Medical Device Biocompatibility Evaluation (ISO 10993): Practical Points for PMDA Submissions

In the approval application for medical devices, biocompatibility evaluation is a crucial and unavoidable element. An evaluation based on the ISO 10993 series is required to demonstrate that devices that come into contact with the human body are biologically safe.

This article explains the practical points of biocompatibility evaluation for PMDA submissions.

What is Biocompatibility Evaluation?

Biocompatibility evaluation is the process of assessing whether a medical device causes adverse biological reactions when it comes into contact with the human body. The ISO 10993 series is widely adopted as an international evaluation standard, and evaluation based on this series is also required in Japan.

Structure of the ISO 10993 Series

ISO 10993 consists of multiple parts, each covering specific evaluation items:

Contact Classification and Required Evaluation Items

ISO 10993-1 determines the evaluation items based on the device's contact type and duration:

Contact Type

• Surface Contact: Skin, Mucous Membrane, Compromised Surface
• External Communicating: Blood, Tissue, Bone, Tooth
• Implant: Tissue, Bone, Blood

Contact Duration

• Limited: Less than 24 hours
• Prolonged: 24 hours to 30 days
• Permanent: Greater than 30 days

Many gastrointestinal endoscope accessories are classified as "mucous membrane contact, limited duration," but devices like those for ESD (Endoscopic Submucosal Dissection) that directly contact tissue require a broader scope of evaluation. Furthermore, devices such as stents and clips are classified as "implant, tissue, permanent" or "external communicating, tissue, permanent."

Practical Aspects for PMDA Submissions

Currently, structuring the evaluation process according to ISO 10993, as outlined below, is key to facilitating PMDA reviews.

Prioritization of Chemical Characterization (ISO 10993-18)

First, identify the chemical components of the materials. ISO 10993-1 stipulates that chemical information (constituent materials, manufacturing process, residues) should be confirmed initially, rather than immediately proceeding with biological testing.

Utilization of Toxicological Risk Assessment (TRA)

If leachables are identified as a result of chemical analysis, calculate the acceptable exposure limits for these substances and logically explain (ISO 10993-17) whether biological testing can be omitted or if safety can be affirmed.

Preparation of Biological Safety Evaluation Report

It is essential to prepare a report that not only attaches test results but also describes, from a risk management perspective, "why these evaluation items were selected" and "why certain tests were deemed unnecessary."

Submission in Japanese

The biocompatibility evaluation report must be submitted in Japanese (or with a Japanese summary attached).

Common Deficiencies

Insufficient Material Identification: If the chemical composition of the materials used is unclear, additional information will be requested. It is crucial to obtain Material Safety Data Sheets (SDS) and material certificates from material manufacturers.

Unclear Basis for Evaluation: Even when a test is deemed "unnecessary," the rationale (existing data, literature, etc.) must be clearly presented.

Omission of Chemical Characterization: In recent years, there has been an increasing number of cases where PMDA requests additional chemical characterization when only toxicity tests were conducted without prior chemical characterization.

Inadequate Sample Preparation Records: If records of sample preparation based on ISO 10993-12 are insufficient, the reliability of the test may be questioned.

Efficient Biocompatibility Evaluation Strategy

Step 1: Material Identification and Documentation

Identify all patient-contacting materials and document their chemical composition. Collect certificates and SDS from material manufacturers.

Step 2: Determination of Contact Classification

Determine the contact type and duration based on ISO 10993-1 and identify the necessary evaluation items.

Step 3: Collection of Existing Data

Collect data on material usage history, literature data, and approval data from other regions to identify items for which testing can be deemed unnecessary.

Step 4: Conduct Necessary Tests

For items that cannot be addressed by existing data, conduct tests at a GLP-compliant testing facility.

Step 5: Preparation of Evaluation Report

Prepare an evaluation report in accordance with the requirements of ISO 10993-1 and incorporate it into the STED (Summary of Technical Documentation).

MK Consulting Support

MK Consulting provides comprehensive support, from developing biocompatibility evaluation strategies to preparing evaluation reports. We also offer advice on selecting testing facilities, planning tests, and interpreting results.

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