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U.S. Department of Health and Human Services

Vaccines, Blood & Biologics

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Medion Diagnostics

July 2, 2007

FEDEX

Peter Schwind, Ph.D.
Managing Director
Medion Diagnostics
Bonnstrasse 9
Düdingen, Switzerland CH-3186

Dear Dr. Schwind:

The Food and Drug Administration (FDA) conducted an inspection of Medion Diagnostics, located at Bonnstrasse 9, Düdingen, Switzerland, between February 22 and March 1, 2007. During the inspection, the FDA investigators documented 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. Notably, deviations included, but were not limited to, the following:

  1. Failure to validate processes with a high degree of assurance and approve according to established procedures, as required by 21 CFR 820.75. For example:
    1. Your Validation #D28.06/05 was conducted for the ------------- cycle of your ----------------------------------------------------------------------. The --------------------- is used in the processing of product containers and closures, manufacturing equipment, and media for media fill testing. Your validation protocol was prepared retrospectively; acceptance criteria were not defined and the protocol was not approved prior to conducting the validation.

       

       

    2. Your Validation #D57.01/05 was conducted to provide evidence that the cleaning procedure used for the -------- filling needles effectively and consistently reduces cleaning agent residues to an acceptable level after the washing process. You did not follow your validation concept/protocol in that:

       

      1) The validation did not include -------- filling needles number ------- as outlined in your validation concept/protocol; your documentation only includes validation data for -------- cleaning process for needles number ---, ---, and ---.

      2) The validation did not include your Search-Cyte and Data-Cyte products, as outlined in your validation concept/protocol; your documentation only includes validation data for Reverse-Cyte. Further, your validation did not utilize a -------------------------------------- solution, as required by your concept/protocol; the Reverse-Cyte product, used in your validation, is a -------------------------------------solution.

      3) There is no documentation indicating that the filling needles were visually inspected to be clean, as required by your concept/protocol.

      4) There is no documentation of ------------ levels on the filling needles before and after the washing process, as required by your concept/protocol.

     

  2. Failure to establish and maintain process control procedures that describe any process controls necessary to ensure conformance to specifications, including the approval of processes and process equipment, as required by 21 CFR 820.70(a)(4). For example, your Validation #D29.00/00 was conducted to evaluate the use of ---------------Containers for the storage of ------------------------------------------- and --------------------------------- used in the preparation of your Reagent Red Blood Cells. Your validation report does not address followup or corrective actions to be implemented for failure to meet defined acceptance criteria.

     

     

  3. Failure to establish and maintain procedures for implementing corrective and preventive action, including requirements for investigating the cause of nonconformities relating to product, processes, and the quality system, as required by 21 CFR 820.100(a)(2). For example:

     

    1. Your standard operating procedure (SOP) QAS1313 entitled "Failure Management" states that the potential risk of a nonconformity is evaluated based on the probability of occurrence and the impact of the failure on the product. The SOP further states that the potential risk is considered low (risk factor ----), medium (risk factor ----), or high (risk factor ------) and that root cause analysis is based on the risk assessment; however, the SOP does not describe how the risk factor is determined.

       

       

    2. Your SOP QAS 1313 does not clearly require investigation of all nonconformities. Your SOP states "At a risk potential of --------------, a failure analysis is mandatory. At a risk potential of ------, the degree of the analysis is dependent on the risk assessment." The SOP does not further clarify this statement or provide details for conducting analysis/investigation for "low" risk nonconformities.

       

     

  4. Failure to maintain device master records that include or refer to device specifications; production process specifications; quality assurance procedures and specifications; packaging and labeling specifications; and installation, maintenance, and servicing procedures and methods; as required by 21 CFR 820.181. You do not maintain device master records for your licensed products, including:

     

    a. Reverse-Cyte A1,B
    b. Reverse-Cyte A1,A2,B
    c. Search-Cyte I + II
    d. Search-Cyte Plus
    e. Search-Cyte TCS
    f. Data-Cyte Plus
    g. Reverse-Cyte A1,B for Tango
    h. Search-Cyte Duo for Tango
    i. Search-Cyte Trio for Tango
    j. Search-Cyte Pool for Tango

     

  5. Failure to establish and maintain procedures to adequately control environmental conditions that could reasonably be expected to have an adverse effect on product quality, as required by 21 CFR 820.70(c). For example:

     

    1. Printouts of nonviable particulate monitoring during product filling are not maintained. Nonviable particulate counts are ------------ and documented on form FOR0921; subsequently, the printouts are discarded.

       

       

    2. Growth promotion testing is not routinely performed on contact plates used for environmental and personnel monitoring. There is no data to support the qualification of the contact plates for their intended use.

       

       

    3. Your SOP MFG0758 entitled "Sterile Assurance Level" requires incubation of media fill samples for -------- days at -------ºC followed by incubation for -------days at -------ºC. However, results of media fills performed from May 2005 through November 2006 do not indicate that media fill samples were incubated for ------- days at -------ºC.

       

     

  6. Failure to establish and maintain procedures to prevent contamination of equipment or product by substances that could reasonably be expected to have an adverse effect on product quality, as required by 21 CFR 820.70(e). For example:

     

    1. Your Validation of the ------------------------------------------------ was conducted to support the use of the test system for analysis of microbial contamination of water. The validation was inadequate in that it did not include testing for yeast and/or molds and therefore did not demonstrate that these organisms can be isolated and/or identified using the test system.

       

       

    2. Your Validation of the --------------------------------------------- does not support the test sample incubation times specified in your QPV 95:2 entitled "-------------------------------------------." All validation test samples were incubated for ---- hours; however, QPV 95:2 specifies that test samples may be incubated for -------- hours.

       

       

    3. There is no SOP that provides instructions for reading plates for analysis of microbial contamination of water.

       

       

    4. There is no data to demonstrate that it is possible to accurately determine the number of colony forming units (CFUs) per mL for analysis of microbial contamination of water. Test samples are not diluted and plate counts are ------------------- to obtain the number of colony forming units (CFUs) per mL. There is no limit on the number of colonies that may be counted on an individual plate. A count of -------- CFUs on a single plate would be required to exceed the established alert level; a count of ---------CFUs on a single plate would be required to exceed the established action level.

       

    We acknowledge receipt of your written response dated April 19, 2007, which addresses the inspectional observations on the Form FDA 483 issued at the close of the inspection. We have reviewed your response and have the following specific comments. The items are numbered to correspond to the observations listed on the Form FDA 483.

FDA 483 item #2
Your response states that you will gather documents that will either be referenced or included in product specific Device Master Records. Please provide a timeframe for completion of this activity.

FDA 483 item #5.A.1.b
Your response requested CBER input regarding which of the ----- product categories of --------------- applies to your Reagent Red Blood Cell products for purposes of conducting ----------------------Testing. Please contact Sheryl A. Kochman in CBER's Division of Blood Applications at (301) 827- 6123 to discuss this issue.

FDA 483 item #5.B
Your response states that a validation protocol will be written retrospectively and added to the ------------- validation. Please be advised that validation protocols should be established prospectively and the protocols should be followed. Protocols should be approved according to established procedures. Validation acceptance criteria should be prospectively defined.

FDA 483 item #5.C
We acknowledge your commitment to repeat the validation of the cleaning process used for the ------------- filling needles.

FDA 483 items #10.A & 10.B.2, #11.D & E, and #12.B & C
Your response states that corrective actions will be carried out in collaboration with an outside service laboratory, --------------. Please provide a timeframe for completion of these corrective actions.

Neither the above deviations, nor the observations listed on the Form FDA 483 presented to your firm at the conclusion of the inspection, are intended to be an all-inclusive list of deviations at your establishment. It is your responsibility to ensure compliance with all requirements of the laws and regulations administered by FDA.

Your reply should be sent to me at the following address: U.S. Food and Drug Administration, Center for Biologics Evaluation and Research, HFM-600, 1401 Rockville Pike, Suite 200 N, Rockville, Maryland 20852-1448. If you have any questions regarding this letter, please contact Anna M. Flynn in the Division of Case Management at (301) 827-6201.

Sincerely,

/s/

Mary A. Malarkey
Director
Office of Compliance and Biologics Quality
Center for Biologics Evaluation and Research

cc:
Mr. Philippe Monod
Authorized Official
Medion Diagnostics
Bonnstrasse 9
Düdingen, Switzerland CH-3186