The rise of complex chemistry in small molecule API development
27th May 2022
Introduction
In this paper, we’ll take a closer look at the rising complexity of small molecules, the challenges associated with navigating this increased complexity, and how biotechnology and pharmaceutical organisations can overcome them by working with the right partner for discovery, development and manufacturing.
Small molecule drugs have long been a critical aspect of modern medicine, representing common therapeutics such as aspirin, penicillin, diphenhydramine, and much more. But with increasing innovation in the pharmaceutical industry and the rise of biologics, what does the future of small molecules look like? Will they continue to dominate? ... Read more
Compared to large molecules, small molecules’ lower molecular weights and less complex structures make it easier to anticipate their pharmacokinetic and pharmacodynamic properties.2 In addition, they offer better targeting than large molecules in many scenarios, and their relative simplicity enables them to be produced more quickly in larger quantities and at lower costs.1 Small molecules also support a variety of formulations and are orally bioavailable, providing more flexibility in the ways they can be administered.2 Given these realities, it is no surprise that small molecules will continue to play a crucial role in medicine, with an anticipated market growth rate of 8.05% through 2027.3
But one aspect of small molecules is rapidly changing: their complexity. While small molecules were recognised for their simplicity, the number of small molecules that have already made it to market, the widespread demand for more targeted treatments, and the role of small molecules in treating complex indications have driven their complexity to an all-time high. This is a challenge for drug developers, as they must find partners that can support this complexity while retaining the historical cost and efficiency benefits of small molecules.Read less
Why are small molecules becoming more complex?
It is evident that small molecules are becoming more complex. But what is driving this complexity? There are several major factors at play.
The first is simply the massive number of small molecules that have already been discovered and developed. More than 20,000 prescription drug products are on the market today, and the vast majority of these are small molecule therapeutics. When a new product goes into clinical trials, it must demonstrate a clear advantage over therapeutics that are already commercially available to treat the same indication. Given that so much research and development has already gone into less complex small molecules, it is only natural that novel small molecules would become increasingly complex. ... Read more
Next is the pervasiveness of targeted treatments. The size and structure of small molecules typically allows them to pass through cell membranes easily, enabling more precise targeting than biologics.2 Small molecules can reach a range of biological targets, and research and development for emerging modalities like RNAtargeting small molecules and proteolysis-targeting chimeras, or PROTACs, has escalated in recent years.6 In addition, antibody drug conjugates, which pair a small molecule drug with a monoclonal antibody, have gained traction for their potential in delivering highly targeted cancer treatment.6 The targeting ability of small molecules has made them a focal point in research for novel and innovative therapeutics, which has correlated with their rising complexity.
Finally, small molecules play a critical role in treating some of the most widely researched disorders around the world. Oncology, diabetes, autoimmune disorders and respiratory disorders are together responsible for half of all global pharmaceutical growth. Small molecules are used in a substantial portion of global innovation for these widespread conditions, which have drug pipelines that are among the most complex and therapeutically-advanced in the world.Read less
The challenges complex molecules bring
Now that we’ve discussed why small molecules have become increasingly complex, we can take a closer look at how this complexity correlates with new challenges in the drug development and manufacturing process. Any API development and manufacturing project brings a multitude of challenges and considerations throughout the product lifecycle, from scalability to costs, efficiency, environmental sustainability and much more. When working with complex molecules, however, these challenges are intensified and accompanied by others that are specific to complex small molecules. Let’s explore some of the challenges associated with customisation, budget and time constraints, scalability and specialised technologies.
As mentioned, a main reason for the rise in small molecule complexity is that so many of the less complex small molecules have already been discovered. This directly relates to a shift away from natural-based small molecule products. Rather than seeking molecules from plants, fungi, and other organisms to act on a particular target, advancements in knowledge of proteins and genetics have enabled scientists to create novel molecules to serve a particular purpose. This can bring added challenges with solubility and bioavailability, necessitating additional structure-activity work to improve biological activity.
Costs are top-of-mind in any pharmaceutical development project, but especially so when complex chemistry is involved. Today, the estimated cost of developing and commercialising a new drug product is $2.8 billion. Given that only 12% of products in clinical trials go on to receive commercial approval,10 organisations are focused on containing costs as much as possible, particularly in their projects’ early phases when there is so much uncertainty around the product’s long-term success.
On top of sticking to budget, organisations aim to get to clinical trials as quickly as possible, which can be difficult when complex chemistry is involved. As a result, it is important to balance budget and time considerations while ensuring ongoing product quality and regulatory adherence.
As processes become more complex, it is critical to ensure ongoing product quality and scalability. Complex processes are often more difficult to replicate, so it is imperative to consider long-term project implications in early stage development. It’s also important to account for process optimisation steps that may need to occur later on and at what point the project must adhere to GMP standards. This will help to proactively mitigate unanticipated challenges and ensure continued quality and compliance as the project scales.
Finally, continued small molecule innovation has resulted in increased demand for specialised technologies, such as hazardous chemistry, high potency APIs and continuous manufacturing, to name just a few. Over the next few years, continuous manufacturing in the pharmaceutical industry has an expected CAGR of 10.2% , while the HPAPI market’s expected CAGR is 8.7%.12 Complex technologies like these require specialised equipment and expertise that can be challenging for organisations to implement internally.
Given the sensitivity to time and budget, as well as the specialised expertise necessary to support complex technologies, it is generally not time- or cost-effective for organisations to handle every aspect of their project in-house. As a result, outsourcing is a preferred approach for many pharmaceutical and biotechnology organisations, particularly as molecules become even more complex.
Navigating molecule complexity through strategic partnerships
Molecule complexity is a key driver for outsourcing. This is evidenced by the fact that top characteristics for an outsourced partner are closely aligned with the key challenges associated with complex molecule development and manufacturing.
These include:
- Technical expertise
- Innovative capabilities
- Flexibility
- Reputation
- Cost
88% of pharmaceutical professionals cite interest in entering a strategic partnership with a CDMO in the near future.
Proven complex chemistry solutions, rooted in 50+ years of expertise
At Sterling, we deliver more than 50 years of expertise in complex and hazardous chemistry to support our customers in researching, developing and manufacturing complex molecules. Our state-of-the-art facilities and 900+ expert team members enable us to support a broad range of complex requirements, all while maintaining close scientific collaboration and partnership with our customers. ... Read more
We deliver the specialised equipment and expertise needed to handle complex project requirements like high potency APIs, controlled substances, hazardous chemistry, continuous manufacturing, biocatalysis and more. Through our Technology and Innovation Programme, we continue to explore emerging technologies within the industry and seek new ways to apply them in our customers’s projects.
Finally, as a full-service partner, we not only have the capabilities and infrastructure needed to support our customers’ molecules from grams to tonnes, but also deliver added support through funding guidance, regulatory support and more. All of this enables us to maximise our customers’ success throughout the entire product lifecycle, even when working with complex molecules.Read less
Your molecule may be complex, but your outsourced partnership shouldn’t be
We are a PDMO, or partnership development and manufacturing organisation. This underscores our commitment to treating our customers’ molecules as our own and providing a uniquely collaborative and transparent outsourcing experience.
