Orphan Drugs

Rare Diseases and Orphan Drug Designations

Rare diseases are typically defined as conditions affecting between 4 and 6 people per 10,000. Therapies in development for rare diseases may receive orphan drug designation, which provides incentives to help offset the financial challenges of addressing the needs of extremely small patient populations. The incentives include seven years of market exclusivity, tax credits for qualified clinical research, and waived US Food and Drug Administration (FDA) user fees, all of which significantly improve the commercial viability of these programs.

Orphan drug development is increasingly central to the R&D strategies of biopharmaceutical companies. Approximately 44% of global clinical trials are for rare diseases, with many focusing on oncology, immunology, cardiovascular, and central nervous system (CNS) indications.¹ These therapies have a higher likelihood of being first-in-class or leveraging novel mechanisms of action, further increasing their strategic value.

Growth of the Orphan Drug Market and Implications for Manufacturing

The orphan drug market continues to outpace traditional therapeutics, driven by scientific innovation, regulatory support, and strong investment. According to Evaluate, orphan drugs are projected to achieve a compound annual growth rate (CAGR) exceeding 10% through 2030, compared to 7.5% for non-orphan drugs.²

This rapid growth has implications for development and manufacturing. Orphan drug production involves small volumes, potentially complex modalities, and the need for a strong foundation of process and quality understanding, all of which require specialized capabilities. Success depends on scalable, flexible manufacturing strategies that can support accelerated development while ensuring the highest standards of quality and regulatory compliance.

Key Considerations When Selecting a CDMO for an Orphan Drug

As orphan drug programs advance through development, the choice of a contract development and manufacturing organization (CDMO) becomes a critical success factor that impacts timelines, cost, and regulatory outcomes.

For both established and emerging biopharmaceutical companies advancing an orphan drug candidate, the right CDMO provides manufacturing capacity, regulatory and technical expertise, and the ability to anticipate and address potential challenges. From navigating accelerated regulatory pathways to aligning development decisions with future commercial requirements, an experienced CDMO helps de-risk the entire program.

Key considerations include specialized chemistry expertise, digitalized process development, flexible manufacturing capabilities, a proven, phase-appropriate approach to quality, and expert project management. Together, these capabilities ensure that programs can move quickly without sacrificing quality.

Specialized Chemistry Expertise for Orphan Drug Manufacturing

Many small molecule programs for rare diseases involve high molecular weight compounds, multi-step syntheses, and structurally complex Active Pharmaceutical Ingredients (API), which demand deep chemistry expertise.

With specialized development and manufacturing expertise for orphan drugs, our small molecule CDMO services brings advanced capabilities in complex API development, including chiral chemistry, crystallization, scalable route design, and advanced purification techniques. With experience across a wide range of molecule types, our team identifies opportunities for optimization and establishes robust, scalable synthetic processes that support rapid clinical advancement and a seamless transition to commercial manufacturing.

Digitalized Process Development from Route Scouting to Scale-Up

Synthetic route scouting using Artificial Intelligence (AI), in-silico approaches, enables identification of efficient, scalable pathways. Techniques such as parallel screening and data-driven decision-making are used to rapidly define optimal reaction conditions.

Developed over two decades, our SYNTHIA^® software platform accelerates development of synthetic routes using expert-coded rules based on proven chemical transformations. With a catalog of over 12 million commercially available starting materials and building blocks, the platform provides access to a broad portfolio of available chemistry.

As an experienced CDMO, we design processes with the end in mind, facilitating the transition from development to clinical and commercial manufacturing. This includes optimizing purification strategies such as reducing reliance on costly chromatography where possible and leveraging strategies such as crystallization to improve efficiency and cost of goods.

Real-time process evaluation and the application of AI and digital tools are additional differentiators. By reviewing data step-by-step rather than at the end, our team can identify trends, address issues early, and continuously refine the process. The result is a faster, more controlled path to production, which is critical given the fast transition from clinical to commercial typical of orphan drug programs.

In silico scalability assessments, crystallization assessments, and filtration assessments as a compliment to wet chemistry serve to derisk programs and reduce cost and time compared to the use of only wet chemistry.

Use of Phase-Appropriate Quality and Quality by Design for Orphan Drug Development

In orphan drug development, applying late-phase quality rigor too early in the process can slow timelines. That’s why our team implements a phase-appropriate quality (PAQ) approach, tailoring development, vendor qualification, and analytical methods to the needs of each stage. Early phases prioritize speed and flexibility, using fit-for-purpose methods and deferring full validation until it adds real value. 

The foundational concept behind a PAQ strategy is to avoid investing in later-phase activities before they’re needed. Applying Phase 2 or 3–level quality standards during Phase 1 can consume significant resources that may never deliver value if the program does not advance.

Using a staged approach ensures resources are deployed efficiently, aligning cost with progress and reducing unnecessary spending. Phase-specific activities are outlined in Table 1.

Drug candidates with Fast Track status (see below) can be eligible for Accelerated Approval, allowing approval based on an early surrogate endpoint before Phase 3 clinical outcomes are finalized. For these programs, integrating Quality by Design (QbD) principles in parallel to PAQ is invaluable to help ensure commercial preparedness. By developing process understanding early, our team can effectively justify changes and maintain flexibility as the program evolves.

Also critical to success is our in-house analytical capability. Keeping method development and testing onsite reduces turnaround time, enables real-time decision-making, and minimizes risk. Combined with templated, experience-driven approaches, this allows programs to advance quickly while generating the data needed for regulatory confidence and eventual commercialization.

FDA Expedited Programs Accelerate Orphan Drug Development

To support faster access to therapies for rare diseases, the FDA offers four expedited development and review pathways.

• Fast Track designation is designed for drugs that address serious conditions and unmet needs, enabling more frequent FDA interactions and rolling submission of application sections. About 50% of orphan drugs receive Fast Track designation.³
• Breakthrough Therapy designation further accelerates development for therapies with early clinical evidence demonstrating substantial improvement over existing options.
• Priority Review shortens the FDA review timeline for drugs offering significant advances in safety or effectiveness.
• Accelerated Approval allows earlier approval based on surrogate endpoints, with required post-approval studies to confirm clinical benefit.

In addition, Rare Pediatric Disease Priority Review Vouchers allow developers of some rare pediatric products to receive a voucher that can be used for a future non-orphan drug, providing significant financial incentives.

From 2003 to 2022, about two-thirds of new drugs received at least one special designation. Of 666 new drug approvals, 55% received priority review, 42% orphan designation, 32% fast track, 29% breakthrough therapy, and 15% accelerated approval.⁴ The percentage of drugs receiving an orphan designation increased from 20% in 2003 to 54% in 2022. Immediately following introduction of the breakthrough therapy designation in 2012, 12% of drugs receiving the designation; this increased to 35% in 2022.

Flexible Manufacturing for Uncertain Orphan Drug Demand

Orphan drug manufacturing must account for small patient populations, evolving demand forecasts, and the potential for rapid geographic expansion or additional indications. As a result, flexibility in scale and capacity is essential.

We offer flexible capacity, from small clinical batches to mid-scale commercial production. This includes the ability to both scale up and scale out, ensuring that manufacturing can adapt as programs expand into new geographies or indications. Access to multiple production suites enhances agility, enabling parallel activities and rapid response to changes in demand.

The ability to rapidly adapt processes ensures programs stay on track despite inevitable changes. For orphan drugs, where traditional economies of scale don’t apply, this agility is a key driver of both cost efficiency and speed to market.

Agile Project Management Supports Orphan Drug Development and Manufacturing Success

Effective project management is essential during the development and manufacturing of orphan drugs. Our CDMO team leverages a proactive, highly collaborative “triad” approach. Along with the project lead, there are dedicated manufacturing science and technology (MSAT) and quality assurance (QA) leads who are customer-facing and accountable for the overall success of the project and deliverables.

Frequent client communication, real-time decision-making, and transparency are essential aspects of our project management approach. Our teams anticipate challenges, identifying risks early, proposing solutions, and guiding clients through trade-offs. Whether it’s adapting to a process deviation, accelerating a review cycle, or preparing for a phase transition, this approach allows us to maintain momentum without compromising quality.

Data review, continuous updates, and open dialogue ensure that clients remain informed and confident throughout the process. In a space where many companies are advancing their first therapy, this level of partnership highlights project management as a strategic advantage.

Conclusion

In orphan drug development, where first-in-class therapies and novel mechanisms of action call for specialized expertise and fast-track know-how, the right CDMO partner can make the difference between delay and success. We support both emerging and established biopharma companies with deep synthetic chemistry expertise, digitalized process development, flexible manufacturing, a PAQ approach, a strong regulatory track record, and agile project management. The result is a faster, more efficient path through the clinic and to commercialization.