The concept of TPDs — including proteolysis-targeting chimeras (PROTACs) and molecular glues — first emerged in the early 2000s as an elegant way to eliminate, rather than inhibit, disease-causing proteins.
Early PROTACs, first reported in 2001 by the Crews and Deshaies laboratories, used peptide linkers to tether a target ligand to an E3 ubiquitin ligase, thereby triggering the target’s destruction.
Ingenious in principle, these large, unstable and mostly impermeable molecules were unsuited to patient therapy.
Molecular glues had precedent in drugs such as thalidomide, but their discovery was often accidental and their mechanisms poorly understood.
For years, TPDs remained in academia because of limited E3 ligase options, no reliable way to predict productive ternary complexes, synthetic challenges and the prevailing belief that such large molecules could not become orally viable.
During the past decade, advances in structural biology, computational design, small-molecule chemistry and clinical proof of concept have changed that picture.
The challenge now is not if TPDs work, but how to deliver these often bulky, poorly soluble molecules in a form that the body can absorb.
Rebecca Coutts, Senior Director of Pharmaceutical Development at PCI Pharma Services, reports.
The CDMO advantage
TPD molecules are often characterised as “brick dust” compounds because of their large structure, which results in poor solubility within the gastrointestinal tract.
Even when dissolution occurs, their bulky structure also limits permeability across intestinal membranes, meaning that significantly less of the original dose enters systemic circulation.
The result is that TPD drug products typically achieve low bioavailability in patients — a scientifically and clinically frustrating paradox whereby highly effective therapeutics for acute and life-threatening conditions such as cancer face a fundamental delivery barrier.
Fortunately, the last two decades have also seen a significant advance in the capabilities of contract development and manufacturing organisations (CDMOs), as well as formulation and process expertise throughout the industry.
The largest and most capable CDMOs have developed and manufactured hundreds, if not thousands, of molecules in that time scale, resulting in a deep understanding of process development and manufacturing best practices.
Also, CDMOs with a legacy of working with highly potent molecules at an OEB5 level (approximately 10 ng/m³) are highly experienced when it comes to safely handling these compounds — a useful capability for TPDs that, although not always highly potent, would be well-managed within such a facility.
However, not all CDMOs — even the larger ones — have the in-house capabilities to improve the bioavailability of complex molecules.
Enabling technologies such as spray drying, hot melt extrusion and nanomilling require specific expertise and the best service providers in this space are usually dedicated to these advanced technologies.
Fortunately, there is an emerging model within the pharmaceutical supply chain that aims to achieve the optimal balance: strategic partnerships.
Strategic partnerships
Bringing a new technology into a CDMO can be a lengthy, labour-intensive and expensive process, with the technical skills gap being one of the most fundamental issues to address.
It therefore begs the question: why not embrace the differing sets of expertise and combine them into a network of experts throughout the entire pharma supply chain?
This collaborative approach enables CDMOs to preserve and broaden their core manufacturing expertise — including process development, technical transfer, scalable manufacturing, clinical and commercial packaging, and on-site supporting functions such as regulatory and analytical services — while leveraging top-tier formulation technologies without encountering costly delays.
However, establishing these partnerships is only part of the process. Effective management of these collaborations is what ensures a client’s product reaches the clinic and, ultimately, the patient, as quickly, efficiently and cost-effectively as possible.
Historically, pharma companies would often approach a CDMO with their drug substance only to learn that it required an enabling technology that existed elsewhere.
The company would then need to approach an upstream expert to evaluate their enabling technology … who might often operate in isolation from the CDMO that eventually inherits the product.
Needless to say, this process is cumbersome, fragmented and ultimately inefficient. It also directly affects the most important stakeholder: the patient.
Forged by decades of handling complex molecules in multiproduct facilities through the various stages of the product development lifecycle, one of a CDMO’s most vital attributes is its project management capabilities.
Therein lies the answer: establish the CDMO as any given project’s single point of contact (SPOC).
This way, the CDMO can liaise directly with each of its strategic partners about the drug substance and the product requirements:
- detailed technical discussions can take place to understand the best solution for that product
- the CDMO is fully aware of the development activities taking place, so there are no data omissions and delays when it comes to downstream development and manufacture.
Enabling technologies
Providing a platform-agnostic approach puts the client’s product first, ensuring the right solution is found rather than shoehorning a product into an existing process.
Going back to the “brick dust” nature of TPDs, there are several established technologies that currently exist to maximise their bioavailability.
Spray drying transforms TPDs into amorphous solid dispersions by dissolving the drug substance in a polymer matrix at the molecular level.
This process eliminates the crystalline structure that typically limits dissolution, creating a high-energy amorphous form that dissolves more readily in gastrointestinal fluids.
For TPDs, this technology dramatically increases the apparent solubility of these large hydrophobic molecules while enabling scalable manufacturing from development through to commercial production.
Hot melt extrusion creates intimate molecular-level mixing between TPDs and pharmaceutical polymers without using solvents. The process applies controlled heat and shear to blend the drug substance with carriers, forming a homogenous solid solution or dispersion.
This continuous manufacturing technique offers excellent content uniformity and can improve both the solubility and permeability of TPDs by disrupting their crystalline structure and creating more favourable thermodynamic conditions for dissolution.
Nanomilling reduces the particle size of TPDs to the nanometre scale, dramatically increasing the surface area available for dissolution.
This mechanical size reduction process can improve dissolution rates by orders of magnitude: smaller particles dissolve faster according to established dissolution principles.
For TPDs, which often suffer from both poor solubility and slow dissolution kinetics, nanomilling provides a direct path to enhanced bioavailability while maintaining stability when combined with appropriate surfactants and polymers.
Looking ahead
Whatever the best technology is for today’s TPD products, one guarantee is that the pharmaceutical industry is ever-evolving.
Enabling technologies will continue to advance as more information is gathered from formulation development throughout the industry.
The collaborative approach between CDMOs and their formulation partners couldn’t come at a more critical time.
The TPD market is projected to grow at a CAGR of approximately 21% to 2035, a more aggressive growth trajectory than even biologic therapies.¹ This reflects the therapeutic potential of these molecules now that there’s a viable commercial pathway for them.
For patients awaiting TPD therapies, this collaborative approach represents more than operational efficiency; it’s the bridge between promising laboratory discoveries and accessible treatments for cancer and other chronic illnesses.
By combining deep manufacturing expertise with cutting-edge formulation and processing technologies, the industry is positioned to fulfil the therapeutic promise that TPDs have held for more than two decades.
As such, it seems that the curse that once plagued these remarkable molecules may finally be lifting.
Reference
- www.rootsanalysis.com/reports/protein-degradation-market/289.html.
