Assessing Biocompatibility Needs: A Roadmap for Manufacturers and Industry Experts

“The primary aim of this ISO 10993 is the protection of humans from potential biological risks arising from the use of medical devices.” (ISO 10993), The best starting point for understanding biocompatibility requirements is ISO Standard 10993, Biological Evaluation of Medical Devices. Part 1 of the standard is the Guidance on Selection of Tests, Part 2 covers animal welfare requirements, and Parts 3 through 19 are guidelines for specific test procedures or other testing-related issues.

Biomaterials History, Qualification, and Diversity

ISO 10993 consists of 19 parts, each covering different aspects of biological evaluation of medical devices. Here are the subparts of ISO 10993:

• 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 8: Selection and Qualification of Reference Materials for Biological Tests
• 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
• 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: Physico-Chemical, Morphological, and Topographical Characterization of Materials

This table presents the different types of tests and procedures categorized under Biocompatibility Tests, QA/QC Testing, Validation Support, and Extracts/Material Characterization, providing a clear and organized overview applicable on the medical devices; 

Biocompatibility Requirement	QA/QC Testing	Validation Support	Extracts/Material Characterization
Cytotoxicity	Bioburden	AAMI/ISO Sterilization Validation	GC/MS
Sensitization	AAMI/ISO Dose Audits	Reusable Device	LC/MS/MS
Irritation	Biological Indicator Tests	Cleaning, Disinfection, and Sterilization Validation	USP Physiochemical Tests – Plastics or Elastomeric Closures
Systemic Toxicity	Environmental Monitoring	Accelerated Aging and Stability Testing	Sterilant Residues
Genotoxicity	Bacterial Endotoxin (LAL)	Package Integrity Testing	AA, IR, GC, HPLC
Implantation	Microbiology/Sterility Testing	.	Total Organic Carbon (TOC)
Hemocompatibility	.	.	Organic Solvent Residues
Surgical Models	.	.	Non-Volatile Residues
Subchronic & Chronic Toxicity	.	.	.
Carcinogenesis	.	.	.

PURPOSE OF BIOCOMPATIBILITY TESTING

Biocompatibility is, by definition, a measurement of how compatible a device is with a biological system. The purpose of performing biocompatibility testing is to determine the fitness of a device for human use, and to see whether use of the device can have any potentially harmful physiological effects. As stated by the International Organization of Standards.

The overall process of determining the biocompatibility of any medical device involves several stages. One should begin by collecting data on the materials comprising the device, then perform in vitro screening (often only on components of the device), and finally conduct confirmatory in vivo testing on the finished device. It is essential to make sure that the finished device is challenged to ensure that human use of the device does not result in any harmful effects.

Conducting Tests and Evaluating the Data

Typically, before any biological testing is done, the materials used in the device are analyzed to understand their properties. This involves taking out any substances that might come out of the device when it's being used, usually by heating it, and then checking these substances to see if they could be harmful. Once the testing in labs is finished, we can move on to testing on living organisms based on how the device will be used. This could include testing for skin reactions, how it interacts with blood, and how it reacts when implanted in the body. The time it takes to get results from these tests can vary a lot, from a few weeks to several months, depending on what exactly we're testing for. Some tests, like ones where the device is implanted for a long time, can take even longer.

Once all the tests are done and we have gathered all the information, it's a good idea to have a knowledgeable person look at the data and results. They can help figure out if we need to do more tests or if the data we already have is enough to understand how safe the device is for people to use.

Introduction to Biocompatibility Testing

Biocompatibility refers to how well a medical device interacts with the tissues and bodily systems of the patient it's used on. Assessing biocompatibility is a crucial part of ensuring a device's overall safety. This evaluation involves various methods, including analytical chemistry, laboratory tests, and studies on animals and humans.

The biocompatibility of a device depends on three factors, including but not limited to:

• the chemical and physical nature of its component materials
• the types of patient tissue that will be exposed to the device
• the duration of that exposure.

It's important to recognize that no device or material is entirely risk-free. Device designers aim to strike a balance between minimizing risks and maximizing benefits for patients when assessing biocompatibility.

Applicability and Need of Biocompatibility Data

Biocompatibility data of one kind or another is almost always required for devices that have significant tissue contact. Below table describes the best to decide;

Device Categories		Examples
Surface Device	Skin	Devices that contact intact skin surfaces only. Examples include electrodes, external prostheses, fixation tapes, compression bandages and monitors of various types.
	Mucous membrane	Devices communicating with intact mucosal membranes. Examples include contact lenses, urinary catheters, intravaginal and intraintestinal devices (stomach tubes, sigmoidoscopes, colonoscopes, gastroscopes), endotracheal tubes, bronchoscopes, dental prostheses, orthodontic devices and IUD’s.
	Breached or compromised surfaces	Devices that contact breached or otherwise compromised external body surfaces. Examples include ulcer, burn and granulation tissue dressings or healing devices and occlusive patches.
External Communicating Device	Blood path indirect	Devices that contact the blood path at one point and serve as a conduit for entry into the vascular system. Examples include solution administration sets, extension sets, transfer sets, and blood administration sets.
	Tissue/bone/dentin communicating	Devices communicating with tissue, bone, and pulp/dentin system. Examples include laparoscopes, arthroscopes, draining systems, dental cements, dental filling materials and skin staples. This category also includes devices which contact internal tissues (rather than blood contact devices). Examples include many surgical instruments and accessories.
	Circulating blood	Devices that contact circulating blood. Examples include intravascular catheters, temporary pacemaker electrodes, oxygenators, extracorporeal oxygenator tubing and accessories, hemoadsorbents and immunoabsorbents.
Implant Device	Tissue/bone	Devices principally contacting bone. Examples include orthopedic pins, plates, replacement joints, bone prostheses, cements and intraosseous devices. Devices principally contacting tissue and tissues fluid. Examples include pacemakers, drug supply devices, neuromuscular sensors and stimulators, replacement tendons, breast implants, artificial larynxes, subperiosteal implants and ligation clips.
	Blood	Devices principally contacting blood. Examples include pacemaker electrodes, artificial arteriovenous fistulae, heart valves, vascular grafts and stents, internal drug delivery catheters, and ventricular assist devices.

DEVICE CATEGORIES – DEFINITIONS & EXAMPLES

Most commonly, companies arrange for their own biocompatibility studies. They may be able to reduce the amount of testing that will need on a specific device if the have some or all of the following types of biocompatibility data.

Data from previous submissions – If data is available from a previous submission, consider the following points as apply it on current device. Manufacturer will need to perform confirmatory testing if there are significant changes in any of these areas.

• Materials selection
• Manufacturing processes
• Chemical composition of materials
• Nature of patient contact
• Sterilization methods

Data from suppliers of materials or components – If vendor data is used, manufacturers should obtain copies of the original study reports. It is important that the laboratory that generated the reports had an experienced staff, a strong track record of cGMP/GLP compliance, and an accredited report. Usually manufacturers will want to conduct at least some confirmatory testing of their own (e.g. cytotoxicity and hemocompatibility studies). Also in case of accessories or any component supplied by supplier in that case the supplier's study report will be accepted subject to the acceptance of regulatory bodies. 

Analytical data – Manufacturers may use analytical data to help demonstrate that a device has a low overall risk or a low risk of producing a given biological effect. Section 18 of ISO 10993, Chemical Characterization of Materials, gives guidance on this process.

Clinical data – Clinical data can be used to satisfy some biological effects categories from the ISO 10993-1 test selection matrix. The data may come from clinical trials of the device in question or from clinical experience with predicate devices or devices containing similar components or materials.

Considerations for Biocompatibility Testing: Evaluating Device Materials and Finished Device Composites

As a manufacturer, it's crucial to collect safety data for each component and material incorporated into your device. Furthermore, conducting testing on the finished device in accordance with ISO 10993-1 is essential. Typically, the recommended approach involves; 

• Assemble vendor data on candidate materials 
• Conduct analytical and in vitro screening of materials 
• Conduct confirmatory testing on a composite sample from the finished device

Screening device materials serves to mitigate this risk effectively. Initial chemical characterization plays a crucial role in identifying leachable materials that may pose a safety hazard to the device. Cost-effective non-animal studies, such as cytotoxicity and hemocompatibility tests, offer an additional layer of screening for material safety. Moreover, conducting material screening tests can help prevent the need for redesigning the device in case of biocompatibility test failures. Many manufacturers compile data on a repository of qualified materials utilized in their products.

Certain test procedures are not conducive to testing composite samples. Physical constraints necessitate separate testing of each device component for agar overlay or direct contact cytotoxicity tests and implant studies.

For all biocompatibility studies, test samples should be sterilized using the same method as will be used for the finished device.

Biocompatibility Requirements

The following table describe some of the specific procedures recommended for biocompatibility testing. This listing does not imply that all procedures are necessary for any given material, nor does it indicate that these are the only available tests.

Requirement	Test Name
Cytotoxicity	ISO Agar Overlay ISO MEM Elution ISO Direct Contact ISO MTT ISO Colony Formation
Sensitization	ASTM Murine Local Lymph Node Assay (LLNA) Maximization Test Closed Patch Test
Irritation	ISO Intracutaneous Test ISO Dermal Irritation ISO Ocular Irritation Mucous Membrane Irritation
Systemic Toxicity	Material Mediated Pyrogen Test ISO Acute Systemic Test Subacute Subchronic Chronic
Genotoxicity	Ames Test Mouse Lymphoma Assay Mouse Micronucleus Assay Chromosomal Aberration Test
Implantation	Implantation Test (Local effects) (All ISO Implant Tests Include Histopathology) (7 days or greater)
Hemocompatibility	Hemolysis – ASTM Direct and Indirect Contact In Vivo Thrombogenicity In Vitro Platelet Aggregation Assay Partial Thromboplastin Time (PTT) Prothrombin Time (PT) Complement Activation
Carcinogenesis	L ifetime Toxicity
Reproductive and Developmental Toxicity	Pharmacokinetic or ADME (Absorption/ Distribution/Metabolism/Excretion)
Biodegradation	Pharmacokinetic or ADME (Absorption/ Distribution/Metabolism/Excretion)
Analytical Test	USP Physicochemical Tests Other Procedures

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