prEN ISO 18362

Manufacture of cell-based health care products - Control of microbial risks during processing (ISO 18362:2016)

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.

Herstellung von zellbasierten Gesundheitsprodukten - Kontrolle der mikrobiellen Risiken während der Verarbeitung (ISO 18362:2016)

Fabrication de produits de santé à base de cellules - Contrôle des risques microbiologiques durant le procédé (ISO 18362:2016)

Proizvodnja izdelkov za zdravstveno nego na osnovi celic - Kontrola mikrobnega tveganja med obdelavo (ISO 18362:2016)

General Information

• Status: Withdrawn
• Publication Date: 02-Feb-2021
• Withdrawal Date: 02-May-2021
• ICS: 11.080.01 - Sterilization and disinfection in general
• Technical Committee: CEN/TC 204 - Sterilization of medical devices
• Drafting Committee: CEN/TC 204 - Sterilization of medical devices
• Current Stage: 4098 - Decision to abandon - Enquiry
• Completion Date: 14-Dec-2020
• Directive: 93/42/EEC - Council Directive 93/42/EEC of 14 June 1993 concerning medical devices
• Mandate: M/023 - Standardization mandate to CEN/CENELEC concerning the development of European standards relating to medical devices
• Ref Project: oSIST prEN ISO 18362:2018 - Manufacture of cell-based health care products - Control of microbial risks during processing (ISO 18362:2016)

Standards Content (Sample)

SLOVENSKI STANDARD
oSIST prEN ISO 18362:2018
01-december-2018
Proizvodnja izdelkov za zdravstveno nego na osnovi celic - Kontrola mikrobnega
tveganja med obdelavo (ISO 18362:2016)

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

processing (ISO 18362:2016)

Herstellung von zellbasierten Gesundheitsprodukten - Kontrolle der mikrobiellen Risiken

während der Verarbeitung (ISO 18362:2016)
Fabrication de produits de santé à base de cellules - Contrôle des risques
microbiologiques durant le procédé (ISO 18362:2016)
Ta slovenski standard je istoveten z: prEN ISO 18362
ICS:
11.080.01 Sterilizacija in dezinfekcija na Sterilization and disinfection
splošno in general
oSIST prEN ISO 18362:2018 en,fr,de

2003-01.Slovenski inštitut za standardizacijo. Razmnoževanje celote ali delov tega standarda ni dovoljeno.

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oSIST prEN ISO 18362:2018
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oSIST prEN ISO 18362:2018
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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oSIST prEN ISO 18362:2018
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

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
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Tel. [phone]
Fax [phone]
[e-mail]
www.iso.org
ii © ISO 2016 – All rights reserved
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oSIST prEN ISO 18362:2018
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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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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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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oSIST prEN ISO 18362:2018
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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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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oSIST prEN ISO 18362:2018
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 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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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; r

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