these include:

• Fast accurate analysis (3-5 seconds)
• Safe, inexpensive light source
• No fluorescence interference
• Easy to operate
• No sample preparation – non destructive
• Through the packaging measurement
• Multi-component quantitative and conformity analysis (described below)

The introduction of PAT techniques within pharmaceutical production whereby processes should be kept in control with less reliance on end-product testing leads naturally to investigating if techniques used for routine identification can also give information on the quality of the material before and during processing. Critical physical parameters affecting processability or even final product performance can be rapidly and accurately assessed using NIR including crystalline form, density, and average particle size amongst others. An example of NIR being used to differentiate microcrystalline cellulose on particle size is shown in figure 2. By monitoring critical process parameters such as particle size, reaction rates can be better controlled and required heat inputs calculated more accurately. At the tabletting stage problems with flowability and compressibility are reduced resulting in the correct tablet hardness – first time.
NIR is also suitable for analysing materials with significant moisture content which may not be possible by IR or Raman. The moisture content of a material has cost per weight implications as well as affecting processability with crumbling tablets as the end product and/or active content degradation on storage; both potentially critical to product efficacy. Pre-processed NIR spectra of samples of a lactose/corn starch blend with moisture content variation of 3-20% are shown in figure 3. PLS methods using cross-validation and independent validation gave correlations (R2) of 0.999 and 0.997 respectively with root-mean square errors of 0.17% and 0.28% moisture, comparable with the reference method.  Therefore, NIR can be used to predict both chemical and physical attributes, providing true material conformity rather than a simple identity verification (table 2). 

If a large investment has already been made creating a raw materials library using NIR based in the laboratory (commonly with a dispersive or FT-NIR benchtop spectrometer) it should be possible to re-use this data for library development for warehouse based analysis. There are many approaches to transferring quantitative and qualitative methods between instruments; typically a successful library transfer between a FT-NIR and a handheld analyser requires instrument characterisation and standardisation using a set of standards (NIST, USP etc) or examples of representative library materials. Spectra can then be matched between instruments using methods such as finite instrument response (FIR) or direct standardisation (DS). An in-house example of calibration transfer of a pharmaceuticals library (containing ethyl cellulose, microcrystalline cellulose, lactose hydrate etc) between a FT-NIR and a PHAZIR Rx showed 100% transfer using an independent test set, with DS results similar to a PHAZIR-native library. Therefore, development work from the lab can be deployed on handheld analysers throughout R&D and production as appropriate. The benefits of using handheld NIR analysers within the pharmaceutical industry can be found from early drug discovery, through manufacture, to post-production degradation analysis and anti-counterfeiting (table 3) and libraries can be transferred routinely between handheld systems. 

The development of handheld analysers offer cost effective 100% inspection of raw materials. However, to maximise the benefits from 100% inspection, a conformity check should be carried out rather than identity verification. By providing information on both the chemical content and physical structure of a material, NIR offers much more than an identity confirmation; it is not only a direct replacement of ID techniques already in use –  it can predict how a material will ultimately process. An in-or-out of specification result for a material analysed by NIR can depend on many parameters such as moisture content, crystallinity, compressibility, density, average particle size and contamination level as well as simply by ‘identity’.   

Furthermore, it is only by taking the analyser into the warehouse and making it fast and easy to use that allows 100% testing to take place efficiently. Sub-sampling for analysis in the laboratory is neither practical nor cost-effective. The PHAZIR Rx is ideally placed as a routine tool for conformity checking for the vast majority of excipients and active materials.

Table 1: A comparison of techniques applied to raw materials testing

Table 2: A comparison of the applicability of techniques

Table 3: Handheld NIR deployment