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Ensuring Safe Vaccine Drug Substance Storage and Shipping

Responding to the emerging challenge of rapid vaccine production and global distribution is at the forefront to ending the global COVID-19 pandemic.

With various vaccine candidates currently in clinical trials, manufacturers are scaling-up their single-use production facilities to address the need for supplying hundreds of millions of doses. Next steps around shipping and filling vials for distribution also requires careful planning, especially as vaccines are sensitive biological products.

Some vaccines are sensitive to freezing, some to heat and others to light.Vaccine potency, meaning its ability to adequately protect the vaccinated patient, can diminish when the vaccine is exposed to inappropriate temperatures. Once lost, vaccine potency cannot be regained. It is therefore paramount that vaccines are protected from temperature extremes.

So, how can vaccine drug substance, the active vaccine ingredient, be appropriately stored and shipped across the globe?

In single-use bioprocessing, a bulk vaccine drug substance is filled into single-use biocontainers and shipped to dedicated formulation and filling facilities, commonly contract manufacturing organizations (CMOs). Outsourcing fill-finish operations to CMOs offers flexible capacity to meet demand, ideally in the country of distribution and administration to patients.

Verification and validation of single-use products, including biocontainers and sterile connectors and disconnectors used to connect and disconnect biocontainers to formulation and filling operations, is key to maintaining sterility assurance. If temperatures down to -80^°C are required for shipping then single-use suppliers must demonstrate that their products meet these requirements without compromising integrity. Loss of product due to leachables or component failures related to biocontainers, tubing or connectors during handling and transit is costly and can reach several millions of dollars in lost product annually.

For added protection from shocks, vibrations and compressions that can occur during air, road or marine shipment, frozen single-use biocontainers and their associated sterile connectors should be carefully stored in specialized freezing shells designed to mitigate these risks.

Whilst freezing sounds simple, there are many challenges. Freezing is known to stress proteins potentially causing denaturation and changes in biological function which may render the drug substance ineffective or even harmful. Denaturation of proteins is complex and many parameters need to be considered during freezing and thawing. The driving forces such as cryoconcentration, the increasing concentration of dissolved buffer salts and proteins in the partially frozen solution and the protein’s interaction with ice, must be taken into account when deciding on the optimum freezing platform for controlling the freezing rate.

Once the frozen vaccine drug substance reaches the dedicated filling facility it must be carefully thawed to ensure stability of the active ingredient. Here suppliers must demonstrate that during thawing cycles the biocontainer remains integral and once thawed, the sterile connectors or disconnectors maintain the sterile path and continue to provide safe transfer of vaccine drug substance.To verify that the connector or disconnect or fluid ports remain free from bacterial ingress, during the component validation, the connectors and disconnectors are exposed to high concentrations of micro-organisms such as Brevundimonas diminuta. Sterility is confirmed by the lack of bacterial growth following the passage of broth through connected devices or in broth used to rinse the disconnected device. Mechanical tests, including pressure leak tests, are also undertaken to demonstrate that the devices continue to operate as designed following controlled freeze-thaw cycles.

Speed is of the essence in vaccine scale-up and distribution during a pandemic. Every step in the supply chain, from vaccine production and safe storage and shipping to patient administration, plays a pivotal role in protecting lives globally.