The Complexities of Manufacturing Orphan Drugs in Product Development

Cornell Stamoran, Vice President, Strategy and Government Affairs and Matt Mollan, Vice President Operations at Catalent for our latest EPM Magazine issue. 

There are approximately 1,500 active pipeline compounds within orphan designation today, and, like the overall pharmaceutical pipeline, small molecules make up the majority of these. Since 2010, 44% of all FDA New Molecular Entity / Biologics License Application approvals, and 67% of all new cancer treatments have been orphan drugs, however, there remains a real patient need for more, as 90% of rare diseases currently have no FDA-approved treatment.

For developers, the Chemistry, Manufacturing and Controls (CMC) challenges for orphan drugs are very similar to other products: incorporating patient factors in early decision making; appropriate formulation development; and selecting the optimal dosage form. However, for manufacturing, the key issues presented by orphan drugs are the high costs, the limited commercial capability for low volume products, and ensuring product consistency during scale up. There must be fit-for-purpose manufacturing and supporting infrastructure to efficiently and successfully scale up and deliver products for patients.

There are two major pressures on orphan drug programmes: time and the availability of the API drug product – every gram of product is precious. Due to challenges like limited bioavailability and the need for targeted release profiles, small molecule oral products are becoming more complex to deliver. Given the constraints of time and resources, it’s crucial to optimise formulation and dosage form design to enhance the likelihood of success.

Challenges of Formulation and Processing

For development, a risk-based CMC plan is strongly recommended, and this should be shared and discussed with regulators ahead of time and throughout the development process. Where possible, predictive tools should be used to minimise API usage, with the goal being to lock in the process as early as possible.

Time pressure means that whatever formulation is used in first-in-human trials is almost certain to become the one that remains through to commercial launch. Formulation needs to be developed using excipients that are transferable to larger scale processing, and once the formulation is fixed at registration, then processing is the key to commercial success. Figure 1 shows the orphan drug pipeline by dosage form, and it is evident that oral tablets and capsules are by far the most favoured by pharma companies. Oral tablets and capsules are a widely used dosage form due to their convenience, versatility, and cost-effectiveness. These advantages make them a preferred choice not only for pharma companies but also for numerous patients and healthcare providers. By selecting the appropriate formulation technology, it becomes possible to orally deliver many drugs that would otherwise be difficult or impossible to administer.

Figure 1: Orphan drug pipeline versus dosage form (Source: PharmaCircle, accessed Jan 2023)

Scale Challenges

Unlike other drug programmes, orphan drugs are unlikely to scale up to traditional, commercial batch size manufacturing, and often, the product will be launched at what would be considered clinical scale.

It is inefficient to be continually making batches of drug products during clinical development, so a choice must be made as to whether to scale up to a level to gain understanding of the process, providing product for all investigations and studies.

Choosing an optimal batch size is not easy, as there will be limited batches per year manufactured when a drug is commercialised, but the scale must be balanced against stability data to align with the determined shelf life. Making too much may lead to waste, but too little could lead to supply disruption. However, it is unwise to scale to a situation where only one or two batches are manufactured per year, because should anything unexpected happen during manufacture, this could incur a huge loss.

Scaling up activities can be done post-approval, and there are less resource pressures once the product is generating sales, however, any manufacturing should be carried out on fill / tableting lines and equipment that is already approved. Pre-launch, available API material is extremely precious, so using a site and equipment that has already been through regulatory approval with different products can de-risk the CMC process and avoid global regulatory queries, which could otherwise cause delay and additional costs.

As products will be distributed around the world, it is best practice to use materials that are globally acceptable and meet all countries’ regulations from the outset. This will prevent any issues if a new country is added to a clinical trial, where there are different standards than others, such as for bovine versus non-bovine capsules, as well as different colourants and dyes.

Time Challenges and Partnering for Success

Orphan drug programmes typically shorten the time to market by 3-8 years through expedited approval pathways when compared to traditional drug development paths. For innovators, this means there may be a reduced amount of real time stability data for commercial material, and initial commercial supplies may need to be provided by a clinical manufacturing facility, should the chosen commercial facility be unavailable.

In the last 10 years, on average, 55% of orphans approved from all company types, approved by the FDA, were outsourced from a finished dose form standpoint.3 Finding a commercial drug product manufacturing partner that can work all the way through from development to commercial scale keeps the process simple, by reducing the number of tech transfers and the process familiarisation phases of each hand off.

To minimise risks, it’s important to have a CDMO partner with experience in manufacturing orphan designated products at a small scale and limited batch. It is beneficial that they have a strong regulatory inspection history with global regulatory authorities and have produced NDA-approved products in the last 3 years so that they are aware of the current expectations and regulatory compliance.

Closely integrating clinical trial logistics with product supply can save time and money, while reducing transition points such as in manufacturing, packaging, clinical supply and analytical support, where possible, along with a strong project management foundation, is key to successful projects in the orphan area.


In summary, when developing orphan drugs, companies need to take certain key measures into consideration. One of the most important steps is to create a risk-based CMC plan, which will help to identify and mitigate potential risks early on. Another crucial aspect is to use predictive tools that can minimise the usage of API, which will conserve resources and speed up the development process. Choosing an optimal batch size for orphan drugs is a delicate balancing act between ensuring a stable supply and minimising waste, while also considering the need for a scalable formulation. Additionally, partnering with a CDMO that has experience in manufacturing orphan drugs can reduce the risk of errors and delays. Finally, it is essential to closely integrate clinical trial logistics with product supply, which will save time and money and ensure that patients have access to the drug as quickly as possible.

Leave a Reply

Your email address will not be published. Required fields are marked *