Department of Health and Human Services
|Public Health Service|
Food and Drug Administration
|New Orleans District|
404 BNA Drive
Building 200 – Suite 500
Nashville, TN 37217
Telephone: (615) 366-7801
FAX: (615) 366-7802
February 14, 2012
WARNING LETTER NO. 2012-NOL-13
UNITED PARCEL SERVICE
DELIVERY SIGNATURE REQUESTED
Walter C. Edge
President and Owner
Edge Biologicals, Inc.
598 North Second Street
Memphis, Tennessee 38105-1634
Dear Mr. Edge:
During an inspection of your firm located in Memphis, Tennessee, on September 13 through September 16, 2011, an investigator from the United States Food and Drug Administration (FDA) determined your firm manufactures Mueller Hinton and Thayer Martin Agar products. Under Section 201(h) of the Federal Food, Drug, and Cosmetic Act (the Act), [21 United States Code (USC) 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 these devices are adulterated within the meaning of Section 501(h) of the Act [21 USC 351(h)], because the methods used in, or the facilities or controls used for, their manufacture, packing, storage, or installation are do not conform with the Current Good Manufacturing Practice requirements of the Quality System regulation found at Title 21, Code of Federal Regulations (CFR), Part 820.
We received a response from (b)(4), dated September 25, 2011, concerning our investigator’s observations noted on the FORM FDA 483 (FDA 483), Inspectional Observations issued to you. We address this response below. We received two additional responses from your firm, dated November 4, 2011, and dated January 9, 2012. We will evaluate these responses along with any other written material provided in response to the violations cited in this warning letter.
(Your firm's violations include, but are not limited to, the following:
1. Failure to adequately ensure when the results of a process cannot be fully verified by subsequent inspection and test, the process shall be validated with a high degree of assurance and approved according to established procedures, as required by 21 CFR 820.75(a).
For example, your firm failed to validate your de-ionized water system and aseptic fill process used in manufacturing IVD products.
2. Failure to establish and maintain written procedures for identification, documentation, validation or, where appropriate, verification, review and approval of design changes before their implementation, as required by 21 CFR 820.30(i).
For example, your firm has not established design change procedures to ensure changes are validated or, where appropriate verified, reviewed, and approved before implementation.
3. Failure to establish and maintain adequate procedures for implementing corrective and preventive action (CAPA) and to document the activities and their results, as required by 21 CFR 820.100(a) and (b).
For example, your firm failed to document all CAPA activities and results associated with the following:
• A CAPA referencing dates January 1, May 4, July 22, and December 13, 2010, was initiated in response to complaints of contamination in bags of UVM media. The cause for contamination documented in the CAPA was "technique" and the corrective action described a change in the filling process. However, your firm's CAPA did not include any documentation that the cause of the contamination was investigated and the corrective action was verified or validated to ensure such action did not adversely affect the finished device.
• A CAPA referencing dates December 8 and 17, 2010, did not document an investigation into the reason(s) the 630 Tryptic Soy Agar plates were damaged during a shipment to a customer. The corrective action documented within the CAPA stated, "In the future we will ship plates to this customer on a pallet only." However, your firm's CAPA document did not include any information regarding your firm's determination if an investigation was needed and/or conducted.
• Monthly trend analysis of sources of quality data, such as complaints, product quality investigations, incoming inspection rejects, and audits, are not being conducted and documented, as described in your written CAPA procedures. Your firm acknowledged the monthly trend analysis was not being conducted and the analysis procedure was not implemented.
4. Failure to maintain adequate complaint files, and to establish and maintain procedures for receiving, reviewing, and evaluating complaints by a formally designated unit, as required by 21 CFR 820.198(a).
For example, your firm's written complaint handling procedures describe the use of a complaint action form to capture the complaint information, as well as the use of risk assessments and factors to consider for potential MDRs; however, these steps were not implemented as described in the following instances:
• Complaints did not include documentation to demonstrate each one was reviewed to determine if it qualified as a MDR. When requested, your firm acknowledged the complaints were not being evaluated to determine whether they required MDRs.
• Thirty-two of the complaints documented bacterial and/or mold contamination, but there was no documented effort to assess all of the products manufactured in an affected lot. While you stated verbally the investigation activities included examining retain samples for evidence of contamination, these investigation activities were not documented.
• Complaints were documented on credit/replacement forms instead of the complaint action form, as described in the complaint procedure.
5. Failure to review and evaluate all complaints to determine whether an investigation is necessary, as required by 21 CFR 820.198(b).
• Investigation activities for 68 of 75 complaints reviewed were not documented according to your firm's procedures.
• A justification for not conducting an investigation and the identity of the person making that decision was not documented.
6. Failure to review, evaluate, and investigate any complaint involving the possible failure of a device's packaging to meet any of its specifications, unless such investigation has already been performed for a similar complaint and another investigation is not necessary, as required by 21 CFR 820.198(c).
For example, a review of the complaint records revealed approximately 30 complaints, received between 2009 and 2010, concerning IVD tubes and ampoules leaking during shipment to customers. However, your firm has no documentation that complaints involving possible packaging failures were reviewed, evaluated and investigated. Your firm failed to ensure device packaging and shipping containers were designed to protect product from damage during the customary conditions of shipping.
7. Failure to establish and maintain adequate procedures for changes to a specification, method, process or procedure, as required by 21 CFR 820.70(b).
For example, your firm implemented a process change as a corrective action to a contamination complaint dated January 11, 2010. However, there was no documentation to demonstrate the process change was validated or verified before the change was implemented.
8. Failure to establish and maintain procedures to adequately control environmental conditions, as required by 21 CFR 820.70(c).
For example, upon request for procedures to control environmental conditions which could reasonably be expected to have an adverse effect on sterilized and aseptically filled IVD products, your firm acknowledged it had no procedures and promised to implement a procedure.
9. Failure to establish and maintain adequate schedules for the adjustment, cleaning and other maintenance of equipment to ensure manufacturing specifications are met, as required by 21 CFR 820.70(g)(1).
For example, on September 13, 2011, the following production equipment used in the manufacture of IVD products was observed to be overdue for the monthly QC preventive maintenance described in your firm's equipment maintenance procedure:
1) (b)(4) due August 26, 2011
2) (b)(4) due September 03, 2011
3) (b)(4) due September 03, 2011
4) (b)(4) due September 06, 2011
5) (b)(4) due September 03, 2011
10. Failure to identify the acceptance status of product, to indicate the conformance or nonconformance of product with acceptance criteria throughout manufacturing, packaging, labeling, installation, and servicing of the product, to ensure only product which has passed the required acceptance activities is distributed, used, or installed, as required by 21 CFR 820.86.
For example, in-process IVD products were observed throughout the production and storage areas without any indication of the acceptance status. Tubes of Tetrathionate, Tryptic Soy, and Urea Broths were stored on unlabeled shelves in the production area with no documentation to identify their acceptance status.
11. Failure to establish and maintain procedures for identifying product during all stages of receipt, production, distribution, and installation, to prevent mix-ups, as required by 21 CFR 820.60.
For example, the Tetrathionate Broth did not include a lot number or the name of the product.
Our inspection also revealed your firm's devices are misbranded under Section 502(t)(2) of the Act, [21 USC 352(t)(2)], because your firm failed or refused to furnish material or information respecting the device which is required by or under Section 519 of the Act, [21 USC 360i], and 21 CFR 803- Medical Device Reporting (MDR). Significant violations include, but are not limited to, the following:
Failure to develop, maintain, and implement written MDR procedures, as required by 21 CFR 803.17.
For example, your firm's written procedures do not include: a standardized review process for determining when an event meets the criteria for reporting; an internal system for timely and effective identification of events which may be subject to MDR requirements; or, requirements for documentation and recordkeeping.
We reviewed your firm's response dated September 25, 2011, and conclude it is not adequate.
Your firm did not provide information about the planned correction or corrective action (including consideration of a systemic corrective action) with this response. In addition, a detailed validation plan or protocol for the de-ionized water system and aseptic fill process was not provided with this response. However, we noted the response indicates your plan to validate the de-ionized water system and aseptic fill process would require three months to complete, and your firm would provide the information on January 9, 2012. Your firm's September 25, 2011, response also stated a plan to implement a corrective action would be provided by the first week of November 2011.
Your firm 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 civil money penalties. In addition, federal agencies may be advised of the issuance of 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 Quality System regulation violations 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) business days from the date you receive this letter of the specific steps your firm has taken to correct the noted violations, as well as an explanation of how your firm plans to prevent these violations, or similar violations, from recurring. Include documentation of the corrections and/or corrective actions (including any systemic corrective actions) your firm has taken. If your firm's planned corrections and/or corrective actions will occur over time, please include a timetable for implementation of those activities. If corrections and/or corrective actions cannot be completed within fifteen business days, state the reason for the delay and the time within which these activities will be completed.
Your firm's response should be comprehensive and address all violations included in this warning letter.
We advise you that your Mueller Hinton Agar and Thayer Martin Agar must be cleared in a 510(k) premarket notification or approved in an application for premarket approval prior to marketing. Failure to obtain FDA clearance or approval would cause your devices to be adulterated under Section 501(f)(1)(B) of the Act, [21 USC 351(f)(1)(B)], and misbranded under Section 502(o) the Act, [21 USC 352(o)]. We have no record indicating you obtained clearance or approval for these devices. If these devices have been cleared or approved, please provide evidence of such in your response.
Your firm's response should be sent to: Kari L. Batey, Compliance Officer, at the above address. Refer to Warning Letter No. 2012-NOL-13, when replying. If you have any questions about the contents of this letter, please contact: Kari L. Batey, Compliance Officer at (615) 366-7808.
Finally, you should know that this letter is not intended to be an all-inclusive list of the violations at your firm's facility. It is your firm's responsibility to ensure compliance with applicable laws and regulations administered by FDA. The specific violations noted in this letter and in the FDA 483 issued at the close of the inspection may be symptomatic of serious problems in your firm's manufacturing and quality management systems. Your firm should investigate and determine the causes of the violations, and take prompt actions to correct the violations and bring the products into compliance.
Patricia K. Schafer
New Orleans District
Enclosure: FDA 483 dated September 16, 2011
cc: Ted Pearson, Quality Assurance Officer
Edge Biologicals, Inc.
598 North 2nd Street
Memphis, Tennessee 38105