ISO/TC 194/WG 11 N59 MARCH 1997 INTERNATIONAL ORGANIZATION FOR STANDARDIZATION ISO/TC 194/WG 11, Ethylene oxide and other sterilization process residues [Joint TC 194-TC 198 WG] Secretariat of ISO/TC 194/WG 11: Association for the Advancement of Medical Instrumentation 3330 Washington Blvd., Suite 400 Arlington, VA 22201-4598 USA Telephone: +703-525-4890 Fax: +703-276-0793 ISO/CD 14538, Method for the establishment of allowable limits for residues and medical devices using the health based risk assessment Secretariat Note: This draft incorporates the changes agreed to in Arlington (October 1996) and reviewed by those present. This draft will serve as the starting point for the group's discussion in April at the York meeting. ------------------------------------------------------------ ISO CD5A: Corrections added for decisions made in Arlington October 1996 and Verified by Participants in late 1996 or early 1997. Committee Draft for discussion in York in April 1997. ISO CD 14538 Method for the Establishment of Allowable Limits For Residues in Medical Devices Using Health Based Risk Assessment 12 March 1997 Draft ------------------------------------------------------------ Introduction The determination of the suitability of a medical device for a particular use involves balancing any identified risks with the clinical benefit to the patient associated with its use. Among the risks to be considered are those arising from exposure to residues of hazardous chemicals present in the device. Risks associated with exposure to hazardous residues are managed by identifying the residues, quantifying the associated risks and limiting exposure within tolerable levels. This standard provides a method by which maximum tolerable levels can be calculated from available data on health risks. The limits derived can be used by manufacturers and processors to optimize processes and aid the choice of materials in order to protect patient health. Where risks associated with exposure to particular residues are unacceptable, this standard can be used to qualify alternative materials or processes. The requirements in this standard are in addition to the biological testing requirements set out in ISO 10993-1. Results of the biological assessment of the device may dictate more stringent limits than those derived by this method which are designed to protect against systemic health effects. For example, irritation effects shall be considered for all devices, particularly small devices. This standard may not take account of the possibility of acute localized effects, for which insufficient data are available. Particularly for small devices, attention should be paid to the potential for such effects. 1 Scope This International Standard specifies the methods to be used to determine allowablelimits for sterilization and process residues in medical devices and 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. Devices that have no patient contact (e.g., in vitro diagnostic devices) are not covered by this International Standard. This method may be used by ISO, other standard setting bodies, government agencies, manufacturers, reprocessors, users, or anyone else seeking to establish allowable limits for residuals in medical devices. 2 Normative reference The following standard contains provisions that, through reference in this text, constitute provisions of this International Standard. At the time of publication the editions indicated were valid. All standards are subject to revision, and parties to agreements based on this International Standard are encouraged to investigate the possibility of applying the most recent edition of the standard indicated below. Members of IEC and ISO maintain registers of currently valid International Standards. ISO 10993-1:1997, Biological evaluation of medical devices -- Part 1: Evaluation and Testing. 3 Definitions For purposes of this International Standard, the definitions given in ISO 10993-1 and the following definitions apply. 3.1 acceptable daily intake (ADI): The largest amount of a chemical, i.e., a sterilization or process residue, that can be taken into the body for a specific route of exposure and/or a specific period without causing appreciable adverse health effects. ADI is expressed in milligrams per day. It is derived as a part of the overall establishment of allowable limits for a chemical residual in a medical device. 3.2 allowable limit: The largest amount of a chemical, i.e., a sterilization or process residue, that is deemed acceptable on a daily basis, when taken into the body through exposure to a medical device. Allowable residue limits are expressed in dose to the patient for each applicable exposure period. The units used are mass per unit time, e.g., milligrams/day. These doses represent acceptable risks for medical devices under the circumstances of intended use. 3.3 benefit factor: A numerical factor that takes into account the health benefit of the medical device(s) with the residue in question. 3.4 default: The 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 device utilization: How the medical device is used in terms of route of entry and frequency and duration of exposure to the residue in question. 3.6 harm to health: Physical injury and/or damage to health. 3.7 health benefit: The probability of maintaining health or the probability and magnitude of improvement to human health. 3.8 health hazard: A potential source of harm to health. 3.9 health risk: The probable rate of occurrence of a health hazard causing harm to health and the degree and severity of the harm to health. 3.10 health risk analysis: The investigation of available information to identify health hazards and to estimate health risks. 3.11 lowest-observed-adverse-effect level (LOAEL): The lowest dosage of a chemical in a study or group of studies that produces statistically or biologically significant increases in frequency or severity of adverse effects between the exposed population and its appropriate control. 3.12 lowest-observed-effect-level (LOEL): The lowest dosage of a chemical in a study or group of studies that produces statistically or biologically significant increases in frequency or severity of effects between the exposed population and its appropriate control. Effects at this dose may not be considered adverse. 3.13 lowest toxic concentration (TCLo): The lowest concentration of a chemical introduced in air that has been reported to cause toxicity in humans or animals. 3.14 lowest toxic dosage (TDLo): The lowest dosage of a chemical introduced by a route other than inhalation that is expected to have caused toxicity in humans or animals. 3.15 median lethal concentration (LC50): A calculated concentration of a chemical in air to which exposure for a specific length of time is expected to cause death in 50% of a defined experimental animal population. This is a standard way of expressing acute toxicity by inhalation. 3.16 median lethal dosage (LD50): The dosage of a chemical that has been calculated to cause death in 50% of a defined population. This is a standard way of expressing acute toxicity by routes of entry other than inhalation. 3.17 modifying factor (MF): A judgment factor in addition to the uncertainty factor used to reflect confidence in the database, including factors relating to the quality and design of the studies. 3.18 multiple exposure: More than one exposure to devices containing the same residue, simultaneously or at different times. 3.19 no-observed-adverse-effect-level (NOAEL): That dosage of a chemical at which there are no statistically or biologically significant increases in frequency or severity of adverse effects seen in the exposed population relative to appropriate control. Effects may be produced at this dosage, but they are not considered to be adverse. 3.20 no-observed-effect-level (NOEL): That dosage of a chemical at which there are no statistically or biologically significant increases in frequency or severity of effects seen in the exposed population relative to appropriate control. 3.21 repeated use: Use of the same device more than once without reprocessing. 3.22 safety: Freedom from unacceptable risk of harm. 3.23 safety margin (SM): The mathematical product of the uncertainty factor multiplied by the modifying factor. 3.24 simultaneous use: The use of more than one device at the same time. 3.25 tolerable intake (TI): An estimate of the average daily intake of a substance over a specified time period, expressed on a body weight basis, that is considered to be without appreciable adverse health effects. Normally expressed in mg/kg/d. It is derived as a part of the overall establishment of allowable limits for a chemical residual in a medical device. 3.26 uncertainty factor (UF) (same as safety factor (SF)): A 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. 3.27 utilization factor (UTF): Numerical factor used to take into account the utilization of the device in terms of frequency of use and utilization in conjunction with other medical devices that can be reasonably anticipated to have the same residue. This factor is the product of the URF and UEF. 3.28 utilization reduction factor (URF): Numerical factor that accounts for patient exposure to many medical devices containing the same residue. This factor is used to adjust the ADI downward. 3.29 utilization enhancement factor (UEF): Numerical factor for patient exposure to a residue that accounts for the fact that a medical device is not typically utilized every day during the entire exposure category of interest. This factor is used to adjust the ADI upwards. 4 Requirements 4.1 General principles The process of establishing allowable limits (see figure 1) for an identified residue on medical devices consists of: (a) collecting data and defining critical end points, (b) determining tolerable intakes (TIs) that are route of entry and duration of exposure specific, (c) determining appropriate patient body weight, (d) modifying the product of these based upon a device utilization evaluation, and (e) further modifying these, as appropriate, based upon benefit and feasibility evaluations. The safety of medical devices requires an absence of unacceptable risk of harm. An analysis of the health risks posed by specific chemicals allows exposure limits to be established that permit an appropriate degree of protection from harm to health in the event that the hazardous chemical would be released into the body during the clinical use of the device. The degree of protection deemed appropriate in any situation is dependent upon a number of factors, such as the nature of the hazard identified, the practicality of risk reduction and the magnitude of the benefit derived from the use of the medical device. Assessment of the acceptability of a health risk thus requires several complex factors to be investigated and balanced. Confidence in the risk assessment is a function of the quality and quantity of data evaluated. The requirements of this standard shall be implemented through the application of professional judgment by knowledgeable and experienced individuals, capable of making informed decisions based on the scientific data available. This requires experience in the interpretation of toxicological data and toxicological risk assessment of medical devices together with a knowledge of the use and benefit of medical devices and the feasibility of achieving allowable limits selected. In the broadest sense, residues from medical devices can be introduced into the body by differing routes ranging from skin absorption, to ingestion, to inhalation, to direct systemic application. In addition devices can be placed into three usage categories according to their durations of use. In turn, each usage category may have multiple limits based upon multiple routes of exposure, as specified in ISO 10993-1. Thus, the overall allowable limit for a particular chemical can have up to three components, a short term limit, a prolonged limit, and a lifetime limit. In turn, each of these limits may need to be protective from multiple routes of exposure. To achieve this, tolerable intake values (TIs) are calculated individually for each route of exposure within each applicable use category. That is, there may be multiple TIs, each route specific, for a given usage category. In many cases the toxicological data may have sufficient consistencies to permit the use of the lowest TI value for either a usage category or a route of entry to best represent the toxicological effects of the chemical residue. The first stage in the establishment of an allowable limit is the identification of a substance that may pose a health hazard. Standards such as ISO 14971 or other hazard identification schemes may be employed to identify potentially hazardous residues. Once a hazard is selected, the process of establishing an allowable limit begins with the establishment of tolerable intakes. 5 Establishment of tolerable intakes (TIs) A review of toxicological data provides the information necessary to establish a no effect level (NOEL or NOAEL). A safety margin approach is then applied to the data so that an appropriate tolerable intake value can be developed. The safety margin takes into account the type, amount and quality of data evaluated, the severity of the hazard identified, the uncertainty inherent in the risk assessment, and the level of safety assurance deemed appropriate, among other considerations. The nature of the hazard identified shall be characterized by evaluating the toxicity of the substance in terms of the type of toxic effects seen and the dosages at which the toxic effects occur via various routes of exposure. 5.1 Exposure considerations for TI calculation Gather exposure data. The following data will be used both as a part of the TI calculation in Section 5 and later as a part of determining the appropriate body weights and utilization factors for the calculation of allowable limits. a) duration of patient exposure to a device, (see 5. 1. 1), b) normal route(s) of exposure to the patient, (see 5.1.3), and c) populations exposed to the device, (see 6.2) For a given population, TIs may be calculated for each exposure category (permanent contact, prolonged exposure, and limited exposure). Within each category TIs may also be calculated for each possible route of exposure (e.g., parenteral, skin, oral, and inhalation). 5.1.1 Categorization of devices by duration of exposure Using the provisions of ISO 10993-1 clause 4, device duration of exposure categories are: a) limited exposure: devices which single or multiple use or contact is likely to be up to 24 hours; b) prolonged exposure: devices whose single, multiple or long term use or contact is likely to exceed 24 hours but not 30 days; c) permanent contact: devices whose single, multiple or long term use or contact exceeds 30 days. The device or device class shall be placed in the category most appropriate to its intended use. If a device can be placed in more than one category, the more rigorous allowable limits are required. With multiple exposures, the decision into which category a device is placed should take into account the potential cumulative effects, bearing in mind the period of time over which these exposures occur. Therefore, TIs need to be calculated for the more rigorous category. These TIs and those from the shorter durations of exposure shall form the basis of the allowable limits for the residue on the device. If TIs had only been calculated for permanent exposure and a device is presented that has only limited or prolonged exposure, TIs for the exposure categories specific to that device shall be calculated and used as the basis for the allowable limits for that device. If a device is in the prolonged category, TIs shall also be determined for the limited category and used as a separate binding constraint. 5.1.2 Exposure duration considerations When TIs are established for residues with no specific device in mind or to cover all devices, permanent contact TIs are calculated with excursions as binding constraints for prolonged and limited exposure as needed based upon the biology of the residue. For sterilant residues covered by ISO 10993, TIs for permanent contact, prolonged exposure, and limited exposure are necessary, e.g., ethylene oxide sterilization residues. When TIs are established for residues for a specific device or class of devices, the category of the device is determined and the TIs are established for that category with binding shorter term excursions, as necessary based upon the biology of the residue. When no data are available to establish TIs for a specific category, for example, when no chronic data are available to establish permanent contact TIs, data from shorter term studies are to be used with a larger safety margin. 5.1.3 Categorization of devices by route of exposure When TIs are established for residues with no specific route in mind, or to cover multiple routes, TIs are calculated for each route of potential exposure within a given exposure category to the extent possible according to ISO 10993-1. If the TIs within a given exposure category are within a factor of 1 0, the lowest TI may be used as the TI for that entire exposure category. However, if the TIs vary by more than 1 0 fold, it may be necessary to have more than one TI for the exposure category. When TIs are established for residues for a specific device or class of devices, TIs are calculated only for the intended route of usage of the device for each applicable exposure category. When no data are available for a specific route, TIs from other routes with data may be used for the route with no data. 5.2 Collection and evaluation of data Once a residue has been selected for evaluation, relevant available data shall be collected. These data may include: a) chemical and physical properties, b) occurrence and use, c) pharmacology, d) biodisposition (absorption, distribution, metabolism, and elimination), e) toxicology, and effects in humans. Data used to set limits should be of high quality and pertinent. The basic approach is based on the premise that acute data should be used to set limited exposure or short-term limits, subchronic effects data should be the basis for prolonged exposure limits and chronic or lifetime data is preferred over subchronic, or short-term data for setting lifetime exposure limits. Human data are preferred over animal data. Although emphasis may be placed upon data corresponding to the specific limit itself, all available data should be considered in the context of understanding the overall toxicity profile of the substance. The data shall be evaluated to identify critical adverse effects and to establish no adverse effect levels for these effects. If the data are inadequate to allow a no adverse effect level to be determined, a low effect level or other value can be used in subsequent calculations, providing appropriate adjustment is made for the additional uncertainty introduced. Where possible, the dose-response relationship should be investigated to assist in determining a no adverse effect level, so that the magnitude of exposure can be related to the probability of toxic effects occurring in the experimental model. Data from multiple routes of exposure, e.g., oral, dermal or tissue contact, parenteral, and inhalation, shall be evaluated. In the case of potential exposure from only a single route of entry, data relevant to that route is the most relevant, although data from other routes should also be considered. Taking into account the intended route of human exposure, the adverse effects that are deemed to be most relevant as a basis for limit setting shall be identified as well as the dosages required to produce these adverse effects. The most relevant no adverse effect level or, exceptionally, a low adverse effect level or other value shall be selected for use in the calculation of a health based allowable limit. This selection shall reflect an evaluation of all adverse effects, based upon professional judgment. It should be made on the basis of the highest no adverse effect level or the lowest effect level for any toxic effect seen, taking into account the applicability and criticality of the toxic effects, the route of experimental exposure, known inter-species differences in susceptibility, confidence in the experimental data, the expected route and duration of human exposure and any other factors considered relevant. The rationale for the choice of dose level shall be documented. 5.3 Set TI for noncancer endpoints For each relevant anticipated route and duration of exposure, a TI shall be calculated from the no effect level or other value determined. Each TI calculation shall take into account the degree of severity of the hazard identified and the uncertainty inherent in the risk analysis. A safety margin approach shall be used whenever possible to calculate TIs. This approach combines the use of uncertainty factors and modifying factors that are determined on the basis of professional judgment, to provide an acceptable safety margin against the adverse effects of most concern. The formula for calculating TI values using the safety margin approach is NOEL, NOAEL, LOEL, etc. (mg/kg/day) TI (mg/kg/day) = ------------------------------------- safety margin where, safety margin = uncertainty factor X modifying factor Limits should be established based upon use by the broadest segment of the anticipated user population. For example, if users are predominately healthy adult males, estimates should be based upon exposure to adult males; if a device is intended for a specific population, such as pregnant women or neonates, estimates should be based upon that population. Typical assumptions for respiration rates, body weights etc., that should be used in this calculation are shown in Annex A (informative). 5.3.1 Determination of uncertainty factor The choice of uncertainty factor encompasses many different considerations as listed above. None of these considerations is easy to quantify in risk analysis. The uncertainty factor for use with human data is smaller than that for use with animal data. The uncertainty factor is smaller when using chronic data to determine permanent TIs than when subchronic data are used. It is also smaller when using NOELs or NOAELs than when using LOELs or LOAELs. Most frequently, the overall uncertainty factor will vary between 1 0 and 1 00 but may be less than 1 0 with good human data or exceed 100 when LOELs are used. The value or degree of influence assigned to each uncertainty factor shall be documented, with justification for its selection. Some considerations in the selection of the appropriate uncertainty factors include variation among humans, species extrapolations, and other uncertainties as described below. lnterindividual variation among humans should be taken into account when deriving a TI value. If variation among humans is judged to be minimal, an allowance at or approaching 1 should be selected. If variation among humans is judged to be significant an allowance approaching or at 1 0 should be selected. If human variation is judged to be intermediate, an intermediate allowance should be taken. In the absence of experimental data to characterize individual variability in human response to a toxic agent, a default uncertainty factor of 1 0 should be used. Idiosyncratic hypersusceptibility shall not normally serve as the basis for a TI value. As a result, the uncertainty factor for interindividual human variability will not necessarily account for exceptionally sensitive subpopulations. The extrapolation from data derived in a species other than man to man should take into account the inherent differences between the other species and man. If the toxicity and toxicokinetics of the substance are well known and similar in man and the experimental model, a smaller allowance for this difference should be made. Similarly, if differences are judged to be of toxicological significance, larger allowances should be made. In the absence of detailed knowledge of inter-species differences in toxicity, a 10-fold safety factor may be appropriate. The uncertainty relating to the appropriateness of the experimental model shall also be taken into consideration. Here allowance shall be made for uncertainties such as, but not limited to, the following situations: a) short term studies being used for extrapolation to longer term exposures or effects, b) having only LOAEL data instead of NOAEL data, c) the absence of supporting studies, d) the use of inappropriate animal models for the end point being assessed, and e) the use of in vitro data as a surrogate for in vivo data. The degree of safety assurance deemed appropriate in view of the severity of the health hazard shall also be considered when establishing TIs. If the health hazard is such that death, very serious harm or an irreversible target organ effect is an expected outcome or used as an end point, an added allowance should be considered. Similarly, if the end point is of limited toxicological significance, a reduced allowance should be considered. The manner in which the material is handled in the body should also be considered in establishing the relevance and magnitude of any uncertainty factor. 5.3.2 Determination of the modifying factor A modifying factor, between 1 and 10, shall be selected to reflect confidence in the database. It shall be based upon professional judgment that takes into account the quality of the data and the design of the studies. If conclusions are drawn based upon studies judged to be poorly designed or executed, or if the amount of relevant data available is limited, a modifying factor approaching or equal to 10 should be selected. If studies that serve as the basis for the TI are judged to be well designed for their intended purposes and executed properly, a modifying factor approaching or equal to 1 should be selected. Intermediate situations would indicate that intermediate modifying factors should be selected. The upper range of the modifying factor may be extended if acute animal data are the only basis for calculation of TI values for permanent exposure. 5.3.3 Determination of the safety margin The safety margin shall then be calculated as the product of the overall uncertainty factor and the modifying factor. This safety margin shall serve as the basis for the determination of the TI and, in turn, the allowable residue limit for each usage category. In most cases an overall safety margin between 10 and 1000 should be sufficiently protective. In a few cases, particularly where only poor or inappropriate data are available, and significant hazards are identified, safety margins as high as 10,000 may be necessary. In some cases, there may be sufficient human data or sufficiently trivial end points to justify safety margins less than 10. 5.4 Set TI for cancer endpoints In line with guidance given in WHO Environmental Health Criteria 170, Clause 3.1.1, there is no clear consensus on appropriate methodology for the risk assessment of chemicals for which the critical effect may not have a threshold, such as genotoxic carcinogens and germ cell mutagens. A number of approaches based largely on characterization of dose - response have been adopted for assessment of such risks. However, these approaches have been based largely on science policy considerations. In such circumstances, the relevant available data for such effects shall be evaluated and the dose: response relationship characterized to the extent possible, based on one or more methods as considered appropriate. These approaches have included'. a) a safety margin approach employing uncertainty factors b) quantitative extrapolation by mathematical modeling of the dose: response curve to estimate the risk at likely human exposures c) relative ranking of potencies in the experimental range. 6 Device utilization evaluation for selection of body weight and UTF determination Once the TIs have been developed for a given chemical residue, a device utilization evaluation shall take place. This evaluation is to be used to determine the appropriate body weight and utilization factor (UTF) for use in the determination of allowable residue limits. It encompasses added modification due to: a) duration of patient exposure to a device, (see 5.1.1 and 5.1.2) b) normal route(s) of exposure to the patient, (see 5.1.3) c) populations exposed to the device, d) predominant body weight of exposed population e) intended usage pattern of the device, and potential for multiple exposures of a patient to the same residue from different devices or other sources This evaluation will be used for the calculation of allowable limits. It already played a role in the selection of device usage categories-in terms of duration of exposure and route of exposure (see 5. 1.1 and 5.1.3) for TI calculations already performed. 6.1 Route of exposure Utilization factors shall reflect the normal routes of residue exposure to the patient from the device or device class. If a single TI had been chosen to represent all TIs for an exposure category, some latitude should be allowed in the calculation of utilization factors for route specific devices. If one TI had been used for all routes of entry in a given duration category, a separate TI may be calculated for a device specific route of entry and used as the basis for the utilization factor for that device or device category. 6.2 Exposure population 6.2.1 Body weight The bulk of medical devices are used in adults. Thus 70 kg shall be used to calculate allowable limits unless the device is intended for use in another population. In that case, the allowable limit shall be based on the body weight derived from the dominant use pattern with special consideration given to devices specifically intended for use with uniquely sensitive groups, such as neonates. See Appendix A for a variety of body weights that may be used. 6.2.2 Idiosyncratic populations Idiosyncratic hypersuseptibility shall not normally be the basis for the allowable limit. 6.2.3 Devices specifically intended for use in neonates and children Data derived from studies in which neonates are exposed to the hazardous material are preferable when calculating TIs for medical devices intended for use by neonates. When such data are not available for calculating TIs, the TIs calculated from adult data can be used to calculate an allowable limit. Allowable limit calculations should be performed using body weights of 3.5 kg for neonates and 1 0 kg for children as the human body weight for that device. Note 1 Permanent device use limits for neonates are generally the same as for adults. However, limits for limited and prolonged usage may be developed specifically for neonates. 6.3 Calculation of utilization factor from intended usage pattern Exposure to a particular residue may arise from several devices. In determining allowable limits for a specific device, account needs to be taken of the possibilities of exposure to the residue from other devices and of the particular pattern of use of the device under consideration. The product of the TI and body weight, i.e., the ADI, is thus adjusted by a multiplication with a utilization factor (UTF). The normal usage pattern of a medical device, including its use as a part of a therapy system shall be determined for the population of interest. Derivation of utilization factors shall, where possible, take account of the anticipated use pattern of medical devices. This will entail the calculation of a utilization reduction factor (URF) and a utilization enhancement factor (UEF). These factors are multiplied together to obtain the utilization factor (UTF) to be multiplied by ADI, i.e., the product of TI and body weight. This UTF shall not exceed 1. See equation (1) below. (1) UTF = URF x UEF =<1 6.3.1 Utilization reduction factor (URF) The extent of usage of devices that can release a specific residue in use shall be assessed. If the residue can be released from only a few devices then the URF is 1. If the residue is likely to arise from exposure to many devices, (see note below), a utilization reduction factor (URF) less than 1 shall be determined, taking into account the pattern of exposure. A default factor shall be used if there is insufficient information to calculate a URF. Note: 'Many medical devices' means at least 5 percent of the devices sold in a calendar year or of more than 5 devices containing the residue the residue are likely to be used in single medical procedure. 'A few medical devices' is less than many medical devices as defined here. The following procedure shall be used for calculating a URF. 1. Determine whether many medical devices that can release the residue are used. If not, use URF default of 1. Note: A URF less than 1 should be used if medical devices containing the same residue represent more than 5% of all medical devices sold in a calendar year, or if more than 5 medical devices containing that same residue are likely to be used in a procedure. 2. If many devices contain the residue, determine whether utilization pattern is known. If the utilization pattern is known, calculate the URF either as: a. The ADI divided by the total amount of residue expected to be released by medical devices during a procedure (equation (2)), or b. The ADI divided by the anticipated mean daily exposure of an average person to the residue from all devices over a lifetime (equation (3)). c. If the utilization pattern is unknown, use URF default of 0.2. (2) URF = ADI (mg/d) / Residue released in procedure (mg/d) or (3) URF = ADI (mg/d) / Summation{all product residue released over lifetime in mg / 25,000 days} 6.3.2 Utilization enhancement factor (UEF) A utilization factor (UTF) can be adjusted upwards to account for a situation where a device is not used for the entire duration of an exposure category. To facilitate this, a utilization enhancement factor (UEF), shall be calculated as the proportion of the exposure category during which actual exposure from the device is anticipated to occur. Thus, as shown in equation (4), the UEF equals the number of days in the exposure category divided by the number of days a device is used before it is discarded. (4) UEF = number of days in exposure category / number of days the specific device is used If the number of days a device is used varies, a reasonable worst case should be used. If a reasonable worst case can not be determined, use a UEF default of 1. As shown in equation (1), under no circumstances can the UTF be greater than 1. 6.3.3 Other reduction considerations Other means should be considered to reduce the residue exposure so that significant reductions in the ADI due to utilization are not needed. For example, a concentration constraint may be employed to reduce the total amount that could reasonably be anticipated to be released during a procedure or over a patient lifetime. Similarly it may be useful to reduce exposure to a single device to avoid significant utilization adjustments. 6.4 Tolerable exposure (5) TE = TI x BW x UTF 7 Feasibility evaluation Cost implications shall be considered in the selection of tolerable exposure to the extent that these impact upon the preservation, promotion or improvement of human health. Feasibility refers to the ability of a manufacturer or reprocessor to achieve tolerable exposure Feasibility has two components: a) technical feasibility; and b) economic feasibility. Technical feasibility refers to the ability of anyone to achieve the allowable limits for a device or device class regardless of cost. Economic feasibility refers to one's ability to meet the limit without putting the operation in an unsound business position. If it is either technically or economically infeasible to meet tolerable exposure benefit evaluation shall be performed. If feasible, benefit evaluation need not be performed. 8 Benefit evaluation The degree of safety assurance deemed appropriate for medical devices can be adjusted on the grounds that the use of all medical devices carries a health benefit. The greater the health benefit anticipated, the greater the health risk that can be accepted. A factor taking account of health benefit may be introduced to modify the tolerable exposure (TE) when toxicity arising from residues present in the device is deemed to be tolerable when balanced against the particular health benefit anticipated from the therapy and that residues have been reduced to the greatest extent possible consistent with the preservation, promotion or improvement of human health in general. In applying a risk assessment to a medical device, allowance can be made for the expectation that no medical procedure is without health risk and that risks associated with the use of medical devices are balanced against the health benefits arising from their use. This may include both the general benefit to be derived from medical devices and benefit from individual medical devices. In cases where significant health benefit arises from the use of a medical device and the use of materials or processes giving rise to residues of toxic compounds cannot readily be avoided by the use of alternative materials or processing methods, an additional benefit factor in the region of 10 or, exceptionally, 100 should be introduced in the calculation of the allowable limit. In such cases, the allowable limit is the product of the TI, body weight, UTF and the additional benefit factor. The tolerable exposure (TE) represents an exposure level that is not expected to carry any appreciable risk of adverse effects in an exposed population. Normally, the allowable limit for a duration of exposure category and route of entry will be the lowest TI calculated for that combination. 9 Allowable Limits After calculation of the TIs and their modification based upon the device evaluation, an allowable limit is calculated for each TI. Meeting all the allowable limits is required. Each allowable limit is calculated using the following general formula. TI x BW x UTF x BF = Allowable Limit (mass/unit time) where, TI = Tolerable intake after modification based upon the device evaluation. It is normally expressed in mg/kg/d. BW = Body weight specific to the intended patient population. Absent specific information, BW = 70 kg. UTF = Utilization Factor used to take into account the utilization of the device in terms of frequency and duration of use and utilization in conjunction with other medical devices that can be reasonably anticipated to have the same residue. BF = Benefit factor. It varies from 1 to 100. Allowable Limit = Allowable limits for a specific medical device. There may be limits for various durations of exposure and/or routes of entry. ----------------------------------------------------------------- Annex A (informative) Some Typical Assumptions for Biological Parameters A.1 General This annex gives the default parameters for use in assessing risk. It specifies the lifetime, daily intake of water, daily intake of air, body weight, and gestation period for the human, rat, mouse, hamster, and dog. These are the most common species for which data are available. These default data can serve as the basis for interspecies comparisons unless other data can be shown to be more appropriate. A.2 Assumptions Human 70-year lifetime 2 liters/day intake of drinking water 20 cubic meters/day air intake in 24 hours; 10 cubic meters/day in 8 hour work day 70 kg body weight for adult men; 58 kg for adult women; 10 kg for children; 3.5 kg for neonates (< 1 year) 9 month gestation period Rat 2 year lifetime 0.025 liter/day of drinking water for males; 0.020 liter/day for females 0.29 cubic meter/24 hour day air intake 0.5 kg body weight for adult males, 0.35 kg for adult females 22 day gestation period Mouse 2 year lifetime 0.005 liter/day of drinking water 0.043 cubic meter/24 hour day air intake 0.03 kg body weight for adult males, 0.025 kg for adult females 20 day gestation period Hamster 2 year lifetime 0.015 liter/day of drinking water 0.086 cubic meter/24 hour day air intake 0.125 kg body weight for adult males; 0. 110kg for adult females 15 day gestation period Dog 11 year lifetime 0.5 liter/day of drinking water 7.5 cubic meters/24 hour day air intake 16 kg body weight 63 day gestation period ----------------------------------------------------------------- Annex B (informative) Bibliography International organization for Standardization (ISO) (1995). Biological Testing of Medical and Dental Materials and Devices, Part 7, Ethylene Oxide Sterilization Residuals. International Standard ISO 10993-7. Brussels, Belgium. Lehman, A.J. and Fitzhugh, O.G. (1954). 100-Fold margin of safety. Association of Food and Drug Officials. U.S. Q. Bull. 18, 33-35. Pharmaceutical Manufacturers Association(PMA)(1989). Procedures for setting limits for volatile organic solvents with methylene chloride as an example of the process. Committee on Rational Specification for Impurities in Bulk Drug Substances. PMA, Washington, DC. Pharmacopeial Forum 15(6), 5748-5759. Pharmaceutical Manufacturers Association(PMA)(1990). Procedures for setting limits for volatile organic solvents with chloroform, 1,4-dioxane, ethylene oxide and trichloroethylene as examples of the process. Committee on Rational Specification for Impurities in Bulk Drug Substances. PMA, Washington, DC. Pharmacopeial Forum 16(3), 541-582. Pharmaceutical Manufacturers Association(PMA)(1991). Procedures for setting limits for volatile organic solvents with benzene as an example of the process. Committee on Rational Specification for Impurities in Bulk Drug Substances. PMA, Washington, DC. Pharmacopeial Forum 17(l), 1441-1458. United States Pharmacopeial Convention (USP)(1991). <467> Organic volatile impurities. USP XXII Supplement 4 NF XVII, pp. 2508-251 0. USP, Rockville, Maryland. Conine, D., Naumann, B. and Hecker. L. (1992). Setting Health-Based Residue Limits For Contaminants in Pharmaceuticals and Medical Devices. Quality Assurance: Good Practice, Regulation, and the Law. 1(3), 171-180. Committee on Carcinogenicity of Chemicals in Food, Consumer Products and the Environment, Guidelines for the evaluation of chemicals for carcinogenicity, Department of Health Report on Health and Social Subjects No 42, HMSO, London, 1991 Dourson, M. and Stara, J. (1 983). Regulatory history and experimental support for uncertainty (safety) factors. Reg. Toxicol. Pharmacol. 3:224-238. Crump, K. (1 984). A new method for determining allowable daily intakes. Fund. Appl. Toxicol. 4:854-871. Lewis, S. Lynch, J. and Nikiforov, A. (1990). A new approach to deriving community exposure guidelines from no-observed-adverse--effect level. Reg. Toxicol. Pharmacol. 11:314-330. Kadry, A., Skowronski, G., and Abel-Rahman, M. (1995) Evaluation of the Use of Uncertainty Factors in Deriving RfDs for Some Chlorinated Compounds. Journal of Toxicol. and Environ. Health. 45:83-95. World Health Organization (WHO) (1994). Environmental Health Criteria 170. Assessing Human Health Risks of Chemicals: Derivation of Guidance Values for Health-Based Exposure Limits. World Health Organization. Geneva, Switzerland. ----------------------------------------------------------------- Figure 1 Method for the Establishment of Allowable Limits for Residues in Medical Devices Using Health-Based Risk Assessment Identify or Select Derive Residue Allowable Limit(s) | for Residue | Device Evaluation | Yes Multiply by BF | ^ ollect & Evaluate | No Toxicity Data | ------- Feasible? Do Ad Obtain Multiply by UTF Data Exist -- No -- Necessary | Data Multiply by BW | Yes Select Lower of | TIs Identify NOAEL or LOAEL for Critical Endpoint(s) Calculate No Cancer TI | Select Appropriate Yes UF and MF Calculate TI for Is Compound Noncancer Endpoints Carcinogenic? 11/l/96 Draft