INTRODUCTION

Orphan drug development addresses the high unmet needs of small populations of patients living with rare diseases, bringing hope in the form of new treatments. Spurred by regulatory incen­tives, such as the US Orphan Drug Act and similar frameworks worldwide, this landscape has expanded rapidly over the past two decades.

The driving force in this expansion is largely small, emerging sponsors. These companies are often agile and innovative but lack the extensive internal resources and institutional knowledge of larger pharmaceutical organizations. The resulting reliance on a fragmented network of external partners can lead to a lack of full process visibility, where critical oversights create downstream problems. According to a 2023 industry report, manufacturing and supply chain challenges are among the top concerns for emerging biopharma companies.¹ Many have learnt that “more haste, less speed” is the key to navigating the complex world of Chemistry, Manufacturing, and Controls (CMC).

Although the unique challenges of orphan drug development are amplified by compressed timelines and limited patient pop­ulations, the common pitfalls in this article also serve as caution­ary tales for other areas of drug development. Seemingly small missteps can not only compromise product quality, but also delay or derail a promising therapy. Where every batch matters, every patient counts, and success means exclusivity, robust CMC exe­cution is essential.

REGULATORY SCRUTINY SETS A HIGH BAR

Orphan drug development is not, and should not be, exempt from the high bar for pharmaceutical quality and safety. While these programs benefit from expedited pathways like the FDA’s Breakthrough Therapy and Regenerative Medicine Advanced Therapy (RMAT) designations, or the EMA’s PRIME scheme, these accommodations apply primarily to the review timeline, not to the fundamental expectations for product quality, safety, and manu­facturing process robustness. Regulators require sponsors to meet the same ICH guidelines for pharmaceutical development (ICH Q8), quality risk management (ICH Q9), and drug substance de­velopment (ICH Q11).^2,3 There is no “wiggle room” on safety.

The challenge is that orphan drugs are often supported by limited clinical data and produced in small batches, which con­strains a sponsor’s ability to conduct full-scale process validation or extensive stability programs. This makes it all the more critical to work meticulously within these constraints to avoid costly re-evaluation. Without end-to-end understanding, scientifically sound development, and a strong risk management framework, sponsors can fall foul of any of the pitfalls outlined below.

PITFALL 1: PRIORITISING PATIENTS BUT UNDERPLAYING PROCESSES

Racing through early development to the first-in-human mile­stone can prove to be a costly efficiency. Sponsors who use non-optimized processes, minimal characterization, and temporary formulations risk compromising a product’s long-term usability and scalability. This approach, while it may expedite a clinical trial, often leads to expensive and time-consuming remedial work once the program matures.

Data Scrutiny or Rejection
The rush to the clinic often means using materials and processes not fit for later-stage development. This can create a critical disconnect between early and piv­otal trial data. For example, one gene therapy sponsor’s use of research-grade plasmid DNA and non-GMP AAV vectors in early trials resulted in a lack of compa­rability data when the program transi­tioned to a GMP process. This oversight, a key concern outlined in FDA guidance on CMC information for human gene ther­apy, prompted regulators to question the integrity of the clinical data, forcing the sponsor to repeat toxicology studies and causing a significant delay.⁴

Unanticipated Impurities
Neglecting fundamental development work can also lead to unanticipated prod­uct quality issues. A small molecule spon­sor learned this when its early solution formulation exhibited recrystallization dur­ing stability testing. The sponsor had not performed polymorph screening or excip­ient compatibility studies upfront. The re­sulting reformulation introduced new impurities and required extensive bridging work, further delaying the program.

PITFALL 2: FAULTY ANALYTICAL PROCESSES

Ongoing patient safety and efficacy rely on 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. 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.⁵ In the rush to meet timelines, many orphan drug programs proceed with methods that lack the robust­ness required for regulatory scrutiny, jeop­ardizing product integrity and delaying development.

Inappropriate Reference Standards
A robust analytical method requires appropriate controls, including a well-de­fined reference standard. In a cell and gene therapy program, a critical potency assay lacked reproducibility because the sponsor had failed to establish a proper reference standard. As a result, the assay failed during a key comparability test, forc­ing regulators to request a new method and additional clinical data to bridge the gap.

Storage & Stability Issues
Analytical methods must be capable of accurately measuring a product’s qual­ity over its shelf-life. A small molecule pro­gram faced a major challenge when its UV-based 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. This raised serious questions about the in­tegrity of the product and highlighted the consequences of not investing in robust stability-indicating analytical tools upfront.

PITFALL 3: FLAWED 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. A lack of process knowledge, a common point of failure noted in ICH Q11, can be the root cause of issues.⁶ Without this un­derstanding, specifications can be generic and poorly justified.

Challenges & Pushback
A common issue arises when spon­sors apply generic specifications from a different product type. In one biologic pro­gram, a fusion protein was assigned mon­oclonal antibody specifications. Regulators challenged these assumptions, pointing out that the protein’s degradation path­ways and immunogenicity risks were fun­damentally different. This oversight required the sponsor to perform additional characterization and caused a several-month delay, highlighting how a one-size-fits-all approach is insufficient.

Missing Toxicological Assessments
In the small molecule space, sponsors face similar issues with impurity limits. In one instance, an uncharacterized impurity approached the ICH Q3A threshold, but the sponsor had not performed structure elucidation or toxicological assessment. The FDA requested a full ICH M7 evalua­tion, including genotoxicity data, that had not been generated. This oversight stalled the regulatory review and forced the spon­sor to halt progress until the required data could be produced.

PITFALL 4: UNJUSTIFIED CHANGES

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. European regulatory agencies, such as the EMA, provide spe­cific guidance on the quality documenta­tion required for biological products.⁷

Better Yield, Different Glycosylation Pattern
Changes intended to improve a process can have unexpected effects. 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.

New Polymorph, Same Dissolution & Bioavailability?
A new polymorph may improve man­ufacturability, but it must be proven not to affect the drug’s performance. A sponsor introduced a new polymorph 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. This misstep re­sulted in a significant delay while the re­quired data was generated.

PITFALL 5: PROBLEMS 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. The need for a life-cycle approach to process validation is a well-established principle in the industry, as de­tailed in both PDA technical reports and EMA guidelines.^8,9 Without this foresight, the transition from lab to clinical or com­mercial scale can be more costly than it is a cause for celebration.

Insufficient Sensitivity
A lack of robust analytical methods or defined process parameters at a larger scale can lead to a failure to detect critical changes. 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. This oversight resulted in wasted material and a costly delay.

Process Change Impurities
Even seemingly minor changes to a process during scale-up can introduce new impurities. 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. The new impurity required a toxi­cology reassessment and repeat valida­tion, demonstrating that simply replicating a lab-scale protocol without understand­ing the new process dynamics can have expensive consequences.

PITFALL 6: WEAK LINKS IN A SUPPLY CHAIN

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.

Lost Certification
For a drug to be manufactured under cGMP, its raw materials must come from a qualified source. 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.

Discontinued Production
A supplier can also stop production for business reasons, leaving a sponsor without a critical material. A small mole­cule program encountered a similar issue when its supplier of a specialized interme­diate discontinued the product line due to cost concerns. The sponsor had not devel­oped a backup plan, so regulatory filings could not proceed until a new material source was requalified.

PITFALL 7: PAPER TRAIL PROBLEMS

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.¹⁰

Unjustified Impurity Limits
One NDA 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. These inconsistencies created enough regulatory doubt to prompt a formal delay.

Incomplete Traceability
The ability to trace every component of a drug to its source is non-negotiable for patient safety. In another case, a BLA was refused at filing due to incomplete traceability of raw materials used in pivotal clinical batches. Despite the batches pass­ing all release testing, the lack of robust GMP documentation created regulatory uncertainty that could not be resolved after the fact.

STRATEGIES FOR NAVIGATING THE CMC LANDSCAPE

The seven pitfalls outlined above are not insurmountable. They are, in fact, en­tirely avoidable with a few key strategic shifts.

Proactive Planning and Cross-Func­tional Alignment
The goal is to design a CMC plan that is not just a collection of discrete tasks but a coherent, risk-based strategy. Decisions made in preclinical development should anticipate their impact on Phase 3 and commercialization, for instance, by select­ing a scalable formulation or establishing a preliminary control strategy.

The Value of Experience
The choice of a development partner is an impactful decision. Whether a single CDMO or multiple organisations, experi­ence of the unique nuances of orphan drug development meaningfully con­tributes to control strategy design, impurity risk assessments, and regulatory author­ing.

Leveraging Risk Management and Data
Since orphan drug programs are often data-poor, sponsors must compen­sate with rigorous, science-based risk management. This involves using orthog­onal analytics, in silico modelling, and process knowledge to build a robust justi­fication for specifications and process pa­rameters. Regular, proactive meetings with regulators can help clarify expectations and align on strategy, preventing surprises at submission.

Engaging with regulators is also ben­eficial. FDA guidance on CMC information for biotech products outlines the types of data that are needed to ensure a smooth review.¹¹

METICULOUS WORK, CHANGES LIVES

While clinical innovation and investor attention are the engines of drug develop­ment, the true driver of ambition in this space is the human element: the unmet needs of patients previously marginalized by medical advances. It is the why that fuels the work. But ambition alone is not enough. A well-executed CMC strategy is the how that transforms that ambition into a tangible reality. It is the framework that turns a scientific breakthrough into a reli­able, safe, and available treatment, ensur­ing that the promise of a drug is ultimately fulfilled for the patients who need it most.