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IPEC Qualification of Excipients for Pharmaceutical Use

By Lloyd Walker,2014-08-10 08:30
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Qualification of Excipients for Pharmaceutical Use 2008 This document offers best practice and guidance in the establishment of an effective relationship between an excipient supplier and excipient users. The excipient supplier may be a manufacturer or a distributor (or both). It concentrates on the issues that the two parties are likely to encounter and offers advice and best practice as to how to address them, thereby ensuring a smoother relationship and easier use of the excipient by the user and in their dealings with the regulatory authorities. Because excipients are diverse and often have uses other than in pharmaceutical applications, a supplier may discover that their product is being used by the pharmaceutical industry as an excipient. This document will be especially valuable in such situations because many of the issues described will be new to the supplier.

    Qualification of

    Excipients for

     Pharmaceutical Use

    2008

    Copyright ? 2008 The International Pharmaceutical Excipients Council

    QUALIFICATION OF EXCIPIENTS FOR PHARMACEUTICAL USES

FOREWORD

    IPEC is an international industry association formed in 1991 by manufacturers and users of excipients. It is an association comprising three regional pharmaceutical excipient industry associations covering the United States, Europe, and Japan (which are known respectively as IPEC-Americas, IPEC Europe, and JPEC). IPEC‟s objective is to contribute to the development and harmonization of international excipient standards, the introduction of useful new excipients to the marketplace and the development of best practice and guidance concerning excipients.

IPEC has three major stakeholder groups;

    1. Excipient manufacturers and distributors, who are considered suppliers in this document,

    2. Pharmaceutical manufacturers, who are called users, and

    3. Regulatory authorities who regulate medicines.

    SuppliersUsers

    IPEC

    Regulatory

    Authorities

    This document offers best practice and guidance in the establishment of an effective relationship between an excipient supplier and excipient users. The excipient supplier may be a manufacturer or a distributor (or both). It concentrates on the issues that the two parties are likely to encounter and offers advice and best practice as to how to address them, thereby ensuring a smoother relationship and easier use of the excipient by the user and in their dealings with the regulatory authorities.

    Because excipients are diverse and often have uses other than in pharmaceutical applications, a supplier may discover that their product is being used by the pharmaceutical industry as an excipient. This document will be especially valuable in such situations because many of the issues described will be new to the supplier.

Copyright ? 2008 The International Pharmaceutical Excipients Council Page i

    QUALIFICATION OF EXCIPIENTS FOR PHARMACEUTICAL USES

    Excipient

    Qualification

    SuppliersUsers

    IPEC

    Regulatory

    Authorities

    Thus any material used in the pharmaceutical drug product will be required to be manufactured under appropriate Good Manufacturing Practices (GMP) and supplied under Good Distribution Practices (GDP). The exact definition of GMP or GDP will depend on the material in question (e.g. excipient, active pharmaceutical ingredient, packaging etc) and legislation where the excipient is supplied or sold. Within this guide the terms GMP and GDP are used to encompass all of these various definitions.

    Like all guides this document is not meant to be proscriptive, and suppliers and users may follow the guideline as written or find their own manner to address the subjects highlighted. The guide is intended to be comprehensive and covers the essential aspects of the supplier-user relationship. In this regard not every topic may be appropriate for all relationships.

    To facilitate reading, the excipient qualification process has been presented in flow charts as a means of linking the activities and steps in a logical manner. This aids comprehension and places these steps into context.

    There is no specific requirement to follow the exact sequences of actions as detailed in the flowcharts although users will find these helpful to ensure all aspects are considered.

    Although excipient qualification does not directly involve the regulatory authorities, they set many of the conditions that have to be satisfied if a user is to employ an excipient in their medicine.

    This document describes the three phases of the excipient qualification process. The layout and content are as follows:

    Section 1 Introduction: describes the scope, purpose, and layout of this guide.

    Phase 1 The Excipient Supplier’s Process

    Section 2 General Guidance: provides background concerning excipient manufacture,

    regulation, and controls.

    Section 3 Excipient Development and Specification Process: provides guidance to

    excipient suppliers on the development of an excipient and its specifications.

    Phase 2 The User’s Process

    Section 4 Excipient User Assessment, Selection, and Specification Process: provides

    Copyright ? 2008 The International Pharmaceutical Excipients Council

    Copyright? 2008 Pharmaceutical Quality Group

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    QUALIFICATION OF EXCIPIENTS FOR PHARMACEUTICAL USES

    guidance on how users should assess the excipients for inclusion in their

    formulations.

    Phase 3 The Negotiation Process

    Section 5 Excipient Supplier-User Negotiation Process: provides guidance on the

    development of an agreement between the excipient supplier and

    pharmaceutical user to define excipient quality requirements.

    Glossary Terms defined in the glossary appear in bold the first time they are used in this

    document.

    Appendices Flow diagrams that illustrate the development of a material for sale as an

    excipient, the approval of the use of an excipient in a dosage form, the

    negotiation process used to determine the appropriateness of the requirements,

    and the specific requirements for the excipient.

    Each Phase of the process is also described by a flowchart illustrating the process:

Phase One- The Excipient supplier‟s Process shows the steps a chemical manufacturer may take to

    evaluate the market and regulatory requirements for the proposed excipient and the steps

    leading up to the market launch,

    Phase Two- The User‟s Process illustrates the path a pharmaceutical company ordinarily follows in

    evaluating the excipient and its manufacturer for use in a formulation, and Phase Three- The Negotiation Process shows the process by which the supplier and user interact to reach a

    mutual agreement on quality requirements.

    As an international guidance document, the guide cannot specify all national legal requirements or cover in detail the particular characteristics of excipient qualification in all territories. Although the details in this

    document highlight European and United States issues, the principles can be applied to any excipient supplier excipient user relationship worldwide.

    By setting out all the stages in excipient qualification both suppliers and users will be better placed to use the itools in ICH Q9 Quality Risk Management to better assess which steps in this guide are most appropriate and necessary for their particular situation.

     i ICH Q9, Quality Risk Management, http://www.ich.org/LOB/media/MEDIA1957.pdf

    Copyright ? 2008 The International Pharmaceutical Excipients Council

    Copyright? 2008 Pharmaceutical Quality Group

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    QUALIFICATION OF EXCIPIENTS FOR PHARMACEUTICAL USES

TABLE OF CONTENTS

    FOREWORD i ACKNOWLEDGEMENTS vi 1. INTRODUCTION 1 1.1 Purpose 1 1.2 Scope 1 1.3 Principles Adopted 1 1.4 Layout 1 2. GENERAL GUIDANCE 2 2.1 Differentiation of Excipient Manufacture 2 2.1.1 Reference Documents 3

    2.2 Preliminary Excipient Marketing Decision 3 2.2.1 Determination of the Intended Target Market and Route of Administration 3

    2.3 Regulatory Assessment 4 2.3.1 Safety, Toxicological, and Precedence of Use Issues 4

    2.3.2 New (Novel) Excipients 5

    2.3.3 Compendial Requirements 6

    General Comments 6

    United States Pharmacopeia 7

    European Pharmacopeia 8

    Japanese Pharmacopeia 8

    New and Novel Excipients not listed in a Pharmacopoeia 8

    Other regulatory requirements 10

    2.3.4 Desired Properties for Intended Use 10 2.3.5 Excipient Master Files and Other Filings 10

    United States Drug Master Files 11

    European Certificates of Suitability (CEP) 11

    Japanese Drug Master Files 12

    2.3.6 International Conference on Harmonisation (ICH) 12 2.3.7 Specific Safety Issues 13

    2.3.8 Concluding Comments on the Regulatory Assessment 14 2.4 Manufacturing and Packaging 14 2.4.1 Process Capability and Validation 15 2.4.2 Test Methods and Validation 16

    2.5 Excipient Specifications 17 2.5.1 Excipient Stability 17

    3. EXCIPIENT DEVELOPMENT AND SPECIFICATION PROCESS 18 3.1 Excipient Consistency and Control 18 3.2 Performance Indicators 19 3.3 Production Specification and Master Batch Record 19 3.4 Marketing Materials 20 3.4.1 Sampling Guidelines 21

    3.5 Customer Feedback 22 3.6 Post Product Launch 22 3.7 Confidential Information 22 4. ASSESSMENT, SELECTION AND SPECIFICATION PROCESS 24 4.1 Project Initiation 24 4.2 New Formulation Development Projects 24 4.2.1 Selecting the Excipient 25

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    QUALIFICATION OF EXCIPIENTS FOR PHARMACEUTICAL USES

    4.2.2 Selecting the Supplier 26

    4.2.3 Regulatory Assessment 28

    4.2.4 Refining the Excipient List 29

    4.2.5 Formulation Design, Development, and Optimization 30

    4.3 Alternative Excipient Source Projects 31 4.4 Negotiation Process Impact 33 5. NEGOTIATION PROCESS 34 5.1 Review of Excipient User Requirements 34 5.2 Quality Agreement 36 5.3 Modification of Requirements 37 5.4 Identification of Potential Solutions 37

    5.4.1 Lot Selection 38

    5.4.2 Manufacture to Order 41

    5.5 Other Approaches 41

    5.5.1 In-House Processing 41

    5.5.2 Reformulate 41

    5.5.3 Supplier Custom Manufacture 42 5.6 Concluding Agreements 42 APPENDIX A: FLOW DIAGRAMS 43 APPENDIX B: DEFINITIONS AND GLOSSARY 51 APPENDIX C: BIBLIOGRAPHY 55

    Copyright ? 2008 The International Pharmaceutical Excipients Council

    Copyright? 2008 Pharmaceutical Quality Group

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    QUALIFICATION OF EXCIPIENTS FOR PHARMACEUTICAL USES

ACKNOWLEDGEMENTS

    This Guide was developed by representatives of many of the member companies of the International

    Pharmaceutical Excipients Council (IPEC), an industry association whose members consist of excipient manufacturers, distributors, and pharmaceutical users. The company representatives who worked on this

    Guide are listed below:

IPEC-AMERICAS

    William F. Busch, Dow Wolff Cellulosics Dale Carter, J.M. Huber Engineered Materials Raymond Croes, SPI Pharma, Inc.

    Sidney A. Goode, Pharm.D, The Dow Chemical Company Maria Guazzaroni Jacobs, Ph.D., Pfizer, Inc. Diana Hickey, EMD Chemicals Inc.

    David B. Klug, M.S., sanofi-aventis U.S. LLC Cindy Libonati, C.P.M., Purdue Pharma L.P. Brian McCarter, EMD Chemicals Inc.

    Philip H. Merrell, Ph.D., Jost Chemical Co. Ann Van Meter, The Dow Chemical Co.

    R. Christian Moreton, Ph.D., FinnBrit Consulting Frank H. Murphy, Dow Chemical

    Londa L. Ritchey, M.S., Wyeth

    David R. Schoneker, M.S., Colorcon, Inc. Alexa Smith, Colorcon, Inc.

    Bob Sulouff, Hercules/Aqualon

    Katherine L. Ulman, Dow Corning Corporation Robert E. Wiens, Eli Lilly Incorporated Priscilla Zawislak, Hercules Incorporated IPEC EUROPE

    Iain Moore, Ph.D., Croda Europe Ltd

    Ariane Etoc, Dow Corning

    Doris Wangel, Flamel Technologies

    IPEC EUROPE QA TEAM

    Karen Hudson, Eli Lilly

    Adrian Bone, Eli Lilly

    EX OFFICIO CONTRIBUTORS

    Irwin B. Silverstein, Ph.D., IBS Consulting in Quality LLC

    Copyright ? 2008 The International Pharmaceutical Excipients Council

    Copyright? 2008 Pharmaceutical Quality Group

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    1. INTRODUCTION

1.1 Purpose

     This document is meant as a guide for the qualification of excipient ingredients by excipient

    suppliers and pharmaceutical users. Its goal is to establish the information needed to support

    the introduction of a material for marketing as an excipient to the pharmaceutical industry as

    well as to indicate the steps used to establish the requirements for use of an excipient by a

    pharmaceutical company.

1.2 Scope

    This guide is applicable to all excipients used in pharmaceutical dosage forms.

1.3 Principles Adopted

     When considering how to use this guide, each excipient supplier must consider how it may

    apply to their material and processes. In addition pharmaceutical formulators should consider

    the proper use of the excipient in their formulation. Although the steps are laid out in a specific

    sequence in this guide, supplier and users are not required to follow that route through the

    excipient qualification process nor indeed cover every aspect described. The diversity of

    excipients means that some principles of the guide may not be applicable to certain materials

    and processes. The terminology “should” and “it is recommended” do not necessarily mean

    “must”.

1.4 Layout

    Flow diagrams are a pictorial display of the process described in detail in this document. They

    outline a logical path with sequential steps and appropriate decision points that should be

    evaluated in the excipient development and qualification process. Decision points show what

    the next phase of the evaluation would be, dependent upon the decision reached.

    The reference number contained in the boxes of the flow diagram refers the reader to the

    corresponding section in this guide where further information is provided. The box number

    appears as bold text between the chevrons () in the text.

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    QUALIFICATION OF EXCIPIENTS FOR PHARMACEUTICAL USES

    PHASE ONE: THE EXCIPIENT SUPPLIER’S PROCESS

    2. GENERAL GUIDANCE

    2.1 Differentiation of Excipient Manufacture

     Many materials used as excipients have applications other than in pharmaceuticals, such as food additives, cosmetics, or industrial products. Thus, environmental conditions, equipment, and operational techniques employed in excipient manufacture are often those of the chemical industry rather than those of the pharmaceutical industry. The excipient starting materials may not be required to be manufactured in accordance with Good Manufacturing Practice (GMP) 1requirements for excipients (for example as in the IPEC-PQG GMP Guide) because these

    other uses of the material do not demand the adoption of GMP. Excipients may be manufactured through significant chemical change, physical modification, blending, or purification which causes many of the other components present in the starting materials to be

    removed or reduced. The effectiveness of these steps is confirmed by chemical, biological, or physical testing of the excipient. Once synthesized or isolated, excipients normally undergo additional purification. Thus while materials manufactured by the chemical industry, primarily for other applications can be used as pharmaceutical excipients, in these cases the principles of GMP will need to be applied when the material is intended for use in the pharmaceutical industry.

    For distributors the same principles apply in that the purity, integrity, and suitability of the excipient for use in pharmaceutical products needs to be assured. In these cases the IPEC 2Good Distribution Practice (GDP) Guide is an appropriate starting point for defining the

    quality assurance standards and systems required.

    The finished dosage formulator is highly dependent on the excipient manufacturer to provide materials that are uniform in chemical and physical characteristics. This is particularly important in the context of the pharmaceutical product approval process where bioequivalence comparisons are made between pivotal, clinical trial batch ("biobatch") production and commercial scale-up lots. The excipient used to manufacture commercial lots should not differ significantly from those used in biobatches to provide adequate assurance of finished product performance. Therefore, it is important to minimize variation between the different batches of excipient, as well as within the excipient batch itself. However if significant differences do occur between excipient lots used in clinical and commercial drug product lots, additional testing by the finished dosage manufacturer may be required to establish the bioequivalence of the drug product.

    The user of the excipient typically does not significantly alter the chemical and/or physical properties of the excipient prior to use. Consequently, other components present in the excipient are likely to be present in the drug product. Excipients frequently function because they are not “pure”. That is to say that there may be concomitant components that are

    necessary for the correct functioning of the excipient. These concomitant components should 3not be confused with “impurities.

    Although dosage form manufacturers may have some limited control over excipient quality through specifications, the excipient manufacturer must be considered to have greater control over physical characteristics, quality, and the presence of other components in the excipient they produce. Control over other components in the excipient should not be taken to mean minimizing or even eliminating concomitant components from the excipient. The presence of concomitant components in the excipient often has a beneficial effect on excipient performance,

     1 The Joint IPEC-PQG Good Manufacturing Practices Guide for Pharmaceutical Excipients 2006 2 The IPEC Good Distribution Practices Guide for Pharmaceutical Excipients, 2006 3 IPEC Excipient Composition Guide (in development)

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    but control is needed to assure that the presence of concomitant components is at a consistent level and other components are kept to a minimum. It is important to remember however that it is the responsibility of the pharmaceutical dosage form manufacturer to ensure the safety of their drug product and the excipients used in the formulation.

     Excipients are frequently used in different types of drug products where physical characteristics, such as particle size, may be important. While the pharmaceutical formulator is primarily responsible for identifying the particular physical characteristics needed, it is the responsibility of the excipient manufacturer to adequately control the excipient manufacturing process to assure consistent excipient conformance to the agreed specifications.

2.1.1 Reference Documents

    Several sources have been used for reference information in the development of this

    guideline and are listed in Appendix C-Bibliography. IPEC has issued several guidelines

    that are referred to in this document. In addition, the pharmacopoeias have pertinent 4information in their general chapters that are applicable. Finally, several ICH

    documents are referenced in various sections of this guideline (and are also included in

    Appendix C-Bibliography).

    2.2 Preliminary Excipient Marketing Decision

     The original manufacturer begins the process of offering a chemical to the pharmaceutical market as a substance suitable for use as an excipient in a drug product <1.1>. It is not

    appropriate for a distributor to make the determination to use a non-pharmaceutical grade as a drug component.

     Alternatively, a pharmaceutical customer may approach the excipient supplier and indicate a desire to utilize their product as an excipient (see Section 4-Phase 2). In either instance the decision to provide the material as an excipient should be made with a good understanding of the suitability of the safety and quality of the material, and the ability to supply this quality on a consistent basis.

    2.2.1 Determination of the Intended Target Market and Route of Administration

    The intended end use of the excipient should be identified and considered in determining

    the appropriate regulatory and GMP requirements for the excipient and its

    manufacturing facility <1.2>. Of particular importance is whether the excipient will be a

    component of a finished drug product. The route of administration is critical to defining

    the requirements for the excipient because the key principle throughout pharmaceutical

    supply is that of protecting the patient. The risks to the patient are proportional to the

    route of administration, approximately increasing in the following sequence:

    ; Topical

    ; Oral, vaginal, and rectal

    ; Pulmonary/Inhalation

    ; Parenteral, ophthalmic, and preparations intended for use in open wounds

    Parenteral dosage forms normally require an excipient to have a low bioburden or be

    produced as pyrogen-free. An excipient to be used in a sterile drug product may be

    required either to be sterile or capable of remaining unaffected by the drug

    manufacturer‟s sterilization process. The excipient supplier is responsible for ensuring

    that excipients meet bacterial endotoxins specifications or are pyrogen-free, only if the

    excipient manufacturer makes such a representation in specifications, labeling,

     4 ICH International Conference on Harmonisation of Technical Requirements for Registration of

    Pharmaceuticals for Human Use: http://www.ich.org

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