23 Questions with Aga & Ashley
23 Questions with Forge is our fast-paced series where our team members are challenged to answer 23 rapid-fire questions about trending topics in gene therapy development.
Forge's GMP manufacturing is a true collaboration of specialized teams working together to ensure the safe production and delivery of our clients' gene therapy products. Hear from Aga Gascoyne, Ph.D., Director of Upstream GMP Manufacturing, and Ashley Craddick, Senior Director of Downstream GMP Manufacturing, as they gown up to walk you through our meticulous process. Watch the full video below!
Read the interview:
Hi! Can we interrupt you for a quick interview? It’s just 23 questions…
Aga and Ashley: Sure!
We’ve never interviewed a pair! Are you two experts up for the challenge?
Aga: Of course! We’ve formed a great partnership within GMP manufacturing and regularly finish each other’s sentences. I’m Aga Gascoyne, Director of Upstream GMP Manufacturing...
Ashley: ...and I’m Ashley Craddick, Senior Director of Downstream GMP Manufacturing.
Can you share why GMP manufacturing plays such a vital role in the development of gene therapies?
Ashley: At this stage in our clients’ journey, they rely on us for operational excellence in GMP manufacturing for delivering material that will be used in clinical trials. This material goes directly into patients, so safety and quality are at the forefront of our minds. At Forge, we have a rich "GMP Culture…"
Aga: …and we pride ourselves on adhering to the highest standards in current good manufacturing practices and ensuring the entire company understands what it means to have a GMP Culture.
Wow, you do finish each other’s sentences! You also both lead critical teams, right?
Aga: Yes, we wouldn’t be able to do what we do without our fabulous teams. They exemplify Forge’s core values of HOPE. Every day when they come in, they understand the impact that their manufacturing work can have on patients’ lives.
Ashley: We kick off every run by talking with our teams about who we are making this for, the disease it’s impacting, the therapy our client is working on, and how it can help that patient community.
THAT is mission driven! We like to toss in a couple of fun questions too. Ashley, who is your dream dinner guest?
Ashley: My dream dinner guest would be Ina Garten and together we would cook for all the amazing women on our team.
How do we get an invite?! Back to GMP. Aga, can you share how Support and QC come into play to ensure a client’s GMP run goes smoothly?
Aga: Of course. Our GMP Support team starts with Buffer Prep to ensure that everything is on track for the runs. We perform a thorough room changeover between each run to prepare for the next client. It includes environmental monitoring, and following specific cleaning and documentation procedures to ensure the suites are up to GMP standards.
Great, that makes sense from an environment perspective. From a process perspective, how do you ensure proper documentation is ready for the client? Ashley?
Ashley: We work with our MSAT and Quality teams to ensure that we have reviewed and approved the clients’ batch records ahead of every run. Then our operators train on those specific batch records. And finally, we’re ready to head into the suite. Actually, I have to go check on something for a client in the lab. See you soon!
Thanks Ashley! Aga, back to you. Can you share the benefits of engineering runs before GMP?
Aga: There are so many! It helps with applying lessons learned; it demonstrates operational success at scale; it provides replicate data for regulatory filings and setting of specification criteria; and also provides material for initial stability studies; etcetera.
Aga, you lead the team in Upstream manufacturing. Tell us about the first step.
Aga: Let’s gown into the cleanroom, and I’ll show you! Welcome to the cleanroom! To answer your question, these are our GMP manufacturing suites where we start the Upstream and Downstream processes. You look good in full PPE!
Thanks! I call this look “sterile casual.” So, what’s that first step in Upstream manufacturing?
Aga: Because we manufacture our own plasmids and have a master cell bank of our own cell line, Upstream is easy to dive into. The first step is cell culture and seed train expansion to the working volume and cell density required for transfection.
What’s happening behind you?
Aga: Right here? Those are our Ignition cells getting ready for transfection. We maintain a rolling seed train of our Ignition cells to help clients produce the batch size they need. These here will be scaled up to a 1,000-liter scale.
How do you make sure the cells are healthy and ready for production?
Aga: We’re looking at the cells daily and ensuring that they are growing appropriately through close monitoring. We look at things like viable cell density and the viability of the cells. The cells need to meet certain specifications, or acceptance criteria as it’s known, for us to move forward with the process. We then transfect them and incubate them in a bioreactor until they are ready for harvest and lysis.
Last question while you’re gowned up! Music or podcasts for road trips?
Aga: Music! Pearl Jam, Peter Gabriel, Enya...depends on the occasion.
That’s quite a mix. Perfect for a bioreactor! Get it? Thanks Aga. With “Even Flow” on our minds, steer us Downstream! Let’s see how Ashley and her team take it from here.
Aga: Just through that door and to the left, and you’ll see her.
Ashley, is that you?! We just learned about the Upstream process. Tell me how you pick up from where Aga left off?
Ashley: After lysis and harvest, the Upstream team passes the material over to the Downstream team. We clarify the bulk lysate using depth filtration to remove cell debris and prepare for our first step in our purification process using Forge’s commercially viable affinity chromatography platform and bespoke process.
We hear a lot about empty-full separation. How does your team enrich for full capsids?
Ashley: Our platform uses CsCl ultracentrifugation. We ensure we’re providing our clients with the required empty-full ratio needed for their final material.
Fun question! You played college softball…what would be your walk-up song today?
Ashley: Swag Surfing by F.L.Y., just like Aaron Judge my birthday twin on the New York Yankees!
Oh, that’s a good one! OK, we’ve seen most of the steps...how do we knock it out of the park?
Ashley: The final step is filling which occurs in a dedicated suite. We can go check it out later! We work with clients to define their specific filling configurations. Our filling is all onsite here at the Hearth, so it is a smooth process to coordinate between our Downstream operators and the filling operators in our facility.
About how long does it take to complete filling?
Ashley: That’s a good question! It depends on our clients’ needs. This client is doing semi-automated filling in our Watson & Marlow semi-automated filler, and needs about 100 vials and that can be done in one 8-hour shift. But we can go up to 400 vials. With filling done, we’re almost near the end of the process. Let’s get out of our bunny suits and go find Aga so we can bring it home for you together.
So filling is completed. What’s next?
Ashley: Now we pass our samples off to QC for testing and inspection then it’s off to the warehouse for storage. Hey Aga!
What’s the most important thing to do once you finish a run?
Aga and Ashley: Documentation!
Ashely: Our batch records are reviewed by the Upstream and Downstream teams to support batch release. Beginning this immediately post-run allows reviews to be completed in parallel with QC release testing and keeps timelines on track.
Hey Aga, how is your final documentation coming along?
Aga: Great! I am passing them off to QA now.
Sounds like you completed everything, what’s next?
Aga: We go right back to a room changeover!
One last fun question…for a Columbus OH summer ice-cream, Graeter's or Jeni's?
Aga and Ashley: Jeni's!
And that is your 23rd question! Ashley, you mentioned that Watson & Marlow filler...will you show me?
Ashley: Sure! But we need to gown back up!
Ok...maybe you can show me next time. Thanks for the tour you two. Have a great summer!