GB/T 16886.17-2005 Biological evaluation of medical devices — Part 17: Establishment of allowable limits for leachable substances
1 Scope
This part of GB/T 16886 specifies a method for the determination of allowable limits for substances leachable from medical devices. It is intended for use in deriving standards and estimating appropriate limits where standards do not exist.It describes a systematic process through which identified risks arising from toxicologically hazardous substances present in medical devices can be quantified.
This part is not applicable to devices that have no patient contact (e.g. in vitro diagnostic devices).
Exposure to a particular chemical substance may arise from sources other than the device, such as food, water or air.This part does not address the potential for exposure from such sources.
2 Normative references
The following normative documents contain provisions which, through reference in this part of GB/T 16886, constitute provisions of this part. For dated references, subsequent amendments to (excluding correction to), or revisions of, any of these publications do not apply. However, parties to agreements based on this part are encouraged to investigate the possibility of applying the most recent editions of the normative documents indicated below. For undated references, the latest editions of the normative document referred to applies.
GB/T 16886.1 Biological evaluation of medical devices - Part 1: Evaluation and testing (GB/T 16886.1-2001, idt ISO 10993-7: 1997)
3 Terms and definitions
For the purposes of this part of GB/T 16886, the terms and definitions given in GB/T 16886.1 and the following apply.
3.1
allowable limit (AL)
largest amount of a leachable substance that is deemed acceptable on a daily basis, when taken into the body through exposure to a medical device
Note: Allowable limits are expressed in dose to the patient for each applicable exposure period. The units used are mass per unit time, e.g. milligrams per day. These doses represent tolerable risks for medical devices under the circumstances of intended use.
3.2
benefit factor (BF)
numerical factor that takes into account the health benefit from use of the medical device(s) containing the leachable substance in question
3.3
concomitant exposure factor (CEF)
numerical factor that accounts for patient exposure to many medical devices containing the same leachable substance
Note: This factor is used to adjust the product of TI and body mass downward.
3.4
default
value to be used, in the absence of data, for an uncertainty or other factor used in the calculation of the allowable limit
3.5
harm to health
physical injury and/or damage to health
3.6
health benefit
likelihood of maintaining or improving health
3.7
health hazard
potential source of harm to health
3.8
health risk
combination of the likelihood of occurrence of harm to health and the severity of that harm
3.9
health risk analysis
use of available information to identify health hazards and to estimate health risk
3.10
leachable substance
chemical removed from a medical device by the action of water or other liquids related to the use of the device
Example: Additives, sterilant residues, process residues, degradation products, solvents, plasticizers, lubricants, catalysts, stabilizers, anti-oxidants, colouring agents, fillers and monomers, among others.
3.11
lowest observed adverse effect level (LOAEL)
lowest concentration or amount of a substance found by experiment or observation which causes detectable adverse alteration of morphology, functional capacity, growth, development or life span of the target organism under defined conditions of exposure
Note: Alterations in morphology, functional capacity, growth, development or life span of the target organism may be detected which are judged not to be adverse.
3.12
minimally irritating level (MIL)
amount of a leachable substance that is minimally irritating to the patient
Note: It is normally expressed in milligrams, although sometimes as milligrams per millilitre, in which case the value must be multiplied by the volume (millilitres) used to get the mass (milligrams).
3.13
modifying factor (MF)
mathematical product of uncertainty factors UF1, UF2 and UF3
3.14
multiple exposure
more than one exposure of the same patient to devices containing the same leachable substance, simultaneously or at different times
3.15
non-irritating level (NIL)
largest amount of a leachable substance that is not irritating to the patient
Note: It is normally expressed in milligrams, although sometimes as milligrams per millilitre, in which case the value must be multiplied by the volume (millilitres) used to get the mass (milligrams).
3.16
no observed adverse effect level (NOAEL)
lowest concentration or amount of a substance found by experiment or observation which causes detectable adverse alteration of morphology, functional capacity, growth, development or life span of the target organism under defined conditions of exposure
Note: Alterations in morphology, functional capacity, growth, development or life span of the target organism may be detected which are judged not to be adverse.
3.17
physiologically based pharmacokinetic modeling (PBPK modeling)
system of modelling biological effects taking into account metabolic and pharmacokinetic differences among species of animal
Note: Such data should be utilized whenever they are available.
3.18
proportional exposure factor (PEF)
numerical factor for patient exposure to a leachable substance that accounts for the fact that a medical device is not typically utilized every day during the entire exposure category of interest
Note: This factor is used to adjust the product of TI and body mass upwards.
3.19
repeated use
use of the same device by the same patient more than once without reprocessing
3.20
safety
freedom from unacceptable health risk
3.21
simultaneous use
use of more than one device by the same patient at the same time
3.22
tolerable contact level (TCL)
tolerable contact exposure to a leachable substance resulting from contact with a medical device
Note: It is normally expressed in milligrams per square centimetre of body surface.
3.23
TCL modifying factor (MFTCL)
mathematical product of uncertainty factors UF4, UF5 and UF6
3.24
tolerable exposure (TE)
product of the tolerable intake, the body mass and the utilization factor
Note: It is normally expressed in milligrams per day to the patient.
3.25
tolerable intake (TI)
estimate of the average daily intake of a substance over a specified time period, on the basis of body mass, that is considered to be without appreciable harm to health
Note: It is normally expressed in milligrams per kilogram of body mass per day. It is derived as a part of the overall establishment of allowable limits for a leachable substance in a medical device.
3.26
tolerable risk
risk which is accepted in a given context based upon the current values of society
3.27
uncertainty factor (UF)
factor intended to account for the uncertainties inherent in estimating potential effects of a chemical on humans from results obtained in human populations or surrogate species
3.28
utilization factor (UTF)
Foreword II
Introduction III
1 Scope
2 Normative references
3 Terms and definitions
4 General principles for establishing allowable limits
5 Establishment of tolerable intake (TI) for specific leachable substances
6 Calculation of tolerable exposure (TE)
7 Feasibility evaluation
8 Benefit evaluation
9 Allowable limits
10 Reporting requirements
Annex A (Informative) Some typical assumptions for biological parameters
Annex B (Informative) Risk assessment for mixtures of leachable substances
Annex C (Informative) Conversion of allowable limits for systemic exposure and for body surface contact to maximum dose to patient from a medical device
Annex D (Informative) Risk analysis report
Bibliography
GB/T 16886.17-2005 Biological evaluation of medical devices — Part 17: Establishment of allowable limits for leachable substances
1 Scope
This part of GB/T 16886 specifies a method for the determination of allowable limits for substances leachable from medical devices. It is intended for use in deriving standards and estimating appropriate limits where standards do not exist.It describes a systematic process through which identified risks arising from toxicologically hazardous substances present in medical devices can be quantified.
This part is not applicable to devices that have no patient contact (e.g. in vitro diagnostic devices).
Exposure to a particular chemical substance may arise from sources other than the device, such as food, water or air.This part does not address the potential for exposure from such sources.
2 Normative references
The following normative documents contain provisions which, through reference in this part of GB/T 16886, constitute provisions of this part. For dated references, subsequent amendments to (excluding correction to), or revisions of, any of these publications do not apply. However, parties to agreements based on this part are encouraged to investigate the possibility of applying the most recent editions of the normative documents indicated below. For undated references, the latest editions of the normative document referred to applies.
GB/T 16886.1 Biological evaluation of medical devices - Part 1: Evaluation and testing (GB/T 16886.1-2001, idt ISO 10993-7: 1997)
3 Terms and definitions
For the purposes of this part of GB/T 16886, the terms and definitions given in GB/T 16886.1 and the following apply.
3.1
allowable limit (AL)
largest amount of a leachable substance that is deemed acceptable on a daily basis, when taken into the body through exposure to a medical device
Note: Allowable limits are expressed in dose to the patient for each applicable exposure period. The units used are mass per unit time, e.g. milligrams per day. These doses represent tolerable risks for medical devices under the circumstances of intended use.
3.2
benefit factor (BF)
numerical factor that takes into account the health benefit from use of the medical device(s) containing the leachable substance in question
3.3
concomitant exposure factor (CEF)
numerical factor that accounts for patient exposure to many medical devices containing the same leachable substance
Note: This factor is used to adjust the product of TI and body mass downward.
3.4
default
value to be used, in the absence of data, for an uncertainty or other factor used in the calculation of the allowable limit
3.5
harm to health
physical injury and/or damage to health
3.6
health benefit
likelihood of maintaining or improving health
3.7
health hazard
potential source of harm to health
3.8
health risk
combination of the likelihood of occurrence of harm to health and the severity of that harm
3.9
health risk analysis
use of available information to identify health hazards and to estimate health risk
3.10
leachable substance
chemical removed from a medical device by the action of water or other liquids related to the use of the device
Example: Additives, sterilant residues, process residues, degradation products, solvents, plasticizers, lubricants, catalysts, stabilizers, anti-oxidants, colouring agents, fillers and monomers, among others.
3.11
lowest observed adverse effect level (LOAEL)
lowest concentration or amount of a substance found by experiment or observation which causes detectable adverse alteration of morphology, functional capacity, growth, development or life span of the target organism under defined conditions of exposure
Note: Alterations in morphology, functional capacity, growth, development or life span of the target organism may be detected which are judged not to be adverse.
3.12
minimally irritating level (MIL)
amount of a leachable substance that is minimally irritating to the patient
Note: It is normally expressed in milligrams, although sometimes as milligrams per millilitre, in which case the value must be multiplied by the volume (millilitres) used to get the mass (milligrams).
3.13
modifying factor (MF)
mathematical product of uncertainty factors UF1, UF2 and UF3
3.14
multiple exposure
more than one exposure of the same patient to devices containing the same leachable substance, simultaneously or at different times
3.15
non-irritating level (NIL)
largest amount of a leachable substance that is not irritating to the patient
Note: It is normally expressed in milligrams, although sometimes as milligrams per millilitre, in which case the value must be multiplied by the volume (millilitres) used to get the mass (milligrams).
3.16
no observed adverse effect level (NOAEL)
lowest concentration or amount of a substance found by experiment or observation which causes detectable adverse alteration of morphology, functional capacity, growth, development or life span of the target organism under defined conditions of exposure
Note: Alterations in morphology, functional capacity, growth, development or life span of the target organism may be detected which are judged not to be adverse.
3.17
physiologically based pharmacokinetic modeling (PBPK modeling)
system of modelling biological effects taking into account metabolic and pharmacokinetic differences among species of animal
Note: Such data should be utilized whenever they are available.
3.18
proportional exposure factor (PEF)
numerical factor for patient exposure to a leachable substance that accounts for the fact that a medical device is not typically utilized every day during the entire exposure category of interest
Note: This factor is used to adjust the product of TI and body mass upwards.
3.19
repeated use
use of the same device by the same patient more than once without reprocessing
3.20
safety
freedom from unacceptable health risk
3.21
simultaneous use
use of more than one device by the same patient at the same time
3.22
tolerable contact level (TCL)
tolerable contact exposure to a leachable substance resulting from contact with a medical device
Note: It is normally expressed in milligrams per square centimetre of body surface.
3.23
TCL modifying factor (MFTCL)
mathematical product of uncertainty factors UF4, UF5 and UF6
3.24
tolerable exposure (TE)
product of the tolerable intake, the body mass and the utilization factor
Note: It is normally expressed in milligrams per day to the patient.
3.25
tolerable intake (TI)
estimate of the average daily intake of a substance over a specified time period, on the basis of body mass, that is considered to be without appreciable harm to health
Note: It is normally expressed in milligrams per kilogram of body mass per day. It is derived as a part of the overall establishment of allowable limits for a leachable substance in a medical device.
3.26
tolerable risk
risk which is accepted in a given context based upon the current values of society
3.27
uncertainty factor (UF)
factor intended to account for the uncertainties inherent in estimating potential effects of a chemical on humans from results obtained in human populations or surrogate species
3.28
utilization factor (UTF)
Contents of GB/T 16886.17-2005
Foreword II
Introduction III
1 Scope
2 Normative references
3 Terms and definitions
4 General principles for establishing allowable limits
5 Establishment of tolerable intake (TI) for specific leachable substances
6 Calculation of tolerable exposure (TE)
7 Feasibility evaluation
8 Benefit evaluation
9 Allowable limits
10 Reporting requirements
Annex A (Informative) Some typical assumptions for biological parameters
Annex B (Informative) Risk assessment for mixtures of leachable substances
Annex C (Informative) Conversion of allowable limits for systemic exposure and for body surface contact to maximum dose to patient from a medical device
Annex D (Informative) Risk analysis report
Bibliography
