Translated English of Chinese Standard: GB/T16886.1-2011 Translated by: www.chinesestandard.net Wayne Zheng et al. Email: Sales@ChineseStandard.net ICS 11.040.01 C 30 NATIONAL STANDARD OF THE PEOPLE S REPUBLIC OF CHINA GB/T 16886.1-2011 / ISO 10993-1: 2009 Replacing GB/T 16886.1-2001 Biological evaluation of medical devices -- Part 1: Evaluation and testing within a risk management process 医疗器械生物学评价第 1 部分 : 风险管理过程中的评价与试验 (ISO 10993-1: 2009, IDT) Issued on: June 16, 2011 Implemented on: November 01, 2011 Issued by: General Administration of Quality Supervision, Inspection and Quarantine of the People s Republic of China; Standardization Administration of the People s Republic of China www.chinesestandard.net Page 1 of 38
Table of Contents Foreword... 3 Introduction... 7 1 Scope... 9 2 Normative references... 9 3 Terms and definitions... 11 4 General principles applying to biological evaluation of medical devices... 13 5 Classification of medical devices... 16 6 Biological evaluation process... 19 7 Interpretation of biological evaluation data and overall biological safety assessment... 27 Annex A (Informative) Biological evaluation trial... 29 Annex B (Informative) Guidance of risk management process... 30 Annex C (Informative) Suggested procedure for document review... 34 Bibliography... 37 Translation References and Original Chinese Standard... 38 www.chinesestandard.net Page 2 of 38
Foreword GB/T 16886 Biological evaluation of medical devices consists of following parts: Part 1: Evaluation and testing within a risk management process; Part 2: Animal welfare requirements; Part 3: Tests for genotoxicity carcinogenicity and reproductive toxicity; Part 4: Selection of trial for interactions with blood; Part 5: Test for in-vitro cytotoxicity; Part 6: Tests for local effects after implantation; Part 7: Ethylene oxide sterilization residuals; Part 9: Framework for identification and quantification of potential degradation products; Part 10: Tests for irritation and delayed-type hypersensitivity; Part 11: Tests for systemic toxicity; Part 12: Sample preparation and reference materials; Part 13: Identification and quantification of degradation products from polymeric medical devices; Part 14: Identification and quantification of degradation products from ceramics; Part 15: Identification and quantification of degradation products from metals and alloys; Part 16: Toxicokinetic study design for degradation products and leachables; Part 17: Establishment of allowable limits for leachable substances; This Part is Part 1 of GB/T 16886. There are other standards for biological trial in other aspects. This Part is drafted according to the rules specified in GB/T 1.1-2009. This Part replaces GB/T16886.1-2001 Biological Evaluation of Medical Devices -- Part 1: Evaluation and Test. Compared with GB/T 16886.1-2001, the main contents modified are as follows: Modified the name of the Standard; www.chinesestandard.net Page 3 of 38
cytotoxicity (ISO 10993-5: 1999, IDT) GB/T 16886.6-1997 Biological evaluation of medical devices -- Part 6: Tests for local effects after implantation (ISO 10993-6: 1994, IDT) GB/T 16886.7-2001Biological evaluation of medical devices -- Part 7: Ethylene oxide sterilization residuals (ISO 10993-7: 2995, IDT) GB/T 16886.9-2001 Biological evaluation of medical devices -- Part 9: Framework for identification and quantification of potential degradation products (ISO 10993-9: 1999, IDT) GB/T 16886.10-2005 Biological evaluation of medical devices -- Part 10: Tests for irritation and delayed-type hypersensitivity (ISO 10993-10: 2002, IDT) GB/T 16886.11-1997Biological evaluation of medical devices -- Part 11: Tests for systemic toxicity (ISO 10993-11: 1993, IDT) GB/T 16886.12-2005 Biological evaluation of medical devices -- Part 12: Sample preparation and reference materials (ISO 10993-12: 2002, IDT) GB/T 16886.13-2001Biogical evaluation of medical devices -- Part 13: Identification and quantification of degradation products from polymeric medical devices (ISO 10993-12: 1998, IDT) GB/T 16886.14-2003Biological evaluation of medical devices -- Part 14: Identification and quantification of degradation products from ceramics (ISO 10993-14: 2001, IDT) GB/T 16886.15-2003 Biological evaluation of medical devices -- Part 15: Identification and quantification of degradation products from metals and alloys (ISO 10993-15: 2000, IDT) GB/T 16886.16-2003Biological evaluation of medical devices -- Part 16: Toxicokinetic study design for degradation products and leachables (ISO 10993-15: 2000, IDT) GB/T 16886.17-2005Biological evaluation of medical devices -- Part 17: Establishment of allowable limits for leachable substances (ISO 10993-17: 2002, IDT) YY/T 0316-2008 Medical devices -- Application of risk management to medical devices (ISO 14971: 2007, IDT) This Part is proposed by SFDA (State Food and Drug Administration) This Part is under the jurisdiction of National Technical Committee (SAC/TC 248) on www.chinesestandard.net Page 5 of 38
Biological Evaluation on Medical Device of Standardization Administration of China. The responsible drafting organization is Jinan Medical Device Quality Supervision Inspection Centre of SFDA. The chief drafting staffs of this Part include Wu Ping, You Shaohua and Liu Chenghu. This Part replaces the following historical editions: GB/T 16886.1-2001; GB/T 16886.1-1997. www.chinesestandard.net Page 6 of 38
Introduction The primary aim of this Part of GB/T 16886 / ISO 10993 is to protect humans from potential biological risks arising from the use of medical devices. This Part is compiled from numerous International and National Standards and Guidelines concerning the biological evaluation of medical devices. It is intended to be a guiding document for the biological evaluation of medical devices for risk management process (as part of overall evaluation and development process for various medical devices). This approach combines the review and evaluation of existing data from all sources with, where necessary, the selection and application of additional trial, so that to perform holistic biological evaluation to the usage safety of various medical devices. It must be appreciated that the term medical device has wide-ranging meaning, it may be consisted of a single material which may be existed in more than one physical form, it may also be consisted of complex instruments which are consisted of multiple components or apparatus components made of multiple materials. GB/T 16886 / ISO 10993 addresses the determination of the effects of medical devices on tissues, under general condition, it does not involve device of special application. Thus, for a complete biological safety evaluation, it classifies medical devices according to the nature and duration of their anticipated contact with human tissues when in use. It indicates, in matrices, the biological data sets that need to be considered by various medical devices. The range of biological hazards is wide and complex. When considering the mutual interaction between tissue and composing material, it cannot be isolated from the overall device design. Thus, in designing a device, choosing the best material with respect to its tissue interaction may not necessarily result good performance of device, the interaction between tissue and material is only one of the characteristics to be considered in making that choice. When implementing device s function, biological evaluation must involve the mutual interaction between the material prediction and tissue. Tissue interactions refer to the adverse reaction caused by a material under the specific application, it might not occur un other applications. Biological trial is usually based upon www.chinesestandard.net Page 7 of 38
in-vitro and semi-vivo trial methods and animal models, it cannot unequivocally conclude that the same reaction will also occur in human body. Therefore, it can only be shown in the form of caution to judge the predicted effect when the device is used in human body. In addition, different individuals may respond differently to the same material, it indicates that some patients can have adverse reactions even to well-established materials. The role of this Part is to provide framework for planning biological evaluation of medical device. Along with the scientific knowledge advancement and understanding of the basic mechanisms of tissue responses, under the conditions that it is possible to obtain the same relevant information as in-vivo model, it shall preferably adopt chemical analysis trial and in-vitro model, so as the quantity of tested animals is minimized. GB/T 16886 / ISO 10993 do not intent to rigidly specify a set of test methods, including pass/fail criteria. As this might result in 2 possibilities. One of the possibilities is that development and application of new medical device may be unnecessarily restrained, another possibility is that a false sense of security may be generated by using the medical device. Under the condition that some special applications have been proved, experts from manufacturing area or usage area may establish special trials and indicators in specific product standard. This Part is intended for use by professionals who have been trained and with practical experience. Under the circumstance that considering device s all relevant factors, specific application, scientific document evaluation and up-to-date knowledge of medical device provided by historical clinical experience, they are able to interpret the standard s requirements and conduct the judgment to evaluation result of device. Annex A contains an informative table, it is generally used to identify biological data sets recommended in the evaluation of medical devices, according to the contact class and clinical contact duration of human body and medical device. Annex B contains application guidance of medical device s risk management process related to biological evaluation. www.chinesestandard.net Page 8 of 38
Biological evaluation of medical devices -- Part 1: Evaluation and testing within a risk management process 1 Scope This Part of GB/T 16886 describes: -- The general principles governing the biological evaluation of medical devices within a risk management process; -- The general classification of devices based on the nature and duration of their contact with the body; -- The evaluation of existing relevant data from all sources; -- The identification of gaps in the available data set on the basis of a risk analysis; -- The identification of additional data sets necessary to analyze the biological safety of the medical device; -- The assessment of the biological safety of the medical device. This Part does not cover trial of materials and devices that do not come into direct or indirect contact with the patient's body, nor does it cover biological hazards arising from any mechanical failure. Other parts of GB/T 16886 cover specific trial, as indicated in the Foreword. 2 Normative references The articles contained in the following documents have become part of this Part when they are quoted herein. For the dated documents so quoted, all the modifications (Including all corrections) or revisions made thereafter shall be applicable to this Part. ISO 10993-2 Biological evaluation of medical devices -- Part 2: Animal welfare requirements ISO 10993-3 Biological evaluation of medical devices -- Part 3: Tests for genotoxicity, www.chinesestandard.net Page 9 of 38
carcinogenicity and reproductive toxicity ISO 10993-4 Biological evaluation of medical devices -- Part 4: Selection of trial for interaction with blood ISO 10993-5 Biological evaluation of medical devices -- Part 5: Tests for in-vitro cytotoxicity ISO 10993-6 Biological evaluation of medical devices -- Part 6: Tests for local effects after implantation ISO 10993-7 Biological evaluation of medical devices -- Part 7: Ethylene oxide sterilization residuals ISO 10993-9 Biological evaluation of medical devices -- Part 9: Framework for identification and quantification of potential degradation products ISO 10993-10 Biological evaluation of medical devices -- Part 10: Tests for irritation and skin sensitization ISO 10993-11 Biological evaluation of medical devices -- Part 11: Tests for systemic toxicity ISO 10993-12 Biological evaluation of medical devices -- Part 12: Sample preparation and reference materials ISO 10993-13 Biological evaluation of medical devices -- Part 13: Identification and quantification of degradation products from polymeric medical devices ISO 10993-14 Biological evaluation of medical devices -- Part 14: Identification and quantification of degradation products from ceramics ISO 10993-15 Biological evaluation of medical devices -- Part 15: Identification and quantification of degradation products from metals and alloys ISO 10993-16 Biological evaluation of medical devices -- Part 16: Toxicokinetic study design for degradation products and leachables ISO 10993-17 Biological evaluation of medical devices -- Part 17: Establishment of allowable limits for leachable substances ISO 10993-18: 2005 Biological evaluation of medical devices -- Part 18: Chemical characterization of materials www.chinesestandard.net Page 10 of 38
ISO/TS 10993-19 Biological evaluation of medical devices -- Part 19: Physico-chemical, morphological and topographical characterization of materials ISO/TS 10993-20 Biological evaluation of medical devices -- Part 20: Principles and methods for immunotoxicology testing of medical devices ISO 14971 Medical Devices -- Application of risk management to medical devices 3 Terms and definitions For the purpose of this Part, the following terms and definitions shall apply. 3.1 medical device Any instrument, apparatus, implement, machine, appliance, implant, in-vitro reagent or calibrator, software, material, or other similar or related article, intended by the manufacturer to be used, alone or in combination, for human beings for one or more of the specific purpose(s) of: -- Diagnosis, prevention, monitoring, treatment or alleviation of disease, -- Diagnosis, monitoring, treatment, alleviation of or compensation for an injury, -- Investigation, replacement, modification, or support of the anatomy or of a physiological process, -- Supporting or sustaining life, -- Control of conception, -- Disinfection of medical devices, -- Providing information for medical purposes by means of in-vitro examination of specimens derived from the human body. It does not achieve its primary design effect in or on the human body by pharmacological, immunological or metabolic means, but which may be assisted in its function by such means. NOTE 1: This definition has been developed by the Global Harmonization Task Force (GHTF). [YY/T 0287-2003, definition 3.7] NOTE 2: Products which might be considered to be medical devices in some jurisdictions but for which there is not yet a harmonized approach, are: www.chinesestandard.net Page 11 of 38
(see ISO 10993-11). Such trials, including pyrogenicity trial, are used to detect material-property pyrogenic reactions of extracts of medical devices or materials. Single test can not differentiate if pyrogenic reaction is caused by material-property or by endotoxin contamination. If feasible, acute systemic toxicity trial may be combined with sub-acute and sub-chronic toxicity and implanted into trial program. 6.2.2.6 Sub-acute and sub-chronic toxicity It shall adopt sub-acute and sub-chronic toxicity trials to determine the effects of medical device with single or multiple effects or contact, materials and (or) their extracts, within a period greater than 24 h to a period not greater than 10 % of the total life-span of the tested animal (e.g. up to 13 weeks for rats). If available chronic toxicity data of the relevant materials are sufficient to evaluate the sub-acute and sub-chronic toxicity, it shall avoid to conduct such trial. The reason for waiving of the trial shall be included in the overall biological evaluation report. These trials shall adapt to the contact route and contact duration of device or material. Sub-acute trial and sub-chronic toxicity trial are given in ISO 10993-11. If feasible, sub-acute and sub-chronic systemic toxicity trial program may be extended to include implantation trial program, so as to evaluate sub-acute, sub-chronic systemic and local effects. 6.2.2.7 Genotoxicity It shall utilize a group of in-vitro genotoxicity trial, and use mammalian or non-mammalian cell culture or other techniques to determine gene mutations, changes of chromosome structure and quantity, and other DNA or gene toxicities caused by medical devices, materials and (or) their extracts. If in-vitro trial shows positive, it shall perform in-vivo mutagenicity trial, otherwise it shall infer that the material is mutagenic (see ISO 10993-3). 6.2.2.8 Implantation It shall utilize implantation trial, under eye s inspection and microscopic inspection, to evaluate the local pathological effects of living tissue. It shall apply surgical method to www.chinesestandard.net Page 23 of 38
The document review shall state the sources of document and data, searching range of database or other information compilation. C.2.4 Assessment of document Document review shall clearly assess the quality of the document, it shall consider the intended usage of the device to evaluate the relation degree between the document AND feature and characterization of the considered material and device. The following factors shall be considered: a) Similarity between the device in the selected documents AND the device under consideration - based on process, critical performance, design and principles of operation, so as to evaluate document applicability; b) Relevance between particular experimental animals used in the selected studies AND biological evaluation of the device under consideration; c) Usage condition of the material or device in the selected documents and the intended use of the device under consideration. C.2.5 Evaluation of importance of document Document review shall evaluate the significance and weightage to studies of different designs AND published and unpublished data. If unpublished data is included in the assessment, the document review shall identify the significance and attach the data. Evaluation factors of importance shall include: -- Whether the author's conclusions can be confirmed by available data; -- Whether the document reflects the current medical practice and technical level; -- Whether references are taken from recognized scientific publications and whether they have been reported by peer reviewed journals; -- The extent to which the published document is derived from research result which complies with one or more scientific principles. The document review shall include evaluation of importance of document. After documents are obtained and assessed, the applicable selection criteria and the exclusion of any document from the importance evaluation shall be demonstrated. Before completing the document evaluation of considered device and its intended usage, it shall www.chinesestandard.net Page 35 of 38
Bibliography [1] ISO 7405, Dentistry -- Evaluation of biocompatibility of medical devices used in dentistry [2] GB/T 19000-2000, Quality management systems -- Fundamentals and vocabulary (GB/T 19000-2000, ISO 9000: 2000, IDT) [3] GB/T 19001-2000, Quality management systems -- Requirements (GB/T 19001-2000, ISO 9001: 2000, IDT) [4] GB/T 19004-2000, Managing for the sustained success of an organization -- A quality management approach (GB/T 19004-2000, ISO 9004-2000, IDT) [5] YY/T 0287-2003, Medical devices -- Quality management systems -- Requirements for regulatory purposes (YY/T 0287-2003, ISO 13485: 2003, IDT) [6] ISO/IEC 17025, General requirements for the competence of testing and calibration laboratories [7] Chemical Testing: OECD Guidelines for the Testing of Chemicals -- Section 4: Health Effects [8] Japan, Good Laboratory Practice for Preclinical Biological Tests of Medical devices; Ordinance of MHLW (03-23-2005) [9] USA, GLP reference in the Federal Register www.chinesestandard.net Page 37 of 38
Translation Reference and Original Chinese Standard [1] GB/T 16886.1-2011 Biological evaluation of medical devices - Part 1: Evaluation and testing of the risk management process. http://www.chinesestandard.net/default.aspx?pdf-english-id=gb/t%2016886.1-2011 www.chinesestandard.net Page 38 of 38