Mark Sawicki, Cryoport09.06.17
The cold chain pharmaceutical market, currently estimated to be in excess of $13.4 billion in 2017, continues to be one garnering specific interest within the logistics space. New therapies such as regenerative therapies and gene therapies as well as a shift toward temperature-managed shipments are currently of significant focus. This is due to the fact that many of the most innovative therapeutics, like regenerative medicines and other advanced cell-based therapies, are close to commercial launch and need to be shipped under very exacting temperature conditions. This shift is contributing to the growth of temperature-controlled products at more than twice the rate of non-temperature-controlled products. Evidence of market interest in the space is evidenced by recent investments, acquisitions such as UPS acquiring Marken and QuickStat’s acquisition of Unitrans, as well as business expansion, including Almac launching their TempEZ service, and Cryoport’s C3, 2-8°C service.
Additionally, The Drug Supply Chain Security Act (DSCSA), along with FDA 21 CFR GMP and GDP requirements, have turned a spotlight on the value of these intelligent temperature-controlled materials requiring better transportation solutions than what has been in the market in recent years. Many companies have turned their focus on three primary areas to respond to these requirements; namely enhanced, reusable packaging, real-time data monitoring, as well as advanced informatics systems to support in transit logistics considerations. Each of these focus areas require their own specific know how as well as state-of-the-art advancements to support the enhanced scrutiny. We will discuss each of them independently.
Packaging
There has been considerable focus on the development of packaging equipment with improved properties over conventional insulated packages. Significant efforts have been made on improved vacuum insulated panels, on-demand systems that do not require pre-conditioning, as well as flexible, actively temperature managed solutions that are now emerging, each with their own strengths and weaknesses, as well as a shift away from outdated solutions such as dry ice toward cryogenic distribution. The common feature with many of these newly emerging technologies is the fact that these shipping systems are reusable and require well developed reverse logistics as well as cleaning procedures to ensure that there is no outside or cross-contamination which poses its own challenges.
Development of consistent, effective decontamination processes poses its own unique challenges. Each type of equipment has its own unique materials, which may be impacted negatively by different solvents commonly utilized in laboratory or clean room disinfection. Alternative, non-contact means of decontamination would be advantageous and could have utility across a wide range of packaging materials. One of these new technologies being developed within the transportation space is xenon-pulsed ultraviolet light disinfection. Pulsed xenon-based ultraviolet light no-touch disinfection systems are being increasingly used for hospital room disinfection after patient discharge. These systems have been shown in multiple studies to effectively reduce aerobic bacteria in the absence of manual disinfection1. In some of the studies, PX-UV exposure resulted in a 5-log CFU reduction for multidrug-resistant organisms (MDROs) on spiked plates. Cryoport is actively developing a xenon-pulsed ultraviolet light disinfection system for its cryogenic and C3 shippers, providing enhanced disinfection as well as the ability to disinfect at cryogenic temperatures, reducing processing time and increasing the number of turns a piece of equipment can be used within a set period. These methods are being developed to reduce cost of goods as well as improve overall equipment performance.
Data monitoring
As mentioned earlier, in 2018, one out of every two pharmaceutical products will be thermo sensitive and will require to be temperature monitored from point of manufacturing to ‘last mile’ delivery. The DSCSA is also pushing companies to adopt newer technologies for chain of condition and chain of custody adherence. Next generation data loggers are now readily present and can track an entire range of specifications in near real time such as location, temperature (inside and out), shock, orientation, anti-tamper, humidity, and pressure.
Most of these devices use lithium metal or lithium ion cells or batteries as a power source. Lithium cells and batteries are classified as dangerous goods and therefore must meet all of the applicable provisions of the Dangerous Goods Regulations (DGR) when shipped by air. This applies regardless of whether the lithium cells or batteries are shipped as cargo in their own right or whether the lithium cells or batteries are installed in a small device such as a data logger that is placed inside or attached to packages of cargo. In addition, to be permitted in transport all lithium cell and battery types must have passed the applicable tests set out in Subsection 38.3 of the UN Manual of Tests and Criteria.
Packages containing lithium batteries installed in equipment such as a data logger may or may not require the lithium battery mark as shown in Figure 7.1.C of the IATA DGR (see Figure 1). The lithium battery mark is not required on packages where there are no more than 4 cells or 2 batteries contained in equipment in each package and there are no more than two packages in the consignment. These limitations may restrict the lifecycle management and lifespan of next generation data loggers in the near future and must be monitored carefully by the industry.
Informatics
It has become clear that effective cold chain logistics management is vitally important to preserving the efficacy of valuable cold chain dependent medicines and for risk mitigation. Unfortunately, most companies do not integrate logistics planning early enough in their clinical trial design, it is often an afterthought once the product is nearing commercialization. Adding complexity, such as adding more links to a supply chain as seen in regenerative therapy programs (see Figure 2), increases the steps and/or temperatures that must be controlled and increases risk of a temperature excursion.
Next generation informatics systems must have the ability to not only collect location and handling information from in field scan codes and airline data, it needs to effectively manage the validation and qualification data for the packaging, as well as verify and control the performance, calibration, and reconditioning status of the packaging, collect and correlate real time data collected from data loggers in the field as well as assess performance and cost of selected logistics partners. In addition, the informatics systems that are required to manage an ever-increasing complex supply chain must have the ability to not only actively monitor the logistics conditions and considerations around any given product distribution, it must also be able to interpret the data coming in from the next generation data loggers in real time, assess risk intelligently, and support defined SOP’s related to escalation procedures if an exception requiring intervention is observed.
Conclusion
As an ever-increasing number of cold-chain dependent therapies move from the bench into clinical trials and finally to approval, and regulatory requirements for packaging, and chain of custody increase, the specialized packaging, tracking, and data capture requirements for these highly valuable and temperature-sensitive biological materials will need to keep pace. Advanced technologies for cold chain management to ensure their safety and efficacy when they reach the patient will become of paramount importance. Next generation packaging technologies, advanced package tracking, intelligent informatics systems and knowledge of international regulations can provide tools that companies and logistics managers need to reduce the risk of failure due to cold chain logistics issues.
References
Deverick J. Anderson, Maria F. Gergen, MT, Emily Smathers, Daniel J. Sexton, Luke F. Chen, David J. Weber, William A. Rutala, (2013) Decontamination of Targeted Pathogens from Patient Rooms Using an Automated Ultraviolet-C-Emitting Device; Infection Control and Hospital Epidemiology, 34, 466-471.
Mark W. Sawicki, PhD, is chief commercial officer at Cryoport. With more than 15 years of business development and sales management experience in senior leadership roles, he has a proven record of consistently delivering on corporate revenue and market share goals in the pharmaceutical and biotechnology industries. Dr. Sawicki holds a doctorate in biochemistry from the State University of New York at Buffalo, School of Medicine and Biomedical Sciences. He also received graduate training at the Hauptman Woodard Medical Research Institute and has authored numerous scientific publications in drug discovery with a focus on oncology and immunology. He can be reached via email at msawicki@cryoport.com.
Additionally, The Drug Supply Chain Security Act (DSCSA), along with FDA 21 CFR GMP and GDP requirements, have turned a spotlight on the value of these intelligent temperature-controlled materials requiring better transportation solutions than what has been in the market in recent years. Many companies have turned their focus on three primary areas to respond to these requirements; namely enhanced, reusable packaging, real-time data monitoring, as well as advanced informatics systems to support in transit logistics considerations. Each of these focus areas require their own specific know how as well as state-of-the-art advancements to support the enhanced scrutiny. We will discuss each of them independently.
Packaging
There has been considerable focus on the development of packaging equipment with improved properties over conventional insulated packages. Significant efforts have been made on improved vacuum insulated panels, on-demand systems that do not require pre-conditioning, as well as flexible, actively temperature managed solutions that are now emerging, each with their own strengths and weaknesses, as well as a shift away from outdated solutions such as dry ice toward cryogenic distribution. The common feature with many of these newly emerging technologies is the fact that these shipping systems are reusable and require well developed reverse logistics as well as cleaning procedures to ensure that there is no outside or cross-contamination which poses its own challenges.
Development of consistent, effective decontamination processes poses its own unique challenges. Each type of equipment has its own unique materials, which may be impacted negatively by different solvents commonly utilized in laboratory or clean room disinfection. Alternative, non-contact means of decontamination would be advantageous and could have utility across a wide range of packaging materials. One of these new technologies being developed within the transportation space is xenon-pulsed ultraviolet light disinfection. Pulsed xenon-based ultraviolet light no-touch disinfection systems are being increasingly used for hospital room disinfection after patient discharge. These systems have been shown in multiple studies to effectively reduce aerobic bacteria in the absence of manual disinfection1. In some of the studies, PX-UV exposure resulted in a 5-log CFU reduction for multidrug-resistant organisms (MDROs) on spiked plates. Cryoport is actively developing a xenon-pulsed ultraviolet light disinfection system for its cryogenic and C3 shippers, providing enhanced disinfection as well as the ability to disinfect at cryogenic temperatures, reducing processing time and increasing the number of turns a piece of equipment can be used within a set period. These methods are being developed to reduce cost of goods as well as improve overall equipment performance.
Data monitoring
As mentioned earlier, in 2018, one out of every two pharmaceutical products will be thermo sensitive and will require to be temperature monitored from point of manufacturing to ‘last mile’ delivery. The DSCSA is also pushing companies to adopt newer technologies for chain of condition and chain of custody adherence. Next generation data loggers are now readily present and can track an entire range of specifications in near real time such as location, temperature (inside and out), shock, orientation, anti-tamper, humidity, and pressure.
Most of these devices use lithium metal or lithium ion cells or batteries as a power source. Lithium cells and batteries are classified as dangerous goods and therefore must meet all of the applicable provisions of the Dangerous Goods Regulations (DGR) when shipped by air. This applies regardless of whether the lithium cells or batteries are shipped as cargo in their own right or whether the lithium cells or batteries are installed in a small device such as a data logger that is placed inside or attached to packages of cargo. In addition, to be permitted in transport all lithium cell and battery types must have passed the applicable tests set out in Subsection 38.3 of the UN Manual of Tests and Criteria.
Packages containing lithium batteries installed in equipment such as a data logger may or may not require the lithium battery mark as shown in Figure 7.1.C of the IATA DGR (see Figure 1). The lithium battery mark is not required on packages where there are no more than 4 cells or 2 batteries contained in equipment in each package and there are no more than two packages in the consignment. These limitations may restrict the lifecycle management and lifespan of next generation data loggers in the near future and must be monitored carefully by the industry.
Informatics
It has become clear that effective cold chain logistics management is vitally important to preserving the efficacy of valuable cold chain dependent medicines and for risk mitigation. Unfortunately, most companies do not integrate logistics planning early enough in their clinical trial design, it is often an afterthought once the product is nearing commercialization. Adding complexity, such as adding more links to a supply chain as seen in regenerative therapy programs (see Figure 2), increases the steps and/or temperatures that must be controlled and increases risk of a temperature excursion.
Next generation informatics systems must have the ability to not only collect location and handling information from in field scan codes and airline data, it needs to effectively manage the validation and qualification data for the packaging, as well as verify and control the performance, calibration, and reconditioning status of the packaging, collect and correlate real time data collected from data loggers in the field as well as assess performance and cost of selected logistics partners. In addition, the informatics systems that are required to manage an ever-increasing complex supply chain must have the ability to not only actively monitor the logistics conditions and considerations around any given product distribution, it must also be able to interpret the data coming in from the next generation data loggers in real time, assess risk intelligently, and support defined SOP’s related to escalation procedures if an exception requiring intervention is observed.
Conclusion
As an ever-increasing number of cold-chain dependent therapies move from the bench into clinical trials and finally to approval, and regulatory requirements for packaging, and chain of custody increase, the specialized packaging, tracking, and data capture requirements for these highly valuable and temperature-sensitive biological materials will need to keep pace. Advanced technologies for cold chain management to ensure their safety and efficacy when they reach the patient will become of paramount importance. Next generation packaging technologies, advanced package tracking, intelligent informatics systems and knowledge of international regulations can provide tools that companies and logistics managers need to reduce the risk of failure due to cold chain logistics issues.
References
Deverick J. Anderson, Maria F. Gergen, MT, Emily Smathers, Daniel J. Sexton, Luke F. Chen, David J. Weber, William A. Rutala, (2013) Decontamination of Targeted Pathogens from Patient Rooms Using an Automated Ultraviolet-C-Emitting Device; Infection Control and Hospital Epidemiology, 34, 466-471.
Mark W. Sawicki, PhD, is chief commercial officer at Cryoport. With more than 15 years of business development and sales management experience in senior leadership roles, he has a proven record of consistently delivering on corporate revenue and market share goals in the pharmaceutical and biotechnology industries. Dr. Sawicki holds a doctorate in biochemistry from the State University of New York at Buffalo, School of Medicine and Biomedical Sciences. He also received graduate training at the Hauptman Woodard Medical Research Institute and has authored numerous scientific publications in drug discovery with a focus on oncology and immunology. He can be reached via email at msawicki@cryoport.com.
