Service Area

Biological Evaluation Plans

A Biological Evaluation Plan (BEP) is the first step of a medical device safety assessment.  A BEP is more than just a compliance document – Gradient will also develop a customized strategy for assessing your medical device and provide comprehensive consulting throughout the entire biological evaluation process to support compliance with the requirements of ISO 10993/18562, US FDA, and the European Union Medical Device Regulation (EU MDR).  Gradient can also provide expert consulting on specific elements of the biological evaluation process, such as gap assessments, assessing the impact of changes to your medical device for safety and regulatory compliance, testing failures, and compliance with regulations regarding endocrine-disrupting (ED) substances or those that are carcinogenic, mutagenic, or toxic to reproduction (CMR).  Gradient’s medical device team takes a practical approach to assessing biocompatibility.  While we leverage existing data whenever possible, our medical device team can also provide expert guidance in the event that testing of a device is required and can interface directly with testing laboratories.  Gradient can advise medical device manufacturers on the proper selection of solvents and test conditions, which can reduce uncertainty in chemical characterization.

Gradient’s team of experts includes board-certified toxicologists (i.e., Diplomates of the American Board of Toxicology [DABTs]), chemists, and biomedical engineers with decades of in-house experience at medical device companies and a strong track record of helping clients achieve regulatory approval and address inquiries from US FDA and EU-notified bodies (e.g., ISO 10993 series, ISO 14971, ISO 18562 series, ICH M7, EU MDR).

Gradient Expertise

  • US FDA and EU MDR Product Approval
  • Biocompatibility gap assessments
  • Review of material/manufacturing changes to a medical device
  • Strategic planning for biological safety analysis
  • Biological Evaluation Plans/Reports (BEPs/BERs)
  • ISO 10993-1 endpoint justification and/or test selection
  • ISO 10993-18 material characterization data collection and solvent selection/justification
  • Laboratory interface support
  • Toxicological risk assessment
  • Product safety and liability support

Sample Projects

EU MDR Biocompatibility and CE Marking Support for Orthopedic Implants

Gradient addressed regulatory deficiencies relating to the biocompatibility and clinical safety of four orthopedic implant systems, for the purpose of CE marking in the EU. Gradient reviewed prior regulatory submissions, compositional profiling, material specifications, biocompatibility data, and clinical histories for these devices. We collated, organized, and documented the relevant information from these sources to establish the safety of each device, their respective components, and their materials of construction. Our reports will aid in the approval of said medical devices under the EU MDR.

510(k) Biocompatibility Assessment of a Neurovascular Medical Device

Gradient provided a comprehensive Biological Evaluation Report (BER) to support a previously rejected 510(k) submission to US FDA for a neurovascular medical device. The report included a comprehensive review of biocompatibility and toxicology test reports, a critical review and risk assessment of tantalum nanoparticle toxicity, and ISO 10993-compliant toxicological risk assessments of extractable and leachable compounds from the device. Our report was submitted to US FDA as part of the device’s revised 510(k) submission.

Change Assessment for New Manufacturing Contact Chemicals

Gradient evaluated the biocompatibility and toxicological risk of several new manufacturing contact chemicals present in a medical device due to a change in its manufacturing process. We first reviewed the available information on these chemicals and developed a biological evaluation strategy for the device, which included a toxicological risk assessment, biocompatibility testing, and leveraging already-available data. We then used this strategy to assess the biocompatibility and safety of the device. Gradient conducted a toxicological risk assessment to identify potential systemic toxicity, genotoxicity, carcinogenicity, and reproductive and developmental toxicity hazards associated with the new manufacturing contact chemicals. We used the results of biocompatibility testing of the device to address local endpoints. Gradient also provided justifications for waiving testing of select endpoints based on available data.

510(k) Comprehensive Biological Evaluation for Humidified Breathing Gas Pathway Device

Gradient provided comprehensive support for a humidified breathing gas pathway device, from its inception to approval of the 510(k) submission. Gradient designed the biocompatibility testing and chemical characterization strategies for the device and identified laboratories with the most appropriate experience to conduct the testing. Pertinent information on the device’s materials of construction and rationales for the selection of testing parameters were documented in a BEP. Gradient also performed a toxicological risk assessment in accordance with the principles of ISO 18562-1 and 10993-17. We also prepared a BER that summarized and evaluated the generated data. Ultimately, Gradient provided satisfactory responses to US FDA’s questions to gain 510(k) clearance for the device.

EU MDR Biocompatibility and CE Marking Support for Implant Accessories

Gradient provided support for an EU MDR submission for implant accessories, from its inception to the approval of the submission. Gradient designed a multi-layered biocompatibility strategy to meet the submission timelines and ensure that the device received a CE mark. The strategy included a mix of testing and leveraging existing and publicly available data. We identified representative test articles and provided justifications for their selection. Ultimately, the accessories received a CE mark under the EU MDR.

EU MDR Biocompatibility and CE Marking Support of an Infusion System

Gradient provided comprehensive support for an EU MDR submission for a large family of polyvinyl chloride (PVC) infusion disposables. We interfaced directly with testing laboratories on behalf of the client to ensure the completion of biocompatibility and chemical characterization testing of the disposables. Gradient also performed toxicological risk assessments for the product line, which included extensive literature searches on specific plasticizers to evaluate their safety. Gradient evaluated the weight of the evidence from the biocompatibility testing, toxicological risk assessment, literature review, and clinical data for the device to determine its biocompatibility and safety.

Our Team