Labeling of Cell Therapy Products: a Review of the Past and a Look Into the Future

Labeling of cell therapy products: a review of the past and a look into the future N.R. HALEY AND J.P.MILLER In early bone marrow transplantation, the cells This simplicity, however, led to a more complex given were thought to be simple replacements of labeling and tracking situation. The cellular products diseased cells after myeloablative therapies. Today were collected, processed, and frozen for the patient’s human cell populations are often used as agents of future use in the same storage space with other therapy. As the uses and cell varieties have multiplied, patients’ grafts. The labeling consisted mainly of the so has the need grown for a labeling system that works patient’s name and Social Security or hospital number. both inside institutions as well as between widely Because multiple collections of cells from each patient separated sites of collection and infusion. had to be made over time, there was a proliferation of The pioneers in cell therapy were Nobel Prize cells to be frozen and stored together. Sometimes cells winner E. Donnall Thomas and colleagues.1,2 These from patients with similar names were mixed up. bone marrow transplanters reasoned that if the bone When blood centers began to collect apheresis marrow was diseased with leukemia, and an HLA- products for transplantation,it was their practice to put matched sibling could be found, the diseased bone unit numbers on the label in addition to the autologous marrow could be eradicated by total body irradiation patient information. These unique numbers allowed and replaced with donated, matched, healthy bone the centers to use their regular routine for typing and marrow. Their success in the late 1970s was a infectious disease testing. As automation in blood phenomenal innovation for treating a disease that had banking progressed, centers started using bar-coded been commonly fatal. The work was highly experi- numbers. mental, and the bone marrow product was usually The success of autologous and related donor bone labeled simply with the name of the donor and that of marrow transplantation led to an expanded search for the patient for whom it was intended. Distance, time, donors. The related, matched-sibling approach could and processing were not major factors. The matched serve only a small number of patients; only about 30 sibling was brought to the place where the patient was percent of patients had an HLA-matched sibling. In being treated, the cells were collected at that site, and 1987, the National Marrow Donor Program (NMDP) the transplant product was given fresh with minimal began to make HLA matches between volunteer processing. donors and patients for unrelated bone marrow Further expansion of cell therapy soon brought transplantation.5 The labeling problems were now new labeling requirements. In the early 1980s, magnified. Cell products had to be collected and oncologists at the University of Nebraska reasoned that shipped, often across countries and continents, yet if they could get a reduced-disease autologous bone donors were promised anonymity. The NMDP marrow (or later, peripheral blood that was likely to constructed a system in which a unique number was contain engrafting bone marrow cells), they could give handwritten on the label and the label was placed on the patient the same kind of high-dose chemotherapy the product immediately after collection. The that the allogeneic transplant patients were receiving information connecting the number to the donor and and achieve a similar improvement or cure.3,4 Because to the matched patient was held by the NMDP. the patient was the donor, there were no problems The limitations of handwritten numbers soon with finding a match or with graft-versus-host disease. became apparent. Many laboratories around the world IMMUNOHEMATOLOGY, VOLUME 23, NUMBER 2, 2007 63 N.R. HALEY AND J.P.MILLER discovered that the way numbers are written, that product labels must have a linear bar code that especially the numbers 1 and 7, can be very different contains, at a minimum, the drug’s NDC number. The and very difficult to read. Fortunately, because there rule also requires machine-readable information on were seldom multiple products traveling to any one blood and blood component labels. In direct questions location at the same time, and because each product to FDA officials concerning the applicability of this rule was transported by a courier, this did not usually pose to cell therapy products, they confirmed that this a problem. requirement would also apply to cell therapy products. Purpose of Labeling System Product Names A labeling system has several essential tasks. These In the pioneer days of bone marrow transplan- include the ability to: tation, the collected early progenitor cells were called • name and uniquely identify each product, hematopoietic stem cells, whether they came from • state the contents (other than the product) and bone marrow or from peripheral blood. Product names conditions of storage, and were quite freeform in those days, but usually • state the status of the product, namely to contained the name of the source material, such as – state whether the product is fully screened and bone marrow or peripheral blood by apheresis,and the tested for allogeneic use or is for autologous designation stem cells. Sometimes this designation was use only, and more hopeful than factual. – state other circumstances limiting use, includ- Culturing of colony-forming units was introduced ing donor ineligibility, as determined by the in research laboratories in the late 1980s to assess the FDA. regenerative power of the cells collected. These assays, A labeling system should also include: however, were (and still are) difficult to perform in a • standard names for standard products, standardized manner. Also, the cultures took 2 to 3 • a machine-readable labeling process, recognized weeks to grow out and be read, making these assays worldwide, that is also eye-readable (allowing impractical for a graft quality measurement. maximum safety and control of the process In the early 1990s, CD34 surface antigen testing of where computerized management is possible, cells by flow cytometry made it possible to predict but not leaving out locations that do not have engraftment potential. As a result, the term stem cell access to those sophisticated systems), and became suspect for these products,because the testing • labels that meet FDA requirements (at least in the found cells that could speed engraftment but did not United States). always find the earliest cells that assured long-term 6 Unique electronically readable identifiers can be hematopoietic engraftment. This led to use of the 7 incorporated into data systems for continuity of term hematopoietic progenitor cell. The AABB and the product identity through processing. These same data Foundation for the Accreditation of Cellular Therapy systems can be accepted into patient charts and (FACT) standards8 required that products be labeled electronic identification systems in laboratories and with their product name as well as with identifying clinics so there can be no inadvertent substitution of numbers or names. The FACT standards of the day the wrong product at the time of shipping or infusion. required that the word Human also be included in the Current thinking among FDA speakers is that cell label. This led to quite complex and lengthy names, therapy products, when they are more than minimally such as “Human Peripheral Blood Hematopoietic manipulated or are from unrelated donors (are other Progenitor Cells.” Although very descriptive, such long than autologous or related products), should be names took up a lot of real estate on the label, espe- approved by the FDA as biologic products. Thus they cially if the font size was large enough to be readable. would require either an FDA-approved investigational Another problem was that different institutions had new drug application or a biological product different names for the same cell therapy products. It application. The FDA published a rule in February was difficult to know whether products with similar 2004 that human drug and biologic products would be names met the same specifications or were collected required to be labeled with a National Drug Code and stored in the same way. They needed a common (NDC) number (21 CFR 201.05). The final rule requires language. 64 IMMUNOHEMATOLOGY, VOLUME 23, NUMBER 2, 2007 Labeling of cell therapy products Circular of Information Product Names to be named. For example, doses of cells rich in A group of cell therapy leaders drawn from the lymphocytes from the allogeneic bone marrow donor professional groups involved in writing standards for were found to be useful after transplantation to treat the field met in 2001 to create a circular of information leukemia relapse and facilitate more complete for cell therapy products (published in 2002). engraftment of the donor immune system in the Although circulars of information had been previously recipient.11 These collections targeted T lymphocytes, required by the standard-setting organizations, they not HPC. Should they be named Donor-specific were quite variable in content and complexity. This Lymphocyte Infusions (DLI), Therapeutic T Cells, or new group agreed that the basic elements should Therapeutic Leukocyte Infusions, because one could include general descriptions of the products, their not guarantee that all the cells collected were T common uses, and possible adverse consequences that lymphocytes? Should the

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