Correct labelling saves lives. That might sound strange given the huge range of labelled products that pose no risk, but in the field of medicine, even a slight mistake in drug dosage can be fatal. The same is true for medical products of human origin (MPHOs), in which biological material from a donor or a patient’s own body is used to create a therapeutic. Unsurprisingly, the most common MPHO is blood. Globally, 118.5 million blood donations are collected every year, and, as Zbigniew Szczepiorkowski, professor of pathology and laboratory medicine at Dartmouth College and chair of the International Council for Commonality in Blood Banking Automation (ICCBBA), points out, 10% of hospital patients will receive a blood transfusion. Relatively few people, in comparison, receive a bone marrow transplant or a bone implant. In contrast, an area that has grown significantly in the past 10-15 years is cell and gene therapies, and these often have special requirements that mean a mistake in the labelling could be fatal.

If correct labelling is important in day-to-day medical practice, then it is even more so in phase 2 or 3 clinical trials, where the possibilities for error are multiplied. The cell- or gene-based product has to pass through several different stages, from apheresis collection through transportation to delivery and infusion, and at each stage mistakes could be made that could put clinical trial subjects at risk. Apheresis centres, for example, often collect source material products for many different clinical trial sponsors or manufacturers, many of whom have different labelling requirements. En route, the product may cross multiple borders and jurisdictions, and frequently a cold chain has to be maintained across the entire journey.

Before a standard labelling system was developed, the methods adopted for labelling products were inconsistent and prone to error. Different organisations used different ways of recording the same information. For example, hematopoietic progenitor cells might be identified by a patient’s name and date of birth, or by their hospital ID number, creating potential for confusion and misidentification once the product had left the hospital. Sometimes, labels were handwritten, meaning poor legibility or missing information could add to the problem.

Accuracy, security and traceability

In 1994, the newly formed ICCBBA introduced a labelling standard, ISBT 128, as a method for labelling blood products. The letters in ISBT 128 stand for International Society of Blood Transfusion, and as a new standard it was comprehensive, mandating standardised terminology for each piece of information on the labels of MPHOs. Every product that conforms to the standard must have the product information encoded in a barcode. But the label must also contain information readable by eye, such as the patient’s name and product description, to reduce the risk of error when products from multiple sources are used. This is particularly useful, says Szczepiorkowski, in countries where there may be no technological means of reading the barcode.

ISBT 128 aims to ensure that information critical to patient safety can pass through the supply chain accurately, securely and in a manner ensuring the product can be traced. As an example, if a recipient experiences an adverse event from an MPHO, other products from the same source can be quickly identified and quarantined.

Standardised terminology for cell therapy

Although the new standard worked well, the landscape of clinical products began to change in the late 1990s. ICCBBA responded by continuing to refine and develop ISBT 128, using technical advisory groups (TAGs) made up of experts to make sure that the standard could adapt to user requirements.

One of the most significant developments has been the growth in MPHOs, and by the turn of the century, some facilities realised that ISBT 128 had the potential to be adapted for use with cellular products. A huge multi-organisational effort spanning multiple countries was required to make the necessary changes, which in 2007 culminated in a standardised terminology for use in cell therapy products.

The new standard had to take account of the importance of maintaining low temperatures, because when certain biological material is transported, any break in the cold chain could have serious adverse consequences. It did this through a new product description database that included three elements: classes (broad descriptions such as cord blood); modifiers, which describe the state of the product (such as “cryopreserved” or “thawed”); and attributes – the elements that make it possible to uniquely identify the product. A mandatory attribute, known as Core Conditions, enables the recording of the storage temperature, which can range from ambient room temperature through to complete immersion in liquid nitrogen.

40 million
The number of products that are labelled with ISBT 128 every year.
National Library of Medicine

A later development involved the creation of a Global Registration Identifier for Donors (GRID), in response to a serious error in 2013, when a patient was given the wrong bone marrow transplant because two registries had used the same identifier for two different donors.

The standard has been an undoubted success. It has been adopted in 80 countries – typically by independent accreditation organisations rather than governments. There are other countries, however, particularly in Africa, where resourcing has proved to be a barrier to adoption. “The problem is that if you don’t have money then it’s difficult for you to print the labels, so they will still do things manually because that is what they can afford,” says Szczepiorkowski. “So their labels, although they may look like ISBT 128 labels, are still filled out in a manual fashion.”

The percentage of the ISBT 128 product description codes (3,000) in the database, that are dedicated to cell therapy and tissue products.
National Library of Medicine

Nonetheless, more than 40 million products are labelled with ISBT 128 every year. These include not only blood and cell products, but tissues (including eye tissue) and human milk. Of the ISBT 128 product description codes in the database, about 25%, or 3,000, are dedicated to cell therapy and tissue products.

“You have to rely on the science of labelling to be sure that the chain of custody is such that at every single point you could be reassured that what you have in your hands is related to the patient at the beginning, so it can go to the patient in the end.”

Crossing borders

Cell and gene products frequently have to be transported across multiple borders. “We have to be able to label those units of bone marrow or stem cells in such a way that we can transport them between the countries fairly easily, so they can be recognised and read in the other country so that we know exactly what’s in the bag,” says Szczepiorkowski.

He notes that cell and gene therapies come in two varieties: Autologous, where the cells are taken from the patient, transported to the manufacturing site for processing, and then returned to the patient; or allogeneic, in which the cells are transferred from one patient to another.

Allogeneic products tend to be more straightforward to handle, in that, once donated, they can be stored and selected once needed. On the other hand, In the autologous process, he points out, the manufacturing site could be in the next building or 5,000 miles away, and the process could vary from days to weeks.

“This final product in an autologous setting is for one patient – it cannot go to another patient,” he says. “Multiple checks on the way have to reassure you that the cells which are sent from your hospital for the manufacturing, and coming back as a new product, are actually the cells from that patient.”

Given what’s at stake, the life of a patient for whom a specific therapy may be their last chance at beating a disease, it is absolutely imperative that no mistakes are made. “You have to rely on the science of labelling to be sure that the chain of custody is such that at every single point, you could be reassured that what you have in your hands is related to the patient at the beginning, so it can go to the patient in the end.”

Flexible coding system

In a clinical trial, the patient (or subject) enrolled in the trial will be assigned a unique code. The coding system needs to be flexible enough to make sure that the code is linked to the subject throughout the entire manufacturing process. To address this, ICCBBA has, in the last two years, developed a split label design for collection products for further manufacturing, so that the ISBT 128 traceability information would be captured on one side of the label, while the other side would provide space for information specific to clinical trial products. The split label design was incorporated in a new supplementary standard, ST-018.

It is not appropriate to assign an internationally standardised product description code to a product that is still at the trial stage, so ICCBBA also developed a mechanism that enables clinical trial sponsors to be assigned a range of unique product description codes for their own use.

“The idea,” says Szczepiorkowski, “is to look at a chain of identity as a process in which the manufacturer has some freedom of calling different things different names, but also there is a stable part which will assure you that the product we collected from the autologous donor, going back to the patient, will be a constant element going through. It doesn’t matter if it’s Bristol Myers Squibb or Novartis – whoever does the study has the opportunity to use their coding in such a way that they know that it’s their patient, their study, but will also be able to connect the patients with the product.”

The success of a standard initially developed for blood products, but which is now being used for a range of other MPHOs is in large part down to its combination of rigour and flexibility. The rigour means that the detail and specificity of the standard vastly reduces the possibility of error, while, as the creation of a split label for clinical trials demonstrates, the flexibility has enabled it to change with the growth in clinical and scientific knowledge.