Supply chains now span the globe and are increasing in complexity as organizations move away from regional business models to manufacturing and distribution on a world scale. A critical byproduct of good manufacturing practice (GMP), an unbroken cold chain ensures product safety, efficacy and overall quality for patients. The need for regulations, industry standards and service providers that can support the cold chain process has grown as fast as the asset value of biologics and new drug delivery systems has increased. While it would be ideal to have one reference standard and best-practices approach, there is no magic bullet. It is important to understand what regulations and industry practice standards do exist in order to craft a practical, manageable approach to a secure and consistent cold chain.
Cold Chain Management
Cold Chain management and logistics is a specialized concentration within supply chain management that utilizes temperature controlled transportation and storage and distribution systems to ensure the product remains within its recommended conditions. A cold chain management program is meant to:
- Ensure the appropriate storage and handling conditions (temperature) are maintained throughout the cold chain.
- Document the storage conditions (temperature) throughout the cold chain.
- Maintain the product safety and integrity throughout the cold chain (temperature, counterfeiting).
- Establishing an effective cold chain strategy requires the thoughtful integration of cold chain requirements starting with product design and extending to environmental control during transit. Integrating Quality Risk Management (QRM) principles at strategic points within product development is the best way to anticipate downstream cold chain challenges.
- Best-in-class organizations undertake primary packaging studies as the first step in answering the larger product stability and environmental label claim requirements. Framing this activity as an integral part of the cold chain design activity rather than perceiving it as a strictly product development activity allows commercial considerations to be included in the product design discussion. This holistic view provides the greatest opportunity for defining any subsequent commercial cold chain alternatives, such as shipper design, active vs. passive container design decisions, and country-specific regulatory requirements.
Regulatory Considerations
The drug sponsor takes primary responsibility for ensuring that the product is fit for use. Specifically, manufacturers of cold chain products have direct control over the correct storage and handling of their products from the start of production through dispatch from their main supply warehouse until the products reach the first point of shipment. This point may be a local operating company, wholesaler, or a hospital. However, while accountable, the drug sponsor can only have an indirect influence on cold chain compliance. The drug sponsor may indicate how the products should be stored and handled based on evidence from preclinical studies and basic knowledge about therapeutic drug physico-chemical properties and requirements. An effective cold chain strategy must also recognize when responsibility lies with a support services component of the supply chain.
Product Stability
ICH
Understanding the impact of environmental variation on a product’s safety and efficacy is a prerequisite to establishing a cold-chain strategy. ICH Q1A (R2), which addresses stability testing of new drug substances and products, is a central industry best practice for building an effective stability program. This data will be used to understand the impact, considering the magnitude and duration of temperature excursions that could occur in the distribution process. Data derived from intermediate and accelerated environmental conditions can be used to determine the potential impact of short-term excursions that could occur in the shipping and distribution process.
Cold Chain Management Trends
1. Regulation is increasing
As the value of new drug therapies and their sensitivity to storage conditions has escalated, one might argue that drug manufacturers do not need any additional incentive to ensure environmental control. For years most countries require that pharmaceutical drug products remain within filed temperature limits. However, the guidance on Good Distribution Practices has extended this requirement to include transportation. While not required we anticipate a similar requirement and many organizations have already adopted temperature-controlled transportation as part of their current cold chain strategy. Biologics are not the only sector driving this practice even controlled room temperature labeled products require refrigerated transport vehicles to minimize the potential for temperatures excursions.
2. Active vs. Passive Shippers
As logistics become more complex the risk profile of new drug therapies has prompted a shift toward greater environmental control. Passive shippers have been the method of choice for many years. Passive shipping configurations are manufactured systems that are typically insulated with polystyrene, polyurethane, or vacuum insulated panels. Many have been pre-qualified to hold a particular temperature for a certain amount of payload capacity for a specified period of time. With these types of configurations, the shipper uses gel packs or similar materials to maintain the desired temperature. On the other hand, active shippers are powered by electricity and/or battery. Active shipping configurations are considered to be more secure than passive systems because units lock and are never opened during transport. As a result, this design helps reduce the risk of theft and may help maintain regulatory compliance. However, they have the disadvantage of requiring reverse logistics, meaning the containers must be returned to be reused adding cost and complexity to the logistical planning process.
3. Training Remains a Big Issue
With increasing regulation, the compliance component becomes even more critical. Training has always been a large part of cold chain management. To facilitate this organizations such as IATA provide a checklist for ground handlers and airlines to use to ensure the minimum verifications are conducted during the transport.
4. Increased Logistic Outsourcing
Cold chain performance is subject to the same pressures as normal supply chain process to push performance and drive down costs. Many pharma companies have turned to third party logistics (3PLs) firms that are incentivized to make the necessary investments in technology, infrastructure, and systems to drive continuous improvement and gain a competitive market edge. Specialized capabilities such as Automated Search and Retrieval Systems (ASRS) and x-ray verification of product are examples of tailored specialized capabilities that some 3PLs have adopted to meet the evolving demands of the cold supply chain.
Conclusion
As the value and criticality of life saving drug therapies escalate, regulatory requirements are moving toward closer control over every facet of the cold chain. Even with the disparity in formal requirements among different markets, drug manufacturers and 3PLs are gravitating to the most conservative requirements to drive standardization and ultimately efficiency. With the informal adoption of more stringent requirements, the ability for each piece of the cold supply chain to comply with industry best practices will be challenged. Training will continue to be an issue as ground crews, freight forwarders, and airlines navigate the confusion between absolute requirements and desired practice. Industry organizations such as IATA have attempted to drive standardized work through the use of checklists for freight forwarders and airlines to follow, however the reality is that the ability of these ground teams to stay on top of these responsibilities remains problematic. The success metrics of today’s cold chain are at best a moving target with formal and informal regulation complicating today’s global supply chain. Collaboration among external service providers could provide the foundation for future compliance risk reduction and potential business success.
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