While pharmaceutical formulations have always been part science, part art, the complexity of todays drugs has shifted the balance toward the former. Aided by analytic tools that detect subtle changes in proteins over time, biomanufacturers employ rigorous science to create formulations that stabilize and enhance sensitive products. Driving formulation technology are a greater appreciation for consistency, novel delivery mechanisms and dosage forms, and the desire to improve therapeutic proteins at the molecular level.
Proteins undergo numerous physical and chemical changes that affect potency and safety. Among these are aggregation, which includes dimerization, trimerization, and higher-order aggregates, plus crystallization and precipitation. During fill-and-finish operations, concentrated protein solutions squeeze through piston pumps, which imparts high-shear and mechanical stresses that cause denaturation and aggregation.
Once formulated, manufacturers rely on additives, such as amino acids (particularly glycine), salts, and surfactants, to enhance protein solubility and inhibit aggregation.
Preventing aggregation has become a major issue for formulators since the trend toward high-concentration solutions increases the likelihood of protein-protein interactions favoring aggregation. Many products are only effective when delivered by injection in relatively high concentration, notes Wayne Gombotz, Ph.D., vp of pharmaceutical operations at Omeros (www.omeros.com).
In some cases manufacturers can exploit proteins inherent tendency to aggregate by delivering them as suspensions, or depots, which are slowly dissolved by interstitial fluid between cells and delivered systemically. No products are currently approved with that type of formulation, notes Dr. Gombotz, but people are looking at this approach.
For example Altus Biologics (www. altus.com), which has long been interested in crystalline protein drugs, has published on a technique for delivering both crystalline vaccines and Mabs.
Every protein exhibits its own peculiar degradation behavior. Degradation occurs through multiple mechanisms, including simple oxidation, deamidation of asparagine residues, disulfide bond rearrangements, chemical hydrolysis of peptide bonds, and enzymatic proteolysis.
Simply formulating at the right pH can sidestep many of these problems. For example, deamidation occurs above pH 7, and proteases have optimal pH ranges that can be avoided in straightforward manner by choice of an appropriate buffer. Adding EDTA or citric acid to the final formulation can prevent many types of chemical oxidation.
Usage and delivery trends are the two emerging factors affecting bioformulation strategies. Insulin is the classic example of a self-administered, injectable biotech drug. As more replacement proteins and Mabs gain approval for chronic, nonlife-threatening diseases, manufacturers will devise formulations, unique to user-friendly devices, such as pre-filled syringes, auto-injectors, and needle-free delivery systems.
Formulation and delivery go hand in hand as part of a drugs life-cycle management. Lyophilization, which is an excellent formulation for stability and shelf-life, may not be appropriate for certain products.
Human growth hormone (HGH) was originally supplied as a freeze-dried preparation that required reformulation in the vial, dispensing an aliquot by syringe and injection. Lyophilization may be appropriate for drugs administered by professionals but is probably not, as is the case with HGH, for drugs administered at home.
Eventually, HGH was available in a pen delivery system that required reconstitution but with easier injection, and finally by needle-free injector that has helped boost sales of this product, according to Dr. Gombotz. HGH is a great example of how a new liquid formulation can help drive a new dosage form, which drives sales.
Enbrel, Amgen/Wyeths rheumatoid arthritis (RA) Mab, was also originally manufactured as a freeze-dried product, but patients with RA had difficulty reformulating and injecting the drug. Enbrel is not available as a solution.