5 Emerging Trends In Complex Small Molecule Drug Production
By Sanobar Syed, BeiGene
Product development of new generic molecules starts early in the life cycle of the originator product (at the time of market launch), so long-term planning is essential and mainly based on product patent expiries. For small molecule generics, the development and manufacturing processes are in most cases straightforward. Generic manufacturers only need to prove that the product contains the identical chemical composition of the innovator product and demonstrate similar pharmacokinetic properties with a bioavailability study. However, the development of complex generics in an era of rising costs and increased focus on global developments and manufacturing operations requires a higher level of expertise. It demands more detailed planning and a deep understanding of the regulatory, quality, and clinical aspects of small molecule development to bring these drugs to the market.
According to a 2022 GlobalData report, sales of biologics are forecast to significantly overtake those of innovative small molecules over the next five years, with biologic sales forecast to be $120 billion greater than small molecule sales by 2027. Despite the significant growth and predicted dominance of biologics in the future, small molecule sales are also forecast to continue to grow, with small molecule sales forecast to grow by 49% in 2027. Small molecules continue to play a role in innovative treatments for the four major indications that account for more than half of global pharma growth: oncology, diabetes, autoimmune, and respiratory diseases.
The small molecule landscape is changing in terms of drug product complexity, molecule potency, manufacturing trends, and industry makeup. How the industry responds will shape the next chapter of small molecule drug development. In particular, how the industry integrates and consolidates across the value chain will be a key enabler of success. Let’s look into some of these emerging trends.
1. Complex Small Molecule Drugs Are Increasingly Complex To Manufacture.
Within the last decade, according to Lonza, the complexity of chemical synthesis has almost doubled from eight chemical steps to an average of 14 in 2021. The increase in steps to manufacture an active pharmaceutical ingredient adds to the complexity of the molecule. From a supply chain perspective, it adds multiple layers of nuances in containing, handling, and transporting different chemical elements, which means that manufacturers must have a strong command of their value chain to ensure that development timelines are consistently met.
The other aspect is the drug product itself, because most drug candidates in the market have some sort of bioavailability challenge. What this means for the manufacturing and development of small molecule drugs is that enabling technologies must be employed to solve these challenges. Particle engineering technologies, such as amorphous solid dispersion or micronization, will be critical in ensuring the efficacy of these drugs.
2. Demand For High-Potency APIs Is On The Rise.
The API industry is moving toward complex APIs to achieve differentiation and competitive edge in the market.
Over a quarter of drug products in development contain highly potent APIs (HPAPIs), driven by improved targeting in treatments for cancer, diabetes, autoimmune diseases, and other indications. For oncology drugs, the proportion with a HPAPI component is closer to three-quarters. These APIs are highly toxic and require specialized manufacturing and handling capabilities, which many smaller innovator firms may not want to build in-house.
According to Research And Markets, the oncology segment dominated the market with 41.8% of the revenue share in 2022, and it is anticipated to register the fastest CAGR of over 7.0% over the next seven years. This growth highlights the high need for HPAPIs. One of the major factors supporting the segment’s growth is the significant number of oncology drugs in the regulatory approval pipeline. When larger firms have a choice to either develop the capabilities in-house or outsource them, outsourcing is the preferred choice, especially when there is a need for speed to market or to be first to launch in the marketplace. The development of HPAPIs will add a unique competitive edge but needs to be carefully aligned with internal resources.
3. Small Companies Are Driving Innovation.
The vast majority of small molecule drugs in development are held by small or “emerging” companies with fewer than 100 employees. There is a growing interest among pharmaceutical companies in outsourcing or having an alliance with smaller niche companies to support core competencies such as sales, marketing, and others, due to associated cost savings. These companies are increasingly bringing successful compounds to commercial production, and they typically require access to enabling technologies, development, and manufacturing partners to do so.
4. There Is An Increased Need For Speed.
Speed has always been important, but today it is more critical than ever because of the rise in specialty drugs and orphan and breakthrough designations, as well as increasing reliance on the FDA’s NDA 505(b)2 pathway. Since smaller companies can be reliant on one or only a few compounds, establishing a clear line of sight to clinical studies and commercialization is imperative. They often need access to phase-appropriate development services, infrastructure, and know-how to accelerate time to first-in-human studies, through later-phase clinical studies, and for rapid scale-up. Generic manufacturing has always been on the podium of speed to market, and it will be increasingly difficult to generate speed while trying to acquire the capabilities to address orphan and rare diseases.
5. One Size Does Not Fit All For Manufacturing Services.
Flexibility is increasingly important when aligning manufacturing services with more specialized and lower-volume drug products. Forecasts are more challenging for specialty products with finite patient populations, and flexible business models and assets are essential. Flexibility further extends across the drug development cycle, where integrated development and commercialization can be of value to certain companies and/or drug programs. CDMOs that offer an end-to-end spectrum of flexible development and manufacturing capabilities, as well as complementary service options such as regulatory expertise and counsel, are natural partners for emerging innovator firms or specific innovator programs.
Consider a pilot program or pilot product that can be supported through integrated support systems, which can then branch out further as the companies progress in the product life cycle. Flexibility and agility are key areas that the companies need to integrate early on into their mindset, from top to bottom, to achieve a well-rounded development and commercialization strategy.
Conclusion
Despite the rise in complex biologically derived molecules (biologics) and other factors, there continue to be record numbers of small molecule candidates in the clinical pipeline. These drugs can reach targets that biologics cannot access by, for example, infiltrating cells to disrupt the disease processes taking place inside them. They can also be formulated to be taken as an oral dose, a choice many patients prefer due to its accessibility.
Looking ahead, we are facing a period of massive consolidation. Some companies will struggle with debt — divesting assets, merging, and selling – and some companies will be acquired or will acquire assets. However, among these challenges there also lie opportunities for the complex small molecules segment. Considering the current market post COVID-19 and geopolitical developments, companies in this segment will need to adapt to survive in the new climate. Some companies will be in a good position to take advantage of the new landscape. The companies that are first to market, are first to file products, or have unique portfolios and good quality cost structures are the ones that will maintain their market positions. The complex generic segment must realize that the industry has changed and is continuing to change. And while there will be a lot of turbulence going forward (especially due to biologics, biosimilars, specialty chemicals venturing, and backward & forward integration by established players), there will also be opportunities. The companies that adapt to the new climate will be left to navigate an even more dynamic industry.
And our increased understanding of complex generic molecule therapeutics will enable patients to have access to treatment at earlier stages, potentially increasing their health span and quality of life.
All the views and opinions expressed are fully independent and belong to the author only. They do not represent the views or opinions of the author's employer or organization.
About The Author:
Sanobar Syed, M.Sc., MBA, is associate director of market insights and strategy at BeiGene. She has more than 14 years of experience in establishing and leading business strategy and forecasting in leading global pharmaceutical firms. She regularly speaks at industry conferences and guest lectures, and has developed academic modules in this field. She has a master’s in organic chemistry and an MBA in marketing.