1、| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | BRITISH STANDARD BS EN 12075 : 1997 The Eu
2、ropean Standard EN 12075 : 1997 has the status of a British Standard ICS 07.080 NO COPYING WITHOUT BSI PERMISSION EXCEPT AS PERMITTED BY COPYRIGHT LAW Biotechnology Large scale process and production Procedures for fermentation and downstream processesBS EN 12075 : 1997 This British Standard, having
3、 been prepared under the direction of the Sector Board for Materials and Chemicals, was published under the authority of the Standards Board and comes into effect on 15 August 1997 BSI 1997 The following BSI references relate to the work on this standard: Committee reference CII/58 Draft for comment
4、 95/124066 DC ISBN 0 580 27949 9 Amendments issued since publication Amd. No. Date Text affected Committees responsible for this British Standard The preparation of this British Standard was entrusted to Technical Committee CII/58, Biotechnology, upon which the following bodies were represented: Ass
5、ociation of Consultants to the Bioscience Industries (ACBI) BLWA Ltd. (The Association of the Laboratory Supply Industry) Bioindustry Association Brewing Research Foundation International British Agrochemicals Association Ltd. Chemical Industries Association Confederation of British Industry Departm
6、ent of Health Department of the Environment (Air Climate and Toxic Directorate) Health and Safety Executive Institution of Chemical Engineers International Society for Pharmaceutical Engineering Ministry of Agriculture, Fisheries and Food National Engineering Laboratory Public Health Laboratory Serv
7、ice Society for Applied Bacteriology Society for General MicrobiologyBS EN 12075 : 1997 BSI 1997 i Contents Page Committees responsible Inside front cover National foreword ii Foreword 2 Text of EN 12075 3ii BSI 1997 BS EN 12075 : 1997 National foreword This British Standard has been prepared by Tec
8、hnical Committee CII/58, and is the English language version of EN 12075 : 1997, Biotechnology Large-scale process and production Procedures for fermentation and downstream processes, published by the European Committee for Standardization (CEN). Compliance with a British Standard does not of itself
9、 confer immunity from legal obligations. Summary of pages This document comprises a front cover, an inside front cover, pages i and ii, the EN title page, pages 2 to 8, an inside back cover and a back cover.CEN European Committee for Standardization Comite Europe en de Normalisation Europa isches Ko
10、mitee fu r Normung Central Secretariat: rue de Stassart 36, B-1050 Brussels 1997 Copyright reserved to CEN members Ref. No. EN 12075 : 1997 E EUROPEAN STANDARD EN 12075 NORME EUROPE ENNE EUROPA ISCHE NORM February 1997 ICS 07.080 Descriptors: Biotechnology, culture (biology), micro-organisms, manage
11、ment, fermentation, definitions, description, generalities, hazards, inspection, contamination, accident prevention, environmental protection English version Biotechnology Large-scale process and production Procedures for fermentation and downstream processes Biotechnologie Proce de a grande e chell
12、e et production Proce dures pour les proce de sd e fermentation et traitement aval Biotechnik Verfahren im Gromastab und Produktion Vorgehensweise fu r die Bereiche Fermentation und Aufarbeitung This European Standard was approved by CEN on 1996-12-29. CEN members are bound to comply with the CEN/CE
13、NELEC Internal Regulations which stipulate 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 Central Secretariat or to any
14、 CEN member. This European Standard exists in 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 Central Secretariat has the same status as the official versions. CE
15、N members are the national standards bodies of Austria, Belgium, Denmark, Finland, France, Germany, Greece, Iceland, Ireland, Italy, Luxembourg, Netherlands, Norway, Portugal, Spain, Sweden, Switzerland and United Kingdom.Page 2 EN 12075 : 1997 BSI 1997 Foreword This European Standard has been prepa
16、red by Technical Committee CEN/TC 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, at the latest by August 1997, and conflicting national standards sha
17、ll be withdrawn at the latest by August 1997. According to the CEN/CENELEC Internal Regulations, the national standards organizations of the following countries are bound to implement this European Standard: Austria, Belgium, Denmark, Finland, France, Germany, Greece, Iceland, Ireland, Italy, Luxemb
18、ourg, Netherlands, Norway, Portugal, Spain, Sweden, Switzerland and the United Kingdom. Contents Page Foreword 2 Introduction 3 1 Scope 3 2 Normative references 3 3 Definitions 3 4 Process description 4 5 Risk management 5 Annex A (informative) Bibliography 8Page 3 EN 12075 : 1997 BSI 1997 Introduct
19、ion This European Standard supports industrial activities in the area of biotechnology covering operations with both non-genetically modified micro-organisms and genetically modified micro-organisms (GMMs), with both non-pathogenic and pathogenic micro-organisms (see annex A 1, 2). Fermentation proc
20、esses vary widely in their nature and design. Generally prokaryotic or eukaryotic micro-organisms, plant cells, mammalian cells or insect cells are cultivated and processed in such a way as to produce a desired end-product such as biomass, pharmaceuticals, additives, metabolites and foodstuffs. 1 Sc
21、ope This European Standard specifies the principles for the assessment and selection of fermentation and downstream operations so that they are carried out in a manner which ensures the safety of personnel, the environment and product and contributes to product quality. This European Standard is int
22、ended for use by those designing and/or operating processes and by other interested parties. Unit operations are not described in detail and individual production processes can require specific equipment or unit operations which are not described here. 2 Normative references This European Standard i
23、ncorporates by dated or undated reference, provisions from other publications. These normative references are cited 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
24、European Standard only when incorporated in it by amendment or revision. For undated references the latest edition of the publication referred to applies. prEN 12460 Biotechnology Large-scale process and production Equipment implementation according to the degree of hazard prEN 12461 Biotechnology L
25、arge scale process and production Guidance for the handling, inactivating and testing of waste 3 Definitions For the purposes of this standard, the following definitions apply: 3.1 bioaerosol Colloid dispersed solid or liquid particles in a gaseous environment presenting negligible gravitational set
26、tling, containing micro-organisms. 3.2 biocontamination Presence of undesired micro-organisms. 3.3 closed system System where a barrier separates micro-organisms/organisms from the environment. EN 1620 3.4 controlled area Area constructed and/or operated in such a manner as to limit contamination of
27、 the other areas by micro-organisms/organisms from within the controlled area EN 1620. 3.5 downstream process Sequence of operations following the fermentation. 3.6 fermentation Biotechnical process where the target product is formed while cultivating the process micro-organism(s) EN 1620. 3.7 ferme
28、nter Closed or open vessel where a culture of micro-organisms is grown under controlled conditions. 3.8 hazard Intrinsic potential property or ability of something (e.g. any agent, equipment, material or process) to cause harm EN 1620. NOTE. Harm is an injury or damage to health of people and/or to
29、the environment. 3.9 inactivation Destruction of micro-organisms. 3.10 master cell bank (MCB) Stock of cells from which all subsequent cell banks are derived EN 1619. NOTE 1. MCB stock is not normally intended for use directly in production. NOTE 2. The term MCB covers all type of cells i.e. micro-o
30、rganisms as defined in 3.11.Page 4 EN 12075 : 1997 BSI 1997 Figure 1. Schematic diagram of a biotechnological manufacturing process 3.11 micro-organism Microbiological entity, cellular or non-cellular, capable of replication or of transferring genetic material EN 1619. The term micro-organism covers
31、 the term of biological agent, according to the Directive 90/679/EEC : micro-organisms, including those which have been genetically modified, cell cultures and human endoparasites which may be able to provoke any infection, allergy or toxicity. 3.12 pathogen Micro-organism causing disease EN 1620. 3
32、.13 physical containment System for confining a micro-organism/organism or other entity within a defined space EN 1620. 3.14 process micro-organism Micro-organism used for production purposes in a biotechnological process or constituting (part of) the product itself. 3.15 risk Probability of occurre
33、nce of a hazard causing harm and the degree of severity of the harm. 3.16 sterilization Validated process used to reach a state free from viable micro- organisms. NOTE. In a sterilization process, the nature of microbiological death or reduction is described by an exponential function. Therefore, th
34、e number of micro-organisms that survive a sterilization process can be expressed in terms of probability. While the probability can be reduced to a very low number, it can never be reduced to zero. 3.17 unit operation Operation to perform a single chemical, physical or mechanical activity. NOTE 1.
35、Examples of unit operations are heat transfer, mixing, separating including filtration and centrifugation, and sterilization. NOTE 2. Combinations of unit operations constitute a process step. For example, downstream process step could consist of separation, extraction, concentration and drying. 3.1
36、8 waste By-product arising from a process or unwanted substance or article derived from any activity. NOTE. Examples of waste are scrap material, effluent, unwanted residue or surplus arising from any process or activity or any substance or article which is discarded or to be disposed of as being br
37、oken, contaminated, spoiled, or worn out. 3.19 working cell bank (WCB) Stocks of cells derived from the master cell bank (MCB), which are used for inoculation EN 1619. NOTE. The term working cell bank covers all type of cells i.e. micro-organisms as defined in 3.11. 4 Process description 4.1 General
38、 Fermentation and downstream processes consist of a number of unit operations linked together to produce a product. There is a wide range of unit operations and a general schematic diagram is shown in figure 1. The unit operations can be categorized into process steps which are described in 4.2 to 4
39、.5.Page 5 EN 12075 : 1997 BSI 1997 4.2 Raw materials Select, transport, store and treat raw materials so that required characteristics are retained and contamination with unwanted materials or micro-organisms is prevented. Carry out medium preparation according to documented procedures for treatment
40、, addition and mixing of the raw materials. NOTE. Guidance on control procedures for raw materials are given in EN 1826. 4.3 Fermentation Ensure that the fermenter and associated equipment are cleaned and sterilized as appropriate to the process and risk assessment (see clause 5). Prepare the inocul
41、um culture from the working cell bank. Typically, this process consists of one or more stages of increasing volume, such that the amount transferred to the production stage in most cases is between 2 % and 10 % of the production volume. Checks on culture against specified requirements can be carried
42、 out at each stage, especially for aseptic operation. Carry out transfers or terminations of each inoculum stage as appropriate in accordance with documented procedures for transfer, including contamination criteria. Run the main fermentation in an appropriate mode such as batch, fed batch, continuo
43、us, semi-continuous or multistep process or any combination of these. The process micro-organism can be contained in the fermenter in a variety of modes such as free suspension, immobilized in a matrix or retained on a membrane. Terminate the fermentation and continue the downstream process. 4.4 Dow
44、nstream process Use appropriate downstream processes for the isolation and/or further purification, concentration and stabilization of the product. These processes can occur either during or after the fermentation process and, in some cases, can occur in the fermenter itself. Unit operations used in
45、 downstream processes can include filtration, centrifugation, precipitation, distillation, lyophilisation, crystallisation, ion exchange, chromatography, electrodialysis, direct and tangential filtration, liquid-liquid extraction, flotation, evaporation. 4.5 Output Package, label, store and transpor
46、t products with due regard to safety and quality according to appropriate documented procedures. NOTE 1. Attention is drawn to relevant European and national regulations. Establish waste management procedures for the waste products from the process including provisions for contaminated or aborted pr
47、ocess material. Waste from biotechnological processes shall be handled and, if necessary, inactivated in accordance with prEN 12461. NOTE 2. Attention is drawn to European and national regulations for the control of waste. 5 Risk management 5.1 Risk assessment A documented risk assessment shall be m
48、ade for the micro-organism and process with regard to the general hazards identified. This will typically be done at the stages of process design, process implementation, significant process change. A relevant method of risk assessment shall be used with regard to personnel, environment and product.
49、 The risk group of the micro-organism shall be considered in preparing the assessment (see annex A 1, 2). NOTE 1. This assessment can be based on methods such as: HACCP (Hazard Analysis Critical Control Points) (see annex A 3 4) HAZOP (Hazard and Operability) (see annex A 5 6) IEC 812:1985 (see annex A 7) EN 1050 (see annex A 8) NOTE 2. In some cases of traditional or empirically processes, the risk assessment can take a simplified form based on a history of safe use. 5.2 Descri
