Simon Jones

	New regulations that will bring added complexity to the labeling of clinical trial supplies are now here. Five years after Clinical Trial Regulation (EU) 536/2014 first came into force, development of the clinical trials portal and database that will trigger its official application is about to begin. Six months after it’s completed, the regulation will take full effect and the rules governing clinical trials will transform quickly, although there is a one-year transition period after that where one can continue to register a trial under the existing EU Clinical Trial Directive. The European Medicines Agency’s (EMA)Management board say that the regulation will take effect in 2020. Its impact on labeling is profound.

	Annex VI of the new regulation mandates the inclusion of “period of use” dates on both immediate and outer packaging, removing the option for companies to reference the information centrally via interactive response technology (IRT) or randomization and trial supply management (RTSM) systems.

	Although adding dates to labels is itself quite straightforward, changing those dates as investigational medicinal product (IMP) stability becomes clearer is much more problematic. For example, with biologics, where stability is often difficult to determine up front, it has meant that expiry date changes during clinical trials are becoming increasingly frequent. However, with repackaging needing to be carried out in a good manufacturing practice (GMP)-controlled environment and overseen by a qualified person (QP), the requirement to update period of use dates on primary and secondary packaging presents major challenges for products that have already been shipped in bulk.

	Many trial or distribution sites don’t have the facilities or infrastructure to relabel products in-country, increasing the risk of costly delays as supplies are reshipped to GMP-controlled environments for repackaging. In some instances, companies may be forced to scrap and remake expensive compounds. Conversely, failure to comply puts them in breach of clinical trial regulations, which could invalidate a study.

	As industry counts down to the official application of the new regulation, companies should rethink their clinical trial supply processes and adopt agile technologies for more efficient and responsive ways of working. The following are some considerations.

	One option is to use smart packaging, which allows labels to be updated without opening an outer pack. This reduces the risk of breaking tamper-proof packs and can be an elegant solution. However, there are costs associated with the adoption and validation of new packaging while the options available are dependent on the IMP being tested in trials. Smart packaging is not always suitable.

	The uncertainty surrounding when the new regulations will become applicable has led some companies to take a pragmatic view, keeping an eye on emergent best practice rather than committing to a solution in advance. This approach is not without risk; once the portal and database finally go live, companies have six months (plus the option of an additional one-year transition period) to implement a workable solution.

	A third option is to leverage existing contract research organization (CRO) and contract sales organization (CSO) partnerships. Many industry partners have good in-country GMP facilities and are well-placed to help pharma meet the new labeling requirements. However, success is not just about a partner’s capabilities, it depends on the availability of their QPs to release products. Moreover, leveraging partner networks still requires pharma companies to change their labeling strategies, which can add time and cost to clinical trial supplies.

	Some organizations are exploring new production models. One example is to produce smaller but more frequent batches of primary packaging. This approach requires no changes to existing processes and, since production volumes are smaller, minimizes the likelihood that packs will carry incorrect expiry dates. The model, often incorrectly referred to as just in time (JIT), is well suited to early phase trials involving lower volumes of patients and studies. However, at scale, this approach can be inefficient. As volume increases, the number of batches required increases too, intensifying the QP effort to release products, particularly in later phases.

	The JIT approach is a procedure for printing, packing, and shipping packs as and when supply plans state they’re required. A similar nuanced option is on-demand labeling, where printing is done in response to confirmed patient attendance at study sites. JIT is different in that printing, packing, and shipping is done in line with a preexisting plan. In both models, labels are printed using the latest data-dosage and period-of-use dates-close to the time products are actually required. This also reduces the need to update inner or outer packaging, providing further flexibility to respond to future trial design changes or regulatory fluctuation. JIT and on-demand offer potential for cost savings and efficiency gains.

	Considerations will vary according to individual company needs; how often do you anticipate the period of use changing throughout your trial? Using your current processes, how much will it cost to make those changes and what’s the associated wastage? What impact will the new regulations have on your QP requirements? Does your planned solution support that QP effort and do enough to mitigate risk? In most cases, JIT is likely to be a good option-but it’s not without its challenges. Companies will need a labeling solution that uses automation and integration to remove manual effort and reduce risk. And they need to apply the same level of automation around QP processes.

	Although the precise timing of the application of Regulation 536/2014 remains uncertain, a new era for clinical trials supply compliance in the EU is almost here.

, Enterprise Pre-Sales Engineer; both with Prisym ID

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A new era for clinical trials supply compliance in the EU is almost here. 

Labeling Challenges From EU Annex VI

	New regulations that will bring added complexity to the labeling of clinical trial supplies are now here. Five years after Clinical Trial Regulation (EU) 536/2014 first came into force, development of the clinical trials portal and database that will trigger its official application is about to begin. Six months after it’s completed, the regulation will take full effect and the rules governing clinical trials will transform quickly although you will have a one-year transition period after that where you can continue to register a trial under the existing EU Clinical Trial Directive. The EMAs Management board say that the regulation will come into effect in 2020. Their impact on labeling is profound.

	Annex VI of the new regulation mandates the inclusion of ‘period of use’ dates on both immediate and outer packaging, removing the option for companies to reference the information centrally via IRT or RTSM systems. 

	Although adding dates to labels is itself quite straightforward, changing those dates as IMP stability becomes clearer is much more problematic. For example, with biologics where stability is often difficult to determine up front, has meant that expiry date changes during clinical trials are becoming increasingly frequent. However, with repackaging needing to be carried out in a GMP-controlled environment and overseen by a Qualified Person (QP), the requirement to update period of use dates on primary and secondary packaging presents major challenges for products that have already been shipped in bulk. 

	As industry counts down to the official application of the new regulation, companies should re-think their clinical trial supply processes and adopt agile technologies for more efficient and responsive ways of working. Following are some considerations”

	The uncertainty surrounding when the new regulations will become applicable has led some companies to take a pragmatic view, keeping an eye on emergent best practice rather than committing to a solution in advance. This approach is not without risk; once the portal and database finally go live, companies have six months (plus the option of an additional one year transition period) to implement a workable solution. 

	A third option is to leverage existing CRO and CSO partnerships. Many industry partners have good in-country GMP facilities and are well-placed to help pharma meet the new labeling requirements. However, success is not just about a partner’s capabilities, it depends on the availability of their QPs to release products. Moreover, leveraging partner networks still requires pharma companies to change their labeling strategies, which can adds time and cost to clinical trial supplies.   

	Some organizations are exploring new production models. One example is to produce smaller but more frequent batches of primary packaging. This approach requires no changes to existing processes and, since production volumes are smaller, minimizes the likelihood that packs will carry incorrect expiry dates. The model, often incorrectly referred to as Just in Time, is well suited to early phase trials involving lower volumes of patients and studies. However, at scale, this approach can be inefficient. As volume increases, the number of batches required increases too, intensifying the QP effort to release products, particularly in later phases.

	The Just in Time (JIT) approach is a procedure for printing, packing and shipping packs as and when supply plans state they’re required. A similar, nuanced, option is On Demand labelling, where printing is done in response to confirmed patient attendance at study sites. JIT is different in that printing, packing and shipping is done in line with a pre-existing plan. In both models, labels are printed using the latest data-dosage and period of use dates-close to the time products are actually required. This also reduces the need to update inner or outer packaging, providing further flexibility to respond to future trial design changes or regulatory fluctuation. JIT and On Demand offer potential for cost savings and efficiency gains. 

	JIT requires a labeling solution that can pull in data in real time and configure it into an approved format to be printed, validated and applied. The best label management solutions leverage integration and automation, ensuring clinical supply teams aren’t required to calculate expiry dates or re-enter data that’s already in the system. Automation and integration are crucial for JIT; since expiry dates will change with greater frequency, teams cannot afford to rely on manual processes to change and validate data. 

	Making the move to JIT may naturally increase a company’s QP requirements. With QPs potentially required to manage and sign off multiple runs-rather than large single batches-organizations will need to redesign and automate their QP processes accordingly. Once again, good labeling software can make a huge difference but it is not all you need. The smartest solutions include ‘vision inspection’, which automates the inspection of labels and provides reports (and audit trails) to help QPs validate the process.   

	Considerations will vary according to individual company needs; how often do you anticipate the period of use changing throughout your trial? Using your current processes, how much will it cost to make those changes and what’s the associated wastage? What impact will the new regulations have on your QP requirements? Does your planned solution support that QP effort and do enough to mitigate risk?

	In most cases, JIT is likely to be a good option-but it’s not without its challenges. To overcome them, organizations need a labeling solution that uses automation and integration to remove manual effort and reduce risk. Crucially, they need to apply the same level of automation around QP processes. 

	Although the precise timing of the application of Regulation 536/2014 remains uncertain, a new era for clinical trials supply compliance in the EU is almost here. 

, Enterprise Pre-Sales Engineer, both with 

https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-1/reg_2014_536/reg_2014_536_en.pdf

https://ec.europa.eu/health/human-use/clinical-trials/regulation_en

Simon Jones and Gordan Alexander, both of Prisym ID, explore the added complexity to the labeling of trial supplies that new regulations to EU 536/2014 will bring, specifically Annex VI. 

Simon Jones

Articles

Labeling Challenges From EU Annex VI

Labeling Challenges from EU Annex VI