Rule2026-11308
Medical Devices; Orthopedic Devices; Classification of the Resorbable Calcium Salt Bone Void Filler Containing a Single Approved Aminoglycoside Antibacterial
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Metadata and text below are from the Federal Register, a public-domain U.S. government work. Always verify the official published version before relying on it for any legal matter.
Published
June 5, 2026
Effective
June 5, 2026
Issuing agencies
Health and Human Services DepartmentFood and Drug Administration
Abstract
The Food and Drug Administration (FDA) is classifying the resorbable calcium salt bone void filler containing a single approved aminoglycoside antibacterial into class II (special controls). The special controls that apply to the product type are identified in this order and will be part of the codified language for classification of the resorbable calcium salt bone void filler containing a single approved aminoglycoside antibacterial. We are taking this action because we have determined that classifying the product into class II will provide a reasonable assurance of safety and effectiveness of the product. We believe this action will also enhance patients' access to beneficial innovative products, in part by reducing regulatory burdens.
Full Text
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<title>Federal Register, Volume 91 Issue 108 (Friday, June 5, 2026)</title>
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[Federal Register Volume 91, Number 108 (Friday, June 5, 2026)]
[Rules and Regulations]
[Pages 34148-34152]
From the Federal Register Online via the Government Publishing Office [<a href="http://www.gpo.gov">www.gpo.gov</a>]
[FR Doc No: 2026-11308]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 888
[Docket No. FDA-2026-N-5195]
Medical Devices; Orthopedic Devices; Classification of the
Resorbable Calcium Salt Bone Void Filler Containing a Single Approved
Aminoglycoside Antibacterial
AGENCY: Food and Drug Administration, HHS.
ACTION: Final amendment; final order.
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SUMMARY: The Food and Drug Administration (FDA) is classifying the
resorbable calcium salt bone void filler containing a single approved
aminoglycoside antibacterial into class II (special controls). The
special controls that apply to the product type are identified in this
order and will be part of the codified language for classification of
the resorbable calcium salt bone void filler containing a single
approved aminoglycoside antibacterial. We are taking this action
because we have determined that classifying the product into class II
will provide a reasonable assurance of safety and effectiveness of the
product. We believe this action will also enhance patients' access to
beneficial innovative products, in part by reducing regulatory burdens.
DATES: This order is effective June 5, 2026. The classification was
applicable on May 17, 2022.
FOR FURTHER INFORMATION CONTACT: Aric Kaiser, Center for Devices and
Radiological Health, Food and Drug Administration, 10903 New Hampshire
Ave., Bldg. 66, Rm. 4518, Silver Spring, MD 20993-0002, 301-796-6425,
<a href="/cdn-cgi/l/email-protection#4d0c3f242e63062c243e283f0d2b292c6325253e632a223b"><span class="__cf_email__" data-cfemail="78390a111b563319110b1d0a381e1c195610100b561f170e">[email protected]</span></a>.
SUPPLEMENTARY INFORMATION:
I. Background
Upon request, FDA (the Agency or we) has classified the resorbable
calcium salt bone void filler containing a single approved
aminoglycoside antibacterial into class II (special controls), which we
have determined will provide a reasonable assurance of safety and
effectiveness of the product. In addition, we believe this action will
enhance patients' access to beneficial innovation, in part by reducing
regulatory burdens by placing the product into a lower device class
than the automatic class III assignment.
The automatic assignment of class III occurs by operation of law
and without any action by FDA, regardless of the level of risk posed by
the new device. Any device that was not in commercial distribution
before May 28, 1976, is automatically classified into, and remains
within, class III and requires premarket approval unless and until FDA
takes an action to classify or reclassify the device (21 U.S.C.
360c(f)(1)). We refer to these devices as ``postamendments devices''
because they were not in commercial distribution prior to the date of
enactment of the Medical Device Amendments of 1976, which amended the
Federal Food, Drug, and Cosmetic Act (FD&C Act).
FDA may take a variety of actions in appropriate circumstances to
classify or reclassify a device into class I or II. We may issue an
order finding a new device to be substantially equivalent under section
513(i) of the FD&C Act (21 U.S.C. 360c(i)) to a predicate device that
does not require premarket approval. We determine whether a new device
is substantially equivalent to a predicate device by means of the
procedures for premarket notification under section 510(k) of the FD&C
Act (21 U.S.C. 360(k)) and part 807 (21 CFR part 807).
FDA may also classify a device through ``De Novo'' classification,
a common name for the process authorized under section 513(f)(2) of the
FD&C Act (see also part 860, subpart D (21 CFR part 860, subpart D)).
Section 207 of the Food and Drug Administration Modernization Act of
1997 (Pub. L. 105-115) established the first procedure for De Novo
classification. Section 607 of the Food and Drug Administration Safety
and Innovation Act (Pub. L. 112-144) modified the De Novo
classification process by adding a second procedure. A device sponsor
may utilize either procedure for De Novo classification.
Under the first procedure, the person submits a premarket
notification (510(k)) for a device that has not previously been
classified. After receiving an order from FDA classifying the device
into class III under section 513(f)(1) of the FD&C Act, the person then
requests a classification under section 513(f)(2).
Under the second procedure, rather than first submitting a 510(k)
and then a request for classification, if the person determines that
there is no legally
[[Page 34149]]
marketed device upon which to base a determination of substantial
equivalence, that person requests a classification under section
513(f)(2) of the FD&C Act.
Under either procedure for De Novo classification, FDA is required
to classify the device by written order within 120 days. The
classification will be according to the criteria under section
513(a)(1) of the FD&C Act. Although the device was automatically placed
within class III, the De Novo classification is considered to be the
initial classification of the device.
We believe this De Novo classification will enhance patients'
access to beneficial innovation, in part by reducing regulatory
burdens. When FDA classifies a device into class I or II via the De
Novo process, the device can serve as a predicate for future devices of
that type, including for 510(k)s (see section 513(f)(2)(B)(i) of the
FD&C Act). As a result, other device sponsors do not have to submit a
De Novo request or premarket approval application to market a
substantially equivalent device (see section 513(i) of the FD&C Act,
defining ``substantial equivalence''). Instead, sponsors can use the
less burdensome 510(k) process, when necessary, to market their device.
II. De Novo Classification
On September 28, 2021, FDA received BONESUPPORT AB's request for De
Novo classification of CERAMENT G. FDA reviewed the request in order to
classify the product under the criteria for classification set forth in
section 513(a)(1) of the FD&C Act.
We classify devices into class II if general controls by themselves
are insufficient to provide reasonable assurance of safety and
effectiveness of the device, but there is sufficient information to
establish special controls that, in combination with the general
controls, provide reasonable assurance of the safety and effectiveness
of the device for its intended use (see section 513(a)(1)(B) of the
FD&C Act). After review of the information submitted in the request, we
determined that the product can be classified into class II with the
establishment of special controls. FDA has determined that these
special controls, in addition to the general controls, will provide
reasonable assurance of the safety and effectiveness of the product.
Therefore, on May 17, 2022, FDA issued an order to the requester
classifying the product into class II. In this final order, FDA is
codifying the classification of the product by adding 21 CFR
888.3046.\1\ We have named the generic type of product ``resorbable
calcium salt bone void filler containing a single approved
aminoglycoside antibacterial,'' and it is identified as 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.
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\1\ FDA notes that the ACTION caption for this final order is
styled as ``Final amendment; final order,'' rather than ``Final
order.'' Beginning in December 2019, this editorial change was made
to indicate that the document ``amends'' the Code of Federal
Regulations. The change was made in accordance with the Office of
Federal Register's (OFR) interpretations of the Federal Register Act
(44 U.S.C. chapter 15), its implementing regulations (1 CFR 5.9 and
parts 21 and 22), and the Document Drafting Handbook.
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FDA has identified the risks to health associated with this type of
product and the measures required to mitigate these risks in table 1.
Table 1--Risks to Health and Mitigation Measures for Resorbable Calcium
Salt Bone Void Filler Containing a Single Approved Aminoglycoside
Antibacterial
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Identified risks to health Mitigation measures
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Recurring or persistent or new Clinical performance testing;
infection. Animal performance testing;
Non-clinical performance
testing; Product
characterization, including
drug substance; Antimicrobial
susceptibility testing;
Container compatibility
testing; Sterilization
validation; Stability and
shelf life testing; Drug
quality attribute performance
testing; Pharmaceutical
manufacturing information; and
Aminoglycoside antibacterial
approval.
Adverse tissue reaction................ Clinical performance testing;
Animal performance testing;
Biocompatibility evaluation;
and Pharmaceutical
manufacturing information.
Antimicrobial resistance............... Antimicrobial susceptibility
testing; Antimicrobial
resistance analysis; and
Labeling.
Transient electrolyte imbalance (e.g., Clinical performance testing;
hyperkalemia, hypercalcemia, or Animal performance testing;
hypocalcemia). and Labeling.
Incomplete bone formation or lack of Clinical performance testing;
bone formation. Animal performance testing;
Postmarket surveillance; and
Labeling.
Pathologic fracture.................... Clinical performance testing;
Animal performance testing;
and Labeling.
Product migration or extrusion......... Clinical performance testing,
Animal performance testing;
and Labeling.
Drug-induced toxicity (e.g., Clinical performance testing;
nephrotoxicity and ototoxicity). Animal performance testing;
Product characterization,
including drug substance; Drug
quality attribute performance
testing; Pharmaceutical
manufacturing information; and
Labeling.
------------------------------------------------------------------------
FDA has determined that special controls, in combination with the
general controls, address these risks to health and provide reasonable
assurance of safety and effectiveness of the product. For a product to
fall within this classification, and thus avoid automatic
classification in class III, it would have to comply with the special
controls named in this final order. The necessary special controls
appear in the regulation codified by this final order. FDA supports the
principles of the ``3Rs,'' to replace, reduce, and/or refine animal use
in testing when feasible. We encourage sponsors to consult with us if
they wish to use a non-animal testing method they believe is suitable,
adequate, validated, and feasible. We will consider if such an
alternative method could be assessed for equivalency to an animal test
method.
Under the FD&C Act, submission of a premarket notification under
section
[[Page 34150]]
510(k) is required to reasonably assure the safety and effectiveness of
class II devices unless FDA determines that the device type should be
exempt under section 510(m) of the FD&C Act. At this time FDA has not
made this determination for resorbable calcium salt bone void fillers
containing a single approved aminoglycoside antibacterial. This product
is therefore subject to premarket notification requirements under
section 510(k) of the FD&C Act.
III. Analysis of Environmental Impact
The Agency has determined under 21 CFR 25.34(b) that this action is
of a type that does not normally have a significant effect on the human
environment. Therefore, neither an environmental assessment nor an
environmental impact statement is required.
IV. Paperwork Reduction Act of 1995
This final order establishes special controls that refer to
previously approved collections of information found in other FDA
regulations and guidance. These collections of information are subject
to review by the Office of Management and Budget (OMB) under the
Paperwork Reduction Act of 1995 (44 U.S.C. 3501-3521). The collections
of information in part 860, subpart D, regarding De Novo classification
have been approved under OMB control number 0910-0844; the collections
of information in 21 CFR part 814, subparts A through E, regarding
premarket approval have been approved under OMB control number 0910-
0231; the collections of information in part 807, subpart E, regarding
premarket notification submissions have been approved under OMB control
number 0910-0120; the collections of information in 21 CFR part 820
regarding quality management system regulation have been approved under
OMB control number 0910-0073; the collections of information in 21 CFR
part 4, regarding combination products, have been approved under OMB
control number 0910-0523; the collections of information in 21 CFR part
211 have been approved under OMB control number 0910-0139; and the
collections of information in 21 CFR part 801, regarding labeling have
been approved under OMB control number 0910-0485.
List of Subjects in 21 CFR Part 888
Medical devices.
Therefore, under the Federal Food, Drug, and Cosmetic Act and under
authority delegated to the Commissioner of Food and Drugs, 21 CFR part
888 is amended as follows:
PART 888--ORTHOPEDIC DEVICES
0
1. The authority citation for part 888 continues to read as follows:
Authority: 21 U.S.C. 351, 360, 360c, 360e, 360j, 360l, 371.
0
2. Add Sec. 888.3046 to subpart D to read as follows:
Sec. 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
[[Page 34151]]
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 Sec. 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 Sec.
211 requirements established in Sec. 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
[[Page 34152]]
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.
Grace R. Graham,
Deputy Commissioner for Policy, Legislation, and International Affairs.
[FR Doc. 2026-11308 Filed 6-4-26; 8:45 am]
BILLING CODE 4164-01-P
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