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U.S. Department of Health and Human Services

Inspections, Compliance, Enforcement, and Criminal Investigations

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BioGenex Laboratories 27-Jul-06

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

Public Health Service
Food and Drug Administration


San Francisco District
1431 Harbor Bay Parkway
Alameda, CA 94502-7070
Telephone: 510/337-6700

Via Federal Express

Warning Letter

July 27, 2006

Krishan L. Karla, President & Chief Executive Officer
BioGenex Laboratories
4600 Norris Canyon Road
San Ramon, CA 94583-1320
Dear Mr. Karla:

During an inspection of your establishment conducted from February 1 through March 9, 2006 our investigator determined that your firm is engaged in operations subject to the requirements of Title 21 Code of Federal Regulations Part 820 (21 CFR § 820). Our inspection revealed that your facility manufactures pathology related stains, antibodies, and in-vitro diagnostic test kits. The articles are devices as defined by section 201(h) of the Federal Food, Drug, and Cosmetic Act (the Act).

The devices manufactured by your firm 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 (GNP) requirements of the Quality System (QS) Regulations for medical devices, as specified in Title 21, Code of Federal Regulations (CFR), Part 820. The FORM FDA-483, List of Inspectional Observations, issued to you at the conclusion of FDA's inspection describes significant deviations including, but not limited to the following:

1. Failure of Management with executive responsibility to ensure that an adequate and effective quality system has been fully implemented and maintained at all levels of the organization as required by 21 CFR § 820.20 (FDA-483 observation #5). Specifically, you have distributed products that failed to meet specifications, failed to provide adequate training and resources, failed to identify and correct deficiencies in your design, complaint and CAPA systems.

2. Failure to control products that do nut conform to specifications as required by 21 CFR § 820.90(a)(FDA-483 observation #9). Specifically, [redacted] out of [redacted] HER-1/neu Test Kits manufactured failed to meet QC Release Criteria but were released for distribution. In addition, [redacted] of out of [redacted] HER-2/neu primary antibody lots failed finished product testing but were released for distribution.

3. Failure to establish procedures for the control of finished devices to ensure that only devices approved for release are distributed as required by 21 CFR§ 820.160(a)(FDA-483 observation #11). Specifically, your procedures used to control finished devices do not accurately describe the actual process used. In addition, you released and distributed [redacted] InSite HER-2/neu IHC test kits prior to QA's review and approval of the Device History Record.

4. Failure to establish and maintain procedures to control the design of the device in order to ensure that specified design requirements are met, as required by 21 CFR§ 820.30. Specifically you have failed to: establish design input procedures [21§ CFR 820.30(c)](FDA-483 observation #1); establish and define acceptance criteria prior to the performance of design verification activities [21 CFR§ 820.30(f)](FDA-483 observation #2); conduct complete risk analysis [21 CFR§ 820.30(g)](FDA-483 observation #3); update and approve design plans as needed as the design and development -evolved [21 CFR § 820.30(b)](FDA-483 observation #4); and ensure that devices conform to defined user/patient needs and intended uses [21 CFR § 820.30(g)](FDA-483 observation #8).

5. Failure to establish procedures for conducting quality audits and to conduct such audits to assure that the quality system is in compliance with the established quality system requirements and to determine the effectiveness of the quality system, as required by 21 CFR § 820.22 (FDA-483 observation #6 and #7). Specifically your Quality Audit Procedures fail to give instructions of when and how re-audits are to be conducted. In addition, you have conducted at least [redacted] Quality Audits in the last [redacted] years and all the audits failed to identify the lack of design procedures for design inputs, design outputs, and design verification.

6. Failure to establish and maintain procedures for implementing corrective and preventive action as required by 21 CFR § 820.100(a)(FDA-483 observation #13). Specifically, your CAPA procedure only requires verification and validation of corrective and/or preventive actions involving engineering changes [21 CFR 820.100(a)(4)] and fails to define the relevant information on quality problems and corrective and preventive actions to be submitted for management review [21 CFR 820.100(a)(7)].

7. Failure to establish and maintain complaint handling procedures to assure that oral complaints are received, reviewed and evaluated by a formally designated unit as required by 21 CFR § 820.198(a) (FDA-483 observation #12). In addition your complaint handling procedures fail to ensure that oral complaints are documented upon receipt as required by 21 CFR § 820.198(a)(2). Specifically, you failed to enter into your complaint handling system reports from field representatives indicating they were experiencing false positives when using the InSite HER-2/neu as directed.

8. Failure to establish and maintain adequate procedures for identifying training needs and documenting personnel training to ensure that all personnel are trained to adequately perform their assigned responsibilities, as required by 21 CFR § 820.25(b)(FDA-483 observation #10). Specifically the personnel that performed testing on the InSite HER-2/neu antibody and the InSite HER-2/neu kits were not trained to the approved Quality Control testing procedure. In addition the personnel reviewing and approving the testing of the InSite HER-2/neu antibody and the InSite HER-2/neu kits were not trained to the approved Quality Control test procedure.

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. 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.

We have reviewed your written responses, dated March 30, 2006 and May 25, 2006, to the above items and have concluded that the responses are inadequate because the specific documentation to demonstrate the implementation of your corrective actions has not been provided. Please submit copies of your revised procedures and documents, re- organizational charts, auditing plans and findings, and re-training records for our review. Your stated corrective actions include, but are not limited to, the development and implementation of a more comprehensive design control procedure and the development and implementation of enhanced procedures related to training, corrective and preventive actions, quality audits, production, quality assurance product release, complaint and MDRs. In addition, you stated that you would be hiring additional personnel.

We acknowledge that you have ceased the sale of and recalled the InSite HER-2/neu kits and antibodies. We also acknowledge that you have voluntarily requested the withdrawal of the associated PMA, P040030 and P040030/S001. While the examples given above may relate to the InSite HER-2/neu kits and antibodies, the deficiencies identified are system failures and transcend these devices.

You should take prompt action to correct these deviations. Failure to promptly correct these deviations 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 penalties. Additionally, no premarket submissions for Class III devices to which QS regulation deficiencies are reasonably related will be cleared until the violations have been corrected. Also, no requests for Certificates for Products for Export will be approved until the violations related to the subject devices have been corrected.

Please notify this office in writing within fifteen (15) working days of receipt of this letter, of the steps you have taken to correct the noted violations, including (1) the time frames within which the corrections will be completed, (2) any documentation indicating the corrections have been achieved, and (3) an explanation of each step being taken to identify and make corrections to any underlying systems problems necessary to assure that similar violations will not recur.

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.

Sincerely yours,


Barbara J. Cassens
District Director