Validation and interpretation of analytical methods, migration testing and analytical data for materials and articles in contact with food - Part 1: General considerations

This Technical Report gives guidance in support of Directives adopted by the European Union in the Food Contact Materials Sector and is intended to aid Food Control Authorities and industry enforce and comply with those Directives.

Validierung und Interpretation analytischer Verfahren, Migrationsprüfung und analytischer Daten von Werkstoffen und Bedarfsgegenständen in Kontakt mit Lebensmitteln - Teil 1: Allgemeine Betrachtungen

Validation et interprétation des méthodes d'analyse, essais de migrations et données analytiques des matériaux et objets en contact avec les denrées alimentaires - Partie 1 : Considérations générales

Validacija in interpretacija analitskih metod, migracijsko preskušanje in analitski podatki za materiale in predmete v stiku z živili – 1. del: Splošne ugotovitve

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Publication Date
14-Mar-2006
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6060 - Definitive text made available (DAV) - Publishing
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15-Mar-2006
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SLOVENSKI STANDARD
SIST-TP CEN/TR 15356-1:2006
01-september-2006

Validacija in interpretacija analitskih metod, migracijsko preskušanje in analitski

podatki za materiale in predmete v stiku z živili – 1. del: Splošne ugotovitve

Validation and interpretation of analytical methods, migration testing and analytical data

for materials and articles in contact with food - Part 1: General considerations
Validierung und Interpretation analytischer Verfahren, Migrationsprüfung und
analytischer Daten von Werkstoffen und Bedarfsgegenständen in Kontakt mit
Lebensmitteln - Teil 1: Allgemeine Betrachtungen

Validation et interprétation des méthodes d'analyse, essais de migrations et données

analytiques des matériaux et objets en contact avec les denrées alimentaires - Partie 1 :

Considérations générales
Ta slovenski standard je istoveten z: CEN/TR 15356-1:2006
ICS:
67.250
SIST-TP CEN/TR 15356-1:2006 en,fr,de

2003-01.Slovenski inštitut za standardizacijo. Razmnoževanje celote ali delov tega standarda ni dovoljeno.

---------------------- Page: 1 ----------------------
TECHNICAL REPORT
CEN/TR 15356-1
RAPPORT TECHNIQUE
TECHNISCHER BERICHT
March 2006
ICS 13.060.20; 23.060.50
English Version
Validation and interpretation of analytical methods, migration
testing and analytical data for materials and articles in contact
with food - Part 1: General considerations

Validation et interprétation des méthodes d'analyse, essais Validierung und Interpretation analytischer Verfahren,

de migrations et données analytiques des matériaux et Migrationsprüfung und analytischer Daten von Werkstoffen

objets en contact avec les denrées alimentaires - Partie 1 : und Bedarfsgegenständen in Kontakt mit Lebensmitteln -

Considérations générales 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.

CEN 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, Switzerland and United Kingdom.
EUROPEAN COMMITTEE FOR STANDARDIZATION
COMITÉ EUROPÉEN DE NORMALISATION
EUROPÄISCHES KOMITEE FÜR NORMUNG
Management Centre: rue de Stassart, 36 B-1050 Brussels

© 2006 CEN All rights of exploitation in any form and by any means reserved Ref. No. CEN/TR 15356-1:2006: E

worldwide for CEN national Members.
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CEN/TR 15356-1:2006 (E)
Contents Page

Foreword............................................................................................................................................................. 3

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 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 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 articles: 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

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CEN/TR 15356-1:2006 (E)
Foreword

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.
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CEN/TR 15356-1:2006 (E)
Introduction

0.1 Requirement for validation of analytical methods for enforcement of Directives

[1]

Regulation (EC) No. 1935/2004 has laid 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.

[2] [3]

Commission Directive 90/128/EEC and its subsequent amendments (e.g. ) introduced specific

migration limits for more than 300 substances. A consolidation of these directives has since been

[4]

issued as Commission Directive 2002/72/EC . 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 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.
[5]

The two Food Control Directives (European Council Directive 89/397/EEC and Council Directive

[6]

93/99/EEC ) 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 Research (SM&T project, MAT1-CT92-0006,

"Development of Methods of Analysis for Monomers") have only been validated by two competent

laboratories. Most methods from technical dossiers have only limited validation data at best.

This Technical Report considers the background to whether or not acceptable validation of analytical

methods could be achieved faster and at less cost. The Technical Report also considers the need for

validation of the whole test procedure for enforcement purposes, for compliance purposes, and for the

creation of data for risk assessment purposes. It should be noted that the considerations apply to both

overall as well as specific migration.

The list of current legislation currently adopted by the Commission is given in Annex A.

The list of current methods adopted by CEN/TC 194/SC 1 is given in Annex B.
0.2 Variability in the migration contact stage

The determination of migration from plastics is quite unlike other measurement tasks in ensuring food

safety and quality. Reliable measurements depend upon more than simply having validated analytical

methods for measuring chemical concentrations in foods. The Directives allows that, as an alternative

to the analysis of foodstuff itself, migration testing can be carried out with food simulants applied

under conditions which simulate actual use of the plastic material or article with food. This introduces

many potential sources of variability in the final migration value. These are discussed in Clause 8.

0.3 Quality of data submitted for risk assessment purposes

Migration data is usually an important part of the petition submitted for a risk assessment carried out

by the Scientific Committee on Food (since 2003, by the European Food Safety Authority, EFSA). For

new substances it is unlikely that a fully validated method in food simulants will exist. A single

laboratory (in-house) system of validation is required as part of the demonstration that the data

submitted is of adequate quality. For example, validation of a method’s intended use, the

determination of accuracy and precision, usually involves replicate analyses of appropriate matrices

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CEN/TR 15356-1:2006 (E)

spiked with known amounts of the additive at concentrations similar to those encountered in the

migration studies and determination of the percentage recovery of the spiked additive.

Where data are supplied to other authorities, e.g. the US-FDA, the data has to be applicable and

acceptable to those authorities.

Even when a validated method exists there is still the need for the laboratory carrying out the test to

ensure the migration testing carried out within the laboratory does not suffer from excessive error. The

possibility of error may be reduced by taking part in proficiency testing schemes. Proficiency testing

schemes aim to assess the competence of laboratories to carry out migration testing. At present there

is at least one scheme which is known to operate in this area. This is the Food Analysis Performance

Assessment Scheme (FAPAS) operated by the FAPAS Secretariat, Central Science Laboratory, Sand

Hutton, York (UK).

Laboratories carrying out these methods will also be able to demonstrate their general competence by

being accredited to EN ISO/IEC 17025:2005, which is administered by the appropriate Accreditation

Agencies in the European Countries. For overall migration testing, samples of plastics with known

overall migration values are available from the IRMM, Geel, Belgium. Spectra and a table of physical

properties of the monomers and additives listed in Directives have been published to assist ensuring

[7], [8]
that substances used for calibration are of adequate and known purity .
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CEN/TR 15356-1:2006 (E)
1 Scope

This Technical Report gives guidance in support of Directives adopted by the European Union in the

Food Contact Materials Sector and is intended to aid Food Control Authorities and industry enforce

and comply with those Directives.
2 Form of regulations
2.1 General

The EU Directives on food contact plastics, provide for various types of quantitative restrictions i.e.

specific migration limits (SML, expressed as mg (of substance) /kg of food), overall migration limit

(OML, expressed as mg/kg of food or mg/dm of surface) and maximal quantity of the substance in

the finished plastic article referred either to the quantity of article (QM, expressed as mg/kg of article)

or to area of the surface in contact with the foodstuffs (QMA, expressed as mg/dm² of surface). The

determination of these quantities implies various procedural steps e.g. sampling, migration tests with

different experimental conditions (OML, SML) or extraction (QM, QMA) as well the usual multi-step

analytical determination. Each of these steps is subject to a certain variability and an overall variability

will affect the value found by one laboratory (repeatability) or by more than one laboratories

(reproducibility). In the past at the level of the Standing Committee for Foodstuffs a discussion took

place on the method of analysis for vinyl chloride. The Commission proposed then that the variability

should be expressed as "Reproducibility" but the majority of Member States were in favour of the

"Repeatability". Therefore the Commission services decided to avoid any further scientific discussion

on this issue and decided to propose a new term, "Analytical Tolerance" which shall comprise the

variability due to all the above-mentioned procedural steps. Until now no Member States objected to

this choice and no fundamental problems were raised from its application. Three options have been

chosen by the Commission services as regards the various existing quantitative restrictions:

a) restrictions affected by a specified analytical tolerance,
b) restrictions affected by an unspecified analytical tolerance, and
c) restrictions not affected by any analytical tolerance.
The three options and their background are explained in 2.2, 2.3 and 2.4.
2.2 Restriction and specified analytical tolerance

This case applies to the overall migration limit, where the value of the OML in fatty simulants

(60 mg/kg (ppm) or 10 mg/dm ) is accompanied by an analytical tolerance of 20 mg/kg (ppm)

(or 3 mg/dm ). In this case the variability should be added to the limit value and, only if the value

found is greater than 80 mg/kg (ppm) (=60+20) or 13 mg/dm (=10+3), the article is considered not in

compliance with the Directive. The choice to increase the OML by the value of the tolerance was due

to the variability of the analysis.

NOTE This approach has the disadvantage that as the variability of sampling and analytical procedures

becomes less, the overall limit becomes, effectively greater. However it is possible to change the value of the

analytical tolerance by an amendment of the Plastics Directive. For example, as practical experience was gained

and as both standardised methods and certified reference materials became available it became clear that many

laboratories struggled to meet the analytical tolerance value of 1 mg/dm set for tests using volatile simulants.

Consequently, Commission Directive 2001/62/EC was issued which, based on expert judgement rather than any

statistical evaluation of the available results, raised this tolerance figure to 2 mg/dm . The same problem would

exist if an EN rather than a Directive establishes the value of the variability. If no value is specified, this issue is

no longer harmonised and this should also be considered as disadvantage. The Member States and professional

organisations requested, at unanimity, that an analytical tolerance should be fixed.

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CEN/TR 15356-1:2006 (E)
2.3 SML restriction which includes non specified analytical tolerance

This case applies to the substances, which are classified by EFSA into EFSA list 4 (carcinogens or

high toxic substances) and, therefore, in principle should not be detectable in foodstuffs. For these

substances a detection limit value (= DL) is fixed. Because there is also a variability in determining the

detection limit, an analytical tolerance was considered also in this case. Therefore the Directive

includes a sentence "Not detectable (Detection Limit = 20 µg/kg (ppb) analytical tolerance included).

This choice, although not scientifically correct, was adopted pending the validation of the specific

methods of analysis for the substances.

NOTE this approach suffers from the same disadvantage as above, except that the variabilities have not

been quantified. However, it may also be argued that this is an advantage. For the analyst the lack of a specified

variability could be a disadvantage and considered scientifically incorrect. But for a jury, a responsible of the

production or enforcement laboratory is a great advantage, from the point of view of the juridical certainty, to

know the limit which cannot be exceeded in any situation. It has also to be considered that the level chosen is so

high that it is quite difficult to raise analytical difficulties in its enforcement and, at the same time, so low that the

protection of the health is fully ensured. In fact the limit is expressed as concentration of the migrant in the food

and not as exposure, which generally is lower, taking into account the current assumptions of the system that

1 kg of food is eaten by a person every day and this food is all in contact with a material that contains the

substance and releases the substance at a concentration is equal to its SML. Moreover a limit expressed in these

terms ("not detectability") avoids the criticism of some organisations, which are not in favour of establishing a limit

for carcinogenic substances.
2.4 SML Restriction without any reference to analytical tolerance

This case applies to the substances affected by an SML of 50 µg/kg (ppb) or greater or to the

substances affected by QM or QMA restrictions. In all three cases there is no indication of the

variability. This choice was justified by the following considerations:
a) variability at this level is not so great,
b) lack of real technical obstacles to the trade, and
c) lack of human and financial resources.

NOTE This is the normal approach for legal limits, but can lead to inconsistencies if the approaches used by

different control authorities are not standardised. In principle, any quantitative limit should be accompanied by a

validated method of analysis establishing the analytical variability. This is the reason why the Commission has

given a mandate to the CEN to validate some methods of analysis for global and specific migration. However the

reality is that this approach requires too much time and human and financial resources. Therefore it is necessary

to decide on a case by case basis if a validation is necessary or not. When the value of SML is high, the

importance of the determination of variability is questionable or, in any case, not a priority. The Commission's

proposal is to restrict the validation process only to those substances, economically very important and/or for

which the restriction is very low (e.g. not detectable or very low concentration).

3 Terms and definitions

For the purposes of this Technical Report, the following terms and definitions apply.

3.1
plastics

organic macromolecular compounds obtained by polymerisation, polycondensation, polyaddition or

any similar process from molecules with a lower molecular weight or by chemical alteration of natural

molecules
NOTE Other substances or matter may be added to such compounds.
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CEN/TR 15356-1:2006 (E)
3.2
final material and article
materials or article in its ready-for-use state or as sold
3.3
sample
material or article under investigation
3.4
test specimen
portion of the sample on which a test is performed
3.5
test piece
portion of the test specimen
3.6
conventional oven

oven where the air within the oven is heated and this heat is then transferred to the food through the

plastic as opposed to a microwave oven where the food itself is heated directly by microwave

irradiation
3.7
food simulant

medium intended to simulate (‘mimic’ or ‘model’) the essential characteristics of a foodstuff

3.8
overall migration

mass of material transferred to the food simulant or test media as determined by the relevant test

method
3.9
specific migration

mass of the substance transferred to the food/simulant as determined in the test method

3.10
residual content
mass of the substance present in the final material or article
3.11
specific migration limit (SML)

maximum permitted level of a named substance migrating from the final material or article into food or

food simulants
3.12
SML(T)

maximum permitted level of a group of named substances migrating from the final material or article

into food or food simulants, expressed as total of chemical moiety or substance(s) indicated

3.13
compositional limit (QM)
maximum permitted amount of the named substance in the material or article
3.14
QM(T)

maximum permitted amount of a group of named substances, in the material or article, expressed as

total of chemical moiety or substance(s) indicated
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CEN/TR 15356-1:2006 (E)
3.15
quantity per surface area (QMA)

maximum permitted amount of residual monomer, additive or substance in the material or article

expressed on an area-related basis as mg/6 dm
3.16
reduction factor

factors in the range 2 to 5 which may be applied to the result of the migration tests relevant to certain

types of fatty foodstuffs and which are conventionally used to take account of the greater extractive

capacity of the simulant for such foodstuffs
3.17
migration test

test for the determination of specific migration of a substance, using food simulant under conventional

test conditions
3.18
substitute fat test

test carried out which uses test media under conventional substitute test conditions when the use of a

migration test into fatty food simulant(s) is not feasible
3.19
test media

substances used in "substitute tests", isooctane, 95 % ethanol in aqueous solution and modified

polyphenylene oxide (MPPO)
3.20
alternative fat test

tests, with volatile test media, that may be used instead of migration tests with fatty food simulants

3.21
‘volatile’ test media
volatile substances used in alternative fat tests
3.22
extraction tests

tests in which media having strong extraction properties under very severe test conditions are used

3.23
dissolution test

tests in which the specimen is dissolved to liberate the substance from the plastics test specimen

3.24
pouch

receptacle of known dimensions manufactured from plastics film/sheet to be tested, which when filled

with food simulant or test medium exposes only the food contact side of the film/sheet to the food

simulant or test medium
3.25
reverse pouch

pouch which is fabricated such that the plastics surface intended to come into contact with foodstuff is

the outer surface

NOTE All of its edges are sealed to prevent the inner surfaces coming into contact with the food simulant or

test medium during the test period. The reverse pouch is intended to be totally immersed in the food simulant or

test medium, exposing only the outer and not the inner surface.
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CEN/TR 15356-1:2006 (E)
3.26
cell

device in which a plastics film to be tested can be mounted and which when assembled and filled with

food simulant or test medium, exposes only the food contact side of the film to the food simulant or

test medium
3.27
repeatability value 'r'

value below which the absolute difference between two single test results obtained under repeatability

conditions may be expected to lie with a probability of 95 %, as defined by ISO 5725

3.28
reproducibility value 'R'

value below which the absolute difference between two single test results obtained under

reproducibility conditions may be expected to lie with a probability of 95 %, as defined by ISO 5725

3.29
repeatability conditions

conditions where mutually independent test results are obtained with the same method on identical

test material in the same laboratory by the same operator using the same equipment within short

intervals of time
3.30
reproducibility conditions

conditions where test results are obtained with the same method on identical test material in different

laboratories with different operators using different equipment
4 Analytical tolerances

In the Food Contact Materials sector the present approach to variability is inconsistent. The three

situations described in Clause 2 are not self-consistent. The normal approach within the EU is that

food analysis limits are specified without any indication of analytical tolerances (i.e. the situation

described in 2.3).

In quantitative chemical analysis many important decisions are based on the results obtained by a

laboratory and so it is important that an indication of the quality of the results reported is available.

Analytical chemists are now more than ever coming under pressure to be able to demonstrate the

quality of their results by giving a measure of the confidence placed on a particular result to

demonstrate its fitness for purpose. Users of the results of chemical analysis, particularly in those

areas concerned with international trade, wish to minimise the replication of effort frequently

expended in obtaining the results. Confidence in data obtained outside the user’s own organisation is

a prerequisite to meeting this objective. In many sectors of analytical chemistry it is now a formal

(frequently legislative) requirement for laboratories to introduce quality assurance measures to ensure

that they are capable of and are providing data of the required quality. Such measures include: the

use of validated methods of analysis; 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 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 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, irrespective 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:
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CEN/TR 15356-1:2006 (E)

 evaluation of the effect of the identified sources of uncertainty on the analytical result 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 proficiency test schemes used to assess the analytical competency of laboratories.

[9]

A practical solution is needed in the short term, and for this a Horwitz equation approach is often

taken. Here the Horwitz value is derived from the Horwitz trumpet and equation, which states that for

any method:
(1-0,5logC)
RSD = 2
and that the value is independent of matrix/analyte.
RSD is the relative standard deviation of the reproducibility (S x 100/MEAN).
The major values are:
Concentration ratio RSD
1 (100 %) 2
10 2,8
10 (1 %) 4
10 5,6
10 8
10 11
10 (ppm) 16
–7 a
10 23
–8 a
10 32
–9 a
10 (ppb) 45
At levels below 120 µg/kg (ppb), the more usual
[10]
value to be used is 22 % of the concentration .

Horwitz derived the equation after assessing the results from many (ca. 3 000) collaborative trials.

Although it represents the average RSD values and is an approximation of the possible precision

that can be achieved, the data points from "acceptable" collaborative trials are less than twice the

predicted RSD 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 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 RSD obtained in the method validation procedure 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 (too imprecise).

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CEN/TR 15356-1:2006 (E)
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 the
...

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