The International Pharmaceutical Excipients Council

Incorporation of
Pharmaceutical Excipients
into Product Developmentusing Quality-by-Design(QbD)

First Version2020
Copyright © 2020 The International Pharmaceutical Excipients Council

This document represents voluntary guidance for the excipient industry and the contents,
unless otherwise specified, should not be interpreted as regulatory requirements.
Alternatives to the approaches in this Guide may be used to achieve an equivalent excipient
quality assurance level.
This guide was created to help companies understand current expectations on this topic andis not intended for use by third parties to conduct audits. The content of this guide cannot bereproduced 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 international excipient
standards development and harmonization, new excipient development and introduction, andbest practice and guide development concerning excipients.
IPEC has three major stakeholder groups;
1. Excipient manufacturers and distributors, defined as suppliers in this document
2. Pharmaceutical manufacturers, defined as users in this document
3. 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 rules and regulations applying to excipients will varyfrom region to region and country to country. In addition, the rules and regulations are continually
evolving. It is the responsibility of users of the Guide to determine whether there are any additional
legal or regulatory requirements, in addition to the recommendation given in this Guide, applicable
to a particular region or country in which they are doing business.

Copyright © 2020 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 2 210 74 40 E: info@ipec-federation.org
VAT: BE 0823931361 - IBAN: BE73363068125160 - RPM Brussels Capital Region

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This Guide offers current best practice and voluntary guidance on the incorporation of excipientsand excipient variability into Quality-by-Design (QbD) pharmaceutical finished productdevelopment programs. It is important that the reader confirms this is the latest version of theguide as found on www.ipec-federation.org or regional IPEC websites.
NOTE: Refer to the “International Pharmaceutical Excipient 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 © 2020 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 2 210 74 40 E: info@ipec-federation.org
VAT: BE 0823931361 - IBAN: BE73363068125160 - RPM Brussels Capital Region

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Table of Contents
FOREWORD........................................................................................................................... 1
ACKNOWLEDGEMENTS ....................................................................................................... 51

INTRODUCTION.............................................................................................................. 6

1.1

Purpose ...................................................................................................................... 61.2

Scope.......................................................................................................................... 6

1.3

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

BACKGROUND AND GENERAL GUIDANCE ................................................................. 82.1

An introduction to Drug and Drug Product Development......................................... 82.2

Quality-by-Design .................................................................................................... 102.3

Excipients................................................................................................................. 152.4

Pharmaceutical products......................................................................................... 18

3

INCORPORATION OF EXCIPIENTS INTO THE FORMULATION .................................. 20

3.1

Excipient selection................................................................................................... 203.2

Formulation and Process Design and Development............................................... 21

3.3

Risk assessment...................................................................................................... 213.4

Design of Experiments............................................................................................. 233.5

Design Space and Control Strategy ........................................................................ 23

4EXCIPIENTS IN QUALITY-BY-DESIGN ......................................................................... 25

4.1

Introduction .............................................................................................................. 25

4.2

Excipient Impact Categorization.............................................................................. 30

4.3

Critical Material Attributes ....................................................................................... 31

4.4

Analysis of the Design of Experiments (DoE) ......................................................... 34

4.5

Scale-up.................................................................................................................... 35

5LIFECYCLE MANAGEMENT ......................................................................................... 36

5.1

Continued monitoring .............................................................................................. 36

5.2

Multivariate Analysis (MVA)..................................................................................... 36

5.3

Continued product verification ................................................................................ 37

5.4

Detection of product/excipient drift and out-of-trend results ................................. 37

5.5

Excipient-related Special Cause Variation in Production ....................................... 37
Copyright © 2020 The International Pharmaceutical Excipients Council
The International Pharmaceutical Excipients Council – Federation (IPEC Federation) asbl
Rue Marie de Bourgogne 52 - 1000, Brussels, BelgiumW: ipec-federation.org T: +32 2 210 74 40 E: info@ipec-federation.org
VAT: BE 0823931361 - IBAN: BE73363068125160 - RPM Brussels Capital Region

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6REFERENCES............................................................................................................... 40

ANNEX A Pharmaceutical Development Process............................................................. 43
ANNEX B Kano Analysis .................................................................................................... 45

Table of Tables
Table 1: The criticality of Lactose Particle Size Distribution in different dose forms ...... 32

Table of Figures
Figure 1
Figure 2
Figure 3
Figure 4

Pharmaceutical Drug Development Timelines .................................................... 8
ICH Quality Roadmap [21].................................................................................. 11
Reducing Product Variability [21]...................................................................... 12
Simple Process Capability Model ...................................................................... 30

Copyright © 2020 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 2 210 74 40 E: info@ipec-federation.org
VAT: BE 0823931361 - IBAN: BE73363068125160 - RPM Brussels Capital Region

4 of 49ACKNOWLEDGEMENTS
This guide was developed by the International Pharmaceutical Excipients Council members
representatives. IPEC Federation, or in short the Federation, is a global organisation thatpromotes quality and safety in pharmaceutical excipients. The Federation consists of the fiveexisting regional IPECs: IPEC-Americas, IPEC China, IPEC Europe, IPEC India, IPEC Japan.
The representatives who worked on this Guide are listed below:

List of Contributors from IPEC-Americas
Brian Carlin, Ph.D. (Chair), DFE Pharma
David Schoneker (Vice-Chair), Black Diamond Regulatory Consulting, LLCGeorge Collins, Vanderbilt Chemicals LLC
Ann Gray, EvonikDavid Klug, Sanofi US
Bretta Lichtenhan, MilliporeSigma
Lisa Milano, Genentech
R. Christian Moreton, FinnBrit Consulting
Meera Raghuram, Lubrizol Advanced Materials, Inc.
Jerry Schalau, DuPont
Chandra Sekhar, Chandra V. Sekhar Consulting
Heather Sturtevant, Johnson & Johnson
Katherine Ulman, KLU Consulting, LLC
Priscilla Zawislak, DuPont
Joseph Zeleznik, IMCD US

List of Contributors from IPEC Europe
Aurelia Defachelles, Roquette
Bastiaan Dickhoff, DFE Pharma
Tobias Hess, Budenheim
Carsten Huettermann, DuPont
Yasemin Koybasi, Kerry
Clara Sachwitz, BIOGRUND
Manuel Streib, Merck Group
Mike Tobyn, Bristol-Myers Squibb
Bhushan Thekedar, Clariant
Kim Verwaest, Johnson & Johnson

List of Contributors from IPEC India
Shraddha Joshi, Evonik

Copyright © 2020 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 2 210 74 40 E: info@ipec-federation.org
VAT: BE 0823931361 - IBAN: BE73363068125160 - RPM Brussels Capital Region

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