| | |
 Department of Health and Human Services
| Public Health Service
Food and Drug Administration |
| | Cincinnati District Office Central Region 6751 Steger Drive Cincinnati, OH 45237-3097 Telephone: (513) 679-2700 FAX: (513) 679-2761 |
January 18, 2011
VIA UPS
WARNING LETTER CIN-11-124848-04
Ms. Susan H. Koss
Regulatory Affairs and Quality Assurance Manager
Tosoh Biosciences, Inc.
3600 Gantz Road
Grove City, Ohio 43123
Dear Ms. Koss:
During an inspection of your firm located in Grove City, Ohio on March 23, 2010 through May 27, 2010, investigator(s) from the United States Food and Drug Administration (FDA) determined that your firm manufactures High Performance Liquid Chromatographs (HPLC) used in the measurement of hemoglobin, Automated Immunoassay Analyzers (AlA) used in the treatment of disease, and hemolysis and wash solution used with the HPLC devices. 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.
Our inspection revealed that the HLC-723G8 HPLC analyzer as marketed for the new intended use of the diagnosis of diabetes is adulterated under section 501 (f)(1)(B) of the Act, 21 U.S.C. 351(f)(1)(B), because you do not have an approved application for premarket approval (PMA) in effect pursuant to section 515(a) of the Act, 21 U.S.C. 360e(a), or an approved application for an investigational device exemption (IDE) under section 520(g) of the Act, 21 U.S.C. 360j(g). The device is also misbranded under section 502(0) the Act, 21 U.S.C. 352(0), because you did not notify the agency of your intent to introduce the device into commercial distribution, as required by section 510(k) of the Act, 21U.S.C. 360(k). For a device requiring premarket approval, the notification required by section 510(k) of the Act, 21 U.S.C. 360(k), is deemed satisfied when a PMA is pending before the agency 21 C.F.R. 807.81(b). The kind of information you need to submit in order to obtain approval or clearance for your device is described on the Internet at http://www.fda.gov/cdrh/devadvice/3122.html. The FDA will evaluate the
information you submit and decide whether your product may be legally marketed.
Our inspection also revealed that your HLC-723G7 device 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 806 - Reports of Corrections and Removals regulation. Significant deviations include, but are not limited to, the following:
Failure to document the justification for not reporting the following corrections to FDA:
a. A letter dated August 2009 was sent to all 22 Beta-thalassemia customers with G7 HPLC instrumentation to update the retention time parameters.
b. A Technical Information Bulletin, dated 4/19/07, was issued to customers to change the column filter material to PEEK material.
c. A Technical Information Bulletin, dated 1/17/08, was sent to customers to change the monitoring range and start time of the column temperature, updated parameters for peak sensitivity in the TBD peak detection file and changed the treatment of the HbF peak when it is <3%.
d. A Technical Information Bulletin, dated 1n/08, was sent to customers and changed one of the criteria used to determine the reportability of results.
We have reviewed your response and have concluded that it is inadequate because you have not provided an adequate explanation for why you did not consider the four specific items listed above to be reportable.
In addition, FDA has noted nonconformance with the following Current Good Manufacturing Practice (CGMP) requirements of the Quality System (QS) regulation found at 21 CFR Part 820. These nonconformities include, but are not limited to, the following:
1. Failure to investigate any complaint involving the possible failure of a device, labeling or packaging to meet any of its specifications, as required by 21 CFR 820.198(c). Specifically, non-routine service reports documenting possible failures of A1A and HPLC analyzers and their components are not considered complaints or investigated. For example:
a. From April 2009 to March 2010, part 019565, "CPU Board, G7" was replaced a total of 10 times at customer sites. This is the HLC723GTs main CPU board, without which the HPLC cannot run. The board failures were not considered to be complaints or investigated.
b. From April 2009 to March 2010, part 021218, the uptake check valve, was replaced a total of 42 times at customer sites, and part 021219, purge check valve, was replaced a total of 39 times at customer sites. These valves are components of the HLC723G7 analyzer. The valve failures were not considered to be complaints or investigated.
We have reviewed your response and concluded that it is inadequate because the response does not adequately explain why the failures are not investigated and what corrective actions will be taken to address the lack of investigation.
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, the definition of the term device "complaint" contained within your complaint handling procedure is not consistent with the definition of "complaint" contained within 21 CFR 820.3(b). Data files documenting service installation and customer incidents (e.g., Ticket Nos. 636-01-000000, 001-00-006169,001-00-002994, 577-01-000016, 579-01-000036, and 58001-00024) document customer communications (some using the term "complains") that involved possible or confirmed failures of A1A and the HPLC analyzers, that were not considered or reacted to as complaints.
We have reviewed your response and concluded that it is inadequate because the response does not explain why when customer calls are labeled as "complaints" they are not handled as complaints. The response does not address a corrective action for this finding.
3. Failure to adequately analyze service reports with appropriate statistical methodology in accordance with 21 CFR 820.100, as required by 21 CFR 820.200(b). For example:
a. Your "Trending Procedure" 10-TSG-018-0 Rev 4.0 requires action if a call category is greater than or equal to 10% of the total number of calls received for the instrument each month. Section 6.1.3.1 states that these calls will be "further trended to determine if it is product performance, training or communication deficiency". No trending was performed to determine if there were performance, training or communication deficiencies.
b. Your "Trending Procedure" specifies that trending should be consistently performed to determine trends in quality problems with reagents or analytes. The trending that was done does not sort the calls by product description as specified in section 6.1.2.1. of your firm's Trending Procedure.
We have reviewed your response and determined that it is inadequate. You have stated that you do not agree with that observation and therefore no corrective actions will be taken.
4. Failure to establish and maintain procedures for implementing corrective and preventive action, as required by 21 CFR 820.100(a). For example, your "Corrective and Preventive Action Policy" does not specify requirements for the verification and validation of methods communicated by the Technical Service Group to solve customers' problems. Corrective actions were communicated to G7 HPLC customers requiring the customer to reverse the direction of the column in the HPLC in order to improve chromatography. This communication was made without verifying or validating the corrective action prior to implementation. This change is contraindicated in the labeling.
Your response to this observation appears to be adequate.
5. Failure to promptly review, evaluate and investigate any complaint that represents an event which must be reported to FDA under 21 CFR 803, as required by 21 CFR 820.198(d). For example, events associated with Medical Device Reports (2010-0003 and 2010-002) regarding incorrect results for the cardiac marker Troponin were not investigated to determine: a) whether the device failed to meet its specification; b) whether the device was being used for treatment or diagnosis; and c) the relationship, if any, of the device to the reported incident or adverse event.
The adequacy of your response cannot be determined at this time. You state that you are instituting corrective actions in documenting MDRs, however, there is no documentation of this included in your response.
6. 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 Hemolysis and Wash Solution (018430US): Mixing of reagents procedure does not specify the calculation used to determine reagent quantities necessary to scale the reagent quantities to match the batch size (actual amount of water added to the batch).
Your response to this observation appears to be adequate.
7. Failure to establish and maintain procedures to ensure that equipment is routinely calibrated, as required by 21 CFR 820.72(a). For example, the calibration notebook for the conductivity meter used in the production of the Hemolysis and Wash Solution does not document the calibration procedure and results.
Your response to this observation appears to be adequate.
8. Failure to adequately maintain a device master record (DMR) for each type of device, as required by 21 CFR 820.181. For example, the DMR for the Hemolysis and Wash Solution does not include finished device acceptance criteria; or, production equipment specifications.
Your response to this observation appears to be adequate.
9. Failure to establish and maintain procedures for acceptance of incoming product, as required by 21 CFR 820.80(b). For example, receiving acceptance procedures for the raw materials used in the manufacture of the Hemolysis and Wash Solution do not include provisions to ensure the raw materials are inspected, tested, or otherwise verified as conforming to specified requirements.
Your response to this observation appears to be adequate.
You should take prompt action to correct the violation(s) addressed in this letter. Failure to promptly correct these violation(s) may result in regulatory action being initiated by the Food and Drug Administration 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.
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 violation(s), or similar violation(s), 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 reply should be sent to: Mr. Stephen J. Rabe, Compliance Officer, Food and Drug Administration, 6751 Steger Drive, Cincinnati, Ohio 45237. If you have any questions about the content of this letter please contact Mr. Rabe at (513)679-2700 extension 163 or you may forward a facsimile to him at (513) 679-2773.
Finally, you should know that this letter is not intended to be an all-inclusive list of the violation(s) at your facility. It is your responsibility to ensure compliance with applicable laws and regulations administered by FDA. The specific violation(s) 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 violation(s), and take prompt actions to correct the violation(s) and to bring your products into compliance
Sincerely,
/S/
Teresa C. Thompson
District Director
Cincinnati District
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