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Department of Health and Human Services
|Public Health Service|
Food and Drug Administration
Waterview Corporate Center
10 Waterview Blvd., 3rd Floor
Parsippany, NJ 07054
Telephone (973) 331-4906
May 24, 2013
UPS OVERNIGHT DELIVERY
Mr. Ken Berger, CEO
Chief Executive Officer
200 Headquarters Park Drive
Skillman, NJ 08558
Dear Mr. Berger:
During an inspection of your firm located at 200 Headquarters Park Drive in Skillman, New Jersey from January 8, 2013 through February 5, 2013, an investigator from the United States Food and Drug Administration (FDA) reviewed your records for Flexi-Seal, Flexi-Seal Signal, and Flexi-Seal Signal (Upgrade). 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 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 (CGMP) requirements of the Quality System (QS) regulation found at Title 21, Code of Federal Regulations (CFR), Part 820. We received responses from Jonathan Hughes, Ph.D, Vice President of Regulatory and Clinical Affairs, dated February 25, 2013, and Katrina Fiedler, Director of US Regulatory Affairs, dated April 11, 2013, concerning our investigator’s observations noted on the Form FDA 483, List of Inspectional Observations, that was issued to you. We address these responses below, in relation to each of the noted violations. These violations include, but are not limited to, the following:
- Failure to establish and maintain procedures for receiving, reviewing, and evaluating complaints by a formally designated unit to ensure that complaints are evaluated to determine whether the complaint represents an event which is required to be reported to FDA under part 803, Medical Device Reporting, as required by 21 CFR 820.198(a)(3). Specifically, complaint handling process procedure, SOP-000535(version 7), states all complaints will be evaluated to determine if an investigation is needed and if they may be reportable. However, not all complaints, such as complaints classified as “Product Issues”, are reviewed and evaluated to determine whether the complaint represents an event which is required to be reported to FDA under part 803, Medical Device Reporting.
a. Complaint 213703, regarding your Flexi-Seal FMS (FMS Fecal Management System Kit), dated June 27, 2012, documents that a “balloon came out, half inflated” and “there was a drip of water from the balloon”. “The company’s representative arrived to the patient’s bedside, tested the FMS SIGANL and discovered a hole in the area between the finger pocket and the balloon body, on the outside surface”. “As a result, the patient was exposed to fecal matter on skin grafting, which can cause life-threatening infection”. There was no documented medical adverse event decision made for this complaint record since the complaint type was designated as a product issue.
b. Complaint 187705, regarding your Flexi-Seal Signal FMS (FMS Fecal Management System Kit), dated January 13, 2012, documents that the balloon was inserted and used for a week but then lost water and leakage was discovered by a Health Care Professional. Your complaint record further states that this was the second product in a month that has leaked, “perhaps a bad batch”. There was no medical/regulatory evaluation made to determine if this complaint was reportable since this complaint type was designated as a product issue.
c. Complaint 218263, regarding your Flexi-Seal FMS Kit (Fecal Management System Kit), dated July 30, 2012, documents a retention balloon that was inflated with 45 ml of water. Four days after introduction of the device, the retention balloon tore into the anal canal, resulting in the leakage of stool. There was no medical/regulatory evaluation made to determine if this complaint was reportable since this complaint type was designated as a product issue.
We have reviewed your responses and have concluded that they are inadequate because by “categorizing” the complaint as a “product issue”, your firm has determined that the complaint does not meet the procedural definition of either an adverse event or product malfunction and therefore it would not meet the “reportability criteria”. All complaints need to be evaluated and not categorized in order to determine whether the complaint represents an event which is required to be reported to FDA under part 803, Medical Device Reporting. In addition, your firm states in your response that a review of your Complaint Handling process and the evidence supporting this observation indicates insufficient specificity in the Complaint Handling process and inadequate documentation of complaint evaluations to include decisions pertaining to the filing of a Medical Device Report (MDR).
- Failure to establish and maintain adequate 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). Specifically, your firm failed to implement your design control and change control procedures for the upgraded Flexi-Seal Signal device, which included the addition of a cinch clamp to allow for medication delivery and the addition of a sampling port on the catheter.
a. Section 126.96.36.199 (Design Verification, SOP-000122, version 5.0) states the Design Verification Plan must include statistical rationale for sample sizes. This rationale is not required if industry standards such as ANSI z1.4 are used. However, the design verification plan for CEP (Change Evaluation Plan) # 786 (Flexi-Seal Signal FMS Upgrade) Version 1.0 did not reference a variable sample standard or provide a statistical rationale for the (b)(4) samples that were required for the cinch clamp leak verification study.
b. According to the Design Verification Matrix for the Flexi-Seal Signal FMS (Signal FMS Upgrade), the acceptance criteria for the cinch clamp leak rate verification study was a flow rate less than (b)(4). However, Lab report AB-0254 (dated December 1, 2011) for Signal FMS Upgrade documents only the (b)(4) cinch clamp measures.
c. There was no assurance that the sample port seal integrity verification study was conducted for (b)(4) as required by your test method. Technical document 0330, (FMS Sample Port Seal Integrity) version 1.0 states that measurements are taken at the (b)(4). However, the study data does not demonstrate that a full (b)(4) had elapsed since there was no start and stop times recorded.
d. Section 2.3 (Change Control Process, SOP-000016, version 12.0) states design reviews must be included in the Change Evaluation Plan. The design review will be conducted to document that the design validation is maintained. In addition, section 4.3 (Design Reviews, SOP-000118, Version 6.0) states that the design review should include the complete review of the design and associated items such as materials, processes, and test methods. However, your firm did not perform a complete design review before all items of the Change Evaluation Plan were completed. For example, your firm failed to perform a design review after completing the risk benefit analysis for hazards not reduced to an acceptable level, approval of product packing specifications for (b)(4) and (b)(4), and design transfer for the contract manufacturer (b)(4), upon conducting a second process validation.
We have reviewed your responses and have concluded that they are inadequate because your firm identified design control deficiencies with respect to the recording of laboratory test results, insufficient documentation of sample size rationale, and inadequate formal design review prior to completion of the Change Evaluation Plan without making any commitments concerning repeating the verification studies in order to determine if the design changes made have affected the safety, performance, and effectiveness of the device.
- Failure to establish and maintain procedures for implementing corrective and preventive action, as required by 21 CFR 820.100(a). Specifically, your firm failed to implement your procedures for Corrective and Preventive Action (SOP-000208, version 3.0 & DIR-0010, Version 3.0) which both require “(b)(4)”. This is a repeat observation from the FDA-483, issued at the conclusion of the July 1, 2010 inspection.
a. Record ID 220845, dated August 23, 2012, states that “the distribution center” found that FMS Signal and FMS Signal Rx were given the same lot code “12-FM-01” by a third party manufacturer during production. Your action plan included updating the product specification (b)(4) to clarify the lot code convention for product differentiation between FMS and FMS RX. However, your action plan summary does not require verifying the effectiveness of revising the specification in order to prevent future lot coding mix ups. Furthermore, your firm stated during the current inspection that no action was taken regarding the mixed lot products where the disposition of the products were not documented within the nonconformance record.
We have reviewed your responses and have concluded that they are inadequate because no promised corrective actions were provided for verifying the effectiveness of revising product specification (b)(4) in order to prevent future lot coding mix ups.
Our inspection also revealed that your Flexi-Seal FMS and Flexi-Seal Signal FMS devices are misbranded within the meaning of 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 § 803 - Medical Device Reporting (MDR) regulation. These violations include, but are not limited to, the following:
1. Failure to include in the FDA Form 3500A known information related to the adverse event, specifically all the information required in subpart E, Manufacturer Reporting Requirements, that was reasonably known to your firm, as required by 21 CFR 803.50(b)(1).
For example: Complaints #243670, 208592, 208586 included information, such as patient outcome and clinical assessments, that was not included in the initial MDR submitted to FDA.
We have reviewed your responses and concluded that they are inadequate. Our records, as of May 7, 2013, indicate that your firm has not provided additional information that is reasonably known to your firm for the events described in Complaints #208592 and #208586.
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: Complaints #127953, 130177, 181385 and 160764 include information that reasonably suggests that your firm’s device may have caused or contributed to a serious injury. The MDRs submitted for the referenced complaints were received by FDA beyond the 30 calendar day timeframe.
The adequacy of your responses cannot be determined at this time. Your firm’s response described corrective actions taken, preventive actions initiated, and stated the actions will be approved and made effective by April 5, 2013. However, your firm did not submit evidence of implementation of any of its corrective/preventive actions.
3. Failure to adequately develop, maintain and implement written MDR procedures, as required 21 CFR 803.17.
For example: your firm’s MDR procedure titled SOP-000411, Adverse Event Handling Medical Device Reporting, Version 10.0, dated October 25, 2012, is deficient. Some examples of the deficiencies include:
a. The MDR 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. Specifically, there are no definitions of what your firm will consider to be a reportable event under 21 CFR Part 803. To facilitate the correct interpretation of reportable events and to assure the quality of MDR submissions, the procedure should include definitions based on 21 CFR 803.3 for the terms “become aware,” “caused or contributed,” “malfunction,” “MDR reportable event,” and “serious injury,” and definitions for the terms “reasonably known” and “reasonably suggests,” found respectively in 21 CFR 803.50(b) and 803.20(c)(1).
b. The MDR 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. Specifically, the procedure does not establish a process for investigating events identified as MDRs to ensure that MDRs are submitted to FDA within the required reporting timeframes.
c. The MDR procedure does not establish internal systems that provide for timely transmission of complete medical device reports. Specifically, the procedure does not address how to obtain and complete the FDA 3500A form; it does not include the requirement to report no later than 5 work days after the day that your firm becomes aware that FDA has made a written request for the submission of a 5 day report; and how your firm will submit all information reasonably known to it for each event.
d. The MDR procedure does not define the circumstances under which your firm must submit initial, supplemental or follow-up reports and the requirements for such reports.
e. The MDR procedure does not include the address for where to submit MDR reports: FDA, CDRH, Medical Device Reporting, P. O. Box 3002, Rockville, MD 20847-3002.
We have reviewed your responses and concluded that they are inadequate. Your firm submitted a revised MDR procedure titled SOP-000411, Adverse Event Handling Medical Device Reporting, Version 12.0, dated April 3, 2013. Your revised MDR procedure does not address the above deficiencies.
4. Failure to submit supplemental or follow up reports to FDA within 1 month of the day that your firm received information that was not provided because it was not known or was not available when your firm submitted the initial report, as required by 21 CFR 803.56.
For example: your firm received the lot number of the device that was involved in the event referenced in Complaint #193268 after the date that the initial MDR was submitted to FDA. Your firm did not submit a supplemental MDR that included the lot number.
5. Failure to include information in your firm’s reports, as required by 21 CFR 803.52.
For example: your firm failed to correctly identify the date of event, as required by 21 CFR 803.52(b)(3). Additionally, your firm failed to correctly identify the date received by your firm, as required by 21 CFR 803.52(e)(4). Specifically, the date of the event included in the complaint file for Complaints #1967347 and 190637 does not match the date of the event included in Section B3 of the initial 3500A form submitted to FDA.
If your firm wishes to submit MDR reports via electronic submission it can follow the directions stated at the following URL: http://www.fda.gov/ForIndustry/FDAeSubmitter/ucm107903.htm
If your firm wishes to discuss MDR reportability criteria or to schedule further communications, it may contact the Reportability Review Team by email at ReportabilityReviewTeam@fda.hhs.gov.
You 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 FDA without further notice. These actions include, but are not limited to, seizure, injunction, and/or civil money penalties. Also, federal agencies are advised of the issuance of all 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. Requests for Certificates to Foreign Governments will not be granted until the violations related to the subject devices have been corrected.
We are requesting that you submit to this office on the schedule below, certification by an outside expert consultant that he/she has conducted an audit of your establishment's manufacturing and quality assurance systems relative to the requirements of the device QS regulation (21 CFR, Part 820). You should also submit a copy of the consultant's report, and certification by your establishment's Chief Executive Officer (if other than yourself) that he or she has reviewed the consultant's report and that your establishment has initiated or completed all corrections called for in the report. The initial certifications of audit and corrections and subsequent certifications of updated audits and corrections (if required) should be submitted to this office by the following dates:
- Initial certifications by consultant and establishment – September 15, 2013
- Subsequent certifications – September 15, 2013, and September 15, 2014
Please notify this office in writing within fifteen (15) working days from the date you receive this letter of the specific steps you have taken to correct the noted violations, including an explanation of how you plan to prevent these violations, or similar violations, from occurring again. Include documentation of the corrective action you have taken. If your planned corrections will occur over time, please include a timetable for implementation of those corrections. If corrective action cannot be completed within 15 working days, state the reason for the delay and the time within which the corrections will be completed.
Your response should be sent to: Robert J. Maffei, Compliance Officer, U.S. Food and Drug Administration, 10 Waterview Boulevard, 3rd Floor, Parsippany, New Jersey, 07054. If you have any questions about the content of this letter, please contact Mr. Maffei at 973-331-4906.
Finally, you should know that this letter is not intended to be an all-inclusive list of the violations at your facility. It is your responsibility to ensure compliance with applicable laws and regulations administered by FDA. The specific violations noted in this letter and in the Inspectional Observations, Form FDA 483 (FDA 483), issued at the closeout of the inspection may be symptomatic of serious problems in your firm’s manufacturing and quality management systems. You should investigate and determine the causes of the violations, and take prompt actions to correct the violations and to bring your products into compliance.
New Jersey District Office