Mitigation of supply chain challenges in cell therapy manufacturing: perspectives from the cord blood alliance

Abstract

Cellular therapies rely on highly specialized supply chains that often depend on single source providers. Public cord blood banks (CBB) manufacturing the first cell therapy to be highly regulated by the FDA and related international agencies are a prime example of being subject to this phenomenon. In addition to banking unrelated donor cord blood units for transplantation, CBBs also source and characterize starting materials for supply to allogeneic cell therapy developers that often employ customized technologies offered by just a small number of manufacturers. As such, these supply chains are especially sensitive to even minor changes which often result in potential major impacts. Regulations can shape supply chain efficiencies, both directly via the definition of restricted technology and process requirements and indirectly by steering strategic business decisions of critical supply or service providers.

We present 3 current supply chain issues with different root causes that are swaying efficiencies in cord blood banking and beyond. Specifically, the shortage of Hespan, a common supplement used in cord blood processing, the decision by the provider to stop supporting medical device marking of the Sepax system broadly used in cord blood banking, and a new European ruling on phasing out plasticizers that are critical for providing flexibility to cord blood collection bags, are all threatening downstream supply chain issues for the biologics field. We discuss overcoming these hurdles through the prism of unified mitigation strategies, defined, and implemented by multi-factorial teams and stakeholders, to negotiate resolutions with providers and regulators alike.

Significance statement.

Cellular therapies rely on highly specialized supply chains that often depend on single source providers. Public cord blood banks (CBB) not only bank unrelated cord blood units for transplantation but also source, characterize, and supply starting materials to allogeneic cell therapy developers that often use customized technologies offered by just a small number of manufacturers. We present root causes and impacts of 3 current supply chain issues affecting efficiencies in cord blood banking and beyond. We discuss overcoming these hurdles by systematic mitigation strategies already implemented by cord blood stakeholders, and applicable to the broader cell therapy field.

Hespan shortage

In North America, Hespan (Hydroxyethyl Starch) is routinely used for cord blood processing with the highest obtainable cell recovery efficiencies.¹ By coating red blood cells (RBCs), Hespan drives RBC agglutination, enabling the separation and isolation of mononuclear and total nuclear cell fractions via sedimentation and centrifugation.² The total nucleated cell (TNC) count of processed cord blood units has been a chief criterion for selection for clinical transplant providing the highest TNC/kg possible to the recipient. The use of Hespan optimizes the separation of fetal red blood cells from fetal lymphocytes and has thus been the favored processing method to create the largest possible TNC content in processed cord blood.^1,2 The decision in 2022 by manufacturer B. Braun Medical Inc. (Bethlehem, PA, USA) to discontinue Hespan production resulted in an industry-wide shortage in 2023, with a sole remaining North American supplier; Pfizer, Inc. (distributor Hospira, Inc., Lake Forest, IL, USA) unable to meet demand.³ Cord blood can be processed in the absence of Hespan, and in the European Union (EU) HES can only be used under limited circumstance,⁴ restricting its use in therapeutic manufacture in the EU. Still, many public cord blood banks are bound by their methods of manufacturing including Hespan as approved by regulatory agencies and accreditation organizations. Reimbursement by the Health Resources and Services Administration, an agency of the U.S. Department of Health and Human Service (HRSA), for CBUs added to the National Cord Blood Inventory (NCBI) in the US is restricted to “licensed” units manufactured with the procedure approved by the Biologics License Application (BLA). When relying on Hespan for manufacture, delivery of contractually agreed numbers of units is imperiled by Hespan shortages.

Short-term mitigation strategies have included good-neighbor commitment of CBBs to sharing available Hespan lots with those in need. Banks could also stockpile larger supplies of Hespan to avoid term short-term shortage; however, this approach is limited by the expiration dates of the manufactured supplies. Longterm strategies for individual CBBs may include qualifying international vendors (eg, WAK-Chemie Medical Gmbh, Germany), and supplementing approved procedures to include minimally manipulated cord blood product manufactured without Hespan, with a demonstration of comparability, stability, and clinical safety. This allows for manufacturing strategies using Hespan when available, with the ability to continue production in periods of shortage but requires significant effort and resources.

Sepax medical device registration

Recent European Union (EU) regulatory changes strongly influenced Cytiva Life Sciences (Marlborough, MA, USA) to stop registering Sepax as a medical device in the EU/UK and US. In the mid-2000s, a set of EU Tissue and Cell Commission Directives were published including 2006/86/EC, which was implemented to set a common safety and quality standard for human tissues and cells across the EU. This Directive’s scope specifically included additional technical requirements including the necessity to use CE (Conformité Européene) marked medical devices while undertaking critical activities related to preparing cells and tissue for human application.⁵ This same requirement to utilize CE marked medical devices has also remained within UK legislation, even after the UK’s exit from the EU in 2020.

As a result, EU and UK cell therapy laboratories were limited to using CE certified pieces of equipment such as the Sepax-2 (marketed by Cytiva Life Sciences) for cell processing. The Sepax-2 is a CE-certified enclosed benchtop medical device used for the processing of cord blood and other similar materials of human origin. It has cell concentration and washing capabilities and utilizes single-use kits and a syringe-like, cylinder-shaped cartridge with chamber centrifugation allowing separation of the red blood cells, plasma, and mononuclear cells.⁶ The Sepax-2 provides a flexible, reasonably priced, and popular solution for cell therapy laboratories to implement, especially cord blood banks and pediatric transplant center laboratories for its cord blood unit cell washing capabilities. However, in 2022, Cytiva wrote to all EU, US, and UK customers stating that after 25 years, the Sepax 2 and related products were being phased out and discontinued as certified medical devices, culminating with all support ending in 2026. The distributor cited the decline in the worldwide cord blood market and a move by customers to non-automated processing solutions, as the primary drivers for this decision. This decision will force many affected cell therapy laboratories to identify and implement alternative solutions, likely at great expense, with potential risk for reduced quality of the final product, and possibly even forcing a return to manual methods with decreased processing robustness.

Looking deeper into the causes of this supply chain issue, 2 more drivers for the discontinuation of the Sepax as a medical device become evident. Firstly, in 2021, the European Union implemented a new Medical Device Regulation (MDR) in response to some deficiencies in the superseded Medical Device Directive (MDD). There had been a growing number of serious safety issues, partly attributed to the Directive which had been in force since 1993. Despite the aim of these new regulations to improve safety and quality for patients, it is perceived to be a stricter, costlier, and a more labor-intensive regulatory framework for medical device manufacturers to navigate.⁷ Secondly, Cytiva has rebranded the Sepax-2 without the medical device designation as the “Sepax C-Pro.” The Sepax C-Pro has a CE mark indicating compliance with the EU Machinery Directive (2006/42/EC) only and is marketed to be used by the growing number of advanced therapeutic cell therapy (ATMP) developers. This pivot by Cytiva has been possible because there is no requirement to utilize certified medical devices within EU pharmaceutical legislation, resulting in emergence of a new customer base.

For mitigation, in the UK, a consortium of cell therapy, the Department of Health, and relevant local regulator organizations was established as a workstream of the UK Stem Cell User Group (SCUG),⁸ to negotiate reasonable timelines with Cytiva and regulatory teams for continued use of Sepax without medical device designation or to test and implement alternatives. At the time of publication, the consortium has successfully identified and implemented several alleviation strategies for its members such as kit stockpiling and the initiation of a joint tender representing both UK public cord blood banks and 8 hematopoietic transplant center affiliated stem cell laboratories. Similarly in the US, NCBI and licensed banks have formed a working group that has informally been discussing a pathway forward with the US FDA to enable validation of the C-Pro Device and related kits at each cord blood bank using a common validation protocol. Some US banks have alternatively decided to abandon using the Sepax, switching to another FDA-approved device (eg, AXP II System, ThermoGenesis Holdings, Inc., CA, USA), or reverting to a manual processing method. In the EU and UK, strategies for the use of non-CE marked devices might be considered, potentially including validating devices already available for extending its usage to cord blood (eg, MacoPress SMART, Macopharma, France).⁹

New REACH group law: impact on collection bags

Plasticizers, essential additives to confer flexibility and pliability to materials such as plastics and rubber, have long been used in various industries, including medical devices.¹⁰ Phthalates, a commonly used type of plasticizer, are used in medical applications, particularly in the production of polyvinyl chloride (PVC) materials used for cord blood collection and processing bags.¹¹ These bags are crucial for the storage and transportation of blood products. However, concerns have arisen regarding the potential health risks associated with phthalates, including their classification as endocrine-disrupting, carcinogenic, and toxic to sexual organs in the human body.¹²

In response, the Official Journal of the European Union (OJEU) published Regulation (EU) No 1907/2006, which amended Annex XIV (Authorization List) to REACH (Registration, Evaluation, Authorization, and Restriction of Chemicals) regulation and amendments to Regulation (EC) No 1907/2006 concerning bis(2-ethylhexyl) phthalate (DEHP) in medical devices. In the 7th update of REACH Annex XIV, 5 substances were added to the Authorization List. The REACH group has imposed strict restrictions on the use of certain phthalates, including DEHP, which at present is included in the most commonly available blood and cord blood banking devices.^13,14 This regulatory change profoundly impacts the global supply chain, with implications for the US. The new law restricts the use of DEHP in the European Union and affects the production, export and import of cord blood collection and processing bags globally. Consequently, manufacturers, suppliers, and cord blood banks outside the EU must ensure compliance with these regulations, posing challenges, and opportunities.

Cord blood banks, crucial for life-saving procedures, face challenges transitioning to non-DEHP alternatives due to possible increased hemolysis, shortened shelf life, and the need to validate various processes thoroughly.¹⁵ The impact extends to the quality and safety of cord blood units, as studies suggest that phthalates may leach from medical devices like cord blood collection and processing bags, potentially affecting the viability and function of hematopoietic progenitor cells.¹⁶ As DEHP will no longer be available for medical devices in the EU from REACH Sunset Dates (set for July 1, 2030, i EC 2023/2482, issued on November 13, 2023), the global supply chain must adapt swiftly to the impending changes.

The supply chain disruption is not limited to regulatory compliance. The impending shortage of DEHP, constituting a significant portion of PVC pricing, presents challenges, with decreasing capacities and increasing logistic prices as well.¹⁷ The current reduction in DEHP suppliers from 7 to 1 within a decade further exacerbates concerns. Moreover, the anticipated raw material shortage demands extensive research, development, testing, and approval of alternative materials, impacting both time and resources.

The implications of this regulatory shift are global, affecting the European market and the interconnected supply chains worldwide. Cord blood banks in the US, and by extension, the broader medical industry, must proactively navigate the transition, considering alternative materials, compliance with regulatory requirements, and managing inventory effectively.¹⁸ Transparent collaboration, tailored support, and strategic partnerships will be integral to ensuring a seamless transition and maintaining the safety and quality of cord blood bags in the face of these regulatory changes.

The US Environmental Protection Agency (EPA) has determined that DEHP is a probable human carcinogen, and initiatives against DEHP have started. California is the first state with a legislation proposal (AB-2300) for a DEHP ban in medical devices, starting for intravenous solution containers as early as January 1, 2026. The bill was voted in in April 2024. It was amended in assembly the following month of May providing an exception as described in Title 21 of the Code of Federal Regulations, for human blood collection and storage bags.¹⁹

Mitigation of supply chain challenges

While supply chain challenges can be unavoidable in certain circumstances, with robust organizational processes, the adverse impact of both pre-identified and unplanned challenges, will allow an organization to adapt to market conditions and continue to deliver the products and services that support the healthcare community.²⁰ While experiencing supply chain challenges, we offer the following roadmap to successfully navigate these scenarios (Figure 1). Resolution of supply chain challenges such as those discussed here (Table 1) will require organizational support and collaboration to effectively navigate any challenges experienced. Specifically, we recommend a 4-part approach involving immediate impact assessments, surveying, and navigating the current supply chain, engaging in associated regulatory actions, and then manifesting and deploying organizational solutions (Figure 1, Table 2).

Figure 1.

Supply chain challenge roadmap.

Table 1.

Current supply chain challenges in cord blood banking.

Supply chain challenge	Hespan shortage	Sepax device	Plastic collection and processing bags
Root cause	Shortage due to discontinuation by one of 2 main suppliers	The strategic business decision to stop clinical device marking	European law changes following the REACH group decision
Year announced	2022	2022	2022
Impact	Approved methods of manufacturing. Processing efficiencies. Licensure and accreditation compliance	Approved methods of manufacturing. Licensure and accreditation compliance	Possible supply monopolies and longer-term unsustainable pricing increases
Mitigation	Lot stockpiling and sharing between industry partners. Obtaining approval for Hespan-free processing	Negotiations with providers for delay of implementation and with regulatory agencies for acceptance of alternative processing technologies	Discussion of expected impact with regulatory agencies outside Europe

Table 2.

Strategic mitigation of supply chain challenges.

Organization	Responsibility	Deliverable
Individual institutions/CGT manufacturers	Creation of “supply chain threat mitigation” teams including laboratory operations, quality, clinical, and regulatory representation Identification of critical materials, equipment, and steps of manufacturing. Definition of preventative measures for supply chain disruptions	Definition of impact and acceptable short- and long-term solutions for delay or mitigation Proactive readiness for implementation of alternatives Engagement with regulators and commercial entities at the root of supply chain challenges
CGT organizations and societies	Assembly of impacted stakeholders into task forces for international collaborations on materials and supplies	Joint engagement with international regulators and commercial entities at the root of supply chain challenges
Commercial service and technology providers	Timely and consistent communication of changes	Provide accessible points of contact / subject matter experts
Regulatory agencies	Awareness of regional and international threats to supply chains Defining pathways for approval of imported materials not sourced from within the region of use	Expedited approvals of alternative supplies or and/or equipment

Upon notification or identification of supply chain challenges that will stress organizational dynamics, rapid impact assessments must be made within the organization and potentially the broader user community to alleviate pressures on product realization. Specifically, when completing impact assessments, care should be taken to ensure any impacted goods navigate the appropriate quarantine or disposition pathways within the Quality Management systems. To effectively identify key decision points and timelines, it is paramount that organizations complete preliminary self-assessments involving supply chain subject matter experts (SMEs), manufacturing personnel, quality units, and regulatory affairs personnel. Navigating Supply Chains and Action should explore alternate solutions, products, and potential supplies/suppliers using a risk-based approach commensurate with the level of risk to the overall process.²¹ Material and vendor/supplier qualification programs must be appropriately integrated into any identified solutions and routinely evaluated to ensure appropriate systems can support current needs and future challenges while adhering to regulatory expectations.^22,23 The involved teams and personnel may participate in multiple process components at different stages, or in parallel (Figure 1).

Regarding interactions with regulatory affairs personnel, it is important to note that throughout initial impact assessments, regulatory affairs SMEs are key stakeholders involved in successful supply chain responses. While organizations are completing the spectrum of activities required to traverse these situations, in parallel to impact assessments and navigating supply chain actions, we recommend regulatory stakeholders begin their assessments, inclusive of any planned interactions with regulators. Engaging regulatory affairs early in the process, both internally and externally with user communities or regulators themselves, it may effectively reduce the impacted timeframe as alternate pathways are identified and mature. Specifically, collaboration and discussion with regulators may enable efficiencies to ensure alignment of a site strategy and response is of the appropriate caliber, reducing overall re-work as an organization if a regulatory authority is not supportive of the strategy or justification associated with a site planned strategy. Defining a regulatory strategy early in this process and embracing collaboration both internally and with regulators may enable significant organizational efficiencies and reduce the time of any associated impact.²⁴

Developing a strategy and enacting solutions for the mitigation of supply chain challenges requires multi-functional and cross-team collaboration to mitigate and minimize adverse impacts on sustainable operations, irrespective of product class in biopharmaceutical manufacturing. With the tools detailed here, teams can effectively navigate these scenarios and ultimately deploy solutions that will meet the organization’s needs.

Conclusions

Cord blood banks depend on limited or single sources for the supply of critical reagents and technologies and as such are highly sensitive to even minor supply chain changes imperiling compliance with procedures and expectations as approved by regulatory agencies and accreditation organizations. As exemplified in this review, although supply chain threats may be started by regional events, such as European law changes, they can still have a global impact based on subsequent business decisions by commercial providers. While this review focused on Cord blood banks, the impacts of disruptions to existing supply chains are only exacerbated in the context of more complex cell therapy manufacturing systems. However, developers in general, can employ systematic internal and collaborative mitigation strategies to address supply chain challenges and safeguard the continued manufacture of products of consistent and acceptable quality. Employment of multifunctional teams within individual organizations and joining forces with other impacted parties and peers provides the strength in numbers for effective negotiation with companies and agencies and optimizes the successful ability to delay and reshape supply chain threats. In coming years, the response of medical supply manufacturers to new European rulings on phasing out plasticizers will affect the global regenerative medicine field, and industry-wide mitigation is required to ensure access to suitable collection bags and tubing that are routine fixtures in CGT manufacturing.

Data availability

No new data were generated or analyzed in support of this research.

Author contributions

P.K., L.F., W.V.H.: Conceptualization, Writing—original draft, review & editing. K.H.: Writing—original draft, review & editing. R.H., J.K.: Conceptualization, Writing—review & editing.

Conflict of interest

J.K. declared patent holder with CryoCell and SinoCell (Supercell technologies); consultant for Matrix Capital; research funding Enzyvant—contract manufacturer for thymus with monetary payments to Duke; research support from the Marcus Foundation; stock ownership in Celularity. The other authors declared no potential conflicts of interest.