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WARNING LETTER

Bioptimal International MARCS-CMS 678281 —

Product:
Medical Devices
Recipient:
Recipient Name
Ms. Lai Chunhong
Recipient Title
Group CEO
Bioptimal International

3A, Unit 1, Building F, Tianebao (Stage Two), No. 2, Xiangshan Middle Street
Nanshan Qu
Shenzhen Shi
Guangdong Sheng,
China

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

United States

WARNING LETTER
CMS # 678281

April 3, 2024

Dear Ms. Chunhong:

During an inspection of your firm located in Singapore, Southwest on November 6, 2023 through November 11, 2023 an investigator from the United States Food and Drug Administration (FDA) determined that your firm manufactures Thermodilution Catheter and Pulmonary Artery Monitoring Catheter. 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. This letter is a correction to the letter issued on April 3, 2024. It communicates identical issues but utilizes the FDA letterhead.

Unapproved Device Violation

You currently have a clearance for the 'Thermodilution Catheter under K101669. Our inspection revealed that your firm made changes to the materials of the cleared device, including removal of the polyvinylchloride (PVC) tubing heparin coating, without submission of a new 510(k) premarket notification. This change could significantly affect the safety or effectiveness of the device and requires the submission of a new 510(k) premarket notification 21 CFR 807.81(a)(3)(i). For example, removal of this coating can increase friction in the tubing and negatively impact the thrombogenicity profile of the device.1 This can lead to increased blood clotting and/or thrombus, which can result in embolization during clinical use, significantly impacting patient safety.

Our inspection also revealed that your firm is marketing a Pulmonary Artery Catheter and claiming this device maintains the same device design as the cleared Thermodilution Catheter (K101669). However, based on the information gathered during the inspection, it appears the Pulmonary Artery Catheter has several technological characteristics that differ from the cleared Thermodilution Catheter. The 510(k) Summary for the Thermodilution catheter states that the device maintains a 4- and 5-lumen design with the extension and includes a thermistor. The Pulmonary Catheter is noted to include a 2- and 3-lumen configuration and does not maintain a thermistor element. Modification to the lumen design and removal of the thermistor change structural device properties and the ability to perform functions such as providing accurate measurements of body temperature during clinical use. Without proper evaluation to demonstrate the device continues to perform to appropriate standards, there is a higher risk of device failure during use, which can significantly impact patient safety. Considering this, a submission of a new 510(k) premarket notification is required according to 21 CFR 807.81(a)(3)(i).2

Accordingly, both the Thermodilution Catheter and the Pulmonary Artery Monitoring Catheter devices are adulterated under section 501(f)(1)(B) of the Act, 21 U.S.C. § 351(f)(1)(B), because your firm does not have an approved application for premarket approval (PMA) in effect pursuant to section 515(a) of the Act, 21 U.S.C. § 360e(a), or an approved application for an investigational device exemption under section 520(g) of the Act, 21 U.S.C. § 360j(g) for either device. The devices are also misbranded under section 502(o) the Act, 21 U.S.C. § 352(o), because your firm did not notify the agency of its intent to introduce the devices into commercial distribution, as required by section 510(k) of the Act, 21 U.S.C. § 360(k). For a device requiring premarket approval, the notification required by section 510(k) is deemed satisfied when a PMA is pending before the agency. 21 CFR 807.81(b). The kind of information that your firm needs to submit in order to obtain approval or clearance for the devices is described on the Internet at https://www.fda.gov/medical-devices/device-advice-comprehensive-regulatory-assistance/how-study-and-market-your-device. The FDA will evaluate the information that your firm submits and decide whether the products may be legally marketed.

Quality System Violations

Our 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. We received a response from you dated November 30, 2023, concerning our investigator's observations noted on the Form 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. These violations include, but are not limited to, the following:

1. Failure to adequately maintain complaint files and establish procedures for receiving, reviewing, and evaluating complaints by a formally designated unit, as required by 21 CFR 820.198(a) and (d). For example:

The complaint handling procedure, BQS-005, does not require that any incoming complaint be evaluated to determine whether the complaint represents an event which is required to be reported to FDA under 21 CFR 803, Medical Device Reporting (MDR). Further, your firm did not review, evaluate, and investigate certain complaints in a timely manner to determine whether they represent an event which must be reported to FDA under 21 CFR part 803, and such complaints did not include the appropriate records including the name of the device, the date the complaint was received, the Unique Device Identifier (UDI), and the name, address, and phone number of the complainant. We also note that your firm's complaint handling procedures do not require that complaint investigation records include the required information above.

The adequacy of your response dated November 30, 2023, cannot be determined at this time because your corrective actions are not yet complete. In your response you state your planned corrective action includes a retrospective review of adverse events to determine MDR reportability, including completeness of adverse event report records, and revision of complaint record procedure to ensure UDI compliance. You stated your corrective actions will be completed by February and March of 2024, but FDA has not received this information by the date of this letter. In response to this Warning Letter, you should provide updated documentation including, but not limited to, the revised version of your complaint record procedure and any associated evidence of the corrective actions.

2. Failure to establish and maintain procedures for implementing corrective and preventive action (CAPA), specifically, verifying or validating the corrective and preventive action to ensure that such action is effective and does not adversely affect the finished device, as required by 21 CFR 820.100(a). For example:

Some procedures of your firm's corrective and preventive actions, BQS-004 and BQS-005, have not been clearly established and your firm is not consistent with compliance/follow-through when it initiates corrective actions. Specifically, your firm has not demonstrated consistent collection of evidence of the completion of previous corrective actions, and your firm lacks procedures for verification or validation of effectiveness conducted after corrective action. In addition, there have been instances where quality data sources indicated data trends, including two or more complaints from the same lot reporting similar failure modes and/or device malfunctioning, which were not investigated further (i.e., no corrective action was taken even though the complaint handling documents required otherwise). Lastly, your firm failed to take corrective action when the actual occurrence rates of several device failure modes exceeded the anticipated occurrence rates specified in the risk management file for the Thermodilution Catheter.

The adequacy of your response dated November 30, 2023, cannot be determined because your corrective actions are not yet complete. In your response, you state your planned corrective action plan includes updating current CAPA procedures to include new device risk assessments and escalating all complaints from different SOP sources. In addition, you plan to initiate CAPAs for current customer complaints to provide resolution retrospectively. You state your corrective actions will be completed by February 2024, but FDA has not received this information by the date of this letter. In response to this Warning Letter, you should provide updated documentation including, but not limited to, the newly updated CAPA procedures and details/strategy for initiating CAPAs for current customer complaints.

3. Failure to establish and maintain procedures to validate device design to ensure that devices conform to defined user needs and intended uses, and include risk analysis where appropriate, as required by 21 CFR 820.30(g). For example:

Your firm's risk analysis procedures are inadequate. The actual occurrence rate of several device failure modes exceeded the anticipated occurrence rates that were specified in the risk management file and your firm did not take appropriate action. Further, your firm's risk analysis plan, BQS-006, specifies that the risk management file be reviewed and updated annually following an analysis of risks related to customer complaints and other items. The main device under consideration for repeated device failure is the Thermodilution Catheter and accessories. The failures include balloon rupture, balloon deflation difficulty, balloon inflation problems, pressure measurement issue, and cardiac output measurement issue. A device change was made to remove the heparin coating from the catheter shaft of the tubing and there was not documented assessment of the impact of friction resistance related to this change.

The adequacy of your response dated November 30, 2023, cannot be determined because your corrective actions are not yet complete. In your response you state your planned corrective action includes updating the risk assessment report for the Thermodilution Catheter, Pulmonary Artery Catheter, and Biotray to account for the number of device failures. In addition, you state that friction resistance testing will be conducted using non-coated tubing materials for the Thermodilution Catheter. You state your corrective actions will be completed by March 2024, but FDA has not received this information by the date of this letter. In response to this Warning Letter, you should provide your updated documentation including, but not limited to, the revised versions of your risk management file with updated device failures for your devices. Please refer to the "Unapproved Device Violation" section above and provide the friction resistance testing as part of a new 510(k) premarket notification.

4. 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, as required by 21 CFR 820.75. For example:

Your firm has not established procedures to conduct sterilization process validation. Without these procedures, your firm has not specified requirements to validate sterilization processes, instructions on testing frequency, and instructions for requalification of sterilization activities. Your firm also does not have a set plan for monitoring and controlling process parameters to ensure that sterilization specifications are met.

Your response dated November 30, 2023, does not completely address this observation. In your response you state your planned corrective action includes establishing and creating a sterilization process validation procedure according to the current practice and sterilization method employed. You also plan to send the new QA staff for process validation concepts and awareness external training. You state your corrective actions will be completed by January 2024, but FDA has not received this information by the date of this letter. In your response to this Warning letter, you should provide updated documentation including, but not limited to, the revised versions of your sterilization validation procedure and QA staff training certification. Further, your response is not adequate because you have not indicated that you will perform validation where appropriate to determine whether action is needed for product already distributed under these procedures.

5. Failure to establish and maintain device history record (DHR) procedures to ensure that DHRs for each batch, lot, or unit are maintained to demonstrate that the device is manufactured in accordance with the device master record, as required by 21 CFR 820.184(e) and (f). For example:

Your firm has not established complete procedures to track device history records (DHR). Specifically, the currently established DHRs do not include or refer to where information regarding the primary identification label for each product unit and the unique device identifier can be found.

The adequacy of your response dated November 30, 2023, cannot be determined at this time as your corrective actions are not yet complete. In your response you state your planned corrective actions include revision and updating of the DHR work instruction to include the CFR reporting requirements and primary packaging label with the UDI. You state your corrective actions will be completed by February 2024, but FDA has not received this information by the date of this letter. In your response to this Warning Letter, you should provide updated documentation including, but not limited to, the revised version of your DHR work instruction and updated primary packaging labels with the device UDI.

Medical Device Reporting Violation

Our inspection also revealed that your firm's Thermodilution Catheter device is misbranded under section 502(0(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. 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. For example, during the inspection, your firm identified the document titled "Vigilance reporting and recalls/FSCA for USFDA", BPI-WI-010, Rev. 01, dated 10/26/2023 as its written MDR procedure. After reviewing the procedure, the following deficiencies were noted:

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:

a) The procedure includes the definition from 21 CFR 803.3 for the terms "MDR reportable event", "become aware", "caused or contributed", "malfunction", and "serious injury". However, the procedure does not provide clear guidance to staff on how they should determine if information "reasonably suggests" that an event should be reported. Refer to the definition of the term "reasonably suggests" found in 21 CFR 803.20(c)(1). The exclusion of such information from the procedure may lead your firm to make an incorrect reportability decision when evaluating a complaint that may meet the criteria for reporting under 21 CFR 803.50(a).

b) 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.

c) The procedure does not establish internal systems that provide for timely transmission of complete medical device reports, as required by 21 CFR 803.17(a)(3). Specifically, the procedure does not include a process for submitting initial and supplement or follow-up reports to FDA in an electronic format that FDA can process, review and archive.

d) The procedure does not describe how your firm will address documentation and recordkeeping requirements, as required by 21 CFR 803.17(b), including:
  a. Documentation of adverse event related information maintained as MDR event files.
  b. Information that was evaluated to determine if an event was reportable.
  c. Documentation of the deliberations and decision-making processes used to determine if a device-related death, serious injury, or malfunction was or was not reportable, as required under 21 CFR 803.18(b)(1)(i).

The adequacy of your response dated November 30, 2023, cannot be determined at this time. In the response, your firm outlined a plan to address each identified deficiency, including projected completion dates. However, as these corrective actions are still in progress, there is no documentation or evidence available yet to confirm their completion.

2. Failure to submit a report to FDA no later than 30 calendar days after the day that 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 CCS23-04-025 reasonably suggests that a patient sustained an injury that resulted in a thrombus, after a procedure using your firm's Central Venous Catheter. This condition necessitated drug treatment. In the absence of the information indicating the contrary, we believe that the drug treatment was necessitated to prevent permanent impairment of a body function or damage to a body structure. Therefore, the information included in the complaint reasonably suggests a serious injury for which an MDR must be submitted. Your firm became aware of this event on March 24, 2023. However, an MDR for the corresponding event has not yet been received by FDA.

Your firm's response dated November 30, 2023, did not address the noted violation as the issue was not included in the FDA Form 483. In response to this Warning Letter, you should provide documentation to address this identified violation.

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.

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 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. Please provide a translation of documentation not in English to facilitate our review. 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 by email to CDRHWarningLetterResponsesafda.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: Establishment Support, Regulatory Inspections and Audits Team, White Oak Building 66, 10903 New Hampshire Ave., Silver Spring, MD 20993. Refer to CMS case #678281 when replying. If you have any questions about the contents of this letter, please contact: Lydia S. Glaw, Ph.D. at 301-796-1456.

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
Dr. Bram Zuckerman
Director
OHT 2: Office of Cardiovascular Devices
Office of Product Evaluation and Quality
Center for Devices and Radiological Health

CC:
Dennis Bassett
BIOMEDICAL SALES INTERNATIONAL, INC.
457 W Virginia Ave
Punta Gorda, FL US 33950
Phone: 513 2586555 Ext
Fax: 513 7728388
Email: Dwbassett@Cs.Com

______________________

1 In October 2017, FDA published the guidance document Deciding When to Submit a 510(k) for a Change to an Existing Device ("510(k) Modifications Guidance"), which provided FDA's current thinking to enhance the predictability, consistency, and transparency of the when a change in a medical device would trigger the requirement that a manufacturer submit a new 510(k) premarket notification to the Agency. Available at https://www.fda.gov/regulatorv-information/search-fda-guidance-documents/deciding-when-submit-510k-change-existing-device. As explained in Section C.4.1 of the guidance, in general, changing the material or device design may affect the performance testing of the device.

2 As explained in Section B.5 of the 510(k) Modification Guidance, in general, changing the device design (e.g., dimensional and component changes) may result in new technological characteristics that raise different questions of safety and effectiveness.

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