FACT Update December 2021
Mikaela VanMoorleghem, MPA, Education and Training Coordinator
Foundation for the Accreditation of Cellular Therapy
Omaha, NE USA
Quality Management Series 10: Program Perspective of the Validation Process Webinar
Open for Registration!
Join us on December 7, 2021, for the Quality Management Series 10 Webinar: Program Perspective of the Validation Process. Dr. Joseph Schwartz, MD, MPH, from Mount Sinai Bone Marrow and Stem Cell Transplantation Program will discuss the clinical approach to process validation and software validation. Jeannette Bloom MBA, MT(ASCP)SBB, will discuss the apheresis and processing approach to validation and software validation from Baylor College of Medicine Stem Cell Transplant program's perspective, and Walid A. Almashaqbeh BS, BB (ASCP), will discuss the cord blood banking approach to validation and software validation from King Abdulaziz Medical City's program perspective.
Register for webinar
Determining Donor Eligibility for Donor Lymphocyte Infusions Aliquoted from a Product Intended for Transplantation
By Patrick J. Hanley, PhD
Chair, FACT Education Committee
Chief & Director, Cellular Therapy Program
Associate Professor of Pediatrics
Center for Cancer and Immunology Research
Children’s National Hospital & The George Washington University
Haploidentical hematopoietic progenitor cell (HPC) transplantation has increased drastically over the past five years. One reason for this increase is the introduction of T cell Receptor (TCR) α/β and CD19 depletion. In this manufacturing process, the α/β T cells and CD19 B cells are depleted, leaving γ/δ T cells, CD34+ stem cells, and other immune cells that are infused into the patient. The hypothesis is that the γ/δ T cells will provide an anti-tumor effect (in the case of malignancies) and anti-viral immunity, while the lack of α/β T cells will reduce the incidence of graft versus host disease (GVHD). However, the very limited CD3+ alpha beta T cell dose (often less than 1x105 CD3+ α/β /kg) may leave the recipient more susceptible to viral infections, or even engraftment failure. Therefore, clinicians often request that the cell processing facility cryopreserve aliquots of the α/β T cell-containing fraction to be used as a potential donor lymphocyte infusion (DLI).
Donor eligibility gurus may already see the conundrum: the TCR α/β/CD19-depleted cellular therapy product is an HPC product, for which donor infectious disease testing is allowed by the U.S. Food and Drug Administration (FDA) up to 30 days prior to collection; DLI is considered a therapeutic, leukocyte-rich tissue and therefore requires infectious disease testing to be done before or after seven days from collection. Programs can be conservative and simply draw samples for testing within seven days to cover both HPC products and therapeutic products. However, this may not align with the existing process for work-up of the donor in preparation for donation. In some cases, it may require an additional blood draw, which is not in the best interest of the donor.
Based on previous clarification from the FDA (which was confirmed by the FACT office in August 2021), the most straightforward way to address this issue is to recognize that separate eligibility determination is NOT required for the T cell product used as DLI if the lymphocytes were collected as a part of the HPC collection. When the donor of the HPC product is screened and tested in accordance with regulations and determined to be eligible for donation, the donor eligibility determination also applies to the remaining portion of the same product that is used for subsequent therapy.
The following example was presented during a FACT webinar by Safa Karandish, MT(ASCP) from the FDA in 2015 as part of a presentation titled, “FDA presents: Using Donor Screening and Testing to Determine Donor Eligibility,” which can be found on the FACT website at: http://www.factweb.org/forms/store/ProductFormPublic/fda-presents-using-donor-screening-and-testing-to-determine-donor-eligibility.
How do you label T Cell products for DLI that were separated from the collected HPC product?
- An allogeneic HPC, Apheresis product was collected from a mobilized matched sibling for a patient undergoing an HPC transplant.
- The sample for donor testing was collected 25 days before the HPC, Apheresis collection. The donor was determined to be eligible based on the results of donor screening and testing.
- A portion of the product was infused, and the remainder was cryopreserved for use post-transplant, as a source of lymphocytes (donor lymphocyte infusion – DLI).
- When the cryopreserved portion of the HPC, Apheresis product is needed for DLI purposes, do we need to consider donor eligibility as incomplete because the specimen for donor testing was obtained more than 7 days before collection of the product?
- Samples for communicable disease testing must be obtained 7 days before or after recovery of the product, with some exceptions.
- For HPC products obtained from peripheral blood or bone marrow, the specimen for donor testing must be obtained up to 30 days before or 7 days after the product collection.
- In the described scenario, the donor of the mobilized HPC, Apheresis product was screened and tested in accordance with the regulations and determined to be eligible for that donation. Therefore, the donor eligibility determination would also apply for the remaining portion of the same product that is used for patient treatment. A second eligibility determination is not required.
Adapted from “FDA Presents: Using Donor Screening and Testing to Determine Donor Eligibility”. Presented by Safa Karandish, MT(ASCP), 2015.
Circulars of Information Contain Important Information for Health Care Personnel
So much information, but so little space on a label. Even the well-designed ISBT 128 labels for cellular therapy products cannot possibly fit all of the information health care personnel need to know about a product. This is where circulars of information come in: these are extensions of container labels that includes the use of the cellular therapy product, indications, contraindications, side effects and hazards, dosage, and administration recommendations.
FACT Standards require Clinical Programs to have a circular of information available to its staff. Other Standards also require the use of biohazard and warning labels as outlined in the interorganizational Circular of Information for the Use of Cellular Therapy Products. This specific circular of information is developed with the input of 13 international organizations (including FACT), the U.S. Food and Drug Administration (FDA), and the U.S. Health Resources Services Administration (HRSA) for nonlicensed, minimally manipulated cellular therapy products such as standard of care hematopoietic progenitor cell (HPC) products.
This circular was updated in June 2021, and the current version can be found on the FACT website. It includes the following topics:
- Cellular therapy product sources.
- Cellular therapy product descriptions.
- Instructions for storage and administration of cellular therapy products.
- Dosing and administration.
- Cellular therapy product labeling and supporting documents.
- Biohazard and warning labels.
- Side effects and hazards.
- Reporting of adverse reactions.
- Table 1A. US Minimal Requirements for Testing for Transmissible Agents in Cellular Therapy Products.
- Table 1B. EU Minimal Requirements for Testing for Transmissible Agents in Cellular Therapy Products.
- Table 2. Biohazard and Warning Labels on Cellular Therapy Products Collected, Processed, and/or Administered in the United States.
At the end of the circular, there is space to include additional information for specific cellular therapy products as needed by the program. Since a new version was released this year, it is a perfect time to re-read and re-train on the content within the circular!
Read the Circular of Information for the Use of Cellular Therapy Products, June 2021
Assessing Outcomes of Non-Traditional Cellular Therapy Products
As cellular therapies expand, accredited cellular therapy programs often become involved in the development, implementation, and performance of protocols and procedures for indications outside of hematological or malignant diseases. Accredited programs must meet the FACT Standards for these nontraditional therapies as they apply, regardless of the patient population served. The lines can become blurred when non-accredited services are also provided in the institution. While accredited Clinical Programs are expected to utilize collection and processing facilities that meet FACT Standards, the converse is not true. An accredited Apheresis Facility or Processing Facility may serve both accredited and non‐accredited clinical programs. A "clinical program" may be simply a medical service in your institution that is not part of your accredited transplant or immune effector cell program, such as neurology or nephrology.
This article will review the responsibilities of Clinical Programs, Collection Facilities, and Processing Facilities for analyzing outcomes of nontraditional cellular therapies. To start, let’s review the requirements for internal clinical outcome analysis. Standards exist in each part of the Standards (clinical, collection, and processing) and all are similar. They require that documentation and review of outcomes and efficacy are outlined in the Quality Management (QM) Plan and/or policies and procedures, that criteria are determined and reviewed at regular time intervals, and that both individual and aggregate data are evaluated for each type of cellular therapy product and recipient.
B/C/D4.7 The Quality Management Plan shall include, or summarize and reference, policies and Standard Operating Procedures for documentation and review of outcome analysis and cellular therapy product efficacy to verify that the procedures in use consistently provide a safe and effective product.
B/C/D4.7.1 Criteria for cellular therapy product safety, product efficacy, and the clinical outcome shall be determined and shall be reviewed at regular time intervals.
B/C/D4.7.2 Both individual cellular therapy product data and aggregate data for each type of cellular therapy product and recipient type shall be evaluated.
If the physicians of the FACT-accredited cellular therapy program have no responsibility for the evaluation or management of patients treated with a cellular therapy, the Clinical Program is not responsible for assessing the efficacy of that cellular therapy because it is administered outside of its control.
However, if the accredited program’s physicians are involved in management of these patients, the Clinical Program is responsible for all aspects of the cellular therapy, whether or not the patients are housed on the accredited program’s unit. If the physicians are involved in the management of these patients, the patients and products are considered part of the program and QM program.
If the patients are housed on the accredited Clinical Program’s unit but the programs’ physicians are not involved, this is essentially "renting space" and considered a "nonaccredited service" ‐ a cellular therapy program existing in the same institution but not under the FACT accreditation. This would not be part of the accredited program or its QM responsibilities.
If collection of nontraditional cellular therapy products is performed within a FACT-accredited Apheresis Collection Facility, the facility is responsible for treating them as it would any other product. All standards for collection apply, including written procedures; training; collection orders; parameters; end points of collection; labelling; transport and shipping; chain of identity/chain of custody; release criteria; and processes to prevent mix‐ups, contamination, or cross‐contamination.
As part of the accreditation process, FACT expects that all cellular therapy products collected be listed on the apheresis collection facility grid, regardless of whether the products ultimately went to the accredited Clinical Program or to patients on another service. If the Collection Facility cannot evaluate efficacy, it should at a minimum evaluate product quality by assessing some designated parameters; for example, achievement of collection goals, contamination rates (or lack thereof), proper product labeling and storage, integrity of the product (e.g., bags are intact).
Measures of cellular therapy product efficacy may be the responsibility of the clinical teams, the FACT-accredited Processing Facility is still responsible for providing a safe product. This includes all the standard laboratory quality attributes: procedures; training; equipment maintenance and calibration; facility cleanliness; chain of identity/chain of custody; labeling; and prevention of mix‐ups, contamination, and cross‐contamination. If performing any processing or cryopreservation of the product, some measure of post‐processing recovery or post‐thaw viability might be used to assess product quality in addition to testing for bacterial or fungal contamination.
FACT would expect all these cellular therapy products to be listed on the Processing Facility grid and incorporated into the QM plan and evaluated as any cellular therapy product.
FACT Joins International Organizations to Renew Support of ISBT 128 Coding and Labeling
In light of continuing adaptation to accommodate the rapidly expanding cellular therapy field, FACT joined 14 other organizations to issue a consensus statement reaffirming its support of ISBT 128 as the global standard for terminology, coding, and labeling of cellular therapy products. With a growing list of stakeholders and cellular therapy products, real-world experiences highlight the importance of standardized terminology, globally unique identifiers, and internationally readability to protect patient safety.
ICCBBA, the organization that manages ISBT 128, has not only retained ISBT 128’s relevance to changes in transplantation and cellular therapy, but has also collaborated with multistakeholder groups to accommodate various needs within its coding and labeling system. This includes the published ISBT 128 Labeling of Collection Products for Cellular Therapy Manufacturing Standard and continued participation on initiatives to streamline chain of identity and chain of custody practices. These are examples of ICCBBA’s abilities to leverage existing standards and infrastructure to meet terminology, coding, and labeling needs that are in high demand.
The consensus statement recognizes the following:
- “the quality and safety benefits of globally unique identification and common and consistent terminology, coding and labeling for all cellular therapy products;
- the importance of an agreed common structured terminology to describe cellular therapy products both for the labeling of product for clinical application, and in the scientific literature to describe the development of products from pre-clinical development, through clinical trials, to clinical use;
- the work done by the ISCT MSC Committee to promote the use of a standardized terminology for mesenchymal stromal cells (MSC) and their source tissue, and the subsequent harmonization between this terminology and ISBT 128;
- the widespread adoption of ISBT 128 as the global standard for the terminology, coding and labeling of cellular therapy products; and,
- the rapidly growing field of cell therapy manufacturing, and the developments within ISBT 128 to provide nonproprietary name and clinical trial specific product description codes.”
The statement goes on to encourage the use of ISBT 128 at all stages of cellular therapy product development, within scientific literature, and by all relevant stakeholders.
Read the full consensus statement
FACT Accreditation a Criterion in the 2020-2021 US Best Hospitals List
U.S. News and World Report released its 2020-2021 Best Hospitals List, and FACT accreditation was again used as a ranking criterion for the cancer specialty. Since 2007, accredited programs receive a point value based on their accreditation. One point was given if accreditation was only for autologous transplants, and two points were given if accreditation was for allogeneic transplants. Congratulations to these programs!
View the list of best hospitals in the cancer specialty
Be the Match Announces Proposed Changes to Collection Center Participation Criteria
The National Marrow Donor Program®(NMDP)/Be the Match® has announced proposed changes to U.S. Apheresis and Collection Center Participation Criteria, which will be published in a combined document.
The changes support simplification and alignment with FACT and/or AABB accreditation. All NMDP/Be The Match apheresis and collection center Network partners are expected to hold the appropriate accreditation or demonstrate application for accreditation by Oct. 1, 2022. If a center is not yet accredited, it should contact the Partner Liaison team at the beginning of 2022 to discuss the plan for pursuing accreditation.
Comments on these proposed changes can be submitted by November 16, 2022 to PartnerLiaisons@nmdp.org. Discussion of the proposed changes can also take place during quarterly meetings with Partner Liaisons in November.
For more details, see the Network website and BeTheMatch.org.
Helen Heslop, MD Elected to National Academy of Medicine
Congratulations, Dr. Heslop!
Dr. Helen Elisabeth Heslop has received the prestigious honor of being elected to the National Academy of Medicine. This honor recognizes outstanding professional achievement and commitment to service in the health and medicine fields, and Dr. Heslop is the epitome of both.
According to the National Academy of Medicine website, Dr. Heslop was elected, “for pioneering work in complex biological therapies, leadership in clinical immunotherapy, and for being the first to employ donor and banked cytotoxic T cells to treat lethal virus-associated malignancies and infections in pivotal trials.”
Not only has Dr. Heslop achieved such remarkable successes for the field of cellular therapy, but she has done so as a servant leader. She dedicates much of her time volunteering for important initiatives to share her knowledge and raise the quality and effectiveness of cellular therapies for health care institutions and patients around the world. Dr. Heslop has tirelessly served FACT as a past President, current chair of the FACT Immune Effector Cell Task Force, and as a co-chair and member of numerous FACT committees such as the Standards and Accreditation Committees. In these positions, she has led FACT-accredited programs, inspectors, and our many stakeholders through transformational changes in the field, embodying the spirit of collaboration in cellular therapy.
Please join us in congratulating and celebrating Dr. Heslop!
Read the full announcement
Free SITC Webinars on Immune Effector Cell-Related Adverse Events Are Now On Demand
SITC created a series of webinars on immune effector cell (IEC)-related adverse events to further educate clinical providers on how to respond to these events. The recordings of the first two are now available on demand. An additional webinar is open for registration. These webinars include:
- SITC Clinical Practice Guideline Webinar – Immune Effector Cell-related Adverse Events (available on demand)
- SITC Clinical Practice Guideline Webinar – Practical Management Pearls for Immune Effector Cell-related Adverse Events (available on demand)
- SITC Clinical Practice Guideline Webinar – Case Studies in Immune Effector Cell-related Adverse (available on demand)
Visit the SITC website for more information.
In late 2020, SITC announced the publication of The Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immune effector cell-related adverse events in the Journal for ImmunoTherapy of Cancer (JITC). FACT was pleased to be a part of this effort, represented by Dr. Elizabeth Shpall, current member of FACT’s Immune Effector Cell Task Force and FACT’s first Board president when it was founded 25 years ago. The guideline addresses risk assessment, identification, and management for clinically significant side effects.