EUROPEAN
`
`PHARMACOPOEIA
`
`FIFTH EDITION
`
`Volume 1
`
`Published in accordance with the
`
`Convention on the Elaboration ofa European Pharmacopoeia
`(European Treaty Series No. 50)
`
`Council of Europe
`
`Strasbourg
`
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`The European Pharmacopoeia is published by the Directorate for the Quality of
`Medicines of the Council of Europe (EDQM).
`
`© Council of Europe, 67075 Strasbourg Cedex, France - 2004
`
`All rights reserved. Apart from any fair dealing for the purposes of research or private study,
`this publication may not be reproduced, stored or transmitted in any form or by any means
`without the prior permission in writing of the publisher.
`
`ISBN: 92-871-5281-0
`
`Printed in France by Aubin, Ligugé
`
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`This material may be protected by Copyright law (Title 17 U.S. Code)
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`

`11
`
`EUROPEAN PHARMACOPOEIA 5.0
`
`5.1.3. Efficacy of antimicrobial preservation
`
`a hazard to the patient from infection and spoilage of the
`preparation. Antimicrobial preservatives must not be used as
`a substitute for good manufacturing practice.
`The efficacy of an antimicrobial preservative may be
`enhanced or diminished by the active constituent of the
`preparation or by the formulation in which it is incorporated
`or by the container and closure used. The antimicrobial
`activity of the preparation in its final container is investigated
`over the period of validity to ensure that such activity has
`not been impaired by storage. Such investigations may be
`carried out on samples removed from the final container
`immediately prior to testing.
`
`During development of a pharmaceutical preparation, it
`shall be demonstrated that the antimicrobial activity of the
`preparation as such or, if necessary, with the addition of
`a suitable preservative or preservatives provides adequate
`protection from adverse effects that may arise from microbial
`contamination or proliferation during storage and use of
`the preparation.
`The efficacy of the antimicrobial activity may be demonstrated
`by the test described below. The test is not intended to be
`used for routine control purposes.
`
`TEST FOR EFFICACY OF ANTIMICROBIAL
`PRESERVATION
`
`The test consists of challenging the preparation, wherever
`possible in its final container, with a prescribed inoculum of
`suitable micro-organisms, storing the inoculated preparation
`at a prescribed temperature, withdrawing samples from the
`container at specified intervals of time and counting the
`organisms in the samples so removed.
`The preservative properties of the preparation are adequate
`if, in the conditions of the test, there is a significant fall or no
`increase, as appropriate, in the number of micro-organisms
`in the inoculated preparation after the times and at the
`temperatures prescribed. The criteria of acceptance, in terms
`of decrease in the number of micro-organisms with time, vary
`for different types of preparations according to the degree of
`protection intended (see Tables 5.1.3.—1/2/3).
`
`Staphylococcus aureus
`
`Test micro-organisms
`ATCC 9027; NCIMB 8626;
`Pseudomonas aeruginosa
`CIP 82.118.
`ATCC 6538; NCTC 10788;
`NCIMB 9518; CIP 4.83.
`ATCC 10231; NCPF 3179; [P 48.72.
`ATCC 16404; IMI 149007;
`IP 1431.83.
`
`Candida albicans
`
`Aspergillus niger
`
`Single-strain challenges are used and the designated
`micro-organisms are supplemented, where appropriate,
`by other strains or species that may represent likely
`contaminants to the preparation. It is recommended, for
`example, that Escherichia coli (ATCC 8739; NCIMB 8545;
`CIP 53.126) is used for all oral preparations and
`Zygosaccharomyces rouxiz' (NCYC 381; IP 2021.92) for oral
`preparations containing a high concentration of sugar.
`Preparation of inoculum
`Preparatory to the test, inoculate the surface of agar
`medium B (2.6.12) for bacteria or agar medium C without
`the addition of antibiotics (2.6.12) for fungi, with the recently
`grown stock culture of each of the specified micro-organisms.
`Incubate the bacterial cultures at 3035 °C for 18-24 h, the
`culture of C. albicans at 20—25 °C for 48 h, and the culture of
`A. niger at 20-25 °C for 1 week or until good sporulation is
`obtained. Subcultures may be needed after revival before the
`
`micro-organism is in its optimal state, but it is recommended
`that their number he kept to a minimum.
`To harvest the bacterial and C. albicans cultures, use
`a sterile suspending fluid, containing 9 g/l of sodium
`chloride R, for dispersal and transfer of the surface growth
`into a suitable vessel. Add sufficient suspending fluid to
`reduce the microbial count to about 108 micro-organisms
`per millilitre. To harvest the A. niger culture, use a sterile
`suspending fluid containing 9 g/l of sodium chloride R and
`0.5 g/l of polysorbate 80 R and adjust the spore count to
`about 108 per millilitre by adding the same solution.
`Remove immediately a suitable sample from each suspension
`and determine the number of colony-forming units per
`millilitre in each suspension by plate count or membrane
`filtration (2. 6.12). This value serves to determine the
`inoculum and the baseline to use in the test. The suspensions
`shall be used immediately.
`
`METHOD
`
`To count the viable micro-organisms in the inoculated
`products, use the agar medium used for the initial cultivation
`of the respective micro-organisms.
`Inoculate a series of containers of the product to be
`examined, each with a suspension of one of the test
`organisms to give an inoculum of 105 to 106 micro-organisms
`per millilitre or per gram of the preparation. The volume
`of the suspension of inoculum does not exceed 1 per cent
`of the volume of the product. Mix thoroughly to ensure
`homogeneous distribution.
`Maintain the inoculated product at 20-25 °C, protected
`from light. Remove a suitable sample from each container,
`typically 1 ml or 1 g, at zero hour and at appropriate
`intervals according to the type of the product and determine
`the number of viable micro—organisms by plate count or
`membrane filtration (2.6.12). Ensure that any residual
`antimicrobial activity of the product is eliminated by dilution,
`by filtration or by the use of a specific inactivator. When
`dilution procedures are used, due allowance is made for
`the reduced sensitivity in the recovery of small numbers of
`viable microorganisms. When a specific inactivator is used,
`the ability of the system to support the growth of the test
`organisms is confirmed by the use of appropriate controls.
`The procedure is validated to verify its ability to demonstrate
`the required reduction in count of viable micro-organisms.
`
`CRITERIA OF ACCEPTANCE
`
`The criteria for evaluation of antimicrobial activity are given
`in Tables 5.1.3.—1/2/3 in terms of the log reduction in the
`number of viable micro-organisms against the value obtained
`for the inoculum.
`
`‘
`
`
`.Table 5.1.3.—1. - Parenteral and ophthalmic preparations
`Log reduction
`24h6h 28d 7d 14d
`
`
`
`
`2
`3
`'
`'
`Bacteria
`A
`NR“
`B
`1
`3
`'
`NI“
`
`NI
`2
`A
`Fungi
`
`1B NI
`’NR: no recover
`“NI: no increase
`
`
`
`The A criteria express the recommended efficacy to be
`achieved. In justified cases where the A criteria cannot be
`attained, for example for reasons of an increased risk of
`adverse reactions, the B criteria must be satisfied.
`
`448
`
`See the information section on general monographs (cover pages)
`
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`5.1.5. Application of the F0 concept to steam sterilisation
`EUROPEAN PHARMACOPOEIA 5.0
`______—________————————
`
`Table 5.1.3.2. - Topical preparations7,—4—
`
` Log reduction
`2 d
`7 d
`14 d
`28 d
`
`Bacteria
`
`A
`B
`
`2
`
`3
`
`'
`3
`
`N]
`N1
`
`NI
`2
`'
`'
`A
`Fungi
`N1
`1
`B
`_—_____.———————-
`
`The A criteria express the recommended efficacy to be
`achieved. In justified cases where the A criteria cannot be
`attained, for example for reasons of an increased risk of
`adverse reactions, the B criteria must be satisfied.
`
`Table 5.1.3.3. - Oral preparations
`____———_————
`Log reduction
`
`14 d 28 (lI,
`
`Bacteria
`3
`N1
`
`1
`N1
`
`Fungi
`
`The above criteria express the recommended efficacy to be
`achieved.
`
`01/2005:50104
`
`5.1.4. MICROBIOLOGICAL
`QUALITY OF PHARMACEUTICAL
`PREPARATIONS
`
`The following chapter is published for information.
`In the manufacture, packaging, storage and distribution of
`pharmaceutical preparations, suitable means must be taken
`to ensure their microbiological quality. The pharmaceutical
`preparations should comply with the criteria given below.
`Category 1
`
`Preparations required to be sterile by the relevant
`monograph on the dosage form and other preparations
`labelled sterile.
`— Test for sterility (2.6.1).
`Category 2
`
`Preparations for topical use and for use in the respiratory
`tract except where required to be sterile and transdermal
`patches.
`— Total viable aerobic count (2.6.12). Not more than
`102 microorganisms (aerobic bacteria plus fungi)
`per gram, per millilitre or per patch (including the
`adhesive and backing layer).
`
`— Transdermal patches: absence of enterobacteria and
`certain other gram-negative bacteria, determined on
`1 patch (including the adhesive and backing layer).
`Other preparations: not more than 101 enterobacteria
`and certain other gram-negative bacteria per gram or
`per millilitre (2.6.13).
`— Absence of Pseudomonas aeruginosa, determined
`on 1 g, 1 ml or one patch (including the adhesive and
`backing layer) (2.6.13).
`- Absence of Staphylococcus aureus, determined on
`1 g, 1 ml or one patch (including the adhesive and
`backing layer) (2.6.13).
`
`Category 3
`A. Preparations for oral and rectal administration.
`— Total viable aerobic count (2. 6.12). Not more than
`103 bacteria and not more than 102 fungi per gram
`or per millilitre.
`— Absence of Escherichia coli (1 g or 1 m1) (2.613).
`B. Preparations for oral administration containing raw
`materials of natural (animal, vegetable or mineral)
`origin for which antimicrobial pretreatment is not
`feasible and for which the competent authority accepts
`microbial contamination of the raw material exceeding
`10" viable micro—organisms per gram or per millilitre.
`Herbal medicinal products described in category 4 are
`excluded.
`— Total viable aerobic count (2.6.12). Not more than
`10" bacteria and not more than 102 fungi per gram
`or per millilitre.
`- Not more than 102 enterobacteria and certain other
`gram-negative bacteria per gram or per millilitre
`(2.6.13).
`— Absence of Salmonella (10 g or 10 ml) (2. 6.13).
`— Absence of Escherichia coli (1 g or 1 ml) (2.6.13).
`— Absence of Staphylococcus aureus (1 g or 1 ml)
`(2.6.13).
`Category 4
`Herbal medicinal products consisting solely of one or more
`herbal drugs (whole, reduced or powdered).
`A. Herbal medicinal products to which boiling water is
`added before use.
`— Total viable aerobic count (2.6.12). Not more than
`107 bacteria and not more than 105 fungi per gram
`or per millilitre.
`— Not more than 102 Escherichia coli per gram or per
`millilitre (2.6.13, using suitable dilutions).
`B. Herbal medicinal products to which boiling water is not
`added before use.
`— Total viable aerobic count (2.6.12). Not more than
`105 bacteria and not more than 10“ fungi per gram
`or per millilitre.
`- Not more than 103 enterobacteria and certain other
`gram-negative bacteria per gram or per millilitre
`(2.6.13).
`— Absence of Escherichia coli (1 g or 1 ml) (2.6.13).
`— Absence of Salmonella (10 g or 10 ml) (2.6.13).
`
`01/2005:50105
`
`5.1.5. APPLICATION OF THE F0
`CONCEPT TO STEAM STERILISATION
`OF AQUEOUS PREPARATIONS
`The following chapter is published for information.
`The F0 value of a saturated steam sterilisation process is
`the lethality expressed in terms of the equivalent time
`in minutes at a temperature of 121 °C delivered by the
`process to the product in its final container with reference to
`microorganisms possessing a Z-value of 10.
`The total F0 of a process takes account of the heating up and
`cooling down phases of the cycle and can be calculated by
`integration of lethal rates with respect to time at discrete
`temperature intervals.
`When a steam sterilisation cycle is chosen on the basis
`of the F0 concept, great care must be taken to ensure
`that an adequate assurance of sterility is consistently
`
`___________—_———————————-
`449
`General Notices {1) apply to all monographs and other texts
`
`
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