Boule Medical AB - 559614 - 10/02/2018

WARNING LETTER

October 02, 2018

VIA UNITED PARCEL SERVICE

Mr. Fredrik O. Dalborg
CEO and Group President
Boule Medical AB
Domnarvsgatan 4
Spanga, Stockholm, Sweden 163 53

Dear Mr. Dalborg:

During an inspection of your firm located in Stockholm, Sweden on May 7, 2018 through May 11, 2018, an investigator from the United States Food and Drug Administration (FDA) determined that your firm manufactures various Class II medical devices comprising the Medonic M-Series Hematology Analyzer. 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 an initial response from Ms. Deborah A. Herrera, Senior V.P. of Quality/Regulatory (Clinical Diagnostic Solutions, Inc.), dated May 31, 2018, the first status update, dated July 5, 2018, and the second status update, dated August 9, 2018, 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 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 adequate procedures for implementing corrective and preventive action (CAPA), as required by 21 CFR 820.100(a).

For example, a total of 15 CAPAs, from January 2016 to April 2018 (pertaining to the Medonic M-series Hematology Analyzers and similar products) were selected for review during the inspection. A review of the CAPAs revealed that there is no documented evidence that your firm has implemented the proposed corrective/preventive actions for the following CAPAs: 26095-1, 27514-2, 27515-2, and 28283-1.

Your firm’s management confirmed and stated that your firm has no documented evidence to show that they have implemented the proposed corrective/preventive actions for the above CAPAs.

We reviewed your firm’s response and conclude that it is not adequate. Your firm provided revised procedures, Complaints and CAPA Meetings, 28798, Rev. 1 (Swedish version: (b)(4)) and Corrective and Preventive Actions, 28799, Rev 1 (Swedish version (b)(4)), which include the requirements for assuring the CAPA record is current including documented evidence of the progress of the CAPA and implementation of the proposed corrective/preventive actions. Your firm also updated the “open” CAPAs (reviewed during the inspection) to their progress as of June 19, 2018. Because of the procedure revisions, CAPAs will be updated with their respective progress in the CAPA record while they are open. Closure of the CAPA indicates that the actions are complete. The closed CAPAs reviewed during the inspection have been verified that the corrective action was implemented, where applicable. Although your firm states that all action items related to Observation 1 have been completed and submitted to FDA in your firm’s response dated July 5, 2018, no evidence of staff training has been provided on the updated/revised procedures and your firm did not provide a plan or evidence that it conducted a systemic corrective action to include a retrospective review of all CAPAs to ensure CAPAs were completed as required. Your firm should provide evidence that you have formally documented these activities which includes consideration of a systemic corrective and retrospective review of documentation in its CAPA system.

2.    Failure to establish and maintain adequate procedures for receiving, reviewing and evaluating complaints by a formally designated unit, as required by 21 CFR 820.198(a).

For example, U.S. service reports/complaints, from January 2016 to April 2018 (pertaining to the Medonic M-series Hematology Analyzers and similar products) were selected for review during the inspection. A review of the U.S. service reports/complaints revealed that the service reports/complaints involving the possible failure of a device/labeling/packaging to meet any of its specifications were not investigated, where necessary. For example, service reports: (b)(4), WBC background above range-replaced WBC Chamber; (b)(4), Hgb errors-replaced Slave Pumps, Pinch Valve Tubing, Pump Restrictor, and (b)(4), High HGB & RBC on Patients-replaced Auto Loader Assembly. None of your firm’s U.S. service reports were investigated (to determine the cause of the component failure); instead, device components were all repaired/replaced.

Your firm’s management stated that your firm considers these U.S. service reports to be complaints because they meet the definition of a complaint; none of these service reports were entered into your firm’s complaint handling system, and Clinical Diagnostic Solutions (CDS) sends a Monthly U.S. Service Log to Boule Medical AB for data analysis.

We reviewed your firm’s response and conclude that it is not adequate. Your firm provided a revised Boule Complaint Procedure, 28800, Rev. 1 (Swedish version: (b)(4)) which includes instruction on how the U.S. service reports/complaints will be reviewed, evaluated, and investigated by the Boule Medical complaint handling unit. Your firm also indicated that a retrospective review (look-back) of U.S. service reports/complaints from January 2016 to April 2018 is on target for completion by the target date of December 31, 2018. However, your firm did not provide evidence that appropriate staff were trained on the revised Boule Complaint Procedure. In addition to providing a retrospective review of U.S. service reports/complaints from January 2016 to April 2018 (on target for completion by December 31, 2018), your firm needs to provide evidence that appropriate staff were trained on the revised (approved and updated) Boule Complaint Handling procedures that clearly outline the procedures to thoroughly address complaints in a timely manner as well as ensure complaints are adequately evaluated for MDR.

3.    Failure to establish and maintain adequate 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, your firm’s Supplier Evaluation Procedure, Document (b)(4), is incomplete in that it fails to require potential suppliers and contractors be evaluated based on their ability to meet specified requirements, including quality requirements. Your firm failed to require that the molding, extrusion, and powdering process be validated (for the manufacturing of the Pumpblocks and the MPA Micro Pipettes Plastic for the Medonic M-series Hematology Analyzers) at the following supplier/manufacturers: (b)(4) (Contract Manufacturer of (b)(4)), and; (b)(4) (Manufacturer of Pumpblocks).

Your firm’s management stated that your firm’s current practice is to evaluate potential suppliers and contractors based on their completion of the self-declaration form. Your firm’s management also stated that your firm’s potential suppliers and contractors are not being evaluated based on their ability to meet specified requirements, including quality requirements.

We reviewed your firm’s response and conclude that it is not adequate. Your firm: 1) provided an updated Supplier Assessment Procedure, 29006 Rev. 1 (Swedish version: (b)(4)) which includes evaluation of the quality and regulatory requirements as part of the supplier qualification and monitoring process. The procedure also includes that the supplier provides evidence of such requirements which are maintained as part of the supplier file; 2) created a Form for the Additional Quality and Regulatory Requirements, 29292 Rev 1 (Swedish version: (b)(4)) to specify these requirements on a supplier-by-supplier basis, including the product or service provided and acknowledgement and documentation of the requirements; 3) revised the Supplier Evaluation/Supplier Follow-up Form, (b)(4) (Swedish version (b)(4)) to include the additional quality and regulatory requirements as part of the evaluation process; 4) clarified the supplier relationship with (b)(4) as to their action role in the manufacturing and labeling of the micropipettes; 5) completed the supplier evaluation including verification that (b)(4) complies with the Quality and Regulatory requirements specified, and; 6) revised the supplier evaluation for (b)(4) to indicate their role as a Distributor and their relationship with (b)(4). Your firm also indicated that the review of all critical suppliers of critical components to identify quality and regulatory requirements is on target for completion by December 31, 2018. However, your firm did not provide evidence of performing retrospective reviews to access whether all (current) suppliers conform to your requirements. Your firm also did not provide evidence of notification and/or training of appropriate staff on the updated/revised Supplier Assessment Procedure, the additional Quality and Regulatory Requirements Form, and the Supplier Evaluation / Supplier Follow-up Form. Your firm should provide this information.

4.    Failure to establish and maintain procedures to ensure that device history records (DHRs) for each batch, lot, or unit are maintained to demonstrate that the device is manufactured in accordance with the Device Master Record (DMR), as required by 21 CFR 820.184.

For example, your firm’s management stated that your firm does not have a written DHR procedure. Review of (b)(4) DHRs from April 2017 to April 2018 (pertaining to the Medonic M-series Hematology Analyzers) revealed that none of the DHRs included or referred to the location of the sub-assemblies and four out of (b)(4) DHRs failed to include or refer to the location of the Primary identification label and labeling used for each production unit. Additionally, manufacturing records for the sub-assemblies are not identified by any specific lot number(s), and therefore, your firm could not link the DHR to the sub-assemblies. Some of the reviewed DHRs were also missing the required UDI labels.

We reviewed your firm’s response and conclude that it is not adequate. You indicate that a Device History Record Procedure and a plan that details the revisions to the manufacturing documentation required to comply with the procedure for the DHR and meet the requirements of complying with the Device Master Record (DMR) were created. Based on this plan, implementation actions and dates will be established with a target date of September 7, 2018. You conducted a look-back of the instruments (Group1 and Group 2) packaging portion of the DHR manufactured from September 2016 to May 11, 2018. The look-back for (b)(4) instrument nor in the DHR. Additional instructions have been written to prepare the UDI label for instruments that do not bear the UDI label. Your firm provided a UDI look-back summary completion of the remediation activities for both failure modes. Your firm indicated that Group (b)(4) (at customer account) is on target for completion by December 31, 2018 and that the DHR implementation plan is on target for completion by September 7, 2018. However, your firm did not provide evidence of employee training on the new DHR Procedure. Also, it is not clear if your firm conducted a comprehensive retrospective review of all product DHRs to ensure the DHRs were documented as required by your firm’s procedures to ensure regulatory requirements are met. Your firm should provide this information.

5.    Failure to establish and maintain process control procedures that describe any process controls necessary to ensure conformance to specifications, as required by 21 CFR 820.70(a).

For example, on May 9, 2018, many sub-assemblies and final assembled units were observed stored on the manufacturing floor without proper documentation. Also, there is no documentation to show the status of the sub-assemblies and final assemblies of the Medonic M-series Hematology Analyzers (i.e. completed steps versus remaining steps). For example: Sub-Assemblies (Rear Plate Assemblies ((b)(4) units) - Part #1091466; Side Plate Base Module ((b)(4) units) – Part #1091482) and Final Assembled Units (Medonic M-Series ((b)(4) units); Swelab Alfa ((b)(4) units)).

Your firm’s management stated that the manufacturing records for the sub-assemblies are not maintained with the sub-assemblies; the manufacturing records for sub-assemblies are not identified by any specific lot number(s), and; once the records are separated from the sub-assemblies, it is impossible to match the manufacturing records to the sub-assemblies. Your firm’s management also stated that: the manufacturing records for the final assemblies are not maintained with the final assembled units; the manufacturing records for assembled units are not identified by any specific serial numbers. The serial numbers are assigned to the units when they are tested at QC, and; once the records are separated from the assembled units, it is impossible to match the manufacturing records to the assembled units.

We reviewed your firm’s response and conclude that it is not adequate. Your firm provided a revised Inventory Management Procedure, (b)(4) (Swedish version: (b)(4)) to clarify the status of goods in the warehouse and address the identification and acceptance status on each instrument by serial number from final assembly through QC testing, and packaging for shipment. Your firm conducted Material Identification and Status Training for Manufacturing, QC, QA, and Service and provided training records. Your firm indicated that: 1) Material Identification and Status Training for R & D is on target for completion by August 30, 2018, and; 2) Identifying the acceptance status of purchased components, sub-assemblies, final assembly, and finished devices is on schedule for complete implementation by September 7, 2018. However, your firm did not provide evidence of implementation of a corrective action to include a retrospective review of all devices requiring associated procedures to ensure they were documented as required. Your firm also did not provide evidence of notification or training of appropriate staff on the revised “Inventory Management Procedure”. Your firm should provide this information.

6.    Failure to establish and maintain procedures to ensure that device history records (DHRs) for each batch, lot, or unit are maintained to demonstrate that the device is manufactured in accordance with the DMR, as required by 21 CFR 820.184.

For example, your firm's (b)(4)-series Basic Procedure, Document (b)(4), is incomplete in that the assembly instruction requires a total of (b)(4) steps to complete the assembly of the Medonic M-series unit. For example: Operation (b)(4) Assembly; Operation Number (b)(4) Assembly; Operation Number (b)(4) Assembly. However, it does not require the technician to document the manufacturing steps/operations in the production record (showing that they were performed). For example: Manufacturing Order/Picking List for S/N 46340, S/N 29702, and S/N 30004.

Your firm’s management stated that: the technicians are following the work instructions to assemble the units; each technician is responsible for assembling three units at the same time; none of the manufacturing processes/assemblies (a total of (b)(4)/operations) are being documented to show that they were performed, and procedures/forms requiring the manufacturing steps/operations to be documented will need to be revised.

We reviewed your firm’s response and conclude that it is not adequate. Your firm provided an updated manufacturing method which will be part of the DHR for the instrument. Your firm indicated that to implement changes to the combined manufacturing method and assembly journal, 42 documents will be updated and the target completion date is September 7, 2018. However, your firm did not provide evidence of notification or training of appropriate staff on the updated manufacturing method and did not present a plan or provide documentation of a comprehensive retrospective review of all product DHRs (pertaining to manufacturing processes/assemblies) to ensure the DHRs were documented as required by your firm’s procedures to ensure regulatory requirements are met. Your firm should provide this information.

Our inspection also revealed that your firm’s Medonic M Series Hematology Analyzers 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. Significant deviations include, but are not limited to:

Failure to adequately develop, maintain and implement written MDR procedures, as required by 21 CFR 803.17.

For example, your firm provided an English version of its MDR procedure titled “Incident Report IVD product procedure (b)(4), Effective date: 2018-05-04 during the time of inspection. After reviewing the English-translated MDR procedure, the following deficiencies were noted:

(1)   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, there are no definitions of what your firm will consider to be a reportable event under 21 CFR Part 803. The exclusion of definitions from 21 CFR 803.3 for the terms “caused or contributed,” “MDR reportable event,” and “serious injury,” and the definition for the term “reasonably suggests,” found in 803.20(c)(1) 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).

(2)   Your procedure does not establish internal systems that provide for a standardized review process to determine when an event meets the criteria for reporting under this part, as required by 21 CFR 803.17(a)(2). For example:

a. There are no instructions for conducting a complete investigation of each event and evaluating the cause of the event.
b. Your procedure, as written does not specify who makes the decision for reporting events to FDA.

(3)   Your 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 following are not addressed:

a. The circumstances under which your firm must submit reports (initial 30 days, supplemental or follow-up, 5-day) and the requirements for such reports.
b. Your procedure does not include a process for submitting MDRs electronically in accordance with the Final Rule for electronic Medical Device Reporting (eMDR) published in the Federal Register on February 14, 2014. Information about the Final Rule for eMDR and the eMDR set-up process can be found on the FDA website at:
http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/PostmarketRequirements/ReportingAdverseEvents/eMDR%E2%80%93ElectronicMedicalDeviceReporting/default.htm
c. How your firm will submit all information reasonably known to it for each event. Specifically, which sections of the 3500A will need to be completed to include all information found in your firm’s possession and any information that becomes available as a result of a reasonable follow up within its firm.

(4)   Your procedure does not describe how your firm will address documentation and record-keeping 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;
d. Systems that ensure access to information that facilitates timely follow-up and inspection by FDA.

In addition, the procedure includes references to baseline reports. Baseline reports are no longer required, and we recommend that all references to a Baseline Report be removed from your firm’s MDR procedure (refer to 73 Federal Register Notice 53686, dated September 17, 2008).

We reviewed your firm’s response and conclude that it is not adequate. Your firm provided an updated MDR procedure titled “Medical Device Reporting Procedure”, Policy No. QP 2.53, Rev. L. As written, the updated MDR procedure appears to meet the requirements of 21 CFR 803.17. However, your firm has not provided evidence of the implementation of the updated procedure for review as it plans to conduct a 2-year retrospective review of the complaints it has received for reportability purposes. In addition, your firm provided an English version of its implemented MDR procedure titled “Incident report IVD product procedure (b)(4), Effective date: June 25, 2018, and stated that a 2-year retrospective review is ongoing with a projected completion date of October 31, 2018. Lastly, your firm indicated it will conduct a 2-year look-back to evaluate whether any complaints require MDRs to be filed and prepare a summary of the complaints reviewed and MDR Decision.

If your firm wishes to discuss the MDR related issues noted above, please contact the Reportability Review Team by email at ReportabilityReviewTeam@fda.hhs.gov.

U.S. federal agencies may be advised of the issuance of Warning Letters about devices so that they may take this information into account when considering the award of contracts. Additionally, premarket approval applications for Class III devices to which the Quality System regulation deviations are reasonably related will not be approved until the violations have been corrected.

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 correct 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.

Your firm’s response should be sent to: Food and Drug Administration, Center for Devices and Radiological Health, Office of Compliance, Field Inspections Support Branch, White Oak Building 66, Rm 3540, 10903 New Hampshire Ave., Silver Spring, MD 20993. Refer to CMS case #559614 when replying. If you have any questions about the contents of this letter, please contact Jeb Monasterial at 301-796-9677.

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 the violations, and take prompt actions to correct the violations and bring the products into compliance.

Sincerely yours,
/S/
Timothy Stenzel, MD, PhD
Director
Office of In Vitro Diagnostics and
Radiological Health (OIR)
Center for Devices and Radiological Health

CC (US AGENT):

Deborah A. Herrera
Clinical Diagnostic Solutions, Inc.
1800 NW 65th Avenue
Plantation, Florida 33313

U.S. Food and Drug Administration

Boule Medical AB MARCS-CMS 559614 — October 02, 2018