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U.S. Department of Health and Human Services

Vaccines, Blood & Biologics

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Amended NOIR Letter to Immucor

June 30, 2009

Express Mail

Dr. Gioacchino DeChirico
President and CEO
Immucor, Inc.
3130 Gateway Drive
P.O. Box 5625
Norcross, Georgia 30091

Dear Dr. DeChirico:

The Food and Drug Administration (FDA) conducted an inspection of Immucor, Inc. (“Immucor” or “You”), 3130 Gateway Drive, Norcross, Georgia, between January 6 and January 16, 2009.  During the inspection, FDA investigators documented violations of Section 501(h) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) and deviations from applicable standards and requirements of your biologics license application approved under Section 351 of the Public Health Service Act (PHS Act), and Title 21, Code of Federal Regulations (21 CFR) Parts 600-680, and 820.  At the close of the inspection, our investigators issued a Form FDA 483, Inspectional Observations which described a number of significant objectionable conditions relating to your facility’s compliance with current good manufacturing practice (CGMP).  Your manufacture of Reagent Red Blood Cells and Anti-E (Monoclonal) Blood Grouping Reagent product fail to conform to the applicable standards established in your license and in above-cited regulatory provisions, all of which are designed to ensure the continued safety, purity, and potency of your Reagent Red Blood Cells and Blood Grouping Reagents.  The significant deviations in the manufacture of Reagent Red Blood Cells and Anti-E (Monoclonal) Blood Grouping Reagent product, which were observed during the inspection include, but are not limited to, the following:

  1. You as management with executive responsibility have not established a commitment to quality nor ensured that the quality policy is understood, implemented, and maintained at all levels of the organization [21 CFR 820.20(a)].  For example:
    1. You failed to establish and maintain procedures for implementing corrective and preventive action, including requirements for identifying the actions needed to correct and prevent the recurrence of nonconforming product and other quality problems [21 CFR 820.100(a)(3)].
    2. You failed to establish and maintain procedures to adequately control environmental conditions which could reasonably be expected to have an adverse effect on product quality [21 CFR 820.70(c)].
    3. You failed to maintain complaint files [21 CFR 820.198(a)].
    4. You failed to review and evaluate all complaints to determine whether an investigation is necessary [21 CFR 820.198(b)].
    5. You failed to review, evaluate and investigate complaints involving the possible failure of a device to meet any of its specifications, and in instances where a review, evaluation and investigation was conducted you failed to maintain a record of such investigation by the formally designated unit [21 CFR 820.198(c) and (e)].
    6. You failed to establish and maintain procedures for monitoring and control of process parameters for validated processes to ensure that specified requirements continue to be met [21 CFR 820.75(b)].
  2. You failed to establish and maintain procedures for implementing corrective and preventive action, including requirements for identifying the action(s) needed to correct and prevent recurrence of nonconforming product and other quality problems [21 CFR 820.100 (a) (3)]. For example:
    1. From January to November 2008, more than 30 out-of-specification events occurred due to microbial contamination during bulk and finished product testing.  Investigations were not conducted in a timely manner.  In many instances, root causes of contamination were not identified, and preventative and corrective actions were not implemented.  For example:
      1. Investigation into deviation #111556, which was initiated on August 18, 2008, for microbial contamination of CAP Survey RBC, Lot ---b(4)---, by Candida railenensis, was closed on November 5, 2008, with no evidence of root cause identified, nor evidence of preventative and corrective actions implemented.
      2. Investigation into deviation #111559, which was initiated on August 18, 2008, for microbial contamination of Panocell-16, Lot #---b(4)--- Cell 1, by Candida railenensis, was closed on November 5, 2008, with no evidence of root cause identified, nor evidence of preventative and corrective actions implemented.
      3. Investigation into deviation #111823, which was initiated on August 20, 2008, for microbial contamination of Panocell-16, Lot #---b(4)-- Cell 14, by Candida railenensis, was closed on November 5, 2008, with no evidence of root cause identified, nor evidence of preventative and corrective actions implemented.
      4. Investigation into deviation #104518, which was initiated on June 5, 2008, for microbial growth of mold observed in a bulk sample of Anti-E (Monoclonal) series 1, Lot #--b(4)--, was closed on June 23, 2008.  The lot was released from hold status on June 26, 2008, with no evidence of root cause identified, nor evidence of preventative and corrective actions implemented.
    1. Investigation into Complaint #102687 was initiated on May 15, 2008, for Panoscreen I and II, Lot #14617 for dark color in Panoscreen II cells.  There were a number of complaints for this lot.  Microbial testing of returned product and retention samples determined that the contaminating organism was yeast.  This complaint investigation remained open until October 10, 2008.  There is no evidence of identification of root cause and no evidence of corrective and preventive actions implemented.
    2. Investigation into Complaint #117264 was initiated on October 10, 2008, for WB corQC1, Lot #236036 for gross hemolysis.  There were at least 6 complaints for this lot.  Microbial testing of retention samples determined that the contaminating organism was Pseudomonas fluorescens.  This complaint investigation remained open at the time of the inspection.  There is no evidence of identification of root cause and no evidence of corrective and preventive actions implemented.
    3. Investigation into Complaint #112614 was initiated on August 28, 2008, for Panoscreen II, Lot #30864 for dark color in Panoscreen II cells.  There were 52 complaints for this lot.  Microbial testing of returned product and retention samples determined that the contaminating organism was yeast.  This complaint investigation remained open until January 6, 2009.  There is no evidence of identification of root cause and no evidence of corrective and preventive actions implemented.
  1. You failed to establish and maintain procedures to adequately control environmental conditions which could reasonably be expected to have an adverse effect on product quality [21 CFR 820.70(c)].  For example:
  1. The Staging Hallway of your Vialing Suite (near the equipment storage room), is not certified with positive pressure.  
  2. You failed to follow your SOP BQA.021, entitled “Environmental Monitoring – Vialing Area” which requires that --b(4)-- viable and non-viable particulate air sampling, point-of-fill sampling, and personnel sampling be performed while vialing rooms are in use, and you failed to establish procedures in this SOP requiring that environmental sampling be performed in Vialing Room -b(4)-.  For example:
    1.  Point-of-fill sampling was not taken in Vialing Room -b(4)- on April 7, 2008, during the filling of corQC Red Cells, Lot #12597.  Subsequent Complaint Investigation #100089, was initiated on April 23, 2008, for unexpected color in this lot of corQC Red Cells, and Candida species was identified as a contaminant. 
    2. Viable and non-viable particulate air sampling, point-of-fill sampling, and personnel sampling were not taken for Vialing Room -b(4)- on September 11, 2008, during the filling of Panoscreen I, Lot #-b(4)-.  Subsequent Out-Of-Specification Detail Report #114540, was initiated on September 15, 2008, for microbial growth in product vial samples for this Panoscreen I lot, and Aureobasidium pullulans was identified as a contaminant.
    3. Point-of-fill sampling was not taken in Vialing Room -b(4)- on September 18, 2008, during the filling of WBcorQC1, Lot #236036.  Subsequent Complaint Investigation#117264, was initiated on October 10, 2008, for hemolysis in this lot of WBcorQC1, and Pseudomonas fluorescens was identified as a contaminant.
    4. Viable and non-viable air samples were not taken in Vialing Room -b(4)-, nor was point-of-fill sampling taken in Vialing Room-b(4)- on May 14, 2008, in which Referencells A1, A2, and O were filled.  Viable and non-viable air samples were not taken in Vialing Room-b(4)-, nor was point-of-fill sampling taken in Vialing Room-b(4)- on April 29, 2008, May 19, 2008, and June 9, 2008.  On the above mentioned dates, the following products were filled:  Panocell 10, Lot #--b(4)--, Panocell-10 Diluent, CAP Serum, and Panoscreen 10, Lot#--b(4)--.  Deviation #100536 revealed that HEPA filters in Vialing Rooms ---b(4)---- were out of tolerance on April 27, 2008.  New HEPA filters were installed on June 22, 2008.
    5. Personnel, viable, and non-viable particulate air samples were not taken on April 15, 2008, and June 20, 2008, in Vialing Room -b(4)-, which is used for hand-filling operations.  On the above-mentioned dates, Panocell-10, Lot #---b(4)--- and Panoscreen I, II, and III, Lot #--b(4)-- were filled in Vialing Room -b(4)-.  Additionally, your SOP BQA.021 is inadequate in that it does not require environmental samples to be taken in Vialing Room -b(4)-.
  3. City water used to generate the steam supply for your autoclaves, is not monitored.  Though you have identified Pseudomonas fluorescens as a contaminant in your investigations, you have not taken water or steam samples at points-of-use to ensure that contamination is not coming from the city water used to generate the autoclave steam supply.
  4. You failed to follow your SOP 400.328, entitled “Gowning for Entry to Reagent Red Blood Cells Processing Room.”  For example, jewelry that might tear through apparel and/or gloves are prohibited in the Reagent Red Blood Cells Processing Room, yet, during the inspection, an employee was observed wearing hanging earrings in this room.
  5. Your SOP BQA.024, entitled “Environmental Monitoring – Red Cell Processing” does not clearly define requirements for environmental monitoring and more specifically does not prohibit the spraying of hands with -b(4)- prior to performing personnel sampling.  During the inspection, a technician was observed spraying her gloved hands with         --b(4)-- prior to touching environmental contact plates.  This is a repeat observation from the January 2008, FDA inspection.
  6. Debris was observed underneath a floor scale in the Reagent Red Blood Cells Processing Suite.
  1. You failed to maintain complaint files [21 CFR 820.198 (a)].  For example:
    1. Customer complaints which were manually recorded onto Complaint Notes Form TS.013F1 were often discarded and not entered into the              --b(4)-- Complaint Database. 
    2. Complaint memo dated December 15, 2008, listed numerous complaints involving your products, including Panocell 16, Referencell, Checkcell 1x10, and Panoscreen III.  These complaints were not entered into the tracking database, --b(4)--, as required by your SOP GEN.109, entitled “Customer Complaint Procedure.” Additionally, there is no record of the complaints ever being evaluated or investigated.  
    3. Complaint Note dated December 29, 2008, was documented for Panoscreen Lot #43031 with a complaint of “Cell II giving mixed filed reactions with a couple of patients.”  There was no record of the complaint in ----b(4)-----, as required by your SOP GEN.109, nor was there a record of the complaint ever being evaluated or investigated. 
    4. There were discrepancies in a number of complaints which were initially written on your Complaint Notes Form, TS.013F1, and later transcribed into ---b(4)-----.  Some of these discrepancies include inconsistencies in dates of complaints as well as the categorization of complaints.  For example, a complaint for Cell III hemolysis in Panoscreen III, Lot #46076 was dated January 5, 2009, on your Complaint Notes Form, but was dated January 8, 2009, when transcribed into ---b(4)--- (as complaint #126290).  Additionally, this complaint was categorized as a “delay in shipping” complaint rather than a “hemolysis” complaint when transcribed into             ---b(4)---. 
  1. You failed to review and evaluate all complaints to determine whether an investigation was necessary [21 CFR 820.198 (b)].  A number of CGMP complaints were handwritten on Complaint Note Form TS.013F1 with specific descriptions, however, these complaints were ultimately transcribed in --b(4)---- as “shipping” complaints.  For example:
    1. Complaint #124728 for Panocell 16, Lot #46066 which was handwritten onto Form TS.013F1 on December 23, 2008, indicated a “grossly hemolyzed” cell of Panocell 16.  This complaint was transcribed into         ---b(4)--- as a complaint for “delayed delivery of shipment.”  The customer was issued a replacement, and there is no record of Immucor having conducted an investigation into the hemolyzed cell.
    2. Complaint #126094 for Checkcells, Panoscreen III, CorQC, and Referencells A1B which was handwritten onto Form TS.013F1 on January 7, 2009, indicated that all cells in Panoscreen III were black in color.  This complaint was transcribed into ---b(4)---- as a complaint for “delay in shipment.”  The customer was issued a replacement, and there is no record of Immucor having conducted an investigation into the discolored cells.
  1. You failed to review, evaluate, and investigate complaints involving the possible failure of a device to meet any of its specifications, and in instances where a review, evaluation, and investigation were conducted, you failed to maintain a record of such investigation by the formally designated unit [21 CRF 820.198(c) and (e)].  From January to December 2008, approximately 2398 Reagent Red Cell product complaints were received.  Approximately 689 of these complaints were related to possible product contamination.  Some examples include: 
    1. Investigation into Complaint #114835 for Panoscreen I, II, and III, Lot #31872 was initiated on September 17, 2008, for small clots and dark color in cell II of Panoscreen III.  There is no record of an investigation having been conducted to determine the reason for the clots. 
    2. Investigation into Complaint #115971 for Panoscreen I, II, and III, Lot #31872R was initiated on September 29, 2008, for clots and darkness in Panoscreen cell II.  There were 12 other complaints of this nature for this lot.  There is no record of an investigation having been conducted to determine the reason for the clots.
  1. You failed to establish and maintain procedures for monitoring and control of process parameters for validated processes to ensure that specified requirements continue to be met [21 CFR 820.75(b)].  For example:
    1. You have not demonstrated that your validation study for the recovery of fungal microorganisms is adequate, as you have not been able to demonstrate consistent recovery of fungal organisms.  You continue to use this method, which has not been validated, as part of your environmental monitoring program.  This is a repeat observation from the March 2006, and January 2008, FDA inspection. 
    2. Validation of the ---b(4)--- Autoclave, the --b(4)--Autoclave, and the         ----b(4)--- Dry Heat oven are incomplete.  You have not defined a standard load pattern configuration for routine component placement in the units. 

While these deviations were documented in the most recent inspection, we note that similar deviations have been documented during past FDA inspections.   The seriousness of these deficiencies have been repeatedly emphasized to you during previous FDA inspections of March 7-16, 2006, and January 8-17, 2008, as well as in a Warning Letter dated May 2, 2008.  Based on the numerous, significant deficiencies identified during the most recent inspection, it is the Agency’s judgment that management at Immucor has failed to exercise control in all matters in relation to compliance with the federal regulations and the standards in your license.

Neither this letter nor the list of inspectional observations (Form FDA 483) is meant to be an all-inclusive list of deficiencies that may exist at your facility.  It is your responsibility as management to assure compliance with all applicable provisions of the FD&C Act, the PHS Act, and federal regulations.

We acknowledge receipt of your written responses dated January 22, 2009, February 6, 2009, March 6, 2009, April 6, 2009, May 6, 2009, and May 7, 2009, which address the inspectional observations on the Form FDA 483 issued at the close of the inspection, and also acknowledge your promise to make improvements, implement corrective action plans, and prevent recurrence of the violations observed during the January inspection.  Nevertheless, we note that your firm has repeatedly promised such corrective actions in the past, but follow-up inspections continue to demonstrate that adequate, effective, and long term corrective action has not been taken.  Accordingly, we have no assurance that the corrective actions that are required will be properly implemented to correct the deficiencies noted during the most recent inspection.

Pursuant to 21 CFR 601.5(b), this letter is to provide you with notice that, unless you demonstrate or achieve compliance with the applicable standards and regulations, it is the intent of FDA to institute proceedings to revoke the biologics license with respect to your Reagent Red Blood Cells and your Anti-E (Monoclonal) Blood Grouping Reagent product, issued to Immucor, Inc., 3130 Gateway Drive, Norcross, Georgia.  The Agency intends to proceed with the revocation of the biologics license with respect to your Reagent Red Blood Cells and your Anti-E (Monoclonal) Blood Grouping Reagent product, unless you do the following:

  1. Within ten (10) working days of receipt of this letter, advise the FDA in writing of your commitment to correct the noted deficiencies.
  2. Within (30) working days of receipt of this letter, submit a comprehensive report and detailed approach addressing the methods which will be used to bring your facility into compliance with all applicable regulations and standards, including a proposed completion date for prompt correction of the noted deficiencies.  Your plan should include corrective actions for all noted deficiencies, and should specifically emphasize your firm’s plan, with respect to the violative products, for the following:
    1. Enhancing your quality assurance program and procedures to correct current deficiencies, prevent recurrence of similar deficiencies, and assure long-term compliance with regulations in all processes performed by your establishment;
    2. Ensuring that the Quality Systems Regulations (QSR) requirements are effectively established and effectively maintained and followed;
    3. Conducting a thorough review of all standard operating procedures to achieve compliance with the QSR requirements, as specified in 21 CFR 820 and with the applicable regulations for biological products specified in 21 CFR 600-680;
    4. Establishing a system of training and evaluation to ensure that personnel have capabilities commensurate with their assigned functions, a thorough understanding of the manufacturing operations they perform, and knowledge of the QSR requirements;
    5. Conducting thorough failure investigations which include an assessment of whether other products, lots, systems, or processes may have been similarly affected or have similar deviations; and
    6. Developing a process that ensures that a review of all appropriate records and process deviations be undertaken with appropriate investigations and risk assessments prior to release of product to ensure that its quality specifications have been met.

Although the above-described plan is intended to focus on your violative Reagent Red Blood Cells and Anti-E (Monoclonal) Blood Grouping Reagent product, we remind you that all of your products must conform to the standards in your license and the regulations.

These submissions should be sent to Ms. Mary Malarkey, Director, Office of Compliance and Biologics Quality, HFM-600, Center for Biologics Evaluation and Research, Food and Drug Administration, 1401 Rockville Pike, Suite 200N, HFM-600, Rockville, MD 20852-1448.  Ms. Malarkey may be reached at (301) 827-6190.  Additionally, a copy of all submissions should be sent to Jacqueline Little, Team Leader, Ph.D., Office of Enforcement, Food and Drug Administration, 15800 Crabbs Branch Way, Suite 110, Rockville, Maryland 20855.

If we do not receive an adequate response within the prescribed time, or if a subsequent inspection of your firm finds your corrective actions to be inadequate, the Agency intends to proceed pursuant to regulations governing formal evidentiary public hearing, as found in 21 CFR 12.21(b), and to publish in the Federal Register a notice of opportunity for a hearing on a proposal to revoke  your biologics license with respect to your Reagent Red Blood Cells and your Anti-E (Monoclonal) Blood Grouping Reagent product.

Consideration of this administrative action does not preclude the Agency from taking other regulatory actions, including, but not limited to, license suspension, seizure or injunction, all without further notice.  If you choose not to bring your establishment into compliance or wish to waive the opportunity for a hearing, you should contact Ms. Malarkey within ten (10) calendar days of receipt of this letter.  The waiver must be confirmed in writing and may be accomplished by your voluntary request that the biologics license with respect to your Reagent Red Blood Cells and Anti-E (Monoclonal) Blood Grouping Reagent product be revoked.

Sincerely,

 

Karen Midthun, M.D.
Acting Director
Center for Biologics Evaluation and Research