The European Agency for the Evaluation of Medicinal Products
`Human Medicines Evaluation Unit
`Veterinary Medicines Evaluation Unit
`
`8 July 1997
`CPMP/CVMP/QWP/115/95
`
`COMMITTEE FOR PROPRIETARY MEDICINAL PRODUCTS (CPMP)
`
`COMMITTEE FOR VETERINARY MEDICINAL PRODUCTS (CVMP)
`
`NOTE FOR GUIDANCE ON
`INCLUSION OF ANTIOXIDANTS AND ANTIMICROBIAL
`PRESERVATIVES IN MEDICINAL PRODUCTS
`
`DISCUSSION IN THE QUALITY WORKING PARTY (QWP)
`
`DISCUSSION IN THE BIOTECHNOLOGY WORKING PARTY
`(BWP)
`
`TRANSMISSION TO THE CPMP AND CVMP
`
`TRANSMISSION TO INTERESTED PARTIES
`
`5-6 October 1995
`1-2 February 1996
`4-5 July 1996
`
`10-11 June 1996
`
`July 1996
`
`July 1996
`
`DEADLINE FOR COMMENTS
`
`31 January 1997
`
`DISCUSSION IN THE QUALITY WORKING PARTY (QWP)
`
`4 - 5 June 1997
`
`FINAL APPROVAL BY CPMP AND CVMP
`
`DATE FOR COMING INTO OPERATION
`(STUDIES COMMENCING AFTER)
`
`July 1997
`
`January 1998
`
`7 Westferry Circus, Canary Wharf, London E14 4HB, UK
`Switchboard: (+44-171) 418 84 00 Fax: (+44-171) 418 85 51
`E_Mail: mail@emea.eudra.org http://www.eudra.org/emea.html
`
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`INCLUSION OF ANTIOXIDANTS AND ANTIMICROBIAL
`PRESERVATIVES IN MEDICINAL PRODUCTS
`
`1. INTRODUCTION
`
`Antioxidants and Antimicrobial Preservatives are substances which are used to extend the
`shelf-life of medicines by respectively retarding the oxidation of active ingredients 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 which lead to certain risks when used in man (and animals).
`
`The purpose of this note for guidance is to describe the information that needs to appear in
`applications for marketing authorisations with regard to the addition of any antioxidants or
`antimicrobial preservatives. For each antioxidant and antimicrobial preservative the
`application should contain:
`
`•
`
`•
`
`•
`
`•
`
`•
`
`reason for inclusion
`
`proof of efficacy
`
`the method of control in the finished product
`
`details of the labelling of the finished product
`
`safety information
`
`2. ANTIOXIDANTS
`
`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 by the presence of mineral
`impurities, due to the formation of free radicals.
`
`There are three types of antioxidants :
`
`Type
`True antioxidants
`
`Reducing agents
`
`Antioxidant 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
`
`ascorbic acid
`
`sodium edetate
`
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`The efficacy obtained for an antioxidant depends on its nature, its concentration, the stage at
`which it is incorporated into 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 proved that their use
`cannot be avoided. This applies to cases where the manufacturing process is optimised to
`minimise the potential for oxidation.
`
`3.
`
`ANTEVEICROBIAL 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-
`organism may proliferate during normal storage conditions or use of the product by the
`patient, particularly in multidose preparations.
`
`On no account should preservatives be used as an alternative to good manufacturing practice.
`
`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 (e.g. injectable multidose preparations and eye-drops).
`
`The level of efficacy obtained will vary according to the chemical structure of the 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 level of activity of
`any antimicrobial preservatives present.
`
`The antimicrobial efficacy of the preservative in the finished product should be assessed
`during product development using the European Pharmacopoeia test.
`
`If products do not contain a preservative and do not have adequate inherent preservative
`efficacy they must not be packaged in multidose presentations without a sound justification.
`
`4.
`
`FORMULATION
`
`Antimicrobial preservative and antioxidants should be chemically defined (reference to existing
`pharmacopoeia monographs may be used) and designated by the Chemical Abstract Service
`(CAS) registry number if they are not referenced in the pharmacopoeia.
`
`The purpose for the inclusion of any antioxidant or antimicrobial preservative should be
`stated (antioxidant for the benefit of active ingredient or excipient or both, or antimicrobial
`preservative).
`
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`5. DEVELOPMENT PHARMACEUTICS
`
`During the pharmaceutical development of the product the applicant should demonstrate:
`
`•
`
`•
`
`the necessity to add an antioxidant or a preservative to the finished product at the level
`chosen.
`
`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 concentration used 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 shown that their use
`cannot be avoided, even if the manufacturing process is optimised to minimise the potential
`for oxidation, for example 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 preservatives may be undesirable under certain
`circumstances e.g. mercury containing preservatives, benzyl alcohol (when used in parenteral
`products for children under the age of 2 years or in newborn animals or in cats), benzoic acid
`esters (when used in any medicinal products for injection), sulphites and metabisulphite.
`
`Parenteral infusions do not contain any added antimicrobial preservatives and no antimicrobial
`preservatives are added when the medicinal product is intended for administration by routes
`where for medical reasons an antimicrobial preservative is unacceptable, such as
`intercisternally or by any other route of administration which gives access to the cerebrospinal
`fluid or retro-ocularly.
`
`6.
`
`CONTROL OF THE EXCIPIENTS
`
`Antimicrobial preservatives and antioxidants are defined as excipients and as such should be
`controlled following the guidance given in The Rules Governing Medicinal Products in the
`European Union, Volume III "Excipients in the Dossier for Application for Marketing
`Authorisation of a Medicinal Product".
`
`7.
`
`CONTROL OF THE FINISHED PRODUCT
`
`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
`
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`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.
`
`The control of antioxidants and antimicrobial preservatives should comply with the
`requirements identified in the guideline "Specifications and control testing of the finished
`product".
`
`8.
`
`STABILITY
`
`The application should follow the current CPMP and CVMP guidelines on the stability of
`new 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 preservatives should be established using the test for efficacy of antimicrobial
`preservation of the European Pharmacopoeia. 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 former is 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 of 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 user. It may also be
`appropriate to examine the efficacy of the antimicrobial preservative following storage of
`opened or used containers for the proposed in use shelf-life.
`
`Further details of in use testing for veterinary products is provided in the current CVMP
`Notes for Guidance on in use stability testing.
`
`9.
`
`LABELLING
`
`Labelling must be in accordance with relevant Community Directives - Council Directive
`92/27/EEC and 81/851/EEC.
`
`However, if a product is presented in a multidose container without a preservative because:
`
`a)
`
`it is intended for single use only (e.g. cytotoxic),
`
`b)
`
`the product is self-preserving,
`
`c)
`
`the product is oils based,
`
`the labelling and product literature should indicate the absence of a 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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