Navigating development in a complex molecule world

For decades, the pharmaceutical industry has relied on accelerated development and manufacturing timelines to bring new therapies to patients quickly. Regulatory agencies worldwide offer numerous expedited approval pathways. These include the US Food and Drug Administration (FDA)'s Fast Track and Breakthrough Therapy designations, as well as a new National Priority Voucher programme introduced in 2025; the European Medicines Agency (EMA)'s PRIME priority medicines designation; and Japan's Pharmaceuticals and Medical Devices Agency (PMDA) Sakigake programme for early practical application of innovative medicinal products.

While therapies for rare and orphan diseases, as well as specialised areas like oncology, are most likely to use accelerated pathways, they frequently involve molecules with extreme handling, formulation, or manufacturing requirements. These therapies may require highly potent active pharmaceutical ingredients (HPAPIs), which present unique risks to personnel and the environment for consideration during product development, manufacturing, and scale-up. Understanding the timing of disease onset and diagnosis is another key early-stage consideration of patient populations (e.g., age, complications from disease state, etc.) that dictates the required dose forms and manufacturing technologies.

Reducing risk through integrated development and early decision-making

For many years, accelerated development and manufacturing timelines have pressured developers to move new therapies to market quickly, while still maintaining a balance of risk/benefit assessment for patients. As development moves rapidly through proof of concept, the demand for having a robust, scalable, commercial-ready drug product approaches faster than generally anticipated. If a company fails to properly characterise and understand the APIs properties early on, they risk advancing a sub-optimal dose form into FIH studies, potentially leading researchers to incorrectly conclude a viable product is ineffective.

Integrated development strategies that combine formulation, manufacturing, and flexible clinical dosing have been proven to help de-risk early phase trials. Concurrent development and screening of multiple formulations in first-in-human (FIH) clinical testing can maximise clinical options. Small drug product batches can be utilised in rapid iteration to assess a product's druggability, thereby reducing cost and limiting active pharmaceutical ingredient (API) usage.

In silico predictive tools, such as modelling and simulation, can be integral to this process. They can assist in selecting suitable dose forms and forecasting critical parameters like pharmacokinetic (PK) profiles to enable data-driven decisions while minimising API usage. Maximising data from minimal resources is necessary not only for conserving expensive or limited API, but also for obtaining meaningful development data and maintaining product quality under compressed timelines.

The need for manufacturing and supply readiness happens much earlier than expected for programmes with (or with anticipated) accelerated approval designations. Refined scale-up strategies prioritise flexibility and just-in-time (JIT) production. Integrated partners can leverage internal synergy between development and manufacturing teams to accelerate early-phase study supplies, often requiring only days of stability data instead of the typical months or years associated with traditional batch manufacturing. Closely coordinated with product development, this JIT production is important for the clinical trial materials supply chain, ensuring that scarce API is efficiently converted into product to generate necessary PK, tolerability, and safety data.

Guidance on meeting new regulatory expectations

When pursuing an expedited approval pathway for a molecule, drug sponsors must seek partners that embrace shared ownership for success and possess deep expertise in mitigating technical and regulatory risks. A proactive and collaborative team approach enables more nimble, faster, and calculated actions when rapid changes in development programmes become necessary.

The molecular and dose form complexity, combined with the speed of the approval pathway, requires late-stage development to overlap with ongoing clinical, Chemistry, Manufacturing and Controls (CMC), and regulatory activities. Often, the drug’s approval is contingent on data that continues to be generated while clinical studies and the production process are ongoing. As a result potential gaps - particularly in process understanding, control strategy and shelf life stability must be identified, characterised, and de-risked. This ensures the product being considered for conditional approval does not present a risk to patients while awaiting full clinical endpoint data and marketing authorisation.

Additionally, if working with HPAPIs, a partner with capabilities for specialised containment and robust manufacturing infrastructure will be necessary to demonstrate adequate controls against cross-contamination. For a compound to successfully navigate an accelerated programme with compressed timelines, development partners must ensure their capacity for safe handling is well-established under strict controls, from the earliest phases of development throughout scale-up and into commercial manufacturing.

Regulatory agencies acknowledge the challenges associated with these expedited timelines and are eager to collaborate with motivated developers. For instance, the FDA launched the Chemistry, Manufacturing and Controls (CMC) Development and Readiness Pilot programme in April 2023 to help companies navigate and prioritise their CMC resources.

The critical issue in developing products, complex or otherwise, via expedited approval pathways is not the presence of inherent risks, but the failure to adequately prepare for and mitigate those risks. An experienced contract research, development, and manufacturing organisation (CRDMO) or integrated partner can play a significant role in providing consistent, dependable support. This includes helping sponsors anticipate and proactively identify gaps and formulate responses for regulators. They can assist in planning regulatory submissions and a pre-approval inspection (PAI), as well as facilitating mock inspections between quality, regulatory, and CMC teams.

As new technologies, geopolitical volatility, and increasing demand for specialised services add to the burdens of drug development and manufacture, it is necessary that sponsors maximise operational efficiency and minimise associated risk. A comprehensive strategy leveraging integrated development, digital tools, and experienced partners is necessary for successfully navigating the journey of a complex molecule to market.

About the authors

Brad Rowe is senior drug development consultant at Quiotient Sciences. He joined the organisation in 2005 and is based in Philadelphia, PA. Rowe joined QS Pharma, later acquired by Quotient Sciences, in 2017, initially working in the lab, and eventually became head of all analytical activities from the Philadelphia site. In his current role, Rowe helps the business unit teams discuss and scope programmes with customers, and supports programme operations as a technical advisor throughout the lifecycle of a programme. Rowe graduated from the University of Pittsburgh at Johnstown with a BSc in Chemistry and then the University of Delaware with a PhD in Analytical Chemistry.

Robert Cornog is senior drug development consultant at Quotient Sciences. Cornog has over 26 years of experience in product development and process design. Across a broad range of dosage forms and technologies, Cornog has focused on advancing pharmaceutical manufacturing through science and technical innovations. Through application of a deep understanding of manufacturing sciences and risk-based methodologies, he has successfully driven the adoption of new technologies and expanding manufacturing capabilities. Within the Integrated Development Services team at Quotient Sciences, Cornog provides technical and scientific support to operational and business development teams for the successful transfer of late-stage and commercial drug product programmes.