Comparative analysis of rule elements for transportation of cell therapy products among regulations and standards

Pharmaceutical modalities are diverse. In addition to conventional small-molecule drugs, antibody-based drugs have emerged. In recent years, although cell therapy products have been used in medicine, regulations for cell therapy products have varied from country to country. A representative example is that of chimeric antigen receptor T-cells, including Kymriah^® (tisagenlecleucel), which was approved in the USA in 2017 [1]. The quality assurance of pharmaceuticals, which determines their efficacy and safety, is indispensable at every stage of delivery to the patient, and this is the same for cell therapy. Cell therapy products must also adhere to current ‘GxPs’, which include GMP [2,3], good laboratory practice and good clinical practice. In the case of cell therapy product manufacturing in Japan, ‘good gene, cellular and tissue-based manufacturing practice' guidelines have been established and are in effect [4]. In addition, manufacturers performing distribution activities with their products must comply with good distribution practice (GDP) [5–8]. It is also necessary to verify transportation, which was added to the Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme (PIC/S) GMP in Annex 15 [9]. The EU’s GDP guidelines [5] incorporate advanced therapy medicinal products such as cell therapy products, whereas Japan’s GDP guidelines [10] exclude cell and gene therapy products [11]. Although cell therapy products are regulated by good tissue practice in the USA [12,13], guidelines on their transport are limited.

The importance of logistics has increased in recent years, making it a strategic tool throughout the product life cycle in cell therapy [14]. Pharmaceutical and biotechnology companies need to build new logistics systems for transporting cell therapy products, which are biological products and require different transport methods than the monoclonal antibodies that have been transported in the past [15]. The transportation of cell therapy products, which are living cells, shares common logistical features with the transport of perishable food products [16] and blood [17], such as temperature control and hygiene control. However, the temperature control requirements for cell therapy products are more stringent because they require a range of temperature controls, from ultra-low temperatures (-150°C or lower) to room temperature, depending on the product. In particular, temperature deviations that lead to low-quality or irreparable autologous cells are unacceptable. In addition, considering the characteristics of cell therapy products and the transportation mode, it is essential to minimize vibrations during transportation [18]. Furthermore, because the use of living cells involves biological risks [16], in the case of cell therapy products that are deemed infectious, the Guidance on Regulations for the Transport of Infectious Substances should be followed [19]. Moreover, in the case of autologous cells, significant efforts are required to manage complex patient-centric supply chains because cell therapy products are manufactured in real time and patients must receive therapy manufactured from their own cells, particularly with autologous cells [15]. For example, it is necessary to establish standardized shipping protocols and product distribution flowcharts to ensure the chain of custody, chain of identity and cell quality through the collection, shipment and receipt stages [20].

As described above, the transportation of cell therapy products is more difficult than that of conventional pharmaceuticals. The EU GDP guidelines [5], which were implemented before the approval of cell therapy products, may not adequately meet the requirements needed to support the transport of cell therapy products. Additionally, some countries do not currently have GDP-like rules for the transportation of cell therapy products. Under these circumstances, the International Organization for Standardization (ISO) enacted ISO 21973 in 2020, which provides general requirements and considerations for transportation service providers, clients and senders to ensure cell quality, safety and efficacy during transportation [21]. Both regulations (GDP) and standards (ISO 21973) exist for the transportation of cell therapy products. Three types of studies have been conducted on the complementarity and dependence between regulations and standards in situations where the two exist together.

First, there are reports on the use of standards by regulators, not limited to the medical field. In certain fields, there is ongoing progress toward the use of relevant international standards as the basis for technical regulations, which is a requirement of the World Trade Organization Technical Barriers to Trade Agreement [22].

Second, in the medical field, regulators have reported the use of standards. The US FDA, for instance, has been reported to be involved in the development of standards that are not under its direct regulation [23]. There is also a growing trend toward the use of standards by regulators. In fact, the guidelines describe the procedures that the FDA follows and the actions it may take during its review and evaluation of requests for standards [24]. The FDA guides on the latest medical technologies and cites standards, and a database of the cited standards is published on its website [25]. It has also been reported that the FDA and other regulatory bodies are likely to incorporate the elements of ISO 21973 into their mandates [26]. However, no specific study has been conducted to determine the elements of ISO 21973 that should be used to develop regulations for cell therapy transportation.

Third, a study analyzing the correspondence between regulations and standards was reported. This study compared the requirements of the Clinical Laboratories Improvement Amendment regulation in the USA with those of ISO 15189; the target scope (targeted product/service and process) of these documents is the same [27]. This study reported that the relationships between regulations and international standards vary across countries. However, no comparative studies have been conducted between regulations and standards with different target scopes. GDP and ISO 21973, which are regulations and standards in transportation, have different target scopes in terms of the coverage of objects and processes (Table 1) and cannot be compared simply.

Thus, by developing a general analytical framework that facilitates the comparison of different document scopes, this study compared one general regulation (GDP) with four transportation standards (ISO 21973 and additional standards). In addition, the differences between these documents were extracted, analyzed and used to develop an ideal transport regulation for cell therapy products.

Materials & methods

Sample selection

Regulation of clinical delivery

In this study, GDP was selected as the regulation governing the transportation of medicines. The oldest GDP is that of the EU, which was enacted in 1994 [5]. Subsequently, the WHO GDP and PIC/S GDP were enacted in 1999 and 2014, respectively [6,7]. PIC/S member countries use the PIC/S GDP as a reference, and each country has established and operates its own GDP. The operational method also differs from country to country; the EU operates in a legally binding manner, whereas other countries do not necessarily do so. Among the various GDPs of each country or region, PIC/S GDP, which is the source of GDP for PIC/S member countries, was selected as the sample for this study.

Standard of clinical delivery

ISO 21973 [25], which was established as the standard for the transport of therapeutic cells, was selected. This document specifies the general requirements and reviews the factors to be considered for the transportation of cells for therapeutic use, including storage during the transportation. Based on studies conducted by the Supporting Industries Committee of the Forum for Innovative Regenerative Medicine in Japan, ISO 21973 was developed by ISO/Technical Committee 276 – Biotechnology. In the standard, the roles of clients and transporters in the transport of cells for therapeutic use are elucidated.

The Foundation for the Accreditation of Cellular Therapy (FACT), an organization founded in 1996, develops guidelines, conducts audits related to cellular therapies and provides institutional accreditation manuals [28]. Among the several standards established by FACT, the FACT Common Standards for Cellular Therapies, Third Edition (hereinafter referred to as the FACT Common Standards), which represents the basic principles of quality in cellular therapy that can be applied to any cell source or therapeutic application [29], was selected as the sample for this study. FACT Common Standards are not transportation-specific standards; they also describe the clinical program, in part B. However, given that part C (collection standards) covers storage and transport from a collection facility to a processing facility or a patient care unit, and part D (processing facility standards) covers storage and transport from a processing facility to the clinical unit, we analyzed both parts.

Standard of general/refrigerated delivery

We also selected ISO 23412, which defines the requirements for general temperature-controlled transportation unrelated to medical products or services [30]. This document specifies the requirements for providing and operating indirect temperature-controlled refrigerated delivery services for refrigerated parcels containing temperature-sensitive goods (including food) during land transportation. It includes all stages of the refrigerated delivery service, from the acceptance (receipt) of a chilled or frozen parcel by the delivery service user to its delivery at the designated destination. The intermediate transfer of refrigerated parcels between refrigerated vehicles or containers via a geographical routing system is also included. This document also includes the requirements for resources, operations and communication for delivery service users. It is intended for refrigerated delivery service providers [30].

The target scopes of the PIC/S GDP, ISO 21973, FACT Common Standards and ISO 23412, which are the documents analyzed in this study, are summarized in Table 1.

Analytical framework

To compare the descriptions of the PIC/S GDP, ISO 21973, FACT Common Standards and ISO 23412, which have different target scopes (transport objects), we developed an analytical framework. This framework covers the transportation process of the objects dealt with in this study, including cell therapy products (Figure 1). To develop our analytical framework, we first defined the value chain-based transportation process. The transportation process was defined as the process from ‘labeling’ to ‘storage’. In this process, ‘acceptance’, ‘intermediate transfer’, ‘sorting’ and ‘receipt’ were defined based on ISO 23412, whereas ‘import and export’ was defined based on PIC/S GDP. This process is summarized in Table 2.

The elements constituting the analytical framework were arranged as essential items. These elements consisted of ‘process-specific elements’, which were items for each transportation process, and ‘process-nonspecific elements’, which included items that were not specific to the transportation process. Process-specific elements are value chain-based processes. Process-nonspecific elements were originally developed based on the description of ISO 23412, which is a general temperature-controlled refrigerated delivery system supplemented with elements necessary for the transport of cell therapy products that are not described in ISO 23412. Process-nonspecific elements are listed in Table 3.

This framework enables a comparison of the contents of the PIC/S GDP, ISO 21973, FACT Common Standards and ISO 23412 for each element within the analytical framework.

Grading degree of description

When comparing documents using this framework, certain elements are described in both documents, but to varying degrees. To evaluate the degree of description in a document, we developed a method based on an existing grading method that analyzes a writing scale composed of the content, structure, expression and accuracy of the sentence [31]. These scales are graded from 1 to 6 in the content analysis. On their content scale, the criteria for grade 6 were ‘orderly, specific and clear’. However, their criterion for grade 1 was ‘a description lacking specificity and quantity’. In this study we utilized the analytical rating scale in content to build our methodology and graded the degree of the description on a four-point scale based on the degree of need. The elements in a document were graded as a single group, even if multiple sections correspond to one element. The level of detail in the description increases from grade 1 to grade 4. The grading criteria were as follows:

• Grade 1: presentation of principles (need to consider practical procedures);

• Grade 2: description of content that should be complied with at multiple points (practical procedures still need to be considered);

• Grade 3: the content that should be complied with on multiple points is described, and specific examples are provided;

• Grade 4: the content to be complied with is described, with subcategories constructed.

Assumptions in the analysis

In conducting this analysis, the assumptions were as follows:

When two documents with different target scopes exist, their target scopes exhibit an inclusion relationship.

• Assumption (1): the descriptions of elements with a wider target scope are more comprehensive than those of elements with a narrower target scope.

• Assumption (2): for elements described in both documents, the extent of the description in the document with a narrower target scope is more detailed than the extent of the description in the document with a wider target scope.

When two texts have a similar target scope, but one covers medical subjects and the other covers nonmedical subjects, the document covering medical subjects is considered to have more items to be complied with.

• Assumption (3): the elements of medical documents are more comprehensive than those of nonmedical documents.

• Assumption (4): for elements described in both documents, the degree of description in the document that covers medical care is more detailed than that in the document that does not cover medical care.

Results

We analyzed the descriptions in the PIC/S GDP, ISO 21973, FACT Common Standards and ISO 23412 for each element using our analytical framework. The correspondence between each element of the analytical framework and each section of the PIC/S GDP, ISO 21973, FACT Common Standards and ISO 23412 is presented in Table 4. The following comparative analysis of documents was conducted based on ISO 21973, the transportation standard for the therapeutic use of cells.

Table 4. Comparison of contents of documents using the analytical framework.

Comparative analysis between PIC/S GDP & ISO 21973

The target scope of ISO 21973 consists of therapeutic cells as transport objects and only transport as a process, both of which are narrower than the PIC/S GDP (Table 1). Based on assumptions (1) and (2), assumptions (1)’ and (2)' were generated, and elements that contradicted these assumptions were identified.

As assumption (1)' was that “The elements listed in PIC/S GDP were more comprehensive than those listed in ISO 21973”, the elements contradicted were ‘acceptance’, ‘traceability’ and ‘non-general operation’. In contrast, as assumption (2)' states, “For elements described in both ISO 21973 and PIC/S GDP, the degree of description in ISO 21973 was more detailed than the degree of description in PIC/S GDP”, four elements that contradict assumption (2)' were identified (Table 5). These elements and a summary of the descriptions leading to each grade are shown in Table 5. These results were unexpected based on our assumptions.

Comparative analysis among ISO 21973 & FACT Common Standards

A comparative analysis between ISO 21973 and FACT Common Standards parts C and D was performed without using the assumptions of the analysis because the target scopes of these standards were almost the same.

Although FACT Common Standards parts C and D shared many parts in common, some elements (‘receipt’ and ‘temperature monitoring’) were not described in part C, while other elements (‘storage’, ‘information to exchange’ and ‘traceability’) in part C had a lower degree of description than in part D. The element described only in ISO 21973 was ‘acceptance’, and the element described only in FACT Common Standards was ‘cold store’. The elements in which the degree of description differed between ISO 21973 and FACT Common Standards part D are listed in Table 6.

Comparative analysis between ISO 21973 & ISO 23412

Although the target scopes of ISO 21973 and ISO 23412 are transportation, ISO 21973 targets medical care, whereas ISO 23412 does not. Based on assumptions (3) and (4) in the analysis, assumptions (3)' and (4)' were generated, and the elements that contradicted these assumptions were identified.

As assumption (3)' was, “Elements of ISO 21973 are more comprehensive than those of ISO 23412”, elements that contradicted this assumption were ‘intermediate transfer’, ‘sorting’, ‘operation site’ and ‘cold store’. In contrast, as assumption (4)' stated that “For elements described in ISO 23412 and ISO 21973, the degree of description in ISO 21973 is more detailed than the degree of description in PIC/S GDP”, four elements that contradicted assumption (4)' were identified (Table 7). A summary of the descriptions of each grade is presented in Table 7. These results were unexpected based on prior assumptions.

Discussion

To develop an ideal transportation regulation for cell therapy products (hereinafter referred to as the proposed regulation), we considered the transportation of cells for therapeutic use based on the international standard ISO 21973. The possible reasons why elements are not described in ISO 21973 and why there are elements with a higher degree of description in documents other than ISO 21973 are considered in Tables 8 & 9, respectively. Most of the possible reasons described in Table 8 are based on the differences in transport characteristics between autologous and allogeneic cell therapy products [32]. On the one hand, possible reasons described in Table 9 are, in essence, differences in the focus of documents. These differences in focus are thought to be a reflection of the differences in main player in each document. Major players are manufacturers and wholesalers for GDP, hospitals for FACT Common Standards and transportation service providers for ISO 21973 or ISO 23412. Each document is focused for its own reasons, but those elements may be important issues for other players as well. Therefore the differences between documents provide hints for designing new regulations. Elements that are not described in ISO 21973 are assumed to be candidates for addition to newly created regulations. Similarly, elements that are described in more detail than in ISO 21973 are candidates for elements that should be described in more detail.

The primary novelty of this research was to identify the differences in descriptions among the selected documents. Although regulations addressing the transport of cell therapy products are not yet in place, no studies have compared the transport regulations and standards for cell therapy. Therefore the identification of differences in the presence or absence of descriptions in each element and the degree of description provided for each element among the one regulation and the four standards analyzed in this study is a new finding. Furthermore, the implications for establishing ideal transport regulations for cell therapy products based on these findings are novel. Another novelty of this study is its methodology. A previous study reported that certain standards that provide a basis or reference for regulations may not necessarily cover the target scope of the regulations [22]. In addition, only regulations and standards with the same target scope have been compared [27]. To the best of our knowledge, this study is the first to compare the description levels of regulations and standards with different target scopes. The comparative analysis in this study was enabled by the methodology used. This novel methodology consisted of the selection of diverse regulations/standards (even if their scopes were different), the construction of an analytical framework covering documents with different scopes, and the grading of the degree of description. In addition, the methodology used in this study for the transportation of cell therapy products could be applied to the development of regulations for other emerging technologies in new areas.

Based on the discussion in the previous paragraph, the issues when developing the proposed regulation for the transportation of cell therapy products could be categorized into the following two situations.

When assuming the transport of allogeneic cell therapy products, intermediate transfer and sorting should be additionally considered based on ISO 21973. Allogeneic cell therapy products, whose demand is expected to increase, may require storage for a certain period during transportation. Multiple products whose destinations are different can be treated as the same shipment until the intermediate stage. In addition, operating sites and cold stores are necessary places for intermediate transfer and sorting. In conjunction with this, temperature mapping in cold stores, as described in the PIC/S GDP, is necessary. Additionally, allogeneic cell therapy products have moved closer to general pharmaceutical products in some aspects of distribution. To correspond to this point, inventory control should be necessary in storage requirements. Moreover, counterfeit drug contamination is possible, and countermeasures against counterfeit drugs are needed.

What should be considered even in the case of autologous cell therapy products, based on ISO 21973, are the requirements for import and export. International transportation has already occurred and has been discussed in the transportation of cell therapy products [33]. In addition, storage at the destination is important when considering the quality assurance of cell therapy products until their administration to patients. Alarm systems, as described in FACT Common Standards part D, should also be added to the storage requirements. Furthermore, the requirements for acceptance, receipt, work instructions and quality management should be detailed to ensure reliable transportation. For example, the process for returning shipments that are found to be defective upon receipt, as described in FACT Common Standards part D, is worth considering.

The framework of this study did not explicitly distinguish between the cells used as starting material and those after processing. GDP generally covers the process from formulation and shipment to delivery to medical institutions. However, because the scope of ISO 21973 includes starting materials, maintaining the quality of starting cells is also important, similar to maintaining the quality of cell therapy products during transportation. Therefore the transportation of cells as starting materials should be included in the target scope of the regulations for the transportation of cell therapy products. However, it is conceivable that the transportation requirements for cells as starting materials may not be as stringent as those required for the final products. Some elements in the FACT Common Standards part C are not described or are described to a lesser extent than those in part D. This may be because it was considered sufficient to meet the release criteria of the final product. However, in the case of autologous cell therapy products, the transportation of cells as a starting material is equally important because any quality loss due to the transportation of cells as a starting material cannot be ignored if the quality of the final product is affected.

To establish governance for the transport of cell therapy products in the short term, a practical and reasonable choice would be to issue a notice requiring ISO 21973 certification to assemble regulations based on GDP with the aid of ISO 21973. However, in the medium term, as proposed in this study, new regulations incorporating the requirements extracted from the element comparison of the five documents should be developed and implemented. When designing a new regulation, options such as whether to set a hard- or soft-law guideline and whether to assume ISO 21973 certification are critical for both innovators and regulators. Because the content of regulations and inspections by regulatory agencies will change depending on these conditions, it is important to examine the requirements for each element and their necessity, together with evidence.

One limitation of this study was that the analysis focused solely on elements of rules selected by rule-makers, which contain essential content for governance, to develop a basic framework for the proposed regulation. While literature was not included as a source for identifying these elements, it could also contain additional information that is important for designing the regulation. Therefore, in the next step of this research, these elements from the literature will also be considered.

Conclusion

This study showed that the methodology of comparing the descriptions in each rule was useful in developing regulations for a new technology area. For the transportation of cell therapy products, we compared one general regulation and four standards: GDP and ISO 21973, which have different coverage of the target scope; FACT Common Standards (parts C and D), which are the same as ISO 21973 in that they target cells for therapeutic use; and ISO 23412, which is a standard for nonmedical fields with temperature control. The presence or absence and differences in the degree of description were determined by constructing an analytical framework that covered the entire process. Based on these differences, the elements that should be reinforced in the detailed regulation of cell therapy product transportation were identified.