It’s a fascinating time to be in the biotherapeutics industry. What will the remarkedly rapid COVID-19 vaccine development effort teach us about how to develop and scale vaccines quickly for future crises? Additionally, the gene therapy sector continues to mature, including the process development approaches that will facilitate the commercialization of more and more products.
I wanted to learn more and was fortunate to have the opportunity to speak with John Kandl, senior consultant, technical operations, at BioTechLogic. John is highly experienced in process validation and quality assurance program development and is bringing this experience and expertise to his gene therapy clients.
Are you seeing significant program delays because of the pandemic?
John: Most of my current clients are in California, and they experienced many restrictions on travel and the number of people who could be in their facilities. For one of my clients this led to a shutdown of the facility. This delayed the existing manufacturing campaign and analytical testing, strategies we had employed to prepare our commercialization batches needed for our approval submission. We had defined a timeline to get the product in stability testing, so we could gather the data we needed for our submission—that timeline has been blown out of the water.
Colleagues at another company were in the process of building a facility to manufacture vaccines for Phase 1 trials. They have now changed course and are working on a COVID-19 vaccine. To accelerate their timeline, they’ve partnered with another manufacturing firm as opposed to building their own facility, which is a complete change of scope and strategy.
Obviously, with the COVID vaccine, they must move quickly and don’t have time to build the facility, validate cleanrooms, and go through all the other necessary processes.
So, I would say it has been a mixed bag. Some client’s programs are moving forward as planned with some modest delays; others have experienced significant disruption.
COVID-19 has delivered plenty of challenges, but what can this era teach us?
John: It will be interesting to see what we learn from the extraordinarily rapid COVID-19 vaccine development process. Maybe someone will come out with technology that people weren’t thinking about before, or maybe a new type of a therapy that doesn’t yet exist will be developed. The global scientific community is pushing aggressively based on the urgency of the needs.
What has given COVID-19 vaccine developers the confidence and ability to move so quickly?
John: On the whole, I think developers are leading with knowledge from vaccine products they’ve already manufactured and are applying a similar strategy to COVID-19 vaccine development. It is great that we have so many companies working on vaccines because they are each bringing their own experience to the table. There is no way we would be able to trial as many products currently in development without the diversity of players working on the problem, each working to develop a vaccine using processes and technologies familiar to them. The expansion of therapeutic approaches in recent years is giving us bandwidth and options we never had before.
How will they be able to make that leap from theory to the actual product? That’s another question. It’s going to be tough scaling production as quickly as needed while ensuring the process is robust, safe, and reliable.
Given the enormous quantity of vaccine that is going to need to be manufactured quickly, do you have any advice as developers approach the process validation and quality assurance aspects of their programs?
John: Nothing comes to mind that would be any different from the normal routine—except for, hopefully, because it is fast-tracked and there are many parties involved, they’ll have more money to work with when it’s time to do the runs.
I think we’ll see a couple of trials with poor outcomes, but hopefully, the program won’t have gone too far down the road in terms of ramping production and stockpiling doses.
Are you foreseeing any other longer-term impacts from the pandemic?
John: I’m interested to see how this era will affect the offshoring of products. I have not heard anything that causes me to conclude that the industry will move production from China and India; it’s just a question in my own mind. Are people are going to have second thoughts about offshoring manufacturing processes? Instead, will they invest more in the US?
You have done a lot of gene therapy work in recent years. What have been the primary process development challenges?
John: The key question is always whether you understand your process—understanding whether your process is robust. It’s expensive to manufacture a batch, so every time you do any large-scale experiments, there is a lot of time and money invested. This is nothing new, though, and is a core challenge to any biotech development process.
Additionally, the yields tend to be very small, especially for gene therapy products. In some cases, it’s just not practical to produce enough product to collect all the data for a traditional process development effort.
The viral removal process is also tricky for gene therapy products. If you can’t ensure that all materials going into the product are free of adenovirus, you must have steps within the manufacturing process to clear them, and then you must validate that your established clearing process is successful. It’s a lot of work and it’s often tricky striking a balance between the virus removal steps and maintaining an acceptable yield.
However, by conducting risk assessments throughout your supply chain, you can determine how much risk you really have in your process. For some clients, they can take robust viral removal steps and achieve a high clearance rate as they have for other products. I have had other clients’ risk assessments conclude high confidence in their supply chain, leading them to the position that they don’t need to conduct these tests, a position that may or may not be acceptable to the FDA. A lot depends on the specific reviewer and their level of confidence in our knowledge of our processes.
Has the FDA been a collaborator in gene therapy product commercialization, or have they been a barrier?
John: The FDA has been excellent collaborators. They work hand in hand with the manufacturers and will schedule meetings where they will answer targeted questions. Also, they give you an idea of what areas that will likely require extra attention.
They have been willing to learn with the industry and definitely have not taken a command-and-control type of approach.
Also, more gene therapies working their way through the approval process allows us to learn from those successes. We work to glean as much information as we can from these successful approvals. As more and more products are approved in the US, we have an increasingly better idea of what the standards truly are. Finally, the gene therapy guidance is more mature, which is really helpful.
Do you expect gene therapy quality guidances to change over time?
John: I would hope so. Your product, of course, must meet the critical quality attributes that ensure the product is safe. As more products are approved and proven to be safe, both the industry and regulators will have a better idea of how to fine-tune quality specifications to ensure product safety.
Some developers and regulators have tried to determine acceptable limits with insufficient knowledge. But the more products out there, the more confidence the FDA will have in setting and adjusting limits.
If your team is challenged by hitting pending deadlines, BioTechLogic’s team of expert, senior-level consultants are happy to work alongside your team to make sure you hit your critical milestones. Feel free to contact us.