ISO 18362:2016

Manufacture of cell-based health care products — Control of microbial risks during processing

ISO 18362:2016 specifies the minimum requirements for, and provides guidance on, a risk-based approach for the processing of cell-based health care products (CBHPs) requiring control of viable and non-viable microbial contamination. It is applicable both to CBHPs labelled 'sterile' and to CBHPs not labelled 'sterile'. ISO 18362:2016 is not applicable to: - procurement and transport of cell-based starting material used in processing of a CBHP, - cell banking, - control of genetic material, - control of non-microbial product contamination, - in vitro diagnostics (IVDs), or - natural medicines. EXAMPLE Vitamins and minerals, herbal remedies, homoeopathic medicines, traditional medicines such as traditional Chinese medicines, probiotics, other products such as amino acids and essential fatty acids. ISO 18362:2016 does not define biosafety containment requirements. ISO 18362:2016 does not replace national or regional regulations that apply to the manufacture and quality control of a CBHP.

Manufacture de produits de soins de santé fondés sur les cellules — Contrôle des risques microbiaux durant le processus

General Information

• Status: Published
• Publication Date: 14-Jan-2016
• ICS: 11.080.01 - Sterilization and disinfection in general
• Technical Committee: ISO/TC 198 - Sterilization of health care products
• Drafting Committee: ISO/TC 198 - Sterilization of health care products
• Current Stage: 9093 - International Standard confirmed
• Completion Date: 20-Oct-2021

Relations

• Amended By: ISO 18362:2016/Amd 1:2022 - Manufacture of cell-based health care products — Control of microbial risks during processing — Amendment 1
• Effective Date: 01-Jan-2022

Standards Content (Sample)

INTERNATIONAL ISO
STANDARD 18362
First edition
2016-02-01
Manufacture of cell-based health care
products — Control of microbial risks
during processing
Manufacture de produits de soins de santé fondés sur les cellules —
Contrôle des risques microbiaux durant le processus
Reference number
ISO 18362:2016(E)
©
ISO 2016

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ISO 18362:2016(E)

COPYRIGHT PROTECTED DOCUMENT
© ISO 2016, Published in Switzerland
All rights reserved. Unless otherwise specified, no part of this publication may be reproduced or utilized otherwise in any form
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ii © ISO 2016 – All rights reserved

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ISO 18362:2016(E)

Contents Page
Foreword .v
Introduction .vi
1 Scope . 1
2 Normative references . 1
3 Terms and definitions . 2
4 Quality system elements . 5
5 Process definition . 5
5.1 General . 5
5.2 Risk management . 6
5.2.1 General considerations . 6
5.2.2 Cell-based starting material risk assessment . 7
5.2.3 CBHP process risk assessment . 7
5.2.4 Use of risk assessment methods and tools for supply of CBHPs for use in
clinical trials . . 8
6 Manufacturing environment . 8
6.1 General . 8
6.2 Alternative processes . 8
6.3 Manufacturing environment design . 8
6.3.1 Containment area . 8
6.3.2 Construction containment features . 8
6.4 Layout . 9
6.5 Material and personnel flow . 9
6.5.1 General. 9
6.5.2 Equipment . 9
6.5.3 Handling of waste material . 9
6.6 HVAC system .10
6.7 Utility services and ancillary equipment .10
6.8 Environmental and personnel monitoring programmes .10
7 Equipment .10
7.1 General .10
7.2 Additional requirements .10
8 Personnel .11
8.1 General .11
8.2 Personnel procedures .11
8.3 Gowning procedures .11
8.4 General employee health .11
9 Manufacture of product .12
9.1 General .12
9.2 Control of starting material .12
9.2.1 Cell-based starting material .12
9.2.2 Other starting materials .12
9.3 Manufacturing procedures .13
9.4 In-process controls and process monitoring .13
9.5 Virus elimination and inactivation .13
10 Process simulation and process confirmation .13
10.1 General .13
10.2 Process simulation .14
10.3 Process confirmation studies .14
10.4 Media selection and growth support .14
11 Finished product release: test for sterility .15
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ISO 18362:2016(E)

11.1 General .15
11.2 Additional requirements .15
12 Finished product release: testing for biological contamination that cannot be
detected by the test for sterility .16
12.1 General .16
12.2 Extrinsic biological contamination .16
12.3 Intrinsic biological contamination .16
Annex A (informative) Examples of microbial risks for CBHP .17
Annex B (normative) Decision trees for application of risk assessment for cell-based
starting materials .18
Annex C (informative) Containment facilities .20
Annex D (normative) CBHP starting material .27
Annex E (normative) Containment requirements for procured, non-sterile starting
materials before entering the manufacturing area.29
Annex F (informative) Typical elements of a process definition .30
Bibliography .31
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ISO 18362:2016(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 on the meaning of ISO specific terms and expressions related to conformity
assessment, as well as information about ISO’s adherence to the WTO principles in the Technical
Barriers to Trade (TBT) see the following URL: Foreword - Supplementary information
The committee responsible for this document is ISO/TC 198, Sterilization of health care products.
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ISO 18362:2016(E)

Introduction
0.1 General
A cell-based health care product (CBHP) comprises prokaryotic or eukaryotic cells or cell derived
biological entities as an essential ingredient. Cell-based or cell derived starting material used in the
manufacture of a CBHP can be viable or non-viable and of human, animal, microbial or plant origin. A
common feature of CBHPs is that their efficacy is based on their biological properties. They are classified
as medicines, medical devices, biologics or combination products depending on the international,
national and/or regional regulations that govern supply of these products.
CBHPs might be limited in their ability to withstand sterilization and purification methods. This
International Standard focuses on process rather than product. It describes the minimum elements
necessary for a risk-based approach to the processing of a CBHP in order to reduce the potential for
an increase in intrinsic contamination of product and to avoid extrinsic contamination of product. The
design of the processes, equipment, facilities, utilities, the conditions of preparation and addition of
buffers and reagents, and training of the operators are key considerations to minimize contamination.
0.2 CBHPs labelled as ‘sterile’
A CBHP that is labelled as ‘sterile’ is sterilized by a terminal sterilization process or is aseptically
processed.
Examples of CBHPs that are terminally sterilized include, but are not restricted to, cancellous bone,
demineralized bone matrix, catgut sutures, biological heart valves and tissue patches. Sterility
assurance for these CBHPs is achieved through suitable design and control of the environment, controls
on starting materials and packaging, suitable design and qualification of manufacturing processes
including the terminal sterilization process, and the application of appropriate in-process controls and
testing. Requirements and guidance for terminal sterilization of CBHPs are contained in ISO 17665-1,
ISO/TS 17665-2, ISO 11137-1, ISO 11137-2, ISO 11137-3, ISO 11135, ISO 14160, ISO 20857, ISO 14937 and
ISO 25424, as applicable.
Controls for some infectious agents, e.g. viruses and protozoa, might require a multifaceted approach to
ensure product quality and safety. Such agents are not specifically considered in the existing standards
for terminal sterilization or aseptic processing.
A CBHP that is labelled ‘sterile’ and which cannot be terminally sterilized is aseptically processed.
Sterility assurance for these CBHPs is achieved through suitable design and control of the environment,
controls on starting materials and packaging, suitable design and qualification of manufacturing
processes, process simulation (in accordance with the requirements of the ISO 13408-series), the
application of appropriate in-process controls during manufacture, and testing to demonstrate
achievement of aseptic processing conditions. As a prerequisite, starting materials and packaging
materials are sterilized by validated processes. In this regard this International Standard does
not reiterate requirements for specific processes that are used during processing of a CBHP that is
labelled ‘sterile’. In cases where a CBHP is aseptically processed and labelled as ‘sterile’ refer to the
ISO 13408-series.
0.3 CBHPs supplied without a label claim for sterility
For a CBHP that is supplied without a label claim for sterility, e.g. corneal tissue or viable skin grafts,
processing involves the use of appropriate aseptic techniques at all stages during the process.
Components might be subject to bioburden reduction during preparation prior to their assembly
or combining to form finished product. This is necessary to minimize the potential for intrinsic
contamination of product to increase during processing and to avoid extrinsic contamination of
product. The controls and techniques to maintain product quality during processing of these CBHPs
might be different from those used for processing of a CBHP that is labelled ‘sterile’.
Controls for some infectious agents, e.g. viruses and protozoa, can require a multifaceted approach to
ensure product quality and safety.
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ISO 18362:2016(E)

Microbiological quality assurance for a CBHP that is supplied without a label claim for sterility is
achieved through control of the environment, controls on starting materials and packaging, suitable
design and qualification of manufacturing processes, process confirmation and process simulation
studies and the application of appropriate in-process controls and testing. Risk assessment underpins
selection of suitable microbiological quality criteria for a CBHP that is supplied without a label claim
for sterility. These criteria define the acceptability of product based on the absence or presence, or
number of microorganisms, per defined quantity of product, to ensure finished product does not pose a
microbiological risk to the patient.
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INTERNATIONAL STANDARD ISO 18362:2016(E)
Manufacture of cell-based health care products — Control
of microbial risks during processing
1 Scope
This International Standard specifies the minimum requirements for, and provides guidance on, a
risk-based approach for the processing of cell-based health care products (CBHPs) requiring control of
viable and non-viable microbial contamination. It is applicable both to CBHPs labelled ‘sterile’ and to
CBHPs not labelled ‘sterile’.
This International Standard is not applicable to:
— procurement and transport of cell-based starting material used in processing of a CBHP,
— cell banking,
— control of genetic material,
— control of non-microbial product contamination,
— in vitro diagnostics (IVDs), or
— natural medicines.
EXAMPLE Vitamins and minerals, herbal remedies, homoeopathic medicines, traditional medicines such as
traditional Chinese medicines, probiotics, other products such as amino acids and essential fatty acids.
This International Standard does not define biosafety containment requirements.
This International Standard does not replace national or regional regulations that apply to the
manufacture and quality control of a CBHP.
2 Normative references
The following documents, in whole or in part, are normatively referenced in this document and are
indispensable for its application. For dated references, only the edition cited applies. For undated
references, the latest edition of the referenced document (including any amendments) applies.
ISO 11135, Sterilization of health-care products — Ethylene oxide — Requirements for the development,
validation and routine control of a sterilization process for medical devices
ISO 11137 (all parts), Sterilization of health-care products — Radiation
ISO 13022:2012, Medical products containing viable human cells — Application of risk management and
requirements for processing practices
ISO 13408-1:2008, Aseptic processing of health care products — Part 1: General requirements
ISO 13408-1:2008/Amd.1:2013, Aseptic processing of health care products — Part 1: General
requirements / Amendment 1
ISO 13408-7:2012, Aseptic processing of health care products — Part 7: Alternative processes for medical
devices and combination products
ISO 14160, Sterilization of health care products — Liquid chemical sterilizing agents for single-use medical
devices utilizing animal tissues and their derivatives — Requirements for characterization, development,
validation and routine control of a sterilization process for medical devices
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ISO 18362:2016(E)

ISO 14644-4, Cleanrooms and associated controlled environments — Part 4: Design, construction and
start-up
ISO 14937, Sterilization of health care products — General requirements for characterization of a sterilizing
agent and the development, validation and routine control of a sterilization process for medical devices
ISO 14971, Medical devices — Application of risk management to medical devices
ISO 17665-1, Sterilization of health care products — Moist heat — Part 1: Requirements for the development,
validation and routine control of a sterilization process for medical devices
ISO 20857, Sterilization of health care products — Dry heat — Requirements for the development,
validation and routine control of a sterilization process for medical devices
ISO 22442 (all parts), Medical devices utilizing animal tissues and their derivatives
ISO 25424, Sterilization of medical devices — Low temperature steam and formaldehyde — Requirements
for development, validation and routine control of a sterilization process for medical devices
ICH Q7, Good manufacturing practice guide for active pharmaceutical ingredients, International
Conference for Harmonization; identical to Annex 18 of the EU-GMP-Guideline
ICH Q9, Quality Risk Management
European GMP Part II — Good Manufacturing Practice — Medicinal Products for Human and Veterinary
Use — Part II: Basic Requirements for Active Substances used as Starting Materials
3 Terms and definitions
For the purposes of this document, the terms and definitions given in ISO 13408-1 and the following apply.
3.1
active ingredient
any chemical or biological component that is included in the formulation of a cell-based health care
product in sufficient concentration to achieve the intended therapeutic purpose of the specific product
3.2
animal
any vertebrate or invertebrate [including amphibian, arthropod (e.g. crustacean), bird, coral, fish,
reptile, mollusc and mammal] excluding humans (Homo sapiens)
[SOURCE: ISO 22442-1:2007, 3.1]
3.3
aseptic technique
conditions and procedures used to exclude the introduction of microbial contamination
[SOURCE: ISO 14161:2009, 3.2]
3.4
biological contamination
presence of cells or biological entities other than the intended components
Note 1 to entry: This can include extrinsic and/or intrinsic contamination.
EXAMPLE Viruses, bacteria, fungi, protozoa, multicellular parasites, contaminating eukaryotic cells,
aberrant proteins known as prions, endotoxins or active DNA/RNA.
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ISO 18362:2016(E)

3.5
biological entity
functional assembly of biological molecules or structures
Note 1 to entry: A biological entity can be an enzyme complex, a membranous structure, ribosomes, etc., or a
combination thereof that is kept assembled to maintain its biological functionality.
3.6
CBHP
cell-based health care product
health care product that contains or consists of pro- or eukaryotic cells or cell derived biological entities
as an essential ingredient
3.7
cell-based starting material
any cell-based or cell derived material, ingredient, component or reagent that is used in the production
of cell-based health care products
Note 1 to entry: Cell derived materials are procured cells, tissues, biological entity, intermediates.
Note 2 to entry: This can include tissue samples and/or biological fluids without a well-defined structure. This
exceeds the scope of the definition of active pharmaceutical ingredients (API) starting material as given in ICH Q7.
3.8
CPA
cell-processing area
area for processing cell-based materials consisting of different zones for processing and, where
applicable, for containment
Note 1 to entry: The zones can include zones for aseptic processing areas (APA) (for a definition for APA see
ISO 13408-1:2008, 3.5) and/or other zones where the processing environment is controlled to minimize extrinsic
contamination of the product.
3.9
closed system
system preventing egress of hazardous agents and ingress of extrinsic contamination
3.10
containment
combination of buildings, engineering functions, equipment and work practices to allow safe handling
of hazardous biological or chemical agents to prevent accidental release of these agents to the
environment outside of the facility
3.11
containment area
designated area that comprises cell processing area and associated degowning room
Note 1 to entry: Isolators are considered to be a containment area.
3.12
containment facility
combination of manufacturing rooms including the containment area and associated rooms within a
physical containment barrier
Note 1 to entry: This can include airlocks, access and support rooms, laboratories and interconnecting corridors.
Note 2 to entry: A containment facility uses a series of barriers (primary, secondary and tertiary) to minimize
the escape of hazardous agents to facility workers, the general population and the environment, e.g. isolators (if
necessary, negative pressure type); biological safety cabinets (Class I, II or III); negative air pressure cleanroom;
personnel protective clothing; appropriate work practices; appropriate disposal of hazardous waste; restriction
of access to the facility.
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ISO 18362:2016(E)

3.13
extrinsic contamination
ingress of extraneous material (viable and non-viable) during the manufacturing process
3.14
health care product(s)
medical device(s), including in vitro diagnostic medical device(s), or medicinal product(s), including
biopharmaceutical(s)
[SOURCE: ISO/TS 11139:2006, 2.20]
3.15
inactive ingredient
any chemical or biological component other than an active ingredient that is included in the formulation
Note 1 to entry: An inactive ingredient is also known as an excipient.
EXAMPLE Buffer agents, scaffolds, water.
3.16
intrinsic contamination
foreign matter (viable and non-viable) present in cell-based starting material
3.17
microbial contamination
presence of unintended bacteria, fungi, protozoa, viruses
Note 1 to entry: This can include extrinsic and/or intrinsic contamination.
3.18
microorganism
entity of microscopic size, encompassing bacteria, fungi, protozoa and viruses
[SOURCE: ISO/TS 11139:2006, 2.26]
3.19
negative air pressure room
room where the ventilation system has been designed in such a way that the pressure in the room is
below that of the surrounding areas
Note 1 to entry: The design of the room and the ventilation syste
...