Review of animal use requirements in WHO biologics guidelines – database of suggested guideline revisions

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Manufacturers are encouraged to avoid the use of materials of animal origin
wherever possible.

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A test should be performed on the purified polysaccharide to verify its identity.
A serological test and/or 1H nuclear magnetic resonance spectroscopy provide convenient methods for this purpose.

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To ensure an acceptable level of pyrogenic activity of the final product, the endotoxin content of the purified polysaccharide should be determined, and shown to be within limits agreed as being acceptable by the national regulatory authority.
Less than 100 International Units of endotoxin per mg of polysaccharide when measured by the Limulus amoebocyte lysate test can be achieved in the production process. Alternatively, a recognized pyrogenicity test can be performed in rabbits.

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The 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.

Original text

The bulk conjugate should be tested for the absence of specific toxicity of the carrier protein where appropriate (e.g. when tetanus or diphtheria toxoids have been used).
Absence of specific toxicity of the carrier protein may also be assessed through validation of the production process.

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The carrier protein should be tested for the absence of specific toxicity of the carrier protein where appropriate (e.g. when tetanus or diphtheria toxoids have been used). Absence of specific toxicity of the carrier protein may also be assessed through validation of the production process. Where available and appropriately validated and with approval from the NRA, an in vitro test should be used. If in vitro assays are scientifically justified as unavailable and inappropriate, a suitable in vivo test may be used.

Original text

An identity test should be performed on each final lot.
A serological test, using antibodies specific for the purified polysaccharide may be used.

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Original text

The vaccine in the final container should be tested for pyrogenic activity by intravenous injection into rabbits or by a Limulus amoebocyte lysate test. Endotoxin content or pyrogenic activity should be consistent with levels found to be acceptable in vaccine lots used in clinical trials and approved by the national regulatory authority.

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The 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.

Original text

The requirement to test lots of meningococcal conjugate vaccine for unexpected toxicity (abnormal toxicity) should be agreed with the national regulatory authority. Such a test may not be required if another animal test (e.g. a test for immunogenicity) is to be performed
and the test for unexpected toxicity can be omitted for routine lot release once consistency of production has been well established to the satisfaction of the national regulatory authority and when good manufacturing practice is in place.

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Organisms grown on media for three passages with or without galactose agglutinate with H : d antiserum but not with Vi antiserum…

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The organisms grown for 6 hours in … broth shall be incoluated into 5 mice by the intrperitoneal route. A suspension continaing at least 5 x 107 bacteria shall not kill any mice within a 7 day observation period. The NIH-G1 strain of mice are suitable for this test.

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Original text

Each final lot shall be tested for abnormal toxicity by the inoculation of 0.01 human dose intraperitoneally into each of 5 mice and by giving a human dose orally to each of 3 guinea pigs. The mice shall be observed for 7 days and the guinea pigs for 14 days. None of the animals shall show signs of infection due to the vaccine.

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