1、STD.BS1 BS EN 13311-Y-ENGL 2001 - lb24bb9 090bBb8 b49 BRITISH STANDARD Biotechnology - Performance criteria for vessels - Part 4: Bioreactors The European Standard EN 13311-4:2001 has the status of a British Standard ICs 07.080 BS EN 133 11-4:200 1 NO COPYING WITHOUT BSI PERMISSION EXCEPT AS PERMITT
2、ED BY COPYRIGHT LAW _ - STD.BS1 BS EN 13311-4-ENGL 2001 Lb24669 0906869 585 BS EN 13311-4:2001 Amd. No. National foreword Date Comments This British Standard is the official English language version of The UK participation in its preparation was entrusted to Technical Committee CIU 58, Biotechnology
3、, which has the responsibility to: EN 13311-42001. - - aid enquirers to understand the text; present to the responsible European committee any enquiries on the interpretation, or proposals for change, and keep the UK interests informed; monitor related international and European developments and pro
4、mulgate 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 implement these international or European publications may be found in the BSI Standards Catalogue under the section entitled ?nte
5、rnational Standards Correspondence Index, or by using the “Find” facility of the BSI Standards Electronic Catalogue. A British Standard does not purport to include all the necessary provisions of a contract. Users of British Standards are responsible for their correct application. Compliance with a
6、British Standard does not of itself confer immunity from legal obligations. This British Standard. having Summary of pages This document comprises a front cover, an inside front cover, the EN title page, been prepared under the - direction of the Sector Committee for Materials and Chemicals was publ
7、ishedunder Daees 2 to 10. an inside back cover and a back cover. *v the authority of the Standards Committee and comes into effect on 15 May 2001 The BSI copyright date displayed in this document indicates when the document was last issued. Amendments issued since publication 8 BSI 05-2001 ISBN O 68
8、0 37600 1 - STD-BSI BS EN L33LL-4-ENGL 2DOL W 1624bb9 0906870 2T7 EUROPEAN STANDARD EN 13311-4 NORME EUROPENNE EUROPISCHE NORM March 2001 ICs 07.080; 07.100.01 English version Biotechnology - Performance criteria for vessels - Part 4: Bioreactors Biotechnologie - Critres de performance des rcipients
9、 - Partie 4: Bioracteurs Biotechnik - Leistungskriterien fr ehlter - Teil 4: Bioreaktoren This European Standard was approved by CEN on 4 February 2001. CEN members are bound to comply with the CENKENELEC Internal Regulations which stipulate the conditions for giving ais European Standard the status
10、 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 three official versions (English, French, German). A versi
11、on in any other language made by transiation 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 Austria, Belgium, Czech Republic, Denmark, Finland, France,
12、 Germany, Greece, Iceland, Ireland, Italy, Luxembourg, Netherlands, Norway, Portugal, Spain, Sweden, Switzerland and United Kingdom. EmOPEAN C0MMi“EE FOR STANDARDIZATION COMITE EUROPEEN DE NORMALISATION EUROPISCHES KOMITEE FUR NORMUNG Management Centre: rue de Stassart, 36 8-1W Brussels Q 2001 CEN A
13、ll rights of exploitation in any form and by any means reserved worldwide for CEN national Members. Ref. No. EN 13311-4:2001 E Contents Page Foreword 3 Introduction 4 1 Scope 4 2 Normative references . 4 3 Terms and definitions 4 4 Hazards . 4 5 Performance classes . 4 6 Classification and verificat
14、ion of performance 5 7 Marking and packaging 5 8 Documentation . 5 Annex A (informative) Guidance on test methods for determining leaktightness of bioreactors . 6 Annex B (informative) Typical hazards and preventive measures 7 Bibliography . 1 0 STD*BSI BS EN L33LL-4-ENGL 2OOL W Lb24bb9 090b872 07T
15、Page 3 EN 1331 1 -4:2001 Foreword This European Standard has been prepared by Technical Committee CEWC 233 “Biotechnology“, the secretariat of which is held by AFNOR. This European Standard shall be given the status of a national standard, either by publication of an identical text or by endorsement
16、, at the latest by September 2001, and conflicting national standards shall be withdrawn at the latest by September 2001. This European Standard has been prepared under a mandate given to GEN by the European Commission and the European Free Trade Association. This standard is one of a series of Euro
17、pean Standards concerned with performance criteria for vessels. These standards are: EN 1331 1 -1, Biotechnology - Performance criteria for vessels - Part I: General performance criteria. EN 1331 1 -2, Biotechnology - Performance criteria for vessels - Part 2: Pressure protection devices. EN 1331 1
18、-3, Biotechnology - Performance criteria for vessels - Part 3: Glass pressure vessels. EN 1331 1-4, Biotechnology - Performance criteria for vessels - Part 4: Bioreactors. EN 1331 1-5, Biotechnology - Performance criteria for vessels - Part 5: Kill tanks. EN 1331 1-6, Biotechnology - Performance cri
19、teria for vessels - Part 6: Chromatography columns. Annexes A and B are informative. This standard includes a bibliography. According to the CENKENELEC Internal Regulations, the national standards organizations of the following countries are bound to implement this European Standard: Austria, Belgiu
20、m, Czech Republic, Denmark, Finland, France, Germany, Greece, Iceland, Ireland, Italy, Luxembourg, Netherlands, Norway, Portugal, Spain, Sweden, Switzerland and the United Kingdom. STDOBSI BS EN 13311-4-ENGL 2001 - Lb24bb9 09Ob873 Tob Page 4 EN 1331 1 -4:2001 Introduction Use of this European Standa
21、rd will aid the equipment manufacturer in the classification of bioreactors with regard to safe performance in biotechnological processes. The classification is easily understandable and readily utilizable for the user and the regulatory authorities. 1 scope This European Standard specifies performa
22、nce criteria for bioreactors used in biotechnological processes with respect to the potential hazards to the worker and the environment from microorganisms in use. This European Standard applies where the intended use of bioreactors includes hazardous or potentially hazardous microorganisms used in
23、biotechnological processes or where exposure of the worker or the environment to such microorganisms is restricted for reasons of safety. 2 Normative references This European Standard incorporates by dated or undated reference, provisions from other publications. These normative references are cited
24、 at the appropriate places in the text and the publications are listed hereafter. For dated references, subsequent amendments to or revisions of any of these publications apply to this European Standard only when incorporated in it by amendment or revision. For undated references the latest edition
25、of the publication referred to applies (including amendments). EN 1331 1-1 2001 Biotechnology - Performance criteria for vessels - Part 1 : General Performance criteria 3 Terms and definitions For the purposes of this standard, the terms and definitions given in EN 1331 1-1:2001 apply. 4 Hazards Typ
26、ical examples for potential hazards of bioreactors and recommendations for proper design and handling are included in annex B. 5 Performance classes The bioreactors shall be classified for leaktightness, cleanability and sterilizability in accordance with 5.1 to 5.4 of EN 1331 1-1 :2001. The selecti
27、on of the appropriate class for performance of a bioreactor shall be made in accordance with 5.5 of EN 1331 1-1 :2001. STD*BSI BS EN 13311-4-ENGL 2001 = 1624669 07Db874 942 Page 5 EN 1331 1 -4:2001 6 Classification and verification of performance 6.1 General The bioreactors shall conform to the gene
28、ral requirements given in 6.1 of EN 1331 1-1 :2001. If the components are classified, the using of an indirect test method to the assembled bioreactor is sufficient for classification. If the bioreactor is made by assembly of components, it shall be tested to verify its overall classification. NOTE
29、EN 12460 provides guidance on selection and installation of equipment relevant to bioreactors. 6.2 Leaktightness The bioreactor shall conform to the requirements given in 6.2 of EN 1331 1-1 :2001. If the bioreactor contains microorganisms for which the release shall be minimized, risk analysis shall
30、 indicate whether the off-gas has to be treated. If the bioreactor contains microorganisms for which the release shall be prevented, the off-gas shall be treated. Guidance on test methods for determining leaktightness of bioreactors is given in annex A. 6.3 Cleanability The bioreactor shall conform
31、to the requirements given in 6.3 of EN 1331 1-1 :2001. 6.4 Sterilizability The bioreactor shall conform to the requirements given in 6.4 of EN 1331 1-1 :2001. 7 Marking and packaging The bioreactor shall conform to the requirements given in clause 7 of EN 1331 1-1 :2001. a Documentation The bioreact
32、or shall conform to the requirements given in clause 8 of EN 1331 1-1 :2001. Page 6 EN 1331 1-42001 Annex A (informative) Guidance on test methods for determining leaktightness of bioreactors A list of test methods for leaktightness is given in table A.l of EN 12298 (see 13). From that list suitable
33、 test methods to the testing of bioreactors are given in table A.l. Table A.l - Suitable alternative leaktightness test methods for bioreactors a Freon is an example of a suitable product available commercially. This information is given for the convenience of the user of this Standard and does not
34、constitute an endorsement of CEN of these products. Page 7 EN 1331 1 -4:2001 Annex 8 (informative) Typical hazards and preventive measures B.l General Cleaning as well as sterilization is facilitated if there are no dead or stagnant areas in all equipment including pipe work, which prevents self dra
35、ining. After draining stagnant areas with a depth of not more than 5 mm or in piping dead legs less than 2 times the internal pipe diameters are considered as not preventing cleaning and sterilization. Any opening or crevice in the surface of the material in contact with the process fluid can preven
36、t cleaning and sterilization if their shape does not allow good cleaning agent penetration and rinsing as well as steam penetration. It is good practice to perform maintenance on the bioreactor only after application of appropriate target microorganism reduction procedures, that can be cleaning in p
37、lace or sterilization of the whole system. 8.2 Backflow of target microorganisms Back flow of target microorganism from the bioreactor into vessels or containers used for additions during cultivation (for example vessels for addition of feed, acid, alkali, antifoam or nutrient) should be prevented f
38、or example through the use of non-return-valve or overpressure. 6.3 Malfunctioning o steam traps The effective operation of steam traps during sterilization is one of the critical requirements of effective sterilization. Proper design for operation and accessibility during monitoring are recommended
39、. 8.4 Hazards associated with couplings, valves and pipes Improper usage is a hazard associated with couplings. If applicable welding instead of couplings can improve cleanability, sterilizability and leaktightness and therefore minimize the risks. Performance of couplings are described in EN 13312-
40、2 (see SI). Reinforced flexible tubes (e.g. metal mantled) can withstand pressure encountered during normal sterilization. If applicable bending is preferable, automatic welding is preferable to improve cleanability. Performance of tubes and pipes are described in EN 1331 2-4 (see 6). 8.5 Leakage th
41、rough valves Stems of valves can be especially well sealed, for example by using bonnet packing rings or O-rings or by incorporating a static membrane between stem and valve chamber. Performance of valves is described in EN 13312-5 (see 7). STD-BSI ES EN 13311-4-ENGL 2001 W 1624bb9 090b877 b5L Page
42、8 EN 1331 1-42001 B.6 Leakage through seals Seals are required for primary containment where shafts pass through the wall of the bioreactor, like stirrer shafts, sampling devices, probe fittings and all other fittings. If seals or gaskets are close to the product side possibility of creating crevice
43、s is reduced. O-rings should be used as static seals between non-moving surfaces. Appropriate seals for rotating stirrer shaft are lip seals or mechanical seals. The probability of leakage can for example be reduced by using a double mechanical seal with an overlaying sealing fluid which is kept at
44、a higher pressure than the medium. In specific cases the need for such seals can be overcome by the use of magnetic couplings. However, aspects like sterilizability and cleanability should be considered with care. Another solution can be the use of for example air-lift fermenters. In such cases off-
45、gas treatment should be properly considered. By addition of disinfectants to the sealing fluid or maintenance of adequate high temperatures microorganisms penetrating the seal after breakage can be inactivated. To control the integrity of the seal a level transmitter or a pressure indicator and alar
46、m system can be installed into the circuit system. Performance of seals is described in EN 12490 (see Pl). 8.7 Release of microorganisms through off-gas systems Treatment to minimize leakage can include the use of suitable centrifugal separators (for example cyclones). Treatment to prevent leakage c
47、an include heat treatment of the off gas stream, or passage through suitable filters (for example depth filters or hydrophobic membrane filters). Consideration can be given to the use of two filters in series in case of failure of the primary filter. Performance of off-gas systems is described in EN
48、 13095 (see gil. B.8 Release of microorganisms by foaming Excessive foaming can be a major hazard in bioreactor operation. Microorganisms can be released by foam leaving the bioreactor or foam can block exhaust filters. Blocked exhaust filters can cause overpressure in the bioreactor. Where foam for
49、mation is likely, suitable means for controlling of the foam should be put into place. Such measures can include: - the use of mechanical foam breakers ; - foam probe with anti-foam agent addition ; - the use of centrifugal separator, linked to a foam probe ; - high level alarm foam probe and shut off valve in the exhaust air duct together with reduction of aeration rate ; - reduced bioreactor working volume. STD.BSI BS EN 13311-4-ENGL 2001 m Lb24bb9 090b878 598 Page 9 EN 1331 1-42001 Combination of different systems and a proper control should enhanc
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