The International Pharmaceutical Excipients Council& The Pharmaceutical Quality GroupThe Joint Good
Manufacturing
Practices Guide
For Pharmaceutical Excipients

Version 5
2022

Copyright © 2022 The International Pharmaceutical Excipients Council
Copyright © 2022 Pharmaceutical Quality Group

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 and PQG Management Bodies.

FOREWORDIPECThe International Pharmaceutical Excipients Council (IPEC) is an international industry
association formed by excipient manufacturers, distributors and 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 excipient development andintroduction, and offer best practice and guidance concerning excipient manufacture.
IPEC has three major stakeholder groups:
1. excipient manufacturers and distributors, defined as suppliers in IPEC documents,
2. pharmaceutical manufacturers, defined as users in this document, and3. public health and regulatory authorities.

Copyright © 2022 The International Pharmaceutical Excipients Council
Copyright © 2022 Pharmaceutical Quality GroupThe International Pharmaceutical Excipients Council – Federation (IPEC Federation) asbl
Rue Marie de Bourgogne 52 - 1000, Brussels, Belgium
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PQG
The PQG was formed in 1977 to promote development of a consistent approach topharmaceutical quality and good manufacturing practice. The group has since expanded, and in1990 the PQG published three codes of practice to cover pharmaceutical raw materials, printed
and contact packaging materials. In 1995 the codes were revised and were integrated with ISO
9002:1994. The code for raw materials was revised and reissued as PS 9100:2002
Pharmaceutical excipients, an application standard and GMP guide for pharmaceutical
excipients.
For further information, visit www.pqg.org.

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 the reader to review the latest version of the applicableregulatory guidance; however, the version referenced in the guide will be based on the version
available at the 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 with reference to specific veterinary guidance andregulations.
Throughout the guide, justification implies that a decision is made based on a scientific, quality
and/or regulatory considerations.

Copyright © 2022 The International Pharmaceutical Excipients Council
Copyright © 2022 Pharmaceutical Quality GroupThe International Pharmaceutical Excipients Council – Federation (IPEC Federation) asbl
Rue Marie de Bourgogne 52 - 1000, Brussels, Belgium
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Table of Contents
FOREWORD ................................................................................................................... 1
TABLE OF CONTENTS................................................................................................. 3
PART 1 - IPEC-PQG GMP GUIDE ............................................................................... 15
1

Introduction..................................................................................................... 15

1.1

Purpose and scope ...................................................................................................15

1.2

Principles adopted ....................................................................................................15

1.2.1

The guide and its use ................................................................................................15

1.2.2

Application.................................................................................................................16

1.2.3

Quality System standard ..........................................................................................16

1.3

Layout and definitions ..............................................................................................16

1.3.1

Layout ........................................................................................................................16

1.3.2

Definitions..................................................................................................................17

2

General Guidance ........................................................................................... 18

3

Excipient GMP implementation ..................................................................... 18

4

Context of the organization ........................................................................... 19

4.1

Understanding the organization and its context .....................................................19

4.2

Understanding the needs and expectations of interested parties .........................19

4.3

Determining the scope of the Quality Management System ..................................19

4.4

Quality Management System and its processes .....................................................20

5

Leadership ...................................................................................................... 21

5.1

Leadership and commitment ....................................................................................21

5.1.1

General .......................................................................................................................21

5.1.2

Customer focus .........................................................................................................21

5.2

Quality policy .............................................................................................................21

5.2.1

Establishing the quality policy .................................................................................21

5.2.2

Communicating the quality policy ...........................................................................22

5.3

Organizational roles, responsibilities, and authorities ...........................................22

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6

Planning .......................................................................................................... 24

6.1

Actions to address risks and opportunities in the Quality Management System .24

6.1.1

Risk Assessment.......................................................................................................24

6.1.2

Preventive action and continual improvement........................................................24

6.2

Quality and GMP objectives and planning to achieve them ...................................24

6.3

Planning of changes .................................................................................................25

7

Support ............................................................................................................ 25

7.1

Resources ..................................................................................................................25

7.1.1

General .......................................................................................................................25

7.1.2

People ........................................................................................................................26

7.1.3

Infrastructure .............................................................................................................26

7.1.3.1 Buildings and facilities .................................................................................................26
7.1.3.2 Equipment ...................................................................................................................27
7.1.3.3 Utilities ........................................................................................................................28
7.1.3.4 Water ..........................................................................................................................28
7.1.3.5 Recycled or recovered materials .................................................................................29
7.1.4

Environment for the operation of processes...........................................................29

7.1.4.1 Environmental air handling ..........................................................................................30
7.1.4.2 Controlled environment ...............................................................................................30
7.1.4.3 Clean and sanitary conditions......................................................................................30
7.1.4.4 Pest control .................................................................................................................31
7.1.4.5 Personnel hygiene.......................................................................................................31
7.1.4.6 Lighting .......................................................................................................................32
7.1.4.7 Drainage .....................................................................................................................32
7.1.4.8 Waste ..........................................................................................................................32
7.1.5

Monitoring and measuring resources......................................................................32

7.1.5.1 General .......................................................................................................................32
7.1.5.2 Measurement traceability ............................................................................................33
7.1.6

Organizational knowledge ........................................................................................33

Copyright © 2022 The International Pharmaceutical Excipients Council
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Rue Marie de Bourgogne 52 - 1000, Brussels, Belgium
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7.2

Competence...............................................................................................................33

7.3

Awareness .................................................................................................................33

7.4

Communication .........................................................................................................34

7.5

Documented information ..........................................................................................35

7.5.1

General documentation requirements .....................................................................35

7.5.2

Creating and updating ..............................................................................................36

7.5.3

Control of documented information.........................................................................37

8

Operation......................................................................................................... 37

8.1

Operational planning and control ............................................................................37

8.2

Requirements for excipients and GMP services .....................................................38

8.2.1

Customer communication ........................................................................................38

8.2.2

Determining the requirements for excipients and GMP services ..........................39

8.2.3

Review of the requirements for excipients and GMP services ..............................39

8.2.4

Changes to requirements for excipients and GMP services ..................................39

8.3

Design and development of excipients and GMP services ....................................39

8.3.1

General .......................................................................................................................39

8.3.2

Design and development planning ..........................................................................39

8.3.3

Design and development inputs...............................................................................40

8.3.4

Design and development controls ...........................................................................40

8.3.5

Design and development outputs ............................................................................41

8.3.6

Design and development changes ...........................................................................41

8.4

Control of externally provided quality critical processes, services and materials ..
....................................................................................................................................42

8.4.1

General .......................................................................................................................428.4.2

Type and extent of control ........................................................................................42

8.4.2.1 Control of externally-provided processes and services ................................................42
8.4.2.2 Control of externally-provided materials ......................................................................42
8.4.3

Information for external providers ...........................................................................43

8.5

Production and GMP service provision ...................................................................44

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8.5.1

Control of production and GMP service provision .................................................44

8.5.1.1 Instructions and records ..............................................................................................44
8.5.1.2 Equipment cleaning .....................................................................................................45
8.5.1.3 Recovery and reuse of materials .................................................................................46
8.5.1.4 Blending of excipients .................................................................................................46
8.5.1.5 Co-processing of excipients ........................................................................................46
8.5.1.6 In-process control ........................................................................................................46
8.5.1.7 Packaging and labeling of excipients ...........................................................................47
8.5.1.8 Validation for production and GMP service provision ...................................................47
8.5.2

Identification and traceability ...................................................................................48

8.5.2.1 Traceability ..................................................................................................................48
8.5.2.2 Inspection and test status ............................................................................................48
8.5.2.3 Labels .........................................................................................................................48
8.5.3

Property belonging to customers or external providers ........................................49

8.5.4

Preservation ..............................................................................................................49

8.5.4.1 Handling, storage, and preservation ............................................................................49
8.5.4.2 Packaging ...................................................................................................................49
8.5.4.3 Delivery and distribution ..............................................................................................50
8.5.5

Post-delivery activities..............................................................................................50

8.5.6

Control of changes....................................................................................................51

8.6

Release of excipients and GMP services.................................................................51

8.6.1

Monitoring and measurement ..................................................................................51

8.6.2

Laboratory controls ..................................................................................................51

8.6.3

Finished excipient testing and release ....................................................................53

8.6.4

Out-of-specification test results ...............................................................................53

8.6.5

Retained samples ......................................................................................................54

8.6.6

Certificates of analysis .............................................................................................54

8.6.7

Impurities ...................................................................................................................54

8.6.8

Stability ......................................................................................................................55

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8.6.9Expiry date or re-evaluation period..........................................................................55

8.7

Control of nonconforming outputs ..........................................................................55

8.7.1

Control of nonconforming intermediates and finished excipients ........................55

8.7.1.1 Reprocessing ..............................................................................................................56
8.7.1.2 Reworking ...................................................................................................................56
8.7.1.3 Returned excipients.....................................................................................................56
8.7.2

Control of nonconforming GMP services ................................................................57

8.7.3

Customer complaint handling ..................................................................................58

8.7.4

Recall / Retrieval........................................................................................................58

9

Performance evaluation ................................................................................. 59

9.1

Monitoring, measurement, analysis and evaluation ...............................................59

9.1.1

General .......................................................................................................................59

9.1.2

Customer satisfaction ...............................................................................................59

9.1.3

Analysis and evaluation ............................................................................................59

9.2

Internal audit..............................................................................................................60

9.3

Management review ..................................................................................................60

9.3.1

General .......................................................................................................................60

9.3.2

Management review inputs .......................................................................................61

9.3.3

Management review outputs ....................................................................................61

10

Improvement ................................................................................................... 62

10.1

General .......................................................................................................................62

10.2

Nonconformity and corrective action ......................................................................62

10.3

Continual improvement ............................................................................................63

11

References ...................................................................................................... 64

PART 2 - IPEC-PQG GMP GUIDE AND NOTES ......................................................... 68
1

Introduction..................................................................................................... 68

1.1

Purpose and scope ...................................................................................................68

1.2

Principles adopted ....................................................................................................68

1.2.1

The guide and its use ................................................................................................68

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1.2.2

Application.................................................................................................................69

1.2.3

Quality System standard ..........................................................................................69

1.3

Layout and definitions ..............................................................................................69

1.3.1

Layout ........................................................................................................................69

1.3.2

Definitions..................................................................................................................70

2

General Guidance ........................................................................................... 72

3

Excipient GMP implementation ..................................................................... 72

4

Context of the organization ........................................................................... 73

4.1

Understanding the organization and its context .....................................................73

4.2

Understanding the needs and expectations of interested parties .........................75

4.3

Determining the scope of the Quality Management System ..................................76

4.4

Quality Management System and its processes .....................................................77

5

Leadership ...................................................................................................... 79

5.1

Leadership and commitment ....................................................................................79

5.1.1

General .......................................................................................................................79

5.1.2

Customer focus .........................................................................................................80

5.2

Quality policy .............................................................................................................80

5.2.1

Establishing the quality policy .................................................................................80

5.2.2

Communicating the quality policy ...........................................................................81

5.3

Organizational roles, responsibilities, and authorities ...........................................81

6

Planning .......................................................................................................... 84

6.1

Actions to address risks and opportunities in the Quality Management System .84

6.1.1

Risk Assessment.......................................................................................................84

6.1.2

Preventive action and continual improvement........................................................85

6.2

Quality and GMP objectives and planning to achieve them ...................................86

6.3

Planning of changes .................................................................................................877

Support ............................................................................................................ 87

7.1

Resources ..................................................................................................................87

7.1.1

General .......................................................................................................................87

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7.1.2People ........................................................................................................................87

7.1.3

Infrastructure .............................................................................................................88

7.1.3.1 Buildings and facilities .................................................................................................88
7.1.3.2 Equipment ...................................................................................................................89
7.1.3.3 Utilities ........................................................................................................................92
7.1.3.4 Water ..........................................................................................................................92
7.1.3.5 Recycled or recovered materials .................................................................................94
7.1.4

Environment for the operation of processes...........................................................94

7.1.4.1 Environmental air handling ..........................................................................................95
7.1.4.2 Controlled environment ...............................................................................................95
7.1.4.3 Clean and sanitary conditions......................................................................................96
7.1.4.4 Pest control .................................................................................................................97
7.1.4.5 Personnel hygiene.......................................................................................................98
7.1.4.6 Lighting .......................................................................................................................99
7.1.4.7 Drainage .....................................................................................................................99
7.1.4.8 Waste ..........................................................................................................................99
7.1.5

Monitoring and measuring resources....................................................................100

7.1.5.1 General .....................................................................................................................100
7.1.5.2 Measurement traceability ..........................................................................................101
7.1.6

Organizational knowledge ......................................................................................101

7.2

Competence.............................................................................................................102

7.3

Awareness ...............................................................................................................103

7.4

Communication .......................................................................................................104

7.5

Documented information ........................................................................................105

7.5.1

General documentation requirements ...................................................................105

7.5.2

Creating and updating ............................................................................................109

7.5.3

Control of documented information.......................................................................109

8

Operation....................................................................................................... 111

8.1

Operational planning and control ..........................................................................111

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8.2

Requirements for excipients and GMP services ...................................................111

8.2.1

Customer communication ......................................................................................111

8.2.2

Determining the requirements for excipients and GMP services ........................112

8.2.3

Review of the requirements for excipients and GMP services ............................112

8.2.4

Changes to requirements for excipients and GMP services ................................113

8.3

Design and development of excipients and GMP services ..................................113

8.3.1

General .....................................................................................................................113

8.3.2

Design and development planning ........................................................................113

8.3.3

Design and development inputs.............................................................................114

8.3.4

Design and development controls .........................................................................115

8.3.5

Design and development outputs ..........................................................................115

8.3.6

Design and development changes .........................................................................116

8.4

Control of externally provided quality critical processes, services and materials ..
..................................................................................................................................117

8.4.1

General .....................................................................................................................117

8.4.2

Type and extent of control ......................................................................................117

8.4.2.1 Control of externally-provided processes and services ..............................................118
8.4.2.2 Control of externally-provided materials ....................................................................118
8.4.3

Information for external providers .........................................................................119

8.5

Production and GMP service provision .................................................................121

8.5.1

Control of production and GMP service provision ...............................................121

8.5.1.1 Instructions and records ............................................................................................121
8.5.1.2 Equipment cleaning ...................................................................................................123
8.5.1.3 Recovery and reuse of materials ...............................................................................123
8.5.1.4 Blending of excipients ...............................................................................................124
8.5.1.5 Co-processing of excipients ......................................................................................124
8.5.1.6 In-process control ......................................................................................................125
8.5.1.7 Packaging and labeling of excipients .........................................................................125
8.5.1.8 Validation for production and GMP service provision .................................................126

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8.5.2

Identification and traceability .................................................................................127

8.5.2.1 Traceability ................................................................................................................127
8.5.2.2 Inspection and test status ..........................................................................................128
8.5.2.3 Labels .......................................................................................................................128
8.5.3

Property belonging to customers or external providers ......................................128

8.5.4

Preservation ............................................................................................................129

8.5.4.1 Handling, storage, and preservation ..........................................................................129
8.5.4.2 Packaging .................................................................................................................130
8.5.4.3 Delivery and distribution ............................................................................................130
8.5.5

Post-delivery activities............................................................................................131

8.5.6

Control of changes..................................................................................................132

8.6

Release of excipients and GMP services...............................................................132

8.6.1

Monitoring and measurement ................................................................................132

8.6.2

Laboratory controls ................................................................................................133

8.6.3

Finished excipient testing and release ..................................................................136

8.6.4

Out-of-specification test results .............................................................................136

8.6.5

Retained samples ....................................................................................................137

8.6.6

Certificates of analysis ...........................................................................................137

8.6.7

Impurities .................................................................................................................137

8.6.8

Stability ....................................................................................................................138

8.6.9

Expiry date or re-evaluation period........................................................................138

8.7

Control of nonconforming outputs ........................................................................139

8.7.1

Control of nonconforming intermediates and finished excipients ......................139

8.7.1.1 Reprocessing ............................................................................................................140
8.7.1.2 Reworking .................................................................................................................140
8.7.1.3 Returned excipients...................................................................................................141
8.7.2

Control of nonconforming GMP services ..............................................................141

8.7.3

Customer complaint handling ................................................................................142

8.7.4

Recall / Retrieval......................................................................................................142

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9Performance evaluation ............................................................................... 143

9.1

Monitoring, measurement, analysis and evaluation .............................................143

9.1.1

General .....................................................................................................................143

9.1.2

Customer satisfaction .............................................................................................143

9.1.3

Analysis and evaluation ..........................................................................................144

9.2

Internal audit............................................................................................................144

9.3

Management review ................................................................................................146

9.3.1

General .....................................................................................................................146

9.3.2

Management review inputs .....................................................................................146

9.3.3

Management review outputs ..................................................................................147

10

Improvement ................................................................................................. 147

10.1

General .....................................................................................................................147

10.2

Nonconformity and corrective action ....................................................................148

10.3

Continual improvement ..........................................................................................149

11

References .................................................................................................... 150

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Part 1
IPEC-PQG GMP Guide

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ACKNOWLEDGEMENTS
This guide was developed by representatives from International Pharmaceutical Excipients
Council (IPEC) and the Pharmaceutical Quality Group (PQG) member companies.
IPEC is an industry association whose members consist of excipient manufacturers, distributors,
and users.
IPEC and PQG greatly appreciate the many hours devoted by the core team of individuals andother contributors listed below, to make this guide available to IPEC members and the broader
excipient community. Equally, IPEC and PQG extend their thanks to the employers of those same
contributors who provide the necessary time and resources, without which, this guide would not
be possible.
The company representatives who worked on this guide are listed below:

List of Contributors from IPEC-Americas
William Dale Carter*, Evonik
George Collins, Vanderbilt Chemicals LLC
Ann Gulau, IFF

List of Contributors from IPEC Europe
Jeffrey Brambora, Consultant
Roberto Mastrantonio, Eli Lilly
Astrid Stockrahm-Uhling*+, DFE Pharma
Beverley Stout, GSK

List of Contributors from PQG
Ian McKeown, PQ Silicas* co-chair+ task force team leader

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PART 1 - IPEC-PQG GMP GUIDE
1Introduction

1.1

Purpose and scope

Excipients are essential components of the medicinal product formulation. The quality of
excipients is critical to ensure the safety, quality, and efficacy of medicinal products, because
excipients provide a wide range of functionality.
Excipients can have multiple uses in medicinal products (see 4.1 Note 1). Therefore, it is essential
to apply principles of appropriate Good Manufacturing Practices (GMP) to excipients.
Additionally, excipient GMP provides the foundation for the understanding and implementation of
all IPEC guides.
Users of excipients are increasingly required by regulatory authorities to ensure patient safety
through the evaluation of risks and application of suitable GMP to the manufacture and supplyof each excipient. This document provides GMP appropriate to the manufacture of all excipientsand to GMP services provided by excipient manufacturers. It covers the quality management
system, including the GMP necessary throughout manufacturing, based on risk assessments,
for both batch and continuous processes.
It should be recognized that once the excipient is in the supply chain, it may be subjected tofurther GMP related activities, such as re-packaging or re-labeling, before it reaches the finaluser. Such activities should be performed in compliance with GMP principles as described in thisguide.
This guide is the result of a joint initiative between the International Pharmaceutical Excipients
Council (IPEC), and the Pharmaceutical Quality Group (PQG).

1.2

Principles adopted

1.2.1

The guide and its use

Excipients are diverse materials that often have uses other than pharmaceutical applications.
Therefore, each manufacturer should consider how this guide applies to their processes,
products, and GMP services (see 4.1).
This revised guide incorporates the principles of risk assessment to identify the controls needed
for GMP according to the manufacturer’s intended use of the excipient. The need for risk
assessments is identified throughout this guide. This approach allows the guide to be used for all

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excipients, including those that are supplied sterile and / or pyrogen free, and those intended forparenteral, ocular, inhalation, or open wound use.
For the purposes of this guide, the terms “Good Manufacturing Practices (GMP)” and “current
Good Manufacturing Practices (cGMP)” are equivalent.
The term “should” indicates recommendations that are expected to apply unless shown to beinapplicable or replaced by an alternative that provides at least an equivalent level of quality
assurance. Note that “should” does not mean “must” or “shall”.
1.2.2

Application

This international guide applies to all excipients and excipient-related GMP services. Therefore,
it cannot specify the manufacturing knowledge or competencies required, the national legal
requirements, or consider excipient characteristics (e.g., chemical, or physical properties) for
every excipient or GMP service. It is the responsibility of each excipient manufacturer to utilize
appropriate expertise when identifying and implementing applicable requirements (see 4.2).
1.2.3

Quality System standard

The quality management system standard chosen as a framework for this guide is ISO
9001:2015.
IPEC and PQG support merging GMP principles for excipient manufacturing with the ISO 9001
quality management system because these principles enhance the organization’s quality
management system, operational processes, and related procedures. The organization may alsoseek certification to an excipient GMP standard.

1.3

Layout and definitions

1.3.1

LayoutRevised in its entirety, this version of the guide, its headings and clause numbers have beendeveloped to align with ISO 9001:2015. Additional headings are included as required to introduce
the additional guidance on GMP when not covered by ISO 9001:2015 clauses.
This guide is published in two parts:•

Part 1 includes Good Manufacturing Practices for excipients.

•

Part 2 includes Good Manufacturing Practices for excipients together with notes that offer
examples for GMP interpretation and implementation without adding further requirements.
oNotes may provide common examples but are not intended as an exhaustive list.

oNotes are presented as indented, italicized text.

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Section 1, Introduction
Section 2, General guidance, identifies the regulatory expectation of following excipient GMP.
Section 3, Excipient GMP implementation, provides an overview of the GMP criteria applicable toservices and excipient manufacture from the point where excipient GMP starts.
Sections 4 through 10 provide guidance on the GMP principles and implementation of a quality
management system suitable for excipient manufacture and service provision.
1.3.2

Definitions

ALCOA+:
The acronym ALCOA defines that data should be Attributable, Legible, Contemporaneous,
Original, and Accurate. In addition, ALCOA+ guidance defines that data should also be Complete,
Consistent, Enduring, and Available.

GMP Service:
GMP-related activities performed by an organization on behalf of their customer, where theorganization’s output is not the product (excipient) but either a tangible or intangible output of anactivity.

Manufacture/Manufacturing Process:All operations from receipt of materials through production, packaging, repackaging, labeling,
relabeling, quality control, release, storage and distribution of excipients and related controls.

Regulatory requirement:
ISO 9000 defines ”regulatory requirement” as “obligatory requirements specified by an authority
mandated by a legislative body”.

Statutory requirement:
ISO 9000 defines ”statutory requirement” as “obligatory requirement specified by a legislativebody”.
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ISO 9000:2015:
ISO 9000:2015 specifies the terms and definitions that apply to all quality management and quality
management system standards (developed by ISO/TC 176). Reference to ISO 9000 is used in
Notes, when definitions are provided for generic terms, such as “nonconformity”. These definitions
are taken from ISO 9000, because they are not available in ISO 9001.
For further definitions refer to the International Pharmaceutical Excipient Council Glossary:
General Glossary of Terms and Acronyms. The first use of a term found in the Glossary will be in
bold.

2

General Guidance

Conforming with excipient GMP is a best practice that benefits excipient users and the patient.
Complying with excipient GMP is a regulatory expectation when statutory or regulatory
requirements exist either in the location of excipient manufacture or intended market.

3

Excipient GMP implementation

The objective of excipient GMP is to ensure that:•

excipients are consistently manufactured with the intended quality and performance
characteristics;•

GMP services lead to consistent results.

The excipient manufacturer should design, control, document, and maintain its manufacturing
processes. Justification is required to determine the point at which excipient GMP should beapplied. This justification should be based on thorough process knowledge and recorded in adocumented risk assessment. GMP usually begins well before the final finishing operation.

Implementation of excipient GMP should also consider at a minimum:•batch versus continuous processing;•

dedicated versus multi-purpose equipment;•

open versus closed processes.

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Throughout this guide, the use of “GMP” will mean “excipient GMP” as outlined in this document.

4

Context of the organization

In a GMP context, the excipient manufacturer is the organization. The two terms are usedinterchangeably throughout this guide.

4.1

Understanding the organization and its context

Manufacturers should identify, within their portfolio, those products manufactured and marketed
as excipients. Excipient manufacturers should define and document the intended use(s) of their
excipients, considering the potential impact on patient safety. They should determine and monitor
external and internal issues that are relevant to the manufacture and marketing of excipients.
These should include outsourced activities that can affect excipient quality and for which theorganization has control and responsibility.
Excipient manufacturers should identify the quality management system processes required toassure excipient quality, accounting for customer, social, legal, technological, and culturalenvironments.

4.2

Understanding the needs and expectations of interested parties

The excipient manufacturer should determine the interested parties that are relevant to the GMP
quality system being maintained. Current applicable customer, compendial, statutory, andregulatory requirements should be determined and met (see 6.1.1).
The excipient manufacturer should monitor information about interested parties and their relevant
requirements (see 4.3, 5.3 and 6.1.1).

4.3

Determining the scope of the Quality Management System

The organization’s overall intentions and approach to GMP should be documented to facilitatecommon understanding and consistent application. The excipient manufacturer should have:•a documented description of the quality management system;•

a quality policy (see 5.2);•

commitment to apply the appropriate quality management principles contained in this guide,
including GMP.

The documented description of the quality management system should include the scope of thequality management system and reference to supporting procedures, considering:

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•boundaries and applicability of GMP;•

products and GMP services in scope;•external and internal issues (see 4.1);•

requirements of relevant interested parties (see 4.2);•

the interaction between quality management system processes (see 4.4).

Documentation should identify and justify the starting point in the process (manufacturing orservice provision) from which the full excipient GMP principles of this guide apply.

4.4

Quality Management System and its processes

Excipient manufacturers should define, implement, maintain, and continually improve the quality
management system and its processes. These processes and their interactions should be
documented.
This documentation should include:•

inputs required and outputs expected from these processes;•

process sequence and interaction;•

criteria and methods needed to ensure the effective operation and control of these processes;•

resources needed for these processes and ensure their availability;•

responsibilities and authorities for these processes;•

risks and opportunities as determined in accordance with the requirements of 6.1 and how
they are addressed;•

evaluation of processes and implementation of any changes needed to ensure that theseprocesses achieve their intended results;•

evaluation of risk assessments and improvements to the quality management system (see10.1).

Records should be maintained to demonstrate achievement of the required quality and theeffective operation of the quality management system.
Where manufacturing, testing or other operations that could affect excipient quality areoutsourced (i.e., externally provided), the responsibility for quality remains with the excipient

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records, results and reports of subcontractor activities are retained and by whom.

5

Leadership5.1

Leadership and commitment

5.1.1

GeneralTop management should be identified.
Top management should demonstrate their commitment to the quality management system andbe accountable for its maintenance and effectiveness. This should be accomplished through thedevelopment of a quality policy (see 5.2.1) and establishment of quality and GMP objectives (see6.2). Current applicable customer, compendial, statutory, and regulatory requirements should bedetermined and met.
Top management should promote risk-based thinking (see 6.1).
Top management should provide adequate resources to ensure conformance to the principles ofthis guide. There should be a process for the identification of resources needed for adherence to
GMP.
Top management should ensure that the quality policy, the quality and GMP objectives, and thedefinition of roles, responsibilities and authorities are communicated, understood, and applied
across the organization. They should ensure that the quality management system achieves its
intended result and should promote continual improvement (see 10.3). Progress towards the
documented quality and GMP objectives should be reviewed at planned intervals.
5.1.2

Customer focus

Top management should ensure that customer requirements related to GMP and other related
matters are determined, understood, agreed with the customer and met.
The excipient manufacturer should be able to demonstrate to the customer the effectiveness of
their quality management system. This may be by audit, third party certification, or other means.

5.2

Quality policy

5.2.1

Establishing the quality policy

Top management should participate in and provide the resources necessary for the development,
implementation, and maintenance of the organization’s quality policy. The quality policy should
include commitment to appropriate GMP, compliance with applicable requirements and continual
improvement of the quality management system.
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5.2.2

Communicating the quality policy

Top management should demonstrate its commitment to the quality policy and appropriate GMP,and ensure that this is communicated and implemented within the organization.

5.3

Organizational roles, responsibilities, and authorities

Top management should ensure that responsibility and authority are clearly defined,
communicated, and understood within the organization.

Top management should assign the responsibility and authority for:•ensuring that the quality management system conforms to the provisions of this guide;•

ensuring that the processes are delivering their intended outputs;•

reporting to top management on the performance of the quality management system,
opportunities for improvement (see 9.3.2) and changes to applicable customer, compendial,
statutory and regulatory requirements (see 4.2);•

ensuring the promotion of customer focus throughout the organization;•

ensuring that the integrity of the quality management system is maintained when changes tothe quality management system are planned and implemented.

Top management should ensure that a quality unit or other appropriate unit, independent of
production, has the responsibility and authority to:•ensure quality-critical activities are identified and undertaken as defined;•

review and approve documents that have the potential to impact product quality;•

approve external providers (suppliers) of quality-critical processes, services and materials;•

ensure that providers of outsourced processes and services comply with the relevant sectionsof this guide (see 8.4);•

approve or reject raw materials, packaging components, intermediates and finishedexcipients, according to current approved specifications and procedures;

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•approve or reject the excipient if it is produced, processed, packaged or held under contractby another company;•

ensure that there is a review of production records prior to excipient release;•

ensure that where errors, deviations, or nonconformities have occurred or are identified in thereview process, they are appropriately investigated and documented;•

ensure corrective and preventative actions are implemented and effective;•

participate in reviewing and authorizing significant changes that have the potential to impact
quality (see 8.5.6);•

review and approve the results of investigations into deviations from production instructions,test or measurement failures, customer complaints, or other nonconformities;•

develop and implement an internal audit program of the quality management system.

Some of the quality unit’s activities may be delegated if appropriate controls are in place anddocumented. However, in all cases the quality unit should be responsible for performing:•

review and approval of documents that impact excipient or GMP service quality;•

approval of significant changes that may impact excipient or GMP service quality;•

approval of quality-critical suppliers;•

release of the finished excipient;•release of GMP services;•

approval of reworking;•evaluating and determining the disposition of returned excipients, including recalled
excipients.

For all of the quality unit’s activities listed in this section, whether performed by the quality unit oranother appropriate unit, records should be available to demonstrate review and approval /rejection. Although quality unit activities may be delegated, the quality unit is ultimately
responsible for the final output and should approve the controls used by any other unit to performthe delegated activity.

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An organizational chart by function should show inter-departmental relationships as well as
relationships to top management. Personnel who have an impact on excipient quality should havejob descriptions (see 7.2).

6Planning

6.1

Actions to address risks and opportunities in the Quality Management System

6.1.1

Risk Assessment

The excipient manufacturer should conduct risk assessments of the issues referred to in 4.1 andthe requirements referred to in 4.2 to determine the risks and opportunities that need to beaddressed to:•give assurance that the quality management system can achieve its intended result(s);•enhance desirable effects;•

prevent, or minimize, undesirable effects;•

achieve continual improvement.

See also “The IPEC Risk Assessment Guide for Pharmaceutical Excipients”.
6.1.2

Preventive action and continual improvement

The excipient manufacturer should plan actions to address risks and opportunities in the quality
management system (see 6.1.1), by:•initiating preventive actions including assignment of responsibilities and timelines for
implementation, to deal with problems at a level corresponding to the risks;•

initiating actions to enhance desirable effects or remove barriers to improvement;•

ensuring that actions are implemented and effective;•

implementing and recording changes in processes or procedures resulting from actions.

6.2

Quality and GMP objectives and planning to achieve them

Top management should set appropriate quality and GMP objectives to ensure that the excipient
manufacturer maintains and improves its performance. These objectives should be:•consistent with the quality policy;

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communicated;•documented;•

updated as appropriate.

When planning to meet these objectives, the excipient manufacturer should determine:•

what will be done;•

who will be responsible;•

what additional resources will be required;•when it will be completed;•

how results will be evaluated.

6.3

Planning of changes

The excipient manufacturer should establish and maintain documented procedures to evaluate
and approve changes that may have an impact on the excipient or GMP service.
Prior to implementation, evaluation and approval of changes should be documented (see 7.5)
and, where appropriate, a formal risk assessment conducted. Consideration should include
potential impact on validation (see 8.5.1.8) or regulatory submissions made by the excipient
supplier. Procedures should describe the means by which a change is determined to besignificant. Where the impact is determined to be significant, such changes should becommunicated to customers and, as applicable, to regulatory authorities. See also “The IPEC
Significant Change Guide for Pharmaceutical Excipients”.

7

Support7.1

Resources

7.1.1

GeneralThe organization should, in a manner consistent with this guide, determine and provide adequate
resources to:•implement, maintain and improve the quality management system;

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produce, package, test, store and release each excipient;•supply each GMP service.

7.1.2

PeopleThe organization should determine and provide adequate numbers of qualified personnel.
7.1.3

Infrastructure

The infrastructure should be designed, managed, operated, cleaned, and maintained inaccordance with GMP principles to ensure excipient quality as well as to minimize the risk ofcontamination, including cross-contamination. It should be designed and controlled to prevent
unauthorized access.
An infrastructure risk assessment should be documented (see 7.1.3.1 - 7.1.3.5), based on theintended use of the excipient, to identify areas in which the excipient is at risk of contaminationfrom infrastructure design and / or deficiencies. See also “The IPEC Risk Assessment Guide for
Pharmaceutical Excipients”.

7.1.3.1 Buildings and facilities
The ability to clean and minimize the risk of contamination (including pest infestation (see 7.1.4.4)
and cross-contamination) should be considered in the design of the manufacturing processes andfacilities, particularly where the excipient is exposed to the environment.
To facilitate cleaning, maintenance, and correct operation appropriate to the type of processing,buildings and facilities used in the supply of GMP services or the production, processing,packaging, testing or storage of an excipient should be:•

appropriate for their purpose,•

maintained in a good state of repair, and•of suitable size, construction, and location.

Manufacturing processes using allergens, highly sensitizing or toxic materials should be locatedin dedicated facilities and / or use equipment not used for excipient manufacture. In somejurisdictions this is a regulatory requirement. If allowed by regulation and when non-dedicatedfacilities or equipment are used, appropriate measures, resulting from a specific risk assessment,
should be implemented to minimize the risk of cross-contamination. The effectiveness of thesemeasures should be demonstrated.

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7.1.3.2

Equipment

To facilitate cleaning, maintenance, and correct operation for the type of processing, equipmentused in the supply of GMP services or the production, processing, transfer, packaging, testing or
storage of an excipient should be:•

appropriate for its purpose,•

maintained in a good state of repair, and•of suitable size, construction, and location.

Consideration of the risk of breakage or damage should be given.
Equipment should be qualified and commissioned before use to ensure that it is functioning as
intended. See also “The IPEC Validation Guide for Pharmaceutical Excipients”.
The use, cleaning and maintenance of quality-critical equipment should be recorded (see 8.5.1.1).
The status of equipment should be readily identifiable.
Where equipment is located outdoors there should be suitable controls to minimize the risk to
excipient quality from the environment.
Equipment construction:
Process equipment should be constructed so that contact surfaces will not be reactive, additive,
or absorptive and thus not alter the quality of the excipient. Substances required for operation,such as lubricants or coolants, should not come into contact with raw materials, packaging
materials, intermediates or finished excipients. Where contact with such substances is possible,
substances at least suitable for use in food applications should be utilized.
Equipment should be designed to minimize the possibility of contamination caused by direct
personnel contact. The sanitary design of transfer and processing equipment should be evaluatedusing a risk assessment.
Equipment and its components should be assessed regarding their potential for erosion anddegradation to control the risk of contamination, including cross-contamination.
Equipment maintenance:
Documented procedures should be established and followed for maintenance of quality-criticalequipment used in the production, processing, packaging, testing, or holding of excipients. There
should be records of the use and maintenance of quality-critical equipment.
Computer systems:

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intended, including:•

procedures for periodic system verification;•

back-up or archiving (see 7.5.1);•

preventing unauthorized access;•assurance that changes are traceable, verified, documented, and only made by authorized
personnel (see 6.3 and 7.5).

See also “The IPEC Validation Guide for Pharmaceutical Excipients”.
Records demonstrating proper performance of the computer systems should be maintained.

7.1.3.3

Utilities

A risk assessment should be performed to consider the risk to excipient quality from utilities usedin the production, storage, or transfer of materials. Appropriate action should be taken to eliminate
or, at a minimum, control the identified risks. Utilities that could impact excipient quality shouldhave documented specifications and be of suitable quality for their intended use. Quality criticalparameters of these specifications should be monitored at a documented frequency (see 8.5.1).

7.1.3.4

Water

A risk assessment should be performed to consider the risk to excipient quality from water usedin the manufacture of excipients. Appropriate action should be taken to eliminate or, at a minimum,
control the identified risks. Water that could impact excipient quality, regardless of its source,
should have documented specifications and be of suitable quality for its intended use. Quality
critical parameters of these specifications should be monitored at a documented frequency (see8.5.1).
Unless otherwise justified, water used in the manufacture of excipients should, at a minimum,
meet WHO guidelines for drinking (potable) water. When drinking water quality is insufficient toensure excipient quality, appropriate chemical and / or microbiological water quality limits should
be defined.
Where water used in the process is treated by the manufacturer to achieve a defined quality, thetreatment process should be specified and monitored with appropriate action limits.
Water contacting the excipient should be produced and distributed to minimize the risk ofcontamination or backflow in the system.

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If interruptions in supply or deviations in the quality of water occur, return to service should not
happen until it is confirmed that water quality has been restored. Appropriate evidence andrationale should be documented to show that interruptions have not compromised the quality ofthe excipient.

7.1.3.5

Recycled or recovered materials

The use of recycled or recovered materials containing recoverable amounts of excipient,
reactants or intermediates should be justified. Where materials are recovered and reused in thesame process or different processes, they should meet appropriate specifications prior to reuseor mixing with other approved material.
Activities to recycle or recover materials should be documented in production records or logs toenable traceability (see 8.5.2).
7.1.4

Environment for the operation of processes

Where the excipient is exposed during manufacture it should be in an appropriately controlledenvironment to minimize the risk of degradation and contamination, including crosscontamination.
A documented assessment should be carried out to identify the related risks and to determine thenecessary controls. The following should be considered, as applicable:•

air handling systems, see 7.1.4.1;•

need for specific environments (controlled environments), see 7.1.4.2;•

cleanliness and sanitary conditions, see 7.1.4.3;•

pest control, see 7.1.4.4;•

personnel hygiene, see 7.1.4.5;•

material (including waste) segregation, see 7.1.4.8;•

waste disposal, see 7.1.4.8;•

other potential sources of contamination, including cross-contamination.

Special consideration should be taken in multi-use areas, where several products are processed
simultaneously.
Where maintaining the work environment is critical to excipient quality, the controls should be
documented and, as appropriate, monitored.

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7.1.4.1

Environmental air handling

Where the documented risk assessment has identified risks associated with air handling, thesystem should be designed and controlled to minimize the risk of degradation, contamination, andcross-contamination of the excipient.
The effectiveness of the air handling system should be demonstrated.

7.1.4.2

Controlled environment

Where the documented risk assessment has identified the need for a controlled environment, it
should be monitored and controlled to assure excipient quality.
Such controlled environments should be designed to minimize the risk of contamination, including
cross-contamination, or degradation of the excipient. The degree of protection required may varydepending on the stage of the process.
Where the documented risk assessment has identified the need for an inert atmosphere, theinerting gas should be treated as a raw material.
If interruptions to the controlled environment occur, sufficient evidence and appropriate rationale
should be documented to show that such interruptions have not compromised the quality of theexcipient.

7.1.4.3

Clean and sanitary conditions

Buildings used in the production, processing, packaging, or holding of an excipient should bemaintained in an appropriately clean and sanitary condition.
Where the documented risk assessment has identified the need for clean / sanitary conditions,documented procedures should be in place according to the type of processing conducted:•

assigning responsibility for cleaning / sanitizing;•describing in sufficient detail the schedules, methods, equipment, and materials to be used incleaning / sanitizing the buildings and facilities.

These activities should be documented (see 7.5.1).
Where disinfectants and / or detergents are used, a documented risk assessment should
demonstrate their suitability. The quality unit should approve the use of quality-critical cleaningand sanitizing agents.

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7.1.4.4

Pest control

A documented risk assessment should be carried out by an internal or external pest control
specialist. This risk assessment should consider the potential for infestation by rodents, birds,
flying and crawling insects and other vermin.
Some raw materials, particularly agriculturally sourced materials, may contain unavoidable
contamination, such as rodent or other animal filth. Appropriate control methods should be inplace to prevent the increase of such contamination in holding areas and its spread to other areasof the manufacturing facility.
Where the risk assessment has identified the need for pest control, the organization should
document the pest control program, including the use of suitable rodenticides, insecticides etc.
Where a service provider is used, there should be a contract in place (see 8.4).

7.1.4.5

Personnel hygiene

Where the documented risk assessment has identified areas in which the excipient is at risk ofcontamination, including cross-contamination, from personnel or their activities, controls shouldbe put in place to minimize the risk. At a minimum the following should be considered anddocumented:•

the personnel themselves;•

suitability of clothing and protective equipment for the activity;•

provision of facilities for showering and / or changing clothes;•

removal or covering of jewelry and other loose items, including those in pockets;•

reporting to supervisory personnel any health conditions, apparent illness or open lesions,that may have an adverse effect on excipients;•

restricting the storage and consumption of food, drink, personal medication, tobacco products
or similar items to designated locations separate from manufacturing areas.

Adequate washing facilities and supplies should be provided so that suitable hygiene standards
can be maintained. Toilet facilities should be clean and separate from but easily accessible toworking areas.

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7.1.4.6

Lighting

Adequate lighting should be provided to facilitate cleaning, maintenance, and proper and safe
operations. Where the excipient is exposed to the work environment or stored, lighting should beshatter-proof or otherwise protected.

7.1.4.7

Drainage

In areas where the excipient is open to the environment or stored, drains should be of adequate
size. Where connected directly to a sewer, drains should be provided with air breaks ormechanical devices to minimize the risk of back-siphoning. Drains should be maintained
appropriately.

7.1.4.8

Waste

Waste should be segregated and disposed of in a timely manner by means appropriate to its type.
If waste is not disposed of immediately, it should be suitably labeled and stored. Excipient
packaging should not be used to hold waste unless clearly labeled as waste.
7.1.5

Monitoring and measuring resources

7.1.5.1 General
The excipient manufacturer should identify measuring and monitoring equipment necessary toadequately control manufacturing processes. Equipment critical to quality should be qualified,commissioned, calibrated, and, where appropriate, maintained.
The control program should include:•

the standardization or calibration of instruments and equipment at suitable intervals inaccordance with a documented program;•specific instructions, schedules, limits for accuracy and precision;•

provisions for remedial action if accuracy and / or precision limits are not met, including:oprevention of future use until suitability can be demonstrated;odocumented investigation to determine the validity for results reported since the last
successful qualification / commissioning / calibration.

Instruments and equipment not meeting established calibration limits should not be used.
For quality-critical monitoring and measurement equipment, the excipient manufacturer should
retain documented evidence demonstrating fitness for purpose.

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7.1.5.2 Measurement traceability
Standards used for the calibration of measuring and monitoring equipment should be traceable
to recognized national, international, or compendial standards, as appropriate.
The qualification / commissioning / calibration status of quality-critical equipment should be known
and verifiable to users.
7.1.6

Organizational knowledge

The excipient manufacturer should determine, apply, and maintain the knowledge necessary for
manufacturing and marketing of excipients. Knowledge of current regulations should be aligned
to the labeling claims made about the excipient, intended use, and the countries in which it ismarketed.

7.2

Competence

The excipient manufacturer should determine, and document in a written job description, theappropriate combination of education, training and experience for roles / personnel performing
tasks that may affect excipient quality (see 5.3). These tasks should be considered in the training
plan.
The excipient manufacturer should establish and maintain procedures for identifying the training
needs of its employees and contracted personnel. A process should be established to provide
effective training to all personnel who perform activities that may affect excipient quality. Training
should be provided prior to independently performing those activities.
Training should address the particular GMP operations that the employee performs as well as
detailed GMP related to the employee’s role.
Appropriate records of training should be maintained.
Retraining requirements should be defined and documented.
Consultants advising on design, production, packaging, testing or storage of excipients shouldhave sufficient education, training and experience or any combination thereof to advise on thesubject for which they are retained. Records should be maintained listing the name, address andqualifications of consultants and the type of advice they provide.

7.3

Awareness

Qualified individuals should develop and provide general GMP training. This training should beconsistent with the quality policy and provided with sufficient frequency to ensure that employees
remain familiar with applicable GMP principles. Training content should include the following
topics – at a minimum – as they relate to the individual’s role and function:
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importance of following instructions and prompt notification of any deviation;•

data integrity;•

precautions necessary to minimize the risk of contamination, including cross-contamination,
through personal hygiene practices;•

understanding of other precautions necessary to minimize the risk of contamination of
excipients, including cross-contamination;•

potential to impact patient safety should the above expectations not be met.

The training program should ensure personnel understand that deviations from procedural
instructions may impact the safety, quality, or efficacy of medicinal products.
The training program should also ensure that personnel know what to do when a deviation has
taken place.

7.4

Communication

The excipient manufacturer should ensure that internal and external communication processes
are established.
Processes for internal communication should be in place for:•

GMP and regulatory requirements;•

quality-relevant policies, including the organization’s overall quality policy;•

quality-relevant procedures;•quality and GMP objectives;•effectiveness of the quality management system;•

prompt notification to top management of quality-critical situations, including excipient
retrievals (see 8.7.4).

External communication processes should include:•

accurate and pertinent information, which may include regulatory documents (see 7.5);•

replies to customer enquiries, contracts and order handling requirements;•

origin and traceability of the excipient to the customer;•

issues detected after delivery of the excipient (see 8.7.1 and 8.7.4);

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responses to customer complaints and feedback;•significant changes (see 6.3 and 8.2.4).

7.5

Documented information

7.5.1

General documentation requirements

The organization’s overall intentions and approach to GMP should be described and documented
to facilitate common understanding and consistent application.
Procedures for manufacturing, control of data and records, as well as other documents related torequirements of the quality management system should be implemented, controlled, andmaintained. This includes regulatory documents and documents of external origin that are part of
the quality management system.
The excipient manufacturer should establish and maintain procedures for the lifecycle of
documented information covering:••

Review, approval, distribution, access, retrieval, and use:ocurrent versions of applicable documents should be available at points of use;oprevent unintended use of obsolete documents;

storage and preservation, including preservation of readability and integrity:oprevent unintended and / or unauthorized changes;ominimize the risk of accidental deletion or damages;•

control of changes (e.g., correction, version control);•periodic review to ensure the document remains current with practice;•retention, including:•oprocess for identifying and labeling obsolete documents;oretention time;

destruction.

Records should be maintained to demonstrate achievement of the required excipient quality andthe effective operation of the quality management system. Records should be legible andidentifiable with the product or process involved.

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The organization should define which results, records and reports of subcontractor activities are
retained, by whom, and for how long.
If electronic signatures are used, they should be authenticated, provide equivalent security tohandwritten signatures, and comply with relevant regulatory requirements.
Data integrity principles i.e., of ALCOA+ should be incorporated throughout the procedures andsystems used for managing documented information.
Data integrity controls for excipient manufacturing and distribution processes should becommensurate with risks associated with the use of the data. A higher level of control should be
implemented where the loss of data integrity could compromise compliance with excipient GMP,
impact confidence in excipient quality, cause the failure or rejection of the medicinal product, orpose potential harm to the patient.
Data integrity requirements apply equally to manual (paper) and electronic data. The inherent
risks to data integrity may differ depending upon the degree to which data (or the systemgenerating or using the data) can be configured, and therefore potentially manipulated.
Entries in records should be clear, indelible, made directly after performing the activity (in theorder performed), signed and dated by the person performing the observed task (unless otherwise
justified). Corrections to records should be signed and dated, leaving the original entry legible.
7.5.2

Creating and updating

Documents should include a unique identifier, date of issue and revision number to facilitate
identification of the most recent document.
Documents that have the potential to impact product quality should have a defined owner and bereviewed and approved by the quality unit (see 5.3) before issuance to the appropriate areas.
Additionally, procedures and forms should indicate from which date they are valid. This dateshould allow sufficient time to provide for employee training (see 7.2).
The department with the responsibility for issuing the documents should be identified.
Changes to approved, quality-relevant documents should be reviewed and approved by thequality unit (see 5.3) before use.
Changes and the reasons for the change should be documented.
All quality-related documented information (i.e., data, records, documents) should meet theabove, independent of the storage medium (i.e., paper, electronic, mixture of both).

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7.5.3Control of documented information

Documented information should be controlled. Controls should provide assurance that only thecurrent version is being used in operational areas and that previous versions of documents havebeen removed.
Copies of controlled documents should be readily identifiable as either controlled or uncontrolled.
Records should be kept for a defined period appropriate to the excipient and as specified inapplicable:•

regulations;•certification standards;•

customer agreements.

The excipient manufacturing record retention period should be at least one year past theexcipient’s expiry or last re-evaluation date, or at least five years from the date of manufacture.
Electronic records should be subject to the same controls as those required for other records.

8

Operation

8.1

Operational planning and control

The excipient manufacturer should plan, implement, and control the processes needed forprovision of excipients and GMP services. According to the actions determined in section 6, theexcipient manufacturer should:•

determine the requirements for the excipients and GMP services;•establish criteria for excipient manufacturing that include:odocumented processes;odocumented testing programmes for quality-critical materials including intermediates andfinished excipients;oappropriate specifications;osampling plans;oenvironmental and hygiene control programmes (see 7.1.4) to minimize the risk ofcontamination, including cross-contamination;
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•

document procedures describing activities related to the storage and distribution of excipients;•

implement actions from relevant documented risk assessments (see 7.1 including subsections);•

generate and maintain records providing evidence that the controls have been followed andmet.

The excipient manufacturer should control planned changes (see 6.3) and have a process tomanage the consequences of deviations (i.e., unintended changes).
The excipient manufacturer should ensure that outsourced processes are controlled (see 8.4) andnotify customers as applicable (see 8.2.1).

8.2

Requirements for excipients and GMP services

8.2.1

Customer communication

There should be processes in place for communication to the customer, including:•provision of accurate and pertinent information, which may include regulatory documents (see
7.5);

•

provision of replies to enquiries, contracts and order handling requirements;•

handling or controlling customer property, as applicable;•communicating the original manufacturer’s identity and production site;•

notifying customers of outsourced activities that may affect excipient quality (see 8.4);•

provision of certificate of analysis for each batch shipped (see 8.6);•

notifying customers of significant changes (see 6.3);•

documenting and responding to customer complaints and feedback;•informing customers of issues, including recalls and critical deviations detected after deliveryof the excipient or provision of the GMP service (see 8.7.1, 8.7.2, and 8.7.4);•

informing if customers are impacted by activation of contingency plans.

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8.2.2

Determining the requirements for excipients and GMP services

The excipient manufacturer should determine the requirements for manufacture of excipients andprovision of GMP services based on the intended use. Customer-specific, legal, and regulatory
requirements should be considered, as found in “The IPEC Qualification of Excipients for Use inPharmaceuticals Guide and Checklist”.
8.2.3

Review of the requirements for excipients and GMP services

The excipient manufacturer and customer should review and mutually agree upon therequirements identified in 8.2.2 before supply begins. The manufacturer should have the facility
and process capability (see 8.5.1) to consistently meet the mutually agreed specifications and
GMP services.
Customer requirements may be documented in agreements, revision of which can be initiated byeither party.
Where the requirements determined in 8.2.2 are changed, this review should be repeated before
supply resumes.
8.2.4

Changes to requirements for excipients and GMP services

The excipient manufacturer should have a process for handling changes related to customer andregulatory requirements. See 6.3 for changes initiated by the excipient manufacturer.

8.3

Design and development of excipients and GMP services

8.3.1

GeneralIn the design and development of excipients and GMP services, the GMP principles of this guide
may not always be fully applicable.
The excipient manufacturer should document in a risk assessment those parts of the guide thatare not applied when developing excipients.
8.3.2

Design and development planning

When designing and developing excipients and GMP services, the excipient manufacturer should
consider the processes and activities necessary to control the desired result, including:•the type, duration, and complexity of the development activities associated with the excipientor GMP service;•stages of the plan, including reviews and approvals;•

verification or validation activities;

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resources (internal and external) (see 7.1);•

interface(s) between people involved;•

customer and user involvement (see 5.1.2);•

customer and user requirements (see 8.2.2);•

facilities and process capabilities needed to consistently meet the desired result (see 8.5.1);•

documented evidence needed to demonstrate that planning requirements have been met.

8.3.3

Design and development inputs

The excipient manufacturer should determine the requirements specific to the excipients and
GMP services being designed and developed, considering, at a minimum:•

functionality and performance;•

information available from similar design and development activities;•

statutory and regulatory environments;•

standards or codes of practice implemented by the organization;•

potential consequences of failure attributable to the type of the excipient or GMP service.

Design and development inputs should be:•adequate for their intended purposes;•

clear and comprehensive;•

consistent in their approach.

Evidence of these inputs should be documented and retained (see 7.5).

8.3.4

Design and development controls

The excipient manufacturer should control the design and development process to ensure that:•desired results are defined;

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verification activities are conducted to confirm that the design and development outputs meetthe input requirements;•

actions verify resulting excipients and GMP services meet the organization’s intended use,and customer and user requirements;•

actions are performed to address problems identified during reviews or verification activities,
as applicable;•

control activities are documented and retained (see 7.5).

8.3.5

Design and development outputs

The excipient manufacturer should ensure that outputs for design and development of excipientsand GMP services:•

meet all input requirements;•

satisfy requirements of the standards and codes of practice implemented by the organization;•

identify process control strategy requirements, as appropriate, and corresponding
acceptance criteria;•

identify release specifications and / or other requirements consistent with the intended
marketed purpose and safe use by the customer, or•

identify other requirements essential for the intended purpose.

Evidence of these outputs should be documented and retained (see 7.5).
8.3.6

Design and development changes

In order to minimize the potential for nonconformance to requirements (see 8.3.3), the excipient
manufacturer should appropriately control changes (see 6.3) made during the design anddevelopment of excipients and GMP services. Documented evidence should be maintained torecord:•the scope of the change;•

review of the change;•

authorization of the change;•

actions implemented to minimize potential negative effects caused by the change.

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8.4

Control of externally provided quality critical processes, services andmaterials

8.4.1

GeneralExternally-provided quality-critical processes, services and materials should be described in
written agreements and the excipient manufacturer should ensure that these activities andmaterials conform to the documented requirements (see 8.4.3).
A documented process should be used to identify quality-critical processes, services andmaterials, and their necessary controls.
Suppliers of quality-critical processes, services and materials should be approved by the quality
unit after a documented evaluation of the supplier's quality management system, including
adequate evidence that they can consistently meet agreed requirements (see 8.4.3). Documented
information of these activities should be retained (see 7.5).
8.4.2

Type and extent of control

The excipient manufacturer should determine the controls necessary to ensure that the externallyprovided quality-critical processes, services and materials meet agreed requirements (see 8.4.3).
These activities should be documented, including controls that apply to both:•the external provider, and•their provided process, service, or material.

These controls may require periodic audits of the supplier’s operations.

8.4.2.1 Control of externally-provided processes and services
Where manufacturing, testing, other operations, or services that could affect excipient quality areoutsourced, the responsibility for quality ultimately remains with the excipient manufacturer, andcontrol measures should be defined. The excipient manufacturer should be able to demonstratethat the applicable GMP principles, in accordance with this guide, are followed for those
operations and services.

8.4.2.2 Control of externally-provided materials
There should be procedures for control of incoming materials. These should describe the process
for approval and release of quality-critical materials, including handling of out-of-specification test
results (see 8.6.4).

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Incoming quality-critical materials, including packaging and preprinted materials, should bephysically or administratively quarantined until they have been tested or otherwise verified andapproved for use by the quality unit or their delegate (see 5.3).
Sampling activities should be conducted under defined conditions in accordance with a definedsampling method and using approved procedures and sampling tools designed to minimize therisk of contamination, including cross-contamination.
Bulk deliveries should have appropriate controls to minimize the risk of contamination, including
cross-contamination.
When quarantine and stock control are managed with computer systems, there should be system
controls to prevent the use of unreleased material.
Quarantine may not be feasible for materials supplied through pipelines. In these cases, theexcipient manufacturer should establish an agreement with the supplier so that they are notified
of material that does not meet specification.
8.4.3

Information for external providers

Excipient manufacturers should have documented agreements with external providers,
communicating:•the quality-critical processes, services and / or materials to be provided, including whereapplicable:oname, type, class, grade, item code number or other precise identification traceable to theraw material and packaging specifications;odrawings, process requirements, inspection instructions and other relevant technical data;orequirements for the approval of:omaterials and services;

methods, processes, and equipment;

the release of processes, services, and materials.

requirements for personnel competence, including appropriate regulatory qualifications.

•the need for adherence to the applicable GMP principles in accordance with this guide;•

which records, results and reports need to be retained, by whom, and for how long;•

how control and monitoring of external provider performance will be applied;

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•change control requirements, including subcontracting;•requirements for verification or validation activities by the external provider, if applicable;•

any need for periodic audits by the excipient manufacturer of the external supplier’s
operations.

8.5

Production and GMP service provision

8.5.1

Control of production and GMP service provision

Activities for provision of excipients and GMP services should be carried out under controlled
conditions (see 8.1). There should be evidence defining:•

the characteristics of the excipients to be produced;•

the GMP services to be provided;•

the activities to be performed;•

the results to be achieved.

Specific controls detailed in sections 8.5.1.1 through 8.5.1.8 apply for the excipients or GMP
services within the scope of operations (see 8.1).

8.5.1.1 Instructions and records
Documents and records (see 7.5.1) describing how the excipient is manufactured or distributed,
or GMP service is provided, should be maintained. Written instructions and forms that become
records should be available at point of use and may differ based on the activity.
Records should be available for each batch of excipient produced and should include complete
information relating to the production and control of each batch. For continuous processes, thebatch and its records should be defined based on time or quantity produced and / or packaged.
Records should also be available for each GMP service provided.
Where critical to demonstrate compliance with this guide and as applicable, records should
comply with data integrity principles (see 7.5.1) and include:•

date / time each step was completed;•documentation of key parameters together with conformance check against specified
operating ranges;•

identification of persons:

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•

identification of major equipment and lines used;•cleaning activities for equipment, lines, and utensils (see 8.5.1.2);•

material inputs (to enable traceability, see 8.5.2);•

in-process control results (see 8.5.1.6);•

inspection of the packaging and labeling area(s) before use, to ensure that materials not
required for the current operation have been removed or destroyed;•labeling controls performed;•

description of excipient containers and closures;•

description of sampling performed;•

failures, deviations, and their investigations;•visual inspection results of packaged excipient (see 9.1.3 for analytical testing of final
excipient);•

the quantity produced for the defined batch and a statement of the percentage of theoreticalyield, as applicable.

8.5.1.2 Equipment cleaning
Equipment and utensils should be cleaned and, if critical to excipient quality, sanitized. Cleaning
can be achieved in several ways, some of which may not result in visually clean equipment. The
excipient manufacturer should design and justify cleaning and sanitization intervals andprocedures and provide documented evidence of their effectiveness based on pre-determined
acceptance criteria.
Cleaning and sanitization procedures should be documented. Where disinfectants or detergentsare required, an assessment of suitability should be documented. Procedures should containsufficient detail to allow operators to clean each type of equipment in a reproducible and effective
manner (see 7.1.4.3). There should be a record confirming that these procedures have been
followed. The cleanliness and, where appropriate, sanitization status of equipment should be
identifiable and documented.

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8.5.1.3 Recovery and reuse of materials
Where materials are recovered and reused, they should meet appropriate specifications prior toreuse or mixing with other approved materials. Processes for recovery and reuse of materials
should be justified. These processes should be documented, and records maintained to enable
traceability.

8.5.1.4 Blending of excipients
If excipients are blended (without the manufacturing elements of co-processing) the process
should ensure homogeneity and should be reproducible from batch to batch (see 8.5.1.8). The
process should be controlled and documented to allow traceability back to the individual batches
that make up the blend.
The blended batch should be tested for conformance to established specifications. The expiry or
re-evaluation date of the blended batch should be justified.
Blending should not be used to dilute contamination (see 8.7.1). Blending should also not be
used where the performance of the resulting excipient could be impacted.

8.5.1.5 Co-processing of excipients
For co-processing of excipients, different technologies such as granulation, melt extrusion, spraydrying, or milling may be used.
To ensure that specified properties and quality are obtained:••

the co-processing of excipients should be:oadequately controlled in-process (see 8.5.1.6);odocumented to allow traceability back to the component excipient batches (see 8.5.2.1);

finished co-processed excipients should be tested to ensure the product conforms tospecifications (see 9.1.3).

The expiry or re-evaluation date of the co-processed excipient should be justified.
See also “The IPEC Co-Processed Excipient Guide for Pharmaceutical Excipients”.

8.5.1.6 In-process control
In-process controls may be based upon in-line monitoring of the process or actual sample analysis
at defined locations and times. In-process sampling, inspection and testing should be performedby trained personnel on representative samples according to documented procedures. In-processsamples should be clearly labeled and not returned to the GMP-process production stream.
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The results of in-process controls should be recorded and should be verified against establishedprocess limits. Written instructions should describe the use of inspection and test data to control
the process. These instructions should detail actions to be taken when the results are outside
specified limits.

8.5.1.7 Packaging and labeling of excipients
Packaging and labeling procedures should be employed to ensure excipient identity, quality, andpurity. To prevent mix-ups, procedural controls should be implemented to ensure:•correct labels are printed and issued;•labels contain the correct information;•

printed information is indelible;•

packaging and labeling facilities are inspected immediately before use, confirming thatmaterials not required for the current packaging operation have been removed or destroyed;•

excipient is packaged into the correct packaging system (see 8.5.4.2);•

excess batch-specific labels are destroyed immediately following packaging operations.

If not required for the subsequent packaging and labeling operation, excess product containers,
closures and / or labels without batch- or product-specific information should be destroyed or
returned to controlled storage immediately following operations.
Repackaging / relabeling activities should follow the same principles outlined above.

8.5.1.8 Validation for production and GMP service provision
The excipient manufacturer should demonstrate consistent operations for the provision of
excipients and GMP services based on knowledge of operational parameters, requirements, andtheir inter-relationship.
The concept of validation is a key element in ensuring that processes are capable of consistently
producing an excipient that meets specifications. The excipient manufacturer may not perform
validation activities in the same manner or to the same extent as the pharmaceutical industry.
However, many activities leading to the same degree of assurance are performed within the
excipient industry.
Validation should be used:•

where testing alone may not be sufficient to reveal variations outside the process limits, or

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The excipient manufacturer should have a process for assessing and documenting the impact ofchange on the validated state of the system.
See also the IPEC Validation Guide.
8.5.2

Identification and traceability

Quality-critical materials and services, including GMP services, should be identifiable andtraceable through records to demonstrate conformance with the principles of this guide.

8.5.2.1 Traceability
Records should allow traceability of the service, including GMP services, or, for excipients, fromreceipt of raw materials through delivery to initial customers and vice versa.
Methods should be defined for traceability and identification of raw materials, equipment used in
excipient manufacturing, and GMP service provision to customers.
Even though one-to-one lot traceability is not possible with continuously supplied materials orbulk deliveries, traceability of use should still be documented in production records.

8.5.2.2 Inspection and test status
The inspection status of quality-critical materials and services, including GMP services, should be
identifiable. Methods for identifying test status should be defined.

8.5.2.3 Labels
Excipient container labels may be subject to regulatory and / or compendial requirements (see8.2.2).
Labels should include at a minimum:•

the names of the excipient (tradename and generic name(s)) and, if applicable, grade, ormaterial code which specifies the grade•

the excipient manufacturer’s and / or supplier’s name and address,•

the batch number from which the complete batch history can be determined,•

special storage conditions, if applicable.

Labeling for excipient packages is subject to national and international regulatory requirements,
which may include transportation and safety measures.

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8.5.3

Property belonging to customers or external providers

The excipient manufacturer should establish and maintain procedures for verification, storage andmaintenance of customer and externally-supplied materials intended for incorporation into thecustomer's excipient. Verification by the manufacturer does not relieve the customer or external
provider of the responsibility to provide acceptable material.
Material that is lost, damaged or is otherwise unsuitable for use should be recorded and reported
to the customer or external provider. In this case, procedures should be in place for acceptabledisposition and replacement of the material.
The manufacturer should also make provisions to protect other real and intellectual property thatis provided by the customer or external provider.
8.5.4

Preservation

8.5.4.1 Handling, storage, and preservation
Appropriate storage conditions should be maintained. If critical to maintaining the quality ofmaterials used in excipient production and packaging, storage conditions should be specified,monitored, and recorded. Deviations from specified storage conditions should be assessed (see8.7). Storage and handling procedures should be defined to:•protect containers, labels, closures, and security seals,•

minimize the risk of contamination, damage, or deterioration, and•prevent mix ups.

Bulk storage containers should be identified and labeled with their contents. Outdoor storage ofmaterials and excipients is acceptable provided the containers give suitable protection against
deterioration, contamination, and loss of traceability.
See also the IPEC Good Distribution Practices Guide.

8.5.4.2 Packaging
The selection of excipient packaging should be justified, documented, and include the following
features:•documented specifications, based on the excipient’s properties, including stability,•

packaging systems that provide adequate protection against deterioration, moisture uptake orcontamination of the excipient during transportation and recommended storage,•

packaging system components that do not interact with or contaminate the excipient,
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If containers are to be reused for the excipient, verified cleaning procedures should be followed
and should include instructions for removing previous labels. Records of cleaning should be
retained.
Excipient packaging should not be used to hold waste unless clearly labeled as waste.

8.5.4.3 Delivery and distribution
Excipients should only be supplied within their expiry date or reevaluation period and, whereapplicable, according to customer and / or regulatory requirements.
Distribution records of excipient shipments to initial customers should be kept. To facilitate
retrieval if necessary, distribution records should include:•

batch number,•customer name and address,•

quantity shipped,•

shipment date, and•where critical to maintaining excipient quality, conditions were met during transportation to theinitial customer.

Where applicable, excipient manufacturers should define and provide transportation conditions toservice providers and customers (see 8.6.8).
For bulk transport, verified cleaning procedures should be justified and applied. Records ofcleaning should be retained. A list of prohibited and / or allowed previous cargos should be
supplied to transportation companies.
See also the IPEC Good Distribution Practices Guide.
8.5.5

Post-delivery activities

The excipient manufacturer should determine and meet post-delivery activities, based on theintended use of the excipient, including:•informing customers of issues, including recalls and critical deviations detected after deliveryof the excipient (see 8.7.1 and 8.7.4), and significant changes (see 6.3),•

provision for country-specific legal and regulatory requirements,•

provision for a complaint handling process (see 8.7.3),
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provision for replies to enquiries and requests

8.5.6

Control of changes

For planning of changes, and changes to requirements for excipients and GMP services, see 6.3
and 8.2.4, respectively.

8.6

Release of excipients and GMP services

The excipient manufacturer should establish procedures and test methods to ensure excipientsand GMP services meet requirements and specifications prior to release. Details are provided in
sections 8.6.1 through 8.6.9.
8.6.1

Monitoring and measurement

Analytical procedures and test methods should be evaluated and verified to demonstrate they
provide reliable test results and are fit for purpose. These may be included in the current editionof the appropriate pharmacopoeia or another accepted standard, but the methods may also be
non-compendial. The responsibility for monitoring the current pharmacopeia or official
compendium should be assigned.
If the excipient is labeled with a compendial designation, then it must meet all requirements of thedesignated compendia.
Without the corresponding GMP, it is not acceptable to upgrade non-excipient grade materials
for excipient use based only on testing results.
Non-compendial, including in-house, analytical test methods should be demonstrated to be atleast equivalent to those in the compendia.
See also the IPEC Validation Guide for Pharmaceutical Excipients, 2.5 “Analytical Methods”.
8.6.2

Laboratory controls

Data integrity principles, i.e., ALCOA+, should be incorporated throughout laboratory procedures
and systems to always maintain data integrity (see 7.5.1).
The excipient manufacturer should establish laboratory controls, requiring complete data derived
from tests, necessary to ensure conformance with specifications and standards. Records (see7.5.3) of these controls should include:•

identification and traceability of samples, i.e., a description of the sample received for testing
together with:

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othe material name;obatch number or other distinctive code;oidentity of the person taking the sample (if applicable);odate the sample was taken;otime the sample was taken (where appropriate).

•

test method reference(s);•for each analysis, raw data required to confirm the test result, including sample preparation,
graphs, chromatograms, charts, and spectra from laboratory instrumentation, identifying thespecific material and batch tested;•

calculations performed;•

test results compared with specifications;•date and identity of the person who performed each test, including time (where appropriate);•the equipment, including ancillary equipment, used to perform the test when multiple
equipment options are available.

Laboratory reagents, solutions, and reference standards may be purchased or preparedinternally. There should be documented procedures for the labeling, handling, use, and storageof laboratory reagents, solutions, and reference standards. Procedures should also be available
for the preparation and standardization of internally prepared materials.
Purchased materials should be verified on receipt.
Purchased and internally prepared materials should be stored appropriately and labeled with thename, concentration, and expiry or re-evaluation date. Purchased materials, once opened, should
also be labelled with the remaining usage period.
Records for the preparation and standardization of reagents, solutions, and reference standards
should be maintained and include at a minimum:•

identity of the prepared material,•

identity, quantities, and batch numbers of components used in the preparation,•

name of preparer,•

equipment used for preparation,

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expiry or re-evaluation date of the prepared material.

When secondary reference standards are used, there should be a documented procedure for
their qualification against primary reference standards. This procedure should include
requirements for preparation, testing, approval, use, and storage.
Expiry or re-evaluation periods should be defined for secondary reference standards. For
secondary reference standards with re-evaluation periods, requalification should be performed
according to a documented procedure.
8.6.3

Finished excipient testing and release

Routine finished excipient testing should be performed on each batch to ensure that the excipient
conforms to documented specifications. Nonroutine testing should be scheduled and justified toconfirm the finished excipient complies with all specifications.
Results from in-process testing, process analytical technology (PAT), or from other processcontrol records may be used to demonstrate that the finished excipient conforms to documented
specifications.
The quality unit should be responsible for the release of the finished excipient. There should be aprocedure to ensure that appropriate manufacturing documentation, in addition to the test results,
is evaluated prior to release of the finished excipient. Excipient shipped to the customer prior toquality unit release should follow a documented quarantine-shipping process that includes
acknowledgement by the customer and any relevant authority.
8.6.4

Out-of-specification test results

Out-of-specification (OOS) test results should be investigated and documented according to a
written procedure (see 10.2).
Results obtained by retesting may only be used to replace original test results if a documented
investigation concludes that the original results are erroneous due to an assignable root cause.
When there is no assignable root cause, the OOS procedure should define:•criteria for retesting and the use of retest sample results,•

criteria for re-sampling,•which statistical techniques are to be used and under what circumstances.

Retesting may not be necessary when product is released under a different specification.
However, an OOS investigation should still be performed and documented.

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Original and retest data should be included in the investigation report, including when the sample
is suspected of not being representative of the material from which it was taken.
8.6.5

Retained samples

A representative sample of each batch of the excipient should be retained, unless otherwise
justified and documented. The retention period should be justified and based on the expiry or reevaluation date.
The retained samples should be stored in a secured location, readily retrievable and in conditions
consistent with the recommended storage conditions for the finished excipient.
Unless otherwise justified, retained samples should be maintained in a packaging format that isequivalent to or more protective than the commercial packaging system.
Unless otherwise justified and documented, the sample size should be at least twice the amountrequired to perform complete specification testing.
8.6.6

Certificates of analysis

Excipient manufacturers should provide certificates of analysis to the required specification foreach batch of excipient. See the IPEC Certificate of Analysis Guide for Pharmaceutical Excipientsfor details on the suitable contents of a certificate of analysis.
8.6.7

Impurities

Where possible, excipient manufacturers should identify impurities as part of the composition
profile. See also the IPEC Composition Guide.
Appropriate limits for impurities should be based upon safety data, limits as described in official
compendia, or other requirements and sound GMP considerations. Manufacturing processes
should be adequately controlled so that impurities do not exceed established limits.
Excipient manufacturers should conduct documented risk assessments to determine whether the
excipient specifications should include tests and limits for impurities. At a minimum,
microbiological bioburden and impurities from raw materials of natural origin should beconsidered.
In some manufacturing processes, insoluble and visible particles cannot be fully excluded. These
particles should not necessarily be considered impurities. However, the excipient manufacturer
should implement mitigation strategies based on a documented risk assessment to maintain theoccurrence of such particles at an acceptable level. See also the IPEC TUPP Guide for guidance
related to technically unavoidable particles.

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8.6.8

Stability

The stability of excipients is an important factor contributing to the overall safety, quality, andefficacy of the medicinal products in which they are used. Excipient manufacturers should
determine the stability of their excipients. They should also consider stability when defining
storage and transportation conditions.
See the IPEC Excipient Stability Program Guide.
8.6.9

Expiry date or re-evaluation period

Based on excipient stability, an expiry date or re-evaluation period should be assigned to each
excipient and communicated to the customer.

8.7

Control of nonconforming outputs

8.7.1

Control of nonconforming intermediates and finished excipientsIntermediates and finished excipients not meeting analytical specifications or other quality
indicators should be clearly identified and controlled to prevent inadvertent use or release for sale.
It is not acceptable to blend contaminated or adulterated batches to reduce the contamination or
adulteration below an acceptable or detectable limit (see 8.5.1.4).
Incidences of nonconformance should be investigated and addressed according to a documented
procedure in order to:•

identify the root cause(s),•assess the potential impact on other:•obatches;ointermediates, finished excipients and other product lines;oprocesses.

evaluate and determine the disposition of the nonconforming intermediate or finishedexcipient in one or more of the following ways:oreprocessing (see 8.7.1.1);oreworking (see 8.7.1.2);oauthorization for release by customer concession (see 8.2.1);ore-grading for use in other applications;

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o•disposal.

define and implement actions to prevent recurrence (see 6.1.2 and 10.2), as appropriate.

All activities of the above-mentioned investigation should be documented and records maintained.
The quality unit should review and approve the results of this investigation (see 5.3).

8.7.1.1 Reprocessing
Reprocessing should only occur when it has been assessed and documented that theintermediate or excipient may be made in this manner (see 8.5.1). Records of reprocessing should
be maintained (see 8.5.1.1 and 8.5.2.1).

8.7.1.2 Reworking
Reworking should only be conducted following a documented risk assessment and approval by
the quality unit. As appropriate, when performing the risk assessment, consideration should begiven to:•new impurities that may be introduced as a result of reworking;•additional testing to control the reworking;•records and traceability to the original batches;•suitable acceptance criteria for the reworked intermediate and / or finished excipient, including
equivalence to established specifications;•

impact on stability or the validity of the re-evaluation period;•

impact on performance of the intermediate and / or finished excipient;•additional controls needed to minimize the risk to excipient quality;•

customer notification.

The method of reworking should be documented and in compliance with the outputs of the risk
assessment. Records of reworking should be maintained.

8.7.1.3 Returned excipients
There should be a documented procedure detailing the process for handling returned excipientsfrom receipt through quarantine and final disposition.
The quality unit should approve disposition of the returned excipient (e.g., resale, re-grade,
reprocess, rework, or disposal).

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Returned excipients should only be considered for resale when the quality unit has evaluated andconfirmed that the excipient’s integrity and conformance to the required storage and / ortransportation conditions have been met for each package.
Excipient integrity factors include at a minimum:•

no evidence of tampering;•original packaging is not compromised;•remaining shelf life does not preclude resale.

Records of the quality unit’s confirmation should be maintained and include at a minimum:•

name of the excipient;•batch (lot) number;•reason for return;•quantity returned;•

identification of customer who returned the excipient;•

any evaluation that was performed;•

final disposition of the returned excipient.

8.7.2

Control of nonconforming GMP services

Incidences of nonconformance should be investigated and addressed according to a documented
procedure in order to:•

identify the root cause(s),•assess the potential impact on:obatches that are in scope of the nonconforming GMP service;oother GMP services that could be affected by the identified root cause(s).

•notify customer(s) (see 8.2.1),•

define and implement actions to prevent recurrence (see 6.1.2 and 10.2), as appropriate.

All activities of the above-mentioned investigation should be documented, and records
maintained. The quality unit should review and approve the results of this investigation (see 5.3).

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8.7.3Customer complaint handling

There should be a documented procedure for management of customer complaints within a timely
manner.
This procedure should include at a minimum:•

receiving and documenting the complaint;•

investigating the complaint;•

concluding and documenting the investigation, identifying:•oroot cause;owhether the complaint is justified;oimpact on other intermediates, finished excipients (see 8.7.1), or GMP services (see8.7.2);ocorrective and / or preventive actions as needed (see 10.2);

responding to the customer and, as appropriate, other interested parties (see 4.2).

Records of complaints, complaint investigations, and resulting actions should be maintained.
Complaints should be regularly evaluated for trends, including recurrence and criticality, in order
to identify needs for corrective or preventive actions.
8.7.4

Recall / Retrieval

There should be a documented procedure for effectively and promptly recalling from the market,
excipients known or suspected to be nonconforming (see 8.7.1). This procedure should include
at a minimum:•

how the recall of an excipient should be conducted;•

which interested parties require notification (see 4.2);•

how, through a mock recall, the effectiveness of this procedure is periodically evaluated;•

how reconciliation discrepancies are addressed.

Recalled excipients should be identified and quarantined until final disposition by the quality unit.
Records of recalls and mock recalls should be maintained.

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9Performance evaluation

9.1

Monitoring, measurement, analysis and evaluation

9.1.1

GeneralThe excipient manufacturer should identify, plan, and implement the monitoring and measurement
activities required to demonstrate conformity and effectiveness:•of the organization’s quality management system according to this guide;•

to applicable requirements (see 4.2).

Monitoring and measurement activities should be documented and consider:•what needs to be monitored and measured;•

what methods are needed to ensure valid results are obtained;•

when these activities should be performed;•

when results should be analyzed and evaluated.

9.1.2

Customer satisfaction

The excipient manufacturer should establish monitoring and measurement activities to assesscustomer satisfaction including the methods for obtaining, monitoring, and reviewing thisinformation. This information should drive activities to continuously improve customer satisfaction.
9.1.3

Analysis and evaluation

The excipient manufacturer should analyze results obtained from monitoring and measurement
activities (see 9.1.1) to evaluate:•

conformity of excipients and GMP services;•the degree of customer satisfaction (see 9.1.2);•

the performance and effectiveness of its quality management system;•

if planning has been implemented effectively;•

the effectiveness of actions taken to address risks and opportunities (see 6.1);•

the performance of external providers (see 8.4.3);•

the need or opportunity for improvements to the quality management system (see 10).

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9.2Internal audit

The excipient manufacturer should plan, establish, implement, and maintain an internal audit
program to:•consider whether its quality management system (see 4.4) conforms to the organization’s own
requirements, and to the GMP principles of this guide;•

confirm that the implementation and maintenance of the quality management system are
effective.

This program should be based on risk and carried out following documented procedures.
For internal audits, the procedures should:•

include the frequency, methods, responsibilities, planning requirements and reporting,considering the site’s activities, changes affecting the organization, and previous audit results;•

require the identification of audit criteria and scope;•

define auditor qualification requirements;•

require that auditors are selected to ensure objectivity and impartiality of the audit process;•describe requirements for audit documentation and reporting, including, at a minimum, report
distribution to relevant management;•

where nonconformity is identified, require timely identification of follow-up actions (see 10.2).

Records should be maintained as evidence of audit program implementation and audit results.

9.3Management review

9.3.1

GeneralTop management of the organization should review the quality management system at plannedintervals to verify the organization’s continued conformance to this guide.
The review should be documented and include a process for:•identifying opportunities for improvement;•

assessing the alignment with the excipient manufacturer’s strategic direction;•

identifying any need for changes to the quality management system (see 4.3);•

checking suitability of the quality policy (see 5.2).

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Records should be maintained as evidence of management review, including actions
recommended and taken.
9.3.2

Management review inputs

Management review should be carried out taking into consideration, at a minimum:•

status of action items from previous management review;•

changes in external and internal issues that are relevant to the quality management system(see 4.1);•

information on the performance and effectiveness of the quality management system,
including trends in:ocustomer satisfaction (see 9.1.2);ocustomer complaints (see 8.7.3);ofeedback from relevant interested parties (see 4.2);othe extent to which quality and GMP objectives have been met (see 6.2);

oprocess performance;oconformity of excipients and GMP services;ononconforming outputs (see 8.7) and resulting actions;ostatus of corrective and preventive actions;omonitoring and measurement results (see 9.1.3);ointernal and external audit results;operformance of external providers (see 8.4.3);•

adequacy of resources (see 7.1);•

effectiveness of actions taken to address risks and opportunities (see 6.1);•

opportunities for improvement (see 10).

9.3.3

Management review outputs

Management review outputs should include decisions and actions related to:•opportunities for improvement (see 10);

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any need for changes to the quality management system (see 4.3);•

any need to update the quality policy (see 5.2).

10 Improvement
10.1 General
The excipient manufacturer should select opportunities for improvement (see 9.3.3), and plan andimplement activities to improve:•

performance and effectiveness of the quality management system and its processes (see
4.4);

•

excipients and GMP services to enhance customer satisfaction, considering the potential
impact on patient safety.

Improvement activities should also include correction, prevention, or reduction of undesired
effects.
Any changes should be assessed and implemented following the change control procedure (6.3).

10.2 Nonconformity and corrective action
The excipient manufacturer should have a documented procedure to:•define the management of nonconformities, as applicable and commensurate with risk;•

control and correct nonconformities;•

address the consequences of nonconformities;•

investigate each nonconformity, determining:othe root cause(s),othe need for actions, including the prevention of recurrence of the same, similar, or
potentially similar nonconformities (see 10.3).

•

define actions as applicable, including responsibilities and timelines for implementation;•

evaluate and optimize the effectiveness of actions taken;

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7.1.4.4, 8.3.1, 8.6.7, and 8.7.1.2), if necessary;•

update the quality management system (see 4.4), if necessary;•record changes (see 6.3) resulting from actions, if necessary.

Records should be maintained as evidence of these activities.

10.3 Continual improvement
The excipient manufacturer should continually improve the quality management system and its
processes (see 4.4). Improvement activities should consider suitability, adequacy, andeffectiveness.
To identify opportunities for continual improvement of the quality management system, theexcipient manufacturer should consider results from analysis and evaluation (see 9.1.3) and theoutputs from management review (see 9.3.3).

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11 References
IPEC References:
IPEC Certificate of Analysis Guide for Pharmaceutical Excipients 2013
IPEC Composition Guide For Pharmaceutical Excipients 2020
IPEC Co-Processed Excipient Guide For Pharmaceutical Excipients 2017
IPEC Excipient Information Package User Guide and Templates 2020
IPEC Excipient Stability Program Guide 2010
IPEC General Glossary of Terms and Acronyms For Pharmaceutical Excipients 2021
IPEC GMP Certification Scheme and Certification Body Qualification Guide For Pharmaceutical
Excipients 2020
IPEC Good Distribution Practices Guide For Pharmaceutical Excipients 2017
IPEC Position Paper: Data Integrity for Pharmaceutical Grade Excipients 2020
IPEC Qualification of Excipients for Use in Pharmaceuticals Guide and Checklist 2020
IPEC Quality Agreement Guide and Template(s) For Pharmaceutical Excipients 2017
IPEC Risk Assessment Guide for Pharmaceutical Excipients, Part 1: Risk Assessment for
Excipient Manufacturers 2017
IPEC Significant Change Guide for Pharmaceutical Excipients 2014
IPEC Technically Unavoidable Particle Profile (TUPP) Guide 2015
IPEC Validation Guide For Pharmaceutical Excipients 2021

Other References:
EXCiPACT cGDP 2021 standard
EXCiPACT cGMP 2021 standard
EXCiPACT cGWP 2021 standard
ISO 9000:2015 Quality management systems – Fundamentals and vocabulary
ISO 9001:2015 Quality management systems — Requirements

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Excipients
WHO Guidelines for drinking-water quality 2022

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Part 2
IPEC-PQG GMP Guide + Notes

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ACKNOWLEDGEMENTS
This guide was developed by representatives from International Pharmaceutical Excipients
Council (IPEC) and the Pharmaceutical Quality Group (PQG) member companies.
IPEC is an industry association whose members consist of excipient manufacturers, distributors,
and users.
IPEC and PQG greatly appreciate the many hours devoted by the core team of individuals andother contributors listed below, to make this guide available to IPEC members and the broader
excipient community. Equally, IPEC and PQG extend their thanks to the employers of those same
contributors who provide the necessary time and resources, without which, this guide would not
be possible.
The company representatives who worked on this guide are listed below:

List of Contributors from IPEC-Americas
William Dale Carter*, Evonik
George Collins, Vanderbilt Chemicals LLC
Ann Gulau, IFF

List of Contributors from IPEC Europe
Jeffrey Brambora, Consultant
Roberto Mastrantonio, Eli Lilly
Astrid Stockrahm-Uhling*+, DFE Pharma
Beverley Stout, GSK

List of Contributors from PQG
Ian McKeown, PQ Silicas* co-chair+ task force team leader

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PART 2 - IPEC-PQG GMP GUIDE AND NOTES
1Introduction

1.1

Purpose and scope

Excipients are essential components of the medicinal product formulation. The quality of
excipients is critical to ensure the safety, quality, and efficacy of medicinal products, because
excipients provide a wide range of functionality.
Excipients can have multiple uses in medicinal products (see 4.1 Note 1). Therefore, it is essential
to apply principles of appropriate Good Manufacturing Practices (GMP) to excipients.
Additionally, excipient GMP provides the foundation for the understanding and implementation of
all IPEC guides.
Users of excipients are increasingly required by regulatory authorities to ensure patient safety
through the evaluation of risks and application of suitable GMP to the manufacture and supplyof each excipient.
Note:

EC document 2015/C 95/02 is one example regulation that requires users to perform
risk assessment of their excipient suppliers. PIC/S PI-045-1 provides guidelines for
implementation.

This document provides GMP appropriate to the manufacture of all excipients and to GMP
services provided by excipient manufacturers. It covers the quality management system,
including the GMP necessary throughout manufacturing, based on risk assessments, for both
batch and continuous processes.
It should be recognized that once the excipient is in the supply chain, it may be subjected tofurther GMP related activities, such as re-packaging or re-labeling, before it reaches the finaluser. Such activities should be performed in compliance with GMP principles as described in thisguide.
This guide is the result of a joint initiative between the International Pharmaceutical Excipients
Council (IPEC), and the Pharmaceutical Quality Group (PQG).

1.2

Principles adopted

1.2.1

The guide and its use

Excipients are diverse materials that often have uses other than pharmaceutical applications.
Therefore, each manufacturer should consider how this guide applies to their processes,
products, and GMP services (see 4.1).
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This revised guide incorporates the principles of risk assessment to identify the controls needed
for GMP according to the manufacturer’s intended use of the excipient. The need for risk
assessments is identified throughout this guide. This approach allows the guide to be used for all
excipients, including those that are supplied sterile and / or pyrogen free, and those intended forparenteral, ocular, inhalation, or open wound use.
For the purposes of this guide, the terms “Good Manufacturing Practices (GMP)” and “current
Good Manufacturing Practices (cGMP)” are equivalent.
The term “should” indicates recommendations that are expected to apply unless shown to beinapplicable or replaced by an alternative that provides at least an equivalent level of quality
assurance. Note that “should” does not mean “must” or “shall”.
1.2.2

Application

This international guide applies to all excipients and excipient-related GMP services. Therefore,
it cannot specify the manufacturing knowledge or competencies required, the national legal
requirements, or consider excipient characteristics (e.g., chemical, or physical properties) for
every excipient or GMP service. It is the responsibility of each excipient manufacturer to utilize
appropriate expertise when identifying and implementing applicable requirements (see 4.2).
1.2.3

Quality System standard

The quality management system standard chosen as a framework for this guide is ISO
9001:2015.
IPEC and PQG support merging GMP principles for excipient manufacturing with the ISO 9001
quality management system because these principles enhance the organization’s quality
management system, operational processes, and related procedures. The organization may alsoseek certification to an excipient GMP standard.

1.3

Layout and definitions

1.3.1

LayoutRevised in its entirety, this version of the guide, its headings and clause numbers have beendeveloped to align with ISO 9001:2015. Additional headings are included as required to introduce
the additional guidance on GMP when not covered by ISO 9001:2015 clauses.
This guide is published in two parts:•

Part 1 includes Good Manufacturing Practices for excipients.

•

Part 2 includes Good Manufacturing Practices for excipients together with notes that offer
examples for GMP interpretation and implementation without adding further requirements.

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oNotes are presented as indented, italicized text.

Each part of the guide has the following sections:
Section 1, Introduction
Section 2, General guidance, identifies the regulatory expectation of following excipient GMP.
Section 3, Excipient GMP implementation, provides an overview of the GMP criteria applicable toservices and excipient manufacture from the point where excipient GMP starts.
Sections 4 through 10 provide guidance on the GMP principles and implementation of a quality
management system suitable for excipient manufacture and service provision.
1.3.2

Definitions

ALCOA+:
The acronym ALCOA defines that data should be Attributable, Legible, Contemporaneous,
Original, and Accurate. In addition, ALCOA+ guidance defines that data should also be Complete,
Consistent, Enduring, and Available.
GMP Service:
GMP-related activities performed by an organization on behalf of their customer, where theorganization’s output is not the product (excipient) but either a tangible or intangible output of anactivity.
Note:

1. ISO 9001:2008 used the term “product” to include all output categories.
ISO 9001:2015 uses “products and services”. The specific inclusion of “services” inISO 9001:2015 and, therefore, this guide is intended to highlight the differences between
products and services in the application of some requirements. For example, conformity
to requirements cannot necessarily be confirmed before service delivery.
2. The organization may sell both GMP services and excipients. For example, an
excipient manufacturer may sell their excipient (product) but also manage theircustomer’s inventory to ensure a safety stock of the excipient is always available to thecustomer (an intangible GMP service).
3. Alternatively, an excipient manufacturer may only sell GMP services, tangible orintangible. For example:

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•a GMP contract manufacturer who does not sell the excipient that they produce but instead
sells their (intangible) manufacturing services (to custom-make the excipient) for theircustomer;•a contract testing lab sells the GMP service of testing excipients for their customers. The
certificate of analysis provided by the contract testing laboratory would be the tangible
output of the GMP service.

Manufacture/Manufacturing Process:All operations from receipt of materials through production, packaging, repackaging, labeling,
relabeling, quality control, release, storage and distribution of excipients and related controls.
Regulatory requirement:
ISO 9000 defines ”regulatory requirement” as “obligatory requirements specified by an authority
mandated by a legislative body”.
Note:

The USFDA is an example of an authority mandated by a legislative body, in this case,the US Congress.
Regulatory requirements specified by the USFDA are found in Title 21 of the US Codeof Federal Regulations (21 CFR).

Statutory requirement:
ISO 9000 defines ”statutory requirement” as “obligatory requirement specified by a legislativebody”.
Note:

The US Food Drug and Cosmetic Act is an example of an obligatory requirement
specified by a legislative body, in this case, the US Congress.

ISO 9000:2015:
ISO 9000:2015 specifies the terms and definitions that apply to all quality management and quality
management system standards (developed by ISO/TC 176). Reference to ISO 9000 is used in
Notes, when definitions are provided for generic terms, such as “nonconformity”. These definitions
are taken from ISO 9000, because they are not available in ISO 9001.

For further definitions refer to the International Pharmaceutical Excipient Council Glossary:
General Glossary of Terms and Acronyms. The first use of a term found in the Glossary will be inbold.

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2

General Guidance

Conforming with excipient GMP is a best practice that benefits excipient users and the patient.
Complying with excipient GMP is a regulatory expectation when statutory or regulatory
requirements exist either in the location of excipient manufacture or intended market.

3

Excipient GMP implementation

The objective of excipient GMP is to ensure that:•

excipients are consistently manufactured with the intended quality and performance
characteristics;•

GMP services lead to consistent results.

The excipient manufacturer should design, control, document, and maintain its manufacturing
processes. Justification is required to determine the point at which excipient GMP should beapplied. This justification should be based on thorough process knowledge and recorded in adocumented risk assessment. GMP usually begins well before the final finishing operation.

Note:

1.

Examples of methods for identifying when excipient GMP should begin include:•

HACCP (Hazard Analysis and Critical Control Point);•

FMEA (Failure Mode and Effects Analysis).

2.

Examples of documenting where excipient GMP begins include:•

risk assessment;•

process flow diagram.

Implementation of excipient GMP should also consider at a minimum:•batch versus continuous processing;•

dedicated versus multi-purpose equipment;•

open versus closed processes.

Throughout this guide, the use of “GMP” will mean “excipient GMP” as outlined in this document.

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4Context of the organization

In a GMP context, the excipient manufacturer is the organization. The two terms are usedinterchangeably throughout this guide.
Note:

ISO 9000 defines the organization as “person or group of people that has its ownfunctions with responsibilities, authorities and relationships to achieve its objectives”.
The organization can include one or more manufacturing site(s), and outside support
references (e.g., company headquarters, regional testing facilities, centralized humanresources, etc.).

4.1

Understanding the organization and its context

Manufacturers should identify, within their portfolio, those products manufactured and marketed
as excipients. Excipient manufacturers should define and document the intended use(s) of their
excipients, considering the potential impact on patient safety. They should determine and monitor
external and internal issues that are relevant to the manufacture and marketing of excipients.
These should include outsourced activities that can affect excipient quality and for which theorganization has control and responsibility.
Note:

1.

Examples for intended use of excipients include:•

function (e.g., pH adjuster, color, flavor, binder, disintegrant);•

dosage form (e.g., tablets, capsules, liquids, aerosols, patch, cream);•route of administration (e.g., parenteral, topical, oral);•grade (suitable for use in e.g., food or medicinal products).

2.

Examples of how the intended use of excipients relates to patient safety include:•

particle size may impact controlled release in the medicinal product;•

excipient bioburden and the route of administration;•colors used in coatings for tablet identification.

For guidance on information needed to support marketing a material for use as anexcipient, refer to the International Pharmaceutical Excipients Council Guide for
Qualification of Excipients for Use in Pharmaceuticals.
3.
Examples of external issues affecting the manufacture and marketing of excipients
include changes to:•regulations;

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requirements for composition / specification;•

import / export / transportation requirements.

4.

Examples of internal issues include:•

succession planning to ensure knowledge is maintained;•changes in organizational structure (e.g., access to expertise and responsibility formonitoring external issues);•changes in operational strategy (e.g., outsourcing, insourcing);•changes to and use of infrastructure (see 7.1.3 for more information on
infrastructure).

Excipient manufacturers should identify the quality management system processes required toassure excipient quality, accounting for customer, social, legal, technological, and culturalenvironments.
Note:

Examples of environmental aspects include:•••

customer aspects such as:ospecifications compliant to multiple compendia;ocustomer-specific requirements.

social aspects such as:oregional differences in animal welfare concerns may result in different pest
control practices;odifferences in privacy concerns may have legal consequences and could limit
availability of records during audits (e.g., health records, training records).

legal aspects such as:oregulations applicable to excipients;onon-permitted ingredients, e.g., GMO;oconfidential Disclosure Agreement;ocontractual Agreements (e.g., Supply Agreement, Quality Agreement);

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•

•

4.2

o

privacy protection, such as reporting names of personnel on COAs, external
review (e.g., customer audits) of individual job descriptions and training
records, use of biometrics (e.g., fingerprint, retina scan);ouse of employee background checks or monitoring cameras.

technological aspects such as:ocontingency plans for failure of automation / computer systems;oEnterprise Resource Planning - software, use of smart packaging (to control /monitor storage conditions or shelf life), electronic record keeping andelectronic signature software;oelectronic data integrity and storage;oupdates and improvements to equipment.

cultural aspects such as:oreligious purity laws, e.g., Kosher, Halal:oethical sourcing, e.g., conflict minerals, child labor;oconsumer preferences, e.g., animal versus plant sourcing.

Understanding the needs and expectations of interested parties

The excipient manufacturer should determine the interested parties that are relevant to the GMP
quality system being maintained. Current applicable customer, compendial, statutory, andregulatory requirements should be determined and met (see 6.1.1).
Note:

Examples of interested parties include:••internal:opersonnel (permanent
management;oother departments in the organization (e.g., quality assurance, regulatory
affairs, sales, marketing).

andtemporary;internal

andexternal),

top

external:opatients;ocustomers;ocompetitors, e.g., market intelligence;

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oregulatory authorities, e.g., health, compendial, supervising / notified bodies,safety, environmental, transportation;osuppliers, consultants, contractors, and service providers (pest control, QC
lab, calibration, warehousing, tolling, contract manufacturer, freight
forwarders, transport companies).

The excipient manufacturer should monitor information about interested parties and their relevant
requirements (see 4.3, 5.3 and 6.1.1).
Note:

4.3

Examples of where monitoring information could be found include:•

management review inputs including results from internal and external audits;•

incident reports and trends;•

relevant industry journals and trade shows;•trade association and regulatory websites;•

regulatory updates and newsletters;•

information requests from interested parties;•

agreed customer requirements (e.g., as defined in Quality / Supply Agreements).

Determining the scope of the Quality Management System

The organization’s overall intentions and approach to GMP should be documented to facilitatecommon understanding and consistent application. The excipient manufacturer should have:•a documented description of the quality management system;•

a quality policy (see 5.2);•

commitment to apply the appropriate quality management principles contained in this guide,
including GMP.

The documented description of the quality management system should include the scope of thequality management system and reference to supporting procedures, considering:•boundaries and applicability of GMP;•

products and GMP services in scope;•external and internal issues (see 4.1);

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the interaction between quality management system processes (see 4.4).

Documentation should identify and justify the starting point in the process (manufacturing orservice provision) from which the full excipient GMP principles of this guide apply.
Note:

1.
Examples for documented description of the quality management system include
Quality Manual, procedures, work instructions.
2.
Examples for commitment of the organization to applying the appropriate GMP
include participation in IPEC, tracking quality metrics, GMP certification, presentations,and posters.

4.4

3.

How to determine boundaries and applicability of GMP?

•

Starting from the specification of raw materials, the excipient manufacturer applies
a justified level of GMP to each operational step to ensure excipient quality.

•

Define at what point industrial production is diverted to excipient or other markets(e.g., food, cosmetic).

•

Initial manufacturing steps may not require full excipient GMP.

•

A risk assessment (e.g., HACCP, FMEA) may help identify the point from which
GMP will be applied.

Quality Management System and its processes

Excipient manufacturers should define, implement, maintain, and continually improve the quality
management system and its processes. These processes and their interactions should be
documented.

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Note:An example of the interaction between quality management processes is illustrated in
the following diagram:This documentation should include:•

inputs required and outputs expected from these processes;•

process sequence and interaction;•

criteria and methods needed to ensure the effective operation and control of these processes;•

resources needed for these processes and ensure their availability;•

responsibilities and authorities for these processes;•

risks and opportunities as determined in accordance with the requirements of 6.1 and how
they are addressed;•

evaluation of processes and implementation of any changes needed to ensure that theseprocesses achieve their intended results;•

evaluation of risk assessments and improvements to the quality management system (see10.1).

Records should be maintained to demonstrate achievement of the required quality and theeffective operation of the quality management system.

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Where manufacturing, testing or other operations that could affect excipient quality areoutsourced (i.e., externally provided), the responsibility for quality remains with the excipient
manufacturer and control measures should be defined. The organization should define which
records, results and reports of subcontractor activities are retained and by whom.
Note:

See 8.4 for more information about “Control of externally provided quality-criticalprocesses, materials and services”.

5

Leadership5.1

Leadership and commitment

5.1.1

GeneralTop management should be identified.
Top management should demonstrate their commitment to the quality management system andbe accountable for its maintenance and effectiveness. This should be accomplished through thedevelopment of a quality policy (see 5.2.1) and establishment of quality and GMP objectives (see6.2). Current applicable customer, compendial, statutory, and regulatory requirements should bedetermined and met.
Top management should promote risk-based thinking (see 6.1).
Top management should provide adequate resources to ensure conformance to the principles ofthis guide. There should be a process for the identification of resources needed for adherence to
GMP.
Note:

See 7.1 for more information about resources.

Top management should ensure that the quality policy, the quality and GMP objectives, and thedefinition of roles, responsibilities and authorities are communicated, understood, and applied
across the organization. They should ensure that the quality management system achieves its
intended result and should promote continual improvement (see 10.3). Progress towards the
documented quality and GMP objectives should be reviewed at planned intervals.
Note:

1.

Examples of communication tools include:•

posters, bulletin boards, monthly reports, email messages, intranet postings;•

reports from management review meetings;•

training and availability of quality policy, organization charts and job descriptions.

2.

Examples for review at planned intervals include:

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5.1.2•

management reviews, monthly team meetings;•

depending on the size of the organization, corporate reviews, not necessarily
limited to the local level.

Customer focus

Top management should ensure that customer requirements related to GMP and other related
matters are determined, understood, agreed with the customer and met.
The excipient manufacturer should be able to demonstrate to the customer the effectiveness of
their quality management system. This may be by audit, third party certification, or other means.
Note:

1.

Examples for determining and understanding customer requirements include:•

review of intended uses;•

sharing of product application information;•

supplying information for regulatory filings.

2.

Examples of other related matters include:•

logistical requirements and details (e.g., delivery times, pallet height);•

correct tools (e.g., hoses, couplings) for unloading bulk tanker deliveries.

3.
Examples of other means to demonstrate to the customer the quality management
system’s effectiveness include:•

virtual meetings (teleconference or videoconference), filming;•

completing written questionnaires;•provision of certification of conformance to other GMP, e.g., food;•on site meetings (F2F) with business, technical or development functions.

5.2

Quality policy

5.2.1

Establishing the quality policy

Top management should participate in and provide the resources necessary for the development,
implementation, and maintenance of the organization’s quality policy. The quality policy should
include commitment to appropriate GMP, compliance with applicable requirements and continual
improvement of the quality management system.
Note:

Frequently asked questions to consider with regards to the quality policy include:

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5.2.2•Is the quality policy a controlled document?

•

Is it reviewed at an adequate frequency to ensure the policy remains appropriate
to the purpose and context of the organization?

•

Who reviews the established policy?

•

How is it communicated internally and to interested parties?

Communicating the quality policy

Top management should demonstrate its commitment to the quality policy and appropriate GMP,and ensure that this is communicated and implemented within the organization.
Note:

5.3

1.

Examples for demonstration of top management’s commitment include:•

signing the quality policy;•

attending annual review meetings;•

providing resources for voluntary certification to a GMP standard.

2.

Examples for communicating the quality policy and appropriate GMP include:•

facility posters;•

confirmation that the policy has been read and understood by all employees;•

distribution of quality reports and results of annual reviews.

Organizational roles, responsibilities, and authorities

Top management should ensure that responsibility and authority are clearly defined,
communicated, and understood within the organization.
Note:

Job descriptions, organization charts and training, may be used to communicate
organizational roles, responsibilities, and authorities.

Top management should assign the responsibility and authority for:•ensuring that the quality management system conforms to the provisions of this guide;•

ensuring that the processes are delivering their intended outputs;•

reporting to top management on the performance of the quality management system,
opportunities for improvement (see 9.3.2) and changes to applicable customer, compendial,
statutory and regulatory requirements (see 4.2);•

ensuring the promotion of customer focus throughout the organization;

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ensuring that the integrity of the quality management system is maintained when changes tothe quality management system are planned and implemented.

Top management should ensure that a quality unit or other appropriate unit, independent of
production, has the responsibility and authority to:•ensure quality-critical activities are identified and undertaken as defined;•

review and approve documents that have the potential to impact product quality;•

approve external providers (suppliers) of quality-critical processes, services and materials;•

ensure that providers of outsourced processes and services comply with the relevant sectionsof this guide (see 8.4);•

approve or reject raw materials, packaging components, intermediates and finishedexcipients, according to current approved specifications and procedures;•

approve or reject the excipient if it is produced, processed, packaged or held under contractby another company;•

ensure that there is a review of production records prior to excipient release;•

ensure that where errors, deviations, or nonconformities have occurred or are identified in thereview process, they are appropriately investigated and documented;•

ensure corrective and preventative actions are implemented and effective;•

participate in reviewing and authorizing significant changes that have the potential to impact
quality (see 8.5.6);•

review and approve the results of investigations into deviations from production instructions,test or measurement failures, customer complaints, or other nonconformities;•

develop and implement an internal audit program of the quality management system.

Note:

Examples for other appropriate unit, independent of production include:•

regulatory group;•

technical service;•product development (R&D).

Some of the quality unit’s activities may be delegated if appropriate controls are in place anddocumented. However, in all cases the quality unit should be responsible for performing:

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approval of significant changes that may impact excipient or GMP service quality;•

approval of quality-critical suppliers;•

release of the finished excipient;•release of GMP services;•

approval of reworking;•evaluating and determining the disposition of returned excipients, including recalled
excipients.

For all of the quality unit’s activities listed in this section, whether performed by the quality unit oranother appropriate unit, records should be available to demonstrate review and approval /rejection. Although quality unit activities may be delegated, the quality unit is ultimately
responsible for the final output and should approve the controls used by any other unit to performthe delegated activity.
Note:

1.

Examples of activities that may be delegated include:•complaint investigations;•approval of incoming raw materials and / or packaging components based on
written procedures approved by the quality unit;•

review of pest control reports and responding to actions.

2.

Examples of controls for delegated responsibilities include:•

design and / or approval of the delegated process, including corresponding
records;•

clear definition of when to notify the quality unit (i.e., well-defined boundaries of thedelegated responsibility);•

periodic review of delegated responsibility (e.g., by internal audit);•

individuals performing the delegated activity are trained, and qualified by the qualityunit.

An organizational chart by function should show inter-departmental relationships as well as
relationships to top management. Personnel who have an impact on excipient quality should havejob descriptions (see 7.2).

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Note:

1. An organizational chart may be embedded into the information technology (IT)systems in use in the company rather than exist as a record.
2. Details in an organization chart may include:•

all functions on site with site manager as “top management”;•

all functions on site and remote functions to the business organization with, e.g.,
CEO as “top management”;•

separation of the quality unit from production unit;•

reporting relationships between departments indicating direct and indirect reporting(e.g., using bold or dotted lines).

6

Planning

6.1

Actions to address risks and opportunities in the Quality Management System

6.1.1

Risk Assessment

The excipient manufacturer should conduct risk assessments of the issues referred to in 4.1 andthe requirements referred to in 4.2 to determine the risks and opportunities that need to beaddressed to:•give assurance that the quality management system can achieve its intended result(s);•enhance desirable effects;•

prevent, or minimize, undesirable effects;•

achieve continual improvement.

See also “The IPEC Risk Assessment Guide for Pharmaceutical Excipients”.
Note:

1. Examples to achieve intended results include:•complying with IPEC PQG GMP;•

developing and achieving quality objectives.

2. Examples of desirable effects include:•

customer satisfaction;•satisfactory regulatory inspections and customer audits;•

minimal quality issues (OOS, complaints, rejected batches);

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processes.

3. Examples of undesirable effects include:•

regulatory sanctions and legal ramifications;•customer complaints, returns, retrieval / recalls;•

loss of current or future business;•increased waste and / or environmental impact;•

loss of reputation or shareholder value;•loss of ability to supply customer;•

failures to make excipients or provide GMP services to the defined process;•deviations.

6.1.2

Preventive action and continual improvement

Note:

What is a preventive action?
ISO 9000 defines “preventive action” as “action to eliminate the cause of a potential
nonconformity or other potential undesirable situation.” ISO 9000 goes on to explain thata “preventive action is taken to prevent occurrence whereas corrective action is taken toprevent recurrence.”

The excipient manufacturer should plan actions to address risks and opportunities in the quality
management system (see 6.1.1), by:•initiating preventive actions including assignment of responsibilities and timelines for
implementation, to deal with problems at a level corresponding to the risks;•

initiating actions to enhance desirable effects or remove barriers to improvement;•

ensuring that actions are implemented and effective;•

implementing and recording changes in processes or procedures resulting from actions.

Note:

1. Examples of preventive action include developing, verifying, and maintaining:•production and supply contingency plans;•disaster recovery plan;

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•business continuity plans.

2. Examples of actions to enhance desirable effects include:

6.2•

enhancing security of supply;•

making processes more sustainable, efficient, and reliable;•

expanding markets, and developing new and improving existing products for new
applications;•creating a quality culture where all personnel can make suggestions to improve
GMP efficiency and performance.

Quality and GMP objectives and planning to achieve them

Top management should set appropriate quality and GMP objectives to ensure that the excipient
manufacturer maintains and improves its performance. These objectives should be:•consistent with the quality policy;•

measurable;•monitored;•

communicated;•documented;•

updated as appropriate.

Note:

Examples for objectives include:•

reduction in number of manufacturing deviations or out-of-specification test results;•

improvement in right-first-time product quality;•

favorable customer audit findings and customer ratings;•

compliance with additional compendia;•

upgrades in facilities / systems to support use in expanded markets.

When planning to meet these objectives, the excipient manufacturer should determine:•

what will be done;•

who will be responsible;•

what additional resources will be required;
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how results will be evaluated.

6.3

Planning of changes

The excipient manufacturer should establish and maintain documented procedures to evaluate
and approve changes that may have an impact on the excipient or GMP service.
Prior to implementation, evaluation and approval of changes should be documented (see 7.5)
and, where appropriate, a formal risk assessment conducted. Consideration should include
potential impact on validation (see 8.5.1.8) or regulatory submissions made by the excipient
supplier. Procedures should describe the means by which a change is determined to besignificant. Where the impact is determined to be significant, such changes should becommunicated to customers and, as applicable, to regulatory authorities. See also “The IPEC
Significant Change Guide for Pharmaceutical Excipients”.

7

Support7.1

Resources

7.1.1

GeneralThe organization should, in a manner consistent with this guide, determine and provide adequate
resources to:•implement, maintain and improve the quality management system;•

produce, package, test, store and release each excipient;•supply each GMP service.

Note:

Recurring GMP and / or quality deficiencies may indicate a lack of adequate resources.

7.1.2

PeopleThe organization should determine and provide adequate numbers of qualified personnel.
Note:

No single formula can accurately determine the adequate number of personnel for all
excipient manufactures. Examples of how to determine the number of qualified personnel
necessary include:•

resource mapping;•work studies of output versus time;

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•
7.1.3

management system reviews
nonconformances, etc.).

(inputfrominternal/

external

audits,Infrastructure

The infrastructure should be designed, managed, operated, cleaned, and maintained inaccordance with GMP principles to ensure excipient quality as well as to minimize the risk ofcontamination, including cross-contamination. It should be designed and controlled to prevent
unauthorized access.
An infrastructure risk assessment should be documented (see 7.1.3.1 - 7.1.3.5), based on theintended use of the excipient, to identify areas in which the excipient is at risk of contaminationfrom infrastructure design and / or deficiencies. See also “The IPEC Risk Assessment Guide for
Pharmaceutical Excipients”.
Note:

Risks associated with deficiencies inherent to the design and location of the facility may
be mitigated using additional controls from the risk assessments described in thefollowing sub-sections.

7.1.3.1 Buildings and facilities
The ability to clean and minimize the risk of contamination (including pest infestation (see 7.1.4.4)
and cross-contamination) should be considered in the design of the manufacturing processes andfacilities, particularly where the excipient is exposed to the environment.
Note:

1. Examples of how to minimize the risk of contamination and cross-contamination
include:•allowing adequate space for activities, including:ocontrolled areas for sampling or dispensing of raw materials, intermediates
and final product;oability to access equipment that needs cleaning or maintenance;oability to separate processing of different materials.

•

use of dedicated pipelines;•

pipelines and tanks from which the previous material can effectively be removed.

2. Examples of where the excipient is exposed to the environment include:•

manual additions of raw materials, including seed crystals, to production
equipment;•

open transport of materials (e.g., on a conveyer belt);

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•packaging or repackaging operations, especially those that take place outdoors.

To facilitate cleaning, maintenance, and correct operation appropriate to the type of processing,buildings and facilities used in the supply of GMP services or the production, processing,packaging, testing or storage of an excipient should be:•

appropriate for their purpose,•

maintained in a good state of repair, and•of suitable size, construction, and location.

Manufacturing processes using allergens, highly sensitizing or toxic materials should be locatedin dedicated facilities and / or use equipment not used for excipient manufacture. In somejurisdictions this is a regulatory requirement. If allowed by regulation and when non-dedicatedfacilities or equipment are used, appropriate measures, resulting from a specific risk assessment,
should be implemented to minimize the risk of cross-contamination. The effectiveness of thesemeasures should be demonstrated.
Note:

1. Examples for toxic materials include: pesticides, carcinogens.
2. Examples for highly sensitizing materials include: antibiotics, hormones.
3. Cleaning and inactivation are examples of appropriate measures that minimize therisk of cross-contamination, when it is not possible to locate highly sensitizing or toxic
materials in dedicated facilities or to use separate equipment.
4. To demonstrate effectiveness of these measures, the following could be documented:

7.1.3.2•

segregation;•

studies of cleaning effectiveness and repeatability;•

environmental monitoring;•monitoring of cleaning effectiveness.
Equipment

To facilitate cleaning, maintenance, and correct operation for the type of processing, equipmentused in the supply of GMP services or the production, processing, transfer, packaging, testing or
storage of an excipient should be:•

appropriate for its purpose,•

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Consideration of the risk of breakage or damage should be given.
Note:

1. Examples of equipment used for transfer include pipelines, hoses, hoppers,
intermediate storage containers and utensils such as scoops.
2.
Examples of how the type of processing could affect size, construction and locationof equipment include:•

batch processing equipment may need to be designed to allow for more frequentcleaning or maintenance versus equipment used in continuous processing;•equipment which must be opened for charging may be inappropriate for outdoor
use;•

for handling materials requiring low bioburden, the need for different surface
finishes, materials of construction, types of welds, etc.

3.

Examples of where breakage or damage may occur, include:•

glass equipment, e.g., glass-lined reactors, vessels or tanks, sight glasses (alsocalled viewing ports), in-line probes e.g., pH or temperature;•

metal sieves, milling equipment and moving parts;•

filters, gaskets, seals.

Equipment should be qualified and commissioned before use to ensure that it is functioning as
intended. See also “The IPEC Validation Guide for Pharmaceutical Excipients”.
The use, cleaning and maintenance of quality-critical equipment should be recorded (see 8.5.1.1).
The status of equipment should be readily identifiable.
Note:

Examples of readily identifying the status of equipment include labels, calibration statussticker, equipment power lock, equipment use log, etc.

Where equipment is located outdoors there should be suitable controls to minimize the risk to
excipient quality from the environment.
Note:

Examples of how to minimize the risk to excipient quality where equipment is locatedoutdoors include:•

processing within a closed system;•

use of temporary enclosures when equipment must be opened;•

use of inline samplers to avoid opening equipment.

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Equipment construction:
Process equipment should be constructed so that contact surfaces will not be reactive, additive,
or absorptive and thus not alter the quality of the excipient. Substances required for operation,such as lubricants or coolants, should not come into contact with raw materials, packaging
materials, intermediates or finished excipients. Where contact with such substances is possible,
substances at least suitable for use in food applications should be utilized.
Equipment should be designed to minimize the possibility of contamination caused by direct
personnel contact. The sanitary design of transfer and processing equipment should be evaluatedusing a risk assessment.
Note:

Examples of direct personnel contact include:•

open unloading of centrifuges;•

manual sampling from open equipment;•

open operating and maintaining of equipment.

Equipment and its components should be assessed regarding their potential for erosion anddegradation to control the risk of contamination, including cross-contamination.
Note:

Examples of equipment and components with potential for erosion or degradation
include:•lubricants, coolants;•

filter screens;•ball bearings.

Equipment maintenance:
Documented procedures should be established and followed for maintenance of quality-criticalequipment used in the production, processing, packaging, testing, or holding of excipients. There
should be records of the use and maintenance of quality-critical equipment.
Note:

These records can be in the form of a paper log, computer database (e.g., maintenancesoftware) or other appropriate documentation. See 7.5.

Computer systems:
Computer systems (i.e., software, hardware, data) that may impact excipient quality should havesufficient controls for operation and maintenance to ensure that the system is performing as
intended, including:•

procedures for periodic system verification;
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•back-up or archiving (see 7.5.1);•

preventing unauthorized access;•assurance that changes are traceable, verified, documented, and only made by authorized
personnel (see 6.3 and 7.5).

See also “The IPEC Validation Guide for Pharmaceutical Excipients”.
Records demonstrating proper performance of the computer systems should be maintained.

7.1.3.3

Utilities

A risk assessment should be performed to consider the risk to excipient quality from utilities usedin the production, storage, or transfer of materials. Appropriate action should be taken to eliminate
or, at a minimum, control the identified risks. Utilities that could impact excipient quality shouldhave documented specifications and be of suitable quality for their intended use. Quality criticalparameters of these specifications should be monitored at a documented frequency (see 8.5.1).
Note:

1. Examples of utilities include steam, water, process air, and compressed gasses.
2. Examples of how improperly controlled utilities could pose a risk to excipient quality
include:•Incorrect air pressure might change a powder’s particle size,•

Introducing contaminants, e.g., moisture, microorganisms, oil, particles.

3. More guidance on water is given in 7.1.3.4.
4. Environmental air handling is not a utility. Section 7.1.4.1 provides relevant
requirements for environmental air handling.

7.1.3.4

Water

A risk assessment should be performed to consider the risk to excipient quality from water usedin the manufacture of excipients. Appropriate action should be taken to eliminate or, at a minimum,
control the identified risks. Water that could impact excipient quality, regardless of its source,
should have documented specifications and be of suitable quality for its intended use. Quality
critical parameters of these specifications should be monitored at a documented frequency (see8.5.1).
Note:

1. Examples of water used in the manufacture of excipients include:

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steam / water used for heating or cooling that has potential for product contact;•water used to flush a line after material transfer;•steam / water used for cleaning.

2. Examples of water sources include:
•

well;

•

municipality;•

condensate;•

recycled.

3. Based on the risk assessment, monitoring activities could include:•

continuous monitoring (inline);•

periodic sampling at appropriate intervals and locations;•periodically receiving documentation attesting to potable water quality from thewater treatment facility.

Unless otherwise justified, water used in the manufacture of excipients should, at a minimum,
meet WHO guidelines for drinking (potable) water. When drinking water quality is insufficient toensure excipient quality, appropriate chemical and / or microbiological water quality limits should
be defined.
Note:

How might a manufacturer determine the quality of water needed?
•

Some process steps (e.g., washing of raw or intermediate materials) may not
require WHO quality water if further purification steps take place later in the
manufacturing process.

•Drinking water quality may not be sufficient based on the manufacturing process(e.g., reaction or sanitization) or customer requirements (e.g., intended use of theexcipient).

•

Where water is used to wash the final excipient, WHO quality water (or higher) may
be necessary, because there is no further purification.

Where water used in the process is treated by the manufacturer to achieve a defined quality, thetreatment process should be specified and monitored with appropriate action limits.

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If interruptions in supply or deviations in the quality of water occur, return to service should not
happen until it is confirmed that water quality has been restored. Appropriate evidence andrationale should be documented to show that interruptions have not compromised the quality ofthe excipient.
Note:

Examples of interruptions include:

7.1.3.5•

planned or unplanned stoppage of the water flow;•

loss of ability to monitor or maintain specified water quality.
Recycled or recovered materials

The use of recycled or recovered materials containing recoverable amounts of excipient,
reactants or intermediates should be justified. Where materials are recovered and reused in thesame process or different processes, they should meet appropriate specifications prior to reuseor mixing with other approved material.
Activities to recycle or recover materials should be documented in production records or logs toenable traceability (see 8.5.2).
7.1.4

Environment for the operation of processes

Where the excipient is exposed during manufacture it should be in an appropriately controlledenvironment to minimize the risk of degradation and contamination, including crosscontamination.
Note: For examples of potential excipient exposure to the environment refer to first “Note 2” in
7.1.3.1.
A documented assessment should be carried out to identify the related risks and to determine thenecessary controls. The following should be considered, as applicable:•

air handling systems, see 7.1.4.1;•

need for specific environments (controlled environments), see 7.1.4.2;•

cleanliness and sanitary conditions, see 7.1.4.3;•

pest control, see 7.1.4.4;•

personnel hygiene, see 7.1.4.5;•

material (including waste) segregation, see 7.1.4.8;
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other potential sources of contamination, including cross-contamination.

Special consideration should be taken in multi-use areas, where several products are processed
simultaneously.
Where maintaining the work environment is critical to excipient quality, the controls should be
documented and, as appropriate, monitored.

7.1.4.1

Environmental air handling

Where the documented risk assessment has identified risks associated with air handling, thesystem should be designed and controlled to minimize the risk of degradation, contamination, andcross-contamination of the excipient.
The effectiveness of the air handling system should be demonstrated.
Note:

1. Process air is a utility, see 7.1.3.3.
2. Environmental air handling describes the management of ambient air to be acceptablefor excipient exposure, e.g., heating / cooling / recirculation or isolation of room / facility
air.
3. Inadequate or malfunctioning air handling systems could cause degradation orcontamination of the excipient by, for example, introduction of:•moisture;•

microorganisms;•

foreign materials,•

industrial / agricultural emissions.

4. Means of demonstrating effectiveness of the air handling system could be describedin a procedure and may include:

7.1.4.2•

regular checks of the air pressure differential;•

reviewing trend data (e.g., continuous dew point monitoring);•

inspection of filters.
Controlled environment

Where the documented risk assessment has identified the need for a controlled environment, it
should be monitored and controlled to assure excipient quality.

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Note:

Examples of controlled environments include:•

protection from light;•

humidity control;•

inert atmosphere;•

temperature control;•

classified areas.

Such controlled environments should be designed to minimize the risk of contamination, including
cross-contamination, or degradation of the excipient. The degree of protection required may varydepending on the stage of the process.
Where the documented risk assessment has identified the need for an inert atmosphere, theinerting gas should be treated as a raw material.
Note:

When the gas is manufactured on site, it is a utility (see 7.1.3.3). When the gas ispurchased, it is an externally-provided quality-critical material (see 8.4).

If interruptions to the controlled environment occur, sufficient evidence and appropriate rationale
should be documented to show that such interruptions have not compromised the quality of theexcipient.
Note:

7.1.4.3

Examples for interruptions to the controlled environment include:•

opening of lines or tanks for maintenance that interrupt the flow of inert gas;•

power outages that interrupt monitoring or control activities;•

filter breach.
Clean and sanitary conditions

Buildings used in the production, processing, packaging, or holding of an excipient should bemaintained in an appropriately clean and sanitary condition.
Note:

Cleaning / sanitizing in this context refers to buildings and facilities. Cleaning / sanitizingof equipment is discussed in 8.5.1.2.

Where the documented risk assessment has identified the need for clean / sanitary conditions,documented procedures should be in place according to the type of processing conducted:•

assigning responsibility for cleaning / sanitizing;

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describing in sufficient detail the schedules, methods, equipment, and materials to be used incleaning / sanitizing the buildings and facilities.

Note:

Examples of different types of processing include open system versus closed system,
continuous production versus batch production, and dedicated equipment versus multipurpose equipment.

These activities should be documented (see 7.5.1).
Where disinfectants and / or detergents are used, a documented risk assessment should
demonstrate their suitability. The quality unit should approve the use of quality-critical cleaningand sanitizing agents.
Note:

7.1.4.4

Examples of what to consider for suitability include:•

intended use as determined by the manufacturer, for example: “technical grade”
may not be appropriate for use in an excipient manufacturing facility;•

effective for their intended use;•

evaluate if odors or residues may adversely affect packaging material or the
excipient (e.g., chemical composition, stability);•

other requirements, such as Halal or Kosher.
Pest control

A documented risk assessment should be carried out by an internal or external pest control
specialist. This risk assessment should consider the potential for infestation by rodents, birds,
flying and crawling insects and other vermin.
Some raw materials, particularly agriculturally sourced materials, may contain unavoidable
contamination, such as rodent or other animal filth. Appropriate control methods should be inplace to prevent the increase of such contamination in holding areas and its spread to other areasof the manufacturing facility.
Note:

1. Infestation means the presence of the actual vermin or the evidence that they were
there, e.g., bird droppings.
2. In case of open facilities, risk mitigation may be used, as appropriate (e.g., usage ofbird net or other screening measures).

Where the risk assessment has identified the need for pest control, the organization should
document the pest control program, including the use of suitable rodenticides, insecticides etc.

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Note:As determined by the documented risk assessment, the quality unit should approve theuse of such rodenticides and / or insecticides.

Where a service provider is used, there should be a contract in place (see 8.4).

7.1.4.5

Personnel hygiene

Where the documented risk assessment has identified areas in which the excipient is at risk ofcontamination, including cross-contamination, from personnel or their activities, controls shouldbe put in place to minimize the risk. At a minimum the following should be considered anddocumented:•

the personnel themselves;•

suitability of clothing and protective equipment for the activity;•

provision of facilities for showering and / or changing clothes;•

removal or covering of jewelry and other loose items, including those in pockets;•

reporting to supervisory personnel any health conditions, apparent illness or open lesions,that may have an adverse effect on excipients;•

restricting the storage and consumption of food, drink, personal medication, tobacco products
or similar items to designated locations separate from manufacturing areas.

Note:

1. Examples of personnel activities that could introduce contamination include:•

maintenance;•

sampling;•

packaging;•other manual process operations.

2. Jewelry and other loose items could include pens, ID cards, piercings, artificial nails,
other cosmetic applications such as nail polish, perfume, after shave, lipstick, false eyelashes and personal protective equipment such as ear plugs, safety monitors, andbandages.
Adequate washing facilities and supplies should be provided so that suitable hygiene standards
can be maintained. Toilet facilities should be clean and separate from but easily accessible toworking areas.
Note:

Adequate washing facilities and supplies can include hot and cold water, soap or
detergent, air dryers or single service towels.

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7.1.4.6

Lighting

Adequate lighting should be provided to facilitate cleaning, maintenance, and proper and safe
operations. Where the excipient is exposed to the work environment or stored, lighting should beshatter-proof or otherwise protected.
Note:

1. Examples of proper operations include:•ability to see instrument read-outs and read batch numbers on labels;•

sufficient lighting to perform visual controls, e.g., titration, identifying the interface
in a phase separation, discerning colors in test methods;•

protecting light sensitive excipients from exposure to light.

2. Temporary lighting (e.g., torches / hand-held flashlights) should be subject to the same
controls as fixed lighting.

7.1.4.7

Drainage

In areas where the excipient is open to the environment or stored, drains should be of adequate
size. Where connected directly to a sewer, drains should be provided with air breaks ormechanical devices to minimize the risk of back-siphoning. Drains should be maintained
appropriately.
Note:

Based on the results of the documented risk assessment, maintenance of drains could
include, for example, routine:•

visual inspection;•

flushing / rinsing;•cleaning / sanitizing.

7.1.4.8

Waste

Waste should be segregated and disposed of in a timely manner by means appropriate to its type.
If waste is not disposed of immediately, it should be suitably labeled and stored. Excipient
packaging should not be used to hold waste unless clearly labeled as waste.
Note:

1. Waste types could include chemical, biological, and hazardous.
2. Examples of labeling include:•

text labels (container labels, tank labels, area labels, etc.);•

color coding (colored containers, colored tape).

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7.1.5

Monitoring and measuring resources

7.1.5.1 General
The excipient manufacturer should identify measuring and monitoring equipment necessary toadequately control manufacturing processes. Equipment critical to quality should be qualified,commissioned, calibrated, and, where appropriate, maintained.
Note: 1. Examples of equipment critical to quality may include:•

in-process instruments;•

equipment used in the laboratory;•

equipment used for the calibration of measuring and monitoring equipment;•

computerized systems.

2. Some quality-critical equipment, based on a documented risk assessment, can be run
to failure provided they are calibrated before each use. In some cases, it might benecessary to calibrate after use as well to ensure equipment suitability. Examples include
pH probes and chromatography columns.
The control program should include:•

the standardization or calibration of instruments and equipment at suitable intervals inaccordance with a documented program;•specific instructions, schedules, limits for accuracy and precision;•

provisions for remedial action if accuracy and / or precision limits are not met, including:oprevention of future use until suitability can be demonstrated;odocumented investigation to determine the validity for results reported since the last
successful qualification / commissioning / calibration.

Instruments and equipment not meeting established calibration limits should not be used.
Note:

Examples to prevent usage of instruments and equipment not meeting establishedcalibration limits include:•

labeling;•

lock-outs;•

removal from area, where feasible, or barrier tape.

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For quality-critical monitoring and measurement equipment, the excipient manufacturer should
retain documented evidence demonstrating fitness for purpose.
Note:

Examples of documented evidence include:•

equipment qualification (design, installation, operation, performance) reports;•

calibration records and certificates of calibration;•

maintenance records;•

computerized system validation reports.

7.1.5.2 Measurement traceability
Standards used for the calibration of measuring and monitoring equipment should be traceable
to recognized national, international, or compendial standards, as appropriate.
The qualification / commissioning / calibration status of quality-critical equipment should be known
and verifiable to users.
Note:

User in this context means “analyst / person qualified to use such equipment”, notexcipient user

7.1.6

Organizational knowledge

The excipient manufacturer should determine, apply, and maintain the knowledge necessary for
manufacturing and marketing of excipients. Knowledge of current regulations should be aligned
to the labeling claims made about the excipient, intended use, and the countries in which it ismarketed.
Note:

1. Application of organizational knowledge can be based on:•internal sources (e.g., intellectual property; knowledge gained from experience;lessons learned from failures and successful projects; deviation and complaintinvestigations; capturing and sharing knowledge and experience so that it is notdependent upon an individual; the results of improvements in processes,
excipients and GMP services);•

external sources (e.g., standards; academia; conferences; gathering knowledge
from customers or external providers).

2. Examples of knowledge include information related to:•formulas and recipes;•

manufacturing equipment;

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regulatory / compendial requirements;•

customer specifications.

3. Examples of maintaining the knowledge include:

7.2•

succession planning;•

mentoring;•

technical reports, databases, e.g., regulatory, product safety;•

ensuring that key knowledge is appropriately shared.

Competence

The excipient manufacturer should determine, and document in a written job description, theappropriate combination of education, training and experience for roles / personnel performing
tasks that may affect excipient quality (see 5.3). These tasks should be considered in the training
plan.
The excipient manufacturer should establish and maintain procedures for identifying the training
needs of its employees and contracted personnel. A process should be established to provide
effective training to all personnel who perform activities that may affect excipient quality. Training
should be provided prior to independently performing those activities.
Training should address the particular GMP operations that the employee performs as well as
detailed GMP related to the employee’s role.
Note:

Examples for detailed GMP related to the employee’s role include:•

supply chain: stock reconciliation deviations are GMP deviations / failures, not only
financial transactions to be made;•security personnel: allowing visitors entry to the facility;•

production operators: impact of process interruptions, e.g., restarting equipment
during production, unplanned maintenance and return to service.

Appropriate records of training should be maintained.
Note:

Examples of appropriate records of training include:•

documented content and evaluation of “training on the job” by e.g., instructor,
supervisor or line manager;

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Retraining requirements should be defined and documented.
Note:

Examples for when retraining could apply:•

after job reassignments or extended absences;•when job details change, i.e., new equipment, procedure changes, new testing and/ or regulations;•following human errors, accidents, or process incidents.

Consultants advising on design, production, packaging, testing or storage of excipients shouldhave sufficient education, training and experience or any combination thereof to advise on thesubject for which they are retained. Records should be maintained listing the name, address andqualifications of consultants and the type of advice they provide.
Note:

1. Consultants are subject matter experts who share their knowledge, in contrast toservice providers, e.g., calibration technicians, who do the actual work.
2. Consultants can advise on topics such as:

7.3•

engineering;•experimental design;•

method validation;•

conformance of the quality management system to excipient GMP;•

development of training materials.

Awareness

Qualified individuals should develop and provide general GMP training. This training should beconsistent with the quality policy and provided with sufficient frequency to ensure that employees
remain familiar with applicable GMP principles. Training content should include the following
topics – at a minimum – as they relate to the individual’s role and function:•

importance of following instructions and prompt notification of any deviation;•

data integrity;•

precautions necessary to minimize the risk of contamination, including cross-contamination,
through personal hygiene practices;

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excipients, including cross-contamination;•

potential to impact patient safety should the above expectations not be met.

Note:

Examples of other precautions include:•

equipment cleaning after invasive maintenance;•

use of approved cleaning materials and lubricants.

The training program should ensure personnel understand that deviations from procedural
instructions may impact the safety, quality, or efficacy of medicinal products.
Note:

Examples of deviations include:•

charging raw materials in wrong order;•

stirring the reactor longer or shorter than the instructions allow;•

using an expired reagent to perform an analytical test;•

using the wrong lubricant during maintenance.

The training program should also ensure that personnel know what to do when a deviation has
taken place.
Note:

7.4

See 8.7 for more information about control of nonconforming outputs.

Communication

The excipient manufacturer should ensure that internal and external communication processes
are established.
Processes for internal communication should be in place for:•

GMP and regulatory requirements;•

quality-relevant policies, including the organization’s overall quality policy;•

quality-relevant procedures;•quality and GMP objectives;•effectiveness of the quality management system;•

prompt notification to top management of quality-critical situations, including excipient
retrievals (see 8.7.4).

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accurate and pertinent information, which may include regulatory documents (see 7.5);•

replies to customer enquiries, contracts and order handling requirements;•

origin and traceability of the excipient to the customer;•

issues detected after delivery of the excipient (see 8.7.1 and 8.7.4);•

responses to customer complaints and feedback;•significant changes (see 6.3 and 8.2.4).

Note:

Examples of external parties include:•

contractors;•

suppliers and service providers;•customers and distributors;•

regulatory agencies;•

certification bodies;•

compendial organizations.

7.5

Documented information

7.5.1

General documentation requirements

The organization’s overall intentions and approach to GMP should be described and documented
to facilitate common understanding and consistent application.
Procedures for manufacturing, control of data and records, as well as other documents related torequirements of the quality management system should be implemented, controlled, andmaintained. This includes regulatory documents and documents of external origin that are part of
the quality management system.
Note:

1. Examples of data, including raw data, include:•

direct measurements, e.g., weights, temperatures, pH;•

calculated results, e.g., yield, concentration.

2. Data reported in a formatted document is called a record. Examples of records include:•

batch (production) records;

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•training records;•

laboratory data sheets;•

certificates of analysis and certificates of conformity;•cleaning lists;•shipping records;•

maintenance logs;•

equipment use record (sometimes available as a log);•

qualification reports.

3. Examples of documents include:•

procedures;•

blank forms and logs;•

master production instruction (also known as master batch record or masterproduction record);•training materials;•

quality manual and policies.

4. Examples of regulatory documents and documents of external origin include:•

excipient DMF and / or CEP;•

EXCiPACT and / or ISO certificate;•

Halal and / or Kosher certificate;•

raw material certifications, e.g., GMO, BSE / TSE.

The excipient manufacturer should establish and maintain procedures for the lifecycle of
documented information covering:••

Review, approval, distribution, access, retrieval, and use:ocurrent versions of applicable documents should be available at points of use;oprevent unintended use of obsolete documents;

storage and preservation, including preservation of readability and integrity:oprevent unintended and / or unauthorized changes;

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control of changes (e.g., correction, version control);•periodic review to ensure the document remains current with practice;•retention, including:•oprocess for identifying and labeling obsolete documents;oretention time;

destruction.

Records should be maintained to demonstrate achievement of the required excipient quality andthe effective operation of the quality management system. Records should be legible andidentifiable with the product or process involved.
Note:

Records may be in different locations and / or formats.

The organization should define which results, records and reports of subcontractor activities are
retained, by whom, and for how long.
If electronic signatures are used, they should be authenticated, provide equivalent security tohandwritten signatures, and comply with relevant regulatory requirements.
Note:

1.
What
does
it
mean
to
authenticate
electronic
Authentication is a method to verify signer’s identity. Examples include:•unique UserID + personal password;•biometric identification (retina scan or fingerprint);•

RFID identity badge + PIN code.

signatures?

2. Information about electronic signatures and expectations of how to control them,including regulatory requirements and the meaning of equivalent security, can be foundin:•

U.S. FDA Code of Federal Regulation, Title 21 Part 11 (21 CFR 11), Electronic
Records; Electronic Signatures;•

EU GMP Annex 11, Computerised Systems, January 2011;•

MHRA: GxP Data Integrity Definitions and Guidance for Industry, July 2016;•

US FDA Guidance for Industry: Part 11, Electronic Records; Electronic SignaturesScope and Application, 2003;

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WHO: TRS 996, Annex 05, Guidance on good data and record management
practices, 2016.

Data integrity principles i.e., of ALCOA+ should be incorporated throughout the procedures andsystems used for managing documented information.
Note:

Compliance with ALCOA+ data integrity principles can be met when data and records
are:•

Attributable (i.e., you know who acquired the data or performed an action andwhen);•

Legible (i.e., you can easily read the data);•

Contemporaneous (i.e., data are documented at the time of the activity);•

Original (i.e., data are recorded from original observations or taken from certified
copies);•Accurate (i.e., data, including metadata (e.g., audit trail) and edits, whereapplicable, are complete and correct);•+Complete (i.e., for each activity, records include all data collected, including,where applicable, metadata (e.g., audit trail), and edits);•+Consistent (i.e., entries in records include all elements in the expected sequence);•+Enduring (i.e., data are maintained throughout their defined lifecycle on media
proven to last throughout the retention period);•+Available (i.e., records can be readily accessed - in human readable form - during
their lifecycle).

Data integrity controls for excipient manufacturing and distribution processes should becommensurate with risks associated with the use of the data. A higher level of control should be
implemented where the loss of data integrity could compromise compliance with excipient GMP,
impact confidence in excipient quality, cause the failure or rejection of the medicinal product, orpose potential harm to the patient.
Note:

Data integrity controls for excipients may be different from controls used for
manufacturing of Active Pharmacuetical Ingredients (APIs) and medicinal products.

Data integrity requirements apply equally to manual (paper) and electronic data. The inherent
risks to data integrity may differ depending upon the degree to which data (or the systemgenerating or using the data) can be configured, and therefore potentially manipulated.

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Entries in records should be clear, indelible, made directly after performing the activity (in theorder performed), signed and dated by the person performing the observed task (unless otherwise
justified). Corrections to records should be signed and dated, leaving the original entry legible.
7.5.2

Creating and updating

Documents should include a unique identifier, date of issue and revision number to facilitate
identification of the most recent document.
Documents that have the potential to impact product quality should have a defined owner and bereviewed and approved by the quality unit (see 5.3) before issuance to the appropriate areas.
Additionally, procedures and forms should indicate from which date they are valid. This dateshould allow sufficient time to provide for employee training (see 7.2).
The department with the responsibility for issuing the documents should be identified.
Note:

1. Examples of how ownership is defined include:•

name and / or function of the owner identified within the document;•

list of procedures with owners for each.

The owner does not have to be the quality unit.
2. How can the quality unit review and approve a document?
•

signing off as reviewed and accepted for final draft version;•

signing off as final approver.

Changes to approved, quality-relevant documents should be reviewed and approved by thequality unit (see 5.3) before use.
Changes and the reasons for the change should be documented.
Note:

It may be practical to only maintain the most recent reasons for revision in an effective
procedure while maintaining the complete revision history offline in a controlled andrestricted space.

All quality-related documented information (i.e., data, records, documents) should meet theabove, independent of the storage medium (i.e., paper, electronic, mixture of both).
7.5.3

Control of documented information

Documented information should be controlled. Controls should provide assurance that only thecurrent version is being used in operational areas and that previous versions of documents havebeen removed.

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Note:

Examples how to control data, records, and documents, including access, include
management by:•procedures;•computerized systems;•

combination of both.

Copies of controlled documents should be readily identifiable as either controlled or uncontrolled.
Note:

Examples of identification include:•watermark;•date and signature;•stamping;•

use of colored paper;•

expiration date (for printed electronic copies).

Records should be kept for a defined period appropriate to the excipient and as specified inapplicable:•

regulations;•certification standards;•

customer agreements.

The excipient manufacturing record retention period should be at least one year past theexcipient’s expiry or last re-evaluation date, or at least five years from the date of manufacture.
Electronic records should be subject to the same controls as those required for other records.
Note:

Examples of how to apply these controls to electronic records include:•

controlled and limited access;•audit trail;•back-up systems;•

readability of records in obsolete software.

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8Operation

8.1

Operational planning and control

The excipient manufacturer should plan, implement, and control the processes needed forprovision of excipients and GMP services. According to the actions determined in section 6, theexcipient manufacturer should:•

determine the requirements for the excipients and GMP services;•establish criteria for excipient manufacturing that include:odocumented processes;odocumented testing programmes for quality-critical materials including intermediates andfinished excipients;oappropriate specifications;osampling plans;oenvironmental and hygiene control programmes (see 7.1.4) to minimize the risk ofcontamination, including cross-contamination;otest and release procedures;odetermination and provision of resources to implement these plans and controls.

•

document procedures describing activities related to the storage and distribution of excipients;•

implement actions from relevant documented risk assessments (see 7.1 including subsections);•

generate and maintain records providing evidence that the controls have been followed andmet.

The excipient manufacturer should control planned changes (see 6.3) and have a process tomanage the consequences of deviations (i.e., unintended changes).
The excipient manufacturer should ensure that outsourced processes are controlled (see 8.4) andnotify customers as applicable (see 8.2.1).

8.2

Requirements for excipients and GMP services

8.2.1

Customer communication

There should be processes in place for communication to the customer, including:

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7.5);

•

provision of replies to enquiries, contracts and order handling requirements;•

handling or controlling customer property, as applicable;•communicating the original manufacturer’s identity and production site;•

notifying customers of outsourced activities that may affect excipient quality (see 8.4);•

provision of certificate of analysis for each batch shipped (see 8.6);•

notifying customers of significant changes (see 6.3);•

documenting and responding to customer complaints and feedback;•informing customers of issues, including recalls and critical deviations detected after deliveryof the excipient or provision of the GMP service (see 8.7.1, 8.7.2, and 8.7.4);•

informing if customers are impacted by activation of contingency plans.

Note:

1. Examples for information communicated to customers include:•

Excipient Information Package, Specification, Product Information Brochure(refer to IPEC Excipient Information Package User Guide and Templates);•

GMP certification from an accredited certification body (refer to IPEC GMP
Certification Scheme and Certification Body Qualification Guide).

2. Information could be communicated in a variety of ways, e.g., company website,
electronic portal, customer’s monitored mailbox.
8.2.2

Determining the requirements for excipients and GMP services

The excipient manufacturer should determine the requirements for manufacture of excipients andprovision of GMP services based on the intended use. Customer-specific, legal, and regulatory
requirements should be considered, as found in “The IPEC Qualification of Excipients for Use inPharmaceuticals Guide and Checklist”.
8.2.3

Review of the requirements for excipients and GMP services

The excipient manufacturer and customer should review and mutually agree upon therequirements identified in 8.2.2 before supply begins. The manufacturer should have the facility
and process capability (see 8.5.1) to consistently meet the mutually agreed specifications and
GMP services.

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Customer requirements may be documented in agreements, revision of which can be initiated byeither party.
Note:

1. Examples of agreements include Quality Agreement, Supply Agreement, Purchase
Agreement, and Service Level Agreement.
2. For guidance on quality agreement responsibilities and review, refer to the IPEC
Quality Agreement Guide and Template(s) for Pharmaceutical Excipients.

Where the requirements determined in 8.2.2 are changed, this review should be repeated before
supply resumes.
8.2.4

Changes to requirements for excipients and GMP services

The excipient manufacturer should have a process for handling changes related to customer andregulatory requirements. See 6.3 for changes initiated by the excipient manufacturer.

8.3

Design and development of excipients and GMP services

Note:

Section 8.3 including its sub-sections may not apply to all excipient manufacturers (seesection 4, Context of the Organization).

8.3.1

GeneralIn the design and development of excipients and GMP services, the GMP principles of this guide
may not always be fully applicable.
The excipient manufacturer should document in a risk assessment those parts of the guide thatare not applied when developing excipients.
Note:

1. Examples of excipients and GMP services include:•

extension of portfolio with different type of excipient;•use of an existing product as an excipient (e.g., food ingredient to be offered into
pharma market);•offering customized GMP services, e.g., non-standard packaging.

2. Adjustments to the established manufacturing and GMP service provision processes
are managed as changes, see 6.3.
8.3.2

Design and development planning

When designing and developing excipients and GMP services, the excipient manufacturer should
consider the processes and activities necessary to control the desired result, including:

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verification or validation activities;•

roles and responsibilities (see 5.3);•

resources (internal and external) (see 7.1);•

interface(s) between people involved;•

customer and user involvement (see 5.1.2);•

customer and user requirements (see 8.2.2);•

facilities and process capabilities needed to consistently meet the desired result (see 8.5.1);•

documented evidence needed to demonstrate that planning requirements have been met.

Note:

1. Examples of customers include:•

distributor;•

medicinal product manufacturer.

2. Examples of users include:

8.3.3

•

medicinal product manufacturer;•

contracted 3rd party.

Design and development inputs

The excipient manufacturer should determine the requirements specific to the excipients and
GMP services being designed and developed, considering, at a minimum:•

functionality and performance;•

information available from similar design and development activities;•

statutory and regulatory environments;•

standards or codes of practice implemented by the organization;•

potential consequences of failure attributable to the type of the excipient or GMP service.

Note: 1. Examples of standards (other than GMP) include:

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•

FSSC 22000, Food Safety Management Systems;•

ISO 14001, Environmental Management Systems;•

ISO 50001, Energy Management Systems.

2. Examples of codes of practice include:•

NACD Responsible Distribution;•

Responsible Care®;•

WHO Sustainable Development Goals.

Design and development inputs should be:•adequate for their intended purposes;•

clear and comprehensive;•

consistent in their approach.

Evidence of these inputs should be documented and retained (see 7.5).
8.3.4

Design and development controls

The excipient manufacturer should control the design and development process to ensure that:•desired results are defined;•

review of results is performed to assess if requirements can be realized;• verification activities are conducted to confirm that the design and development outputs meetthe input requirements;• actions verify resulting excipients and GMP services meet the organization’s intended use,and customer and user requirements;• actions are performed to address problems identified during reviews or verification activities,
as applicable;•

control activities are documented and retained (see 7.5).

8.3.5

Design and development outputs

The excipient manufacturer should ensure that outputs for design and development of excipientsand GMP services:•

meet all input requirements;

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identify process control strategy requirements, as appropriate, and corresponding
acceptance criteria;

Note:

Examples of process steps for which controls might be needed include:•

phase changes involving the desired molecule, solvent, inert carrier or vehicle (forexample dissolution, crystallization, evaporation, drying, sublimation, distillation orabsorption);•

phase separation (for example filtration or centrifugation);•chemical changes involving the desired molecule (for example removal or additionof water of hydration, acetylation or formation of a salt);•

adjustments of the solution containing the molecule (for example pH adjustment);•

precise measurement of added excipient components, in-process solutions,
recycled materials (for example weighing or volumetric measurements);•

mixing of multiple components;•changes that occur in surface area, particle size or batch uniformity (for example
milling, agglomeration or blending).

•

identify release specifications and / or other requirements consistent with the intended
marketed purpose and safe use by the customer, or•

identify other requirements essential for the intended purpose.

Evidence of these outputs should be documented and retained (see 7.5).
8.3.6

Design and development changes

In order to minimize the potential for nonconformance to requirements (see 8.3.3), the excipient
manufacturer should appropriately control changes (see 6.3) made during the design anddevelopment of excipients and GMP services. Documented evidence should be maintained torecord:•the scope of the change;•

review of the change;•

authorization of the change;•

actions implemented to minimize potential negative effects caused by the change.

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8.4

Control of externally provided quality critical processes, services andmaterials

8.4.1

GeneralExternally-provided quality-critical processes, services and materials should be described in
written agreements and the excipient manufacturer should ensure that these activities andmaterials conform to the documented requirements (see 8.4.3).
Note:

Examples of:•“processes” include contracted manufacturing operations related to the excipientsuch as micronization, packaging, coating, and irradiation;•“services” include additional activities such as warehousing, transportation, pest
control, cleaning, and laboratory testing;•“materials” include purchased products such as raw materials, pre-printed labels,
lubricants, process aids, (primary or barrier) packaging materials.

A documented process should be used to identify quality-critical processes, services andmaterials, and their necessary controls.
Note:

Examples of documented processes to identify quality-critical processes, services andmaterials include:•

risk assessment;•

supplier qualification and approval.

Suppliers of quality-critical processes, services and materials should be approved by the quality
unit after a documented evaluation of the supplier's quality management system, including
adequate evidence that they can consistently meet agreed requirements (see 8.4.3). Documented
information of these activities should be retained (see 7.5).
8.4.2

Type and extent of control

The excipient manufacturer should determine the controls necessary to ensure that the externallyprovided quality-critical processes, services and materials meet agreed requirements (see 8.4.3).
These activities should be documented, including controls that apply to both:•the external provider, and•their provided process, service, or material.

These controls may require periodic audits of the supplier’s operations.

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8.4.2.1 Control of externally-provided processes and services
Where manufacturing, testing, other operations, or services that could affect excipient quality areoutsourced, the responsibility for quality ultimately remains with the excipient manufacturer, andcontrol measures should be defined. The excipient manufacturer should be able to demonstratethat the applicable GMP principles, in accordance with this guide, are followed for those
operations and services.
Note:

Examples for controls of outsourced operations and services include:•

specific agreed controls and procedures, based on outcome of risk assessment,e.g.,:oreview of records and approval of operations or services by the excipient
manufacturer;oon-site presence of the excipient manufacturer during execution of outsourced
activity;oanalytical testing of the externally-processed excipient.

•review and approval for use of cleaning agents and pest control materials;•

inspections of the supplier’s operations and / or services;•periodic audits of the supplier.

8.4.2.2 Control of externally-provided materials
There should be procedures for control of incoming materials. These should describe the process
for approval and release of quality-critical materials, including handling of out-of-specification test
results (see 8.6.4).
Incoming quality-critical materials, including packaging and preprinted materials, should bephysically or administratively quarantined until they have been tested or otherwise verified andapproved for use by the quality unit or their delegate (see 5.3).
Note:

1. Quality-critical preprinted materials provide information as described in section 8.5.2.3,
Labels.
2. Examples of verification include:•

confirming that material received from approved supplier matches purchase order,
which may be done manually or by a computer system;•

check of the supplier certificate of analysis or certificate of conformance;•

identification testing;
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testing of quality-critical specifications.

Sampling activities should be conducted under defined conditions in accordance with a definedsampling method and using approved procedures and sampling tools designed to minimize therisk of contamination, including cross-contamination.
Bulk deliveries should have appropriate controls to minimize the risk of contamination, including
cross-contamination.
Note:

Examples of controls for bulk deliveries include verification of:•

dedicated tankers and, where appropriate, couplings and hoses;•

details of prior container contents;•

tamper-evident seals;•

certificate of cleaning;•

analytical results (i.e., supplier certificate of analysis, in-house testing).

When quarantine and stock control are managed with computer systems, there should be system
controls to prevent the use of unreleased material.
Note:

For more information about control of computer systems refer to section 7.1.3.2, subparagraph “Computer Systems”.

Quarantine may not be feasible for materials supplied through pipelines. In these cases, theexcipient manufacturer should establish an agreement with the supplier so that they are notified
of material that does not meet specification.
8.4.3

Information for external providers

Excipient manufacturers should have documented agreements with external providers,
communicating:•the quality-critical processes, services and / or materials to be provided, including whereapplicable:oname, type, class, grade, item code number or other precise identification traceable to theraw material and packaging specifications;odrawings, process requirements, inspection instructions and other relevant technical data;orequirements for the approval of:materials and services;

methods, processes, and equipment;
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the release of processes, services, and materials.

orequirements for personnel competence, including appropriate regulatory qualifications.

•the need for adherence to the applicable GMP principles in accordance with this guide;•

which records, results and reports need to be retained, by whom, and for how long;•

how control and monitoring of external provider performance will be applied;•change control requirements, including subcontracting;•requirements for verification or validation activities by the external provider, if applicable;•

any need for periodic audits by the excipient manufacturer of the external supplier’s
operations.

Notes: 1. Examples of documented agreements with external providers include:•purchasing agreement;•

quality agreement;•

service level agreement;•

supply agreement.

2. Examples of regulatory qualifications of personnel competence include:•

pest control applicator’s license;•

permit for bioIID handling;•

license for transporting hazardous materials.

3. Examples of requirements for verification or validation activities include:•

on-site presence during manufacturing activities;•

review and approval of critical process steps or operations by excipient
manufacturer that are subcontracted to another external provider;•permission for excipient manufacturer’s customer to visit and / or audit;•

defining any revalidation frequency.

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8.5

Production and GMP service provision

8.5.1

Control of production and GMP service provision

Activities for provision of excipients and GMP services should be carried out under controlled
conditions (see 8.1). There should be evidence defining:•

the characteristics of the excipients to be produced;•

the GMP services to be provided;•

the activities to be performed;•

the results to be achieved.

Specific controls detailed in sections 8.5.1.1 through 8.5.1.8 apply for the excipients or GMP
services within the scope of operations (see 8.1).

8.5.1.1 Instructions and records
Documents and records (see 7.5.1) describing how the excipient is manufactured or distributed,
or GMP service is provided, should be maintained. Written instructions and forms that become
records should be available at point of use and may differ based on the activity.
Note:

Examples of how written instructions and forms may differ based on the activity, include:•

batch process may have a blending record whereas continuous process may havea statistical process control (SPC) chart;•

customer specific requirements for packaging / labeling;•

consideration of seasonal effects on shipping e.g., due to temperature and humidity
variations.

Records should be available for each batch of excipient produced and should include complete
information relating to the production and control of each batch. For continuous processes, thebatch and its records should be defined based on time or quantity produced and / or packaged.
Records should also be available for each GMP service provided.
Where critical to demonstrate compliance with this guide and as applicable, records should
comply with data integrity principles (see 7.5.1) and include:•

date / time each step was completed;•documentation of key parameters together with conformance check against specified
operating ranges;

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identification of persons:operforming / checking each operation;overifying control parameters.

•

identification of major equipment and lines used;•cleaning activities for equipment, lines, and utensils (see 8.5.1.2);•

material inputs (to enable traceability, see 8.5.2);

Note:

Examples of material input traceability include batch numbers, quantities, time added,
etc.

•

in-process control results (see 8.5.1.6);•

inspection of the packaging and labeling area(s) before use, to ensure that materials not
required for the current operation have been removed or destroyed;•labeling controls performed;•

description of excipient containers and closures;•

description of sampling performed;•

failures, deviations, and their investigations;•visual inspection results of packaged excipient (see 9.1.3 for analytical testing of final
excipient);

Note:

•

Examples of visual inspection controls of packaged excipient include:•

seal integrity;•

package integrity;•

correct label;•external surface cleanliness.

the quantity produced for the defined batch and a statement of the percentage of theoreticalyield, as applicable.

Note:

Continuous processes are an example where the calculation of theoretical yield may not
be applicable because the theoretical yield is not quantifiable.

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8.5.1.2 Equipment cleaning
Equipment and utensils should be cleaned and, if critical to excipient quality, sanitized. Cleaning
can be achieved in several ways, some of which may not result in visually clean equipment. The
excipient manufacturer should design and justify cleaning and sanitization intervals andprocedures and provide documented evidence of their effectiveness based on pre-determined
acceptance criteria.
Note:

1. Equipment cleaning and sanitization justification may be documented in a risk
assessment. For example, during a production campaign incidental carry-over frequently
occurs and can be acceptable when cleaning between successive batches of the same
excipient is not required to maintain quality.
2. The use of a model product (i.e., groups of products of similar type) approach or matrix
design may be used in justifying a suitable procedure.
3. Provided that risks from bioburden or degradation are appropriately controlled, productflushes may be an adequate method for cleaning dedicated equipment. This method isoften used with powdered excipients and may not result in visually clean equipment, i.e.,
residue of the flush material will still be visible after cleaning.
4. Evidence of effectiveness may be provided in various ways, e.g., in a cleaningvalidation report, cleaning effectiveness assessment report, video recording of visualinspections, or through analytical test results.

Cleaning and sanitization procedures should be documented. Where disinfectants or detergentsare required, an assessment of suitability should be documented. Procedures should containsufficient detail to allow operators to clean each type of equipment in a reproducible and effective
manner (see 7.1.4.3). There should be a record confirming that these procedures have been
followed. The cleanliness and, where appropriate, sanitization status of equipment should be
identifiable and documented.

8.5.1.3 Recovery and reuse of materials
Where materials are recovered and reused, they should meet appropriate specifications prior toreuse or mixing with other approved materials. Processes for recovery and reuse of materials
should be justified. These processes should be documented, and records maintained to enable
traceability.
Note:

Examples of process streams from which materials may be recovered and reused
include:•solvents;•

mother liquors;
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8.5.1.4 Blending of excipients
If excipients are blended (without the manufacturing elements of co-processing) the process
should ensure homogeneity and should be reproducible from batch to batch (see 8.5.1.8). The
process should be controlled and documented to allow traceability back to the individual batches
that make up the blend.
The blended batch should be tested for conformance to established specifications. The expiry or
re-evaluation date of the blended batch should be justified.
Note:

Examples of acceptable blending operations include:•

blending that is part of the defined manufacturing process;•blending small batches to increase batch size;•

blending batch tailings (i.e., relatively small quantities of isolated excipient) frombatches of the same excipient to form a single batch;•

blending of packages that do not conform to weight specifications (i.e., under orover weight);•

blending of different excipients to produce a mixed excipient.

Blending should not be used to dilute contamination (see 8.7.1). Blending should also not be
used where the performance of the resulting excipient could be impacted.
Note:

1. Examples of unacceptable blending operations include:•

blending contaminated excipients to dilute contamination below detectable limits;•

blending to bring the technically unavoidable particles profile into the typicalprofile range (refer to IPEC Technically Unavoidable Particle Profile (TUPP)
Guide).

2. Examples where the performance of the resulting excipient could be impacted include:•

if blending alters the particle size distribution profile outside normal ranges;•

if blending introduces undesirable characteristics, e.g., changes in bulk density,
flowability, viscosity.

8.5.1.5 Co-processing of excipients
For co-processing of excipients, different technologies such as granulation, melt extrusion, spraydrying, or milling may be used.
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To ensure that specified properties and quality are obtained:••

the co-processing of excipients should be:oadequately controlled in-process (see 8.5.1.6);odocumented to allow traceability back to the component excipient batches (see 8.5.2.1);

finished co-processed excipients should be tested to ensure the product conforms tospecifications (see 9.1.3).

The expiry or re-evaluation date of the co-processed excipient should be justified.
See also “The IPEC Co-Processed Excipient Guide for Pharmaceutical Excipients”.

8.5.1.6 In-process control
In-process controls may be based upon in-line monitoring of the process or actual sample analysis
at defined locations and times. In-process sampling, inspection and testing should be performedby trained personnel on representative samples according to documented procedures. In-processsamples should be clearly labeled and not returned to the GMP-process production stream.
Note:

An example of why in-process control samples should not be returned to the GMPprocess production stream is because the handling of samples increases the risk ofcontamination to the sample. Returning samples contradicts the overall effort to reducerisk of contamination during excipient manufacturing.

The results of in-process controls should be recorded and should be verified against establishedprocess limits. Written instructions should describe the use of inspection and test data to control
the process. These instructions should detail actions to be taken when the results are outside
specified limits.

8.5.1.7 Packaging and labeling of excipients
Packaging and labeling procedures should be employed to ensure excipient identity, quality, andpurity. To prevent mix-ups, procedural controls should be implemented to ensure:•correct labels are printed and issued;•labels contain the correct information;•

printed information is indelible;•

packaging and labeling facilities are inspected immediately before use, confirming thatmaterials not required for the current packaging operation have been removed or destroyed;

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excipient is packaged into the correct packaging system (see 8.5.4.2);•

excess batch-specific labels are destroyed immediately following packaging operations.

If not required for the subsequent packaging and labeling operation, excess product containers,
closures and / or labels without batch- or product-specific information should be destroyed or
returned to controlled storage immediately following operations.
Repackaging / relabeling activities should follow the same principles outlined above.

8.5.1.8 Validation for production and GMP service provision
The excipient manufacturer should demonstrate consistent operations for the provision of
excipients and GMP services based on knowledge of operational parameters, requirements, andtheir inter-relationship.
Notes

Examples of how to demonstrate knowledge of operational parameters include:•

process capability studies;•development and scale-up reports;•

periodic product reviews.

The concept of validation is a key element in ensuring that processes are capable of consistently
producing an excipient that meets specifications. The excipient manufacturer may not perform
validation activities in the same manner or to the same extent as the pharmaceutical industry.
However, many activities leading to the same degree of assurance are performed within the
excipient industry.
Validation should be used:•

where testing alone may not be sufficient to reveal variations outside the process limits, or•where the resulting output cannot be verified by subsequent monitoring or measurements.

Note:

Examples where process output cannot be verified by subsequent monitoring or
measurement include:•

where hazardous environments and / or materials prohibit sampling or exposure;•when sampling or sampling techniques expose the material to degradation orcontamination;•

where the process requires heat treatment to reduce or eliminate bioburden.

The excipient manufacturer should have a process for assessing and documenting the impact ofchange on the validated state of the system.
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See also the IPEC Validation Guide.
8.5.2

Identification and traceability

Quality-critical materials and services, including GMP services, should be identifiable andtraceable through records to demonstrate conformance with the principles of this guide.
Note:

Examples of quality-critical materials and services include:•

raw materials, packaging materials, intermediates and finished excipients;•

calibration and maintenance;•

testing services (insourced and outsourced);•

vendor managed inventory services.

8.5.2.1 Traceability
Records should allow traceability of the service, including GMP services, or, for excipients, fromreceipt of raw materials through delivery to initial customers and vice versa.
Note:This traceability applies to the excipient manufacturer. However, the end user will want
to document the entire supply chain.

Methods should be defined for traceability and identification of raw materials, equipment used in
excipient manufacturing, and GMP service provision to customers.
Note:

Examples of traceability and identification methods include:•

batch numbering system;•

system based on time or quantity produced and / or packaged;•

documents that facilitate traceability, e.g., logbooks, worksheets.

Even though one-to-one lot traceability is not possible with continuously supplied materials orbulk deliveries, traceability of use should still be documented in production records.
Note:

1. “One-to-one lot traceability” refers to the batch of raw material which is used in aparticular lot of finished excipient.
2. Traceability of continuously supplied materials or bulk deliveries may be possible byusing time and production rates, relating a period of raw material receipt to a period of
production.

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8.5.2.2 Inspection and test status
The inspection status of quality-critical materials and services, including GMP services, should be
identifiable. Methods for identifying test status should be defined.

8.5.2.3 Labels
Excipient container labels may be subject to regulatory and / or compendial requirements (see8.2.2).
Labels should include at a minimum:•

the names of the excipient (tradename and generic name(s)) and, if applicable, grade, ormaterial code which specifies the grade•

the excipient manufacturer’s and / or supplier’s name and address,•

the batch number from which the complete batch history can be determined,•

special storage conditions, if applicable.

Labeling for excipient packages is subject to national and international regulatory requirements,
which may include transportation and safety measures.
8.5.3

Property belonging to customers or external providers

The excipient manufacturer should establish and maintain procedures for verification, storage andmaintenance of customer and externally-supplied materials intended for incorporation into thecustomer's excipient. Verification by the manufacturer does not relieve the customer or external
provider of the responsibility to provide acceptable material.
Material that is lost, damaged or is otherwise unsuitable for use should be recorded and reported
to the customer or external provider. In this case, procedures should be in place for acceptabledisposition and replacement of the material.
The manufacturer should also make provisions to protect other real and intellectual property thatis provided by the customer or external provider.
Note:

Examples of customer or externally provided property include:•

test equipment;•

test methods;•

specifications.

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8.5.4Preservation

8.5.4.1 Handling, storage, and preservation
Appropriate storage conditions should be maintained. If critical to maintaining the quality ofmaterials used in excipient production and packaging, storage conditions should be specified,monitored, and recorded. Deviations from specified storage conditions should be assessed (see8.7). Storage and handling procedures should be defined to:•protect containers, labels, closures, and security seals,•

minimize the risk of contamination, damage, or deterioration, and•prevent mix ups.

Note:

1. Examples of materials used in excipient production and packaging include:•

raw materials;•

intermediates, including those processed by third parties•

process aids;•

packaging materials (primary and secondary), printed and unprinted.

2. Examples of specified storage conditions include:•

temperature;•humidity;•

light;•

atmosphere;•

sanitary (e.g., odorless, free from pest infestation, visibly clean).

Bulk storage containers should be identified and labeled with their contents. Outdoor storage ofmaterials and excipients is acceptable provided the containers give suitable protection against
deterioration, contamination, and loss of traceability.
Note:

Examples of outdoor storage and controls include:•

movable containers designed to withstand weather are kept in designatedlocations;•

unpackaged pre-GMP materials (e.g., minerals or vegetation) that will undergo
extensive processing (e.g., dissolving, extraction, washing, melting, etc.);

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tank farms and silos designed to provide adequate protection and segregation toprevent mix ups.

See also the IPEC Good Distribution Practices Guide.

8.5.4.2 Packaging
The selection of excipient packaging should be justified, documented, and include the following
features:•documented specifications, based on the excipient’s properties, including stability,•

packaging systems that provide adequate protection against deterioration, moisture uptake orcontamination of the excipient during transportation and recommended storage,•

packaging system components that do not interact with or contaminate the excipient,

Note:

•

Examples of packaging system components include:•

containers (small volume and bulk), closures, and seals;•

inert gas blanket;•

moisture barriers;•

desiccants.

tamper-evident seals, where feasible

If containers are to be reused for the excipient, verified cleaning procedures should be followed
and should include instructions for removing previous labels. Records of cleaning should be
retained.
Excipient packaging should not be used to hold waste unless clearly labeled as waste.

8.5.4.3 Delivery and distribution
Excipients should only be supplied within their expiry date or reevaluation period and, whereapplicable, according to customer and / or regulatory requirements.
Distribution records of excipient shipments to initial customers should be kept. To facilitate
retrieval if necessary, distribution records should include:•

batch number,•customer name and address,

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shipment date, and•where critical to maintaining excipient quality, conditions were met during transportation to theinitial customer.

Where applicable, excipient manufacturers should define and provide transportation conditions toservice providers and customers (see 8.6.8).
Note

1. Defined transportation conditions may be applicable, e.g., in the case of excipients forwhich transportation conditions outside recommended storage conditions have thepotential to result in deterioration of the excipient.
2. Examples of defined transportation conditions include:•

temperature;•humidity;•

light;•

atmosphere;•

sanitary (e.g., odorless, free from pest infestation, visibly clean).

3. Examples of how transportation conditions may be provided include:•

container label;•shipping documents;•

product specification;•

safety data sheet.

For bulk transport, verified cleaning procedures should be justified and applied. Records ofcleaning should be retained. A list of prohibited and / or allowed previous cargos should be
supplied to transportation companies.
See also the IPEC Good Distribution Practices Guide.
8.5.5

Post-delivery activities

The excipient manufacturer should determine and meet post-delivery activities, based on theintended use of the excipient, including:•informing customers of issues, including recalls and critical deviations detected after deliveryof the excipient (see 8.7.1 and 8.7.4), and significant changes (see 6.3),

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provision for a complaint handling process (see 8.7.3),•

provision for a returned goods handling process (see 8.7.1.3),•

provision for replies to enquiries and requests

Note:

1. Examples of:••enquiries include:omaterial handling;odisposal topics;osafety data questions;oallergens;ocompendia changes.

requests include:oretain samples;oshelf-life extension;otechnical support.

2. Enquiries and requests may originate from customers, authorities (e.g., regulatory
bodies), or other interested parties (e.g., distributors, agents, contract manufacturers,
and third-party service providers).
8.5.6

Control of changes

For planning of changes, and changes to requirements for excipients and GMP services, see 6.3
and 8.2.4, respectively.

8.6

Release of excipients and GMP services

The excipient manufacturer should establish procedures and test methods to ensure excipientsand GMP services meet requirements and specifications prior to release. Details are provided in
sections 8.6.1 through 8.6.9.
8.6.1

Monitoring and measurement

Analytical procedures and test methods should be evaluated and verified to demonstrate they
provide reliable test results and are fit for purpose. These may be included in the current editionof the appropriate pharmacopoeia or another accepted standard, but the methods may also be

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non-compendial. The responsibility for monitoring the current pharmacopeia or official
compendium should be assigned.
If the excipient is labeled with a compendial designation, then it must meet all requirements of thedesignated compendia.
Note:

The word “must” is used instead of the word “should” because use of the compendial
designation requires compliance with all compendial requirements including:•material monograph;•

general notices;•mandatory general chapters.

Without the corresponding GMP, it is not acceptable to upgrade non-excipient grade materials for
excipient use based only on testing results.
Non-compendial, including in-house, analytical test methods should be demonstrated to be atleast equivalent to those in the compendia.
Note:

Sources of non-compendial analytical test methods include:•

national testing standards, e.g., ASTM (American Society for Testing andMaterials), EN (European Norms), BS (British Standards);•

industry testing standards, e.g., AOAC (Association of Official Analytical
Chemists), ICUMSA (International Commission for Uniform Methods of Sugar
Analysis);•customer specific analytical test methods

See also the IPEC Validation Guide for Pharmaceutical Excipients, 2.5 “Analytical Methods”.
8.6.2

Laboratory controls

Data integrity principles, i.e., ALCOA+, should be incorporated throughout laboratory procedures
and systems to always maintain data integrity (see 7.5.1).
The excipient manufacturer should establish laboratory controls, requiring complete data derived
from tests, necessary to ensure conformance with specifications and standards. Records (see7.5.3) of these controls should include:•

identification and traceability of samples, i.e., a description of the sample received for testing
together with:othe material name;

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obatch number or other distinctive code;oidentity of the person taking the sample (if applicable);odate the sample was taken;otime the sample was taken (where appropriate).

•

test method reference(s);•for each analysis, raw data required to confirm the test result, including sample preparation,
graphs, chromatograms, charts, and spectra from laboratory instrumentation, identifying thespecific material and batch tested;•

calculations performed;•

test results compared with specifications;•date and identity of the person who performed each test, including time (where appropriate);

Note:

•

Examples of reasons to provide time of analysis include:•

unstable samples or reagents may deliver invalid results over time;•

the order of testing may impact analytical results;•

documenting time may support root cause investigations.

the equipment, including ancillary equipment, used to perform the test when multiple
equipment options are available.

Note:

1. Examples of ancillary equipment include:•

thermometers;•

electronic pipettes;•

pH-meters;•balances.

2. Examples of reasons to document laboratory equipment used include:•

to facilitate laboratory investigations, e.g., information about correct setup,
traceability to equipment qualification / calibration status (see 7.1.5.1);•

to facilitate other investigations, e.g., manufacturing investigations, customer
complaints.

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Laboratory reagents, solutions, and reference standards may be purchased or preparedinternally. There should be documented procedures for the labeling, handling, use, and storageof laboratory reagents, solutions, and reference standards. Procedures should also be available
for the preparation and standardization of internally prepared materials.
Purchased materials should be verified on receipt.
Purchased and internally prepared materials should be stored appropriately and labeled with thename, concentration, and expiry or re-evaluation date. Purchased materials, once opened, should
also be labelled with the remaining usage period.
Records for the preparation and standardization of reagents, solutions, and reference standards
should be maintained and include at a minimum:•

identity of the prepared material,•

identity, quantities, and batch numbers of components used in the preparation,•

name of preparer,•

equipment used for preparation,•

date of preparation,•

expiry or re-evaluation date of the prepared material.

When secondary reference standards are used, there should be a documented procedure for
their qualification against primary reference standards. This procedure should include
requirements for preparation, testing, approval, use, and storage.
Expiry or re-evaluation periods should be defined for secondary reference standards. For
secondary reference standards with re-evaluation periods, requalification should be performed
according to a documented procedure.
Note:

Examples of secondary reference standards include:•

microbiological stock cultures, which may be used for positive and negative control
testing, for media testing;•internally produced material tested against a primary reference standard, which
may be used for performing system suitability.

Secondary reference standards may also be referred to as working standards (FDA.
Guidance for industry: analytical procedures and methods validation—chemistry,
manufacturing, and controls documentation. Rockville: FDA; 2000.)

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8.6.3Finished excipient testing and release

Routine finished excipient testing should be performed on each batch to ensure that the excipient
conforms to documented specifications. Nonroutine testing should be scheduled and justified toconfirm the finished excipient complies with all specifications.
Note:

Examples of nonroutine testing (i.e., not performed on each lot) include:•

micro testing when verified by process controls;•

functionality related characteristics.

Results from in-process testing, process analytical technology (PAT), or from other processcontrol records may be used to demonstrate that the finished excipient conforms to documented
specifications.
The quality unit should be responsible for the release of the finished excipient. There should be aprocedure to ensure that appropriate manufacturing documentation, in addition to the test results,
is evaluated prior to release of the finished excipient. Excipient shipped to the customer prior toquality unit release should follow a documented quarantine-shipping process that includes
acknowledgement by the customer and any relevant authority.
8.6.4

Out-of-specification test results

Out-of-specification (OOS) test results should be investigated and documented according to a
written procedure (see 10.2).
Results obtained by retesting may only be used to replace original test results if a documented
investigation concludes that the original results are erroneous due to an assignable root cause.
Note:

Examples of assignable root cause that invalidates original results include:•

sampling error (e.g., pulled from wrong tank, used uncleaned sampling device);•

test equipment settings were incorrect;•

wrong weight of sample used in analysis;•

wrong analytical procedure used.

When there is no assignable root cause, the OOS procedure should define:•criteria for retesting and the use of retest sample results,•

criteria for re-sampling,•which statistical techniques are to be used and under what circumstances.
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Retesting may not be necessary when product is released under a different specification.
However, an OOS investigation should still be performed and documented.
Original and retest data should be included in the investigation report, including when the sample
is suspected of not being representative of the material from which it was taken.
8.6.5

Retained samples

A representative sample of each batch of the excipient should be retained, unless otherwise
justified and documented. The retention period should be justified and based on the expiry or reevaluation date.
The retained samples should be stored in a secured location, readily retrievable and in conditions
consistent with the recommended storage conditions for the finished excipient.
Unless otherwise justified, retained samples should be maintained in a packaging format that isequivalent to or more protective than the commercial packaging system.
Note:

Reasons for using more protective packaging for retained samples include:•

to ensure the results obtained at retesting are on a sample that has not changed
during storage;•

because finished packaging sizes may not be practical for sample storage;•

because samples for microbiological testing need to be stored in specialized
containers.

Unless otherwise justified and documented, the sample size should be at least twice the amountrequired to perform complete specification testing.
8.6.6

Certificates of analysis

Excipient manufacturers should provide certificates of analysis to the required specification foreach batch of excipient. See the IPEC Certificate of Analysis Guide for Pharmaceutical Excipientsfor details on the suitable contents of a certificate of analysis.
8.6.7

Impurities

Where possible, excipient manufacturers should identify impurities as part of the composition
profile. See also the IPEC Composition Guide.
Appropriate limits for impurities should be based upon safety data, limits as described in official
compendia, or other requirements and sound GMP considerations. Manufacturing processes
should be adequately controlled so that impurities do not exceed established limits.

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Excipient manufacturers should conduct documented risk assessments to determine whether the
excipient specifications should include tests and limits for impurities. At a minimum,
microbiological bioburden and impurities from raw materials of natural origin should beconsidered.
Note:

Reasons for adding impurity limits to specifications include:•

use of metal catalysts;•

presence of impurities in raw materials•

potential presence of pyrogen for parenteral excipients;•

use of solvents;•

use of processing aids such as flocculants or filter aids;•

reprocessing or reworking.

In some manufacturing processes, insoluble and visible particles cannot be fully excluded. These
particles should not necessarily be considered impurities. However, the excipient manufacturer
should implement mitigation strategies based on a documented risk assessment to maintain theoccurrence of such particles at an acceptable level. See also the IPEC TUPP Guide for guidance
related to technically unavoidable particles.
8.6.8

Stability

The stability of excipients is an important factor contributing to the overall safety, quality, andefficacy of the medicinal products in which they are used. Excipient manufacturers should
determine the stability of their excipients. They should also consider stability when defining
storage and transportation conditions.
See the IPEC Excipient Stability Program Guide.
8.6.9

Expiry date or re-evaluation period

Based on excipient stability, an expiry date or re-evaluation period should be assigned to each
excipient and communicated to the customer.
Note:

Examples of how to communicate expiry date or re-evaluation period to customers
include:•printed information on packages, certificate of analysis;•

shelf-life statement, which may be included in an excipient information package ormade available separately.

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8.7

Control of nonconforming outputs

Note:

1. Outputs include intermediates, finished excipients and GMP services.
2. ISO 9000 defines:

8.7.1

•

“Output” as the result of a process.

•“Process” as a set of interrelated or interacting activities that use inputs to deliver
an intended result.

Control of nonconforming intermediates and finished excipientsIntermediates and finished excipients not meeting analytical specifications or other quality
indicators should be clearly identified and controlled to prevent inadvertent use or release for sale.
Note:

Examples of other quality indicators include:•compliance with GMP;•

free of foreign matter;•

required documentation available and complete, e.g., deviations closed prior torelease.

It is not acceptable to blend contaminated or adulterated batches to reduce the contamination or
adulteration below an acceptable or detectable limit (see 8.5.1.4).
Incidences of nonconformance should be investigated and addressed according to a documented
procedure in order to:•

identify the root cause(s),•assess the potential impact on other:obatches;ointermediates, finished excipients and other product lines;oprocesses.
Note:

Examples of other processes to be assessed for potential impact, include:•

maintenance;•

inspections;•cleaning.

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define and implement actions to prevent recurrence (see 6.1.2 and 10.2), as appropriate.

All activities of the above-mentioned investigation should be documented and records maintained.
The quality unit should review and approve the results of this investigation (see 5.3).

8.7.1.1 Reprocessing
Reprocessing should only occur when it has been assessed and documented that theintermediate or excipient may be made in this manner (see 8.5.1). Records of reprocessing should
be maintained (see 8.5.1.1 and 8.5.2.1).

8.7.1.2 Reworking
Reworking should only be conducted following a documented risk assessment and approval by
the quality unit. As appropriate, when performing the risk assessment, consideration should begiven to:•new impurities that may be introduced as a result of reworking;•additional testing to control the reworking;•records and traceability to the original batches;•suitable acceptance criteria for the reworked intermediate and / or finished excipient, including
equivalence to established specifications;•

impact on stability or the validity of the re-evaluation period;•

impact on performance of the intermediate and / or finished excipient;•additional controls needed to minimize the risk to excipient quality;•

customer notification.

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The method of reworking should be documented and in compliance with the outputs of the risk
assessment. Records of reworking should be maintained.

8.7.1.3 Returned excipients
There should be a documented procedure detailing the process for handling returned excipientsfrom receipt through quarantine and final disposition.
The quality unit should approve disposition of the returned excipient (e.g., resale, re-grade,
reprocess, rework, or disposal).
Returned excipients should only be considered for resale when the quality unit has evaluated andconfirmed that the excipient’s integrity and conformance to the required storage and / ortransportation conditions have been met for each package.
Excipient integrity factors include at a minimum:•

no evidence of tampering;•original packaging is not compromised;•remaining shelf life does not preclude resale.

Records of the quality unit’s confirmation should be maintained and include at a minimum:•

name of the excipient;•batch (lot) number;•reason for return;•quantity returned;•

identification of customer who returned the excipient;•

any evaluation that was performed;•

final disposition of the returned excipient.

8.7.2

Control of nonconforming GMP services

Incidences of nonconformance should be investigated and addressed according to a documented
procedure in order to:•

identify the root cause(s),•assess the potential impact on:

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obatches that are in scope of the nonconforming GMP service;oother GMP services that could be affected by the identified root cause(s).

•notify customer(s) (see 8.2.1),•

define and implement actions to prevent recurrence (see 6.1.2 and 10.2), as appropriate.

All activities of the above-mentioned investigation should be documented, and records
maintained. The quality unit should review and approve the results of this investigation (see 5.3).
8.7.3

Customer complaint handling

There should be a documented procedure for management of customer complaints within a timely
manner.
Note:

The procedure for management of customer complaints may also be applied tocomplaints from internal customers, i.e., intra-company or inter-departmental complaints.

This procedure should include at a minimum:•

receiving and documenting the complaint;•

investigating the complaint;•

concluding and documenting the investigation, identifying:•oroot cause;owhether the complaint is justified;oimpact on other intermediates, finished excipients (see 8.7.1), or GMP services (see8.7.2);ocorrective and / or preventive actions as needed (see 10.2);

responding to the customer and, as appropriate, other interested parties (see 4.2).

Records of complaints, complaint investigations, and resulting actions should be maintained.
Complaints should be regularly evaluated for trends, including recurrence and criticality, in order
to identify needs for corrective or preventive actions.
8.7.4

Recall / Retrieval

Note:

Is there a difference between the terms “recall” and “retrieval”?
In some regions / countries regulatory authorities may have specific definitions for theseterms.

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In this document “recall” has the same meaning as “retrieval”.
There should be a documented procedure for effectively and promptly recalling from the market,
excipients known or suspected to be nonconforming (see 8.7.1). This procedure should include
at a minimum:•

how the recall of an excipient should be conducted;•

which interested parties require notification (see 4.2);•

how, through a mock recall, the effectiveness of this procedure is periodically evaluated;•

how reconciliation discrepancies are addressed.

Recalled excipients should be identified and quarantined until final disposition by the quality unit.
Records of recalls and mock recalls should be maintained.

9

Performance evaluation

9.1

Monitoring, measurement, analysis and evaluation

9.1.1

GeneralThe excipient manufacturer should identify, plan, and implement the monitoring and measurement
activities required to demonstrate conformity and effectiveness:•of the organization’s quality management system according to this guide;•

to applicable requirements (see 4.2).

Monitoring and measurement activities should be documented and consider:•what needs to be monitored and measured;•

what methods are needed to ensure valid results are obtained;•

when these activities should be performed;•

when results should be analyzed and evaluated.

9.1.2

Customer satisfaction

The excipient manufacturer should establish monitoring and measurement activities to assesscustomer satisfaction including the methods for obtaining, monitoring, and reviewing thisinformation. This information should drive activities to continuously improve customer satisfaction.
Note:

Examples of monitoring and measurement activities include:

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9.1.3•trending of customer complaints (see 8.7.3) and customer audit results;•

surveying and evaluation of customer perceptions, including business review
meetings, sales contacts, and activities at expositions;•trending of customer returns (see 8.7.1.3) and rejections.

Analysis and evaluation

The excipient manufacturer should analyze results obtained from monitoring and measurement
activities (see 9.1.1) to evaluate:•

conformity of excipients and GMP services;

Note:

Examples include process capability, product / service reviews and customer complaints.

•

the degree of customer satisfaction (see 9.1.2);•

the performance and effectiveness of its quality management system;

Note:
•

Examples include results from internal and certification audits.

if planning has been implemented effectively;

Note:

Examples include planned actions completed on time and in full.

•the effectiveness of actions taken to address risks and opportunities (see 6.1);•

the performance of external providers (see 8.4.3);•

the need or opportunity for improvements to the quality management system (see 10).

Note:

9.2

The results of these evaluations may be used as part of the input for management review(see 9.3.2).

Internal audit

The excipient manufacturer should plan, establish, implement, and maintain an internal audit
program to:•consider whether its quality management system (see 4.4) conforms to the organization’s own
requirements, and to the GMP principles of this guide;•

confirm that the implementation and maintenance of the quality management system are
effective.

This program should be based on risk and carried out following documented procedures.

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Note:A review of the internal audit program performed not less than once per year is
considered best practice (see 9.3.2).

For internal audits, the procedures should:•

include the frequency, methods, responsibilities, planning requirements and reporting,considering the site’s activities, changes affecting the organization, and previous audit results;

Note:

1. Frequency of internal audits may be determined based on risk assessment.
2. Examples of internal audit methods include:•

onsite, remote, and desktop audits;•checklist and systems-based audits;•face-to-face interviews and written questionnaires.

3. Examples of changes affecting the organization include:••changes in strategy by top management;•changes in organizational structure (e.g., access to expertise and responsibility formonitoring external issues);•changes in operational strategy (e.g., outsourcing, insourcing);•changes to and use of infrastructure (see 7.1.3).

require the identification of audit criteria and scope;

Note:

1. Examples of audit criteria include the internal and external requirements used as
references during internal audits.
Examples of these requirements and references include policies and procedures, IPEC
Guides, and external standards or regulations, as applicable.
2. Examples of audit scope include the extent and boundaries of an audit, such as
physical locations, departments, activities, processes, and product grades.
3. Where applicable, audit criteria and audit scope may need to consider corporate andlocal aspects.

•

define auditor qualification requirements;•

require that auditors are selected to ensure objectivity and impartiality of the audit process;Note:

An example of how auditors can be selected to ensure objectivity and impartiality is by
ensuring that auditors are independent of the area / process being audited.

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describe requirements for audit documentation and reporting, including, at a minimum, report
distribution to relevant management;•

where nonconformity is identified, require timely identification of follow-up actions (see 10.2).

Records should be maintained as evidence of audit program implementation and audit results.

9.3Management review

9.3.1

GeneralTop management of the organization should review the quality management system at plannedintervals to verify the organization’s continued conformance to this guide.
Note:Management review performed not less than once per year is considered best practice.

The review should be documented and include a process for:•identifying opportunities for improvement;•

assessing the alignment with the excipient manufacturer’s strategic direction;•

identifying any need for changes to the quality management system (see 4.3);•

checking suitability of the quality policy (see 5.2).

Records should be maintained as evidence of management review, including actions
recommended and taken.
9.3.2

Management review inputs

Management review should be carried out taking into consideration, at a minimum:•

status of action items from previous management review;•

changes in external and internal issues that are relevant to the quality management system(see 4.1);•

information on the performance and effectiveness of the quality management system,
including trends in:ocustomer satisfaction (see 9.1.2);ocustomer complaints (see 8.7.3);ofeedback from relevant interested parties (see 4.2);othe extent to which quality and GMP objectives have been met (see 6.2);

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oprocess performance;oconformity of excipients and GMP services;ononconforming outputs (see 8.7) and resulting actions;ostatus of corrective and preventive actions;omonitoring and measurement results (see 9.1.3);ointernal and external audit results;operformance of external providers (see 8.4.3);•

adequacy of resources (see 7.1);•

effectiveness of actions taken to address risks and opportunities (see 6.1);•

opportunities for improvement (see 10).

Note:

1. Trending may include statistical analysis.
2. The term “resulting actions” includes immediate corrections (i.e., actions to eliminate
a detected nonconformity), corrective actions and preventive actions.

9.3.3

Management review outputs

Management review outputs should include decisions and actions related to:•opportunities for improvement (see 10);•

resource needs;•

any need for changes to the quality management system (see 4.3);•

any need to update the quality policy (see 5.2).

10 Improvement
10.1 General
The excipient manufacturer should select opportunities for improvement (see 9.3.3), and plan andimplement activities to improve:•

performance and effectiveness of the quality management system and its processes (see
4.4);

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excipients and GMP services to enhance customer satisfaction, considering the potential
impact on patient safety.

Improvement activities should also include correction, prevention, or reduction of undesired
effects.
Any changes should be assessed and implemented following the change control procedure (6.3).

10.2 Nonconformity and corrective action
Note:

1. What is a nonconformity?
ISO 9000 defines “nonconformity” as “non-fulfilment of a requirement”.
“Nonconformity” is also known as “nonconformance”. These terms may be usedinterchangeably.
See 4.2 for more information about determining applicable requirements.
See 8.7 for more information about control of nonconforming outputs.
2. What is a corrective action?
ISO 9000 defines “corrective action” as “action to eliminate the cause of a nonconformity
and to prevent recurrence”. ISO 9000 goes on to explain that a “corrective action is taken
to prevent recurrence whereas preventive action is taken to prevent occurrence.”

The excipient manufacturer should have a documented procedure to:•define the management of nonconformities, as applicable and commensurate with risk;•

control and correct nonconformities;•

address the consequences of nonconformities;•

investigate each nonconformity, determining:othe root cause(s),
Note:

o

Identifying “human error” as a root cause may overlook a deficiency of systems,
such as training, procedures, or tools.

the need for actions, including the prevention of recurrence of the same, similar, or
potentially similar nonconformities (see 10.3).
Note:

Examples of identification of (potential) similar nonconformities include:•

impact on other batches of the same or different product;•

impact on other systems or processes.

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evaluate and optimize the effectiveness of actions taken;

Note:

Optimizing the effectiveness of actions may be achieved through risk assessment. For
example, it would not be necessary to install a new reactor for a light sensitive excipientwhen covers on the windows can provide adequate protection.

•

evaluate and update risk assessments as described in this guide (see 3, 7.1.3, 7.1.4, 7.1.4.3,
7.1.4.4, 8.3.1, 8.6.7, and 8.7.1.2), if necessary;•

update the quality management system (see 4.4), if necessary;•record changes (see 6.3) resulting from actions, if necessary.

Records should be maintained as evidence of these activities.

10.3 Continual improvement
The excipient manufacturer should continually improve the quality management system and its
processes (see 4.4). Improvement activities should consider suitability, adequacy, andeffectiveness.
To identify opportunities for continual improvement of the quality management system, theexcipient manufacturer should consider results from analysis and evaluation (see 9.1.3) and theoutputs from management review (see 9.3.3).

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11 References
IPEC References:
IPEC Certificate of Analysis Guide for Pharmaceutical Excipients 2013
IPEC Composition Guide For Pharmaceutical Excipients 2020
IPEC Co-Processed Excipient Guide For Pharmaceutical Excipients 2017
IPEC Excipient Information Package User Guide and Templates 2020
IPEC Excipient Stability Program Guide 2010
IPEC General Glossary of Terms and Acronyms For Pharmaceutical Excipients 2021
IPEC GMP Certification Scheme and Certification Body Qualification Guide For Pharmaceutical
Excipients 2020
IPEC Good Distribution Practices Guide For Pharmaceutical Excipients 2017
IPEC Position Paper: Data Integrity for Pharmaceutical Grade Excipients 2020
IPEC Qualification of Excipients for Use in Pharmaceuticals Guide and Checklist 2020
IPEC Quality Agreement Guide and Template(s) For Pharmaceutical Excipients 2017
IPEC Risk Assessment Guide for Pharmaceutical Excipients, Part 1: Risk Assessment for
Excipient Manufacturers 2017
IPEC Significant Change Guide for Pharmaceutical Excipients 2014
IPEC Technically Unavoidable Particle Profile (TUPP) Guide 2015
IPEC Validation Guide For Pharmaceutical Excipients 2021

Other References:
EC document 2015/C 95/02
EU GMP Annex 11, Computerised Systems, January 2011
EXCiPACT cGDP 2021 standard
EXCiPACT cGMP 2021 standard
EXCiPACT cGWP 2021 standard

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FDA Guidance for industry: analytical procedures and methods validation—chemistry,
manufacturing, and controls documentation. Rockville: FDA; 2000
ISO 9000:2015 Quality management systems – Fundamentals and vocabulary
ISO 9001:2015 Quality management systems — Requirements
MHRA: GxP Data Integrity Definitions and Guidance for Industry, July 2016
NSF/IPEC/ANSI 363 – 2019 Good Manufacturing Practices (GMP) for Pharmaceutical
Excipients
PIC/S PI-045-1
Title 21 of the US Code of Federal Regulations (21 CFR)
U.S. FDA Code of Federal Regulation, Title 21 Part 11 (21 CFR 11), Electronic Records;
Electronic Signatures
US FDA Guidance for Industry: Part 11, Electronic Records; Electronic Signatures-Scope andApplication, 2003
WHO Guidelines for drinking-water quality 2022
WHO: TRS 996, Annex 05, Guidance on good data and record management practices, 2016

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