1、Juni 2006 Preisgruppe 17DIN Deutsches Institut fr Normung e.V. Jede Art der Vervielfltigung, auch auszugsweise, nurmit Genehmigung des DIN Deutsches Institut fr Normung e. V., Berlin, gestattet.ICS 67.250!,j“9715696www.din.deDDIN-Fachbericht CEN/TR 15356-1Validierung und Interpretation analytischer
2、Verfahren, Migrationsprfungund analytischer Daten von Werkstoffen und Bedarfsgegenstnden inKontakt mit Lebensmitteln Teil 1: Allgemeine Betrachtungen;Englische Fassung CEN/TR 15356-1:2006Validation and interpretation of analytical methods, migration testing and analytical data for materials andartic
3、les in contact with food Part 1: General considerations;English version CEN/TR 15356-1:2006Alleinverkauf durch Beuth Verlag GmbH, 10772 Berlin www.beuth.deGesamtumfang 46 SeitenB55EB1B3E14C22109E918E8EA43EDB30F09CC9B7EF8DD9NormCD - Stand 2007-032 Nationales Vorwort Dieses Dokument CEN/TR 15356-1 wur
4、de vom Technischen Komitee CEN/TC 194 Bedarfsgegenstnde in Kontakt mit Lebensmitteln erarbeitet, dessen Sekretariat vom BSI (Vereinigtes Knigreich) gehalten wird. Das zustndige deutsche Gremium ist der Arbeitsausschuss NMP 893 Bedarfsgegenstnde aus Kunststoff in Kontakt mit Lebensmitteln Prfung der
5、Migration aus Kunststoffen im Normenausschuss Materialprfung (NMP). Auf Wunsch der an der Erarbeitung des nachfolgenden Technischen Berichts beteiligten interessierten Kreise in Deutschland, wird das Dokument der ffentlichkeit unverndert in der englischen Sprachfassung zur Verfgung gestellt. DIN-Fac
6、hbericht CEN/TR 15356-1:2006-06 B55EB1B3E14C22109E918E8EA43EDB30F09CC9B7EF8DD9NormCD - Stand 2007-03TECHNICAL REPORT RAPPORT TECHNIQUE TECHNISCHER BERICHT CEN/TR 15356-1 March 2006 ICS 13.060.20; 23.060.50 English Version Validation and interpretation of analytical methods, migration testing and ana
7、lytical data for materials and articles in contact with food Part 1: General considerations Validation et interprtation des mthodes danalyse, essais de migrations et donnes analytiques des matriaux et objets en contact avec les denres alimentaires Partie 1: Considrations gnrales Validierung und Inte
8、rpretation analytischer Verfahren, Migrationsprfung und analytischer Daten von Werkstoffen und Bedarfsgegenstnden in Kontakt mit Lebensmitteln Teil 1: Allgemeine Betrachtungen This Technical Report was approved by CEN on 16 January 2006. It has been drawn up by the Technical Committee CEN/TC 194. CE
9、N members are the national standards bodies of Austria, Belgium, Cyprus, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Netherlands, Norway, Poland, Portugal, Romania, Slovakia, Slovenia, Spain, Sweden, Swit
10、zerland and United Kingdom. EUROPEAN COMMITTEE FOR STANDARDIZATION COMIT EUROPEN DE NORMALISATION EUROPISCHES KOMITEE FR NORMUNG Management Centre: rue de Stassart, 36 B-1050 Brussels 2006 CEN All rights of exploitation in any form and by any means reserved worldwide for CEN national Members. Ref. N
11、o. CEN/TR 15356-1:2006: EB55EB1B3E14C22109E918E8EA43EDB30F09CC9B7EF8DD9NormCD - Stand 2007-03CEN/TR 15356-1:2006 (E) 2 Contents Page Introduction 4 1 Scope 6 2 Form of regulations 6 3 Terms and definitions. 7 4 Analytical tolerances 10 5 Limits 12 6 Existing general legislation . 14 7 Difficulties w
12、ith present situation regarding method validation 17 8 Analytical interpretation of results and limits 19 9 Single laboratory method validation - General protocol. 23 10 Single laboratory and second laboratory validation - For the food contact materials sector. 23 11 FDA requirements with respect to
13、 validation of analytical methods 25 12 Recovery 25 13 Reference materials 27 14 Costs 28 15 Sampling 29 16 Enforcement 30 17 Conclusions. 30 Annex A (informative) Food contact materials and articles: EU legislation. 31 Annex B (informative) List of methods currently available 37 Annex C (informativ
14、e) Codex proposed draft guidelines on measurement uncertainty. 39 Annex D (informative) Characteristics of available certified reference materials 41 Bibliography . 42 B55EB1B3E14C22109E918E8EA43EDB30F09CC9B7EF8DD9NormCD - Stand 2007-03CEN/TR 15356-1:2006 (E) 3 Foreword This document (CEN/TR 15136-1
15、:2006) has been prepared by Technical Committee CEN/TC 194 Utensils in contact with food, the secretariat of which is held by BSI. According to the CEN/CENELEC Internal Regulations, the national standards organizations of the following countries are bound to announce this Technical Report: Austria,
16、Belgium, Cyprus, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Netherlands, Norway, Poland, Portugal, Slovakia, Slovenia, Spain, Sweden, Switzerland and the United Kingdom. B55EB1B3E14C22109E918E8EA43EDB30F
17、09CC9B7EF8DD9NormCD - Stand 2007-03CEN/TR 15356-1:2006 (E) 4 Introduction 0.1 Requirement for validation of analytical methods for enforcement of Directives Regulation (EC) No. 1935/20041has laid down the requirements that may be included in specific Directives to protect human health. It allows for
18、 specific Directives to set overall migration limits and specific limits on the migration of certain constituents or groups of constituents into foodstuffs. Commission Directive 90/128/EEC2and its subsequent amendments (e.g.3)introduced specific migration limits for more than 300 substances. A conso
19、lidation of these directives has since been issued as Commission Directive 2002/72/EC4. In addition, some substances are subject to a maximum permitted quantity of the residual substance in the material or article. Some substances are subject to group limits. Continuously, additional substances are
20、being evaluated and added to the Directive. New technical dossiers are being prepared for substances which could eventually be listed in future amendments to Directive 2002/72/EC. Methods of control will be required for the majority of the abovementioned substances. The two Food Control Directives (
21、European Council Directive 89/397/EEC5and Council Directive 93/99/EEC6) require that methods used for control purposes must be correctly and fully validated. So far only the methods developed by CEN as parts of EN 13130 have been so validated. Methods developed in the project sponsored by DG Researc
22、h (SM the use of defined internal quality control procedures; participation in proficiency testing schemes; accreditation based on EN ISO/IEC 17025, and establishing traceability of the results of the measurements. Whenever decisions are based on analytical results, it is important to have some indi
23、cation of the quality of the results, that is, the extent to which they can be relied on for the purpose in hand. In analytical chemistry, there has been great emphasis on the precision of results obtained using a specified method, rather than on their traceability to a defined standard or SI unit.
24、This has led the use of “official methods“ to fulfil legislative and trading requirements. The use of official methods is not in itself a complete answer. To demonstrate fitness for purpose, irrespective of the analytical methods used, one useful indicator is measurement uncertainty. A number of way
25、s are available for analysts to estimate their measurement uncertainty. These included: B55EB1B3E14C22109E918E8EA43EDB30F09CC9B7EF8DD9NormCD - Stand 2007-03CEN/TR 15356-1:2006 (E) 11 evaluation of the effect of the identified sources of uncertainty on the analytical result for a single method implem
26、ented as a defined measurement procedure in a single laboratory; results from defined internal quality control procedures in a single laboratory; results from collaborative trials used to validate methods of analysis in a number of competent laboratories; results from proficiency test schemes used t
27、o assess the analytical competency of laboratories. A practical solution is needed in the short term, and for this a Horwitz equation9approach is often taken. Here the Horwitz value is derived from the Horwitz trumpet and equation, which states that for any method: RSDR= 2(1-0,5logC)and that the val
28、ue is independent of matrix/analyte. RSDRis the relative standard deviation of the reproducibility (SRx 100/MEAN). The major values are: Concentration ratio RSDR1 (100 %) 2 1012,8 102(1 %) 4 1035,6 1048 10511 106(ppm) 16 10723a10832a109(ppb) 45aaAt levels below 120 g/kg (ppb), the more usual value t
29、o be used is 22 % of the concentration10. Horwitz derived the equation after assessing the results from many (ca. 3 000) collaborative trials. Although it represents the average RSDRvalues and is an approximation of the possible precision that can be achieved, the data points from “acceptable“ colla
30、borative trials are less than twice the predicted RSDR values at the concentrations of interest. This idealised smoothed curve was found to be independent of the nature of the analyte or of the analytical technique that was used to make the measurement. In general the values taken from this curve ar
31、e indicative of the precision that is achievable and acceptable of an analytical method by different laboratories. Its use provides a satisfactory and simple means of assessing method precision acceptability. A comparison of the RSDRobtained in the method validation procedure and that predicted by t
32、he Horwitz equation is increasingly being used by organisations to assess the acceptability of the precision characteristics of their methods. If the ratio between the two is significantly greater than 2, then many organisations would deem the method to be unacceptable (too imprecise). B55EB1B3E14C2
33、2109E918E8EA43EDB30F09CC9B7EF8DD9NormCD - Stand 2007-03CEN/TR 15356-1:2006 (E) 12 5 Limits 5.1 General The analytical difficulty, and hence the intrinsic uncertainty of measurements, will vary according to the nature of the limitation in the Directive. A number of these instances are addressed in 5.
34、2 to 5.6. 5.2 High SML values When the value for the specific migration limit is high, for example 1-octene with an SML of 15 mg/kg, then the uncertainty of measurement is likely to be low compared to the limit. 5.3 Low SML values When the value for the specific migration limit is low, for example t
35、he many substances with a migration limit of 0,05 mg/kg, then the uncertainty of measurement may become a significant problem when establishing compliance, or otherwise, with the limit. This problem is exacerbated if the substance is volatile or of limited stability or if interfering substances are
36、present in the plastics. 5.4 Substances “Not to be detectable“ There are a number of substances with a limit stated as “the specific migration of this substance shall not be detectable (when measured by a method with a limit of detection of 0,01 mg/kg)“, for example acrylamide. Also, there are subst
37、ances with a limit stated as “the specific migration of this substance shall not be detectable (when measured by a method with a limit of detection of 0,02 mg/kg, analytical tolerance included)“, for example acrylonitrile. The definition of what constitutes “not detectable“ and the low limits gives
38、rise to significant problems when establishing the uncertainty of any method. The relevant parts of EN 13130 give advice and instruction upon the analytical methods for substances with these limitations and how to report the results. 5.5 Group limits A number of substances in the Directive are subje
39、ct to group limits, i.e. QM(T) or SML(T) limitations. The imposition of group limits causes particular difficulties. Except for the epoxy moiety, there is usually no obvious derivatisation route to determine the functional group quantitatively. This means that each member of the group needs to be de
40、termined individually and the total amount of the moiety migrating has to be derived by calculation, i.e. by summing the levels of each individual member of the group multiplied by the appropriate conversion factor. Many of the group restrictions cover substances that differ considerably from each o
41、ther in molecular weight, boiling point, polarity etc. and so they cannot all be determined by a single analytical procedure. This could lead to greater analytical errors when summing the total amount of the individual substances present. Determination of the total of a group of substances requires
42、that for each member of the group a value needs to be given which is either the level actually determined, together with the tolerance on this determination, or the limit of detection for that member of the group. The total is then the sum of these values. This means that if, for example a limit for
43、 a group was 0,05 mg/kg and there were more than five substances in the group, each of which was subject to a detection limit of 0,01 mg/kg, even if none of the substances were in fact present it would not be possible to prove that the group limit was not exceeded. It also means that, even for a sma
44、ll group of two or three substances, if two were present at, for example, the 0,02 mg/kg level but with an analytical tolerance of 0,01 mg/kg for the group total, then it would not be possible to prove that a group limit of 0,05 mg/kg had not been exceeded. The relevant parts of EN 13130 give advice
45、 and instruction upon the analytical methods for these groups and how to report the results. B55EB1B3E14C22109E918E8EA43EDB30F09CC9B7EF8DD9NormCD - Stand 2007-03CEN/TR 15356-1:2006 (E) 13 5.6 Future Issues 5.6.1 Compositional limits In some cases substances in the Directive are subject to residual l
46、imits, marked as QM. A QM limit is set to avoid any problem with instability of the substance during migration, or because the determination of the substance in food simulants or real foodstuffs is not feasible. The limit requires the determination of the total amount of the substance in the polymer
47、. The QM value was derived from the available toxicity data assuming that 1 % of the substance present in 1 kg polymer may migrate into 1 kg of food. The basis for this reasoning was derived from experiments with vinyl chloride in polyvinylchloride. A QM limit is difficult to enforce in case of mult
48、ilayer materials. For thin multilayer materials the whole film can be extracted and if the QM limit is not exceeded then the material is in compliance. However, in case of thick materials (e.g. 0,17 mm) the QM limit should be determined from the layer containing that substance. This is generally not
49、 possible. The relevant parts of EN 13130 give advice and instruction upon the analytical methods for the determination of the residual amount of relevant substances and how to report the results. 5.6.2 QMA limits (mg/unit area) A new type of restriction was introduced with the fifth amendment (1999/91/EC) of Directive 90/128/EEC. This restriction called QMA is a limit for the substance expressed in mg/6 dm2surface area. There are various reasons to establish a QMA, e.g.: no analytical method for
