The availability of a wide range of therapeutic biologics has revolutionised modern medicine. Whilst the majority of pharmaceutical drug products remain conventional, small-molecule medicines; the emergence of biotherapeutics has allowed for the treatment of many disease areas which were previously out of reach.1 Despite the positive growth in biotherapeutics (Figure 1), significant challenges will need to be overcome in order to fulfil the promise of biotherapeutics across society. With a growing number of protein therapeutics and vaccines in development2,3 one of the biggest challenges facing product developers is the stability of these molecules.4 Biologics including vaccines are inherently unstable and prone to degradation. Therefore, these medicines typically require low-temperature (cold chain) transport and storage. The result is a much higher economic burden and, in some cases, limited access.
Stability Challenges Slowing Future Growth
Biopharmaceuticals comprise of medium to large, complex, macromolecules that can be divided into 4 major classes: proteins, nucleic acids, lipids, and carbohydrates. For the purposes of this article, the focus will be proteins.
Protein structure can be divided into four levels as shown in Figure 2. The 3D structure of the protein is highly complex and inherently linked to therapeutic effectiveness. If the 3D structure is not maintained, there is a risk the therapeutic effect of the drug is reduced or lost entirely. There is also the possibility the molecule can present an immunogenicity risk to the patient. It is therefore vital to maintain the structure of the protein.
The difficulty arises due to the structure of a protein being relatively weak, compared to small molecules. Numerous chemical, physical and colloidal degradation pathways can occur in biologics, a full review of these pathways is beyond the scope of this article. Henceforth, a simplified term of “stability” will be taken to mean that all degradation pathways that negatively impact activity or safety are reduced.
As a result of these numerous degradation pathways, it is typically the case that biopharmaceutics requires a cold chain to be maintained throughout the supply chain, and ultimately until the medicine is administered. If the material cannot be maintained under the required conditions, then the consequence may be reduced availability of medicines, product waste, loss of therapeutic effect, or even risk of immunogenicity.
Even if a robust cold chain is in place, the financial impact of maintaining it is a significant contributor to the high price of biological medicines. Additionally, when a cold chain is available and the medicine affordable, the shelf life of biological drug products is typically short relative to conventional small molecule medicines. Below we briefly discuss the multiple strategies employed to enhance the stability of biologics and thus potentially reduce the cold chain burden.