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U.S. Department of Health and Human Services

Inspections, Compliance, Enforcement, and Criminal Investigations

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Nanogen Point-of-Care Diagnostic Division 17-Jul-07

Department of Health and Human Services' logoDepartment of Health and Human Services

Public Health Service
Food and Drug Administration

 

2098 Gaither Road
Rockville MD 20850


WARNING LETTER

VIA FEDERAL EXPRESS {AND FACSIMILE}

JUL 17 2007

David H. Ray
Vice President Operations
Nanogen Point-of-Care
Diagnostic Division
135-2 The West Mall
Toronto, M9C 1C2
CANADA

Dear Mr. Ray:

During an inspection of your firm located in Toronto, Canada, on February 9, 19, 2007, through February 23, 2007, an investigator from the United States Food and Drug Administration (FDA) determined that your firm manufactures Cardiac STATus, Decision Point and i-Lynx. 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 (C.F.R.), Part 820. The violations include, but are not limited to, the following:

1. Failure to maintain procedures that adequately ensure that control of products that do not conform to specified requirements, as required by 21 CFR 820.90(a). For example:

a. The firm failed to follow their procedures, [redacted], Control of Nonconforming Products/Product Components, revision [redacted] when finding non-conformances for [redacted] lots of monoclonal antibody [redacted] that did not meet specifications. This product is used in the firm's Cardiac Status Myoglobin/Triponin I/CK-MB Tandem Test or Decision Point Myoglobin/Triponin I/CK-MB.

b. The firm failed to initiate a non-conformance report (NCR) as required in [redacted] which requires the initiation of an NCR when products/product components are identified as not conforming to their specifications. The [redacted] lots of monoclonal antibody [redacted] were from the same bioreactor [redacted]. The tests for the [redacted] lots, which show the lots did not pass acceptance criteria for activity (using ELISA testing), were conducted from [redacted]. There were no NCRs initiated for these nonconformities as of [redacted]

We acknowledge the initiation of an NCR during and as a result of the FDA inspection. However, we have concluded that this correction alone is inadequate because there was noevaluation made for corrective and preventive actions. Completing an NCR does not resolve the issue; it is merely a correction.

2. Failure to document the evaluation and investigation of nonconforming products, as required by 21 CFR 820.90(a). For example:

a. The firm was unable to provide documentation indicating that a failure investigation had been initiated as to the root cause of the lower than accepted values for activity of the [redacted] lots of monoclonal antibody [redacted]

b. The firm was unable to provide documentation that they had analyzed and/or compared the device history records (DHR) for the cell propagation and bioreactor data for lot # [redacted] the DHR of the [redacted] lots of monoclonal antibody [redacted] or other failure activities.

c. The firm was unable to provide documentation of an NCR, or of an investigation into the root cause of the higher than accepted concentration of the Preparation of Lyophilizer 3 in l Cardiac Status Level 3, which required a deviation from procedure, deviation [redacted]

d. The firm was unable to provide documentation of an NCR, or an investiation to determine the root cause of the nonconformance for [redacted] using [redacted] regarding the low purity; as described in deviation [redacted]

3. Failure to establish and maintain procedures for the rework of nonconforming products, as required by 21 CFR 820.90(b) (2). For example:


a. The firm was unable to provide documentation describing rework procedures for any of the finished components or products at the firm, which includes the re-testing and re-evaluation of the nonconforming product after rework, to ensure that the product conforms to its current approved specifications.

b. The firm was unable to provide documentation describing the rationale, test method, device/sample preparation or acceptance criteria for the proposed rework of the: [redacted] lots of monoclonal antibody [redacted](except for the corrective action, dated 2/22/07).

4. Failure to establish and maintain procedures for implementing corrective and preventive actions that include requirements for analyzing other sources of quality data to identify existing and potential causes of nonconforming product, or other quality problems, as required by 21 CFR 820.100(a)(1). For example:

Not all data from quality data sources area analyzed to identify existing and potential causes of nonconforming product and other quality problems. The firm failed to analyze data from complaints that are processed by the firm as [redacted] according to their procedures [redacted]. The requirements for trending are found in section [redacted] of the firm's procedures "Evaluation of Non-Complaints," [redacted]

5. Failure to 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:

The firm failed to establish the production process for the manufacturing of the Gold Conjugate [redacted] to ensure that this product conforms to its specifications. The actual processes, observed by the investigator, for the manufacturing of the Gold Conjugate, manufactured on 2/19/07, did not correspond to procedures [redacted] dated [redacted] such as: [redacted]

6. Failure to establish and maintain procedures ensuring that all equipment used in the manufacturing process meets specified requirements and is appropriately designed, constructed, placed and installed to facilitate maintenance, adjustments, cleaning and use, as required by 21 CFR 820.70(g). For example:

a. The firm was unable to provide documentation for the installation qualification and validation studies for the [redacted], bioreactor [redacted] which has been in the production area since received on 2/14/06.

b. The firm did not follow their procedures [redacted] dated [redacted] for identifying the status of the [redacted]

7. Failure to establish and maintain procedures to ensure periodic inspections are conducted in accordance with established procedures, to ensure adherence to applicable equipment maintenance schedules, as required by 21 CFR 820.70(g)(2). For example:

a. The firm was unable to provide documentation of any inspection activities of the [redacted] bioreactor, [redacted] that includes the reason, date and individual responsible for the firm discontinuing the use of the bioreactor for production: which was last used to make lot [redacted] for production of 5 lots of monoclonal antibody [redacted] all of which failed to meet specifications for activity. Also, the firm did not follow their procedures [redacted] revision [redacted] for identifying the status and the required [redacted] of the [redacted] bioreactor, [redacted] their procedures [redacted] revision [redacted] for identifying the status and the required [redacted] of the [redacted] bioractor, [redacted]

b. The firm's [redacted] has a printed label indicating the calibration was due 11/30/06, and the firm's [redacted] database for equipment list indicated that the equipment was "waiting for validation-file in qa." The investigator was unable to verify if the bioreactor had been used after it was due for calibration.

8. Failure to establish and maintain procedures for defining, documenting, reviewing and approving design output before release. The approval including the date and signature of the individual(s) approving the output should be documented, as required by 21 CFR 820.30(d).
For example:

The firm was unable to provide documentation that the design outputs for the design project No. [redacted] StausFirst™ NT-proBNP Point-of-Care Test, had been approved. The investigator found that the design review meeting to approve the design outputs held on, 12/14/05, did not have any approval signatures. This was also the case when the design outputs records were reviewed.

9. Failure to establish and maintain procedures for verifying and validating the device design, as required by 21 CFR 820.30(f) & (g). For example:

The investigator found the [redacted] for NT-proBNP POC Device, dated [redacted] had not been approved. This verification and validation testing conducted at the request of the FDA, after the initial review of the PMA, was to include linearity. The original protocol, dated [redacted] had been signed by [redacted] of the contract manufacture; however [redacted] the [redacted] of the firm had signed the protocol dated [redacted]

10. Failure to 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). For example:


a. The firm's design control procedures used for the design project, [redacted] Design Review, [redacted] do not include procedures for managing design changes that establish the identification, documentation, validation or verification, review and approval of design changes prior to implementation.

b. The firm's current design control procedures, [redacted], Design Control, [redacted] also do not include specific procedures for managing design changes, that establish the identification, documentation, validation or verification, review and approval of design changes prior to implementation.

11. Failure to establish and maintain procedures to ensure that participants at each design review include representatives of all-functions concerned with the design stage being reviewed and an individual(s) who does not have direct responsibility for the design stage being reviewed, as well as any specialist needed, as required by 21 CFR 820.30(e). For example:

a. The firm's design review meeting for the design project No. [redacted] StausFirst™ NT-proBNP Point-of-Care Test, which were held on [redacted] and [redacted] did not include an independent participant that did not have direct responsibility for the design phase being reviewed.

b. The firm's design control procedures used for this project, [redacted] Design Review, [redacted] did not include the requirements for the attendance of an independent participant.

12. Failure to establish and maintain procedures to designate an individual(s) to review for adequacy and approve prior to issuance all documents established to meet the requirements of this part, as required by 21 CFR 820.40(a). For example:

The firm is currently using unapproved procedure [redacted] for verification of product labeling containing a barcode to be checked with the [redacted] barcode reader. The unapproved version of [redacted] has been used since initiation of [redacted] on [redacted]

We acknowledge the initiation of an approval of this SOP during and as a result of the FDA inspection. However, we have concluded that this correction alone is inadequate because there was no evaluation made for corrective and preventive actions. Signing off on the corrected SOP version does not resolve the issue; it is merely a correction.

You should take prompt action to correct the violations addressed in this letter. Failure to promptly correct these violations may result in regulatory action, which may include detaining your devices without physical examination upon entry into the United States until the corrections are completed. (Section 801(a) of the Act (21 U.S.C. § 381(a)) Also, U.S. 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, pre-market 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 (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. If the documentation is not in English, please provide a translation to facilitate our review.

Your response should be sent to: James Woods, Deputy Director, Patient Safety and Product Quality, 2098 Gaither Road, Rockville, Maryland 20850. If you have any questions about the content of this letter please contact: Dana C. Jones at 240-276-1323 or 240-276-0663 fax.

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 assurance 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.

Sincerely yours,

/S/

Steve I. Gutman
Director
Office of In Vitro Diagnostic Device
Evaluation and Safety
Center for Devices and Radiological Health