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 centers began to collect 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.

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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 name reflect the content of patients might experience, be observed for, and be the collection or the intent or probable use of the treated for, if necessary. collection? This debate continues. An updated Circular of Information for the Use of Cell Therapy Products was published in 2005. It was FDA Regulation and Guidance prepared jointly by the AABB,America’s Blood Centers As the field of cell therapy and transplantation (ABC),American Association of Tissue Banks,American progressed from a few research centers to much larger Red Cross (ARC), American Society for Blood and operations,potentially affecting more of the population Marrow Transplantation, FACT, International Council of the United States, the FDA became increasingly for Commonality in Automation (ICCBBA), involved. In May 2005, it established labeling regula- International Society for Cellular Therapy (ISCT), and tions pertaining to cell therapy products defined in 21 NMDP. In this document, the interested parties CFR §1271 and covered by the Public Health Service accepted a simplified system of mutually agreed-upon Act (PHSA) in §361.12 21 CFR §1271(c) requires that names, using the abbreviation HPC in place of human cells, tissues, and cellular and tissue-based hematopoietic progenitor cells. The most commonly products (HCT/P) have: collected and labeled products were given the names • a distinct identification code, e.g., alphanumeric, HPC,Apheresis; HPC, Marrow; and HPC, Cord. that relates to the donor and all associated Stimulated peripheral blood did not merit a records that assist in tracking the product from separate product name, as it could only be collected by the donor to the recipient (except in the case of apheresis procedures to get sufficient numbers for autologous or directed family donations, cannot transplantation. Because apheresis procedures could be the person’s name, Social Security Number, or not be used to collect marrow or cord blood,the group medical records number), reasoned that it was sufficient to use HPC,Apheresis as • a description of the type of HCT/P, the name of this product. Similarly, Human Umbilical • an expiration date, if any, and Cord Blood Hematopoietic Progenitor Cells was • warnings, if applicable, as defined in considered too long a name for the label; HPC, Cord – 21 CFR §1271.60. If the donor has not had was accepted. evaluation for infectious disease completed,the This kind of agreement was timely because cord product must be held or shipped in quarantine. blood banking and transplantation opened a whole If the product is released for urgent medical new area of cell therapy.9 Many features were similar need before the evaluation of the donor can be to more traditional blood banking, such as the need to completed, the product must be prominently perform screening and infectious disease testing on labeled with “NOT EVALUATED FOR INFEC- unrelated, anonymous donors and mothers before the TIOUS SUBSTANCES” and “WARNING: Advise units could be banked and offered for general use. But patient of communicable disease risks.” the old system of using name, hospital number, or both – 21 CFR §1271.65. If an HCT/P is from an was clearly inadequate, especially inasmuch as large ineligible donor, but is intended for use under allogeneic, public cord blood banks were being set up special circumstances, such as use in a first- worldwide.10 Establishing agreed-upon product names degree or second-degree blood relative; was a very good direction for a field already exploding reproductive cells or tissue from a reproductive with new uses for cell therapies and new cell products donor who knows and is known by the specific

IMMUNOHEMATOLOGY, VOLUME 23, NUMBER 2, 2007 65 N.R. HALEY AND J.P.MILLER

recipient;or there is an urgent medical need. In ISBT 128 has gained widespread acceptance. As of this case the product must bear the Biohazard 2005, facilities in 40 countries on five continents and legend and the statement: “WARNING: Advise 44 worldwide vendors for software, bags, and labels patient of communicable disease risks.” had registered with ICCBBA to use ISBT 128. The The following information must accompany the number of registrants increases each year. Interna- HCT/P either on the label or in accompanying tional organizations, including the AABB, European information: Plasma Fractionators Association, European Blood • name and address of the establishment that Alliance, and FDA, have endorsed ISBT 128. In June determined that the HCT/P meets release criteria 2000,the FDA issued a guidance document recognizing and makes the HCT/P available for distribution, ISBT 128 as an acceptable standard for uniform • storage temperature, labeling. Despite this acceptance, adoption of the • other warnings, where appropriate, and system has been slow with cost cited as the reason. •instructions for use when related to the However, now that it is being accepted and slowly put prevention of the introduction, transmission, or into use around the country, it seems unlikely that spread of communicable disease. hospitals and centers would be anxious to adopt multiple systems to take care of each cell and tissue type. ISBT 128 Bar-coded Product Labels and Unique Identifiers Minimally Manipulated Products Although there are any number of possible solutions to the internationally readable bar-coded The cell therapy minimally manipulated, label requirements, one system under consideration in homologous-use cell preparations are described in the United States is already internationally accepted. PHSA §361, and the regulations for these products are The Working Party on Automation and Data Processing found in 21 CFR §1270 and §1271. A simple, general of the International Society of (ISBT) bar-coding system as described in a previous section proposed the ISBT 128 system in 1989. The AABB,ABC, for minimally manipulated, homologous-use products and ARC established the Council for Commonality in covered under PHSA §361 has been constructed by a Blood Banking Automation (CCBBA) to implement coalition of industry groups and presented to the FDA ISBT 128 in the United States. The standard,data identi- as an official recommendation. The Office of Cell and fiers, and application specification were developed Gene Therapy (OCGT) at the FDA Center for Biologic between 1990 and 1994. In 1994, the ISBT council Evaluation and Research has considered the naming of approved the ISBT 128 application specification and the minimally manipulated products, and the issue is as established the office for the ICCBBA from the CCBBA yet undecided. The FDA has asked for public comment to ensure that any new standard designed around code on whether NDC codes, the same type of bar codes as 128 would be maintained. In 1995, ICCBBA was those required for pharmaceuticals and highly incorporated (not-for-profit) in Virginia. Facilities processed cell products, are appropriate considering collecting blood, HPC, and tissue and manufacturers of that bar coding is currently required. equipment or software that use ISBT 128 are required to register with ICCBBA, Inc. For further information, More Than Minimally Manipulated Products visit the ICCBBA, Inc., Web site at http://www. What happens if the cell therapy products are iccbba.com. more complex in their preparation and production and ISBT 128 specifies the following: are covered under PHSA §351? They are covered in • use of a unique donation identifier worldwide, regulations by 21 CFR §211 and §600. These more- • data structures for important information on the than-minimally manipulated products will be named by product label, a new plan devised especially for them. A naming plan • the assignment of product codes by ICCBBA, was devised and accepted by the Cellular Therapies • a data structure for software developers to Working Group from the American Medical Association interface necessary input and output messages, and the OCGT. These products will be covered under and PHSA §351,13 meaning that these products must be • a standard label format that ensures a consistent produced under full good manufacturing practices and layout of critical product information. regulatory oversight.

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In this plan, the name of a product is created using regulation. An international standard is desperately the following components to construct the name. needed. For example, one-half of all of the allogeneic • Prefix: established by the United States Adopted bone marrow transplantation products from unrelated Names council to provide uniqueness donors in Australia come from international sources as • Infix: may be derived from the following: reported by Dr. Kerry Atkinson at the 2006 ISCT – manipulation meeting in Berlin. L -gen = transduced; In the United States, if industry does not agree on L -pul = pulsed with peptide or other agent; and present bar codes and labels to the FDA, the FDA L -fus = fused with peptide,cells,or other agent will provide an issued bar code for only those products – cell type, e.g., that are nationally recognized; these will be structured L -myo = myoblast the same as the bar codes issued for pharmaceutical L -isle = islet cell products. This action will limit the computerized L -den = dendritic cell control of both domestic and international products • Suffix that might be required for hard-to-match patients. – -cel (stem for cell therapies); used for all cell Because blood transfusion services are accepting ISBT therapies 128 coding for transfusion components, hospital – -imut (stem for immunomodulators); used for computer systems are being modified to accept this all noncellular cell therapy products, which electronic language internationally. include cell lysates, peptides, or proteins used Cell therapy laboratories are rightfully concerned for cancer vaccines. Substems for these about the expense of installing a new labeling system vaccines are as follows: when they have not been required to have one in the L -lisimut (stem for cell lysates) past. This is a positive aspect because, to date, large L -pepimut (stem for peptides) sums of money have not been spent on competing and L -protimut (stem for protein) incompatible systems. By extending the system that • Qualifiers: letter after hyphen at the end of name the transfusion service will have in place, the – T = autologous regulatory requirements can be met with a system that – L = allogeneic may have extended utility. It is clear that a unique, – X = xenogenic machine-readable as well as eye-readable system will Following these guidelines, a product name would have to be put in place. Using this opportunity to be composed of a prefix, infix 1, infix 2, and a suffix install an internationally recognized system will make with a qualifier. For example, the name for a neuronal future labeling steps more useful in identifying and stem cell would be derived from neuro (infix for the tracking products through the shipping process, cell), prog (second infix for progenitor), and cel (stem integrating the cell therapy products into patient of the product) followed by a qualifier letter T, L, or X charting, and promoting the patient’s safety by using to indicate the source. Similarly, a dendritic cell that the checks and balances available to assure certainty of has been fused with a tumor cell would be a fusdencel. identification that can eventually be extended to both The remainder of this plan, including more cell therapy product and patient. examples, can be found at Web site http://www. ama-assn.org/ama/pub/category/15395.html. References 1. Thomas ED, Buckner CD, Banaji M, et al. One- View of the Future hundred patients with acute leukemia treated by The starting point to solve the current label puzzle chemotherapy, total body irradiation, and is the consensus established by the two circulars of allogeneic marrow transplantation. Blood 1977; information from the professional societies. A label 49:511–33. design task group is now meeting to construct ISBT 2. Thomas ED, Storb R, Clift RA, et al. Bone marrow 128 bar-coded labels for cell therapy products transplantation. N Engl J Med 1975;292:895–902. currently covered by 21 CFR §1271 and by professional 3. Philip T, Armitage JO, Spitzer G, et al. High-dose standards. This is a critically important task because therapy and autologous bone marrow transplan- there are no standard label formats and no widely tation after failure of conventional therapy in accepted label designs although these are required by adults with intermediate-grade or high-grade

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non-Hodgkin’s lymphoma. N Engl J Med 10.Kurtzberg J, Laughlin M, Graham ML, et al. 1987;316:1493–8. Placental blood as a source of hematopoietic cells 4. Kessinger A, Armitage JO. The evolving role of for transplantation into unrelated recipients. N autologous peripheral stem cell transplantation Engl J Med 1996;335:157–66. following high dose chemotherapy for 11. Kolb H, Mittermüller J, Clemm C, et al. Donor malignancies. Blood 1991;77:211–3. leukocyte transfusions for treatment of recurrent 5. Stroncek D, Bartsch G, Perkin HA, et al. The chronic lymphocytic leukemia in marrow National Marrow Donor Program. Transfusion transplant patients. Blood 1990;76:2462–5. 1993;33:567–77. 12. Current Good Tissue Practice for Human Cellular 6. Mavroudis D, Read EJ, Cuttler-Fox M, et al. CD34+ and Tissue-Based Products and Cellular and Tissue- cell dose predicts survival, transplant morbidity, Based Product Establishments; Inspection and and rate of hematologic recovery after allogeneic Enforcement, 69 Federal Register 68611 (2004) marrow transplants for hematologic malignancies. (codified at 21 CFR Parts 16, 1270, and 1271). Blood 1996;88:3223–9. http://www.fda.gov/cber/rules/gtp.pdf. 7. Szczepiorkowski ZM, ed. Standards for cellular 13. 21 CFR 1271.1 (b) (2) therapy products and services. Bethesda: American Association of Blood Banks, 2004. N. Rebecca Haley, MD, (corresponding author) Vice 8. Warkentin PI, ed. Standards for hematopoietic President, Clinical and Regulatory Affairs, Aldagen, progenitor cell collection, processing and Inc., 2810 Meridian Parkway, Suite 148, Durham, NC transplantation. 2nd ed. Omaha, NE: Foundation 27713; and John P.Miller, MD, PhD, Medical Director, for the Accreditation of Cellular Therapy, 2002. National Marrow Donor Program, Minneapolis, MN. 9. Gluckman E, Broxmeyer HE, Auerbach AD, et al. Hematopoietic reconstitution in a patient with Fanconi’s anemia by means of umbilical cord blood from an HLA-identical sibling. N Engl J Med 1989;321:1174–8.

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