YY/T 1512-2017 English PDF (YYT1512-2017)
YY/T 1512-2017 English PDF (YYT1512-2017)
See Chinese contents: YY/T 1512-2017
YY/T 1512-2017: Biological evaluation of medical devices—Guidance on the conduct of biological evaluation within a risk management process
PHARMACEUTICAL INDUSTRY STANDARD
OF THE PEOPLE’S REPUBLIC OF CHINA
Biological Evaluation of Medical Devices -
Guidance on the Conduct of Biological
Evaluation within a Risk Management Process
(ISO/TR 15499.2016, MOD)
ISSUED ON. JULY 17, 2017
IMPLEMENTED ON. JULY 1, 2018
Issued by. China Food and Drug Administration
Table of Contents
Foreword ... 3
Introduction ... 5
1 Scope ... 7
2 Normative References ... 7
3 Terms and Definitions ... 8
4 Biological Evaluation is a Risk Management Activity ... 9
5 Risk Management Guidance ... 13
6 Guidance of Biological Evaluation in Specific Aspects ... 17
References ... 25
This Standard is drafted in accordance with stipulations in GB/T 1.1-2009. This Standard is modified in accordance with the Law of Redrafting on the basis of ISO/TR 15499.2016 Biological Evaluation of Medical Devices - Guidance on the Conduct of Biological Evaluation within a Risk Management Process.
In comparison with ISO/TR 15499.2016, there are several technical differences and causes for these differences as follows.
-- In terms of normative references, there is an adjustment of technical differences in this Standard to comply with national-level technical conditions. The condition of such adjustment is intensively reflected in Chapter 2 “Normative References”. Please see the specific adjustment below.
GB/T 16886.1-2011, which adopts equivalent international standards, is adopted to replace ISO 10993-1.2009;
GB/T 16886.7, which adopts equivalent international standards, is adopted to replace ISO 10993-7;
GB/T 16886.9, which adopts equivalent international standards, is adopted to replace ISO 10993-9;
GB/T 16886.12, which adopts equivalent international standards, is adopted to replace ISO 10993-12;
GB/T 16886.13, which adopts equivalent international standards, is adopted to replace ISO 10993-13;
GB/T 16886.14, which adopts equivalent international standards, is adopted to replace ISO 10993-14;
GB/T 16886.15, which adopts equivalent international standards, is adopted to replace ISO 10993-15;
GB/T 16886.16, which adopts equivalent international standards, is adopted to replace ISO 10993-16;
GB/T 16886.17, which adopts equivalent international standards, is adopted to replace ISO 10993-17;
GB/T 16886.18, which adopts equivalent international standards, is adopted to replace ISO 10993-18;
GB/T 16886.19, which adopts equivalent international standards, is adopted to replace ISO 10993-19;
YY/T 0287-2017, which adopts equivalent international standards, is adopted to replace ISO 13485.2016;
YY/T 0316-2016, which adopts equivalent international standards, is adopted to replace ISO 14971.2007;
CNAS-CL01, which adopts equivalent international standards, is adopted to replace ISO/IEC 17025.
Please be noted that certain content in this Standard might involve patents. The institution that issues this Standard shall not undertake any responsibility of identifying these patents.
This Standard is proposed by State Food and Drug Administration of the People’s Republic of China.
This Standard is summarized by National Technical Committee 248 on Medical Device Biological Evaluation Standardization (SAC/TC 248).
This Standard is drafted by. Shandong Quality Inspection Center for Medical Devices. The main drafters of this Standard include. Liu Chenghu, Houli, Wuping. Introduction
0.1 General Principles
This Standard provides guidance on the conduct of biological evaluation of medical devices in accordance with the requirements in GB/T 16886.1-2011. Although GB/T 16886.1-2011 provides a general framework to the biological evaluation of medical devices, more specific guidance is necessary during the practical application of this Standard. Therefore, this Standard is formulated to provide guidance to users of GB/T 16886.1-2011. This Standard facilitates better understanding of the requirements in GB/T 16886.1-2011 and elaborates various modes and methods that comply with the requirements in GB/T 16886.1-2011.
Biological evaluation is a group of relatively broad design and verification activities within the category of risk management process. Therefore, this Standard includes the guidance of applying GB/T 16886.1-2011 during the risk management process in accordance with the requirements in YY/T 0316-2016. As a part of the general evaluation and development of medical devices, concepts and methods described in this Standard can be taken into consideration during the establishment and maintenance of a risk management process of biological evaluation.
With the scientific development, we have continuously intensified our grasp of the fundamental mechanism of tissue reaction. Biological evaluation can be established on the basis of the review of relevant scientific data, chemical analysis and necessary in-vivo and in-vitro test. GB/T 16886.1-2011 stipulates a framework of planning biological evaluation. Through the preferred adoption of chemical components, and in- vitro models that can obtain equivalent relevant information with in-vivo models, the quantity of experimental animals and the degree of exposure are controlled to the minimum. The selection of an appropriate method for a specific medical device will depend on the characteristics of the device, the availability of of relevant scientific data and risk assessment.
During the assessment of the availability of the guidance in this Standard, the requirements and guidance of applicable laws and regulations shall be taken into consideration.
Organization groups can voluntarily include the whole or any part of the guidance in this Standard in their risk management process.
The guidance included in this Standard can be assessed as background information by assessors in the risk management process in institutions and regulatory authorities. 0.2 The Relations Among other Standards, Guidance Standards and
The relations among GB/T 16886.1-2011, this Standard, and medical device biological Biological Evaluation of Medical Devices -
Guidance on the Conduct of Biological
Evaluation within a Risk Management Process
This Standard is applicable to the biological evaluation of medical devices in accordance with the requirements in GB/T 16886.1-2011. This Standard does not add or modify the requirements in GB/T 16886.1-2011. This Standard does not include requirements of regulatory inspection or certification and assessment activities. This Standard is applicable to all the biological evaluation of various types of medical devices, including active, passive, implantable and non-implantable medical devices. 2 Normative References
The following documents are indispensable to the application of this Standard. In terms of references with a specified date, only versions with a specified date are applicable to this Standard. The latest version (including all the modifications) of references without a specified date is also applicable to this Standard.
GB/T 16886.1-2011 Biological Evaluation of Medical Devices - Part 1. Evaluation and Testing within a Risk Management Process (ISO 10993-1.2009, IDT)
GB/T 16886.7 Biological Evaluation of Medical Devices - Part 7. Ethylene Oxide Sterilization Residuals (GB/T 16886.7-2015, ISO 10993-7.2008, IDT)
GB/T 16886.9 Biological Evaluation of Medical Devices - Part 9. Framework for Identification and Quantification of Potential Degradation Products (GB/T 16886.9- 2001, ISO 10993-9.1999, IDT)
GB/T 16886.12 Biological Evaluation of Medical Devices - Part 12. Sample Preparation and Reference Materials (GB/T 16886.12-2005, ISO 10993-12.2002, IDT)
GB/T 16886.13 Biological Evaluation of Medical Devices - Part 13. Identification and Quantification of Degradation Products from Polymeric Medical Devices (GB/T 16886.13-2001, ISO 10993-13.1998, IDT)
GB/T 16886.14 Biological Evaluation of Medical Devices - Part 14. Identification is a fundamental element of this biological evaluation plan. Patients obtain benefits from the application of medical devices, and meanwhile, they also undertake potential risks. These risks might differ in accordance with the characteristics and expected purposes of specific medical devices. The acceptable level of risks of a specific medical device is determined by the expected earnings of the medical device. The consideration of biological (toxicological) risks of medical devices is merely an aspect of various aspects that need to be taken into consideration during risk assessment. Under some circumstances, the earnings of other characteristics, other than the biological safety of materials, deserve special attention. For instance, the optimal biologically safe material that can be obtained might not manifest acceptable mechanical strength. Under this circumstance, it is necessary to consider materials with a higher strength and acceptable biological safety. The premise of conducting biological evaluation is to recognize that this is merely a part of the whole risk management process that is needed for the design and development of medical devices.
Material selection and risk analysis are organic constituent parts of medical device design. The selection of materials plays a decisive role in biological safety evaluation. Furthermore, relevant data can be collected by starting with a systematic mode. In accordance with YY/T 0287-2017 and Y/T 0316-2016, criteria of acceptable biological (toxicological) risks shall be determined at the beginning of design. Since the variation of primitive materials, ingredients and process might influence the biocompatibility of products, these considerations shall be included in risk assessment. Biological safety evaluation shall be designed and conducted to verify the compliance with specific safety criteria. As a constituent part of risk management plan, this evaluation is centralized in the identification of hazards and the estimation of relevant risks. In thorough risk assessment, toxicological hazards and the degree of exposure shall be characterized.
A main content of hazard identification is material characterization, including. -- Definition and characterization of each variety of material (including appropriate alternative material);
-- Identification of hazards, additives and processing aids in materials; -- Identification of the potential influence of downstream processing process (for example, chemical reaction in material composition or sterilization of ultimate products) on chemicals in the ultimate products;
-- Identification of chemicals that might be released during the usage of products (for example, the intermediate or ultimate degradation product of a certain degradable implant);
-- Estimation of intake (total intake or clinical intake);
of exposure of material composition. In risk analysis, each route of exposure and toxic effect of risk of each variety of material/material composition shall be estimated in a well-organized order.
Therefore, materials and material compositions on medical devices that are directly and indirectly exposed to patients shall be identified and characterized first in risk analysis. In consideration of the existence of any production additives, processing aids or other potential pollutants, for example, disinfectant, risk analysis shall be conducted on the ultimate product under the state of manufacture. Furthermore, the influence of the processing process on material compositions and chemicals shall also be taken into consideration (including the influence on the basal body and the surface). The possibility of generating toxic residues in continuous application of medical devices, or in the production, processing, storage or degradation of medical devices shall be especially considered. In addition, pollutants that are included in the packaging materials and the interaction between the packaging materials and the pollutants shall also be considered.
Since physical and chemical characteristics of materials are related with biological safety, identification is also needed in this stage. This might involve any or several aspects of content as follows.
-- Abrasion, loading and fatigue (especially load-bearing devices, for example, the whole joint prosthesis) and relevant particles and material degradation products; -- Abrasion and relevant stimulation, for example, the application of catheter; -- Interaction (chemical action) among material compositions, such as different flexibility, potential corrosion and abrasion;
-- Heat (for example, material variation caused by thermal degradation or other heat);
-- The manufacturing process, for example, the generated internal stress can stimulate environmental stress cracking (ESC), morphological change or
-- The role of the environment, such as, endoscope (stomach aid), dressing (external environment), ultraviolet light, detergent, and decontamination and sterilization process;
-- Electricity, such as short circuit, degradation, heating and muscle stimulation; -- The potential effect among different components;
-- The role of physical form, for example, particle.
Material information can be obtained through literature review, supplier’s information, speaking, there are no rigorous material requirement in terms of materials indirectly exposed to patients, medical devices that are merely exposed to intact skin, and devices that are not directly exposed to human tissue, infusion, mucous membrane or damaged skin tissue.
5.1.4 Risk evaluation
Risk evaluation is established on the basis of risk analysis. In risk analysis, it is defined that the next step after defining risks is to evaluate the significance of risks and identify relatively severe risks that need to be reduced (risk control). After risk estimation, risks that exceed a certain stipulated level need to be reduced. It shall be recognized that evaluation that includes the evaluation of all the compositions of medical devices can be considered as complete evaluation of the whole medical devices.
In terms of a specific material, biocompatibility can only be verified in a clarified sequence of relevant events. The sequence of events includes purposes of usage and tissues that are exposed to the medical device. For instance, the toxicology of extractable/leachable chemical compounds shall be considered in accordance with the channels and time of exposure, and the actual intake of toxic substances. It shall be considered that it is of great importance to obtain human exposure data through any clinical usage history or relevant similar application. For instance, it is suggested by clinical research that a certain ultimate product is non-irritating and can be adopted for verification without animal stimulation study. However, the clinical research of general implantable materials might not be sufficient for verification of implantation study of a certain ultimate product, because the combination of several materials might lead to certain biological side effect.
It is important that the assessment team conducting the biological evaluation shall be equipped with necessary and appropriate evaluation strategies, and the knowledge and skills to obtain data for rigorous assessment and make reasonable judgments of additional tests of demands. This is of great significance to the completeness of biological risk evaluation (refer to Chapter 7 in GB/T 16886.1-2011).
5.1.5 Risk control
Risk control is a process of identifying and adopting measures to reduce risks. In terms of biological safety, this can include the reduction of unacceptable risks through certain activities, for example, design modification. There are several possible strategies, such as.
-- Modify design, avoid channels of exposure or reduce the time of exposure that might cause severe hazards;
-- Reduce toxicity by modifying ingredients or materials;
-- Modify the production process to decrease or eliminate hazardous residues or process additives.
-- Leachable/analytical chemical research can be easily conducted.
6.1.2 The application of chemical characterization data in biological evaluation Several chapters/stipulations in GB/T 16886.1-2011 request medical device users to conduct chemical characterization during biological evaluation of medical devices. For instance, 4.3 indicates that users shall consider the correlation between expected additives, process pollutants, residuals and leachables, and the overall biological evaluation of medical devices. However, no specific guideline is provided regarding how to consider a certain specific substance during biological evaluation. From the perspective of hazard identification, information of compounds released from medical devices might be conducive to the selection of appropriate tests for biological evaluation. For instance, if it is already known that a certain compound has toxic effect on kidney, this terminal point deserves special attention when acute or sub-chronic toxicity test is conducted in accordance with GB/T 16886.11. This information can motivate biological testing strategies to be centralized in the statement of the most correlated clinical terminal point.
Chemical characterization data might also be conducive to risk characterization. Under simulated environment and conditions of usage, the data of the release rate of compounds from medical devices can be obtained. In addition, if the method stipulated in GB/T 16886.17 is adopted, adequate data of the compounds’ tolerable intake (TI) can be obtained, and the possibility of triggering adverse effect can be assessed by comparing the dose of compounds accepted by patients and TI or “safe” dose. By means of this method, the data of compounds released from medical devices needs to be identified, and more importantly, the data of the compounds’ release rate under relevant clinical conditions is also necessary.
GB/T 16886.9, GB/T 16886. 12, GB/T 16886.13, GB/T 16886. 14, GB/T 16886. 15, GB/T 16886. 18 and GB/T 16886. 19 are related with material characterization. 6.1.3 Patent material formula
When device manufacturers cannot obtain necessary data (for example, complete data of formula) from material suppliers due to the information confidentiality of patents, device manufacturers shall consult material suppliers whether the biological evaluation of relevant recommended application is available. Under certain circumstances, material suppliers can solve the confidentiality management of patent formula through the mode of submitting their respective biological evaluation data to independent assessment institutions or management institutions for the record (also known as “main document” in certain jurisdictions). In accordance with regulatory requirements, device manufacturers only need to submit the filing number of the data, then, compliant assessment institutions or management institutions shall conduct assessment in a confidential mode in accordance with the submitted information of the devices. released from medical devices. In comparison with independent injection of compounds, being simultaneously exposed to multiple compounds might increase or decrease the toxicity of the mixture (if the compound is injected separately). Figure 1 in GB/T 16886.1-2011 requests users to consider whether the toxicity data of a single compound is applicable to the mixture of compounds being exposed to the patients. Since it is quite difficult to obtain the reaction data of certain compounds in the mixture, this requests that a tremendously rigorous stan...