Strategizing Biocompatibility Evaluation in Changing Manufacturing Environments

When do you Approach Subject Matter Experts?

In a dynamic manufacturing environment, changes are inevitable. Ensuring medical device safety is very crucial, particularly when changes occur in suppliers, raw materials, manufacturing processes, and sites. These changes are sometimes necessary for improving process efficiency, cost-effectiveness, meeting supply chain demands or complying with upcoming regulations. However, these changes may introduce potential biological risks to medical devices that should be meticulously evaluated to protect consumer health as well as to maintain regulatory compliance.

The ISO 10993-1 standard outlines a systematic approach to the biological evaluation of medical devices. Per Clause 4.9 of ISO 10993-1, the biological risk assessment of materials or final products should be re-evaluated if any of the following changes occur:

1. Source or specification of materials
2. Formulation, processing, packaging, or sterilization
3. Manufacturer’s instructions or storage expectations
4. Intended use of the product
5. Evidence of adverse biological effects in humans

In addition, these changes must be evaluated according to the current standards. This blog will provide high level insights into some of the above scenarios, focusing on the requirements for the biological evaluation and the associated risk assessments.

Before Implementation:

It is highly recommended to consult with subject matter experts before implementing changes in manufacturing. The role of subject matter experts, biocompatibility specialists, and regulatory experts cannot be underestimated. Engaging them at the very early stages will help to avoid unnecessary costs with testing or potential failures. These specialists provide invaluable insights into the potential biological risks associated with new materials and processes, ensuring that all components meet stringent safety standards for the medical devices.

1) Change in Raw Materials or Supplier Change

Raw materials are the building blocks for any product, and changes in these materials can significantly impact the safety of the product. The new composition, presence of potential additives, color pigments, or impurities should be thoroughly evaluated. Manufacturers need to ensure the raw materials are safe by rigorous testing and validation processes. In the case of supplier change, supplier reliability, quality control, consistency in composition and manufacturing process must be evaluated. Conducting a risk assessment to identify any potential issues and understanding the new material’s biological and toxicological properties is a must.

2) Change in Formulation, Processing, Packaging or Sterilization

For formulation changes, the chemical composition, potential interactions between the new ingredients with overall composition, and stability of the product need to be assessed. Processing changes require a thorough evaluation of manufacturing conditions, any new equipment, manufacturing aids and potential contamination risks from those new materials. For packaging modifications, the type of packaging material, the new material’s compatibility with the product, barrier properties, and stability under various environmental and shipping conditions should be verified. Sterilization changes need to confirm the product integrity is not compromised while removing the bioburden. All these manufacturing changes should be documented clearly and evaluated through a risk assessment process to ensure regulatory compliance and product safety.

3) Change in Manufacturer’s Instructions or Storage Expectations

For manufacturing instructions, the changes need to be clearly documented. The impact of new or changed instructions on the manufacturing processes, operating personnel, final product and the intended clinical use should be evaluated. For storage conditions, product integrity under the new storage conditions and other environmental factors must be evaluated. A thorough risk assessment may help to avoid any unnecessary testing.

4) Change in Intended Use

Whether the new intended use can introduce any different risks that were not previously evaluated, the effect of those risks in the patient populations, and any new at-risk populations should be identified and evaluated. The level of regulatory requirements may be determined by the extent of the change in the new intended use. This may even trigger the need for updated submissions, labelling changes, and possibly require new clinical data to support the change. Risk assessments should be performed to identify any new hazards, training requirements or revisions to existing Instructions For Use to reflect the modifications.

5) Evidence of Adverse Biological Effects in Humans

This is the most important change of all the above scenarios. Any new, unexpected adverse effects require immediate attention and thorough evaluation. This may also include reviewing post-market surveillance data, clinical reports, and customer complaints to understand the nature and severity of the new adverse effects. A detailed risk assessment may include review of product design, materials of construction, or manufacturing processes. Root cause analysis, and corrective and preventive actions may also be needed.

When is Biological Testing Not Necessary?

It should be noted that not all changes to a medical device or its components, including manufacturing changes, require additional biological testing. For example, if the material characterization (e.g., physical and chemical) demonstrates equivalence to a previously assessed medical device or the material and if there is sufficient information to perform the risk assessment, biological equivalence to the existing approved device can be established. The key to a strong biological equivalency argument lies in physical and chemical data and a thorough understanding of the toxicological and biological mechanisms involved. If the material characterization suggests appropriate chemical equivalency cannot be established, further testing might be needed. Regulatory variations can lead to additional challenges and may influence the requirements of biological testing. Refer to our previous post on Challenges of Demonstrating Biological Equivalence per ISO 10993-18 and EU MDR – MED Institute.

When is Biological Testing Required?

If the biological risk assessment reveals gaps in evidence, testing may be required. Extractable testing can help to address deficiencies in chemical properties, while surface characterization may help to address a data gap in physical properties. If the bench testing cannot provide sufficient evidence, biological testing should be considered. It is not necessary to repeat all biocompatibility tests; only the biological endpoints where there is a lack of evidence should be performed. Refer to our previous posts Physical Characterization and Chemical Characterization to understand more on this topic.

In conclusion, ensuring product safety amid manufacturing changes, including changes in suppliers, raw materials, cleaning agents, processes, and manufacturing sites requires a diligent and systematic biological evaluation. As stated in the 10993-1 standard, expert assessors with the necessary knowledge and experience should evaluate the biological hazards. By conducting thorough testing and validation at each stage of the manufacturing process, experts can identify and mitigate potential biological risks, thereby ensuring the safety and efficacy of the medical device.

MED Institute offers a wide range of services in testing and consulting, providing expertise in many areas including biological evaluation planning to support a variety of manufacturing changes. Contact us today to discuss your needs.