Biosimilars Need A New Transport Validation Approach
The development of environmentally-sensitive biosimilars by the pharmaceutical industry will require a new approach to characterization when conducting transport validation in controlled-environment logistics networks.
Manufacturers are obligated to include distribution as part of their overall quality system and should be continuously monitoring and updating their approach to adhere to industry best practices.
Maintaining a GDP quality system for transportation, third-party distribution and product protection is a difficult challenge that is only increased by the shortened development cycle of biosimilars. Coupled with the increased focus on large molecule biosimilars that are exponentially more environmentally sensitive, the concerns during transportation are heightened because of significant and cumulative hazards to product quality: temperature control needs coupled with shock, vibration, pressure and humidity.
Quality concerns during transport
Biosimilars are potentially more vulnerable during transport. But do they receive greater scrutiny?
Our experience with clients is that they have answered this question with a resounding “Yes!” This greater scrutiny is directly related to the shortened approval path.
Since the US FDA proposed a “stepwise” approach to demonstrating biosimilarity, the data submitted in the Biologics License Applications (BLA) for transport validation and the questions raised during pre-approval inspections have increased. Specifically, the approach to stability studies for distribution have been challenged.
Additional hazards other than temperature control must be explored and a comparison of pre-transport or ‘reference’ standard to a stressed drug product after transport are increasingly more common. All of our agency interactions on behalf of clients have required this approach.
As noted by the FDA: The foundation for an assessment of biosimilarity between a proposed biosimilar product and its biologic involves the robust characterization of the proposed biosimilar product, including comparative physicochemical and functional studies. The information gained from these studies is critical to the overall product assessment that as a scientific matter is necessary for the development of a proposed biosimilar product.
The ability to discern relevant differences between the proposed product and its biologic / reference product will depend on the available analytical technology and complexity of the product. Any information regarding differences between the proposed product and the reference product should be considered to determine whether the statutory standard for biosimilarity can be met.
This guidance, along with the preceding concern of environmental hazards in addition to temperature, clearly show a new approach is required.
The robustness of drug product formulation
The FDA has determined the scope of clinical studies will depend upon the uncertainty level about the biosimilarity after structure and functional characterization.
Early testing of your commercial drug product formulation to better understand the interaction of the drug product and its primary container is an excellent way to better understand both the robustness of – and challenges to – your drug product formulation.
Regulators are increasingly aware of the public health implications of particle formation. Our interactions with the agencies have focused specifically on this issue with biosimilars and expect a manufacturer to address transport hazards other than temperature control needs in their stability studies and have confirmation of the absence of particle formation. Additional clinical studies may be required to demonstrate safety and effectiveness depending upon what residual uncertainties remain about biosimilarity.
These uncertainties must be addressed up front to avoid a potential delay in approval for your biosimilar.
In recent guidance, the FDA recommends “an appropriate physicochemical and functional comparison of the stability of the proposed biosimilar.” They further suggest that accelerated and stress stability studies, or forced degradation studies, should be used to establish degradation profiles and provide direct comparison of the proposed biosimilar product with the reference product. These comparative studies should be conducted under multiple stress conditions (e.g. high temperature, freeze thaw, light exposure, and agitation) that can cause incremental product degradation over a defined time period.
A concerning knowledge gap
Accelerated registration (or static) stability studies are inadequate for the transport process especially when dealing with biosimilars.
The standard stability studies are normally terminated without returning samples of the exposed product to normal storage conditions and without conducting assay testing to the end of shelf life to confirm product quality.
A gap in understanding could exist on biosimilarity and formulation behavior after exposure to significant and cumulative hazards during transport. This gap should be a cause for concern.
Stability study requirements
Best-demonstrated practice for the proposed stability study requirements is an operational qualification of the drug product. These studies should ideally 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 examined to the end of shelf life for biosimilars.
Paths to degradation of biosimilars 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, along with 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.
How do these challenges impact the validation of your cold chain for biosimilars?
Agency feedback is great clue. The expectation to include data from studies for the worst-case anticipated shipping route in terms of duration for both temperature and other hazards are clear. The need to include an assessment of product quality pre- and post-shipment for all shipping configurations intended for use has also been requested.
The assessment of product quality following real-time shipment and/or data from studies that simulate the worst-case conditions that the product would encounter based on the shipping route and method(s) of transport: shaking, vibration, shock and pressure included with possible temperature excursions has been a recommended approach by the FDA during interactions with our clients.
More importantly, the feedback when these are not properly addressed is increasingly blunt: concerns of an incomplete shipping qualification study for drug product centered around whether product quality and CCI can be properly maintained during shipping with drug product operational qualification.
These concerns are not only focused on the biosimilar and its interaction with primary container, but also include the delivery system. If manufacturers must address the essential performance of the delivery system (e.g. syringe) after transport, they are expected to provide data on the essential performance of the syringe after shipping (e.g. dose accuracy, break loose, liquid leakage, etc.).
Biosimilars do require a new approach.
1. Clearly define all your risks up front: understand environmental hazard challenges other than temperature and how they could affect biosimilarity after interactions with the primary container
2. Understand interactions between multiple hazards and how they impact drug product quality
- Temperature and shock/vibration to particulate formation
- Shock/vibration and pressure to CCI and sterility
3. Consider using simulation studies to conduct drug product operational qualification
- Controlled versus uncontrolled environment
- Full range of testing hazards in your ‘design space’
4. Write it all down in a validation master plan focused on your cold chain processes
- Execute a risk assessment and prepare a mitigation plan for your biosimilar cold chain
- Clearly identify hazards other than temperature
- Justify your approach for operational qualification and performance qualification
Continuous challenges attached to biosimilars
The concerns of biosimilar formulation, biosimilarity and eventual degradation during transport are significant; especially with the cumulative the effects of environmental hazards unique to the transport environment.
These effects are hard to predict and have offered continuous challenges for the traditional drug formulation processes, let alone for the accelerated path for approval of biosimilars.
Understanding the environmental hazards and conducting drug product operation qualification for your biosimilar specifically for the hazards encountered during distribution are the best way to alleviate product quality concerns during transport.