Kurt Lumsden, Director, Client Services at PAREXEL's Perceptive Informatics.

Kurt Lumsden

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 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

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. 


  1. Annex 13 MANUFACTURE OF INVESTIGATIONAL MEDICINAL PRODUCTS, Section 26 (j,)
  

http://ec.europa.eu/health/files/eudralex/vol-4/2009_06_annex13.pdf

, 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

Articles

Investigational Product Expiry Management

Q. How can interactive response technologies be used to manage investigational product temperature excursions?

  A.Effective and efficient management of investigational product (IP) temperature excursions at each stage of the clinical supply chain is crucial to trial success. The increasingly global nature of clinical trials--and the supply chain that supports them--combined with IP manufacturing, packaging, labeling, and storage constraints, increases the importance of IP temperature excursion management to trial, program, and business success. In fact, a recent report predicted global healthcare cold-chain logistics spending to increase by 4% compound annual growth rate (CAGR) between 2012 and 2016, reaching $10.7 billion by 2017 (1).     

Weather (recent examples including hurricanes Katrina and Sandy)

Other factors (such as inappropriate storage by subjects after allocation but prior to administration, or unexpected intervention by customs officials).

Effective temperature excursion management seeks to mitigate the impact of temperature excursions on trial execution in cost, time, and effort. This is accomplished by:

Ensuring IP that has exceeded its exposure limits is not allocated to patients

Preventing depot and site stock-outs related to IP temperature excursions

Avoiding missed or extra subject clinic visits due to excursion related stock-outs

Eliminating additional unplanned labeling/packaging of supplies due to IP temperature management issues.

Fundamental IRT excursion management approach


  Interactive response technologies (IRT) systems have long been used to manage temperature excursions. Typical systems provide functionality for depots and sites to quarantine shipments or individual kits. This functionality prevents subsequent ordering of the affected product to a potential destination or allocation to subjects until IP viability can be confirmed. Another option may be configured to replace IP immediately, or only if the product is damaged. The shipment temperature-logging device is returned to the sponsor for analysis of excursion severity and duration against current stability data. Data loggers that provide downloadable human readable reports eliminate the need to send the device back to the sponsor for analysis. The IRT system can be configured to link individual data loggers to specific IP units in the shipment if required (where there are multiple loggers in a shipment). The output is simply uploaded to a portal with document-sharing capabilities. After IP usability is determined, a further IRT transaction allows the sponsor to release the IP for use or make it permanently unavailable. 
  
  


  There are many advantages to this approach. It is a relatively straightforward process supported by standard IRT functionality and can be configured to replace IP immediately after the transaction. 
  
There are, however, downsides to this methodology. It does not reduce adjudication cycle time or the time taken to render a decision on usability. It also carries the risk of increased stock-outs and subject resupply issues if IP is not immediately replaced after an excursion occurs. Finally, manual analysis of every excursion is still required before a decision on usability can be rendered.

In practice, it often becomes necessary to pre-emptively replace site IP stock to allow enrollment and resupply of existing subjects to continue. This replacement of stock places further strains on the supply chain in a number of ways: 

Reducing supply chain flexibility as relatively more IP is transferred to sites

Creating additional overage requirements to compensate for damaged product or delays in usability decisions

Increasing required effort to gather and analyze temperature excursion data

Increasing likelihood of additional shipments  

Impacting site storage constraints due to the need to store quarantined IP until usability is confirmed

Potentially increasing drug wasted if additional orders are required and the site becomes overstocked in relation to the number of patients

Affecting overall accountability and reconciliation activities at each impacted location.

So how can IRT systems further automate the process to reduce cycle time, cost, and effort? IRT solutions can actually be designed to automate the adjudication of IP usability. To facilitate this, the IRT must ‘know’ the IP’s storage and excursion parameters. These values can be stored, in most cases, at the IP ‘pack type’ level or ‘packaged lot’ level. Parameters can be pre-selected and stored in the IRT database or updated by an IRT transaction, providing an intuitive modality for data entry, or supplied through data integration if required.

An IRT excursion transaction then allows users to record excursion severity, maximum temperature deviation, and duration. The IRT system will then automatically adjudicate IP usability based on excursion details and parameters previously entered into the system. Decisions can be rendered immediately on IP usability, saving time and avoiding unnecessary additional shipments due to temperature excursion.  Reports provide additional visibility into individual and cumulative excursion details. Additionally, the IRT can be programed to account for cumulative excursions against specific IP units. Excursion reasons and frequency of excursions (by location) can also be reported and tracked for enhanced visibility and metrics. 

IRT provides flexible options for the sponsor to manage IP temperature excursions effectively and efficiently. These options include management of shipment and IP unit status, integration with distribution management systems, and inclusion of advanced functionality to automatically adjudicate IP usability. Success factors include careful system design (including impact assessment to other systems/processes), implementation, and adequate reporting of excursion data that includes frequency and distribution. Training delivery, reporting, and compliance monitoring are also important key success factors. 


  1.	IMARC, Global Healthcare Cold Chain Logistics Market Report & Forecast: 2012-2017 (November 2012), 

www.imarcgroup.com/healthcare-cold-chain-logistics-market

Guidance for Industry E6 Good Clinical Practice: Consolidated Guidance

, Section 5.13.2 (Rockville, Md, April 1996), 

www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM073122.pdf

.
3.	C. Milligan, E. Sadler-Williams, and K. Gram, Pharmaceutical Engineering Vol. 3, No 4 (July 2013).

Kurt Lumden, Director, Client services at PAREXEL's Perceptive Informatics, discusses the management of investigational product temperature excursions.