Consumers may take it for granted that a therapeutic drug product in the household medicine cabinet effectively does what its label claims. Likewise, medical professionals expect prescribed products to comply with efficacy, safety and stability requirements. The confidence of both parties is based on the expectation that biopharmaceutical companies thoroughly test therapeutic products long before they reach the market.
Considering stability, biopharmaceutical manufacturers need to know that as a product sits on a shelf, it won’t lose its effectiveness or degrade into something dangerous to consume. For finished product stability testing, a product is stored in controlled conditions and then periodically removed from those conditions and examined to ensure it adheres to standards. Various characteristics are measured to create a degradation line over the shelf life of a product. In some cases, a study may span many years.
For a substance in development and not yet approved for clinical use, companies cannot wait years due to competitive pressures, market demands and the clock ticking on patent expiration dates. To accelerate the stability testing process, scientists put the substance in stress conditions such as high humidity and temperature to highlight stability issues sooner.
If they have standardized technology, practices and data to support an integrated approach to stability testing and analytics, they may also use virtual models. Virtual testing, also known as in silico testing, can often predict stability issues early in the research and discovery phases.
BIOLOGICS INTRODUCE NEW CHALLENGES
The laboratory processes involved in testing small molecules that comprise pills and tablets are well established. Biologics, however, bring unique challenges, driving a need to reexamine methods, protocols and systems for stability testing. For biologics, tablet-based delivery is not yet a commercially viable option. Instead, the most common method of delivery is via subcutaneous bolus injection. Measuring, predicting and managing stability is very different for an injectable than for a hard tablet or ingestible liquid.
To create an injectable dose that ensures good patient compliance, particularly if the goal is a self-administered auto-injector, drug developers need to ensure that the drug can be administered as painlessly as possible. They must put the biologic into a very small volume of liquid and be able to inject the drug via a very narrow-bore needle. These delivery requirements must still ensure that efficacy is retained. As a result, a very high concentration is required (typically ca. 150 mg/ml), which introduces unique stability issues related to aggregation, viscosity and thermal volatility.
Protein aggregation is becoming increasingly better understood. For a variety of reasons including environmental stress, a protein can irreversibly bind to itself in solution, causing what effectively looks like a snow globe in a vial or syringe — a phenomenon that chemists informally refer to as “crashing out.” In its aggregated form, it may no longer be efficacious and it can be immunogenic.
Another issue related to storing and administering a biologic at high concentration is viscosity. A highly viscous biologic may be impossible to push through a desired narrow-bore syringe needle. To mitigate viscosity issues, it might become necessary to reduce the concentration of the drug, leading to a larger volume. This can impact the market delivery form of the drug. In a worst-case scenario, patients could find themselves staring down the needle of a large-volume syringe that one might expect to be used on a horse. Patient compliance could become a major issue.
Biologics can exhibit narrow thermal stability profiles, meaning they can easily become unstable and denature (lose their biologic activity) unless they are maintained at a specific temperature range. In extreme cases, a biologic may have a short lifespan, even when stored in a refrigerator. This would make it extremely difficult to get enough of the medicine to hospitals, clinics and the wider patient population. Biopharmaceutical companies want a highly stable biologic that can be stored for long periods of time in ambient conditions so viable quantities of the drug can be delivered and stored by medical professionals and patients.
Comprehensive testing is essential for determining these stability issues. Biologics present additional challenges in physical testing phases because the material to be studied is not always readily available. It takes time to generate sufficient material for the required trials. Small molecule drugs are synthesizable by chemists, and there is typically a cost-effective and efficient chemistry route to scale them up. Biologics in comparison co-opt a biological pathway. Scientists must use cell lines to manufacture a biologic and culture it over time in order to generate enough of the biologic for testing and ultimately for production.
IMPLICATIONS OF OUTDATED METHODS
The biologics business is becoming the mainstay of the biopharmaceutical industry, by some estimates representing as many as half of all new drugs now coming to market. A single biologic can account for $5 to 15 billion per year in sales. Because a company can spend up to three months managing a stability issue in formulation stages, mitigation efforts can represent $1 to 4 billion in lost sales in a drug’s first year on the market. That doesn’t include those that don’t ever make it to market because stability issues could not be resolved. A significant portion of a company’s product pipeline can be jeopardized by stability issues.