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

This document provides guidance for ancillary material (AM) users. It is applicable to cellular therapeutic products, including those gene therapy products whereby cells form part of the final product. It does not apply to products without cells. This document focuses primarily on ancillary materials (AMs) of biological (human and animal) origin and their potential impurities and contaminants. NOTE 1 The decision chart in Figure 1 illustrates the rationale underlying the scope of this document. However, diverse biological sources, including plants, insects and marine organisms, can also be used in the development of a cellular therapeutic product. Therefore the fundamental principles of risk management also apply for these sources of AMs. This document does not cover the selection, assessment or control of starting materials and excipients. However, it is anticipated that these are still covered by general risk management procedures. This document is applicable for users at all stages of clinical development and supply; however maximum benefits can be gained by the implementation of the recommendations in the early stages of development. NOTE 2 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 20399-3:2018 - Biotechnology -- Ancillary materials present during the production of cellular therapeutic products
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TECHNICAL ISO/TS
SPECIFICATION 20399-3
First edition
2018-11
Biotechnology — Ancillary materials
present during the production of
cellular therapeutic products —
Part 3:
Best practice guidance for ancillary
material users
Biotechnologie — Matériaux auxiliaires présents lors de la production
de produits thérapeutiques cellulaires —
Partie 3: Lignes directrices de bonne pratique pour les utilisateurs de
matériaux auxiliaires
Reference number
ISO/TS 20399-3:2018(E)
ISO 2018
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ISO/TS 20399-3:2018(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

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Published in Switzerland
ii © ISO 2018 – All rights reserved
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ISO/TS 20399-3:2018(E)
Contents Page

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

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

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

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

3 Terms and definitions .................................................................................................................................................................................... 2

4 Abbreviated terms .............................................................................................................................................................................................. 2

5 Quality declarations for manufactured biological materials used in the

manufacture of a cellular therapeutic product .................................................................................................................... 3

6 E valuation criteria and mitigation of risk .................................................................................................................................. 4

6.1 Evaluation criteria ................................................................................................................................................................................ 4

6.2 Mitigation of risk ................................................................................................................................................................................... 6

6.2.1 Scientific approach ......................................................................................................................................................... 6

6.2.2 Supplier audit and questionnaires ................................................................................................................... 7

6.2.3 Risk assessments ............................................................................................................................................................. 8

7 Characterization of biological materials ..................................................................................................................................... 9

8 Managing changes to materials ............................................................................................................................................................. 9

8.1 Impact of changes to materials ................................................................................................................................................. 9

8.2 Supplier agreement considerations ...................................................................................................................................10

Bibliography .............................................................................................................................................................................................................................11

© ISO 2018 – All rights reserved iii
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ISO/TS 20399-3:2018(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 20399-3:2018(E)
Introduction

Ancillary materials (AMs) 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 and growth factors, among other biological and non-biological components.

They can be a complex mixture of many components and variation in their lot-to-lot composition can

hamper the ability to produce a consistent cellular therapeutic product with specified quality attributes.

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

product. Appropriate control of ancillary material is determined by a risk-based approach.

This document specifies guidelines to AM users on best practice considerations for use of AMs,

particularly those of biological origin, in the manufacture of cellular therapeutic product and

contributes to their control by suppliers and users of such materials.

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 material (AM) products and documentation provided by the AM suppliers can help

AM users.
© ISO 2018 – All rights reserved v
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TECHNICAL SPECIFICATION ISO/TS 20399-3:2018(E)
Biotechnology — Ancillary materials present during the
production of cellular therapeutic products —
Part 3:
Best practice guidance for ancillary material users
1 Scope

This document provides guidance for ancillary material (AM) users. It is applicable to cellular

therapeutic products, including those gene therapy products whereby cells form part of the final

product. It does not apply to products without cells.

This document focuses primarily on ancillary materials (AMs) of biological (human and animal) origin

and their potential impurities and contaminants.

NOTE 1 The decision chart in Figure 1 illustrates the rationale underlying the scope of this document.

However, diverse biological sources, including plants, insects and marine organisms, can also be used

in the development of a cellular therapeutic product. Therefore the fundamental principles of risk

management also apply for these sources of AMs.

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

However, it is anticipated that these are still covered by general risk management procedures.

This document is applicable for users at all stages of clinical development and supply; however

maximum benefits can be gained by the implementation of the recommendations in the early stages of

development.

NOTE 2 International, regional or national regulations or requirements can also apply to specific topics

covered in this document.
© ISO 2018 – All rights reserved 1
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ISO/TS 20399-3:2018(E)
Figure 1 — Decision chart
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
AM ancillary material
ADCF animal-derived component free
AOF animal origin free
CAPA corrective and preventative action
CEP certificate of suitability
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ISO/TS 20399-3:2018(E)
CoA certificate of analysis
CoO certificate of origin
EDQM European Directorate for the Quality of Medicines and Healthcare
(c)GMP (current) good manufacturing practice

ICH International Council for Harmonization of Technical Requirements for Pharmaceuticals

for Human Use
IVUO in vitro use only
QC quality control
QMS quality assurance/management system
RUO research use only
TSE transmissible spongiform encephalopathy
5 Quality declarations for manufactured biological materials used in the
manufacture of a cellular therapeutic product

A number of different quality declarations can be applied by suppliers to the biological AMs they market.

Table 1 provides a list of suppliers’ quality declarations that confirm that the AM has been approved

by a regulatory body and/or complies with a recognized quality grade. However, compliance with any

grade/standard does not necessarily mean that the AM is suitable for a specific process, even if it is

of demonstrable quality. The user should ensure that the product has the requisite properties, e.g.

functionality and safety profile.

Table 1 — Examples of recognized quality declarations used by suppliers of materials in the

manufacture of cellular therapeutic product
Quality declaration Technical and regulatory description

Licensed medicinal By definition, a licensed medicinal product/drug has demonstrated quality, safety and

product/ drug efficacy for its intended use and can therefore be viewed as the highest standard in

terms of quality.

Pharmacopoeia grade If an AM used in the manufacture of a cellular therapeutic product has a monograph

in an appropriate pharmacopoeia, the user can reference it as a way of demonstrating

conformance with a level of quality deemed sufficient for use in the manufacture of

cellular therapeutic product. Chapters may contain more general measures for groups

of AMs but they are not measures that relate to any specific AM.

510(k) (pre-market Cell culture media can fulfil the criteria for being Class II medical devices (medium

notification) risk) and therefore can be approved under the 510(k) pre-market notification path-

way. Under the provision, users can gain approval for a device by showing substantial

equivalence with a Class II device that has already been approved. The 510(k) notifica-

tion demonstrates that the product has been manufactured under a QMS.

EDQM Certification of In order for a supplier of a biological AM (in this context) to be granted a CEP, the

Suitability EDQM appoint a panel of assessors to review a detailed dossier that contains a descrip-

tion of the manufacturing process and the tests performed on the AMs used along with

the final product. The applicant also needs to agree to comply with the relevant GMP

and to accept a site inspection at any time at the request of the EDQM.

The CEP is recognized in all EU member states and some additional non-EU countries,

such as Canada, New Zealand and Australia.
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ISO/TS 20399-3:2018(E)

Table 2 contains examples of quality declarations that are used by suppliers of AMs in the manufacture

of cellular therapeutic product. The descriptions provided are commonly used but there is no consensus

on the meaning of the terms used and Table 2 is not intended to endorse these descriptions.

AMs bearing these quality declarations should still be assessed thoroughly for their quality, safety and

suitability. In particular, the presence or use of animal- or human-derived components as part of the AM

or as production material should be assessed, taking into account the considerations regarding animal

derived component free (ADCF) or animal origin free (AOF) or xeno-free (see ISO/TS 20399-1).

Table 2 — Frequently used quality declarations made by suppliers of materials in the

manufacture of cellular therapeutic product
Quality declaration Description

GMP or cGMP grade Manufacturing an AM in compliance with GMP requirements demonstrates that

the AM has been manufactured under a robust QMS. However, GMP compliance

is not a quality grade, as GMP does not apply to the quality of the product itself,

but the systems, processes and procedures used to manufacture it. Some form of

regulatory oversight, e.g. inspection, is required to demonstrate that a manufac-

turing process is GMP compliant, as is the case for the manufacture of medicinal
products and active pharmaceutical ingredients. If there is no regulatory over-
sight, the supplier should only claim to comply with the principles of GMP.

Clinical grade The term “clinical grade” is used to describe an AM that is suitable for clinical ap-

plication, i.e. use in humans. However, the term “clinical grade” in isolation is not

a recognized quality grade and the use of this term by suppliers is discretionary

and a thorough quality and risk assessment should still be carried out.

RUO grade Commonly available from suppliers, the grade makes no claims about suitability

for human or clinical application. Therefore, the suitability of a RUO AM for use in

(sometimes referred to as

clinical applications needs to be assessed on a case by case basis, by undergoing a

IVUO)
risk assessment by the product user before being considered for use.

Specific regulatory “ready” Suppliers sometimes use specific regulatory “ready” definitions as measures of

or “approved” quality. However, the use of these terms by suppliers of AMs is either discretion-

ary (and a thorough quality and risk assessment should still be carried out) or it

is not a guarantee of quality when used in isolation. If a material in question has

been approved for a similar use/application, e.g. by another user, this does not
automatically qualify it for use in a different process.

ADCF, AOF, xeno-free In the context of a cellular therapeutic product, the terms imply the absence of

animal or human components e.g. in cell culture media formulations.
6 E valuation criteria and mitigation of risk
6.1 Evaluation criteria

A number of different grades of AMs, certificates, terminologies and compliance with quality

management systems, can be applied or used by suppliers for their product (see Table 1 and Table 2).

However, a number of factors should be considered by users when evaluating a biological material for

its suitability in the manufacture of cellular therapeutic product, irrespective of the grade or quality

standard that is claimed by the supplier of that AM (see Table 3).
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ISO/TS 20399-3:2018(E)

Table 3 — Key factors and considerations when evaluating biological materials for use in the

manufacture of a cellular therapeutic product
Factor Key considerations and guidance Key questions
Source The need to ensure the ident
...

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