Keywords

Introduction

In the global field of cellular therapy, including stem cell transplantation, traceability of the cellular product is of essential importance to be able to ensure the patient’s safety [1]. During the process of donation, transportation, processing and infusion, storage, or disposal, it is critical that the product can be traced from donor to patient and vice versa. Also, in case of any adverse event, such as poor or non-engraftment or infection, traceability is paramount.

Unambiguous identification of a cellular product can only be achieved through unique donation identifiers and uniform, standardized product description. Stem cell products are regularly transported across national borders, thus creating the need for international agreement on product descriptions and unique donation identification.

Another key element in traceability and identification of cellular products is the transfer of product information. To further enhance safety, accuracy and efficiency, increasing numbers of facilities use electronic systems. Transfer of information between such systems also requires international standardisation of electronic donation and product information.

In compliance with the JACIE standards, standardisation and encoding of cellular product descriptions shall be performed according to the ISBT 128 standard terminology or the EuroCode standard.

In this chapter, the basic principles and means to standardisation of product information will be discussed, using the ISBT128 standard as an example. However, these basic principles also apply to the EuroCode standard [2].

Information Environment

Several elements are necessary to create an environment in which information is standardized and transferable between facilities on a global level [1]. Together these elements form the information environment (Fig. 10.1).

Fig. 10.1
figure 1

Information environment [1]

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The base element is terminology. Without a common international understanding of product descriptions, further attempts to standardisation are useless.

Standardisation in terminology is required to be able to make a distinction between variations in the following product characteristics:

  1. 1.

    Cell type and source, for instance the haematopoietic stem cell, can be derived from blood (apheresis), bone marrow or umbilical cord blood

  2. 2.

    Core attributes, such as storage temperature or the type of anticoagulant used

  3. 3.

    Additional modifications, meaning any manipulation that changes the ‘core’ state of the product

Product descriptions vary between facilities, nationally as well as internationally. Variations may relate to, for example, storage temperature, the amount of DMSO used in cryopreservation or additional additives after processing. Standardisation in terminology needs a high level of detail to provide the means to make a distinction between different products or track alternations to a product. Once an international consensus in terminology is achieved, this information can be used to generate a product description, based on the three characteristics as mentioned above.

This information should be managed with great care and be accessible to users around the world.

So, with a consensuson terminology, the next layers in the information environment are the reference tables in which this information is stored. With the provided accessibility, facilities around the world are now able to define their products. By combining this standardized information, a unique description of the product is achieved, which can subsequently be uniquely encoded.

Example 1

An autologous apheresis product which is frozen in 10% DMSO solution, with no other additives:

Source:

HPC, apheresis from a mobilized patient

Core conditions:

 Anticoagulant:

Citrate

 Storage temperature:

≤ −150 °C

Manipulation:

Adding cryoprotectant 10% DMSO

Together this would generate the unique product description:

  • HPC, APHERESIS|Citrate/XX/<=−150C|10% DMSO|Cryopreserved|Mobilized

Example 2

An allogeneic bone marrow product enriched for mononuclear cells (MNC) with added human serum albumin

Source:

HPC, marrow from a non-mobilized donor

Core conditions:

 

 Anticoagulant:

None, removed during processing

 Storage temperature:

Refrigerated

Manipulation:

MNC enriched

Together this would form the unique product description:

  • HPC, MARROW|None/XX/refg|3rd Party Comp:Yes|Mononuclear cell enriched

With the unique product description in place, now one must be able to transfer this information electronically. To achieve this, the product description needs to be converted into a unique, electronically readable, product code and a delivery mechanism is needed, the next two layers in the information environment. Product codes provide the structure and context to be able to decode them to meaningful information. They also provide the link to the reference table so that each product code can be traced to the corresponding product description. Next to the product description, the product code must encode whether or not the product has been divided into separate containers (e.g. a cryopreserved autologous product). Only then, each separate product bag can be traced regarding storage and infusion.

The most commonly used delivery mechanism to transfer information electronically is the linear barcode. As the information that a linear barcode can contain is limited, delivery mechanisms with a higher capacity are also available such as 2D (data matrix) codes. A single data matrix code can hold the same amount of information as several linear barcodes, as shown in Fig. 10.2. The use of a data matrix code is therefore more efficient, especially on smaller labels, and will contribute to a safer and more reliable transfer of electronic information. By using a universal delivery mechanism, such as a barcode, information can now be exchanged between different electronic systems on a global scale.

Fig. 10.2
figure 2

Comparative size of information stored in linear barcode and a data matrix symbol [1]

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In the last layer, all previous elements come together to generate a label that contains all the information, eye-readable and electronic, necessary to identify the product and to be able to process that information to maintain traceability. Standardizing the label format and layout such that critical information is placed at fixed positions, as shown in Fig. 10.3, greatly reduces the risk of errors in the interpretation and (electronic) transfer of information.

Fig. 10.3
figure 3

Standardized ISBT128 label format [3]

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Donation Identification

Product coding alone, however important, is not sufficient in the unique identification of a cellular product. Without the ability to uniquely trace the donation of a cellular product to the original donor, product coding is meaningless.

Unique identification of a donor is hampered by the sheer number of volunteer donors as well as different donor identification strategies used by international centres [4]. To further enhance safety and reliability in donor identification, the WMDA (World Marrow Donor Association) has developed a global donor identifier (GRID). The GRID comprises identifying information about the facility issuing the GRID and a donor identifier.

Next to unique donor identification, the donation itself also needs a unique, uniform identification.

Similar to the GRID, the donation information contains a donation sequence number and identifying information about the facility that issued the donation number, e.g. a collection facility or registry. In the ISBT 128 coding standard, the year in which the donation took place is also embedded in the donor identification number.

Combining Donation and Product Information

In April 2017, legislation became effective to apply the Single European Code (SEC) on tissue and cell products in compliance with Directive 2004/23/EC of the European Parliament. The purpose of the SEC is that donation and product information are represented in a consistent, combined manner, further aiding the traceability of such products. Basically, the first part of the SEC contains the donation information (facility, sequence number) preceded by a country identifier. The second half contains the product information including a split number and the expiry date. Where the donation identification sequence will not change, the product information sequence changes when the core state of the product is altered.

If necessary, products imported from outside the EU for distribution within the EU will be assigned a donation and product sequence assigned by the importing tissue establishment in order to be able to create an SEC. Records of the original donation and product information and the newly assigned SEC should be maintained in order to link this information for traceability purposes.

In summary, the key elements to the effective, safe, and reliable traceability of cellular products are as follows:

  • Unique global donor identification

  • Unique donation identification

  • Global standardisation of product description

  • Data structures to enable digital transfer of information

  • Uniform product labelling