X-ray technology is an effective way of inspecting pharmaceutical products for a range of factors, among them being certain kinds of contaminants, fill levels, damaged or missing components, and damaged packaging.
Without a doubt, the pharma sector is waking up to how useful X-ray inspection can be, and how it can improve matters of cost, efficiency and waste. The European Medicines Agency (EMA) has issued rules regulating the exposure of drugs to X-rays, in its document “The Use of Ionising Radiation in the Manufacture of Medicinal Products” (3AQ4a). This guidance advises that irradiation may be used for microbial decontamination, sterilisation or other treatments in the manufacture of medicinal products and that manufacturers doing so should refer to the Guide to Good Manufacturing Practice (Volume IV of “The Rules Governing Medicinal Products in the European Union”) and in particular to Annex 12, on ionising radiation used in the manufacture of medicinal products.
The Annex explains the responsibilities and processes required for using ionising radiation with medicinal products, including different types of irradiation, validation and documentation processes, and dosimetry to measure absorbed doses. However, there is often still a sticking point – a nagging doubt that some manufacturers have about installing X-ray inspection on their pharma production and packing lines. It is the worry that inspecting products using X-rays will cause the product’s therapeutic efficacy to be compromised. This means that radiation from X-ray inspection will fundamentally alter chemical compounds and break the covalent bonds of the molecules that constitute the drug.
At Mettler-Toledo, we are asked about this issue often, and of course, it is not something to make light of. Any responsible manufacturer would want to ensure that its product reaches the end user in optimum condition. Our answer to this kind of query, however, is threefold.
Firstly, the radiation levels used in this type of inspection are incredibly low and are directed upon each product for a fraction of a second. Secondly, the research so far carried out in this area (see below) supports the hypothesis that there is no evidence of damage to pharmaceutical products after x-ray product inspection (1). Finally, we can reassure them that, as a responsible manufacturer, we would be happy to work with them on testing and analysing what effect, if any, our inspection technology would have on their specific pharmaceutical product.
The nature of X-ray
One aspect of this subject that needs to be understood at the outset by pharmaceutical manufacturers is the nature and intensity of the radiation produced by X-ray systems for product inspection. There are many natural sources of radiation that surround us – whether they be cosmic rays from space, or naturally occurring radioactive materials on Earth, including uranium or radon gas. Wherever you may be on the planet, you are being subjected to some level of this “background” radiation.
Alongside these natural sources of radiation are manmade sources, which include medical equipment, security scanning and inspection systems such as those used in X-ray inspection. Those created within inspection equipment are only transmitted when the equipment is switched on. They can be turned on and off at will, unlike background radiation. Provided that safety guidelines are followed, there is no risk to the operators of such x-ray inspection systems.
In respect to the effect of these x-rays on pharma products, it should be noted that the radiation dosage to which products might be exposed is very small in comparison to other man-made sources such as those noted above and that the length of time exposure to this energy is very short – typically, pharma products such as tablets are exposed to x-ray inspection energy of around 0.11 milligray (mGy) for less than 0.2 seconds. A frequent airline flyer will be exposed to around 200 μSv (microsieverts) per year, which is around double the dosage size (note: 0.1 mGy equals 100 μSv).
The US Food and Drug Administration (FDA) has estimated that the dose level received by an object going through an X-ray inspection system is lower than the background radiation dose level that the same object will be exposed to over a single day. The FDA also emphasises that whether consuming medicines or other products that have been inspected by x-ray, no real danger has ever been established, stating on its website that “there are no known adverse effects from eating food, drinking beverages, using medicine or applying cosmetics that have been irradiated by a cabinet x-ray system used for security screening” (2).
Formal research
There has been some scientific research into the effect of X-ray inspection on pharma products. The main study was conducted and published in 2015 by scientists at the Department of Drug Delivery and Nano Pharmaceuticals, in the Graduate School of Pharmaceutical Sciences, Nagoya City University, Japan In this study, three pharma drug tablets were exposed to x-ray doses from 0.34 milligray, which is three times the typical dose delivered by x-ray inspection, up to 300 Gray (Gy), which is about one million times the typical dose. The drugs tested were acetaminophen, loxoprofen and mefenamic acid tablets. Following exposure, the samples were evaluated in formulation tests for dissolution, disintegration and hardness and were found to exhibit almost the same profile as samples that had been exposed to 0 Gy of radiation, revealing, according to the researchers, that exposure to x-rays did not affect the pharma quality of the tablets.
The samples were also subjected to accelerated temperature and humidity tests in combination with X-ray exposure, and this also did not affect the pharma quality. The conclusion made was that even exposure to X-rays at much higher levels than product inspection systems use had no significant effect on the efficiency or other properties of these drug tablets (3).
An earlier study in 2012 – by Robert Bosch Packaging Technology and the PHAST Society for Pharmaceutical Quality Standards (4) looked at the effect of two hours of x-ray exposure on the pharma substances tramadol HCI and nifedipine. No degradation was observed in either substance, even after this much longer x-ray inspection exposure time.
Test and analyse
While these results strongly suggest that the low radiation dosages and split-second exposure times of X-ray inspection systems have no significant effect on pharma products, it would be unscientific to say that these results apply across the board. The simple fact is that not all formulations have been studied. However, there is a growing weight of evidence from the day-to-day operation of x-ray inspection in the pharma field, where inspected drugs continue to operate as they should, without detriment to patient safety. Even so, if pharma manufacturers still have concerns in this regard, their X-ray suppliers should move to address them quickly. At Mettler-Toledo, we are very happy to work with pharma companies, combining our Safeline x-ray inspection systems with the manufacturer’s laboratory capabilities to undertake thorough testing and analysis. We are confident that the results achieved would put their mind at rest.
To conclude, the advantages of X-ray inspection are considerable, giving pharma manufacturers the opportunity to perform presence and integrity checks, physical contamination checks, and fill-level checks that would otherwise be difficult and time-consuming to carry out. These quality assurance checks are completed within energy dosage levels that available research and experience suggest are safe and have no negative effect on the quality of the product.
References:
- https://www.fda.gov/radiation-emitting-products/security-systems/frequently-askedquestions-cabinet-x-ray-syste ms
- https://www.fda.gov/radiation-emitting-products/security-systems/frequently-askedquestions-cabinet-x-ray-syste ms
- Kazuaki Uehara, Tatsuaki Tagami, Itaru Miyazaki, Norikazu Murata, Yoshifumi Takahashi, Hiroshi Ohkubo & Tetsuya Ozeki (2015) Effect of X-ray exposure on the pharmaceutical quality of drug tablets using X-ray inspection equipment, Drug Development and Industrial Pharmacy, 41:6, 953-958, DOI: 10.3109/03639045.2014.917093
- Martin Vogt, Elke Sternberger-Rutzel, Manuel Birke & Christoph Jacobs (2012) Influence of X-ray radiation as PAT method on the model substances tramadol HCl and nifedipine compared to the influence of UV-Vis radiation, TechnoPharm 2, Nr. 3, 1–12