The Push for Momentum, Not Mistakes in Orphan Drug Development

Drug target identification and lead optimization of hit compound candidates for orphan diseases | Image Credit: © HYUNGKEUN -stock.adobe.com

An estimated 300 million people worldwide are affected by more than 7000 rare diseases (1). The vast majority of these conditions lack an approved therapy. Orphan drugs, in the United States, are defined as having a target population of fewer than 200,000 patients, with comparable threshold elsewhere (2). While the unmet needs are profound, the rarity of these conditions creates a high-stakes environment for orphan drug development, one which comes with built-in restrictions: limited patient populations, small batch sizes, and a scarcity of development data.

Regulatory help and hurdles

To energize the challenging landscape of orphan drug development, regulatory incentives, such as the Orphan Drug Act in the US, have helped encourage a wave of agile new sponsors. Smaller sponsors, often without in-house manufacturing or regulatory infrastructure, must navigate the inherent challenges of orphan drug development alongside the high bar of regulatory standards for quality and safety.

While expedited pathways, such as FDA’s Breakthrough Therapy and the European Medicines Agency’s (EMA) PRIME designations, can accelerate review, they do not lessen the fundamental expectations for product quality, safety, and manufacturing process robustness. Regulators require sponsors to meet the same International Council for Harmonisation (ICH) guidelines for pharmaceutical development (3), quality risk management (4), and drug substance development (5).

CMC challenges

Ensuring a drug’s quality, safety, and purity with meticulous chemistry, manufacturing and controls (CMC) is what transforms discoveries into tangible medicine. However, CMC in the orphan drug space is not a straightforward task. The same factors that define rare diseases—scarcity and urgency—create unique technical and operational challenges that can easily disrupt a program's momentum.

In this environment, sponsors and patients often cannot afford the lost time and resources of backward steps. Success requires a zero-waste approach, where every resource, every batch, and every minute is optimized. This article uses anonymized examples to highlight how to navigate seven common CMC problems, offering a guide for maintaining development momentum and avoiding costly mistakes.

Problem 1: underestimating early-phase CMC

Non-optimized processes and temporary formulations may accelerate first-in-human milestones but can lead to expensive and time-consuming remedial work. Sponsors who use non-optimized processes, minimal characterization, and temporary formulations risk compromising a product's long-term usability and scalability.

Example 1: one gene therapy sponsor’s use of research-grade plasmid DNA and non-GMP adeno-associated virus (AAV) vectors in early trials resulted in a lack of comparability data. This prompted regulators to question the integrity of the clinical data, forcing the sponsor to repeat toxicology studies and causing a significant delay.

Example 2: a small-molecule drug sponsor learned this lesson when its early solution formulation exhibited recrystallization during stability testing. The sponsor had not performed polymorph screening or excipient compatibility studies upfront, and the resulting reformulation introduced new impurities that required extensive bridging work, further delaying the program.

Solution: start with the end in mind

A successful program must begin with a CMC strategy that anticipates late-stage and commercial requirements. For gene therapy, this means using a manufacturing process that can be scaled up to good manufacturing practice (GMP) standards from the start. As outlined in FDA guidance on CMC information for human gene therapy, the quality of starting materials is a key concern (6). When this foresight is neglected, it can lead to a critical disconnect between early and pivotal trial data, forcing sponsors to repeat toxicology studies or re-evaluate product integrity.

Problem 2: analytical blind spots

Ongoing patient safety and efficacy rely on robust quality control. If the analytical methods used to assess a product are flawed, incomplete, or poorly validated, it sets the stage for significant downstream complications.

Example 1: a cell and gene therapy program faced a major problem when a critical potency assay lacked reproducibility. The sponsor had failed to establish a proper reference standard, and as a result, the assay failed during a key comparability test, forcing regulators to request a new method and additional clinical data.

Example 2: a small-molecule program faced a major challenge when its ultraviolet (UV)-based high-performance liquid chromatograph (HPLC) method failed to resolve a critical degradant that formed under long-term storage conditions. By the time the issue was discovered, several clinical batches had been released using a method that was not stability-indicating, raising serious questions about product integrity.

Solution: invest in a robust analytical framework

Investing in a robust analytical framework upfront prevents downstream issues. For complex modalities, this is even more critical. Journal articles on the manufacturing of gene and cell therapies highlight that the complexities of these products can lead to challenges with quality control assays (7). Analytical methods must be sufficiently robust to ensure product quality and detect degradants over a product's shelf life.

Problem 3: taking short-cuts to control strategies

Generic or poorly justified specifications fail to instill confidence in product quality. While orphan drug programs often deal with a low number of batches, they must still demonstrate an adequate control strategy to ensure safety and efficacy. The risk of failure leads to significant regulatory hurdles as regulators scrutinize a product’s specifications as the foundation of its quality.

Example 1: a biologic program applied generic specifications from a different product type. Regulators challenged the assumptions, pointing out that the product’s degradation pathways were fundamentally different. This oversight required the sponsor to perform additional characterization and caused a several-month delay.

Example 2: in the small-molecule space, an uncharacterized impurity approached a regulatory threshold, but the sponsor had not performed a toxicological assessment. FDA requested a full evaluation, and progress stalled until the required data could be produced.

Solution: build a scientifically sound strategy

Control strategies must be product-specific, risk-based, and supported by a strong scientific rationale. A lack of process knowledge is often the root cause of issues, as noted in ICH Q11 (5). Establishing a well-defined control strategy from the beginning enables regulators to assess a product on its own merits, preventing costly delays.

Problem 4: change without big-picture visibility

Changes, even positive improvements, must be managed carefully. A seemingly minor change in formulation, process, or site can trigger unintended consequences and raise regulatory concerns if it is not supported by robust comparability data.

Example 1: in one biologics program, a purification change introduced to improve yield unintentionally affected the product’s glycosylation pattern. Because the change had not been thoroughly studied and the assays lacked sensitivity, regulators required the sponsor to generate new clinical bridging data, postponing the drug's approval.

Example 2: a sponsor introduced a new polymorph to improve manufacturability but did not adequately characterize its impact on dissolution or bioavailability. Without an in vitro-in vivo correlation to justify the change, regulators requested additional pharmacokinetic data, resulting in a significant delay.

Solution: proactively manage the product lifecycle

Change is inevitable, but it must be managed with a proactive approach and a well-defined comparability protocol to maintain development momentum. By anticipating and planning for these changes, sponsors can prevent surprises and keep their program on track. European regulatory agencies, such as the EMA, provide specific guidance on the quality documentation required for biological products (8).

Problem 5: surprises of scale

Scaling up is an exciting stage of development, but minimizing issues requires a deep understanding of how new equipment and different process dynamics can impact a product. Without this foresight, the transition from lab to clinical or commercial scale can be more costly than it is a cause for celebration.

Example 1: in one viral vector program, a change in chromatography resin during scale-up unexpectedly altered the ratio of empty to full capsids. Because the sponsor lacked sufficiently sensitive release assays, they only discovered the issue after the clinical material failed potency testing.

Example 2: a small-molecule program experienced an undesirable change in its impurity profile during scale-up crystallization. The increase in mixing speeds and thermal gradients introduced new stress points, and the new impurity required a toxicology reassessment and repeat validation.

Solution: design for scalability from the outset

Minimizing scale-up issues requires a deep understanding of how new equipment and different process dynamics can impact a product. The need for a life-cycle approach to process validation is a well-established principle in the industry, as detailed in both Parenteral Drug Association (PDA) technical reports and EMA guidelines (9, 10).

Problem 6: precarious supply chains

For many orphan drug programs, a single vendor for a critical raw material or intermediate represents a weak link in the supply chain. While this reliance can be manageable in early development, it creates a serious point of failure as a program scales toward regulatory approval.

Example 1: in one gene therapy program, the sponsor’s single-source plasmid supplier lost its GMP certification, halting vector production. Without a qualified backup, the sponsor faced a six-month delay while it had to revalidate a new supply chain.

Example 2: A small-molecule program encountered a similar issue when its supplier of a specialized intermediate discontinued the product line. The sponsor had not developed a backup plan, so regulatory filings could not proceed until a new material source was requalified.

Solution: mitigate single-source risk

Sponsors must identify and mitigate these risks early in development by establishing dual sourcing where possible and qualifying alternate vendors. This strategic foresight provides a critical layer of resilience against unforeseen disruptions.

Problem 7: documentation gaps

Even with brilliant scientific breakthroughs, inconsistencies raise questions. Documentation could be considered a regulatory product pitch; inconsistencies, gaps, or ambiguity undermine even the most robust science, eroding regulatory confidence and stalling a program. Guidance on drug master files underscores the need for clear and complete documentation, as this information is used by regulatory agencies to assess the manufacturing process (11).

Example 1: one new drug application was delayed when reviewers found inconsistencies between batch records and process descriptions. In this case, impurity limits were not adequately justified, and the history of excipient sourcing was ambiguous.

Example 2: the ability to trace every component of a drug to its source is non-negotiable for patient safety. Yet, one biologics license application was refused at filing due to incomplete traceability of raw materials used in pivotal clinical batches.

Solution: master the regulatory narrative

Engaging with regulators throughout the process can help sponsors prioritize documentation from the start, ensuring that every detail tells a coherent story that builds regulatory confidence. A meticulously maintained paper trail is as important as the quality of the product itself; without it, the regulatory review process can be brought to a halt. FDA guidance on CMC information for biotech products outlines the specific types of data needed to ensure a smooth review (11).

Moving past rare successes to treating rare diseases

The successful approval of an orphan drug is a milestone worth celebrating, but it is too often treated as a rare event. The industry's true goal is to move beyond individual successes and establish a reliable, repeatable process for delivering therapies to rare disease patients. The common CMC problems outlined in this article are not just technical issues; they are obstacles that steal momentum and create costly detours. By addressing them proactively, sponsors can transform the development process, and strategic collaboration with partners experienced in end-to-end orphan drug development can be a key part of that. Ultimately a focus on operational excellence is what ensures that a groundbreaking therapy is not lost to a preventable mistake, joining the dots between processes and patients who have already had to be patient for far too long.

References

1. The Lancet Global Health. The Landscape for Rare Disease in 2024. 2024 12 (3). https://www.thelancet.com/journals/langlo/article/PIIS2214-109X(24)00056-1/fulltext
2. FDA. 21 CFR Part 316. https://www.govinfo.gov/content/pkg/FR-2013-06-12/pdf/2013-13930.pdf
3. ICH. Q8(R2) Pharmaceutical Development (ICH, 2009).
4. ICH. Q9 Quality Risk Management (ICH, 2005).
5. ICH. Q11 Development and Manufacture of Drug Substances (ICH, 2012).
6. FDA. CMC Information for Human Gene Therapy INDs, Guidance for Industry (FDA, 2020).
7. Kumar M.; et al. CMC Challenges in Gene and Cell Therapy. Mol Ther Methods Clin Dev. 2020 17:523–530.
8. EMA. Quality Documentation for Biological IMPs (EMA, 2022).
9. PDA. Technical Report 60-2: Process Validation Lifecycle (PDA, 2021).
10. EMA. Process Validation for Finished Products (EMA, 2016).
11. FDA. CMC Information and Establishment Description for Biotech Products. (FDA, 2023).

About the author

Hibreniguss Terefe, is director, Product Development Somerset at Ardena.