1、March 2008DEUTSCHE NORM English price group 14No part of this standard 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).ICS 11.100.99!$M b) providin
2、g valid scientific evidence to demonstrate the ability of the production processes to eliminate or inactivate viruses and/or TSE agents (this part of ISO 22442). Requirements for a quality system for medical devices for regulatory use are specified in ISO 13485. The standards for quality management
3、systems recognize that, for certain processes used in manufacturing, the effectiveness of that process cannot be fully verified by subsequent inspection and testing of the product. The elimination and/or inactivation of viruses and TSE agents is an example of a special process because process effica
4、cy cannot be verified by inspection and testing of the product. For this reason, the following need to be considered in particular: definition of the process(es) and materials to be used; adequate inactivation validation before routine use; performance monitoring of the process during manufacture; a
5、ppropriate equipment maintenance; staff training, etc. Historically there have been many instances of unknown or unsuspected viral contamination during manufacture. For this reason, evaluation of the manufacturing process can provide a measure of confidence that a wide number of viruses, including u
6、nknown pathogenic viruses are eliminated. Similar principles may apply to TSE agents. NOTE To show compliance with this part of ISO 22442, its specified requirements should be fulfilled. The guidance given in the Notes and informative annexes is not normative and is not provided as a checklist for a
7、uditors. 4 DIN EN ISO 22442-3:2008-03 EN ISO 22442-3:2007 (E) 1 Scope This part of ISO 22442 specifies requirements for the validation of the elimination and/or inactivation of viruses and TSE agents during the manufacture of medical devices (excluding in vitro diagnostic medical devices) utilizing
8、animal tissue or products derived from animal tissue, which are non-viable or have been rendered non-viable. It applies where required by the risk management process as described in ISO 22442-1. It does not cover other transmissible and non-transmissible agents. NOTE 1 Analysis and management of ris
9、k is described in ISO 22442-1. Conventional processes used for sterilization, when used for the treatment of animal tissues for medical devices, have not been shown to be completely effective in inactivating the causative agents of transmissible spongiform encephalopathy. Selective sourcing is extre
10、mely important (see ISO 22442-1 and ISO 22442-2). NOTE 2 ISO 11135, ISO 11137, ISO 11737-1, ISO 13408, ISO 14160, ISO 14937 and ISO 17665 may be relevant for bacteria, moulds and yeast (see Bibliography). This part of ISO 22442 does not cover the utilization of human tissues in medical devices. This
11、 part of ISO 22442 does not specify a quality management system for the control of all stages of production of medical devices. NOTE 3 It is not a requirement of this part of ISO 22442 to have a full quality management system during manufacture, but it does specify requirements for some of the eleme
12、nts of a quality management system. Attention is drawn to the standards for quality management systems (see ISO 13485) that control all stages of production or reprocessing of medical devices. The quality management system elements that are required by this part of ISO 22442 can form part of a quali
13、ty management system conforming to ISO 13485. This part of ISO 22442 does not consider the effect of any method of elimination and/or inactivation on the suitability of the medical device for its intended use. 2 Normative references The following referenced documents are indispensable for the applic
14、ation 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 22442-1:2007, Medical devices utilizing animal tissues and their derivatives Part 1: Application of risk managem
15、ent ISO 22442-2, Medical devices utilizing animal tissues and their derivatives Part 2: Controls on sourcing, collection and handling 5 EN ISO 22442-3:2007 (E) DIN EN ISO 22442-3:2008-03 3 Terms and definitions For the purposes of this document, the terms and definitions given in ISO 22442-1 and the
16、 following apply. 3.1 model TSE agent TSE agent that displays a known resistance to physical and/or chemical processing used as reference by analogy for the inactivation of relevant TSE agents, and thereby demonstrating the effectiveness of the process used for inactivation 3.2 model virus virus tha
17、t displays a known resistance to physical and/or chemical processing used as reference by analogy for the inactivation of relevant viruses, and thereby demonstrating the effectiveness of the process used for inactivation NOTE This includes viral models (RNA, DNA, enveloped, non-enveloped) and bacter
18、iophage models. 3.3 overall reduction factor sum of the reduction factors of the individual process steps 3.4 permissive cell cell that can become infected with the virus under study and in which that virus replicates 3.5 reduction factor ratio of the virus or TSE agent load in the relevant material
19、 used or the device prior to the inactivation or elimination step and the virus or TSE agent load after the inactivation or elimination step when it is ready for the next step in the manufacturing process, expressed as the number of ten fold reduction (log10) 3.6 relevant TSE agent TSE agent known t
20、o, or likely to, contaminate the source material or other materials used in the manufacturing process 3.7 relevant virus virus known to, or likely to, contaminate the source material or other materials used in the manufacturing process 3.8 revalidation set of documented procedures to confirm an esta
21、blished validation 3.9 scaled down process scaling down process at a specified reduced scale which simulates the performance parameters as used in the full scale production process 3.10 sterilization validated process used to render a product free of all forms of viable microorganisms 6 DIN EN ISO 2
22、2442-3:2008-03 EN ISO 22442-3:2007 (E) 3.11 validation documented procedure for obtaining, recording and interpreting the results required to establish that a process will consistently yield product complying with predetermined specifications ISO/TS 11139:2006, definition 2.55 4 General requirements
23、 4.1 Risk management Analysis and management of risk shall be carried out in accordance with ISO 22442-1. Due account shall be taken of manufacturing processes that are considered to be effective for certain animal materials as discussed in Annex C of ISO 22442-1:2007. 4.2 Sourcing and manufacturing
24、 process A documented system shall be established and maintained to control the source of raw materials of animal origin. ISO 22442-2 shall be used to meet this requirement as far as applicable. The manufacturing process shall be established to minimize the load of viruses and TSE agents in starting
25、 materials, intermediate products and finished products. Appropriate documented protocols and procedures shall be established to ensure that the validated processing parameters will be applied during the routine manufacturing processes. NOTE Employing a quality management system complying with ISO 1
26、3485 could be used to meet the requirements of this subclause. 4.3 General requirements related to validation 4.3.1 Documented procedures The documented procedures and requirements of this part of ISO 22442 shall be implemented. Documentation and records shall be reviewed and approved by designated
27、personnel (see 4.3.2). Procedures for any literature review and/or any inactivation study shall be documented and records shall be retained for a period defined by the manufacturer. 4.3.2 Personnel Responsibility for the implementation of this part of ISO 22442 shall be assigned to qualified personn
28、el. The requirements for the qualification, training or experience of personnel shall be documented and appropriate to the individuals work, responsibility and authority. NOTE The level of qualification, training and experience required by personnel at various levels depends upon the activities bein
29、g performed. 4.3.3 Calibration An effective system shall be established, documented and maintained for the calibration of all controlling, indicating and recording instruments used for validation. 7 EN ISO 22442-3:2007 (E) DIN EN ISO 22442-3:2008-03 4.3.4 Equipment Appropriate equipment as specified
30、 in a protocol shall be used. All equipment requiring planned maintenance shall be maintained in accordance with documented procedures. Records of maintenance shall be retained. In particular, any equipment shall be capable of delivering its intended process within defined limits. In addition, if th
31、e equipment used during validation is not identical to that used in normal production cycles, adequate documentation shall be available to demonstrate that the performance parameters are equivalent to those used in the production cycle. 4.3.5 Experimental systems Additional parts of the experimental
32、 systems used for validation studies such as chemicals, cell systems and laboratory animals shall be adequately identified, justified, controlled and documented. 5 Literature review 5.1 Conduct of the literature review A literature review shall be performed as specified in Annex A, in order to ident
33、ify and analyse data on the elimination and/or inactivation of viruses and TSE agents. 5.2 Application of literature review output Technical information from the literature review shall be used in optimizing the design of an inactivation and/or elimination study. Any extrapolation based on the inact
34、ivation of viruses and TSE agents shall be justified and documented. Intrinsic variability of materials of animal origin utilized in medical devices and of manufacturing processes can lead to misinterpretation of the validity of published data and shall be taken into account. 5.3 Viruses The manufac
35、turer shall demonstrate whether the literature review provides an indication of which inactivation and/or elimination steps are likely to be effective. A literature review is a prerequisite to performing a viral inactivation study. In exceptional cases, if a manufacturer chooses not to perform a stu
36、dy, this shall be justified and documented. If the available information does not support the elimination and/or inactivation of viruses, then an alternative risk management strategy shall be implemented (see ISO 22442-1). 5.4 TSE agents The literature review shall consider which of the published me
37、thods for elimination and/or inactivation of TSE agents are likely to be suitable for the medical device under consideration. In particular, the materials of animal origin and manufacturing processes referred to in the literature shall be comparable to those used for the medical device under conside
38、ration (see Annex A). A validated inactivation study shall be performed when the comparability of materials and processes cannot be demonstrated or specific claims are made for inactivation of TSE agents by the manufacturer (see Clause 6). If the available information does not support the eliminatio
39、n and/or inactivation of TSE agents, then an alternative risk management strategy shall be implemented (see ISO 22442-1). Special considerations for the manufacture of some animal materials are provided in ISO 22442-1:2007, Annex C. 8 DIN EN ISO 22442-3:2008-03 EN ISO 22442-3:2007 (E) 6 Elimination
40、and/or inactivation study of viruses and TSE agents 6.1 General If the need for an elimination and/or inactivation study is identified (see 5.3 and 5.4) this shall be performed so that it substantiates the effectiveness for the selected steps of manufacture against selected agents (see Annexes B and
41、 C). If the manufacturer uses sterilization processes that have been validated for bacteria, moulds and yeast, these processes shall also be supported by relevant validation data for the elimination and/or inactivation of viruses and TSE agents. 6.2 Protocol The protocol for a study to demonstrate t
42、he elimination and/or inactivation of viruses and TSE agents during manufacture shall detail the following including, if applicable, values and acceptability criteria: a) the identified risks associated with the tissue concerned (see ISO 22442-1); b) identification of the relevant agent(s); c) the r
43、ationale for the choice of the particular combinations of model agents: the models for an elimination and/or inactivation study shall be chosen by the manufacturer; the justification for the choice of model(s) shall be documented; NOTE 1 Such models include viral models (RNA, DNA, enveloped, non-env
44、eloped, see also Table B.1), and TSE agent models. NOTE 2 As part of the studies, it is possible to use bioassay of TSE agents (mouse or hamster models) for the validation of the inactivation of agents by the manufacturing process(es) of the medical device or components. Such studies have been consi
45、dered to be predictive of inactivation efficacy for TSE agents which may cause disease, e.g. bovine spongiform encephalopathy, scrapie and Creutzfeldt-Jacob disease. d) identification and definition of the manufacturing stage(s) chosen to eliminate and/or inactivate the relevant viruses and TSE agen
46、ts; e) documentation of any scaling down, including demonstration of the validity of the scaled down version of the manufacturing process; NOTE 3 Guidance on scaling down is given in Annex D. NOTE 4 Consideration should be given to the potential for one processing stage to have an adverse effect on
47、the inactivation/elimination efficacy of subsequent processing stages. Reliance on literature information on individual processing stage efficacy might be inappropriate if the available information does not relate to the same sequence of processes intended for use by the manufacturer. NOTE 5 The ove
48、rall reduction factor is unlikely to equal the sum of the reduction factors from individual processing stages which use similar physical, chemical, enzymatic or thermal mechanisms or reagents to reduce the viral or TSE agent load. There may be a loss of efficacy in subsequent application of the same
49、 processing stage. f) the methods of calculation for the reduction factors; g) the method of the estimation of reduction kinetics, if applicable (see Annexes E and F). NOTE 6 Careful consideration should be given to the statistical and physical limitations in sampling, and limits of sensitivity of detection methods (see also B.3.5 and Annexes C, E and F). 9 EN ISO 22442-3:2007 (E) DIN EN ISO 22442-3:2008-03 6.3 Conduct of the study The study shall be conducted in accordance with the protocol. 6.4 Interpretation of data The reduction factor shall be determined (see B.3.5 and
