Global Registration Identifier for Donors (GRID) of Hematopoietic Stem Cells: Road to Automation and Safety

At the time of the Persian Gulf War (1990-1991) the need for blood products became essential, and requests from different countries in a variety of sources were made. This massive and rapid use of donated blood revealed major problems in labeling and barcoding [1]. A report of the US Department of Defense summarized thousands of labeling mistakes and listed key sources of errors: different labeling languages, errors in barcode substitutions, non-standardized donation identification start codes, improper start codes in registration number, duplication of donation numbers, noncompliance with labeling guidelines [2]. To overcome these problems, the International Society of Blood Transfusion (ISBT) created a new coding system called ‘ISBT 128' using a uniquely defined product identifier and standardized barcode information. The ISBT, the American Association of Blood Banks (AABB), and the American Red Cross established the International Council for Commonality in Blood Bank Automation (ICCBBA) to manage and develop the standard [1,2,3,4]. In 2005, a serious problem concerning tissue recovery was discovered, in which an organization recovered donors without their families' permission or any adequate medical screening, finally resulting in many falsified records. More than 8% of tissues distributed all over the world at any one time were untraceable [5]. After this scandal, the US Center for Disease Control and Prevention (CDC), the Food and Drug Administration (FDA), and the Health Resources and Services Administration (HRSA) convened a workshop including members of blood, organ, and tissue communities as well as government representatives. The main conclusion was to increase safety by developing a communication network for tracking and reporting of distributed organs and tissues with the prerequisite of a unique donor identifier [6]. At the same time, the new Cellular Therapy Coding and Labeling Advisory Group also came to the conclusion that, because of increasing numbers of exported hematopoietic stem cell (HSC) products, distinct identification codes linking donors and products are mandatory for traceability [7]. In 2010, the World Health Assembly Resolution WHA63.22 called on member states to ‘encourage the implementation of globally consistent coding systems for human cells, tissues, and organs as such in order to facilitate national and international traceability of materials of human origin for transplantation'. ICCBBA is working closely with the World Health Organization (WHO) in order to achieve this objective using the ISBT 128 Information Standard [8]. In 2015 the European Commission finalized the requirements for a Single European Code (SEC) for tissues and cells as a common format representing the information required in the EU [9]. Currently, there is wide recognition of the need to standardize the terminology, coding, and labeling of medical products of human origin in order to improve traceability and transparency [10].

The explicit identification of unrelated donors is an inherent part of the hematopoietic stem cell transplantation (HSCT) field since its beginnings. During the 1990s the first big shift evolved from the use of HSC products within spatially determined institutions to regional distributions within clinical networks and groups [11]. No later than in the 2000s, the second big shift evolved towards international distribution, irrespective of borders [12]. Both shifts extended the varieties of donor identifiers to be dealt with, hence intensifying the requirement of interoperability. With respect to the reported problems of the whole blood field, and to prevent impractical or even inconsistent regulations, it was an important step for the World Marrow Donor Association (WMDA) to become active.

In this article, we will discuss the envisaged implementation of a new global donor identifier (ID) in relation to existing problems, projected changes, and the challenges of a proactive and collaborative project involving many departments and organizations on a national and international level. The most important and most frequently asked question is: ‘Why do we need a globally standardized donor ID although we already have a consistent taxonomy in our country?' First, we should consider two different aspects of IDs: eye-readable and electronically readable presentations. A person's cognitive process often fade out unnecessary parts like delimiters (e.g. spaces) between parts of IDs whereas IT systems simply count every single character. Taking that into consideration, the initial assumption of having a unique donor ID within a country is often not true. In practice, many more problems can result in a time delay for the patient or the risk of choosing the wrong donor (table 1).

Several incidents of donor mix-ups were reported, from recoverable mistakes in handwritten IDs to a completely HLA-mismatched allogeneic unrelated HSCT due to a series of inadvertences and lack of controls (table 1) [13].

Each organization that starts recruiting donors is confronted with the same question: ‘What kind of taxonomy will be implemented for determination of a donor identifier?' As long as there is no common standard, individual solutions will be used, resulting in a global ‘alphabet soup'. When the first transport of HSCs crosses borders, it requires every country (including all involved organizations) to ensure acceptability of and acquaintance with all existing donor ID formats. This leaves the organizations receiving requests, blood samples or HSC products with two possibilities: either simply accepting all incoming IDs without any kind of plausibility check, or setting up an extensive test system based on as many control procedures as possible. An exemplary part of the list of German National Bone Marrow Donor Registry's (Zentrales Knochenmarkspender-Register für die Bundesrepublik Deutschland; ZKRD) cooperating registries and, if applicable, their donor ID formats, are shown in table 2.

As shown in table 2, there are plenty of formats using different lengths, numeric or alphanumeric coding, added characters, miscellaneous delimiters, or even multiple variations within some countries. Even after a number of inquiries, it was not possible to define rules applicable for all organizations facilitating HSCT. In addition, keeping this list up to date became more challenging over time. Despite this, and taking into account the hundreds of donor IDs search or work-up coordinators have to deal with in their daily work, today we are able to detect many, if not substantially all, errors. How is it possible to reduce the error rate towards a minimum, thus improving safety of patients and donors?

In 2005, 7,921 HSC products were collected and a total of 10,730,712 donors were registered worldwide. A substantial portion, 39%, of collected HSC products were shipped abroad, i.e. involved two donor ID numbering schemes [14]. With increasing numbers of donors, collections, and international shipments (2016: 17,297 HSC products; 30,973,284 donors; 50% shipped abroad [12]), the WMDA recognized that a standardized donor identification is necessary to fulfill future requirements in the field of HSCT. The GRID was designed to be compatible with both IT-based systems and manual transfers, allowing the transition to safer technological solutions to develop alongside existing manual systems. The purpose is to uniquely identify HSC donors on a global scale, facilitate communication, prevent errors in identification, and provide a standard machine-readable format (e.g. barcode scanner) for electronic processing as well as a standard eye-readable format [15]. Until 2010, a WMDA project group in cooperation with the ICCBBA developed a donor identifier called Global Registration Identifier for Donors (GRID), which was first approved by the WMDA board in 2014 and revised before implementation could start in 2017. The major changes are summarized in table 3.

In HSCT, several options of cell sources are available. Siblings or other relatives do not need a special identifier, since the number of family members is usually manageable, patient and donor know each other, and no difficulties in documentation and product tracing are expected. Consequently, the GRID concept initially included potential donors of unrelated HSCs, and also cord blood products. This, unfortunately, would have mixed the distinct paradigms of a person (donor) and a product (HSCs from umbilical cord blood cryopreserved long time ago). Grafts are products in a pharmaceutical sense, and are legally obliged to bear a donation number [9]. An umbilical cord blood unit is a product including a unique donation number from the beginning. Due to other obligatory systems for tissues and cells of human origin like ISBT 128 and the SEC for the terminology, identification, coding and labeling [16], it was decided to abandon GRID for umbilical cord blood products and to focus on registered unrelated HSC donors.

To achieve optimal traceability, the so-called ‘GRID for life' concept was initially envisaged, meaning that once a GRID is assigned to a donor, the donor will keep this GRID permanently, independent of temporal and spatial migration behavior. To accomplish such a goal, a huge effort would have had to be taken to enable every single partner to implement the concept. Thus, the concept of ‘GRID for life' was withdrawn, allowing every issuing organization (IO) to assign a new GRID to an existing but relocated donor.

The fact that an external check character can be easily omitted in manual transfers led to the decision of using an integral checksum, taking into account the current and future situation of some small- and medium-sized registries.

To facilitate accurate manual transcription a standardized layout for the eye-readable presentation of the GRID has been specified using blocks of characters in a 4,4,4,4,3 pattern. Consistency of electronic presentation is achieved by use of the ISBT 128 standard data structure 039 that includes the data identifier ‘&:' specifically reserved for the GRID [17]. The structure that met all criteria defined above is shown in fig. 1.

The GRID must be of a fixed length of 19 characters, composed of three specified elements (fig. 1, E1-E3). The first four-digit number represents the issuing organization number (ION), which is allocated by ICCBBA in collaboration with the WMDA and provides the necessary part to create uniqueness on a global scale. The last two digits of the GRID (E3) display the checksum as internal part of the GRID for validation of manual data entry, in order to detect the misidentification of HSC donors due to transmission or typing errors. Element 2 provides space for 13 alphanumeric characters for integration of the existing or newly assigned ID prefixed with leading zeros if required. In Germany, IDs for HSC donors are assigned locally by donor centers but listed in the central database of the ZKRD to ensure comprehensive results for donor searches for national and international patients. Therefore, arbitrary three-digit numbers were assigned to all German donor centers (positions 5-7), that are called donor center number (DCN). This additional element is necessary to fulfill the requirement of uniqueness (fig. 1, E1) and limits the length of donor identifiers to 10.

Regarding privacy, the coding elements ensure donor anonymity as the ION is the only part publicly available and traceable. In order to ensure a long-term usage of the GRID, the WMDA and ICCBBA entered into a memorandum of understanding, defining mutual benefits and interests, arrangements, and the annual license fee for the use of ION that will be charged to GRID issuing organizations [18]. The ION definition provides sufficient alternatives for inactivation, reactivation, or the assignment of new issuing organization numbers in the future. In order to guarantee uniqueness, reassignment of previously existing IONs is not allowed [15].

Any successful project requires a clear goal, open and honest communication, a specified timetable including appropriate transition periods, and a collaborative implementation process involving all relevant collaborators and stakeholders. After dismissing the idea of using GRID for umbilical cord blood products, the new goal is to achieve a globally unique ID for donors of hematopoietic stem cells to guarantee a high level of safety. What kinds of entities are involved? At the top level is the WMDA, a global association that strives to facilitate the exchange of high-quality blood stem cells for clinical transplantation, and to promote the interests of donors. There are substantial differences between the roles and operational models of WMDA members to facilitate HSCs for transplantation in various countries. Figure 2 shows, for example, ZKRD's role in relation to its major stakeholders.

From the recruitment of a donor up to the final infusion of the transplant, the donor ID is the central identifying attribute throughout the entire process, enabling anonymity, or more precisely, pseudonymity and traceability. In this long process, many different organizations are involved, either on the side of the donor or the patient. Donor centers are competent in recruiting and communicating with their donors and incorporate or collaborate with collection centers responsible for collection and preparation of the HSC products. Transplantation centers attend to the patient and, if indicated, initiate the search for an unrelated donor, either directly or via a collaborating search center which requests a match list of potential donors, in Germany supplied by the ZKRD, to identify the best donor possible. Both, patient and donor side cooperate with HLA laboratories to initially type or confirm patients' or donors' HLA data. Finally, when a donor meets all criteria and a product is collected, the transportation of the HSCs to the patient is performed by courier companies or trained volunteers.

Once the GRID is incorporated into the first IT system, it should remain there over the whole supply chain, meaning that all involved partners should be able to handle the GRID without manual transfers or transcriptions into other ID schemes. In Germany there are 26 donor centers, 18 search centers, and 72 transplantation centers cooperating with the ZKRD for unrelated HSCT using many different IT systems [19]. This means that there is a high variability and that many individual adjustments have to be done to adopt the new standard in each center. Therefore, the big challenge for a successful implementation in Germany and worldwide is to clearly show future advantages in interdisciplinary interactions with respect to automation and to emphasize an overall increase in safety for patients and donors at any stage of the whole complex process. This challenge is a balancing act between standardized rules and definitions in the consensus of WMDA as well as the consideration of all variable requirements from the biggest to the smallest stakeholder. Our approach to solving this problem is first to share all necessary information on a common platform, which is available to all German partners. Second, to provide a ready-to-run system for search purposes and requests as well as a system with the interface to directly incorporate donors into the central database. Finally, the ZKRD shares new developments with the entire community involved in the process so that all partners benefit from the most up-to-date information and overall efforts and costs are reduced. Nonetheless, to reach maximum quality, the most important part is the collaborative work towards the common goal, meaning that every single partner contributes to the success of the project as a whole.

What is needed to achieve a successful outcome of implementing the GRID? In figure 3 the ten most important steps under the umbrella of the WMDA are outlined, and setbacks of the GRID project that occurred in the past are shown. The repeated setbacks resulting in inclusion of more and more representatives of registries that had already begun with the implementation of GRID, clearly indicates the utmost importance of collecting project requirements as early as possible and providing all stakeholders with up-to-date planning. A specific schedule defining distinct limits and including well-defined transition periods that are adaptable for every country has to be provided. We think adhering to a top-down approach is of paramount importance, allowing the partners to implement the GRID and populate the database with reassigned and newly assigned GRIDs, not showing them until a globally concerted point of time.

Another important aspect will be how to make available the display of listed GRIDs. For search purposes, in particular the generation of long lists of potential donors, the GRID will be the mandatory ID. For example, it is imperative when requesting extended or verification typing but will not be essential for the physicians to make their final decision. In the global comprehensive database Bone Marrow Donors Worldwide and the data exchange system European Marrow Donor Information System all relevant information, i.e. origin of registered donors or non-HLA criteria, is already implemented as separate attributes. It means in effect that the actually practiced procedure of deriving information from the donor ID will change with the introduction of the GRID, mainly focusing on attributes and building the foundation for future filtering or sorting and real-time updates.

For the work-up process, the goal is to make forms redundant by providing and transferring information, whenever possible, in an integrated systemic way. Therefore, once a GRID has been incorporated into the database, no manual transcription must occur. In case of necessity of a hardcopy or printed document, there should also be a possibility of generating reports at every relevant step. Where manual entry of a GRID into an IT system occurs, it is essential that the receiving IT system performs a checksum calculation to verify the integrity of the number entered.

After the collection of HSCs, the resulting product must be labeled as described in the German Standards for Unrelated Blood Stem Cell Donations according to current laws, guidelines, and regulations [20,21,22,23]. Examples of potential future labels for a HSC product newly distributed are shown in figure 4. All potential IDs, including the SEC with its integral parts, the DIS (donation identification sequence) and the PIS (product identification sequence), as well as the GRID, are included as eye-readable numbers and the GRID additionally as a scanner-readable barcode. To differentiate between different identifiers on a product label, both the SEC and the GRID have to be preceded with the respective uppercase letters and a colon, i.e. ‘SEC:' or ‘GRID:' [9,15]. The other information currently mandatory in the Eurocode Standard or in the ISBT 128 international standard is depicted on the labels (fig. 4A,B). Due to limited space on a label and the growing need to include further information, in the future, new qualities of barcodes, like 2D barcodes and other developments, will be required.

Seen from an operational point of view, we are only one step away from combining all essential information on the product label within a 2D barcode, allowing for the secure and anonymous transfer of information and traceability from the donor to the recipient. Considering the fact that very different regulations are defining individual labeling instructions (legal vs. community-based regulations; national vs. international regulations), this will be the main obstacle to overcome in the future by uniform global standards.

In a changing world with continuous technological progress, rapid migration around the globe and ever increasing processing speeds, accomplishing global standards which can guarantee high levels of safety for patients and donors by preventing errors is becoming more and more important. In order to meet the needs for donors in the field of HSCT, the GRID was developed and still has to undergo global implementation, overcoming all obstacles. To quote Henry Ford after his successful production and commercialization of self-propelled vehicles: ‘If I had asked people what they wanted, they would have said faster horses'. This enlightening quote exemplifies the importance of a vision for our collaborative pursuit of a promising goal.

We would like to thank all participants who contributed to the development of the GRID from beginning until today. Our special thanks go to Martin Maiers, Jack Bakker, Felix Bussmann, John Ord (Subcommittee of the Working Group Information Technology) for their great and pioneering work in developing the GRID, Dr. Julia Pingel (Chair of the Working Group Quality and Regulation) and Salmah Ahmed (Chair of the GRID Task Force) for their persistent pursuit of the project and Pat Distler (ICCBBA) for her manifold support to realize standardization.

We thank Dr. Heiko Müller (IMP Computersysteme AG) for his support in generating an exemplary HSC product label.

The authors have no conflict of interest to disclose.