Inspections, Compliance, Enforcement, and Criminal Investigations
Amico Laboratories, Inc. 03-Jan-08
Department of Health and Human Services
Public Health Service
New Orleans District
Telephone: (615) 366-7801
January 3, 2008
WARNING LETTER NO. 2008-NOL-06
Abdallah M. Isa, Ph. D., Owner/President
Amico Laboratories, Inc.
5012 Illinois Avenue
Nashville, Tennessee 37209
Dear Dr. Isa:
On September 10-14, 18, and 20, 2007, a U.S. Food and Drug Administration (FDA) investigator inspected your firm, located at 5012 Illinois Avenue, Nashville, Tennessee. Our investigator determined your firm manufactures In-Vitro Diagnostic Test Kits. These products are Medical Devices as defined by Section 201(h) of the Federal Food, Drug, and Cosmetic Act (the Act) [21 United States Code (USC) 321(h)]. More specifically, they are Class I, II, and III Medical Devices as defined in Title 21, Code of Federal Regulations Parts 862 and 866 (21 CFR 862 and 866). You may find the specific regulations through links in FDA's Internet home page at http://www.fda.gov.
Your devices are adulterated within the meaning of Section 501(h) of the Act [21 USC 351(h)], as the methods used in, or the facilities or controls used for, their manufacture, packing, or storage are not in conformity with the current Good Manufacturing Practices (CGMP) requirements set forth in FDA's Quality System (QS) Regulation, codified in 21 CFR 820. On September 20, 2007, our investigator documented significant violations of CGMP and QS regulations, which were discussed with you, including, but not limited to, the following:
1. Failure to establish and maintain adequate procedures for validating device design to ensure design risk analysis is conducted and documented, each device conforms to user needs and intended uses, acceptance criteria are established before performing validation activities, design testing is conducted under actual or simulated use conditions, and design testing results are documented, as required by 21 CFR 820.30(g). [Reference: Form FDA 483, Observations 2 and 3] Specifically, you have not conducted any risk analyses on your devices to ensure each device is safe and effective for its intended use; and, you have not conducted or documented real time stability tests for each of your devices to support your expiration date of one year for each of your test kits.
2. Failure to validate your processes to ensure each device will function consistently according to predetermined specifications, as required by 21 CFR 820.75(a). For example, the following have not been validated:
• Production protocols for antigens, reagents, and positive and negative controls;
• Recommended absorbance test result interpretations referenced in device label inserts;
• Test kit one-year expiration dating;
• Preservative effectiveness (i.e. used in test kit antigens and controls); and,
• Test kit container/closure systems. [Reference: Form FDA 483, Observation 3]
3. Failure to develop, conduct, control, and monitor production processes to ensure each device conforms to its specifications, as required by 21 CFR 820.70(a). Specific examples include:
• You cannot establish the quality of antigens, which you produce from live cultures of viruses and bacteria. Our investigator documented you have no records documenting the origin of the live culture "stock" from which you (re)propagate your cultures. You stated to our investigator you purchased the original "stock" cultures approximately five years ago. You continue to use the same original "stock" organisms to manufacture your antigens; however, you cannot ensure the quality of the "stock" organisms;
• Our investigator observed approximately eight different species of Leptospira culture dated July 10, 1998, stored at room temperature in your laboratory. According to your records,-on July 22, 2006, your firm prepared, labeled, and shipped Leptospira IGM Latex; and,
• Our investigator documented the temperature of the freezer where you store (re)propagated cultures and serums is monitored only once every three months. You have no method to ensure the freezer temperature is maintained continually at an appropriate temperature. Therefore, you cannot ensure the (re)propagated organisms are stored according to required temperature specifications to guarantee they remain at the level of quality required. [Reference: Form FDA 483, Observation 4]
4. Failure to ensure all inspection, measuring, and test equipment, including mechanical, automated, or electronic inspection and test equipment, are suitable for their intended purposes and capable of producing valid results, as required by 21 CFR 820.72(a). Specifically, our investigator observed a pH 4.0 buffer solution concentrate with an expiration date of 1983 and a pH 7.0 buffer solution concentrate with an expiration date of September 1988. These were the only pH buffer solutions observed in your facility. We note several of your finished product and component production protocols require the use of pH buffer solutions. [Reference: Form FDA 483, Observation 4]
5. Failure to establish and maintain procedures to adequately control environmental conditions where the environmental conditions could reasonably be expected to have an adverse effect on product quality, as required by 21 CFR 820.70(c). For example:
• You have no written procedures which address protecting your components and finished products from potential environmental contaminants during processing;
• You do not conduct any environmental monitoring in your processing area, including your laminar flow hood;
• Your laminar flow hood, which you purchased approximately eight years ago, contains the original HEPA filter;
• You disinfect the laminar flow hood with paraformaldehyde, yet you do not have a procedure describing the process, and you have not established whether the use of paraformaldehyde on the hood is appropriate; and,
• You do not have documentation stating whether your facility, which is housed in a duplex, has a separate air handling system. [Reference: Form FDA 483, Observation 5]
6. Failure to establish and maintain procedures to prevent contamination of equipment and/or product by substances which could reasonably be expected to have an adverse effect on product quality, as required by 21 CFR 820.70(e). Specific examples are:
• Your water distillation unit which processes water used to manufacture your components and finished products is located next to the hand-washing sink in the only restroom within your facility. The only toilet in your facility is approximately 4-5 feet from the distillation unit and sink;
• Your facility, including walls, ceilings, floors, and work surfaces, is in poor repair and of material which cannot be properly sanitized; and,
• A [redacted] bottle containing hydrochloric acid was observed on a laboratory work counter next to coated antigen plates being used for stability purposes. Our investigator documented the hydrochloric acid is used for cleaning purposes. [Reference: Form FDA 483, Observations 6 and 11]
7. Failure to ensure buildings are of suitable design and contain sufficient space to perform necessary operations, prevent mix-ups, and assure orderly handling, as required by 21 CFR 820.70(f). Specific examples include:
• Your water distillation unit which processes water used to manufacture your components and finished products is located next to the hand-washing sink in the only restroom within your facility. The only toilet in your facility is approximately 4-5 feet from the distillation unit and sink; and,
• Your manufacturing and storage areas were observed overcrowded with laboratory equipment, cleaning solution, raw components, microbiological cultures, test items, in-process material, and finished products. [Reference: Form FDA 483, Observations 6 and 11]
8. Failure to ensure all equipment used in the manufacturing process meets specified requirements and is appropriately designed, constructed, placed, and installed to facilitate maintenance, adjustment, cleaning, and use, as required by 21 CFR 820.70(g). Specifically, our investigator observed:
• There is accumulated ice due to temperature variation in the freezer where you store (re)propagated cultures and serums. You have no method to ensure the freezer is maintained continually at an appropriate temperature;
• Distilled water, used to manufacture your components and finished products, is manufactured from a hand-washing sink in the only restroom within your facility. The sink was observed in poor repair and unclean;
• Manufacturing supplies are stored on top of the facility dishwasher; and,
• The wall behind and ceiling above the autoclave is peeling and collapsing. There is exposed fiberglass insulation due to the deterioration. [Reference: Form FDA 483, Observations 4 and 6]
9. Failure to maintain device master records (DMR), as required by 21 CFR 820.181; and, to ensure each DMR is prepared and approved in accordance with document and data controls, as required by 21 CFR 820.40. For example, your document entitled "DEVICE MASTER RECORD" provides a general description of what each DMR should contain. However, you do not have specific DMR-required documents, such as product specifications, production process specifications, and environmental specifications for the production of antigens, reagents, and controls for your ELISA and Latex Agglutination test kits. [Reference: Form FDA 483, Observation 7]
10. Failure to maintain device history records (DHR), as required by 21 CFR 820.184. Specifically, your DHRs do not include, or refer to the location of, data which demonstrate each device is manufactured in accordance with an appropriate DMR. [Reference: Form FDA 483, Observation 8]
11. Failure to establish and maintain procedures for the acceptance of incoming product and/or components, as required by 21 CFR 820.80(b). Specifically, you failed to maintain records documenting you are following your procedure entitled [redacted]. [Reference: Form FDA 483, Observation 9]
12. Failure to establish and maintain acceptance procedures, where appropriate, to ensure specified requirements for in-process product are met, as required by 21 CFR 820.80(c). Specifically, you do not have acceptance procedures addressing in-process product. [Reference: Form FDA 483, Observation 10]
13. Failure to establish procedures for quality audits and conduct such audits to assure the quality system is in compliance with established quality system requirements and to determine the effectiveness of the quality system, as required by 21 CFR 820.22. Specifically, you do not have any procedures addressing quality audits, nor do you have any records documenting quality audits of your facility and suppliers ever were conducted. [Reference: Form FDA 483, Observation 12]
The inspection also revealed your devices are misbranded within the meaning of Section 502(t)(2) of the Act [21 USC 352(t)(2)], as your firm failed to furnish material or information respecting the devices, as required by Section 519 of the Act [21 USC 360i, and 21 CFR 803 - Medical Device Reporting (MDR) regulations]. Specifically, you failed to develop, maintain, or implement MDR procedures, as required by 21 CFR 803.17. [Reference: Form FDA 483, Observation 1] And, though not documented on the FDA 483, our investigator reported you also failed to establish and maintain procedures for implementing corrective and preventive action, as required by 21 CFR 820.100(a).
Regarding your firm's marketing of your immunology and microbiology devices, we advise you to contact the Office of In-Vitro Diagnostic Devices (OIVD) in the Center for Devices and Radiological Health (CDRH) to determine which of your devices requires a 510(k) submission and equivalency approval for marketing and distribution within the United States. You may find more specific information through links in FDA's Internet home page at http://www.fda.gov/cdrh/oivd. The kind of information you need to submit in order to obtain approval or clearance for your devices is available through the FDA Internet home page at http://www.fda.gov/cdrh/devadvice/3122.html. The FDA will evaluate the information you submit and decide whether your product(s) may be marketed legally within the United States.
You explained to our investigator about [redacted] percent of your devices are shipped to foreign countries. We must remind you all unapproved devices intended for export must be properly labeled as "for export only" and are prohibited from distribution in the United States unless your firm has prior approval. See Section 801(e)(1)(D) of the Act [21 USC 381(e)(1)(D)]. You must clearly identify which devices are marketed solely for export only or are not for distribution in the United States. Additionally, unapproved devices intended for foreign markets must be manufactured in substantial conformance with the CGMP requirements of the QS regulation, as required by 21 CFR 820, and Section 802(f)(1) of the Act [21 USC 382(f)(1)].
With this letter, we also acknowledge receipt of your September 22, 2007 letter in reply to our September 20, 2007, FDA 483. Your replies to Observations 1, 2, 3, 7, 8, 9, 10, and 11 are inadequate as you have not provided documentation of any corrective actions made or those you intend to make. Your replies to Observations 4, 5, 6, and 12 are unacceptable as it appears you either do not accept or recognize the deficiencies or you refuse to respond with any corrective actions.
This letter may not list all the deficiencies at your facility. You are responsible for ensuring your firm adheres to all requirements of the Act and regulations applicable to medical devices. Federal agencies are advised of the issuance of all warning letters about devices so 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.
You should take prompt action to correct these deviations. Failure to promptly correct these deviations may result in regulatory action, including seizure, injunction, and/or civil penalties, without further notice.
Please respond in writing within 15 working days of your receipt of this letter outlining the specific steps you have taken to bring your firm into compliance with the law. Your response should include each step taken to correct the violations and prevent their recurrence. You should include in your response documentation, such as written procedures, and other useful information to assist us in evaluating your corrective actions. If corrective action cannot be completed within 15 working days, we expect you to explain the reason for the delay and state when the remaining deviations will be corrected.
Please send your reply to the U.S. Food and Drug Administration, Attention: Rebecca A. Asente, Compliance Officer, at the above address. If you have questions regarding issues in this letter, please contact Ms. Asente at (504) 219-8818, extension 104.
H. Tyler Thornburg
New Orleans District
Enclosure: Form FDA 483, dated September 20, 2007