ISO 20404:2023

INTERNATIONAL ISO
STANDARD 20404
First edition
2023-04
Biotechnology — Bioprocessing —
General requirements for the design
of packaging to contain cells for
therapeutic use
Biotechnologie — Bioprocédés — Exigences générales pour la
conception d'emballages destinés à contenir des cellules à usage
thérapeutique
Reference number
© ISO 2023
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ii
Contents Page
Foreword .iv
Introduction .v
1 Scope . 1
2 Normative references . 1
3 Terms and definitions . 1
4 General strategy for packaging design . 3
4.1 General . 3
4.2 Configuration of cells for therapeutic use . 4
4.2.1 General . 4
4.2.2 Suspension of cells . 4
4.2.3 Tissue. 4
4.3 Process of containing cells for therapeutic use in packaging . 5
4.4 Disturbances in storage and transportation including contamination . 5
4.5 Impact on external environment when cells for therapeutic use leak from
packaging . 5
4.6 Interaction between cells for therapeutic use and packaging . 5
4.7 Usability of packaging in clinical facilities . 5
4.8 Environmental impact . 5
5 Design for packaging .5
5.1 General . 5
5.2 Enclosing process . 5
5.2.1 Explanation of the enclosing process . 5
5.2.2 Packaging for the enclosing process . 6
5.3 Processes from enclosing to usage . 6
5.3.1 Disturbances that affect cells for therapeutic use. 6
5.3.2 Leakage . 7
5.3.3 Interactions between cells for therapeutic use and packaging . 7
5.4 Usage . 9
6 Implementing packaging design .10
6.1 General . 10
6.2 Shape . 10
6.3 Layers . 11
6.4 Ports . 11
6.5 Packaging materials. 11
6.6 Communication between packaging supplier and packaging user . 11
7 Quality management .12
8 Examples of test methods .12
8.1 General .12
8.2 Test methods related to disturbance .12
8.3 Test methods related to leakage .12
8.4 Test methods related to interaction between cells for therapeutic use and
packaging . 12
8.5 Other test methods .13
Annex A (informative) Illustrated examples of packaging, packages and shipping
containers .15
Bibliography .18
iii
Foreword
ISO (the International Organization for Standardization) is a worldwide federation of national standards
bodies (ISO member bodies). The work of preparing International Standards is normally carried out
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www.iso.org/iso/foreword.html.
This document was prepared by Technical Committee ISO/TC 276, Biotechnology.
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iv
Introduction
Medicinal products containing cells as active substances, which are employed in cell therapy or gene
therapy, are expected to deliver novel therapeutic value to patients who are currently untreated or
under-treated. These products have potential capabilities to repair, replace or regenerate tissues
affected by disease or injury. Development of such products is at the forefront of scientific innovation.
Therefore, manufacturers of cells for therapeutic use are expected to maintain product quality
throughout the product life cycle by continuously improving their ability to process cells with advanced
technology.
Cells for therapeutic use are complex products, as compared with conventional pharmaceuticals.
They are produced in a variety of culture systems, such as a system in which cells are suspended
in a medium, or a system in which tissue formed by cells is immersed in a medium. At the point of
their administration, various methods such as surgery or infusion are applied. In addition, special
attention is taken in their storage and transportation, which is not always considered in conventional
pharmaceuticals. This includes the need to store products in a precisely controlled, closed environment
to prevent contamination by foreign substances (viruses, bacteria, mycoplasmas, etc.) at a certain
temperature, such as culture environment or at a cryogenic temperature. Even with these complexities,
it is indispensable to maintain the quality of cells for therapeutic use from manufacturing to usage.
Packaging is important for cells for therapeutic use to keep their quality. Therefore, a standard for
packaging to contain cells for therapeutic use is necessary. Existing standards, such as ISO 3826-1,
however, do not provide information for handling cells for therapeutic use.
This document provides general requirements to design packaging intended to contain cells for
therapeutic use. It provides useful information for packaging suppliers to manufacture packaging with
consideration given to the specific configurations needed for cells for therapeutic use. It is also useful
for packaging users when they need to consult with packaging suppliers for custom-made packaging.
This document is intended to help packaging suppliers to design and manufacture packaging in
consideration of enclosing, storage, transportation, and utilization processes of cells for therapeutic
use. This document is also intended to help packaging users to design and employ packaging in
consideration of the above-mentioned processes.
v
INTERNATIONAL STANDARD ISO 20404:2023(E)
Biotechnology — Bioprocessing — General requirements
for the design of packaging to contain cells for therapeutic
use
1 Scope
This document specifies general requirements and considerations for the design of packaging used to
contain cells for therapeutic use.
This document is applicable to packaging intended to contain the final products of cells for therapeutic
use, as well as their starting and intermediate materials.
This document does not apply to:
a) receptacles used for processing cells in manufacturing processes, e.g. cell culture flask or bag;
b) shipping containers containing packages for transportation;
c) services that utilize packages, e.g. storage services.
NOTE 1 Examples of packaging, packages and shipping containers are illustrated in Annex A.
NOTE 2 The design of packaging includes processes to ensure that the designed packaging is manufactured to
a required specification through trial manufacturing, testing and implementation of quality management.
NOTE 3 International, national or regional regulations or requirements can also apply to specific topics
covered in this document.
2 Normative references
There are no normative references in this document.
3 Terms and definitions
For the purposes of this document, the following terms and definitions apply.
ISO and IEC maintain terminology databases for use in standardization at the following addresses:
— ISO Online browsing platform: available at https:// www .iso .org/ obp
— IEC Electropedia: available at https:// www .electropedia .org/
3.1
cells for therapeutic use
product containing cells as the active substance
EXAMPLE Cell therapy medicinal product, tissue engineered product.
Note 1 to entry: The term “cells” refers to cells and tissues (3.12) for autologous, allogeneic and xenogeneic use.
Note 2 to entry: This term includes cells as starting materials and those cultured as intermediate materials of the
product.
Note 3 to entry: The term “therapeutic use” includes clinical research, hospital exemption and testing use.
Note 4 to entry: Cells for therapeutic use are often used with additional components. Furthermore, they are
sometimes shipped with a pre-treatment drug, concomitant drug or coping drug.
[SOURCE: ISO 21973:2020, 3.1, modified — Notes 2 and 3 to entry modified. Note 4 to entry added.]
3.2
package
packaging (3.3) with its contents
Note 1 to entry: The term “contents” includes the following:
a) cells or a suspension of cells (3.11), or both;
b) buffer or medium where a) is immersed;
c) additional components, e.g. cryopreserving agent, pre-treatment drug, concomitant drug, coping drug.
Note 2 to entry: Examples of packages are illustrated in Annex A.
[SOURCE: ISO 11683:1997, 3.3, modified — Notes 1 and 2 to entry added.]
3.3
packaging
form of receptacle intended to contain cells for therapeutic use (3.1)
Note 1 to entry: In the field of transportation, packaging can be considered as the primary receptacle.
Note 2 to entry: Examples of packaging are illustrated in Annex A.
3.4
packaging material
material used in primary packaging (3.7) and secondary packaging (3.8)
3.5
packaging supplier
entity who either manufactures or supplies, or both, packaging (3.3) for the packaging user (3.6)
3.6
packaging user
entity who makes use of packaging (3.3) for cells for therapeutic use (3.1)
Note 1 to entry: The packaging user includes the manufacturer of cells for therapeutic use and the provider of
starting material, e.g. a cell bank, blood bank, clinical site.
Note 2 to entry: The term “packaging user” excludes clinical facilities and clinical workers.
3.7
primary packaging
packaging (3.3) that comes into direct contact with cells for therapeutic use (3.1)
Note 1 to entry: This term can be used in the singular form or the plural form.
Note 2 to entry: Primary packaging is designed to come into direct contact with additives, substrates or
preservation solutions.
Note 3 to entry: The content of cells for therapeutic use can have various compositions, which can also be in close
contact with the packaging.
3.8
secondary packaging
packaging (3.3) that contains one or more primary packaging (3.7)
Note 1 to entry: This term can be used in the singular form or the plural form.
Note 2 to entry: Secondary packaging can have single or multiple layer(s).
3.9
shipping container
type of container intended to contain and protect packages (3.2) during transportation
Note 1 to entry: Examples of shipping containers are illustrated in Annex A.
Note 2 to entry: A shipping container can have functionalities such as repeated use, temperature-regulation, gas
composition-regulation and traceability.
3.10
storage container
part of container intended to protect packages (3.2) during storage
3.11
suspension of cells
individual cells or aggregates of cells dispersed in a liquid matrix
Note 1 to entry: The liquid matrix can include viscous or gel-like matrices.
[SOURCE: ISO 20391-2:2019, 3.1.6, modified — Term changed from “cell suspension”. “individual cells”
replaced “single cells” in the definition. Note 1 to entry added.]
3.12
tissue
organization of cells, cells and extra-cellular constituents, or extra-cellular constituents
[SOURCE: ISO 11139:2018, 3.303]
4 General strategy for packaging design
4.1 General
Cells for therapeutic use are stored and transported within packaging from the cell-supplying site
to the manufacturing site, or from the manufacturing site to another manufacturing site, storage or
clinical site. The cells are in direct contact with the packaging. Table 1 summarizes the general strategy
for the design of packaging for cells for therapeutic use. Table 1 shows the factors that are important
when using or manufacturing packaging for cells for therapeutic use. Table 1 also provides cross-
references to the requirements for packaging, packaging design and applicable test methods given in
this document for each factor.
Table 1 — General strategy for the design of packaging for cells for therapeutic use
Factor Requirement of Packaging Applicable test
packaging design methods
Configuration of cells for therapeutic use Not applicable 6.2 Not applicable
(see 4.2)
Process of containing cells for therapeutic 5.2 6.2, 6.3, 6.4 Not applicable
use in packaging (see 4.3)
Disturbances in storage and transportation 5.3.1 6.2, 6.3, 6.4, 6.5 8.2
including contamination (see 4.4)
Impact on external environment when cells 5.3.2 6.2, 6.3, 6.4 8.3
for therapeutic use leak from packaging
(see 4.5)
Interaction between cells for therapeutic 5.3.3 6.3, 6.5 8.4
use and packaging (see 4.6)
Usability of packaging in clinical facilities 5.4 6.2, 6.3, 6.4 8.5
(see 4.7)
Environmental load (see 4.8) Not applicable 6.5 Not applicable
4.2 Configuration of cells for therapeutic use
4.2.1 General
One of the significant characteristics of cells for therapeutic use is that they have various configurations.
Therefore, the configuration of cells for therapeutic use shall be taken into account when designing,
manufacturing and using the packaging. In this document, the configuration of cells for therapeutic use
is categorized into two types: suspension of cells (see 4.2.2) and tissue (4.2.3).
4.2.2 Suspension of cells
Since cells for therapeutic use in the category “suspension of cells” are dispersed in a medium in the
packaging, the methods applied to administer this type of cells to patients in clinical facilities can be
intravenous infusion, injection, catheter, etc. Examples of preparation work for administration at clinical
facilities include dilution and removal of the storage solution used during storage and transportation,
or transfer from packaging to an administration device, or both, if not directly administered from the
packaging.
NOTE Examples of clinical facilities include hospitals and authorized infusion centres.
4.2.3 Tissue
Cells for therapeutic use, which maintain their organized structures by coexisting with biomaterials
such as collagen and those supported by scaffold, are included in the category “tissue”.
Tissue often has a function closer to that of a living body than individual or aggregated cells dispersed
in a solution, and the function is often maintained by retaining the structure that resembles the tissue
from which the cells are derived. Therefore, maintaining structural integrity and cell viability during
storage and transportation shall be taken into account for the packaging design.
In addition, surgical treatment is generally the method used for administering this type of the cells
to patients. Therefore, either packaging selection or design, or both, shall take into account the
environment in which the cells are used in clinical facilities.
NOTE Tissue can include primary as well as artificially generated tissues, such as microtissues or other in
vitro generated tissue-like structures.
4.3 Process of containing cells for therapeutic use in packaging
A suspension of cells shall be contained in the packaging together with the dispersion medium, such as
a storage solution.
Tissue shall also be contained in the packaging with the dispersion medium, so that its structure is
retained to ensure its effectiveness. In addition, the containing process of tissue using a support or
biomaterial such as collagen as adjunct to the cells can be performed to maintain the structure.
4.4 Disturbances in storage and transportation including contamination
Disturbances in storage and transportation including contamination affect cell quality. Therefore,
protection of the cells from influential disturbances shall be taken into account when designing
packaging.
NOTE Cell quality can be ensured by demonstrating that the physical, chemical, biological or microbiological
properties are within an appropriate limit, range or distribution.
4.5 Impact on external environment when cells for therapeutic use leak from
packaging
When either cells for therapeutic use or their related contents, or both, leak out from the packaging, it
can affect one or all of the external environment, workers or quality of the contents. Therefore, avoiding
leakage shall be taken into account when designing packaging.
4.6 Interaction between cells for therapeutic use and packaging
The packaging user shall be aware that either the packaging material itself or its components, or both,
can affect the cell quality of cells for therapeutic use.
4.7 Usability of packaging in clinical facilities
The packaging user shall be aware that the process of using cells for therapeutic use in clinical facilities
can affect cell quality.
4.8 Environmental impact
Materials and processes that have a low environmental load should be applied to manufacture
packaging where possible and meaningful.
5 Design for packaging
5.1 General
This clause describes in detail the issues to be taken into account for the strategies described in
Clause 4.
Based on the issues, a risk assessment should be conducted that considers the characteristics of the
target cells for therapeutic use, the relationship between the cells for therapeutic use and the packaging,
and the packaging itself.
5.2 Enclosing process
5.2.1 Explanation of the enclosing process
The process to enclose cells for therapeutic use in primary packaging can affect the cell quality of such
cells. Therefore, an enclosing process that does not impair cell quality shall be performed, and shall
take cell characteristics into account. The packaging shall be sele
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