IDBS Blog | 22nd July 2019

Challenges in Formulating Biologics

Historically, small molecule pharmaceutical products dominated the medical drugs market, from treatments for diabetes to broad-spectrum antibiotics, they worked, and the pharma industry bloomed.

However, in today’s day and age, as the prevalence of different types of diseases and ailments continues to grow, this has resulted in a shift in scientific interest; biological therapeutics have come to the forefront of this industry. Different diseases require different modes of treatment, and biologics fit the bill. Demand for this class of medications is continuing to increase, adding pressure to push the boundaries of research and development.

Regulatory bodies such as the FDA in the US are approving more drugs than ever before, with the number of new molecular entities (NMEs) climbing from 46 in 2017 to 59 just a year later, of which 17 were biologics. And while research has branched out from monoclonal antibodies and vaccines to more novel therapies such as cell and gene therapies and fusion proteins, monoclonal antibodies continue to dominate, making up 50% of the current biologics market. But even with this boom in the market, challenges remain, especially in formulations.

Biologics come with their own formulation challenges

Producing an effective biologic, available to treat a patient as quickly as possible, often results in organizations going with the easiest or cheapest option to produce a molecule. But this approach can cause delays, costing both the company and patients precious time and money. One of those challenges is ensuring the product is safe and stable throughout production and continues to retain its structure until administered to a patient.

Biologics are vulnerable at every stage of the development process, and they need to be formulated accordingly. Points formulation scientists need to consider include exposure to oxidation and agitation, as well as drastic changes to pressure, and temperatures outside the normal limits can make the formula unstable.

And during the production process itself, freezing and thawing the product can have an effect; it needs to be protected from extreme conditions. But it doesn’t stop there – biologics are generally administered by infusion or injection, so the formulation must account suitably for the delivering device.

A poor formulation can result in wasted resources and data sets riddled in anomalies, especially if the biologic is introduced into a clinical trial. It needs to be formulated in such a way that it gets to the correct place in the body, at the right time, in a stable condition, and at the appropriate concentration. In biologics development specifically, there are two main issues to look out for when developing a formulation – aggregation and degradation.

Making a safe biologic for patient use

A poorly formulated biologic can affect patient safety, especially if it contains undesirable entities such as protein aggregates or pieces of a stopper or glass vial from the delivery device or vehicle. Contamination is a problem in any medical industry, but for biologics, it’s particularly dangerous, as they are used to treat chronic conditions or serious illnesses. The product’s stability can be affected, which can lead to a shorter shelf life. For practical reasons, industry guidelines recommend that a biologic should have a shelf life of at least two years, particularly if it’s expensive, or not in high demand. But if there are formulation issues, the product will go to waste.

Given the nature of their structure, proteins tend to aggregate. So, how can we avoid it? To ensure product quality and patient safety, we must understand the causes and risks of protein aggregation in biologic formulations and prevent it.

If the proteins aggregate and the medicine is administered to a patient, it could perform ineffectively, trigger an unwanted immune response or the patient could even go into anaphylactic shock. For a patient relying on this medication, such as when fighting cancer, this could have a significant impact on their recovery, and could potentially prove fatal.

Aggregates can be taken out of the formula in a later stage of the process, but this could dilute the active molecule in the end product. A potential solution lies in introducing an excipient from the limited list of those approved for use in biologics. For example, Roquette added hydroxypropyl modified betacyclodextrin to several of their formulations to prevent or reduce aggregation.

Preventing degradation to ensure stability

An important aspect of formulation is making sure that the biologic doesn’t begin to degrade before it’s used. Since most biologics are proteins, they can’t be taken orally (yet), as they would degrade. Instead, they must be injected or infused, which is costly.

Along with maintaining an acceptable shelf-life, there are other considerations: within manufacturing, packaging and shipping, the product can be put under stress. Environmental factors can have a significant impact on the stability during storage and transportation. For example, if a product is taken out of optimal temperature conditions while travelling in the air, where it is much colder, it can become unstable. A biologic can also lose its stability if it’s unable to withstand variations in light and chemicals that it might encounter.

These are all considerations that a formulation scientist must think about, drawing upon historical data from past and related projects and using innovative technology to predict potentially winning combinations to create a stable formula so sought-after in the industry. One that works for the patient, ensuring their safety in continued treatment.

This is where introducing certain excipients can either make or break the formula. Earlier this month, we wrote a blog post dedicated to the role of excipients in medicines. The article focused on excipients used in the pharmaceutical industry. When it comes to a biologic, the excipients ensure high bioavailability, prevent degradation and protect the biologic itself from damage.

Technology tackles these challenges head-on

Making sure organizations have a good formulation early in the development process is important, as issues down the line could trigger significant changes, causing costly delays in the pipeline and a drain on resources. Each stage in the process needs to be monitored, with reams of accurate and integrated data sets, a ‘right fist time’ approach that flags deviations, and information from past experiments available with a simple search.

IDBS’ Bioprocess Solution supports scientists in their bioprocess workflows, throughout cell line development and formulations to downstream processing and analytical development. The intuitive library of interoperable workflows provides researchers with a way to track their biological inventory, as well as manage it, and highlight any issues with reagents to be used in the development process. The ability to monitor the changes to data ensures traceability and shortens the QA review cycle by days, if not weeks.

With this technology, searching for relevant information has never been easier. Researchers can search with context, enabling formulators to spot trends and trace past decisions. With all the information in a single location, there are no more data silos. This also makes sharing ideas and data a breeze, knocking down barriers and organizational silos often stated as a blocker for formulation scientists. One can quickly see what works and what combinations don’t, what formulation is the best for a patient so that they can receive their medication when they need it– a stable, effective and safe treatment.