Biotechnology — Bioprocessing — General requirements for the design of packaging to contain cells for therapeutic use

This document provides minimum requirements, and general considerations for the design of packaging used to contain cells for therapeutic use. This document is intended to help the supplier of packaging 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 the users of packaging to design and employ packaging in consideration of the above-mentioned processes. This document is also applicable to packaging intended to contain final products of cells for therapeutic use, as well as their starting materials and intermediate materials. This document does not specify: a) receptacles used for processing cells in manufacturing processes, e.g., cell culture flask or bag; b) shipping container, in which to contain package for transportation; c) services performed with package, e.g. storage service. NOTE 1 Examples of packaging, package and shipping container are illustrated in Annex A. NOTE 2 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

Status

Not Published

ICS

07.080 - Biology. Botany. Zoology

Technical Committee

ISO/TC 276 - Biotechnology

Drafting Committee

ISO/TC 276 - Biotechnology

Current Stage

6000 - International Standard under publication

Completion Date

04-Mar-2023

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© 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

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.

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

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

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
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THEY ARE AWARE AND TO PROVIDE SUPPOR TING
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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
© 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

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.

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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

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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

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.
© ISO 2022 – All rights reserved
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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.

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.