The International Pharmaceutical Excipients Council

Significant ChangeGuide
For Pharmaceutical Excipients

Version 52023

Copyright © 2023 The International Pharmaceutical Excipients Council

This document represents voluntary guidance for the excipient industry and the contents
should not be interpreted as regulatory requirements. Alternatives to the approaches in thisguide may be used to achieve an equivalent level of assurance for excipient quality.
This guide was created to help companies understand current expectations on this topic and is
not intended for use by third party certification bodies to conduct audits or to certify
compliance with the guide.
The content of this guide cannot be reproduced without the written authorisation of the IPEC
Federation Management Body.

FOREWORD
The International Pharmaceutical Excipients Council (IPEC) is an international industry
association formed by excipient manufacturers, distributors and end-users. At the current writing
there are regional pharmaceutical excipient industry associations located in the Americas,
Europe, Japan, China, and India. IPEC’s objective is to contribute to the international excipient
standards development and harmonization, provide information useful for new excipientdevelopment and introduction, and offer best practice and guidance concerning excipientdevelopment.
IPEC has three major stakeholder groups:
1. Excipient manufacturers and distributors, defined as suppliers in this document,
2. Medicinal (drug) manufacturers, defined as excipient users in this document, and3. Public health and regulatory authorities

This guide is intended to be voluntary, to indicate best practice, and to be globally applicable.
However, it should be recognized that the laws and regulations applying to excipients will varyfrom region-to-region and country-to-country. In addition, rules and regulations are continually

Copyright © 2023 The International Pharmaceutical Excipients Council
The International Pharmaceutical Excipients Council – Federation (IPEC Federation) asbl
Rue Marie de Bourgogne 52 - 1000, Brussels, Belgium
W: ipec-federation.org T: +32 2 213 74 40 E: info@ipec-federation.org
VAT: BE 0823931361 - IBAN: BE73363068125160 - RPM Brussels Capital Region

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evolving. It is the responsibility of the reader to review the most current version of any applicableregulatory requirement. Versions referenced in the guide were based on versions available atthe time the guide was published.
In this guide, pharmaceutical excipient(s) will be referred as excipient(s). This guide may be
applied to veterinary medicines, as appropriate and include reference to specific veterinary
guidances and regulations.
Throughout the guide, “justification” means that a decision is made based on a scientific, quality
and/or regulatory considerations.
This document offers best practice and guidance on the content of an excipient Significant
Change Guide. It is important that the reader confirm this is the latest version of the guide as
found at https://ipecamericas.org/ or https://www.ipec-europe.org/ or https://ipec-federation.org/
NOTE: Refer to the “International Pharmaceutical Excipients Council Glossary: General
Glossary of Terms and Acronyms” for definitions [1]. The first use of a term found in theglossary will be in BOLD.

Copyright © 2023 The International Pharmaceutical Excipients Council
The International Pharmaceutical Excipients Council – Federation (IPEC Federation) asbl
Rue Marie de Bourgogne 52 - 1000, Brussels, Belgium
W: ipec-federation.org T: +32 2 213 74 40 E: info@ipec-federation.org
VAT: BE 0823931361 - IBAN: BE73363068125160 - RPM Brussels Capital Region

3 of 30ACKNOWLEDGEMENTS
This Guide was developed by representatives of the associations which constitute the IPEC
Federation (IPEC). The IPEC Federation greatly appreciates the many hours devoted by the coreteam of individuals and other contributors listed below, to make this guide available to IPEC
members and the broader excipient community. Equally, IPEC extends its thanks to theemployers of those same contributors who provided the necessary time and resources, without
which, this guide would not be possible.

List of Contributors from IPEC-Americas
Courtney Arumugam, GADAAnn Gulau, IFF
Jennifer Putnam, Perrigo
Katherine Ulman, KLU Consulting, LLC
Priscilla Zawislak, IFF

List of Contributors from IPEC Europe
Jeffrey Brambora, BlackTower Quality GroupAnne Reiff, Hedinger
Rebecca Teversham, Colorcon

Copyright © 2023 The International Pharmaceutical Excipients Council
The International Pharmaceutical Excipients Council – Federation (IPEC Federation) asbl
Rue Marie de Bourgogne 52 - 1000, Brussels, Belgium
W: ipec-federation.org T: +32 2 213 74 40 E: info@ipec-federation.org
VAT: BE 0823931361 - IBAN: BE73363068125160 - RPM Brussels Capital Region

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ACKNOWLEDGEMENTS ............................................................................................... 41

INTRODUCTION .................................................................................................. 7

1.1

Purpose ......................................................................................................................... 7

1.2

Scope ............................................................................................................................ 7

1.3

Principles Adopted ....................................................................................................... 72

GENERAL CONSIDERATIONS........................................................................... 82.1

Excipient Composition ................................................................................................. 82.2

Differentiation of Excipient Manufacture .................................................................... 82.3

Excipient GMP .............................................................................................................. 83

SIGNIFICANT CHANGE ...................................................................................... 93.1

Definition of Significant Change ................................................................................. 93.2

Change Risk Levels...................................................................................................... 94

DETERMINATION OF SIGNIFICANCE / RISK ASSESSMENT ........................ 104.1

General .........................................................................................................................104.2

Guiding Principles .......................................................................................................104.3

Change Management Documentation ........................................................................114.4

Justification for Level 1 Change.................................................................................114.5

Data Analysis ...............................................................................................................115

NOTIFICATION REQUIREMENTS .................................................................... 126

POST IMPLEMENTATION................................................................................. 12

7SPECIFIC CHANGES ........................................................................................ 13

7.1

Types of Changes........................................................................................................137.1.1

Manufacturing Site ...................................................................................................13

7.1.2

Scale ..........................................................................................................................13

7.1.3

Production and Packaging Equipment ...................................................................14

7.1.4

Raw Materials............................................................................................................147.1.5

Manufacturing Process ............................................................................................17

7.1.6

Packaging .................................................................................................................18

7.1.7

Labeling.....................................................................................................................19

Copyright © 2023 The International Pharmaceutical Excipients CouncilThe International Pharmaceutical Excipients Council – Federation (IPEC Federation) asbl
Rue Marie de Bourgogne 52 - 1000, Brussels, Belgium
W: ipec-federation.org T: +32 2 213 74 40 E: info@ipec-federation.org
VAT: BE 0823931361 - IBAN: BE73363068125160 - RPM Brussels Capital Region

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7.1.8

Excipient Specifications and Test Methods ...........................................................19

7.1.9

Supply Chain ............................................................................................................20

7.1.10Discontinuation of an Excipient ..............................................................................20

7.2

Criteria used to Evaluate the Impact of Changes on Excipient ................................207.2.1

Introduction ..............................................................................................................207.2.2

Physical Properties ..................................................................................................217.2.3

Chemical Properties .................................................................................................217.2.4

Microbiological Properties .......................................................................................22

7.2.5

Composition Profile..................................................................................................227.2.6

Stability .....................................................................................................................227.2.7

Intended Performance based on the Manufacturer ’s Marketed Use ....................23

7.2.8

Regulatory Status .....................................................................................................237.3

Multiple Changes .........................................................................................................238

REFERENCES ................................................................................................... 24

ANNEX 1: CASE STUDIES ......................................................................................... 26
ANNEX 2: DECISION TREES ..................................................................................... 28

Copyright © 2023 The International Pharmaceutical Excipients Council
The International Pharmaceutical Excipients Council – Federation (IPEC Federation) asbl
Rue Marie de Bourgogne 52 - 1000, Brussels, Belgium
W: ipec-federation.org T: +32 2 213 74 40 E: info@ipec-federation.org
VAT: BE 0823931361 - IBAN: BE73363068125160 - RPM Brussels Capital Region

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