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Abstract
A threat to human health in developed and, in particular, in developing countries, counterfeit medicines represent the largest identified fraud market worldwide. 3D screen printing (3DSP), an additive manufacturing technology that enables large-scale production, offers unique opportunities to combat counterfeit drugs. One such possibility is the generation of oral dosage forms with a distinct colored inner structure that becomes visible upon breakage and cannot be copied with conventional manufacturing methods. To illustrate this, we designed tablets containing a blue cross.
Owing to paste properties and the limited dimensions of the cross, the production process was chosen to be continuous, involving two screen and paste changes. The two pastes (tablet body, cross) were identical except for the blue color of the latter. This ensured the build-up and mechanical stability of the resulting tablets in a mass production environment. The ensuing tablets were found to be uniform in weight and size and to comply with regulatory requirements for hardness, friability, and disintegration time (immediate release). Moreover, all tablets exhibited the covert anticounterfeit feature. The study delivers a proof-of-concept for incorporating complex structures into tablets using 3DSP and showcases the power of the technology offering new avenues for combating counterfeit drugs.
Keywords:
3D printing; additive manufacturing; anti-counterfeiting; tablet geometry; 3D screen printing; drug delivery system; solid oral dosage forms
Introduction
Since the early 1990s, an increasing number of counterfeit drugs in circulation can be observed [1,2]. Counterfeit medicines amount to an estimated USD 200 billion market annually, making it the largest identified fraud market globally [3]. In 2022 there were 6615 pharmaceutical crime incidents, corresponding to an increase of 10% compared to 2021 [4]. The World Health Organization (WHO) reports that 10% of the global pharmaceutical trade [5] and as much as 25% in developing countries [6] involves counterfeit drugs. Some sources even state that in in parts of Africa and Asia, this figure exceeds 50% [4,7]. In 2021 Interpol’s worldwide operation discovered more than 3 million counterfeit medicines and medical devices in the UK supply chain worth GBP 9 million [8]. Another operation by Europol seized more than 25 million units of medicines with a value of around EUR 63 million [9]. Already 10 years ago, piracy and counterfeiting cost US businesses more than USD 200 billion annually [10] and causes a total loss of life of between 100,000 and 1,000,000 people worldwide per year [11].
Highly prone to counterfeiting are anti-malaria drugs such as artesunate, where 30 to 50% of all packets bought in southeast Asia were fake [12,13]. Thus, the counterfeiting of pharmaceutical products is a global challenge [5]. According to the WHO definition, a counterfeit medicine is “A medicine that is deliberately and fraudulently mislabeled with respect to identity and/or source. Counterfeiting can apply to both branded and generic products and counterfeit products may include products with the correct ingredients or with the wrong ingredients, without active ingredients, with insufficient active ingredients or with fake packaging” [14]. This poses a growing threat to public health as they can deliver hazardous treatment or even cause death [15].
Counterfeit drugs are hard to detect. Possible techniques for detection are visual features such as packaging, labeling, including spelling mistakes and product security features, and physical (surface discoloration, disintegration, dissolution), or chemical analysis (spectroscopy, chromatography, spectrometry) [16,17,18]. This emphasizes the need for the development of advanced technologies for improved anti-counterfeiting measures for drugs, which should be hard to duplicate, easy to prepare, high-throughput, convenient to recognize, inexpensive [19,20], and legally accepted. However, the FDA supports a wide range of anti-counterfeiting techniques and detection methods [14,21].
Several anti-counterfeiting technologies [22] include: tamper-resistant packaging [23,24,25], track and trace technology [26,27], and product authentication. These can either be covert [16] (such as embedded images, digital watermarks) or overt features [15,19,28]. Even features of a forensic nature, where chemical or biological taggants are introduced into a tablet, are already in development [29,30,31,32].
However, the forensic technique requires licensed technologies for read-out and is thus expensive and unlikely to be available to authorities and the public. The currently most employed anti-counterfeiting measures are data carriers, such as RFID (radio-frequency identification) tags [33,34], or 2D identification methods [19,35,36]. For example, Pfizer uses RFID tags for its Viagra® product, GlaxoSmithKline for Trizivir®, and Purdue Pharma labels its Oxycodone product with an RFID tag [33]. Several drawbacks of these anti-counterfeiting measures are that they need to be varied frequently, but patients and the authorities would need information to know which features to look for. Furthermore, covert, or overt features on the packaging would be useless if the product is repackaged.
Therefore, the implementation of anti-counterfeiting measures directly onto the tablet is a necessity. If possible, even a combination of hidden anti-counterfeiting measures and easily recognizable visual features would be the goal.
Herein, we present a novel approach to anti-counterfeiting techniques specifically utilizing the advantages of 3D screen printing (Laxxon Medical GmbH, Jena, Germany, US Patent 20140065194). By employing the 3D screen printing technique where an aqueous dispersion of excipients and API are printed through a screen mesh onto a substrate, thousands of strongly defined tablets can be printed per screen simultaneously. The geometry is defined by the layout of an impermeable emulsion which blocks certain areas on the mesh. After one printing cycle, the deposited layer is dried. The next layer is printed precisely on top of the previous one after lifting the screen by thickness of the dried layer. Subsequently, a three-dimensional geometry is constructed [37,38,39].
Laxxon Medical Corp. (New York, NY, USA) already developed a proof-of-concept work with 3DSP (SPID®-Technology, Stetten, Switzerland) having shown its anticounterfeiting potential by printing QR codes directly on tablets as small as r = 5 mm during and as integral part of the manufacturing process [39].
Since 3D screen printing with SPID® technology is a controlled and licensed manufacturing technology that is not generally available, it is impossible to mimic these features in an uncontrolled environment and without extensive technological and development resources. Therefore, this technology does not lend itself to easy duplication.
In addition to the proof-of-concept work on overt anti-counterfeiting measures such as QR-codes imprinted to the surface of a tablet [39], 3DSP offers a new level of anti-counterfeiting strategies, that is, the implementation of covert features within oral dosage forms, which are impossible to counterfeit using conventional techniques. In this paper we present a proof-of-concept study for embedding a covert cross structure into a tablet. With only two screen and paste changes, a structure can be integrated into a tablet which exhibits a distinct pattern upon the breakage of the tablet in either the middle or slightly off-center. Additionally, the only difference in the paste compared to the overall tablet material is the addition of food coloring, meaning only a subtle change in API content due to the addition of food coloring and no strongly irregular API distribution in the tablet. This means that no alteration in the biopharmaceutical performance would be expected compared to a homogenous tablet without the embedded cross. Read the rest of the full article here.
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