Rafael Bravo- Client Success Manager, Be The Match BioTherapies; Sara Butler- Senior Network Liaison, Be The Match BioTherapies
Introduction
Many allogeneic cell therapies in development today require the use of starting material collected at an apheresis center from a healthy adult donor. As a therapy reaches late-stage clinical trials and gains regulatory approval, a cell therapy sponsor must be able to quickly scale up its apheresis center collection network. The therapy’s collection protocol requirements and specifications will impact a sponsor’s apheresis center network selection strategy and ability to efficiently scale processes.
An early, careful collection process review along the entire product collection pathway is critical to avoid delays to the first collection. The product collection pathway includes:
- Donor assessments and testing
- Product collection
- Product processing and transport
Decisions a cell therapy sponsor makes at each point impact how quickly an apheresis center can begin collections. Delays often occur when a cell therapy company’s protocols or processes differ from those in place at an apheresis center because those differences have implications for training, forms, and standard operating procedures (SOPs).
It is advantageous for cell therapy developers to leverage apheresis center staff expertise and use existing apheresis center processes whenever possible. Many apheresis centers follow similar best practices and standard processes. If a cell therapy sponsor adopts these processes for its own therapy protocols, it can help the center get up and running as quickly and efficiently as possible.
A cell therapy sponsor must make protocol decisions early as these decisions will help it select the apheresis centers best suited to collect for the protocol.
Day-of Collection Donor Assessments and Testing
Donor assessments and testing that occur at an apheresis center happen on collection day. This is a logical point where a cell therapy sponsor can integrate processes apheresis centers already use.
Donor Assessments
Typically, apheresis center donor assessment standards include at minimum:
- Identity verification using a minimum of two forms of identification. Examples include a government issued ID, verbal verification, or medical record/institution verification.
- Health History Screening Questionnaires (HHSQ) review for healthy allogeneic donor assessments. The HHSQ review verifies there have been no changes to donor suitability and eligibility on collection day for donation.
- Physical exam data point review. Examples include blood pressure, temperature, or hemoglobin (these data points can vary depending on regulatory body requirements).
A cell therapy developer should consider the specific information needed in the HHSQ to ensure day-of donor suitability for its protocol. In addition, it should consider the physical assessment requirements needed for protocol and regulatory compliance.
Donor Testing
While determining donor testing requirements, a cell therapy sponsor should consider:
- When the donor will provide samples
- Which tests are necessary prior to collection (e.g., donor CBC with differential or a donor CD34 screen)
- The timeline for receiving the results (e.g., CBC results needed prior to collection start or leukopak packout)
A cell therapy sponsor should try to minimize the number of required blood draws for donor testing on collection day because each skin break increases infection risk. It can do so by identifying pre-collection donor testing requirements and the most efficient way to obtain those samples.
For example, certain regulatory bodies may require infectious disease marker (IDM) testing on collection day. However, other samples could be collected from the donor at a screening prior to collection day.
Considerations for Collecting Starting Material
There are many aspects to consider at this point in the product collection pathway. These considerations range from requirements around apheresis equipment to anticoagulant and concurrent plasma use to product labeling.
Apheresis Equipment
The apheresis devices centers use can vary. A cell therapy sponsor must consider if its product requires the use of a specific apheresis instrument for cellular material collection.
To deliver quality starting material, a center validates the apheresis devices implemented at the center as well as the SOPs in place for all protocols. Any request by a cell therapy sponsor to deviate from the validated instruments or procedures can cause delays. The center will likely be required to validate any collection protocol or procedure changes
Therefore, a cell therapy sponsor must determine if the apheresis instrument used impacts its final therapy. If not, allowing an apheresis center to use the instruments validated at its center will reduce the likelihood for delays and broaden the number of centers that could collect for a company’s therapy.
Processed Blood Volume
Processed total blood volume (TBV) is a key parameter for apheresis collections. Apheresis professionals determine processing volume targets based on:
- Donor size
- Sponsor’s requested cell count
- Product volume targets
When developing protocols, cell therapy companies must assess the product targets to determine what the likely processed TBV would need to be to meet those targets.
Anticoagulants
A cell therapy sponsor must know if its manufacturer requires the use of specific anticoagulants, which prevent product clumping during collections, for manufacturing.
If so, the sponsor may need to require that centers use a specific anticoagulant during starting material collection. For example, a sponsor may require the use of ACD-A only if heparin has negatively impacted manufacturing results. If the sponsor doesn’t have any anticoagulant restrictions, then the apheresis center will follow its standard processes for the collection of the starting material.
Concurrent and Autologous Plasma
Before collection is complete, apheresis centers can collect concurrent plasma from the donor in a separate bag. It can be added to the final product or sent with the source material. In addition, autologous plasma may be collected directly into the product bag during the procedure if required. A cell therapy sponsor must understand how and where its product will be shipped when it determines its concurrent and autologous plasma needs.
Key considerations for concurrent and autologous plasma protocol development include:
- If the product travels long distances to manufacturing
- If the product will be cryopreserved
- What amount of plasma will be required if autologous plasma will be added to the source material
It is particularly beneficial to add additional autologous plasma to fresh products being shipped long distance because the plasma has a buffering effect and helps maintain cell viability. However, it is less common to add autologous plasma to products that are being cryopreserved at the apheresis center because of the plasma reduction step required for cryopreservation.
Product Volume Target
Cell therapy companies should consider the expected collection yield and if there are minimum or maximum product volume requirements from the manufacturer.
Product volume targets allow the apheresis operators to gauge processing volumes and adjust the collection parameters as needed. The volume target has implications on:
- Materials used during collections (e.g., the size of the leukopak)
- Materials used for processing and shipment (e.g., the size of the cryobag)
- Downstream processing steps
Product Labeling
ISBT-128 is the global labeling standard for blood, cell and tissue products. Most apheresis centers have ISBT-128 labeling practices in place because it is required for FACT or AABB accreditation. A cell therapy sponsor should review ISBT-128 labeling standards when developing its protocol to determine if an additional product-specific label is needed.
If so, the International Council for Commonality in Blood Banking Automation (ICCBBA), which oversees ISBT-128 labeling standards, collaborated with cell therapy sponsors and manufacturers, accrediting bodies, and service providers in the space to develop a new standard label specifically for use on products collected for further manufacturing. The label is appropriate for therapies in clinical trials or used commercially.
It builds on the ISBT-128 label with standard ISBT-128 information on the left and information specific to the clinical trial or manufactured product on the right. The information included on the right is flexible but presented in a standardized way. In addition, the new label uses the same dimensions as the ISBT-128 label for ease of implementation at apheresis centers.1
If a cell therapy sponsor elects to use a different label, the apheresis center must have it prior to the scheduled apheresis date as the label size will have implications on how all labels are positioned on the leukopak base label.
Considerations for Post-Collection Processing
At this point in the product collection pathway, a cell therapy sponsor must think through key product processing and post-product processing requirements.
Product Processing
When developing product processing protocols, such as cryopreservation, a cell therapy sponsor must consider:
- Specific processing requirements a center must follow (e.g., cell isolation, CD34 selection)
- Specific cryobags or cryomedia required
- If a center must implement a specific cryopreservation program
- If the sponsor must provide the center with any materials to use
These considerations are important because an apheresis center uses validated SOPs for any processing services it offers. Deviations a sponsor requires may necessitate steps that can impact the collection timelines, such as:
- Revisions to the center SOPs
- New procedure validation prior to use
- Staff training on protocol-specific steps
Deviations from a center’s SOPs and procedures will absolutely be needed for some sponsor collection protocols. However, leveraging the center’s expertise and procedures is the most efficient path forward if the sponsor does not have processing restrictions for its product.
Product Transport and Logistics
While seemingly simple, sponsors must ensure they carefully coordinate the logistics of the collection, the product pack out, and the manufacturing slots. The apheresis center needs to understand the manufacturer’s limitations on when it can receive starting material. This can impact when a donor is scheduled for collection if the manufacturer can only accept shipments on specific days and at specific times.
The location of the apheresis center also comes into play; the farther out the center is from the manufacturer the riskier the transport lanes and flights can be if the product must arrive by a certain date and time.
Apheresis Center Capabilities Assessment
Only after a cell therapy sponsor has developed its scalable collection protocol requirements and specifications can it begin assessing an apheresis center’s capabilities along the product collection pathway. It is critical for cell therapy companies to understand not all apheresis centers have the specific capabilities, or skillsets, to collect for a protocol.
A cell therapy sponsor should assess if a center:
- Can deliver on the required specification
- Has enough collection slot availability to meet the expected timeframes and volumes
- Is in a location where the source material can get from the apheresis center to the manufacturer in the required timeframe
A cell therapy sponsor can work with an organization that has an established apheresis center network to assist with the capabilities assessment. This approach is advantageous to the cell therapy sponsor because the organization understands the strengths and weaknesses of each center. It can target the apheresis centers most likely to be able to deliver on a sponsor’s requirements.
When the organization has an integrated apheresis center network and managed logistics team, the sponsor also benefits from efficiency across the allogeneic cell therapy supply chain.
In addition, the organization can help the cell therapy sponsor implement best practices and processes in its requirements based on its experience working with apheresis centers that collect source material for cell therapies.
Conclusion
Many crucial considerations will impact a cell therapy sponsor’s center selection strategy and its ability to efficiently scale its processes. Thinking through the process early allows a cell therapy company to maximize quality and scalability throughout its supply chain and leverage existing expertise for efficient protocol implementation.
Reference
- ICCBBA. ISBT 128 STANDARD Labeling of Collection Products for Cellular Therapy Manufacturing. Accessed November 10, 2022. https://e1631fc6-80a8-4371-9da1- 0ebe6534f591.filesusr.com/ugd/83d6e1_30ae72bf9dba4532a0179f053bc02a76.pdf
About the Authors
Rafael Bravo is a Client Success Manager for Be The Match BioTherapies. He is responsible for end-to-end experience and ensuring that cellular starting material delivery runs smoothly for BioTherapies’ clients. Rafael has experience operationalizing allogeneic and autologous therapy protocols and provides technical expertise to improve processes and product quality. Prior to joining Be The Match BioTherapies, Rafael worked as a Quality Improvement Coordinator for the Children’s Hospital Los Angeles Transplant and Cellular Therapy program. He has also worked in operations for DKMS as well as organ and tissue transplant procurement organizations.
Sara Butler serves as a senior network liaison between Be The Match BioTherapies stakeholders, clients, and network centers. Sara also provides technical expertise and consultation to improve operational processes and Be The Match BioTherapies’ product quality. She brings to Be The Match BioTherapies nearly a decade of cell therapy experience and knowledge of the industry
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