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Dosage-level authentication provides an added digital layer of security for pharmaceutical companies to ensure their products are not exposed to falsification.
Global counterfeit pharmaceuticals trade is estimated to be worth billions and has grown during the coronavirus pandemic (1,2). Various regulatory measures have been implemented to tackle the issue of counterfeit medicines, such as the Drug Supply Chain Security Act (DSCSA) in the United States and the Falsified Medicines Directive in Europe (3,4), which require the implementation of safety features, chiefly aimed at secondary packaging.
However, as counterfeiters become more sophisticated and technology advancements enable the falsification of packaging authentication measures, such as barcodes, there is a growing need to improve anti-counterfeiting solutions. One such approach to improved authentication is verification at the dosage level. To discuss the issues surrounding counterfeit pharmaceutical products and the advantages of dosage-level authentication, Pharmaceutical Technology spoke with Ali Rajabi-Siahboomi, vice-president and chief scientific officer, and Gary Pond, global program lead—Authentication, both at Colorcon.
PharmTech: How are current regulatory-required methods of pharmaceutical product security lacking, and what potential technological advances are available to overcome these limitations?
Pond (Colorcon): Many countries have done a good job of meeting the regulatory requirements of serialization to address pharma product security, which has required significant investment and changes to many company processes. Despite the implementation of serialization, there is still significant growth in diverted and falsified medicines, and illegal online pharmacies are contributing to this increase.
The main challenge of serialization is that it is primarily focused on the secondary packaging. Serialization is rarely used to secure primary packaging and can’t be applied directly on the tablets. So, if the packaging is copied or separated from the primary package or tablets, it can’t be identified and referenced back to the original batch. Counterfeiters have become more sophisticated, using the latest print technologies to copy barcodes, holograms, and ID numbers.
Also, once a product moves out of a country-specific supply channel the ability to use serialization for verification purposes is reduced, as there is no way to trace the provenance or be sure that the product is authentic.
On-product microtaggants provide a digital way to directly mark and verify at the dosage level and/or primary packaging; this provides an additional layer of security that enables quick identification of real versus fake products that is independent of the packaging.
PharmTech: With more and more medicines being purchased online, do you believe there may be a stronger case for more stringent regulatory product authentication measures to be implemented?
Pond (Colorcon): The rise of Internet sales and the impact of COVID-19 has contributed to a significant increase in online sourcing of pharmaceuticals as well as vitamins/dietary supplements. There is widespread agreement that the Internet has become the primary market for counterfeit pharmaceutical products, and as far back as 2015, the World Health Organization (WHO) estimated that 50% of the drugs for sale on the Internet were fake. The COVID-19 pandemic has led to a dramatic rise in online sales, and it is estimated that one in four US consumers now buy their medicines online.
In 2018, FDA estimated that only 3% of online pharmacies complied with US pharmacy laws and practice standards (5). The remaining online pharmacies frequently operate without certification, prescribe drugs without adhering to legal guidelines, and may knowingly distribute counterfeit medicines.
In December 2020, WHO identified the issue of counterfeit drugs as one of the urgent health challenges for the next decade (6). Despite pharma being a conservative industry, this warning from WHO is likely to result in more stringent product authentication requirements and robust regulatory enforcement.
PharmTech: Could you provide some more detail about on-dose authentication, on-product microtaggants, and how tagging an individual pill/dose is achieved?
Rajabi-Siahboomi (Colorcon): On-dose authentication provides a security layer that pharmaceutical companies can employ to directly protect their products. FDA is one of the few regulatory bodies that has recognized the value of on-dose authentication and issued guidance for use as far back as 2011. In the FDA publication, Guidance for Industry, Incorporation of Physical-Chemical Identifiers into Solid Oral Dosage Form Drug Products for Anticounterfeiting, a combination of track and trace with product authentication technologies is recommended to provide a greater level of security for drug products; recognizing there is no single ‘magic bullet’ approach (7).
A physical chemical identifier (PCID) is described by FDA in its guidance document as “a substance, or combination of substances, possessing a unique physical or chemical property that unequivocally identifies and authenticates a drug product or dosage form” (7). The PCID guidance directs pharmaceutical manufacturers who want to incorporate PCIDs in solid oral dosage forms to provide greater protection for drug products. FDA recommends that the PCIDs be pharmacologically inactive and as such they can be treated as excipients and be added to the product at the lowest level that will ensure identification of the dosage unit (7).
Microtaggants are technical innovations developed for application to pharmaceutical products, they are incorporated directly on-dose during the manufacturing process through the use of Colorcon’s film coating and/or on-dose monogramming inks. Two different types of microtaggant have been developed that are suitable for pharma use, one produced from non-biologic DNA and the other from silica, both inert materials.
DNA is robust and easy to apply, and its structure means that it is possible to have unique DNA sequences that can be coded to identify by product, company, or region. These codes or sequences can then be read using advanced detection technology, with the DNA and reagent acting as a lock and key.
The silica tagging technology uses microparticles that are spectrally encoded and can be detected by the way they reflect light. Silica microtaggants can be customized with unique information for product verification and traceability. Proof of concept shows that silica microtaggants can be identified using a mobile lab-based reader and/or shortly, a smartphone app.
The development of these technologies using Colorcon’s Opadry film coating systems is at an advanced stage in terms of the application process, in-use stability, and detection methodologies. These technologies can be implemented by pharmaceutical companies with little to no impact on their current film coating process. The only requirement is readers to detect the microtaggants for verification and quality assurance purposes. As the technology is applied using a standard film coating process, there is no additional capital expenditure required on the production line.
PharmTech: What specific advantages are gained through dosage level authentication versus packaging authentication?
Pond (Colorcon): Traceability and security measures focused on the packaging are not enough to protect to the patient level. Even if a package is authentic, it may be impossible to determine whether the medicine inside is real, fake, or diverted. As serialization matures it will be valuable for track and trace, but to achieve true supply chain security, on-dose authentication measures are the only viable option, and manufacturers recognize that they can no longer rely solely on packaging security features to ensure the authenticity of the product within.
On-dose authentication solutions are difficult to replicate or reverse engineer, provide a robust and reliable means of deterring and identifying counterfeiting and verifying product identity. Perhaps the most significant benefit of on-dose authentication is to increase the speed of decision-making in the supply chain for counterfeit or illegally diverted drugs. When a suspect event occurs, pharma companies will be able to react faster to determine if the product is real or fake, regardless of whether they have access to the packaging. Sometimes this process can take days to weeks, but with on-dose authentication, it is possible to authenticate a product in real-time.
Another application of on-dose authentication is incorporation in the clinical supply program, as on-dose microtaggants can reduce the opportunity for error in the allocation and administration of these expensive trials. Introducing on-dose authentication into clinical trials allows for validated patient engagement at any stage in the trial, ensuring the right patients are taking the right drugs at the right dosage. This validation is all done without impacting the blinding process.
PharmTech: Is there special manufacturing equipment required to implement dosage level authentication during the manufacture of tablets or pills?
Rajabi-Siahboomi (Colorcon): By leveraging current tablet coating and print technologies, new investment is not needed to incorporate the microtaggants into standard manufacturing procedures; they are simply added to a standard tablet film coating or capsule printing process. The film coating process doesn’t change and there is no impact on the final tablet finish. Relative to other manufacturing expenditures, the overall cost to the producer of the finished dosage form with microtaggants incorporated is negligible.
The quantities of the microtaggants added to the film coatings or printing inks are small, so their inclusion does not affect how coatings are applied and will not have an impact on the stability or finished appearance of the final product. Additionally, as the ingredients of the microtaggants are inert, degradation or impurities should not occur over time. Although the use of microtaggants is not considered to be a safety issue, manufacturers must notify the regulator that a product has been tagged as part of their annual disclosure in the drug master file.
PharmTech: What future developments do you anticipate, both for regulatory requirements for product authentication and for dosage-level authentication approaches?
Rajabi-Siahboomi (Colorcon): We don’t anticipate any new regulatory requirements to implement on-dose authentication for either existing or new drug products. As with any new technology, it will take time for people to understand the offering and think about how it best supports their security strategy for the product and supply chain. We are working with the industry to explore how it integrates with serialization and confirm how this innovation brings advantages to product security, quality assurance, and also the commercial side, by engaging with patients to help manage their regimens and improve outcomes.
We have invested in the development of the technology and demonstrated the ease of implementation and robustness of the technology. The exciting future development will be to enhance patient engagement through the smartphone app. As well as verifying the drug product for a patient, other types of information could be linked through the smartphone, such as regimen reminders, dosing information, and other details regarding the medication.
Another interesting application is for clinical trials use, which are now being performed virtually because people can’t go to testing centers, due to COVID. How can we ensure that people who take clinical trial medication at home follow the correct medication regime? This is an important consideration as failure to take the medication as directed will give rise to misleading results, which can be enormously costly to companies as they develop new drug products. Currently, there’s a lot of interest in the clinical trial aspect of the technology.COVID has accelerated a lot of these advances and the future is with us now.
1. EUIPO, “Trade in Counterfeit Pharmaceutical Products,” euipo.europa.eu, accessed Mar. 11, 2021.
2. OECD, “Coronavirus (COVID-19) and the Global Trade in Fake Pharmaceuticals,” oecd.org, accessed Mar. 11, 2021.
3. FDA, “Drug Supply Chain Security Act (DSCSA),” fda.gov, accessed Mar. 11, 2021.
4. EMA, “Falsified Medicines: Overview,” ema.europa.eu, accessed Mar. 11, 2021.
5. FDA, “BeSafeRx: Your Source for Online Pharmacy Information,” fda.gov, Feb. 13, 2018.
6. WHO, “Substandard and Falsified Medical Products” who.int, accessed Mar. 11, 2021.
7. FDA, Incorporation of Physical-Chemical Identifiers into Solid Oral Dosage Form Drug Products for Anticounterfeiting (October 2011).
Felicity Thomas is the European editor for Pharmaceutical Technology Group.
Supplement: Solid Dosage Drug Development and Manufacturing
When referring to this article, please cite it as F. Thomas, “Securing Each Dose,” Solid Dosage Drug Development and Manufacturing Supplement (April 2021).