ISO 20404:2023
(Main)Biotechnology — Bioprocessing — General requirements for the design of packaging to contain cells for therapeutic use
Biotechnology — Bioprocessing — General requirements for the design of packaging to contain cells for therapeutic use
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.
Biotechnologie — Bioprocédés — Exigences générales pour la conception d'emballages destinés à contenir des cellules à usage thérapeutique
General Information
Buy Standard
Standards Content (Sample)
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 20404:2023(E)
© ISO 2023
---------------------- Page: 1 ----------------------
ISO 20404:2023(E)
COPYRIGHT PROTECTED DOCUMENT
© ISO 2023
All rights reserved. Unless otherwise specified, or required in the context of its implementation, no part of this publication may
be reproduced or utilized otherwise in any form or by any means, electronic or mechanical, including photocopying, or posting on
the internet or an intranet, without prior written permission. Permission can be requested from either ISO at the address below
or ISO’s member body in the country of the requester.
ISO copyright office
CP 401 • Ch. de Blandonnet 8
CH-1214 Vernier, Geneva
Phone: +41 22 749 01 11
Email: copyright@iso.org
Website: www.iso.org
Published in Switzerland
ii
© ISO 2023 – All rights reserved
---------------------- Page: 2 ----------------------
ISO 20404:2023(E)
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
© ISO 2023 – All rights reserved
---------------------- Page: 3 ----------------------
ISO 20404:2023(E)
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
through ISO technical committees. Each member body interested in a subject for which a technical
committee has been established has the right to be represented on that committee. International
organizations, governmental and non-governmental, in liaison with ISO, also take part in the work.
ISO collaborates closely with the International Electrotechnical Commission (IEC) on all matters of
electrotechnical standardization.
The procedures used to develop this document and those intended for its further maintenance are
described in the ISO/IEC Directives, Part 1. In particular, the different approval criteria needed for the
different types of ISO documents should be noted. This document was drafted in accordance with the
editorial rules of the ISO/IEC Directives, Part 2 (see www.iso.org/directives).
Attention is drawn to the possibility that some of the elements of this document may be the subject of
patent rights. ISO shall not be held responsible for identifying any or all such patent rights. Details of
any patent rights identified during the development of the document will be in the Introduction and/or
on the ISO list of patent declarations received (see www.iso.org/patents).
Any trade name used in this document is information given for the convenience of users and does not
constitute an endorsement.
For an explanation of the voluntary nature of standards, the meaning of ISO specific terms and
expressions related to conformity assessment, as well as information about ISO’s adherence to
the World Trade Organization (WTO) principles in the Technical Barriers to Trade (TBT), see
www.iso.org/iso/foreword.html.
This document was prepared by Technical Committee ISO/TC 276, Biotechnology.
Any feedback or questions on this document should be directed to the user’s national standards body. A
complete listing of these bodies can be found at www.iso.org/members.html.
iv
© ISO 2023 – All rights reserved
---------------------- Page: 4 ----------------------
ISO 20404:2023(E)
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
© ISO 2023 – All rights reserved
---------------------- Page: 5 ----------------------
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.
1
© ISO 2023 – All rights reserved
---------------------- Page: 6 ----------------------
ISO 20404:2023(E)
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.
2
© ISO 2023 – All rights reserved
---------------------- Page: 7 ----------------------
ISO 20404:2023(E)
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.
3
© ISO 2023 – All rights reserved
---------------------- Page: 8 ----------------------
ISO 20404:2023(E)
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
© ISO 2023 – All rights reserved
---------------------- Page: 9 ----------------------
ISO 20404:2023(E)
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
5
© ISO 2023 – All rights reserved
---------------------- Page: 10 ----------------------
ISO 20404:2023(E)
take cell characteristics into account. The packaging shall be selected by the packaging user or supplied
by the packaging supplier to the packaging user, taking the enclosing process into account.
During the enclosing process of the suspension of cells, there is a risk that shear stress or air bubbles
can cause functional decline or cell death. Therefore, the process condition(s) shall be adjusted to avoid
excessive stress to the cells and to prevent air bubbles mixing with the suspension of cells.
NOTE When the enclosing speed is set to be excessively slow in order to avoid applying stress and forming
air bubbles, the operation time increases, which can result in cell function deterioration or cell death.
5.2.2 Packaging for the enclosing process
The packaging used for containing the cells shall be suitable for the enclosing process and shall maintain
the cell quality.
Requirements for packaging shall be taken into account when applying the process to contain cells
for therapeutic use in the packaging. Where ready-made packaging is employed, the packaging user
should evaluate its impact by taking into account both the characteristics of the cells and the types
of influences applied to the cells during the enclosing process, e.g. contact of cells to the packaging
material. Where undesired influences are detected, the causes of the influences shall be eliminated by
tailoring the enclosing process or changing the packaging employed.
The concept of packaging differs depending on the environment in which the enclosing process is
performed, e.g. contained in a closed system using aseptic joining, in isolators or safety cabinets where
foreign substances are controlled, or in an open environment.
The following factors shall be taken into account in the enclosing process:
a) the type of cells for therapeutic use (cells dispersed in solution or cells retaining their structure);
b) the temperature when enclosing;
c) the atmospheric composition when enclosing;
d) the cleanliness when enclosing;
e) cross-contamination (microorganisms, other cells from another batch or another production
campaign);
f) the duration from the start to the end of the enclosing process;
g) the variation in cell number when subdividing;
h) the agents used to dilute the cells.
NOTE The above items can be interrelated.
5.3 Processes from enclosing to usage
5.3.1 Disturbances that affect cells for therapeutic use
The packaging user shall identify disturbances and shall establish the critical level for each identified
item that affects cell quality. Moreover, the packaging user shall use packaging with sufficient protection
against the identified disturbances and their critical level.
When the packaging user provides information about disturbances, the packaging supplier shall
provide the packaging user with sufficient protection based on the provided information. For cases
where the packaging supplier does not receive information about disturbances from the packaging
user, the conditions of the disturbances shall be estimated and packaging that has sufficient protection
capability for the estimated conditions shall be supplied. For cases where the packaging supplier cannot
6
© ISO 2023 – All rights reserved
----------------------
...
© ISO 2022 – All rights reserved
ISO/FDIS 20404:2022(E)
Date: 2022-12-0223
ISO/TC 276/WG 4
Secretariat: DIN
Biotechnology — Bioprocessing — General requirements for the
design of packaging to contain cells for therapeutic use
---------------------- Page: 1 ----------------------
ISO/FDIS 20404:2022(E)
© ISO 2022
All rights reserved. Unless otherwise specified, or required in the context of its implementation, no part of
this publication may be reproduced or utilized otherwise in any form or by any means, electronic or
mechanical, including photocopying, or posting on the internet or an intranet, without prior written
permission. Permission can be requested from either ISO at the address below or ISO’s member body in the
country of the requester.
ISO Copyright Office
CP 401 • CH-1214 Vernier, Geneva
Phone: + 41 22 749 01 11
Email: copyright@iso.org
Website: www.iso.org
Published in Switzerland.
ii © ISO 2022 – All rights reserved
---------------------- Page: 2 ----------------------
ISO/FDIS 20404:2022(E)
Contents
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 . 6
5.2.1 Explanation of the enclosing process . 6
5.2.2 Packaging for the enclosing process . 6
5.3 Processes from enclosing to usage . 7
5.3.1 Disturbances that affect cells for therapeutic use . 7
5.3.2 Leakage . 7
5.3.3 Interactions between cells for therapeutic use and packaging . 8
5.4 Usage . 9
6 Implementing packaging design . 11
6.1 General . 11
6.2 Shape . 11
6.3 Layers . 11
6.4 Ports . 11
6.5 Packaging materials . 12
6.6 Communication between packaging supplier and packaging user . 12
7 Quality management . 12
8 Examples of test methods . 12
8.1 General . 12
8.2 Test methods related to disturbance . 13
8.3 Test methods related to leakage . 13
8.4 Test methods related to interaction between cells for therapeutic use and packaging . 13
8.5 Other test methods . 14
Annex A (informative) Illustrated examples of packaging, packages and shipping
containers . 16
Bibliography . 19
iii © ISO 2022 – All rights reserved
---------------------- Page: 3 ----------------------
ISO/FDIS 20404:2022(E)
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
through ISO technical committees. Each member body interested in a subject for which a technical
committee has been established has the right to be represented on that committee. International
organizations, governmental and non-governmental, in liaison with ISO, also take part in the work. ISO
collaborates closely with the International Electrotechnical Commission (IEC) on all matters of
electrotechnical standardization.
The procedures used to develop this document and those intended for its further maintenance are
described in the ISO/IEC Directives, Part 1. In particular, the different approval criteria needed for the
different types of ISO documents should be noted. This document was drafted in accordance with the
editorial rules of the ISO/IEC Directives, Part 2 (see www.iso.org/directives).
Attention is drawn to the possibility that some of the elements of this document may be the subject of
patent rights. ISO shall not be held responsible for identifying any or all such patent rights. Details of any
patent rights identified during the development of the document will be in the Introduction and/or on
the ISO list of patent declarations received (see www.iso.org/patents).
Any trade name used in this document is information given for the convenience of users and does not
constitute an endorsement.
For an explanation of the voluntary nature of standards, the meaning of ISO specific terms and
expressions related to conformity assessment, as well as information about ISO’s adherence to the World
Trade Organization (WTO) principles in the Technical Barriers to Trade (TBT), see
www.iso.org/iso/foreword.html.
This document was prepared by Technical Committee ISO/TC 276, Biotechnology.
Any feedback or questions on this document should be directed to the user’s national standards body. A
complete listing of these bodies can be found at www.iso.org/members.html.
iv © ISO 2022 – All rights reserved
---------------------- Page: 4 ----------------------
ISO/FDIS 20404:2022(E)
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 © ISO 2022 – All rights reserved
---------------------- Page: 5 ----------------------
FINAL DRAFT INTERNATIONAL STANDARD ISO/FDIS 20404:2022(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.
© ISO 2022 – All rights reserved 1
---------------------- Page: 6 ----------------------
ISO/FDIS 20404:2022(E)
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)
2 © ISO 2022 – All rights reserved
---------------------- Page: 7 ----------------------
ISO/FDIS 20404:2022(E)
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". “single cells”
changed to”. “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 cellcells 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
© ISO 2022 – All rights reserved 3
---------------------- Page: 8 ----------------------
ISO/FDIS 20404:2022(E)
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 5.3.2 6.2, 6.3, 6.4 8.3
cells 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, and
transfer from packaging to an administration device if not directly administered from the packaging.
NOTE Examples of clinical facilities include hospitals and authorized infusion centerscentres.
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.
4 © ISO 2022 – All rights reserved
---------------------- Page: 9 ----------------------
ISO/FDIS 20404:2022(E)
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.
© ISO 2022 – All rights reserved 5
---------------------- Page: 10 ----------------------
ISO/FDIS 20404:2022(E)
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 selected by the packaging user or supplied by the
packaging supplier to the packaging user, taking the enclosing process into account.
During the enclosing process of the suspension of cells, there is a risk that shear stress or air bubbles can
cause functional decline or cell death. Therefore, the process condition(s) shall be adjusted to avoid
excessive stress to the cells and to prevent air bubbles mixing with the suspension of cells.
NOTE When the enclosing speed is set to be excessively slow in order to avoid applying stress and forming air
bubbles, the operation time increases, which can result in cell function deterioration or cell death.
5.2.2 Packaging for the enclosing process
The packaging used for containing the cells shall be suitable for the enclosing process and shall maintain
the cell quality.
Requirements for packaging shall be taken into account when applying the process to contain cells for
therapeutic use in the packaging. Where ready-made packaging is employed, the packaging user should
evaluate its impact by taking into account both the characteristics of the cells and the types of influences
applied to the cells during the enclosing process, e.g. contact of cells to the packaging material. Where
undesired influences are detected, the causes of the influences shall be eliminated by tailoring the
enclosing process or changing the packaging employed.
The concept of packaging differs depending on the environment in which the enclosing process is
performed, e.g. contained in a closed system using aseptic joining, in isolators or safety cabinets where
foreign substances are controlled, or in an open environment.
The following factors shall be taken into account in the enclosing process:
a) the type of cells for therapeutic use (cells dispersed in solution or cells retaining their structure);
b) the temperature when enclosing;
c) the atmospheric composition when enclosing;
d) the cleanliness when enclosing;
e) cross-contamination (microorganisms, other cells from another batch or another production
campaign);
f) the duration from the start to the end of the enclosing process;
g) the variation in cell number when subdividing;
h) the agents used to dilute the cells.
NOTE The above items can be interrelated.
6 © ISO 2022 – All rights reserved
---------------------- Page: 11 ----------------------
ISO/FDIS 20404:2022(E)
5.3 Processes from enclosing to usage
5.3.1 Disturbances that affect cells for therapeutic use
The packaging user shall identify disturbances and shall establish the critical level for each identified item
that affects cell quality. Moreover, the packaging user shall use packaging with sufficient protection
against the identified disturbances and their critical level.
When the packaging user provides information about disturbances, the packaging supplier shall provide
the packaging user with sufficient protection based on the provided information. For cases where the
packaging supplier does not receive information about disturbances from the packaging user, the
conditions of the disturbances shall be estimated and packaging that has sufficient protection capability
for the estimated conditions shall be supplied. For cases where the packaging supplier cannot disclose
the level for identified disturbances to the packaging user, the packaging user shall ensure the packaging
protection capability.
Disturbances can include:
a) force, including:
1) force that causes deformation;
2) vibration;
3) impact;
4) sheer stress;
b) light;
c) temperature, including:
1) cryogenic temperatures below −150 °C;
2) temperature change during freezing and thawing;
3) temperature change or uneven temperature distribution, or both, during the shipment of
unfrozen cells (e.g. 37 °C);
d) contamination, including:
1) microbes such as bacteria, fungi algae, protozoa and viruses;
2) particulates;
3) gas and gas exchange, or the limitation of that (e.g. carbon dioxide or oxygen);
e) delay in shipment caused by unforeseen circumstances such as, but not limited to, custom delays.
5.3.2 Leakage
The packaging shall prevent the cells for therapeutic use, including the cell preservation solution and
substrates that are enclosed in the packaging, from leaking from the packaging. Any leakage can affect
cell quality, and can negatively influence the external environment.
© ISO 2022 – All rights reserved 7
---------------------- Page: 12 ----------------------
ISO/FDIS 20404:2022(E)
The packaging shall also prevent external liquid from leaking inside to avoid contamination.
Custom-made packaging solutions shall undergo continual improvement cycles, which shall be used to
ensure that the products to be packaged determine the packaging design.
5.3.3 Interactions between cells for therapeutic use and packaging
5.3.3.1
...
FINAL
INTERNATIONAL ISO/FDIS
DRAFT
STANDARD 20404
ISO/TC 276
Biotechnology — Bioprocessing —
Secretariat: DIN
General requirements for the design
Voting begins on:
2023-01-06 of packaging to contain cells for
therapeutic use
Voting terminates on:
2023-03-03
RECIPIENTS OF THIS DRAFT ARE INVITED TO
SUBMIT, WITH THEIR COMMENTS, NOTIFICATION
OF ANY RELEVANT PATENT RIGHTS OF WHICH
THEY ARE AWARE AND TO PROVIDE SUPPOR TING
DOCUMENTATION.
IN ADDITION TO THEIR EVALUATION AS
Reference number
BEING ACCEPTABLE FOR INDUSTRIAL, TECHNO-
ISO/FDIS 20404:2023(E)
LOGICAL, COMMERCIAL AND USER PURPOSES,
DRAFT INTERNATIONAL STANDARDS MAY ON
OCCASION HAVE TO BE CONSIDERED IN THE
LIGHT OF THEIR POTENTIAL TO BECOME STAN-
DARDS TO WHICH REFERENCE MAY BE MADE IN
NATIONAL REGULATIONS. © ISO 2023
---------------------- Page: 1 ----------------------
ISO/FDIS 20404:2023(E)
FINAL
INTERNATIONAL ISO/FDIS
DRAFT
STANDARD 20404
ISO/TC 276
Biotechnology — Bioprocessing —
Secretariat: DIN
General requirements for the design
Voting begins on:
of packaging to contain cells for
therapeutic use
Voting terminates on:
COPYRIGHT PROTECTED DOCUMENT
© ISO 2023
All rights reserved. Unless otherwise specified, or required in the context of its implementation, no part of this publication may
be reproduced or utilized otherwise in any form or by any means, electronic or mechanical, including photocopying, or posting on
the internet or an intranet, without prior written permission. Permission can be requested from either ISO at the address below
or ISO’s member body in the country of the requester.
RECIPIENTS OF THIS DRAFT ARE INVITED TO
ISO copyright office
SUBMIT, WITH THEIR COMMENTS, NOTIFICATION
OF ANY RELEVANT PATENT RIGHTS OF WHICH
CP 401 • Ch. de Blandonnet 8
THEY ARE AWARE AND TO PROVIDE SUPPOR TING
CH-1214 Vernier, Geneva
DOCUMENTATION.
Phone: +41 22 749 01 11
IN ADDITION TO THEIR EVALUATION AS
Reference number
Email: copyright@iso.org
BEING ACCEPTABLE FOR INDUSTRIAL, TECHNO
ISO/FDIS 20404:2022(E)
Website: www.iso.org
LOGICAL, COMMERCIAL AND USER PURPOSES,
DRAFT INTERNATIONAL STANDARDS MAY ON
Published in Switzerland
OCCASION HAVE TO BE CONSIDERED IN THE
LIGHT OF THEIR POTENTIAL TO BECOME STAN
DARDS TO WHICH REFERENCE MAY BE MADE IN
ii
© ISO 2023 – All rights reserved
NATIONAL REGULATIONS. © ISO 2022
---------------------- Page: 2 ----------------------
ISO/FDIS 20404:2022(E)
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
© ISO 2022 – All rights reserved
---------------------- Page: 3 ----------------------
ISO/FDIS 20404:2022(E)
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
through ISO technical committees. Each member body interested in a subject for which a technical
committee has been established has the right to be represented on that committee. International
organizations, governmental and nongovernmental, in liaison with ISO, also take part in the work.
ISO collaborates closely with the International Electrotechnical Commission (IEC) on all matters of
electrotechnical standardization.
The procedures used to develop this document and those intended for its further maintenance are
described in the ISO/IEC Directives, Part 1. In particular, the different approval criteria needed for the
different types of ISO documents should be noted. This document was drafted in accordance with the
editorial rules of the ISO/IEC Directives, Part 2 (see www.iso.org/directives).
Attention is drawn to the possibility that some of the elements of this document may be the subject of
patent rights. ISO shall not be held responsible for identifying any or all such patent rights. Details of
any patent rights identified during the development of the document will be in the Introduction and/or
on the ISO list of patent declarations received (see www.iso.org/patents).
Any trade name used in this document is information given for the convenience of users and does not
constitute an endorsement.
For an explanation of the voluntary nature of standards, the meaning of ISO specific terms and
expressions related to conformity assessment, as well as information about ISO’s adherence to
the World Trade Organization (WTO) principles in the Technical Barriers to Trade (TBT), see
www.iso.org/iso/foreword.html.
This document was prepared by Technical Committee ISO/TC 276, Biotechnology.
Any feedback or questions on this document should be directed to the user’s national standards body. A
complete listing of these bodies can be found at www.iso.org/members.html.
iv
© ISO 2022 – All rights reserved
---------------------- Page: 4 ----------------------
ISO/FDIS 20404:2022(E)
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
undertreated. 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 abovementioned processes.
v
© ISO 2022 – All rights reserved
---------------------- Page: 5 ----------------------
FINAL DRAFT INTERNATIONAL STANDARD ISO/FDIS 20404:2022(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.
1
© ISO 2022 – All rights reserved
---------------------- Page: 6 ----------------------
ISO/FDIS 20404:2022(E)
Note 4 to entry: Cells for therapeutic use are often used with additional components. Furthermore, they are
sometimes shipped with a pretreatment 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.
2
© ISO 2022 – All rights reserved
---------------------- Page: 7 ----------------------
ISO/FDIS 20404:2022(E)
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.
3
© ISO 2022 – All rights reserved
---------------------- Page: 8 ----------------------
ISO/FDIS 20404:2022(E)
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, and transfer from packaging to an administration device 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 tissuelike structures.
4
© ISO 2022 – All rights reserved
---------------------- Page: 9 ----------------------
ISO/FDIS 20404:2022(E)
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
5
© ISO 2022 – All rights reserved
---------------------- Page: 10 ----------------------
ISO/FDIS 20404:2022(E)
take cell characteristics into account. The packaging shall be selected by the packaging user or supplied
by the packaging supplier to the packaging user, taking the enclosing process into account.
During the enclosing process of the suspension of cells, there is a risk that shear stress or air bubbles
can cause functional decline or cell death. Therefore, the process condition(s) shall be adjusted to avoid
excessive stress to the cells and to prevent air bubbles mixing with the suspension of cells.
NOTE When the enclosing speed is set to be excessively slow in order to avoid applying stress and forming
air bubbles, the operation time increases, which can result in cell function deterioration or cell death.
5.2.2 Packaging for the enclosing process
The packaging used for containing the cells shall be suitable for the enclosing process and shall maintain
the cell quality.
Requirements for packaging shall be taken into account when applying the process to contain cells
for therapeutic use in the packaging. Where ready-made packaging is employed, the packaging user
should evaluate its impact by taking into account both the characteristics of the cells and the types
of influences applied to the cells during the enclosing process, e.g. contact of cells to the packaging
material. Where undesired influences are detected, the causes of the influences shall be eliminated by
tailoring the enclosing process or changing the packaging employed.
The concept of packaging differs depending on the environment in which the enclosing process is
performed, e.g. contained in a closed system using aseptic joining, in isolators or safety cabinets where
foreign substances are controlled, or in an open environment.
The following factors shall be taken into account in the enclosing process:
a) the type of cells for therapeutic use (cells dispersed in solution or cells retaining their structure);
b) the temperature when enclosing;
c) the atmospheric composition when enclosing;
d) the cleanliness when enclosing;
e) crosscontamination (microorganisms, other cells from another batch or another production
campaign);
f) the duration from the start to the end of the enclosing process;
g) the var
...
Questions, Comments and Discussion
Ask us and Technical Secretary will try to provide an answer. You can facilitate discussion about the standard in here.