Inspections, Compliance, Enforcement, and Criminal Investigations
Louisville APL Diagnostics, Inc. 18-Jul-07
Department of Health and Human Services
Public Health Service
July 18, 2007
RETURNED RECEIPT REQUESTED
Dr. Silvia S. Pierangeli, Technical Director and Owner
Louisville APL Diagnostics, Inc.
2622 NASA Parkway, Suite G2
Seabrook, Texas 77586-3447
Dear Dr. Pierangeli:
During an inspection of your firm located at the above-referenced address on April 24 through May 18, 2007, an investigator from the United States Food and Drug Administration (FDA or Agency) determined that your firm manufactures the semi quantitative enzyme linked immunosorben assay (ELISA) kits for use as an aid in diagnosing the Antiphospholipid Syndrome (APS) in patients presenting with thrombosis and/or thrombocytopenia. These kits include the APhL® ELISA Kit and the APL® ELISA Kit for the detection of lgG, lgM, and IgA antiphospholipid (aPL) antibodies in human serum. 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 any function of the body.
In 2004 and 2005, your firm was located in Doraville, Georgia, and later moved to Seabrook, Texas in March 2006. The May 18, 2007 inspection revealed that your firm had not consulted the Recall Coordinator of the FDA's Dallas District Office (DAL-DO) for a product recall you initiated in July 2006 or the Atlanta District Office (ATL-DO) for two product recalls initiated in October 2005 and July 2004 in order to determine whether these recalls are reportable to the Agency as required by 21 CFR § 806. For any future product recalls, please report them to or consult DAL-DO's Recall Coordinator Sean Cheney at 214-253-5222.
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 conformity 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.
The FDA investigator issued the observations, which are listed on the Form FDA 483 (Inspectional Observations), to you at the end of the inspection on May 18, 2007. You verbally promised corrections but have not responded in writing to the inspectional observations. The Agency requests that you submit a written response to adequately address all specific items cited in this warning letter and the inspectional observations and provide a timeframe for completing corrective actions. The FDA follow-up inspections will be necessary to assure that your firm's corrections are adequate. These violations include, but are not limited to, the following:
Quality System Violations
1. Failure to establish and maintain adequate procedures to control labeling and packaging activities to prevent labeling mixups and inspect product labeling for accuracy including, where applicable, the correct expiration date, control number, storage instructions, handling instructions, and any additional processing instructions, as required by 21 CFR § 820.120(b). See FDA 483 Item 1 and 2. Your firm has initiated three product recalls since 2004 due to its failure to adequately inspect product labeling for accuracy. Specifically:
a. Your firm failed to identify a value error in the positive control range in the Quality Control Fact Sheet (shipped with the test kits) of Lot # 050723 for the HRP IgM single test kits before distributing this lot in October 2005. The QC Fact Sheet for the double test kits also had the same error. Consequently, your firm received a customer complaint of aberrant laboratory test results, instructed the customer to discard the incorrect QC Fact Sheets, and sent them the correct QC Fact Sheets.
b. Your firm failed to adequately inspect the labels of the test kit components before proceeding to the next step of manufacturing operations. The IgG and IgM conjugates were switched during manufacturing (the IgG conjugate was placed in bottles labeled the IgM conjugate and vice versa). Consequently, your firm received a customer complaint of aberrant laboratory test results in Lot # 040414 for the IgG Test Kits in July 2004 and later sent the replacement conjugates to this customer, and instructed them to discard the mislabeled conjugates.
c. Your firm failed to exam the box labels (external labels) of the double HRP test kits [K-HRP-00GM] to ensure that their lot numbers were correct before shipping the product in July 2006. The boxes of the HRP test kits of Lot 060425 were sealed with the labels of an incorrect lot number (Lot 060308). An incorrect lot number may result in determining an incorrect manufacturing date or product expiration date.
2. Failure to ensure that all equipment used in the manufacturing process meets specified requirements, as required by 21 CFR § 820.70(g). FDA 483 Item 4. Specifically, although your 14 temperature readings exceeded the required storage temperature range [redacted]°C - [redacted]°C) for the QC test components, your firm did not take action to adjust the refrigerator's operating temperature to prevent an adverse impact on these components and document your evaluation of the potential impact.
3. Failure to establish and maintain procedures for the identification, documentation, validation or verification, review, and approval of design changes before their implementation, as required by 21 CFR § 820.30(i). FDA 483 Item 6. Specifically:
a. Neither your GMP Manual Version, LAPL-GMP-100-15, dated 1/31/07, nor your Design Control Document 300-05, dated 12/30/06, addresses how design changes are to be verified or validated, approved, and documented.
b. Your firm did not create a design change record that documents your approval to release a new product flyer "Reappraisal of the cut-off and value of the low positive aPL titers," published in 2006, and document the results of your validation or verification of this flyer prior to shipping it with the product insert for the IgG and IgM isotype of the APhI ELISA Kits. You stated that the data of this "Reappraisal Study" was to clarify the meaning of the "low positive aPL titers" which improves users' understanding and interpretation of the patient test results, and therefore, enhances the safety and reduce risks of the use of the test kits.
4. Failure to establish and maintain adequate procedures for validating the device design to ensure that design risk analysis is conducted and documented, that the device conforms to user needs and intended uses, that acceptance criteria are established prior to performing validation activities, that design testing is conducted under actual or simulated use conditions, and that the design testing results are documented, as required by 21 CFR § 820.30(g). FDA 483 Item 6 and 9.
a. Your firm did not conduct and document real time stability testing to support your expiration date of [redacted] days) for the HRP IgA ELISA test kits, where HRP is a new conjugate. You confirmed to the investigator that your firm had not conducted the real time stability testing after [redacted] days of shelf life.
b. Your firm did not maintain raw testing data (e.g. actual dates of testing and temperatures recorded, and actual test results generated by the ELISA test reader), acceptance criteria, explanation, and conclusion to support that your firm had adequately performed the "Storage Conditions and Stress Shipping Studies" for the HRP IgA ELISA Kit.
c. Page 7 of your Design Control Document 300-05, dated 12/30/06, documented that a user validation study had been conducted for the ELISA kits but that your firm had not documented the actual-user validation test results.
d. Your firm did not conduct and document a risk analysis for the IgA ELISA kits using the HRP and AP conjugates or justify why not.
5. Failure to establish and maintain a design history file for each type of device to include or reference the records necessary to demonstrate that the design was developed in accordance with the approved design plan and the design control requirements of 21 CFR § 820, as required by 21 CFR § 820.30(j). FDA 483 Item 7.
a. Your firm did not establish and approve a design plan prior to initiating your actual design of the IgA ELISA kit using the HRP conjugate.
b. Your Design Control Document 300-05 referenced your 510(k) file for the design input requirements and design validation for the HRP IgA ELISA kit. However, K021398 for the APL® IgA ELISA kit was cleared for use with the Alkaline Phosphatase (AP) conjugate, not the Peroxidase (HRP) conjugate. The section "Materials and Components used in the APL® IgA ELISA Kit" in the K021398 submission only documented the use of the AP conjugate.
c. You did not maintain any design review agenda and design review results for the IgA ELISA kit using the AP or the HRP conjugate.
6. Failure to establish and maintain procedures to ensure that the device history records for each batch, lot, or unit are maintained to demonstrate that the device is manufactured in accordance with the device master record, as required by 21 CFR § 820.184. FDA 483 Item 8. Specifically, your DHRs do not document your inspection of package sealing activities. The sealing process is significant in that the micro-well plates are sensitive to light and moisture.
Our inspection also revealed that your above-referenced devices are also 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 devices that is required by or under by Section 519(f)(1) of the Act, 21 U.S.C. § 360i(f)(1), and 21 CFR § 806 Reports of Corrections and Removals Regulation. Significant deviations include, but are not limited to, the following:
Reports of Corrections and Removals Violations
1. Failure to maintain records of justification for not reporting the correction or removal action to the FDA, which shall contain conclusions and any follow-up, and be reviewed and evaluated by a designated person, as required by 21 CFR § 806.20(b)(4). FDA 483 Item 1. Specifically, your firm has conducted three product recalls since 2004 but has not documented your justification for not reporting these recalls to FDA. Your GMP Manual requires your firm report product recalls to Health Canada only.
2. Failure to promptly report to FDA any correction or removal of a device to reduce a risk to health within 10 working days, as required by 21 CFR § 806.10(a)(1). FDA 483 Item 1 and 2. Specifically:
a. Your firm received a customer (user) complaint of aberrant laboratory test results due to your firm's failure to adequately identify a value error in the positive control range in the Quality Control Fact Sheet (shipped with the test kits) of Lot # 050723 for the HRP IgM single test kits before distributing this lot in October 2005. Consequently, your firm instructed the customer to immediately discard the incorrect QC Fact Sheets and sent them the correct ones. The incorrect positive control range may result in users incorrectly reading patient test results, or the delay/repeat of testing patient samples and transmitting their test results to their attending physicians. These conditions pose a potential risk to health.
b. Your firm received a customer (user) complaint of aberrant laboratory test results in Lot # 040414 for the IgG Test Kits due to your firm's failure to adequately exam the labels of the test kit components before proceeding to the next step of manufacturing operations. The IgG and IgM conjugates were switched during manufacturing (the IgG conjugate was placed in bottles labeled the IgM conjugate and vice versa). Your firm instructed the customer to immediately discard the mislabeled conjugates and sent the replacement (correct) conjugates to them in July 2004. The use of the mislabeled conjugates may result in incorrect patient test results, or the delay/repeat of testing patient samples and transmitting their test results to their attending physicians. These conditions pose a potential risk to health.
Your firm's actions to ask the users to discard the defective products and later send them the replacement products meet the definition of a "removal" in 21 CFR § 806.2(i), yet no report was submitted to FDA, in violation of 21 CFR § 806.10(a)(1), which requires manufacturers or importers to submit a written report to FDA of any correction or removal of a device if the correction or removal was initiated to reduce a risk to health.
Responding to This Warning Letter
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 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. Additionally, premarket approval applications for Class III devices to which the Quality System regulation (21 CFR Part 820) 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 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 response should be sent to Thao Ta, Compliance Officer, Dallas District Office, Food and Drug Administration, HFR-SW140, 4040 N. Central Expressway, Suite 300, Dallas, Texas 75204. If you have any questions about the content 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 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 violations, and take prompt actions to correct the violations and to bring your products into compliance.
Virginia R. Connelly
Acting Dallas District Director
Dr. Christine Yvette Williams, M.D., Co-Owner
Dr. Eon Nigel Harris, M.D., Co-Owner
Louisville APL Diagnostics, Inc.
2622 NASA Parkway, Suite G2
Seabrook, Texas 77586-3447