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WARNING LETTER

Biosensors Interventional Technologies Pte Ltd MARCS-CMS 662943 —


Delivery Method:
Via Email
Product:
Medical Devices

Recipient:
Recipient Name
Mr. Tee Wee Hong
Recipient Title
Quality and Regulatory Affairs Director
Biosensors Interventional Technologies Pte Ltd

36 Jalan Tukang
619266
Singapore

Issuing Office:
OHT2: Office of Cardiovascular Devices, Office of Product Evaluation and Quality

United States


July 21, 2023

WARNING LETTER

Dear Mr. Hong,

During an inspection of your firm located in Tukang Singapore on April 17 through April 20, 2023, an investigator from the United States Food and Drug Administration (FDA) determined that your firm is a medical device manufacturer of the BioFreedom Drug Coated System which is intended for improving coronary luminal diameter in patients at high risk for bleeding for the treatment of de novo lesions in native coronary arteries with a reference diameter ranging between 2.25 mm and 4.0 mm. 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 function of the body.

Our inspection revealed that your firm's device, the BioFreedom Drug Coated System is misbranded under section 502(t)(2) of the Act, 21 U.S.C. § 352(t)(2), in that your firm failed or refused to furnish material or information respecting the device that is required by or under section 519 of the Act, 21 U.S.C. § 360i, and 21 CFR Part 803 - Medical Device Reporting.

We received responses from Mr. Tee Wee Hong, Quality and Regulatory Affairs Director dated May 11, 2023, and June 27, 2023, concerning our investigator's observations noted on the Form FDA 483 (FDA 483), List of Inspectional Observations, which was issued to your firm. We address this response below, in relation to each of the noted violations. Significant violations include, but are not limited to, the following:

1. Failure to adequately develop, maintain, and implement written MDR procedures as required by 21 CFR 803.17(a)(1). For example: during the inspection, your firm identified the following two documents as its written MDR procedure.

  • "Patient Safety Incident Reporting and Recalls/FSCAs", QS-32, Rev.33, dated 4/19/2023
  • "Country Specific Requirements — Patient Safety Incident Reporting", WI-10570, Rev. 12, dated 4/19/2023

The procedure does not establish internal systems that provide for timely and effective identification, communication, and evaluation of events that may be subject to MDR requirements, as required by 21 CFR 803.17(a)(1). For example, the procedure, as written, combines language from the requirements of other regulatory or competent authorities with the requirements in 21 CFR Part 803 in a manner that will result in incomplete, inadequate, or even non-reporting of adverse events that meet the reportability requirements under 21 CFR Part 803.

Additionally, your firm is recommended to finalize the establishment of an active Electronic Submissions Gateway (ESG) production account for the electronic submission of MDR reports. FDA verified that, as of June 28, 2023, your firm does not have such an account. Information about the ESG and enrollment in the eMDR can be found at: How to Enroll in eMDR Program' FDA.

We reviewed your firm's responses and concluded that it is not adequate. Your response includes your firm's updated documents, namely:

  • "Product Event Handling", WI-10610, Rev. 16, dated 4/19/2023
  • "Medical Device Reporting, Recalls, Corrections and Removals in US", WI-11937, Rev. 1, dated 4/19/2023
  • "Patient Safety Incident Reporting and Recalls/FSCAs", QS-32, Rev. 34, dated 5/10/2023

Your firm's MDR procedures still combine language from the requirements of other regulatory or competent authorities. This might result in incomplete, inadequate, or even non-reporting of adverse events that meet the reportability requirements under 21 CFR Part 803. Additionally, your firm has not yet finalized the establishment of an active ESG production account for the electronic submission of MDR reports.

2. Failure to submit a report to FDA no later than 30 calendar days after the day your firm received or otherwise became aware of information, from any source, that reasonably suggests that a device that your firm markets may have caused or contributed to a death or serious injury, as required by 21 CFR 803.50(a)(1).

For example, the information included for complaint CB22-10-004 reasonably suggests that a patient sustained an injury (i.e., acute stent thrombosis) after the implantation of your firm's BioFreedom Drug Coated Coronary Stent system. Subsequently, a balloon dilatation procedure was performed.

The procedure referenced represents medical or surgical intervention necessary to preclude permanent impairment of a body function or permanent damage to a body structure. There is no information included for the complaint that rules out that the referenced device would not be likely to cause or contribute to the serious injury. As such, the referenced event represents a reportable serious injury event as defined in 21 CFR 803.3. Your firm became aware of the event on October 14, 2022, but the corresponding MDR has not yet been received by the FDA.

The adequacy of your firm's response dated May 11, 2023, cannot be determined at this time. In the response, your firm states that they conducted a retrospective review of complaints received after the PMA approval on April 14, 2022, and no further reportable events were identified. Additionally, your firm is in the process of establishing an eMDR account to file the referenced event and aligning their MDR reporting process with requirements outlined in the MDR regulations. The effectiveness of the planned corrective actions will be verified once they are implemented. However, your firm has not provided any documentation or evidence indicating completeness of the planned corrective actions as they are still ongoing. The response dated June 27, 2023, does not contain any additional information regarding the noted deficiencies.

3. Failure to submit a report to FDA no later than 30 calendar days after the day that your firm receives or otherwise become aware of information, from any source, that reasonably suggests that a device that your firm markets has malfunctioned and this device or a similar device that it markets would be likely to cause or contribute to a death or serious injury, if the malfunction were to recur, as required by 21 CFR 803.50(a)(2).

For example, complaint CB23-02-001 reasonably suggests that your firm's BioFreedom Drug Coated Coronary Stent malfunctioned (i.e., dislodgement) while in use. Per the 1995 Preamble, a malfunction is reportable if the malfunction involves a device that is considered to be life-supporting or life-sustaining and thus is essential to maintaining human life. There is no information included for the complaint that justifies that the malfunction would not be likely to cause or contribute to a death or serious injury, if it were to recur. As such, the referenced complaint represents a reportable malfunction event, as defined in 21 CFR 803.3.

Your firm became aware of the event on February 8, 2023, but as of the date of issuance of this letter, the corresponding MDR was not received by the FDA.

The adequacy of your firm's responses dated May 11, 2023, and June 27, 2023, cannot be determined at this time. In the response, your firm states that they conducted a retrospective review of complaints received after the PMA approval on April 14, 2022, and no further reportable events were identified. Additionally, your firm is in the process of establishing an eMDR account to file the referenced event and aligning their MDR reporting process with requirements outlined in the MDR regulations. The effectiveness of the planned corrective actions will be verified once they are implemented. However, your firm has not provided any documentation or evidence indicating completeness of the planned corrective actions as they are still ongoing.

This inspection also 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, 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. These violations include, but are not limited to the following:

1. Failure to establish procedures for corrective and preventive action, as required by 21 CFR 820.100 (a). For example, your firm has not fully implemented Section 6.7 of its procedure for Corrective and Preventive Action, requiring investigation and requiring determination of the "root cause" of the identified quality problem. Specifically,

A. Your firm's CAPA No. 23-0008, initiated 16-MAR-2023, addresses an action limit deviation for air sampling for microorganisms found in the clean room area (b)(4) used for production of the BioFreedom Drug Coated Stent System. Your firm's investigation is not adequate because it did not include a review of the procedures for qualification of clean rooms, review of records covering qualification of the subject clean room, or a review of your procedure for control of the environment within the clean room. More specifically, your firm did not evaluate procedures for monitoring and control for condition of furniture, the facility, and the HEPA filters. Additionally, your firm's corrective action does not address modification of control limits for temperature within the subject clean room.

B. CAPA No. 22-0006, initiated 21-SEP-2022, addresses an action limit deviation for air sampling for microorganisms found in the clean room area used to produce the catheter portion of your BioFreedom Drug Coated Stent System. Your firm's investigation was inadequate because you did not include a review of the procedures for qualification of clean rooms, a review of records covering qualification of the subject clean room, or a review of your procedure for control of the environment within the clean room. Further, your firm's investigation did not include an evaluation of procedures for monitoring conditions, positioning of furniture, and monitoring and controlling temperature. Your firm's investigation also did not evaluate if there were similar concerns regarding the qualification and control of other clean room areas. Additionally, your firm's corrective action to was not adequate because it did not address modifying the control limits for temperature within the subject clean room.

C. CAPA No. 22-0002, initiated 28-JAN-2022, addresses an (b)(4) during the sterilization process for a load of devices which included your BioFreedom Drug Coated Stent System devices not intended for the U.S. market. These records do not demonstrate a full investigation to determine the causes for this problem, to include review of procedures for vendor evaluation and review of records for the evaluation of the contract sterilizer. Additionally, your firm's records do not demonstrate that your firm identified a corrective action to prevent deviations from the maximum dose identified for the process. Further, your firm's records do not demonstrate retrospective evaluation of any affect the identified problem may have had on the qualification effort for the sterilization process developed for the BioFreedom Drug Coated Stent System devices intended for the U.S. market.

The adequacy of your firm's responses dated May 11, 2023, and June 27, 2023, cannot be determined because your firm has not completed implementation of their root cause analysis procedure on all open CAPAs. Your firm determined that there was no direct reference of work instruction WI-1 1690 (Root Cause Analysis Tools) to standard operating procedure QS-26 Corrective and Preventive Action Rev 29 Section 6.7, which could lead to ineffective / lack of usage of root cause analysis tools. The use of root cause analysis tool was not made mandatory.

Work instruction WI-1 1689 (Guidelines for Corrective and Preventive Action Forms) does not specify that a retrospective evaluation has to be carried out upon completion of investigation and identification of root cause. As a result, impact to other related products and processes was not assessed. Upon closure of this CAPA, the root cause analysis for all remaining open CAPAs (up till the VOE phase) shall be re-evaluated by the individual CAPA owners based on the requirements in the revised QS-26 Rev 30 and WI-11689 Rev 05. Update F00779 CAPA Action Plan Form / F00780 CAPA Completion Form / F00781 CAPA Verification of Effectiveness Form accordingly if necessary.

2. Failure to adequately ensure that when the results of a process cannot be fully verified by subsequent inspection and test that the process shall be validated with a high degree of assurance and approved according to established procedure per 21 CFR 820.75(a). Specifically, the firm's current work instruction for the Spray Coating Machine, WI-10726, a process used to apply the drug coating to the stent of the BioFreedom Drug Coated Stent System devices, does not fully define the specifications (b)(4)

A. Table 5.9 listing process parameter settings for 6 crown and 9 crown stems features a "Note" listing that operator and engineers are permitted to (b)(4) parameter to achieve (b)(4)

B. Section 9.10 of this work instruction lists tables which list the Target, USL (upper specification limit), and LSL (lower specification limit) for In-Process acceptance of (b)(4) but this section features a "Note" listing that the Engineer (b)(4)

Your firm's responses dated May 11, 2023, and June 27, 2023, appear to be acceptable. However, you noted in your response that twelve manufacturing procedures (i.e., WI-10726, WI-10784, WI-11357, WI-11239, D00244, D00249, WI-10495, D00361, D00280, D00284, D00285, and WI-10459) have been revised. Be aware that you will need to submit the relevant manufacturing changes to FDA in an appropriate post-approval submission.

Of note, your firm registered for Fiscal Year 2023 on December 6, 2022, but you have not listed the BioFreedom Drug Coated System. Your film listed P190020 and have listed BioFreedom as the proprietary name. Please update your listing to include the full proprietary name (BioFreedom Drug Coated System) for the device to be considered listed. Further, you have not listed any other devices, and this is a requirement if you plan to import other devices to the United States.

Other federal agencies may take your compliance with the FD&C Act and its implementation 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.

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, including 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 action (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. Please provide a translation of documentation not in English to facilitate our review. We will notify you regarding the adequacy of your firm's responses and the need to re-inspect your firm's facility to verify that the appropriate corrections and/or corrective actions have been made. 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 CDRHWarningLetterResponses@fda.hhs.gov or by mail to Food and Drug Administration, Center for Devices and Radiological Health, Office of Regulatory Programs, Division of Regulatory Programs 2, FDA Regulatory Inspections and Audits Team, White Oak Building 66, 10903 New Hampshire Ave., Silver Spring, MD 20993. Refer to CMS case #662943 when replying. If you have any questions about the contents of this letter, please contact: Lydia Glaw, Assistant Director of Coronary Interventional Devices at Lydia.Glaw@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 yours,
/S/

Bram Zuckerman, M.D.,
Director
OHT2: Office of Cardiovascular Devices
Office of Product Evaluation and Quality
Center for Devices and Radiological Health

CC:
Debashis Dutta,
US Agent
Biosensors International USA, Inc.
1104 Philadelphia Pike
Wilmington, DE 19809
Via email: D.Dutta@Biosensors.com

 
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