- Email: [email protected]
Biocompatibility
Biocompatibility SE Gad, Gad Consulting Services, Cary, NC, USA Ó 2014 Elsevier Inc. All rights reserved.
Biomaterial use includes stents, intraocular lenses, wound dressings, total hip replacements, total knee replacements, tooth implants, and sutures, and can be naturally occurring or made of polymer, ceramic, or metal. It can also include submicron or nanotechnology components, in situ polymerizing, and bioabsorbable materials. Medical devices typically undergo a battery of safety tests before being cleared by regulatory authorities for marketing. The biological evaluation of medical devices is performed to determine the potential toxicity resulting from contact of the component materials of the device with the body. The device materials should not produce adverse local or systemic effects, be carcinogenic, or produce adverse reproductive and developmental effects, either directly or through the release of their material constituents. Systemic testing must ensure that the benefits of the final product will outweigh any potential risks produced by device materials. Among these are tests to evaluate the biological safety, or biocompatibility, of the device, and appropriate function of the device. Guidance on how to conduct these tests is provided in standards developed by the United States or by international consensus standards bodies such as the International Organization for Standardization and their ISO 10993: Biological Evaluation of Medical Devices series. When designing a medical device, it is important to first select appropriate materials, and then a sterilization method before searching for relative information on the materials and beginning testing. It is advisable to test individual components of a device prior to testing the complete device in case one component has toxic properties. Premarket approval (PMA) applicants often use another party’s product or facility in the manufacture of their device. Many manufacturers keep data on qualified materials used in their products. This information regarding the product is pertinent to its review; the third party may choose to submit confidential information directly to the US Food and Drug Administration (FDA) in a device master file. This is not a marketing application, and additional testing or information may be necessary. When selecting the appropriate tests for biological evaluation of a medical device, one must consider the chemical characteristics of device materials, and the nature, degree, frequency, and duration of its exposure to the body. In general, the tests include acute, subchronic, and chronic toxicity; irritation to skin, eyes, and mucosal surfaces; sensitization; hemocompatibility; genotoxicity; carcinogenicity; and effects on reproduction, including developmental effects. However, depending on varying characteristics and intended uses of devices as well as the nature of contact, these general tests may not be sufficient to demonstrate the safety of some specialized devices. Additional tests for specific target organ toxicity, such as neurotoxicity and immunotoxicity, may be necessary for some devices. Since the immune response and repair functions in the body are highly complicated, it is inadequate to describe the biocompatibility of a single material in relation to a single cell type or tissue. The specific clinical application and the
464
materials used in the manufacture of the new device determine which tests are appropriate. The material or device used for biocompatibility studies should contain the same colorants, fragrances, flavors, powders, lubricants, and processing chemicals as what is intended to be placed on the market. A material or device to be tested should be processed, packaged, and, if appropriate, sterilized by the same methods as the product that will be distributed. Biocompatibility studies may need to be repeated if subsequent changes are made in composition, manufacturing materials, or processing. Some devices are made of materials that have been well characterized chemically and physically in the published literature, and have a long history of safe use. For the purposes of demonstrating the substantial equivalence of such devices to other marketed products, it may not be necessary to conduct all the tests suggested in the FDA matrix of this guidance. FDA reviewers are advised to use their scientific judgment in determining which tests are required for the demonstration of substantial equivalence under section 510(k). In such situations, the manufacturer must document the use of a particular material in a legally marketed predicate device, or a legally marketed device with comparable patient exposure.
Regulations There are several regulatory guidances in place to guide one through biocompatibility evaluation of a medical device, and depending on which country a device is to be registered in, some variations exist. The US FDA and European Union commonly accept the ISO 10993 standards for biocompatibility. USP (US Pharmacopeia) and ASTM standards are accepted by the US FDA, are generally regarded as more stringent, and may be used by manufacturers as a marketing tool, or for specific uses. Finally, Japan’s Ministry of Health, Labor, and Welfare has test criteria that are different from both the ISO 10993 and USP protocols. ISO 10993 Biological evaluation of medical devices includes the following parts: Part 1: Evaluation and testing within a risk management process Part 2: Animal welfare requirements Part 3: Tests for genotoxicity, carcinogenicity and reproductive toxicity Part 4: Selection of tests for interactions with blood Part 5: Tests for in vitro cytotoxicity Part 6: Tests for local effects after implantation Part 7: Ethylene oxide sterilization residuals Part 9: Framework for identification and quantification of potential degradation products Part 10: Tests for irritation and skin sensitization Part 11: Tests for systemic toxicity Part 12: Sample preparation and reference materials Part 13: Identification and quantification of degradation products from polymeric medical devices
Encyclopedia of Toxicology, Volume 1
http://dx.doi.org/10.1016/B978-0-12-386454-3.00821-6
Biocompatibility
Part 14: Identification and quantification of degradation products from ceramics Part 15: Identification and quantification of degradation products from metals and alloys Part 16: Toxicokinetic study design for degradation products and leachables Part 17: Establishment of allowable limits for leachable substances Part 18: Chemical characterization of materials Part 19: Physicochemical, morphological and topographical characterization of materials Part 20: Principles and methods for immunotoxicology testing of medical devices The following tests are recommended: l l l l l l l l
Cytotoxicity Acute systemic toxicity Sensitization Genotoxicity Skin irritation Implantation Intracutaneous reactivity Hemocompatibility
Subchronic and chronic toxicities and also carcinogenicity may also be appropriate. For use in the United States, the blue book memorandum includes an FDA-modified matrix designating the type of testing required for various medical devices and also a flow chart entitled Biocompatibility Flow Chart for the Selection of Toxicity Tests for 510(k)s. The matrix also consists of two tables: Table 1 – initial evaluation tests for consideration; and Table 2 – supplementary evaluation tests for consideration. In general, the agency does not have a list of approved materials. Some materials that have been well characterized both chemically and physically in published literature, and which have a long history of safe use, may prove themselves not to be in need of all tests, if substantial equivalence to marketed products under 510(k) is shown. In this case, the manufacturer must document the use of a particular material in a legally marketed predicate device, or a legally marketed device with comparable patient exposure. It may be necessary to repeat biocompatibility tests when modifying a device based on the changes made. Medical device toxicity problems are most often caused by leachable or extractable toxins. Extracts of materials are often tested for biocompatibility. Section 17 of 10993 entitled Establishment of Allowable Limits of Leachable Substances gives guidance on the use of analytical data (e.g., extraction studies) to reduce biocompatibility test requirements. The extraction media should comprise a series of media with various polarities to capture results found in different solubilities. The temperature at which the extraction should be carried out varies throughout various guidelines. For in vitro cytotoxicity testing, complete cell-culture medium is most commonly used, with extraction performed at 37 C for 24 h. Inexpensive nonanimal studies such as cytotoxicity and hemocompatibility tests can be used to screen device materials. Biological control tests are recommended to determine sources of possible contamination and to ensure safety of the final product. Microbiological tests to determine the status of
465
the final product (e.g., sterility, bacteria, contaminants, and microbial count limits) are necessary. Devices should be tested for endotoxins, as cell wall lipopolysaccharides (from Gramnegative bacteria) may be present even after sterilization. Assessment of nonspecific toxicological effects should be performed by intravenous injection of device eluate in mice. When positive (indicative of a toxic response) biocompatibility results are reported, development discontinuation is not the only option. First it should be confirmed that no mistakes were made in the testing laboratory, including the testing of the proper article, and formulation. In addition, it should be made certain that the article was properly manufactured, cleaned, stored, and tested (e.g., the extractant used, the testing conditions, and the procedure). Finally, reproducibility of positive biocompatibility results should be confirmed. In a certain situation, where the possible benefits outweigh the risks, or when quality of life is a factor, a level of toxicity may be acceptable. The following are special considerations that must be considered when testing devices and their component materials for safety.
Color Additives A color additive is a dye, pigment, or other substance, whether derived from a plant, animal, mineral, or other source, which imparts a color when added to a food, drug, cosmetic, or the human body. The US Food, Drug and Cosmetic (FD&C) Act states: “Devices containing a color additive are considered unsafe, and thereby adulterated, unless a regulation is in effect listing the color additive for such use.” The FD&C Act limits applicability of these color additives for devices that directly contact the body for a significant period of time (undefined by FDA). Manufacturers of devices should choose a color additive listed for use in foods, drugs, or cosmetics as a starting point, but keep in mind that these may not be appropriate for devices. The color listing regulation may permit the use of the color additives or may place limitations on its use; PMA applicants must demonstrate their safety. Color additives listed for use in medical devices are provided in 21 CFR 73 (Color additives exempt from batch certification) and 21 CFR 74 (Color additives subject to batch certification). FDA considers the addition of color, flavor, or any chemical to a medical glove to be a significant change that should have a new 510(k) submission (21 CFR 807.81(a)(3)). The applicant should provide full characterization and chemical identity of the color, flavor, or scent additives. They may submit a 510(k) submission for a modification to an existing glove as a ‘Special 510(k)’. Color additive and flavor additive regulations are in 21 CFR parts 70 to 82 and 21 CFR part 172, Subpart F, respectively.
Combination Products A combination product is a product consisting of two or more regulated components (drug/biologic/device, etc.) that are combined as a single entity or is a product labeled for use with a separate device or biologic where both are required to achieve the intended use, indication, or effectiveness. Intercenter
466
Initial evaluation tests for consideration Device categorization by nature of body contact (see 5.2)
Category
Contact
Surface device
Intact skin
Biologic effect
Contact duration (see 5.3) A-limited (24 h) B-prolonged (>24 h–30 days) Irritation of C-permanent intracutaneous Systemic Subchronic toxicity (>30 days) Cytotoxicity Sensitization reactivity toxicity (acute) (subacute toxicity) Genotoxicity Implantation Hemocompatibility
A B C Mucosal membrane A B C Breached or compromised surface A B C External communicating device Blood path, indirect A B C A Tissue/bone/dentina B C Circulating blood A B C Implant device Tissue/bone A B C Blood A B C
X X X X X X X X X X X X X X X X X X X X X X X X
X X X X X X X X X X X X X X X X X X X X X X X X
X X X X X X X X X X X O X X X X X X X X X X X X
X ¼ ISO evaluation tests for consideration. O ¼ These additional evaluation tests should be addressed in the submission, either by inclusion of the testing or a rationale for its omission. a Tissue includes tissue fluids and subcutaneous spaces. b For all devices used in extracorporeal circuits. http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM348890.pdf.
O O O O O X X X O X X X X X O X X X X X
O X
X
O O
O X
X
O O
O X X X X X X X X X X
X X X
X
O
X X Ob X X
X X X X
X X X
X X
X X X X X
X X X
X X
Biocompatibility
Table 1
Biocompatibility
Table 2
467
Supplementary evaluation 1142 tests for consideration
Device categorization by nature of body contact (see 5.2)
Category
Contact
Surface device
Intact skin
Biologic effect Contact duration (see 5.3) A-limited (24 h) B-prolonged (>24 h–30 days) C-permanent Reproductive/ (>30 days) Chronic toxicity Carcinogenicity Developmental Biodegradable
A B C Mucosal membrane A B C Breached or compromised surface A B C External communicating device Blood path, indirect A B C A Tissue/bone/dentina B C Circulating blood A B C Implant device Tissue/bone A B C Blood A B C
O
O
O
O
O
O
O
O
O
O
O
O
X ¼ ISO evaluation tests for consideration. O ¼ These additional evaluation tests should be addressed in the submission, either by inclusion of the testing or a rationale for its omission. a Tissue includes tissue fluids and subcutaneous spaces. http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM348890.pdf.
agreements have been made within FDA to review and oversee these categories. More information can be found at FDA website for the CBER (Center for Biologics Evaluation and Research) and CDRH (Center for Devices and Radiological Health) Intercenter agreement, and the CDER (Center for Drug Evaluation and Research) and CDRH Intercenter agreement.
circuit in such product. If a medical device emits electronic product radiation, additional requirements apply through the Radiation Control for Health and Safety Act. Additional information concerning radiation-emitting products can be found at the FDA website.
In Vitro Diagnostic (IVD) Products
Software
These are medical devices that analyze human body fluids, such as blood or urine, to provide information for the diagnosis, prevention, or treatment of a disease. Classification for these devices can be found within regulations: 21 CFR 862, 21 CFR 864, and 21 CFR 866.
If a device contains software, the PMA submission must include documentation of software testing appropriate to the level of risk of the device. The FDA recognizes certain consensus standards of conformance when making regulatory decisions. In addition, sterility assurance is necessary, and FDA validated method for sterilization should be used and included in the PMA.
Radiation-Emitting Products Phthalates Electronic product radiation means any ionizing or nonionizing electromagnetic or particulate radiation, or any sonic, infrasonic, or ultrasonic wave, that is emitted from an electronic production because of the operation of an electronic
Within the past few decades, specific additives to some plasticizers (such as DEHP and bis-phenol-A) have been identified as toxic to animals and thus have come under scrutiny.
468
Biocompatibility
The impact of these formulation aids to human health has not been fully characterized. Regardless, an effort is underway to reformulate device materials without them. Fibrosarcomas are another example of a biocompatibility measure that has been noted in animal and not yet determined if it will translate into humans. Known as the Oppenheimer effect, smooth materials with a minimum surface area, and implantation time in rats produce an increased occurrence of hard, tumorlike masses. The same material when implanted in a different configuration will not produce the same response.
Latex Testing: Testing for Skin Sensitization to Chemicals The labeling may include special claims regarding reduced potential chemical sensitization in a 510(k), such as: l
reduced potential for sensitizing users to rubber chemical additives, or l reduced potential for causing reaction in individuals sensitized to rubber chemical additives. The applicant should support these claims by data from human testing. Additional guidance on testing for skin sensitization to chemicals in latex products is available in the guidance document listed in the Relevant Websites section.
See also: Foreign Body Response; Implant Studies; Medical Textiles.
Further Reading Black, J., 1999. Biological Performance of Materials. Marcel Dekker, Inc, Boca Raton, FL. Chu, C.C., von Fraunhofer, J.A., Greisler, H.P. (Eds.), 1997. Wound Closure Biomaterials and Devices. CRC Press, Washington, DC. Cronin, E., 1980. Contact Dermatitis. Churchill Livingston, Edinburgh. Dart, R.C., 2004. Medical Toxicology, third ed. Lippincott Williams & Wilkins, Philadelphia, PA. Freitas Jr., R.A., 2003. Nanomedicine. In: Biocompatibility, vol. IIA. Landes Bioscience, Georgetown, TX.
Fries, R.C., 1998. Medical Device Quality Assurance and Regulatory Compliance. Marcel Dekker, Inc, New York. Gad, S.C., 2009. Safety Evaluation of Medical Devices, third ed. CRC Press, Boca Raton, FL. Gad, S.C., McCord, M.G., 2008. Safety Evaluation in the Development of Medical Devices and Combination Products, third ed. Informa, New York. Greco, R.S., 1994. Implantation Biology. CRC Press, Boca Raton, FL. Guelcher, S.A., Hollinger, J.O. (Eds.), 2006. An Introduction to Biomaterials. Taylor and Francis, Boca Raton, FL. Heller, M.A., 2002. Guide to Medical Device Regulation, vol. 1 & 2. Thompson Publishing Company, Washington, DC. Kammula, R.G., Morris, J.M., 2001. Considerations for the Biocompatibility Evaluation of Medical Devices. MDDI 23, 82–92. Medical Device Register, 1997. Medical Economics. Hospital Marketing Services, Inc. ODE, 1995. FDA Blue Book Memo 95-1. CDRH. Rutner, B.D., Hoffman, A.C., Schoen, F.J., Lemons, J.E., 1996. Biomaterials Science. Academic Press, San Diego. Silvio, L.D., 2009. Cellular Response to Biomaterials. Woodhead Publishing Limited and CRC Press, Cambridge, England. Thompson, B.M., 1995. FDA Regulations of Medical Devices. Interpharm Press, Inc, Buffalo Grove, IL. von Recum, A.F. (Ed.), 1998. Handbook of Biomaterials Evaluation, second ed. Taylor & Francis, Ann Arbor, MI. Wise, D.L. (Ed.), 2000. Biomaterials and Bioengineering Handbook. Marcel Dekker, Inc, New York. Wise, D.L., Trantolo, D.J., Altobelli, D.E., Yaszemski, M.J., Gresser, J.D., Schwartz, E.R. (Eds.), 1995. Encyclopedic Handbook of Biomaterials and Bioengineering. Marcel Dekker, New York.
Relevant Websites http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/ GuidanceDocuments/ucm073792.htm – Premarket Notification [510(k)] Submissions for Testing for Skin Sensitization to Chemicals in Natural Rubber Products. http://www.fda.gov – US Food and Drug Administration (FDA) website. See index pages for ‘Required Biocompatibility Training and Toxicology Profiles for Evaluation of Medical Devices, Blue Book Memo, G95-1. May 1, 1995’. ‘US FDA. Special Considerations. Biocompatibility.’ More information can be found at the website for the CBER (Center for Biologics Evaluation and Research) and CDRH (Center for Devices and Radiological Health) Intercenter agreement, and the CDER (Center for Drug Evaluation and Research) and CDRH Intercenter agreement. http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/ GuidanceDocuments/UCM348890.pdf – Use of International Standard ISO-10993, "Biological Evaluation of Medical Devices Part 1: Evaluation and Testing" Draft Guidance for Industry and Food and Drug Administration Staff Document issued on: April 23, 2013. http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/ GuidanceDocuments/UCM348890.pdf – Food and Drug Administration.
Biomaterial use includes stents, intraocular lenses, wound dressings, total hip replacements, total knee replacements, tooth implants, and sutures, and can be naturally occurring or made of polymer, ceramic, or metal. It can also include submicron or nanotechnology components, in situ polymerizing, and bioabsorbable materials. Medical devices typically undergo a battery of safety tests before being cleared by regulatory authorities for marketing. The biological evaluation of medical devices is performed to determine the potential toxicity resulting from contact of the component materials of the device with the body. The device materials should not produce adverse local or systemic effects, be carcinogenic, or produce adverse reproductive and developmental effects, either directly or through the release of their material constituents. Systemic testing must ensure that the benefits of the final product will outweigh any potential risks produced by device materials. Among these are tests to evaluate the biological safety, or biocompatibility, of the device, and appropriate function of the device. Guidance on how to conduct these tests is provided in standards developed by the United States or by international consensus standards bodies such as the International Organization for Standardization and their ISO 10993: Biological Evaluation of Medical Devices series. When designing a medical device, it is important to first select appropriate materials, and then a sterilization method before searching for relative information on the materials and beginning testing. It is advisable to test individual components of a device prior to testing the complete device in case one component has toxic properties. Premarket approval (PMA) applicants often use another party’s product or facility in the manufacture of their device. Many manufacturers keep data on qualified materials used in their products. This information regarding the product is pertinent to its review; the third party may choose to submit confidential information directly to the US Food and Drug Administration (FDA) in a device master file. This is not a marketing application, and additional testing or information may be necessary. When selecting the appropriate tests for biological evaluation of a medical device, one must consider the chemical characteristics of device materials, and the nature, degree, frequency, and duration of its exposure to the body. In general, the tests include acute, subchronic, and chronic toxicity; irritation to skin, eyes, and mucosal surfaces; sensitization; hemocompatibility; genotoxicity; carcinogenicity; and effects on reproduction, including developmental effects. However, depending on varying characteristics and intended uses of devices as well as the nature of contact, these general tests may not be sufficient to demonstrate the safety of some specialized devices. Additional tests for specific target organ toxicity, such as neurotoxicity and immunotoxicity, may be necessary for some devices. Since the immune response and repair functions in the body are highly complicated, it is inadequate to describe the biocompatibility of a single material in relation to a single cell type or tissue. The specific clinical application and the
464
materials used in the manufacture of the new device determine which tests are appropriate. The material or device used for biocompatibility studies should contain the same colorants, fragrances, flavors, powders, lubricants, and processing chemicals as what is intended to be placed on the market. A material or device to be tested should be processed, packaged, and, if appropriate, sterilized by the same methods as the product that will be distributed. Biocompatibility studies may need to be repeated if subsequent changes are made in composition, manufacturing materials, or processing. Some devices are made of materials that have been well characterized chemically and physically in the published literature, and have a long history of safe use. For the purposes of demonstrating the substantial equivalence of such devices to other marketed products, it may not be necessary to conduct all the tests suggested in the FDA matrix of this guidance. FDA reviewers are advised to use their scientific judgment in determining which tests are required for the demonstration of substantial equivalence under section 510(k). In such situations, the manufacturer must document the use of a particular material in a legally marketed predicate device, or a legally marketed device with comparable patient exposure.
Regulations There are several regulatory guidances in place to guide one through biocompatibility evaluation of a medical device, and depending on which country a device is to be registered in, some variations exist. The US FDA and European Union commonly accept the ISO 10993 standards for biocompatibility. USP (US Pharmacopeia) and ASTM standards are accepted by the US FDA, are generally regarded as more stringent, and may be used by manufacturers as a marketing tool, or for specific uses. Finally, Japan’s Ministry of Health, Labor, and Welfare has test criteria that are different from both the ISO 10993 and USP protocols. ISO 10993 Biological evaluation of medical devices includes the following parts: Part 1: Evaluation and testing within a risk management process Part 2: Animal welfare requirements Part 3: Tests for genotoxicity, carcinogenicity and reproductive toxicity Part 4: Selection of tests for interactions with blood Part 5: Tests for in vitro cytotoxicity Part 6: Tests for local effects after implantation Part 7: Ethylene oxide sterilization residuals Part 9: Framework for identification and quantification of potential degradation products Part 10: Tests for irritation and skin sensitization Part 11: Tests for systemic toxicity Part 12: Sample preparation and reference materials Part 13: Identification and quantification of degradation products from polymeric medical devices
Encyclopedia of Toxicology, Volume 1
http://dx.doi.org/10.1016/B978-0-12-386454-3.00821-6
Biocompatibility
Part 14: Identification and quantification of degradation products from ceramics Part 15: Identification and quantification of degradation products from metals and alloys Part 16: Toxicokinetic study design for degradation products and leachables Part 17: Establishment of allowable limits for leachable substances Part 18: Chemical characterization of materials Part 19: Physicochemical, morphological and topographical characterization of materials Part 20: Principles and methods for immunotoxicology testing of medical devices The following tests are recommended: l l l l l l l l
Cytotoxicity Acute systemic toxicity Sensitization Genotoxicity Skin irritation Implantation Intracutaneous reactivity Hemocompatibility
Subchronic and chronic toxicities and also carcinogenicity may also be appropriate. For use in the United States, the blue book memorandum includes an FDA-modified matrix designating the type of testing required for various medical devices and also a flow chart entitled Biocompatibility Flow Chart for the Selection of Toxicity Tests for 510(k)s. The matrix also consists of two tables: Table 1 – initial evaluation tests for consideration; and Table 2 – supplementary evaluation tests for consideration. In general, the agency does not have a list of approved materials. Some materials that have been well characterized both chemically and physically in published literature, and which have a long history of safe use, may prove themselves not to be in need of all tests, if substantial equivalence to marketed products under 510(k) is shown. In this case, the manufacturer must document the use of a particular material in a legally marketed predicate device, or a legally marketed device with comparable patient exposure. It may be necessary to repeat biocompatibility tests when modifying a device based on the changes made. Medical device toxicity problems are most often caused by leachable or extractable toxins. Extracts of materials are often tested for biocompatibility. Section 17 of 10993 entitled Establishment of Allowable Limits of Leachable Substances gives guidance on the use of analytical data (e.g., extraction studies) to reduce biocompatibility test requirements. The extraction media should comprise a series of media with various polarities to capture results found in different solubilities. The temperature at which the extraction should be carried out varies throughout various guidelines. For in vitro cytotoxicity testing, complete cell-culture medium is most commonly used, with extraction performed at 37 C for 24 h. Inexpensive nonanimal studies such as cytotoxicity and hemocompatibility tests can be used to screen device materials. Biological control tests are recommended to determine sources of possible contamination and to ensure safety of the final product. Microbiological tests to determine the status of
465
the final product (e.g., sterility, bacteria, contaminants, and microbial count limits) are necessary. Devices should be tested for endotoxins, as cell wall lipopolysaccharides (from Gramnegative bacteria) may be present even after sterilization. Assessment of nonspecific toxicological effects should be performed by intravenous injection of device eluate in mice. When positive (indicative of a toxic response) biocompatibility results are reported, development discontinuation is not the only option. First it should be confirmed that no mistakes were made in the testing laboratory, including the testing of the proper article, and formulation. In addition, it should be made certain that the article was properly manufactured, cleaned, stored, and tested (e.g., the extractant used, the testing conditions, and the procedure). Finally, reproducibility of positive biocompatibility results should be confirmed. In a certain situation, where the possible benefits outweigh the risks, or when quality of life is a factor, a level of toxicity may be acceptable. The following are special considerations that must be considered when testing devices and their component materials for safety.
Color Additives A color additive is a dye, pigment, or other substance, whether derived from a plant, animal, mineral, or other source, which imparts a color when added to a food, drug, cosmetic, or the human body. The US Food, Drug and Cosmetic (FD&C) Act states: “Devices containing a color additive are considered unsafe, and thereby adulterated, unless a regulation is in effect listing the color additive for such use.” The FD&C Act limits applicability of these color additives for devices that directly contact the body for a significant period of time (undefined by FDA). Manufacturers of devices should choose a color additive listed for use in foods, drugs, or cosmetics as a starting point, but keep in mind that these may not be appropriate for devices. The color listing regulation may permit the use of the color additives or may place limitations on its use; PMA applicants must demonstrate their safety. Color additives listed for use in medical devices are provided in 21 CFR 73 (Color additives exempt from batch certification) and 21 CFR 74 (Color additives subject to batch certification). FDA considers the addition of color, flavor, or any chemical to a medical glove to be a significant change that should have a new 510(k) submission (21 CFR 807.81(a)(3)). The applicant should provide full characterization and chemical identity of the color, flavor, or scent additives. They may submit a 510(k) submission for a modification to an existing glove as a ‘Special 510(k)’. Color additive and flavor additive regulations are in 21 CFR parts 70 to 82 and 21 CFR part 172, Subpart F, respectively.
Combination Products A combination product is a product consisting of two or more regulated components (drug/biologic/device, etc.) that are combined as a single entity or is a product labeled for use with a separate device or biologic where both are required to achieve the intended use, indication, or effectiveness. Intercenter
466
Initial evaluation tests for consideration Device categorization by nature of body contact (see 5.2)
Category
Contact
Surface device
Intact skin
Biologic effect
Contact duration (see 5.3) A-limited (24 h) B-prolonged (>24 h–30 days) Irritation of C-permanent intracutaneous Systemic Subchronic toxicity (>30 days) Cytotoxicity Sensitization reactivity toxicity (acute) (subacute toxicity) Genotoxicity Implantation Hemocompatibility
A B C Mucosal membrane A B C Breached or compromised surface A B C External communicating device Blood path, indirect A B C A Tissue/bone/dentina B C Circulating blood A B C Implant device Tissue/bone A B C Blood A B C
X X X X X X X X X X X X X X X X X X X X X X X X
X X X X X X X X X X X X X X X X X X X X X X X X
X X X X X X X X X X X O X X X X X X X X X X X X
X ¼ ISO evaluation tests for consideration. O ¼ These additional evaluation tests should be addressed in the submission, either by inclusion of the testing or a rationale for its omission. a Tissue includes tissue fluids and subcutaneous spaces. b For all devices used in extracorporeal circuits. http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM348890.pdf.
O O O O O X X X O X X X X X O X X X X X
O X
X
O O
O X
X
O O
O X X X X X X X X X X
X X X
X
O
X X Ob X X
X X X X
X X X
X X
X X X X X
X X X
X X
Biocompatibility
Table 1
Biocompatibility
Table 2
467
Supplementary evaluation 1142 tests for consideration
Device categorization by nature of body contact (see 5.2)
Category
Contact
Surface device
Intact skin
Biologic effect Contact duration (see 5.3) A-limited (24 h) B-prolonged (>24 h–30 days) C-permanent Reproductive/ (>30 days) Chronic toxicity Carcinogenicity Developmental Biodegradable
A B C Mucosal membrane A B C Breached or compromised surface A B C External communicating device Blood path, indirect A B C A Tissue/bone/dentina B C Circulating blood A B C Implant device Tissue/bone A B C Blood A B C
O
O
O
O
O
O
O
O
O
O
O
O
X ¼ ISO evaluation tests for consideration. O ¼ These additional evaluation tests should be addressed in the submission, either by inclusion of the testing or a rationale for its omission. a Tissue includes tissue fluids and subcutaneous spaces. http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM348890.pdf.
agreements have been made within FDA to review and oversee these categories. More information can be found at FDA website for the CBER (Center for Biologics Evaluation and Research) and CDRH (Center for Devices and Radiological Health) Intercenter agreement, and the CDER (Center for Drug Evaluation and Research) and CDRH Intercenter agreement.
circuit in such product. If a medical device emits electronic product radiation, additional requirements apply through the Radiation Control for Health and Safety Act. Additional information concerning radiation-emitting products can be found at the FDA website.
In Vitro Diagnostic (IVD) Products
Software
These are medical devices that analyze human body fluids, such as blood or urine, to provide information for the diagnosis, prevention, or treatment of a disease. Classification for these devices can be found within regulations: 21 CFR 862, 21 CFR 864, and 21 CFR 866.
If a device contains software, the PMA submission must include documentation of software testing appropriate to the level of risk of the device. The FDA recognizes certain consensus standards of conformance when making regulatory decisions. In addition, sterility assurance is necessary, and FDA validated method for sterilization should be used and included in the PMA.
Radiation-Emitting Products Phthalates Electronic product radiation means any ionizing or nonionizing electromagnetic or particulate radiation, or any sonic, infrasonic, or ultrasonic wave, that is emitted from an electronic production because of the operation of an electronic
Within the past few decades, specific additives to some plasticizers (such as DEHP and bis-phenol-A) have been identified as toxic to animals and thus have come under scrutiny.
468
Biocompatibility
The impact of these formulation aids to human health has not been fully characterized. Regardless, an effort is underway to reformulate device materials without them. Fibrosarcomas are another example of a biocompatibility measure that has been noted in animal and not yet determined if it will translate into humans. Known as the Oppenheimer effect, smooth materials with a minimum surface area, and implantation time in rats produce an increased occurrence of hard, tumorlike masses. The same material when implanted in a different configuration will not produce the same response.
Latex Testing: Testing for Skin Sensitization to Chemicals The labeling may include special claims regarding reduced potential chemical sensitization in a 510(k), such as: l
reduced potential for sensitizing users to rubber chemical additives, or l reduced potential for causing reaction in individuals sensitized to rubber chemical additives. The applicant should support these claims by data from human testing. Additional guidance on testing for skin sensitization to chemicals in latex products is available in the guidance document listed in the Relevant Websites section.
See also: Foreign Body Response; Implant Studies; Medical Textiles.
Further Reading Black, J., 1999. Biological Performance of Materials. Marcel Dekker, Inc, Boca Raton, FL. Chu, C.C., von Fraunhofer, J.A., Greisler, H.P. (Eds.), 1997. Wound Closure Biomaterials and Devices. CRC Press, Washington, DC. Cronin, E., 1980. Contact Dermatitis. Churchill Livingston, Edinburgh. Dart, R.C., 2004. Medical Toxicology, third ed. Lippincott Williams & Wilkins, Philadelphia, PA. Freitas Jr., R.A., 2003. Nanomedicine. In: Biocompatibility, vol. IIA. Landes Bioscience, Georgetown, TX.
Fries, R.C., 1998. Medical Device Quality Assurance and Regulatory Compliance. Marcel Dekker, Inc, New York. Gad, S.C., 2009. Safety Evaluation of Medical Devices, third ed. CRC Press, Boca Raton, FL. Gad, S.C., McCord, M.G., 2008. Safety Evaluation in the Development of Medical Devices and Combination Products, third ed. Informa, New York. Greco, R.S., 1994. Implantation Biology. CRC Press, Boca Raton, FL. Guelcher, S.A., Hollinger, J.O. (Eds.), 2006. An Introduction to Biomaterials. Taylor and Francis, Boca Raton, FL. Heller, M.A., 2002. Guide to Medical Device Regulation, vol. 1 & 2. Thompson Publishing Company, Washington, DC. Kammula, R.G., Morris, J.M., 2001. Considerations for the Biocompatibility Evaluation of Medical Devices. MDDI 23, 82–92. Medical Device Register, 1997. Medical Economics. Hospital Marketing Services, Inc. ODE, 1995. FDA Blue Book Memo 95-1. CDRH. Rutner, B.D., Hoffman, A.C., Schoen, F.J., Lemons, J.E., 1996. Biomaterials Science. Academic Press, San Diego. Silvio, L.D., 2009. Cellular Response to Biomaterials. Woodhead Publishing Limited and CRC Press, Cambridge, England. Thompson, B.M., 1995. FDA Regulations of Medical Devices. Interpharm Press, Inc, Buffalo Grove, IL. von Recum, A.F. (Ed.), 1998. Handbook of Biomaterials Evaluation, second ed. Taylor & Francis, Ann Arbor, MI. Wise, D.L. (Ed.), 2000. Biomaterials and Bioengineering Handbook. Marcel Dekker, Inc, New York. Wise, D.L., Trantolo, D.J., Altobelli, D.E., Yaszemski, M.J., Gresser, J.D., Schwartz, E.R. (Eds.), 1995. Encyclopedic Handbook of Biomaterials and Bioengineering. Marcel Dekker, New York.
Relevant Websites http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/ GuidanceDocuments/ucm073792.htm – Premarket Notification [510(k)] Submissions for Testing for Skin Sensitization to Chemicals in Natural Rubber Products. http://www.fda.gov – US Food and Drug Administration (FDA) website. See index pages for ‘Required Biocompatibility Training and Toxicology Profiles for Evaluation of Medical Devices, Blue Book Memo, G95-1. May 1, 1995’. ‘US FDA. Special Considerations. Biocompatibility.’ More information can be found at the website for the CBER (Center for Biologics Evaluation and Research) and CDRH (Center for Devices and Radiological Health) Intercenter agreement, and the CDER (Center for Drug Evaluation and Research) and CDRH Intercenter agreement. http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/ GuidanceDocuments/UCM348890.pdf – Use of International Standard ISO-10993, "Biological Evaluation of Medical Devices Part 1: Evaluation and Testing" Draft Guidance for Industry and Food and Drug Administration Staff Document issued on: April 23, 2013. http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/ GuidanceDocuments/UCM348890.pdf – Food and Drug Administration.