Richard Segiel

In an increasingly global clinical trials market, and with the increasing complexity of good distribution practice (GDP) and good clinical practice (GCP) regulations (

), pharmaceutical companies must be equipped with the ability to fully track and trace the entire journey of their investigational medicinal product (IMP). However, the existing methods of collating such disparate data have made it difficult for sponsors to maintain 100% oversight of their products from manufacture to patient administration. As a result, it is becoming more of a challenge to provide assurance that regulations are being met and that product integrity has been maintained.  

	Sponsors recognize that during the transportation process, a drug product is exposed to a range of temperature fluctuations, leading to excursions that could impact its stability, making the treatment unfit for patient administration. It is, therefore, increasingly vital to provide a fully comprehensive picture of a product’s lifecycle, in order to prove its quality and integrity and more specifically, that the drug has maintained its labeled temperature limits throughout the entire supply chain.

	Comprehensive, GDP-compliant monitoring of all temperature-controlled material is essential throughout all shipments of clinical materials to active sites. The most appropriate method to ensure all relevant information is captured is to include a temperature monitor, which collects essential primary data, offering accurate readings that correlate to specific dates and times during transit and storage. Any temperature excursion experienced can support decisions on the product and can be easily associated with the transit route. This can enable retrospective comparison and analysis of the methods of transport chosen, offering a level of control and visibility that provides information to support decisions, processes that are followed, and how future material should be shipped and stored.

	The existing method of collecting and manually assessing this essential temperature data often means managing multiple vendors and software applications. The analysis of this data is hugely valuable; however, it is also labor intensive and time consuming, issues that have the potential to impact study timelines or cause interruptions in the supply chain. Single-source temperature management systems offer a more sophisticated solution to house all collated data on one single platform in the most efficient way possible. Across the entire clinical supply chain, the speed at which the information is available offers data for interrogation and instant analysis, empowering companies to quickly put logistics strategies in place to reduce risk. This single-source also better aligns companies with new regulations concerning patient safety and saving money, time, and lives. 

	An increasing number of sensitive and sophisticated pharmaceuticals are required to be maintained at a controlled temperature. For example, in 2016, 75% of the shipments that Almac Clinical Services managed required temperature controls-up from 25% just five years earlier.  These new temperature requirements are proving to be a real challenge for drug manufacturers. Typically, developing a supply chain strategy has been a complex process involving a sequential series of decisions, including:

 These are specific details, including mandatory temperature storage range, any allowable excursions, optional “excursion budget” (the product may withstand multiple excursions up to a certain cumulative limit), and other pertinent information relating to the product. Trials may be early in the development phase and all data not fully available.

Mapping the journey of the product during transit to destination

, including identifying any specific challenges associated with the footprint of countries that will be involved in the trial, the shipping lanes needed, and the various storage facilities required. 

Establishing the product’s varying requirements and ensuring adequate facilities throughout the entire distribution chain.

 This will guarantee complete compliance throughout. The varying complexities and environments associated with the supply chain are challenging and every product is unique, particularly when the trials being conducted are truly global. Every shipment makes its way to patients via an array of different storage and handling conditions (e.g., a diverse range of phase change shippers, temperature monitors, different couriers, and depots). Each mode of transport, period of storage, and change of hands has the potential to expose the packaged product to temperature changes. Clinical sites offer a variety of storage facilities and conditions, making it harder to maintain control over the drug product. In addition, holding all sites to a common standard is very difficult. The personnel responsible for handling the product must be adequately trained to ensure they are packing, receiving, unpacking, and storing the material in the most compliant way. However, this often varies and human error can also impact the product.  

	Reporting temperature data on each stage, location, and handling across multiple, unrelated databases means there is no one central source providing a complete oversight of the temperature data throughout the product lifecycle, resulting in unrelated data silos across the entire supply chain (see Figure 1; click to enlarge).

	It is considerably complex to address all of the planned factors. But, of course, even with the best-laid plans, there is the potential for an unplanned event that could easily jeopardize the product’s condition. Traffic congestion between an airport and a site could delay delivery until a site reopens after closing for a weekend. Material could be removed from a plane and sit in a store for hours. Customs officials could open shippers and remove the temperature monitors. Each change in location and stoppage throughout a product’s journey will impact temperature conditions caused by exposure to varying climate changes and conditions.  

	It is, therefore, essential for supply chain managers to plan a product’s path, taking into consideration the risks and costs associated with the different climate, timelines, and regulatory hurdles presented by varying modes of transport (air, sea, or land), shipping lanes, package options, and storage locations, and they must implement a suitable strategy to deal with each planned event throughout the journey. This strategy must be robust enough to prove regulatory compliance and drug supply assurance to the patient, while also reducing the strain at sites and allowing improvements to be made in the future.

	Clinical sites are involved in much more than dosing patients with the IMP. They can manage tens to hundreds of protocols with various sponsors, who all require completion of a host of documentation, reports, and other tasks. Today, due to tightening of regulations on temperature monitoring, some sponsors are requiring sites to place separate temperature monitors within controlled storage (2-8oC, 15-25oC, -20 oC, etc.) and download the readings monthly. Sponsors are attempting to comply with these regulations to ensure that IMPs are stored within the allowed limits, but doing extra monitoring can be challenging for sites.

	Storage compliance of IMP can also present hurdles (e.g., validated refrigeration). With this burden comes the associated struggle for the sponsor to execute a successful site-level monitoring plan, which is almost always dependent on staff diligence and adherence to agreed expectations.

	Finding an auditable and GCP-compliant platform that can support and ease the data collection burden on these sites and their individual staffs-and which facilitates excursion management and recording of storage temperature history-can be the solution. Combining that with adjudication staff who can provide an immediate response to reported excursions, make a decision about product viability, and determine a course of action, especially if the situation will impact patient treatment, is the most suitable strategy for clinical site compliance.

	Mitigating against risk is vital and, while risks cannot be eliminated, fully assessing transportation and temperature management is the first step. Fine-tuning product stability data is the next.

	Most quality assurance departments manually assess and evaluate each out-of-spec temperature excursion as and when it occurs.  Clearly, due to the nature of this process, mistakes happen and efficiencies are low, causing potential delays. If a system could track all excursions cumulatively for a particular product lot, shipment, or kit to document the product history, as well as hold predetermined excursion allowances based on the product stability, quality assurance could make product quality evaluations more accurately and quickly because the decision-making and justification is performed up front.  

	For products with appropriate temperature stability profiles, the data can be used to create predetermined allowable excursion criteria and support a more flexible approach to product evaluation. This could minimize the need to discard material that may be viable due to temperature excursions. For example, a product labeled with storage conditions of 2-8°C may actually be stable at 9-15°C for 180 minutes and at temperatures of 15-25°C for 30 minutes before the product is deemed not viable. Giving quality assurance groups predetermined and visible criteria for excursion adjudication allows for a robust and justifiable process for product disposition that is based on data and risk to the patient.

	Advances in temperature-controlled shipping systems, courier services, airline infrastructure, and services are all enabling significant improvements in temperature control during transit. This offers the best physical infrastructure for distribution, providing the same robust performance and level of assurance to that of the temperature-controlled warehousing that the industry employs today. However, in the same way that the industry would not operate temperature control warehousing without collecting and reviewing the data on a regular basis, so too should we be as diligent with regards to the data that is, and can be collected as the product moves throughout the clinical supply chain. 

	While this physical infrastructure has historically been the best practice approach for drug manufacturers, with increasing regulations (both in transit and in storage), this is no longer solely sufficient to achieve compliance. The only way to prove this is to lead with a data-driven strategy, using a platform that provides a complete view of the physical supply chain and which facilitates robust data collection and analysis across a universal data repository. Moreover, the platform should be flexible to support what is a varied supply chain of numerous stakeholders (e.g., insulated shipping systems, temperature monitors, distribution centers, couriers, and clinical sites).

	By consulting data on the end-to-end supply chain and each touchpoint of the product’s journey-in transit and at the clinical site-it is then possible to adopt a proactive approach to distribution that drives improvements and regulatory compliance, lowering the risk of unplanned temperature excursions while providing controls for planned excursions-when products are intentionally removed from ideal conditions to allow for processing. A platform that also integrates with interactive response technologies (IRTs) is a best practice. This allows material that has undergone an excursion to be quarantined while the excursion is reviewed, and can trigger resupply shipments to avoid stock-outs.

	Manufacturers can gain added assurance by working with a team of dedicated temperature experts, who can support in-depth data analysis, creating an audit trail of each shipment, analyzing problems, and ultimately learning from and building on experience. For global clinical trials, this requires having global staff available 24 hours a day across different time zones. With this data-driven approach, drug manufacturers can create a better global supply chain with full assurance that their physical infrastructure is working and that their drug product is safe to administer to the patient. 

	In order to ensure companies are minimizing risk associated with shipping temperature-sensitive material from origin to destination in an ever evolving market-with tough GDP and GCP regulations in place to protect the patient-it is important to combine valuable data analysis and assessment with appropriate distribution methods. The best supply chain strategy needs both the physical and the data components, in order for a complete temperature record to be available. Combined on one platform and supported by a temperature management expert team, this data-driven strategy will form the foundation for in-depth data tracking and analysis, driving decisions and improvements as well as management of different stakeholders and the clinical sites. 

	As technology advances, companies must also take a proactive approach to avail themselves of new solutions offering more efficient and effective methods of temperature management. This not only provides sponsors with the opportunity to maintain their competitive advantage by saving time and money associated with distribution, but also enables them to ensure patient safety through a compliant approach applied throughout the entire shipping process.  This strategic planning will essentially ensure that the product’s journey is as important as the destination.

 is Vice President, Business Development, Almac Clinical Services

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