1、| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | BRITISH STANDARD BS EN 12296:1998 The Euro
2、pean Standard EN 12296:1998 has the status of a British Standard ICS 07.080; 07.100.01 NO COPYING WITHOUT BSI PERMISSION EXCEPT AS PERMITTED BY COPYRIGHT LAW Biotechnology Equipment Guidance on testing procedures for cleanabilityThis British Standard, having been prepared under the direction of the
3、Sector Board for Materials and Chemicals, was published under the authority of the Standards Board and comes into effect on 15 August 1998 BSI 1998 ISBN 0 580 30067 6 BS EN 12296:1998 Amendments issued since publication Amd. No. Date Text affected National foreword This British Standard is the Engli
4、sh language version of EN 12296:1998. The UK participation in its preparation was entrusted to Technical Committee CII/58, Biotechnology, which has the responsibility to: aid enquirers to understand the text; present to the responsible international European committee any enquiries on the interpreta
5、tion, 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-references The British Standards which im
6、plement 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 pu
7、rport 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. Summary of pages This document comprises a front cover, an inside front
8、 cover, the EN title page, pages 2 to 7 and a back cover.CEN European Committee for Standardization Comite Europe en de Normalisation Europa isches Komitee fu r Normung Central Secretariat: rue de Stassart 36, B-1050 Brussels 1998 CEN All rights of exploitation in any form and by any means reserved
9、worldwide for CEN national Members. Ref. No. EN 12296:1998 E EUROPEAN STANDARD EN 12296 NORME EUROPE ENNE EUROPA ISCHE NORM March 1998 ICS Descriptors: Biotechnology, medical equipment, cleaning, disinfection, contamination, micro-organisms, noxious micro-organisms, tests, safety, hygiene conditions
10、, inspection, accident prevention, environmental protection, work safety English version Biotechnology Equipment Guidance on testing procedures for cleanability Biotechnologie Equipement Guide des proce dures dessai pour le contro le de la capacite au nettoyage Biotechnik Gera te und Ausru stungen L
11、eitfaden fu r Verfahren zur Pru fung der Reinigbarkeit This European Standard was approved by CEN on 2 March 1998. CEN members are bound to comply with the CEN/CENELEC Internal Regulations which stipulate the conditions for giving this European Standard the status of a national standard without any
12、alteration. Up-to-date lists and bibliographical references concerning such national standards may be obtained on application to the Central Secretariat or to any CEN member. This European Standard exists in three official versions (English, French, German). A version in any other language made by t
13、ranslation under the responsibility of a CEN member into its own language and notified to the Central Secretariat has the same status as the official versions. CEN members are the national standards bodies of Austria, Belgium, Czech Republic, Denmark, Finland, France, Germany, Greece, Iceland, Irela
14、nd, Italy, Luxembourg, Netherlands, Norway, Portugal, Spain, Sweden, Switzerland and United Kingdom.Page 2 EN 12296:1998 BSI 1998 Foreword This European Standard has been prepared by Technical Committee CEN/TC 233, Biotechnology, the secretariat of which is held by AFNOR. This European Standard shal
15、l be given the status of a national standard, either by publication of an identical text or by endorsement, at the latest by September 1998, and conflicting national standards shall be withdrawn at the latest by September 1998. According to the CEN/CENELEC Internal Regulations, the national standard
16、s organizations of the following countries are bound to implement this European Standard: Austria, Belgium, Czech Republic, Denmark, Finland, France, Germany, Greece, Iceland, Ireland, Italy, Luxembourg, Netherlands, Norway, Portugal, Spain, Sweden, Switzerland and the United Kingdom. Contents Page
17、Foreword 2 Introduction 3 1 Scope 3 2 Definitions 3 3 Testing 4 4 Documentation 4 Annex A (informative) Selection guide on test methods for cleanliness 5 Annex B (informative) Information on test methods for cleanliness 6 Annex C (informative) Bibliography 7Page 3 EN 12296:1998 BSI 1998 Introduction
18、 The cleaning of plant and equipment is an essential element of biotechnology processes in order to protect the safety of people and the environment and to avoid harmful operational effects through the accumulation of soil. Testing procedures should be developed and documented to ensure that relevan
19、t information on cleanability is available. Standards (e.g. EN ISO 9000 series, see annex C 9), guidelines (e.g. Good Manufacturing Practice (GMP) see annex C 10) state general procedures of good practice which facilitate high quality manufacturing if followed. This European Standard refers to asses
20、sing the cleanability of equipment used in biotechnology, where additional specific requirements related to safety and to special features of biotechnological processes are required. It should be read in association with the more general standards and guidelines as mentioned above. In particular thi
21、s European Standard states the principles on which test methodology is based. Informative guidance on selection of test methods is provided in annex A. The extent to which it is necessary to remove soil from equipment and plant varies substantially with the process. In some cases abundant residues a
22、fter cleaning do not harm people or the environment or do not cause difficulties in the process. In others very low residues are essential. The complete removal of soil on surfaces cannot be achieved, because for example all surfaces are adsorptive to some degree. 1 Scope This European Standard give
23、s guidance on general testing procedures to assess the cleanability of equipment (components and units of equipment) used in biotechnological processes. This European Standard applies primarily if the intended use of equipment includes the use of potentially hazardous micro-organisms. This European
24、Standard also applies to non-hazardous micro-organisms and/or to residual soil which can adversely affect sterilization processes or which can cause cross-contamination of products or processes. This European Standard applies to plants or components such as, valves and fitting, tanks, pumps, piping,
25、 separating and filling devices as well as instrumentation in contact with process fluids. 2 Definitions For the purposes of this standard, the following definitions apply: 2.1 clean condition of (a) product, surface, device, gases and/or liquids with residual soil below a defined threshold level 2.
26、2 cleanability ability to be made clean 2.3 cleaning removal of soil 2.4 Cleaning-In Place (CIP) cleaning without dismantling of components of equipment and/or unit of equipment 2.5 components of equipment technical entity which forms part of a unit of equipment NOTE Examples of components of equipm
27、ent are vessels, valves and sensors. 2.6 contamination presence of soil 2.7 residual soil soil left after cleaning 2.8 soil material, including micro-organisms, metabolites and components of process media present on a surface 2.9 unit of equipment assembly of components used to perform one or more u
28、nit operationsPage 4 EN 12296:1998 BSI 1998 3 Testing 3.1 General The requirements for cleanability vary with process, especially in relation to its assessed risk. Therefore cleanability classes for biosafety are defined in individual equipment standards. This will allow the manufacturers of plant a
29、nd equipment to state the performance of their equipment using test methods, including visual inspection, developed according to the principles described in 3.2. It will also allow users of equipment to define their requirements in simple terms. These classes define performance only in relation to a
30、 defined indicator substance(s) and one or more defined cleaning protocol(s) and are relevant to the proposed use in the equipment. The cleanability class assigned to the equipment is likely to vary with the indicator and cleaning protocol chosen. The soil adhering to surfaces at the end of a biotec
31、hnology process will contain many constituents. The indicator substance chosen to demonstrate the cleanability should be representative of those constituents that have an impact on safety aspects in relation to the need to protect people, the environment or features of the process. A brief descripti
32、on of indicators and test methods is given in annex B. 3.2 Methodology To determine the cleanability of plant and equipment, choose and specify an appropriate test method or combination of test methods (see annexes A and B): a) specify an appropriate indicator related to the proposed use of the equi
33、pment; b) select the sampling procedure and the analytical procedure to be used to determine the quantity of this indicator which is present on relevant equipment surfaces or on surfaces in the plant ; c) specify a cleaning protocol including, as a minimum, the specification of the constituents of t
34、he cleaning material and the mode of application. NOTE 1 Potential hazards to the operator during cleaning should be assessed. NOTE 2 Factors such as the duration, temperature and fluid flow rates of cleaning should be included in the protocol. NOTE 3 The cleaning protocol can consist of a number of
35、 successive operations. 3.3 Testing procedure Carry out the testing procedures as follows: a) load the equipment or plant with the indicator under normal operating conditions or in a way which simulates these; b) run the equipment and/or plant under normal or simulated-normal conditions until the lo
36、ad containing the indicator has been discharged from the equipment and the equipment and/or plant is ready to be cleaned; c) using the analytical procedure selected in 3.2, determine the quantity of indicator substance present after discharge of the load but before cleaning; d) apply the cleaning pr
37、otocol specified in 3.2 to the plant or equipment being tested for cleanability; e) using the analytical procedure selected in 3.2, determine the quantity of indicator substance present on the relevant surface(s) of the equipment and/or plant after application of the cleaning protocol; f) using the
38、data obtained, express the cleanability of the equipment or plant; g) determine the appropriate cleanability class to the equipment under test as described in the equipment standards with respect to the chosen indicator substance and cleaning protocol. NOTE The procedure described by European Hygien
39、ic Design criteria Group (EHEDG) (see annex C 2) can be quoted as an example of the application of 3.2 above, in which the indicator substance is the spores of a specific bacterium, the analytical procedure is a culturing method which detects the number of this bacterium present before and after cle
40、aning and in which the cleaning protocol is described (see annex C 3). Clearly other approaches can be used for the indicator substances could be another microorganism, a specific member of a chemical group such as a defined protein, carbohydrate or lipid, a specific compound known to be harmful to
41、people or to the environment, or to future processing (see annex B). Potential cleaning protocols can be simple, for example a wash with water applied through a hosepipe or complex, as with sophisticated in-place cleaning involving the use of hazardous chemicals at high temperature. Many test method
42、s are possible, ranging from the use of a biological indicator to the use of chemical assays, immunological techniques, fluorescence assays and physical test methods, including microscopy (see annex B). 4 Documentation The equipment manufacturer/supplier and/or the user should establish and document
43、 the procedure(s) used for the assessment of the cleanability of the component or unit of equipment. This documentation should include the applied test conditions (testing method, indicator, analytical procedure and cleaning protocol) and the results of the test.Page 5 EN 12296:1998 BSI 1998 1 rinse
44、 (see B.4), visual inspection (see B.2), swab (see B.3), optional 2 rinse, test following batch for contamination (see B.5) 3 rinse *, visual inspection, swab * 4 rinse, test following batch for contamination optional * compare results, if they are consistent sample rinse-fluid only Figure A.1 Decis
45、ion tree for selection of a cleanability test method Annex A (informative) Selection guide on test methods for cleanliness Figure A.1 gives guidance on the selection of test methods for cleanability. It represents a decision tree for selection of a cleanability test method based on scale, and access
46、 of the equipment.Page 6 EN 12296:1998 BSI 1998 Annex B (informative) Information on test methods for cleanliness B.1 General Essentially four test methods are available to determine the level of cleanliness of equipment (see annex C 3). They are visual inspection, swabbing the inner surfaces, sampl
47、ing the final rinse and testing the following batch for contamination. B.2 Visual inspection Residual soil, adsorbed microbial populations or relevant tracer indicators may be detected by a visual inspection of the equipment under investigation. This detection can be done by the eye or by using micr
48、oscopic techniques such as light microscopy, scanning or transmission electron microscopy (see annex C 4). In most cases it will be necessary to gain access to the equipment under investigation in order to be able to use these techniques. B.3 Swabbing the inner surfaces Indicator substances (chemica
49、l or (micro-)biological) can be measured by swabbing exactly defined areas of equipment that come into contact with the product. Swabbing of easily accessible flat surfaces may cause over-optimistic results with regard to the cleaning. Swabbing poorly accessible spots can produce over-pessimistic results. Vitally important for statistically relevant results are a correct choice of places where to swab in the equipment and the area to be swabbed when using this test method. Swabbing can be done either direct e.g. with ag
