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.