Mastering complex small molecule APIs and formulations

April 9, 2024 by Staff Writer (15 minute read)

Active pharmaceutical ingredients (APIs) are the cornerstone of drug development, serving as the fundamental building blocks that dictate the efficacy and safety of medicines. These ingredients encompass a wide range of substances, including synthetic compounds, natural extracts, and more, each playing a pivotal role in the therapeutic effectiveness of a drug.

The development and production of APIs are critical steps in the journey from laboratory to market-ready pharmaceutical products. Over the years, the nature of APIs has evolved significantly, thanks to groundbreaking advancements in research and development. The deepening understanding of how deviations in cellular processes cause diseases and how APIs work to correct them has enabled the design of increasingly specific APIs, which has led to a rise in the complexity of their synthesis, the techniques used to give them form, and their overall formulation. These advances have introduced new challenges. A more complex synthesis is harder to scale up, and the products are frequently highly potent, requiring special handling. These products also require more attention to formulations to render them soluble and able to act with the intended pharmacological effect.

In the past decade, there has been a notable surge in the utilization of complex APIs, as highlighted in a 2018 report by the US Food and Drug Administration (FDA)¹. This increase is contributing to the expansion of the overall API market, which, according to a 2023 analysis, is projected to reach a valuation of $339 billion by 2030². This growth trajectory can be attributed to several key factors, including:

The rising demand for both generic and novel drug formulations, which often incorporate complex APIs due to their advanced therapeutic potential
The prevalence of chronic diseases, particularly in aging populations worldwide, necessitating more sophisticated treatment options, many of which rely on the complex interplay of formulation and API
The global expansion of the pharmaceutical industry itself, which is fueling the need for and development of these intricate substances

As the pharmaceutical industry continues to advance, the role of complex APIs becomes increasingly significant. They not only contribute to expanding the scope of treatable conditions but also highlight the industry's commitment to innovative, safe, and effective drug development. A focus for the future is highly potent APIs in therapeutic areas such as cancer, neurodegenerative diseases (e.g., Alzheimer’s disease), diabetes, obesity, and autoimmune diseases.

Navigating the complexities of these APIs requires specialized knowledge, cutting-edge technologies, and a robust regulatory understanding, underscoring the importance of ongoing innovation and strategic collaboration in the pharmaceutical sector. When working with a contract development and manufacturing organization (CDMO) it is essential to select a partner that has the experience, expertise, and operational flexibility to manage the diverse and evolving landscape and adapt to emerging trends such as personalized therapies and the growing emphasis on niche or orphan drug products. These shifts demand not only advanced manufacturing capabilities but also the agility to handle smaller, more specialized batches of medication.

In many cases, the existing hardware and infrastructure for pharmaceutical manufacturing is not suitable for such projects, so new approaches and new technology must be considered.

Several recent advances in technology help mitigate these and other challenges, including artificial intelligence (AI). AI can help with target detection, as well as characterizing solubility and other API characteristics much faster than traditional methods. Automation, modularization, and nanotechnology further support complex API development, meeting the demands of complex APIs and formulations in ways that traditional methods cannot.

Because of their expertise, developed through involvement in a wide variety of projects, CDMOs can serve as useful advisors and invaluable partners to help companies navigate the complicated processes involved in complex API and formulation development.

Among their many applications, computational models can be used to:

Characterize drugs more accurately and predict the best path for development, including bioavailability and solubility modelling.
Inform formulation development and clinical trial design, including dose selection and optimization.
Support the evaluation of critical regulatory review considerations, including evaluation of in silico absorption, distribution, metabolism, excretion, and pharmacokinetics (ADME-PK).
Identify process development and optimization issues.
Accelerate stability determination.
Aid in the development of lifecycle plans in the post-approval setting.

Key considerations for complex small molecule API development

Complex small molecules API development presents a unique set of challenges, including the complex chemistry of these molecules, drug substance properties, longer synthetic pathways, concerns about solubility and permeability, and a multitude of potential interactions with other materials within a possible formulation.

Compliance with API quality, testing, and documentation regulations requires diligent attention, as the regulatory environment is constantly changing to incorporate new understanding and to address new innovations and new technologies in API development. Developers should be specifically familiar with the purity, potency, and quality control requirements for complex APIs. For example, the control of the physical form of an API (e.g., identification of the correct polymorph, particle size distribution, flowability) becomes increasingly important as the complexity of the API and formulation increases. This technical precision is not just about enhancing the efficacy of the drug, but also about tailoring it to the needs of patients. By considering factors such as ease of use, palatability, and dosing frequency, pharmaceutical developers can create formulations that not only meet therapeutic goals but also support treatment adherence and compliance, ultimately ensuring a more patient-centric approach to drug development.

As with all products, cost and economic viability assessment, as well as supply chain management must be carefully considered. Originators of new APIs expect supply chains to be reliable and resilient. This opens options for Western suppliers of starting materials. APIs can be protected by intellectual property laws, in some cases limiting access and/or driving up costs.

Environmental and safety concerns, especially the handling and development of high potency APIs with their detailed safety protocols and containment strategies, are often overlooked during early development phases when volumes are small and the risk of project failure is still high. Importantly, CDMOs are expected to have the competences to handle these environmental and safety expectations after launch. The growing awareness of the impact of large-scale manufacturing operations on the environment requires a forward-looking and careful process design, taking into account new regulatory requirements. Accordingly, CDMOs are also expected to have robust waste-reduction and recycling strategies.

Other considerations within the growing field of complex API development include keeping up with technological advancements, optimizing stability and shelf life, and meeting the increasing need for targeted therapies through customization and flexible manufacturing of smaller quantities.

Navigating challenges in API development through CDMO partnerships

With all the challenges associated with complex small molecules API and formulations, developers may choose to partner with an experienced CDMO to ensure all key considerations are anticipated and addressed to avoid costly errors or oversights. A well-established CDMO has experienced research and development teams in place to innovate and streamline development processes. CDMOs are expected to be aware of potential pitfalls of complex small molecules API development (e.g., reagents may not be available on a larger scale, additional runs for process validation may be required) and to make suggestions to avoid them.

A CDMO partner may have relationships already in place (e.g. with universities or research institutions) with whom they collaborate for knowledge exchange and sharing of technical advancements. These partnerships, often global in reach, ensure that the best solutions and most robust support can be provided to their clients and that innovation reaches companies who are actively developing unique APIs and formulations. Finding successful or advantageous combinations of APIs and advanced formulations may become a very important field of innovation.

Regulatory, quality, and safety considerations

As mentioned, the regulatory environment around API development is constantly evolving. CDMOs should have a robust process in place for global and regional regulatory compliance. A dedicated regulatory affairs team that manages submissions, audits, and queries and stays vigilant in their understanding of current requirements can ensure nothing is overlooked or forgotten. In addition, an experienced legal team should be available to handle any issues around intellectual property rights, patents, or proprietary technology issues.

Quality control systems and standard operating procedures should be implemented and maintained to ensure purity and consistency. Because of the unique nature of complex APIs, extensive stability testing under various conditions is needed. Innovative packaging solutions may also be considered to support stability and shelf life. Stringent safety protocols, especially for high potency APIs, should be established, and all staff trained to follow them. These protocols may require the expertise of safety, engineering, toxicology, and operations professionals to ensure employees are kept from harm.

Cost management and supply chain management support the goal of optimizing production processes to reduce costs without compromising on quality. Cost-effective raw material sourcing and efficient resource utilization are pillars of cost management that should be employed regardless of the complexity of the API or formulation. An experienced CDMO can help develop resilient and flexible supply chains that can adapt to market disruptions. Solutions may include approaches such as “make or buy” options that render supply chains more resistant to unexpected disruptions. Successful CDMOs create this resilience, in part, through strong relationships with reliable suppliers and logistics providers globally.

Technological advancements

New and emerging technologies, such as continuous manufacturing and AI/machine learning, currently contribute to the growing excitement around complex APIs and finished formulations. In fact, these new technologies are credited as one of the major factors supporting the growth of this market. These advancements offer the potential for improved safety profiles, faster, more efficient development, and many other improvements to existing practices.

Environmentally sustainable practices and technology are also an important focus for innovation with a goal to minimize the ecological impact of API development and other manufacturing processes in the pharmaceutical industry. For example, approaches that involve computer modelling, such as Design of Experiments (DoE) and Quality by Design (QbD), can optimize processes and make laboratory development more efficient while lessening the potential impact on the environment. Automation for process optimization and process control not only minimizes errors, but it also improves efficiency and reduces energy consumption and waste. Other initiatives aim to minimize use of hazardous substances, altogether.

Integration of drug substance and drug product activities

Because of the increasing complexity of formulations, where the physical properties of a tailored drug substance are key to successful formulation and manufacturing, integration of drug substance and drug product activities is particularly important. Early integration of these two sets of activities, which often operate as silos, could lead to a more efficient and subsequently shorter development timeline. It allows the experts from one area to share knowledge that would be critical to the work of the other and vice versa. This is particularly important given the potential interactions between more complex APIs and the excipients or other materials used in the development of the drug product. Integration represents a more agile approach that can contribute to faster, optimized development.

Integrating drug substance and drug product development through a single CDMO partner can also support sustainability goals. The multistep synthesis for even a single dose of a complex, highly potent API may require large volumes of solvents that can be harmful to the environment if not handled properly. CDMOs that prioritize clean chemistry and sustainability have the competencies and procedures in place to develop recovery concepts for re-using and recycling materials across all phases, minimizing waste and reducing the environmental impact.

The role of partnerships and collaboration

Today, many pharmaceutical companies consider CDMOs as extensions of their own business, serving as advisors in some cases and completely managing full development projects in others. The importance of these collaborative efforts cannot be overstated, and they are driving a large part of the growth observed in the current markets. An experienced CDMO houses a wide array of experts, with knowledge gained through years of partnering with multiple companies across a broad range of projects. This experience lends itself to the development of innovative solutions and highly successful approaches to drug development projects, resulting in cost efficiencies, faster time to market, risk mitigation, and added flexibility and scalability.

Conclusion

As the complexity of APIs and formulations increases, so do the possibilities for finding safe and effective treatments for patients. Alongside this complexity, however, come new and more intricate sets of considerations and challenges.

In this evolving landscape, innovation plays a pivotal role. From the perspective of CDMO partnership, innovation manifests as a commitment to creating value for customers through precise knowledge of their needs and consistently applying technical and procedural capabilities to serve them. This ethos is encapsulated in the principle of striving to 'find a better way every day.' Such an approach demands daily engagement with customers, ensuring a deep understanding of their needs. It also requires the continuous honing of technical and procedural skills, and a conscious, ongoing search for better methods and solutions.

Partnering with an experienced CDMO that has specialized facilities and equipment required for complex API development, along with essential scientific, technical, and regulatory expertise, ensures pharmaceutical companies are well-positioned to address these challenges. This partnership fosters not just compliance with the current standards, but also a drive toward innovation, thereby optimizing speed to market, cost, and quality of the drug.

For more information about how Thermo Fisher Scientific can help support your complex small molecule API development, visit https://www.patheon.com/us/en/our-capabilities/small-molecule/api-development.html.

References

¹ US Food and Drug Administration. FYs 2013-2017 regulatory science report: Complex mixtures and peptides. 2018. Available at: https://www.fda.gov/industry/generic-drug-user-fee-amendments/fys-2013-2017-regulatory-science-report-complex-mixtures-and-peptides.

² Smith J. Active pharmaceutical ingredient market predicted to hit $339 billion by 2030. 2023. Available at: https://www.outsourcing-pharma.com/Article/2023/09/12/Active-pharmaceutical-ingredient-market-predicted-to-hit-339-billion-by-2030.