LIVEL The European Agencyforthe Evaluation ofMedicinal Products
`
`Evaluation of Medicines for Human Use
`
`London, 20 February 2003
`CPMP/QWP/419/03
`
`
`
`(CPMP)
`
`COMMITTEE FOR PROPRIETARY MEDICINAL PRODUCTS
`
`<DRAFT>
`
` DISCUSSION IN THE QUALITY WORKING PARTY
`
`NOTE FOR GUIDANCE ON EXCIPIENTS, ANTIOXIDANTS AND
`ANTIMICROBIAL PRESERVATIVES IN THE DOSSIER FOR
`APPLICATION FOR MARKETING AUTHORISATION OF A
`MEDICINAL PRODUCT
`
`April 2002,
`January 2003
`
`February 2003
`TRANSMISSION TO CPMP
`
`
`February 2003
`RELEASE FOR CONSULTATION
`
`
`August 2003
`DEADLINE FOR COMMENTS
`
`
`Note:
`
`This Note for Guidance replaces 3AQ9a Excipients in the Dossier for Application for
`Marketing Authorisation of a Medicinal Products and CPMP/CVMP/QWP/115/95 Note for
`Guidance on Inclusion of Antioxidants and Antimicrobial Preservatives
`in Medicinal
`Products
`
`7 Westferry Circus, Canary Wharf, London, E14 4HB, UK
`Tel. (44-20) 74 18 8400 Fax (44-20) 74 18 8595
`E-mail: mail@emea.eu.int —http:/Avww.emea.eu.int
`©EMEA 2003 Reproduction and/or distribution of this document is authorised for non commercial purposes only provided the EMEA is acknowledged
`
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`NOTE FOR GUIDANCE ON EXCIPIENTS, ANTIOXIDANTS AND
`ANTIMICROBIAL PRESERVATIVES IN THE DOSSIER FOR
`
`PRODUCT
`
`APPLICATION FOR MARKETING AUTHORISATION OF A MEDICINAL
`
`INTRODUCTION
`
`This note for guidance is concerned with the application to excipients, antioxidants and
`antimicrobial preservatives of Module 3, sections P.1, P.2, P.4, P.5, P.8 of the Common
`Technical Document with a view to granting a marketing authorisation for a new medicinal
`product.
`
`The data should be presented according to the standard format described in the CTD Module
`3, part P.
`Antioxidants and Antimicrobial Preservatives are substances which are used to extend the
`shelf-life of medicines by respectively retarding the oxidation of active substances
`and
`excipients, and by reducing microbial proliferation.
`
`The properties of these substances are due to certain chemical groups which are usually
`aggressive towards living cells and whichlead to certain risks when used in man.
`
`If it is not absolutely necessary to add these substances in medicinal products they must be
`avoided.
`
`The purpose of this note for guidance is to describe the information that needs to appear in
`application for marketing authorisations with regards to the addition of any antioxidants or
`antimicrobial preservatives.
`
`For each anuioxidants and antimicrobial preservative the application should contain :
`
`°
`
`°
`
`°
`
`°
`
`°
`
`reason for inclusion
`
`proofof efficacy
`
`the method ofcontrol in finished product
`
`details of the labelling of the finished product
`
`safely information
`
`Several guidelines should be also taken into account:
`
`.
`
`°
`
`°
`
`°
`
`ICH Topic Q 6 A: Specifications : Test Procedures and Acceptance Criteria for New
`Drug Substances and New Drug Products : Chemical Substances (3.3.2.2. Oral liquids :
`d) Antimicrobial preservative content, e) Antioxidants preservative content ; 3.3.2.3.
`Parenteral Drug Products : g) h) and Decision Tree 8: Microbiological Attributes of
`Non-sterile drug products).
`
`Note for Guidance on Development Pharmaceutics: 3.3. Liquid and Semi-solid
`Formulations.
`
`3BC7A : Excipients in the Label and Package leaflet of Medicinal Products for Human
`Use
`
`Note for guidance on maximum shelf-life for sterile products
`following reconstitution.
`
`after first opcning or
`
`CPMP/QWP/41 9/03
`
`©EMEA 2003
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`SECTION P.1
`
`Description and Composition of the Drug Product
`
`Excipients must be listed, specifying their common name, their quantity and the use and
`reference to any relevant standard. When the common nameis not sufficient to indicate
`functional specifications, the brand name with commercial grade should be specified. Tn the
`case of excipients presented as a mixture of compounds, details as to the composition should
`be provided in qualitative and quantitative terms. However,
`for flavouring agents and
`aromatic substances, it is permitted to give the qualitative composition only.
`
`Antimicrobial preservatives and antioxidants should be chemically defined (reference to
`existing European Pharmacopoeia monographs maybe used) and designated by the Chemical
`Abstract Service Registry Number (RN-CAS).
`
`The purpose for the inclusion of any antioxidant or microbial preservative should be stated
`(antioxidant for the benefit of active substance or excipient or both, or antimicrobial
`preservative).
`
`SECTION P.2
`
`Pharmaceutical development
`
`SECTIONP.2.1
`
`Components of the Drug Product
`
`The section P.2.1.2 should comprise an explanation of the choice of the excipient (and grade
`where necessary) and the level of excrpient according to the note for guidance "Development
`pharmaceutics and process validation”.
`
`For antimicrobial preservatives and antioxidants, during the pharmaceutical development of
`the product the applicant should demonstrate:
`
`°
`
`°
`
`the necessity to add an antioxidant or preservative to the finished product at the chosen
`level
`
`the physical and chemical compatibility of the antioxidant and of the preservative with
`other constituents of the finished product, the container and the closures.
`
`The used concentration must be justified in terms of efficacy and safety, such that the
`minimum concentration of preservative is used which gives the required level of efficacy. The
`appropriate test method for efficacy of antimicrobial preservation is that of the European
`Pharmacopoeia. This should be used to determine whether the required level of activity is
`achieved.
`
`In the case of antioxidants, these should only be used once it has been shownthat their use
`cannot be avoided, even if the manufacturing process is optimised to minimise the potential
`for oxidation, for instance by manufacturing and filling products under an inert headspace
`gas.
`
`The safety of the antioxidant or preservative should be supported by bibliographic and /or
`experimental data.
`
`Some antioxidants or antimicrobial preservalives may be undesirable under certain
`circumstances:
`
`°
`
`see the CPMP Position Paper on Thiomersal,
`mercury containing preservatives:
`Implementation of the Warning Statement Relating to Sensilisation (CPMP/2612/99)
`and EMEA Position Statement on recent developments concerning thiomersal
`in
`vaccines (EMEA/CPMP/1578/00). This kind of preservative should be strictly avoided
`except if no other possibility may be considered but in this case the choice should be
`fully justified.
`
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`2/9
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`©EMEA 2003
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`°
`
`.
`
`°
`
`benzyl alcohol : when used in parenteral products for children under the age of two
`years. Its degradation product and metabolite 1s the benzaldehyde, toxic for the CNS.
`
`Benzoic acid esters (Para hydroxy benzoate and their derivates etc) : when used in any
`dosage-form for parenteral use.
`
`Sulphites and Metabisulphites.
`
`and no
`infusions do not contain any added antimicrobial preservatives
`Parenteral
`antimicrobial preservatives
`are added when the medicinal product
`is
`intended for
`administration by roules where for medical
`reasons an antimicrobial preservalive is
`unacceptable, such as intercisternally or by any other route of administration which gives
`access to the cerebrospinal fluid or retro-ocularly.
`
`SECTION P.4
`
`Control of Excipients
`
`Examples of different kinds of excipients are given in the annex.
`
`1. Specifications (P.4.1), Analytical Procedures (P.4.2), Validation of Analytical Procedures
`(P.4.3) and Justification of Specifications (P.4.4):
`
`1.1 Excipients described in the European Pharmacopocia or, if not described in the European
`Pharmacopoeia, pharmacopoeia of a MemberState
`
`The routine tests which are to be carried out on cach batch ofstarting materials must be stated
`in the application for marketing authorisation. If tests other than those mentioned in the
`pharmacopoeia are used, proof must be supplied that the test methods used are suitable to
`establish that the starling materials meet the quality requirements of that pharmacopoeia.
`When the monographcovers a family of related products, the particular specifications chosen
`for the cxcipicnts must be submitted. In addition and when necessary,
`the test used to
`determine the quality of the excipient should be shownto be in relation to the function thatit
`fulfils in the medicinal product.
`
`Data on microbiological contamination of the excipients used in the manufacture ofsterile
`products should always be given where membranefiltration is used to achievesterility.
`
`Antimicrobial preservatives and antioxidants are defined as excipients and as such should be
`controlled following the rules governing medicinal products in the European Union. These
`data should be provided in part P.4.
`
`1.2. Excipients not described in the European Pharmacopoeia or in the pharmacopoeia
`of a Member State
`
`An appropriate specification of the excipient must be established, based on the following
`types oftests:
`
`Physical characteristics
`Identification tests
`
`Purity tests, including limits for total or individual impurities, which should be named.
`Purity tests may be physical, chemical, biological and, if appropriate, immunological.
`
`Wheresterile filtration is used in the manufacture of a parental medicinal product, data
`and routine tests on microbiological contamination of excipients should always be
`given.
`
`*
`*
`
`*
`
`*
`
`Other relevant tests including, e.g.
`performance of the dosage form.
`
`the tests on parameters which may influence the
`
`CPMP/QWP/41 9/03
`3/9
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`©EMEA 2003
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`*
`
`Assay orlimit tests if necessary.
`
`Whenan excipient is not described in the European Pharmacopoeia or in the pharmacopoeia
`of a MemberState or in an other compendium ofestablished use (c.g. USNF Pharmacopocia
`and Japanese Pharmacopoeia), validation data of the test methods used should be presented,
`where appropriate.
`
`1.3
`
`Justification of Specifications
`
`Justifications of specifications takes into account the choice and use of an excipient which is
`used for a particular purpose: it will determine the properties which must be checked during
`the routine tests and which will be the subject of certain specifications in connection with the
`bioavailability of the product (see Note for Guidance "Specifications and control tests on the
`finished product").
`
`Nevertheless, justification of specifications are not systematically required for well-known
`excipients. For example, they are not required for excipients which have been used in similar
`medicinal products for a long period of time and whentheir characteristics and properties
`have not changedsignificantly.
`
`For solid and semi-solid dosage forms, the justification of specifications should, if necessary,
`provide information on the relevant characteristics of the excipient. Special
`tests are often
`necessary (c.g. to verify the capacity of the excipient to emulsify and disperse, or to measure
`the viscosity...).
`
`Appropriate data are necded for excipicnts used in a new route of administration.
`
`Justification of specifications on excipients already included in the European Pharmacopoeia,
`or if not included in the European Pharmacopoeia, in the pharmacopoeia of a MemberState
`and other well-knownexcipients already used in a medicinal product.
`
`For these excipients, justification of specifications will normally not be required. However,
`any particular specification concerning the characteristics, as defined in Section P.2.1.2,
`should be justified (e.g. sieve analysis, in relation to microcrystallinity).
`
`Excipienis of Human or Animal Origin (P.4.5)
`
`Viral Safety and TSE Risk should be documented in accordance with the relevant directives.
`
`Novel Excipients (P.4.6)
`
`Fornovel cxcipicnts : a dossicr should be established containing the same data as required for
`new active substances:
`
`a)
`
`b)
`
`A strict definition of the excipicnt, its function andits conditions ofuse. If the excipient
`is complex or is made of a mixture of compounds, the composition must be specified in
`qualitative and quantitative terms.
`
`For new excipients and for excipients presented as a mixture of compounds the
`following should be taken into consideration:
`
`1.
`
`li.
`
`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 foodstuff any criteria which
`are based onthe 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.
`
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`iii.
`
`iv.
`
`v.
`
`The international specifications (FAO/WHO/JECFA), and other publications such
`as the Food Chemical Codex.
`
`For medicinal products for topical use, data on the starting matcrial in cosmetic
`products (Directive 76/768/EEC).
`
`Data concerning the toxicology of the new cxcipicnt should be presented
`according to the dosage form and the route of administration of the medicinal
`product(if applicable).
`
`c)
`
`Documentation on chemistry of excipients is required for all new excipients, taking as
`its basis the Note for Guidance "Chemistry of Active Substances".
`
`*
`
`*
`*
`
`*
`
`*
`
`*
`
`*
`
`*
`
`The origin of the excipient, including the name and address of manufacturer.
`
`A general outline ofthe synthesis (manufacture and purification).
`Structure.
`
`Physical, chemical propertics, identification and puritytests.
`
`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.
`
`The routine test procedures and limits should be established on the basis of the documentation
`given in the dossier.
`
`SECTION P.5 Control of Drug Product
`
`Apart from those situations envisaged in the note for guidance "Specifications and control
`tests on the finished product" it is not usually necessary to carry out identity testing and an
`assay of the excipients in the finished product at release.
`
`Nevertheless, the finished product release specifications should include an identification test
`and limits for any antioxidants and antimicrobial preservatives present in the formulation. The
`finished product specification against which the product is tested throughout its shelf-life
`should also include limits for the antimicrobial preservatives present.
`
`Where antioxidants are used up during the manufacture of the product, the release limits
`should be justified by batch data. The adequacy of 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 product throughout its entire shelf-life and during the proposed in-use
`period.
`
`should comply with the
`The control of antioxidants and antimicrobial preservatives
`requirements identified in the guideline : ICH Topic Q 6 A: Specifications : Test Procedures
`and Acceptance Criteria for New Drug Substances and New Drug Products : Chemical
`Substanccs .
`
`The antimicrobial preservative and antioxidants must be routinely identified and quantified at
`release.
`
`P.8 Stability
`
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`The maintenance of the physico-chemical properties of the finished product depend on the
`properties and the stability of the excipients (see note for guidance "Specifications and control
`tests on the finished product").
`
`For new excipients, stability data should be provided as required for new active substances.
`
`The application should follow the current QWP/CPMP guidclines on the stability of ncw
`dosage forms and should ensure that antimicrobial preservative and antioxidants levels are
`quantified periodically throughout the shelf-life of the finished product. In addition the
`efficacy of the preservatives should be established using the European Pharmacopoeialest for
`efficacy of antimicrobial preservation. This should be performed on the finished product at
`the end of the shelf-life and at
`the lower preservative limit
`in the end of shelf-life
`specification. The formeris necessary, even if no evidence of degradation of the antimicrobial
`preservative and of the antioxidant is observed on storage, as other chemical and physical
`changes in the finished product may influence the efficacy of the antimicrobial preservative
`and the antioxidant.
`
`In the case of products presented in multidose containers, the efficacy of the antimicrobial
`preservative under simulated in-use conditions must be established. The tests should be
`performed under the same condition as it is expected to be used by the final user. It may also
`be appropriate to examine the efficacy of the antimicrobial preservative following storage of
`opened or used containers for the proposedin use shelf-life.
`
`R LABELLING
`
`°
`
`in accordance with relevant EC directive 2001/83/EC, Note for
`Labelling must
`Guidance : Excipients in the Label and Package leaflet of Medicinal Products for
`Human Use and CPMPPosition Paper on Thiomersal, Implementation of the Warning
`Statement Relating to Scnsitisation (CPMP/2612/99).
`
`However, if a product is presented in a multidose container without a preservative because:
`
`a)
`
`it is intended [or single use only (e.g. cytotoxic),
`
`b)_the productis self-preserving,
`
`c)
`
`the product is oils based,
`
`the labelling and product literature should indicate the absence ofa preservative. This
`would not only emphasise the increased risk associated with the use of such products,
`but also aid the physician to specifically identify a product without preservative.
`
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`ANNEX
`
`EXAMPLES OF REQUIREMENTS CONCERNING DIFFERENT KINDS OF
`EXCIPIENTS
`
`1.
`
`2.
`
`Excipients, which are a single chemical entity,
`inorganic acids andtheir salts, sugars and alcohols.
`
`include, for example, organic and
`
`They may have undergone physical treatments, which gave them special technological
`characteristics (e.g. micronisation).
`
`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 wayas 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, maltitolsyrup. 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 additives which may be present.
`
`4. Mixed excipients are ready-for-use preparations, for example for direct compression or
`film coating.
`
`*
`
`The qualitative and quantitative composition of the mixed excipient should be
`submitted, the specifications of the product as a whole and of each component
`mustbe stated.
`
`5.
`
`6.
`
`7.
`
` Excipients of natural origin, so called "natural" products have often undergone some
`kind of chemical treatment. 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
`ofsterilisation or decontamination, with a description of the effect of these processes on
`the excipient (e.g. modification of the physical structure).
`
`the risk of transmitting
`For biological excipients of animal or human origin,
`adventitious agents should be considered and appropriate documentation submitted
`(e.g.; method of preparation and control of tissues and body fluids used as starting
`material). In addition, the name of the manufacturer and site of manufacture should be
`specified.
`
` 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).
`
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`Most constituents of artificial flavours have internationally accepted purity criteria in
`food use (FAO/WHO). Reference to these standards is acceptable for medicinal
`products.
`
`8.
`
`Colouring matters:
`products is applicable.
`
`ANTIOXIDANTS
`
`- Community legislation on colouring matters in medicinal
`
`Antioxidants are used to reduce the oxidation of active substances and excipients in the
`finished 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 bythe presence of mineral or
`metallic impurities, due to the formation offree radicals.
`
`There are three types of antioxidants :
`
`Type
`Definition
`Example
`True antioxidants to block|ButylatedThese are thought hydroxytoluene
`
`
`
`chain reactions by reacting|(BHT)
`with free radicals
`
`Reducing agents redox|Ascorbic acidThese have a lower
`
`potential
`than the drug or
`excipient they are protecting
`These enhance the effects of|Sodium cdetate
`antioxidants
`
` Antioxidants synergists
`
`
`
`
`
`
`
`the stage at which it is
`The efficacy obtained for an antioxidants depends on its nature,
`incorporated within the finished product, the nature of the container and the formulation.
`
`The efficacy of antioxidants must be assessed in the finished product in conditions, which
`simulate actual use by measuring the extent of degradation in the finished product, with and
`without the antioxidant.
`
`Antioxidants should only be included in a formulation if it has been proven hat their use
`cannot be avoided. This applies to cases where the manufacturing process is optimised to
`minimise the potential for oxidation.
`
`ANTIMICROBIAL PRESERVATIVES
`
`Antimicrobial Preservatives are used to prevent or inhibit the growth of micro-organisms
`which could present a risk of infection 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 preservatives be used as an allernalive 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, solution for external use, creams and sterile
`preparations used repeatedly (c.g. injectable multidose preparations and cye-drops).
`
`The level of efficacy will vary according to the chemical structure of the preservative, its
`concentration, the physical and chemical characteristics of the medicinal product (cspecially
`pH) and the type and level of initial microbial contamination. The design of the pack and the
`
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`temperature at which the product is stored will also affect of activity of any antimicrobial
`preservatives present.
`
`The antimicrobial efficacy of the preservative in the finished should be assessed during
`product development, particularly during stability studies and at the end of the proposed
`shelf-life, using Pharmacopoeia Europeantest.
`
`Tf products do not contain a preservative and do not have inherent preservative efficacy they
`must not be packaged in multidose presentations without a sound justification.
`
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`€EMEA 2003
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