European Medicines Agency
`Inspections
`
`London, 19 June 2007
`Doc. Ref. EMEA/CHMP/QWP/396951/2006
`
`COMMITTEE FOR MEDICINAL PRODUCTS FOR HUMAN USE
`(CHMP)
`
`GUIDELINE ON EXCIPIENTS IN THE DOSSIER FOR APPLICATION
`FOR MARKETING AUTHORISATION OF A MEDICINAL PRODUCT
`
`DRAFT AGREED BY QUALITY WORKING PARTY
`
`ADOPTION BY CHMP FOR RELEASE FOR CONSULTATION
`
`END OF CONSULTATION (DEADLINE FOR COMMENTS)
`
`NEW DRAFT AGREED BY QUALITY WORKING PARTY
`
`ADOPTION BY CHMP FOR RELEASE FOR CONSULTATION
`
`END OF CONSULTATION (DEADLINE FOR COMMENTS)
`
`NEW DRAFT AGREED BY QUALITY WORKING PARTY
`
`ADOPTION BY CHMP
`
`DATE FOR COMING INTO EFFECT
`
`February 2003
`
`February 2003
`
`August 2003
`
`September 2006
`
`October 2006
`
`February 2007
`
`June 2007
`
`July 2007
`
`January 2008
`
`For human medicinal products, this Guideline replaces the Guideline on Excipients in the Dossier for
`Application for Marketing Authorisation of a Medicinal Products (Eudralex 3AQ9a) and the Note for
`Guidance on Inclusion of Antioxidants and Antimicrobial Preservatives in Medicinal Products
`(CPMP/CVMP/QWP/115/95).
`
`The latter Guideline remains a CVMP guideline and remains applicable to Veterinary products.
`
`KEYWORDS
`
`excipients, human, novel excipient, antioxidant, preservative
`
`7 Westferry Circus, Canary Wharf, London, E14 4HB, UK
`Tel. (44-20) 74 18 84 00 Fax (44-20) 74 18 85 95
`E-mail: mail@emea.europa.eu http://www.emea.europa.eu
`©EMEA 2007 Reproduction and/or distribution of this document is authorised for non commercial purposes only provided the EMEA is acknowledged
`
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`

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`GUIDELINE ON EXCIPIENTS IN THE DOSSIER FOR APPLICATION
`FOR MARKETING AUTHORISATION OF A MEDICINAL PRODUCT
`
`TABLE OF CONTENTS
`
`EXECUTIVE SUMMARY ....................................................................................................................3
`INTRODUCTION (BACKGROUND) .........................................................................................3
`1.
`
`2.
`
`SCOPE
`
`............................................................................................................3
`
`3. LEGAL BASIS
`
`............................................................................................................4
`
`4. MAIN GUIDELINE TEXT ...........................................................................................................4
`
`4.1 DESCRIPTION AND COMPOSITION OF THE DRUG PRODUCT (3.2.P.1)........................4
`
`4.2 PHARMACEUTICAL DEVELOPMENT (3.2.P.2)......................................................................4
`4.3 SPECIFICATIONS (3.2.P.4.1)..............................................................................................................4
`a) Excipients described in the European Pharmacopoeia or in the pharmacopoeia of an EU
`Member State...........................................................................................................................................4
`b) Excipients described in a third country pharmacopoeia ...................................................................5
`c) Excipients not described in any pharmacopoeia................................................................................5
`4.4 JUSTIFICATION OF SPECIFICATIONS (3.2.P.4.4) .............................................................................5
`4.5 EXCIPIENTS OF HUMAN OR ANIMAL ORIGIN (3.2.P.4.5)................................................................5
`4.6 NOVEL EXCIPIENTS (3.2.P.4.6).........................................................................................................5
`4.7 CONTROL OF DRUG PRODUCT (3.2.P.5) ..........................................................................................6
`4.8 STABILITY (3.2.P.8)...........................................................................................................................7
`...........................................................................................................................7
`4.9 LABELLING
`............................................................................................................8
`DEFINITIONS
`
`REFERENCES
`
`............................................................................................................8
`
`ANNEX 1
`
`ANNEX 2
`
`ANNEX 3
`
`............................................................................................................9
`
`..........................................................................................................10
`
`..........................................................................................................12
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`EXECUTIVE SUMMARY
`
`This guideline describes the information that needs to be submitted in relation to excipients including
`antioxidants and antimicrobial preservatives,
`in
`the context of applications for marketing
`authorisations or variations relating to an excipient in authorised medicinal products.
`
`INTRODUCTION (BACKGROUND)
`1.
`Excipients are the constituents of a pharmaceutical form apart from the active substance.
`Excipients include e.g. fillers, disintegrants, lubricants, colouring matters, antioxidants, preservatives,
`adjuvants, stabilisers, thickeners, emulsifiers, solubilisers, permeation enhancers, flavouring and
`aromatic substances etc., as well as the constituents of the outer covering of the medicinal products,
`e.g. gelatine capsules.
`
`Examples of different types of excipients are given in annex 1. Information on the excipients used in a
`medicinal product should be provided in part 3.2.P.1, 3.2.P.2, 3.2.P.4 and 3.2.A.3 of the dossier.
`
`Excipients to be used in formulations for the paediatric population should be selected with special
`care. Possible sensitivities of the different age groups should be taken into consideration. For example,
`colouring agents with documented safety risks, e.g. azo dyes and other synthetic colouring agents,
`should not be used in medicinal products for paediatric use when only intended for aesthetic purposes.
`
`Antioxidants are excipients which are used to improve stability of medicines by delaying the oxidation
`of active substances and other excipients. Antimicrobial preservatives are normally added to prevent
`microbial proliferation arising under in use conditions. These properties are due to certain chemical
`groups which are usually harmful to living cells and might therefore be associated with certain risks
`when used in humans. Thus inclusion of antimicrobial preservatives or antioxidants in a medicinal
`product needs special justification. Wherever possible the use of these substances should be avoided,
`particularly in case of paediatric formulations. The concentration used should be at the lowest feasible
`level. Further information is given in annex 2.
`Parenteral infusions should not contain added antimicrobial preservatives. Antimicrobial preservatives
`must not be added to medicinal products intended for use by any route of administration that will give
`access to the cerebrospinal fluid or in products that will be injected retro-ocularly.
`
`Permeation enhancers are excipients which have the ability to modify the penetration of active
`substances through the skin and therefore could influence significantly the in-vivo performance of a
`transdermal formulation. Information and control of these substances is essential for all transdermal
`formulations, where a constant and persistent release of active substances over several hours, or even
`days, is necessary for therapeutic efficacy. Further information is given in annex 3.
`
`2.
`
`SCOPE
`
`This guideline is applicable to all excipients in medicinal products for human use, in the context of
`applications for marketing authorisations or variations relating to an excipient in authorised medicinal
`products.
`
`The guideline does not apply to excipients used in products in the clinical research stages of drug
`development. However, the principles in this guideline are important to consider during those stages
`as well.
`
`The data should be presented according to the standard format described in the Common Technical
`Document (CTD) Module 3 sections P.1, P.2, P.4, P.5, P.8 and A.3.
`
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`3.
`LEGAL BASIS
`Directive 2001/83/EC, as amended
`
`4.
`
`MAIN GUIDELINE TEXT
`
`4.1 Description and Composition of the Drug Product (3.2.P.1)
`
`Excipients should be listed specifying their common name, the quantity present, their function and a
`reference to a relevant standard. When the common name is not sufficient to indicate functional
`properties, the brand name with commercial grade should be specified. In the case of excipients
`presented as a mixture of compounds, details of the composition should be provided in qualitative and
`quantitative terms. However, for flavouring agents it is allowed to state the qualitative composition
`only.
`
`4.2 Pharmaceutical Development (3.2.P.2)
`
`According to the Notes for Guidance on Pharmaceutical Development (CHMP/ICH/167068/04 and
`CHMP/QWP/055/96), this section should include an explanation of the choice of the excipient(s) (and
`grade where necessary). Compatibility of the excipients with active substances and, where relevant,
`with other excipients, should be established. The excipients chosen, their concentration, and the
`characteristics that can influence the drug product performance (e.g., stability, bioavailability) or
`manufacturability should be discussed in relation to the respective function of each excipient. Tests in
`addition to the pharmacopoeial ones, identified through development, should be described in section
`3.2.P.4.2 and 3.2.P.4.3.
`
`4.3 Specifications (3.2.P.4.1)
`
`Colouring matters shall, in all cases, satisfy the requirements of Directives 78/25/EEC, as amended
`and/or 94/36/EC (colours for use in foodstuffs). In addition, colouring matters in medicinal products
`have to comply with the specifications of the Annex of Directive 95/45/EC, laying down specific
`purity criteria concerning colours for use in foodstuffs.
`
`The references in Directive 78/25/EEC, as amended are interpreted in a way, which permits the use in
`medicinal products of all colourants mentioned in Annex I of Directive 94/36/EC.
`
`The bioburden and, where relevant, the endotoxin limits for excipients used in the manufacture of
`sterile medicinal products shall be stated. However, if bioburden/endotoxin content of the bulk
`solution prior to sterilisation is checked using appropriate in process controls, the testing of the
`individual excipient may be omitted.
`Data concerning residual solvents in excipients should be submitted in accordance with the Note for
`Guidance on Impurities: Residual Solvents (CPMP/ICH/283/95).
`
`a) Excipients described in the European Pharmacopoeia or in the pharmacopoeia of an EU
`Member State
`
`Reference to the current edition of the pharmacopoeia should be included in the dossier for marketing
`authorisation. When the monograph covers a group of related materials (i.e. polymers), the particular
`specification chosen for the excipient, should be submitted, together with the rationale for its selection.
`If tests other than those mentioned in the pharmacopoeia are used, proof should be supplied that the
`test methods are at least equivalent to those described in the pharmacopoeia (see European
`Pharmacopoeia, 1.1. General Statements). It may be necessary to add tests and acceptance criteria to
`the pharmacopoeial specification, depending on the intended use of the excipient (functionality-related
`characteristics).
`
`
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`b) Excipients described in a third country pharmacopoeia
`
`Where an excipient is neither described in the European Pharmacopoeia nor in the pharmacopoeia of a
`Member State, compliance with the monograph of a third country pharmacopoeia (e.g. United States
`Pharmacopoeia/National Formulary and Japanese Pharmacopoeia) can be accepted.
`
`The applicant should justify the reference to such pharmacopoeia and submit justified specifications in
`accordance with
`the general monograph of
`the European Pharmacopoeia: Substances for
`Pharmaceutical use.
`
`c) Excipients not described in any pharmacopoeia
`
`An appropriate specification for the excipient should be established, based on the following types of
`tests:
`• Physical characteristics
`•
`Identification tests
`• Purity tests, including limits for total and individual impurities, which should be named, e.g. by
`reference to a chromatographic relative retention time. Purity tests may be physical, chemical,
`biological and, if appropriate, immunological.
`• Assay or limit tests if necessary and corresponding validation parameters.
`• Other relevant tests e.g. tests on parameters (quantitative), which have been determined to
`influence the performance of the dosage form.
`
`4.4 Justification of Specifications (3.2.P.4.4)
`Justification of a specification takes into account the choice and particular use of the excipient (see
`Note for Guidance on Specifications: Test Procedures and Acceptance Criteria for New Drug
`Substances and New Drug Products: Chemical Substances (CPMP/ICH/367/96)).
`For excipients described in the European Pharmacopoeia, or in the pharmacopoeia of an EU Member
`State, justification of specifications will normally not be required. However, any particular acceptance
`criteria concerning the characteristics, as defined in Section 3.2.P.2.1.2, should be justified (e.g.
`particle size testing of a micronised substance). In addition, justification of a specification is not
`systematically required for well-known excipients. For example, it is not required for excipients which
`have been used in similar medicinal products for a long period of time and when their characteristics
`and properties have not changed significantly.
`
`information on excipient
`justification of specifications should provide
`the
`Where critical,
`characteristics relevant to the medicinal product performance. For example, for solid and semi-solid
`dosage forms, special tests may be necessary to demonstrate the capability of the excipient to emulsify
`and disperse, or to provide appropriate viscosity (Functionality related characteristics).
`
`4.5 Excipients of Human or Animal Origin (3.2.P.4.5)
`
`Viral Safety and TSE Risk should be documented in accordance with the relevant directives and
`guidelines (see European Pharmacopoeia General Chapter 5.1.7 Viral Safety and 5.2.8. Minimising
`the Risk of Transmitting Animal Spongiform Encephalopathy Agents via Human and Veterinary
`Medicinal Products).
`
`4.6 Novel Excipients (3.2.P.4.6)
`
`Full details of manufacture, characterisation and controls with cross references to supporting safety
`data should be provided for novel excipients, according to the drug substance format.
`
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`a) A detailed description of the excipient, its function and its conditions of use should be
`provided. If the excipient is complex or consists of a mixture of compounds, the composition
`should be specified in qualitative and quantitative terms.
`
`b) For novel excipients and for excipients presented as a mixture of compounds the following
`should be taken into consideration:
`
`•
`
`•
`
`Any bibliographical data on the chemistry and on the toxicology and the field in which
`the product is already used.
`The Community provisions concerning additives in foodstuffs: any criteria which are
`based on the toxicological data, with cross-references to these data.
`The quality specifications which have been laid down in the directives are satisfactory as
`long as the routine control tests used are validated.
`The international specifications (FAO/WHO/JECFA), and other publications, such as the
`Food Chemical Codex.
`For medicinal products for cutaneous use, data on the ingredient used in cosmetic
`products (see Directive 76/768/EEC, as amended).
`Data concerning the toxicology of the novel excipient according to the dosage form and
`the route of administration of the medicinal product (if applicable) in Module 4, the
`safety section of the dossier.
`c) Documentation on chemistry of excipients is required for all novel excipients, taking as its
`basis the CPMP Guideline on the Chemistry of New Active Substances (CPMP/QWP/130/96)
`and should include:
`
`•
`
`•
`
`•
`
`•
`•
`•
`•
`•
`•
`•
`•
`
`•
`
`The origin of the excipient, including the name and address of manufacturer.
`A general outline of the manufacturing and purification procedures.
`Structure.
`Physical, chemical properties, identification and purity tests.
`Validated methods of analysis with a presentation of batch results.
`Miscellaneous information (microbiological tests, etc).
`Contamination, presence of foreign substances, residual solvents, etc.
`In the case of an excipient obtained from a mixture of several components, the quality of
`each component and the physico-chemical tests for the mixture should be described.
`Stability data should be provided as required for the active substances in the Note for
`Guidance on Stability Testing of New Drug Substances
`and Products
`(CPMP/ICH/2736/99).
`
`The routine test procedures and limits should be established on the basis of the documentation
`given in the dossier.
`
`4.7 Control of Drug Product (3.2.P.5)
`
`Apart from those situations envisaged in the Note for Guidance on Specifications: Test Procedures and
`Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances
`(CPMP/ICH/367/96), it is not necessary to carry out identity testing and an assay of the excipients in
`the medicinal product at release. The control of antioxidants and antimicrobial preservatives, however,
`should comply with the requirements outlined in the guideline mentioned above.
`
`The medicinal product release specifications should include an identification test and a content
`determination test with acceptance criteria and limits for each antioxidant and antimicrobial
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`preservative present in the formulation. The medicinal product shelf-life specification should also
`include limits for antimicrobial preservatives when present.
`
`Where antioxidants are used during the manufacture of the medicinal product, the release limits should
`be justified by batch data or a sound justification has to be provided, if the proposed specifications do
`not include an identification test and a content determination test for the antioxidant. If needed, the
`adequacy of the specified limits should be justified on the basis of controlled conditions and (in-use)
`stability testing, to ensure that sufficient antioxidant remains, to protect the medicinal product
`throughout its entire shelf-life and during the proposed in-use period.
`
` 4.8 Stability (3.2.P.8)
`
`The maintenance of the physico-chemical properties of the medicinal product is partly dependent upon
`the properties and the stability of the excipients.
`
`For the medicinal product the application should follow current CHMP/ICH stability guidelines and
`should ensure that antimicrobial preservative and, if appropriate, antioxidant levels are quantified
`periodically throughout the shelf-life. The antimicrobial preservative content should be monitored
`throughout the shelf-life to ensure that antimicrobial preservative levels remain above the level
`challenged for preservative efficacy and within the specifications.
`
`In the case of non-solid medicinal products presented in multidose containers that contain
`preservatives, the efficacy of the antimicrobial preservative under simulated in-use conditions should
`be established. The
`tests should be performed under conditions simulating
`the dosage
`recommendations, as stated in the SPC.
`
`4.9 Labelling
`For all excipients included in a medicinal product, the relevant guidance documents: Excipients in the
`Label and Package leaflet of Medicinal Products for Human Use (Eudralex 3BC7A) and CPMP
`Position Paper on Thiomersal, Implementation of the Warning Statement Relating to Sensitisation
`(CPMP/2612/99) have to be taken into account.
`
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`DEFINITIONS
`
`Novel excipient: A novel excipient is an excipient which is being used for the first time in a drug
`product, or by a new route of administration (ICH). It may be a new chemical entity or a well
`established one which has not yet been used for human administration and /or for a particular human
`administration pathway in the EU and/or outside the EU.
`
`REFERENCES
`
`This guideline should be read in conjunction with:
`• Note for Guidance on Specifications: Test Procedures and Acceptance Criteria for New Drug
`Substances and New Drug Products: Chemical Substances (CPMP/ICH/367/96)
`• Note for Guidance on Impurities: Residual Solvents (CPMP/ICH/283/95)
`• Note
`for Guidance on Stability Testing of New Drug Substances and Products
`(CPMP/ICH/2736/99)
`• Guideline on the Chemistry of New Active Substances (CPMP/QWP/130/96)
`• European Pharmacopoeia General Monograph, Substances for Pharmaceutical Use (2034)
`• European Pharmacopoeia General Chapter 5.1.3 Efficacy on Antimicrobial Preservation
`• European Pharmacopoeia General Chapter 5.1.7 Viral Safety
`• European Pharmacopoeia General Chapter 5.2.8 Minimising the Risk of Transmitting Animal
`Spongiform Encephalopathy Agents via Human and Veterinary Medicinal Products
`•
`Individual monographs of the European Pharmacopoeia
`• Note for Guidance on Development Pharmaceutics (CPMP/QWP/155/96)
`• Note for Guidance on Pharmaceutical Development (CHMP/ICH/167068/2004)
`• Rules governing Medicinal Products in the European Community, Notice to Applicants,
`Volume 3B – “Excipients in the Label and Package leaflet of Medicinal Products for Human Use”
`(Eudralex 3BC7A)
`• Note for Guidance on Maximum Shelf-life for Sterile Products for Human Use After First
`Opening or Following Reconstitution (CPMP/QWP/159/96 corr)
`• Note
`for Guidance on
`In-use Stability Testing of Human Medicinal Products
`(CPMP/QWP/2934/99).
`
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`ANNEX 1
`
`DIFFERENT TYPES OF EXCIPIENTS AND THEIR REQUIREMENTS
`
`1.
`
`Excipients that are a single chemical entity include, for example, organic and inorganic acids
`and their salts, sugars and alcohols.
`
`They may have undergone physical treatments, which gave them special technological
`characteristics (e.g. micronisation).
`
`2.
`
`Chemically transformed excipients include excipients which have undergone a special chemical
`treatment in order to confer certain technological characteristics (e.g. modified starch).
`
`The name and quality of such excipients should be defined in such a way as to avoid confusion
`with an unmodified excipient.
`
`3. Mixtures of chemically related components include, for example, polyol esters (mixture of
`mono, di and tri esters), hydrogenated glucose syrup, maltitol syrup.
`
`For these products the dossier should specify the following characteristics of the excipient:
`•
`the nature and content of each component with a statement of its acceptable limits;
`•
`technological criteria (appropriate criteria to the performance of dosage form);
`•
`any additive which may be present and their quality if appropriate.
`4. Mixed excipients are ready-for-use preparations, to be used for example for direct compression
`or film coating.
`• The qualitative and quantitative composition of the mixed excipient should be submitted,
`the specifications of the mixture as a whole and of each component should be stated.
`Excipients of natural origin, so called "natural" products have often undergone some kind of
`chemical treatment.
`
`5.
`
`In general and if relevant for the quality control of the product, data should give an outline of
`the operations carried out to obtain and to purify the product, and any special characteristics:
`decomposition products, specific impurities, chemical substances used during the treatment with
`residual limits, methods of sterilisation or decontamination, with a description of the effect of
`these processes on the excipient (e.g. modification of the physical structure).
`
`6.
`
`Flavouring agents (flavours and aromatic substances) are either natural products and/or products
`obtained by chemical synthesis. Because of the complexity of their composition, it is only
`necessary to describe the general qualitative composition mentioning the main constituents with
`an appropriate process of identification to ensure the consistency of the composition (in
`particular, identification of the main constituents and if necessary carriers). Most constituents of
`artificial flavours have internationally accepted purity criteria in food use (FAO/WHO).
`Reference to these standards is acceptable for medicinal products.
`
`7.
`
`An adjuvant is a substance that helps and enhances the pharmacological effect of a drug or
`increases the ability of an antigen to stimulate the immune system.
`
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`ANNEX 2
`
`ANTIOXIDANTS & ANTIMICROBIAL PRESERVATIVES
`
`For each antioxidant and antimicrobial preservative the application should contain:
`•
`reason for inclusion and justification of level of inclusion
`• proof of safety and efficacy
`•
`the method of control in medicinal product (not applicable for synergists e.g. sodium edetate)
`•
`levels on storage of broached and unbroached containers
`• details on the labelling of the medicinal product
`The safety of the antioxidant or antimicrobial preservatives should be supported by bibliographic
`and/or experimental data unless the antioxidant or antimicrobial preservative is well known and
`generally used at same concentrations and by the same route of administration.
`
`ANTIOXIDANTS
`
`Antioxidants are used to reduce the oxidation of active substances and excipients in the medicinal
`product. Antioxidants should not be used to disguise poorly formulated products or inadequate
`packaging. The need to include an antioxidant should be explained and fully justified. Oxidative
`degradation can be accelerated by light and by the presence of mineral or metallic impurities, due to
`the formation of free radicals.
`
`The effect obtained from an antioxidant depends on its nature, the stage at which it is incorporated into
`the medicinal product, the nature of the container and the formulation.
`
`Types of antioxidants.
`
`Type
`True antioxidants
`
`Reducing agents
`
`Antioxidants synergists
`
`
`
`Definition
`These are thought to block chain
`reactions by reacting with free
`radicals
`These have a lower redox
`potential than the drug or
`excipient they are protecting
`These enhance the effects of
`antioxidants
`
`Example
`Butylated hydroxytoluene
`(BHT)
`
`Ascorbic acid
`
`Sodium edetate
`
`ANTIMICROBIAL PRESERVATIVES
`
`Antimicrobial preservatives are used to prevent or inhibit the growth of micro-organisms which could
`present a risk of infection to or degradation of the medicinal product. These micro-organisms may
`proliferate during normal conditions of use of the product by the patient, particularly in multidose
`preparations.
`
`On no account should antimicrobial preservatives be used as an alternative to Good Manufacturing
`Practice (GMP).
`
`Preparations at greatest risk of contamination are those which contain water such as solutions,
`suspensions and emulsions to be taken orally, solutions for external use, creams and sterile
`preparations used repeatedly (e.g. injectable multidose preparations and eye-drops).
`
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`The level of efficacy will vary according to the chemical structure of the antimicrobial preservative, its
`concentration, the physical and chemical characteristics of the medicinal product (especially pH) and
`the type and level of initial microbial contamination. The design of the pack and the temperature at
`which the product is stored will also affect the activity of any antimicrobial preservatives present.
`
`The antimicrobial efficacy of the antimicrobial preservative in the medicinal product should be
`assessed during product development, and at the end of the proposed shelf-life, using the method
`described in the respective Ph. Eur. General Chapter 5.1.3.
`
`If non-solid medicinal products do not contain an antimicrobial preservative and do not have self-
`preserving properties or the container closure system is not able to prevent microbial ingress into the
`formulation they should not be packaged in multidose presentations without a sound justification.
`
`EMEA/CHMP/QWP/396951/2006
`
`
`
`©EMEA 2007
`
`Page 11/12
`
`Opiant Exhibit 2076
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00685
`Page 11
`
`

`

`ANNEX 3
`
`SOLUBILISERS AND PERMEATION ENHANCERS
`
`Solubilisers and permeation enhancers incorporated in transdermal formulations (e.g. transdermal gel
`or patches) modify the delivery of an active substance into the systemic circulation via the transdermal
`application route. Strategies to chemically enhance or modify the in-vivo flux comprise disrupture of
`the stratum corneum structure (effect on diffusion), alter the solubility of the active substance in the
`stratum corneum (effect on partition) or influencing the thermodynamic activity of an active substance
`-the driving force for the passive diffusion process- within the formulation (vehicle). Chemical
`permeation enhancers can alter the barrier function and the effect can be either reversible or
`irreversible.
`
`Different types of substances are known for their ability to enhance the permeation through the skin
`and are commonly used in transdermal formulations. Although representing partly different
`mechanisms by which they alter the stratum corneum (e.g. extracting lipids from lipid bilayer,
`partition into bilayers and disrupting its order or fluidisation of the lipid structure), those substances
`have one property in common: they increase the active substance permeability through the skin.
`
`Excipients able to modulate the in vivo performance of a transdermal formulation are often not
`identified and declared as substances with a distinctive influence on the permeation (e.g,: terpene
`containing oils, declared as fragrances; propylenglycol, declared as solubiliser although permeation
`enhancing effects can be observed).
`
`Groups of chemical substances known for their ability to act as permeation enhancers or solubilisers in
`transdermal formulations are for example (list is not exhaustive) surfactants, fatty acids and their salts,
`fatty esters, alkyl amines, alcohols, azone like molecules, pyrrolidones, sulfoxides and terpenes.
`
`If one of the above mentioned chemical substances is incorporated into a transdermal formulation, a
`permeation enhancing or influencing effect on the barrier function of the stratum corneum can be
`expected, unless otherwise shown by experimental data. The need to include a permeation enhancer or
`solubiliser and the amount necessary to guarantee adequate flux rates should be explained in detail and
`justified by skin permeation studies during pharmaceutical development. The degree of enhancement
`by a permeation enhancer is depending on its concentration, other excipients in the formulation and
`the physico-chemical properties of the respective active substance. It is necessary to evaluate those
`effects on a case by case basis; no generalization for a certain group of excipients is possible.
`
`A release and shelf life specification based on the results of clinical or