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Formulation Factors

Formulation factors. The adjuvant used, for example, the stabilizer that we use to prevent aggregation. The scavenger that we use to prevent adsorption to the glass wall or to the container wall. Or the surfactant that we use to increase the solubility of the protein. Manufacturing procedure also affect immunogenicity. For example, different freeze-dried conditions the temperature or the pressure cycle.
Generally speaking, formulation instability such as aggregation or adsorption contributed to immunogenicity. This slide shows the formulation factors on five Interferon(IFN) alpha formulations. There are five interference formulations. Process under different freeze drying conditions. The y-axis is the Interferon(IFN) neutralizing units. The more neutralizing units that you have, it indicated more immunogenic. So as you can tell from this graph, E, product E is the least immunogenic. Bioproduct A is the most immunogenic. So process conditions affect immunogenicity Ingredients, impurities also affect immunogenicity. Host cell component, bacteria or cell cultures. Enzymes that are used to activate the product. Resin residues…resin that are used for purification and the residues can cause immunogenicity. Adjuvant used in the formulation.
As mentioned earlier, that adsorbent anti adsorbent stabilizer and surfactant. And the chemicals or the component leached out from the container. The plasticizer, for example, also causes immunogenicity. Storage effect. Storage conditions affect immunogenicity. For example, interferon alpha 2a stored at room temperature is more immunogenic than those stored at two to eight degree. And that’s why the interferon product are stored under two to eight degree but no freezing because freezing, as you know, would destroy the protein structure or denature the protein. And what is their explanation for it? Why interferon alpha 2a stored at room temperature is more immunogenic? And the researchers found out that at room temperature, alpha, interferon alpha 2a becomes poorly or partially oxidized.
They oxidizez molecules for interferon form aggregated with the unmodified interferon, the original interferon, and the human albumin. And the aggregate, of course, become more immunogenic. Dosing factors. Route of administration. So, any route of administration can be immunogenic. But intravenous route is most immunogenic because the massive appearance of the biologics at one time, and they’re quickly detected by the host system. And therefore, the clearance is speed up or clearance is increased in order to get rid of the protein. Subcutaneous route, on the other hand, is less immunogenic because the slower input, slower appearance of the protein in the host system and therefore low clearance. And a longer residence time in the host system. Dose. High dose, more immunogenic, faster clearance.
Smaller dose, less immunogenic, and slower clearance. Concomitant medication. Methotrexate, for example, inhibit immunogenic response to Enbrel because methotrexate is also an immunosuppressive. Patients receiving immunosuppressant generally less likely to produce immunogenic response but, of course, for biologics therapy we try not to administer other drugs concomitantly. because of potential drug interaction.

Biologic drugs are highly complex molecules produced by living cells/organisms through a multistep manufacturing process. The key characteristics of these molecules, known as critical quality attributes (CQAs), can vary based on post-translational modifications or during the manufacturing process. The extent of the variation in each of the CQAs contributes to the quality of the biologic products. To this end, preventing deviation from the required specifications over time and avoiding the various implications is of paramount importance.

Formulation factors presented herein include adjuvants used for the injectable solution, manufacturing condition (e.g., freeze-dry cycle) and impurities. Impurities could be attributed to the host organ or cell components, resin residues for purification or container plasticizer. All the above-mentioned formulation components contribute individually or collectively to the stability, immunogenicity and thus efficacy and safety of the biologic products.

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Pharmacotherapy: Understanding Biotechnology Products

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