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U.S. Department of Health and Human Services

Inspections, Compliance, Enforcement, and Criminal Investigations

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Tosoh Bioscience, Inc. 22-Mar-05

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

Public Health Service
Food and Drug Administration


San Francisco District
f431 Harbor Bay Parkway
Alameda. CA 94502-7070
Telephone : 510/337-6700

March 22, 2005

Via Federal Express

Masanobu Kasai, Executive Vice President
Tosoh Bioscience, Inc.
347 Oyster Point Blvd., Ste. 201
South San Francisco, CA 94080-1913


Dear Dr. Kasai:

We are writing to you because during inspections of your firm from June 1-14, 2004 and August 20-September 15, 2004, the Food and Drug Administration (FDA) became aware of information that revealed serious regulatory problems involving immunoassay diagnostic packs and immunoassay systems. Immunoassay diagnostic packs and immunoassay systems are devices as defined in Section 201(h) of the Federal, Food, Drug, and Cosmetic Act (the Act) (21 U.S.C. 321). Our review of your operations found that you not only are the initial distributor for these products, but that you also perform limited manufacturing operations such as relabeling/repacking and design of some of the labeling. As the initial distributor and manufacturer of these products, your firm is responsible for these violations.

Our inspection disclosed that these devices are adulterated within the meaning of Section 501(h) of the Act (21 U.S.C. 351), in that the methods used in, or the facilities or controls used for their manufacturing, packing, storage, or installation are not in conformance with the Good Manufacturing Practice (GMP) requirements of the Quality System (QS) Regulations for medical devices, as specified in Title 21, Code of Federal Regulations (CFR), Part 820. While your manufacturing operations are limited, your firm failed to comply with those requirements applicable to the operations in which it is engaged as follows:

1 . Failure to establish and maintain procedures to control the design of the device to ensure that the specified design requirements are met as required by 21 CFR 820.30(a) . Specifically, you made significant design changes to the product inserts for the CA 19-9, CA 125, and CA 27.29 Cancer Marker A1}A Pack kits in that you added the Caution Statement, Name and Intended Use, Calibration tables, and Clinical Performance Studies Sections to the product inserts.

Your October 4, 2004 response is inadequate as it fails to provide specific procedures for the control of Design Changes, Design Inputs, Design Outputs, Design Review, Design Verification, Design Validation, and Design Transfer . In addition, your response fails to address the establishment and maintenance of a Design History File.

2. Failure to maintain a Device Master Record which includes device quality assurance procedures and packaging and labeling specifications as required by 21 CFR 820.18(c) and (d). Specifically, you fail to have procedures describing the removal of the Japanese labeling and replacement with English labeling for the AIA 600 II Analyzer. You also fail to have approved specifications for the English labeling and fail to have procedures for any quality assurance activities associated with the relabeling of the device.

Your October 4, 2004 response is inadequate. The attachment that you provided representing a Device Master record is limited to an English version product insert revision history.

3. Failure to establish and maintain procedures to ensure that device history records (DHRs) for each batch, lot, or unit are maintained to demonstrate that the device is manufactured in accordance with the Device Master Record and the requirements of Part 820, as required by 21 CFR 820.184. For example, the replacement of the Japanese version of the AIA-600 Analyzer's Operator's Manual with the English version for each serialized unit is not documented and maintained.

Your October 4, 2004 response is inadequate as it fails to include a copy of the new procedures or an example of a completed Device History File.

4. Failure to establish procedures to control labeling activities, as required by 21 CFR 820.120. For example, you failed to document the approval and release of the English version of the AIA-600 Analyzer Operator's Manual, including the date and signature of the examiner. In addition, you failed to have written procedures for the examination of incoming English Version Operator's Manuals to assure the labeling is accurate.

Your October 4, 2004 response is inadequate as it fails to include a copy of the new procedures and the associated acceptance records.

5. Failure to establish and maintain procedures to control all documents that are required by Part 820 as required by 21 CFR 820.40.

Your October 4, 2004 response is inadequate as it fails to include a copy of the new procedures.

Your AIA-600 II Analyzers are misbranded within the meaning of Section 502(t)(2) of the Act (2l U.S.C. 352(t)(2)) in that a report of correction or removal was not submitted to FDA as required by Section 519(f)(1) of the Act (21 U.S.C. 360i(f)(1)). The Correction and Removal Regulation (21 CFR 806), promulgated under Section 519(f)(1), requires manufacturers and importers to promptly report to FDA, within 10 working days, any correction or removal of a device to reduce a risk to health . 21 CFR 806.10(b).

Specifically, our inspections revealed that on or about March 27, 2003, your firm was notified by Tosoh Corporation, Tokyo, Japan that a new software revision, version 3.12, was being released to correct washing errors in the analyzer that resulted in discrepant troponin results. FDA has classified your software upgrade to your customer's analyzers as a Class I recall . A Class I designation indicates a situation in which there is a reasonable probability that the use of, or exposure to, a violative product will cause serious adverse health consequences or death (21 CFR 7.41). FDA regulations require manufacturers and importers to promptly report to FDA any correction or removal of a device if the correction or removal was initiated to reduce a risk to health . See 2I CFR 806.10(a)(1). Your firm's action described above meets the definition of a "correction" in 21 CFR 806.2(d). In addition, FDA has found that the removal was initiated to reduce a risk to health . You therefore failed to report the product removal, as required by 21 CFR 806. 10(a)(1), until the issue was raised by our investigator.

Additionally, our inspections revealed your AIA-600 II analyzers and AIA-NexIA-TLA analyzer are misbranded within the meaning of Section 502(t)(2) of the Act because your firm failed to furnish certain information to the FDA as required by the MDR regulation set forth in 21 CFR 803. Significant deviations include, but are not limited to, the following:

You failed to submit a report to FDA, and a copy of such report to the manufacturer, containing the information required by 21 CFR 803.42 on Form FDA 3500A as soon as practicable, but no later than 30 days after becoming aware that one of your marketed devices has malfunctioned and that such device or a similar device marketed by you would likely cause or contribute to a death or serious injury if the malfunction were to recur 21 CFR 803.50(a)(2). Specifically, our June 2004 inspection found that you failed to submit MDR reports to FDA within 30 days for complaints concerning discrepant troponin results obtained by the AIA-600I1 analyzer.

Your June 28, 2004 response stated that you had corrected the problem regarding the reporting of MDRs to FDA. However; our August/September inspection found that you failed to file a complaint involving your AIA-NexIA-TLA analyzer (Incident #f 0050485) as an MDR within 30 days. Your October 4, 2004 response promises corrections to your MDR reporting system. These corrections will be verified during our next inspection.

Furthermore, although your firm is registered as an initial importer, you have not registered your firm as a medical device manufacturer with FDA to ensure compliance with 21 CFR 807. Failure to register your firm and list your devices with FDA means your devices are misbranded under Section 502(o) of the Act. You can obtain the registration form from our website at. www.fda.gov for the filing of your firm's establishment registration and device listing.

This letter is not intended to be an all-inclusive list of deficiencies at your facility. It is your responsibility to ensure adherence to each requirement of the Act and regulations. The specific violations noted in this letter may be symptomatic of serious underlying problems in your firm's manufacturing and quality assurance systems. You are responsible for investigating and determining the causes of the violations identified by FDA.

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. Also, no requests for Certificates for Products for Export will be approved until the violations relating to the subject devices have been corrected.

You should take prompt action to correct these violations. 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 penalties.

Please notify this office in writing within 15 days of the specific steps you have taken to correct the noted violations, including an explanation of each step being taken to identify and make correction to any underlying systems problems necessary to assure that similar violations will not recur. Please include any and all documentation to show that adequate correction has been achieved. In the case of future corrections, an estimated date of completion, and documentation showing plans for correction should be included with your response to this letter. Please address your response and any questions to the Food and Drug Administration, San Francisco District, 1431 Harbor Bay Parkway, Alameda, CA 94502, attention: Russell A. Campbell, Compliance Officer.

Should you require any assistance in understanding the contents of this letter, do not hesitate to contact Mr. Campbell at the above address or at 510-337-6861.

Sincerely yours,


Barbara J. Cassens
District Director