1、 Reference number ISO/TR 22442-4:2010(E) ISO 2010TECHNICAL REPORT ISO/TR 22442-4 First edition 2010-12-01 Medical devices utilizing animal tissues and their derivatives Part 4: Principles for elimination and/or inactivation of transmissible spongiform encephalopathy (TSE) agents and validation assay
2、s for those processes Dispositifs mdicaux utilisant des tissus animaux et leurs drivs Partie 4: Principes dinactivation et/ou dlimination des agents transmissibles de lencphalopathie spongiforme bovine (ESB) et essais de validation de ces procds ISO/TR 22442-4:2010(E) PDF disclaimer This PDF file ma
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7、ry of 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 2010 All rights reservedISO/TR 22442-4:2010(E) ISO 2010 All rights reserved iiiContents Page Foreword iv In
8、troduction.v 1 Scope1 2 Normative references1 3 Terms and definitions .2 4 Elimination of TSE agents: basic considerations2 4.1 General .2 4.1.1 TSEs of concern 2 4.1.2 Animal tissues of concern2 4.1.3 Tissues infected with TSE agents .2 5 Potential methods to eliminate TSE agents .3 5.1 Methods for
9、 inactivating infectivity.3 5.1.1 General .3 5.1.2 Physical methods for inactivating TSE infectivity.3 5.1.3 Chemical methods for inactivating TSE infectivity4 5.2 Methods for removing TSE infectivity without inactivating infectivity5 6 Experimental validation of methods for eliminating TSE agents f
10、rom medical devices utilizing non-viable animal tissues6 6.1 General .6 6.2 Defining of product families for purposes of designing TSE process validation studies.6 6.3 Selection and testing of product for establishing and verifying the infecting dose of TSE agent .6 6.4 TSE agent spiking materials 6
11、 6.5 Availability of bioassay animals (conventional and transgenic mice, other rodents, farm animals) 7 6.6 Potential development of cell culture assays for infectivity.7 6.7 Correlations between PrP TSEand infectivity assays7 6.8 Reductions in infectivity compared with failure to detect at limits o
12、f detection 8 6.9 Determining numbers of replicate validations needed to support inferences of reduction in infectivity rather than variations in assay performance .8 6.10 Requirements for step-wise reductions in PrP TSE and infectivity verses whole-process validation8 Bibliography9 ISO/TR 22442-4:2
13、010(E) iv ISO 2010 All rights reservedForeword 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. Each member body
14、 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 International Electrotec
15、hnical 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 Standards adopted by
16、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. In exceptional circumstances, when a technical committee has collected data of a different kind from that which is
17、 normally published as an International Standard (“state of the art”, for example), it may decide by a simple majority vote of its participating members to publish a Technical Report. A Technical Report is entirely informative in nature and does not have to be reviewed until the data it provides are
18、 considered to be no longer valid or useful. Attention is drawn to the possibility that some of the elements of this document may be the subject of patent rights. ISO shall not be held responsible for identifying any or all such patent rights. ISO/TR 22442-4 was prepared by Technical Committee ISO/T
19、C 194, Biological evaluation of medical devices, Subcommittee SC 1, Tissue product safety. ISO 22442 consists of the following parts, under the general title Medical devices utilizing animal tissues and their derivatives: Part 1: Application of risk management Part 2: Controls on sourcing, collectio
20、n and handling Part 3: Validation of the elimination and/or inactivation of viruses and transmissible spongiform encephalopathy (TSE) agents Part 4: Principles for elimination and/or inactivation of transmissible spongiform encephalopathy (TSE) agents and validation assays for those processes Techni
21、cal Report ISO/TR 22442-4:2010(E) ISO 2010 All rights reserved vIntroduction Certain medical devices utilize materials of animal origin. Animal tissues and their derivatives are used in the design and manufacture of medical devices to provide performance characteristics that were chosen for advantag
22、es over non-animal based materials. The range and quantities of materials of animal origin in medical devices vary. These materials can comprise a major part of the device (e.g. bovine/porcine heart valves, bone substitutes for use in dental or orthopaedic applications, haemostatic devices), can be
23、a product coating or impregnation (e.g. collagen, gelatine, heparin), or can be used in the device manufacturing process (e.g. tallow derivatives such as oleates and stearates, fetal calf serum, enzymes, culture media). This document is a Technical Report (TR) to offer suggestions for designing and
24、conducting validation assays to help determine if processes used in the manufacture of medical devices derived from non-viable animal tissues might serve to reduce the risk of iatrogenic transmission of transmissible spongiform encephalopathies (TSEs). This document will refer to the infective vecto
25、r as “TSE agent” rather than prion to remain consistent with the other Parts of ISO 22442. Some current information on human tissues and TSEs is also presented which may be applied by analogy to other animal tissues. Iatrogenic transmission of the human TSE Creutzfeldt-Jakob disease (CJD) has been c
26、onvincingly attributed to exposure to the human dura mater allograft (Hannah, E. L., E. D. Belay, et al. 2001) used in surgery as a patching material and to hormones extracted from human pituitary glands (Mills, J. L., L. B. Schonberger, et al. 2004)both non-viable tissues; recently, sub-clinical in
27、fection with the vCJD agent was detected at autopsy in a patient with hemophilia and plausibly attributed to his treatment with processed human plasma- derived coagulation factor (UK Health Protection Agency 2009 at: http:/www.hpa.org.uk/webw/HPAweb Peden, Head et al 2004; Peden, Ritchie and Ironsid
28、e 2005). Exposure to the agent of bovine spongiform encephalopathy (BSE) has been responsible for more than 210 cases of vCJD worldwide, most of them thought to have resulted from dietary exposure to infected beef products. Although, except for the iatrogenic vCJD infections just described, no trans
29、missions of a BSE- derived agent via medical or veterinary products have been recognized, there is no reason to doubt that a medical device contaminated with BSE agent of ruminant origin could transmit infection to a susceptible subject. Indeed, two veterinary vaccines derived from non-viable ovine
30、tissues transmitted the ovine/caprine TSE scrapie to sheep (World Health Organization 2006). Humans are not known to have been infected with the scrapie agent. This Technical Report generally uses terminology suggested by the World Health Organization (WHO Guidelines on Tissue Infectivity Distributi
31、on in Transmissible Spongiform Encephalopathies, 2006 (World Health Organization 2006), while recognizing that there is no international consensus regarding either preferred terminology, the probable molecular nature of the transmissible agents (the all-protein or “prion” theory (Prusiner 1982) curr
32、ently most widely held) or the precise role of various forms of the host-coded prion protein in the replication of the infectious agents or pathogenesis of disease. The sole intent of the TR is to suggest strategies to validate the effectiveness of methods that might reduce the risk of accidentally
33、transmitting TSEs by medical devices prepared using non-viable animal tissues. ISO/TR 22442-4:2010(E) vi ISO 2010 All rights reservedThe following referenced documents are standards helpful for the proper interpretation of this document: ISO 22442-1, Medical devices utilizing animal tissues and thei
34、r derivatives Part 1: Application of risk management ISO 22442-2, Medical devices utilizing animal tissues and their derivatives Part 2: Controls on sourcing, collection and handling ISO 22442-3, Medical devices utilizing animal tissues and their derivatives Part 3: Validation of the elimination and
35、/or inactivation of viruses and transmissible spongiform encephalopathy (TSE) agents ISO 14160, Sterilization of health care products Liquid chemical sterilizing agents for single-use medical devices utilizing animal tissues and their derivatives Requirements for characterization, development, valid
36、ation and routine control of a sterilization process for medical devices These documents include both normative and informative annexes also directly relevant to the topic of this ISO TR. All terms defined in those documents are used verbatim in this report. Due to the lack of consistent process ste
37、ps that can reliably eliminate TSEs, it is important that one must use low-risk source animals and tissues. Although not directly applicable to validating methods purported to reduce the TSE risk from medical devices manufactured from non-viable animal tissues, UK and US competent authorities have s
38、olicited expert advice on desirable features of validation studies for devices intended to remove TSE infectivity from human blood potentially contaminated with TSE agents, and this advice may be helpful in evaluating methods for animal- derived tissues as well. These features included preliminary e
39、valuation using TSE-spiked material with high titers of infectivity, selecting experimental agents relevant to the infection of concern, and accepting studies using assays for PrP TSEas a preliminary screening strategy to dismiss unpromising methods. These methods were required to indicate significa
40、nt reduction in infectivity demonstrated by bioassays in known susceptible experimental animals. To qualify a method as potentially useful, the assay needed to demonstrate similar results for the same candidate method with two TSE agent-bioassay combinations, whenever possible. These criteria should
41、 be met before concluding that the method offers sufficient promise to consider in practice. Demonstration that a method reduces TSE infectivity for tissues endogenously infected, and that the complete manufacturing process eliminates all detectable infectivity, while desirable, are not currently fe
42、asible. Very low titers of infectivity in most tissues outside the nervous system and limited animals known to be susceptible to naturally occurring TSE agents without adaptation to a new species are limiting factors. The lack of standard reference infected materials of known titer and biological pr
43、operties from humans and animals with TSEs is thought to be an additional impediment to developing validation studies (World Health Organization (2006), Annex 2). Considering the extremely limited attempted validation efforts for methods for improving TSE safety of human blood-derived and other huma
44、n tissue-derived medical products products with demonstrated iatrogenic transmissions care must be taken not to discourage new efforts to validate methods that might improve the TSE safety of medical devices derived from animal tissues. It should be noted again that, as summarized above, animal tiss
45、ues have not been directly implicated in causing any iatrogenic TSE infections of humans (Minor, Newham et al. 2004). However, experience with food-borne BSE and field transmissions of scrapie to sheep by ovine tissue-derived veterinary vaccines suggests that the risk of iatrogenic transmissions of
46、TSEs (other than BSE) from animals to humans, while theoretical, remains worthy of continued attention. TECHNICAL REPORT ISO/TR 22442-4:2010(E) ISO 2010 All rights reserved 1Medical devices utilizing animal tissues and their derivatives Part 4: Principles for elimination and/or inactivation of trans
47、missible spongiform encephalopathy (TSE) agents and validation assays for those processes 1 Scope This Technical Report offers suggestions for designing and conducting validation assays to help determine if processes used in the manufacture of medical devices derived from non-viable animal tissues m
48、ight serve to reduce the risk of iatrogenic transmission of transmissible spongiform encephalopathies (TSEs). The TSE-removal methods used to process animal tissues should also reduce the risk of transmitting TSE infections via non-viable tissues of human origin; this Technical Report does not addre
49、ss this issue. Some current information on human tissues and TSEs is presented which may be applied by analogy to other animal tissues. This Technical Report does not intend to imply a need for validation of methods involving specific materials identified as having a “negligible risk” of contamination with TSE agents as listed in Annex C of ISO 22442-1:2007. This Technical Report is intended to clarify final draft international standards included in the ISO 22442 series, as well as in ISO 14160. This Technical R
