Department of Health and Human Services
|Public Health Service|
Food and Drug Administration
|10903 New Hampshire Avenue|
Silver Spring, MD 20993
JUL 24, 2013
VIA UNITED PARCEL SERVICE
Northern Digital, Inc.
103 Randall Drive
Waterloo, ON N2V 1C5
Dear Mr. Rath:
During an inspection of your firm located in Waterloo, ON, on March 25, 2013, through March 28, 2013, an investigator from the United States Food and Drug Administration (FDA) determined that your firm manufactures Reflective Passive Marker Spheres for Image Guided Surgical 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 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 responses from David Hoover, Vice President, Research & Development, dated April 16, 2013, and May 28, 2013, and from you, dated June 19, 2013, 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 ensure that, when the results of a process cannot be fully verified by subsequent inspection and test, 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, Development Project X-14-13 “Sphere Process” resulted in manufacturing of your firm’s passive spheres being relocated to Mexico in 2009 from Waterloo, Ontario, where it had been established since 1997. One of the approving officials stated that IQ/OQ/PQ was not performed at the time the sphere process proprietary tooling was relocated. He further stated that the IQ/OQ/PQ has subsequently been performed on the sphere process proprietary tooling, “just recently when we realized it would be a good thing to do,” and that IQ/OQ/PQ never was performed during the time manufacturing took place in Waterloo, Ontario.
The adequacy of your firm’s responses cannot be determined at this time because corrective actions are ongoing. Your firm and its contract manufacturer performed a (b)(4) of the process validation and will address any identified shortcomings. CAPA CAR157 was opened to review relevant Northern Digital Inc. (NDI) and contractor procedures to ensure compliance with 21 CFR 820. Training will be provided on the revised procedures. NDI will verify the effectiveness of the (b)(4) and ensure that current validation activities are comprehensive. Audits will be performed on the contract manufacturer. These activities will be completed by August 30, 2013.
2. Failure to establish and maintain procedures for verifying the device design to confirm that the design output meets the design input requirements, as required by 21 CFR 820.30(f).
For example, the “Verification Report for Talon Spheres,” TR-0365, Revision 001, February 17, 2005, associated with Design Project MP-10-04 “Orthopedic Sphere,” reported significant variation in (b)(4) test results for spheres produced in this manual production process, and stated that it “is not stable.” (b)(4) was selected as (b)(4). The report summed up as follows: “(b)(4).”
The verification report was included as part of Engineering Change Request/Order EC-05-0049, which was approved on April 25, 2005, and implemented without any revalidation or re-characterization of the test.
The adequacy of your firm’s responses cannot be determined at this time because corrective actions are ongoing. Your firm conducted a retrospective review of “Verification Report for Talon Sphere” TR-0365 and determined that the statistical analysis that concluded that the process was unstable was flawed. A re-examination of the data confirmed that the (b)(4).
Your firm also performed a retrospective review of all Engineering Change Requests (ECRs) related to Disposable Reflective Market Spheres from June 2011 to March 2013. CAPA CAR166 was initiated as a result of the retrospective review because project documentation was incomplete for ECR-2071 and ECR-1702, changes made to (b)(4). Your firm revised procedure QP-737-302, Engineering Verification and Operations Implementation Board, and training is scheduled. Documentation of training will be provided in the next update. CAPA CAR156 was opened and is in progress to address future design projects and ensure (b)(4) will not be changed retrospectively. CAPA CAR156’s target date for completion is September 30, 2013.
3. Failure to establish and maintain procedures for implementing corrective and preventive action, as required by 21 CFR 820.100(a).
For example, your firm’s Improvement Procedure QP-850-201, revision 006, January 31, 2013, which includes your firm’s corrective and preventive (CAPA) procedures, requires that Corrective Action Reports (CAR) document evidence and clearly state if an incident was or was not considered MDR-reportable to FDA (6.3.3 – 6.3.4). However, no evidence or statement concerning reportability was included with CAR096 and CAR140.
Additionally, your firm’s procedure requires follow-up evaluation of the effectiveness of corrective actions before any CAPA can be considered closed. “Verification of Effectiveness” activities as captured on the CARs appear inadequate; for example, CAR075 states, “Verified that CAR was complete.” Although the CAPA was closed, there was no further documentation showing what verification activities were performed.
The adequacy of your firm’s responses cannot be determined at this time because corrective actions are ongoing. The root cause was identified as there being no dedicated fields for medical device reporting (MDR) reportability in (b)(4), which is used to manage your firm’s CAPA system. The CAR record could not be amended once closed out. Also, the CAR owner was not directed to include a rationale for why a CAR was verified as effective. CAPA CAR160 was opened to address this observation. Your firm’s corrective actions were to (1) (b)(4); and (2) (b)(4). Your firm performed a retrospective review of CAPAs and complaints received over the last (b)(4) for MDR reportability, including CAPA 75, 96, and 140. The retrospective review confirmed that there were no MDR reportable situations. Your firm also performed a retrospective review of CAPAs for adequate verification for effectiveness and found (b)(4) instances of unsatisfactory documentation; subsequently, CAR167 was opened to address these occurrences. An internal audit will be conducted to verify effectiveness and confirmation of closure of CAR160 will be provided at the next update.
4. Failure to maintain complaint files and establish and maintain procedures for receiving, reviewing, and evaluating complaints by a formally designated unit, as required by 21 CFR 820.198(a).
For example, your firm’s Complaint Handling Procedure QP-850-302, revision 001, of February 13, 2013, provides for your firm’s (b)(4) to assign a person to review and evaluate complaints rather than direct complaints to a formally designated unit. The assignee may be the (b)(4) himself. Complaints # 001, 002, 003, 004, and 005 of 2012 and # 001, 003, and 007 of 2013 were reviewed and it was found that, besides the (b)(4), other assignees to handle complaints in 2012-2013 included various personnel in (b)(4). All these complaints were found to be lacking documentation of any MDR reportability determination.
The adequacy of your firm’s responses cannot be determined at this time because corrective actions are ongoing. Your firm designated a complaint handling unit in procedure QP-850-302, Complaint Handing, Rev 002, and notified and trained affected personnel. A retrospective review of complaints over the past (b)(4) was conducted for MDR reportability and confirmed that no MDR reportable complaints existed. An internal audit was conducted to verify effectiveness of the corrective action. Closure of CAPA CAR 158 will be provided at the next update.
5. Failure to maintain all records required by 21 CFR 820 at the manufacturing establishment or other location that is reasonably accessible to responsible officials of the manufacturer and to employees of FDA designated to perform inspections, as required by 21 CFR 820.180.
For example, training records for the QA unit of the contract manufacturer were not readily available on-site for review and copying as verification of training on the transferred sphere production process.
The adequacy of your firm’s responses cannot be determined at this time because corrective actions are ongoing. The root cause was determined to be that your firm’s supplier agreement between NDI and the contract manufacturer did not fully describe each party’s roles and responsibilities in regard to training record retention and FDA access to quality system records. The records requested during the inspection were retrieved and are stored at NDI. CAPA CAR161 was opened to address this observation. The corrective action has included drafting a supplier agreement amendment to ensure that quality system records are readily accessible during holidays and factory shutdowns. A test of records retrieval was performed on May 3, 2013, during a factory shutdown. The test successfully documented retrieval of (b)(4) different quality system records. This issue will be audited in the future. CAR161 is in progress and closure will be documented in the next update.
6. Failure to establish policy and objectives for, and commitment to, quality by management with executive responsibility, as required by 21 CFR 820.20(a).
For example, your firm’s Management Responsibility Procedure, QP-500-201, revision 001, March 13, 2013, in section 6.1.1. refers to senior management establishing “the mission statement (AKA Quality Policy).” However, your firm’s NDI Quality Management System Manual QM-9000, revision 022, of January 31, 2013, contains a separate, distinct Quality Policy and Mission Statement. These procedures contain conflicting information and do not adequately define the statements regarding the mission and the quality policy.
The adequacy of your firm’s responses cannot be determined at this time because corrective actions are ongoing. Your firm initiated a correction that includes top management review of procedure QP-500-201, revision 011, to improve the distinction between the Quality Policy and the Mission Statement. CAPA CAR162 was opened and procedure QP-500-201 was revised (revision 012) with improved distinction between the Quality Policy and the Mission Statement. Management was trained in the revised procedure and staff were reminded of the difference between the Quality Policy and the Mission Statement. An internal audit was performed which sampled personnel on their knowledge of the distinction between the Quality Policy and the Mission Statement. Confirmation of closure of CAPA CAR162 will be provided at the next update.
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 (MDR). Significant violations include, but are not limited to, the following:
Failure to adequately develop, maintain, and implement written MDR procedures, as required by 21 CFR 803.17(a)(1). For example, after reviewing your firm’s MDR procedure titled “Quality Procedure – USA Regulatory Medical Device Reporting (MDR),” QP-821-302, revision 002, dated March 20, 2013, the following issue was noted:
Your firm’s 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. For example:
Your firm’s procedure includes definitions from 21 CFR 803.3, but omits the definitions of “reasonably known” and “reasonably suggests,” found respectively in 21 CFR 803.50(b) and 803.20(c)(1). The exclusion of these terms from the procedure 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).
We reviewed your firm’s responses and conclude that they are not adequate. Your firm has not submitted an updated MDR procedure.
A follow-up inspection will be required to assure that corrections and/or corrective actions are adequate.
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. 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, 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 (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. Please provide a translation of documentation not in English to facilitate our review.
Your firm’s response should be sent to: Food and Drug Administration, Center for Devices and Radiological Health, Office of Compliance, Field Operations Branch, White Oak Building 66, Rm 2609, 10903 New Hampshire Ave., Silver Spring, MD 20993. Refer to CMS case #406130 when replying. If you have any questions about the contents of this letter, please contact: LaShanda Long at (301) 796-5465 or fax (301) 847-8137.
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.
Steven D. Silverman
Office of Compliance
Center for Devices and