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WARNING LETTER

Integra LifeSciences Corporation MARCS-CMS 698850 —

Delivery Method:
VIA Electronic Mail
Product:
Medical Devices
Recipient:
Recipient Name
Mr. Jan De Witte
Recipient Title
President and CEO
Integra LifeSciences Corporation

1100 Campus Road
Princeton, NJ 08540
United States

(b)(4)@integralife.com
Issuing Office:
Center for Devices and Radiological Health

United States

WARNING LETTER
CMS # 698850

December 19, 2024

Dear Mr. DeWitte:

The United States Food and Drug Administration (FDA) conducted the following inspections of your firm’s medical device facilities:

  • Integra LifeSciences Corporation, located at 11 Cabot Blvd, Mansfield, MA, FEI 3014334038, from March 12, 2024 through June 5, 2024
  • Integra LifeSciences Corporation, located at 105 And 109 Morgan Ln, Plainsboro, NJ, FEI 1121308, from April 9, 2024 through August 22, 2024
  • Integra LifeSciences Corporation, located at 1100 Campus Rd, Princeton, NJ, FEI 3003418325, from March 12, 2034 through August 22, 2024

During these inspections, FDA investigators and a microbiologist determined that the above firms manufacture a variety of neurological and neurosurgical devices, including but not limited to, cranial perforators, disposable cottonoid patties and strips as well as collagen based medical devices, that are used for wound care, soft tissue repair and reconstruction surgery. 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.

The above inspections revealed that the above 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, their 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 responses from Jeffrey Caldwell, Vice President, Quality Operations dated June 27, 2024, August 27, 2024, and October 25, 2024 concerning our investigator’s and microbiologist’s observations noted on the Form FDA 483 (FDA 483), List of Inspectional Observations, that was issued to your firm’s Mansfield, MA location on June 5, 2024.

We received responses from Brenda Romero, Director, Quality Operations, CMC dated September 27, 2024 and December 5, 2024 concerning our investigator’s observations noted on the Form FDA 483 (FDA 483), List of Inspectional Observations, that was issued to your firm’s Plainsboro, NJ location on August 22, 2024.

We received responses from Jessica Smith, Corporate Vice President, Chief Regulatory Officer, and interim Chief Quality Officer dated September 13, 2024 and from Lacey Gigante, Sr. Director, CAPA & Compliance November 15, 2024 concerning our investigator’s observations noted on the Form FDA 483 (FDA 483), List of Inspectional Observations, that was issued to your firm’s Princeton, NJ location on August 22, 2024.

We address these responses below, in relation to each of the noted violations. These violations include, but are not limited to, the following:

1. Failure to establish and maintain procedures to control product that does not conform to specified requirements. The procedures shall address the identification, documentation, evaluation, segregation, and disposition of nonconforming product. The evaluation of nonconformance shall include a determination of the need for an investigation and notification of the persons or organizations responsible for the nonconformance. The evaluation and any investigation shall be documented, as required by 21 CFR § 820.90(a).

Specifically, during an inspection of your Mansfield, MA location, a review of 4 non-conforming reports from October 2022 through June 2023 (NC-101352, NC-101446, NC-101628, and NC-101642) were opened due to Out of Specification (OOS) endotoxin results on three separate lots of surgical patties and one lot of Duraform. In the above instances, after the laboratory investigation concluded there was no assignable laboratory error or root cause, your firm retested the lots, even though your Pyrogen Testing procedure, MPS-PC340, did not specify that a retest was allowed. Your firm then released the above referenced lots without conducting a complete investigation of the manufacturing processes, as required by your Non-Conformance procedure, GSOP-773 and MPS-PC340.

We reviewed your firm’s responses and the adequacy cannot be determined. We acknowledge that your firm initiated a recall of Duraform, lot CT007694 on September 6, 2024 as well as a recall of multiple lots of surgical patties and strips manufactured between 2022 and 2023 on September 20, 2024. However, your firm continues to implement a number of corrective actions at your Mansfield, MA facility that will not be completed until May 2025.

2. Failure to establish and maintain procedures for acceptance activities. Acceptance activities include inspections, tests, or other verification activities; as required by 21 CFR § 820.80(a).

Specifically, your Plainsboro, NJ location utilizes procedure CMC-MB-049 “Determination of Endotoxin in (b)(4) Product Using the (b)(4) Methods” to determine the bacterial endotoxin concentration in products manufactured at the Integra LifeSciences Collagen Manufacturing Center (CMC), Buildings (b)(4) and (b)(4), including (b)(4). According to section 9.6.3.3 of this procedure, “the Coefficient of Variation (CV%) for each pair of standard series samples must be less than (b)(4)” for the overall test to be considered valid. However, during our inspection we observed that ten of fifty-two tests conducted in 2023 failed due to the CV% exceeding the (b)(4) limit. These ten tests were observed to be repeatedly retested until the CV% fell below (b)(4). For example, endotoxin test (LAL-24-2012) and its two subsequent retests (LAL-24-0012 Retest, LAL-24-0012 Retest 2) all failed to meet CV% criteria. It was then retested on a different day under a new ID (LAL-24-0013) and finally passed on the fourth attempt (LAL-24-0013 Retest 3). Your firm’s microbiology manager attributed the CV% failures to low endotoxin concentration in the controls. Additionally, your CMC-MB-049 procedure does not specify the circumstances under which a retest could be performed or which result should be utilized if a retest was conducted.

We reviewed your firm’s responses and the adequacy cannot be determined. We acknowledge that your firm initiated three CAPAs (CAPA-00133, CAPA-00134, and CAPA-00135) to address the observations. As part of these CAPAs, we acknowledge that your firm has performed a statistical assessment of historical reagent qualification data for CV% in which you determined that the appropriate CV% for the (b)(4) EU/mL standard concentration would be (b)(4)% and made updates to affected procedures, including CMC-MB-049. However, verification of the effectiveness of the corrective actions are still ongoing with a target date of June 2025. Please provide the results of your firm’s planned 6-month effectiveness check when it becomes available.

3. Failure to establish and maintain procedures for finished device acceptance to ensure that each production run, lot, or batch of finished devices meets acceptance criteria, as required by 21 CFR § 820.80(d).

Specifically, your Mansfield, MA location utilizes MPS-PC340, Preparing Products for Pyrogen Testing (Rev: 068, Effective Date: 30Mar2023) to describe the procedures and materials needed to prepare test samples for pyrogenicity and how to investigate results that exceed acceptable criteria. However, review of this procedure determined it lacks the following requirements to ensure devices meet established endotoxins specifications for device sterility prior to release. For example,

 Adequate instructions for OOS laboratory investigations where the original endotoxins results are determined to be valid because no laboratory error or assignable cause was found.
 Documentation of how many times the device lot or device extract may be re- analyzed or retested during the investigation after an OOS result is reported.
 Lack of details regarding sample selection to ensure samples are representative of the entire lot to account for endotoxins not evenly distributed within the lot.
 No requirement to include documentation of endotoxin test result units (EU/ml or EU/device) on the Post-Sterile Release section of your Device History Records.

For example, verification of Pyrogen Lab Results receipt for Lot # 7260687 of Product Code (b)(4) lists the Lab Result as “(b)(4).” The Endotoxin Action Limit for this product code is (b)(4) EU/Device. Your Bacterial Endotoxin Test Final Report (Study Number 1621708-S01), dated June 15, 2023 concluded that the pooled test articles for Lot # 7260687 “exceeded the endotoxin limit of not more than (b)(4) EU/device.”

We reviewed your firm’s responses and the adequacy cannot be determined. We acknowledge that your firm initiated NC-001411 on June 7, 2024 and CAPA-100183 on June 11, 2024 to address updates needed to the procedural requirements, updates to DHRs so that BET result units are accurately recorded among other actions. However, your firm continues to implement a number of corrective actions that will not be completed until March 2025.

4. Failure to establish and maintain procedures for corrective and preventive action, as required by 21 § CFR 820.100(a). For example,

During the inspection of the Princeton, NJ corporate headquarters, your Corrective and Preventive Action (CAPA) Process (GSOP-758; Rev 007), specifically, Section 7.1, describes the process of CAPA Escalation. Section 7.1.2.3 of GSOP-758 describes when a decision is made to not initiate a CAPA, including documentation of the justification for not initiating a CAPA on Form GSOP-758A (CAPA Escalation Decision Form). A review of quality data sources over individual Integra sites, including corrective and preventive actions (CAPAs) and quality plans (QPs) taken at numerous Integra firm locations revealed that site specific CAPAs are not evaluated for escalation to corporate wide CAPAs.

For example, CAPA 23-008 opened on April 7, 2023 at the (b)(4) manufacturing location in (b)(4) was related to endotoxin testing at that location. Endotoxin testing is performed at other locations, including collagen manufacturing in Plainsboro, NJ and neurological manufacturing in Mansfield, MA. The decision and justification to not escalate endotoxin testing to a corporate wide CAPA was not documented.

Additionally, per Section 5.2.1 of the Quality Objectives & Quality Planning document (GSOP-763; Rev. 003) “quality planning is not used to investigate or correct actual or potential problems or concerns arising from the QMS or its data sources.” However, during our inspections, you provided several quality plans that were being utilized for investigating or correcting actual and potential problems with the quality systems. The GSOP-763 procedure used for quality planning does not include pertinent sections required for corrective and preventive actions such as: investigating the cause of nonconformities, identifying the actions needed to correct and prevent recurrence, and verifying or validating the action to ensure it is effective. These sections are found within the CAPA procedure GSOP-758. At the time of our inspections, CAPAs had not been opened to address these issues. Examples of quality plans currently being used to correct problems with the quality system are:

• At your Princeton, NJ location
    o QP-2023-12, Quality Plan for Assessing Endotoxin Program Compliance, initiated on March 25, 2024 to assess endotoxin issues across Integra organizations. This quality plan lists a target completion date for site-specific gap assessments as 12/31/2026 and the target due date for developing an action plan to close and/or mitigate any identified compliance gaps as 6/30/2027.
• At your Plainsboro, NJ location
    o QP-2023-02, Quality Plan for the Closure of Overdue SCARs at the Collagen Manufacturing Center, initiated on December 7, 2023 to document the closure of overdue SCARs at the Collagen Manufacturing Center (CMC). Eleven SCARs were identified as overdue in section 2.2 of this document.
• At your Mansfield, MA location
    o QP-20-001, Quality Plan for CerebroFlo EVD Catheter design history file remediation initiated on April 9, 2020, to address 30 observations found during a third-party review of the CerebroFlo EVD catheter design project.

We reviewed your firm’s responses and the adequacy cannot be determined. We acknowledge that your firm initiated several CAPAs at multiple sites, including a corporate-wide CAPA-00143 on September 6, 2024 to address the extension of CAPAs and Quality Plans across multiple Integra locations including planned implementation of a CAPA escalation decision tree and form by December 15, 2024; planned review of all CAPAs initiated at Integra corporate and all manufacturing sites since November 2, 2022; and planned updates to GSOP-758 to require an evaluation of each CAPA to determine whether it may be applicable to multiple manufacturing sites. However, your firm continues to implement corrective actions that will not be completed until November 2025 when verification of effectiveness is targeted to be completed.

5. Failure to review and evaluate process changes and deviations and perform revalidation when changes or process deviations occur, as required by 21 CFR § 820.75(c).

For example, at your Mansfield, MA location, your firm failed to assess the impact of annual sterilization requalification parameter failures for Ethylene Oxide (EO) cycle #(b)(4) used to demonstrate a continued sterility assurance level of (b)(4) EO sterilization is performed by (b)(4). EO cycle #(b)(4) is used sterilization of several devices manufactured at Mansfield, MA including neurological surgical patties. For example,

• On December 2, 2020, a deviation occurred with eight temperature sensors recording temperatures below the minimum (b)(4) degrees Fahrenheit for the product temperature during the EO exposure dwell phase, failing to meet the predetermined validation acceptance criteria of (b)(4).
    o Your firm failed to investigate the cause of the temperature failure and the potential effect on the EO cycle for routine sterilization.

• The 2022 requalification of the EO cycle (b)(4) for Vessel #1 and Vessel # 2, ((b)(4)-0007898) approved by your firm on November 23, 2022, exceeded your firm’s predetermined acceptance criteria for product load relative humidity (RH) of (b)(4) when RH readings ranged from (b)(4) during the preconditioning product phase, exceeding the allowable upper RH limit of (b)(4).
    o Your firm reported this RH protocol deviation as part of the 2022 requalification. However, your firm concluded: “…the re-qualification using dunnage devices has no effect on finished goods and no immediate actions are needed. There is no impact to sterility assurance of EO devices due to this event.” This conclusion was reached without an adequate investigation into the failed re-validation and determination of the root causes of the failure.

• The 2023 requalification of the EO cycle (b)(4) for Vessel # 1 and Vessel #2 ((b)(4)-0009433) approved by your firm on March 15, 2024, failed to meet your firm’s predetermined acceptance criteria that all internal and external biological indicators (BI) were required to be negative for growth as one external process challenge devices (PCD) resulted in positive growth. Further, the RH specification of (b)(4) was not met as RH readings ranged from (b)(4) during the preconditioning product phase, exceeding the allowable upper RH limit of (b)(4).
    o As a result of the 2023 requalification failures, Vessel #2 was disqualified for EO cycle (b)(4). However, your firm continues to use Vessel #1 which also failed to meet the same EO requalification predetermined acceptance criteria (RH) that caused your firm to disqualify Vessel #2 and similar conclusions used during the 2022 deviation report were again restated in 2023 to justify continued use of Vessel #1.

We reviewed your firm’s responses and the adequacy cannot be determined. We acknowledge that your firm initiated NC-001007 on June 7, 2024 which was later escalated to CAPA-00179 on June 11, 2024 to address, in part, annual parameter failures associated with EO cycle (b)(4) including revisions made to your Annual EO Revalidation (b)(4) work instruction (WI-10007) and planned performance of requalification for EO cycle (b)(4) for the current year utilizing the updated WI. However, this requalification has not occurred as it has a target date of December 31, 2024.

Additionally, at your Princeton, NJ location, your firm initiated a Supplier Change Request (SCAR #NC-101873) to change the pouch sealing machine to (b)(4), which supplies pouches (product number (b)(4)) to your firm’s Le Locle, Switzerland facility for packaging of sterile medical devices after detection that the pouch was opened on the (b)(4) sealing side. Investigation into the seal strength caused your supplier to perform a revalidation of (b)(4) to challenge the ability to produce product that meets specifications.

In the performance qualification protocol performed by your supplier ((b)(4)-24010), a minimum acceptable seal value lower specification limit (LSL) of (b)(4) lb/in was utilized. In your Retrospective Validation Report for Bactiseal Pouch Supplier Sealer Performance (Document ENG-199915-MEMO) the seal strength lower spec. is listed as (b)(4) lbf/in. However, the validation qualification report for Package Performance and Package Stability Study for Bactiseal EVD (applicable to your Le Locle, Switzerland and Mansfield, MA locations) concluded that the (b)(4) minimum specification will meet the (b)(4) lb/in post sterilization requirement specified in the BSN 868-5 standard. This validation qualification report was performed in 2021 prior to the change to your supplier’s (b)(4) and does not account for your supplier’s use of a (b)(4) lb/in LSL.

We reviewed your firm’s responses and the adequacy cannot be determined. We acknowledge that your firm initiated CAPA-00146 on September 6, 2024 to address the lack of consistent assessment of validations when changes occur, as well as state a commitment to: update your product and process change decisions tree; create a global procedure for assessment of supplier changes; obsolete your supplier change process at Mansfield and Le Locle; and perform a retrospective review of Integra supplier change procedures. However, your firm continues to implement a number of corrective actions that will not be completed until January 2025

6. Failure to establish and maintain procedures to prevent contamination of equipment or product by substances that could reasonably be expected to have an adverse effect on product quality, as required by 21 CFR 820.70(e).

For example, the Controlled Environment and Cleanroom Operating and Monitoring Procedure (Rev: 065, Effective Date: 20 April 2021) utilized at your Mansfield, MA location was not followed. Multiple (18) viable and non-viable particulate environmental excursion results, occurring from January 2023 to April 2024, for your (b)(4) cleanroom were observed near a (b)(4), equipment identification #(b)(4)) located in room (b)(4). As a result, your firm updated the (b)(4) cleaning procedure to “include routine cleaning of the locations which had visible particulate accumulation on the surface” and determined the risk to product quality as “Low – no product impact” without adequate investigation or a risk-based assessment to evaluate product impact. Several devices, including surgical patties, are manufactured using the identified (b)(4) machine, where the (b)(4) cleanroom failed your firm’s pre-established alert and action limits.

We reviewed your firm’s responses and the adequacy cannot be determined. We acknowledge that your firm initiated CAPA-100180 on June 11, 2024 to address updates needed to address this observation. We also acknowledge that your firm has updated your non-routine cleaning frequency for the (b)(4) machine, plans to complete a Health Hazard Evaluation, and develop a contamination control plan. However, your firm continues to implement these corrective actions that have a target date in January 2025.

For your Plainsboro, NJ location, during review of Particulate Air Sampling records (CNS-G-630A), it was observed that your firm set the (b)(4) cleanroom action limit at (b)(4) um sized particles per cubic meter. This action limit selected is the maximum allowance specified in the (b)(4) standard. Your firm’s action limit being set at the maximum allowable level does not provide an opportunity to take action before exceeding the specification.

We reviewed your firm’s responses and the adequacy cannot be determined. We acknowledge that your firm initiated CAPA-00151 on September 5, 2024 to address updates needed to resolve the observation. We also acknowledge that your firm plans to establish alert/action limits for (b)(4) cleanrooms that allow proactive actions to prevent exceeding particulate specifications along with planned changes to associated procedures. However, these corrective actions have not been implemented as a number of corrective actions have target completion dates in February 2025.

7. Failure to validate with a high degree of assurance, a process whose results cannot be fully verified by subsequent inspection and test, as required by 21 CFR § 820.75(a).

Specifically, your firm failed to follow your corporate-wide procedure for Process Validation (GSOP-738; Rev 007), in that section 5.2.5 states a protocol may be generated for each qualification, and section 5.2.6.6 states a qualification report is required for each qualification activity.

For example, at your Plainsboro, NJ location, your firm’s validation of procedure CMC-AH-10, (determination of bacterial endotoxins in Integra products, (b)(4) and (b)(4) using the (b)(4)), lacks a validation protocol and validation report. The validation for the inhibition and enhancement testing for Limulus Amebocyte Lysate (LAL) was performed in 2004 under a previous process validation procedure (MD-029; obsoleted 5/5/2022). The only record for validation of this LAL test were results from Inhibition/Enhancement Testing – (b)(4) performed on four lots of INTEGRA Dermal Regeneration Template (IRDT)-TS (b)(4). Approximately (b)(4) lots of IDRT have been produced since 12/1/2004.

We reviewed your firm’s responses and the adequacy cannot be determined. We acknowledge that your firm initiated CAPA-00136 on September 10, 2024 to address the lack of protocol and report for the validation of inhibition/enhancement Testing of LAL, as well as a commitment to (b)(4) validations for all Collagen Manufacturing Center (CMC) products, revisions to your CMC-AH-10 test method, and revisions to your change control procedures. However, your firm continues to implement a number of corrective actions that will not be completed until January 2025.

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.

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 Assistant Director Gina Brackett at CDRHWarningLetterResponses@fda.hhs.gov. Please include in the subject line CMS Case 698850 when replying. If you have any questions about the contents of this letter, please contact: Sean Moynihan, Consumer Safety Officer at sean.moynihan@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/

RDML Sean M. Boyd, MPH, USPHS
Director Office of Regulatory Programs
Office of Product Evaluation and Quality  
Center for Devices and Radiological Health

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