Inspections, Compliance, Enforcement, and Criminal Investigations
NeuroTherm, Inc. 7/11/12
Department of Health and Human Services
|Public Health Service|
Food and Drug Administration
New England District
CMS # 306318
VIA United Parcel Service
July 11, 2012
Laurence M. Hicks
President and CEO
30 Upton Drive, Suite 2
Wilmington, Massachusetts 01887-1083
Dear Laurence M. Hicks:
During an inspection of your firm located in Wilmington, Massachusetts, on April 2, 2012, through April 26, 2012, an investigator from the United States Food and Drug Administration (FDA) determined that your firm manufactures Reusable RF Electrodes and Radiofrequency (RF) products including generators, cannulas, electrodes, grounding pads, and the Controlled Disc Stimulation System. 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 are intended 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 you dated May 15, 2012, concerning our investigator’s observations noted on the Form FDA 483 (FDA 483), List of Inspectional Observations, that 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 establish and maintain procedures for validating the device design to ensure that devices conform to intended uses, and failure to include the results of the design validation, including identification of the design, methods, the date, and the individuals performing the validation, in the Design History File (DHF), as required by 21 CFR 820.30(g).
For example, the product’s instructions for use indicate that the device can be reused after cleaning and sterilization and instructions contain specific sterilization methods. However, your firm did not conduct design validation activities such as sterilization durability validation testing to support multiple sterilization cycles for the Nitinol RF electrodes. The Data Sheet for the adhesive, (b)(4) , states, (b)(4) maintains bond strength after 1 cycle of steam autoclave... consult with (b)(4) for a product recommendation if your device will see more than 3 sterilization cycles.” Your firm did not provide documentation of the epoxies maintaining adherence after multiple sterilization cycles.
We reviewed your firm’s response and conclude that it is not adequate. Your firm has not provided a correction to the DHF and it has not provided any validation studies. Your firm states that it will change its Engineering Change Order Form so that a thorough narrative explanation will document why a change does not require validation, and this will be ensured by a validation checklist. Your firm has not provided the modified Engineering Change Order Form or the validation checklist. Additionally, your firm has not considered systemic corrections to ensure that the Engineering Change Order Forms for other changes, not mentioned in this observation, have been adequately validated and documented.
2. Failure to adequately establish and maintain procedures for the identification, documentation, validation, or, where appropriate, verification, review, and approval of design changes before their implementation, as required by 21 CFR 820.30(i).
a. Your firm’s Quality Manual, (b)(4) states that “All product changes are reviewed to determine if design controls are warranted. All changes in NeuroTherm products which affect form, fit, or function are required to be conducted under design control procedures.” However:
i. Your firm’s design change to the Nitinol material requires material not previously included in the manufacture of stainless steel electrodes, specifically a, (b)(4), and (b)(4). The components affect the form of the device, but this change was not made in accordance with design control procedures.
ii. In CAPA (b)(4), the actions recommended state that “A ring should be added to the tube as well as increase the length by at least (b)(4).” This addition changed the form of the device, yet your firm did not review or conduct the addition of a ferrule jacket (ring) to the Nitinol Reusable RF Electrode in accordance with design control procedures.
b. Your firm’s Design Control Procedure, (b)(4), states that minor revisions to products or processes are covered by your firm’s Engineering Change Order Procedure. When the procedure was requested by the investigator to determine the adequacy of the Engineering Change Order for the change to Nitinol material, your firm’s management stated that the Engineering Change Order Procedure did not exist.
We reviewed your firm’s response and conclude that it is not adequate. Your firm states that it will conduct a design review meeting to document, review, and formally capture NeuroTherm’s analysis of the Nitinol material and that it will document a retrospective design control analysis for any design changes that affect form, fit, or function. Your firm did not directly address the addition of the ferrule jacket nor did it submit any documentation to show implementation of corrections or corrective actions. Additionally, your firm did not indicate that it would analyze its design control procedure for inadequacies. Your firm did not indicate that it would create an Engineering Change Order Procedure, nor did it provide us with modified procedures or the modified Engineering Change Order form.
3. Failure to establish and maintain a Design History File (DHF) for each type of device, which shall contain or reference the records necessary to demonstrate that the design was developed in accordance with the approved design plan, as required by 21 CFR 820.30(j).
For example, your firm’s (b)(4), Quality Manual states, “A Design History File is created for each product or family. The Design History File shall consist of all records tracing the history of the design from conception to production.” Your firm failed to establish and maintain a complete DHF for the Reusable RF Electrode, the Disposable RF Electrode-Classic, the Disposable RF Cannula-Classic, and the RF Grounding Pad.
We reviewed your firm’s response and conclude that it is not adequate. The response states that your firm will review and update all DHFs for existing products and that your firm will update the Quality Manual, Document Control and Distribution Procedure (b)(4), and Design Control Procedure (b)(4) to state that your firm will review or update all documents for the DHF of all future acquisitions. This response is not adequate since your firm did not provide any of the updated DHFs or procedures. Your firm also did not provide a timeline of when activities will be completed.
4. Failure to adequately develop, conduct, control, and monitor production processes to ensure that a device conforms to its specifications, as required by 21 CFR 820.70(a).
For example, your firm’s Reusable Electrode Inspection procedure, (b)(4) states that all electrodes in a batch shall receive a testing of length confirmation. The FDA investigator observed a NeuroTherm inspector not performing (b)(4) testing of length on all reusable electrodes.
We reviewed your firm’s response and conclude that it is not adequate. Your firm states that it will update the Device History Record (DHR) such that all inspection steps in the procedure will appear as a separate line item for that product. Your firm’s response is not adequate because your firm did not consider systemic corrective actions to include the review of DHRs for other products to ensure that all inspection steps are being adequately documented and followed. Your firm did not provide any evidence of correction or corrective action or provide a timeline for completion. Your firm also did not address why the inspector was not testing products according your firm’s specifications and procedures.
5. Failure to adequately establish and maintain procedures for receiving, reviewing, and evaluating complaints by a formally designated unit, as required by 21 CFR 820.198(a).
a. Your firm’s Complaint Handling/Adverse Event Reporting procedure (b)(4) states, “For each complaint, it shall be recorded whether or not there was patient involvement. If so, the clinical outcome must be asked and recorded as death, serious injury, required intervention, or malfunction.”The investigator interviewed a Customer Service Supervisor, who explained that she does not ask customers or sales representatives if a complaint involves a death, serious injury, required intervention, or malfunction according to your firm’s procedures, since the information is volunteered. In all (b)(4) complaints reviewed involving RF Electrode Malfunctions, your firm did not document whether or not there was patient involvement.
b. Your firm’s Complaint Handling/Adverse Event Reporting Procedure states, “Within 14 days of the aware date of a complaint, Quality must determine whether a malfunction which could cause death or serious injury if it recurred has occurred. If yes, appropriate adverse event reporting must be initiated.” In all (b)(4) complaints reviewed involving RF Electrode Malfunctions, your firm’s Quality Department’s evaluation for adverse event reporting was documented more than (b)(4) days after the awareness date.
We reviewed your firm’s response and conclude that it is not adequate. Your firm has not provided evidence of implementation of its modified complaint form or provided a timetable for when that will be available. Your firm has not considered modifying its procedure to clarify the correct use of the modified complaint form to ensure that procedures are being followed for reporting complaints associated with adverse events.
6. Failure to adequately establish and maintain procedures for acceptance of incoming products that shall be inspected, tested, or otherwise verified as conforming to specified requirements, as required by 21 CFR 820.80(b).
For example, according to your firm’s Acceptance Sampling for Incoming Materials procedure, (b)(4), a lot size of (b)(4) would require a sample size of (b)(4). However, the (b)(4) specified that (b)(4) cannulas would be pressure tested. Your firm failed to provide a statistical rationale for its protocol of pressure testing (b)(4) StimJect cannulas for leakage during incoming inspection of lot sizes consisting of (b)(4) pieces.
We reviewed your firm’s response and conclude that it is not adequate. Your firm states that it will review all sampling plans in use and decide on a single standard for implementation.
Your firm will also review other areas where statistical techniques are utilized and verify conformance. The response is not adequate since your firm did not submit evidence of implementation of its corrections or corrective actions or indicate a time frame for completion of corrections and corrective actions.
Our inspection also revealed that your firm’s devices are 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 violations include, but are not limited to, the following:
Failure to report to the 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 it markets may have caused or contributed to a death or serious injury, as required by 21 CFR 803.50(a)(1).
For example, Complaint C13175 describes an event involving the RF Cannula, Lot (b)(4), and RF generator, (b)(4), where the patient sustained a burn that required surgical removal of burned tissue. The information in the complaint describes a reportable serious injury that necessitated surgical intervention to preclude permanent impairment to a body structure. Your firm’s awareness date of the event was documented as June 16, 2011. Your firm submitted MDR (b)(4) for the event. The MDR was received by FDA on July 25, 2011.
The adequacy of your firm’s response cannot be determined at this time. Although your firm referenced in its response that, as part of CAPA (b)(4), it plans to update the Complaints and Adverse Event Reporting, (b)(4), procedure to document the MDR requirements in more detail, your firm did not include in its response evidence of systemic corrective actions, such as its revised version of the “Complaints and Adverse Event Reporting,” (b)(4), procedure and evidence of its implementation.
Your firm should take prompt action to correct the violations addressed in this letter. Failure to promptly correct these violations 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. Also, 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 violations are reasonably related will not be approved until the violations have been corrected. Requests for Certificates to Foreign Governments will not be granted until the violations related to the subject devices 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, as well as 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 (including any systemic corrective actions) 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. Your firm's response should be comprehensive and address all violations included in this Warning Letter.
Your firm's response should be sent to: New England District Office, One Montvale Ave., 4th Floor, Stoneham, MA 02180. Refer to the Unique Identification Number CMS case # 306318 when replying. If you have any questions about the contents of this letter, please contact: Todd J. Maushart at (617) 428-4996, extension 114.
Finally, you should know that this letter is not intended to be an all-inclusive list of the violations at your firms 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.
Mutahar S. Shamsi
New England District