For any new drug, a cornerstone of a molecule’s long-term success is how it is developed within the early phase, but this has to be weighed up against the costs and time spent at this stage, and when a return on investment on a program is likely. Current estimates put the time a molecule takes in preclinical discovery and development to typically be between three and six years,¹ and the cost of progressing a project from discovery to commercialization to be up to $2.8 billion.²

An overall strategy to mitigate any challenges that could arise in later stages, is to keep the finished product in mind even at the outset of a project, including how the molecule will be manufactured, and ultimately formulated. This can be difficult, as early-phase development is often about speed of progression, but proactive planning is crucial to avoid the potential significant added costs and delays at a later stage.

For this reason, it is often beneficial to work with an outsourcing partner that has capabilities and expertise that span the full lifecycle of a project. The outsourcing partner should share its experiences and challenges at all stages of development, while providing a wider viewpoint on the implications of decisions being made, and how they may impact on later, essential steps. To counteract these challenges and develop solutions proactively, a partner must also be flexible and transparent, ensuring vital communication as the project progresses.

Early-phase development often includes intensive research and analytical work, and for companies with limited resources or expertise in these areas, outsourcing can offer the best method of increasing the input to a project. The additional experience that a development partner can bring should also increase the quality of drug candidates being progressed towards the clinical phases, and reduce the chances of failure.

Although there are many reasons why small molecule drugs fail in clinical trials, there are some measures that can be taken during early-phase development to avoid these. Six factors that organizations should carefully consider to minimize future setbacks are: funding, analytical capabilities, solid state science, regulatory considerations, hazard evaluation, and a full-lifecycle perspective.

Funding

Global pharmaceutical R&D spending is now upwards of $186 billion,³ and in part, this is down to the rise in therapeutic complexity and increased cost of biologic and advanced medicines such as cell and gene therapies. One study showed that 22% of failed Phase 3 candidates resulted from insufficient funding,⁴ and even for small molecule programs, securing adequate funding for a new project can be challenging, particularly for smaller biotechs focused on a single molecule.

In a project’s earliest stages, there could be limited data or results to show investors that may be keen to see a potential return on investment as soon as possible, as well as a lack of name recognition. It is possible, and even probable, that an organization may not secure all of the funding it desires in one financing round. By partnering with a credible and experienced outsourcing partner, guidance and advice can be offered on how to be resourceful and prioritize the allocation and use of funds while an organization works its way through multiple fundraising rounds.

It is also important to consider geography in the funding process, as it is typical for grants to require that a certain portion of the project is carried out where the grant was issued, and this may be prohibitive when looking to outsource, or allocate funds for parts of the development.

Analytical capabilities

Satisfying stringent regulatory requirements, characterizing the product’s properties, and affirming its safety and efficacy in a robust manner requires a comprehensive analytical approach and experienced scientists using specialized equipment. Ensuring a safe product is essential, with 17% of Phase 3 trial failures resulting because of safety reasons,⁴ the second largest factor behind a lack of efficacy. Target identification, method development, and method validation are key analytical steps that must take place early in any drug project, as this information will be carried through the entire development process. It is important to compile all of the necessary data while also adhering to time and budget constraints, it is therefore crucial to tailor the analytical strategy based on the organization’s specific project requirements and priorities.

When developing a process, chemists must be aware of concerns around raw materials and intermediates that are classed as potential genotoxic impurities (PGIs). M7 guidelines released by the International Council for Harmonization (ICH) in 2017⁵ advise on the assessment and control of mutagenic impurities, and any early phase synthetic route must ensure that as the molecule moves through the clinical phases, the risk of exposure to the patient does not reach dangerous levels. This is also true for elemental impurities, so an appropriate strategy for analytical method development is necessary.

The route of synthesis can sometimes be changed to avoid the use of reagents or materials that are themselves PGIs or elemental impurities, but this is not always possible, and as such, the development of a robust analytical process in these cases to ensure any impurities can be detected accurately within specifications will be a priority.

Solid state chemistry

A product’s solid form has a significant impact on its solubility, bioavailability, and other properties that factor into its safety and efficacy. For this reason, the identification and development of the active pharmaceutical ingredient’s (API) optimal solid form early on is another key component of eventual success.

Solid form investigations should be considered as a development objective as early as possible, especially if the API is considered to be in either Class II or IV of the biopharmaceutics classification system (BCS),⁶ which have low aqueous solubility. Salt and cocrystal screening may identify a version of the API that has improved solubility and can improve bioavailability. Understanding the polymorph landscape of an API can not only identify a preferred form, but also assist in development. These investigations will guide the developability of the API, as well as drug product formulation.

A situation that could potentially curtail the development of an API is if a metastable form or version is taken forward into further evaluation—and shown to be efficacious—and subsequent batches of the API are produced and found to not perform to the same extent or, indeed at all. This can indicate that a more stable form of the API has been produced in following batches. Such a scenario presents questions that can extend the development timeline, such as whether the more stable form can be used; can the metastable form be produced; and what the stability implications could be moving forward?

All salt and cocrystal investigations can be tailored to the clients’ requirements. This might require a focused salt or cocrystal screen of the API with co-forms that may increase the melting point or enhance aqueous solubility, or a broader screening program of the behavior of an amorphous API in various conditions.

Achieving the desired solid form may require a variety of different investigations, including salt, co-crystal and polymorphs, before crystallization development. This is especially important considering that around 90% of small molecule drugs are commercialized in their crystalline form.⁷ While it can be a time-consuming process, arriving at the ideal solid form of an API early in the lifecycle avoids later challenges regarding the formulated drug product. Having to change the solid form during clinical development means having to repeat many of the previous steps, with potentially huge impacts on costs and timelines.

Solid state screening should be completed at the very latest before a drug enters Phase III clinical trials and generation of the registrational stability batches—whichever is earlier. If the initial batches of API are generated before a polymorph screen then solubility and stability of the drug substance may be impacted and may need to be re-established.

Regulatory considerations

Before a product enters clinical trials, organizations must submit an Investigational New Drug (IND) application, which affirms the product’s safety and efficacy by supplying all the necessary supporting data, and provides manufacturing information. Regulatory requirements are therefore another important factor to be addressed in the early phases of a project to avoid setbacks in the later stages.

An effective initial Chemistry, Manufacturing and Controls (CMC) strategy needs to be developed that will ensure ongoing quality and compliance as the project scales up, while at the same time striking a balance between speed and cost. To achieve this, a fit-for-purpose approach is often used, where certain process optimization steps are reserved for after the preclinical stage and as a result, an organization can better allocate resources as the product progresses through trials, maximizing its chance of success.

Very little in terms of the chemistry needs to be finalized and “locked in” during early phase clinical trials. It is expected that there will be some specifications for raw materials, intermediates and the API, and some level of testing executed for intermediates and API. As the programs progress, there will be evolution in terms of the addition of test methods/specifications, as well as potential tightening of the specifications as process knowledge is gained. Raw materials will need further testing, as opposed to using initial Certificate of Analysis release in early phase, and analytical validation will need to take place. During this evolution of the process, test methods/specifications of the drug substance will continue to be updated in Module 3 of the common technical document (CTD) in preparation for the final new drug application (NDA) submission.

Hazard evaluation

While an API can be synthesized safely at laboratory scale, hazards can often arise as processes are carried out at a larger scale. Medicinal chemists may not always appreciate the challenges that using certain reagents or solvents may have as the scale of synthesis increases, but working with a company which has experience of process development, measures to eliminate or substitute materials and processes from the project that may be unsuitable for scale-up, and eventual commercialization, as well as continually monitoring potential hazards throughout the project lifecycle, can avoid pitfalls that could present setbacks later on.

Full lifecycle perspective

The early phase considerations outlined above all have implications for the project’s later development stages, and should inform every decision in the API product’s lifecycle.
Having an end-to-end perspective gives an understanding of the potential demand upon scale up and enables the proactive mitigation of challenges that could surface as the project moves into later stages, and ultimately, on to commercial approval.

An outsourcing partner with the flexibility, expertise and facilities to progress projects from the laboratory to a commercial scale can maintain critical project continuity, and minimize time-consuming external tech transfers. Furthermore, if special considerations such as controlled substances are relevant, a partner with the infrastructure in place to handle such compounds eliminates the need to move the project elsewhere, avoiding additional delays since the transfer of a process to another provider can take significantly longer.

Integrated approach

Drug development presents many challenges, and there is not one defined path or a “one size fits all” approach towards undertaking each project. Early phases of development require a difficult trade-off between generating results and data, while balancing the time and cost spent to achieve that. For many companies with restricted time and budget, ensuring efficient use of resources can be assisted by using outsourcing partners.

When companies are searching for a partner, major selection criteria include compliance, the ability to fully understand project requirements, reputation, cost effectiveness, and risk evaluation. A partner with end-to-end expertise and integrated development services can help strike the right balance between short-term efficiencies and long-term requirements, while prioritizing timeliness and quality at all times. For smaller research organizations that may lack in-house resource or experiences in all the stages of development, this approach provides an ideal solution for progressing their candidates through to commercialization. 

References

1. DiMasi, J.; Grabowski, H.; Hansen, R. Innovation in the pharmaceutical industry: New estimates of R&D costs. Journal of Health Economics [Online], May 2016, 20-33. ScienceDirect. https://www.sciencedirect.com/science/article/abs/pii/S0167629616000291?via%3Dihub (accessed August 30, 2021).
2. Biopharmaceutical Research & Development: The Process Behind New Medicines, 2015. Pharmaceutical Research and Manufacturers of America. http://phrma-docs.phrma.org/sites/default/files/pdf/rd_brochure_022307.pdf (accessed May 20, 2021).
3. Total global spending on pharmaceutical research & development from 2012 to 2016. Statista. https://www.statista.com/statistics/309466/global-r-and-d-expenditure-for-pharmaceuticals/ (accessed October 19, 2021)
4. Fogel, D. Factors associated with clinical trials that fail and opportunities for improving the likelihood of success: A review. Contemp Clin Trials Commun. [Online], Sept 2018, 156-164. National Center for Biotechnology Information.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6092479/ (accessed October 19, 2021).
5. https://www.ema.europa.eu/en/ich-m7-assessment-control-dna-reactive-mutagenic-impurities-pharmaceuticals-limit-potential
6. Amidon, G.L., Lennernäs, H., Shah, V.P. et al. A Theoretical Basis for a Biopharmaceutic Drug Classification: The Correlation of in Vitro Drug Product Dissolution and in Vivo Bioavailability. Pharm Res 12, 413–420 (1995). https://doi.org/10.1023/A:1016212804288
7. Variankaval, N.; Cote, A.; Doherty, M. From form to function: Crystallization of active pharmaceutical ingredients. AIChE Journal [Online], June 2008. 1682-1688. https://aiche.onlinelibrary.wiley.com/doi/full/10.1002/aic.11555 (accessed October 5, 2021).