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U.S. Department of Health and Human Services

Medical Devices

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Suggested Analytical Testing Protocol for In Vitro Diagnostic Devices Manufactured with Heparin Contaminated With Oversulfated Chondroitin Sulfate

A number of in vitro diagnostic devices, such as heparinized blood collection tubes/dispensers and diagnostic assay kits/reagents, might have been manufactured using heparin contaminated with oversulfated chondroitin sulfate (OSCS). To determine whether analytical performance is affected by this contaminant, the following analytical testing protocol should be taken into consideration. This protocol is offered as one possible approach toward answering questions about the effect of contaminated heparin on the in vitro diagnostic devices described above.

  1. Determine which specific device(s) containing or utilizing heparin in their manufacturing. If none, no further action is needed. 
  2. If such device(s) exists, determine those manufactured with the highest level of OSCS-contaminated heparin, and perform the following analytical testing under a clearly written protocol: 
    • 2.1. For blood collection tubes/dispensers:
    • Identify the analytes that can be assayed in various clinical laboratory settings (e.g., chemistry, hematology, immunology, microbiology, toxicology) using blood specimens collected in these tubes/dispensers.
    • Select at random tubes/dispensers containing contaminated heparin from the same lot. Collect paired blood samples from 40 volunteer subjects in tubes/dispensers containing contaminated and uncontaminated heparin as controls, respectively.
    • Perform comparative analytical testing of the concerned analytes, preferably in duplicate, using one or more common analytical platforms.
    • For clinically significant analytes that may be physiologically undetectable or exist in relatively low levels in healthy subjects, and for which no clinical samples are readily available (e.g., troponin, creatine kinase-MB), perform spiking tests with a range of concentrations (e.g., low, intermediate, and high) of the analyte(s).
      • Retain left-over samples, if possible, for additional testing at a later time, should that become necessary.
    • 2.2. For diagnostic kits/reagents:
      • Select at random five to ten kits/reagents manufactured with contaminated heparin, and two or more retained kits/reagents from a lot known to be free of contaminated heparin as control. 
      • Perform comparative testing between contaminated and non-contaminated kits of the concerned analyte(s) using either quality control materials, or spiked blood samples (whole blood, plasma, and/or serum, as appropriate), covering a wide range of concentrations (e.g., low, intermediate, and high) of the analyte(s). Test the analyte(s), preferably in duplicate, at each concentration. 
      • If no retained control kits/reagents are available, use appropriate blood samples spiked with known concentrations of the analyte(s) for a recovery study. 
    • 2.3. For accessory reagent(s)/components (e.g., flushing, cleaning, or rinse solution) 
      • Identify if the accessory reagent /component influences any test result. If so, perform applicable testing as described in section 2.2 above.
  3. Examine analytical comparison data for evidence of potential analytical interference (e.g., positive or negative bias) by OSCS using appropriate descriptive statistics and statistical tests. Investigate further any pattern of interference to identify the root cause, and to establish appropriate actions to mitigate the risk. 
  4. Adhere to applicable institutional rules (e.g., informed consent, IRB, HIPPAA Privacy Rule) governing testing involving human subjects. Retain all records (e.g., calibrations, quality controls, instrument maintenance, source data) as described in the E6 Good Clinical Practice: Consolidated Guidance.

The points of contact in this office are Eugene Reilly, MS (eugene.reilly@fda.hhs.gov), or Tara Goldman, MS (tara.goldman@fda.hhs.gov).