Transcription
EN5.3.2011Official Journal of the European UnionC 73/1IV(Notices)NOTICES FROM EUROPEAN UNION INSTITUTIONS, BODIES, OFFICES ANDAGENCIESEUROPEAN COMMISSIONNote for guidance on minimising the risk of transmitting animal spongiform encephalopathy agentsvia human and veterinary medicinal products (EMA/410/01 rev.3)(2011/C 73/01)This note provides guidance for minimising the risk of transmitting animal spongiform encephalopathyagents via human and veterinary medicinal products.This 3rd technical revision of the TSE (Transmissible Spongiform Encephalopathy) Note for Guidance hasbeen undertaken to take into account advancement of science in the area of transmissible spongiformencephalopathies, as well as the evolving situation regarding Bovine Spongiform Encephalopathy (BSE)across the world.For the classification of countries or regions according to their BSE risk, the revised Note for Guidance willmake reference to the rules laid down by the World Organisation for Animal Health (OIE), replacing theprevious GBR classification. Nevertheless, for countries that were classified according to the GBR criteria butnot yet according to the OIE criteria, the existing GBR classification should apply, provided that there is noevidence of significant change in their BSE risk.New criteria for the sourcing and processing of gelatin and bovine blood derivatives used in the manu facture of medicinal products for human or veterinary use have been introduced, as well as a newsubsection on Peptones.It replaces the previous revision of the Note for Guidance (EMEA/410/01 Rev. 2 published in the OfficialJournal of the European Union (C 24, 28.1.2004, p. 6)). The proposed date of application of this revised Notefor Guidance is 1 July 2011.1. INTRODUCTION1.1. Scientific backgroundTransmissible Spongiform Encephalopathies (TSEs) are chronicdegenerative nervous diseases characterised by the accumulationof an abnormal isoform of a cellular glycoprotein (known asPrP or prion protein). The abnormal isoform of PrP (PrPTSE)differs from normal PrP (PrPc) in being highly resistant toprotease and heat denaturation treatments. PrPTSE is consideredto be the infective agent responsible for transmitting TSEdisease.— scrapie in sheep and goats,— chronic wasting disease (CWD) in cervids (deer and elk),— transmissible mink encephalopathy (TME) in farmed mink,— feline spongiform encephalopathy (FSE) in felids (specificallydomestic cats and captive large cats), and— spongiform encephalopathy of exotic ungulates in zoos.TSE diseases in animals include:— bovine spongiform encephalopathy (BSE) in cattle,In humans, spongiform encephalopathies include differentforms of Creutzfeldt-Jakob Disease (CJD), Kuru, GerstmannSträussler-Scheinker Syndrome (GSS), and Fatal FamilialInsomnia (FFI).
C 73/2ENOfficial Journal of the European UnionIatrogenic transmission of spongiform encephalopathies hasbeen reported. In sheep, scrapie has been accidentally trans mitted by the use of Louping Ill vaccine prepared frompooled, formaldehyde treated ovine brain and spleen in whichmaterial from scrapie-infected sheep had been inadvertentlyincorporated. Also, transmission of scrapie to sheep and goatsoccurred following use of a formol-inactivated vaccine againstcontagious agalactia, prepared with brain and mammary glandhomogenates of sheep infected with Mycoplasma agalactiae. Inman, cases of transmission of CJD have been reported whichhave been attributed to the parenteral administration of growthhormone and gonadotropin derived from human cadavericpituitary glands. Cases of CJD have also been attributed to theuse of contaminated instruments in brain surgery and with thetransplantation of human dura mater and cornea.Interspecies TSE transmission is restricted by a number ofnatural barriers, transmissibility being affected by the speciesof origin, the prion strain, dose, route of exposure and, insome species, the host allele of the PRNP gene. Speciesbarriers can be crossed under appropriate conditions.5.3.2011currently unquantifiable risk that some BSE-contaminatedprotein supplement may have been fed to sheep. Further, itshould also be assumed that any BSE agent introduced intothe small ruminant population via contaminated feed is likelyto be recycled and amplified (2).There is interest in infecting cells with TSE agents to developassays and for basic scientific reasons. Some success has beenreported, usually but not always with neural cell lines. Theconditions needed to infect a cell are not well understoodand the process is difficult requiring particular combinationsof agent and cell. It is not considered appropriate to makespecific recommendations in terms of cell substrates to beused for production of biological / biotechnology-derivedsubstances. Nevertheless, the possibility of infection of celllines with TSE agents should be taken into account in riskassessments.1.2. Regulatory ComplianceBSE was first diagnosed in the United Kingdom in 1986 and alarge number of cattle and individual herds have been affected.It is clear that BSE is a food borne disease associated with feed(e.g. meat and bone meal) derived from TSE affected animals.Other countries have experienced cases of BSE, either in animalsimported from the United Kingdom or in indigenous animals.There is convincing evidence to show that the variant form ofCJD (vCJD) is caused by the agent which is responsible for BSEin cattle. Therefore, a cautious approach continues to bewarranted if biological materials from species naturallyaffected by TSE diseases, especially bovine species, are usedfor the manufacture of medicinal products.In the course of active surveillance programs, two previouslyunrecognized forms of atypical BSE (BSE-L, also named BASE,and BSE-H) have been identified in rare sporadic cases fromEurope, North America, and Japan. The ‘L’ and ‘H’ identify thehigher and lower electrophoretic positions of their proteaseresistant PrPTSE isoforms. It is noteworthy that atypical caseshave been found in countries that did not experience classicalBSE so far, like Sweden, or in which only few classical BSE caseshave been found like Canada or USA. The atypical BSE agenthas been experimentally transmitted to transgenic miceexpressing the human prion protein and to a cynomolgusmonkey.Scrapie occurs worldwide and has been reported in mostEuropean countries. It has the highest incidence in Cyprus.While humans have been exposed to naturally occurringscrapie for over 250 years, there is no epidemiologicalevidence directly linking scrapie to spongiform encephalopathiesin humans (1). However, there remains a theoretical and(1) This is currently being assessed by EFSA and ECDC. For updatedinformation, please refer to the following link: end/questionsListLoader?mandate M-2009-0221Risk assessment – Since the use of animal-derived materials isunavoidable for the production of some medicinal products andthat complete elimination of risk at source is rarely possible, themeasures taken to manage the risk of transmitting animal TSEsvia medicinal products represent risk minimisation rather thanrisk elimination. Consequently, the basis for regulatorycompliance should be based on a risk assessment, taking intoconsideration all pertinent factors as identified in this Note forGuidance (see below).Legal basis – This Note for Guidance is published by theEuropean Commission following— Annex I, part I, module 3, section 3.2: Content: basic prin ciples and requirements, point (9) of Directive 2001/83/EC ofthe European Parliament and of the Council of 6 November2001 on the Community code relating to medicinalproducts for human use (3), as amended, and— Annex I, Title I, part 2, section C Production and control ofstarting material of Directive 2001/82/EC of the EuropeanParliament and of the Council of 6 November 2001 onthe Community code relating to veterinary medicinalproducts (4), as amended.(2) In January 2005, after confirmation of BSE in a goat in France,additional legislative measures were taken related to monitoringand an increased testing of small ruminants. The increasedsurveillance did not identify additional cases of BSE in sheep andgoats in the EU.(3) OJ L 311, 28.11.2001, p. 67.(4) OJ L 311, 28.11.2001, p. 1.
5.3.2011ENOfficial Journal of the European UnionThese Directives require that applicants for Marketing Authori sation for human and veterinary medicinal products mustdemonstrate that medicinal products are manufactured inaccordance with the latest version of this Note for Guidancepublished in the Official Journal of the European Union. This is acontinuing obligation after the Marketing Authorisation hasbeen granted.By definition, the principle of Specified Risk Materials as definedin Regulation (EC) No 999/2001 of the European Parliamentand of the Council (5) does not apply to medicinal products.However, Regulation (EC) No 1774/2002 of the EuropeanParliament and of the Council (6), which applies since 1st May2003, lays down health rules concerning animal by-productsnot intended for human consumption. As a general rule, andunless properly justified, all animal by-products used as startingmaterials in the manufacture of medicinal products should be‘Category 3 (i.e. safe) materials or equivalent’, as defined inRegulation (EC) No 1774/2002. Justification for the use ofsubstances derived from other, high infectivity materials mustfollow an appropriate benefit/risk evaluation (see further below).C 73/3Medicines Agency and taken into consideration accordingly inthe scope of the certification of the European Directorate for theQuality of Medicines & Health Care (EDQM).2. SCOPETSE-relevant animal species – Cattle, sheep, goats and animalsthat are naturally susceptible to infection with transmissiblespongiform encephalopathy agents or susceptible to infectionthrough the oral route other than humans (7) and non-humanprimates are defined as ‘TSE-relevant animal species’ (8).Materials – This Note for Guidance is concerned with materialsderived from ‘TSE-relevant animal species’ that are used for thepreparation of:— active substances,— excipients and adjuvants, andThis Note for Guidance should be read in conjunction with thevarious European EU legal instruments including CommissionDecisions progressively implemented since 1991. Where appro priate, references to these Decisions are given in the text.Position statements and explanatory notes made by theCommittee for Medicinal Products for Human Use (CHMP)and Committee for Medicinal Products for Veterinary Use(CVMP) are still applicable for the purpose of regulatorycompliance unless otherwise superseded by this Note forGuidance.A general monograph entitled: ‘Products with risk of trans mitting agents of animal spongiform encephalopathies’ isincluded in the European Pharmacopoeia. This monograph,which refers to a general chapter of the European Phar macopoeia, is identical to this Note for Guidance. Themonograph forms the basis for issuing Certificates of Suitabilityas a procedure for demonstrating TSE compliance forsubstances and materials used in the manufacture of humanand veterinary medicinal products.Clarification of Note for Guidance – As the scientific under standing of TSEs, especially the pathogenesis of the diseases, isevolving, from time to time CHMP and its Biologics WorkingParty in collaboration with CVMP and its ImmunologicalsWorking Party may be required in the future to develop supple mentary guidance in the form of position statements orexplanatory notes for the purpose of clarifying this Note forGuidance. The supplementary guidance shall be published bythe Commission and on the website of the European(5) OJ L 147, 31.5.2001, p. 1.(6) OJ L 273, 10.10.2002, p. 1. Regulation (EC) 1774/2002 has beenrepealed by Regulation (EC) 1069/2009 that will apply from4 March 2011 (OJ L 300, 14.11.2009, p. 1).— raw and starting materials and reagents used in production(e.g. bovine serum albumin, enzymes, culture mediaincluding those used to prepare working cell banks, ornew master cell banks for medicinal products which aresubject to a new Marketing Authorisation).This Note for Guidance is also applicable to materials that comeinto direct contact with the equipment used in manufacture ofthe medicinal product or that come in contact with themedicinal product and therefore have the potential for contami nation.Materials used in the qualification of plant and equipment, suchas culture media used in media fill experiments to validate theaseptic filling process, shall be considered in compliance withthis Note for Guidance provided that the constituent orconstituents are derived from tissues with no detectable infec tivity (category IC tissues), where the risk of cross-contami nation with potentially infective tissues has been considered(see section 3.3) and where the materials are sourced fromcountries with negligible BSE risk or controlled BSE risk(Categories A and B, respectively - see section 3.2). Suchinformation shall be provided in the dossier for a MarketingAuthorisation and verified during routine inspection forcompliance with Good Manufacturing Practice (GMP).(7) Regulatory guidance and position papers have been issued by theCommittee for Medicinal Products for Human Use and its BiologicsWorking Party on human tissue derived medicinal products inrelation to CJD and vCJD. Such guidance can be found on http://www.ema.europa.eu.(8) Pigs and birds, which are animal species of particular interest for theproduction of medicinal products, are not naturally susceptible toinfection via the oral route. Therefore they are not TSE-relevantanimal species within the meaning of this Note for Guidance.Also dogs, rabbits and fish are non TSE-relevant animal specieswithin the meaning of this Note for Guidance.
C 73/4ENOfficial Journal of the European UnionOther materials such as cleaning agents, softeners and lubricantsthat come into contact with the medicinal product during itsroutine manufacture or in the finishing stage or in the primarypackaging are considered in compliance with this Note forGuidance if they are tallow derivatives prepared using therigorous physicochemical processes as described in section 6.5.3.2011However, where materials derived from the ‘TSE-relevant animalspecies’ are used in fermentation/routine production processesor in the establishment of working seeds and working cellbanks, the applicant must demonstrate that they fulfil therequirements of this Note for Guidance.3. GENERAL CONSIDERATIONSSeed lots, cell banks and routine fermentation/production (9) – For the purpose of regulatory compliance,master seeds or master cell banks in Marketing Authorisationapplications lodged after 1 July 2000 (for human medicinalproducts) or 1 October 2000 (for veterinary medicinalproducts) shall be covered by this Note for Guidance.Master seeds and master cell banks,— for vaccine antigens,— for a biotechnology-derived medicinal product as describedin the Annex to Regulation (EC) No 726/2004 of theEuropean Parliament and of the Council (10), and— for other medicinal products using seed lots or cell bankingsystems in their manufacture,that have already been approved for the manufacture of aconstituent of an authorised medicinal product shall beconsidered in compliance with this Note for Guidance even ifthey are incorporated in Marketing Authorisation applicationslodged after 1 July 2000 (for human medicinal products) or1 October 2000 (for veterinary medicinal products).Master cell banks and master seeds established before 1 July2000 (for human medicinal products) or 1 October 2000 (forveterinary medicinal products), but not yet approved as aconstituent of an authorised medicinal product shall demon strate that they fulfil the requirements of this Note forGuidance. If, for some raw or starting materials or reagentsused for the establishment of these cell banks or seeds, fulldocumentary evidence is no longer available, the applicantshould present a risk assessment as described in Section 4 ofthis Note for Guidance.Established working seeds or cell banks used in the manufactureof medicinal products authorised before 1 July 2000 (forhuman medicinal products) or 1 October 2000 (for veterinarymedicinal products), which have been subjected to a properlyconducted risk assessment by a Competent Authority of theMember States or the European Medicines Agency anddeclared to be acceptable, shall also be considered compliant.(9) See also: Position paper on the assessment of the risk of trans mission of animal spongiform encephalopathy agents by masterseed materials used in the production of veterinary vaccines (EMEA/CVMP/019/01 - February 2001 adopted by the Committee forVeterinary Medicinal products (CVMP) in July 2001 (OJ C 286,12.10.2001, p. 12)).(10) OJ L 136, 30.4.2004, p. 1.3.1. Scientific principles for minimising riskWhen manufacturers have a choice the use of materials from‘non TSE-relevant animal species’ or non-animal origin ispreferred. The rationale for using materials derived from ‘TSErelevant animal species’ instead of materials from ‘non-TSErelevant species’ or of non-animal origin should be given. Ifmaterials from ‘TSE-relevant animal species’ have to be used,consideration should be given to all the necessary measures tominimise the risk of transmission of TSE.Readily applicable diagnostic tests for TSE infectivity in vivo arenot yet available. Diagnosis is based on post mortem confir mation of characteristic brain lesions by histopathology and/ordetection of PrPTSE by Western Blot or immunoassay. Thedemonstration of infectivity by the inoculation of suspecttissue into target species or laboratory animals is also usedfor confirmation. However, due to the long incubationperiods of all TSEs, results of in vivo tests are available onlyafter months or years.Several immunochemical tests have been developed fordetection of PrPTSE in post-mortem samples and some arenow considered to be extremely sensitive. However, theirability to detect an infected animal depends on the timing ofsample collection in relation to timing of exposure, the type oftissue collected and infectious dose acquired, together withconsequential timing of onset of clinical disease. There iscurrently insufficient information on how this might beaffected by strain variations.Although screening of source animals by in vitro tests mayprevent the use of animals at late stages of incubation of thedisease and may provide information about the epidemiologicalstatus of a given country or region, none of the tests areconsidered suitable to unambiguously confirm the negativestatus of an animal.Minimising the risks of transmission of TSE is based upon threecomplementary parameters:— the source animals and their geographical origin,— nature of animal material used in manufacture and anyprocedures in place to avoid— cross-contamination with higher risk materials,— production process(es) including the quality assurancesystem in place to ensure product consistency and tracea bility.
EN5.3.2011Official Journal of the European Union3.2. Animal sourceThe source materials used for the production of materials forthe manufacture of medicinal products shall be derived fromanimals fit for human consumption following ante- and postmortem inspection in accordance with EU or equivalent (thirdcountry) conditions, except for materials derived from liveanimals, which should be found healthy after clinical exam ination.C 73/5For the purposes of this Note for Guidance the BSE classifi cation based on the OIE rules should be used. If a country,which was previously classified in accordance to the SSC GBRcriteria, has not been classified yet according the OIE rules, theGBR classification can be used until OIE classification has takenplace, provided that there is no evidence of significant change inits BSE risk (16).3.2.1. Geographical sourcing3.2.1.1. Bovine materialsThe World Organisation for Animal Health (OIE) (11) lays downthe criteria for the assessment of the status of countries in thechapter of the International Animal Health Code on bovinespongiform encephalopathy. Countries or regions are classifiedas follows:A. countries or regions with a negligible BSE risk;B. countries or regions with a controlled BSE risk;Where there is a choice, animals should be sourced fromcountries with the lowest possible BSE risk (negligible BSErisk countries (Category A)) unless the use of material fromcountries with a higher BSE risk is justified. Some of thematerials identified in Section 6., ‘Specific Conditions’ can besourced from countries with controlled BSE risk (Category B)and, in some cases, from countries with undetermined BSE risk(Category C), provided that the controls and requirements asspecified in the relevant sections below are applied. Apart fromthese exceptions, animals must not be sourced from countrieswith undetermined BSE risk (Category C), and justifications forthe use of animals from countries with undetermined BSE risk(Category C) must always be provided.C. countries or regions with an undetermined BSE risk.As stipulated in Commission Regulation (EC) No 999/2001, asamended (12), the classification of countries or regions thereofaccording to their BSE risk, based on the rules laid down byOIE, is legally binding in the EU since 1 July 2007. CommissionDecision 2007/453/EC (13) as amended, provides the classifi cation of countries or regions according to their BSE risk.Previously, the European Commission Scientific SteeringCommittee (SSC) (14) had established a temporary system forclassifying the countries according to their geographical BSErisk (GBR) (15)3.2.1.2. Sheep and goats (small ruminants)Naturally occurring clinical scrapie cases have been reported ina number of countries worldwide. As BSE in sheep and goatscould possibly be mistaken for scrapie, as a precautionarymeasure, sourcing of materials derived from small ruminantsshall take into account the prevalence of both BSE andscrapie in the country and the tissues from which thematerials are tus/BSE/en BSE free.htmRegulation (EC) No 722/2007 (OJ L 164, 26.6.2007, p. 7).OJ L 172, 30.6.2007, p. 84.The Scientific Steering Committee established by CommissionDecision 97/404/EC (OJ L 169, 27.6.1997, p. 85) shall assist theCommission to obtain the best scientific advice available on mattersrelating to consumer health. Since May 2003, its task have beentaken over by the European Food Safety Authority (EFSA): http://www.efsa.europa.eu(15) The European Scientific Steering Committee classification forgeographical BSE risk (GBR) gives an indication of the level oflikelihood of the presence of one or more cattle clinically or preclinically infected with BSE in a given country or region. A defi nition of the four categories is provided in the Table:GBR levelIIIIIIIVPresence of one or more cattle clinically or pre-clinicallyinfected with BSE in a geographical region/countryHighly unlikelyUnlikely but not excludedLikely but not confirmed or confirmed at a lower levelConfirmed at a higher level ( 100 cases/1 Millionadult cattle per year)Reports of the GBR assessment of the countries are available onthe SSC website (http://ec.europa.eu/food/fs/sc/ssc/outcome en.html).The principles related to ‘BSE negligible risk (closed) bovineherds’ (see section 3.2.2) could equally be applied in thecontext of small ruminants in order to develop a frameworkto define the TSE status of a flock of small ruminants. Forsheep, because of the concern over the possibility of BSE insheep, the use of a genotype(s) showing resistance toBSE/scrapie infection could be considered in establishing TSEfree flocks (17). However, the possibility that genotypesresistant to scrapie could be susceptible to BSE (experimentaloral exposure) or atypical scrapie (natural cases) should also betaken into account. Goats have not been studied sufficientlywith regard to a genotype specific sensitivity.(16) Experts consider that the GBR classification system is stable enough,so that it can continue to be used, during the interim period, forthe demonstration of compliance with this guidance.(17) Opinion of the Scientific Panel on Biological Hazards on ‘thebreeding programme for TSE resistance in sheep’: http://www.efsa.europa.eu/EFSA/efsa locale-1178620753812 1178620775678.htm
C 73/6ENOfficial Journal of the European UnionMaterial of small ruminant origin should preferably be sourcedfrom countries with a long history of absence of scrapie. Justifi cation shall be required if the material is sourced from someother origin.3.2.2. BSE negligible risk (closed) bovine herdsThe safest sourcing is from countries or regions with anegligible BSE risk (Category A countries). Other countriesmay have or have had cases of BSE at some point in timeand the practical concept of ‘Negligible risk (closed) bovineherds’ has been developed by the SSC and endorsed by theCHMP and CVMP. Criteria for establishing and maintaining a‘BSE negligible risk (closed) bovine herd’ can be found in theSSC opinion of 22-23 July 1999 (18).For the time being it is not possible to quantify the reduction ofthe geographical BSE risk for cattle from BSE ‘Negligible risk(closed) bovine herds’. However, it is expected that this riskreduction is substantial. Therefore, sourcing from such closedbovine herds shall be considered in the risk assessment inconjunction with the OIE classification of the country.3.3. Animal parts, body fluids and secretions as startingmaterialIn a TSE infected animal, different organs and secretions havedifferent levels of infectivity. If materials from ‘TSE-relevantanimal species’ have to be used, consideration should begiven to use materials of the lowest category of risk. Thetables in the Annex of this Note for Guidance (19) summarisecurrent data about the distribution of infectivity and PrPTSE incattle with BSE, and in sheep and goats with scrapie (20).The information in the tables is based exclusively upon obser vations of naturally occurring disease or primary experimentalinfection by the oral route (in cattle) but does not include dataon models using strains of TSE that have been adapted toexperimental animals, because passaged strain phenotypes candiffer significantly and unpredictably from those of naturallyoccurring disease. Because immunohistochemical and/orwestern blot detection of misfolded host protein (PrPTSE) haveproven to be a surrogate marker of infectivity, PrPTSE testingresults have been presented in parallel with bioassay data.Tissues are grouped into three major infectivity categories, irre spective of the stage of disease:Category IA: High-infectivity tissues: central nervous system(CNS) tissues that attain a high titre of infec tivity in the later stages of all TSEs, and(18) SSC Scientific Opinion on the conditions related to ‘BSE NegligibleRisk (Closed) Bovine Herds’ adopted at the meeting of 22-23 July1999. http://ec.europa.eu/food/fs/sc/ssc/out56 en.html(19) The tissue classification tables are based upon the most recentWHO Guidelines on Tissue Infectivity Distribution in y.pdf(20) A Scientific opinion on BSE/TSE infectivity in small ruminanttissues is currently being reviewed by EFSA (Question No EFSAQ-2010-052). For updated information please follow this Frontend/questionsListLoader?mandate M-2010-00415.3.2011certain tissues that are anatomically associatedwith the CNS.Category IB: Lower-infectivity tissues: peripheral tissues thathave tested positive for infectivity and/or PrPTSEin at least one form of TSE.Category IC: Tissues with no detectable infectivity: tissuesthat have been examined for infectivity,without any infectivity detected, and/or PrPTSE,with negative results.Category IA tissues and substances derived from them shall notbe used in the manufacture of medicinal products, unlessjustified (see Section 5).Although the category of lower-infectivity tissues (category IBtissues) almost certainly includes some (e.g. blood) with a lowerrisk than others (e.g. lymphoreticular tissues), the data aboutinfectivity levels in these tissues are too limited to subdividethe category into different levels of risk. It is also evident thatthe placement of a given tissue in one or another category canbe disease and species specific, and subject to revision as newdata emerge.For the risk assessment (see section 4), manufacturers and/orMarketing Authorisation Holders/applicants shall take intoaccount the tissue classification tables in the Annex to thisNote for Guidance.The categories in the tables are only indicative and it isimportant to note the following points.— In certain situations there could be cross-contamination oftissues of different categories of infectivity. The potential riskwill be influenced by the circumstances in which tissueswere removed, especially by contact of tissues with lowerinfectivity or no detectable infectivity (categories IB and ICtissues) with high-infectivity tissues (category IA tissues).Thus, cross-contamination of some tissues may beincreased if infected animals are slaughtered by brainstunning (penetrative or non-penetrative) or if the brainand/or spinal cord is sawed. The risk of cross-contaminationwill be decreased if body fluids are collected with minimaldamage to tissue and cellular components are removed, andif foetal blood is collected without contamination fromother maternal or foetal tissues including placenta,amniotic and allantoic fluids. For certain tissues, it is verydifficult or impossible to prevent cross-contamination withCategory IA tissues (e.g. skull). This has to be considered inthe risk assessment.
5.3.2011ENOfficial Journal of the European Union— For certain classes of substances the stunning/slaughteringtechniques used may be important in determining thepotential
minimising the risks of transmission of tse is based upon three complementary parameters: — the source animals and their geographical origin, — nature of animal material used in manufacture and any procedures in place to avoid — cross-contamination with higher risk materials, — production process(es) including the quality assurance system in
