Aggregates in MAbs and Recombinant Therapeutic Proteins: A Regulatory Perspective - FDA perspectives on specifications and effective control strategies - BioPharm International

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Aggregates in MAbs and Recombinant Therapeutic Proteins: A Regulatory Perspective
FDA perspectives on specifications and effective control strategies


BioPharm International
Volume 21, Issue 11

New delivery systems have increased the complexity of container compatibility, along with the potential for protein aggregate formation. Glass from vials, rubber from stoppers, silicone from stoppers and syringes, and tungsten from syringes are some of the foreign particles that may find their way into a protein drug product. Many of these foreign particles are electrostatically charged, and therefore, have the potential to interact with proteins, protein aggregates, and protein aggregate precursors, to form heteronuclei. Such was the case with prefilled syringes containing tungsten particles shed during syringe barrel manufacturing, which served as nuclei for aggregate formation.18

STUDYING AGGREGATES

Based on aggregate kinetic models, protein aggregates may be more hydrophobic than their monomeric counterparts. This is because protein aggregation may occur when the protein transitions to a native, partially unfolded state, exposing its hydrophobic residues.8,9 Studies revealed that aggregates are precipitated better than monomers by ammonium sulfate, and that they bind more strongly to polyvinylidene fluoride (PDVF) membranes.19

Commonly, aggregates are studied by exposing the protein solution to extreme conditions of temperature, pH, humidity, and photon incidence, in what are known as forced and photodegradation studies. The rationale is based on the expectation that protein degraded in this manner reflects the degradation pathway(s) experienced during the protein lifecyle. These parameters may also be of value when establishing a stress stability program.20

Another important part of protein aggregation studies is evaluating the biological activity of the aggregate. Differences in biological activity of the aggregates compared to the activity of the monomeric protein can profoundly influence the potency of a protein-based drug. In such cases, product efficacy may be compromised. In general, a risk-based assessment of aggregates may warrant specific studies that may help elucidate which types of aggregates are more worrisome. A thorough investigation of the different environments to which the drug product is exposed during its lifecycle, including manufacture, storage, shipping freeze and thaw cycles, oxygen exposure, light, and physical stress, can provide a rationale for special degradation studies such as seeding or spiking of a specific aggregate or impurity into a protein solution to observe the potential for further aggregation.


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