IsoTis OrthoBiologics, Inc.(CMS #723370)

Issuing Office:

Center for Devices and Radiological Health

United States

WARNING LETTER 

CMS #723370

February 24, 2026

Dear Mr. Nalbach:

During an inspection of your firm located in Irvine, CA from October 6, 2025, through October 17, 2025, investigators from the United States Food and Drug Administration (FDA) determined that your firm manufactures resorbable calcium salt bone void filler devices, branded under the Accell Family of products, to include the Accell Evo3c. Under section 201(h) of the Federal Food, Drug, and Cosmetic Act (the Act), 21 U.S.C. § 321(h), these products are devices because they are intended for use in the diagnosis of disease or other conditions or in the cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the body.

Quality System Regulation Violation(s)
This inspection revealed that these devices are adulterated within the meaning of section 501(h) of the Act, 21 U.S.C. § 351(h), in that the methods used in, or the facilities or controls used for, your manufacture, packing, storage, or installation are not in conformity with the current good manufacturing practice requirements of the Quality System regulation found at Title 21, Code of Federal Regulations (CFR), Part 820.

We received a response from your Director Quality Systems, dated November 7, 2025, concerning our investigator’s observations noted on the Form FDA 483 (FDA 483), List of Inspectional Observations, that was issued to your firm. We address this response below, in relation to each of the noted violations. These violations include, but are not limited to, the following:

1. Failure to adequately establish procedures for corrective and preventive action, as required by 21 CFR 820.100(a). For example:

Your firm failed to adequately take action to correct the cause of nonconformities in order to prevent recurrence. Your firm's corrective and preventative action procedure, Corrective and Preventive Actions CP-1001 Rev. J Effective: 8/22/2022, requires your firm to perform an investigation, determine the need for containment, and assess the risk associated with the issue.

Your firm opened CAPA 157738 on 7/27/23 to address potential (b)(4) particulate contamination occurring during the demineralization process of bone tissue, due to the propeller blade contacting the bottom of the demineralization vessel. The issue was discovered by a manufacturing engineer and documented in emails dating back to 06/22/2023.

As part of CAPA 157738, your firm conducted a risk assessment for the demineralization process. In your risk analysis document, PFMEA-011 Rev. 12, effective October 23, 2023, your firm identified (b)(4) as a risk for particulate contamination. This risk was assigned a severity rating of Moderate and a probability of Improbable, resulting in an overall Acceptable risk rating. Despite discovering that the propeller blade was potentially shedding (b)(4) particles during demineralization, your firm did not investigate whether this finding affected your risk probability rating. In CAPA 157738, your firm classified the risk as low without providing justification for this conclusion and determined that containment action was not required due to your determined low risk. Your firm's CAPA investigation and actions are inadequate because it did not assess the potential impact to finished devices, including distributed product.

Additionally, your firm’s Verification of Effectiveness included reviewing 18 work orders to confirm that visual inspection of the propeller was performed. The verification of effectiveness does not demonstrate that visual inspection of the propeller is sufficient to identify potential (b)(4) particulate in your firm's demineralized bone matrix (DBM). Your firm did not verify if the corrective actions performed were sufficient to correct the potential (b)(4) particulate contamination.

Your firm closed CAPA 157738 on 12/17/2024 without evidence that (b)(4) particulate contamination was no longer occurring during your demineralization process.

We reviewed your firm’s response and conclude that it is not adequate. While your firm’s response acknowledges procedural deficiencies and proposes process improvements, the CAPA defers critical product risk elements to separate CAPAs without clear indication that all deficiencies identified in CAPA-157738 have been adequately addressed. For example, in HHE-(b)(4), your firm identified (b)(4) complaints determined to be relevant now that (b)(4) contamination has been identified as a potential contributing factor. However, none of the related CAPAs indicate whether an MDR assessment was performed for these complaints.

Additionally, it is not clear why the scope of the CAPA retrospective review is from 01/01/2022 to present.

2. Failure to revalidate a validated process when changes or process deviations occurred, as required by 21 CFR 820.75(c). For example:

Your firm’s procedure, Validation Program QA-035 Effective: 6/11/21, requires revalidation for previously validated process parameters, component changes, and major design changes; however, your firm did not revalidate your demineralization press when a major design change was made.

Your firm opened CAPA 157738 on 7/27/23 to address a finding that during the manufacturing process of demineralizing bone tissue, the propeller blade contacts the bottom of the demineralization vessel creating the potential shedding of (b)(4) particulates. Two corrective actions were implemented:

• (b)(4)

• (b)(4)

Your firm updated TL-0091 for the Demineralization Press in design change order (DCO), DCO 6306 Released: 5/24/24, which changed the equipment design by (b)(4). Your firm determined that qualification or validation is not required, though the DCO describes the change category as Major. Your firm answered No to the question: Is there a change in the manufacturing equipment while maintaining the existing process? on your Form CPF-0302-001 Decision Tree, although your firm changed the equipment design by (b)(4). Your firm’s Director of Quality Systems and Assurance told the investigator that they considered the demineralization press to be a tool and not equipment.

Additionally, your firm determined that (b)(4) inspection was sufficient to identify potential (b)(4) contaminants and required training of your demineralization team to (b)(4) inspect the propellers, however your firm has not validated the (b)(4) inspection process for the propeller blades to demonstrate it is sufficient in identifying potential (b)(4) contaminants in your firm’s demineralized bone matrix (DBM). In an email from your firm’s manufacturing engineer, they note that (b)(4) particulates are (b)(4).

We reviewed your firm’s response and conclude that it is not adequate. Your firm opened CAPA-100520 to address production and process related deficiencies identified in Observation 2. Actions include validating the (b)(4) inspection method with (b)(4) study, completing Installation Qualification for all (b)(4) demineralization assemblies, and establishing preventative maintenance and calibration programs. However, while your firm validated the inspection method and qualified equipment, there is no objective evidence that:

• An evaluation of the existing process validation was conducted to determine if the changes to the demineralization assemblies could impact the applicability of the existing Operational and Performance Qualifications.

• (b)(4) particulate contamination is no longer occurring in production and that the (b)(4)" clearance is sufficient to prevent all contact under all operating conditions

• Testing has been performed to confirm absence of (b)(4) particles in DBM

Furthermore, the verification of effectiveness plan measures compliance to procedures and execution of preventative maintenance but does not include testing for (b)(4) particulates in finished product.

Additionally, it is not clear why the scope identified in CAPA-100520 for reviewing tooling changes is January 2022 to present, when the affected timeframe extends back to 2008.

3. Failure to establish an adequate risk analysis, as required by 21 CFR 820.30(g). For example:

Your firm’s procedure, CP-0305 Risk Management Rev. J1 Effective: 5/27/22, requires in Section 6.26.2 Perform Risk Reassessment (As Necessary), that if new or updated risk information is identified, it will be fed back into the risk management system and documented via update and approval of the appropriate risk management forms (such as the Hazard Analysis or FMEA).

Your firm opened CAPA 157738 on 7/27/23 to address a finding, during the manufacturing process of demineralizing bone tissue, the propeller blade contacts the bottom of the demineralization vessel creating potential shedding of (b)(4) particulates. The CAPA identified the risk in PFMEA-001 for OrthoBlast II and PFMEA-002 DynaGraft II as (b)(4) for Supplier error leading to particulate contamination resulting in transient inflammation, which defined a severity of Moderate and a probability occurrence of Improbable, and the Risk Acceptability as Acceptable.

Your firm identified the propeller blade was potentially shedding (b)(4) particulates during the demineralization process; however, your firm did not update PFMEA-001 for OrthoBlast II and PFMEA-002 DynaGraft II to identify this new risk factor. (b)(4) only addresses potential contaminants from your supplier resulting in transient inflammation and does not address the risk of contaminants during your firm’s manufacturing processes. Your firm did not identify the risk of (b)(4) contaminants and the potential impact to patient harm. Your firm’s risk management files were not updated after identifying this new risk, including identifying the severity of patient harm, as required by your procedure.

Additionally, your firm did not reevaluate the probability of occurrence for potential contaminants. (b)(4) Supplier error leading to particulate contamination resulting in transient inflammation defines a probability occurrence of Improbable. Your firm did not update the occurrence probability after identifying the new risk of potential (b)(4) contaminants.

According to your firm’s Senior Manager, New Product Initiatives and Sustaining Engineering, since your firm implemented the demineralized process in 2008, (b)(4) particulates may have been present in your DBM, potentially impacting over (b)(4) devices.

We reviewed your firm’s response and conclude that it is not adequate. Your firm opened CAPA-100520 to address risk management deficiencies identified in Observation 3. Although your firm acknowledges that risk assessment associated with CAPA 157738 and related PFMEAs and Hazard Analysis (HA-(b)(4)) required revision and initiated procedural changes, your response is still inadequate. Your firm’s actions included:

• Updated PMFEAs ((b)(4)) to include (b)(4)

• Updated Hazard Analysis HA-(b)(4) to (b)(4)

• Conducted a retrospective Health Hazard Evaluation (HHE-(b)(4))

HHE-(b)(4) concluded that no correction, removal, or recall recommended, as the risk level assessed as Low and Acceptable. Your firm acknowledges that (b)(4) contamination occurred from 2008-2024, with over (b)(4) devices potentially affected, however no actual testing was performed to confirm the absence of (b)(4) in distributed product. The HHE is deficient in that:

• Your firm reviewed (b)(4) complaints and deemed (b)(4) clinically relevant for your probability calculation. There was no clear indication on which were not deemed clinically relevant and why. Your firm concluded that (b)(4) complaints related to (b)(4) contamination without adequately documenting an investigation showing how they ruled out (b)(4) contamination as a contributing factor.

• Your firm’s Probability Assessment disregards potential inflammation or foreign body reaction due to (b)(4) particles as typical post-surgical inflammation

• Severity Assessment deemed Moderate, which firm has defined in your firm’s procedure, Risk Management Rev. J1 Effective: 5/27/22 and identified in the Severity Ratings Table in HHE-(b)(4) as a minor intervention (i.e. Medical intervention that may result in procedural delay, requiring removal and re-insertion of device resulting in additional patient discomfort or increased anesthesia requirements; Minor, transient, or self-limiting injury not requiring medical intervention; Cancellation of an elective medical procedure / surgery). While complaint data included in HHE includes revision surgery, hospitalization, IV antibiotics, osteolysis consistent with a higher severity rating as noted in your procedure.

• Biocompatibility has not been adequately evaluated. Your firm states that (b)(4) is used in permanently implanted devices (stents, pledgets, endoprostheses), therefore, (b)(4) exposure is not expected to cause adverse effects. However, the cited devices use intact (b)(4) structures, not particulate contamination. Your firm provides no data demonstrating that they have:
  o Characterized potential particle generation during normal use and wear.
  o Conducted biocompatibility testing per ISO 10993 standards if particle release is expected.
  o Assessed the clinical significance of any particle elution through risk analysis.

Your firm should take prompt action to address any violations identified in this letter. Failure to adequately address this matter may result in regulatory action being initiated by the FDA without further notice. These actions include, but are not limited to, seizure, injunction, and civil money penalties.

On February 2, 2024, the FDA issued a final rule amending the device current good manufacturing practice (CGMP) requirements of the Quality System (QS) Regulation under 21 CFR 820 to align more closely with the international consensus standard for Quality Management Systems for medical devices used by many other regulatory authorities around the world. The revised part 820, referred to as the Quality Management System Regulation (QMSR), became effective on February 2, 2026. Your most recent inspection on October 6, 2025 through October 17, 2025 was conducted pursuant to the QS Regulation, which was in effect at the time of the inspection. However, any corrective actions you propose, or implement must be pursuant to the QMSR requirements in effect as of February 2, 2026. For more information on the QMSR please refer to our frequently asked questions webpage: https://www.fda.gov/medical-devices/quality-system-qs-regulationmedical-device-current-good-manufacturing-practices-cgmp/quality-management-system-regulation-final-rule-amending-quality-system-regulation-frequently-asked.

Other federal agencies may take your compliance with the FD&C Act and its implementing regulations into account when considering the award of federal contracts. Additionally, should FDA determine that you have Quality System regulation violations that are reasonably related to premarket approval applications for Class III devices, such devices will not be approved until the violations have been addressed. Should FDA determine that your devices or facilities do not meet the requirements of the Act, requests for Certificates to Foreign Governments (CFG) may not be granted.

Please notify this office in writing within fifteen business days from the date you receive this letter of the specific steps your firm has taken to address the noted violations, as well as an explanation of how your firm plans to prevent these violations, or similar violations, from occurring again. Include documentation of the corrections and/or corrective actions (which must address systemic problems) that your firm has taken. If your firm’s planned corrections and/or corrective actions will occur over time, please include a timetable for implementation of those activities. If corrections and/or corrective actions cannot be completed within fifteen business days, state the reason for the delay and the time within which these activities will be completed. Your firm’s response should be comprehensive and address any violations included in this Warning Letter. If you believe that your products are not in violation of the FD&C Act, include your reasoning and any supporting information for our consideration as part of your response.

Your firm’s response should be sent via email to CDRHEnforcement@fda.hhs.gov. Please include in the subject line, “CMS Case 723370” when replying. If you have any questions about the contents of this letter, please contact: Shaquenta Perkins at shaquenta.perkins@fda.hhs.gov.

Finally, you should know that this letter is not intended to be an all-inclusive list of the violations at your firm’s facility. It is your firm’s responsibility to ensure compliance with applicable laws and regulations administered by FDA. The specific violations noted in this letter and in the Inspectional Observations, FDA 483, issued at the close of the inspection may be symptomatic of serious problems in your firm’s manufacturing and quality management systems. Your firm should investigate and determine the causes of any violations and take prompt actions to address any violations and bring the products into compliance.

Sincerely,
/S/

Barbara C. Marsden  
Acting Director
Office of Regulatory Programs
Office of Product Evaluation and Quality  
Center for Devices and Radiological Health