ISO/TS 22456:2021
(Main)Sterilization of healthcare products — Microbiological methods— Guidance on conducting bioburden determinations and tests of sterility for biologics and tissue-based products
Sterilization of healthcare products — Microbiological methods— Guidance on conducting bioburden determinations and tests of sterility for biologics and tissue-based products
1.1.1 This document provides guidance for bioburden testing and tests of sterility for biologics and tissue-based products, where this testing is in relation to product sterilization. NOTE This document is intended to be used in conjunction with ISO 11737-1 and ISO 11737-2. 1.1.2 Guidance in this document can be applicable to biologics and tissue-based products that are not sterile but are microbiologically controlled.
Stérilisation des produits de santé — Méthodes microbiologiques — Recommandations pour la réalisation de déterminations de la charge biologique et de contrôles de stérilité des produits biologiques et des produits à base de tissus
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TECHNICAL ISO/TS
SPECIFICATION 22456
First edition
2021-03
Sterilization of healthcare products —
Microbiological methods—
Guidance on conducting bioburden
determinations and tests of sterility
for biologics and tissue-based
products
Reference number
©
ISO 2021
© 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: +41 22 749 01 11
Email: copyright@iso.org
Website: www.iso.org
Published in Switzerland
ii © ISO 2021 – All rights reserved
Contents Page
Foreword .iv
Introduction .v
1 Scope . 1
1.1 Inclusions . 1
1.2 Exclusions . 1
2 Normative references . 1
3 Terms and definitions . 2
4 Definition and maintenance of product families . 3
5 Selection and testing of product for bioburden and tests of sterility .3
5.1 General . 3
5.2 Nature of product . 4
5.3 Sample Item Portion (SIP) . 4
5.4 Sampling conditions . 4
5.4.1 General. 4
5.4.2 Considerations for human tissue donor batches in sterilization . 4
5.4.3 Use of multiple batches . 5
5.4.4 Considerations for packaging . 5
5.5 Microbiological testing . 5
5.5.1 Bioburden test considerations for biologics/tissues. 5
5.5.2 Test of sterility considerations for biologics/tissues . 8
5.5.3 Verification of microbiological methods .10
5.5.4 Rapid microbiology tests .11
Bibliography .12
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 198, Sterilization of health care products.
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 2021 – All rights reserved
Introduction
The sources and types of some microorganisms, as well as the test methods used to evaluate biologics
and tissue-based products, can be unique relative to other health care products, such as plastic and
metal medical devices. This document provides guidance to address issues that are applicable to the
microbiological testing of biologics and tissue-based products, where this testing constitutes bioburden
testing or a test of sterility performed in relation to product sterilization. Except where otherwise
indicated in this document, the requirements in ISO 11737-1:2018 and ISO 11737-2:2019 apply.
TECHNICAL SPECIFICATION ISO/TS 22456:2021(E)
Sterilization of healthcare products — Microbiological
methods— Guidance on conducting bioburden
determinations and tests of sterility for biologics and
tissue-based products
1 Scope
1.1 Inclusions
1.1.1 This document provides guidance for bioburden testing and tests of sterility for biologics and
tissue-based products, where this testing is in relation to product sterilization.
NOTE This document is intended to be used in conjunction with ISO 11737-1 and ISO 11737-2.
1.1.2 Guidance in this document can be applicable to biologics and tissue-based products that are not
sterile but are microbiologically controlled.
1.2 Exclusions
1.2.1 This document does not include guidance for validation requirements for testing, eliminating
and/or inactivating viruses and prions or sterilization of tissue-based products.
NOTE Guidance on inactivating viruses and prions can be found in ISO 22442-3.
1.2.2 This document does not include guidance for containment or biosafety issues for biologics and
tissue-based products.
1.2.3 This document does not include guidance for testing biologics and tissue-based products for
specific infectious agents as listed in relevant national or international guidance (e.g. viruses/protozoa/
parasites, intracellular microorganisms or mycoplasma screening).
1.2.4 This document does not include guidance for the acceptance criteria for biologics and tissue-
based products during procurement or tissue to be processed and/or released for use.
1.2.5 This document does not include guidance for the testing associated with procurement and
screening of biologics and tissue-based products.
2 Normative references
The following documents are referred to in the text in such a way that some or all of their content
constitutes requirements of this document. For dated references, only the edition cited applies. For
undated references, the latest edition of the referenced document (including any amendments) applies.
ISO 11737-1:2018, Sterilization of health care products — Microbiological methods — Part 1: Determination
of a population of microorganisms on products
ISO 11737-2:2019, Sterilization of health care products — Microbiological methods — Part 2: Tests of
sterility performed in the definition, validation and maintenance of a sterilization process
3 Terms and definitions
For the purposes of this document, the terms and definitions given in ISO 11737-1:2018, ISO 11737-2:2019
and the following 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
biologics
product that is synthesized from living organisms, or their products, and used as a diagnostic,
preventive or therapeutic agent
3.2
companion tissue
tissue from the same donor(s) that is not intended to be used for transplantation
Note 1 to entry: For the purposes of this document, companion tissue is expected to be processed in the same
manner as tissue that is used for transplantation. Companion tissue is representative of tissue intended for
transplantation but is only used for evaluation and/or testing purposes.
3.3
donor identification
unique identifier assigned to all biologics (3.1)/tissue and companion tissue (3.2) that originates from
the same donor
3.4
method suitability test
bacteriostasis/fungistasis (B/F) test
technical operation performed to detect the presence of substances that inhibit microbial multiplication
Note 1 to entry: This testing is also referred to as “method verification.”
[SOURCE: ISO 11139:2018, 3.20, modified — Note 1 to entry has been added]
3.5
processing
any activity performed in the preparation, manipulation,
preservation for storage and packaging of a biological or tissue-based product
3.6
product family
group or subgroup of product characterized by similar attributes determined to be equivalent for
evaluation and processing purposes
[SOURCE: ISO 11139:2018, 3.218]
3.7
tissue-based product
product consisting of organization of cells, cells and extra-cellular constituents, or extra- cellular
constituents
Note 1 to entry: This can include tissues from tissue banks or material of animal origin.
2 © ISO 2021 – All rights reserved
4 Definition and maintenance of product families
4.1 Product families can be organized for a multitude of purposes. The purpose for which the family
is being organized will dictate the criteria for that family. Care should be taken in organizing families to
ensure that appropriate and relevant criteria are in place.
4.2 In cases where a product family representative is tested instead of each type of health care product,
an appropriate rationale should be written to ensure that results for the product family representative
are representative of the whole family. The applicable standards, i.e. ISO 11137-2, ISO 11135, etc. provide
guidance specific to establishment of a product family. Some of that guidance can be applicable to
establishment of a product family for other testing purposes. For other sterilization modalities, refer to
the applicable standard for additional guidance. Additionally, the following items can be considered:
a) the purpose for which the family is being established (e.g. for sterilization purposes, or for
bioburden testing purposes);
b) processing procedures that are applied to the biologic/tissue;
c) storage conditions that are applied to the various tissue types or sizes;
d) tissue collection methods.
4.3 For biologics or tissue-based product that is sterilized, the final determination of the product
family representative is based on recommendations per the relevant sterilization process standard (e.g.
ISO 11137-2 for radiation, ISO 11135 for EO, etc.).
4.4 In considering the relative size of biologic/tissue products, a larger size might not necessarily
correspond to a higher product bioburden if processing of the product is the same. If equivalence can
be demonstrated within a family of products, a rationale should be p
...
TECHNICAL ISO/TS
SPECIFICATION 22456
First edition
2021-03
Sterilization of healthcare products —
Microbiological methods—
Guidance on conducting bioburden
determinations and tests of sterility
for biologics and tissue-based
products
Reference number
©
ISO 2021
© 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: +41 22 749 01 11
Email: copyright@iso.org
Website: www.iso.org
Published in Switzerland
ii © ISO 2021 – All rights reserved
Contents Page
Foreword .iv
Introduction .v
1 Scope . 1
1.1 Inclusions . 1
1.2 Exclusions . 1
2 Normative references . 1
3 Terms and definitions . 2
4 Definition and maintenance of product families . 3
5 Selection and testing of product for bioburden and tests of sterility .3
5.1 General . 3
5.2 Nature of product . 4
5.3 Sample Item Portion (SIP) . 4
5.4 Sampling conditions . 4
5.4.1 General. 4
5.4.2 Considerations for human tissue donor batches in sterilization . 4
5.4.3 Use of multiple batches . 5
5.4.4 Considerations for packaging . 5
5.5 Microbiological testing . 5
5.5.1 Bioburden test considerations for biologics/tissues. 5
5.5.2 Test of sterility considerations for biologics/tissues . 8
5.5.3 Verification of microbiological methods .10
5.5.4 Rapid microbiology tests .11
Bibliography .12
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 198, Sterilization of health care products.
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 2021 – All rights reserved
Introduction
The sources and types of some microorganisms, as well as the test methods used to evaluate biologics
and tissue-based products, can be unique relative to other health care products, such as plastic and
metal medical devices. This document provides guidance to address issues that are applicable to the
microbiological testing of biologics and tissue-based products, where this testing constitutes bioburden
testing or a test of sterility performed in relation to product sterilization. Except where otherwise
indicated in this document, the requirements in ISO 11737-1:2018 and ISO 11737-2:2019 apply.
TECHNICAL SPECIFICATION ISO/TS 22456:2021(E)
Sterilization of healthcare products — Microbiological
methods— Guidance on conducting bioburden
determinations and tests of sterility for biologics and
tissue-based products
1 Scope
1.1 Inclusions
1.1.1 This document provides guidance for bioburden testing and tests of sterility for biologics and
tissue-based products, where this testing is in relation to product sterilization.
NOTE This document is intended to be used in conjunction with ISO 11737-1 and ISO 11737-2.
1.1.2 Guidance in this document can be applicable to biologics and tissue-based products that are not
sterile but are microbiologically controlled.
1.2 Exclusions
1.2.1 This document does not include guidance for validation requirements for testing, eliminating
and/or inactivating viruses and prions or sterilization of tissue-based products.
NOTE Guidance on inactivating viruses and prions can be found in ISO 22442-3.
1.2.2 This document does not include guidance for containment or biosafety issues for biologics and
tissue-based products.
1.2.3 This document does not include guidance for testing biologics and tissue-based products for
specific infectious agents as listed in relevant national or international guidance (e.g. viruses/protozoa/
parasites, intracellular microorganisms or mycoplasma screening).
1.2.4 This document does not include guidance for the acceptance criteria for biologics and tissue-
based products during procurement or tissue to be processed and/or released for use.
1.2.5 This document does not include guidance for the testing associated with procurement and
screening of biologics and tissue-based products.
2 Normative references
The following documents are referred to in the text in such a way that some or all of their content
constitutes requirements of this document. For dated references, only the edition cited applies. For
undated references, the latest edition of the referenced document (including any amendments) applies.
ISO 11737-1:2018, Sterilization of health care products — Microbiological methods — Part 1: Determination
of a population of microorganisms on products
ISO 11737-2:2019, Sterilization of health care products — Microbiological methods — Part 2: Tests of
sterility performed in the definition, validation and maintenance of a sterilization process
3 Terms and definitions
For the purposes of this document, the terms and definitions given in ISO 11737-1:2018, ISO 11737-2:2019
and the following 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
biologics
product that is synthesized from living organisms, or their products, and used as a diagnostic,
preventive or therapeutic agent
3.2
companion tissue
tissue from the same donor(s) that is not intended to be used for transplantation
Note 1 to entry: For the purposes of this document, companion tissue is expected to be processed in the same
manner as tissue that is used for transplantation. Companion tissue is representative of tissue intended for
transplantation but is only used for evaluation and/or testing purposes.
3.3
donor identification
unique identifier assigned to all biologics (3.1)/tissue and companion tissue (3.2) that originates from
the same donor
3.4
method suitability test
bacteriostasis/fungistasis (B/F) test
technical operation performed to detect the presence of substances that inhibit microbial multiplication
Note 1 to entry: This testing is also referred to as “method verification.”
[SOURCE: ISO 11139:2018, 3.20, modified — Note 1 to entry has been added]
3.5
processing
any activity performed in the preparation, manipulation,
preservation for storage and packaging of a biological or tissue-based product
3.6
product family
group or subgroup of product characterized by similar attributes determined to be equivalent for
evaluation and processing purposes
[SOURCE: ISO 11139:2018, 3.218]
3.7
tissue-based product
product consisting of organization of cells, cells and extra-cellular constituents, or extra- cellular
constituents
Note 1 to entry: This can include tissues from tissue banks or material of animal origin.
2 © ISO 2021 – All rights reserved
4 Definition and maintenance of product families
4.1 Product families can be organized for a multitude of purposes. The purpose for which the family
is being organized will dictate the criteria for that family. Care should be taken in organizing families to
ensure that appropriate and relevant criteria are in place.
4.2 In cases where a product family representative is tested instead of each type of health care product,
an appropriate rationale should be written to ensure that results for the product family representative
are representative of the whole family. The applicable standards, i.e. ISO 11137-2, ISO 11135, etc. provide
guidance specific to establishment of a product family. Some of that guidance can be applicable to
establishment of a product family for other testing purposes. For other sterilization modalities, refer to
the applicable standard for additional guidance. Additionally, the following items can be considered:
a) the purpose for which the family is being established (e.g. for sterilization purposes, or for
bioburden testing purposes);
b) processing procedures that are applied to the biologic/tissue;
c) storage conditions that are applied to the various tissue types or sizes;
d) tissue collection methods.
4.3 For biologics or tissue-based product that is sterilized, the final determination of the product
family representative is based on recommendations per the relevant sterilization process standard (e.g.
ISO 11137-2 for radiation, ISO 11135 for EO, etc.).
4.4 In considering the relative size of biologic/tissue products, a larger size might not necessarily
correspond to a higher product bioburden if processing of the product is the same. If equivalence can
be demonstrated within a family of products, a rationale should be p
...
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