Felicity Thomas is the former Associate Editorial Director of Pharmaceutical Technology, Pharmaceutical Technology Europe, BioPharm International.

Felicity Thomas

Counterfeit pharmaceutical products are a global issue that has a significant financial impact and, more worryingly, poses potential dangers to patients’ health. “The topic of counterfeit medicines has been a concern for a number of decades, and it affects the Western nations as well as emerging markets,” explains Raja Sharif, CEO and founder of FarmaTrust—a provider of blockchain and artificial intelligence (AI) provenance systems for the pharmaceutical and healthcare sectors.

There is a general belief that counterfeit medicines is a low- and middle-income country issue rather than one that affects Europe and the United States, but if you look over the past five to 10 years, it becomes apparent that there are a lot of counterfeit medicines in Europe, and the issue is getting worse, Sharif continues. In fact, it is estimated by the European Union Intellectual Property Office (EUIPO) that nearly €10 billion of direct sales, within the pharmaceutical sector, are lost through counterfeiting per year (1).

Additionally, there is an increasing prevalence of purchasing medicines online, which is exacerbating the problem of counterfeit medicines. “Absolutely, there has been a trend for online purchases, a trend that was even recognized a number of years ago by Amazon who purchased an online pharmacy, PillPack,” notes Sharif. “But, irrespective of this trend, it mustn’t be underestimated that counterfeit drugs can be infiltrated into the national supply chains.”

Even looking at recent prosecutions by the Medicines and Healthcare products Regulatory Agency (MHRA) of the United Kingdom, it is clear to see that counterfeiters are using pill presses bought from China to make and distribute counterfeit medicines in the UK, Sharif underscores. “So, it is not just an online problem; although, online sales are of course much easier and the issue is getting worse, there are also cases of counterfeit medicines being purchased within UK pharmacies as well,” he says.

To tackle the issue of counterfeit medicines within the European Union (EU), a directive was formulated and published setting out various safety features that must be included on pharmaceutical packaging to assure product authenticity (2). “The issue of counterfeit medicines was obviously in discussion for a long time and resulted in what we now call the Falsified Medicines Directive [FMD] regulations in Europe,” confirms Sharif. “Essentially, what this directive allows you to do is to ensure that each packet of medicines is uniquely labelled, and then you scan the labels, which tell you whether there’s a duplicate or whether the product is actually genuine.”

In the United States, anti-counterfeiting measures have been enacted through the Drug Supply Chain Security Act (DSCSA) (3). “Both the EU and US systems generally require unique labelling, which is usually achieved by two-dimensional dot matrix codes,” says Sharif. “Some countries are using Quick Response codes these days as well as tamper-proof packaging, but legislations tend to require the matrix codes as a minimum.”

The main difference between the EU FMD and the DSCSA regulations is that in Europe, the labels are issued on the drug packaging line and then scanning of the unique identifier only happens when the product is scanned out of the pharmacy or hospital, explains Sharif. “Whereas the DSCSA regulations require data collection at each transfer of the chain of custody (i.e., when one company transfers the product to another or one person gives it to another person),” he states.

As there is not a requirement for tracing each step of the product’s transition in Europe, there is a danger that counterfeit products can infiltrate the supply chain. It’s a race to the end, notes Sharif, if a counterfeit product with a duplicate unique label gets scanned first before the authentic product, it will be accepted to the pharmacy or hospital, he asserts.

Through working with the US Food and Drug Administration on blockchain pilots, Sharif reveals that it became apparent that if a product is tracked at each transfer of the chain of custody, not only is it possible to more easily prevent counterfeit medicines entering the supply but the process is more data-rich overall. “So, for data analytics purposes and efficiency gains, the DSCSA regulations are much better,” he adds.

However, for the UK, which fully exited the EU on 1 Jan. 2021, the EU FMD legislation is no longer applicable. “The Brexit situation means that the UK has actually pulled out of the FMD process,” adds Sharif. As a result of the UK no longer being covered by the European legislation, the country is now exposed as there is no longer the ability to verify the unique labels within the central European verification system, he emphasizes.

At the time of writing, a bill concerning UK medicines regulations has gained Royal Assent (the final stage of bill passage in the UK)—the Medicines and Medical Devices Act 2021 (4). This bill is aimed at ways to make the UK more attractive in terms of innovative new solutions and technologies being approved, and it covers not just medicines and medical devices, but other aspects, such as clinical trials, states Sharif.

Sharif believes that a system akin to the US DSCSA would be most beneficial for the UK, to keep up its competitive landscape in terms of pharmaceutical anti-counterfeiting measures. “This route is potentially interesting given the fact that the UK’s regulator, MHRA, has been working closely with FDA and the Australian regulator post-Brexit,” he says.

Much of the work that will be implemented into amendments to regulations and anti-counterfeiting measures in pharmaceuticals is expected to be delegated powers given to the parliamentary ministers, Sharif anticipates. For application, however, Sharif recommends tracking each transfer of custody and even the condition of the medicines as well, as that level of information will give a high level of patient safety.

Additionally, with such a data-rich approach, it is possible to improve demand planning and prevent medicine wastage, Sharif stresses. “For example, there are a lot of medicines that are wasted each year,” he says. “So, if you have a much more efficient ordering process, demand process, and planning process, the National Health Service can be saved billions of pounds, which can be spent on other vital areas.”

A compulsory infrastructure technology should be implemented for anti-counterfeiting measures, in Sharif’s opinion. “One of the areas blockchain is particularly useful is to ensure the immutability and incorruptibility of data,” he says. “So, that means once a record is written, it cannot be changed. The record can be updated, of course, but the information on who updated it, when it was updated, and what the update was itself, will be available.”

Another aspect of blockchain that lends itself to anti-counterfeiting applications is the fact that it is very good at breaking down data silos, Sharif continues. “In a multi-stakeholder environment, such as track-and-trace solutions, you need to be able to allow different companies using different systems to be able to communicate with each other,” he says. “Blockchain is a very good interoperable, technology-neutral kind of solution, and so I would advocate using blockchain.”

In terms of any potential future anti-counterfeiting challenges, such as stricter requirements, blockchain is considered to be ‘future proof’. When looking at tools such as artificial intelligence or machine learning, Sharif highlights that there are potential limitations in terms of data corruptibility. As the solutions are only as good as the data that are input into them, should the data become corrupted then the results being obtained will be bad, Sharif confirms. Whereas, with blockchain solutions, data integrity is assured. Furthermore, blockchain platforms consume less energy than other technologies and will be required for automated processes, such as ordering and supply chain tracking.

A good example of how blockchain can aid with assurances of data integrity, particularly in the landscape of clinical trials, would be to take the recent approvals of COVID-19 vaccines, Sharif notes. MHRA was the first to approve a vaccine, as a result of the innovative way it considered data—assessing the clinical trial results in a rolling review capacity. “Imagine if MHRA could review the data digitally from a data platform with the assurance that the data hadn’t been altered, that would really revolutionize the way clinical trials are performed and data are approved by regulators,” Sharif summarizes.

 (Alicante, Spain, June 2019).
2. EMA, “Falsified Medicines: Overview,” 

 [Accessed 16 March 2021].
3. FDA, “Drug Supply Chain Security Act (DSCSA),” 

 [Accessed 16 March 2021].
4. UK Parliament, “Medicines and Medical Devices Act 2021,” 

Felicity Thomas is the European editor for Pharmaceutical Technology Group.


Vol. 33, No. 4
April 2021
Pages: 43–44

When referring to this article, please cite it as F. Thomas, “Blocking the Threat of Counterfeit Medicines,” 

Articles

After Brexit there is an increased risk of the UK being exposed to counterfeit medicines, but regulations implementing blockchain as infrastructure technology could be the answer.

Blocking the Threat of Counterfeit Medicines

The importance and criticality of dissolution testing throughout the pharmaceutical drug development lifecycle is well-known and has been well-documented in literature. “Dissolution testing measures the extent and rate of solution formation from a dosage form, such as a tablet, capsule, or ointment,” says Sool Yeon Cho, department scientist, Nelson Laboratories. “The dissolution of a drug is important for its bioavailability and therapeutic effectiveness.”

Dissolution rate specifications vary depending on the design of the dosage form. In 2018, FDA updated its guidance on recommendations for dissolution testing and specification criteria for immediate-release dosage forms that contain highly soluble compounds (1). However, not all drug products are covered by this guidance, which is applicable only to solid orally administered immediate-release drugs that are intended to be swallowed. Generally, when measuring the dissolution rate for an immediate-release dosage form, a single-time point specification is used—exceptions may occur when evaluating slow-dissolving drugs where two time points can be used—with samples taken between 30 and 45 minutes, and when approximately 75–80% of the active ingredient is dissolved (2).

However, for modified-release dosage forms, multiple time points are specified for characterization of the 

 dissolution rate—for delayed-release forms two time points are required and for extended-release at least three time points are required (3). For modified/extended-release dosage forms, dissolution testing should show the rate a solution is formed with the release of active ingredients over specified time intervals, explains Cho. Relevant guidance has been published to address the challenges of dissolution of modified or extended-release dosage forms (4,5).

When testing dissolution rates of solid-oral dosage form drug products, immediate-release and modified-release, standardized apparatus as described in the 

 General chapter <711> Dissolution includes four standardized apparatus: basket, paddle, reciprocating cylinder, and flow-through cell,” Cho notes. “Where specified in a monograph, 

 dissolution tests are legal requirements.”

Yet, these standardized approaches are not without limitations, as have been previously reported in the literature (7–9). Issues relating to not only the equipment used in standardized approaches but also the analysts performing the tests can lead to dissolution profile variability.

Furthermore, for some dosage forms there are limited test methods described in the literature. As Speer 

 reported in 2019, for oromucosal film preparations with a modified release profile, despite there being a regulatory requirement to provide dissolution test data for this dosage form, there are no suitable recommendations of methods or established specifications available to follow (10). Therefore, when the test article may not respond to the standardized approaches and regulatory recommended methods, it may be necessary to employ new techniques or devices, Cho asserts.

“The most noticeable analytical method or technological advancement in recent years to aid with dissolution testing is automation,” confirms Cho. Although automated dissolution has been explored for some time, more

recent advancements have been seen in the use of computerized software that aids with the regulatory audit trail required, he adds. For Cho, full dissolution automation—sampling station and analysis—and a paperless dissolution workstation will be important trends in the near future.

 described an automatic method for dissolution testing with high-temporal resolution using high-speed capillary electrophoresis (HSCE) (11). In their work, the researchers’ proposed a system comprised of three components—a flow-through-cell for tablet dissolution, an automatic sequential injection with high-temporal resolution, and on-line separation/detection using HSCE. Validation of the methodology was performed according to FDA guidelines. Immediate and fixed-dose products were assessed by Chi 

 who found that with their fully integrated on-line automatic system it was possible to monitor dissolution with high-temporal resolution in real-time, which is promising particularly for fixed-dose combination drug products.

 in 2019, an artificial neural network (ANN) model was built to predict the dissolution profile of extended-release tablets (12). Using data collected by near-infrared and Raman spectroscopy, as well as the compression force measured by the tablet press as input data for the ANN model, the researchers were able to predict the in-vitro dissolution profile of extended-release tablets. The predictions of dissolution profiles were within the acceptance limit of the similarity factor, f2, and the authors concluded that with more work it could be possible to build models that consider more process parameters, allowing for a deeper understanding of product quality.

“Real-time release testing (RTRT) and how a multivariate model could create a surrogate for dissolution testing is certainly a trend for the industry,” Cho adds. “Since dissolution testing is not favored by industry—it is time consuming and does not always correspond to 

 dissolution—RTRT measurements, as a part of continuous manufacturing platforms are emerging to replace the traditional dissolution tests.”

Dissolution Testing and Acceptance Criteria for Immediate-Release Solid Oral Dosage Form Drug Products Containing High Solubility Drug Substances

 (August 2018).
2. M. Powell, “Specifications for Small-Molecule Drug Products,” PTI Webinar (Nov. 22, 2016).
3. F.R. Lourenço, et al., 

Extended Release Oral Dosage Forms: Development, Evaluation, and Application of 

Guideline on Quality of Oral Modified Release Products

 (London, UK, March 2014).
6. USP, General Chapter <711>, “Dissolution” 

 (Rockville, MD, 2011).
7. S.A. Quershi and I.J. McGilveray, 

, 7 (3) 249–258 (1999).
8. J.L. Baxter, J. Kukura, and F.J. Muzzio, 

, 292 (1–2) 17–28 (2005).
9. Z. Gao, et al., 

, 96 (7) 1794–1801 (2007).
10. I. Speer, M. Preis, and J. Breitkreutz, 

., 9 (Nov.) 17114 (2019).
12. D.L. Galata, et al., 

When referring to this article, please cite it as F. Thomas, “Limitations and Advances in Dissolution Testing,” 

Despite its importance in drug development, dissolution testing still has some limitations, but advances in automation and real-time monitoring are producing promising results.

Limitations and Advances in Dissolution Testing

As vaccine programmes throughout the world are kicking into a higher gear and more of the population are receiving vaccinations, a watchful gaze over side effects, efficacy results, and bio/pharma companies in general has taken hold of the world’s media. AstraZeneca’s woes seem to be compounded, with Germany becoming the latest country to limit the use of the vaccine due to concerns over a rare blood-clotting disorder (1), despite regulatory authorities’ assurances that the benefits of the vaccine significantly outweigh any risks (2).

Yet, it is also important to remember that bio/pharma companies are not solely focused on COVID-19, even though a significant concerted effort has been made by the industry overall in this area over the past year. There is, in fact, a vast selection of drugs in development pipelines on the cusp of approval, some with the potential to become game-changers for certain disease areas that affect millions of people globally.

 list, there are four new treatments in particular that have been deemed as likely to gain blockbuster status in the near future (3). All four in Clarivate’s list are predicted to deliver more than US $1 billion (€852 million) in sales within five years (3).

The four drugs highlighted by Clarivate are aducanumab from Biogen and Eisai, bimekizumab from UCB, relugolix from Takeda, and vericiguat from Bayer and Merck. These drugs are targeting Alzheimer’s disease, psoriasis, prostate cancer and female reproductive health issues (endometriosis and uterine fibroids), and chronic heart failure with reduced ejection fraction, respectively.

Several other prospective treatments in development were also highlighted within the report, which, despite not fitting within the inclusion criteria for Clarivate’s study, are considered to have ‘notable potential’ (3). These promising therapies included chimeric antigen receptor T-cell therapies idecabtagene vicleucel (Bristol Myers Squibb) and ciltacabtagane autoleucel (Janssen), anti-inflammatory bardoxolone methyl (Reata), nerve growth factor inhibitor tanezumab (Pfizer and Lilly), monoclonal antibodies tralokinumab (LEO Pharma) and nemolizumab (Galderma), and experimental pneumonia vaccine PF-06482077 (Pfizer).

“In the last five years we have seen an increase in approvals of innovative medicines at a rate more than double what it was a decade ago,” said Mike Ward, global head of Thought Leadership, Life Sciences and Healthcare, Clarivate, in a press release (4). “A number of drivers have aligned to achieve this improvement, including greater insight into the biological roots of diseases, oncology research benefitting from the routine introduction of biomarkers to better target therapies, the emergence of gene and cell therapies, and efforts by regulatory agencies to introduce processes to accelerate medicine assessment.”

Undoubtedly, COVID-19 has changed the bio/pharma landscape for the future. The general public have become more invested in details, such as clinical trials and supply chains, and have increased expectations for innovative solutions and therapeutic access, changes that have a likelihood of being permanent in the future (5).

Speed of development has been unprecedented during the COVID-19 pandemic, a reversion of which will be hard to accept for industry and patients. This change of development model, if it is to continue into the future, will require agreement and partnership with industry, regulators, and patients, as well as other stakeholders (3,5).

Key tools to aid with development timeline acceleration, which have found prominence during the pandemic, will be in the form of digital technologies. Whether it be increased digitalization of development and manufacturing, or the use of digital solutions to help with quality inspections and clinical trials, the industry’s pace in the direction of the digital transformation has quickened and will likely continue (5).

Finally, increased collaboration throughout the industry has proven to be invaluable during the COVID-19 pandemic. Cross-industry and cross-enterprise collaborations are anticipated to become the new normal, meaning that companies will need to adapt to this changing landscape (6).

1. BBC, “Covid: Germany Limits Use of AstraZeneca Covid Jab for Under-60s,” News Release, 31 March 2021.
2. PharmTech, “Regulators Confirm Benefits of AstraZeneca Vaccine Outweigh Risks,” 

, Report (March 2021).
4. Clarivate, “Clarivate Drugs to Watch Report Highlights Four Likely Blockbusters Among Drugs Launching in 2021,” Press Release, 9 March 2021.
5. G. Agrawal, H. Ahlawat, and M. Dewhurst, “Biopharma 2020: A Landmark Year and a Reset for the Future,” McKinsey & Company, 8 Jan. 2021.
6. F. Thomas, 

When referring to this article, please cite it as F. Thomas, “A Watchful Eye on Pharma,” 

COVID-19 has placed bio/pharma in the spotlight of global media, but away from vaccines there are other prospective pipeline treatments that will be worth watching.

A Watchful Eye on Pharma: Promising Drugs and Changing Bio/Pharma Landscape

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, 

 spoke with Ali Rajabi-Siahboomi, vice-president and chief scientific officer, and Gary Pond, global program lead—Authentication, both at Colorcon.

 How are current regulatory-required methods of pharmaceutical product security lacking, and what potential technological advances are available to overcome these limitations?

 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.

 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?

 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.

 Could you provide some more detail about on-dose authentication, on-product microtaggants, and how tagging an individual pill/dose is achieved?

 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.

 What specific advantages are gained through dosage level authentication versus packaging authentication?

 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.

 Is there special manufacturing equipment required to implement dosage level authentication during the manufacture of tablets or pills?

 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.

 What future developments do you anticipate, both for regulatory requirements for product authentication and for dosage-level authentication approaches?

 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,” 

, accessed Mar. 11, 2021.
2. OECD, “Coronavirus (COVID-19) and the Global Trade in Fake Pharmaceuticals,” 

, accessed Mar. 11, 2021.
3. FDA, “Drug Supply Chain Security Act (DSCSA),” 

, accessed Mar. 11, 2021.
4. EMA, “Falsified Medicines: Overview,” 

, accessed Mar. 11, 2021.
5. FDA, “BeSafeRx: Your Source for Online Pharmacy Information,” 

, Feb. 13, 2018.
6. WHO, “Substandard and Falsified Medical Products” 

, accessed Mar. 11, 2021.
7. FDA, Incorporation of Physical-Chemical Identifiers into Solid Oral Dosage Form Drug Products for Anticounterfeiting (October 2011).


Supplement: Solid Dosage Drug Development and Manufacturing
April 2021
Pages: s29–s31

When referring to this article, please cite it as F. Thomas, “Securing Each Dose,” Solid Dosage Drug Development and Manufacturing Supplement (April 2021).

Dosage-level authentication provides an added digital layer of security for pharmaceutical companies to ensure their products are not exposed to falsification.

Securing Each Dose: Reducing Falsification Risk with Dosage Level Authentication

A lab-scale process does not always successfully translate to production scale, and this potential failure can be a costly risk in the biopharmaceutical field. To mitigate this risk, an initiative was launched in Sweden in 2018 to provide access to equipment and expertise in bioprocess scale-up—the Testa Center. To find out more about this initiative, 

 spoke with the center’s director, Jesper Hedberg.

What is the mission of Testa Center and how was it conceived?

Our vision is that together we accelerate the journey of world changing innovations. We do this by making our production-like facilities available to researchers for verification of innovations and scalability experiments.

Testa Center is a private-public partnership, making the facility available for the life science community at large. The center is a joint effort between the Swedish government and Cytiva, and its main objective is to promote growth of the life science sector and bridge the gap between discovery and industrialization.

Testa Center is owned and operated as a non-profit company by Cytiva in Uppsala, Sweden. Since its inauguration in September 2018, more than 30 projects have been performed by clients in the center.

What services are offered at the Testa Center?

Testa Center is an open access, non-good manufacturing practice (non-GMP) production-like environment/facility and testbed for education, innovation, and proof-of-concept experiments around production of biological products (e.g., monoclonal antibodies, peptides, and proteins as well as cell and gene therapy products).

In the Testa Center, researchers have access to both equipment and expertise to drive their biological production process from lab bench scale to industrial pilot scale. The offering includes access to expertise, labs, and equipment for scaling up. Projects typically come with aims such as showing scalability or manufacturability or generation of larger amounts of material.

For cell culturing, Testa Center offers bioreactors from 1–500 L. For harvest, the center has instrumentation for filtration as well as batch and continuous centrifugation. For protein purification, instrumentation from lab bench scale all the way up to pilot- and full-scale production, including a variety of column sizes, are available. The complete instrumentation list can be downloaded from the 

Are there any capabilities/services that are not yet available at the Testa Center that may be added in the future?

We have just recently commissioned a BioSafety Lab class 2 in Testa Center available for vaccine and cell therapy applications. Also, we are in the middle of commissioning a larger bioreactor (200 L) for microbial purposes. This new bioreactor will be available for clients in Q2 2021.

In addition, at the end of 2020, we launched an activity in the center inspired from open innovation and hackathon events—the Testa Challenge. This was an effort to make Testa Center capabilities available to a larger extent for technical and digital projects and at the same time test out a new way of verifying innovations in the bioprocessing space.

How might bio/pharma companies (both those from Sweden and globally) benefit from using the Testa Center?

Taking an innovation from bench scale to industrial scale is accompanied with a lot of risks. In Testa Center, start-ups and research groups have the possibility to reduce technical risks when going up in scale and thereby increasing the chances of surviving the phase when going from a successful proof of concept in lab scale to production.

Also, as projects and companies have access to the expertise inside Testa Center, it is possible to have consultations during the experiment design and execution phases, which allows for quick iterations in experimental design and to adjust and pivot when needed.

Has the pandemic created particular challenges or opportunities for the Testa Center?

The pre-pandemic plan was to make 2020 the year of European outreach. This plan did not come to fruition, and the Testa Center had to, during 2020, focus on the Swedish and Nordic regions.

Now, during 2021, we are running a project, ‘Testa Center Outreach’, together with Business Sweden and STUNS to reach out to the wider European market. Naturally, we need to follow the pandemic carefully as running a project in Testa Center very often requires travel. Projects have the possibility to engage local contractors for project execution, and we are actively working to expand this offering.

Additionally, we have had several requests for projects related to the fight against COVID-19. One of these projects has just finalized their execution phase in Testa Center. At this point, we cannot share more info due to confidentiality, but we will shortly share more around these activities in our channels.

What is the main vision for the Testa Center in the next 10 years?

The overarching aim is to support the life science space and to enable researchers to take the leap into commercialization. The vision is (as stated above) that in 10 years’ time from now the journey of innovation is accelerated and completely changed. To elaborate a bit further, the new natural will be to build value and competence in organizations in a completely different way.

New drugs and new molecules (sometimes referred to ‘the new Zoo’) are being discovered at an increasingly higher pace and the complexity of molecules and modes of actions are also getting more complex. To answer to these challenges, we need to be better, faster, and more efficient. Biological production is an intricate part of bringing new drugs to patients, and Testa Center is here to support researchers to succeed in their efforts to establish scalable production processes.

The Testa Center in Sweden provides access to equipment and expertise to help bridge the gap between biopharmaceutical discovery and industrialization. 

Mitigating Risk in Scale-Up

Oral solids remain the most widely used dosage forms for pharmaceuticals to date, namely as a result of the convenience the form offers developers, manufacturers, and patients. Despite significant industry growth being witnessed in the area of large-molecule drugs, the oral solid dosage (OSD) pharmaceutical formulation market is anticipated to be worth more than US $926.1 billion by the end of 2027 (1).

However, it is also extensively reported that a sizable proportion of drug candidates in development are poorly water-soluble, an aspect that can contribute to higher attrition rates and is directly related to poor oral bioavailability. Low bioavailability is a frequent cause of failure in drug development (2) and is known to lead to high variability and poor control of therapeutic effects (3).

Oral bioavailability of a drug product can be affected via several factors, such as poor solubility, gastrointestinal degradation, and high first-pass metabolism rates. Aqueous solubility and membrane permeability have been identified as key influencers of oral bioavailability of drug products (4). Strategies employed to overcome the challenges that result in low oral bioavailability include manipulation of drug properties or methods to interfere with physiological barriers to drug absorption (3).

Drug properties can be altered via formulation strategies, manufacturing processes, or by modifying physicochemical properties to improve solubility and hence bioavailability. Many techniques have been well documented and researched over the years, providing valuable insight into the mechanism of action of various strategies and pathways for potential future advancement.

A review paper, authored by van der Merwe 

 in 2020, provided a comprehensive overview of selected excipients suitable for use to improve oral bioavailability. In their review, the authors noted that despite the variety of approaches available and the indication from several studies that functional excipients can have a beneficial effect on the bioavailability of APIs, there were also some clinical limitations. When evaluating specific excipient groups, such as pH-adjusting excipients, there were limited 

 and clinical data available and mostly, the studies only evaluated one poorly soluble API, demonstrating a clear need for further research (4).

However, it is patently clear that excipients are rightfully considered as more than an ‘inert’ vessel in drug delivery. As the complexity of drug development has increased, so too has the requirement for more sophisticated excipients to manipulate the properties of the final product, for example, multifunctional (co-processed) and high functionality excipients, which are able to fulfill multiple roles in performance improvement of a dosage form (4).

Specifically focusing on amorphous solid dispersions (ASDs), there are several specific excipient functionalities that should be considered. These considerations include the solubilizing effect of the excipient, the capability of the excipient to provide a strong molecular interaction with the API, whether the excipient exhibits thermoplastic behavior, and if the excipient displays a broad range of dissolution behaviors. Critically, the API and the polymer systems in ASDs must have a strong affinity for one another, and if the solubilization of the API within the polymer is done properly, it is possible to gain a thermodynamically stable end product (5).

Despite the capability of ASDs to improve solubility and bioavailability of drug products, there are complexities to overcome to ensure commercial success. In seeking to provide a greater understanding of the mechanisms underlying how ASDs improve bioavailability, Schittny, Huwyler, and Puchkov performed a literature review of all available research in 2019. Reflecting on both theoretical considerations and experimental data, the authors’ literature review led them to the conclusion that dissolution of an ASD can be attributed to three main mechanisms—carrier controlled, dissolution controlled, and drug controlled—and that dissolution is influenced by drug load, homogeneity of the solid ASD, interactions between the polymer and the drug, and surfactants (6).

Other key findings from the research included the fact that the dissolved states of ASDs are in a dynamic equilibrium; the higher drug absorption of ASDs can be mainly credited to the increased concentrations of molecularly dissolved API and is aided by diffusion by drug-rich particles. Additionally, it was found that, although polymers have the capacity to stabilize supersaturated solutions, they can also lower the amorphous solubility, and surfactants, although useful for enhancing dissolution properties, can not only stabilize but also destabilize supersaturated solutions. Furthermore, translational studies, moving from 

 absorption performance following oral dosage of a high-drug load formulation. The researchers evaluated enzalutamide in particular, as it is a lipophilic compound, Biopharmaceutics Classification System class II, that has low drug loading in its current commercially available formulation. As a result of low drug loading, the pill burden for patients is high, and, therefore, there is a desire to increase the drug loading without compromising absorption of the API (7).

Choosing two newly synthesized cellulose derivatives for ASD formulation, Wilson et al. determined that it is important for the polymer used in ASD formulations to have the correct balance of hydrophilic and hydrophobic substituent groups to be effective. Ultimately, after performing both in-vitro and in-vivo tests, the authors discerned that ASD formulation with the cellulose derivative, CPHPC-106, provided a five-fold improvement in enzalutamide absorption relative to crystalline control. Conversely, the polymer that was more effective an inhibiting crystallization yielded minimal improvements in oral absorption, highlighting the fact that ASD performance is a “complex interplay of drug and polymer properties” (7).

Another research paper on ASDs, published in 2020, detailed the possibility of reducing tablet mass using novel architecture. Compared with a typical ASD formulation, in which the dispersion polymer allows for physical stability of the solid-state and the maintenance of dissolution rate in the gastrointestinal tract, the novel high loaded dosage form (HLDF) architecture combines two different polymers to achieve physical stability and dissolution. The drug product evaluated was erlotinib, which is a rapidly crystallizing drug with a low glass transition temperature, formulated as an ASD with Eudragit L100 as the dispersion polymer and hydroxypropyl methyl cellulose acetate succinate as the concentration-sustaining polymer. The authors found that by using the novel HLDF architecture comprising two different polymers—one inside the ASD and the other outside—it was possible to achieve equivalent 

 performance as a single dispersion polymer ASD with a reduced dosage form size by 40% (8).

This brief review of some of the recent work being performed to assess various strategies to improve bioavailability demonstrates significant advances in mechanistic understanding and developments to approaches. Furthermore, thanks to research being undertaken in this area, commercial opportunities to improve dosage forms for patient convenience and reduce development attrition rates of poorly-water soluble compounds are coming to the fore.

1. FutureWise, Oral Solid Dosage Pharmaceutical Formulation Market by Dosage Form, by Drug Release Mechanism, by Distribution Channel, and by Region: Industry Analysis, Market Share, Revenue Opportunity, Competitive Analysis, and Forecast 2020–2027, Market Report, January 2021.
2. M.J. Waring, et al., 

, 14 (7) 475–486 (2015).
3. P. Fasinu, et al., 

., 32 (4) 185–209 (2011).
4. J. van der Merwe, et al., 

, 12 (5) 393 (2020).
5. F. Romanski, “Role of Excipients in Amorphous Solid Dispersions,” Solubilizer Symposium (Ludwigshafen, Germany), Oct. 11, 2017.
6. A. Schittny, J. Huwyler, and M. Puchkov, 

, 27 (1) 110–127 (2019).
7. V.R. Wilson, et al., 

, 10 (Oct.) 18535 (2020).
8. D.M. Mudie, et al, 


Vol. 45, No. 3
March 2021
Pages: 30–31

When referring to this article, please cite it as F. Thomas, “Reviewing Recent Bioavailability Research,” 

Various strategies to improve bioavailability are being continuously evaluated, affording greater commercial prospects for the future.