Part 3 of 3:

When Justifications Must Work Harder

Building Defensible Strategies for Complex

Surface-Contacting Devices

This is the final post in a three-part series on biocompatibility justifications. Part 1 established the foundation of FDA's evaluation framework. Part 2 covered the Attachment G opportunity for intact skin contact devices. This post addresses the complex cases where Attachment G doesn't apply. 

When the Easy Path Closes 

Part 2 covered the most successful justification pathway—Attachment G for intact skin contact devices. But many devices don't qualify: those contacting mucosal membranes, compromised skin, or used long-term in ways that trigger exclusions. For these devices, justifications become substantially more complex and must work harder to succeed.

Our recurring example illustrates this perfectly. The compression bandage with intact skin contact (Scenario A) succeeds via Attachment G with minimal testing—as covered in Part 2. But the same materials in a wound management application (Scenario B, long-term compromised skin contact) requires a fundamentally different approach.

This post addresses how to build defensible justification strategies when the easy path isn't available, common failure modes that derail submissions, and how to determine the right balance between testing and justification. 

The Complex Case: Our Wound Management Scenario

For our compression bandage in wound management application:

• Contact type: Compromised/broken skin (wound bed)

• Contact duration: Long-term (>30 days for chronic wounds)

• Materials: Same medical-grade silicone, acrylic adhesive, polyester fabric

This scenario triggers significantly more biocompatibility requirements. Per ISO 10993-1 and FDA guidance, surface devices contacting compromised skin for long-term duration require multiple endpoints:

Typically Required Testing:

• Cytotoxicity (ISO 10993-5)

• Sensitization (ISO 10993-10)

• Irritation (ISO 10993-23)

Potentially Required Testing:

• Acute Systemic Toxicity (ISO 10993-11)

• Subacute/Subchronic Toxicity (ISO 10993-11)

• Genotoxicity (ISO 10993-3)

• Material-Mediated Pyrogenicity

The strategic question becomes: Of these required endpoints, which absolutely must be tested, which can be justified through other evidence, and how? 

Strategic Justification Approaches 

When Attachment G doesn't apply, the goal shifts from avoiding testing entirely to minimizing testing while maintaining defensibility. Several strategies work in combination: 

Strategy 1: Chemical Characterization as Foundation

Chemical characterization combined with toxicological risk assessment (TRA) provides the strongest justification approach for compromised skin contact devices. Chemical characterization can be considered supportive or an alternative to biological testing for evaluating some biocompatibility endpoints when followed by a toxicological risk assessment described in the ISO 10993-17 standard.

The Approach:

1. Conduct comprehensive ISO 10993-18 chemical characterization on the final, sterilized device

2. Identify all extractables and leachables at appropriate Analytical Evaluation Thresholds (AET).

3. Have qualified toxicologist conduct ISO 10993-17 toxicological risk assessment (TRA)

4. Use TRA results to justify reduced biological testing where appropriate

What This Enables:

• Acute systemic toxicity, subchronic toxicity, and genotoxicity may be addressed via TRA when extractables are well-characterized and below toxicological thresholds

• Reduced burden on biological testing for endpoints where chemical data provides clear answers

• Defensible scientific rationale for testing reductions

What This Doesn't Eliminate:

• Cytotoxicity, irritation, and sensitization typically still require biological testing for compromised skin contact

• These tests are relatively quick and inexpensive—FDA expects them

• Chemical data alone does not substitute for these endpoints 

Strategy 2: Master Access File Leverage 

OEMs may be able to reduce the amount of testing needed by leveraging biocompatibility data provided by their material suppliers in the form of a Master Access File (MAF). Master Access Files may include formulation information, sterilization compatibility, recommended processing methods, ISO 10993 test results, and other data that can help FDA reviewers assess biocompatibility. 

How MAFs Work:

• Material supplier submits comprehensive data to FDA

• Supplier authorizes you to reference their MAF in your submission

• FDA reviews the MAF to verify supplier's data

• You avoid duplicating testing the supplier has already conducted

Critical Considerations:

• MAFs cover raw material, not your finished device, so if you are not modifying the finished device in any way from the raw material, it may apply directly.

• Your manufacturing process may alter biocompatibility

• MAF authorization requires explicit supplier permission

• Not all suppliers maintain MAFs—ask explicitly during supplier selection

Practical Tip: When selecting material suppliers for new devices, MAF availability should be a major selection criterion. The question "Do you have a Master Access File registered with FDA, and will you authorize us to reference it?" can save tens of thousands of dollars in testing. 

Strategy 3: Leveraging Your Own Cleared Devices

While Attachment G doesn't apply to our wound management scenario, your existing portfolio still provides value:

For Our Scenario: If your company already markets a similar compression bandage for intact skin (Scenario A is already cleared), this provides a foundation: 

• Established materials with internal performance history

• Validated manufacturing processes

• Quality system maturity for these material types

• Documented supplier qualifications 

What This Provides: 

• Strong starting point for new device biological evaluation

• Reduces overall risk assessment burden

• Supports rationale for testing strategy decisions

• Demonstrates manufacturing controls 

What This Doesn't Eliminate:

• Additional endpoints required for new application (compromised skin, long-term)

• Need for chemical characterization specific to new device

• Required testing for endpoints not previously evaluated

The change from intact to compromised skin is material:

• Wound contact involves greater extractable absorption

• Compromised skin barrier function increases systemic exposure risk

• Longer duration changes risk profile

• Wound exudate may interact with materials differently

Strategy 4: Predicate Device Context

Identifying legally marketed wound dressings using similar materials supports overall reasonableness but cannot replace required testing:

• Document predicate clinical history (years on market, complaint rates)

• Use to support reasonableness of your testing strategy

• Provides context for risk assessment

• Cannot stand alone as primary justification 

What the Complete Submission Looks Like 

For the wound management scenario, the biocompatibility section becomes substantially more involved: 

Section 1: Device Description and Risk Analysis (5-10 pages)

• Complete device description with materials and components

• Manufacturing process overview

• Intended use and clinical context

• Risk analysis per ISO 14971

• Categorization rationale per ISO 10993-1

Section 2: Biological Evaluation Plan (10-15 pages)

• Device categorization (surface device, compromised skin, long-term)

• Required endpoints identification with rationale

• Testing strategy with justifications for each endpoint

• Reference to FDA guidance and standards

• Clear statement of what's tested, what's justified, and why

Section 3: Materials Information (5-10 pages)

• Detailed materials specifications

• Supplier qualification documentation

• MAF references where applicable

• Material history of use in similar applications

• Manufacturing process details

Section 4: Chemical Characterization Report (20-40 pages)

• ISO 10993-18 study report

• Analytical methods used (GC-MS, LC-MS, ICP-MS)

• Identified extractables with concentrations

• Analytical Evaluation Threshold justification

• Complete extractables profile

Section 5: Toxicological Risk Assessment (10-30 pages)

• ISO 10993-17 evaluation by qualified toxicologist

• Patient exposure calculations

• Comparison to safety thresholds

• Risk characterization for each identified compound

• Conclusion on biocompatibility risks

Section 6: Biological Testing Reports (varies by testing)

• Cytotoxicity test report

• Sensitization test report

• Irritation test report (using appropriate compromised skin model)

• Additional endpoints as required

Section 7: Biological Evaluation Report (10-15 pages)

• Synthesis of all evidence

• Conclusion on overall biocompatibility

• Justification for any tests not conducted

• Clear traceability from risk to evidence to conclusion

Total Submission Length: 60-130 pages compared to 5-10 pages for the Attachment G submission in Part 2. 

Common Failure Modes 

Understanding why complex justifications fail helps you avoid these pitfalls: 

Failure Mode 1: "Same Material" Confusion

The Mistake: "Our device uses silicone, which is biocompatible. We don't need to test."

Why It Fails: "Silicone" describes a chemical class with thousands of formulations. Different silicones have different additives, fillers, and curing systems. Medical-grade silicone from one supplier ≠ medical-grade silicone from another.

The Fix: Specify exact material grade, supplier, and specifications. Reference supplier MAF when available. Provide certificate of analysis for production lots.

Failure Mode 2: Ignoring Manufacturing Effects

The Mistake: "This is the same material used in cleared device XYZ. Therefore biocompatibility is established."

Why It Fails: Manufacturing process affects extractables. Cleaning agents, mold release agents, machining residues, sterilization effects—all can change biocompatibility regardless of starting material.

The Fix: Address full manufacturing chain. Document any differences from the referenced device. Consider chemical characterization to confirm equivalence.

Failure Mode 3: TRA Without Proper Expertise

The Mistake: Quality engineer or regulatory specialist conducts toxicological risk assessment based on internet research.

Why It Fails: TRA requires specialized toxicology training. Threshold determinations require nuanced understanding. Database interpretations require expertise. FDA reviewers can identify amateur work quickly.

The Fix: Engage qualified toxicologist (DABT, ERT, or equivalent credentials). Document toxicologist's qualifications in submission. Use established methodologies (ICH Q3D, M7, etc.).

Failure Mode 4: Long-Term Contact Assumptions

The Mistake: "We tested for limited contact biocompatibility on a similar device. This new long-term contact device should be fine."

Why It Fails: Long-term contact requires additional endpoints (subchronic toxicity, genotoxicity). Longer exposure means more cumulative dose. Different testing models may apply.

The Fix: Test specifically for the contact duration of your device. Don't assume limited-contact data covers long-term contact.

Failure Mode 5: Outdated Predicate References

The Mistake: "Our device is similar to the predicate K-XXXXXX cleared in 2008. They didn't do extensive biocompatibility testing, so we shouldn't need to either."

Why It Fails: Standards have evolved significantly. ISO 10993-1:2018 and now 2025 emphasize chemical characterization and risk-based assessment that older submissions didn't address.

The Fix: Test to current standards. Don't assume what was acceptable for older predicates is acceptable for new submissions.

Failure Mode 6: Insufficient Documentation Quality

The Mistake: Submitting supplier certificates and brief statements as biocompatibility justification.

Why It Fails: FDA wants to see actual data and rigorous analysis, not just claims and certifications. Supplier biocompatibility statements are often based on general data, not your specific device.

The Fix: Obtain detailed test reports. Reference MAFs through proper channels. Document specific testing performed. Build comprehensive Biological Evaluation Reports.

The Decision Framework

When facing a complex biocompatibility evaluation, work through these strategic questions:

Question 1: What Endpoints Are Absolutely Required?

Some endpoints almost always require biological testing for compromised skin contact:

• Cytotoxicity (relatively quick and inexpensive—test it)

• Irritation (different testing for compromised skin—test it)

• Sensitization (may be justifiable with very strong chemical data, but usually test)

Question 2: What Can Be Justified Through TRA?

These endpoints can often be addressed via comprehensive chemical characterization plus toxicological risk assessment:

• Acute systemic toxicity (if extractables well-characterized)

• Subchronic toxicity (with adequate exposure analysis)

• Genotoxicity (if no genotoxic compounds identified)

Question 3: What Evidence Do You Have?

Map your available evidence to the endpoints:

• Prior cleared devices in your portfolio?

• Material supplier MAFs available?

• Chemical characterization data?

• Toxicological expertise on staff or contracted?

Question 4: Where Are Your Highest Risks?

Focus testing investment on highest-risk areas:

• Novel material combinations

• Longer contact durations

• More sensitive tissue contact

• Patient populations with elevated risk

Question 5: Should You Use a Q-Submission?

For ambiguous situations, FDA's Q-Submission process provides invaluable guidance:

• "Is our proposed testing strategy adequate?"

• "Can we justify [specific endpoint] based on [specific evidence]?"

• "Does our chemical characterization approach meet expectations?"

Q-Sub feedback within 75-90 days can prevent months of misdirected effort.

When to Test vs. When to Justify

Use this framework to determine the right balance:

Test (don't try to justify):

• Cytotoxicity for compromised skin contact

• Irritation for compromised skin or mucosal contact

• Endpoints where your evidence is Tier 3 (literature/predicates only)

• New material combinations without precedent

• Standards-required tests with reasonable cost/timeline

Justify (with appropriate evidence):

• Systemic toxicity endpoints when chemical characterization is comprehensive

• Endpoints covered by your own cleared devices with equivalent manufacturing

• Endpoints addressed by qualified TRA based on identified extractables
  

• Areas where supplier MAFs provide robust supporting data

The Strategic Insight: Don't approach biocompatibility justifications as testing avoidance. Approach them as risk management. The question isn't "How do we avoid testing?" but rather "What's the appropriate evidence to demonstrate our device is biologically safe for its intended use?"

Real-World Cost and Timeline Impact

The complexity of compromised skin contact submissions has real business implications:

Attachment G Path (Scenario A):

• Cost: $5,000-$10,000 for documentation

• Timeline: 1-2 months to prepare

• Submission section: 5-10 pages

• Review impact: Generally smooth review

Full Biocompatibility Path (Scenario B):

• Cost: $80,000-$200,000+ for testing and characterization

• Timeline: 6-12 months for testing and report generation

• Submission section: 60-130 pages

• Review impact: More questions, longer review

The Cost of Failed Justifications:

• Initial path: 6-9 months of work

• Failure detected at FDA: Additional 6-9 months minimum

• Additional testing: $75,000-$200,000 unexpected costs

• Market opportunity cost: Often the largest impact

This is why getting the strategy right at the start matters. Investment in proper biological evaluation planning pays dividends across the development lifecycle.

Key Takeaways from Part 3

1. When Attachment G doesn't apply, justifications become substantially more complex—but strategic approaches still reduce burden significantly.

2. Chemical characterization plus TRA is your most powerful tool—it can justify reduced testing for some endpoints while supporting overall biocompatibility conclusions.

3. Cytotoxicity, irritation, and sensitization typically require testing for compromised skin contact regardless of other evidence.

4. Common failure modes are predictable: same material confusion, ignoring manufacturing effects, inadequate toxicology expertise, long-term contact assumptions, and outdated predicates.

5. Strategic balance matters: don't avoid all testing, but don't accept unnecessary testing either. Match evidence to risk thoughtfully.

Conclusion: The Three-Part Picture

Across this series, we've built a complete picture of biocompatibility justification strategy:

Part 1 established that FDA's standards are narrower than most manufacturers assume, with a three-tier hierarchy of evidence strength. Justifications based on Tier 3 (literature/predicates alone) typically fail. Tier 1 (your own cleared devices) and Tier 2 (Attachment G) succeed reliably when applicable.

Part 2 detailed the Attachment G opportunity for intact skin contact devices—a genuine pathway to skip biocompatibility testing for qualifying devices. Our compression bandage scenario A (limited intact skin) succeeds via this pathway with dramatically reduced submission burden.

Part 3 (this post) addressed the complex cases where Attachment G doesn't apply. Our compression bandage scenario B (long-term compromised skin) requires significant testing but allows strategic justification to reduce overall burden through chemical characterization, TRA, and leveraging existing evidence.

The Overarching Insight: Quality and regulatory professionals who excel at biocompatibility justifications match evidence to risk thoughtfully. They:

• Recognize when justifications can succeed and pursue them aggressively

• Recognize when testing is necessary and budget appropriately

• Build comprehensive Biological Evaluation Plans that demonstrate genuine safety analysis

• Engage qualified expertise for toxicological risk assessment

• Use FDA's Q-Submission process for ambiguous cases

The manufacturers who get this right save substantial time and money while maintaining high safety standards. Those who get it wrong face delays, additional costs, and sometimes regulatory rejection.

The difference isn't about being clever or aggressive with regulatory strategy. It's about understanding the standards genuinely, applying frameworks appropriately, and building submissions that demonstrate real safety analysis—not just compliance gymnastics.

For your next submission, start with the Tier framework from Part 1, evaluate Attachment G applicability per Part 2, and apply the strategic frameworks from this post for complex cases.

The investment in proper biocompatibility justification strategy pays dividends in faster clearances, lower costs, and stronger regulatory positions throughout your product portfolio.

Previous posts in this series: Part 1 — The Justification Mindset Part 2 — The Attachment G Opportunity

Estimated length: 7 pages Reading time: 14-16 minutes

Need help evaluating your specific biocompatibility justification strategy? Contact our team for a consultation on your device development pipeline.