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1、BRITISH STANDARD BS EN13640:2002Stability testing of in vitro diagnostic reagentsThe European Standard EN 13640:2002 has the status of aBritish StandardICS 11.100NO COPYING WITHOUT BSI PERMISSION EXCEPT AS PERMITTED BY COPYRIGHT LAWBS EN 13640:2002National forewordThis British Standard is the offici
2、al English language version ofEN 13640:2002.The UK participation in its preparation was entrusted to Technical CommitteeCH/69, In vitro diagnostic systems, which has the responsibility to:aid enquirers to understand the text;present to the responsible European committee any enquiries on the interpre
3、tation, or proposals for change, and keep the UK interests informed;monitor related international and European developments and promulgate them in the UK.A list of organizations represented on this committee can be obtained on request to its secretary.Cross-referencesThe British Standards which impl
4、ement international or European publications referred to in this document may be found in the BSI Standards Catalogue under the section entitled “International Standards Correspondence Index”, or by using the “Find” facility of the BSI Standards Electronic Catalogue.A British Standard does not purpo
5、rt to include all the necessary provisions of a contract. Users of British Standards are responsible for their correct application.Compliance with a British Standard does not of itself confer immunity from legal obligations.This British Standard, having been prepared under the direction of the Healt
6、h and Environment Sector Policy and Strategy Committee, was published under the authority of the Standards Policy and Strategy Committee on3 May 2002 BSI 3 May 2002ISBN 0 580 39653 3Summary of pagesThis document comprises a front cover, an inside front cover, the EN title page,pages 2 to 10, an insi
7、de back cover and a back cover.The BSI copyright date displayed in this document indicates when the document was last issued.Amd. No.DateCommentsAmendments issued since publicationEUROPEAN STANDARD NORME EUROPENNEEUROPISCHE NORMEN 13640March 2002ICS 11.100English versionStability testing of in vitro
8、 diagnostic reagentsEssais de stabilit des ractifs de diagnostic in vitroHaltbarkeitsprfung von Reagenzien fr in-vitro- diagnostische UntersuchungenThis European Standard was approved by CEN on 27 December 2001.CEN members are bound to comply with the CEN/CENELEC Internal Regulations which stipulate
9、 the conditions for giving this European Standard the status of a national standard without any alteration. Up-to-date lists and bibliographical references concerning such national standards may be obtained on application to the Management Centre or to any CEN member.This European Standard exists in
10、 three official versions (English, French, German). A version in any other language made by translation under the responsibility of a CEN member into its own language and notified to the Management Centre has the same status as the official versions.CEN members are the national standards bodies of A
11、ustria, Belgium, Czech Republic, Denmark, Finland, France, Germany, Greece, Iceland, Ireland, Italy, Luxembourg, Malta, Netherlands, Norway, Portugal, Spain, Sweden, Switzerland and United Kingdom.EUROPEAN COMMITTEE FOR STANDARDIZATION C O M I T EUR O P EN DE NOR M A L I S A TI ON EUR O P I S C H ES
12、 KOM I TEE F R NOR M UNG Management Centre: rue de Stassart, 36 B-1050 Brussels 2002 CENAll rights of exploitation in any form and by any means reserved worldwide for CEN national Members.Ref. No. EN 13640:2002 EEN 13640:2002 (E)ForewordThis document EN 13640:2002 has been prepared by Technical Comm
13、ittee CEN/TC 140 In vitro diagnostic medical devices, the secretariat of which is held by DIN.This European Standard shall be given the status of a national standard, either by publication of an identical text or by endorsement, at the latest by September 2002, and conflicting national standards sha
14、ll be withdrawn at the latest by September 2002.This document has been prepared under a mandate given to CEN by the European Commission and the EuropeanFree Trade Association, and supports essential requirements of EU Directive(s).For relationship with EU Directive(s), see informative annex ZA, whic
15、h is an integral part of this document. Annexes A and ZA are for information only.This standard includes a Bibliography.According to the CEN/CENELEC Internal Regulations, the national standards organizations of the following countries are bound to implement this European Standard: Austria, Belgium,
16、Czech Republic, Denmark, Finland, France, Germany, Greece, Iceland, Ireland, Italy, Luxembourg, Malta, Netherlands, Norway, Portugal, Spain, Sweden, Switzerland and the United Kingdom.91 ScopeThis European Standard is applicable to the stability testing of in vitro diagnostic reagents including reag
17、ent products, calibrators, control materials and kits, hereinafter called IVD reagents. It specifies general requirements for stability testing and gives specific requirements for real-time testing and accelerated testing when generating stability data in the determination of IVD reagent shelf-life
18、including transport stability; determination of stability of the IVD reagent in use after the first opening of the primary container(e. g. on-board stability); monitoring of stability of IVD reagents already placed on the market; verification of stability after IVD reagent modifications that may aff
19、ect stability.This standard does not apply to instruments, apparatus, equipment, systems, or specimen receptacles.2 Terms and definitionsFor the purposes of this European Standard, the following terms and definitions apply.2.1accelerated stability studystability study designed to increase the rate o
20、f chemical or physical degradation of an in vitro diagnostic reagent by using exaggerated conditions with the purpose of predicting the shelf-lifeNOTE The design of an accelerated study may include elevated temperature, high humidity, light and vibration.2.2 batch lotdefined amount of material, eith
21、er starting material, intermediate or finished product, which is uniform in itsproperties and has been produced in one process or series of processesEN 375:20012.3expiry datedate up to which product performance is assured by the manufacturer based on the stability of the IVD reagentEN 375:20012.4in
22、vitro diagnostic reagentIVD reagentin vitro diagnostic medical device which is a reagent, reagent product, calibrator, control material or kitNOTE 1 For the definition of an in vitro diagnostic medical device see Bibliography.NOTE 2 In some cases a particular IVD reagent, as defined for use in human
23、 medicine, may serve also in veterinary medicine.EN 375:20012.5real-time stability testingexposing the IVD reagent to the conditions anticipated by the manufacturer to which an IVD reagent is exposed during transportation, storage and use, and investigating robustness and stability under these condi
24、tions2.6shelf lifeperiod until expiry dateEN 375 : 20012.7 stabilityability of an IVD reagent, when kept under specified conditions, to retain throughout the shelf life its propertiesand/or performance within limits specified by the manufacturerEN 375 : 20013 General requirements3.1 ProtocolConclusi
25、ons on IVD reagent stability shall be based on data that are generated in accordance with a pre-established protocol including details at least on: responsibilities; clear IVD reagent identification; presumed storage conditions; objective and purpose of testing; information about the samples (e.g. n
26、umber of batches, amount , container, identification); storage conditions recommended for the samples (e.g. frozen, refrigerated, room temperature); simulation of transport as appropriate; intervals between examinations; examinations to be performed at the end of each interval (e. g. procedure and e
27、xtent of testing); stability criteria to be met; interpretation of data.3.2 Final reportA final report shall be prepared to complete each study. This report shall at least include or refer to the protocol which was followed; the batch(es) involved; all testing results obtained; summary and conclusio
28、ns regarding stability.The final report shall be part of the technical documentation related to the IVD reagent.4 Procedures4.1 GeneralStability assessment shall in principle be based on data derived from real-time testing. Depending on the risk associated with the IVD reagent, data derived from acc
29、elerated testing as well as experience gained with similar IVD reagents that can reasonably be expected to be comparable as regards their stability profile may also be taken into account. If at the time of placing an IVD reagent onto the market, stability claims are based on such previous data, thes
30、e data shall be subsequently verified by real-time testing.Testing may be performed on any IVD reagent batch provided that the manufacturing conditions do not essentially differ from the routine production conditions.To cover remaining uncertainties, the stability claims shall include an adequate sa
31、fety margin.The manufacturer shall consider the need for regular monitoring of the stability of an IVD reagent already placed on the market and, where necessary, establish an appropriate monitoring programme. Examinations at the end of shelf-life can be sufficient for this purpose.The minimum number
32、 of batches to be investigated depending on the objective of testing shall be 3 batches for the verification of a new IVD reagent shelf-life (long-term stability); 1 batch for transport simulation; 1 batch for in-use stability of IVD reagents, for example those which are to be reconstituted or were
33、initially packed under vacuum.In other cases at least the following number of batches shall be investigated: 3 batches for extension of an IVD reagent shelf-life; 1 batch for IVD reagent modification.In any case, at the time of placing the IVD reagent onto the market, all stability claims shall be j
34、ustified by adequate data, considering the risks associated with the IVD reagent and the potential influence of critical raw materials, where appropriate.NOTE Critical is meant with respect to stability.4.2 Real-time stability testing4.2.1 Objectives of real-time stability testing4.2.1.1 GeneralReal
35、-time stability testing shall include long-term stability covering the shelf-life, transport simulation and in-use stability.4.2.1.2 Long-term stabilityDuring long-term stability testing the IVD reagent shall be stored under the conditions recommended by the manufacturer (e. g. temperature, humidity
36、).Examinations shall be undertaken at specified time intervals as indicated in the protocol. The time intervals shall be chosen to encompass at least the whole of the target shelf life and, if appropriate, continue until significant degradation in the performance of the IVD reagent can be determined
37、. The number of time intervals shall be appropriately chosen so that trends may be discerned from variability of the data.4.2.1.3 Transport simulationThe simulation of the transport stress shall be based on the knowledge of the transport conditions (e. g. duration of transport, expected temperatures
38、 and humidity). Where appropriate, an investigation shall be performed to determine the real transport conditions as a basis for this simulation.4.2.1.4 In-use stabilityThe real-time stability testing for the purpose of determining the in-use stability shall reflect the routine conditions of use as
39、specified by the manufacturer.4.2.2 Procedure4.2.2.1 MaterialThere shall be a sufficient amount of the IVD reagent batch to be tested to last for the whole test period. If the IVD reagent is not stored or exposed in the final configuration, in particular in terms of volume and material of the primar
40、y container, the manufacturer shall base this decision on an adequate justification.4.2.2.2 Examinations and assessmentIn designing analytical procedures the manufacturer shall consider the variability which may be encountered due to equipment and IVD reagents.The number of examinations to be perfor
41、med with an IVD reagent depends on the precision of the test methods used. Assessment of the individual test results shall be based on pre-established stability criteria.4.3 Accelerated stability testing4.3.1 Storage conditions and testing intervalsAlthough other factors may also be of interest (e.
42、g. sensitivity to light, humidity, low temperature), typically IVD reagents are exposed to different elevated temperatures. The manufacturer shall specify these stress conditions and the testing intervals. The test conditions chosen should, where appropriate, demonstrate significant deterioration of
43、 the IVD reagent over the testing period in order to allow for a mathematical extrapolation.4.3.2 Procedure4.3.2.1 MaterialThe material under investigation shall be stored under the conditions defined until the accelerated testing programme starts. Sufficient amounts of the material shall then be ex
44、posed to the defined stress conditions. Samples shall be removed at the specified times and stored under the defined conditions until analysis. If the IVD reagent is not exposed in the final configuration, in particular in terms of volume and material of the primary container, the manufacturer shall
45、 base this decision on an adequate justification.4.3.2.2 Examinations and assessmentExaminations shall be performed according to the procedures described in the protocol. The number of examinations to be performed with an IVD reagent representing a specific storage condition and time depends on the
46、precision of the test methods used.4.3.3 Interpretation of resultsIf the results of accelerated testing are to be used to predict the shelf-life under the recommended storage conditions in the absence of sufficient real-time data, this shall be done on the basis of experience with similar IVD reagen
47、ts and/or by using the Arrhenius equation or other stated models.Annex A(informative)Procedure for predicting the shelf-life from accelerated stability testing based on the Arrhenius equationIf a prediction of stability for a given storage temperature is intended to be based on the Arrhenius equatio
48、n, the calculation can be done as follows:a) For each temperature the decimal log of concentration (y axis) is plotted versus time (x axis) and the regression equation y = ax + b is calculated.b) The percentage of the time zero value, at which the IVD reagent is no longer acceptable, is calculated o
49、n the basis of the defined stability criteria. The result is converted to decimal log concentration.c) For each temperature in the equation according to a) y is substituted by decimal log concentration according to b) and the stability time (x) is calculated.d) The times according to c) are converte
50、d to decimal log time. Decimal log time (y axis) is plotted versus the reciprocal value of the absolute temperature (x axis). The regression equation y = mx + n is calculated.e) Using the equation according to d) the expected stability time can be calculated for a given storage temperature.Annex ZA(
51、informative)Clauses of this European Standard addressing essential requirements or other provisions ofEU DirectivesThis European Standard has been prepared under a mandate given to CEN by the European Commission and theEuropean Free Trade Association, and supports essential requirements of the Direc
52、tive 98/79/EC.WARNING Other requirements and other EU Directives may be applicable to the product(s) falling within the scope of this standard.The following clauses of this standard, as detailed in Table ZA.1, are likely to support requirements of the EU Directive 98/79/EC.Compliance with these clau
53、ses of this standard provides one means of conforming with the specific essential requirements of the Directive concerned and associated EFTA regulations.Table ZA.1 - Correspondence between this European Standard and EU Directive 98/79/ECClauses/subclauses of this European StandardCorresponding esse
54、ntial requirements ofDirective 98/79/ECQualifying remarks/Notes4.1A.3, A.4, A.54.2.1A.4, A.5, B.8.4 (e), B.8.7 (a)4.2.1.2B.8.4 (e), B.8.7 (a)4.2.1.3A.4, A.54.2.1.4B.8.7 (c)BibliographyEN 375:2001, Information supplied by the manufacturer with in vitro diagnostic reagents for professional use.Directi
55、ve 98/79/EC of the European Parliament and of the Council of 27 October 1998 on in vitro diagnostic medical devices, OJEC, 1998, No L 331blankBS EN13640:2002BSI389 Chiswick High RoadLondonW4 4ALBSI British Standards InstitutionBSI is the independent national body responsible for preparingBritish Sta
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【BS英國標準】BS EN 13640-2002 Stability testing of in vitro diagnostic reagents.doc
