1、PUBLISHED DOCUMENTPD CEN/TR 15356-1:2006Validation and interpretation of analytical methods, migration testing and analytical data for materials and articles in contact with food Part 1: General considerationsICS 13.060.20; 23.060.50g49g50g3g38g50g51g60g44g49g42g3g58g44g55g43g50g56g55g3g37g54g44g3g5
2、1g40g53g48g44g54g54g44g50g49g3g40g59g38g40g51g55g3g36g54g3g51g40g53g48g44g55g55g40g39g3g37g60g3g38g50g51g60g53g44g42g43g55g3g47g36g58PD CEN/TR 15356-1:2006This Published Document was published under the authority of the Standards Policy and Strategy Committee on 31 May 2006 BSI 2006ISBN 0 580 48304
3、5National forewordThis Published Document is the official English language version of CEN/TR 15356-1:2006.The UK participation in its preparation was entrusted to Technical Committee CW/47, Materials in contact with food, which has the responsibility to: A list of organizations represented on this c
4、ommittee can be obtained on request to its secretary.Cross-referencesThe British Standards which implement international or European publications referred to in this document may be found in the BSI Catalogue under the section entitled “International Standards Correspondence Index”, or by using the
5、“Search” facility of the BSI Electronic Catalogue or of British Standards Online.This publication does not purport to include all the necessary provisions of a contract. Users are responsible for its correct application. Compliance with a Published Document does not of itself confer immunity from le
6、gal obligations. aid enquirers to understand the text; present to the responsible international/European committee any enquiries on the interpretation, or proposals for change, and keep UK interests informed; monitor related international and European developments and promulgate them in the UK.Summa
7、ry of pagesThis document comprises a front cover, an inside front cover, the CEN/TR title page, pages 2 to 44, an inside back cover and a back cover.The BSI copyright notice displayed in this document indicates when the document was last issued.Amendments issued since publicationAmd. No. Date Commen
8、tsTECHNICAL REPORTRAPPORT TECHNIQUETECHNISCHER BERICHTCEN/TR 15356-1March 2006ICS 13.060.20; 23.060.50English VersionValidation and interpretation of analytical methods, migrationtesting and analytical data for materials and articles in contactwith food - Part 1: General considerationsValidation et
9、interprtation des mthodes danalyse, essaisde migrations et donnes analytiques des matriaux etobjets en contact avec les denres alimentaires - Partie 1 :Considrations gnralesValidierung und Interpretation analytischer Verfahren,Migrationsprfung und analytischer Daten von Werkstoffenund Bedarfsgegenst
10、nden in Kontakt mit Lebensmitteln -Teil 1: Allgemeine BetrachtungenThis Technical Report was approved by CEN on 16 January 2006. It has been drawn up by the Technical Committee CEN/TC 194.CEN members are the national standards bodies of Austria, Belgium, Cyprus, Czech Republic, Denmark, Estonia, Fin
11、land, France,Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Netherlands, Norway, Poland, Portugal, Romania,Slovakia, Slovenia, Spain, Sweden, Switzerland and United Kingdom.EUROPEAN COMMITTEE FOR STANDARDIZATIONCOMIT EUROPEN DE NORMALISATIONEUROPISCHES KOMIT
12、EE FR NORMUNGManagement Centre: rue de Stassart, 36 B-1050 Brussels 2006 CEN All rights of exploitation in any form and by any means reservedworldwide for CEN national Members.Ref. No. CEN/TR 15356-1:2006: E2 Contents Page Foreword. 3 Introduction 4 1 Scope 6 2 Form of regulations 6 3 Terms and defi
13、nitions. 7 4 Analytical tolerances 10 5 Limits 12 6 Existing general legislation . 14 7 Difficulties with 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
14、 laboratory validation - For the food contact materials sector. 23 11 FDA requirements with respect to 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 article
15、s: EU legislation. 31 Annex B (informative) List of methods currently available 37 Annex C (informative) Codex proposed draft guidelines on measurement uncertainty. 39 Annex D (informative) Characteristics of available certified reference materials 41 Bibliography . 42 CEN/TR 15356-1:20063 Foreword
16、This document (CEN/TR 15356-1:2006) has been prepared by CEN /TC 194, “Utensils in contact with food“, the secretariat of which is held by BSI. CEN/TR 15356-1:20064 Introduction 0.1 Requirement for validation of analytical methods for enforcement of Directives Regulation (EC) No. 1935/20041has laid
17、down the requirements that may be included in specific Directives to protect human health. It allows for 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
18、 subsequent amendments (e.g.3)introduced specific migration limits for more than 300 substances. A consolidation 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 ma
19、terial or article. Some substances are subject to group limits. Continuously, additional substances are 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 contr
20、ol will be required for the majority of the abovementioned substances. The two Food Control Directives (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 C
21、EN as parts of EN 13130 have been so validated. Methods developed in the project sponsored by DG Research (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
22、 the measurements. Whenever decisions are based on analytical results, it is important to have some indication 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
23、 obtained using a specified method, rather than on their traceability to a defined standard or SI unit. 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, irres
24、pective of the analytical methods used, one useful indicator is measurement uncertainty. A number of ways are available for analysts to estimate their measurement uncertainty. These included: CEN/TR 15356-1:200611 evaluation of the effect of the identified sources of uncertainty on the analytical re
25、sult for a single method implemented 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
26、proficiency test schemes used to 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: RSD
27、R= 2(1-0,5logC)and that the value 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/k
28、g (ppb), the more usual value to 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
29、 points from “acceptable“ collaborative 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
30、values taken from this curve are 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 pr
31、ocedure and that predicted by the 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
32、 (too imprecise). CEN/TR 15356-1:200612 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 5.2 to 5.6. 5.2 High SML values When the val
33、ue 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 the many substances with a migration limit
34、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 present in the plastics. 5.4 Substances “N
35、ot 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 substances with a limit stated as “the specific
36、 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 rise to significant problems when establis
37、hing 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 subject to group limits, i.e. QM(T) or SML(T) l
38、imitations. 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 determined individually and the total amount
39、 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 other in molecular weight, boiling point, p
40、olarity 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 that for each member of the group a value
41、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 a group was 0,05 mg/kg and there were mor
42、e 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 small group of two or three substances, if tw
43、o 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 and instruction upon the analytical metho
44、ds for these groups and how to report the results. CEN/TR 15356-1:200613 5.6 Future Issues 5.6.1 Compositional limits In some cases substances in the Directive are subject to residual limits, marked as QM. A QM limit is set to avoid any problem with instability of the substance during migration, or
45、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. The QM value was derived from the available toxicity data assuming that 1 % of the substance present in 1 kg poly
46、mer 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 multilayer materials. For thin multilayer materials the whole film can be extracted and if the QM limit is not exceeded
47、 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 possible. The relevant parts of EN 13130 give advice and instruction upon the analytical methods for the determina
48、tion 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 dm2surf
49、ace area. There are various reasons to establish a QMA, e.g.: no analytical method for the determination of the migration of the substance is provided; substance is not stable under conditions of migration; substance is very volatile. Establishing a QMA limit is a careful consideration at the state of petitioning and is considered case by case. The QMA limit is based on available toxicity data, while assuming 100 % migration from the polymer into the food simulant. In other words the QMA limit is equal to the SML limit, bu
