1、September 2011 Translation by DIN-Sprachendienst.English price group 13No part of this translation may be reproduced without prior permission ofDIN Deutsches Institut fr Normung e. V., Berlin. Beuth Verlag GmbH, 10772 Berlin, Germany,has the exclusive right of sale for German Standards (DIN-Normen).
2、ICS 11.080.01!$tk$“1817201www.din.deDDIN EN ISO 13408-4Aseptic processing of health care products Part 4: Clean-in-place technologies (ISO 13408-4:2005)English translation of DIN EN ISO 13408-4:2011-09Aseptische Herstellung von Produkten fr die Gesundheitsfrsorge Teil 4: Reinigung vor Ort (ISO 13408
3、-4:2005)Englische bersetzung von DIN EN ISO 13408-4:2011-09Traitement aseptique des produits de sant Partie 4: Technologies de nettoyage sur place (ISO 13408-4:2005)Traduction anglaise de DIN EN ISO 13408-4:2011-09Together with DIN EN ISO 13408-1:2011-09, DIN EN ISO 13408-2:2011-09, DIN EN ISO 13408
4、-3:2011-09,DIN EN ISO 13408-5:2011-09 and DIN EN ISO 13408-6:2011-09 supersedes DIN EN 13824:2005-02Supersedes: see belowwww.beuth.deDocument comprises pagesIn case of doubt, the German-language original shall be considered authoritative.2509.11 DIN EN ISO 13408-4:2011-09 National foreword This stan
5、dard has been prepared by Technical Committee ISO/TC 198 “Sterilization of health care products” (Secretariat: ANSI, United States) in collaboration with Technical Committee CEN/TC 204 “Sterilization of medical devices” (Secretariat: BSI, United Kingdom). The responsible German body involved in its
6、preparation was the Normenausschuss Medizin (Medical Standards Committee), Working Committee NA 063-01-12 AA Aseptische Herstellung. ISO 13408 consists of the following parts, under the general title Aseptic processing of health care products: Part 1: General requirements Part 2: Filtration Part 3:
7、Lyophilization Part 4: Clean-in-place technologies Part 5: Sterilization in place Part 6: Isolator systems The following parts are in preparation: Part 7: Alternative processes for atypical medical devices and combination products Part 8: Cell based health care products Parts 1 to 6 of the DIN EN IS
8、O 13408 series supersede DIN EN 13824, Sterilization of medical devices Aseptic processing of liquid medical devices Requirements. The DIN Standards corresponding to the International Standards referred to in this standard are as follows: ISO 9000 DIN EN ISO 9000 ISO 13408-1 DIN EN ISO 13408-1 ISO 1
9、4937 DIN EN ISO 14937 Amendments This standard differs from DIN EN 13824:2005-02 as follows: a) the specifications relating to clean-in-place technologies have been updated and rendered more precise. Previous editions DIN EN 13824: 2005-02 2 DIN EN ISO 13408-4:2011-09 National Annex NA (informative)
10、 Bibliography DIN EN ISO 9000, Quality management systems Fundamentals and vocabulary DIN EN ISO 13408-1, Aseptic processing of health care products Part 1: General requirements DIN EN ISO 14937, Sterilization of health care products General requirements for characterization of a sterilizing agent a
11、nd the development, validation and routine control of a sterilization process for medical devices 3 DIN EN ISO 13408-4:2011-09 4 This page is intentionally blank EUROPEAN STANDARD NORME EUROPENNE EUROPISCHE NORM EN ISO 13408-4 June 2011 ICS 11.080.01 Supersedes EN 13824:2004English Version Aseptic p
12、rocessing of health care products - Part 4: Clean-in-place technologies (ISO 13408-4:2005) Traitement aseptique des produits de sant - Partie 4: Technologies de nettoyage sur place (ISO 13408-4:2005)Aseptische Herstellung von Produkten fr die Gesundheitsfrsorge - Teil 4: Reinigung vor Ort (ISO 13408
13、-4:2005) This European Standard was approved by CEN on 10 June 2011. 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 alteration. Up-to-date lists and bibliographic
14、al references concerning such national standards may be obtained on application to the CEN-CENELEC Management Centre or to any 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
15、of a CEN member into its own language and notified to the CEN-CENELEC Management Centre has the same status as the official versions. CEN members are the national standards bodies of Austria, Belgium, Bulgaria, Croatia, Cyprus, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hung
16、ary, Iceland, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Netherlands, Norway, Poland, Portugal, Romania, Slovakia, Slovenia, Spain, Sweden, Switzerland and United Kingdom. EUROPEAN COMMITTEE FOR STANDARDIZATION COMIT EUROPEN DE NORMALISATION EUROPISCHES KOMITEE FR NORMUNG Management Centr
17、e: Avenue Marnix 17, B-1000 Brussels 2011 CEN All rights of exploitation in any form and by any means reserved worldwide for CEN national Members. Ref. No. EN ISO 13408-4:2011: EContents Page Foreword. 3 Introduction 4 1 Scope . 5 2 Normative references . 5 3 Terms and definitions. 5 4 Quality syste
18、m elements 6 4.1 General. 6 4.2 Management responsibility . 6 4.3 Design control. 6 4.4 Measuring instruments and measuring systems 6 5 Process and equipment characterization 7 5.1 General concepts 7 5.2 Effectiveness of CIP . 7 5.3 Equipment . 8 6 Cleaning agent characterization . 9 6.1 Selection o
19、f cleaning agent(s). 9 6.2 Quality of cleaning agent(s). 9 6.3 Safety and the environment. 10 7 CIP process . 10 7.1 Process parameters 10 7.2 Process control. 10 7.3 Residues of cleaning agent(s). 12 8 Validation. 12 8.1 Validation protocol . 12 8.2 Evaluation of the CIP process . 12 8.3 Design qua
20、lification 12 8.4 Installation qualification. 12 8.5 Operational qualification 13 8.6 Performance qualification 13 8.7 Review and approval of validation 14 8.8 Requalification 14 9 Routine monitoring and control 14 9.1 CIP process control 14 9.2 Procedures 14 9.3 CIP process records. 15 9.4 Change c
21、ontrol 15 9.5 Maintenance and calibration . 15 10 Personnel training 15 Annex A (informative) Description of sampling methods 16 Annex B (informative) Calculation examples for acceptance criteria. 17 Bibliography . 21 Annex ZA (informative) Relationship between this European Standard and the Essenti
22、al Requirements of EU Directive 90/385/EEC on Active Implantable Medical Devices 18Annex ZB (informative) Relationship between this European Standard and the Essential Requirements of EU Directive 93/42/EEC on Medical Devices .19Annex ZC (informative) Relationship between this European Standard and
23、the Essential Requirements of EU Directive 98/79/EC on in vitro diagnostic medical devices 20EN ISO 13408-4:2011 (E) DIN EN ISO 13408-4:2011-09 2Foreword The text of ISO 13408-4:2005 has been prepared by Technical Committee ISO/TC 198 “Sterilization of health care products” of the International Orga
24、nization for Standardization (ISO) and has been taken over as EN ISO 13408-4:2011 by Technical Committee CEN/TC 204 “Sterilization of medical devices” the secretariat of which is held by BSI. This European Standard shall be given the status of a national standard, either by publication of an identic
25、al text or by endorsement, at the latest by December 2011, and conflicting national standards shall be withdrawn at the latest by December 2011. Attention is drawn to the possibility that some of the elements of this document may be the subject of patent rights. CEN and/or CENELEC shall not be held
26、responsible for identifying any or all such patent rights. This document supersedes EN 13824:2004. This document has been prepared under a mandate given to CEN by the European Commission and the European Free Trade Association, and supports essential requirements of EU Directives. For relationship w
27、ith EU Directives, see informative Annexes ZA, ZB, or ZC, which are integral parts of this document. According to the CEN/CENELEC Internal Regulations, the national standards organizations of the following countries are bound to implement this European Standard: Austria, Belgium, Bulgaria, Croatia,
28、Cyprus, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Netherlands, Norway, Poland, Portugal, Romania, Slovakia, Slovenia, Spain, Sweden, Switzerland and the United Kingdom. Endorsement notice The text of IS
29、O 13408-4:2005 has been approved by CEN as a EN ISO 13408-4:2011 without any modification. EN ISO 13408-4:2011 (E) DIN EN ISO 13408-4:2011-09 3Introduction During the process of preparing ISO 13408-1 several items, e.g. filtration, lyophilization drying and sterilization-in-place technologies, were
30、found to be in need of supplementary information that was too voluminous to be given in corresponding annexes. This part of ISO 13408 includes requirements and guidance that are to be observed during clean-in-place processes. The purpose of this part of ISO 13408 is to achieve standardization in the
31、 field of validation and routine control of clean-in-place processes used in the manufacture of health care products. Clean-in-place processes allow parts of the equipment or an entire process system to be cleaned without being dismantled, reducing the need for disassembling and connections under cl
32、ean conditions. For example, tanks, vessels, freeze-dryers piping and other processing equipment used for manufacture may be cleaned in place. The clean-in-place process is in most instances followed by sterilization-in-place process (described in ISO 13408-5). While clean-in-place and sterilization
33、-in-place methods differ considerably in technology, the concept of in situ treatment is similar. Design considerations of all systems are critical to ensure that clean-in-place technologies can be successfully applied to clean manufacturing equipment to the desired level of cleanliness. EN ISO 1340
34、8-4:2011 (E) DIN EN ISO 13408-4:2011-09 41 Scope This part of ISO 13408 specifies the general requirements for clean-in-place (CIP) processes applied to product contact surfaces of equipment used in the manufacture of sterile health care products by aseptic processing and offers guidance on qualific
35、ation, validation, operation and control. This part of ISO 13408 is applicable to processes where cleaning agents are delivered to the internal surfaces of equipment designed to be compatible with CIP, which may come in contact with the product. This part of ISO 13408 is not applicable to processes
36、where equipment is dismantled and cleaned in a washer. This part of ISO 13408 does not supersede or replace national regulatory requirements, such as Good Manufacturing Practices (GMPs) and/or compendial requirements that pertain to particular national or regional jurisdictions. 2 Normative referenc
37、es The following referenced documents are indispensable for the application of this document. For dated references, only the edition cited applies. For undated references, the latest edition of the referenced document (including any amendments) applies. ISO 13408-1, Aseptic processing of health care
38、 products Part 1: General requirements ISO/IEC 90003, Software engineering Guidelines for the application of ISO 9001:2000 to computer software 3 Terms and definitions For the purposes of this document, the terms and definitions given in ISO 13408-1 and the following apply. 3.1 cleaning agent organi
39、c or inorganic chemical including water, detergent or mixture thereof, used as an aid in the cleaning process for cleaning equipment 3.2 clean-in-place CIP method of cleaning of the internal surfaces of parts of the equipment or an entire process system without or with minimal disassembly NOTE CIP a
40、lso includes the removal of remaining residual cleaning agent to an acceptable level which is defined based on the nature of the product and the process tolerance. EN ISO 13408-4:2011 (E) DIN EN ISO 13408-4:2011-09 53.3 dead leg location which, by design, does not permit adequate accessibility of th
41、e cleaning agent 3.4 design qualification documented verification that the proposed design of the facilities, equipment, or system is suitable for the intended use 3.5 material safety data sheet document specifying the properties of a material, its potential hazardous effects for humans and the envi
42、ronment, and the precautions necessary to handle and dispose of the material safely 3.6 worst-to-clean most difficult conditions for cleaning EXAMPLES Materials to be removed, surface types to be cleaned, process parameters to be met or position(s) to be reached. 4 Quality system elements 4.1 Genera
43、l 4.1.1 The requirements of ISO 13408-1 shall apply. 4.1.2 Documented procedures for each phase of the development, validation, routine monitoring and control of the CIP process shall be prepared and implemented. 4.1.3 Documents required by this part of ISO 13408 shall be reviewed and approved by de
44、signated personnel. 4.1.4 Records of development, validation, routine control and monitoring shall be maintained to provide evidence of conformity to the requirements of this part of ISO 13408. 4.2 Management responsibility 4.2.1 The responsibilities and authority for implementing and performing the
45、 procedures described in this part of ISO 13408 shall be specified. 4.2.2 If the requirements of this part of ISO 13408 are undertaken by organizations with separate quality management systems, the responsibilities and authority of each party shall be specified. 4.3 Design control Characterization o
46、f the cleaning agent(s), cleaning method, equipment to deliver CIP and the equipment subject to CIP, shall be undertaken in accordance with a documented plan. At defined stages, design reviews shall be planned, conducted and documented. 4.4 Measuring instruments and measuring systems 4.4.1 A documen
47、ted system shall be specified for the calibration of all measuring instruments or measuring systems. 4.4.2 The accuracy and tolerance of the measuring instrument shall be justified for the process to be measured. EN ISO 13408-4:2011 (E) DIN EN ISO 13408-4:2011-09 65 Process and equipment characteriz
48、ation 5.1 General concepts 5.1.1 The specification for the CIP process shall include but not be limited to: a) physical and chemical properties of the material to be removed and the strength of its adherence to the surface from which it is to be removed; b) physical and chemical properties and mecha
49、nism of action of cleaning agent(s); c) compatibility of the equipment with the cleaning agents and processing conditions; d) pre-cleaning period and conditions prior to cleaning; e) the number of passes (single-pass cleaning, and/or multi-pass cleaning); f) filling and immersing period with cleaning agent(s); g) agitation or spraying of cleaning agent(s); h) cleaning agent(s) elimination; i) post-cleaning drying; j) post-cleaning protection of the cleanliness of the equipment; k) maximum post-cleaning hold period and conditio
