Inspections, Compliance, Enforcement, and Criminal Investigations
Biotecx Laboratories, Inc. 08-Dec-06
Department of Health and Human Services
Public Health Service
December 8, 2006
RETURNED RECEIPT REQUESTED
Dr. Mohan Mehra, Ph.D., President
Biotecx Laboratories, Inc.
6023 South Loop East
Houston, Texas 77033-1041
Dear Dr. Mehra:
During an inspection of your firm located at the above referenced address on September 5 through 8, 11, 22, and 25, 2006; investigators from the United States Food and Drug Administration (FDA) determined that your firm manufactures the Opticoat T3 and T4 EIA (Enzyme Immunoassay) kits intended to measure the hormone triiodothyronine in serum used in the diagnosis and treatment of thyroid diseases such as hyperthyroidism, and other in vitro diagnostic (IVD) devices. According to your firm's product label, the Opticoat T4 EIA kit includes six T4 standards at various concentrations, the T4 antibody coated wells, the Control Serum, the Stop Solution, the T4 Conjugate (HRP), and the One Blue TMB Substrate Solution. 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 conformance with the Current Good Manufacturing Practice (CGMP) requirements of the Quality System (QS) regulation found at Title 21, Code of Federal Regulations (CFR), Part 820.
These violations include, but are not limited to, the following:
1. Failure to establish and maintain adequate procedures for finished device acceptance to ensure that each production run, lot, or batch of finished devices meets acceptance criteria prior to releasing the devices for distribution, as required by 21 CFR § 820.80(d), and failure to adequately document acceptance activities, as required by 21 CFR § 820.80(e). FDA 483 Item 4, 5, and 8. For example:
a. Your firm failed to calculate the zero binding for the T4 Standard Lot #2618 manufactured and released on 10/7/03 In accordance with your firm's MM5 procedure, effective 2/7/96, used for preparing and assaying the six T4 standards. At the time of the inspection, you calculated the zero binding values for this lot and found them to be outside of your approved binding specification of [redacted]. This lot of the T4 standards was used in all of the T4 ElA kits manufactured in the last two years.
b. Your firm failed to document your calculation for the T4 Conjugate Lot #4270 and 4272 manufactured on 5/3/05 and 1/11/06, respectively, prior to releasing these lots. For example, the results of your dilutions and absorbance readings of the T4 conjugates were left blank in the device history records of these two lots. T4 Conjugate Lot # 4273 manufactured on 3/30/06 was released for distribution with its absorbance readings exceeding your acceptable limit of [redacted] for the T4 zero standard.
c. Your firm failed to document the results of your quality control testing for the Control Serum Lot # 2693 manufactured in 11/2004 in accordance with your procedure entitled "Establishment of QC Control Values and Establishment Criteria," No. 242, dated 8/12/04. This lot of Control Serum was used in the manufacture of your firm's ELISA/EIA kits, including the T3 and T4 EIA kits.
d. Your firm failed to assign the appropriate product expiration dates for T4 EIA Kit Lot # 2057 and 2058 in accordance with your procedure entitled"Expiry Date Assignment Procedure," No. 240, dated 6/4/04, in that these two lots were assigned longer expiration dates while their kit components had shorter expiration dates. Additionally, their certificates of analysis do not document the expiration date for each of the six kit components.
2. Failure to establish and maintain procedures for changes to a specification, method, process, or procedure, including verification or validation of such changes according to 21 CFR § 820.75, as required by 21 CFR § 820.70(b), and failure to review and approve changes to documents, including a description of the change, the signature of the individual(s) approving the change, the approval date, and when the change becomes effective, as required by 21 CFR § 820.40. FDA 483 Item 6, 7, and 9. For example:
a. Your firm changed the user test procedure in the product insert of the T4 EIA Kit (Section Vlll for changes in the mixing amount of the One Blue TMB Substrate and Stop Solutions) and the expected testing ranges of Euthyroid without conducting appropriate testing and documenting an appropriate explanation to determine the impact of the changes on patient test results. Additionally, there is no record documenting a description of the changes, the signature of the individual(s) approving the changes, the approval date, and when the changes become effective.
b. Your firm changed the concentrations of the reagents required to prepare the T4 EIA Plates without explaining and documenting your calculations or testing to determine if the changes impact on the device performance or patient test results. See your procedures entitled "9447 and 9447a T4 EIA Plates," dated 9/11/97. Additionally, there is no record documenting a description of the changes, the signature of the individual(s) approving the changes, the approval date, and when the changes become effective.
3. Failure to establish and maintain procedures for validating the device design to ensure that the device conforms to user needs and intended uses, and the failure to ensure that design testing is conducted under actual or simulated use conditions, that risk analysis is conducted, and that written design testing results are maintained, as required by 21 CFR § 820.30(g). FDA 483 Item 7(a). For example:
At the time of the inspection, your firm was not able to provide stability test results that confirm and document your expiration dating for the reagents (kit components) in the T4 EIA Kit. The kit components include the six T4 Standards, Control Serum, T4 Conjugate (HRP), T4 Antibody Coated Microtiter Plates, One Blue TMB Substrate, and Stop Solution.
4. Failure to ensure that the calibration of the inspection, measuring, and test equipment is traceable to national or international standards, as required by 21 CFR § 820.72(b)(1). FDA 483 Item 2. For example:
Your firm developed an in-house procedure entitled "Verification of Linearity of Response for Elisa Strip Reader" based on an accepted calibration standard called [redacted]. Your calibration procedure is used to calibrate your Elisa Strip Reader [redacted] which is used to measure the absorbance of the EIA plates during final product testing. Your calibration procedure is not traceable to the referenced standard in that.
a . You have no documentation to show that the accuracy of your Elisa Strip Reader's [redacted] wavelength has been certified by the use of a [redacted] as referenced in the accepted standard.
b. You tested the linearity of the Elisa Strip Reader's detector response at the [redacted] wavelength using [redacted] solutions while the accepted standard references the use of [redacted] solutions at the [redacted] wavelengths. According to the accepted standard, the detector response should exhibit linearity at aIl [redacted] wavelengths over the entire concentration range used.
c. Your use of the number of duplicate wells of the test strips was not consistent to calculate and plot the absorbance. For example, one test strip was used for calibration on 8/31/06, and four test strips were used for calibration on 4/15/05. Additionally, your calibration records did not document the values of the slope.
5. Failure to establish and maintain procedures to ensure that all inspection, measuring, and test equipment is routinely calibrated, inspected, checked, and maintained, as required by 21 CFR § 820.72(a). FDA 483 Item 1 and 3. For example:
a. Your pH meter used to measure the pH of the reagents of the EIA and ELISA kits were not checked for accuracy nor calibrated at the time of each use according to your procedure entitled "GMP ELISA Kits Operational Flow Chart Documentation as of July 15, 2002" in that your calibration notebook did not document your firm's calibration checks of the pH meter when your firm manufactured the One Blue TMB Substrate Lot # 9642 on 8/5/05, Lot # 9651 on 5/11/06, and Lot # 9652 on 7/24/06.
Additionally, the pH buffer solutions used for calibration checks were observed expired two to five years ago.
b. Your [redacted] and [redacted] were not calibrated at the time of each use in accordance with your procedure entitled "GMP ELISA Kits Operational Flow Chart Documentation as of July 15,2002."
c. Although you provided calibration records of one 10-microliter, one 10 microliter, and one 1-milliliter pipette for review by the FDA investigator, you could not provide documentation showing which pipette was actually calibrated since these pipettes were not marked. The FDA investigator observed at feast 12 pipettes of various dispensing volumes located at various manufacturing areas.
Regarding your firm's marketing of certain specific ELISA kits for diagnosis or detection of herpes (IgG and IgM), measles (IgG and igM), Rubella (IgG and IgM), and other immunology and microbiology devices on your firm's website at http://www.biotecx.com, your firm is advised to contact the Office of In Vitro Diagnostic Devices (OIVD) of CDRH to determine whether each of these devices needs a 510(k) submission for their marketing and distribution in the United States. You indicated to the FDA investigator that most of your IVD devices, including the specific referenced devices, were shipped internationally to foreign markets. We want to remind you that unapproved devices intended for export must be properly labeled as "for export only" and are prohibited for distribution in the United States unless your firm has a cleared 510(k) for each of the referenced devices. See section 801(e)(1)(D) of the Act, 21 U.S.C. § 381(e)(1)(D). Your website must clearly identify that these specific devices are marketed for export only or are not for distribution in the United States.
Additionally, unapproved devices intended for foreign markets must be manufactured in conformance with the Current Good Manufacturing Practice (CGMP) requirements of the Quality System (QS) regulation, 21 CFR § 820, and section 802(f)(1) of the Act, 21 U.S.C. § 382(f)(1).
You should take prompt action to correct the violations addressed in this letter. Failure to promptly correct these violations may result in regulatory action being initiated by the FDA without further notice. These actions include, but are not limited to, seizure, injunction, and/or civil 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.
Additionally, premarket approval applications for Class III devices to which the QS 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 these corrections. If the 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 response should be sent to Thao Ta, Compliance Officer, DAL-DO, Food and Drug Administration, HFR-SW140, 4040 N. Central Expressway, Suite 300, Dallas, TX 75240. If you have any questions about the contents of this letter, please contact Mr. Ta at 214-253-5217.
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 Form 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.
Michael A. Chappell
Dallas District Director