The problems are large enough to have prompted reports such as this Forbes piece headlined: “Is Big Pharma Addicted To Fraud?”. As it states here, “over the past decade, whistleblowers and government investigations in the US have exposed a never-ending series of problems by numerous pharma companies in all facets of the industry, starting with fraudulent ‘research’ papers used to bolster marketing and continuing through to the manufacture of contaminated and defective products, the marketing of drugs for unapproved and life-threatening uses and the mispricing of prescription drugs.”
And it’s not limited to small companies, with each of the years listed above seeing huge fines handed out to one of the world’s biggest of the pharmaceutical manufacturers – GlaxoSmithKline*. Indeed, 2018 saw the “largest ever health care fraud” investigation in US history, with 600 charged in an attempt to stop the country’s opioid crisis – which killed over 63,000 people in 2016 alone. Among the 600 charged were those involved in a pill press organisation manufacturing 40,000 counterfeit oxycodone pills per week.
The issues are significant. Counterfeit malaria pills have been responsible for an estimated 116,000 deaths a year in Sub-Saharan Africa and the WHO (World Health Organization) estimates that a third of all medicines sold worldwide are illegitimate – with higher figures in low and middle-income countries. The reasons for this are hardly surprising: money. According to forecasts by The Business Research Company, the global pharmaceuticals market was worth $934.8 billion in 2017 and will reach $1.17 trillion in 2021.
IR spectroscopy shows contamination
IR energy excites the covalent bonds in a molecule, with the resulting vibrational modes being a unique identifier for a specific chemical structure. This gives regulators such as the FDA a fingerprint for identification. Despite the FDA statement that it is not up to the agency to inspect such overseas manufacturers on a regular basis, much academic research has been undertaken to understand how spectrometry – especially infrared (IR) spectroscopy – can be used identify contaminants.
Going back to the PIP breast scandal, one of the better papers comes from 2013, published by Beretta et al. in the Journal of Pharmaceutical and Biomedical Analysis. It examined PIP implants with virgin prostheses using a range of techniques including IR spectrometry to show that the PIP prostheses lacked “a significant part of the cross-linking sites necessary for the high-cohesive properties of the gel,” and that they could also see “significant amounts of cholesterol had been absorbed from the breast tissue by the silicone material, demonstrating the lack of impermeability of its elastomer shell.”
In addition to this, one of our favourite papers is Lawson et al. published 2018 in PLoS One. This uses paracetamol to demonstrate IR’s effectiveness in showing the absorption spectra of a drug… even in full tablet form.
Fig 1 – Absorbance spectral features of paracetamol (crushed – black; the whole tablet from above – blue; whole tablet from below – red). Reproduced by Lawson et al. 2018.
This means manufacturers can use IR detectors to cost-effectively monitor all ingredients for authenticity right down to the atomic-structural level, identifying the presence of elements, the molecular interactions and the overall sample composition.
It should be noted that several forms of IR are used today – with Lawson’s paper using an FTIR method to detect the absorbance level of wavenumbers between 2000 and 400 cm−1 – and mid-IR radiation has been shown to provide among the most useful of spectral fingerprints.
Near-IR spectroscopy is ideal for non-homogeneous samples and traces analysis, however, in comparison with mid-IR spectroscopy, the spectra derived from the fundamental bands measured are lower in intensity and more convoluted than the overtone/harmonic bands derived from mid-IR radiation. Additionally, the range of applications for mid-IR sensors is increasing with mid-IR devices becoming available for some trace detection requirements. In particular, passive pyroelectric sensors, which convert changes in temperature from IR radiation into an electric signal, are particularly useful in chemical-structure analyses such as those needed for the pharmaceutical industry.
Considerations in choosing the sensors for IR spectrometry
IR detectors are already being used in the drug industry to minimise the accidental use of counterfeit ingredients. These can deliver material identity verification, even through sealed packaging, in seconds. The consequences of getting it wrong in the medical industry mean testing has to be rigorous and regular. Therefore size, cost and portability are key. But accuracy is the most important metric.
The following are common principles for engineers developing such an IR spectroscopy system for the pharmaceutical industry – and while the priority may change from sector to sector, these principles hold up across a wide range of industry sectors – from food, testing to fuel analysis.
Principal 1: accuracy
Systems should be easy to set up without extensive calibration in order to give stable, accurate operation with no degradation. This also means sensors should be physically robust enough to cope with the shock, vibration and high operating temperatures.
Sensors should use smaller manufacturing processes in order to achieve denser, higher-resolution arrays and modules; and should also have a high signal-to-noise ratio, responsivity, and sensitivity. To enable a sensor to focus on specific frequencies or wavelengths, an optical filter can be placed in front of the sensor. An optical band-pass filter can be used to limit spectral response, block certain radiation wavelengths, to avoid false alarms, for example, or to detect specific substances.
Principal 2: portability
Portability is key to make testing easy, and therefore regular. Again, the first step to enable this is using small sensor manufacturing processes as this helps to minimise the device footprint. Cooling adds to device size and power consumption so sensors that need cooling should be avoided. Additionally, low-power sensors are crucial to enabling the development of handheld spectroscopy devices with small (lightweight) batteries.
However, because an IR sensor measures small changes in electrical voltages, a pre-amplifier with an internal voltage regulator will likely be required. An A2D converter will be needed for analogue signal outputs. Pyreos supplies both analog and digital products to suit customer requirements. The Pyreos ezPyroTM digital product range removes the need for these components.
Passive pyroelectric sensors made from piezoelectric materials (see Pyreos offering here) match these specifications and come with three additional benefits: they’re manufactured in a standard semiconductor foundry, so taking advantage of competitive process options and they are economical. They’re scalable for both high and low volumes and the technology is benefiting from significant R&D, giving continued improvements in performance.
The problem of fraudulent drugs is only set to get worse
The value of the pharmaceutical and medical materials market makes it ripe for fraud and counterfeiting, both by criminal gangs and by the industry itself. The problem is particularly worrisome in fast-developing economies. For example, a 2015 paper published by the industry body ASSOCHAM and entitled Fake and Counterfeit Drugs In India –Booming Biz showed that India faces exacerbated versions of those problems raised in the US by the FDA; with the paper stating “what drives trade in fake drugs is lack of adequate regulations, shortage of drug inspectors and a lack of lab facilities to check purity of drugs.” It also says “the other key factors include storages of spurious drugs by the chemists, weaknesses in drug distribution system, lack of awareness among consumers and lack of law enforcement.”
Three factors are combining to suggest this trend is set to continue:
1) The growth of the industry is accelerating, from 5.2% industry growth per year (2013 to 2016) to 5.8% forecasted (2017 to 2021).
2) More people in developing economies are coming online. This is by far the easiest way for consumers to buy counterfeit drugs, thinking they’re just low-cost versions of the real thing.
3) There is still limited tracking of long-term outcomes from surgery. For example, a November 2018 report by the International Consortium of Investigative Journalists into the breast implant industry finding that over 1,200 serious incidents had been reported since the start of 2015 in the UK alone. And, worryingly, evidence was found of the use of non-clinical-grade materials by leading manufacturers.
However, the use of mid-IR sensors, based on PZT pyroelectric materials gives regulators a cost-effective way to undertake more regular testing – both in developed and developing countries.
* In 2012, Glaxo paid $3 billion to resolve civil and criminal allegations of, among other things, marketing widely used prescription drugs for unapproved treatments and using kickbacks to promote sales. In 2009, Glaxo paid $750 million to resolve civil and criminal charges that quality failures led to serious contamination of drug products at its manufacturing operations in Puerto Rico.