Developing drugs to target rare diseases (orphan drugs) is not undertaken by many pharmaceutical companies as these diseases affect a relatively small section of the population. But rare diseases can be extremely debilitating for the affected, and present a true unmet medical need.

Over the last few years, interest in orphan drug development has grown due to efforts by advocacy groups and incentives provided by the government. For example, the Orphan Drug Act (ODA) grants a special designation to a drug targeting a rare disease, if it meets specified criteria. Orphan drug designation qualifies the sponsor for various development incentives, including shortened clinical programs, fee waivers, faster review and approval, tax credits and longer drug market exclusivities.

According to the National Organization for Rare Disorders (NORD), more than 25 million Americans are affected by one of 7,000 rare diseases—for which 90 percent have no FDA-approved treatment. While the FDA approved 599 drugs under the ODA between its passage in 1983 and July 2020, the vast majority—75 percent—treat just one condition. Thousands more rare diseases, which NORD defines as affecting 200,000 people or less, await drug remedies.

As more companies delve into the development of a rare disease drug, some may want to consider partnering with a contract development and manufacturing organization (CDMO) to bring potential treatments to patients faster. When embarking on this journey with a CDMO partner, it’s critical to consider a few key challenges and understand how best to overcome them.

Working with limited time and funds
Orphan drugs are brought to market on a highly compressed runway that’s typically 3-8 years faster than that of a traditional drug. But the quality of an orphan drug must not suffer due to taking a shorter development path—some components of chemistry, manufacturing, and controls (CMC) cannot be compressed or redone. As such, it’s a significant challenge for sponsors and their partner CDMOs to balance the risk of reduced process development and optimization with earlier access to the drug.

Furthermore, developers usually have to work with limited funds. But orphan drugs developed on compressed timelines require more investment in CMC earlier, while the overall program risks remain high. Many smaller companies struggle with securing sufficient funds without meaningful clinical data, which is a key factor dictating funding mechanisms.

The best way to tackle these time and money constraints is through proactive and effective communication between sponsor and CDMO, and early strategic planning. It’s critical to have a close collaboration that balances communication with overall program management of budget and timelines. On the part of the CDMO, it’s essential to be transparent about the complexity of the development process, yet resourceful and respectful of the sponsor’s needs.

When choosing a CDMO partner, first and foremost, sponsors should consider the CDMO’s experience and technical capability to work optimally with the program funds at hand. A strong and experienced team of process chemists, engineers, analytical chemists and regulatory experts can make a significant difference in the efficiency of development, and ultimately, how quickly a process can be optimized and validated for commercialization.  

Ensuring product availability and managing stress on the supply chain
As sponsors move toward commercialization, the biggest challenge is appropriately forecasting and preparing for finished dosage supply requirements at launch. But the limited time available to commercialize the product stresses the supply chain. For orphan drug programs, the commercial route must be validated years in advance of the typical time it takes for a traditional drug filing.

Under these circumstances, both the sponsor company and the CDMO may be faced with the predicament of how much optimization is actually required. To guide this understanding, sponsors should work closely with regulatory authorities, and ensure the chemical process is reliable, reproducible, robust and complies with regulatory guidelines.

To ensure product availability at launch, sponsors must think about building out a commercial manufacturing plan early on. It’s recommended to work backwards from the intended new drug application (NDA) filing timeline to develop a manufacturing plan that involves all supply chain parties, i.e., raw material supply through finished dosage, packaging and distribution. The partner CDMO must collaborate closely with the sponsor to understand the filing timeline, patient market for the therapeutic being commercialized and estimated market forecast demand for launch and post-launch. In this way, the CDMO can effectively:

• Plan for technology, labor and equipment/facility capacity;
• Implement a robust supply chain of raw materials; and
• Ensure that the manufacturing process is validated at scale.

A few important factors that orphan drug sponsors and their CDMOs must consider when planning ahead for process development are the type of drug being made, target population and its size, and dosage. To illustrate these considerations, a good example would be making a very potent drug for a very rare disease. In this case, the patient population is narrow and the quantity of drug needed per patient dose is small, so drug production happens in small batches. As such, the process chemistry development can tolerate more risk.

In contrast, drugs that target a larger population and are needed in higher doses require more scrutiny as significant amounts of drug are produced. The bigger the batches, the higher the potential for issues with the chemical route. This type of large-scale development can result in a great deal of pressure for the CDMO, in terms of safety and expense. To mitigate that pressure and risk, the CDMO must keep in close collaboration with the sponsor to understand key CMC decisions and develop a robust commercial route.

No matter how well-planned a manufacturing project may be, unexpected program delays, natural disasters and shipping issues can occur, causing major stress on the supply chain. For example, the COVID-19 pandemic has hindered supply chains across the globe in various industries. Therefore, it’s crucial for any manufacturing organization to have appropriate business continuity plans established. Orphan drug sponsors and their CDMOs must have contingency planning for raw material shortages, facility changes, equipment downtime and surges in product demand.

Curia, a global CDMO that provides drug discovery, development, cGMP manufacturing and aseptic fill and finish to the pharmaceutical and biotechnology industries, was well-prepared to face the COVID-19 pandemic due to its strong contingency planning tactics. These included dual sourcing and raw material stockpiling to assure uninterrupted supply. For example, Curia, formerly AMRI, had implemented effective dual sourcing strategies in which both sources were located in different geographies and each had its own distinct supply chain in place.

Managing the regulatory aspects
As product quality and patient safety are the top-most priorities for both sponsor and CDMO, CMC teams should initiate interactions with the FDA or other relevant regulatory agencies as early as possible. Proper direction from regulatory authorities can be immensely helpful for sponsors and their partner CDMOs to rapidly develop a plan for the best chemical process and efficient commercial manufacture.

Developing an orphan drug does not always allow for sufficient time or funds to fix every single issue that comes up during manufacturing. Therefore, it’s vital to know what to prioritize. Sponsors and their CDMO must work together to identify issues requiring immediate attention and careful troubleshooting, while de-prioritizing minor issues that can be tolerated in a robust and reliable manufacturing process. CMC teams should focus only on solving the most critical process chemistry issues, while taking advantage of every learning opportunity.

This is where experience in orphan drug development becomes important, as it will be easier for veteran teams to spot significant vulnerabilities and strike the right balance on what needs to be fixed. Proactive and clear communication between sponsor and CDMO is vital, especially related to CMC challenges.

Conclusion
A path to advancing a rare disease drug to market comes with its own set of challenges that drug sponsors must be aware of and prepared to address upfront, if they are to succeed in CMC development on an expedited timeline. The fastest and most pragmatic way forward may be to consult and partner with a CDMO that has the exact expertise, technical capability, and experience that is required in this arena. If choosing to go this route, sponsors should consider partnering with a CDMO that prioritizes effective communication and proficient planning, and can also offer strong regulatory knowledge and support.