Risk Mitigation for Single-Use Frozen Distribution

Strategic choices in packaging materials are at the core of reducing loss for a qualified cold chain solution

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The increasing use of biological, biosimilar, gene, and cell therapies greatly impacts the drug substance and bioproduction paradigms. The current trend of decentralizing manufacturing sites maintains the needed flexibility to service the global community, post- downstream cold chain transport links them.

Typically, product is packaged, frozen, stored then transferred within the facility or shipped to another site where it is thawed and dispensed for further processing or final use. Frozen distribution is a critical, yet nebulous, step in the process. After the product leaves the facility potential exposure to damaging external factors must be mitigated effectively.

To illustrate, during frozen cold chain handling, a manufacturer experiences 3–5% product loss from packaging damage. At the global level this translates to the industry absorbing an annual loss of almost $35B from many avoidable temperature-controlled logistics failures. Costs include not only product loss and replacement, but also wasted logistics, root cause analysis efforts, and clinical trial or treatment delays.

Cold chain logistics are poised to grow significantly driven by the growth of more complex and sensitive biotherapeutics and vaccines, such as those under development to address the Covid-19 pandemic. By 2022, 30 of the top 50 global biopharma products will require cold chain handling with increased logistics complexity.

In a recent Entegris webinar, Muhammad Siddiqui, applications engineer, discusses the importance of the cold chain process, the risks, and mitigation strategies associated with each step. He then shares a distribution study using Aramus™ single-use bag assemblies and stainless-steel secondary shells.

Mitigation approaches encompass defining environmental hazards, product fragility, and evaluating the product packaging system to qualify it for the distribution environment. The webinar focuses on frozen/ultralow shipping in passive containers with single-use shippers, the most commonly used method.

Within a distribution lane, an average shipment is handled 10 times en route, with vehicle vibrations varying depending on transport mode as well as road conditions. Temperature excursions, both the frequency and number of degrees, can contribute to product loss and batch-to-batch inconsistency. Monitoring these conditions and where deviations can occur provides a deeper understanding of the process and required controls.

Single-use bags for primary packaging are the first line of defense and provide inherent advantages: a closed system, scalability for batch size flexibility, storage density, and freezer compatibility. Bags protect, store, and facilitate valuable product identification. A secondary container augments protection.

The bag film needs to be compatible and robust at low temperatures, as well as meet sterility, extractables, and chemical inertness standards. Preferably material properties remain the same at filling and frozen temperatures. Aramus bag assemblies use a single layer fluoropolymer; a free-fall drop test demonstrates its temperature robustness compared to other film materials. Secondary container materials and paradigms vary, such as Entegris’ stainless steel shells, to provide additional low temperature protection.

Regulatory bodies do not provide detailed guidance for validated shipping protocols. The end user is responsible to qualify single-use product shipping and provide documented evidence that the product will ensure product quality with high confidence. Simulated laboratory standards are commonly used as is monitored, real-world shipping.

A distribution study comparing an Aramus bag in a corrugated shipper to the same bag with a stainless-steel shell in a corrugated shipper demonstrates the stainless-steel shell’s effectiveness in both real-world shipping and simulated tests. Both packaging methods used dry ice and engineers employed the most stringent simulated tests. All shipments maintained temperature below -60°C for a week. The study concludes that the bag and stainless-steel shell combination was more robust illustrating the value of an additional secondary package.

Entegris products address product fragility and mitigate risks in cold chain logistics. Compatible with standard freezing systems and a range of secondary transport containers. Aramus single-use assemblies and stainless-steel shells provide maximum flexibility for integration into new or existing frozen shipping infrastructure.

View the webinar