Brian Keesee is Executive Director for North America Operations, PCI Clinical Services.

Brian Keesee

The emergence of personalized and patient-tailored medicines, such as immuno-oncology treatments, cell therapies, and gene therapies, has given rise to high hopes for a revolutionary new field of treatment for some of the most challenging diseases. Within the pharmaceutical and biotech market, considerable investment is being made in gene and cell therapy. These personalized medicines pose significant logistical and manufacturing challenges. With extreme temperature requirements, short logistical cycles, and effectively invaluable biological materials, careful consideration must be given to ensure success at each node of the cycle in the complex logistical path.

	Exciting business prospects for cell and gene therapies have generated considerable market investment in these areas (1). The number of companies with personalized medicine products in pipeline development has expanded considerably in the past decade. Reports suggest that more than 500 distinct companies are involved in the development of cell therapy, not including academic development, with more than 170 of those companies investigating stem-cell-focused therapies.

	The prospects for the industry are validated by the presence of two commercially approved therapies in the United States and Europe, and other promising therapies successfully being recognized recently with FDA Breakthrough Therapy status, established in 2012 to help accelerate the development and review of new drugs for serious or life-threatening conditions. Being granted Breakthrough Therapy can help a developer realize many potential benefits, including intensive FDA guidance and eligibility for priority review, a pathway to expedited approval. 

	Because many of the drugs in development are primarily being researched by small biotech companies with a reasonable number of cooperative funding agreements, the presence of more established pharmaceutical and biotech companies working in the area of cell and gene therapy has risen considerably in recent years. Furthermore, the valuation of deals has increased substantially. An IMS report (2) notes that, not only has the number of cell and gene therapy deals spiked since 2014, the average value of deals has jumped by a factor of over five fold in that short time.

	Currently, 83% of cell and gene therapies in investigational development are being brought forth by small biotech firms. However, recent investment and acquisition activity has large pharma presence, including leading firms such as Novartis, Amgen, Pfizer, BMS, Sanofi, GSK, Valeant, and others (2). Oncology is the focus of  more than three-quarters of all cell therapies now in the pipeline, and close to one quarter of gene therapies (2).

	The nature of cell and gene therapies, as with other tissue-based investigational materials, demands considerable collaboration by all parties involved, in logistical planning and execution to ensure a successful supply chain. Whether treatments are autologous or non-autologous, the cells or tissue materials obtained, processed, stored, and ultimately delivered to the patient are inherently limited and invaluable. Risk mitigation is a primary consideration when establishing an effective supply chain. This is exacerbated by the ultra-cold chain requirements and tight logistical windows that these therapies require.

	Understanding the key logistical considerations is paramount to success, and all stakeholders must be engaged early in the development process to ensure a robust project plan.  Communication at the onset of the program, as well as at each stage of development and execution, is critical to provide a seamless and well-functioning supply chain.

	Autologous treatments can create a different logistical pathway as compared to nonautologous treatments. A well-documented therapy currently on the market is said to have an 18-hour window from the extraction of cells from the patient to the direct delivery to the manufacturer.

	Likewise, the reverse logistics of the prepared therapy from manufacturer to the injection of the patient is also just 18 hours point-to-point. These logistics require highly specialized ultra-cold chain technologies and a sophisticated infrastructure for monitoring and risk mitigation at each stage of the journey. Treatment could involve several rounds of this complex cycle within a short timeframe, or, for some therapies, may only be a single application and opportunity for success.

	For investigational medicines, these types of considerations can be extended out to a broader set of logistical pathways. Third-party manufacturers for cell and gene therapies are limited in the market and highly specialized, with limited capacity. This predicament can make it difficult to predict time requirements, thereby demanding a flexible and responsive downstream supply chain for associated storage and distribution of these materials. 
	Studies may be executed by commercial pharmaceutical or biotech companies, independent research groups, or academic oriented institutions. These temperature-sensitive materials may be tissue derived or they may be blood-borne derivatives that are extracted from humans, or, alternatively, may be animal derived.

	Materials might be intended only for investigational study, or they could ultimately be intended for human treatment.  Substantially different than the requirements for a typical clinical study of traditional pharmaceutical or biotech medicine or device, the material movements and destination of biologically derived materials or therapies can have substantial regulatory impact on the CMO service provider, including specific FDA regulatory filings and communications to be filed with each receipt and shipment.

	Regulatory requirements demand a very granular level of information sharing between stakeholders, to the level where the recipient’s FDA Form 3356 filing must include where from the biological host the sample was derived (e.g., cartilage, cornea, bone, blood, ligament, etc.(3).

	Samples may have a very short and efficient logistical cycle, or, conversely, may be captured and stored for considerable lengths of time.  Transfer units utilize highly specialized precharged liquid nitrogen technologies and, by their nature, need to be meticulously prescheduled and prepared.  These transfer packages often have a closely monitored functional shelf life of 10 days, creating one more logistical consideration for all stakeholders to align around. The inherent value of these therapies has given rise to emerging integrated connectivity for supply chain technologies that can provide point-to-point monitoring and detailed supply chain visibility for additional assurance.

	The technologies utilized to transport these materials can vary but must align to both transfer vessels as well as storage infrastructure and capacity, ensuring the proper fit and application, as well as impact on cost. Sponsors may also factor in risk-mitigation strategies that could include sample storage at multiple geographic locations.

, 2016, researchandmarkets.com.
	2. IMS Health, 

Cell and Gene Therapies: Can Industry Bridge the Gap?

 Futurehealthinsights.com, February 2015.
	3. FDA, Form FDA 3356, 

Establishing Registration and Listing for Human Cell

, Tissues, and Cellular and Tissue-Based Products, FDA.gov.


	Vol. 41, No. 2
	Supplement
	February 2017
	Pages: s6-s7

	When referring to this article, please cite it as B. Keesee, " Careful, Early Cold-Chain Planning is Crucial for New Biologics," Supplement to 

Articles

Cold-chain requirements and the tight logistical windows needed for cell and gene therapies demand a focus on early communication and risk mitigation.