Quality Management
Last Updated: 08 July 2026
International medical device compliance requires an understanding of biological safety evaluation frameworks. The ISO 10993 biological evaluation of medical devices provides the main structure for placing biological safety within risk management workflows. Manufacturers cannot rely on generic safety checklists when entering new markets.The main standard used for these evaluations is the ISO 10993 series. The ISO 10993 series was revised from the 2018 edition to the 2025 edition described in this document. For an overseas manufacturer, compliance with the updated clauses is not a surface-level, post-production activity. It is a technical process that continues throughout the medical product lifecycle and requires knowledge of device categorization, material analysis sequencing, and documentation standards.
ISO 10993 Biological Evaluation of Medical Devices and Medical Device Risk Management
Medical device manufacturers seeking biological compliance must place the biological evaluation inside a structured biological evaluation plan. This plan must directly connect with medical device risk management and the risk management framework in ISO 14971. A biological evaluation must be completed before clinical trials begin. Manufacturers have to consider the entire device lifecycle, from initial design and development through use of the finished device and final withdrawal from service. The evaluation must address biological hazards that may result from device changes over time or from tissue exposure to new materials if the device fails unexpectedly. Under the legacy provision described in the 2025 edition, manufacturers do not have to re-test devices already on the market when an acceptable safety profile has been established.
The main change from the earlier edition is that testing is no longer treated as a standalone process. The biological evaluation must form part of a structured plan under ISO 14971. Each manufacturer must identify potential hazards, estimate biological risks, locate gaps in existing data, and perform targeted assessments such as chemical analysis or hazard identification to determine the overall risk estimate.
Applicability Boundaries and Scope Exclusions
The standard applies to materials and medical devices expected to have direct or indirect contact with a patient's body during intended use or foreseeable misuse. It also applies to a user's body when the device provides protection, such as surgical gloves and masks. This includes active, non-active, implantable, and non-implantable medical devices. Certain risks are outside the scope. Manufacturers do not need to address hazards or environmental impacts from decommissioning, and risks from infectious agents such as bacteria, moulds, yeasts, viruses, transmissible spongiform encephalopathy agents, and other pathogens are excluded.
Understanding the nature of tissue contact is important when defining the testing scope. Direct contact means physical contact between a medical device or component and tissue or circulating blood. Indirect contact occurs when a device or component has no physical contact with tissue, but a fluid, semi-solid, or solid passes through it before reaching the tissue. A device or component with no direct or indirect tissue contact is non-contacting, and biocompatibility data is generally not required.
Medical Device Categorization Rules
Manufacturers must maintain risk management files using defined tissue-contact and exposure-duration boundaries. Devices are categorized by the nature of body contact, beginning with non-contacting devices and moving to surface-contacting devices. Surface-contacting devices are divided into those that contact intact skin, intact mucosal membranes, or breached and compromised body surfaces.
The latest revision replaces the term externally communicating with language that reflects the specific tissue contact of device components. It also replaces effects after implantation with local effects after tissue contact so that non-implanted devices requiring assessment are included. The invasive categories cover devices located partly or wholly outside the body that have direct or indirect contact with internal body fluids or tissues through an indirect blood path, tissue, bone, dentin, or circulating blood. Implant devices include products introduced completely into the human body or used to replace an epithelial or eye surface by clinical intervention and intended to remain after the procedure.
Exposure duration is divided into limited, prolonged, and long-term contact. Limited exposure is a cumulative duration of up to 24 hours. Prolonged exposure is more than 24 hours and up to 30 days. Long-term exposure is more than 30 days. Transitory contact is very brief, such as a lancet or hypodermic needle used for less than one minute, and testing is generally waived unless a coating or lubricant remains behind. If a device falls into more than one category, the manufacturer must apply the more rigorous evaluation rules. A contact day is counted as any day on which contact occurs, regardless of the duration of contact during that day.
International Organization for Standardization Framework and ISO 10993 Alignment
The international organization for standardization places biological evaluation within a broader group of risk, quality, and laboratory standards. This alignment helps manufacturers connect the biological safety plan with ISO 14971, laboratory controls, chemical characterization, and documented risk decisions. The ISO 10993 framework also supports consistent terminology across device categories and biological endpoints.
ISO 10993 Biological Evaluation of Medical Devices: Chemical Characterization and Testing Exemptions
A mandatory sequence governs the technical evaluation. Chemical constituents and material characterization under Part 18 must be described before biological testing begins. Physical and chemical information must be gathered first to support the overall evaluation and determine whether biological testing is needed. A testing exemption is available when sufficient information already exists for a risk assessment. If a manufacturer demonstrates biological equivalence by showing that the chemical and physical characteristics and manufacturing processes are sufficiently similar to those of a comparator device with relevant safety data, testing may be omitted through a documented rationale.
This prioritization of characterization prevents unnecessary testing and supports a focused compliance pathway. Manufacturers may use existing datasets for a medical device family when the devices share the same basic design, materials, manufacturing processes, and performance characteristics. Guidance from the international organization for standardization treats chemical data as a foundation of the biological safety file.
Technical Parameters for Material Considerations
The biological evaluation must document and assess risks for every direct and indirect tissue-contacting material. This includes intentional and unintentional compounds described as constituents. A constituent is any chemical present in or on the finished device or its materials, including additives such as plasticizers, lubricants, stabilizers, antioxidants, colouring agents, and fillers. It also includes manufacturing residues such as monomers, catalysts, solvents, sterilants, and cleaning agents, along with degradation products, reaction products, impurities, and contaminants.
Manufacturers must also document process contaminants, packaging materials that may transfer chemicals to the device and patient, leachable substances, and degradation products. Physical characteristics of the final product, including porosity, particle size, shape, and surface morphology, must be evaluated because biological hazards can arise from both chemical exposure and physical configuration.
Mandatory Assessment Documentation Requirements
A permanent Biocompatibility Evaluation Report must be prepared. It must include a general device description, geometry, engineering drawings, and quantitative material compositions for every direct or indirect contact element. Manufacturing process descriptions must identify possible contaminants, such as mould-release agents, cutting fluids, and sterilization residuals.
The technical file must also include a systematic review of toxicity literature and historical clinical exposure data, together with complete biological test reports produced under Good Laboratory Practice. It must contain a formal gap analysis that justifies the selection or waiver of endpoint tests, a statement confirming that risk analysis and controls follow ISO 14971, and the signatures and date of the expert assessors. These records support medical device risk management by linking each biological conclusion to the corresponding evidence and control.
Mandatory Re-Evaluation of Biological Risk
The biological risk assessment is not static. It must be re-evaluated when the source or specification of a material changes, or when there is a change in formulation, processing, primary packaging, or sterilization. Re-evaluation is also required when storage, transport, or shelf-life instructions change. Any change in intended use or new clinical evidence of adverse biological effects must trigger an immediate review of the biological risk profile. This continuing medical device risk management process keeps the assessment aligned with post-market information.
Laboratory Operations, Testing Conditions, and Animal Welfare
When data gaps require biological testing, the work must be performed under appropriate quality-system controls and Good Laboratory Practice. Testing facilities must maintain compliance with ISO/IEC 17025 or an equivalent internationally recognized governmental verification scheme. Chemical extracts must be prepared under Part 12, and the solvents and extraction conditions must suit the nature of the finished product and represent, at minimum, an exaggeration of use conditions.
Test method selection must also support animal welfare principles under Part 2. Manufacturers should reduce, refine, and replace animal models by using in vitro or ex vivo alternatives where possible. An animal model should be used only when chemical characterization and in vitro evidence cannot resolve the identified risk gaps. This approach reflects the relevant guidance for biological evaluation programmes.
Regulatory Frameworks for Special Materials and Pathways
Specific technical allowances and standards apply when manufacturers use non-standard materials or pathways:
Nanomaterials: Devices containing, generating, or made of materials in the nanoscale range of about 1 nm to 100 nm must address properties that differ from bulk materials. Characterization and testing should use the relevant guidance in Technical Report 22, and the release of nanoparticles through wear debris must be assessed.
Absorbable materials: Rapid release of soluble products from degrading polymers, metals, or ceramics may alter in vitro measurements by changing pH or osmolality. The test system may be adjusted to maintain physiological relevance when a scientific justification is documented and the standard and adjusted assays are compared. Toxicokinetic studies under Part 16 are required for absorbable devices.
Breathing gas pathways: Devices with gas-pathway components and indirect body contact should use product-specific standards, including the ISO 18562 series, rather than relying only on general biological evaluation parameters.
Special populations: The evaluation must identify risks to groups that may be more susceptible to biological harm, including infants, older people, chronically ill or immunocompromised patients, pregnant women, and women of childbearing age. Reproductive and developmental toxicity assessment under Part 3 applies to novel materials and relevant device uses.
Medical Device Regulatory Consulting Services from Morulaa
Morulaa HealthTech provides medical device regulatory consulting services for chemical characterization, toxicological risk assessment, biological evaluation planning, gap analysis, and regulatory submission support. Our team prepares practical compliance plans and helps manufacturers connect laboratory evidence with the technical file.
Our medical device regulatory consulting services also cover documentation review, testing strategy, comparator assessments, and responses to regulator or notified-body questions. For manufacturers updating an existing product, the team reviews material, process, packaging, sterilization, and intended-use changes before recommending additional work.
Through these medical device regulatory consulting services, manufacturers can organize evidence from ISO 10993 and related standards without repeating tests that are already supported by a sound scientific rationale. The international organization for standardization references used in the evaluation are mapped clearly to the supporting records.
Morulaa applies this regulatory support to ISO 10993 biological evaluation of medical devices projects from planning through submission, while maintaining a clear link between biological evidence, risk controls, and the final report.
Frequently Asked Questions
Does the updated framework require immediate re-testing of devices already on the market?
No. The legacy provision described in the document does not mandate re-testing when a device has an established and acceptable safety profile. Re-testing is triggered by changes such as a new material source, formulation, processing method, sterilization process, intended use, or new evidence of adverse biological effects in humans.
What must happen before biological testing begins?
Chemical constituent information and material characterization must be gathered first. The manufacturer must identify data gaps and determine whether existing information is sufficient for a risk assessment before starting biological testing
Is biological evaluation required before clinical trials?
Yes. The biological evaluation must be completed before a clinical trial begins. Clinical trials should not be used to establish the basic biocompatibility profile of the device.
How is exposure duration calculated for very brief contact?
The contact-day principle counts every day on which tissue contact occurs, regardless of how long the contact lasts during that day. Truly transitory contact of less than one minute may be exempt when no coating or lubricant remains behind.
What laboratory evidence belongs in the final biocompatibility report?
The report should include complete biological test reports produced under Good Laboratory Practice. Testing laboratories should maintain ISO/IEC 17025 compliance or an equivalent recognized verification scheme.
Can biological testing be avoided by using a comparator device?
Yes, when biological equivalence is demonstrated through a documented rationale. The chemical and physical characteristics and manufacturing processes must be sufficiently similar to a comparator with relevant safety data for the same body-contact type and duration.