Virus, inactivation

J. J. Morgenthaler, ed.. Virus Inactivation in Blood Products, Karger, Basel, 1989. 

Viral vaccines present problems of safety testing far more complex than those experienced with bacterial vaccines. With killed viral vaccines the potential hazards are those due to incomplete virus inactivation and the consequent presence of residual live virus in the preparation. The tests used to detect such live virus consist of the inoculation of susceptible tissue cultures and of susceptible animals. The cultures are examined for cytopathic effects and the animals for symptoms of disease and histological evidence of infection at autopsy. This test is of particular importance in inactivated poliomyelitis vaccine, the vaccine being injected intraspinally into monkeys. At autopsy, sections of brain and spinal cord are examined microscopically for the histological lesions indicative of proliferating poliovirus. 

Type 1 patients unresponsive to desmopressin, patients with types 2 and 3 von Willebrand s disease, and major surgery patients require replacement therapy with plasma-derived intermediate- and high-purity factor VIII virus-inactivated factor VIII concentrates containing von Willebrand factor. 

In cases where a virus inactivation or removal process is performed during manufacture, measures should be taken to avoid the risk of recontamination of treated products by non-treated products. 

Mohr, H., Bachman, B., Klein-Struckmeier, A., and Lambrecht, B. (1997). Virus inactivation of blood products by phenothiazine dyes and light. Photochem. Photohiol. 65,441 45. 

A fundamental requirement for LC-MS/MS calibration materials is that matrix effects exerted by these materials are most similar to the matrix effects exerted by actual patients sample materials. Lyophilisation, virus inactivation and other procedures applied during the industrial production of calibration and control materials, may notably impact the ionization behaviour of extracts from such samples and can result in differential matrix effects in calibrators and actual patients samples. If the internal standard peak areas found for calibration samples systematically differ from those found in patients samples, inappropriateness of the calibration materials should be suspected. However, we have previously observed that calibration materials from different commercial sources lead to inaccurate tacrolimus results in an instrument specific manner, without showing deviations in the internal standard peak area. This effect was most likely related to ionization enhancement affecting the target analyte but not the homologue internal standard (ascomycin) ionization and being restricted to calibrator samples. This resulted in systematically low tacrolimus results of clinical samples in one instrument for one specific calibrator lot [52],... 

Boyd MR, Gustafson KR, McMahon JB et al (1997) Discovery of cyanovirin-N, a novel human immunodeficiency virus-inactivating... 

Rywkin S, Ben-Hur E, Malik Z, et al. New phthalocyanines for photodynamic virus inactivation. Photochem Photobiol 1994 60 165-70. 

Implicit to our recommendation for IMBPs is that viral expression system derived DNA or excipient derived contaminant carcinogens are no longer an issue. Although, for example, host cell DNA can be a risk factor for neoplasia [3], the current stringent biochemical characterization, purification, and virus inactivation steps taken with all well-characterized biopharmaceuticals adequately mitigate any potential risk from these sources. 

The technology also proved to be very efficient for virus inactivation. Figure 6.9 shows results of Adenovirus H40 inactivation in tap water. Again the diamond... 

Kapuscinski RB, Mitchell R (1980) Processes controlling virus inactivation in coastal waters. Wat Res 14 363—... 

Joachim Walter (Boehringer Ingelheim Pharma KG) presented results on the use of microwave technology for virus inactivation in biopharmaceutical products. By using microwaves, viral inactivation can be carried out with the exposure time of the product solution to high temperatures being limited to 500 ms or less. For antibodies, viral inactivation can be effectively carried out using peak temperatures up to 95°C with hold times as low as 5 ms. 

Prothrombin complex is the combination of Factors E, VE, DC, and X. It is indicated for individuals with hemophdia B. In a typical production process, the supernatant resulting from the separation of cryoprecipitate is filtered to remove particles and applied to an anion-exchange column. The coagulation factors are eluted, ultrafiltered, and exposed to 60°C for 10 h for virus inactivation. This is followed by diafiltration, ultrafiltration, and sterile filtration. 

The capacity of expensive sterile and virus filters is usually increased through prefiltration. Typically 0.1 p,m-rated membranes are used for prefiltration before virus filtration. Sterile filters are protected by depth filters or 0.45 p,m membranes. Some virus inactivation operations such as solvent detergent exposure also require prefiltration for the removal of particulates that can shield vimses from the inactivating effects of solvent detergent agents. 

Another microbiological purity issue that has been associated with human blood is the possibility of adventitious contamination with viral pathogens. Likewise, if animal blood is used as the red cell source, a spectrum of viruses have been identified as potential contaminants and possibly as zoonotic agents that may be infectious to humans. " Therefore, in addition to the careful control of the blood used as the Hb source, the process for Hb solution preparation should employ robust virus inactivation and removal steps to reduce the risk of disease transmission. 

During inactivation steps, viral infectivity is reduced by treatment with chemicals and/or physical methods. Remnants of virus particles (e.g., viral nucleic acids) may remain in the product-containing fraction but are not infectious. Chemical methods of virus inactivation, such as treatment with solvent-detergent or acetone, must be placed upstream, since subsequent steps are needed to remove or reduce the levels of the toxic chemicals. Terminal inactivation is often achieved using physical methods, such as heat and low pH, because these methods leave no chemical residues. After treatment, the final products are delivered to patients, so aseptic processing conditions must be maintained throughout terminal inactivation steps and the parameters for virus inactivation must be balanced with the conditions to preserve product quality and yield. 

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