One of the most encouraging shifts is regulatory momentum around rare and ultra-rare diseases. Agencies like the FDA are taking more nuanced, risk-based approaches. They recognize that you cannot expect a therapy for an ultra-rare pediatric condition to follow the exact same pathway as a blockbuster primary care drug. 

That flexibility is a positive development. Regulators are listening more, particularly in cell and gene therapy, where many programs target very small patient populations. But while regulatory pathways may be evolving, the responsibility to ensure safety remains unchanged. There’s a careful balance between enabling access for underserved patients and ensuring therapies are safe and effective.

At the same time, manufacturing and quality expectations have not been lowered – and rightly so. The bar for GMP remains high. For small biotech companies, especially those in rare disease, that combination of regulatory evolution and unchanged GMP rigor can be challenging to navigate. 

I like to define quality in a very simple way: it’s about understanding. You must fully understand your product and fully understand your process. That means knowing the science, knowing which parameters affect your final product, and knowing what truly matters for patient safety.

In early research and first-in-human development, you don’t have complete knowledge – and that’s expected. Understanding is built iteratively. A risk-based approach becomes essential: identify what is critical to patient safety and focus your early efforts there. As development progresses, you expand that knowledge base.

With cell and gene therapies, the challenge is that the industry itself is still maturing. We went through a similar learning curve with biologics. Today, we have a more established playbook for biologics. Gene therapy is still earlier in that journey. That doesn’t necessarily make it harder – but it does mean teams need to be deliberate about what they prioritize and when.

Sponsors sometimes underestimate how foundational communication and documentation are within GMP systems. Quality systems still require robust controls, thorough documentation, validated equipment, disciplined change management, and clear deviation handling.

There can be a misconception that regulatory flexibility in rare disease translates to flexibility in manufacturing controls. It does not. Manufacturing quality must be rigorous regardless of patient population size.

Another area that can be underestimated is partnership. Quality cannot be managed in a vacuum. If there’s a deviation or a change control, it must be handled transparently and collaboratively. Strong communication between CDMO and sponsor is not optional – it’s part of the quality journey.

Data integrity is grounded in established regulations – such as 21 CFR Part 11 – covering audit trails, user access controls, password policies, backup and restore capabilities, and electronic record management. On paper, it may seem straightforward.

In practice, however, implementation can become overwhelming. For example, reviewing 100 percent of audit trails across all systems may not be practical. That’s where a risk-based approach again becomes critical. Higher-risk systems should receive deeper scrutiny than lower-risk ones.

Fundamentally, data integrity is about good science. Data must be attributable, legible, contemporaneous, original, and accurate. If an experiment cannot be reconstructed or defended, it’s not meaningful. Organizations sometimes struggle when they treat data integrity as a checklist rather than a culture. Commitment and discipline are essential.

Quality Control (QC) and Analytical Development (AD) operate in the laboratory, but their roles differ. QC performs testing to confirm that materials and products meet established specifications. AD develops and refines the assays and methods that QC will ultimately use in GMP testing.

AD works closely with process development and manufacturing to ensure methods are fit for purpose before they’re transferred into QC. Even with platform methods, each product has nuances that require careful attention.

Quality Assurance (QA), by contrast, oversees the systems that ensure compliance and patient safety. QA is involved in vendor qualification, equipment and facility validation, batch record review, investigations, change controls, and overall lifecycle management.

QA is sometimes viewed as the “police” or the final gatekeeper – and it is the last safeguard before product release. But effective QA is embedded throughout the process. It ensures that the systems supporting product development are robust from the beginning, not just at the end.

Quality-by-Design (QbD) means beginning with the end in mind. The end is a safe, effective therapy delivered to patients – whether in clinical development or commercial supply.

QbD should start in research and development. Teams should define intended use, target patient population, and long-term vision early. From there, they build knowledge iteratively, identifying critical quality attributes and critical process parameters and deepening understanding over time.

Quality is not something you test into a product at the end. You build it in intentionally. That requires risk-based thinking, structured development plans, and a long-term perspective from the earliest stages.

Sponsors should look for a partner, not simply a vendor. This is especially important for emerging biotech and rare disease innovators, which may have small teams and limited resources.

An effective CDMO should offer cross-functional integration – where QA, manufacturing, process development, and analytical teams operate cohesively. Early collaboration supports smoother tech transfer, facility fit assessments, batch record design, contamination control strategies, and GMP readiness. 

Experience across modalities and an integrated, under-one-roof model can also provide tighter control over raw materials and ensure continuity from discovery through GMP.

For smaller rare disease organizations – sometimes founded by patients or family members — guidance is particularly important. Many have one opportunity to advance their therapy. Early engagement around Quality-by-Design, scalable batch strategies, and realistic development planning can make a critical difference.

Ultimately, quality must begin earlier than most teams expect. It cannot be added at the end. It must be built in – thoughtfully, collaboratively, and with patients firmly in mind.