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International Clinical Trials

Cracking the Code

There is a significant amount of activity in the pharmaceutical industry in mobilising to meet the requirements of the recent Drug Quality and Safety Act (DQSA), passed by the US Congress with the intention of limiting the spread of counterfeit or otherwise falsified medicines to patients for prescription drug products.

This US requirement is aligned to the spirit of the Falsified Medicines Directive (FMD) in the EU. Reports suggest that approximately 61% of all global spending on pharmaceuticals happens in North America and Europe (1). Estimates vary widely, but the WHO believes that between 1-10% of all global drugs are counterfeit, with those in developing countries being as high as 50% (2).

Many of these products find their way into the US and Europe through illegitimate or sometimes legitimate channels. In Mexico, for example, WHO reports from more than a decade ago suggest that up to 10% of pharmaceutical products may be counterfeit or illegitimate. Here, the illegal trade has not slowed, but decidedly accelerated (3).

With the rise in access to internet-based pharmacies, which may or may not be legitimate, as well as licensed pharmacies, the lines are being further blurred in the traditional healthcare supply chain. Pfizer has recently undertaken a campaign to draw attention to the proliferation of counterfeit Viagra from internet pharmacies, citing its own investigations that proved the Viagra supplied by 22 top internet sellers was counterfeit. In fact, the pills examined contained dangerous ingredients, such as amphetamines, drywall, and blue printer ink (4).

Progressive Action

The genesis of the DQSA was rooted in a rash of high-profile incidents where counterfeit or adulterated drug products significantly sickened or led to the death of unsuspecting patients in the US, many of whom were particularly susceptible due to compromised immune systems as a condition of their cancer treatment or otherwise. An investigative book titled Dangerous Doses highlighted how these falsified medicines found their way into the legitimate pharmaceutical supply chain in the US, and highlighted the poorly regulated wholesaler licensing structure in the state of Florida.

Reaction to the public outcry and scandal led to a patchwork of state laws and regulations across the US, with Florida enacting a requirement for drug pedigree to outline each transaction through the complicated supply chain. At the time, this allowed for a paper-based pedigree trail – an amazingly antiquated system even for the times.

As is often the case in the US, the state of California led the way to more progressive action. The Board of Pharmacy in California pushed firmly for a system whereby a unique identifier would be created for each drug package sold in the state and tracked throughout the entirety of the supply chain, implemented by the pharma companies and drug wholesalers – generally referred to as 'track and trace'. This was met with stiff resistance from the industry and its associated lobbying organisations. Despite several mandated deadlines and postponements, the California Board of Pharmacy forced the hand of the national government in creating and passing the DQSA, unifying a vague but firm national standard to take effect in 2017. Legislation in Europe followed a similar path, with varying national standards among EU member countries, although recent changes have moved back a unified implementation standard to 2018.

Unique Identifier Code

Much of the initial resistance to an industry-wide track and trace system was the expectation that radio frequency identification (RFID) chips would be the technological platform for implementation. While effectively established in many industries including automotive and aerospace, RFID showed a promising but perhaps premature path in pharma. The high cost of individual RFID chips, the significant cost of technological infrastructure to support portals and IT architecture, together with the technological limitations due to interference with certain product types, ultimately led the industry to look to a scaled down solution to meet the requirements.

Where the government legislation and expectation settled was the application of a combination of two-dimensional barcodes and human readable text such that each saleable package featured a unique serialised identifi er code applied in the manufacturing process and also confirmed to be valid at the time of packaging. In addition, this code would reflect the legitimate factory in which the medicine had been packaged. Physical packages and accumulated code data would then travel through the supply chain in parallel to the final destination of hospital, clinic or pharmacy. In theory, a patient, pharmacist or practitioner could scan and verify this code to authenticate it as a legitimate product fit for use. A substantial amount of work remains to establish the end authentication process and methodology.

The passage of the DQSA and FMD legislation has significantly ramped up activity and investment to meet the rapidly approaching deadlines for implementation. Pharma companies and outsourced partners – including the vast network of global contract manufacturing organisations (CMOs) – are scrambling to invest in the manufacturing technologies for code application and verification, as well as the IT infrastructure to enable data transactions for inbound and outbound codes between businesses and within their own manufacturing networks and plant systems. Investment is funded exclusively by manufacturers, with no provision in the DQSA for the capital and resource expense. The integration of IT data exchange to manufacturing processes marks a signif cant turn for the industry.

Trials Experience

Clinical trial professionals may be asking what all the fuss is about. Trials have been utilising serialised codes for decades in the form of randomised identifi ers for individual investigational study kits. The use of randomised codes is essential in the blinding of materials to ensure unbiased results and the integrity of blinded trials.

At the onset of a study, a series of randomised codes are established that are assigned to individual packages in the packaging and labelling operation for the investigational materials. The use of these unique identifiers is intended to mask whether the drug product is active or placebo, one strength to another, or potentially disguising the investigation of the experimental product versus the established 'comparator' therapy.

In principle, the application and use of randomised codes in clinical studies draws many parallels to the systems and architecture of commercial serialisation. The initiating party – either the sponsor company or a CRO – establishes a listing of codes that it applies to a specific subset of the drug product. The packager receives those codes as a highly protected list and utilises them in the labelling operation to create a unique identifier on each individual package – before verifying back to the initiator which codes were used and which were not.

As in many manufacturing processes, there are marginal waste products generated, so some codes may be scrapped through manufacturing ineffi ciencies or procedural activities. Ultimately, the packager creates an inventory of packages with proper unique codes for use in the investigational study, typically communicated through a centralised interactive web/voice response computer-based system with protected and restricted access granted to multiple parties in the clinical supply chain.

Commercial Implementation

The most pressing concern in the commercial side of the pharma supply chain is the scale of implementation for enabling commercial serialisation. Billions of drugs are created and consumed each year in the US alone, never mind the broader global healthcare system.

Traditionally in the US, the only identifier on a commercial prescription – other than the manufacturer’s name – is the lot or batch code. A typical commercial batch could contain hundreds of thousands of packages, with no differentiation among them and no distinguishable feature that would indicate where the product was made or packaged. This often causes sizeable and very costly challenges when drug products need to be recalled by the manufacturer, as the drugs have travelled through a highly complicated supply chain to reach end consumers. In theory, the implementation of unique serialised codes for each package would provide infinitely more visibility, compared to the current practice of recalling commercially distributed medicines.

The other primary concern for the industry is the scope and infrastructure to support the data generated in the serialisation process, as well as the transactional nature of the supply chain. In addition to the billions of serialised codes that will be created and tracked, the concept of aggregation exacerbates the scope of the challenge.

In aggregation, the packager ties together the parent-child relationship of the individual drug package to its tertiary and ancillary packaging, up to and commonly including the pallet. For example, a bottle may be the unit of sale and therefore receive the primary serialised code; 12 bottles would then be bundled with shrink film to unitise them. Those 12 individual codes would be married to a serialised code for the bundle. Four bundles would then be loaded into a corrugated shipper, which in turn would have its own serialised code. Shipping cases would then be loaded on the pallet, also having its own serialised code.

What is created is a family of interrelated and structured codes identifying the inventory of the pallet. If, in the course of distribution, any product is removed or damaged, the data would need to be properly updated to reflect the change in connectivity. Taking this concept and extrapolating it across the scope of the global pharma supply chain can make one's head swim.

Rush to Deadline

The respective US and EU deadlines of 2017 and 2018 loom large over pharma. Progressive minded companies have accepted their fate and moved forward with pilot studies or broader adoption. A large proportion of the industry quite simply has not, and will be hard pressed to meet the timescales. What will happen with regards to enforcement is a topic of debate, but many believe the FDA will impose fines for those companies not complying with the requirements.

Serialisation equipment manufacturers and integrators, IT developers, and supply chain consultants are working feverishly to address the considerable demand today and the anticipated mad rush of orders for the numerous pharma companies which have procrastinated in their implementation plans and sizeable capital expenditure requirements. Select CMOs have positioned themselves to aid pharma companies in meeting the requirements, and the demands on these providers will be substantial. Even established outsourced partners that have invested hugely in serialisation for many years have found that rapid scale-up has yielded new learnings and considerations as they engage customers in serialisation adoption.

In the end, the industry will be transformed in the drive to meet serialisation and anti-counterfeiting legislation. How quickly it adopts the related technologies will be crucial in keeping pace with the global bad actors to combat fake drugs reaching patients.

1. Global Outlook for Medicines Through 2018, IMS Institute for Healthcare Informatics. Visit:
2. Visit:
3. Visit:
4. Visit:

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Justin Schroeder is Executive Director, Marketing, Business Development and Design at PCI. He is responsible for new account development, global marketing and creative package design, with a focus on the development and commercialisation of unitdose and compliance-prompting packaging. Justin holds a Bachelor of Science degree from the School of Packaging at Michigan State University, and a Master of Business Administration in Marketing from Northern Illinois University. He is a certifi ed packaging professional and is Vice Chairman of the US Healthcare Compliance Packaging Council.
Justin Schroeder
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