Kabe Labortechnik GmbH

During an inspection of your firm located in Numbrecht, North Rhine-Westphalia, Germany, on January 6 through 9, 2025, an investigator from the United States Food and Drug Administration (FDA) determined that your firm manufactures blood collection tubes including the SAFE-TFILL Capillary Blood Collection Systems. 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.

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 Mr. Andre Kolpe, CEO and Managing Director, dated January 17, 2025, 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. These violations include, but are not limited to, the following:

1. 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(a). For example, your firm has not validated the manufacturing process of the SAFET-FILL Capillary Blood Collection Systems. The blood collection systems are manufactured and filled onsite with an anticoagulant which is coated in a capillary rod, a critical component for the device, and inspected using software. However, these processes were not validated.Specifically:

a. Your firm’s procedure, “QM VA_0026”, Validation of Production Machines, Rev I, dated December 19, 2023, requires “existing machines and process equipment” that are “used for the production of medical devices and in-vitro diagnostics” to be validated using installation qualification, functional qualification, and performance qualification; however (b)(4) have not been validated. Mr. Sven Nahring, Supervisor of Quality, stated that since the machines (b)(4) 30 years ago, your firm was still trying to figure how to retrospectively validate them.

b. Your firm’s procedure, “VA_0002” Software Validation, Rev I, dated June 25, 2024, requires that “software used in the company that requires validation is validated or that only validated software is used in the company.” However, the software used to inspect the coated capillary rods and (b)(4) product is not validated. During a demonstration of the software during the inspection, (b)(4) capillary rods were (b)(4). When asked, the production employee and your firm’s management concurred that the software was not performing as it should. The software showed capillary rods outside the (b)(4) as accepted in the system which should (b)(4). Mr. Dirk Kogelheide, Quality Management, and Mr. Sabastian Bchner, Quality Manager Department, confirmed that this software was installed many years ago and has not been validated.

The adequacy of your response dated January 17, 2025, cannot be determined at this time. Your response states that “to meet the requirements of our procedure for validating manufacturing processes, VA_0026, dated December 19, 2023, we are preparing a plan of the affected manufacturing processes.” However, you have not provided the plan and timeline for validation of the machines and software used to produce the SAFE-T-FILL Capillary Blood Collection Systems. Because the machines and software remain unvalidated, it is unclear how you ensure that the current production of the SAFE-T-FILL Capillary Blood Collection Systems meet quality specifications. Additionally, your response states that “the claimed deviation that the (b)(4).” However, you have not provided evidence to support this statement (e.g. such as (b)(4)). You have also stated in your response that a “(b)(4).” However, you have not provided evidence of this validation.

Your firm should provide a systemic corrective action plan to address the validation of manufacturing processes for all devices manufactured at this facility including evidence of implementation. Copies of revised procedures and evidence of training on new or revised procedures should also be provided.

2. Failure to adequately ensure that all equipment used in the manufacturing process meets specified requirements and is appropriately designed, constructed, placed, and installed to facilitate maintenance, adjustment, cleaning, and use, as required by 21 CFR 820.70(g). For example, it appears that (b)(4) machines used in manufacturing have not been qualified for their intended use. As a result, capillary tubes made by these (b)(4) machines were partially damaged. Specifically, your firm’s CAPA-ID 23G4429_1 described failure of (b)(4) machine that resulted in damaged capillaries in the finished products for batches 23G4429 and 23H4113. The root cause of the failure was identified as that the “(b)(4).” Mr. Nahring, Supervisor of Quality, provided a supplement to CAPA #06.2023 which stated under the section Detected Deviation “(b)(4).” The CAPA has already been closed, therefore it is not clear whether this (b)(4) machine has been qualified for its use. Mr. Nahring along with the management further stated the validation plans for those machines are still in process and have not been executed.

The adequacy of your response dated January 17, 2025, cannot be determined at this time since you did not provide evidence that (b)(4) machines have been retroactively qualified nor a corrective action to ensure that all future equipment used during manufacturing will be qualified for their intended use. You also have not provided a systemic corrective action to ensure that all equipment used in the manufacturing process meets specified requirements and is appropriately designed, constructed, placed, and installed to facilitate maintenance, adjustment, cleaning, and use, as required by 21 CFR 820.70(g).

3. Failure to adequately establish and maintain procedures to control the design of the device in order to ensure that specified design requirements are met, as required by 21 CFR 820.30(a). For example, your firm does not have a design control procedure that details design input, design output, design verification, design validation, design transfer, design review, and design history, specifically:

a. Your firm provided flow charts to describe these design control processes in “QM_AA_0019,” Project Process, Rev. I, Effective Date June 19, 2024. Additionally, the design change procedure “AA_0011,” Change of a Medical Device, Effective Date August 07, 2024, and “VA_0028,” Change Management – Change Control, Effective Date March 12, 2024, simply list changes that need to be checked by management before implementation, but do not describe how your firm manage changes to the device to ensure the quality of their products are unaffected. The inspector requested written procedures that address 21 CFR 820.30 and Mr. Sven Nahring, Supervisor of Quality, confirmed that your firm does not have any other procedures other than QM_AA_0019, AA_0011, and VA_0028.

b. Your firm has not maintained an adequate design history file for the SAFE-T-FILL Capillary Blood Collection Systems. Specifically, the design history file does not contain or refer to the initial design documents that address original design input, design output, verification and validation, design review and approval. During the inspection, such records were requested, however, Mr. Sven Nahring, Supervisor of Quality, stated that (b)(4) firm may not have maintained such documents.

The adequacy of your response dated January 17, 2025, cannot be determined at this time. You stated in your response that you will review and amend all documents for recording the design control process. However, you did not provide corrected procedures for review. You also stated that “QM_AA_0019” is presented in more detail “in an existing Excel-based document created from a project work,” however, you did not provide the Excel file for review. Finally, you stated that specifically for the SAFE-T-FILL Capillary Blood Collection Systems, you plan to collect “all activities carried out to date in terms of creation, recording, specifications (design, intended use, etc.) and changes” in a database supported system that is yet to be developed by the (b)(4) department. However, you did not provide a record of these changes in the database for review.

Your firm should provide a systemic corrective action to address design history files for all devices manufactured and sold in the US and provide your plans for remediation of those devices. You should also assess if the collected documents comprising the design history file support the current design and performance specifications for the SAFE-T-FILL Capillary Blood Collection Systems. Design changes, including the impact of cumulative changes should be assessed to determine if a new 510(k) is needed. For more information on the Agency’s current thinking for deciding whether to submit a new 510(k) for a change to an existing device, see FDA’s Guidance "Deciding When to Submit a 510(k) for a Change to an Existing Device".1 Evidence that the software used to document the design history file is adequately validated should also be provided.

4. Failure to adequately establish and maintain procedures for implementing corrective and preventive action, as required by 21 CFR 820.100(a). For example, your firm’s CAPA procedure “QM_VA_0006,” Deviations, Complaints, and CAPA Management, Effective Date April 03, 2023, does not adequately describe the procedure for conducting root cause investigations, implementing corrective actions effectively, verifying the effectiveness of corrective and preventive actions, and using statistical methodology (to detect trends) where necessary. As a result, the CAPA investigations were inadequate to address problems in the device manufacturing. The following CAPAs were provided as examples of CAPAs not adequately handled:

a. CAPA 06.2023 was initiated because your firm failed to assess the validation for assembling cannulas with extension tubes which was identified during the external audit conducted by (b)(4), an independent service company that inspects and certifies technical systems. This CAPA was closed on November 23, 2023, without establishing and implementing the corrective actions adequately.

b. CAPA 23G4429-1 was initiated because the capillaries were getting damaged by an (b)(4) machine. The CAPA failed to reference the evidence of training activities as established by the CAPA action plan. The CAPA also failed to establish the verification of effectiveness check plan based on statistical rationale before verifying the CAPA as effective.

c. CAPA 23B4355-1 was initiated on July 05, 2023, due to a customer complaint that the specified fill level in the tube was not reached and some of the blood samples could not be drawn completely. Your firm identified the diaphragm rubber had been pushed through the venting needles; however, your firm failed to identify why the diaphragm rubber was pushed. This CAPA failed to perform a complete root cause analysis and failed to establish and implement corrective actions effectively.

Your firm’s response dated January 17, 2025, is not adequate. In your response you provided a brief plan to correct the CAPA process (b)(4), however, you have not corrected these CAPAs. You also stated in your response that you have revised QM_VA_0006 and your staff have been trained accordingly, however, you did not provide the revised QM_VA_0006 for review nor did you provide any training records of trained personnel. Your firm should provide a plan to correct the deficient CAPAs noted during the inspection and systemic corrective action to address other CAPAs that may also be deficient under the new revised procedure. Evidence to show that the new CAPA process is effective should also be provided for review.

5. Failure to adequately establish and maintain procedures to control product that does not conform to specified requirements, as required by 21 CFR 820.90. Your firm did not address the identification, documentation, evaluation, segregation, and disposition of nonconforming product. For example, while the “QS_VA_0009,” Management of Defective Products, Rev. I dated June 01, 2023, defined the responsibility for review and the authority for the disposition of nonconforming product and its documentation, your firm did not document the disposition of nonconforming products in accordance with your standard operating procedures. As a result, nonconforming product identified during the (b)(4) as outlined in your standard operating procedure.

You did not provide a response to this deficiency in your firm’s response dated January 17, 2025.

6. Failure to adequately establish and maintain procedures to ensure that all purchased or otherwise received product and services conform to specified requirements, as required by 21 CFR 820.50. For example, the categorization of “primary suppliers” for materials to produce the SAFE-T-FILL Capillary Blood Collection Systems were not consistent. As a result, a review of quality agreements with two class A suppliers were found to have inconsistencies in the requirements to be met by the suppliers. The inconsistencies were also identified in the classification of suppliers who provide similar raw materials for the SAFE-T-FILL Capillary Blood Collection Systems. For example:

a. Your firm’s supplier management procedure, “VA_0004,” Evaluation and Selection of Suppliers, Effective Date June 04, 2024, classifies suppliers into categories A to D (A being the highest risk supplier and D being the lowest risk supplier). However, suppliers of similar critical components were classified into different categories. For example, suppliers for “(b)(4)” used in the manufacturing of the SAFE-T-FILL Capillary Blood Collection Systems received from both category A and B designations: One supplier, (b)(4), received a Category A designation while another supplier, (b)(4) located at (b)(4) received a Category B designation. During the inspection Mr. Sebastian Bchner, Quality Manager Department, confirmed that both the suppliers provide (b)(4), for the SAFE-T-FILL Capillary Blood Collection Systems and both the (b)(4) have a direct influence on the conformity of the medical device and the quality of the device.

The adequacy of your response dated January 17, 2025, cannot be determined at this time. You stated in your response that your firm has revised your Evaluation and Selection of Suppliers, VA_0004 rev. II that addresses the classification of your suppliers, however, you did not provide this revised standard operating procedure and evidence of its implementation. You also stated in your response that you have worked with your Purchasing and Quality Management departments to ensure the agreements between suppliers are consistent, however, you did not provide an example or copies of the revised agreements. Your firm should provide an updated procedure for how you categorize suppliers, and an example of the revised agreement with your supplier as evidence that quality agreements, at the minimum, between category A suppliers are consistent across the different suppliers.

Our inspection also revealed that you have failed to develop, maintain, and implement written Medical Device Reporting (MDR) procedures, as required by 21 CFR 803.17. It was noted during the inspection that your firm has an agreement with ASP Global, your U.S. distributor, for ASP Global to file adverse event reports for devices received by ASP Global. However, your firm stated it, as the manufacturer of medical devices, does not have a written procedure that provides for timely and effective identification, communication, evaluation, and reporting to FDA of events that may be subject to MDR requirements. We note that a device is deemed to be misbranded under section 502(t)(2) of the Act, 21 U.S.C. § 352(t)(2), if there was a failure or refusal to furnish any material or information required by or under section 519 of the Act, 21 U.S.C. § 360i, which includes adverse event reports required under 21 CFR Part 803, respecting the device.

You did not provide a response to this deficiency in your firm’s response dated January 17, 2025. You should develop, maintain, and implement written MDR procedures as required by 21 CFR 803.17 and provide evidence that the procedure has been successfully implemented. Evidence of successful implementation may include providing a MDR standard operating procedure for review, staff training records and/or any MDR reports that were correctly addressed.

Given the serious nature of the violations of the Act, all devices manufactured by your firm are subject to refusal of admission under section 801(a) of the Act, 21 U.S.C. § 381(a), in that they appear to be adulterated. As a result, FDA is taking steps to refuse entry of these devices into the United States, known as “detention without physical examination,” until these violations are addressed. In order to remove the devices from detention, your firm should provide a written response to this Warning Letter as described below and address the violation(s) described in this letter. We will notify you regarding the adequacy of your firm’s response(s) and the need to reinspect your firm’s facility to verify that the appropriate corrections and/or corrective actions have been made.

Your firm should take prompt action to address any violations identified in this letter.

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 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. Your firm’s response should be sent via email to CDRHWarningLetterResponses@fda.hhs.gov. Refer to CMS case 704563 when replying. If you have any questions about the contents of this letter, please contact: Uyen Chu at uyen.chu@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.