Reducing Risk: Establishing Consistency and Scalability of Cell Therapy Starting Material

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The pace of cell therapy development continues to accelerate in both the autologous and allogeneic spaces. With autologous cell and gene therapies approved by regulators in the United States and abroad, many biopharma companies are turning their sights to allogeneic cell therapies, which often use starting material from a healthy adult donor.

The quality and consistency of the source material can impact the quality of the final manufactured allogeneic cell therapy. Considerations and case examples along the allogeneic cell therapy supply chain illustrate why it is crucial for cell therapy developers to understand which donor attributes are critical to product efficacy and how those attributes impact supply chain requirements and ability to scale; how a cell therapy developer’s collection network strategy can impact quality, agility, and scalability; and why partnering with experienced vendors is critical for the development of a reliable, high-quality supply chain.

These considerations will help cell therapy developers determine if a potential partner has the expertise and relationships required to identify, source, and collect allogeneic donors and continually deliver high-quality starting material for manufacture as the therapy scales.

Donor identification

The allogeneic cell therapy supply chain starts with donor identification. At this step, there are two key considerations: critical quality attributes of the donor starting material and geographic reach planned for the therapy.

Donor starting material

The critical quality attributes of the donor starting material can have a major impact on the ability to source donors at scale. Every requirement added narrows the donor pool. Figure 1 is a case example of how screening parameters can limit the number of donors that might be available to support that therapy. The client did not have stringent non-human leukocyte antigen requirements but did have stringent additional screening criteria. The scenario begins at screenings completed and shows the average number of donors it takes to get to one collection. Prior to this point, the donor pool started with a segment of approximately 7 million potential donors out of an overall database of 22 million. Then, any donors who did not meet demographic-based requirements (e.g., ethnicity, gender, age) were filtered out prior to contact for screening samples.

Figure 1: This case example shows how quickly an allogeneic donor pool narrows when a client adds stringent donor attribute requirements. Eliminating requirements that do not impact therapy efficacy or safety broadens the pool of potential donors (1).

At the screening stage during a Be The Match BioTherapies case study, the donors were evaluated for specific attributes not captured in the registry data, such as performance in culture or a specific assay. Five potential donors passed the screening parameters. The next steps included an information session for the potential donor, gathering donor consent, and scheduling the collection. Only one donor out of 37 screened donors completed collection (1).

As this case example demonstrates, the stringency and type of donor requirements can drastically limit the number of donors who meet the requirements to donate for a therapy. Cell therapy developers must consider the size of the starting donor pool required to meet the attributes that are critical to the efficacy or safety of the therapy. The more requirements that a cell therapy developer adds, the fewer donors who meet the requirements (2).

Therapy geographic reach

Cell therapy developers must think about the desired geographic reach of their therapy from the beginning. Allogeneic starting material has the potential to be used to create therapies for multiple patients who may reside in a different country than where the starting material is collected. This is especially true once a company broadens its scope beyond its initial clinical trials.

Any starting material collected from a donor must comply with requirements set by the regulatory bodies in the countries where the resulting therapy may be administered, and requirements between countries differ.

Figure 2 shows a sampling of regulatory requirements for donor screening, donor testing, and source material collection in the United States, Canada, Australia, and the European Union (3–10). The blue circles indicate requirements that differ from FDA requirements.

Figure 2: Examples of country-to-country regulatory differences for source material. Inconsistencies with FDA regulations identified in blue (3-10).

If the cell therapy developer requests collections using only US regulations and later decides to broaden its reach to another country, the starting material most likely will not meet that country’s requirements and cannot be used. A cell sourcing vendor with an understanding of international donor guidelines can help cell therapy developers collect starting material in a way that meets requirements for multiple countries.

A cell sourcing vendor with a large, diverse registry and an understanding of the US and international donor guidelines can help cell therapy developers avoid pitfalls that could put the therapy at risk (2).

Cell collection

Once a cell therapy developer selects and screens donors, the supply chain moves to cell collection. There are three key considerations when developing a cell collection network strategy: geographic distribution of collection centers, alignment of collection and cell processing requirements with collection center capabilities, and therapy-specific training requirements and ongoing center management.

Geographic distribution to lower risk

A broad geographic distribution of cell collection centers allows cell therapy developers to scale and be agile. When a company relies on a few centers with limited geographic reach, it opens its supply chain up to risk. A geographically diverse network lowers that risk.

The COVID-19 pandemic serves as a case example. Prior to COVID, it was not unusual for a donor to travel across the country to the apheresis center collecting for a company’s therapy. However, COVID-19 made that kind of travel virtually impossible. This was particularly true early in the pandemic with travel restrictions and quarantine requirements in place in many US states (11). A geographically diverse apheresis center network allowed donors to stay within a two- to three-hour driving distance of home so collections could continue despite the pandemic.

The advantage of having access to a network of apheresis centers across the US goes beyond lowering risks. It gives companies the ability to quickly scale as the therapy moves from early-stage clinical trials into commercialization and collection needs grow. Apheresis centers do not have unlimited capacity; therefore, companies need additional options for starting material collection.

Collection center capabilities alignment

Not every apheresis center has the same collection and cell processing capabilities. A cell therapy developer must have a clear understanding of an apheresis center’s capabilities and select centers that can meet the therapy protocol requirements.

For example, some centers do not have cryopreservation capabilities. Others do not have a clean room for cell processing. In addition, some apheresis centers have more experience collecting starting material for cell therapies than others. When developing its cell collection network strategy, cell therapy developers must keep these considerations in mind so starting material is collected consistently and at a high quality across the centers it has selected.

Training and ongoing management

Training and center management is an essential piece of a cell therapy developer’s collection network strategy. Robust, therapy-specific training procedures and network management practices help maintain consistency across centers in the network.

Figure 3 illustrates a case example of the benefits of robust training procedures and network management practices. The data collected over three years for one client shows consistent performance in product cell count and product volume across trained centers in the client’s network. Consistency in the released product was maintained even when centers were added as the client’s collection needs grew over time. The centers were selected based on their ability to support the protocol. All centers received therapy-specific training and ongoing support (12).

Figure 3: Five different collection centers collected mononuclear cells by apheresis for a developer. The total cell count and total volume collected were tracked over three years (2017-2020). Similar donor-to-donor variability is seen across centers.

Developing a cell collection network strategy that includes geographically diverse centers, aligns center capabilities with protocol requirements, and uses robust training procedures and management sets cell therapy developers up to consistently collect high quality starting material for manufacture (2).

Supply chain

The entire cell therapy supply chain is time-sensitive and susceptible to variability. Therefore, there are three key considerations when developing a supply chain vendor strategy: demonstrated experience overcoming cell therapy supply chain disruptions, understanding shipping lanes to meet product-release timelines, and single courier or courier-agnostic logistics model.

Supply chain disruptions

Disruptions can occur at any point along the supply chain—from scheduling cell collection through product delivery—that require experience and relationships to navigate.

For example, if a collection slot becomes unavailable, having a geographically diverse network of apheresis centers could allow the collection to move to a new center to keep it on time. If a weather event happens, such as a flood, hurricane, or blizzard, established relationships with the emergency management community allow for the continued movement of product.

For products that cross international borders, customs complexities can be difficult to navigate. This was especially true early in the COVID-19 pandemic when borders closed suddenly. Companies were required to lean on existing relationships and experience to keep products moving.

One COVID-19 case example comes from the allogeneic hematopoietic stem cell transplant community where country-to-country transports of fresh product from an allogeneic donor to a patient are common. Just days after the US president closed the US border to foreign nationals, the National Marrow Donor Program (NMDP)/Be The Match requested and received a waiver from the Centers for Disease Control and Prevention (CDC). The waiver allowed foreign nationals from Europe to deliver products into the US on behalf of the NMDP/Be The Match despite the border restrictions.

The NMDP/Be The Match has a long-standing relationship with the US government. It worked with Vice President Mike Pence, the CDC, the Department of Homeland Security, and the State Department to get the exemption (13).

Shipping lanes

Cell therapy developers and supply chain vendors must have a complete understanding of product-release timelines, product-expiration timelines, and shipping lanes between the collection center and manufacturing facility. Whether starting material is shipped fresh or cryopreserved, it must reach the manufacturing facility in a specific timeframe because delayed delivery could mean a manufacturing slot is no longer available or the product may no longer be viable.

Experienced cell therapy supply chain management vendors have this full picture and can collaborate with the cell therapy developer to determine ideal shipping lanes based on the location of the manufacturer and/or collection center. A collection center that does not have easy access to an airport, for example, may not be the best choice for products with short product-expiration timelines.

Figure 4 provides a case example of client data collected over two years of domestic shipments. Starting material needed to be delivered from the apheresis center to the manufacturing facility within 48 hours. All 128 starting material shipments were delivered within 40 hours; 120 products were delivered to the manufacturer within 24 hours. Even with most collections and shipments occurring during the COVID-19 pandemic, the hours in transport trended downward (14).

Figure 4: Hours in transport for starting material for was tracked for 128 domestic shipments over two years. Overall timeframes trended down over time with all shipments delivered to the manufacturer from the collection center within the cell therapy developer’s contracted deadline.

Logistics model

The logistics model a cell therapy supply chain management vendor employs can minimize quality incidents related to logistics. There are generally two types of models. In one model, the vendor works with one courier company to transport cells. In the other, the vendor works with multiple courier companies and selects the courier that best suits the shipping lane. This is also called a managed logistics model.

In a managed logistics model, a cell therapy supply chain manager has oversight of the entire supply chain, from collection scheduling through product delivery. The supply chain manager works closely with a logistics team that is managing the shipments and making necessary adjustments if a disruption occurs. The supply chain manager stays in close contact with all stakeholders to communicate any changes.

Figure 5 demonstrates how Be The Match BioTherapies managed logistics model minimizes quality incidents. In one case, the organization used a single third-party courier to manage shipments. The other relied on the managed logistics model to manage shipments. The managed logistics model with shipment oversight by an experienced team drastically reduced quality incidents (15).

Figure 5: International shipments from October 2020-September 2021 using a managed logistics model had significantly fewer quality incidents than those that did not use a managed logistics model (i.e., third-party managed).

An experienced cell therapy supply chain management partner can help cell therapy developers lower the risk inherent to cell therapy supply chains and deliver starting material to manufacturing without delay (2).

Conclusion

With the pace of cell therapy development, companies must have strong partners that can deliver consistent, high-quality starting material for allogeneic therapies. Donor attributes, cell collection network strategies, and a vendor’s experience and partnerships all play important roles in a cell therapy developer’s ability to scale from early clinical trials into the commercial phase. By keeping the considerations presented here in mind, cell therapy developers can determine if a potential partner has the right expertise and relationships to consistently deliver.

References

1. Be The Match BioTherapies, Assessment of Be The Match BioTherapies Client Conversion Rates 2018-2021.

2. J. Aho, “Reducing Risk: Establishing Consistency and Scalability of Cell Therapy Starting Material,” presentation at the 2022 Advanced Therapies Week Conference (Miami, Fla., Jan. 25-28, 2022).

3. CFR Title 21, Part 1271 (Government Printing Office, Washington, DC) 928-955.

4. CSA Group, CAN/CSA-Z900.1-17: Cells, Tissues, and Organs for Transplantation: General Requirements(Nov. 2017).

5. CSA Group, CAN/CSA-Z900.2.5-17: Lymphohematopoietic Cells for Transplantation (Nov. 2017).

6. EC Directive 2004/23/EC, Setting Standards of Quality and Safety for the Donation, Procurement, Testing, Processing, Preservation, Storage and Distribution of Human Tissues and Cells(March 31, 2004).

7. EC Commission Directive 2006/17/EC, Implementing Directive 2004/23/EC of the European Parliament and of the Council as Regards Certain Technical Requirements for the Donation, Procurement and Testing of Human Tissues and Cells(Feb. 8, 2006).

8. EC Directive 2002/98/EC, Setting Standards of Quality and Safety for the Collection, Testing, Processing, Storage and Distribution of Human Blood and Blood Components and Amending Directive 2001/83/EC (Jan. 27, 2003).

9. EC Commission Directive 2004/33/EC, Implementing Directive 2002/98/EC of the European Parliament and of the Council as Regards Certain Technical Requirements for Blood and Blood Components(March 22, 2004).

10. TGA, Therapeutic Goods Order 108, Standard for Human Cell and Tissue Products – Donor Screening Requirements(Sept. 24, 2021).

11. D. Studdert, M. Hall, and M. Mello, N Engl J Medonline, DOI: 10.1056/NEJMp2024274 (Aug. 5, 2020).

12. Be The Match BioTherapies, Assessment of Be The Match BioTherapies Contracted Apheresis Center Performance 2017-2020.

13. National Marrow Donor Program/Be The Match, “Trump Administration Grants Waiver of European Travel Ban to Be The Match to Continue Delivering Life-Saving Bone Marrow to U.S. Patients,” Press Release, March 19, 2020.

14. Be The Match BioTherapies, Assessment of Starting Material Transport Time from Apheresis Center to Manufacturer for Be The Match BioTherapies Client from Sept. 1, 2019–Aug. 31, 2021.

15. National Marrow Donor Program/Be The Match, FY21 Courier Review of International Shipments from October 2020–September 2021.

About the author

Joy Aho is the senior project manager for Be The Match BioTherapies.

Article details

BioPharm International
Vol. 35, No. 4
April 2022
Pages: 30–34

Citation

When referring to this article, please cite it as J. Aho, “Reducing Risk: Establishing Consistency and Scalability of Cell Therapy Starting Material,” BioPharm International 35 (4) 2022.