KUROPEAN
`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
`
`UCB Biopharma SPRL(IPR2019-00400)
`Exhibit 2021 Page 1
`
`UCB Biopharma SPRL (IPR2019-00400)
`Exhibit 2021 Page 1
`
`

`

`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 anyfair dealing for the purposes of researchor private study,
`this publication may notbe reproduced, stored or transmitted in any form or by any means
`withoutthe prior permission in writing of the publisher.
`
`ISBN: 92-871-5281-0
`
`Printed in France by Aubin, Ligugé
`
`UCB Biopharma SPRL(IPR2019-00400)
`Exhibit 2021 Page 2
`
`UCB Biopharma SPRL (IPR2019-00400)
`Exhibit 2021 Page 2
`
`

`

`This material may be protected by Copyright law (Title 17 U.S. Code)
`
`UCB Biopharma SPRL (IPR2019-00400)
`Exhibit 2021 Page 3
`
`

`

`5.1.3. Efficacy of antimicrobial preservation
`
`EUROPEAN PHARMACOPOEIA5.0
`
`micro-organismis in its optimalstate, but it is recommended
`that their number be kept to a minimum.
`To harvest the bacterial and C. albicans cultures, use
`a sterile suspendingfluid, containing 9 g/1 of sodium
`chloride R, for dispersal and transfer of the surface growth
`into a suitable vessel. Add sufficient suspendingfluid to
`reduce the microbial count to about 10® micro-organisms
`per millilitre. To harvest the A. niger culture, usea sterile
`suspendingfluid containing 9 g/1 of sodium chloride R and
`0.5 g/1 of polysorbate 80 R and adjust the spore count to
`about 10° per millilitre by adding the samesolution.
`Remove immediately a suitable sample from each suspension
`and determine the numberof colony-forming units per
`millilitre in each suspension by plate count or membrane
`filtration (2.6.12). This value serves to determine the
`inoculum andthebaselineto 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 oneof the test
`organisms to give an inoculum of 10° to 10° 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
`homogeneousdistribution.
`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 numberof viable micro-organisms by plate count or
`membranefiltration (2.6.12). Ensure that any residual
`antimicrobialactivity of the productis 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 micro-organisms. Whena specific inactivator is used,
`the ability of the system to support the growth of the test
`organismsis confirmed by the use of appropriate controls.
`The procedureis validated to verify its ability to demonstrate
`the required reduction in countof viable micro-organisms.
`
`CRITERIA OF ACCEPTANCE
`
`Thecriteria for evaluation of antimicrobialactivity are given
`in Tables 5.1.3.-1/2/3 in terms of the log reduction in the
`numberofviable micro-organisms against the value obtained
`for the inoculum.
`~ Table 5.1.3.1. - Parenteral and ophthalmic preparations
`
`Log reduction
`6h 24h 7d
`
`
`
`14d
`28d
`2
`3
`j
`4
`NR*
`Bacteria
`A
`B
`1
`3
`s
`NI**
`
`NI
`s
`2
`.
`A
`A
`Fungi
`
`
`1B NI
`"NR: no recover
`**NI: no increase
`
`The A criteria express the recommendedefficacy 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 besatisfied.
`
`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
`enhancedor diminished by the active constituent of the
`preparation or by the formulation in whichit is incorporated
`or by the container and closure used. The antimicrobial
`activity of the preparationinits final containeris 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 thefinal container
`immediately prior to testing.
`
`During developmentof a pharmaceutical preparation,it
`shall be demonstrated that the antimicrobial activity of the
`preparation as suchor, 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.
`Theefficacy of the antimicrobial activity may be demonstrated
`by the test described below. Thetest is not intended to be
`used for routine control purposes.
`
`TEST FOR EFFICACY OF ANTIMICROBIAL
`PRESERVATION
`
`Thetest 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.
`Thepreservative properties of the preparation are adequate
`if, in the conditionsof the test, thereis a significantfall or no
`increase, as appropriate, in the numberof micro-organisms
`in the inoculated preparation after the times and at the
`temperatures prescribed. Thecriteria of acceptance, in terms
`of decrease in the numberof micro-organismswith time, vary
`for different types of preparations accordingto the degree of
`protection intended (see Tables 5.1.3.-1/2/3).
`
`ok
`O|
`®s
`os
`oFx
`
`n
`
`©o
`
`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; IP 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 forall oral preparations and
`Zygosaccharomyces rouxii (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
`grownstock culture of each of the specified micro-organisms.
`Incubate the bacterial cultures at 30-35 °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 neededafter revival before the
`
`448
`
`See the information section on general monographs (cover pages)
`
`UCB Biopharma SPRL(IPR2019-00400)
`Exhibit 2021 Page 4
`
`UCB Biopharma SPRL (IPR2019-00400)
`Exhibit 2021 Page 4
`
`

`

`5.1.5. Application of the F, concept to steam sterilisation
`EUROPEAN PHARMACOPOEIA 5.0
`Ns—<<
`
`Table 5.1.3.-2. - Topical preparationsoS
`Log reduction
`7d
`14d
`
`28d
`
`2d
`
`Category 3
`A. Preparationsfor oral and rectal administration.
`— Total viable aerobic count(2.6.12). Not more than
`103 bacteria and not more than 10? fungi per gram
`or per millilitre.
`— Absence of Escherichia coli (1 g or 1 ml)(2.6.13).
`B. Preparations for oral administration containing raw
`NI
`2
`A
`Fungi
`materials of natural (animal, vegetable or mineral)
`
`
`1B NInnnLEE
`origin for which antimicrobialpretreatmentis not
`feasible and for which the competent authority accepts
`microbial contaminationofthe raw material exceeding
`10° viable micro-organismsper gram orper millilitre.
`Herbal medicinal products described in category 4 are
`excluded.
`— Total viable aerobic count(2.6.12). Not more than
`Table 5.1.3.-3. - Oral preparationsnnnEE
`10! bacteria and not more than 10? fungi per gram
`Log reduction
`or per millilitre.
`4d 28daadeaeaeeeee
`— Not more than 10? enterobacteria and certain other
`gram-negative bacteria per gram orpermillilitre
`
`Bacteria
`3
`NI
`(2.6.13).
`1 NI
`
`— Absence of Salmonella (10 g or 10 ml) (2.6.13).
`Fungi
`— Absence of Escherichia coli (1 ¢ or 1 ml) (2.6.13).
`The above criteria express the recommended efficacy to be
`— Absence of Staphylococcus aureus(1 g or 1 ml)
`achieved.
`(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 wateris
`addedbefore use.
`— Total viable aerobic count (2.6.12). Not more than
`107 bacteria and not more than 10° fungi per gram
`or per millilitre.
`— Not more than 10? Escherichia coli per gram or per
`millilitre (2.6.13, using suitable dilutions).
`B. Herbal medicinal products to which boiling wateris not
`added before use.
`— Total viable aerobic count(2.6.12). Not more than
`10° bacteria and not more than 104 fungi per gram
`or per millilitre.
`— Not more than 10? enterobacteria and certain other
`gram-negative bacteria per gram or per millilitre
`(2.6.13).
`— Absenceof Escherichia coli (1 g or 1 ml) (2.6.13).
`— Absence of Salmonella (10 g or 10 ml)(2.6.13).
`
`Bacteria
`
`A
`B
`
`2
`
`3
`
`NI
`NI
`
`3
`
`The A criteria express the recommendedefficacy to be
`achieved. In justified cases where the A criteria cannot be
`attained, for example for reasonsof an increasedrisk of
`adverse reactions, the B criteria must be satisfied.
`
`
`
`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 andother preparations
`labelled sterile.
`— Testfor sterility (2.6.1).
`Category 2
`Preparations for topical use and for use in the respiratory
`tract except where requiredto be sterile and transdermal
`patches.
`— Total viable aerobic count (2.6.12). Not more than
`10? micro-organisms(aerobic bacteria plus fungi)
`per gram,per millilitre or per patch (including the
`adhesive and backinglayer).
`— Transdermalpatches: absence of enterobacteria and
`certain other gram-negative bacteria, determined on
`1 patch (including the adhesive and backing layer).
`Other preparations: not more than 10’ enterobacteria
`and certain other gram-negative bacteria per gram or
`per millilitre (2.6.13).
`— Absence of Pseudomonas aeruginosa, determined
`on 1g, 1 mlorone patch (including the adhesive and
`backing layer) (2.6.73).
`— Absence of Staphylococcus aureus, determined on
`1 g, 1 ml orone patch(including the adhesive and
`backinglayer) (2.6.13).
`
`General Notices (1) apply to all monographs andothertexts
`
`
`
`yo‘e]
`
`5
`es
`.
`‘3
`
`01/2005:50105
`
`5.1.5. APPLICATION OF THEF,
`CONCEPT TO STEAM STERILISATION
`OF AQUEOUS PREPARATIONS
`Thefollowing chapter is published for information.
`The F,value ofa saturated steam sterilisation processis
`the lethality expressed in terms of the equivalent time
`in minutes at a temperature of 121 °C delivered by the
`processto the productinits final container with reference to
`micro-organisms possessing a Z-value of 10.
`The total F, of a process takes accountof the heating up and
`cooling down phasesof the cycle and can be calculated by
`integration of lethal rates with respect to time at discrete
`temperatureintervals.
`Whena steamsterilisation cycle is chosen on the basis
`of the F, concept, great care must be taken to ensure
`that an adequateassuranceofsterility is consistently
`
`449
`
`UCB Biopharma SPRL(IPR2019-00400)
`Exhibit 2021 Page 5
`
`UCB Biopharma SPRL (IPR2019-00400)
`Exhibit 2021 Page 5
`
`