YY/T 1512-2017 (YY/T1512-2017, YYT 1512-2017, YYT1512-2017)
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Biological evaluation of medical devices—Guidance on the conduct of biological evaluation within a risk management process
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YY/T 1512-2017
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| Standard ID | YY/T 1512-2017 (YY/T1512-2017) | | Description (Translated English) | Biological evaluation of medical devices--Guidance on the conduct of biological evaluation within a risk management process | | Sector / Industry | Medical Device & Pharmaceutical Industry Standard (Recommended) | | Classification of Chinese Standard | C30 | | Classification of International Standard | 11.040.01 | | Word Count Estimation | 14,135 | | Date of Issue | 2017-07-17 | | Date of Implementation | 2018-07-01 | | Drafting Organization | Shandong Province Medical Device Product Quality Inspection Center | | Administrative Organization | National Medical Device Biology Evaluation Standardization Technical Committee (SAC/TC 248) | | Proposing organization | China Food and Drug Administration | | Issuing agency(ies) | State Food and Drug Administration | YY/T 1512-2017
YY
PHARMACEUTICAL INDUSTRY STANDARD
OF THE PEOPLE’S REPUBLIC OF CHINA
ICS 11.040.01
C 30
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
Foreword
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
Regulatory Requirements
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
1 Scope
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
degradation;
-- 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 standard shall be established
when the toxicity data of separate compounds is to be adopted for the biological
evaluation of medical device. However, when the release rate of several compounds
in a medical device is apparently lower than their respective TI value, and the structure
of the compounds is not similar, the possibility of interaction among the compounds in
the mixture will be extremely small. Furthermore, chemical reaction might be triggered
among the compounds, which will further general a new chemical substance. This
might trigger similar or new toxicology risks. Appendix B in GB/T 16886.17 provides
the method of mixture risk assessment.
6.4.4 What is the content of dose and channel correlation that constitute
“adequate toxicology data”?
Although it is possible to determine the mass of various compounds released from
medical devices, it is impossible to obtain the toxicology data of clinically related
channels of exposure of certain compounds.
Although there are methods of estimating the dose from one channel to the other
channel, including PBPK model described in 6.2.2.14 in GB/T 16886.1-2011, these
methods shall be adopted with discretion, and the “entrance” effect shall also be taken
into consideration.
When the dose adopted in tests is much higher than the actual dose being clinically
exposed to the patients, the observed effect in the tests shall be explained with
discretion. Similarly, the concentration of samples in the in-vitro test system might need
to be adjusted to guarantee that the test system represents physiological conditions,
especially during the evaluation of absorbable materials (refer to 6.2.2 for pH and
osmotic pressure compensation of absorbable materials).
GB/T 16886.17 discusses different factors that shall be considered in the introduction
of animal test data to clinical application conditions.
6.4.5 What is the content of biological safety assessment report?
Biological safety assessment report shall include the following content, as long as it is
feasible and necessary.
-- General description or illustration of medical devices;
-- Quantitative information of all the material compositions and/or formulas being
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