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`INTERNATIONAL PHARMACEUTICAL EXCIPIENTS COUNCIL
`
`Qualification of
`Excipients for
`Use in
`Pharmaceuticals
`
`Printed in the USA by IPEC-Americas
`1655 N. Ft. Myer Drive, Suite 700
`Arlington, VA 22209
`
`Copyright © 2008 International Pharmaceutical Excipients Council
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`Page 1 of 66
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`AstraZeneca Exhibit 2023
`Lannett v. AstraZeneca
`IPR2015-01629
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`QUALIFICATION OF EXCIPIENTS FOR USE IN
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`PHARMACEUTICALS
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`FOREWORD
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`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.
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`Suppliers
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`Users
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`IPEC
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`Regulatory
`Authorities
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`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.
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`Excipient
`Qualification
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`Suppliers
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`Users
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`IPEC
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`Regulatory
`Authorities
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`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.
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`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.
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`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.
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`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.
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`This document describes the three phases of the excipient qualification process. The layout and content are as
`follows:
`
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`Section 1
`
`Introduction: describes the scope, purpose, and layout of this guide.
`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.
`The User’s Process
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`Copyright © 2008 The International Pharmaceutical Excipients Council Page. iii
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`Phase 1
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`Phase 2
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`Phase 3
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`Section 4 Excipient User Assessment, Selection, and Specification Process: provides
`guidance on how users should assess the excipients for inclusion in their
`formulations.
`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.
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`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
`tools in ICH Q9 Quality Risk Managementi 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
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`TABLE OF CONTENTS
`FOREWORD
`ACKNOWLEDGEMENTS
`1. INTRODUCTION
`1.1 Purpose
`1.2 Scope
`1.3 Principles Adopted
`1.4 Layout
`2. GENERAL GUIDANCE
`2.1 Differentiation of Excipient Manufacture
`2.1.1 Reference Documents
`2.2 Preliminary Excipient Marketing Decision
`2.2.1 Determination of the Intended Target Market and Route of Administration
`2.3 Regulatory Assessment
`2.3.1 Safety, Toxicological, and Precedence of Use Issues
`2.3.2 New (Novel) Excipients
`2.3.3 Compendial Requirements
`General Comments
`United States Pharmacopeia
`European Pharmacopeia
`Japanese Pharmacopeia
`New and Novel Excipients not listed in a Pharmacopoeia
`Other regulatory requirements
`2.3.4 Desired Properties for Intended Use
`2.3.5 Excipient Master Files and Other Filings
`United States Drug Master Files
`European Certificates of Suitability (CEP)
`Japanese Drug Master Files
`2.3.6 International Conference on Harmonisation (ICH)
`2.3.7 Specific Safety Issues
`2.3.8 Concluding Comments on the Regulatory Assessment
`2.4 Manufacturing and Packaging
`2.4.1 Process Capability and Validation
`2.4.2 Test Methods and Validation
`2.5 Excipient Specifications
`2.5.1 Excipient Stability
`3. EXCIPIENT DEVELOPMENT AND SPECIFICATION PROCESS
`3.1 Excipient Consistency and Control
`3.2 Performance Indicators
`3.3 Production Specification and Master Batch Record
`3.4 Marketing Materials
`3.4.1 Sampling Guidelines
`3.5 Customer Feedback
`3.6 Post Product Launch
`3.7 Confidential Information
`4. ASSESSMENT, SELECTION AND SPECIFICATION PROCESS
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`4.1 Project Initiation
`4.2 New Formulation Development Projects
`4.2.1 Selecting the Excipient
`4.2.2 Selecting the Supplier
`4.2.3 Regulatory Assessment
`4.2.4 Refining the Excipient List
`4.2.5 Formulation Design, Development, and Optimization
`4.3 Alternative Excipient Source Projects
`4.4 Negotiation Process Impact
`5. NEGOTIATION PROCESS
`5.1 Review of Excipient User Requirements
`5.2 Quality Agreement
`5.3 Modification of Requirements
`5.4 Identification of Potential Solutions
`5.4.1 Lot Selection
`5.4.2 Manufacture to Order
`5.5 Other Approaches
`5.5.1 In-House Processing
`5.5.2 Reformulate
`5.5.3 Supplier Custom Manufacture
`5.6 Concluding Agreements
`APPENDIX A: FLOW DIAGRAMS
`APPENDIX B: DEFINITIONS AND GLOSSARY
`APPENDIX C: BIBLIOGRAPHY
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`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
`
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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.
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`1.2 Scope
`This guide is applicable to all excipients used in pharmaceutical dosage forms.
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`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 (<number>) in the text.
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`Copyright © 2008 The International Pharmaceutical Excipients Council
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`PHASE ONE: THE EXCIPIENT SUPPLIER’S PROCESS
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`2. GENERAL GUIDANCE
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`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)
`requirements for excipients (for example as in the IPEC-PQG GMP Guide1) 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.
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`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 Good
`Distribution Practice (GDP) Guide2 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 not be confused with
`“impurities”.3
`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, but control is
`needed to assure that the presence of concomitant components is at a consistent level and other
`
`
`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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`Phase 1
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`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
`information in their general chapters that are applicable. Finally, several ICH4 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.
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`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, contractual agreement, a Drug
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`4 ICH International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals
`for Human Use: http://www.ich.org
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`Phase 1
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`Master File (DMF), or a Certificate of Suitability to the European Pharmacopeia
`(CEP).
`
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`2.3 Regulatory Assessment
`
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`2.3.1 Safety, Toxicological, and Precedence of Use Issues
`There are several safety related issues that should be assessed by the potential excipient
`manufacturer as part of their decision to introduce an excipient to the pharmaceutical
`market <1.3>.
`
`First an assessment should be made as to whether there is a precedence of use for the
`material in a drug product or a similar application such as a food additive, food contact
`packaging component. If a precedence of use can be shown in applications where there is
`human exposure, the safety of the material might already be appropriate for potential
`application as an excipient in the pharmaceutical industry.
`
`In the U.S., the Food and Drug Administration (FDA) maintains a database of excipients
`that is posted on their website as the Inactive Ingredient Database (IID) 5. The IID should
`be used to establish precedence of use since it lists each excipient which has been allowed
`as a consequence of its presence in an approved innovator drug product. Each excipient is
`listed by name, dosage form, and the maximum amount of excipient contained in an
`approved drug of that listed dosage form. Care must be exercised in searching the database
`because an excipient can be listed by various names, including trade name, compendia
`name, chemical name, or generic description (for dyes and flavors).
`
`In Japan, an assessment for precedence of use can be made by referring to the Japanese
`Pharmaceutical Excipients Dictionary (JPED) which is edited by the Japan Pharmaceutical
`Excipients Council in conjunction with the Ministry of Health, Labor, and Welfare. The
`JPED is a compilation of all excipients for which there is a precedence of use in drug
`products in Japan. It includes monographs from the JP or Japanese Pharmaceutical
`Excipients (JPE) as well as all non-monograph excipients that have been previously used.
`Each monograph lists the nonproprietary name and synonyms along with the application
`and maximum dosages for the various routes of administration in approved drugs6.
`
`In Europe, there is no comprehensive European Union list of excipients that have been
`approved in drug products. Therefore, in order to establish precedence of use, it is
`necessary to review the drug catalogues such as the “Dictionnaire Vidal” (France),“Die
`Rote Liste” (Germany), or “The Electronic Medicines Compendium” (UK)7.
`
`At the time this Guide was prepared, the European Union had mandated the application of
`GMP principles to “certain excipients”8. Materials in this category are those that could pose
`a higher safety risk to the patient including excipients:
`• prepared from materials derived from a TSE-relevant animal species (excluding
`lactose)
`• derived from human/animal material with potential viral contamination risk
`
`5 Instructions: http://www.fda.gov/cder/iig/iigfaqWEB.htm,
`Database: http:www.accessdata.fda.gov/scripts/cder/iig/index.cgm
`6 Maximum dosage information is only contained in the Japanese language version of the JPED.
`7 Electronic Medicines Compendium; http://www.medicines.org.uk/emc.aspx
`8 Draft: Specific Conditions of the Application of the Principles and Guidelines of Good Manufacturing Practice
`for Certain Excipients EC-Directive 2001/83/EC, as amended by EC-Directive 2004/27/EC
`
`Phase 1
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`•
`claimed to be sterile (or sold as sterile) and used without further sterilization
`• with the specification or claim that they are endotoxin/pyrogen controlled, or
`•
`the following specific materials:
`o propylene glycol
`o glycerol
`Following a public and industry consultation in the summer of 2007, an economic impact
`assessment suggested that it was not in the public benefit to mandate the application of GMP
`for certain excipients. However, a final decision has not been taken; nevertheless IPEC
`recommends the application of the GMP principles described in the IPEC-PQG Excipient
`GMP Guide to all excipients.
`
`If there is no precedence of use in a drug product, then the material is to be considered a new
`excipient (see Sections 2.3.2 and 2.3.5).
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`2.3.2 New (Novel) Excipients
`An excipient used for the first time in a drug product or by a new route of administration is
`classified as new according to the ICH Guideline M49, Organisation of the Common
`Technical Document for the Registration of Pharmaceuticals for Human Use. Conversely,
`this guideline defines known excipients as “excipients that are well-established and
`commonly used in registered drug products and are usually included in pharmacopoeias”.
`
`When an excipient has not previously been used in a pharmaceutical dosage form then
`there are a number of conditions set out by the US and European regulatory authorities to
`allow for its use.
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`The U.S. FDA has issued a Guidance concerning the safety testing required for novel
`excipients10 as has IPEC in their IPEC New Excipient Evaluation Guidelines dated October
`199611 which were the basis for the USP-NF 26 General Chapter Excipient Biological
`Safety Evaluation Guidelines <1074>12 on this topic. The information contained in these
`documents is useful for assessing the safety of a chemical for use as an excipient. The IPEC
`Europe Safety Committee has published a similar guideline13. The manufacturer of a new
`or novel excipient should develop the safety information recommended in these guidelines
`appropriate to their intended use. This information provides the basis for establishing the
`suitability of the material for use as an excipient in a particular type of dosage form.
`
`The terms “new” and “novel” as related to excipients are difficult to define precisely.
`Clearly an excipient is new if it is not listed in:
`•
`the FDA Inactive Ingredient database,
`•
`any of the 3 major compendia, U.S. Pharmacopeia (USP-NF), European
`Pharmacopoeia (Ph. Eur.), or Japanese Pharmacopoeia (JP), or
`• other widely known compendia such as the “Handbook of Pharmaceutical
`Excipients” or “Fiedler: Lexikon der Hilfsstoffe für Pharmazie, Kosmetik und
`angrenzende Gebiete” (Encyclopedia of excipients for pharmaceutical, cosmetic
`
`9 ICH M4, Organisation of the Common Technical Document for the Registration of Pharmaceuticals for Human
`Use, Step 4, 2004.
`10 U.S. FDA, Nonclinical Studies for Development of Pharmaceutical Excipients (final version May 2005)
`11 Steinberg, M., Borzelleca, J.F., Enters, E.K., Kinoshita, F.K., Loper, A., Mitchell, D.B., Tamulinas, C.B., and
`Weiner, M.L., A New Approach to the Safety Assessment of Pharmaceutical Excipients, Regulatory Toxicology
`and Pharmacology, 24, 2, 1996.
`12 USP-NF General Chapter <1074> Excipient Biological Safety Evaluation Guidelines
`13 The Proposed Guidelines for the Safety Evaluation of New Excipients (European Pharmaceutical Review,
`November 1997)
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`Phase 1
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`and related use).
`
`
`The industry recognizes that any change in the chemical composition of an excipient
`produces a new excipient, no matter how minor the modification to the chemical
`composition. Mixtures of excipient ingredients can result in a novel excipient when the
`subject mixture is to be used in a dosage form for which its constituent excipients have not
`already independently been used in that intended route of administration. Physical
`modification of an excipient, such as micronizing or compaction does not generally
`produce a new or novel excipient.
`
`However, co-processing can produce a synergistic physical interaction between two or
`more excipients that is patentable and create unique properties that cannot be achieved
`through simple blending3. The safety assessment for these co-processed excipients made
`with commonly used pharmaceutical excipients will generally be less stringent than for a
`new chemical entity.
`
`If the excipient is already described in a pharmacopoeia or used as such in other
`pharmaceutical dosage forms, the excipient is neither new nor novel and the detailed safety
`review recommended in the above guidelines will not be necessary.
`
`2.3.3 Compendial Requirements
`General Comments
`There are three major compendia that are routinely referenced globally; the United States
`Pharmacopeia – National Formulary (USP-NF), the European Pharmacopoeia (Ph.Eur.),
`and the Japanese Pharmacopoeia (JP). These compendia describe the quality of substances
`to be regularly used in pharmaceutical products, how to test them and the other general
`conditions required to assure the quality of pharmaceutical substances so that they are not
`harmful to the patient. The descriptions of substances for pharmaceutical use are called
`monographs and these list the analytical specification and other quality attributes required
`to assure the safety and quality of the excipient.
`
`In order to market an excipient, there is no regulatory requirement that there must be a
`compendial monograph for the material. However, if a compendial monograph exists for an
`excipient in a particular region’s pharmacopoeia, then the excipient should comply with
`that monograph because the regulatory authorities require conformance. However, other
`regulations may define a suitable quality which could be used (e.g. Food Chemical Codex).
`In all cases, the use of a specification that at least meets a compendial monograph or a
`similar standard is preferable to the supplier’s own internal document. In particular
`conformance to a pharmacopoeial monograph and other relevant general notices and
`chapters of the compendia means that the excipient already has a suitably defined quality
`for pharmaceutical use.
`
`In some instances, other specific regulations apply for a specific use such as for parenteral
`applications as discussed above (see Section 2.2.1).
`
`In the United States, certain food additive materials are produced in conformance with the
`Food Chemical Codex (FCC) while in Japan, there is the Japanese Pharmaceutical Codex
`and also a series of supplementary books called the Japanese Pharmaceutical Excipients
`(JPE). Many other national pharmacopoeias delineate the quality requirements of
`pharmaceutical ingredients and these will take precedence over the three major
`pharmacopoeias.
`
`Phase 1
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`Copyright © 2008 The International Pharmaceutical Excipients Council
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`Where an excipient is described in a pharmacopoeia, the quality of material for
`pharmaceutical use must comply with this monograph (regulatory requirement).
`
`The compendia are concerned with the presence of additives and processing aids in
`excipients. While the issue is still under active consideration by the pharmacopoeias, it is
`suggested that excipient manufacturers compile information on the identity and quantity of
`additives and processing aids that are or may be present in excipient products.
`
`For an excipient listed in multiple compendia that may be marketed for global use, the
`manufacturer is advised to ascertain the conformance of the excipient to the monograph
`requirements found in all those compendia. While considerable efforts are underway to
`harmonize the requirements for excipients with monographs in the three major compendia,
`currently there are ofte