—
`
`r rt ~sNE, The EuropeanAgencyforthe EvaluationofMedicinal Products
`
`Human Medicines Evaluation Unit
`Veterinary Medicines Evaluation Unit
`
`8 July 1997
`CPMP/CVMP/QWP/1 15/95
`
`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)
`
`5-6 October 1995
`1-2 February 1996
`4-5 July 1996
`
`(BWP)
`
`(STUDIES COMMENCING AFTER)
`
`DATE FOR COMING INTO OPERATION
`
`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:/Awww.eudra.org/emea.html
`
`UCB Biopharma SPRL(IPR2019-00400)
`Exhibit 2018 Page 1
`
`UCB Biopharma SPRL (IPR2019-00400)
`Exhibit 2018 Page 1
`
`

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`
`
`
`UCB Biopharma SPRL (IPR2019-00400)
`Exhibit 2018 Page 2
`
`

`

`The efficacy obtained for an antioxidant dependsonits 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 assessedin 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.
`
`ANTIMICROBIAL PRESERVATIVES
`
`Antimicrobial Preservatives are used to prevent or inhibit the growth of micro-organisms
`which could presenta risk of infection or degradation of the medicinal product. These micro-
`organism mayproliferate during normal storage conditions or use of the product by the
`patient, particularly in multidose preparations.
`
`Onno 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 emulsionsto be taken orally, solution for external use, creams, and sterile
`preparations used repeatedly (e.g. injectable multidose preparations and eye-drops).
`
`The antimicrobial efficacy of the preservative in the finished product should be assessed
`during product development using the European Pharmacopoeiatest.
`
`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 soundjustification.
`
`4.
`
`FORMULATION
`
`Antimicrobial preservative and antioxidants should be chemically defined (reference to existing
`pharmacopoeia monographs maybe used) and designated by the Chemical Abstract Service
`(CAS)registry numberif 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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`Thelevel 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 andlevel of initial microbial contamination. The design of the
`pack and the temperature at which the productis stored will also affect the level of activity of
`any antimicrobial preservatives present.
`
`CPMP/CVMP/QWP/115/95
`
`2/4
`
`UCB Biopharma SPRL(IPR2019-00400)
`Exhibit 2018 Page 3
`
`UCB Biopharma SPRL (IPR2019-00400)
`Exhibit 2018 Page 3
`
`

`

`

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`
` 
`
`UCB Biopharma SPRL (IPR2019-00400)
`Exhibit 2018 Page 4
`
`

`

`basis of controlled conditions and in-use stability testing to ensure that sufficient antioxidant
`remains to protect the product throughoutits 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
`
`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
`openedor used containers for the proposedin 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)
`
`b)
`
`itis intended for single use only (e.g. cytotoxic),
`
`the product is self-preserving,
`
`c)
`
`the productis 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.
`
`The application should follow the current CPMP and CVMPguidelines 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
`productat 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 of the antioxidant.
`
`

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`CPMP/CVMP/QWP/115/95
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`UCB Biopharma SPRL(IPR2019-00400)
`Exhibit 2018 Page 5
`
`UCB Biopharma SPRL (IPR2019-00400)
`Exhibit 2018 Page 5
`
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