Biotechnology -- General requirements for transportation of cells for therapeutic use

This document specifies general requirements and reviews the points to consider for the transportation of cells for therapeutic use, including storage during transportation. Transportation starts from the transfer of the packaged cells by the sender to the transportation service provider and ends when the package is delivered to the receiver at its destination. This document does not apply to transportation of cells within one facility. This document includes the development of a transportation plan including verification and validation, communication between the client and the transportation service provider, and associated documentation. This document does not specify particular conditions for transportation such as specification for shipping container, ambient temperature control, etc.

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Status
Published
Publication Date
28-Jun-2020
Technical Committee
Current Stage
6060 - International Standard published
Start Date
29-Jun-2020
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INTERNATIONAL ISO
STANDARD 21973
First edition
2020-06
Biotechnology — General
requirements for transportation of
cells for therapeutic use
Reference number
ISO 21973:2020(E)
ISO 2020
---------------------- Page: 1 ----------------------
ISO 21973:2020(E)
COPYRIGHT PROTECTED DOCUMENT
© ISO 2020

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 2020 – All rights reserved
---------------------- Page: 2 ----------------------
ISO 21973:2020(E)
Contents Page

Foreword ........................................................................................................................................................................................................................................iv

Introduction ..................................................................................................................................................................................................................................v

1 Scope ................................................................................................................................................................................................................................. 1

2 Normative references ...................................................................................................................................................................................... 1

3 Terms and definitions ..................................................................................................................................................................................... 1

4 General concepts .................................................................................................................................................................................................. 4

5 Cell transportation specification ......................................................................................................................................................... 5

5.1 General ........................................................................................................................................................................................................... 5

5.2 Items specified in the cell transportation specification ...................................................................................... 5

5.2.1 General...................................................................................................................................................................................... 5

5.2.2 Information reflected in the cell transportation specification ................................................. 5

5.2.3 Capability of the cell transportation service provider and its external

service provider(s)......................................................................................................................................................... 6

5.3 Risk management, verification and validation ............................................................................................................ 9

5.3.1 Risk management ............................................................................................................................................................ 9

5.3.2 Verification and validation ...................................................................................................................................10

6 Best practices for shipping container and labelling .....................................................................................................10

6.1 General ........................................................................................................................................................................................................10

6.2 Shipping container............................................................................................................................................................................11

6.2.1 Shipping container systems ................................................................................................................................11

6.2.2 Shipping container requirements ..................................................................................................................11

6.3 Labelling of the shipping container ...................................................................................................................................12

6.3.1 Information to be labelled ....................................................................................................................................12

6.3.2 Physical requirements for the label ..............................................................................................................13

6.3.3 Handling of labels.........................................................................................................................................................13

7 Operation ..................................................................................................................................................................................................................13

7.1 General operation ..............................................................................................................................................................................13

7.1.1 General...................................................................................................................................................................................13

7.1.2 Preparation of shipment ........................................................................................................................................13

7.1.3 Transportation ................................................................................................................................................................13

7.1.4 Inspection at the time of delivery...................................................................................................................14

7.2 Traceability .............................................................................................................................................................................................14

7.3 System to handle exceptional operations .....................................................................................................................15

7.3.1 Emergency handling ..................................................................................................................................................15

7.3.2 Management in case of an incident...............................................................................................................15

8 Organization ..........................................................................................................................................................................................................16

8.1 General ........................................................................................................................................................................................................16

8.2 Personnel training .............................................................................................................................................................................16

8.2.1 General...................................................................................................................................................................................16

8.2.2 Training plans ..................................................................................................................................................................16

8.2.3 Training records ............................................................................................................................................................17

8.3 Quality management system (QMS) considerations ...........................................................................................17

9 Storage facility .....................................................................................................................................................................................................18

9.1 General ........................................................................................................................................................................................................18

9.2 Storage facility considerations ...............................................................................................................................................18

10 Documented information .........................................................................................................................................................................18

Bibliography .............................................................................................................................................................................................................................19

© ISO 2020 – All rights reserved iii
---------------------- Page: 3 ----------------------
ISO 21973:2020(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 2020 – All rights reserved
---------------------- Page: 4 ----------------------
ISO 21973:2020(E)
Introduction

Cells for therapeutic use provide potential cures for the most challenging disease conditions. However,

in contrast to the unprecedented clinical benefits, managing the production and logistics of cells for

therapeutic use proves to be challenging. Not only the cost is exceedingly high to produce and transport

these products, the concerns over product safety and efficacy due to potential manufacturing or

transportation deficiencies have started mounting as more products are being developed and tested.

The cell therapy workflow begins with collection of cells (including tissues). With autologous cells for

therapeutic use, cells are collected from patients in the clinical setting before shipping to manufacturing

sites for processing and production. After manufacturing and testing for release, cells for therapeutic

use are transported to clinical sites for administration into patients.

Issues related to cell transportation have been identified in the product workflow. Some of these issues

include monitoring and controlling transportation conditions, managing traceability and maintaining

chain of custody, and establishing clear expectations and communications between cell product

manufacturer and transportation service provider. These issues all have significant impact on cells for

therapeutic use quality that can ultimately affect product safety and effectiveness. Therefore, there is

a need for standards to ensure cell transportation is appropriately and adequately planned, executed,

traced and documented.

This document intends to provide general requirements and points to consider for transportation

service providers, clients and senders to ensure cell quality, safety and efficacy during the transportation

process.

Application of this document presupposes awareness of applicable legal requirements.

ISO 13022:2012, Annex G contains guidance for transport of human cells.
© ISO 2020 – All rights reserved v
---------------------- Page: 5 ----------------------
INTERNATIONAL STANDARD ISO 21973:2020(E)
Biotechnology — General requirements for transportation
of cells for therapeutic use
1 Scope

This document specifies general requirements and reviews the points to consider for the transportation

of cells for therapeutic use, including storage during transportation.

Transportation starts from the transfer of the packaged cells by the sender to the transportation

service provider and ends when the package is delivered to the receiver at its destination.

This document does not apply to transportation of cells within one facility.

This document includes the development of a transportation plan including verification and

validation, communication between the client and the transportation service provider, and associated

documentation.

This document does not specify particular conditions for transportation such as specification for

shipping container, ambient temperature control, etc.
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 terminological databases for use in standardization at the following addresses:

— ISO Online browsing platform: available at https:// www .iso .org/ obp
— IEC Electropedia: available at http:// 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: For the purpose of this document, “cells” mean human cells and tissues of autologous as well as

allogeneic.

Note 2 to entry: For the purpose of this document, this term includes cells collected as starting materials and

cultured as intermediate materials.

Note 3 to entry: The expression “therapeutic use” includes clinical research, hospital exception and testing use.

3.2
chain of custody

responsibility for or control of materials as they move through each step of a process

Note 1 to entry: For the purpose of this document, “chain of custody” is the proven path starting from the

transfer of the packaged cells from the sender (3.11) to the transportation service provider (3.13) and ends when

the package is received at its destination.
© ISO 2020 – All rights reserved 1
---------------------- Page: 6 ----------------------
ISO 21973:2020(E)
3.3
client

entity requesting cell transportation by contract with transportation service provider (3.13)

3.4
document
information and the medium on which it is contained
EXAMPLE Record, specification, procedure document, drawing, report, standard.

Note 1 to entry: The medium can be paper, magnetic, electronic or optical computer disc, photograph or master

sample, or combination thereof.

Note 2 to entry: A set of documents, for example specifications and records, is frequently called “documentation”.

Note 3 to entry: Some requirements (e.g. the requirement to be readable) relate to all types of documents.

However there can be different requirements for specifications (e.g. the requirement to be revision controlled)

and for records (e.g. the requirement to be retrievable).
[SOURCE: ISO 9000:2015, 3.8.5]
3.5
documented information

information required to be controlled and maintained by an organization and the medium on which it

is contained

Note 1 to entry: Documented information can be in any format and media and from any source.

Note 2 to entry: Documented information can refer to:
— the management system, including related processes;
— information created in order for the organization to operate (documentation);
— evidence of results achieved [records (3.8)].

Note 3 to entry: This constitutes one of the common terms and core definitions for ISO management system

standards given in Annex SL of the Consolidated ISO Supplement to the ISO/IEC Directives, Part 1.

[SOURCE: ISO 9000:2015, 3.8.6]
3.6
inspection
determination of conformity to specified requirements
[SOURCE: ISO 9000:2015, 3.11.7, modified — Notes to entry have been deleted.]
3.7
receiver

entity that gets cells for therapeutic use (3.1) from the transportation service provider (3.13)

3.8
record

document (3.4) stating results achieved or providing evidence of activities performed

Note 1 to entry: Records can be used, for example, to formalize traceability (3.12) and to provide evidence of

verification (3.15), preventive action and corrective action.
Note 2 to entry: Generally records need not be under revision control.
[SOURCE: ISO 9000:2015, 3.8.10]
2 © ISO 2020 – All rights reserved
---------------------- Page: 7 ----------------------
ISO 21973:2020(E)
3.9
risk assessment
overall process comprising a risk analysis and a risk evaluation
[SOURCE: ISO/IEC Guide 51:2014, 3.11]
3.10
risk control

process in which decisions are made and measures implemented by which risks are reduced to, or

maintained within, specified levels
[SOURCE: ISO/IEC Guide 63:2019, 3.12]
3.11
sender

entity that hands over cells for therapeutic use (3.1) to transportation service provider (3.13)

3.12
traceability
ability to trace the history, application or location of an object

Note 1 to entry: When considering a product or a service, traceability can relate to:

— the origin of materials and parts;
— the processing history;
— the distribution and location of the product or service after delivery.

Note 2 to entry: In the field of metrology, the definition in ISO/IEC Guide 99 is the accepted definition.

[SOURCE: ISO 9000:2015, 3.6.13]
3.13
transportation service provider

entity that provides international and domestic transportation service of cells for therapeutic use (3.1)

Note 1 to entry: Transportation service provider can outsource the whole or part of cell transportation to

external service providers. In that case, some requirements described in this document [e.g. the requirement

regarding documented information (3.5)] can be met by the activities of external service providers. The activities

of external service providers vary according to the agreement between the transportation service provider and

external service provider, but its activities are managed by transportation service provider.

3.14
validation

confirmation, through the provision of objective evidence, that the requirements for a specific intended

use or application have been fulfilled

Note 1 to entry: The objective evidence needed for a validation is the result of a test or other form of determination

such as performing alternative calculations or reviewing documents (3.4).

Note 2 to entry: The word “validated” is used to designate the corresponding status.

Note 3 to entry: The use conditions for validation can be real or simulated.
[SOURCE: ISO 9000:2015, 3.8.13]
3.15
verification

confirmation, through the provision of objective evidence, that specified requirements have been

fulfilled

Note 1 to entry: The objective evidence needed for a verification can be the result of an inspection (3.6) or of

other forms of determination such as performing alternative calculations or reviewing documents (3.4).

© ISO 2020 – All rights reserved 3
---------------------- Page: 8 ----------------------
ISO 21973:2020(E)

Note 2 to entry: The activities carried out for verification are sometimes called a qualification process.

Note 3 to entry: The word “verified” is used to designate the corresponding status.

[SOURCE: ISO 9000:2015, 3.8.12]
4 General concepts

Consistent quality in transportation of cells for therapeutic use is enabled by establishing:

a) a cell transportation specification based on appropriate sharing information between the

transportation service provider and the client, including:

1) information provided by the client regarding biosafety of cells for therapeutic use during

transportation;

2) information provided by the client regarding storage/handling conditions to preserve cell

quality and ensure the therapeutic cell functions.

NOTE 1 Cell quality can be ensured by demonstrating that the physical, chemical, biological, or

microbiological properties are within an appropriate limit, range, or distribution.

b) an operational procedure for cell transportation supported by risk management, verification and/

or validation;

c) organizational requirements for transportation of cells for therapeutic use; including the

establishment of an appropriate quality management system, training for personnel assigned to a

specific cell transportation process, tracking systems, scheduling systems to ensure appropriate

protocols are followed;

d) container and facilities requirements including the secure and access control of the facility,

ensuring that cells for therapeutic use are not contaminated or tampered;

e) documentation for all stages of cell transportation that demonstrates chain of custody throughout

the transportation cycle, including but not limited to equipment performance, cleaning and

equipment-use history;
NOTE 2 Documentation can be a part of quality management system.
f) a system to record each process of cell transportation.

NOTE 3 The following are examples of the records associated with cell transportation:

1) objective measurements (e.g. temperature);
2) transportation logs (e.g. time, name, commodity and signature);
3) records of data logger;
4) visual inspection;
5) shipping containers;
— unit type (e.g. dry shipper);

— qualification (in the case of dry shipper, weight, nitrogen evaporation rate and liquid nitrogen

capacity);
— cleaning and disinfection records.

Items of requirements for transportation of cells for therapeutic use agreed between the transportation

service provider and the client should be documented and confirmed in writing by each party that they

accept the agreed conditions.
4 © ISO 2020 – All rights reserved
---------------------- Page: 9 ----------------------
ISO 21973:2020(E)
5 Cell transportation specification
5.1 General

A cell transportation specification provides a list of requirements that cover the different procedures of

transportation operation.

The transportation service provider conducts transportation in accordance with the cell transportation

specification.
5.2 Items specified in the cell transportation specification
5.2.1 General

The transportation service provider determines the cell transportation specification, implementing:

a) information submitted by the client and clarified through communication between the client and

the transportation service provider;

b) capability of the cell transportation service provider and its external service providers;

c) risk management.

NOTE Items for which the transportation service provider is not responsible for are excluded from the

cell transportation specification unless otherwise agreed by both client and transportation service provider.

For example, when the client sets up temperature control containers and forwards it to the transportation

service provider, the temperature recorder is excluded from the cell transportation specification. The client is

responsible for recording the temperature during transport.
5.2.2 Information reflected in the cell transportation specification
5.2.2.1 General

The transportation service provider shall receive necessary information on cells from the client.

Information provided by the client shall be reflected in the cell transportation specification.

5.2.2.2 Classification information

The client should be aware of applicable classification information concerning the cells and their

medium to be transported in.

NOTE Categories of goods for transportation can be subject to regulatory classification.

The transportation service provider should retain this information and implement it into the cell

transportation specification.
Information on cell and medium classification can include:
a) infectious substances;
b) genetically modified microorganisms / genetically modified organisms;
c) poisonous and deleterious substances.

NOTE The transportation service provider can use this information to control each reusable shipping

container.
© ISO 2020 – All rights reserved 5
---------------------- Page: 10 ----------------------
ISO 21973:2020(E)
5.2.2.3 Storage and handling conditions

The client should determine proper storage and handling conditions, based on the result derived from

stability testing on cells by the client, and additional transportation testing when needed.

The transportation service providers should retain this information and implement it into the cell

transportation specification.
The following are examples of storage and handling conditions:
a) temperature;

b) necessary precautions (e.g. vibrations, locational and orientational placement, UV light,

humidity, etc.);
c) maximum shelf life and expiration dates;

d) segregation of human vs. animal derived products to prevent cross contamination;

e) special security requirements (e.g. tamper evident seals or locking mechanisms preventing

unauthorized access to shipper contents).

NOTE In some cases, human and animal derived materials have specific requirements for transportation

and storage conditions.
5.2.2.4 Shipping information
The client should provide shipping information on cells to be transported.

The transportation service provider should incorporate this into the cell transportation specification.

The following are examples of shipping information:

a) description of goods (including list of contents, condition of goods, intended use of goods, etc.);

b) price/commercial value (e.g. cost of goods as a basis for customs valuation/insurance purposes);

c) dimension;
d) number of pieces;
e) weight;

f) sender’s name and address for domestic shipments plus exporter of record's name, address for

international shipments;

g) receiver’s name and address for domestic shipments plus importer of record's name, address for

international shipments;

h) other available information for international shipment, such as VAT-ID, Customs Reg.-Nr., deferment

account, HS or commodity code, and any required import permits based on destination country.

5.2.3 Capability of the cell transportation service provider and its external service provider(s)

5.2.3.1 General

The transportation service provider shall determine its capability and its external service provider's

capability and shall implement it into the cell transportation specification.
Capability can include:

a) availability and suitability of transportation means (e.g. vehicle, airplane);

6 © ISO 2020 – All rights reserved
---------------------- Page: 11 ----------------------
ISO 21973:2020(E)

b) control tool (e.g. temperature-controlled containers able to meet and maintain the required

temperature requirements for the duration of the shipment);
c) human resources;

d) control of container use (e.g. segregation shipment human derived product from animal derived

product);
e) protection tool (e.g. locking mechanisms, tamper evident seals).
5.2.3.2 Temperature

The transportation service provider shall establish a transportation temperature range by specifying

either upper and lower temperatures, or both, based on the acceptable temperature range during

transportation provided by the client and qualified temperature control container ranges.

The following are examples of transportation temperature ranges:
a) ultra-low temperature: below −150 °C;
b) deep freeze: below −20 °C, −40 °C or −80 °C (depending on specification);
c) in a refrigerator: +2 to +8 °C;
d) cold or cool: +8 to + 15 °C;
e) room temperature: +15 to + 25 °C;
f) human body temperature: +32 to +38 °C.

NOTE The acceptable transportation temperature range provided by the client can be different from the

temperature specified by storage conditions (see 5.2.2.3) of cells for the
...

FINAL
INTERNATIONAL ISO/FDIS
DRAFT
STANDARD 21973
ISO/TC 276
Biotechnology — General
Secretariat: DIN
requirements for transportation of
Voting begins on:
2020­03­10 cells for therapeutic use
Voting terminates on:
2020­05­05
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 21973:2020(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 2020
---------------------- Page: 1 ----------------------
ISO/FDIS 21973:2020(E)
COPYRIGHT PROTECTED DOCUMENT
© ISO 2020

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
CH­1214 Vernier, Geneva
Phone: +41 22 749 01 11
Fax: +41 22 749 09 47
Email: copyright@iso.org
Website: www.iso.org
Published in Switzerland
ii © ISO 2020 – All rights reserved
---------------------- Page: 2 ----------------------
ISO/FDIS 21973:2020(E)
Contents Page

Foreword ........................................................................................................................................................................................................................................iv

Introduction ..................................................................................................................................................................................................................................v

1 Scope ................................................................................................................................................................................................................................. 1

2 Normative references ...................................................................................................................................................................................... 1

3 Terms and definitions ..................................................................................................................................................................................... 1

4 General concepts .................................................................................................................................................................................................. 4

5 Cell transportation specification ......................................................................................................................................................... 5

5.1 General ........................................................................................................................................................................................................... 5

5.2 Items specified in cell transportation specification ................................................................................................ 5

5.2.1 General...................................................................................................................................................................................... 5

5.2.2 Information reflected in cell transportation specification .......................................................... 5

5.2.3 Capability of cell transportation service provider and its external service

provider ................................................................................................................................................................................... 6

5.3 Risk management, verification and validation ............................................................................................................ 9

5.3.1 Risk management ............................................................................................................................................................ 9

5.3.2 Verification and validation ...................................................................................................................................10

6 Best practices for shipping container and labelling .....................................................................................................10

6.1 General ........................................................................................................................................................................................................10

6.2 Shipping container............................................................................................................................................................................11

6.2.1 Shipping container systems ................................................................................................................................11

6.2.2 Shipping container requirements ..................................................................................................................11

6.3 Labelling of shipment container ...........................................................................................................................................12

6.3.1 Information to be labelled ....................................................................................................................................12

6.3.2 Physical requirements for the label ..............................................................................................................13

6.3.3 Handling of labels.........................................................................................................................................................13

7 Operation ..................................................................................................................................................................................................................13

7.1 General operation ..............................................................................................................................................................................13

7.1.1 General...................................................................................................................................................................................13

7.1.2 Preparation of shipment ........................................................................................................................................13

7.1.3 Transportation ................................................................................................................................................................13

7.1.4 Inspection at the time of delivery...................................................................................................................14

7.2 Traceability .............................................................................................................................................................................................14

7.3 System to handle exceptional operations .....................................................................................................................15

7.3.1 Emergency handling ..................................................................................................................................................15

7.3.2 Management in case of an incident...............................................................................................................15

8 Organization ..........................................................................................................................................................................................................16

8.1 General ........................................................................................................................................................................................................16

8.2 Personnel training .............................................................................................................................................................................16

8.2.1 General...................................................................................................................................................................................16

8.2.2 Training plans ..................................................................................................................................................................16

8.2.3 Training records ............................................................................................................................................................17

8.3 Quality management system (QMS) considerations ...........................................................................................17

9 Storage facility .....................................................................................................................................................................................................18

9.1 General ........................................................................................................................................................................................................18

9.2 Storage facility considerations ...............................................................................................................................................18

10 Documented information .........................................................................................................................................................................18

Bibliography .............................................................................................................................................................................................................................19

© ISO 2020 – All rights reserved iii
---------------------- Page: 3 ----------------------
ISO/FDIS 21973:2020(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 2020 – All rights reserved
---------------------- Page: 4 ----------------------
ISO/FDIS 21973:2020(E)
Introduction

Cells for therapeutic use provide potential cures for the most challenging disease conditions. However,

in contrast to the unprecedented clinical benefits, managing the production and logistics of cells for

therapeutic use proves to be challenging. Not only the cost is exceedingly high to produce and transport

these products, the concerns over product safety and efficacy due to potential manufacturing or

transportation deficiencies have started mounting as more products are being developed and tested.

The cell therapy workflow begins with collection of cells (including tissues). With autologous cells for

therapeutic use, cells are collected from patients in the clinical setting before shipping to manufacturing

sites for processing and production. After manufacturing and testing for release, cells for therapeutic

use are transported to clinical sites for administration into patients.

Issues related to cell transportation have been identified in the product workflow. Some of these issues

include monitoring and controlling transportation conditions, managing traceability and maintaining

chain of custody, and establishing clear expectations and communications between cell product

manufacturer and transportation service provider. These issues all have significant impact on cells for

therapeutic use quality that can ultimately affect product safety and effectiveness. Therefore, there is

a need for standards to ensure cell transportation is appropriately and adequately planned, executed,

traced and documented.

This document intends to provide general requirements and points to consider for transportation

service providers, clients and senders to ensure cell quality, safety and efficacy during the transportation

process.

Application of this document presupposes awareness of applicable legal requirements.

ISO 13022:2012, Annex G contains guidance for transport of human cells.
© ISO 2020 – All rights reserved v
---------------------- Page: 5 ----------------------
FINAL DRAFT INTERNATIONAL STANDARD ISO/FDIS 21973:2020(E)
Biotechnology — General requirements for transportation
of cells for therapeutic use
1 Scope

This document specifies general requirements and reviews the points to consider for the transportation

of cells for therapeutic use, including storage during transportation.

Transportation starts from the transfer of the packaged cells by the sender to the transportation

service provider and ends when the package is delivered to the receiver at its destination.

This document does not apply to transportation of cells within one facility.

This document includes the development of a transportation plan including verification and

validation, communication between the client and the transportation service provider, and associated

documentation.

This document does not specify particular conditions for transportation such as specification for

shipping container, ambient temperature control, etc.
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 terminological databases for use in standardization at the following addresses:

— ISO Online browsing platform: available at https:// www .iso .org/ obp
— IEC Electropedia: available at http:// 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: For the purpose of this document, “cells” mean human cells and tissues of autologous as well as

allogeneic.

Note 2 to entry: For the purpose of this document, this term includes cells collected as starting materials and

cultured as intermediate materials.

Note 3 to entry: The expression “therapeutic use” includes clinical research, hospital exception and testing use.

3.2
chain of custody

responsibility for or control of materials as they move through each step of a process

Note 1 to entry: For the purpose of this document, “chain of custody” is the proven path starting from the

transfer of the packaged cells from the sender (3.11) to the transportation service provider (3.13) and ends when

the package is received at its destination.
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3.3
client

entity requesting cell transportation by contract with transportation service provider (3.13)

3.4
document
information and the medium on which it is contained
EXAMPLE Record, specification, procedure document, drawing, report, standard.

Note 1 to entry: The medium can be paper, magnetic, electronic or optical computer disc, photograph or master

sample, or combination thereof.

Note 2 to entry: A set of documents, for example specifications and records, is frequently called “documentation”.

Note 3 to entry: Some requirements (e.g. the requirement to be readable) relate to all types of documents.

However there can be different requirements for specifications (e.g. the requirement to be revision controlled)

and for records (e.g. the requirement to be retrievable).
[SOURCE: ISO 9000:2015, 3.8.5]
3.5
documented information

information required to be controlled and maintained by an organization and the medium on which it

is contained

Note 1 to entry: Documented information can be in any format and media and from any source.

Note 2 to entry: Documented information can refer to:
— the management system, including related processes;
— information created in order for the organization to operate (documentation);
— evidence of results achieved [records (3.8)].

Note 3 to entry: This constitutes one of the common terms and core definitions for ISO management system

standards given in Annex SL of the Consolidated ISO Supplement to the ISO/IEC Directives, Part 1.

[SOURCE: ISO 9000:2015, 3.8.6]
3.6
inspection
determination of conformity to specified requirements
[SOURCE: ISO 9000:2015, 3.11.7, modified — Notes to entry have been deleted.]
3.7
receiver

entity that gets cells for therapeutic use (3.1) from the transportation service provider (3.13)

3.8
record

document (3.4) stating results achieved or providing evidence of activities performed

Note 1 to entry: Records can be used, for example, to formalize traceability (3.12) and to provide evidence of

verification (3.15), preventive action and corrective action.
Note 2 to entry: Generally records need not be under revision control.
[SOURCE: ISO 9000:2015, 3.8.10]
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3.9
risk assessment
overall process comprising a risk analysis and a risk evaluation
[SOURCE: ISO/IEC Guide 51:2014, 3.11]
3.10
risk control

process in which decisions are made and measures implemented by which risks are reduced to, or

maintained within, specified levels
[SOURCE: ISO/IEC Guide 63:2019, 3.12]
3.11
sender

entity that hands over cells for therapeutic use (3.1) to transportation service provider (3.13)

3.12
traceability
ability to trace the history, application or location of an object

Note 1 to entry: When considering a product or a service, traceability can relate to:

— the origin of materials and parts;
— the processing history;
— the distribution and location of the product or service after delivery.

Note 2 to entry: In the field of metrology, the definition in ISO/IEC Guide 99 is the accepted definition.

[SOURCE: ISO 9000:2015, 3.6.13]
3.13
transportation service provider

entity that provides international and domestic transportation service of cells for therapeutic use (3.1)

Note 1 to entry: Transportation service provider can outsource the whole or part of cell transportation to

external service providers. In that case, some requirements described in this document [e.g. the requirement

regarding documented information (3.5)] can be met by the activities of external service providers. The activities

of external service providers vary according to the agreement between the transportation service provider and

external service provider, but its activities are managed by transportation service provider.

3.14
validation

confirmation, through the provision of objective evidence, that the requirements for a specific intended

use or application have been fulfilled

Note 1 to entry: The objective evidence needed for a validation is the result of a test or other form of determination

such as performing alternative calculations or reviewing documents (3.4).

Note 2 to entry: The word “validated” is used to designate the corresponding status.

Note 3 to entry: The use conditions for validation can be real or simulated.
[SOURCE: ISO 9000:2015, 3.8.13]
3.15
verification

confirmation, through the provision of objective evidence, that specified requirements have been

fulfilled

Note 1 to entry: The objective evidence needed for a verification can be the result of an inspection (3.6) or of

other forms of determination such as performing alternative calculations or reviewing documents (3.4).

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Note 2 to entry: The activities carried out for verification are sometimes called a qualification process.

Note 3 to entry: The word “verified” is used to designate the corresponding status.

[SOURCE: ISO 9000:2015, 3.8.12]
4 General concepts

Consistent quality in transportation of cells for therapeutic use is enabled by establishing:

a) cell transportation specification based on appropriate sharing information between transportation

service provider and client, including:

1) information provided by the client regarding biosafety of cells for therapeutic use during

transportation;

2) information provided by the client regarding storage/handling conditions to preserve cell

quality and ensure the therapeutic cell functions.

NOTE Cell quality can be ensured by demonstrating that the physical, chemical, biological, or

microbiological properties are within an appropriate limit, range, or distribution.

b) operational procedure for cell transportation supported by risk management, verification and/or

validation;

c) organizational requirements for transportation of cells for therapeutic use; including the

establishment of an appropriate quality management system, training for personnel assigned to a

specific cell transportation process, tracking systems, scheduling systems to ensure appropriate

protocols are followed;

d) container and facilities requirements including the secure and access control of the facility,

ensuring that cells for therapeutic use are not contaminated or tampered;

e) documentation for all stages of cell transportation that demonstrates chain of custody throughout

the transportation cycle, including but not limited to equipment performance, cleaning and

equipment-use history;
NOTE Documentation can be a part of quality management system.
f) system to record each process of cell transportation.

NOTE The following are examples of the records associated with cell transportation:

1) objective measurements (e.g. temperature);
2) transportation logs (e.g. time, name, commodity and signature);
3) records of data logger;
4) visual inspection;
5) shipping containers;
— unit type (e.g. dry shipper);

— qualification (in the case of dry shipper, weight, nitrogen evaporation rate and liquid

nitrogen capacity);
— cleaning and disinfection records.

Items of requirements for transportation of cells for therapeutic use agreed between transportation

service provider and client should be documented and confirmed in writing by each party that they

accept the agreed conditions.
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5 Cell transportation specification
5.1 General

Cell transportation specification provides a list of requirements that cover the different procedures of

transportation operation.

The transportation service provider conducts transportation in accordance with the cell transportation

specification.
5.2 Items specified in cell transportation specification
5.2.1 General

The transportation service provider determines cell transportation specification, implementing:

a) information submitted by client and clarified through communication between the client and the

transportation service provider;

b) capability of cell transportation service provider and its external service providers;

c) risk management.

NOTE Items for which the transportation service provider is not responsible for are excluded from the

cell transportation specification unless otherwise agreed by both client and transportation service provider.

For example, when the client sets up temperature control containers and forwards it to the transportation

service provider, the temperature recorder is excluded from the cell transportation specification. The client is

responsible for recording the temperature during transport.
5.2.2 Information reflected in cell transportation specification
5.2.2.1 General

The transportation service provider shall receive necessary information on cells from the client.

Information provided by the client shall be reflected in cell transportation specification.

5.2.2.2 Classification information

The client should be aware of applicable classification information concerning cell and its medium to be

transported.

NOTE Categories of goods for transportation can be subject to regulatory classification.

The transportation service provider should retain this information and implement it into cell

transportation specification.
Information on cell and medium classification can include:
a) infectious substances;
b) genetically modified microorganisms / genetically modified organisms;
c) poisonous and deleterious substances.

NOTE The transportation service provider can use this information to control each reusable shipping

container.
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5.2.2.3 Storage and handling conditions

The client should determine proper storage and handling conditions, based on the result derived from

stability testing on cells by the client, and additional transportation testing when needed.

Transportation service providers should retain this information and implement it into cell

transportation specification.
The following are examples of storage and handling conditions:
a) temperature;

b) necessary precautions (e.g. vibrations, locational and orientational placement, UV light,

humidity, etc.);
c) maximum shelf life and expiration dates;

d) segregation of human vs. animal derived products to prevent cross contamination;

e) special security requirements (e.g. tamper evident seals or locking mechanisms preventing

unauthorized access to shipper contents).

NOTE In some cases, human and animal derived materials have specific requirements for transportation

and storage conditions.
5.2.2.4 Shipping information
The client should provide shipping information on cells to be transported.

The transportation service provider should incorporate this into cell transportation specification.

The following are examples of shipping information:

a) description of goods (including list of contents, condition of goods, intended use of goods, etc.);

b) price/commercial value (e.g. cost of goods as a basis for customs valuation/insurance purposes);

c) dimension;
d) number of pieces;
e) weight;

f) sender’s name and address for domestic shipments plus exporter of record's name, address for

international shipments;

g) receiver’s name and address for domestic shipments plus importer of record's name, address for

international shipments;

h) other available information for international shipment, such as VAT­ID, Customs Reg.­Nr., deferment

account, HS or commodity code, and any required import permits based on destination country.

5.2.3 Capability of cell transportation service provider and its external service provider

5.2.3.1 General

The transportation service provider shall determine its capability and its external service providers

capability and shall implement it into the cell transportation specification.
Capability can include:

a) availability and suitability of transportation means (e.g. vehicle, airplane);

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b) control tool (e.g. temperature-controlled containers able to meet and maintain the required

temperature requirements for the duration of the shipment);
c) human resources;

d) control of container use (e.g. segregation shipment human derived product from animal derived

product);
e) protection tool (e.g. locking mechanisms, tamper evident seals).
5.2.3.2 Temperature

The transportation service provider shall establish a transportation temperature range by specifying

either upper and lower temperatures, or both, based on the acceptable temperature range during

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