ISO/TS 23565:2021

Biotechnology — Bioprocessing — General requirements and considerations for equipment systems used in the manufacturing of cells for therapeutic use

This document specifies minimum requirements and general considerations for equipment, consisting of hardware, software and consumables, used in the manufacturing of cells for therapeutic use. This includes equipment for processing cells for therapeutic use starting from cell isolation/selection, expansion, washing and volume reduction, from cell finish through to cryopreservation for the storage of cells for therapeutic use. This document gives guidance on the design, use and maintenance of equipment and equipment systems to both suppliers and users from aspects including the target parties, i.e. supplier or user, and phase of involved task, i.e. design, use or maintenance. This document is applicable to any unit operation system that is used, alone or in combination, for the manufacturing of cells for therapeutic use, meeting user requirements. It is applicable to devices used for the purpose of monitoring equipment status. It does not apply to: processing equipment for cells for therapeutic use used at the point of care; devices used for analytical purposes; biosafety cabinets, general cell culture equipment (such as CO2 incubators, etc.), and software to control multiple equipment systems or multiple unit operations.

Biotechnologie — Bioprocédés — Exigences et considérations générales pour les systèmes d'équipement utilisés dans la fabrication de cellules à usage thérapeutique

General Information

• Status: Published
• Publication Date: 30-Sep-2021
• ICS: 07.080 - Biology. Botany. Zoology
• Technical Committee: ISO/TC 276 - Biotechnology
• Drafting Committee: ISO/TC 276/WG 4 - Bioprocessing
• Current Stage: 6060 - International Standard published
• Start Date: 01-Oct-2021
• Due Date: 01-Sep-2021
• Completion Date: 01-Oct-2021

Standards Content (Sample)

TECHNICAL ISO/TS
SPECIFICATION 23565
First edition
2021-10
Biotechnology — Bioprocessing
— General requirements and
considerations for equipment systems
used in the manufacturing of cells for
therapeutic use
Biotechnologie — Bioprocédés — Exigences et considérations
générales pour les systèmes d'équipement utilisés dans la fabrication
de cellules à usage thérapeutique
Reference number
ISO/TS 23565:2021(E)
© ISO 2021

---------------------- Page: 1 ----------------------
ISO/TS 23565:2021(E)
COPYRIGHT PROTECTED DOCUMENT
© ISO 2021
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: [phone]
Email: [e-mail]
Website: www.iso.org
Published in Switzerland
ii
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ISO/TS 23565:2021(E)
Contents Page
Foreword .iv
1 Scope . 1
2 Normative references . 1
3 Terms and definitions . 1
4 General considerations .4
4.1 General . 4
4.2 Incorporating equipment and testing into the manufacturing workflow of cells for
therapeutic use . 5
4.3 Unit operation equipment systems . 6
4.4 Connecting to upstream or downstream processing equipment, or both . 6
4.5 Monitoring and surveillance software . 6
4.6 Impurity and toxicity contribution to final cells for therapeutic use . 6
4.7 Sterility and non-pyrogenicity . 6
5 Equipment overall performance characteristics and evaluation .7
5.1 General . 7
5.2 Description of performance characteristics . 7
5.3 Performance parameters and correlation to cell quality attributes . 8
6 Components of the equipment system . 8
6.1 Hardware . 8
6.1.1 General . 8
6.1.2 Physical integrity . 8
6.1.3 Physical strength . 9
6.1.4 Packaging . 9
6.1.5 Recovery of cells . 9
6.1.6 Validation of performance qualification . 9
6.1.7 Physical evaluation of equipment and cell sample interaction . 9
6.1.8 Damage to cells . 9
6.1.9 Impact to clean room environment . 10
6.1.10 Monitoring . 10
6.2 Equipment software for manufacturing of cells for therapeutic use . 10
6.3 Consumables . . . 11
6.3.1 General . 11
6.3.2 Biocompatibility . 11
6.3.3 Toxicity of chemical sterilants . 11
6.3.4 Toxicity of extracted and leached materials .12
6.3.5 Particulates .12
6.3.6 Stability of disposable single-use components .13
7 Documentation and notification of changes .13
7.1 Documentation . 13
7.1.1 General .13
7.1.2 Documentation for off-the-shelf equipment or instruments .13
7.1.3 Custom-designed supplier documentation package for equipment or
instruments . 14
8 Use and maintenance of equipment .14
8.1 Use of equipment . 14
8.2 Maintenance of equipment .15
Bibliography .16
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ISO/TS 23565:2021(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
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TECHNICAL SPECIFICATION ISO/TS 23565:2021(E)
Biotechnology — Bioprocessing — General requirements
and considerations for equipment systems used in the
manufacturing of cells for therapeutic use
1 Scope
This document specifies minimum requirements and general considerations for equipment, consisting
of hardware, software and consumables, used in the manufacturing of cells for therapeutic use. This
includes equipment for processing cells for therapeutic use starting from cell isolation/selection,
expansion, washing and volume reduction, from cell finish through to cryopreservation for the storage
of cells for therapeutic use.
This document gives guidance on the design, use and maintenance of equipment and equipment systems
to both suppliers and users from aspects including the target parties, i.e. supplier or user, and phase of
involved task, i.e. design, use or maintenance.
This document is applicable to any unit operation system that is used, alone or in combination, for the
manufacturing of cells for therapeutic use, meeting user requirements. It is applicable to devices used
for the purpose of monitoring equipment status.
It does not apply to:
— processing equipment for cells for therapeutic use used at the point of care;
— devices used for analytical purposes;
— biosafety cabinets, general cell culture equipment (such as CO incubators, etc.), and software to
2
control multiple equipment systems or multiple unit operations.
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
batch
quantity of material regarded as a single unit, and having a unique reference
Note 1 to entry: Batch is primarily a processing term.
[SOURCE: ISO 15270:2008, 3.3]
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ISO/TS 23565:2021(E)
3.2
cells for therapeutic use
product containing cells as the active substance
EXAMPLE A cell therapy medicinal product (allogenic, autologous, somatic, genetically modified), 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.
[SOURCE: ISO 21973:2020, 3.1, modified — The example has been replaced. Notes 2 and 3 to entry have
been deleted.]
3.3
consumable
tubing, filter, culture vessel, bag or bottle used to transfer, culture or act as a container for the biologics
or another consumable used in the production of cells for therapeutic use (3.2)
3.4
corrective action
action to eliminate the cause of a nonconformity and to prevent recurrence
Note 1 to entry: There can be more than one cause for a nonconformity.
Note 2 to entry: Corrective action is taken to prevent recurrence whereas preventive action (3.15) is taken to
prevent occurrence.
[SOURCE: ISO 9000:2015, 3.12.2, modified — Note 3 to entry has been deleted.]
3.5
critical quality attribute
CQA
physical, chemical, biological or microbiological property or characteristic that is within an appropriate
limit, range or distribution to ensure the desired quality and consistency of a cellular therapeutic
product
Note 1 to entry: CQA is generally related to the clinical efficacy and safety of the product.
3.6
equipment
device or machine that performs a specific field operation
[SOURCE: ISO 11783-1:2017, 3.20, modified — Note 1 to entry has been deleted.]
3.7
equipment system
set of equipment (3.6) that act together in a common purpose of producing cells for therapeutic use (3.2)
3.8
impurity
constituent of the product not intended to be part of the final formulation
3.9
installation qualification
IQ
process of establishing by objective evidence that all key aspects of the process equipment (3.6) and
ancillary system installation comply with the approved equipment specification
[SOURCE: ISO 11139:2018, 3.220.2, modified — “approved equipment specification” has replaced
“approved specification”.]
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ISO/TS 23565:2021(E)
3.10
line clearance
removal (line purge) of everything associated with the prior production run
[SOURCE: ISO 15378:2017, 3.5.4, modified — Note 1 to entry has been deleted.]
3.11
lot
unit of production that, as far as practicable, consists of production units of a single type, class, size and
composition, manufactured under the same conditions, and at substantially the same time
[SOURCE: ISO 24408:2005, 3.1]
3.12
monitoring
continuous or repeated checking, supervising, critically observing, measuring or determining the
status of a system to identify variance from an expected performance level or baseline, intended to
control the system
3.13
operational qualification
OQ
process of obtaining and documenting evidence that installed equipment (3.6) operates within
predetermined limits when used in accordance with its operational procedures
[SOURCE: ISO 11139:2018, 3.220.3]
3.14
performance qualification
PQ
process of establishing by objective evidence that the process, under anticipated conditions, consistently
produces a product which meets all the required product specifications
[SOURCE: ISO 11139:2018, 3.220.4, modified — “all the required product specifications” has replaced
“all predetermined requirements”.]
3.15
preventive action
action to eliminate the cause of a potential nonconformity or other potential undesirable situation
Note 1 to entry: There can be more than one cause for a potential nonconformity.
Note 2 to entry: Preventive action is taken to prevent occurrence whereas corrective action (3.4) is taken to
prevent recurrence.
[SOURCE: ISO 9000:2015, 3.12.1]
3.16
quality by design
QbD
systematic approach to development that begins with predefined objectives and emphasizes product
and process understanding and process control, employing statistical, analytical and risk-management
methodology in the design, development and manufacture of goods
3.17
risk-based approach
methodology that allows to prioritize activities based on a previous analysis of data
3.18
shelf life
specific time for which a product can be stored under recommended conditions and can maintain
acceptable product quality
3
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ISO/TS 23565:2021(E)
3.19
software
all or part of the programs, procedures, rules, and associated documentation of an information
processing system
[SOURCE: ISO/IEC 2382:2015, 2121278, modified — Notes 1 to 3 to entry have been deleted.]
3.20
stability
characteristic of a material, when stored under specified conditions, to maintain a value(s) for stated
property(ies) within specified limits for a specified period of time
[SOURCE: ISO Guide 30:2015, 2.1.15, modified — “material” has replaced “reference material”, “a
value(s) for stated property(ies)” has replaced “a specified property value”. Note 1 to entry has been
deleted.]
3.21
sterility
state of being free from viable microorganisms
Note 1 to entry: In practice, no such absolute statement regarding the absence of microorganisms can be proven.
[SOURCE: ISO 11139:2018, 3.274]
3.22
supplier
entity who manufactures cell processing equipment (3.6) for a user (3.25)
3.23
toxicity
ability of a substance to produce an adverse effect upon a living organism
[SOURCE: ISO 472:2013, 2.767]
3.24
unit operation
defined part of a manufacturing process
[SOURCE: ISO 11139:2018, 3.309]
3.25
user
sponsor
therapeutic manufacturer
entity who makes use of cell processing equipment (3.6) for the manufacturing of cells for therapeutic
use (3.2)
3.26
validation
confirmation, through the provision of objective evidence, that the requirements for a specific intended
use or application have been fulfilled
[SOURCE: ISO 9000:2015, 3.8.13, modified — Notes 1 to 3 to entry have been deleted.]
4 General considerations
4.1 General
This document specifies minimum requirements and general considerations for equipment and
equipment systems, used in the manufacturing of cells for therapeutic use. There are regulatory
4
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ISO/TS 23565:2021(E)
guidance documents available for cell processing equipment. Documents on bioprocessing equipment
used in biologics manufacturing are also available (see the Bibliography for examples).
NOTE In this document, the subject of a sentence that contains requirement(s) related to the supplier or
the user, or both, of an equipment is the equipment itself. The subject of a sentence that contains requirement(s)
related only to the supplier of an equipment is the supplier. The subject of a sentence that contains requirement(s)
related only to the user of an equipment is the user.
In the manufacturing of cells for therapeutic use, various types of equipment systems are used for:
a) cell harvest or cell collection;
b) cell extraction or cell purification (e.g. centrifuge, biosafety cabinet);
c) cell cultivation or cell expansion or cell differentiation (e.g. bioreactors);
d) cell washing and volume reduction (e.g. automated washing devices);
e) final formulation or fill or finish;
f) cell storage (e.g. programmed freezer).
Equipment systems for manufacturing cells for therapeutic use generally comprise three distinct
components that entail different approaches to quality assurance and risk management: hardware,
software and consumables. A high level of assessment should encompass the whole equipment system as
the sum of the individual components and together with the implications of upstream and downstream
processes for the complete workflow.
Hardware and software should be qualified. Associated processes should be validated. The impact of
the hardware to the cell product quality, as well as to the clean room environment, if applicable, should
be assessed.
Software should be validated. A system should be in place to ensure accessibility control, traceability,
data integrity and storage.
Consumables are important to ensure safety. As cellular products cannot be sterilized at the end of the
production, they are produced under aseptic conditions. Equipment that utilizes single-use consumables
such as tubing and collection bags should be used, as this can allow for processing to be performed in a
lower-grade clean room space on a risk-based approach.
Where open processing steps are performed, a suitable operating environment is required. The user
should determine the enclosure degree of equipment, based on operating the environment (e.g. clean
level) and necessary requirements to maintain patient safety.
4.2 Incorporating equipment and testing into the manufacturing workflow of cells for
therapeutic use
Carrying out the cell processing workflow generally requires a series of unit operations to be performed
using different processing methods and equipment types.
In-process and release testing should be in place to ensure that each instrument or machine operates as
intended.
NOTE For in-process tests or controlling (critical) process parameters, or both, it is generally accepted that
the criteria are set based on QbD, if applicable. QbD focuses on the fact that quality is built into a product with an
understanding of the product and process by which it is developed, and manufactured along with the knowledge
regarding the risks involved in manufacturing the product and how best to mitigate those risks.
Successful incorporation of equipment into the manufacturing workflow of cells for therapeutic use
includes the maintenance of sterility and integrity, which is achieved by using suitable environmental
controls, connectors or closed systems, or multiples of these to maintain uniformity and exclude
potential external contaminants.
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ISO/TS 23565:2021(E)
The responsibility of assembling a workflow composed of different equipment pieces lies exclusively
with the user. The supplier, however, should develop their products in a way that enables the
construction of said workflow(s).
4.3 Unit operation equipment systems
Wherever practical, best practice should include the use of a closed system for each unit operation step.
When unit operations or systems are not fully closed, processing steps or the systems should be
operated in appropriately designed facilities, biosafety cabinets or other suitable systems to reduce the
potential for product contamination or adulteration, or both.
4.4 Connecting to upstream or downstream processing equipment, or both
When equipment needs to be connected to upstream or downstream processing equipment, suitable
sterile connectors shall be used and operated in a manner that maintains sterility to minimize the risk of
introducing contaminants into the process. The selection of connectors depends on the manufacturing
environment and type of operation (closed system versus biosafety cabinet), and the nature, rate and
volume of the transfer. Sterile connectors or tubing that can be sterile welded and sterile sealed, or
both, should be used. Alternatively, qualified and sterile transfer bags with appropriate attachments
and tubing should be used to transfer materials between unit operations.
Connectors should be designed by the supplier to be compatible and suitable for the designated
task. Prior to using in manufacturing, the designer and the user shall verify that the connectors are
compatible and suitable for the designated task as equipment and connectors do not necessarily come
from the same supplier.
Consumable joint designs not validated by the supplier shall be validated by the user.
4.5 Monitoring and surveillance software
Suppliers of cell processing equipment should introduce means of monitoring critical parameters of
the instrument and software applications. If the embedded software does not have the surveillance
functionality, external software and hardware (e.g. pharma surveillance systems) should be connected
by users to monitor errors or technical issues of the equipment.
Users of cell processing equipment should evaluate the need for monitoring while connecting different
devices in a single workflow. Mitigation strategies based upon corrective action and preventive action
should be in place to allow curbing the risk to the cells for therapeutic use in the event of equipment
failure.
4.6 Impurity and toxicity contribution to final cells for therapeutic use
Any process-related impurities, such as leachables from equipment components with direct cell contact,
can potentially be carried over to the final cells for therapeutic use. Suppliers as well as users should
understand and acquire as much information as possible on impurities generated from each piece of
processing equipment.
If downstream unit operations include washing the drug substance intermediates or drug product,
certain risks associated with impurities from upstream processes can be mitigated.
Refer to 6.3.4 for the evaluation of consumables and extracted and leached materials.
4.7 Sterility and non-pyrogenicity
The qualification and maintenance of sterility and non-pyrogenicity of equipment to process cells for
therapeutic use is of particular importance due to limited downstream processing steps for removal of
pyrogens, lack of terminal sterile filtration, and the reduced window for microbial testing associated
with cells for therapeutic use. Sterility and endotoxin certifications shall be obtained for all materials
6
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ISO/TS 23565:2021(E)
for which suppliers have made a sterility claim. Sterile in place and clean in place techniques should be
properties of multi-use devices.
The equipment should be designed and utilized in such a way that the number of in-process connections,
such as tube welding, is minimized in order to reduce the risk of contaminations. The sampling
frequency and technique should be assessed for the risk to compromise sterility and non-pyrogenicity
(e.g. sanitization of the sample port with alcohol prior to entry can help to reduce the bioburden load).
To minimize the risk of containment breach, closed systems should be assessed for integrity pre- or
post-use, such as demonstration of pressure hold. Sterilizing grade filters should be assessed for
integrity post-use.
Non-endotoxin pyrogens, including material-mediated pyrogens, should be considered, when
[43]
applicable .
5 Equipment overall performance characteristics and evaluation
5.1 General
The equipment performance should be characterized, and performance data should be generated
by suppliers, to demonstrate the intended use of the equipment with consistency. The equipment
performance can be used as a frame of reference for users to select and qualify equipment.
5.2 Description of performance characteristics
Performance characteristics define the operational characteristics of the equipment in order to
best specify how and which of the available equipment can accomplish the work. Robust statistical
methodology should be in place to accept or reject a given validation of a biological process.
Performance characteristics are specific to the type of equipment and the role that it is intended to
perform. Generally, performance characteristics of cell processing equipment include yields, processing
efficiency, instrument response times, sensitivity and mechanical properties among others. Control
levels of operating conditions such as temperature, air flow rate, pH of media or buffer should be
considered when determining performance characteristics.
An assessment of properly functioning equipment shall be made based on the qual
...

TECHNICAL ISO/TS
SPECIFICATION 23565
First edition
Biotechnology — Bioprocessing
— General requirements and
considerations for equipment systems
used in the manufacturing of cells for
therapeutic use
PROOF/ÉPREUVE
Reference number
ISO/TS 23565:2021(E)
©
ISO 2021

---------------------- Page: 1 ----------------------
ISO/TS 23565:2021(E)

COPYRIGHT PROTECTED DOCUMENT
© ISO 2021
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: [phone]
Email: [e-mail]
Website: www.iso.org
Published in Switzerland
ii PROOF/ÉPREUVE © ISO 2021 – All rights reserved

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ISO/TS 23565:2021(E)

Contents Page
Foreword .iv
1 Scope . 1
2 Normative references . 1
3 Terms and definitions . 1
4 General considerations . 4
4.1 General . 4
4.2 Incorporating equipment and testing into cells for therapeutic use manufacturing
workflow . 5
4.3 Unit operation equipment systems . 6
4.4 Connecting to upstream or downstream processing equipment, or both . 6
4.5 Monitoring and surveillance software . 6
4.6 Impurity and toxicity contribution to final cells for therapeutic use . 6
4.7 Sterility and non-pyrogenicity . 6
5 Equipment overall performance characteristics and evaluation . 7
5.1 General . 7
5.2 Description of performance characteristics . 7
5.3 Performance parameters and correlation to cell quality attributes . 8
6 Components of equipment system . 8
6.1 Hardware . 8
6.1.1 General. 8
6.1.2 Physical integrity . 8
6.1.3 Physical strength . . 9
6.1.4 Packaging. 9
6.1.5 Recovery of cells . 9
6.1.6 Validation of performance qualification . 9
6.1.7 Physical evaluation of equipment and cell sample interaction . 9
6.1.8 Damage to cells. 9
6.1.9 Impact to clean room environment .10
6.1.10 Monitoring .10
6.2 Equipment software for manufacturing of cells for therapeutic use .10
6.3 Consumables .11
6.3.1 General.11
6.3.2 Biocompatibility .11
6.3.3 Toxicity of chemical sterilants .11
6.3.4 Toxicity of extracted and leached materials .12
6.3.5 Particulates .12
6.3.6 Stability of disposable, single-use components .13
7 Documentation and notification of changes .13
7.1 Documentation .13
7.1.1 General.13
7.1.2 Documentation for off-the-shelf equipment or instruments .13
7.1.3 Custom-designed supplier documentation package for equipment or
instruments .14
8 Use and maintenance of equipment .14
8.1 Use of equipment .14
8.2 Maintenance of equipment .15
Bibliography .16
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ISO/TS 23565:2021(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 PROOF/ÉPREUVE © ISO 2021 – All rights reserved

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TECHNICAL SPECIFICATION ISO/TS 23565:2021(E)
Biotechnology — Bioprocessing — General requirements
and considerations for equipment systems used in the
manufacturing of cells for therapeutic use
1 Scope
This document specifies minimum requirements and general considerations for equipment, consisting
of hardware, software and consumables, used in the manufacturing of cells for therapeutic use. This
includes equipment for processing cells for therapeutic use starting from cell isolation/selection,
expansion, washing and volume reduction, from cell finish through to cryopreservation for the storage
of cells for therapeutic use.
This document gives guidance on the design, use and maintenance of equipment and equipment systems
to both suppliers and users from aspects including the target parties, i.e. supplier or user, and phase of
involved task, i.e. design, use or maintenance.
This document is applicable to any unit operation system that is used, alone or in combination, for the
manufacturing of cells for therapeutic use, meeting user requirements. It is applicable to devices used
for the purpose of monitoring equipment status.
It does not apply to:
— processing equipment for cells for therapeutic use used at the point of care;
— devices used for analytical purposes;
— biosafety cabinets, general cell culture equipment (such as CO incubator, etc.), and software to
2
control multiple equipment systems or multiple unit operations.
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
batch
quantity of material regarded as a single unit, and having a unique reference
Note 1 to entry: Batch is primarily a processing term.
[SOURCE: ISO 15270:2008, 3.3]
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ISO/TS 23565:2021(E)

3.2
cells for therapeutic use
product containing cells as the active substance
Note 1 to entry: A cell therapy medicinal product (allogenic, autologous, somatic, genetically modified), tissue
engineered product.
Note 2 to entry: For the purpose of this document, “cells” mean human cells and tissues of autologous as well as
allogeneic.
[SOURCE: ISO 21973:2020, 3.1, modified — The example has been replaced. Notes 2 and 3 to entry have
been deleted.]
3.3
consumable
tubing, filter, culture vessel, bag or bottle used to transfer, culture or act as a container for the biologics
or another consumable used in cells for therapeutic use (3.2) production
3.4
corrective action
action to eliminate the cause of a nonconformity and to prevent recurrence
Note 1 to entry: There can be more than one cause for a nonconformity.
Note 2 to entry: Corrective action is taken to prevent recurrence whereas preventive action (3.15) is taken to
prevent occurrence.
[SOURCE: ISO 9000:2015, 3.12.2, modified — Note 3 to entry has been deleted.]
3.5
critical quality attribute
CQA
physical, chemical, biological or microbiological property or characteristic that is within an appropriate
limit, range or distribution to ensure the desired quality and consistency of a cellular therapeutic
product
Note 1 to entry: CQA is generally related to the clinical efficacy and safety of the product.
3.6
equipment
device or machine that performs a specific field operation
[SOURCE: ISO 11783-1:2017, 3.20, modified — Note 1 to entry has been deleted.]
3.7
equipment system
set of equipment (3.6) that act together in a common purpose of producing cells for therapeutic use (3.2)
3.8
impurity
constituent of the product not intended to be part of the final formulation
3.9
installation qualification
IQ
process of establishing by objective evidence that all key aspects of the process equipment (3.6) and
ancillary system installation comply with the approved equipment specification
[SOURCE: ISO 11139:2018, 3.220.2, modified — “approved equipment specification” has replaced
“approved specification”.]
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3.10
line clearance
removal (line purge) of everything associated with the prior production run
[SOURCE: ISO 15378:2017, 3.5.4, modified — Note 1 to entry has been deleted.]
3.11
lot
unit of production that, as far as practicable, consists of production units of a single type, class, size and
composition, manufactured under the same conditions, and at substantially the same time
[SOURCE: ISO 24408:2005, 3.1]
3.12
monitoring
continuous or repeated checking, supervising, critically observing, measuring or determining the
status of a system to identify variance from an expected performance level or baseline, intended to
control the system
3.13
operational qualification
OQ
process of obtaining and documenting evidence that installed equipment (3.6) operates within
predetermined limits when used in accordance with its operational procedures
[SOURCE: ISO 11139:2018, 3.220.3]
3.14
performance qualification
PQ
process of establishing by objective evidence that the process, under anticipated conditions, consistently
produces a product which meets all the required product specifications
[SOURCE: ISO 11139:2018, 3.220.4, modified — “all the required product specifications” has replaced
“all predetermined requirements”.]
3.15
preventive action
action to eliminate the cause of a potential nonconformity or other potential undesirable situation
Note 1 to entry: There can be more than one cause for a potential nonconformity.
Note 2 to entry: Preventive action is taken to prevent occurrence whereas corrective action (3.4) is taken to
prevent recurrence.
[SOURCE: ISO 9000:2015, 3.12.1]
3.16
quality by design
QbD
systematic approach to development that begins with predefined objectives and emphasizes product
and process understanding and process control, employing statistical, analytical and risk-management
methodology in the design, development and manufacture of goods
3.17
risk-based approach
methodology that allows to prioritize activities based on a previous analysis of data
3.18
shelf life
specific time for which product can be stored under recommended conditions and maintain acceptable
product quality
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3.19
software
all or part of the programs, procedures, rules, and associated documentation of an information
processing system
[SOURCE: ISO/IEC 2382:2015, 2121278, modified — Notes 1 to 3 to entry have been deleted.]
3.20
stability
characteristic of a material, when stored under specified conditions, to maintain a value(s) for stated
property(ies) within specified limits for a specified period of time
[SOURCE: ISO Guide 30:2015, 2.1.15, modified — “material” has replaced “reference material”, “a
value(s) for stated property(ies)” has replaced “a specified property value”. Note 1 to entry has been
deleted.]
3.21
sterility
state of being free from viable microorganisms
Note 1 to entry: In practice, no such absolute statement regarding the absence of microorganisms can be proven.
[SOURCE: ISO 11139:2018, 3.274]
3.22
supplier
entity who manufactures cell processing equipment (3.6) for a user (3.25)
3.23
toxicity
ability of a substance to produce an adverse effect upon a living organism
[SOURCE: ISO 472:2013, 2.767]
3.24
unit operation
defined part of a manufacturing process
[SOURCE: ISO 11139:2018, 3.309]
3.25
user
sponsor
therapeutic manufacturer
entity who makes use of cell processing equipment (3.6) for the manufacturing of cells for therapeutic
use (3.2)
3.26
validation
confirmation, through the provision of objective evidence, that the requirements for a specific intended
use or application have been fulfilled
[SOURCE: ISO 9000:2015, 3.8.13, modified — Notes 1 to 3 to entry have been deleted.]
4 General considerations
4.1 General
This document specifies minimum requirements and general considerations for equipment and
equipment systems, used in the manufacturing of cells for therapeutic use. There are regulatory
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guidance documents available for cell processing equipment. Documents on bioprocessing equipment
used in biologics manufacturing are also available (see the Bibliography for examples).
NOTE In this document, the subject of a sentence that contains requirement(s) related to the supplier or
the user, or both, of an equipment is the equipment itself. The subject of a sentence that contains requirement(s)
related only to the supplier of an equipment is the supplier. The subject of a sentence that contains requirement(s)
related only to the user of an equipment is the user.
In the manufacturing of cells for therapeutic use, various types of equipment systems are used for:
a) cell harvest or cell collection;
b) cell extraction or cell purification (e.g. centrifuge, biosafety cabinet);
c) cell cultivation or cell expansion or cell differentiation (e.g. bioreactors);
d) cell washing and volume reduction (e.g. automated washing devices);
e) final formulation or fill or finish;
f) cell storage (e.g. programmed freezer).
Equipment systems for manufacturing cells for therapeutic use generally comprise three distinct
components that entail different approaches to quality assurance and risk management: hardware,
software and consumables. A high level of assessment should encompass the whole equipment system as
the sum of the individual components and together with the implications of upstream and downstream
processes for the complete workflow.
Hardware and software should be qualified. Associated processes should be validated. The impact of
the hardware to the cell product quality, as well as to the clean room environment, if applicable, should
be assessed.
Software should be validated. A system should be in place to ensure accessibility control, traceability,
data integrity and storage.
Consumables are important to ensure safety. As cellular products cannot be sterilized at the end of the
production, they are produced under aseptic conditions. Equipment that utilizes single-use consumables
such as tubing and collection bags should be used, as this can allow for processing to be performed in a
lower-grade clean room space on a risk-based approach.
Where open processing steps are performed, a suitable operating environment is required. The user
should determine the enclosure degree of equipment, based on operating the environment (e.g. clean
level) and necessary requirements to maintain patient safety.
4.2 Incorporating equipment and testing into cells for therapeutic use manufacturing
workflow
Carrying out the cell processing workflow generally requires a series of unit operations to be performed
using different processing methods and equipment types.
In-process and release testing should be in place to ensure that each instrument or machine operates as
intended.
NOTE For in-process tests or controlling (critical) process parameters, or both, it is generally accepted that
the criteria are set based on QbD, if applicable. QbD focuses on the fact that quality is built into a product with an
understanding of the product and process by which it is developed, and manufactured along with the knowledge
regarding the risks involved in manufacturing the product and how best to mitigate those risks.
Successful incorporation of equipment into the cells for the therapeutic use manufacturing workflow
includes the maintenance of sterility and integrity, which is achieved by using suitable environmental
controls, connectors or closed systems, or multiples of these to maintain uniformity and exclude
potential external contaminants.
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The responsibility of assembling a workflow composed of different equipment pieces lies exclusively
with the user. The supplier, however, should develop their products in a way that enables the
construction of said workflow(s).
4.3 Unit operation equipment systems
Wherever practical, best practice should include the use of a closed system for each unit operation step.
When unit operations or systems are not fully closed, processing steps or the systems should be
operated in appropriately designed facilities, biosafety cabinets or other suitable systems to reduce the
potential for product contamination or adulteration, or both.
4.4 Connecting to upstream or downstream processing equipment, or both
When equipment needs to be connected to upstream or downstream processing equipment, suitable
sterile connectors shall be utilized and operated in a manner that maintains sterility to minimize the
risk of introducing contaminates into the process. The selection of connectors is dependent upon the
manufacturing environment and type of operation (closed system versus biosafety cabinet) and the
nature, rate and volume of the transfer. Sterile connectors or tubing that can be sterile welded and
sterile sealed, or both, should be used. Alternatively, qualified and sterile transfer bags with appropriate
attachments and tubing should be used to transfer materials between unit operations.
Connectors should be designed by the supplier to be compatible and suitable for the designated
task. Prior to using in manufacturing, the designer and the user shall verify that the connectors are
compatible and suitable for the designated task as equipment and that the connectors do not necessarily
come from the same supplier.
Consumable joint designs not validated by the supplier shall be validated by the user.
4.5 Monitoring and surveillance software
Suppliers of cell processing equipment should introduce means of monitoring critical parameters of
the instrument and software applications. If the embedded software does not have the surveillance
functionality, external software and hardware (e.g. pharma surveillance systems) should be connected
by users to monitor errors or technical issues of the equipment.
Users of cell processing equipment should evaluate the need for monitoring while connecting different
devices in a single workflow. Mitigation strategies based upon corrective action and preventive action
should be in place to allow curbing the risk to the cells for therapeutic use in the event of equipment
failure.
4.6 Impurity and toxicity contribution to final cells for therapeutic use
Any process-related impurities, such as leachables from equipment components with direct cell contact,
can potentially be carried over to the final cells for therapeutic use. Suppliers as well as users should
understand and acquire as much information as possible on impurities generated from each piece of
processing equipment.
If downstream unit operations include washing the drug substance intermediates or drug product,
certain risks associated with impurities from upstream processes can be mitigated.
Refer to 6.3.4 for the evaluation of consumables and extracted and leached materials.
4.7 Sterility and non-pyrogenicity
The qualification and maintenance of sterility and non-pyrogenicity of equipment to process cells for
therapeutic use is of particular importance due to limited downstream processing steps for removal of
pyrogens, lack of terminal sterile filtration, and the reduced window for microbial testing associated
with cells for therapeutic use. Sterility and endotoxin certifications shall be obtained for all materials
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for which suppliers have made a sterility claim. Sterile in place and clean in place techniques should be
properties of multi-use devices.
The equipment should be designed and utilized in such a way that the number of in-process connections,
such as tube welding, is minimized in order to reduce the risk of contaminations. The sampling
frequency and technique should be assessed for the risk to compromise sterility and non-pyrogenicity
(e.g. sanitization of the sample port with alcohol prior to entry can help to reduce the bioburden load).
To minimize the risk of containment breach, closed systems should be assessed for integrity pre- or
post-use, such as demonstration of pressure hold. Sterilizing grade filters should be assessed for
integrity post-use.
Non-endotoxin pyrogens, including material-mediated pyrogens, should be considered, when
[43]
applicable .
5 Equipment overall performance characteristics and evaluation
5.1 General
The equipment performance should be characterized, and performance data should be generated
by suppliers, to demonstrate the intended use of the equipment with consistency. The equipment
performance can be used as a frame of reference for users to select and qualify equipment.
5.2 Description of performance characteristics
Performance characteristics define the operational characteristics of the equipment in order to
best specify how and which of the available equipment can accomplish the work. Robust statistical
methodology should be in place to accept or reject a given validation of a biological process.
Performance characteristics are specific to the type of equipment and the role that it is intended to
perform. Generally, performance characteristics of cell processing equipment include yields, processing
efficiency, instrument response times, sensitivity and mechanical properties among others. Control
levels of operating conditions such as temperature, air flow rate, pH of media or buffer should be
considered when determining performance characteristics.
An assessment of properly functioning equipment shall be made based on the quality of the final
...