Inspections, Compliance, Enforcement, and Criminal Investigations
General Atomics 13-Mar-06
Department of Health and Human Services
Public Health Service
Los Angeles District
Return Receipt Requested
March 13, 2006
Chong S. Yuan, Ph.D
Diazyme Laboratories Division,
3550 General Atomics Court
San Diego, CA 92121
Dear Dr. Yuan:
During an inspection of your medical device firm located in Brea, California, conducted from October 31 to November 9, 2005, our investigators determined that your firm manufactures a wide variety of in-vitro diagnostics. These in-vitro diagnostics are devices as defined by Section 201(h) of the Federal Food, Drug, and Cosmetic Act (the Act) (21 U.S.C. § 321).
Our inspection disclosed that the 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 manufacturing, packing, and storage are not in conformance with the Good Manufacturing Practice (GMP) requirements for the Quality System Regulation, as specified in Title 21, Code of Federal Regulations (CFR), Part 820, as follows:
Failure to ensure that complaints involving the possible failure of a device to meet any of its specifications are investigated where necessary, as required by 21 CFR 820.198 (a)(3)(c). Specifically, 6 of 11 complaints reviewed were not investigated to determine the root cause of complaints such as cloudiness and low absorbance, turbidity and precipitation of controls, failing specifications, and low and negative values of products.
Failure to establish and implement procedures for rework of nonconforming product, to include retesting and reevaluation of the nonconforming product after rework, as required by 21 CFR 820.90(b)(2). Specifically, no procedures have been established for rework and retesting of reagents not meeting in-process testing specifications and employees were observed reworking and retesting product of reagents that had not met specifications.
Failure to prevent the release of finished devices prior to documenting that all finished testing was performed, reviewed and authorization of release was documented, as required by 21 CFR 820.80(d). Specifically, no documentation could be produced showing that final Q.C. testing and testing results were acceptable prior to the release of a lot of enzymatic homocysteine assay on 7/20/05, a lot of lithium enzymatic assay on 7/20/05, and a lot of potassium assay on 6/30/05. Additionally, acceptance records lacked the signatures of the individuals conducting the acceptance activities and/or dates the acceptance activities were performed.
Failure to ensure that all equipment used in the manufacturing process meet specified requirements and are appropriately designed, constructed, placed, and installed to facilitate maintenance, adjustment, cleaning, and use, as required by 21 CFR 820.70(g). Specifically, no documentation was provided describing the installation and qualification activities for three fermentors used in fermentation processes and a Cobas Mira analyzer used for in-process and quality control testing.
Failure to control procedures to ensure that equipment is routinely calibrated and maintained, as required by 21 CFR 820.72(a). Specifically, a microplate reader used to detect enzyme activity during the enzyme purification and a balance used in the enzyme purification did not have current calibration documentation.
Failure to ensure that incoming product was adequately inspected or tested to verify conformance to specifications, as required by 21 CFR 820.80(b). Specifically, a component of Reagent 3 of the Enzymatic Homocysteine Assay was accepted even though it did not come from an approved supplier.
Failure to implement procedures to control the design process of a device as required by 21 CFR 820.30(a). Specifically,
design validation conducted to support the stability claim for Enzymatic Homocysteine Assay was not performed on reagents in kit configuration under the 510(k) for that device.
no design history file was established for the Homocysteine ELISA Assay.
management failed to approve each design milestone prior to proceeding to the next milestone for the Enzymatic Homocysteine Assay as specified in the written procedure.
design input requirements for acceptance criteria for sensitivity of the Enzymatic Homocysteine Assay was not documented.
Failure to ensure that quality audits were conducted at sufficient intervals, as prescribed by internal procedures, to verify that the quality system is effective in fulfilling the quality system objectives, as required by 21 CFR 820.22. Specifically, no internal audit was performed in 2004, and in the 2005 internal audit, the Quality Assurance Manager audited the functions that he is responsible for overseeing.
Failure to ensure that employee training is documented, as required by 21 CFR 820.25(b). Specifically, there is no documented training for five current employees listed in the current versions of the quality system procedures.
Failure of management with executive responsibility to conduct reviews of the suitability and effectiveness of the quality system at defined intervals as required by 21 CFR 820.20(c). Specifically, no management review was conducted in the year 2004.
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 and in the Form FDA 483 issued at the conclusion of the inspection may be symptomatic of serious underlying problems in your firm's manufacturing and quality assurance system. You are responsible for investigating and determining the causes of the violations identified by the FDA. If the causes are determined to be systems problems, you must promptly initiate permanent corrective actions.
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 Exportability will be approved until the violations related to the subject devices have been corrected.
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.
Please notify this office in writing within 15 working days of receipt of this letter, of the specific steps you have taken to correct the noted violations, including 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. 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 you have any questions relating to this letter please contact Senior Compliance Officer, Dannie E. Rowland at 949-608-4448. You may obtain general information about all of FDA's requirements for manufacturers of medical devices through the Internet at http://www.fda.gov.
Please submit your response to:
Pamela B. Schweikert
Director, Compliance Branch
Food and Drug Administration
Irvine, CA 92612-2445
Alonza E. Cruse
Los Angeles District Office