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Sep 15, 2013 (Vol. 33, No. 16)

Fine-Tuning Formulation Processes

  • Stability = Quality

    To Ahmed Yasin, Ph.D., head of formulation and stability research at GlaxoSmithKline’s Stevenage, U.K. facility, the greatest formulation-related challenges are promoting stability, minimizing aggregation on storage, and dealing with viscosity in high-dose formulations. These issues are related.

    Because some monoclonal antibodies are administered at high doses by injection, viscosity problems are more or less built into the product. Highly viscous solutions are more concentrated, so molecules have a greater opportunity to interact and therefore aggregate. That being said, Dr. Yasin noted that highly viscous monoclonal antibody therapeutics are common and, without elaborating, stated that strategies exist for dealing with them.

    Aggregation sometimes affects a molecule’s activity by shielding the active region from its binding site. This effect is not always noticeable. Regulators and bioprocessors are more concerned about aggregates being immunogenic.

    Selecting from among the many techniques that quantify aggregation is difficult. Many methods lack robustness and reproducibility. Those based on light scattering do not always distinguish aggregates from non-protein interferences. The presence of even small amounts of silicone oil can sometimes thwart accurate characterization of aggregates.

    Aggregates are typically monitored using size-exclusion chromatography, but the gold standard analytical method is analytical ultracentrifugation (AUC). Even with AUC, results depend on who runs the method and on what instrument.

    Another concern with monoclonal antibodies is deamidation. By transforming an amide to a carboxylic acid, deamidation alters a protein’s physical and biological properties. “It is essentially a chemical reaction that takes place in a highly ionic environment,” says Dr. Yasin.

    The process involves isomerization followed by elimination of –NH2. Deamidation is one of several degradation mechanisms that are innate to proteins. Particularly affected are proteins containing exposed asparagine and glutamine sidechains with nearby glycine residues.

    Development teams will therefore seek formulations that minimize or eliminate deamidation. “If deamidation occurs in the complementary-determining region (CDR), which contains the binding points of the monoclonal, there’s a huge chance it will affect stability,” notes Dr. Yasin.

    However, if it occurs in the heavy or light chains, or far from the CDR, the effect will be lessened.

    Deamidation is also a possible avenue toward immunogenicity. While this idea is entrenched in theory, finding real-life examples, even experimental evidence, is difficult.

  • Small Molecule Drug Formulations

    One of the most common challenges in small molecule drug development is formulating low-solubility drugs as manufacturable and bioavailable products. At least 40% of new chemical entities (NCEs) in the global pipeline have poor solubility and low bioavailability.

    For these compounds, low aqueous solubilities in the region of 0.1 µg/mL are common. The implication is that a 10 mg dose requires 100 L of aqueous media to dissolve, making administration practically impossible.

    Significant bioavailability issues include variable absorption due to precipitation in the gut, food effects, and atypical gastrointestinal physiology in some patient populations.

    “Typically, for a drug molecule to be absorbed into the systemic circulation it must be adequately soluble in the aqueous milieu of the gut,” observes Peter Pekos, CEO of Dalton Pharma Services. “The drug must also be sufficiently permeable to cross the intestinal barrier by passive diffusion, the primary process involved in drug absorption.”

    Drug solubility and permeability work in opposite directions, giving rise to a seesaw effect. To deal with this effect and ensure that therapeutic goals are met requires skill and art.

    “It follows that potential drug compounds that are highly soluble tend to be poorly permeable, and vice versa,” Pekos adds. Formulation scientists must balance the impact of these two competing properties to achieve the desired solubility and bioavailability goals.

    Given that most molecules Dalton Pharma sees are poorly soluble, the company draws on myriad strategies to provide these compounds with the best opportunity to succeed in early-stage clinical trials. These include liposomes, nanoparticles, photo activation, and amorphous dispersions within a dissolving polymer matrix.

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