1、BSI Standards PublicationPD CEN/TS 16826-1:2015Molecular in vitro diagnosticexaminations Specificationsfor pre-examination processesfor snap frozen tissuePart 1: Isolated RNAPD CEN/TS 16826-1:2015 PUBLISHED DOCUMENTNational forewordThis Published Document is the UK implementation of CEN/TS16826-1:20
2、15.The UK participation in its preparation was entrusted to TechnicalCommittee CH/212, IVDs.A list of organizations represented on this committee can beobtained on request to its secretary.This publication does not purport to include all the necessaryprovisions of a contract. Users are responsible f
3、or its correctapplication. The British Standards Institution 2015. Published by BSI StandardsLimited 2015ISBN 978 0 580 85026 4ICS 11.100.10Compliance with a British Standard cannot confer immunity fromlegal obligations.This Published Document was published under the authority of theStandards Policy
4、 and Strategy Committee on 31 August 2015.Amendments issued since publicationDate Text affectedPD CEN/TS 16826-1:2015TECHNICAL SPECIFICATION SPCIFICATION TECHNIQUE TECHNISCHE SPEZIFIKATION CEN/TS 16826-1 August 2015 ICS 11.100.10 English Version Molecular in vitro diagnostic examinations - Specifica
5、tions for pre-examination processes for snap frozen tissue - Part 1: Isolated RNA Tests de diagnostic molculaire in vitro - Spcifications relatives aux processus pranalytiques pour les tissus conglation rapide - Partie 1: ARN extrait Molekularanalytische in-vitro-diagnostische Verfahren - Spezifikat
6、ionen fr pranalytische Prozesse fr schockgefrorene Gewebeproben - Teil 1: Isolierte RNS This Technical Specification (CEN/TS) was approved by CEN on 6 July 2015 for provisional application. The period of validity of this CEN/TS is limited initially to three years. After two years the members of CEN
7、will be requested to submit their comments, particularly on the question whether the CEN/TS can be converted into a European Standard. CEN members are required to announce the existence of this CEN/TS in the same way as for an EN and to make the CEN/TS available promptly at national level in an appr
8、opriate form. It is permissible to keep conflicting national standards in force (in parallel to the CEN/TS) until the final decision about the possible conversion of the CEN/TS into an EN is reached. CEN members are the national standards bodies of Austria, Belgium, Bulgaria, Croatia, Cyprus, Czech
9、Republic, Denmark, Estonia, Finland, Former Yugoslav Republic of Macedonia, France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Netherlands, Norway, Poland, Portugal, Romania, Slovakia, Slovenia, Spain, Sweden, Switzerland, Turkey and United Kingdom. EURO
10、PEAN COMMITTEE FOR STANDARDIZATION COMIT EUROPEN DE NORMALISATION EUROPISCHES KOMITEE FR NORMUNG CEN-CENELEC Management Centre: Avenue Marnix 17, B-1000 Brussels 2015 CEN All rights of exploitation in any form and by any means reserved worldwide for CEN national Members. Ref. No. CEN/TS 16826-1:2015
11、 EPD CEN/TS 16826-1:2015CEN/TS 16826-1:2015 (E) 2 Contents Page European foreword .3 Introduction .4 1 Scope 5 2 Normative references 5 3 Terms and definitions .5 4 General considerations .6 5 Outside the laboratory 7 5.1 Primary tissue collection manual.7 5.1.1 Information about the primary sample
12、donor .7 5.1.2 Information on the primary tissue sample 7 5.1.3 Information on the primary tissue sample processing 8 5.2 Transport requirements 8 6 Inside the laboratory .9 6.1 Information on the primary tissue sample receipt .9 6.2 Evaluation of the pathology of the specimen and selection of the s
13、ample.9 6.3 Cryo-storage of the specimen 9 6.4 Storage requirements . 10 6.5 Isolation of the total RNA . 11 6.5.1 General information for RNA isolation procedures 11 6.5.2 Using commercial kits 11 6.5.3 Using the laboratories own protocols . 12 6.6 Quality assessment of isolated RNA 12 6.7 Storage
14、of isolated RNA . 12 Annex A (informative) Impact of preanalytical variables on RNA profiles obtained from frozen liver tissue samples collected during and after routine surgery . 13 A.1 Comparison of stable and unstable genes identified under ischemic conditions 13 A.2 Recommendations based on the
15、results . 15 Bibliography . 16 PD CEN/TS 16826-1:2015CEN/TS 16826-1:2015 (E) 3 European foreword This document (CEN/TS 16826-1:2015) has been prepared by Technical Committee CEN/TC 140 “In vitro diagnostic medical devices”, the secretariat of which is held by DIN. Attention is drawn to the possibili
16、ty that some of the elements of this document may be the subject of patent rights. CEN and/or CENELEC shall not be held responsible for identifying any or all such patent rights. According to the CEN-CENELEC Internal Regulations, the national standards organizations of the following countries are bo
17、und to announce this Technical Specification: Austria, Belgium, Bulgaria, Croatia, Cyprus, Czech Republic, Denmark, Estonia, Finland, Former Yugoslav Republic of Macedonia, France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Netherlands, Norway, Poland, P
18、ortugal, Romania, Slovakia, Slovenia, Spain, Sweden, Switzerland, Turkey and the United Kingdom. PD CEN/TS 16826-1:2015CEN/TS 16826-1:2015 (E) 4 Introduction Molecular in vitro diagnostics has enabled a significant progress in medicine. Further progress is expected by new technologies analysing sign
19、atures of nucleic acids, proteins, and metabolites in human tissues and body fluids. However, the profiles and/or integrity of these molecules can change drastically during primary sample collection, transport, storage, and processing thus making the outcome from diagnostics or research unreliable o
20、r even impossible because the subsequent analytical assay will not determine the situation in the patient but an artificial profile generated during the pre-examination process. Therefore, a standardization of the entire process from primary sample collection to RNA analysis is needed. Studies have
21、been undertaken to determine the important influencing factors. This Technical Specification draws upon such work to codify and standardize the steps for frozen tissue with regard to RNA analysis in what is referred to as the preanalytical phase. PD CEN/TS 16826-1:2015CEN/TS 16826-1:2015 (E) 5 1 Sco
22、pe This Technical Specification gives recommendations for the handling, documentation and processing of frozen tissue specimens intended for RNA analysis during the preanalytical phase before a molecular assay is performed. This Technical Specification is applicable to molecular in vitro diagnostic
23、examinations (e.g., in vitro diagnostic laboratories, laboratory customers, developers and manufacturers of in vitro diagnostics, institutions and commercial organisations performing biomedical research, biobanks, and regulatory authorities). RNA profiles in tissues can change significantly before a
24、nd after collection and can change differently in tissues from different donors / patients. Therefore, it is essential to take special measures to minimize the described profile changes and modifications within the tissue for subsequent RNA analysis. Tissues that have undergone chemical stabilisatio
25、n pre-treatment before freezing are not covered in this document. 2 Normative references The following documents, in whole or in part, are normatively referenced in this document and are indispensable for its application. For dated references, only the edition cited applies. For undated references,
26、the latest edition of the referenced document (including any amendments) applies. EN ISO 15189:2012, Medical laboratories Requirements for quality and competence (ISO 15189:2012, Corrected version 2014-08-15) ISO 15190, Medical laboratories Requirements for safety 3 Terms and definitions For the pur
27、poses of this document, the terms and definitions given in EN ISO 15189:2012 and the following apply. 3.1 ambient temperature unregulated temperature of the surrounding air 3.2 analytical phase processes that start with the isolated analyte and include all kinds of parameter testing or chemical mani
28、pulation for quantitative or qualitative analysis 3.3 cold ischemia condition after removal of the tissue from the body until its stabilization or fixation 3.4 pre-examination processes preanalytical phase preanalytical workflow processes that start, in chronological order, from the clinicians reque
29、st and include the examination request, preparation and identification of the patient, surgical procedure, collection of the primary sample(s), temporary storage, transportation to and within the analytical laboratory, aliquoting, retrieval, isolation of analytes, and end when the analytical examina
30、tion begins PD CEN/TS 16826-1:2015CEN/TS 16826-1:2015 (E) 6 SOURCE: EN ISO 15189:2012, definition 3.15, modified An additional term was added and more details were included. Note 1 to entry: The preanalytical phase may include preparative processes that may influence the outcome of the intended exam
31、ination. 3.5 primary sample specimen discrete portion of a body fluid, breath, hair or tissue taken for examination, study or analysis of one or more quantities or properties assumed to apply for the whole SOURCE: EN ISO 15189:2012, 3.16, modified The term and definition is used here without the ori
32、ginal notes. 3.6 quantitative RNA profile RNA profile amounts of the individual RNA molecules that are present in a sample and that can be measured in the absence of any losses, inhibition and interference 3.7 RNA ribonucleic acid polymer of ribonucleotides occurring in a double-stranded or single-s
33、tranded form SOURCE: EN ISO 22174:2005, 3.1.3 3.8 room temperature temperature which is defined as 18 C to 25 C for the purposes of this document 3.9 sample one or more parts taken from a primary sample SOURCE: EN ISO 15189:2012, 3.24, modified The example was not taken over. 3.10 stability ability
34、of a sample material, when stored under specified conditions, to maintain a stated property value within specified limits for a specified period of time SOURCE: ISO Guide 30:1992, 2.7 Note 1 to entry: The measured constituent for the purpose of this document is RNA. 3.11 warm ischemia warm Ischemia
35、is the condition where the tissue is deprived of its normal blood supply containing oxygen and nutrients while the tissue is at body temperature 4 General considerations For general statements on primary sample collection and handling (including avoidance of cross contaminations) see EN ISO 15189:20
36、12, 5.4.4, 5.2.6. Consumables including kits shall be verified before use in examination (see EN ISO 15189:2012, 5.3.2.3); EN ISO 15189:2012, 5.5.1.2 and 5.5.1.3 can also apply. PD CEN/TS 16826-1:2015CEN/TS 16826-1:2015 (E) 7 As all steps of a diagnostic workflow can influence the final analytical p
37、erformance, the entire workflow comprising the preanalytical steps, including information on biomolecule stability and storage conditions, and analytical steps should be verified and validated (see EN ISO 15189). The stability of the specific quantitative RNA profile(s) of interest should be investi
38、gated throughout the entire preanalytical workflow prior to the development and implementation of an analytical test. Before tissues stabilized by freezing, quantitative RNA profile can change e.g., by gene induction, gene down regulation and RNA degradation. These effects depend on the duration of
39、warm and cold ischemia and the ambient temperature before freezing. In addition, the described effects can vary in tissues from different donors / patients. Generally, the longer the warm and cold ischemia times and the higher the ambient temperature before freezing the tissue specimen, the higher i
40、s the risk that changes in the RNA profile can occur. NOTE Intraoperative warm ischemia can result in more pronounced changes of RNA profiles than during postoperative cold ischemia. RNA profiles can also vary, depending on the origin and type of tissue, the underlying disease, the surgical procedur
41、e, the drug regime, and drugs administered for anaesthesia or treatment of concomitant disease and on the different environmental conditions after the tissue removal from the body. As warm ischemia cannot be easily standardized, its time and duration should be documented. When it is not possible to
42、avoid cold ischemia, its time of onset, duration shall be documented and temperatures of the specimen transport containers surroundings should be documented. Where the specimen is transported to another facility for freezing, the transport duration shall be documented and the ambient conditions shou
43、ld also be documented. Safety regulations on transport and handling shall be considered (see EN ISO 15189:2012, 5.2.3 and 5.4.5 and ISO 15190). During the whole preanalytical workflow precautions shall be taken to avoid cross contamination between different samples. If a commercial product is not us
44、ed in accordance with the manufacturers instructions, responsibility for its use and performance lies with the user. 5 Outside the laboratory 5.1 Primary tissue collection manual 5.1.1 Information about the primary sample donor The documentation should include, but is not limited to: a) the primary
45、donor / patient ID, which can be in the form of a code; b) the health status of the primary sample donor (e.g., healthy, disease type, concomitant disease); c) the information about routine medical treatment and special treatment prior to tissue collection (e.g., anaesthetics, medications, surgical
46、or diagnostic procedures (e.g., biopsy device used for the collection); d) the start of ischemia within the body (warm ischemia) by documenting the ischemia-relevant vessel ligation/clamping time point (usually arterial clamping time). 5.1.2 Information on the primary tissue sample The documentation
47、 shall include, but is not limited to: PD CEN/TS 16826-1:2015CEN/TS 16826-1:2015 (E) 8 a) the time point when tissue is removed from the body; b) the description of tissue type, tissue condition (e.g., diseased, unaffected by the disease) and organ tissue of origin, including references to any marki
48、ng applied in the operating theatre made by surgeon, radiologist or pathologist; c) the documentation steps described under 6.3, if freezing is performed outside the laboratory. 5.1.3 Information on the primary tissue sample processing The following steps shall be performed: 1. the documentation of
49、any additions or modifications to the primary sample after removal from the body (e.g., labelling for the orientation of the specimen (e.g., ink-marking, stitches), incision(s); 2. the selection and use of transport containers and packages (e.g., cooling box, box for storing and transportation, vacuum packaging); 3. the selection and use of stabilisation procedures (e.g., cooling methods) for transport; NOTE 1 Accidentally freezing and thawing the tissue (e.g., by using cool packs in a wrong manner) will lead to RNA degradation when the tissue t
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