Caltag Medsystems Ltd

August 31, 2023 Dear Dr. Tim Almond:

During an inspection of your firm located in Buckingham, United Kingdom on May 2 through May 4, 2023, an investigator from the United States Food and Drug Administration (FDA) determined that your firm manufactures the TransFix/EDTA Vacuum Blood Collection Tubes (TVTs). 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 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, 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 Nicki Kaenzig, Chief Scientific Officer, and Quality Manager/Management Representative, dated May 26, 2023 concerning our investigator’s observations noted on the Form FDA 483 (FDA 483), List of Inspection 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 establish and maintain adequate procedures for implementing corrective and preventive action, including 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. For example, SOP10-001, Version 6 (v6), titled “Corrective and Preventive Action (CAPA)” dated, February 2, 2023, describes the procedures and documentation for implementing preventive actions. In the “CAPA Effectiveness” section of the SOP10-001 v6, it states “The CAPA is approved and closed by a member of the Management Team.” However, CP2019/017 lacked documentation of verification or validation of effectiveness. Specifically, CP2019/017 was not reviewed and signed.

We reviewed your firm’s response and concluded that it is not adequate. Your firm states that the CAP SOP (SOP10-001 v7) has been updated and a new investigation report template has been created (10-008.01 v1) and a new Quality Review Form (01-011.02v1) has been created for review of non-conformances, complaints & CAPA which is signed by the CAPA Leader/Non- Conformance Lead and the Reviewer which is attached to all the documents. However, no documents were provided as evidence that the three CAPAs noted during the inspection were corrected nor were evidence or training provided to ensure that the procedures for implementing corrective and preventive actions are adequate or have been implemented. Also, your firm did not indicate whether there are plans to perform a retrospective review. Your firm should provide evidence that CAPA record CP2019/017 was corrected and that the corrective actions were verified or validated. Your firm should also provide a copy of their revised and new documents and evidence of training. Further, your firm should perform a retrospective review to ensure that other CAPAs were appropriately handled.

2. Failure to establish and maintain adequate procedures to ensure that formal documented reviews of the design results are planned and conducted at appropriate stages of the device's design development, as required by 21 CFR 820.30(e). For example:

a. SOP12-002 Version 7 (v7), titled “New Product Design and Development” dated May 2022, describes your firm’s procedures for design review. However, the procedure does not define how your firm will ensure that the results of a design review, including identification of the design, the date, and the individual(s) performing the review, will be documented in the design history file (DHF). Nor does this procedure ensure that all of the functions and people involved with the stage under design review are included in the design review.

b. During the inspection records of design reviews for the TransFix/EDTA Vacuum Blood Collection Tubes were requested; however, Mrs. Nicki Kaenzig, Chief Scientific Officer/Management Representative, stated that the results of the design review have not been maintained.

We reviewed your firm’s response and concluded that it is not adequate. Your firm’s response did not include a systemic corrective action, including how they plan to remediate the TransFix/EDTA Vacuum Blood Collection Tubes DHF or perform a systemic review of other DHFs to ensure they are complete. Your firm also states that they plan to revise SOP12-002 to ensure that design review is adequately covered. However, no documents were provided. Your firm should provide a copy of the revised procedure for review and evidence of training. Your firm should provide their plans to remediate the TransFix/EDTA Vacuum Blood Collection Tubes DHF and their plan to ensure other DHFs are complete.

3. Failure to establish and maintain adequate procedures to ensure that the device design is correctly translated into production specification, as required by 21 CFR 820.30(h). For example:

a. SOP12-002 Version 7 (v7), titled “New Product Design and Development” dated May 2022, describes your firm’s procedures for design transfer. However, this procedure does not explain how your firm will conduct the final review and approval of design and development activities in order to transfer the design to manufacturing. Nor does it describe what design documents comprise the device master record.

b. During the inspection, design transfer records for the TransFix/EDTA Vacuum Blood Collection Tubes were requested; however, Mrs. Nicki Kaenzig, Chief Scientific Officer/Management Representative, stated that no design transfer records were created as part of the Design History File.

We reviewed your firm’s response and concluded that it is not adequate. Your firm states that they plan to revise SOP12-002 with design transfer procedures and ensure that the design transfer procedure is followed by the contract manufacturer. However, no documents were provided as evidence. Also, your firm’s proposal to revise their SOP did not address how they plan to ensure that the TransFix/EDTA Vacuum Blood Collection Tubes were correctly transferred into production nor did your firm indicate whether there are plans to perform a systemic review of other products. Your firm should provide a copy of the revised procedure for review and evidence of training. Your firm should provide their plans to ensure that the TransFix/EDTA Vacuum Blood Collection Tubes were correctly translated into production and their plan to ensure other devices were correctly translated in addition to evidence of implementation.

4. Failure to 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 procedures, as required by 21 CFR 820.75(a). Specifically, your firm uses a (b)(4) process for packing and labeling of TransFix Vacuum Blood Collection Tubes. (b)(4) is a process for which the results cannot be fully verified and your firm failed to validate this packing and labeling process, as there were no process validation record and no record of the parameter settings. During the inspection, the process validation records were requested; however, Mrs. Nicki Kaenzig, Chief Scientific Officer/Management Representative, stated that you have chosen to verify the process via a visual check.

We reviewed your firm’s response and concluded that it is not adequate. This is a repeat violation from the 2019 inspection which has not been adequately corrected. Your firm stated “that they performed validation of (b)(4)”. However, no documentation of the validation procedure(s) or individual validation plan(s) for each process that will be validated for the device under review or the results were provided. Your firm did not address the corrective action to ensure future processes which cannot be verified are validated nor did the firm conduct a systemic review of other processes. Your firm should include the validation protocols and final reports for the heat sealing process. The protocols should contain or refer to objective and measurable acceptance criteria and describe how appropriate statistical method for data collection and analysis are used. Your firm should provide documentation and evidence of their corrective action as well as perform a systemic review to ensure all process which cannot be fully verified are appropriately validated.

5. Failure to establish and maintain procedures to ensure that equipment is routinely calibrated, inspected, checked, and maintained. These activities shall be documented, as required by 21 CFR 820.72(a). For example:

a. PLAN-VAL-005v3, titled “Validation of the (b)(4) Flow Cytometer for use in the QC of CE/IVD TVTs and FDA cleared TVTs for the US Market”, dated Feb 2020, describes procedures to validate the (b)(4) Flow Cytometer for use the Quality Control testing of CE/IVD TVTs and FDA-cleared TVTs. However, your firm has not adequately documented, reviewed and approved the procedures. Specifically, your firm’s Installation Qualification (IQ) phase of Flow Cytometer was not adequately reviewed and approved. During the inspection, validation records were requested, and the records showed that the “Reviewer/Approver” signatures had not been signed. Further, on May 8, 2014 (b)(4) performed onsite maintenance of instrument and reported to your firm that the instrument is run in a room with “no or little air conditioning” which may affect the instrument.

b. During the inspection the procedures were requested and reviewed; however, there was not record of performance qualification (PQ) phase. Mrs. Nicki Kaenzig, Chief Scientific Officer/Management Representative had agreed to correct the deficiency.

We reviewed your firm’s response and concluded that we could not determine the adequacy at this time. Your firm plans to perform IQ/PQ validation of (b)(4) flow cytometer. However no documentation was provided nor did your firm include a corrective action or systemic corrective action. Your firm should provide a copy of the (b)(4) Flow Cytometer qualification protocol and report. Your firm should also provide their corrective action to ensure that all equipment will be suitable for its intended purpose and capable of producing valid results. Your firm should also conduct a systemic review to determine if other equipment has been appropriately qualified.

6. Failure to establish and maintain adequate procedures to control labeling activities, including ensuring that labeling shall not be released for storage or use until a designated individual(s) has examined the labeling for accuracy including, where applicable, among other things, the correct unique device identifier (UDI) or universal product code (UPC), as required by 21 CFR 820.120(b). For example, SOP07-009 Version 12 (v12), titled “Dispensing and Packaging Cytomark Products Containing TransFix” dated January 15, 2021, describes your firm’s process for labeling and packaging the product. SOP07-009 v12 includes steps to verify and check for accuracy and completion before use of labeling. However, your procedures do not describe the process of examining the labeling for accuracy. Specifically, Manufacturing Batch Record of Transfix for lots 29985.33, 29985.34, 29990 and 29943 show no record of UDI compliant labels.

We reviewed your firm’s response and concluded that it is not adequate. Your firm’s response did not include a systemic corrective action, in that they did not indicate whether there are plans to perform a systemic review of other device labeling. Your firm states that they plan to perform the following corrective actions:

“Prevent any more TVT 3ml IVD products entering the USA. Email all staff with immediate message to this effect.

Ensure UDI information on EUDAMED and GUDID is the same to enable a single harmonised label for TVT-03-50 and TVT-03-2 pouch label.

Master new labels with barcode to replace existing stock immediately.

Review Form 01-013.03 Label CE Marking Checklist to ensure FDA requirements are fully included.

Prepare new Technical Sheet for (b)(4) and ensure transfer conducted properly.”

However, no documents were provided for review. Your firm should provide copies of their revised procedures and evidence of training and their plans to review all device labeling practices to ensure that all devices conform to the UDI requirements.

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 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 response(s) 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. Refer to CMS case #662115 when replying. If you have any questions about the contents of this letter, please contact: Christopher Blackwood, Ph.D. at +1 (240)-402-1665 or Christopher.blackwood@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.