Patient access to medicines is a key objective of the pharmaceutical industry with significant resources devoted to supply chain management and patient safety.
Most companies employ specific strategies to mitigate risk in their pharmaceutical supply chains inclusive of manufacturing, suppliers, sales, product design, as well as logistics activities including bulk packaging, transportation and distribution strategies. With the advances in the industry related to the development and maturation of biopharmaceuticals in areas such as CAR-T cell therapies that require strict temperature management to maintain dose efficacy. This dictates that legacy distribution strategies be re-evaluated and challenged. Serialized inventory tracking has a new meaning when tracking an autologous therapies engineered from a patient’s own cells. These “regenerative therapies” that are patient specific have added a new paradigm to drug distribution – not only in tracking but in time sensitivity. Essential areas of focus are packaging and distribution to maintain the both the serialized tracking and the thermal environment ensuring product integrity and patient safety.
If one were to review the current packaging configurations supporting supply chains for regenerative therapies, there are two critical challenges: 1. Collection and transportation of apheresis blood product from clinic to manufacturing location, and 2. Distribution of drug product (typically T-cells) from manufacturing center to administration site. Apheresis blood product must be moved rapidly (typically within 48 hours) from collection site to manufacturing site; any delays adversely impacts the quality of the product obtained. Currently, the standard practice is to move the cells to the manufacturing facility at 2-8°C in passive packaging systems that maintain temperature using phase change materials. Drug product that leaves the manufacturing site to be moved to the site of administration is most often frozen at either -80°C (dry ice) or at -196°C (cryogenically frozen). Most current 2-8°C and dry ice options don’t provide adequate control when subjected to any significant disruption event such as weather, or a transportation event such as an airport strike. Current distribution strategies of both the collection and distribution of these therapies are insufficient and will lead to an unacceptable failure rate.
Regulatory bodies are starting to take notice and establish specific criteria related to the storage and distribution of these types of therapies. The International Organization for Standardization (“ISO”) is currently reviewing guidelines for their storage and distribution. ISO /TC 212 and ISO/TC 276 will be the standards by which all regulations are likely to be established. ISO 212 specifically outlines the testing requirements that must be met and maintained when evaluating the quality and potency of these therapies. ISO 276 will define the standards for storage and distribution of these therapies including storage and packaging validation, comparability, and metrology. It is anticipated that part of these standards will dictate the limits of environmental excursions acceptable during distribution of these therapies and the level of detail required for the packaging qualification and validation. We believe that it will be standard practice to be able to correlate historical performance of a particular piece of packaging equipment to any given shipment.
Due to the sensitivity of regenerative therapies, any future logistics and packaging solution must have the ability to support a number of key criteria:
1. Manage temperature within a very narrow range (typically 2-4 degrees)
with zero tolerance for excursions
2. Have the ability to control temperature for an extended period of time (7-
3. Be able to be actively monitored with real time, GPS enabled data logging
linked to a smart IT system that can evaluate the impact of an external
event to the risk of sample failure
4. Consolidate all data (transportation carrier scans, temperature, location,
event, equipment qualification and validation) in a single data stream that
can correlate external events with commodity impact
5. Have the ability to resist transit related impacts (weather, equipment,
volume based risks) either through immunity to events via superior
insulative properties or the ability to be actively managed without opening
Current phase change and dry ice solutions do not support the criteria listed above. Phase change materials can be adversely impacted by the external environment unfavorably shortening holding time and are highly susceptible to delays. Any intervention would require opening the package and potentially impacting the commodity being shipped. Dry ice options usually only have a three day window for temperature hold time, have a tendency for volatile temperature control issues that are highly dependent on packaging, can subject the commodity to temperature fluctuation of up to 60 degrees C, can impact the commodity shipped by changing the pH, and require specialized handling and transport due to the fact that it is designated a hazardous substance.
The Future of Temperature Managed Delivery
The future of temperature managed delivery of critical, irreplaceable samples will be dominated by two primary packaging options. Any critical shipments that fall in the range of -20°C to 40°C will be packaged in active, reusable systems that have very exacting temperature control ability and can be plugged in when subjected to significant transportation delays eliminating any potential commodity exposure to external temperatures and handling. Any critical shipments that require frozen conditions -80°C to -196°C will be transported in cryogenic dry vapor liquid nitrogen dewars which have superior holding times of up to 14 days, and are largely immune to external temperature changes. Both of these transportation options provide superior risk mitigation competencies. The packaging alone however won’t be sufficient in meeting the regulatory requirements (ISO 212 & 276) necessary for supporting distribution of these types of therapies.
Since both of these types of packaging are reusable, significant care must be used to ensure that the qualification and validation procedures, cleaning protocols, data management, and historical performance details are captured and adequately managed. IT and data management systems must be in place to support the management and interpretation of the data supporting these packaging configurations. These systems must be able to correlate an external transportation related event (delay, damage, shock, temperature change, etc…) to the condition of the commodity being shipped. In addition, smart IT systems need to be able to dynamically calculate the impact of the external event on the “holding time” of the system being used to control the commodity environment and automatically and proactively identify a solution that mitigates any risk of a temperature excursion on the sample.
Author – Mark W. Sawicki, Ph.D., Chief Commercial Officer, Cryoport
Mark Sawicki brings 15 years of business development and sales management experience, having consistently delivered on corporate revenue and market share goals in the pharmaceutical and biotechnology industries. Sawicki was most recently the chief business officer at AAIPharma Services Corporation/Cambridge Major Laboratories Inc. Additionally, he has served in senior business development roles at CMC Biologics and Albany Molecular Research Inc. (AMRI), where he increased revenue at rates far outpacing industry standards. Sawicki holds a bachelor’s in biochemistry from the State University of New York at Buffalo and a Ph.D. 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. Sawicki has authored a dozen scientific publications in drug discovery with a focus on oncology and immunology.