Guest Column | September 14, 2022

EU Reg. 536/2014's Expiry Label Requirement Forces Us Backward, Not Forward

By Haneen Mazahreh-Boivert, Pivot Consulting and Services LLC


In a world that is shifting toward AI, EFTs, and blockchain technology, the new EU Regulation No. 536/2014, specifically Annex VI, is forcing us back into the paper age.

Annex VI is replacing Annex XIII, which governs investigational material products (the medications used in clinical trials). The most impactful change is the new requirement to print the expiry date on the primary container label, not just the external carton label. Colleagues across the clinical supply chain lamented in unison in anticipation of the additional risk, cost, and inefficiency this non-value added step will impose onto the supply chain.

The initial printing of the current expiry date is not an issue; it is the management and upkeep of the date that is problematic. Expiry dates are often extended in clinical research and, as such, external carton labels are often updated with new dates. Per the previous Annex XIII regulations, this exercise typically consisted of a simple over-labeling exercise that could even be performed at the clinical site. With the new Annex VI requirement, in addition to over-labeling the external carton, the tamper seals of the kit would have to be broken and the contents of the kit would have to be removed, relabeled, and repacked. This introduces risks to the integrity of the kit, availability of product while in process, and unblinding of product - as well as adding unnecessary costs and complications to the supply chain. The European Federation of Pharmaceutical Industries and Associations has conducted and published a robust risk assessment. EFPIA’s conclusion was to advocate for either omitting the expiry date from the primary container or including a line on the primary container label that refers to the external carton for the most up-to-date expiry date (i.e., “see carton for most up-to-date use by date”). The International Society of Professional Engineers (ISPE) also published an article highlighting the risks of the new mandate as well as suggesting potential strategies for managing it, admittedly noting the need for additional discussions for successful implementation.

How Did We Get Here?  

It is important to highlight that the U.S. currently does not mandate an expiry date on any IMP label (either primary container or carton) for trials utilizing a validated system (e.g., IRT systems) to manage expiry dates and control the dispensation of kits based on these expiry dates and study design. Most Phase 2 and Phase 3 trials utilize an IRT software to track and dispense IMP, and this automation clearly aids in controlling what medication is allowed to be dispensed to a patient. There is little published peer-reviewed data comparing the frequency of patient ingestion of expired IMPs in the U.S. vs. EU. In fact, a search of VAERS and FAERS databases resulted in no instances of adverse effects due to patients’ ingestion of expired materials. Instead, they published articles such as Don’t be Tempted to Use Expired Medicines, suggesting that even if containers reflect an outdated expiry date, consumers would still ingest the material. The absence of documented incidents or statistical drivers for the new mandate leads to the conclusion that this is a change regulatory authorities preferred to see. As there was no documentation of a gap between U.S. and EU adverse events due to expiry, nor was the impact of these events significant, it is difficult to pinpoint the genesis of the mandate.

Anecdotally, over the past 15 years or so, several of my label submissions to EU country operations authorities resulted in feedback requesting that an expiry date be added to the primary container label. My response would always be the same – omitting the date violated no mandate and there was instruction on the eternal carton to always keep the primary container together with the external carton that reflected the expiry date. Based on this experience and the lack of evidence pertaining to frequency and impact to patients who’ve consumed expired IMP, it seems that this requirement was inspired by regulatory reviewers who, with the best of intentions, viewed this as a patient advocacy or protective change. In actuality, the new mandate introduces much risk and is a giant step backward for the clinical supply chain and global automation efforts.

The Regulation Ignores The Benefits Of Automation

Mandating the expiry date on the primary label will introduce limitations to the IRT systems and advertently or inadvertently shifts the onus and responsibility from the systems to the patient, thus providing a disservice to the patient and the industry. Automated systems such as IRT systems have introduced much stability, efficiency, and controls to clinical trials. Oftentimes, automated systems achieve a level of accuracy that humans may miss.

Consider the following example:

A kit contains a 30-day supply and has an expiry of June 30. A site staff member dispenses this kit on May 25 and tells the patient to bring it back on June 25. Now, the windows for this trial are +/- one week, so there will be enough drug until July 7. The patient is late and brings the kit back on July 2, all the while dosing from the kit.

In this instance, the patient has consumed expired drug product, and this is now an out of specification event. Now, if this kit is dispensed via an IRT system with all of its regular controls, the system would not allow for the kit to be dispensed beyond May 23, as it considers the windows when dispensing.

One may argue that even if an IRT system dispenses this kit correctly, the subject may still bring the kit back late. Even in this case, all of the drug product would be consumed prior to the expiry date. Given the controls surrounding the clinical trial processes and systems, the fact that patients need to return the drug, the strict accounting in place, and the frequency of the site visits and touch points, printing the date on the primary label simply adds no value. Taking full advantage of automated systems is safer than relying on a human to dispense kits, as algorithms consider the treatment period as well as long windows when allowing for dispensing. Printing the date on the primary label will hinder this tried and true automation.

How Can We Move Our Industry Forward?

Instead of shifting the onus back to the patient and relying on more archaic tools, the industry should look to using AI and new technologies such as e-labels and QR codes. There are smart labels that could actually alarm or push a message to a patient’s phone indicating that the medication is expired or approaching expiry. QR codes that can be scanned by a patient’s phone to reflect the expiry date (and be updated by sponsors to reflect updated use by dates) should also be explored as viable options. Instead of looking forward and authoring new guidances on validating these new tools and encouraging thought leadership and discussions surrounding them, we’ve taken a step backward not only in innovation but in the status quo.

It's true that we are heavily regulated and pivoting is more difficult for our industry, but regulatory agencies seemingly encourage innovation for quicker times to market. We need a few large companies to adopt some innovative methods to mainstream innovations at an accelerated rate. Breakthroughs seems to live and die in the initial discovery space, but we can do much more to achieve goals faster downstream. 

About The Author:

Haneen is president and founder of Pivot Consulting and Services LLC. She is a global clinical supply expert and end-to-end supply chain advocate with more than 15 years of experience. Throughout her career, she has worked and consulted for numerous companies of varying footprints, including British Petroleum, Schering-Plough, Merck, Celgene, KPMG, and OptiNose. She is a graduate of the American University, Rowan University, and Yale University with a B.S. in chemical engineering, a M.S. in chemical engineering, and a Certification of Executive Leadership, respectively. She is active in women in engineering groups.