SK pharmteco’s Tatiana Nanda, chief technical officer of SK pharmteco Viral Vector North America discusses what gene therapy sponsors must account for sooner rather than later when preparing for GMP manufacturing.
Preclinical manufacturing isn’t simply about generating material. Done well, it generates the data and process understanding needed to make better development decisions.
By the time a gene therapy program reaches Good Manufacturing Practice (GMP) manufacturing,
opportunities to address issues identified during earlier development can become more limited, costly and time-consuming.
SK pharmteco’s Tatiana Nanda, chief technical officer of Viral Vector North America, spoke to BioSpace about how sponsors can set themselves up for success before they reach the GMP manufacturing stage so they can avoid costly delays and dose shortages.
1. Three Key CMC goals
Many gene therapy programs focus on getting material into preclinical studies as quickly as possible. However, at initiation, program developers should consider the purpose of their preclinical campaigns, according to Nanda. From a chemistry, manufacturing and controls (CMC) perspective, she said, there are ultimately three goals:
- Answer scientific questions about scalability and manufacturability. This allows sponsors to determine whether an early research process can be developed into one suitable for GMP manufacturing.
- Generate the large volumes of material needed before GMP. Very often, companies underestimate the amount required for nonhuman primate studies, stability tests, analytical and drug product development.
- Derisk GMP, especially as GMP manufacturing is very expensive in terms of time and finances. Small-scale studies often mask issues that appear at full scale, such as longer hold times, higher impurity loads and modality‑specific sensitivities.
Nanda also noted that pilot-scale runs help determine whether a process is truly GMP‑ready and prevent costly surprises once in the GMP suite.
2. Preclinical or pilot-scale manufacturing insights
A well-designed preclinical or pilot-scale manufacturing campaign can help ensure that sponsors have critical information before entering GMP manufacturing. Pilot campaigns, for example, can uncover the operator‑dependent steps that are often underestimated, according to Nanda.
Depending on the program’s maturity and objectives, early development-scale studies or pilot-scale manufacturing campaigns can provide different levels of process understanding, helping sponsors determine where further optimization is needed before GMP.
“We have a very good understanding of platforms,” she said. “However, depending on the specific modality, and in the case of AAV-specific serotypes, you may be able to identify operator-dependent steps early on in your preclinical campaign.”
In addition, Nanda noted, a preclinical campaign allows a sponsor to educate GMP operators early on and provide training on how to identify and mitigate errors and recover any losses across different unit operations.
“Frequently, a week or two of additional optimization work will result in significantly better yields,” she said.
Plus, well-designed pilot-scale campaigns, in addition to resolving yield issues, provide early insight into cost of goods sold, dose availability and the number of GMP batches required, according to Nanda. She also noted that full-scale pilot runs validate assumptions, such as whether one batch can support an entire Phase 1 trial, and help prevent situations in which a sponsor plans to dose 20 patients but ultimately has sufficient material for only 10.
3. Analytical testing and process characterization
Analytical testing and process characterization can influence development strategy beyond generating release data. Analytics, for example, guide development decisions, according to Nanda.
“Having robust analytics actually tells you whether you’re on the right path or not,” she said. Nanda added that fit‑for‑purpose assays with proper sensitivity and accuracy help sponsors identify impurities, quantify them and ensure that potency assays measure attributes that meaningfully inform dose and product performance.
While the field is still learning how to interpret gene therapy analytics, according to Nanda, collecting robust data early and throughout the preclinical campaign is essential for connecting process, quality, safety and dose metrics. She recommended drafting a critical quality attribute document early to define what matters and build a set of assays around those factors. In turn, those assays can allow a sponsor to devise the analytical strategy.
4. Early process knowledge capture
Capturing process knowledge early can make technology transfer, GMP execution and future regulatory interactions more successful. As Nanda explained, sponsors must document decision rationale, not just the steps taken. She noted that this is important because as the CMC life cycle extends from early development to late-phase and commercial manufacturing, regulators may ask about the rationale behind parameter selection and process changes. Technology transfers may occur at multiple points in a product’s life cycle.
Consequently, having documentation properly formulated, stored and connected as the product moves through the CMC cycle supports regulatory submissions and future commercial manufacturing campaigns, Nanda said.
5. Finding the right CDMO
When selecting a viral vector contract development and manufacturing organization (CDMO), it’s important to know what separates a CDMO that simply manufactures batches from one that actively helps sponsors reduce technical and development risk.
A strong CDMO serves as an extension of the sponsor’s CMC capabilities by challenging assumptions, prioritizing development work, advising how and where to invest in process development and integrating analytical and manufacturing teams, according to Nanda. Cross‑trained teams, not only in GMP and quality control, but also process and analytical, manufacturing science and technology, and regulatory expectations can address challenges, she said.
In addition, she noted that CDMOs with commercial experience provide early insight into future challenges and help avoid expensive late‑phase tech transfers.
6. Mistakes sponsors make
Before entering GMP manufacturing, sponsors tend to make a few common mistakes. For example, Nanda said, they often underestimate analytical development and understanding their drug product.
Too often, the focus is on the amount of drug substance to be made rather than understanding formulation, stability and product handling, she explained. Nanda said this is particularly important when it comes to particularly sensitive modalities such as lentiviral vectors, where storage, thawing, preparation and administration can all affect product performance.
Downstream yield and purity are also overlooked, according to Nanda. When it comes to short-term innovation in the gene therapy space, she said, downstream recovery is a major opportunity, as upstream scale is irrelevant if downstream recovery is only 10%.
The path forward
For sponsors preparing for IND/IMPD-enabling studies, the message is clear: the path to GMP manufacturing begins well before the GMP batch. Early process development, analytical strategy, pilot-scale manufacturing and careful knowledge capture can help sponsors understand whether their process is scalable, their assays are informative and their material strategy can support the next stage of development. By addressing these areas earlier, gene therapy developers can move toward GMP manufacturing with greater confidence and fewer avoidable surprises.
This article was written in partnership with SK pharmteco.
