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1、 Reference number ISO 13408-4:2005(E) ISO 2005 INTERNATIONAL STANDARD ISO 13408-4 First edition 2005-11-01 Aseptic processing of health care products Part 4: Clean-in-place technologies Traitement aseptique des produits de sant Partie 4: Technologies de nettoyage sur place ISO 13408-4:2005(E) PDF di
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6、f the requester. ISO copyright office Case postale 56 CH-1211 Geneva 20 Tel. + 41 22 749 01 11 Fax + 41 22 749 09 47 E-mail copyrightiso.org Web www.iso.org Published in Switzerland ii ISO 2005 All rights reserved -,-,- ISO 13408-4:2005(E) ISO 2005 All rights reserved iii Contents Page Foreword iv I
7、ntroduction v 1 Scope . 1 2 Normative references. 1 3 Terms and definitions. 1 4 Quality system elements 2 4.1 General. 2 4.2 Management responsibility . 2 4.3 Design control. 2 4.4 Measuring instruments and measuring systems 2 5 Process and equipment characterization 3 5.1 General concepts 3 5.2 Ef
8、fectiveness of CIP . 3 5.3 Equipment . 4 6 Cleaning agent characterization . 5 6.1 Selection of cleaning agent(s). 5 6.2 Quality of cleaning agent(s). 5 6.3 Safety and the environment. 6 7 CIP process . 6 7.1 Process parameters 6 7.2 Process control. 6 7.3 Residues of cleaning agent(s). 8 8 Validati
9、on. 8 8.1 Validation protocol . 8 8.2 Evaluation of the CIP process. 8 8.3 Design qualification 8 8.4 Installation qualification. 8 8.5 Operational qualification 9 8.6 Performance qualification 9 8.7 Review and approval of validation 10 8.8 Requalification 10 9 Routine monitoring and control 10 9.1
10、CIP process control 10 9.2 Procedures 10 9.3 CIP process records. 11 9.4 Change control 11 9.5 Maintenance and calibration . 11 10 Personnel training 11 Annex A (informative) Description of sampling methods 12 Annex B (informative) Calculation examples for acceptance criteria. 13 Bibliography. 14 -,
11、-,- ISO 13408-4:2005(E) iv ISO 2005 All rights reserved Foreword ISO (the International Organization for Standardization) is a worldwide federation of national standards bodies (ISO member bodies). The work of preparing International Standards is normally carried out through ISO technical committees
12、. Each member body interested in a subject for which a technical committee has been established has the right to be represented on that committee. International organizations, governmental and non-governmental, in liaison with ISO, also take part in the work. ISO collaborates closely with the Intern
13、ational Electrotechnical Commission (IEC) on all matters of electrotechnical standardization. International Standards are drafted in accordance with the rules given in the ISO/IEC Directives, Part 2. The main task of technical committees is to prepare International Standards. Draft International Sta
14、ndards adopted by the technical committees are circulated to the member bodies for voting. Publication as an International Standard requires approval by at least 75 % of the member bodies casting a vote. Attention is drawn to the possibility that some of the elements of this document may be the subj
15、ect of patent rights. ISO shall not be held responsible for identifying any or all such patent rights. ISO 13408-4 was prepared by Technical Committee ISO/TC 198, Sterilization of health care products. ISO 13408 consists of the following parts, under the general title Aseptic processing of health ca
16、re products: Part 1: General requirements Part 2: Filtration Part 3: Lyophilization Part 4: Clean-in-place technologies Part 5: Sterilization in place Part 6: Isolator systems ISO 13408-4:2005(E) ISO 2005 All rights reserved v Introduction During the process of preparing ISO 13408-1 several items, e
17、.g. filtration, lyophilization drying and sterilization-in-place technologies, were 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 p
18、rocesses. The purpose of this part of ISO 13408 is to achieve standardization in the 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 wi
19、thout being dismantled, reducing the need for disassembling and connections under clean 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
20、-in-place process (described in ISO 13408-5). While clean-in-place and sterilization-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 appli
21、ed to clean manufacturing equipment to the desired level of cleanliness. -,-,- -,-,- INTERNATIONAL STANDARD ISO 13408-4:2005(E) ISO 2005 All rights reserved 1 Aseptic processing of health care products Part 4: Clean-in-place technologies 1 Scope This part of ISO 13408 specifies the general requireme
22、nts 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 qualification, validation, operation and control. This part of ISO 13408 is applicable to processes where clean
23、ing 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 where equipment is dismantled and cleaned in a washer. This part of ISO 13408 does not supersede or rep
24、lace national regulatory requirements, such as Good Manufacturing Practices (GMPs) and/or compendial requirements that pertain to particular national or regional jurisdictions. 2 Normative references The following referenced documents are indispensable for the application of this document. For dated
25、 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 products Part 1: General requirements ISO/IEC 90003, Software engineering Guidelines for the applicati
26、on 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 organic or inorganic chemical including water, detergent or mixture thereof, used as an aid in the cleaning p
27、rocess 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 also includes the removal of remaining residual cleaning agent to an acceptable level which is defined b
28、ased on the nature of the product and the process tolerance. ISO 13408-4:2005(E) 2 ISO 2005 All rights reserved 3.3 dead leg location which, by design, does not permit adequate accessibility of the cleaning agent 3.4 design qualification documented verification that the proposed design of the facili
29、ties, 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 environment, and the precautions necessary to handle and dispose of the material safely 3.6 worst-to-clean m
30、ost 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 General 4.1.1 The requirements of ISO 13408-1 shall apply. 4.1.2 Documented procedures for each phase of the d
31、evelopment, 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 designated personnel. 4.1.4 Records of development, validation, routine control and monitoring shall be ma
32、intained 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 procedures described in this part of ISO 13408 shall be specified. 4.2.2 If the requirements of this pa
33、rt 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 of the cleaning agent(s), cleaning method, equipment to deliver CIP and the equipment subject to CIP, sha
34、ll 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 documented system shall be specified for the calibration of all measuring instruments or measuring systems. 4.4
35、.2 The accuracy and tolerance of the measuring instrument shall be justified for the process to be measured. ISO 13408-4:2005(E) ISO 2005 All rights reserved 3 5 Process and equipment characterization 5.1 General concepts 5.1.1 The specification for the CIP process shall include but not be limited t
36、o: 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 mechanism of action of cleaning agent(s); c) compatibility of the equipment with the cleaning agents and proce
37、ssing 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-clea
38、ning drying; j) post-cleaning protection of the cleanliness of the equipment; k) maximum post-cleaning hold period and conditions. 5.1.2 Cleaning agent(s) shall be reproducibly delivered in effective quantities and concentrations to all parts of the system. 5.1.3 In order to ensure effective CIP, al
39、l parameters necessary to control the cleaning conditions shall be established and documented. These conditions shall be maintained and monitored within specified limits. 5.1.4 When a large system is to be subjected to CIP, by dividing it into several segments, the segments should overlap to ensure
40、that all portions of the system are adequately and effectively cleaned. NOTE Although the entire processing system can be cleaned as a single entity in CIP, it can be advantageous to divide the system into several parts in order to simplify the cleaning procedures. 5.1.5 Complex sequences of opening
41、 and shutting of valves in the pipes of a system could be required. Where this is controlled manually, detailed documentation of individual steps shall be established. Where automation is used, electronic automation systems should be carefully designed and validated. 5.2 Effectiveness of CIP 5.2.1 T
42、he necessary level of cleanliness shall be established and documented. Justification of the process parameters and the permitted levels of residual substances shall be included in the documentation. There shall be no residue that poses a significant risk to patient safety. NOTE Residual substances c
43、an include previous product or decomposition products thereof and/or cleaning agents. 5.2.2 Criteria for cleanliness are dependent in part, on the nature of the product that was previously processed in the equipment to be cleaned taking into account potency, toxicity, biocompatibility, carcinogenici
44、ty, mutagenicity, potential for tissue sensitization where equipment is not dedicated, etc. Where removal of product is not possible with sufficient efficacy, it may be necessary to use dedicated equipment. -,-,- ISO 13408-4:2005(E) 4 ISO 2005 All rights reserved 5.3 Equipment 5.3.1 Equipment to be
45、subjected to CIP 5.3.1.1 The equipment shall be designed and manufactured to ensure its cleanability by taking into account ease of cleaning with regard to the characteristics of the products to be processed. Worst-to-clean locations shall be minimized through the use of smooth, impervious, non-groo
46、ved, continuous and polished surfaces. NOTE Dead legs, locations with stagnant liquid in piping, shoulders of tanks, intricate irregular internal surfaces such as gasket interfaces and pump internal parts can usually be regarded as worst-to-clean locations. 5.3.1.2 Design considerations shall includ
47、e but not be limited to: a) smoothness of inner surface of equipment; b) distribution of the cleaning agent(s) to all relevant surfaces (e.g. valves, connections, filter assemblies); c) necessity to use special equipment such as spray devices, their number, location and coverage; d) absence of dead
48、legs in piping systems; e) drainability of the system (e.g. slope of piping to ensure the complete removal of remaining liquid in the system); f) compatibility of materials of construction (e.g. pipes, tanks, valves, nozzles, filters, gaskets, sensors) with the cleaning agent(s) and process conditio
49、ns selected; g) access to allow monitoring of cleaning conditions in appropriate locations; h) protection of the cleaned equipment from re-contamination. 5.3.1.3 Specification of the equipment shall include but not be limited to: a) physical description of the equipment, together with any necessary ancillary item