PRIVILEGED AND CONFIDENTIAL — ATTORNEY-CLIENT COMMUNICATION / ATTORNEY WORK PRODUCT
CALDERWOOD & HARKNESS LLP Attorneys at Law 1401 K Street NW, Suite 900 Washington, D.C. 20005 Telephone: (202) 555-7400 Facsimile: (202) 555-7401
MEMORANDUM
To: Dr. Niamh Tierney, Vice President of Regulatory Affairs, Solstice Biomedical Devices Ltd. Marcus Hale, Vice President of U.S. Operations, Solstice Biomedical Inc. Dr. Aisling Burke, Chief Technology Officer, Solstice Biomedical Devices Ltd. Fiona Drennan, Quality Assurance Director, Solstice Biomedical Devices Ltd.
From: Miriam Calloway, Partner, Calderwood & Harkness LLP Amy Whitfield, Associate, Calderwood & Harkness LLP
Date: May 12, 2025
Re: Biocompatibility Testing Strategy — Solstice Lumina™ CGM System (Lumina C14 Sensor and Lumina R7 Reader/Transmitter)
Engagement Reference: 1037-00002
This memorandum is a confidential attorney-client communication and constitutes attorney work product prepared in anticipation of regulatory proceedings. It is intended solely for the addressees listed above and authorized representatives of Solstice Biomedical Devices Ltd. and Solstice Biomedical Inc. (collectively, "Solstice" or "SBD"). This document should not be disclosed to any third party without the prior written consent of Calderwood & Harkness LLP. Inadvertent disclosure of this memorandum does not constitute a waiver of any applicable privilege or work-product protection.
Right-click to update Table of Contents
I. Executive Summary
This memorandum analyzes the proposed biocompatibility testing program for the Solstice Lumina™ Continuous Glucose Monitoring ("CGM") System, encompassing both the Lumina C14 implantable sensor (the "C14 Sensor") and the Lumina R7 wearable reader/transmitter (the "R7 Reader"), in support of Solstice's planned traditional 510(k) premarket notification submission covering both the C14 Sensor and R7 Reader as an integrated system. The purpose of this memorandum is to evaluate the adequacy and regulatory defensibility of the proposed testing scope, identify gaps against applicable FDA expectations, and provide actionable recommendations to position the testing program for successful review by the U.S. Food and Drug Administration ("FDA").
Biocompatibility testing is being conducted by Whitmore Laboratories Inc. ("Whitmore"), located at 1625 Shady Grove Road, Suite 300, Gaithersburg, Maryland 20878. Whitmore holds A2LA Certificate No. 3847.01 and is accredited under ISO/IEC 17025:2017 for biological testing of medical devices. The engagement with Whitmore commenced on March 3, 2025, under the direction of Dr. James Haverford, Whitmore's Director of Biocompatibility Testing. The estimated total testing budget is $485,000, per Whitmore's formal quotation dated March 3, 2025.
The target completion date for all biocompatibility testing is August 31, 2025. This date represents a critical path item in the overall regulatory timeline. Completion by this date is necessary to support: (a) commencement of the LUMINA-US pivotal clinical study on September 15, 2025, as biocompatibility data forms part of the Investigator's Brochure and study safety documentation; and (b) the ultimate 510(k) submission target of April 30, 2026. Preliminary biocompatibility data or testing plan summaries will also be relevant to the Pre-Submission ("Pre-Sub") meeting currently scheduled for August 14, 2025, with the meeting package due to FDA by June 16, 2025.
The biocompatibility testing program has been designed in accordance with ISO 10993-1:2018 (Biological evaluation of medical devices — Part 1: Evaluation and review within a risk management process) and FDA's current guidance document titled "Use of International Standard ISO 10993-1, 'Biological evaluation of medical devices — Part 1: Evaluation and review within a risk management process'" (updated September 2020). Additionally, Pinnacle Regulatory Consulting Group LLC ("Pinnacle"), through its principals Dr. Sandra Ellison and Thomas Greenbaum, contributed to technical summaries and protocol design for the testing program and will play an ongoing role in preparing the biocompatibility section of the 510(k) submission.
Our principal finding is that the proposed testing scope is broadly adequate to satisfy FDA's biocompatibility data expectations for both the C14 Sensor and R7 Reader. However, certain areas warrant close attention and potential supplementation. Most notably, the novel PtIr-4G electrode coating employed on the C14 Sensor — Solstice's proprietary fourth-generation platinum-iridium alloy technology — represents a material composition that differs from the standard platinum electrode used in the primary predicate device and may draw additional FDA scrutiny during 510(k) review. The PtIr-4G coating lacks the extensive historical biocompatibility data available for platinum-only electrodes, and FDA may characterize this as a new technological characteristic requiring independent, standalone biocompatibility evaluation.
We also note that Solstice has obtained EU MDR CE certification for the Lumina CGM System (certificate number MCA-2024-07319, issued September 12, 2024, by Meridian Conformity Assessment GmbH, Notified Body 0483). Biocompatibility testing data generated in support of the EU certification may partially support the FDA submission. However, supplementation will be needed to address U.S.-specific requirements, including alignment with current ISO 10993 standard editions and FDA's September 2020 guidance expectations regarding chemical characterization.
The sections that follow provide a detailed analysis of the applicable regulatory framework, the proposed testing scope for each device component, a gap analysis against FDA expectations, special considerations relating to the PtIr-4G electrode coating, budget and timeline analysis, and specific recommendations for action.
II. Regulatory Framework for Biocompatibility Assessment
A. Applicable Standards and Guidance
The biocompatibility evaluation of medical devices in the United States is governed by an interlocking framework of international standards and FDA-specific guidance. The following standards and guidance documents form the primary regulatory basis for the Lumina CGM System biocompatibility testing program:
ISO 10993-1:2018 — Biological evaluation of medical devices — Part 1: Evaluation and review within a risk management process. This is the foundational international standard for biocompatibility evaluation. It establishes a risk-based framework for determining the appropriate biological evaluation endpoints for a given device based on the nature, duration, and frequency of body contact. Table A.1 of ISO 10993-1:2018 provides the endpoint matrix that maps device contact categories to recommended biological evaluation tests. This standard is recognized by FDA as a consensus standard for biocompatibility evaluation.
FDA Guidance Document: "Use of International Standard ISO 10993-1, 'Biological evaluation of medical devices — Part 1: Evaluation and review within a risk management process'" (updated September 2020). This guidance document reflects FDA's recommended approach to biological evaluation and supplements the ISO standard with FDA-specific expectations. Notably, the September 2020 update incorporates a strengthened emphasis on chemical characterization as a foundational element of the biological evaluation process — potentially reducing the need for certain animal-based tests where adequate chemical characterization data demonstrates low risk. The guidance also provides FDA's perspective on the use of risk-based arguments to justify modifications to the testing scope recommended under ISO 10993-1.
In addition to the overarching ISO 10993-1 standard, multiple individual parts of the ISO 10993 series are applicable to specific test endpoints within the testing program. These include, among others, ISO 10993-3 (genotoxicity), ISO 10993-4 (hemocompatibility), ISO 10993-5 (cytotoxicity), ISO 10993-6 (implantation), ISO 10993-10 (sensitization), ISO 10993-11 (systemic toxicity), ISO 10993-12 (sample preparation), ISO 10993-18 (chemical characterization), and ISO 10993-23 (irritation). The specific applicable editions are detailed in the test-by-test analysis in Sections III and IV below and compiled in Appendix C.
From a device classification standpoint, the Lumina CGM System falls under 21 C.F.R. § 862.1355 (glucose test system), which is classified as a Class II medical device under FDA product code QKQ. As a Class II device, the Lumina CGM System is subject to the premarket notification (510(k)) pathway, and the 510(k) submission must include adequate biocompatibility data to support a determination of substantial equivalence to the identified predicate devices.
FDA's expectations for biocompatibility data in 510(k) submissions are well established. Biocompatibility data must be included in the submission package, and the biological evaluation is assessed based on the nature and duration of body contact, the types of patient-contacting materials used in the device, and the degree to which the device's materials and patient contact characteristics differ from those of the predicate device. For the Lumina CGM System, the presence of the novel PtIr-4G electrode coating on the C14 Sensor introduces a material difference from the predicate that will require specific attention.
B. Device Contact Classification Under ISO 10993-1
The biological evaluation endpoints applicable to a medical device are determined by its contact classification under ISO 10993-1:2018. The Lumina CGM System comprises two distinct components with fundamentally different contact profiles, which must be evaluated separately.
Lumina C14 Sensor
The C14 Sensor is an implantable device designed for subcutaneous insertion. It is placed beneath the skin surface, typically in the upper arm or abdomen, where the sensor electrode resides in the interstitial fluid space for continuous glucose measurement over a 14-day (336-hour) wear period.
Under ISO 10993-1:2018 Table A.1, the C14 Sensor is classified as follows:
• Body contact nature: Implant device (subcutaneous placement)
• Contact duration category: Prolonged — under ISO 10993-1:2018, contact exceeding 24 hours but not exceeding 30 days is classified as "prolonged" contact. The C14 Sensor's 14-day continuous wear period (336 hours) falls squarely within this category.
• Tissue contact type: Subcutaneous tissue and blood. The sensor's insertion into the interstitial fluid space involves direct contact with subcutaneous tissue. Additionally, the insertion process and ongoing subcutaneous presence involve potential incidental blood contact, as the sensor electrode may contact capillary blood in the interstitial space.
This classification — implant device, prolonged contact, tissue and blood contact — triggers the most extensive set of biological testing endpoints under ISO 10993-1:2018 Table A.1. The applicable endpoints include cytotoxicity, sensitization, irritation or intracutaneous reactivity, acute systemic toxicity, subchronic toxicity (subacute toxicity), implantation, hemocompatibility, and genotoxicity. All eight of these endpoints are included in the proposed Whitmore testing program for the C14 Sensor.
Lumina R7 Reader/Transmitter
The R7 Reader is an arm-worn external device that affixes to the skin surface overlying the implanted C14 Sensor. It communicates wirelessly with the C14 Sensor to receive glucose data, processes and displays glucose readings, and transmits data to the user's smartphone application. The R7 Reader is worn continuously on the upper arm during the 14-day sensor wear period and is attached to the skin via an adhesive patch.
Under ISO 10993-1:2018 Table A.1, the R7 Reader is classified as follows:
• Body contact nature: Surface-contacting device (external communicating — skin contact)
• Contact duration category: Prolonged — the R7 Reader is worn continuously during the 14-day sensor wear period, exceeding 24 hours.
• Tissue contact type: Intact skin surface. The R7 Reader contacts only the external, intact skin surface and does not penetrate the skin barrier.
This classification — surface-contacting device, intact skin, prolonged contact — triggers a more limited set of biological testing endpoints compared to the C14 Sensor. Under ISO 10993-1:2018 Table A.1, the applicable endpoints for this category include cytotoxicity, sensitization, and irritation. These three endpoints are included in the proposed Whitmore testing program for the R7 Reader, and no additional endpoints are recommended under the standard for this device category.
C. Comparison to Predicate Device Biocompatibility Data
The selection and scope of biocompatibility testing for a 510(k) submission must be considered in the context of the identified predicate devices and the degree to which the subject device's patient-contacting materials differ from those of the predicates. Two predicate devices have been identified for the Lumina CGM System:
Primary Predicate: NovaSense GlucoTrack NX-500 (K211034). The NX-500 was cleared by FDA on June 18, 2022. It is a CGM system featuring a 10-day subcutaneous sensor with a platinum electrode and a handheld reader device. Biocompatibility data for the NX-500 is on file with FDA and covers both the platinum-based subcutaneous sensor and the external reader component. The NX-500's biocompatibility data establishes a baseline for FDA's expectations regarding platinum electrode sensors in this device category.
Secondary Predicate: NovaSense GlucoTrack NX-700 (K230489). The NX-700 was cleared by FDA on March 7, 2024. It represents an update to the NX-500 platform with an extended 14-day sensor wear period and updated materials. FDA accepted biocompatibility data for the NX-700's extended 14-day wear duration, establishing a precedent for FDA acceptance of biocompatibility data supporting a 14-day subcutaneous CGM sensor.
The critical difference between the Lumina C14 Sensor and the predicate devices lies in Solstice's use of the proprietary platinum-iridium (PtIr-4G) electrode coating on the C14 Sensor, as compared to the platinum electrode used in the NX-500 primary predicate. This new material composition constitutes a significant difference in patient-contacting materials and represents a technological characteristic that is not present in either predicate device. As a result, Solstice cannot rely on predicate biocompatibility data alone to support the PtIr-4G electrode coating. Independent biocompatibility evaluation of the PtIr-4G material is required.
FDA is likely to scrutinize the PtIr-4G material as a new technological characteristic during 510(k) review. While the overall device design and intended use are substantially equivalent to the predicate devices, the introduction of a new electrode material that directly contacts subcutaneous tissue and interstitial fluid represents a change that FDA consistently identifies as requiring standalone biocompatibility testing data. The Whitmore testing program appropriately accounts for this by including PtIr-4G-specific test specimens in the C14 Sensor testing battery.
Summaries of publicly available biocompatibility data for both predicate devices are compiled in Appendix E for reference.
III. Proposed Biocompatibility Testing Scope — Lumina C14 Sensor
A. Overview
As discussed in Section II.B above, the C14 Sensor is classified as a subcutaneously implanted device with prolonged tissue and blood contact. This classification triggers the full battery of biological evaluation endpoints recommended under ISO 10993-1:2018 Table A.1 for implant devices with prolonged contact. The proposed Whitmore testing program includes eight (8) test categories for the C14 Sensor, each of which is described in detail below. These eight categories collectively address all endpoints identified in the ISO 10993-1:2018 Table A.1 matrix for this device contact classification.
All test specimens for the C14 Sensor will be representative of the final, finished commercial design, including the PtIr-4G electrode coating, sensor housing polymers, adhesive components, and all other patient-contacting materials. Sample preparation will follow ISO 10993-12:2021 requirements for extraction conditions, surface area-to-volume ratios, and extraction vehicle selection. Test specimens were prepared and submitted to Whitmore beginning in March 2025, with testing expected to initiate in May 2025 following sample conditioning and preparation activities.
B. Cytotoxicity (ISO 10993-5)
Test standard: ISO 10993-5:2009 — Biological evaluation of medical devices — Part 5: Tests for in vitro cytotoxicity.
Test method: Direct contact and/or extract methods using L-929 mouse fibroblast cell line. In the direct contact method, device material samples are placed directly on the cell monolayer; in the extract method, extracts of the device materials are prepared under standardized conditions and applied to the cell culture. Cell viability is assessed qualitatively (morphological evaluation of cell damage) and/or quantitatively (e.g., MTT, XTT, or neutral red uptake assays).
Purpose: Cytotoxicity testing evaluates whether device materials or their extractable constituents are toxic to mammalian cells. This is considered the baseline biological screening test for any medical device material, as it provides a rapid and sensitive indication of general cellular toxicity.
Applicability: Cytotoxicity testing is required for all medical device types under ISO 10993-1:2018, regardless of contact nature, duration, or tissue type. It serves as the foundational test in the biological evaluation hierarchy.
Specific considerations for the C14 Sensor: All patient-contacting materials must be represented in the test specimens, including the PtIr-4G electrode coating, sensor housing polymers, and any adhesives or polymeric encapsulation materials used in the sensor assembly. Given the novel PtIr-4G coating, cytotoxicity screening of this material is particularly important as an initial indicator of cellular biocompatibility.
Expected timeline: Four to six weeks from receipt of test specimens by Whitmore.
C. Sensitization (ISO 10993-10)
Test standard: ISO 10993-10:2021 — Biological evaluation of medical devices — Part 10: Tests for skin sensitization.
Test method: Guinea pig maximization test ("GPMT") or murine local lymph node assay ("LLNA"). The GPMT involves intradermal injection and topical application of device extracts in guinea pigs, with challenge after a sensitization period to assess delayed-type hypersensitivity response. The LLNA, as an alternative, measures lymph node cell proliferation in mice following topical application of device extracts. Both methods are accepted by FDA; selection of the specific method will be determined by Whitmore based on material characteristics and test design considerations.
Purpose: Sensitization testing assesses the potential for device materials or their extractable constituents to induce delayed-type hypersensitivity (allergic sensitization) in patients. This is a critical safety endpoint because sensitization reactions can develop after repeated or prolonged exposure to an allergenic material, and such reactions may not be apparent from short-term testing.
Applicability: Sensitization testing is required for all medical devices with tissue contact under ISO 10993-1:2018.
Relevance to PtIr-4G: The sensitization evaluation of the PtIr-4G electrode coating is of particular importance. While platinum has a well-established biocompatibility profile with low sensitization potential, iridium-containing compounds are relatively rare in subcutaneous medical device applications, and the sensitization potential of iridium in this context has not been extensively studied. Although iridium is generally considered to be a rare allergen, the combination of iridium with platinum and any proprietary surface treatments or processing aids used in the PtIr-4G deposition process must be evaluated. This is a novel area where limited historical data exists for FDA comparison, which reinforces the need for robust, standalone sensitization testing data.
Expected timeline: Six to eight weeks from initiation of the in-life phase.
D. Irritation (ISO 10993-23)
Test standard: ISO 10993-23:2021 — Biological evaluation of medical devices — Part 23: Tests for irritation.
Test method: In vitro reconstructed human epidermis ("RhE") model or in vivo intracutaneous reactivity test. The RhE model uses commercially available three-dimensional human skin constructs (e.g., EpiDerm™ or SkinEthic™) to assess tissue irritation potential of device extracts in a non-animal test system. The in vivo intracutaneous reactivity test involves intradermal injection of device extracts in rabbit models, with evaluation of erythema, edema, and necrosis at the injection sites.
Purpose: Irritation testing evaluates the potential for device materials to cause local tissue irritation upon contact. For implant devices such as the C14 Sensor, this testing is particularly relevant because the device materials are in direct, prolonged contact with subcutaneous tissue, and local irritation responses could compromise device performance, patient comfort, and tissue integrity at the implant site.
Applicability: Irritation testing is required for implant devices under ISO 10993-1:2018 Table A.1.
FDA's September 2020 guidance specifically notes a preference for in vitro models where scientifically justified, consistent with the broader regulatory trend toward reducing animal testing in biocompatibility evaluation. The use of an RhE model for irritation testing may be appropriate for the C14 Sensor provided that the in vitro method is validated for the specific material types and extraction conditions involved.
Expected timeline: Four to six weeks.
E. Acute Systemic Toxicity (ISO 10993-11)
Test standard: ISO 10993-11:2017 — Biological evaluation of medical devices — Part 11: Tests for systemic toxicity.
Test method: Single-dose extract injection study in a mouse model, using both intravenous and intraperitoneal administration routes. Device extracts are prepared under standardized conditions per ISO 10993-12:2021 and injected into mice at specified volumes. Animals are observed for 24 to 72 hours for signs of systemic toxicity, including changes in body weight, behavior, clinical signs, and mortality. At study termination, gross pathological examination of major organs is performed.
Purpose: Acute systemic toxicity testing is designed to detect the potential for device extractables to cause acute systemic toxic effects when distributed systemically. This endpoint evaluates whether substances released from the device under simulated use conditions could cause organ damage, systemic inflammation, or other adverse systemic responses following acute exposure.
Applicability: Acute systemic toxicity testing is required for implant devices with prolonged contact under ISO 10993-1:2018 Table A.1.
Specific consideration for PtIr-4G: The extractable and leachable profiling of the PtIr-4G electrode coating and all polymer components of the C14 Sensor should ideally be completed prior to or in parallel with this test to inform extract preparation conditions and ensure that worst-case extraction scenarios are captured. The identity and quantity of extractable species from the PtIr-4G coating will inform the interpretation of acute systemic toxicity results and help contextualize any findings.
Expected timeline: Four to six weeks.
F. Subchronic Toxicity (ISO 10993-11)
Test standard: ISO 10993-11:2017 — subchronic (subacute) toxicity protocol.
Test method: Repeated-dose systemic toxicity study in a rodent model, typically involving daily administration of device extracts over a period of 28 days or, in some cases, extending to 90 days. The study includes comprehensive evaluation of organ weights, histopathological examination of major organs and tissues, hematology parameters (complete blood count, differential), clinical chemistry panels (liver function, renal function, electrolytes), urinalysis, and clinical observations throughout the dosing period. Both test and control (vehicle-treated) groups are included.
Purpose: Subchronic toxicity testing assesses the cumulative systemic toxic effects of prolonged exposure to device extractables. Unlike the acute systemic toxicity test, which evaluates single-dose effects over hours, the subchronic study evaluates repeated exposure over weeks, providing a more comprehensive assessment of potential organ-level toxicity from chronic low-level chemical exposure.
Applicability: Subchronic toxicity testing is required under ISO 10993-1:2018 Table A.1 for implant devices with prolonged contact (greater than 24 hours up to 30 days). The C14 Sensor's 14-day continuous wear duration places it squarely within this contact duration category, making subchronic toxicity testing a required endpoint.
Budget consideration: Subchronic toxicity is one of the most resource-intensive individual tests in the entire biocompatibility testing program. The estimated cost for this test alone is $80,000 to $120,000, representing approximately 16% to 25% of the total $485,000 testing budget. The significant cost reflects the study's duration, the number of animals required, the comprehensive analytical endpoints (histopathology, clinical chemistry, hematology), and the regulatory-quality reporting requirements.
Expected timeline: Twelve to sixteen weeks from study initiation. This is the longest-duration test in the C14 Sensor testing program and, along with the implantation study, defines the critical path for completion of the overall biocompatibility testing program by August 31, 2025. Any delays in study initiation or unexpected findings requiring additional evaluation could push the completion date beyond the target.
Risk: If subchronic toxicity testing reveals adverse findings related to PtIr-4G extractables — for example, elevated levels of iridium ions or alloy degradation products causing organ-level histopathological changes — design modifications to the PtIr-4G coating or sensor architecture may be required. Such modifications would not only necessitate re-testing but would also have significant implications for the overall regulatory timeline, clinical study schedule, and budget. This risk underscores the importance of thorough chemical characterization (ISO 10993-18) and extractables/leachables profiling as foundational elements that should precede or run concurrently with the subchronic toxicity study.
G. Implantation (ISO 10993-6)
Test standard: ISO 10993-6:2016 — Biological evaluation of medical devices — Part 6: Tests for local effects after implantation.
Test method: Subcutaneous implantation in a rabbit or rat model. Test specimens representing the C14 Sensor materials (including the PtIr-4G electrode coating) are surgically implanted subcutaneously. The implantation duration is designed to match or exceed the intended clinical use period (14 days minimum). At study termination, implant sites and surrounding tissue are excised for histopathological evaluation, including assessment of inflammatory cell infiltration, fibrosis, neovascularization, fatty infiltration, necrosis, and overall tissue response grading according to a standardized scoring system. Control implants of reference materials (e.g., USP-grade HDPE) are included for comparison.
Purpose: Implantation testing evaluates the local tissue reaction to the implanted device materials under conditions that simulate actual clinical use. This is a directly relevant test for the C14 Sensor, which is inserted subcutaneously and remains in the tissue for the 14-day wear period. The histopathological evaluation of the tissue response provides critical data on whether the device materials cause unacceptable local inflammation, tissue damage, or foreign body reaction.
Applicability: Implantation testing is directly applicable to the C14 Sensor given its subcutaneous placement. This test provides device-specific, clinically relevant biocompatibility data that cannot be fully substituted by other in vitro or systemic toxicity tests.
Critical relevance to PtIr-4G: The implantation study is particularly important for the PtIr-4G electrode coating. FDA will specifically look for local tissue response data around the novel electrode material to assess whether the PtIr-4G coating causes any localized adverse tissue reactions that differ from those observed with standard platinum electrodes. The histopathological data from this study will be a key element of the substantial equivalence argument regarding material biocompatibility.
Expected timeline: Eight to twelve weeks, including the implantation period and histopathological processing and evaluation.
H. Hemocompatibility (ISO 10993-4)
Test standard: ISO 10993-4:2017 — Biological evaluation of medical devices — Part 4: Selection of tests for interactions with blood.
Test method: The hemocompatibility testing battery may include the following in vitro assessments, as applicable based on the device's blood contact characteristics:
• Hemolysis: Evaluation of the device's potential to cause red blood cell lysis, measured by quantification of free hemoglobin release.
• Complement activation: Assessment of whether device materials activate the complement cascade, a component of the innate immune system.
• Thrombogenicity: Evaluation of the device's potential to promote thrombus (blood clot) formation.
• Coagulation: Assessment of effects on the coagulation cascade, including activated partial thromboplastin time (aPTT) and prothrombin time (PT).
• Platelet assessments: Evaluation of platelet adhesion, activation, and aggregation in response to device materials.
The specific panel of hemocompatibility tests to be performed will be determined based on the C14 Sensor's blood contact profile and in consultation with Whitmore. Given the sensor's primary contact with interstitial fluid (with incidental blood contact), the hemolysis and thrombogenicity assessments are likely to be the most directly applicable endpoints.
Purpose: Hemocompatibility testing evaluates the interaction between device materials and blood components. The C14 Sensor is inserted subcutaneously and resides in the interstitial fluid space, where it may contact blood during the insertion process and throughout the wear period due to the proximity of capillary beds in the subcutaneous tissue.
Applicability: Under ISO 10993-4:2017, hemocompatibility testing is required for devices with direct or indirect blood contact. The C14 Sensor's subcutaneous placement involves incidental blood contact, making this endpoint applicable.
Predicate comparison: The primary predicate device (NovaSense GlucoTrack NX-500, K211034) included hemocompatibility data in its 510(k) submission. Maintaining hemocompatibility testing in the Lumina C14 program is important for the substantial equivalence argument, as it demonstrates that the same biological evaluation endpoints were assessed for both the subject and predicate devices, notwithstanding the difference in electrode materials.
Expected timeline: Six to eight weeks.
I. Genotoxicity (ISO 10993-3)
Test standard: ISO 10993-3:2014 — Biological evaluation of medical devices — Part 3: Tests for genotoxicity, carcinogenicity and reproductive toxicity.
Test method: The genotoxicity assessment typically includes a tiered battery of tests:
• In vitro bacterial reverse mutation assay (Ames test): This test evaluates the mutagenic potential of device extracts using several strains of Salmonella typhimurium and Escherichia coli bacteria, with and without metabolic activation (S9 fraction). It detects point mutations caused by base-pair substitutions and frameshift mutations.
• In vitro mammalian chromosome aberration test or mouse lymphoma assay: This test evaluates the clastogenic potential of device extracts by assessing structural chromosome damage in mammalian cells (e.g., Chinese hamster ovary cells) or by detecting gene mutations and chromosomal events in mouse lymphoma cells.
• In vivo micronucleus test: If warranted by results from the in vitro tests or the chemical characterization profile, an in vivo micronucleus assay in rodent bone marrow or peripheral blood may be conducted to assess genotoxic potential under physiological conditions.
Purpose: Genotoxicity testing assesses the potential for device extractables to cause genetic damage, including gene mutations, chromosomal aberrations, and DNA strand breaks. Genotoxic effects are of particular concern because they can contribute to carcinogenic processes.
Applicability: Genotoxicity testing is required under ISO 10993-1:2018 Table A.1 for implant devices with prolonged contact. The C14 Sensor's subcutaneous placement and 14-day wear duration place it in this required testing category.
Special note regarding PtIr-4G: Certain platinum-group metal compounds are known to exhibit genotoxic properties at elevated concentrations. For example, some platinum coordination complexes (though distinct from metallic platinum) have documented genotoxic activity. While the PtIr-4G coating comprises metallic platinum-iridium alloy rather than reactive coordination compounds, the genotoxicity testing of PtIr-4G extracts is particularly important to confirm that extractable platinum and iridium species at physiologically relevant concentrations do not exhibit genotoxic activity. The test protocols must include appropriate positive controls to validate assay sensitivity and appropriate extraction conditions to ensure worst-case extractable levels are captured.
Expected timeline: Eight to ten weeks, including the in vitro and any warranted in vivo phases.
IV. Proposed Biocompatibility Testing Scope — Lumina R7 Reader/Transmitter
A. Overview
The R7 Reader/Transmitter is an arm-worn external device with prolonged intact skin contact. As described in Section II.B above, this device is classified as a surface-contacting device (skin) with prolonged contact duration under ISO 10993-1:2018. The applicable biological evaluation endpoints for this device category are limited to cytotoxicity, sensitization, and irritation — a total of three (3) test categories. The testing scope proposed by Whitmore for the R7 Reader is consistent with these requirements.
All test specimens for the R7 Reader will include the patient-contacting materials of the finished device, including the adhesive patch material, housing polymer surfaces, and any wristband or attachment strap materials that contact the skin.
B. Cytotoxicity (ISO 10993-5)
Test standard: ISO 10993-5:2009 — Biological evaluation of medical devices — Part 5: Tests for in vitro cytotoxicity.
The test methodology for the R7 Reader cytotoxicity evaluation is the same as described in Section III.B above for the C14 Sensor. The L-929 mouse fibroblast cell line will be used, with direct contact and/or extract methods employed to evaluate cellular toxicity of device materials.
Specific focus for R7: Testing specimens should focus on the skin-contact materials that define the R7 Reader's patient interface, including:
• The adhesive patch material used to attach the R7 Reader to the skin surface
• The exterior housing polymer material that contacts or is in close proximity to the skin
• Any wristband, strap, or secondary attachment materials
• Colorants, dyes, or surface coatings applied to the housing that may contact skin
Expected timeline: Four to six weeks from receipt of test specimens. Cytotoxicity testing for the R7 Reader can be run concurrently with C14 Sensor cytotoxicity testing, allowing efficient use of laboratory resources.
C. Sensitization (ISO 10993-10)
Test standard: ISO 10993-10:2021 — Biological evaluation of medical devices — Part 10: Tests for skin sensitization.
The test methodology is the same as described in Section III.C above for the C14 Sensor (GPMT or LLNA). The focus for the R7 Reader sensitization evaluation is on the adhesive components and any dye or colorant materials used in the device housing, as these are the materials most likely to have sensitization potential in a skin-contact wearable device.
Adhesive sensitization is a well-documented concern for wearable medical devices, as prolonged adhesive contact with skin under occlusive conditions can create conditions favorable for sensitization reactions. The selection of adhesive materials for the R7 Reader should be supported by robust sensitization data.
Expected timeline: Six to eight weeks.
D. Irritation (ISO 10993-23)
Test standard: ISO 10993-23:2021 — Biological evaluation of medical devices — Part 23: Tests for irritation.
The test methodology is the same as described in Section III.D above. For the R7 Reader, the skin irritation focus is appropriate given the device's prolonged (14-day continuous) skin-contact wear profile. The RhE in vitro model or intracutaneous reactivity test will be used to evaluate the potential for the R7 Reader's skin-contact materials to cause local skin irritation.
Prolonged adhesive wear on the skin is a recognized source of skin irritation in wearable device applications. The irritation data for the R7 Reader will be important for establishing that the device can be worn safely and comfortably for the full 14-day sensor wear period without causing clinically significant skin irritation.
Expected timeline: Four to six weeks.
E. Justification for Reduced Testing Scope for R7
The three-test scope proposed for the R7 Reader (cytotoxicity, sensitization, and irritation) represents a reduced testing battery compared to the eight-test scope for the C14 Sensor. This reduced scope is fully justified under the applicable regulatory framework:
Under ISO 10993-1:2018, the biological evaluation endpoint matrix (Table A.1) specifies that surface-contacting devices with intact skin contact and prolonged duration require only cytotoxicity, sensitization, and irritation endpoints. The standard does not recommend systemic toxicity (acute or subchronic), implantation, hemocompatibility, or genotoxicity endpoints for this device contact category. The rationale is that an intact skin surface provides an effective barrier against systemic exposure to device materials, and the risk profile of external skin-contact devices is fundamentally different from that of implant devices.
FDA's September 2020 guidance aligns with this risk-based approach. The guidance does not recommend additional biological evaluation tests beyond the ISO 10993-1 Table A.1 endpoints for external skin-contact devices. FDA recognizes that the intact skin barrier significantly mitigates the risk of systemic exposure to device extractables.
Additionally, Solstice completed biocompatibility testing for the R7 Reader as part of the EU MDR CE certification process (certificate MCA-2024-07319 issued by Meridian Conformity Assessment GmbH). The EU biocompatibility data for the R7 Reader may be leverageable in the FDA 510(k) submission, subject to verification that the test conditions and ISO standard editions used in the EU testing match current FDA expectations. If the EU data is found to be fully compliant, it may be possible to cross-reference this data rather than conducting fully duplicative testing, which could result in cost savings for the R7 Reader portion of the testing program.
V. Gap Analysis Against FDA Biocompatibility Guidance
A. Methodology
Calderwood & Harkness, in coordination with Pinnacle Regulatory Consulting Group LLC, conducted a gap analysis comparing the proposed Whitmore testing program against FDA's September 2020 guidance on the use of ISO 10993-1. This analysis identifies areas where the proposed testing program may fall short of FDA's current expectations or where supplemental data or testing may be warranted to strengthen the 510(k) submission.
The gap analysis focused particular attention on FDA's recommendations regarding chemical characterization and extractables/leachables analysis, which the September 2020 guidance elevated to a foundational role in the biological evaluation process. FDA's current approach emphasizes that chemical characterization should inform and may, in some cases, supplement or replace certain biological tests, and that a thorough understanding of the chemical composition of device materials and their extractable constituents is essential to a complete biological evaluation.
Five gaps were identified, as detailed below.
B. Gap 1: Chemical Characterization
FDA's September 2020 guidance strongly recommends performing chemical characterization of device materials — specifically, extractables and leachables profiling under ISO 10993-18 — as a foundational first step in the biological evaluation process. The guidance positions chemical characterization as a prerequisite to animal testing, as the results inform the selection of appropriate biological test endpoints, extraction conditions, and risk assessment. In some cases, a thorough chemical characterization demonstrating that extractable levels are below established toxicological thresholds can reduce or eliminate the need for certain animal-based tests.
The current Whitmore testing protocol includes extractables/leachables analysis as part of the ISO 10993-18:2020 chemical characterization framework. However, the scope of this analysis should be confirmed to include all patient-contacting materials and constituents in both the C14 Sensor and R7 Reader, specifically:
• All PtIr-4G electrode coating constituents, including the platinum-iridium alloy matrix, any binder materials, surface treatment chemicals, and processing residuals
• Polymer components of the sensor housing and reader housing
• Adhesive materials for both the C14 insertion adhesive patch and the R7 attachment adhesive
• Any brazing, soldering, or welding materials used in the sensor or reader assembly that may be in the exposure pathway
• Colorants, dyes, and surface coatings
Recommendation: Confirm with Dr. James Haverford at Whitmore that the ISO 10993-18:2020 chemical characterization is included in the testing program at a scope that covers all materials in both the C14 Sensor and R7 Reader. If the current scope does not cover all of the materials listed above, the testing scope should be expanded accordingly. The potential budget impact of an expanded chemical characterization scope is estimated at $25,000 to $40,000 above the current $485,000 budget.
C. Gap 2: Extractables/Leachables Specific to PtIr-4G Electrode Coating
The PtIr-4G electrode coating is Solstice's proprietary platinum-iridium technology and represents the single most significant material difference between the Lumina C14 Sensor and the primary predicate device (NovaSense GlucoTrack NX-500, K211034), which uses a platinum-only electrode. FDA will require specific extractables/leachables data on the PtIr-4G coating to evaluate whether this novel material releases substances that may pose toxicological concerns.
Key elements that should be addressed in the extractables/leachables characterization of the PtIr-4G coating include:
• Identification and quantification of iridium ions released from the coating under simulated use conditions
• Identification and quantification of platinum ions released from the coating
• Characterization of any platinum-iridium alloy degradation products that may form under physiological pH, temperature, and ionic strength conditions
• Assessment of accelerated aging extraction conditions that simulate the full 14-day subcutaneous exposure period, including worst-case conditions (elevated temperature, extended extraction duration)
• Use of both polar and non-polar extraction solvents to capture the full range of potential extractable species, as specified in ISO 10993-12:2021
Recommendation: Verify that the extraction conditions specified in the Whitmore protocol include worst-case conditions consistent with ISO 10993-12:2021 (Biological evaluation of medical devices — Part 12: Sample preparation and reference materials). Extraction should be performed at elevated temperatures (e.g., 50°C or 70°C for accelerated extraction) and at physiological temperature (37°C), using both polar (e.g., purified water, saline, culture medium) and non-polar (e.g., isopropanol, hexane, or DMSO) extraction vehicles, to ensure comprehensive capture of extractable species. The extraction duration should be designed to simulate or exceed the 14-day (336-hour) clinical use period.
D. Gap 3: Biocompatibility of Adhesive Materials
Both the C14 Sensor and R7 Reader incorporate skin-contact adhesive materials — the C14 Sensor uses an adhesive patch for securing the insertion site, and the R7 Reader uses an adhesive for skin attachment during the 14-day wear period. These adhesive materials represent a significant component of the patient-contacting surface area for both devices.
FDA frequently requests specific biocompatibility data on adhesive materials in the review of wearable and skin-contact medical devices. Adhesive-related skin reactions — including contact dermatitis, sensitization, and irritation — are among the most common adverse events reported for wearable devices. As a result, FDA may expect that the biocompatibility data presented in the 510(k) submission specifically addresses the adhesive materials, either through testing of adhesive-only specimens or through confirmation that the adhesive materials are adequately represented in the overall device extract testing.
It is important to note that the overall device extract data may not fully capture the biocompatibility profile of the adhesive materials if the adhesive constitutes a small proportion of the total device mass or surface area in the extract preparation. In such cases, the adhesive extractables may be diluted below detectable or toxicologically relevant levels in the overall device extract, even if they would be present at higher concentrations at the actual skin-adhesive interface.
Recommendation: Ensure that adhesive-specific testing specimens are included in the cytotoxicity, sensitization, and irritation test matrices for both the C14 Sensor and R7 Reader. This may involve preparing separate extract specimens from the adhesive materials alone, in addition to the whole-device extracts, to ensure that adhesive-specific biocompatibility data is available for the 510(k) submission.
E. Gap 4: Shelf-Life / Aged Sample Testing
FDA may request that biocompatibility testing be performed on both fresh (newly manufactured) samples and shelf-life aged samples to demonstrate that material degradation over the device's stated shelf life does not alter the biocompatibility profile. This concern is particularly relevant for devices that include polymeric materials, adhesives, or coatings that may undergo chemical changes during storage.
The current Whitmore testing program appears to be designed using representative production samples, but it is unclear whether the testing program includes or plans to include testing of shelf-life aged samples. If the Lumina CGM System has a stated shelf life of, for example, 12 to 24 months, FDA may ask whether the biocompatibility data is representative of the device at the end of its shelf life — i.e., the worst-case condition for potential material degradation.
Recommendation: Discuss with Whitmore and Pinnacle Regulatory whether aged sample testing should be included in the current testing program or whether it should be addressed through a separate stability/biocompatibility correlation study. Options include:
• Performing accelerated aging of device samples per ASTM F1980 (accelerated aging protocols for sterile barrier system packaging or device materials) and then subjecting the aged samples to the full or partial biocompatibility testing battery
• Preparing a scientific justification, based on the chemical characterization data and material stability data, that the biocompatibility profile is not expected to change over the stated shelf life
If aged sample testing is added to the program, the estimated budget increase is $30,000 to $50,000, depending on the number of aging conditions and the scope of biocompatibility tests repeated on aged samples.
F. Gap 5: Reference to EU Biocompatibility Data
Solstice completed biocompatibility testing for the Lumina CGM System in support of the EU MDR CE certification process (certificate MCA-2024-07319, issued by Meridian Conformity Assessment GmbH, Notified Body 0483, on September 12, 2024). Some or all of this data may be referenceable in the FDA 510(k) submission, potentially reducing duplicative testing and associated costs.
FDA's general position is that it will accept ISO 10993 testing data conducted by accredited laboratories regardless of geographic location, provided the testing meets the following conditions:
• Testing was conducted in accordance with the current editions of the applicable ISO 10993 standards
• The testing laboratory is appropriately accredited (e.g., ISO/IEC 17025 or GLP-compliant)
• Test conditions (extraction conditions, sample preparation, test methods) are consistent with FDA guidance expectations
• Reports include full raw data, statistical analysis, and conclusions meeting ISO 10993 reporting requirements
Identified gap: The EU biocompatibility testing may have been conducted under slightly different conditions or using earlier editions of certain ISO 10993 standards. For example, if the EU testing was conducted under ISO 10993-10:2010 (rather than the current 2021 edition) or if the extraction conditions did not match the worst-case requirements of the current ISO 10993-12:2021, the data may not be fully acceptable to FDA without supplementation. Additionally, if the EU testing did not include the FDA-recommended chemical characterization under ISO 10993-18:2020, this gap would need to be addressed in the U.S. testing program regardless of the EU data.
Recommendation: Obtain the complete EU biocompatibility test reports from Fiona Drennan, Quality Assurance Director at Solstice's Dublin headquarters, and transmit them to Whitmore for a detailed gap assessment. Whitmore should review each EU test report to determine:
(a) Whether the test was conducted in accordance with the current edition of the applicable ISO 10993 standard;
(b) Whether the extraction conditions and sample preparation methods are consistent with FDA expectations and ISO 10993-12:2021;
(c) Whether the test report meets FDA's documentation and reporting requirements; and
(d) Whether any of the EU tests can be cross-referenced in the 510(k) submission in lieu of duplicative testing at Whitmore.
Any EU tests that are confirmed to meet current FDA standards can be cross-referenced in the 510(k) submission, potentially reducing the scope and cost of the Whitmore testing program — particularly for the R7 Reader, where the EU data may cover all three required endpoints (cytotoxicity, sensitization, and irritation).
VI. PtIr-4G Electrode Coating — Risk Assessment and Special Considerations
A. Material Description
The PtIr-4G designation refers to Solstice's fourth-generation enzymatic electrochemical biosensor electrode coating. This coating is composed of a platinum-iridium alloy deposited on the C14 Sensor's working electrode surface using a proprietary deposition process developed by Solstice's materials science team in Dublin. The PtIr-4G coating represents a key technological advancement over the primary predicate device's platinum-only electrode (NovaSense GlucoTrack NX-500, K211034), offering what Solstice has characterized as improved sensor sensitivity, faster response time, and enhanced long-term stability over the 14-day wear period.
The PtIr-4G coating includes a multi-layer enzyme immobilization structure with glucose oxidase (GOx) as the primary enzyme, along with interference rejection membranes and biocompatibility-enhancing outer layers. The complete material composition, alloy ratios, deposition parameters, and layer architecture of the PtIr-4G coating are proprietary and are documented in Solstice's Device Master Record ("DMR"). Full material specifications have been provided to Whitmore for test specimen preparation purposes under the terms of the Whitmore engagement agreement and associated confidentiality provisions.