Biotechnology -- Ancillary materials present during the production of cellular therapeutic products

This document provides guidance for ancillary material (AM) suppliers to maintain a high level of lot-to-lot consistency in the aspects of identity, purity, stability, biosafety, performance, as well as the accompanying documentation. This document is applicable to cellular therapeutic products, including gene therapy products whereby cells form part of the final product. It does not apply to products without cells. The AMs described in this document include those of biological origin [e.g. sera, media (including media additives), growth factors, and monoclonal antibodies] and chemical origin. This document does not address dimethyl sulfoxide (DMSO) for cryopreservation, beads, scaffolds, feeder cells, apparatus and instruments, or additives used post bioprocessing. This document does not cover the selection, assessment or control of starting materials and excipients. 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

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Status
Published
Publication Date
03-Dec-2018
Technical Committee
Current Stage
6060 - International Standard published
Start Date
15-Nov-2018
Completion Date
04-Dec-2018
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ISO/TS 20399-2:2018 - Biotechnology -- Ancillary materials present during the production of cellular therapeutic products
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TECHNICAL ISO/TS
SPECIFICATION 20399-2
First edition
2018-11
Biotechnology — Ancillary materials
present during the production of
cellular therapeutic products —
Part 2:
Best practice guidance for ancillary
material suppliers
Biotechnologie — Matériaux auxiliaires présents lors de la production
de produits thérapeutiques cellulaires —
Partie 2: Lignes directrices de bonne pratique pour les fournisseurs de
matériaux auxiliaires
Reference number
ISO/TS 20399-2:2018(E)
ISO 2018
---------------------- Page: 1 ----------------------
ISO/TS 20399-2:2018(E)
COPYRIGHT PROTECTED DOCUMENT
© ISO 2018

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
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Phone: +41 22 749 01 11
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Email: copyright@iso.org
Website: www.iso.org
Published in Switzerland
ii © ISO 2018 – All rights reserved
---------------------- Page: 2 ----------------------
ISO/TS 20399-2:2018(E)
Contents Page

Foreword ........................................................................................................................................................................................................................................iv

Introduction ..................................................................................................................................................................................................................................v

1 Scope ................................................................................................................................................................................................................................. 1

2 Normative references ...................................................................................................................................................................................... 1

3 Terms and definitions ..................................................................................................................................................................................... 1

4 Abbreviated terms .............................................................................................................................................................................................. 1

5 General considerations .................................................................................................................................................................................. 2

6 AM characteristics and quality attributes .................................................................................................................................. 3

6.1 AM components, identity and purity ................................................................................................................................... 3

6.1.1 General...................................................................................................................................................................................... 3

6.1.2 Identity and quantity of component(s) ........................................................................................................ 3

6.1.3 Purity/impurity ................................................................................................................................................................ 3

6.1.4 Lot-to-lot consistency for AMs containing proprietary components ................................. 3

6.2 AM storage and stability ................................................................................................................................................................. 4

6.2.1 General...................................................................................................................................................................................... 4

6.2.2 Storage conditions .......................................................................................................................................................... 4

6.2.3 Stability and expiration dating ............................................................................................................................ 4

7 AM manufacturing and biosafety ........................................................................................................................................................ 5

7.1 Quality management system ....................................................................................................................................................... 5

7.2 Manufacturing process..................................................................................................................................................................... 5

7.3 Container and closure systems ................................................................................................................................................. 5

7.4 Animal- and human-derived materials .............................................................................................................................. 6

7.5 Safety to cells and humans ............................................................................................................................................................ 6

8 AM performance ................................................................................................................................................................................................... 6

8.1 General ........................................................................................................................................................................................................... 6

8.2 Performance assay ............................................................................................................................................................................... 7

8.2.1 General...................................................................................................................................................................................... 7

8.3 Cells used for performance assays ......................................................................................................................................... 7

8.4 Performance assay results ............................................................................................................................................................ 8

9 AM documentation ............................................................................................................................................................................................. 8

9.1 General ........................................................................................................................................................................................................... 8

9.2 Certificat e of analysis (CoA) ........................................................................................................................................................ 8

9.3 Additional certificates ....................................................................................................................................................................... 9

9.3.1 Certificate of origin (CoO) ........................................................................................................................................ 9

9.3.2 Certificate of compliance (CoC) .......................................................................................................................... 9

9.3.3 Certificate of irradiation (CoI) .............................................................................................................................. 9

9.4 Other items ................................................................................................................................................................................................. 9

Bibliography .............................................................................................................................................................................................................................10

© ISO 2018 – All rights reserved iii
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ISO/TS 20399-2:2018(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.
A list of all parts in the ISO/TS 20399 series can be found on the ISO website.

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 2018 – All rights reserved
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ISO/TS 20399-2:2018(E)
Introduction

Ancillary materials (AM) are materials that come into contact with the cellular therapeutic product

during the manufacturing process, but are not intended to be in the final product.

AMs include culture media, growth factors, and other biological and non-biological components. They

can be a complex mixture of multiple components and variation in their lot-to-lot compositions can

hamper the ability to produce a consistent product based on therapeutic cells with specified quality

attributes.

As such, AMs can have implications with regard to the safety and effectiveness of a therapeutic product.

Appropriate control of ancillary material may be determined by a risk-based approach.

This document provides guidelines to AM suppliers on best practice to ensure consistent manufacture

of AM products. It also describes the information that should be obtained and provided to the AM user

to demonstrate lot-to-lot consistency of the AM product with respect to AM characteristics and quality

attributes, biosafety, and performance.

A number of standards and guidance documents define the proper processing of cell based therapeutic

products to ensure safety and efficacy. However, these standards only indirectly relate to the suppliers

of AM products. This document clarifies the expectations for AM suppliers which are distinct from the

standards governing cell processing requirements.

The ISO/TS 20399 series provides general requirements and guidance regarding ancillary materials

to maintain a high level of lot-to-lot consistency, as well as the accompanying documentation, so that

consistent ancillary materials (AM) products and documentation provided by the suppliers can help

AM users.
© ISO 2018 – All rights reserved v
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TECHNICAL SPECIFICATION ISO/TS 20399-2:2018(E)
Biotechnology — Ancillary materials present during the
production of cellular therapeutic products —
Part 2:
Best practice guidance for ancillary material suppliers
1 Scope

This document provides guidance for ancillary material (AM) suppliers to maintain a high level of

lot-to-lot consistency in the aspects of identity, purity, stability, biosafety, performance, as well as the

accompanying documentation.

This document is applicable to cellular therapeutic products, including gene therapy products whereby

cells form part of the final product. It does not apply to products without cells.

The AMs described in this document include those of biological origin [e.g. sera, media (including media

additives), growth factors, and monoclonal antibodies] and chemical origin. This document does not

address dimethyl sulfoxide (DMSO) for cryopreservation, beads, scaffolds, feeder cells, apparatus and

instruments, or additives used post bioprocessing.

This document does not cover the selection, assessment or control of starting materials and excipients.

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/TS 20399-1, Biotechnology — Ancillary materials present during the production of cellular therapeutic

products — Part 1: General requirements
3 Terms and definitions

For the purposes of this document, the terms and definitions given in ISO/TS 20399-1 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/
4 Abbreviated terms
ADCF animal-derived component free
AM ancillary material
CoA certificate of analysis
© ISO 2018 – All rights reserved 1
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ISO/TS 20399-2:2018(E)
CoC certificate of compliance
CoI certificate of irradiation
CoO certificate of origin
DNA deoxyribonucleic acid
EP European Pharmacopoeia (Ph. Eur.)
JP Japanese Pharmacopoeia
RP-HPLC reverse phase high performance liquid chromatography
SDS safety data sheet
SDS-PAGE sodium dodecyl sulfate poly acrylamide gel electrophoresis
USP United States Pharmacopeia
5 General considerations

This document provides guidance for AM suppliers to maintain a high level lot-to-lot consistency, as

well as for the accompanying documentation for AM users.
Aspects covered include the following.

a) Information of AM products, including characteristics and quality attributes (i.e. identity, purity,

stability, functionality and performance).

b) Documentation for all AM products including composition, the source of each component, the

concentration, and purity.

c) Demonstration of lot-to-lot consistency of AM products for the intended cell culture process,

specifically regarding the identity and performance of the AM product.

d) Appropriate level of biosafety, including avoidance of introduction of unwanted agents that may

cause harm to the therapeutic products, and directly or indirectly to patients.

e) Risk of introduction of pathogenic or toxic contaminations from biological and non-biological

agents; relevant index, such as limit of detection (LOD) or limit of tolerance (LOT) to be determined

and validated when feasible.

f) Performance of AM products in delivering the intended effects with consistency and robustness;

an AM product should perform its intended function within a model cell manufacturing process

selected by the AM supplier appropriate for AM’s intended use.

g) Accompanying documentation from the AM supplier to provide sufficient information on AM

products for the purpose of AM users ensuring the quality of their cellular therapeutic products.

NOTE Though not provided to AM users, AM suppliers can choose to prepare a drug master file (DMF) for an

AM product to support AM user’s regulatory submission where DMF is accepted. Where DMF is not accepted, a

regulatory support file (RSF) can be provided to AM users.
2 © ISO 2018 – All rights reserved
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ISO/TS 20399-2:2018(E)
6 AM characteristics and quality attributes
6.1 AM components, identity and purity
6.1.1 General

The AM supplier should make every effort to demonstrate the lot-to-lot consistency with respect to the

composition of AM products. If a monograph exists for the AM product (e.g. USP, EP, or JP monograph), it

is expected to comply with those tests in the country where the AM product will be used. Otherwise the

minimum tests listed below apply, as applicable.
6.1.2 Identity and quantity of component(s)

For AM products that consist of chemically defined substance(s), the identity of that substance should

be documented. For products that are mixtures of several components, the identity of all known

molecular components and their relative concentrations should be documented. Information regarding

the variation of lots and the general acceptable range should be recorded.

If the identity of all substances cannot be defined and/or cannot be disclosed, the quantity of active

components can be documented by its activity.

The inclusion of any proprietary component(s) individually or collectively and its relative concentrations

should be noted; any information that can be shared regarding the type of molecular composition or

purpose should be provided.

For animal-derived materials, a certificate of origin (CoO) should document, for each batch, the country

of origin, a health statement of the animal, and evidence documenting absence of pathogens. When

feasible, the age of the animals at the time of collection should be documented.

For human derived materials, viral panel testing is required. Requirements in the country of use

shall be met.
6.1.3 Purity/impurity

For AM products that consist of one isolated and/or purified molecular substance, the purity of that

substance within the product should be defined, measured and provided. For products that consist of

multiple components, the purity of active ingredients should be defined, measured and documented.

If the purity varies from lot to lot within an acceptable range, the acceptable range should be provided

as well as information on the distribution of lots within the acceptable range if possible.

Impurities need to be identified and documented. Tests to measure i
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