Establishing Best Practice Qualification Metrics For Smart Shipping Containers

By Kevin O’Donnell, Vice President, Cold Chain Standards, Practices & Compliance, BioLife Solutions, Inc.

Wernher von Braun, the father of modern rocketry famously stated, “one test is worth a thousand expert opinions.” The FDA has put their own regulatory spin on this axiom: “if you didn’t document it; it didn’t happen.” This extends beyond the drug therapies themselves to the packaging and logistics practices that are used to distribute them; what the FDA refers to as the “holding” of a drug.¹

The fragile nature of cell therapies requires special consideration with regard to temperature variation and other hazards known to exist in the distribution environment. Well-designed tests and documenting the robustness of transport packaging are essential for ensuring cell viability and function, especially during the clinical trial phases before commercialization.

Not all specialty-packaging companies go through the time and expense of qualifying their packaging products to meet the rigors of transportation. Some do, but only to the extent that they meet basic minimum standards. Others perform to a self-designed standard. All of these practices can lead to inadequate performance and detrimental risk to the products they are intended to protect.

REGULATORY IMPERATIVES

Most global regulatory authorities have followed Health Canada’s lead: “it is incumbent upon the license holder of a drug to ensure that all persons and companies including fabricators, packagers/labelers, testers, distributors, importers, and wholesalers have the responsibility for ensuring appropriate storage and transportation conditions from the point of manufacturing up to the delivery of the drug products to the final distribution point.”² The FDA is a little more succinct: “A drug or device shall be deemed to be adulterated if the methods used in, or the facilities or controls used for, its manufacture, processing, packaging or holding do not conform to or are not operated or administered in conformity with current good manufacturing practices…”³ The European Union goes even further. The most recent, (October 2015), and to date most stringent of regulations comes from the European Commission EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use,⁴ which requires verification of transportation. There are three areas of focus related to transportation requirements.

• “It is recognized that verification of transportation may be challenging due to the variable factors involved however, transportation routes should be clearly defined. Seasonal and other variations should also be considered during verification of transport.”
• “A risk assessment should be performed to consider the impact of variables in the transportation process other than those conditions which are continuously controlled or monitored, e.g. delays during transportation, failure of monitoring devices, topping up liquid nitrogen, product susceptibility and any other relevant factors.”
• Due to the variable conditions expected during transportation, continuous monitoring and recording of any critical environmental conditions to which the product may be subjected should be performed, unless otherwise justified.

This is just a sampling of the global expectations that have evolved regarding understanding, controlling, monitoring and documenting the packaging and logistics practices used to ship medicinal products. Meeting these requirements is challenging. There are only a few current standards that can help comply with these requirements.

PICK A STANDARD

The test protocols, materials, processes, test equipment, calibration, and facilities used in the execution of a packaging qualification process should meet or exceed the minimum requirements established by known industry standards. Three of the most rigorous and thorough standards include:

• The International Safe Transit Association (ISTA) Standard 20: Design and Qualification of Insulated Shipping Containers (2011). This is a design and qualification process that provides the structure and path to design, test, verify and independently certify a specific Insulated Shipping Container (ISC) for use.
• The Parenteral Drug Association Journal of Pharmaceutical Science and Technology Technical Report No. 39 Guidance for Temperature Controlled Medicinal Products: Maintaining the Quality of Temperature-Sensitive Medicinal Products through the Transportation Environment. This guidance document provides a design approach to develop and implement specialized packages and systems that protect temperature-sensitive products during transport, especially between climactic zones and by various modes of transportation.
• The World Health Organization Technical Supplement to Annex 9: Model guidance for the storage and transport of time- and temperature-sensitive pharmaceutical products, Qualification of Shipping Containers. This procedure covers the qualification of all single-use and reusable active, passive, hybrid, and cryogenic dry/vapor shipping containers or systems used for the transport of time- and temperature-sensitive pharmaceutical products in external distribution.

It should be noted that each of these documents have their own areas of strong focus. The evoTM Smart Shipper has been qualified to meet or exceed the minimum requirements for all of three standards, not just one. But as thorough as these documents are, none address the operational capabilities of on-board electronic monitoring, data collection, radio transmission and Software as a Service (SaaS) integrated into the insulated shipping container. This is a technology powered by the evoTM Smart Shipper; the first of its kind. No standards for performance exist. Likewise, the industry has yet to adequately address the demanding requirements for shipping sensitive cell therapies. Given no available precedents, very stringent standards needs to be written, resulting in a new level of performance acceptability.

WHAT WAS OUR PROCESS?

The qualification of all evoTM Smart Shippers (2° C to 8° C, Controlled Room Temperature – CRT – and the CRYO -80° C), follows FDA CDER IQ/OQ/PQ Principles of Process Validation, wherein;

• IQ/DQ –Design Qualification: the process of establishing confidence that designed components are capable of consistently operating within established limits and tolerances.
• OQ – Operational Qualification: Documented verification that under simulated test conditions, the packaging system, performs as intended throughout anticipated operating ranges.
• PQ –Performance Qualification: Documented verification that transport tests of product or representative product contained within the packaging system and subjected to actual transportation and distribution routes, can perform effectively and reproducibly.

INDEPENDENTLY VERIFIED

While the design qualifications were initially performed by the container manufacturer, they were repeated and verified by an independent, 3rd Party ISTA Certified Thermal Test Lab to remove bias. The same independent lab performed all subsequent Operational Qualifications.

All of the best practice documents cited above call for the use of a preapproved protocol with established acceptance criteria. The qualification must be performed on new, randomly selected production components and run in triplicate to ensure repeatability. It is recommended that thermal performance is measured against rigorous but representative heat and cold ambient temperature profiles to account for seasonal variation, crossing of hemispheres, changes in geography and differences in modes of transport. It is crucial that the qualification is bracketed to perform with any combination of payload - maximum and minimum. Since payloads can be of an undetermined form factor (powder, liquid, solid, semi-solid), a minimum payload consisting of no payload ensures thermal mass of the product will not unduly influence performance.

Data collection should be at a resolution sufficient to capture subtle changes to product payload. Ideally every 5 to 15 minutes.

NO MATHEMATICAL ROUNDING

Maintaining a specific temperature range of a product, particularly in transportation can be incredibly challenging given the complexity of supply chains, exposure to potential hazards, logistical unknowns and the distances packages travel within a distribution environment. Relying on the practice of whole number rounding as it relates to temperature is fraught with risk. Stretching the boundaries of 2-8 ° C for example, can literally mean to 1.5° C to 8.4° C. However, that additional 9/10ths of a degree translates into a 15% increase in overall temperature range – a range likely outside of a product’s stability profile. When a packaging will not or cannot meet the standard, some packaging providers take it upon themselves to change the standard by conveniently implementing whole number rounding. This falls far short of best practices.

MULTIPLE DATA POINT COLLECTION

Temperature stratification is common in all insulated shipping systems. Dynamics of conduction and convection cause temperature variability within the payload. Therefore, it is essential to place multiple probes in various locations throughout the container, not just in a single location.

MECHANICAL TESTS:

In addition to thermal reliability, protective performance of a packaged-product related to vibrations, shock, pressure, light and other stresses normally encountered during handling and transportation must be evaluated. Since no standards for reusable insulated containers with on-board electronic monitoring exists, it is recommended that each reusable container is subjected to multiple general simulations of actual transport hazards, i.e. drop and vibration sequences such as those outlined in ISTA 3A Packaged-products for parcel delivery system shipments 70 kg (150 lbs) or less. Additionally, between each series of 3A Transportation Tests, a 24 -hour Temperature Verification test should be performed on each package to ensure thermal integrity and repeatability and verification of electronic data monitoring, collection and radio transmission.

CONCLUSIONS

• Fragile cell therapies and regenerative medicine products call for an increased level of care typically not found in the transport of most other pharmaceuticals and biological drugs.
• The transport of cell therapies does not typically follow the transportation routes, lanes, modes and logistics paths of commercial drug products.
• Not all specialty-packaging containers are qualified. There is no single qualification process embraced by industry.
• Self-qualification of insulated packaging products presents a conflict of interest. Qualification should be performed by an independent, 3rd party testing facility with critical expertise.
• The advent of smart shippers with on-board electronic monitoring, data collection and a web-based user interface enables increased visibility, security, and protection from environmental hazards at the individual package level.
• No current standards exist for the qualification of smart shippers but rigorous testing to multiple standards can ensure that well designed smart shippers can meet or exceed global regulatory requirements.
• The increase of global regulations requiring a higher degree of accountability of other stakeholders in the supply chain has placed an additional burden on drug license holders ultimately responsible for the drug product.
• Smart shippers can help mitigate gaps in the supply chain and are considered best practice for their ability to maintain thermal integrity while providing visibility in the supply chain and protection from various environmental hazards associated with handling and transportation through the use of on-board sensor-based data collection.
• Inadequate and insufficient package qualification can lead to unexpected or unknown failures in the field related to hazards in transportation.
• Repeated mechanical tests of insulated packaging systems in conjunction with thermal verification tests are necessary for a reusable packaging system and are directly related to maintaining thermal integrity and performance over time.

PERFORMANCE OF THE EVO

SMART SHIPPER

The qualification process for the line of evo™ Smart Shippers involves extraordinary thermal and mechanical testing to ensure best-in-class performance for temperature stability, durability and cloud-based monitoring and reporting capabilities.

1. Federal Food, Drug and Cosmetic Act, Section 501 (a)(2)(B)
2. Guidelines for Temperature Control of Drug Products during Storage and Transportation (GUI-0069),Health Canada, April 28, 2011
3. Federal Food, Drug and Cosmetic Act, Section 501 (a)(2)(B)
4. European Commission EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use. Section 6 (October 1, 2015) in Annex 15: Qualification and Validation