The pharmaceutical industry has spent billions of dollars trying to tackle the issue of fake medicines, from working with global regulatory authorities and educating healthcare professionals and patients to using technology such as radio frequency identification (RFID) tags and 3D barcodes. Yet, despite these efforts, criminals are still able to move huge quantities of counterfeit drugs through the supply chain and into the hands of millions of unsuspecting patients.
Experts at Ceram Surface and Materials Analysis (Stoke-on-Trent, UK) are responding to this issue by using surface analysis techniques not only to successfully detect fake medicines, but also to determine whether the drugs in question were manufactured using licensed or unlicensed manufacturing processes. Pharmaceutical companies can effectively use many of these analytical technologies in their battle against counterfeiters.
A Global Issue
The problems associated with counterfeit medicines are global and well documented; their costs to patients, drug manufacturers, governments, and society have been in the media spotlight for many years. The World Health Organization estimates that sales of fraudulent drugs will hit $75 billion by 2010, and the pharmaceutical industry estimates that counterfeit medicines account for 10% of the global supply chain—a figure that rises to 70% in some developing countries. Currently, counterfeit drugs can be split into the following categories:
• products without active pharmaceutical ingredients (APIs);
• products with incorrect quantities of APIs;
• products with the wrong ingredients;
• products with the correct quantities of APIs but with fake packaging;
• products with high levels of impurities and contaminants; and
• copies of the original product made using unlicensed manufacturing pro- cesses.
The contents of counterfeits are always unreliable because their sources are unknown or vague. Those with the wrong chemical composition or contaminants can be investigated using a range of techniques, including nuclear magnetic resonance spectroscopy, infrared spectroscopy, thin layer chromatography, desorption electrostatic ionization, Raman spectroscopy, X-ray diffraction, and liquid chromatography-mass spectrometry.
More difficult to identify are counterfeit products that contain the correct ingredients in the correct amounts. These drugs, which are copies of originals, can actually be just as deadly as those with the incorrect ingredients. Other tools that can detect fake drugs and unlicensed manufacturing methods include X-ray photoelectron spectroscopy (XPS), secondary ion mass spectroscopy (SIMS), depth profiling, and time-of-flight secondary ion mass spectrometry (ToF-SIMS).
Reveal More Than Face Value
Surface analysis techniques have proven invaluable to the pharmaceutical industry in the rapid identification of counterfeit drugs, in the trace contamination of pharmaceuticals, and in the assessment of manufacturing processes.
XPS, for example, is a quantitative spectroscopic technique that is able to measure the elemental composition, empirical formula, and chemical state of the elements at the surface of a material and can also detect the elements that contaminate a surface. The technique uses X-rays to dislodge photoelectrons from the surface of the sample; the kinetic energies of the electrons that escape from the top 1–10 nm of the material are then analyzed. This non-destructive quantitative testing method can detect elements down to 0.1 At% concentration (atomic percent, or the ratio of atoms of a particular element to all atoms in a given volume). Every element except hydrogen and helium can be detected with a typical sampling depth of 5–8 nm.
SIMS can examine the surfaces and sub-surfaces of a drug using a depth profiling technique involving continuous bombardment of the surface with a primary beam of ions, resulting in the emission of secondary ions from the sample. The secondary ions are then analyzed, and the associated mass spectra and chemical maps reveal the chemical composition (elemental, isotopic, or molecular) that lies within several microns of the drug surface. SIMS is an incredibly sensitive surface analysis technique, enabling elemental detection in the parts per billion range.
In one form of SIMS, ToF-SIMS, a primary focused ion beam is also used, but the beam is pulsed to provide packets of primary ions that generate packets of secondary ions when they make contact with the sample surface. These secondary ions are then passed through a mass analyzer. Given that the "time of flight" of the ions to the detector is related to their mass, the mass analyzer reveals an extremely detailed breakdown of the molecular composition of the pharmaceutical surface.
Most importantly, the low primary ion doses and sampling depth of 1-2 nm used in this technique means that the sample is effectively undamaged by the analysis. The ion beam can be rastered across the surface under examination to produce a color-coded chemical map. A full spectrum can then be obtained for every pixel point within the image. Although the technique is not quantitative like XPS, it does provide more detailed structural information, particularly for organic and polymeric components.
Used individually or together, these three techniques can provide a very clear picture of the composition of a pharmaceutical product.
Identify Manufacturing Routes
Identifying whether a medicine was manufactured using unlicensed processes is critical to patients. The manufacturing process determines certain characteristics of the drug, and any deviations from the approved practice can threaten the lives of patients who take it.
For example, Ceram Surface and Materials Analysis has used surface analysis techniques to identify differences in the distribution of magnesium stearate, a common pharmaceutical lubricant readily detectable by XPS and ToF-SIMS. This technique pinpoints differences in the manufacturing processes of tablets that have the same chemical composition but are prepared using direct compression and wet granulation.
The analysis also involves careful sectioning of different test tablets in a controlled atmosphere to expose an inner surface. Conventional microscopy and ToF-SIMS (see Figure 1, left) can be used to determine variations in the surface composition and distribution of the lubricant between the two pharmaceutical tablet samples.
It is vital that the pharmaceutical industry have the techniques and expertise to detect counterfeits in order to protect its own reputation and commercial interests and to ensure that patients receive the correct medication. Many pharmaceutical companies now regularly turn to surface analysis techniques, not only for the detection of fakes, but also for routine detailed analysis as part of a long-term quality assurance process. n
Dr. Bentley is a technical sales consultant at Ceram Surface and Materials Analysis. Reach her at justine.bentley @ceram.com.
1. World Health Organization. Counterfeit medicines. WHO Web site. November 14, 2006. Available at: http://www.who.int/medicines/services/counterfeit/impact/ImpactF_S/en/. Accessed May 7, 2009.
2. Center for Medicine in the Public Interest. Moderator’s guide: 21st century health care terrorism: the perils of international drug counterfeiting. September 20, 2005. Available at: www.cmpi.org/uploads/File/21st-Century-Terrorism.Report.pdf. Accessed May 7, 2009.
3. Bentley J. The counterfeit detective. Pharm Technol Eur. 2008;20(9):20-23.