From Sequence to Vial: A Seamless RNA LNP Manufacturing Solution

Transcript

0:01	Yes, I'm happy to be here to talk RNA, LNP,
0:03	end-to-end sequence vial with Scott.
0:07	Mark Wetzel here.
0:08	I'm a 23-year veteran of Danaher,
0:11	and I thought I'd start a little bit with,
0:16	you know, just some thoughts around Danaher
0:18	and some things we're good at.
0:19	And Danaher's good at a number of things,
0:21	M&A, running businesses.
0:23	We have some great leaders,
0:24	but there are two things that I think
0:26	really sort of differentiate us.
0:27	One is DBS, our business system.
0:31	We talk about that a lot.
0:32	It's our engine for continuous improvement.
0:37	And it is based on the Toyota production system.
0:41	It's not unlike Six Sigma,
0:43	but it's the culture that threads
0:45	all of our companies together.
0:46	And what's different about it is our discipline
0:50	around applying it and living and breathing it
0:52	every day from top to bottom in the organization.
0:55	And also what it is, and we don't talk about this a lot,
0:58	in addition to the foundation of lean
1:00	and the Toyota production system and continuous improvement,
1:03	it's also the toolkit that we talk about
1:07	is a collection of best practices
1:09	that Danaher has acquired over 40 years
1:13	and hundreds of acquisitions.
1:15	Because what we're really good at
1:16	is identifying a best practice in a business
1:19	and carving it out, turning it into a tool,
1:22	deploying it to all our other businesses, right?
1:24	And that's one of the ways that we maintain consistency
1:27	from business to business
1:28	and how we're all more or less being run in the same way.
1:33	So that's one thing.
1:34	The second thing is the networking that's available
1:37	in the portfolio and the family of companies, right?
1:39	And how we help each other for the benefit of clients.
1:42	And there's no better example of that
1:44	than what we're doing here today with this event.
1:48	But it's two things that I think are important
1:51	and I'll explain why I bring those two things up.
1:54	For one, when we talk about Aldevron,
1:57	for those of you that are familiar
1:59	with the Aldevron business,
2:01	it's a different business today
2:04	than it was three years ago
2:05	when Danaher acquired that business.
2:08	And partially the reason is that
2:10	this DBS continuous improvement system is alive and well,
2:15	driving really breakthrough improvements in the business
2:17	and things that are material like on-time delivery
2:20	and lead time reduction and quality improvements
2:23	and customer experience, right?
2:24	So it's really a different business
2:26	than it was even three years ago, even one year ago,
2:29	for those of you that are familiar with Aldevron.
2:32	Second reason I bring that up,
2:33	this idea of the network and the way that OPCOs
2:37	or OPCOs and the Danaher family
2:39	work together for client benefit.
2:41	This couldn't be a better example
2:43	of how we've made that happen.
2:45	What Scott's business, the Cytiva Nanomed team
2:48	and the Aldevron team has built
2:50	into an end-to-end sequenced vial RNA LNP offering
2:55	that we believe is best in class.
2:57	And we're really in a privileged place because of that.
3:02	That makes sense.
3:07	So you may have seen some of these,
3:10	how am I doing?
3:19	This may be a slide that you've seen today,
3:20	but it is a one-pager that sort of lays out
3:26	how we connect the dots
3:28	between all of our Danaher businesses
3:30	and the ways we interact with clients
3:32	to accelerate LNP for RNA development and manufacturing.
3:35	So you've got the steps in the timeline
3:38	and the development process.
3:40	You've got swim lanes down on the left
3:43	and the Danaher portfolios
3:45	that are represented,
3:48	where the offerings fit into the workflow.
3:55	And of course, Scott and I are going to talk
3:57	about that bottom swim lane of services together here.
4:02	But important to point out that for us at Danaher
4:07	in this space, we feel like we are,
4:11	I'm going to steal one of Scott's guys' terms here.
4:14	We're an incubator for optionality.
4:17	We've got a lot of different options available
4:19	to solve the same problem.
4:22	So we have operating businesses,
4:24	Cytiva, Aldevron and others.
4:27	We have very complementary offerings,
4:30	but we also have overlapping offerings in some cases.
4:34	And we also have occasions to work with competitors
4:38	of Danaher businesses when it makes sense,
4:40	again, with the client in mind.
4:42	But the key here and the takeaway is we all know
4:45	how to wear the Danaher hat when we need to.
4:55	So our end-to-end sequenced vial offering
5:00	in Fargo, North Dakota, where Aldevron is based
5:05	is a workflow business that simplifies logistics
5:11	and eliminates timeline risk.
5:13	Full stop, that's the key value in what we're offering.
5:18	We, of course, can handle all of these pieces,
5:22	but the key benefit is removing shipping time.
5:27	Most of our clients are using multiple partners
5:31	or sometimes multiple sites with the same partner.
5:36	And what they are doing is, you know,
5:40	multiple tech transfers in their process.
5:44	With Aldevron and in Fargo, we, and I would call that,
5:49	many of our competitors, sort of a collection of parts
5:53	versus what we have at Aldevron,
5:54	which is a true workflow business from sequence to vial.
5:59	And we are the only ones in the market that I'm aware of
6:03	that have at the front end,
6:05	the capabilities of Precision Nanosystems,
6:08	now the Nanomed team at Cytiva,
6:11	where they're working on LNP and they can provide lipids,
6:15	they can provide formulation and particle design,
6:18	and also a proprietary encapsulation platform.
6:22	And with that strength of competency, you know,
6:27	provided in this solution in a seamless way,
6:30	we think we have a winning proposition here.
6:35	So Aldevron, for those of you familiar, well-known,
6:45	it's the gold standard in nucleic acid production,
6:48	very well-known for plasmids and DNA production,
6:52	25 years GMP experience.
6:55	We've done 5,000 GMP DNA batches and 165,000 batches,
7:02	if you include research grade,
7:04	which is sort of mind-boggling.
7:07	So well-entrenched in that space.
7:09	What is less known about Aldevron
7:12	is how competent and experienced we are in RNA.
7:16	This year, we will have produced 120 GMP RNA batches
7:23	for clients in phase one, two, three,
7:26	commercial programs with PPQ.
7:29	Our first RNA batch was in 2017.
7:34	We have a robust quality system,
7:36	and we'll talk about analytics and quality
7:39	in a bit more detail later.
7:42	An analytical testing panel with sterility and potency,
7:47	21 CFR compliance.
7:49	And this year we produced our first drug product batch
7:52	in Fargo in January with the help
7:55	of the Cytiva Nanomed team.
7:58	We're producing our second GMP batch next month.
8:01	And if you combine that with the experience
8:03	that they have in the Vancouver operation,
8:06	where they've produced three GMP drug product batches
8:10	end-to-end, you can see our trajectory
8:13	and experience is climbing.
8:16	We also have two client programs signed on board
8:21	where we plan to deliver GMP material
8:25	for their clinical programs in the first half of next year.
8:28	So our competence and experience
8:31	is definitely growing here.
8:33	This is a high-level process map.
8:43	Couple takeaways here.
8:45	Our preference for hardware consumables
8:49	and reagents is clearly Cytiva.
8:51	We've got some sole source hardware mitigations
8:56	throughout our operation,
8:57	but predominantly that's our preference.
8:59	Cytiva is our partner.
9:06	We have strong analytical and regulatory support.
9:10	With analytics, our team is very experienced
9:15	in things like multi-analyte detection,
9:18	as well as antibody conjugates.
9:22	And if you combine the experience of the Aldevron team
9:26	with the 20 years of LNP-focused analytics experience
9:31	with Scott's team in Vancouver,
9:33	this is really a good example of one plus one equals three
9:37	to the benefit of our client
9:38	in the analytics space for sure.
9:42	From a quality standpoint,
9:44	we have an experienced regulatory team
9:47	that has experience filing INDs on behalf of our clients,
9:52	but also can help with regulatory guidance
9:56	from start to finish
9:57	and help our clients define their regulatory pathway.
10:01	We are also well audited.
10:04	We passed an FDA site inspection less than three years ago.
10:10	We have a client audit almost every week,
10:16	Danaher GMP audits.
10:18	When we launched our drug product offering,
10:20	we also conducted a simulated FDA inspection
10:25	with a team of 20 year FDA former auditors.
10:30	We were hard on ourselves.
10:32	We had a couple of gaps that we have since closed
10:38	since that time in January.
10:40	So we have a high level of confidence
10:42	around our regulatory compliance in our site in Fargo
10:46	as a result.
10:49	Thanks for joining everybody.
10:51	Scott's going to talk a lot more about this,
10:53	but yeah, I don't want to steal his thunder
10:58	other than to say that our aspiration at Aldevron in Fargo
11:04	is to be the world's leading CDMO, LNP provider
11:11	on the NanoAssembler NextGen platform.
11:17	And we believe in the promise of the systems.
11:21	We think that Danaher and Cytiva's investment
11:24	in the innovation and the architecture of the new GMP system
11:27	that you can see in the middle of the screen there
11:29	is pretty special.
11:32	Scaling up, scaling out, repeatability,
11:36	cost of consumables coming down.
11:38	We're really excited about this.
11:39	It was just launched this year.
11:41	We have two of them in Fargo
11:43	and we've provisioned and qualified these instruments
11:47	and we're ready to roll.
11:48	And the GMP run that we're planning next month
11:50	is going to be on that equipment.
11:59	Yeah, so all that said about Cytiva
12:05	and beating the Cytiva drum,
12:07	we also know that we have to have a platform,
12:10	an LNP platform agnostic strategy.
12:13	In addition to offering the Cytiva solution,
12:17	we also entered an agreement with Acuitas this year,
12:20	well-known in the industry, and ran a pilot.
12:24	We are certified on their tech
12:26	and we are now a preferred CDMO partner
12:29	that they are now recommending to their licensed partners.
12:32	So we're happy and having conversations
12:35	with those clients today.
12:36	So it's opened up another avenue
12:38	it's opened up another window of opportunity for Aldevron.
12:43	As we have become familiar with this microfluidic platform,
12:49	we have also provisioned an off-the-shelf
12:51	generic T-Mix platform
12:54	that we also are now provisioning in GMP.
12:56	It's a Knauer-based platform.
13:01	And again, we have clients with that preference
13:04	and it opens up even more opportunities
13:07	for the Aldevron business.
13:09	So if we profile opportunity funnel,
13:12	we have those that are on the PNI platform,
13:14	we have clients that are licensed with Acuitas,
13:18	happy to talk to them.
13:19	We have folks that are just on a generic
13:22	T-Mix microfluidic platform and we can talk to them.
13:27	And then there's the rest of the opportunities
13:31	that are on more or less a proprietary platform
13:34	of their own or something else.
13:38	And we're opportunistically speaking to those folks as well.
13:47	We have analytical platforms well-defined
13:52	for both drug substance and drug product.
13:55	And by doing this
13:57	with the most up-to-date regulatory guidance,
14:01	to me, this is the way that we best operationalize
14:04	the promise of our end-to-end solution.
14:09	Fancy way of saying maybe that when we have clients
14:12	that are using multiple partners or multiple locations,
14:15	the place, the bottleneck or the pain point
14:17	often is the analytics or the acceptance criteria
14:21	for moving from one place to another.
14:23	At Aldevron, in our solution,
14:26	it's the same methods performed by the same people
14:30	in the same location in an optimized way.
14:33	So you can imagine the way that we're shrinking the timeline
14:36	just by having this in place with our teams.
14:44	So it's pretty important for us.
14:47	And of course we do product-specific development
14:49	as required from clients.
14:51	And this isn't a comprehensive list.
14:53	There are compendial assays not included,
14:57	pH, endotoxin, et cetera, et cetera.
15:04	A quick moment on something we're really excited about.
15:06	We've entered into an agreement with a company called Codexis
15:12	and obtained an exclusive license
15:15	for their Codex high-cap RNA polymerase.
15:20	This is an enzyme that has a lot of promise
15:24	and there's a lot of excitement around this.
15:26	There are three key benefits of this enzyme.
15:30	There are three key benefits of this enzyme
15:33	that we will use both for our internal manufacturing,
15:36	but also for global supply.
15:39	Significant cost savings
15:41	because it produces 95% capping efficiency.
15:45	There's an up to 62% lower requirement for clean cap.
15:51	It's a really expensive reagent
15:54	and that's really a significant savings to clients.
15:57	Yeah.
16:01	In my experience, even worst case,
16:03	my rationale of capping,
16:06	I never got less than 90%.
16:08	Okay, we're-
16:09	So, I'm just curious,
16:11	this 62% might be used for another method.
16:15	That is really low.
16:17	Really low?
16:18	You think it's conservative?
16:25	We have some experts out at the table here.
16:28	I think that the efficiency,
16:30	he's talking about the efficiency is over 95.
16:32	But the use of the clean cap is 62%.
16:39	I never got below 95%.
16:43	Capping efficiency?
16:45	Yeah, capping efficiency, 95%.
16:51	Well, because-
16:53	Yeah.
16:54	I'm just curious, how come?
16:57	I think it means that you don't have to use
16:59	as much clean cap, right?
17:00	Right.
17:01	If I understand it correctly.
17:02	Yes.
17:03	You can use much less clean cap
17:04	because efficiency is already very high.
17:07	It's clean, if I understand it correctly.
17:09	Yes, because this enzyme improves
17:11	the capping efficiencies to 95%,
17:14	which we see repeatedly.
17:18	Okay, yeah.
17:19	Let's take it offline.
17:20	We can talk more about that, for sure.
17:24	And of course, optimal manufacturing
17:26	has a second benefit: higher yields
17:28	and integrity, even with long, complicated transcripts.
17:32	But most importantly, the safety profile.
17:35	We see significantly less immunogenic
17:39	double-stranded RNA produced.
17:48	The SA25 is an acquisition of Cytiva,
17:50	a company formerly known as VanRx.
17:53	Really innovative aseptic isolator approach
17:59	using software and robotics to minimize human intervention
18:06	while providing a lot of flexibility
18:08	and things like bioburden.
18:09	This instrument can fill syringes as well.
18:14	For us, we have it qualified and ready
18:19	through media fill and CCIT for 2R vials, 10R vials.
18:25	And we're using the shot vials, Diokyo caps,
18:29	AR, Raymond, life caps for 10R vials.
18:33	Our current scale is 4,800 vials, 2R,
18:36	or 2,300 vials for 10R, but we have plans
18:39	to expand this from what is two carousels
18:42	to five carousels and multiple shifts
18:45	that get us to almost 10 or 12,000 vials.
18:48	And that's planned in the next year.
18:49	So we're planning on scaling this,
18:52	but we're happy about this instrument
18:54	and what it provides for us.
19:03	This is a represented pressure-tested timeline,
19:09	a managed timeline that our clients really appreciate
19:12	when we're sort of level-setting expectations.
19:15	They appreciate the thought and the detail
19:17	that we've provided here all the way
19:19	into the phase and the workflow,
19:22	how long things should take in a managed way.
19:27	But importantly, this also calls out
19:30	what we feel is a really differentiated capability
19:34	at Aldebaran, and that is our program
19:36	and project management capabilities.
19:39	We think we have a best-in-class team,
19:42	highly engaged and efficient,
19:44	and working directly with clients
19:46	and pretty effective.
19:52	It's just a case study of our pilot program this year.
19:55	I'm not going to spend too much time
19:56	on this in interest of time.
20:00	This is a represented pressure-tested timeline, a managed timeline, that our clients really appreciate when we're sort of level-setting expectations.
20:15	They appreciate the thought and the detail that we've provided here all the way into the phase and the workflow, how long things should take in a managed way.
20:28	It's just a case study of our pilot program this year. I'm not going to spend too much time on this in interest of time.
20:54	Last slide for me is just a picture of our world-class breakthrough campus in Fargo, North Dakota. This is a facility that we're quite proud of. And we're happy to have clients and partners visit and take a tour. And it's a really, it's a gem for us. And we're excited about it.
21:19	Sort of happy and lucky to be able to work in this facility. There's nothing like it. And that's it for me. Sequence to vial.