In this interview, Brian Hawkins (Chief Technology Officer at Pluristyx™, WA, USA) discusses how protocols surrounding advanced therapy medicinal product (ATMP) cryopreservation have changed over recent years. In addition to this, we hear more about what lessons have been learned from COVID vaccine distribution that can be translated to the ATMP cryopreservation process, including the most difficult aspects of establishing a strong cryopreservation protocol.
This interview is part of the RegMedNet In Focus on cell cryopreservation and cold chain. Discover expert opinions on cold chain process control in advanced therapies now.
Please can you introduce yourself and tell us more about your role?
My name is Brian Hawkins and I am the Chief Technology Officer at Pluristyx, an advanced therapy tools and services company based in Seattle, Washington. Pluristyx provides seamless client support by offering cell therapy CMC consulting, contract development services and research- and clinical-grade Ready-To-Differentiate™ (RTD™) pluripotent stem cells and Ready-to-Use™ (RTU™) differentiated cells at a commercial scale. A core strength of Pluristyx contract development is the ability to provide CMC consulting and wet-lab services to develop a scalable cryopreservation fill/finish process that can be transferred to either an internal or outsourced manufacturing facility.
My role is to head up Pluristyx’s research and development activities, and to manage our cryopreservation development suite to assist clients with their fill–finish challenges. As part of this role, I engage in cryopreservation outreach in numerous professional organizations, provide cryopreservation education services to both academic and industrial groups, and lead the Parenteral Drug Association’s Cryopreservation Standard Initiative to develop an American National Standards Institute (ANSI) Standard reference document.
How have protocols surrounding ATMP cryopreservation changed over recent years?
Typical ATMP cryopreservation protocols are largely based on historical precedence, meaning that they closely mirror processes developed by their scientific founders, which sometimes might have been for decades. This works fine for product development and early-stage trials, which are closely aligned with the original research lab or are within physical proximity. Unfortunately, historical precedence in many cases does not readily adapt to the scale-up, tech transfer and late-stage clinical trials that occur during commercialization. When historical protocols break down during later stages of development, cryopreservation becomes a critical path that may be hurriedly modified ‘just-in-time’ to address critical process parameters. To overcome ‘just-in-time’ quick fixes, companies are beginning to consider optimizing cryopreservation protocols earlier in the development lifecycle. One of the most common changes that occurs during cryopreservation optimization involves the implementation of a risk-based approach to product freezing, storage and shipping. A typical example of such an approach is the transition from in-house media formulations toward chemically defined cryopreservation media, which reduces product variability and simplifies the manufacturing workflow.
What are the main challenges associated with ATMP cryopreservation from development through to commercialization?
The numerous challenges of ATMP cryopreservation have been outlined individually in textbooks and published work. Industry has stepped up to deliver solutions to these challenges, and tools providers are currently consolidating into portfolio offerings to aid ATMP developers in establishing their manufacturing workflow. The main challenge with this approach is that an end-to-end solution for large-scale ATMP production does not currently exist. As such, ATMP developers must navigate the varied portfolios to select manufacturing solutions from multiple sources and then struggle to incorporate these individual parts into a whole. Development support to aide ATMP producers is currently lacking and building internal capabilities is often difficult, expensive and time-consuming.
In your opinion, how might these challenges be addressed?
I lead a PDA team to develop a Parenteral Drug Association standard document designed to consolidate current best practices and provide guidance on how to build complete ATMP cryopreservation solutions. We envision this guidance document will become a key resource for ATMP developers who are looking to optimize their cryopreservation workflow. Organizations such as United States Pharmacopeia (USP), the International Society for Cell and Gene Therapy (ISCT) and the International Society for Biological and Environmental Repositories (ISBER) also provide guidance documents on ATMP cryopreservation. Developers can also reach out to consulting services (especially those with knowledge in ATMP chemistry, manufacturing and controls), cryopreservation tools providers and specialized contract development organizations for assistance on how to optimize cryopreservation for their specific cell-based product.
What lessons have been learned from COVID vaccine distribution that can be translated to the ATMP cryopreservation processes?
The speed at which COVID vaccines were developed was unprecedented in modern medicine and led to multiple approved vaccines with diverse mechanisms of action. In some cases, these vaccines require specialized storage and transportation solutions. Vaccines that are based on mRNA technology must be stored and transported at temperatures colder than needed for traditional vaccines such as the seasonal flu. Unfortunately, the ultra-low temperature requirements for some COVID vaccines have strained the existing healthcare infrastructure and have revealed potential limits to widespread global distribution. ATMPs require storage and transport EVEN COLDER than that of COVID vaccines and thus, pose an even greater challenge to their commercialization and widespread adoption. ATMP cryopreservation is further tested by the need to implement appropriate temperature controls both to and from the manufacturing facility. To foster the adoption of ATMPs in the clinic, providers must expand on what was learned with the COVID vaccine rollout to develop flexible temperature options for ATMPs along with new technologies to maintain storage and transport at temperatures colder than the surface of Antarctica.
What are the most difficult aspects of establishing a strong cryopreservation protocol?
Development of an optimized ATMP cryopreservation protocol is challenging for even seasoned cryobiologists and cell therapy professionals. Each cell type and process requires specialized support during the freezing, storage and thawing process that must be established and empirically backed for eventual regulatory filling. While there are growing numbers of cryopreservation tools providers that can offer solutions for cell manufacturing, adapting these off-the-shelf options to their specific workflow is challenging. Alternatively, building the internal capabilities to address this challenge is time-consuming and costly, and there are relatively few options available to optimize cryopreservation early in the development lifecycle. However, failure to identify a trusted cryopreservation development partner or build out internal expertise early in product development can result in significant delay or a difficulty in scaling a manufacturing process for commercialization.
In what ways do you see cryopreservation protocols evolving over the next 5–10 years?
Increased movement of ATMPs into the clinic ensures that there will be continued consolidation in the cryopreservation space. Consolidation will inevitably increase institutional knowledge of the freezing and thawing process and allow providers to guide clients on how to implement an end-to-end cryopreservation workflow into cell-based manufacturing. New tools will also become available to increase options for cryopreservation media, fill–finish operations, storage temperatures and transport logistics. Appropriate contract development resources will also form to help groups implement these new tools and develop optimized cryopreservation processes that are amenable to scalable manufacturing. Rollout of these new tools and services will modularize the cryopreservation process into manageable unit operations that can be implemented wholesale or customized by knowledgeable contract development providers to speed commercialization.
What more could be done to ensure a simplified clinical delivery of ATMPs to patients?
Efficient clinical delivery of ATMPs will require a more robust cold chain than is currently available. However, while the ATMP cold chain is under development, clinical delivery could be simplified by the incorporation of on-site ultra-low temperature storage devices, standardized thawing devices, appropriate pharmacy manuals and practices, and the use of excipient grade cryopreservation reagents that eliminate the need for further processing. If possible, cryopreservation of ATMPs at high density in syringe format would speed patient administration and increase adoption by healthcare providers.
If readers would like more information, how can they contact you?
The opinions expressed in this interview are those of the interviewee and do not necessarily reflect the views of RegMedNet or Future Science Group.
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