Investigational Product Expiry Management

Kurt Lumsden, Director, eCDS Client Services at PAREXEL Informatics, discusses the use of interactive response technologies in investigational product expiry management.

Q. How can interactive response technologies enable IP expiry management and removal of ‘use-by’ dates from the label?

A. Investigational product (IP) manufacturing and packaging for clinical trials is costly. Every effort must be made to ensure optimal utilization and reduced waste. One way this can be accomplished is to effectively manage product expiration or retest dates.

Packaging and labeling requirements often vary by jurisdiction, requiring different labels for each country to be affixed to the package. Expiry or retest dating may also vary by jurisdiction.

Interactive response technologies (IRT) have long been used to manage IP expiry. Flexible systems typically allow updating product expiry at the lot level (with an option to update all unallocated kits now or later and by location), for single-panel labels that do not include the expiry date or by lot/kit and location where the expiry dating requires a relabeling campaign.

Expiry updates for countries that accept removal of expiry from the label follow this process:

• Updating one expiry date (per lot, per country) for all kits

• Updating kits by lot

• Updating IP kits at all locations immediately

• Updating all kits of status “available” or “in transit”.

Countries that do not accept removal of expiry date follow the process outlined below:

• Updating multiple expiry dates (per lot, per country)

• Allowing supplies to be placed on “hold” or “quarantined” to prevent ordering/allocation during re-labeling

• Updating by lot/kit number location or lot, quantity, and location (for non-uniquely numbered supplies) as supplies are relabeled

• Allowing multiple users to perform updates (drug-supply manager for depots; monitors or pharmacist for site locations)

• Ensuring that “in-transit” medication is not automatically updated- to allow for relabeling before status is changed to “available”.

There is no mandatory requirement in the United States or Japan to include expiry on the label. In the European Union, the requirement is covered by Annex 13 (1), which states that labels should include: “the period of use (use-by date, expiry date or re-test date as applicable)”, “unless its absence can be justified, e.g., use of a centralized electronic randomization system.”

After consulting with the industry, the European Medicines Agency (EMA) published a reflection paper outlining circumstances in which expiry could be removed from the label barring these conditions (2):
• A copy of the QP signed and dated certificate (CofA or CofC) containing the expiry date and available to site staff
• IP is only administered by dedicated, qualified trial staff on site and is not retained by the study subject
• IRT assigns IP kits that all have an expiry date good through the period between visits for all kits identified by a unique Med ID (or Batch Number for non-uniquely numbered supplies).. in order to avoid the issues with short dated supplies where situation of administering kits with different expiry dates out of ascending expiry order that could cause administration of expired product
• Assignment confirmations or notifications are available to site staff in for each allocated kit, and contain information on study subject, unique kit identifier or Med ID (where available) and associated expiry date
• The IP expiry date is valid beyond the planned administration, with adequate buffer to cover any delay in dosing and account for visit windows (covering last possible day of dosing)

In addition to IP labeling,  packaging and ordering, allocation, and dosing, design considerations should also account for any third-party distributor processes for release and expiry updates, impact on pooled supplies (that may have variable pack life depending on trial design), just in time (JIT) and point of dispatch labeling capabilities, as well as QP considerations. This is especially important when sites are running more than one protocol supported by pooled supplies.
Use of smartphone applications that can communicate with the IRT system allow verification of current IP kit expiry from a bar code on the label, as well as the capability to provide IP storage and administration instructions to the user.

IRT systems that support removal of expiry from the IP label have the following characteristics:

• Full end-to-end inventory management capabilities from IP release through returns and destruction

• Flexible country status management (accepting vs. non accepting)

• Ordering based on location needs and visit date windows

• Concurrent, consecutive, and partial allocations with unscheduled resupply availability

• Management of pack life vs. treatment group/dose level and visit window

• Visibility of product expiry and availability of documentation via portal

• Transparency of kit expiry date in reports, notifications, and alerts

• Ability to handle single-dose kits vs. cartons and IP pooling across protocols

• Forecasting and supply simulation to time batch manufacture, labeling, and packaging

• Ability to make changes.

Planning and workflow are essential to allow optimization of IP expiry management for clinical trials. The system configuration needs to be specified in advance but changes in requirements supported (i.e., additional product or countries) can be accommodated. The system should be intuitive and allow for real-time updates of expiry and flexibility to support different label configurations and regulatory requirements.

In conclusion, IRT systems provide an efficient and effective way to manage IP expiry in clinical trials. Keys to success include clear definition of requirements, risk analysis, adequate user training, and compliance monitoring.

References
1. Annex 13 MANUFACTURE OF INVESTIGATIONAL MEDICINAL PRODUCTS, Section 26 (j,)
http://ec.europa.eu/health/files/eudralex/vol-4/2009_06_annex13.pdf, accessed Sept. 10, 2014.
2. EMA, Reflection paper on the use of interactive response technologies (interactive voice/web response systems) in clinical trials, with particular emphasis on the removal of expiry dates, EMA/INS/GCP/600788/2011, Section 2.3.1. Conduct of phase I to phase IV clinical trials (December 2013), http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2013/12/WC500158536.pdf, accessed Sept. 10, 2014.