Save Time and Money in Your Cold Chain via Dynamic Stability Testing

Stability testing outlined in the ICH guidelines primarily addresses the establishment of expiry dating and storage conditions. Temperature-sensitive product may exceed long-term storage conditions established by the manufacturer at any time during manufacturing, distribution, and customer handling steps (e.g. bulk transport, filling and packaging operations, final product distribution operations, end user administration) intentionally (i.e. exposure) or not (i.e. excursion). The allowable time and temperature exposure to ranges outside of the long-term storage conditions for manufacturing is currently justified by using accelerated stability data gathered during static stability studies conducted under ICH guidelines.

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However, these accelerated registration (or static) stability studies may be inadequate for the transport process especially when dealing with protein formulations in solution. The accelerated studies are normally terminated without returning samples of the exposed product to normal storage conditions and conduct assay testing to the end of shelf life to confirm product. The cumulative effects of other environmental hazards on product outside long-term storage recommendations are essentially unknown with standard static stability studies as currently recommended under ICH guidelines.

Product stability for distribution is a relatively new concept for biopharmaceuticals. Driven by increasing complex regulations, the more typical registration or ‘static’ stability studies used to set expiry date are being augmented with ‘dynamic’ stability studies for distribution. These distribution stability studies typically stress the drug product formulation is either an extreme ‘real world’ shipment of is a controlled laboratory setting.

The same stability indicating assays used to set expiry date are executed on these ‘stressed’ samples. At each time points, the degradation, if any, is compared to the registration stability study. If the degradation pathway is comparable, these studies can show that temperature exposures outside of labeled storage conditions do not have an impact on product quality. These types of studies are powerful in an integrated approach which allows the operating range of the temperature-controlled network to be significantly broadened – reducing costs, increasing service levels, and diminishing non-conformances.

Without dynamic stability testing for distribution, the manufacturer is left with a difficult choice: either significantly slow down the flow of final drug product to allow critical information to be made available for proper product disposition of potentially compromised drug product or scrap the potentially compromised drug product and reship. Either choice will add significant costs in the logistics network and potentially ration or ‘short’ the supply to patients. Continuous review of potentially compromised drug product during transport could lead toFDA review, review of the manufacturing process, or looking for tighter and tighter logistics controls: all these options are very time consuming and costly.

How should dynamic stability studies be conducted to provide us with the answers to these concerns?

These studies need to be designed and conducted based on expected shipment durations, possible product temperature exposure ranges outside labeled storage conditions, and coupled with other hazards during transport and distribution. The cumulative effects of these hazards on product quality, potency, and efficacy must be determined to the end of shelf life. Most importantly, dynamic stability studies for distribution should show the drug product is not impacted by the following environmental hazards in the controlled-environment logistics network:

· Temperature

· Shock

· Vibration

· Pressure

· Humidity

Paths to degradation of product should be established through dynamic stability testing by defining variables clearly and establishing ranges of acceptable variances to support temperature excursions experienced during transport concurrently with the other environmental hazards listed above. Once these degradation paths are understood, the required shipping conditions, appropriate handling techniques, specialized packaging should be defined and communicated to all parties in the controlled-logistics network, and any required maintenance and monitoring of such procedures. Appropriate means of control (e.g. procedural, visual, marking and labeling, etc.) and monitoring (e.g. data loggers, threshold indicators, time/temperature indicators, etc.) should be implemented once the potential hazards are understood.

The concerns during transport are many: the risk of compromised or diverted product in a global contracted third-party network allow little direct control, the variables in equipment, facilities, and controls in a global controlled-environment logistics network make consistent handling difficult, and the effects of product temperatures outside of long-term storage recommendations combined with environmental hazards unique to the transport environment. These effects are hard to predict and have offered continuous challenges for the traditional drug formulation processes. Understanding the environmental hazards especially to protein formulations that are relatively new but increasingly wide spread, and conducting product testing specifically for the hazards encountered during distribution are the best way to alleviate product quality concerns during transport.