349 results
| WHO guideline title | Product | TRS | Test name | Test category | 3Rs approach | Toggle to view all updates |
|---|---|---|---|---|---|---|
| Recommendations to assure the quality, safety and efficacy of enterovirus 71 vaccines (inactivated) |
Enterovirus 71 vaccine (inactivated)
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1030 Annex 3
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Endotoxin content
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Pyrogenicity/endotooxin testing
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MAT
rFC
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Original textThe endotoxin content of each final lot should be determined using a method approved by the NRA. Endotoxin levels should be consistent with levels found to be acceptable in vaccine lots used in pre-licensure clinical trials and should be approved by the NRA. New textThe need for pyrogenicity testing should be assessed during the manufacturing development process and be re-evaluated following any significant changes in the production process or relevant reported production inconsistencies that may influence pyrogenicity. A risk-based approach should be implemented which is suitable to the manufacturing process and the product depending on the potential presence of endotoxins and non-endotoxin pyrogens. The endotoxin content of the final product should be determined using a suitable in vitro assay, such as the recombinant factor C (rFC) or limulus/tachypleus amoebocyte lysate (LAL/TAL) tests. The rFC method is strongly recommended due to concerns over the impact on the sustainability of limulus stocks. The endotoxin content should be consistent with levels found to be acceptable in final product lots used in clinical trials and within the limits agreed upon with the NRA. A monocyte activation test (MAT) may be used for pyrogen testing after a product-specific validation. The use of the rabbit pyrogen test should be avoided due to its inherent variability, high retesting rates, and interspecies differences in pyrogenic responses as compared to humans.ReferencesMAT:Schindler, S., von Aulock, S., Daneshian, M. and Hartung, T. (2009) “Development, validation and applications of the monocyte activation test for pyrogens based on human whole blood”, ALTEX - Alternatives to animal experimentation, 26(4), pp. 265–277. doi: 10.14573/altex.2009.4.265.
rFC: Biotechniques 2021 May;70(5):290-300. doi: 10.2144/btn-2020-0165. Epub 2021 May 6.
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| Recommendations for inactivated rabies vaccine for human use produced in cell substrates and embryonated eggs |
Rabies vaccine
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941 Annex 2
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Strains of virus
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Miscellaneous
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Original textVaccine strains should be characterized by molecular and serological methods, including the use of monoclonal antibodies for the characterization of rabies virus. This should also include animal inoculation. In addition, sequencing of at least the glycoprotein and nucleoprotein genes of master or working seed should be considered New textKeep original text
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| Recommendations for inactivated rabies vaccine for human use produced in cell substrates and embryonated eggs |
Rabies vaccine
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941 Annex 2
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Additional tests if chick cell cultures are used for production of virus seed
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Adventitious agents
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RT-PCR or PCR. For avian leucosis viruses used DF-1 cells
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Original textIf chicken cell cultures are used, a sample of fluids pooled from the control cultures should be tested for avian retroviruses such as avian leukosis virus, by a method approved by the national regulatory authority. A test for retroviruses using a sensitive polymerase chain reaction (PCR)-based reverse transcriptase (Rtase) assay may be used. The results of such assays need to be interpreted with caution because Rtase activity is not unique to retroviruses and may derive from other sources, such as retrovirus-like elements that do not encode a complete genome (22). Nucleic acid amplification tests for retrovirus may also be used. New textEach virus seed lot propagated in avian tissues and each virus harvest propagated in primary avian tissues should be tested for avian viruses if the risk assessment, approved by the NRA, indicates that this test provides a risk mitigation taking into account the overall testing package. Relevant culture methods and/or molecular biology or broad molecular methods approved by the NRA should be part of the overall testing package. Animal testing (including fertilised SPF eggs) may only be used to qualify virus seed lots if the risk assessment indicates that such testing provides a risk mitigation taking into account the overall testing package. Animal testing is not performed on virus harvest for routine batch release.ReferencesSee the Ph. Eur . 2.6.16
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| Recommendations for inactivated rabies vaccine for human use produced in cell substrates and embryonated eggs |
Rabies vaccine
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941 Annex 2
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Additional tests if duck embryos are used for production of virus seed
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Adventitious agents
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NGS
Cell culture method
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Original textIf duck embryos are used for the production of virus seed, tests for Mycobacteria and avian viruses should be performed. New textIf duck embryos are used for the production of virus seed, tests for Mycobacteria and avian viruses should be performed.Relevant culture methods and/or molecular biology or broad molecular methods approved by the NRA should be part of the overall testing package. Animal testing (including fertilised SPF eggs) may only be used to qualify virus seed lots if the risk assessment indicates that such testing provides a risk mitigation taking into account the overall testing package. Animal testing is not performed on virus harvest for routine batch release.ReferencesBiologicals 2020 Sep;67:94-111. doi: 10.1016/j.biologicals.2020.06.002. Epub 2020 Jul 11.
"Gombold et al , 2014 “Systematic evaluation of in vitro and in vivo adventitious virus assays for the detection of viral contamination of cell banks and biological products”
Vaccine 2014 May 19;32(24):2916-26. doi: 10.1016/j.vaccine.2014.02.021. Epub 2014 Mar 25.
Charlebois R. L. et al, 2020 . “Sensitivity and breadth of detection of high-throughput sequencing for adventitious virus detection”
npj Vaccines volume 5, Article number: 61 (2020) "
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| Recommendations for inactivated rabies vaccine for human use produced in cell substrates and embryonated eggs |
Rabies vaccine
|
941 Annex 2
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Virus content
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Virus content
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Original textA titration of the virus content of each seed lot should be made. Such titrations may be done either in cell culture or by the inoculation of mice. If mice are used, they should be inoculated by the intracerebral route with 0.03 ml quantities of suitable dilutions of the virus seed lot. Although the previously recommended end-point for this in vivo titration was death of the mice, it is reasonable instead to use clinical signs of paralysis as the end-point and to kill the animals when they reach this stage. New textA titration of the virus content of each seed lot should be made. Such titrations may be done using a suitable cell culture method. If a cell culture method is not avaiable or suitable, inoculation of mice may be used. |
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| Recommendations for inactivated rabies vaccine for human use produced in cell substrates and embryonated eggs |
Rabies vaccine
|
941 Annex 2
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Tests for haemadsorbing viruses
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Adventitious agents
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Reduction - Limit to one species
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Original textAt the end of the observation periods, 25% of the control cells should be tested for the presence of haemadsorbing viruses by using guinea-pig erythrocytes. If the guinea-pig erythrocytes have been stored, the duration of storage should not have exceeded 7 days and the temperature of storage should have been in the range of 2–8 °C. In some countries the national regulatory authority requires that tests for haemadsorbing viruses should also be done with erythrocytes from other species, including human beings (blood group 0), monkeys, and chickens (or other avian species). New textAt the end of the observation period a fraction of culture comprising not less than 25% of the total should be tested for the presence of haemadsorbing viruses, using red blood cells from guinea-pig or other suitable red blood cells. It is not necessary to use red blood cells from multiple species. If the red blood cells have been stored prior to use in the haemadsorption assay, the duration of storage should not have exceeded 7 days and the temperature of storage should have been in the range of 2–8 °C. |
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| Recommendations for inactivated rabies vaccine for human use produced in cell substrates and embryonated eggs |
Rabies vaccine
|
941 Annex 2
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Additional tests on control cells if avian embryo cells are used for production
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Adventitious agents
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NGS
Cell culture method
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Original textA sample of the control fluid taken at the end of the observation period of the control cell cultures should be tested for avian retroviruses such as avian leukosis virus, by a method approved by the national regulatory authority. In some countries the complement fi xing test (COFAL) is used for detecting avian leukosis viruses, and liver or kidney cell cultures of embryos are used for detecting adenoviruses New textEach virus seed lot propagated in avian tissues and each virus harvest propagated in primary avian tissues should be tested for avian viruses if the risk assessment, approved by the NRA, indicates that this test provides a risk mitigation taking into account the overall testing package. Relevant culture methods and/or molecular biology or broad molecular methods approved by the NRA should be part of the overall testing package. Animal testing (including fertilised SPF eggs) may only be used to qualify virus seed lots if the risk assessment indicates that such testing provides a risk mitigation taking into account the overall testing package. Animal testing is not performed on virus harvest for routine batch release.ReferencesBiologicals 2020 Sep;67:94-111. doi: 10.1016/j.biologicals.2020.06.002. Epub 2020 Jul 11.
"Gombold et al , 2014 “Systematic evaluation of in vitro and in vivo adventitious virus assays for the detection of viral contamination of cell banks and biological products”
Vaccine 2014 May 19;32(24):2916-26. doi: 10.1016/j.vaccine.2014.02.021. Epub 2014 Mar 25.
Charlebois R. L. et al, 2020 . “Sensitivity and breadth of detection of high-throughput sequencing for adventitious virus detection”
npj Vaccines volume 5, Article number: 61 (2020) "
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| Recommendations for inactivated rabies vaccine for human use produced in cell substrates and embryonated eggs |
Rabies vaccine
|
941 Annex 2
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Control of (uninoculated) embryonated duck eggs
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Adventitious agents
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Original textAt the time of virus harvest, the uninoculated eggs should be processed in the same manner as the inoculated eggs, and the extract from the control embryos should be shown to be free from haemagglutinating agents and from adenoviruses, avian retroviruses such as avian leukosis virus, and other extraneous agents by tests approved by the national regulatory authority. New textKeep text and refer to specific preceeding sections in TRS for appropriate test methodology.
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| Recommendations for inactivated rabies vaccine for human use produced in cell substrates and embryonated eggs |
Rabies vaccine
|
941 Annex 2
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Identity
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Identity
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Original textThe single harvest contains virus that should be identified as rabies virus using specific antibodies. New textKeep original text
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| Recommendations for inactivated rabies vaccine for human use produced in cell substrates and embryonated eggs |
Rabies vaccine
|
941 Annex 2
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Virus titration for infectivity
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Miscellaneous
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Original textEach virus harvest or pool of harvests should be tested for infectivity in a sensitive assay. Both mice and cell culture of defined sensitivity are suitable for testing infectivity. Manufacturers should set an in-house specifi cation for the titre of each harvest or pool of harvests. New textEach virus harvest or pool of harvests should be tested for infectivity in a sensitive assay. Infectivity may be testedusing a suitable cell culture method. If a cell culture method is not avaiable or suitable, inoculation of mice may be used. |
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