Top 10 Biocompatibility Pitfalls That Cause Retesting

Why Biocompatibility Still Delays Medical Device Approvals

Biocompatibility testing is one of the most common reasons medical device submissions are delayed  or returned for costly retesting. Although the expectations under ISO 10993 are well defined, manufacturers frequently encounter avoidable pitfalls that trigger additional/repeated studies, regulatory questions, and as such, prolonged timelines. 

Below are the top 10 biocompatibility pitfalls that most often lead to retesting, supported by insights from current regulatory and technical literature.

 1.Incorrect Contact Classification

Misclassifying a medical device’s contact type or duration is one of the primary reasons biocompatibility test plans fall short. Even small misinterpretations of ISO 10993-1 exposure categories can lead to incomplete testing and predictable regulatory pushback. 

Why it causes retesting:
Incorrect classification leads to inadequate test endpoints which leads to regulators request additional testing. 

With the newly introduced version of ISO 10993-1:2025, device classifications have changed and manufacturers may find the risk classification of their device has increased. Additionally, the new inclusion of reasonably foreseeable misuse considerations in the standard may highlight changes in contact type and contact duration based on deviations from intended use, user behaviour, or the use environment. As a result, devices may fall into higher biological risk categories than previously assessed, potentially triggering the need for additional biocompatibility endpoints, updated biological risk evaluations, and revised justification within the Biological Evaluation Plan and Report.

2.Incomplete or Inappropriate Test Selection

Many failed test plans stem from selecting tests directly from the ISO 10993-1 endpoints without conducting a proper risk-based assessment. This oversight often results in either missing required endpoints or running unnecessary tests. The recommended endpoints are not a checklist for testing. It is important that the biological evaluation plan is properly documented with justifications for the testing strategy. 

3.Insufficient Risk Assessment & Justification

Biological safety evaluations that rely solely on historical data or literature, without proper bridging studies or toxicological rationale, rarely satisfy regulators. Missing or shallow justifications for test selection are a well‑documented reason for retesting, because regulators need clear evidence that past data truly applies to the current device. Without a strong scientific link between historical information and the specific materials, processes, and clinical use of the device, reviewers often insist on fresh testing to close the gaps and validate the safety profile.

4.Poor Chemical Characterisation (ISO 10993‑18 Issues)

Insufficient extractables/leachables testing such as using incorrect solvents, temperatures, or detection limits is a frequent cause of regulatory deficiencies. Chemical characterisation is the backbone of the toxicological risk assessment; gaps here almost always force retesting. It is as equally important to ensure a worst-case extraction protocol is used, as it is to ensure that the protocol is in line with expected clinical use. 

5.Testing Non‑Representative Articles

Testing raw materials, early prototypes, or simplified components instead of the final manufactured device leads to data that regulators view as invalid. Final processing conditions, such as medical device cleaning, sterilisation and packaging, often alter chemical profiles, meaning results may not reflect real-world exposure. Manufacturing cleanliness is a common cause for failure in biocompatibility testing, so ensuring this is risk assessed and considered in testing is paramount.  

Supplier datasheets are useful, but they’re not a substitute for proper material characterisation. Variability in raw materials, surface treatments, or coatings can introduce extractables that suppliers haven’t accounted for,  and regulators often flag this as insufficient evidence.

6.Material Changes Without Reassessment

Changes in resin suppliers, colorants, coatings, sterilisation parameters, or process additives can all affect biological safety. When such changes occur without updated justification or testing, regulatory bodies typically require retesting to validate safety. It is important that manufacturers have robust change notification processes with material suppliers to ensure formulation alterations can be duly assessed before coming into effect.  

7.Using Outdated or Non‑Compliant Test Methods

Standards evolve, and what was compliant three years ago may not satisfy regulators today. Using old methodologies or not meeting GLP expectations is a guaranteed way to be asked for updated testing. Additionally, re-testing without completing a gap analysis to the new standard is also not acceptable and does not meet the ethical requirements of the 3Rs (Reduce, Refine, Replace) for animal testing. Re-testing should only be considered if the gap analysis indicates sufficient data gaps that need to be addressed through new or repeated studies. 

 8.Laboratory or Protocol Deviations

Using non‑accredited labs, incorrect extraction conditions, or test protocols that don’t meet ISO/FDA expectations will almost always result in invalidation of data. Retesting becomes unavoidable when studies fail to replicate clinical worst‑case conditions, because regulators can’t rely on results that don’t accurately reflect how the device behaves in use. When the testing environment or methodology isn’t robust enough to capture realistic exposure scenarios, reviewers typically require fresh studies to ensure the safety assessment is both reliable and scientifically defensible. 

9.Overlooking Real‑World Use Conditions

Devices may pass controlled laboratory tests yet fail when exposed to real‑world conditions such as temperature fluctuations, sterilisation cycles, humidity, or clinical chemical exposures. Failure to simulate worst‑case scenarios in extractables and leachables testing frequently triggers additional analysis, because regulators need confidence that the device will remain safe under the harshest conditions it could reasonably encounter. When testing doesn’t capture these real‑world stresses, reviewers often request further studies to ensure the chemical profile reflects true clinical use rather than idealised laboratory settings. 

This is why it is important to include life-cycle within the risk evaluation of the biological evaluation plan. Considerations of aged devices, reprocessed devices, transport and storage should all be considered.  

10.Inadequate Integration with Risk Management

Biocompatibility is not a standalone exercise – it sits within the broader ISO 14971 risk management process, and the two must move in lockstep. When biological evaluation plans (BEPs) aren’t aligned with the risk files, gaps start to appear in the narrative of how the device’s safety has been assessed. These inconsistencies make it difficult for regulators to follow the logic behind your medical device testing strategy, often prompting requests for additional evidence or confirmatory testing to close the loop. Ensuring your BEP clearly connects materials, chemistry, hazards, and mitigations to the overall risk management framework is essential to avoid unnecessary retesting. The updates to ISO 10993-1:2025 now harmonises terminology with ISO 14971 to allow for smoother integration. 

Endnote

Retesting is costly, delays approvals, and complicates manufacturing timelines. Fortunately, each of these pitfalls is preventable. A strong risk-based strategy, robust chemical characterisation, accurate medical device classification, and alignment with current regulatory expectations form the foundation of a successful biocompatibility program. 

At Test Labs UK, we help manufacturers design biocompatibility strategies that avoid these pitfalls, reduce retesting, and accelerate submission timelines.