EX VIVO-ACTIVATED MONONUCLEAR LEUKOCYTE QUALITY CONTROL

EX VIVO-ACTIVATED MONONUCLEAR LEUKOCYTE QUALITY CONTROL should include lot-by-lot testing for viability, sterility, purity, and potency, according to a recently released "Points to Consider" document prepared by FDA. In addition to the lot-by-lot testing, a more detailed characterization of the cultured cell types, and tests for cytokine production, endotoxins and clonality may also be needed to validate the process for early lots or following process changes, FDA said. Specifications for lot acceptability, FDA notes, "should be developed on the basis of actual experience."

Regarding lot-by-lot sterility testing, FDA suggests that "aliquots of the culture medium be taken at regular intervals beginning three to four days after initiation of the culture and including a sample taken approximately 24 hours before infusion of cells into the patient." Yield and viability of each lot should also be assessed prior to infusion and periodically during a culture of longer than a few days, the document explains, as "low viability suggests poor process control or lack of consistency, and might also indicate the presence of toxins or other contaminants."

The FDA guidance document, entitled "Points to Consider in the Collection, Processing, and Testing of Ex Vivo-Activated Mononuclear Leukocytes for Administration to Humans," was released by FDA's Center for Biologics Evaluation and Research on August 22. The "points" are intended to assist manufacturers in filing for INDs involving activated leukocytes, including LAK and TIL cell treatments.

Noting that infection rates of 25% have been reported by some centers administering the activated mononuclear leukocytes, the FDA guidance emphasizes the need for monitoring of recipients for bacteremia or fungemia and for viral illnesses. When infection occurs, FDA states, "the source of infection (e.g., contaminated culture, catheter-related sepsis) should be determined." In turn, "all incidents of contamination of cultures and/or infection of recipients should be investigated immediately and reported to the FDA."

FDA's "Points to Consider" document is available from FDA's Division of Cytokine Biology, 8800 Rockville Pike, Room 2D-20, HFB-800, Bethesda, MD 20892 (Tel: [phone]).

The National Cancer Institute has recently made available a number of new interim reference reagents for human cytokines. Included among the new reference standards are: IL-1 alpha and beta, IL-4, IL-6, GM-CSF, G-CSF and TNF-alpha.

The cytokine standards were originally prepared by Britain's National Institute for Biological Standards and Control (NIBSC) in conjunction with the World Health Organization, and are available for distribution within the U.S. by NCI's Biological Response Modifiers Program (BRMP). Each interim standard is of defined unitage and is intended to be used for calibration of laboratory standards.

NCI will be running ads in medical journals announcing the availability of the new interim standards beginning in September. Laboratories can obtain one vial of each lyophilized reference material by writing to Dr. Craig W. Reynolds, Building 321, BRMP, NCI-Frederick Cancer Research Facility, Frederick, MD 21701.