CERAMENT G

K234008 · Bonesupport AB · QRR · Mar 13, 2024 · Orthopedic

Device Facts

• Record ID: K234008
• Device Name: CERAMENT G
• Applicant: Bonesupport AB
• Product Code: QRR · Orthopedic
• Decision Date: Mar 13, 2024
• Decision: SESE
• Submission Type: Traditional
• Regulation: 21 CFR 888.3046
• Device Class: Class 2
• Attributes: Therapeutic

Intended Use

CERAMENT G is a resorbable, gentamicin-eluting ceramic bone void filler intended for use in defects in the extremities of skeletally mature patients as an adjunct to systemic antibiotic therapy and surgical debridement as part of the standard treatment approach to bone infection and open fractures. By eluting gentamicin, CERAMENT G can reduce the occurrence and reoccurrence of bone infection from gentamicin-sensitive microorganisms in order to protect bone healing. CERAMENT G can augment provisional hardware to help support bone fragments during the surgical procedure. The cured paste acts only as a temporary support media and is not intended to provide structural support during the healing process. CERAMENT G resorbs and is replaced by bone during the healing process.

Device Story

CERAMENT G is an implantable, resorbable bone void filler composed of hydroxyapatite, calcium sulfate, and gentamicin; functions as a device/drug combination product. Used in surgical settings by orthopedic surgeons to fill bone defects in extremities. During surgery, the paste is applied to the defect site; it elutes gentamicin to reduce infection risk from sensitive microorganisms and supports bone fragments as a temporary media. The material is osteoconductive and resorbs over time, being replaced by natural bone. It serves as an adjunct to systemic antibiotic therapy and surgical debridement. Benefits include reduced deep infection rates, high limb salvage, and promotion of bone union in complex fracture cases.

Clinical Evidence

Retrospective real-world evidence study of 81 patients with Gustilo-Anderson IIIB fractures treated between 2013 and 2021. Primary endpoints included deep infection rate, limb salvage, and bone union. Results: 3.7% deep infection rate (vs. 5.3%-33.6% SOC), 96.3% limb salvage (vs. 93.2%-98.2% SOC), and 96% bone union (vs. 71.4%-94.7% SOC).

Technological Characteristics

Composition: Hydroxyapatite, calcium sulfate, and gentamicin. Form factor: Resorbable paste/bone void filler. Principle: Osteoconductive scaffold with local antibiotic elution. Sterilization: Not specified. Connectivity: None. Software: None.

Indications for Use

Indicated for skeletally mature patients with bone defects in the extremities requiring bone void filling, specifically as an adjunct to systemic antibiotic therapy and surgical debridement for bone infection and open fractures.

Regulatory Classification

Identification

CERAMENT G is a resorbable, gentamicin-eluting ceramic bone void filler intended for use as a bone void filler in skeletally mature patients as an adjunct to systemic antibiotic therapy and surgical debridement as part of the surgical treatment of osteomyelitis in defects in the extremities. It is intended to reduce the recurrence of chronic osteomyelitis from gentamicin-sensitive microorganisms to protect bone healing and can augment provisional hardware to help support bone fragments during the surgical procedure.

Special Controls

In combination with the general controls of the FD&C Act, the resorbable calcium salt bone void filler containing a single approved aminoglycoside antibacterial is subject to the following special controls: (1) Clinical performance testing must demonstrate that the product performs as intended under anticipated conditions of use. Clinical testing must evaluate recurrence of chronic osteomyelitis of long bones. Testing must describe safe aminoglycoside serum levels below toxic concentrations. Imaging data (e.g., radiographs) must evaluate product resorption and new bone formation at the location where the product has been placed. (2) Animal performance testing must demonstrate that the product performs as intended under anticipated conditions of use. Testing must include the following: (i) Testing must characterize the performance of the product in an appropriate animal model. The model must mimic the identified clinical use, e.g., in a large animal infection model of osteomyelitis. Testing must characterize aminoglycoside serum levels and characterize product resorption and replacement by new bone, including the characterization of the rates of product resorption and new bone formation over clinically relevant timeframes. (ii) Testing must be conducted in a relevant animal model to evaluate the pharmacology and toxicology of the final, finished product. (3) Non-clinical performance testing must demonstrate that the product performs as intended under anticipated conditions of use. Testing must characterize the product in appropriate in vitro models. (i) Elution kinetics studies must be conducted to determine the in vitro drug release profile of the aminoglycoside from the product lot(s) used for the clinical performance testing studies. (ii) Dissolution testing must characterize the resorption profile of the product. (iii) The following physical and chemical properties must be characterized for in situ setting products: (A) Setting pH and reaction temperature; (B) Setting and working times; (C) Force required to transfer the product from the mixing container to the site of action; (D) Chemical composition of the in vivo-cured product; and (E) Dimensional stability of the in vivo-cured product. (4) Characterization of the product, including the drug substance and drug constituent part components (as applicable), must demonstrate that critical quality attributes and specifications, including compendial requirements, are met and must include: (i) Identification of, and justification for, the specification for each individual component (including the drug substance) of the drug constituent part of the product. (ii) Confirmation that the aminoglycoside and drug constituent part components (if present) specifications conform to any corresponding United States Pharmacopeia (USP) monographs. In addition, the aminoglycoside specification must also include other tests that ensure the quality of the product. These tests may, for example, include appearance, solubility, identification, related substances, ratios of active components, assay measured using high performance liquid chromatography (HPLC), or potency measured using a bioassay. (iii) Identification of, and justification for, the product specification(s) to be met on release of each batch and on stability, including description, identification, aminoglycoside assay, in vitro elution, degradation products, elemental impurities, content uniformity, residual solvents, sterility, and endotoxin. If the aminoglycoside is prepared as a solution before mixing with the other components, that specification must include appearance, pH, and particulates. (iv) Identification of, and justification for, the specifications that apply to the freshly mixed product (pre-setting configuration) and the mixed product administered from the mixing device/device constituent part and allowed to set over a specified time (post-setting configuration). For in vitro elution/drug release specifications, the acceptance criteria must include data from the product lot(s) used in clinical performance (or equivalent) studies. (A) The specification must include tests adequate to ensure the quality attributes of the pre-setting configuration considering the product design, including but not limited to, tests for appearance, setting time, and injectability or extrusion force. (B) The specification must include tests adequate to ensure the quality attributes of the post-setting configuration considering the product design, including but not limited to, tests for appearance, aminoglycoside assay, aminoglycoside degradants, aminoglycoside elution/drug release, uniformity, sterility, endotoxins, setting reaction temperature, working time, and usable amount of the product. (v) For the specifications noted in (i)-(iv) above, a description of the analytical procedures and a summary of the analytical procedures development and validation must be provided. For in vitro elution/drug release specifications, data must be provided to demonstrate method adequacy, e.g., in terms of discriminating power for changes/differences in critical quality attributes that could impact product performance, stability-indicating potential, and/or in vitro-in vivo correlation. (5) An analysis must be provided that identifies and evaluates any contribution to the development and spread of antimicrobial resistance. (6) Susceptibility testing to the aminoglycoside must be conducted for all bacterial isolates identified during the clinical performance testing specified in special control (1). (7) If FDA determines that the clinical performance testing specified in special control (1) is insufficient to evaluate long-term safety of the product, post-market surveillance (PMS) must evaluate new bone formation at the location where the product has been placed in accordance with an FDA-agreed upon protocol. (8) The product, including the delivery device constituent part(s) (e.g., delivery syringes) and patient-contacting surgical instruments, must be demonstrated to be biocompatible. (9) The product and each of its components (i.e., aminoglycoside and the drug constituent part components (if present)) must be demonstrated to be compatible with their respective commercial container closure system/packaging. (10) Performance data must support the sterility and pyrogenicity of the product. The performance data must confirm that the sterilization process has no significant adverse impact (e.g., the generation of new degradants) on the drug quality attributes (e.g., assay, elution) of the product. (11) Performance data must support the claimed expiration dating period/shelf life by demonstrating continued sterility, stability (see special control (12)(ii)), package integrity, and product functionality over the identified expiration/shelf life. Data to demonstrate continued sterility, stability, and package integrity must be collected for each component and the final, finished product. In addition, product functionality must be demonstrated for the final finished product. Extension of the expiration/shelf life must be submitted in a premarket notification and supported by the data described in this special control (11). (12) Performance data from testing batches at release and on stability must characterize the drug quality attributes of the final, finished product (see special control (4)), demonstrate product specifications are consistently met, and support the claimed expiration/shelf-life date. This information must include the following: (i) Batch Release Testing: Batch release data on multiple lots of the final, finished product manufactured using the proposed commercial process must demonstrate that specifications for each component and the final, finished product are met. Data on multiple lots of the mixed product (pre- and post-setting) obtained when the final, finished product is used according to the directions in the instructions for use must demonstrate that the pre- and post-setting specifications are met. (ii) Stability Testing: The final, finished product manufactured using the proposed commercial process and in the proposed commercial packaging must be stored under tightly controlled conditions and periodically tested to demonstrate the stability of the drug constituent part (all components) and the final, finished product. In addition, at each pre-determined stability time point the product must meet the pre- and post-setting specifications. Testing must include three batches placed under long-term storage and accelerated stability conditions and then one batch placed on long-term stability each year. Testing must verify that the acceptance criteria for each specification are met at each stability time point. Parameters that are not expected to change on stability, e.g., elemental impurities, only need to be tested at batch release, and a justification must be provided. (13) Pharmaceutical manufacturing information must be provided, and appropriate documentation be available on inspection or if requested by FDA, for the drug constituent part and the final, finished product to demonstrate that the production processes are properly developed, conducted, controlled, and monitored. This information must include the following: (i) A description of the manufacturing process and controls, including in-process controls, to ensure consistent quality. Such information may be provided by reference to a drug master file (DMF). (ii) A description of the commercial batch formula, including the quality standard (e.g., USP/National Formulary) to be met for each excipient, and representative Certificates of Analysis (COAs) for excipients to confirm quality. (iii) Information or reference to one or more DMFs regarding the drug substance to understand the impurity profile, and representative COAs for the drug substance to confirm quality. (iv) Identification and qualification of in-process hold times for the drug constituent part, where applicable. (v) A description of how compliance with the current good manufacturing practice (CGMP) requirements is achieved at the facilities manufacturing the drug constituent part and final, finished product. This includes identification of the activities that occur at each site, and for any facilities for which 21 CFR 211 is not the established CGMP operating system, a description of how the facilities perform the responsibilities related to the subset of 21 CFR 211 requirements established in 21 CFR 4 subpart A. (14) The product must contain a single approved aminoglycoside antibacterial. (15) Labeling must include the following: (i) Identification of the maximum volume of the product that may be safely implanted; (ii) A detailed summary of the product’s technical parameters; (iii) An expiration date/shelf life; (iv) A list of probable adverse events associated with the use of the product, including those observed during clinical performance studies; (v) Warning about the risk of antimicrobial resistance and the risk of systemic adverse effects from the aminoglycoside; (vi) Precaution against implanting into patients with calcium-metabolism issues; overfilling; adding other substances other than those provided (in absence of data on the use of the product mixed with other substances); overpressuring the product because this may lead to extrusion of the product beyond the site of its intended application and damage to surrounding tissues, and since this may lead to fat embolization or embolization of the product material into the bloodstream; and disturbing the product (over a specific time frame) once it begins to harden; (vii) Instructions about proper placement and containment in the desired treatment area; adequate fixation (as necessary); product working time and setting time with any special instructions with respect to drying the surgical field and/or not irrigating the defect site prior to final setting of the product (for a product intended to set in vivo); how and when excess material should be removed from the defect site; (viii) When available, and according to the timeframe included in the post-market surveillance (PMS) protocol agreed upon with FDA as specified in special control (7), a detailed summary of the PMS data must be provided, including: (A) Updates to the labeling to accurately reflect outcomes or necessary modifications based upon data collected during the PMS experience; and (B) Inclusion of results and adverse events associated with utilization of the product during the PMS.

Predicate Devices

• CERAMENT G (DEN210044)

Submission Summary (Full Text)

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March 13, 2024

Image /page/0/Picture/1 description: The image contains the logo of the U.S. Food and Drug Administration (FDA). On the left is the Department of Health & Human Services logo. To the right of that is the FDA logo, which consists of the letters "FDA" in a blue square, followed by the words "U.S. FOOD & DRUG ADMINISTRATION" in blue text.

BoneSupport AB Blerta Shuka Sr. Regulatory Affairs Specialist Scheelevagen 19 Ideon Science Park SE-223 70 Lund. Sweden

Re: K234008

Trade/Device Name: Cerament G Regulation Number: 21 CFR 888.3046 Regulation Name: Resorbable Calcium Salt Bone Void Filler Containing A Single Approved Aminoglycoside Antibacterial Regulatory Class: Class II Product Code: QRR Dated: December 19, 2023 Received: December 19, 2023

Dear Blerta Shuka:

We have reviewed your section 510(k) premarket notification of intent to market the device referenced above and have determined the device is substantially equivalent (for the indications for use stated in the enclosure) to legally marketed predicate devices marketed in interstate commerce prior to May 28, 1976, the enactment date of the Medical Device Amendments, or to devices that have been reclassified in accordance with the provisions of the Federal Food, Drug, and Cosmetic Act (the Act) that do not require approval of a premarket approval application (PMA). You may, therefore, market the device, subject to the general controls provisions of the Act. Although this letter refers to your product as a device, please be aware that some cleared products may instead be combination products. The 510(k) Premarket Notification Database available at https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpmn/pmn.cfm identifies combination product submissions. The general controls provisions of the Act include requirements for annual registration, listing of devices, good manufacturing practice, labeling, and prohibitions against misbranding and adulteration. Please note: CDRH does not evaluate information related to contract liability warranties. We remind you, however, that device labeling must be truthful and not misleading.

If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to additional controls. Existing major regulations affecting your device can be found in the Code of Federal Regulations, Title 21, Parts 800 to 898. In addition, FDA may publish further announcements concerning your device in the Federal Register.

Additional information about changes that may require a new premarket notification are provided in the FDA guidance documents entitled "Deciding When to Submit a 510(k) for a Change to an Existing Device"

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(https://www.fda.gov/media/99812/download) and "Deciding When to Submit a 510(k) for a Software Change to an Existing Device" (https://www.fda.gov/media/99785/download).

Your device is also subject to, among other requirements, the Quality System (QS) regulation (21 CFR Part 820), which includes, but is not limited to, 21 CFR 820.30, Design controls; 21 CFR 820.90. Nonconforming product; and 21 CFR 820.100, Corrective and preventive action. Please note that regardless of whether a change requires premarket review. the OS regulation requires device manufacturers to review and approve changes to device design and production (21 CFR 820.30 and 21 CFR 820.70) and document changes and approvals in the device master record (21 CFR 820.181).

Please be advised that FDA's issuance of a substantial equivalence determination does not mean that FDA has made a determination that your device complies with other requirements of the Act or any Federal statutes and regulations administered by other Federal agencies. You must comply with all the Act's requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Part 801); medical device reporting of medical device-related adverse events) (21 CFR Part 803) for devices or postmarketing safety reporting (21 CFR Part 4, Subpart B) for combination products (see https://www.fda.gov/combination-products/guidance-regulatory-information/postmarketing-safety-reportingcombination-products); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820) for devices or current good manufacturing practices (21 CFR Part 4, Subpart A) for combination products; and, if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR Parts 1000-1050.

Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR 807.97). For questions regarding the reporting of adverse events under the MDR regulation (21 CFR Part 803), please go to https://www.fda.gov/medical-device-safety/medical-device-reportingmdr-how-report-medical-device-problems.

For comprehensive regulatory information about mediation-emitting products, including information about labeling regulations, please see Device Advice (https://www.fda.gov/medicaldevices/device-advice-comprehensive-regulatory-assistance) and CDRH Learn (https://www.fda.gov/training-and-continuing-education/cdrh-learn). Additionally, you may contact the Division of Industry and Consumer Education (DICE) to ask a question about a specific regulatory topic. See the DICE website (https://www.fda.gov/medical-device-advice-comprehensive-regulatoryassistance/contact-us-division-industry-and-consumer-education-dice) for more information or contact DICE by email ([e-mail]) or phone [phone] or 301-796-7100).

Sincerely.

Jesse Muir -S

Jesse Muir, Ph.D. Assistant Director DHT6C: Division of Restorative, Repair and Trauma Devices OHT6: Office of Orthopedic Devices Office of Product Evaluation and Quality Center for Devices and Radiological Health

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Enclosure

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# Indications for Use

510(k) Number (if known) K234008

Device Name CERAMENT G

#### Indications for Use (Describe)

CERAMENT G is a resorbable, gentamic bone void filler intended for use in defects in the extremntes of skeletally mature patients as an adjunct to systemic antibiotic therapy and surgical debridement as part of the standard treatment approach to bone infection and open fractures.

By eluting gentamicin, CERAMENT G can reduce the occurrence of bone infection from gentamicinsensitive microorganisms in order to protect bone healing.

CERAMENT G can augment provisional hardware to help support bone fragments during the surgical procedure. The cured paste acts only as a temporary support media and is not intended to provide structural support during the healing process. CERAMENT G resorbs and is replaced by bone during the healing process.

| Type of Use (Select one or both, as applicable) | |
|------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------|
| <span style="font-size:16px">✖</span> Prescription Use (Part 21 CFR 801 Subpart D) | <span style="font-size:16px">❏</span> Over-The-Counter Use (21 CFR 801 Subpart C) |

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Image /page/4/Picture/0 description: The image shows the logo for BONESUPPORT. The logo consists of a blue abstract shape resembling two interlocked "S" letters on the left, followed by the word "BONESUPPORT" in black, sans-serif font. A small "TM" symbol is placed to the upper right of the word "SUPPORT".

# 510(K) SUMMARY

| Device Trade Name: | CERAMENT® G |
|--------------------|------------------------------------------------------------------------------------------------------------------------|
| Manufacturer: | BONESUPPORT AB<br>Scheelevägen 19,<br>Ideon Science Park,<br>SE-223 70 Lund,<br>Sweden |
| Contact: | Blerta Shuka<br>Sr. Regulatory Affairs Specialist<br>[phone] |
| Prepared by: | MCRA, LLC<br>803 7th Street, NW, 3rd Floor<br>Washington, DC 20001<br>Office: 202.552.5800 |
| Date Prepared: | February 20, 2024 |
| Regulation: | 21 CFR 888.3046 Resorbable calcium salt bone void filler<br>containing a single approved aminoglycoside antibacterial. |
| Classification: | Class II |
| Product Code: | QRR |
| Primary Predicate: | CERAMENT G (DEN210044) |

# Indications For Use:

CERAMENT G is a resorbable, gentamicin-eluting ceramic bone void filler intended for use in defects in the extremities of skeletally mature patients as an adjunct to systemic antibiotic therapy and surgical debridement as part of the standard treatment approach to bone infection and open fractures.

By eluting gentamicin, CERAMENT G can reduce the occurrence and reoccurrence of bone infection from gentamicin-sensitive microorganisms in order to protect bone healing.

CERAMENT G can augment provisional hardware to help support bone fragments during the surgical procedure. The cured paste acts only as a temporary support media and is not intended to provide structural support during the healing process. CERAMENT G resorbs and is replaced by bone during the healing process.

### Device Description:

CERAMENT G is an implantable bone void filler (device/ drug combination product) indicated for use as an adjunct to systemic antibiotic therapy and surgical debridement (standard treatment approach to a bone infection) where there is a need for supplemental bone graft. It is composed

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of hydroxyapatite, calcium sulfate and gentamicin, and is identical to the device cleared in DEN210044.

This submission expands the device's indication to include use in patients with open fractures in need for bone void filling.

## Performance Testing Summary:

The subject device was granted under DEN210044, which serves as the predicate device. This submission is leveraged to support the device's sterility, shelf-life, endotoxin, biocompatibility, and characterizations/bench performance as recommended in FDA 's Class II Special Controls listed in DEN210044 and the "Resorbable Calcium Salt Bone Void Filler Devices" guidance document including:

- Bench testing of finished combination product
- Dissolution O
- O pH
- Setting reaction temperature O
- Force required to transfer paste from mixing syringe to delivery syringe O
- Compressive strength O
- Working time O
- Setting time о
- Augmentation of hardware and bone alignment O
- Bench testing of drug components and drug constituent parts ●
- Compliance with current monograph of Gentamicin Sulfate O
- Antimicrobial activity O
- Elution study O
- Stability of gentamicin ●
- Sterility ●
- Biocompatibility
- Pyrogenicity testing
- Animal Testing
- Serum levels of gentamicin o
- Osteoconductivity O
- Resorbable properties O

### Clinical Performance of CERAMENT G:

Clinical data on the performance of CERAMENT G were collected on a consecutive series of 81 patients with Gustilo-Anderson IIIB fractures who were treated by the Manchester Orthoplastic

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Group between June 2013 and April 2021.4 This Real World Evidence from the Manchester Cohort support the substantial equivalence of CERAMENT G as evidenced by:

- . Low Rate of Deep Infection: CERAMENT G demonstrated an extremely low rate of deep infection (i.e., 3.7%) which compares favorably to the standard of care infection rates which range from 5.3% to 33.6%, with a weighted mean infection rate of 14.5%.
- . Limb Salvage: Patients who received CERAMENT G demonstrated a high rate of limb salvage (i.e., 96.3%). These results compare favorably to the limb salvage rates for the SOC group which ranged from 93.2% to 98.2%.
- . Bone Union: Patients who received CERAMENT G demonstrated high rates of limb union (96%). These results demonstrate that CERAMENT G supports formation of new bone, and they compare favorably to the rates of union for the SOC group which ranged from 71.4% to 94.7%.

# Substantial Equivalence:

The CERAMENT G which is the subject of this 510(k) is identical to the product granted in DEN210044.

The technology and intended use for the product are the same as the product, CERAMENT G (DEN210044). The predicate indications (i.e., use as a resorbable, gentamicineluting ceramic bone void filler intended for use in defects in the extremities as an adjunct to systemic antibiotic therapy and surgical debridement as part of the standard treatment approach to bone infection). The subject indications (i.e., use as a resorbable, gentamicin-eluting ceramic bone void filler intended for use in defects in the extremities as an adjunct to systemic antibiotic therapy and surgical debridement as part of the standard treatment approach to open fractures) differ slightly from the predicate indications: however, the differences do not alter the intended therapeutic use of the device, nor do they affect the safety and effectiveness of the device relative to the predicate.

Real World Evidence demonstrates that patients who received CERAMENT G as part of the treatment of their open fracture achieved a low rate of deep infection: a high rate of limb salvage: and a high rate of bone union. As summarized in the "Clinical Performance of CERAMENT G," these clinical results compare favorably to the results for the standard of care.

These results demonstrate that CERAMENT G is as safe, as effective, and performs as well as the predicate device.

¹ Henry JA, Ali A, Elkhidir IH, Reid A, Wong J, Pillai A. Long-Term Follow-Up of Open Gustilo-Anderson IIIB Fractures Treated With an Adjuvant Local Antibiotic Hydroxyapatite Bio-Composite. Cureus. 2023 May 16;15(5):39103. doi: 10.7759/cureus.39103. PMID: 37332443; PMCID: PMC10270668.