Regulatory agencies around the world have been steadily increasing pressure on cell, gene, and tissue-engineered drug development companies to put safety first and find ways to control the inherent risks present in many of the raw materials used in the downstream processing of their advanced therapies. The industry has been largely transitioning away from animal-derived products in favor of human-derived products for some time now, but of course, human-derived products present their own set of safety challenges which manufacturers and suppliers must consider.
The potential for the transmission of viruses via human-derived material is a major focus for regulators looking to increase the safety of advanced medical products. The FDA, World Health Organization (WHO), International Council for Harmonization (ICH), European Medicine Agency (EMA), and others define the standard test requirements for human blood and blood components for transfusion or further manufacturing of a drug/therapeutic product. These test methods should be validated to reduce the risk of adventitious viruses and bloodborne pathogens in plasma-derived ancillary materials and ultimately, the final drug/therapeutic product.
Sourcing safe raw material is the first critical step for ancillary material and final drug manufacturers. For blood-derived products, the major regulatory bodies have put together standards for donor screening, blood testing, donor referral, quarantine, and investigation — all of which must be documented and traceable.
Because donor screening is an imperfect system, additional layers of safety must be considered by suppliers and manufacturers using these materials. There are various approaches to virus and pathogen inactivation. While all popular methods achieve some level of virus inactivation or removal, the same methods can have unintended negative effects on the ancillary material, often stripping or inactivating critical proteins essential to the product’s ability to promote cell growth and intended function.
The most popular methods of virus reduction are outlined below. It is important to remember when choosing a virus inactivation/reduction method: there is no “one-size-fits-all.”
Serums are generally heat-inactivated (56 °C for 30 min) with the main intention being effective inactivation of complement proteins present in donated blood/serum, not for the purposes of effective virus inactivation. However, it has been shown to reduce the titer counts of several viruses. Complement proteins can interfere with the growth of certain cell-types in culture, and their inactivation is often required for successful use in immunoassays.
Solvent Detergent treatment is a longtime standard for virus reduction and has proven to be highly efficient for enveloped virus inactivation, especially for the most transfusion-relevant viruses such as HIV, HBV, and HCV, but also for many other adventitious agents, e.g., newly emerging viruses that are enveloped such as West-Nile virus (WNV). To address non-enveloped viruses, this technique is often paired with extra screening upfront, such as Nucleic Acid Testing (NAT) and minimum level requirements for neutralizing antibodies to relevant viruses in the production pool. Solvent detergent treatment is a core risk-reducing technology applied to multiple virus inactivated Akron products.
Virus filtration is an effective size-based strategy that can be implemented in multiple places during the manufacturing process. Many products are sterile filtered using a 0.22 µm filter before being filled into their final packaging, but filters are available with many different pore sizes. When filtering for virus removal, the size of the virus must be considered and usually requires an especially small pore size. This presents a challenge in many industrial applications. This approach is most common for medium and large virus particles, but certain membrane filters can also be used for small virus removal.
Many different chromatographic techniques are known to offer moderate virus reduction. These include affinity, anion exchange, cation exchange, and hydrophobic interaction chromatography. Because these techniques are often applied during purification of proteins, it is sometimes possible to optimize the chromatography buffers allowing for a simultaneous purification and virus reduction step.
Irradiation techniques can utilize different frequencies of electromagnetic energy to inactivate viruses in the material of interest. Ultraviolet light, typically at 254nm (UVC) results in virus inactivation that is most effective for single-stranded viruses with large genomes. There have been historical viral transmission problems when applying UVC to whole plasma infusions. Gamma irradiation utilizes higher energy electromagnetic waves in a similar fashion and has shown very effective virus reduction rates. Both forms of irradiation treatment are known to affect the structural and functional integrity of the proteins or material of interest, so this must be considered when applying.
Many viruses are irreversibly denatured and destroyed around pH 5.0, though some viruses have been shown to require pH around 3.5 to see effective reduction. Because prolonged exposure to low pH has the potential to interfere with the beneficial aspects of certain materials, especially a complex biomaterial like human blood or plasma, it is important to verify that using this method will not significantly reduce the desired effect.
The responsibility to source and use increasingly safe materials in the development of cell, gene, and tissue-engineered therapies ultimately falls to the final drug manufacturers themselves. The increasing expectations from regulators are raising both the safety of the final therapies and the challenges in place to get those therapies to market. Knowing this, Akron continues to push forward high quality, cGMP-compliant ancillary materials and adaptive solutions to support the next generation of tomorrow’s medicines.
This product is manufactured, tested, and released following relevant cGMP guidelines for ancillary materials and is specifically formulated for cell and gene therapy manufacturing applications. This product leverages pharmaceutically licensed virus and prion inactivated plasma as raw material, offering greater batch-to-batch consistency and a unique safety profile.
This product is manufactured, tested, and released following relevant cGMP guidelines for ancillary materials and is specifically formulated for cell and gene therapy applications. This product leverages a virally inactivated, licensed pharmaceutical grade plasma product (Octaplas®) to support research and development requirements with a view to eventual commercialization.
Octaplas® is Octapharma’s pooled, solvent/detergent treated human plasma product. For more on the benefits of manufacturing virus inactivated Human AB Serum, read our press release: Akron Biotech Signs Exclusive Global Agreement with Octapharma to Produce Virally Inactivated Human AB Serum derived from Octaplas® for the Cell Therapy Market.
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