§ 888.3046 — Resorbable calcium salt bone void filler containing a single approved aminoglycoside antibacterial.

§ 888.3046 Resorbable calcium salt bone void filler containing a single approved aminoglycoside antibacterial.

(a) Identification. A resorbable calcium salt bone void filler containing a single approved aminoglycoside antibacterial is a resorbable implant intended to fill bony defects of the extremities where there is an increased risk of infection. It is intended to resorb over time and be replaced by new bone. The product is intended for reduction of recurrence of chronic osteomyelitis of long bones. It is not intended to treat infection.

(b) Classification. Class II (special controls). The special controls for this product are:

(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 specifications for the aminoglycoside and drug constituent part components (if present) 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, 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 paragraphs (b)(4)(i) through (b)(4)(iv) of this section, 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 paragraph (b)(1) of this section.

(7) If FDA determines that the clinical performance testing specified in special control (b)(1) of this section 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 paragraph (b)(12)(ii) of this section), 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 paragraph.

(12) Performance data from testing batches at release and on stability must characterize the drug quality attributes of the final, finished product (see paragraph (b)(4) of this section), 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 § 211 of this chapter is not the established CGMP operating system, a description of how the facilities perform the responsibilities related to the subset of § 211 requirements established in § 4 subpart A of this chapter.

(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 PMS protocol agreed upon with FDA as specified in paragraph (b)(7) of this section, 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.

[91 FR 34150, June 5, 2026]