FDA Issues Guidance for Warning Labels on All Drugs Produced Using Blood Products including Plasma-derived Albumin

By on June 13, 2012

When animal-derived or human-derived blood products are used in biomanufacturing there is always a risk of contamination from adventitious agents, such as viruses and prions. In May 2010, the Food and Drug Administration (FDA) issued “Guidance for Industry: Revised Preventative Measures to Reduce the Possible Risk of Transmission of Creutzfeldt-Jakob Disease (CJD) and variant Creutzfeldt-Jakob Disease (vCJD) by Blood and Blood Products.” This guidance established a warning label on all blood transfusions that stated, “Because this product is made from human blood, it may carry a risk of transmitting infectious agents, e.g., viruses, the variant Creutzfeldt-Jakob disease (vCJD) agent and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent.”, according to FDA’s Guidance.

Last week, the FDA issued a new draft guidance “Amendment to “Guidance for Industry: Revised Preventive Measures to Reduce the Possible Risk of Transmission of Creutzfeldt-Jakob Disease and Variant Creutzfeldt- Jakob Disease by Blood and Blood Products,” which would expand the current CJD and vCJD warning labels to include plasma-derived albumin and products containing plasma-derived albumin. As currently written, this new draft guidance would require labeling on biologics using plasma-derived albumin in manufacturing. For example, vaccines that include plasma-derived albumin in their cell culture media and recombinant protein therapeutics, such as clotting factors that use plasma-derived albumin as a stabilizer would need to carry the new warning label.

While the FDA does state in the draft guidance that the risk of transmission of CJD and vCJD is very low, they go on to say, “based on animal studies, as well as on FDA risk assessments, the possibility of vCJD transmission by a U.S.-licensed plasma derivative, while extremely small, cannot be absolutely ruled out. For these reasons, the recommendations for labeling for plasma derivatives will include mention of vCJD for the first time, and the potential risk for its transmission.” The draft guidance is available for comment through September 10, 2012.

CJD and vCJD are two forms of transmissible spongiform encephalopathy (TSE) affecting humans. CJD and vCJD are caused by a protein called a prion. Prions cause abnormal protein folding, thus negatively affecting protein function. vCJD is the form of the disease related to mad cow disease and is caused by the same prion that can infect both humans and cows. Please see our blog, “Mad Cow Case: Animal Component Free is the Way Forward,” for more information on recent mad cow disease developments. Both CJD and vCJD have very poor outcomes, including severe dementia, disability and death usually occurring within 8 months. There is no cure for the disease.

Whereas this guidance mandates labeling for vaccines manufactured with plasma-derived albumin, it should also be a strong incentive for vaccine manufacturers to remove all animal products from production processes due to the risk of residual amounts remaining as an impurity in the final product. In fact, most biopharmaceutical companies using CHO cells for manufacturing have already transitioned into serum-free culture systems and some take this all the way to completely animal component free production systems. There can be a significant reduction in performance by removing blood products from cell culture, but now there are animal origin free (AOF) alternatives to the key proteins needed in cell culture including albumin, transferrin, insulin, and growth factors. Please see “An Easy Method to Reduce or Eliminate Serum in Cell Culture” for an example.

For the vaccine industry, this is a more acute issue because the majority of vaccines still employ manufacturing practices developed decades ago and still use fetal bovine serum and blood products during manufacturing. Since vaccines are typically administered to healthy patients, the attention to manufacturing systems using the highest standards is a reasonable expectation, so it is not surprising that FDA is specifically interested in improving standards.

Vero, MDCK, and human dipoid lines (MRC-5, Wi-38), commonly used in vaccine manufacturing, are not able to be easily grown without blood products or fetal bovine serum and, as a result, cell health and productivity often suffered when serum was removed. However, there is now recombinant albumin available, which is completely animal-free and can replace plasma-derived albumin in these applications. Please see “Improving Media to Increase Virus Yield in Vaccine Production,” for more information on eliminating animal components from vaccine media. Recombinant albumin would eliminate the need for warning labels and more importantly would eliminate the risk of viral or prion contamination including CJD and vCJD. Several companies including Sigma, Fisher Scientific, InVitria, Sheffield Bioscience and Mediatech supply recombinant albumin that can replace animal-derived albumin (please see the table below).

As FDA stated in the new guidance, the risk of contamination is low, but cannot be ruled out completely. CJD and vCJD are not the only safety risks identified by FDA. There is also the possibility of other known or unknown viral contaminants. With blood products including serum and plasma-derived albumin still commonly used in human vaccines, animal vaccines, and stem cell therapies, there are many risks of contamination. The Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have specific requirements for the use of animal-derived ingredients in cell culture media and both require stringent testing of all raw materials and the final product for viral clearance. Despite regulatory testing requirements, there are concerns about what testing can catch in terms of contamination and the biggest risk may be the fact that we can only test for viral contaminants where we have diagnostics that can detect contamination. Reports have been made of bovine viruses being found in commercial vaccines and therapeutic proteins. Please see “Recombinant Protein Supplements Reduce the Threat of Adventitious Agents in Biomanufacturing,” to learn more.

As recent as two years ago, Genzyme’s contamination of its Cerezyme product shutdown its facility shaving more than a billion dollars off its market value and expediting competing products to Cerezyme from Shire (human cell derived) and Protalix (plant made pharmaceutical). The impact to patients and Genzyme shareholders from this event is an indication of the serious consideration that should be made to developers early in clinical development to eliminate use of blood products.

What do you think about the new labeling requirements? Will this encourage vaccine manufacturers to eliminate animal products?

Table of Recombinant Albumin Sources
Type Product Cost Per Liter of Media Source
Recombinant Albumin InVitria Cellastim $1-6 Animal-free
Sigma recombinant albumin
Fisher Scientific recombinant albumin
Sheffiled Bioscience rAlbumin ACF
Mediatech cellgro rhAlbumin
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