ISO 20399:2022
(Main)Biotechnology — Ancillary materials present during the production of cellular therapeutic products and gene therapy products
Biotechnology — Ancillary materials present during the production of cellular therapeutic products and gene therapy products
This document specifies requirements and gives guidance to suppliers and users of ancillary materials (AMs) to improve the consistency and quality of AMs of biological (human and animal) and chemical origin used in the production of cellular therapeutic products and gene therapy products for human use. This document is applicable to materials that are used for cell processing and that come into contact with the active substance and that do not intentionally form part of the final cell and gene therapy product. EXAMPLE 1 Reagents, anticoagulants, cytokines, growth factors, enzymes, antibodies, serum (human or bovine), buffered solutions, culture media, dishes (coated with biological material), beads (coated with biological material), cryoprotectants (agents for cryopreservation), activation agents/reagents, non-mammalian cell (e.g. insect cell, bacterial cell), plasmid, viral vector. This document does not apply to materials that are not used for cell processing, materials that do not come into contact with the active substance, or materials that intentionally form part of the final cell and gene therapy product. EXAMPLE 2 Cells that are either starting materials, intermediates or final form of a cellular therapeutic product, feeder cells, additives used post bioprocessing, scaffolds, non-biological consumables (e.g. beads, dishes, tissue culture flasks, bags, tubing, pipettes, needles), other plasticware that come into contact with the cell or tissue, apparatus, instruments. A decision flowchart is given in Annex A. NOTE International, regional or national regulations or requirements can also apply to specific topics covered in this document.
Biotechnologie — Matériaux auxiliaires présents lors de la production de produits thérapeutiques cellulaires et de produits de thérapie génique
General Information
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Standards Content (Sample)
INTERNATIONAL ISO
STANDARD 20399
First edition
2022-12
Biotechnology — Ancillary materials
present during the production of
cellular therapeutic products and
gene therapy products
Biotechnologie — Matériaux auxiliaires présents lors de la production
de produits thérapeutiques cellulaires et de produits de thérapie
génique
Reference number
ISO 20399:2022(E)
© ISO 2022
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ISO 20399:2022(E)
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© ISO 2022
All rights reserved. Unless otherwise specified, or required in the context of its implementation, no part of this publication may
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ISO 20399:2022(E)
Contents Page
Foreword .v
Introduction . vi
1 Scope . 1
2 Normative references . 1
3 Terms and definitions . 1
4 Abbreviated terms . 4
5 Strategy . 5
5.1 Key concepts on AM . 5
5.2 AM-related responsibilities . 5
5.3 Qualification considerations of AM . 6
5.4 Animal-derived components of AM . 7
5.4.1 General . 7
5.4.2 Key considerations in the use of animal-derived components . 7
5.4.3 Viral inactivation . 8
6 Evaluation criteria and risk mitigation for AM containing biological material .8
6.1 Evaluation criteria for AM selection . 8
6.2 Mitigation of risk . 10
6.2.1 Scientific approach . 10
6.2.2 Supplier audit and questionnaires . 11
6.2.3 Risk assessment .12
7 AM characteristics and quality attributes .12
7.1 AM components, identity and purity .12
7.1.1 General .12
7.1.2 Identity and quantity of component(s) . 13
7.1.3 Purity and impurity .13
7.1.4 Lot-to-lot consistency for AMs containing proprietary components .13
7.2 AM storage and stability . 14
7.2.1 General . 14
7.2.2 Stability and storage conditions . 14
8 AM manufacturing and biosafety . .15
8.1 Quality management system . 15
8.2 Manufacturing process . 16
8.3 Container and closure systems . 16
8.4 Animal and human-derived components . 16
8.5 Safety to cells and humans . 17
9 AM performance .17
9.1 General . 17
9.2 Quality and testing . 18
9.3 Qualification activity . 18
9.4 Performance assay . 19
9.5 Performance assay results . 19
10 AM documentation .19
10.1 General . 19
10.2 Reporting requirements . 20
10.3 Certificate of analysis . 21
10.4 Additional certificates .22
10.4.1 Certificate of origin .22
10.4.2 Certificate of compliance . 22
10.4.3 Certificate of irradiation . 22
11 Managing changes to components .22
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ISO 20399:2022(E)
11.1 Impact of changes to components . 22
11.2 Measures for managing changes to components . 22
Annex A (informative) Decision chart of AMs .24
Annex B (informative) Example workflow from AM supplier to AM user .26
Annex C (informative) Information on AM and materials used to produce AMs .27
Annex D (informative) Considerations for the characterization of AMs .29
Annex E (informative) Quality declarations for manufactured biological materials used in
the manufacture of a cell-based therapeutic product.30
Bibliography .31
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ISO 20399:2022(E)
Foreword
ISO (the International Organization for Standardization) is a worldwide federation of national standards
bodies (ISO member bodies). The work of preparing International Standards is normally carried out
through ISO technical committees. Each member body interested in a subject for which a technical
committee has been established has the right to be represented on that committee. International
organizations, governmental and non-governmental, in liaison with ISO, also take part in the work.
ISO collaborates closely with the International Electrotechnical Commission (IEC) on all matters of
electrotechnical standardization.
The procedures used to develop this document and those intended for its further maintenance are
described in the ISO/IEC Directives, Part 1. In particular, the different approval criteria needed for the
different types of ISO documents should be noted. This document was drafted in accordance with the
editorial rules of the ISO/IEC Directives, Part 2 (see www.iso.org/directives).
Attention is drawn to the possibility that some of the elements of this document may be the subject of
patent rights. ISO shall not be held responsible for identifying any or all such patent rights. Details of
any patent rights identified during the development of the document will be in the Introduction and/or
on the ISO list of patent declarations received (see www.iso.org/patents).
Any trade name used in this document is information given for the convenience of users and does not
constitute an endorsement.
For an explanation of the voluntary nature of standards, the meaning of ISO specific terms and
expressions related to conformity assessment, as well as information about ISO's adherence to
the World Trade Organization (WTO) principles in the Technical Barriers to Trade (TBT), see
www.iso.org/iso/foreword.html.
This document was prepared by Technical Committee ISO/TC 276, Biotechnology.
This first edition cancels and replaces ISO/TS 20399-1:2018, ISO/TS 20399-2:2018 and
ISO/TS 20399-3:2018, which have been technically revised.
The main changes are as follows:
— merging of the three parts of the ISO 20399 series;
— change in definitions of key terms including “ancillary material” and “cellular therapeutic product”;
— addition of Clause 5 “Strategy”, including key concepts, animal-derived components, mutual
responsibilities and qualification;
— revision and rearrangement of requirements and recommendations with emphasis on clarifying
responsibility of involved parties and emphasis of a risk-based approach.
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.
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ISO 20399:2022(E)
Introduction
Ancillary materials (AMs) refer to materials that come into contact with the cellular therapeutic product
during cell processing but are not intended to be part of the final product formulation. See Annex A for
a list of AM examples.
AM can be a complex mixture of many components. AMs include, for example, salts, buffers, culture
media, supplements such as growth factors, enzymes and antibodies for immuno-purification. Where a
material is composed of multiple materials such as culture media, all components are AMs. Variation in
their lot-to-lot composition can hamper the ability to produce consistent cell and gene therapy products
with specified quality attributes.
As such, AMs can have implications with regard to the safety and effectiveness of cell and gene therapy
products. Appropriate control of AMs is determined by a risk-based approach.
This document specifies definitions for AMs.
This document provides recommendations and requirements to the AM suppliers and the AM users to
ensure consistent manufacture and performance of AMs. This document also describes the information
that can be obtained and provided to the AM users to demonstrate lot-to-lot consistency of the AM with
respect to identity, purity, storage and stability, traceability, biosafety, and performance. Furthermore,
this document provides recommendations and requirements to ensure that the quality of AMs enables
the production of safe and effective final products.
Presently, a number of standards and guidance documents define the proper processing of cell and gene
therapy products to ensure safety and efficacy. However, these standards only indirectly relate to AMs.
This document is separate from the standards governing cell processing requirements. This document
addresses issues with AMs and makes the expectations of the AM suppliers and the AM users clear.
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INTERNATIONAL STANDARD ISO 20399:2022(E)
Biotechnology — Ancillary materials present during the
production of cellular therapeutic products and gene
therapy products
1 Scope
This document specifies requirements and gives guidance to suppliers and users of ancillary materials
(AMs) to improve the consistency and quality of AMs of biological (human and animal) and chemical
origin used in the production of cellular therapeutic products and gene therapy products for human
use.
This document is applicable to materials that are used for cell processing and that come into contact
with the active substance and that do not intentionally form part of the final cell and gene therapy
product.
EXAMPLE 1 Reagents, anticoagulants, cytokines, growth factors, enzymes, antibodies, serum (human or
bovine), buffered solutions, culture media, dishes (coated with biological material), beads (coated with biological
material), cryoprotectants (agents for cryopreservation), activation agents/reagents, non-mammalian cell (e.g.
insect cell, bacterial cell), plasmid, viral vector.
This document does not apply to materials that are not used for cell processing, materials that do not
come into contact with the active substance, or materials that intentionally form part of the final cell
and gene therapy product.
EXAMPLE 2 Cells that are either starting materials, intermediates or final form of a cellular therapeutic
product, feeder cells, additives used post bioprocessing, scaffolds, non-biological consumables (e.g. beads, dishes,
tissue culture flasks, bags, tubing, pipettes, needles), other plasticware that come into contact with the cell or
tissue, apparatus, instruments.
A decision flowchart is given in Annex A.
NOTE International, regional or national regulations or requirements can also apply to specific topics
covered in this document.
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 8601-1, Date and time — Representations for information interchange — Part 1: Basic rules
3 Terms and definitions
For the purposes of this document, the following terms and definitions apply.
ISO and IEC maintain terminology databases for use in standardization at the following addresses:
— ISO Online browsing platform: available at https:// www .iso .org/ obp
— IEC Electropedia: available at https:// www .electropedia .org/
3.1
active substance
substance that has biological activity in a cellular therapeutic product (3.9) for its intended use
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ISO 20399:2022(E)
3.2
AM
ancillary material
raw material
material that comes into contact with the cellular therapeutic product (3.9) during cell processing, but is
not intended to be part of the final product formulation, excluding scaffold, non-biological consumable
and plasticware
Note 1 to entry: An AM can be critical to the quality and safety of a cellular therapeutic product due to its contact
during cell processing.
Note 2 to entry: A decision chart that indicates whether or not a material is in scope of this document is given in
Annex A.
3.3
AM impurity
ancillary material impurity
any component present in an AM (3.2) that is not the desired entity
3.4
AM supplier
ancillary material supplier
entity who manufactures or supplies, or both, AMs (3.2) for the AM user (3.5)
3.5
AM user
ancillary material user
entity who makes use of AMs (3.2) and conducts cell-processing for a cellular therapeutic product (3.9)
3.6
animal-derived component free
ADCF
absence of animal or human origin material(s)
Note 1 to entry: The main purpose of defining the types of ADCF is to provide necessary information for a user’s
risk assessment (3.13) of ancillary material (3.2).
Note 2 to entry: In some cases, ADCF is described as “animal origin free (AOF)”.
Note 3 to entry: In cases where there is absence of non-human animal components, the term “xeno-free” is
commonly used.
3.7
biological material
any substance derived or part obtained from an organic entity such as a human, animal, plant,
microorganism(s) or multicellular organism(s) that is(are) neither animal nor plant (e.g. brown
seaweed, fungi)
[SOURCE: ISO 20387:2018, 3.7]
3.8
biosafety
practices and controls that reduce the risk of unintentional exposure or release of biological materials
(3.7)
Note 1 to entry: This definition includes unintentional exposure, for example, to pathogens and toxins, or their
accidental release as a biosafety risk.
[SOURCE: ISO 35001:2019, 3.22, modified — Note 1 to entry added.]
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ISO 20399:2022(E)
3.9
cellular therapeutic product
product containing cells as the active substance (3.1) used for cell therapy or gene therapy
EXAMPLE Cell and gene therapy products, tissue engineered products, drug products.
Note 1 to entry: Products produced from cells for gene therapies are included in the definition of cellular
therapeutic product, as cells are not necessarily the active substance for all gene therapies.
Note 2 to entry: Recombinant proteins are not included in this definition of cellular therapeutic product.
3.10
chain of custody
responsibility for, or control of, materials as they move through each step of a process
Note 1 to entry: Chain of custody is the unbroken path of an ancillary material (AM) (3.2) from the production of
the AM to the end AM user (3.5). It covers controls, distribution and logistics to the AM user.
3.11
chemically defined component
substance whose chemical structure is identified/known at the molecular level
3.12
CoA
certificate of analysis
document attesting that an ancillary material (AM) (3.2) has undergone specified testing with specified
results
Note 1 to entry: A CoA commonly contains the actual results obtained from the testing performed as a part of
quality control of an individual batch of an AM.
Note 2 to entry: Often the CoA represents an agreement between the AM supplier (3.4) and the AM user (3.5).
3.13
risk assessment
overall process of risk identification, risk analysis and risk evaluation
[SOURCE: ISO Guide 73:2009, 3.4.1]
3.14
risk management
coordinated activities to direct and control an organization with regard to risk
[SOURCE: ISO Guide 73:2009, 2.1]
3.15
shelf life
period during which an ancillary material (3.2) is expected to comply with the specifications (3.16), if
stored under defined conditions
3.16
specification
list of tests, references to analytical procedures and appropriate acceptance criteria that are expected
to be met to demonstrate suitability for its intended use
3.17
stability
characteristic of a material, when stored under specified conditions, to maintain a value(s) for a stated
property(ies) within specified limits, for a specified period of time
[SOURCE: ISO Guide 30:2015, 2.1.15, modified — “reference material” replaced by “material”. “a
specified property value” replaced by “a value(s) for a stated property(ies)”. Note 1 to entry deleted.]
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ISO 20399:2022(E)
3.18
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]
3.19
user requirement specification
URS
document that states specifications (3.16) for an ancillary material (AM) (3.2) based on the AM user’s
(3.5) requirements for the manufacture of a desired cellular therapeutic product (3.9) and gene therapy
product
4 Abbreviated terms
ADCF animal-derived component free
AM ancillary material
AOF animal origin free
BSE bovine spongiform encephalopathy
CoA certificate of analysis
CoC certificate of compliance
CoI certificate of irradiation
CoO certificate of origin
EDQM CEP European Directorate for the Quality of Medicines and Healthcare certificate of suitability
GMP good manufacturing practice
ICH International Council for Harmonization of Technical Requirements for Pharmaceuticals
for Human Use
QC quality control
QMS quality management system
RP-HPLC reverse phase high performance liquid chromatography
SDS safety data sheet
SDS-PAGE sodium dodecyl sulfate poly acrylamide gel electrophoresis
TSE transmissible spongiform encephalopathy
USP United States Pharmacopeia
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ISO 20399:2022(E)
5 Strategy
5.1 Key concepts on AM
AMs for each cellular therapeutic product are defined by the manufacturing process and the final form
of the cellular therapeutic product (see Annex A).
AM users have the responsibility to establish and maintain a qualified status for AMs within their
processes, including any oversight required for any AM. The level of such oversight should be
proportionate to the risks posed by a specified AM, with reference to origin, manufacture or supply
chain integrity. It is necessary to undertake a risk-based approach to AM selection and qualification.
AM can affect quality attributes of cell-based therapeutic products:
a) quality and consistency are important for AMs known to be critical for cell manufacturing;
b) safety and the chain of custody are critical for AMs of cellular therapeutic products.
Activities to assess and control the impact of AMs on the quality attributes of a cellular therapeutic
product by the AM user are based on:
— information provided by the AM supplier;
— information obtained by either the AM user or the AM supplier, or both, through either
characterization and testing of AMs or manufacturing of cellular therapeutic product;
— published standards or other peer-reviewed scientific methods (or equivalent).
5.2 AM-related responsibilities
A typical workflow to determine the supply of an AM from the AM supplier to the AM user is described
in Annex B.
The AM user and the AM supplier can agree upon the specifications of AMs intended for cellular
therapeutic products by using such workflow.
The general workflow is intended to hold the accountabilities of AM user(s) and AM supplier(s) for using
an AM in the production of a cellular therapeutic product.
Table 1 describes recommendations for responsibilities and responsible parties leading these activities.
NOTE It is important that the relationship between the AM user and the AM supplier is cooperative and
transparent. Many responsibilities are determined together as their combined efforts. These activities benefit
from a supplier-user relationship. Without such relationship, an additional risk for the user, e.g. lack of technical
support from the supplier, can happen. Although the responsibility for these activities is determined on a case-
by-case basis.
Table 1 — Recommendations of responsibilities and responsible parties leading this activity
Activity Responsible Reference for more
party information
Provide documented evidence that the AM is safe with respect AM supplier 6.1 (Table 2), 6.2.1
a
to source-relevant animal diseases (e.g. BSE/TSE) (Table 3), 8.4 P3 ,
Annex C, Annex E
Prepare and submit a master file for AM, if applicable AM supplier 7.1.4 P3, Annex C
Assess the stability of the AM AM supplier 7.2.2
Inform the AM user of any changes that will very likely or with AM supplier 8.1 P1, Clause 11
certainty impact the AM (e.g. under a quality agreement)
a
“P” represents paragraph. For example, “8.4 P3” means “8.4 Paragraph 3.
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ISO 20399:2022(E)
TTabablele 1 1 ((ccoonnttiinnueuedd))
Activity Responsible Reference for more
party information
Conduct an assessment of the AM container closure system AM supplier 8.3
Provide a CoA, CoO and SDS for the AM AM supplier 10.2 P2 and P4, 10.3, 10.4.1
Conduct characterization testing of the AM and prepare a AM supplier and 6.1 (Table 2), 6.2.1
specifications document (e.g. identity, purity, functionality, AM user (Table 3), 6.2.2 P1,
viral contamination, animal origin) Clause 7, 8.4, 8.5, Clause 9,
10.3, Annex C, Annex D
Execute a quality and supply agreement AM supplier and 9.3 P6, 10.2 P2, 11.2,
AM user Annex C
Provide user requirement specifications to the AM supplier AM user Annex B
Conduct a risk-based AM supplier qualification process, AM user 5.3, Clause 6, 8.4 NOTE, 9.2,
generally including initial screen
...
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