The American Association of Pharmaceutical Scientists (AAPS) conference is four days of meetings and presentations primarily focused on the needs of formulators and regulatory. A large section of the sizable exhibitor floor dedicated to displays presenting specific findings from members in their specialized areas. They detail the work done in creating novel formulations that enhance the effectiveness of a variety of drugs. I was overwhelmed by the exciting and informative presentations focused on new technology and processes!
What was missing? While there is an acknowledgement of the distributed nature of drug manufacture and filling to sites all over the globe, there is little to no recognition of the risks involved in distributing these products from the point of manufacturer to the point of use. Clinical trials with adaptive studies to strategies for commercialization presuppose that neither heat, nor shock, pressure, nor vibration will in any way be present to damage the structure or potency of these compounds.
From experience, the industry knows otherwise and so do regulators. Over 60 countries have published laws mandating the means and methods that comprise their expectations regarding the importation and distribution of temperature sensitive products into their respective countries.
Innovators need to create the necessary design space and to build product knowledge at the front end of the lifecycle. This design space should address the need for physical stability of the formulation to withstand the rigors of shipping and handling. Gaining this knowledge early in the lifecycle will accelerate the development at all critical stages of scale-up. These stages are prior to the product being produced in the quantities needed to supply Phase 3 clinical trials. Stability studies should assure that the product will retain its critical quality parameters from the point of manufacture to the point of use, wherever the location.
How to start? Just as the formulation and process design-of-experiment (DoE) are standard elements of the development lifecycle, an assessment of the risks during shipping and handling should be performed. Following the assessment, a distribution DoE should be employed to increase the confidence in the formulation selected. Key elements in the distribution DoE are exposure to the environmental hazards of temperature, pressure, shock, and vibration that are known to work in concert. These concurrent hazards create aggregates, sub-visible particles and denatured proteins.
Some companies use test shipments along the routes they intend to use for the distribution. These results may provide some insight to the expected damage, but they take time and are expensive to execute. Due to the inherent variability in distribution, there is a need for many such shipments in specific seasons to separate the normal variation from special cause events. And if damage occurs, it is difficult to determine the root cause.
A second option would be to expose the formulation to distribution hazards in a controlled fashion. This practice is new. It conserves the amount of product necessary for the study. Not only is the study repeatable, extremes can be selected by the formulator to reflect the intended severity of the distribution environment and can be incorporated into a stability program. The quality attributes from the point of manufacture to the point of use at the end of shelf life can be tested to provide assurance that the product would be retained.