As technology and materials have improved our ability to measure, monitor and maintain controlled temperatures in clinical trials, regulators are paying close attention as products are submitted for approval. Good Distribution Practice (GDP) guidelines were updated in 2013 for the EU, and the United States Pharmacopeia (USP) has submitted updates (October 2016 – not yet approved) to the guidelines.

Additionally, regulators are starting to ask for more data regarding trial shipment monitoring. What does this mean for clinical trial management? How can we meet this challenge? Will these practices reduce risk? These questions as well as a discussion around technology and supporting systems will be covered in this article. As compounds used in treatment and trials are becoming more complex, agencies are looking deeper into the documentation of trial data to support stability claims and label parameters.

Review of Regulation Changes – EU/US

In the U.S., section 1079 of the USP was updated in September 2016. However, that update has not been released. The USP is the primary rule book for pharmaceutical development. Section 1079.1, as the update is enumerated, is titled “New General Chapter – Storage and Transportation of New Investigational Products (IDPs).” The revision sparked considerable review within the USP of GDP and supply chain recommendations. In addition to revising 1097, the USP tried to clear up overlap with 1197 and created a new chapter 1083 to address GDP – with 1083.2 addressing environmental conditions management specifically.

Section 1079.1 largely addresses the latest IDPs and the difference from commercial products – especially calling out product stability with respect to both storage and transportation. The chief risk of IDPs is the duration of travel time after manufacture for distribution, and the temperature of the material during transit. Section 1083.2 addresses temperature monitoring for all compounds under GDP, and details many aspects of the distribution process (see Figure 1).

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The longer reach of these changes will affect raw materials, APIs (Active Pharmaceutical Ingredients) and commercial products in addition to IDPs, and are bound to figure in the stability declarations for approval and final label specifications. While the USP had amended its guidance, the FDA has not. This has not stopped inspectors from asking, during an inspection, to verify that a container maintains temperature conditions throughout distribution. The FDA has also asked for more details around excursions:

  • Process for in-transit excursions
  • Process for site excursions
  • Methods for ensuring site compliance
  • Consideration of data integrity across systems

In each case, the FDA is looking for measurements, data storage, notification and decision records, and integrity.

Adopting a ‘Risk-based’ Approach

In Europe, a risk-based approach has been adopted with the GDP guidance covering more sections – calling out specifics such as:

  • Temperature parameters
  • Complexity of importing country processes
  • Mode of transportation
  • Stability parameters
  • Seasonal variants
  • Storage conditions at airport and destination

Furthermore, the EU documents require that care be given when planning routes, selecting contractors and destination, and transfer points. There is also an effort to address the entire process with chapters covering equipment and packaging, in addition to transportation and customs issues.

In either case, taking a risk-based approach, using a decision tree that addresses each section of the appropriate guidance, will highlight a need for more data to support both stability claims and transport conditions/packaging. This will also provide a firm background for adjudicating excursions that occur, and are recorded. These changes, and a deeper review in the approval process (for commercial approval), strongly supports the monitoring of all shipments even when using qualified shippers. The longer the transit time, including transfer and customs clearance, the greater the need for monitoring and the ability to record multiple alarms and events.

“If there were no controls over shipment conditions, then the use of stability data as a ‘routine’ means to justify such an excursion would not be acceptable” – MHRA Inspectorate1

This is all in addition to the use of qualified packaging and carriers, and even qualified shipping lanes, where practical. The agencies are less and less inclined to accept claims without backing data regarding stability. In other words, if you are monitoring the storage of components and compounds during development and manufacture, the same practices should be carried out in distribution. There is no substitute for having data to verify the quality of material delivered. The risk-based approach also should support a better planning of processes, route selection, and time to qualify clinics and depots. One aspect of this renewed scrutiny to bear in mind refers to room temperature (RT) conditions. Making sure the monitoring and definition of RT parameters are consistent throughout study locations should now be on one’s checklist.

While these changes and increased scrutiny may present challenges, the advantages that come from proper planning, monitoring and data collection will smooth the process for a successful candidate. There is also an opportunity for the sponsor to standardize packaging, shipping lanes, depots and partners where possible. This will reduce the overhead for individual projects and ensure consistency across programs and campaigns.

Technology as an Enabler to Greater Data Collection

Technology is becoming both the enabler of more monitoring and data collection, and the biggest hurdle to the collection and use across platforms. Some of this challenge arises from proprietary software and devices, and the distribution of these products. There exist today many different manufacturers of sensing and recording devices that make the option of monitoring shipments easier and less costly.

The new challenges that these sensors bring to the table is the record keeping that ties a specific sensor to a specific package or dose, the collection of the data in a timely manner, and the long-term retention of the data. Some clinical trial management software can accommodate sensor identities with a package tracking number to tie the two together, though sometimes this is via a ‘notes’ field. Data collection at the site or depot is another matter entirely.

The issue can be compounded by requiring software to accommodate the data collection process. If the trial is international in scope, these challenges can increase the cost if the sponsor needs to provide equipment. The challenge of data collection can also increase the burden on site personnel, providing them with an additional protocol and a possible return of the sensor. This also creates some pressure where the data should be reviewed, or at least the occurrence of excursions, prior to the patient receiving the therapy. All planning and monitoring efforts are lost if this review cannot happen in a timely fashion.

One emerging option is sensors that use a wireless means of transferring data. This can enable the transfer of data to occur automatically where the site or depot has wireless receiver connectivity. One manufacturer, using a Bluetooth® frequency, merely needs connectivity to the web, and the data can be transferred. This system would make the data available to all parties as soon as the device can communicate with the web, thus reducing the burden on site and depot personnel.

The last piece of the puzzle is to integrate these practices into the sponsor’s quality management system (QMS). While this process may highlight data format issues and remote data collection, it enables consistent application of temperature ranges and excursion definitions. This provides a seamless application of standards from procurement of raw materials, development and manufacture through distribution, and ultimately receipt by the patient.

While the integration of monitoring and data collection into the QMS could be a chapter on its own, sponsors must ensure this step is not overlooked. Additionally, temperature data can very readily be utilized for continuous improvement efforts, improving the design and function of shippers, lanes and data quality. Some have reported a reduction in nuisance alarms by 30 percent through such efforts.

Despite the Opportunities Novel Technology Offers, Challenges Remain

While the regulations are changing, the regulators are asking the questions that support investing in better systems, and more complete monitoring. Regulators are asking for end-to-end data and are looking out to maintain the quality and integrity of drugs. The technology is available, and the software developers are improving the trial management software. There are still challenges; however the path forward is clear, we will be monitoring more, and this is a good change.

By completely monitoring the process, from raw material through administering to patients, the quality of compounds can be warranted and maintained. These tools will enable new compounds to be safely administered for trials, and ultimately as approved products. The regulators understand that there are risks and demand that we, as an industry, adopt these new tools (logging devices, software, communication technology) to safeguard our patients and products. We can and should adopt these new paradigms.



MHRA Inspectorate –