Inspections, Compliance, Enforcement, and Criminal Investigations
BioMerieux, Inc. 29-Jul-05
Department of Health and Human Services
Public Health Service
Center for Biologics Evaluation and Research
July 29, 2005
RETURN RECEIPT REQUESTED
Mr. Eric Bouvier
President and CFO, North America
100 Rodolphe Street
Durham, NC 27712
Dear Mr. Bouvier:
The Food and Drug Administration (FDA) conducted an inspection of bioMerieux, Inc., located at 100 Rodolphe Street, Durham, North Carolina, between March 15 and March 24, 2005. During the inspection, the FDA investigator documented violations of Section 501.(h) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) and deviations from the applicable standards and requirements of Subchapter H, Part 820, Title 21, Code of Federal Regulations (CFR). At the close of the inspection, FDA issued a Form FDA 483, Inspectional Observations, that described a number of significant objectionable conditions relating to the facility's compliance with current good manufacturing practice (CGMP). Significant deviations in the manufacture of in vitro diagnostic devices observed during the inspection include, but are not limited to, the following:
1. You failed to establish and maintain procedures for implementing corrective and preventive action including requirements for investigating the cause of nonconformities and identifying the action(s) needed to correct and prevent recurrence of nonconforming product and other quality problems, and you failed to document your corrective and preventive actions, and their results [21 CFR 820.100(a) and (b)], in that:
a. There was no documentation of an out-of-specification (OOS) investigation of the failed stability assay for Vironostika HTLV-I/II Iot # 170232.
b, Out-of-specification (OOS) investigations of failed stability assays for Vironostika HTLV-I/II lots #170230 and #170231 (dated October 7, 2004) had not been completed at the time of the inspection. No conclusions or corrective/preventive actions had been documented on the investigation reports.
c. Revalidation of the Normal Goat Serum [redacted] process was not conducted when two material discrepancies were documented in October 2004. Material Discrepancy Notice documentation attributed the root cause of the discrepancies as failure to perform mixing studies with scale-up validation.
d. A complete manufacturing investigation was not conducted for rejected [redacted].
2. You failed to establish and maintain procedures to control product that does not conform to specified requirements [21 CFR 820.90]. Although OOS investigations of failed stability assays for Vironostika HTLV I/II lots #170230 and #170231 had not been completed, lot #170230 was dispositioned as "approved" on September 22, 2004, by the QC Immunodiagnostics Manager and lot #170231 was dispositioned as "approved" on October 5, 2004.
3. You failed to establish and maintain procedures for receiving, reviewing, and evaluating complaints by a formally designated unit to ensure that complaints are processed in a timely manner [21 CFR 820.198(a)]. For example, complaint numbers 70842, 70843, 70844, initiated in July 2004, remained open as of the date of the FAA inspection.
4. You failed to establish and maintain adequate acceptance procedures for incoming and in process products [21 CFR 820.80], in that:
a, [Redacted] specifications for Goat anti-Human [redacted] have not been established.
b. [Redacted] specifications for incoming Goat anti-Human [redacted] have not been established.
5. You failed to validate processes with a high degree of assurance and approve the validation according to established procedures [21 CFR 820.75(a)], in that you have not validated the final filtration steps of various components of your HIV-1, HTLV-I/II, and Oral Fluid HIV-1 test kits to provide a high degree of assurance that the [redacted] filters you are using for those steps consistently achieve the necessary results.
6. You failed to establish mid maintain procedures to adequately control environmental conditions that could reasonably be expected to have an adverse effect on product quality (21 CFR.820.70(c)), in that studies have not been completed to support the effectiveness of disinfectants used in the cleaning of manufacturing areas.
7. You failed to establish and maintain procedures for the control of storage areas and stock rooms for product to prevent mixups [21 CFR 820.150(a)]. The FDA investigator observed finished products awaiting shipment, in-process products awaiting quality assurance release, quarantined products, and released/unreleased raw materials commingled in the receiving and shipping warehouse. Further, open boxes of finished product, loose product on storage shelves, and quarantined finished products were observed stored in the finished products freezer.
8 . You failed to maintain complete device history records [21 CFR 820.184], in that information regarding product lots that have bum reworked is not consistently documented in your device history records.
The deviations identified above are not intended to be an all-inclusive list of deficiencies at your establishment. It is your responsibility as management to assure compliance with all requirements the federal regulations and the standards in your license. While these deviations were documented during the most recent inspection of your facility, we note that similar significant deviations were documented during the inspection of August 6-12, 2002. We also note that your firm promised corrective actions in response to the Form FDA 483 issued at the close of the August 2002 inspection, but the recent inspection has shown that adequate and effective corrective actions have not been implemented.
Federal agencies are advised of the issuance of all Warning Letters about drugs and devices so that they may take this information into account when considering the award of contracts.
We acknowledge receipt of your written response dated April 12, 2005, which addresses the inspectional observations on the Form FDA 483 issued at the close of the inspection. We have reviewed your response and the accompanying documents. Corrective actions addressed in your response may be referenced in your reply to this letter, as appropriate; however, your April 12, 2005 response did not provide sufficient detail to fully assess the adequacy of your corrective actions. For example, while there are numerous inspectional observations pertaining to the lack of thorough investigations into complaints and/or out of specification test results, your response fails to discuss implementation of adequate quality assurance oversight to ensure prompt identification, documentation, correction, and follow up for all problems associated with the manufacture of your products.
We have the following specific comments regarding your response. The items are numbered to correspond to the observations listed on the Form FDA 483.
FDA 483 item 1.A and #1.B
Your response states that you will discontinue the use of raw materials and in-process materials that exceed microbial limits of [redacted].Your response also indicates that you will set microbial limits, as appropriate, for raw materials and in-process materials, including [redacted]. Please provide representative documentation to support this corrective action, e.g., revised standard operating procedures (SOPs), testing protocols, etc.
FDA 483 item #1.C
Your response states that the cleaning procedure for the [redacted] Column will be revised. A copy of your revised procedure should be available for review at the next inspection. Further, your response indicates that the cleaning procedure for the [redacted] Column will be validated by August 15, 2005. We acknowledge your commitment to complete this validation. Please provide a copy of your validation study to this office upon completion.
FDA 483 item #3.A
Your response states that your SOP TR 50.105 will be modified to ensure products are not released for distribution prior to completion of investigations. Please provide a copy of your revised SOP.
FDA 483 item #3.B and 3.C
Your response states that your SOP MO-QC.1001 will be revised to ensure that a) investigations require management and QA approval prior to release of lots, and b) documentation for failure investigations will be completed prior to rework and release of lots. Please provide a copy of your revised SOP. Further, your response indicates that you will review-your lot release history and submit a merno notifying CBER of any lots that were previously approved by CBER but not distributed. A copy of your memo should be submitted to this office upon completion. In addition, please provide a copy of your current SOP for rework.
FDA 483 item #3.D
Your response indicates that your Release E procedure (Tart #s 259751/259752/259850) will be revised to require that all testing be completed prior to submitting test kits to CBER for lot release. Your response also indicates that SOP TR 50.113 will be updated to include a requirement to a) complete the [redacted] stability testing prior to submitting test kits CBER lot release, and b) document e reworking or re-kiitting of lots on the FDA Lot Release Protocol form. Please provide copies of your revised SOPs.
FDA 483 item #4
Your response states that you will "evaluate the kit optimization process." Please clarify what is meant by this term and explain specifically how this preventive action addresses the Form FDA 483 observation. Please be advised that information regarding reworked lots must be consistently documented in your device history records for the final production lots. Also, please advise us whether your device history records for the original lot will cross-reference the lot numbers for the reworked lots.
FDA 483 item #5
Your response states that you have revised your SOP MG-AD.0505. Please provide a copy of your revised SOP. Your response also states that disinfectant effectiveness studies for each disinfectant used in your processes will be completed by May 30, 2006. We recommend that you reevaluate the proposed timeframe for implementing corrective action so that these studies are completed in a timely manner.
FDA 483 item #6.A
Your response states that you will reassess your complaint handling process and establish controls that bring outstanding complaints to management for actions in a timely manner. Further, your response indicates that you will reassess your CAPA process and make necessary corrections, as needed. Please be aware that your reply to this letter should provide specific details of corrective actions and timeframes for implementation of those actions that will bring your establishment into conformity with the applicable regulations.
FDA 483 item #6.B.3
Your response states that you will assess the current [redacted] process for Goat Serum to identify the need for validation and subsequently complete the validation of any identified steps. Please provide the results of your assessment and the timeframe for completing the identified validations.
FDA 483 item #'7
Your response states that several SOPs have been revised to maintain product in closed containers in the finished goods location. Please submit copies of the revised referenced procedures. Your response also indicates that dedicated areas will be established for material and product storage based on status. We recommend that you reevaluate your proposed timeframe of December 2005 so that this corrective action is implemented in a timely manner.
Please notify this office in writing, within 15 working days of receipt of this letter, of any steps you have taken or will take to correct the noted violations and to prevent their recurrence. If corrective actions cannot be completed within 15 working days, state the reason for the delay and the time within which the corrections will be completed. Failure to promptly correct these deviations may result in regulatory action without further notice. Such actions include seizure, injunction, license suspension, and/or revocation.
Your reply should be sent to Ms. Mary A. Malarkey, Director, Office of Compliance and Biologies Quality, U.S. Food and Drug Administration, Center for Biologies Evaluation and Research, 1401 Rockville Pike, Suite 200 N, Rockville, Maryland 20852-1448.
We acknowledge your request for a meeting to discuss the status of product affected by specific Form FDA 483 observations. Please contact Ms. Anna M. Flynn in the Division of Case Management at (301) 827-6201 to schedule a meeting or to discuss any questions regarding this letter.
David K. Elder
Office of Enforcement
Office of Regulatory Affairs