April 3, 2024
Participants
Introduction and Welcome
Oliver Ball: Hey! Hello! To those who are dialing in. We're just going to give it a minute for everybody to join the webinar, and then we'll get started in just a second.
Okay, I think we can get started and some other folks can dial in as they want to. So Hello, everybody! Welcome to the sixth Unbridled Excellence webinar in the series. I'm your series host, Oliver Ball, Director of Business Development for Dark Horse.
We really set up this webinar series to share some of the insights and experience that Dark Horse has generated over 10 years of operating in the cell and gene space. Now, we've had over 350 clients over that time, and one of the things that I think we've noticed a lot through the work that we've been doing has been really the cost of goods and manufacturability of cell and gene therapy products has become a very significant issue for the field, and arguably one of the major bottlenecks to the industry's development and maturation. So I think it's very relevant for us to have a webinar today on the enabling tools and technologies that are going to be providing a solution to this issue.
We at Dark Horse work quite a lot on tools and tech, as we call them, novel processing tools, analytical tools, and those companies who are taking those types of products to market. Not only do we help them on understanding the product market fit and helping them to understand customer needs, but also actually the ins and outs of product design and development, regulatory compliance of those devices - things that will be covered in more detail in the talk today.
So I'm really excited to have this expert panel with us today. Michael Kinzie, Dark Horse principal, who's been an engineer for 28 years in this field, who will introduce himself a little bit more later on. Richard Grant, a master, perhaps expert and veteran of the industry, who's been in the field, I think, 35 years. And Madeline St. Onge, she's a senior consultant with us. Previously was at ISCT, and got her MBA before joining Dark Horse.
Just before we get into the webinar today, just a reminder that we are going to have a series of webinars coming up throughout the year on other topics, too. So keep your eyes peeled for other announcements on those webinars soon, and there'll be one on preclinical strategy and roadmap to IND, another on IND authorship, and a third on facility operations, optimization and capacity planning, which should be a really interesting topic, too.
We will accept questions from the audience for discussion at the end of the presentation today. So if you have any questions that come up either now or during the presentation, please submit them in the Q&A box at the bottom of the Zoom interface, and the panel will be very happy to discuss those with you. If we don't have time to cover them all, then we can always talk to you afterwards separately.
Just a reminder also that the webinar will be available to watch on demand following today. So if you want to share it with anybody else, your colleagues, or we want to watch it again later on, then information on how to access that will be circulated following the webinar today.
So without further ado, I will hand over to the panel for today to get into the contents. I will start off, Richard, I think, with introductions of yourself, and then the panel. So over to you.
Richard Grant: Thank you, Oli. I'm Richard Grant, a mechanical engineer by training. My career has been in equipment and consumable development. So when I talk product development, it's about equipment and consumables rather than drug products themselves.
Oli's giving me 35 years in the industry. Actually, it's 20 years in the cell therapy industry, so I started with Argos almost, well, exactly 20 years ago today to help close and automate the dendritic cell therapy. I spent 17 years at Invitrogen, so a couple of years before that in product development and managing the cell therapy group, running cell therapy projects before being recruited to Fluidigm in Massachusetts to help them commercialize their acoustic cell selection and cell washing technologies that were then taken over by Merck and incorporated into Merck Millipore. And I've been with Dark Horse about a year. So, Michael, introduce yourself, please.
Michael Kinzie: Right. Thank you, Richard. My name is Michael Kinzie. I'm a principal at Dark Horse, and I've been with the stable for 2 years. I have 20 plus years of medical devices and cell and gene therapy from a bioprocessing manufacturing equipment perspective. My relevant experience was with Terumo BCT, which is located in Lakewood, Colorado, just west of Denver.
Terumo BCT is a global leader in blood component therapeutic apheresis and cellular technologies. My first part of time there I spent 10 years plus in the high volume manufacturing of complex, say, for instance, consumables in operations. I was a lead engineer on designing and developing a fully automated RF welding system for blood component bags. The system had a 12 second cycle time welding for bags per cycle. So what I call a 3 second leak tested bag.
I was the product engineer on the design team for the COBE Spectra Optia product. Then I jumped over to product development. I spent 10 plus years as the engineering manager and system engineer for the development of the Quantum cell expansion system, now called the Quantum Flex. This is real good experience for a full product development life cycle from prototype to commercial launch and then post market support thereafter. Madeline.
Madeline St. Onge: Hi, everyone! My name is Madeline St. Onge, senior consultant here at Dark Horse. I've been in the cell and gene therapy industry for 9 years. As Oli mentioned, the first 6 and a half, 7 of those were at the International Society for Cell and Gene Therapy, where I was heading up the industry affairs activities. I've been at Dark Horse also 2 years. And here I work primarily on our commercial strategy, market research and diligence projects, including those for clients developing tools and tech like we're going to discuss today.
So I'll dive right in. We're not going to spend too long on the agenda. This is just to give you a preview of the major considerations we're going to discuss throughout the webinar today. And as Oli mentioned, I'll remind everybody we do have time devoted at the end of the session today for Q&A. So please use that Zoom functionality and submit any questions for the panel. We'll do our best to get to those before we wrap up.
So we're really focused today on the development of bioprocessing equipment and key steps to consider once you have a novel idea with proven science behind it. So our goal is to cover best practices and opportunities to streamline these development milestones and also to ensure that commercialization is top of mind early in your product development journey. Some of the content that we're going to focus on today: how you consider your customer needs and start to think about market sizing and potential business models, how you consider your minimum viable product through prototyping and early customer research, looking at consumables and starting to secure your supply chain, your manufacturing process, and your alignment with regulatory requirements, testing your prototype with a group of early adopters so you have that customer engagement and can work to reduce your cost of goods early on, and then finally launch readiness, particularly with an emphasis on the ability to scale up your manufacturing.
Product Market Fit and Customer Understanding
So we're going to first look at product market fit and really looking at the question, what problem am I solving? And we're going to use a case study to showcase some of the major steps we take in supporting our clients with answering this question, and in this case the case study will extend beyond just product market fit.
The client in this case had a prototype and some established partnerships in place for their delivery platform for gene editing constructs, but was looking to deepen their understanding of user requirements and market opportunities. So to help them with this exercise, DHC started by performing a voice of customer survey, and the objective was to really gather insights to help frame target applications for this platform, expected performance metrics and pain points customers are experiencing with existing technologies that this product could help overcome.
Then, using a combination of what we learned from the voice of customer survey as well as some initial planning the client had done, we considered who would be the target customers for this platform and started to frame what that total number of potential customers could look like both today and in the future.
Then we evaluated pros and cons of competitive technologies to help frame where the client's platform could fit in the market. And that was really steps one to 3 were really phase one of the project, and in this case we didn't use House of Quality to refine design further at this stage. But that could be another step deployed that Michael will talk about a little bit later on.
So the next set of tasks, tasks 4 and 5 focused on developing the client's GMP strategy. So building out a GMP roadmap, performing a gap analysis and risk assessment and then supporting the client in managing their work with a contract engineering firm to develop the equipment itself.
And we use this case study because it's a good example of an integrated workflow with the outcome for the client being they were able to refine their understanding of their target market, make adjustments to their minimum viable product, plan for GMP with roadmap support and then also benefit from some project management work that helped oversee their other vendors.
And over the course of this engagement there were about 6 to 8 Dark Horse team members involved at various points in time depending on the subject matter expertise required, and I should also mention that while in this case we were doing this over the course of 18 months for one specific client, we can also do each of these steps or tasks individually, if somebody was looking just for one of these, so that's really the benefit of the integrated support there. So I'll pass it off to Richard now to discuss product market fit a little further.
Richard Grant: Thanks, Madeline. So I'm the supplier of a tool or technology for the cell and gene therapy market. What are my responsibilities? Well, the first one here is to demonstrate that your product works, and that's not just works in your engineer's mind, and it fills its requirements, but to demonstrate that it fills a market need, and that by fulfilling that market need, it's better than your competitors on at least one meaningful parameter, preferably more. That could be viability or recovery, definitely cost as we move towards a more cost focused environment for therapies. But more than just one would be important.
You need to continue, or you need to ensure that you have availability. So many of the products that have been launched in the market, I've noticed over the last few years, have struggled to either provide equipment properly when ordered, and worse and more common is the lack of consumable supply, reliable, obviously sterile, and confident supply of consumables in a timely manner is where a lot of equipment providers have been falling down.
You need to provide technical support for the use of your equipment and consumables in product development and manufacturing. And those 2 things are different in that the product development one needs your engineers to support the customers in refining your equipment workflows to the customer's process, and then you need to be able to lock down that equipment in manufacturing so it's only used for the recommended and approved process. So there's a difference in focus in the support.
And a lot of the equipment that's been developed or used in the cell therapy market was initially developed as a lab instrument, a research instrument. So it has some of that flexibility, but it's not ideally suited for manufacturing. So if you're coming into the market now, you need to almost have 2 modes in the product, one that can be used for product development and process development, and one that is locked down and reports well to manufacturing. And you've also got to remember that your customer is going to be the sponsor of the cell and gene therapy, and your product will be part of the CMC. And they need to know everything about that, and we'll touch on what that means from a master file perspective later on. But your responsibility is to develop your product in a way that enables the customer to use it in their process, and it has to add value and not complication to that process.
So I'll pass on to Michael.
Product Development and Requirements
Michael Kinzie: So for product development, how am I solving the problem? Just as in real estate, it's all about location, location, location. For product development in cell and gene therapy, it's all about requirements. It begins and ends with requirements. So a good requirements document is just as long as it needs to be and no longer. So there's a very fine balance of written and unwritten requirements.
There also are many strategies and approaches that can be taken to generate requirements, especially if you think about the minimal viable product which we'll get into later on. But you could have a minimal threshold performance to get it into the market, and then align that with a future objective value that's really superior in the marketplace. And then there's also certain requirements, such as functionalities and features that can be introduced into later versions. So that sort of helps the design team understand where they're going. So a well written requirements document gives the vision of what the design needs to do and then lets the design team decide how the design will meet those needs.
It also, the requirements document provides clarity of what I call definition of done for the engineering team, because design engineers are very good at designing and designing and designing. So it's a, it could be an infinite loop. But also with the requirements, it forms the basis of the traceability matrix, because some of these systems can get very complex and have multiple requirements, especially software and a variety of test cases that need to be managed throughout the whole design cycle.
Validating requirements, you know, confirms that they're the right ones, because every requirement has a cost to it. And as Madeline mentioned from after VOC, there is another tool that you may consider: the House of Quality. And briefly, it is essentially an efficient quality function deployment. It really translates the user needs of a voice of customer into engineering design requirements as features and functionality. One of my favorite user needs is ease of use. So, spoiler, this is a challenge, if not impossible, to validate.
The House of Quality also prioritizes resources and makes efficient use of resource utilization. It defines a working superior product benchmark to market products. It also gets a start on resolving conflicting requirements. As an example in the airline industry, there's a desire to minimize the cost per flight and the consumption of the amount of fuel that is consumed while maximizing the number of passengers per flight. More weight will burn more fuel. So you've got a conflict. What's the optimal design for that?
So requirements have attributes that they should be singular, unambiguous, and design agnostic. For unambiguous, not open for interpretation, really has one meaning, so you can avoid that what I call eleventh hour syndrome when a design engineer says, "Oh, is that what that requirement means?"
Also establish, the requirements should be measurable. So I have a nominal specification with tolerances, and if it's well written, it provides a predetermined acceptance criteria for the test or verification protocol. If it can't be measured, it's not a requirement.
Richard Grant: Yep, so I just wanted to comment here that requirements are really the foundational documents of your product development. So they need to be very clear, as Michael's pointed out, they need to be acceptable. But it's a living document. It can change through the process. But it is the foundation of your product, and you need to get that right very early on. It's very important. Back to you, Michael.
Michael Kinzie: Right. The other thing is the risk based approach. So for bioprocessing manufacturing equipment, it's highly recommended that you comply with ICH Q9. Your customer will most likely, or should be following this standard. It's very similar to medical devices ISO 14971. They're very sound risk management standards, and if there is an opportunity that your product may be classified as a device in the future, you'll already be complying with that standard. But either way they're very similar. GAMP 5 is also a risk based approach to comply with computerized systems.
Now, the key to a risk management process is that it's comprehensive and systematic and identifies the hazards that could cause harm. And there's a variety of tools that can be used for risk analysis. FMEA uses a severity and occurrence scoring system that leads you into what I would call the stoplight evaluation, where you can then score your hazards and the harms that they cause. But keep in mind typically a red, that means typically death or irreversible severe harm. You really don't have a product. You probably should not be shipping that product. So in this case severity of harm is not typically reduced because the harm is the harm.
And so the only other way to reduce risk is reducing the occurrence of the cause or the causes of the failure mode. So this is another way of prioritizing the work, effort, and resources, tackling the show stopper risks first. And then many of the non critical risks can be resolved by the application of design controls if you have them. You can continue to work on those, but it is a time and money effort.
Now, a challenge for you as a supplier, you may not know how your customer is using your product, and thus you may not know what harm could occur to the patient. However, there are the usual suspects of particulates, endotoxin, the extractables and leachables that are in essence impurities. So really with risk control, start as soon as possible, and it is a living process that gives a design team the time and information to be able to design the defect out of the product.
Richard Grant: And the one comment I would make on risk is it's important for your therapy risks to be, and your performance risks from a biological and a scientific background. Those are the risks I call show stopping risks. They need to be resolved early on before you progress with simple, difficult challenges in engineering. So there's really a measure of risks around, will this affect whether we have a product or not? Or is this a risk that just affects our ability to deliver the project on time? And you need to target the scientific and the risks you don't know that you have an answer for need to be dealt with early. Thanks, Michael.
Michael Kinzie: So forming the development engineering and support teams, what does it take to launch a novel cell and gene therapy tech tool and technology? And again, it's going to depend on the complexity and the novelty of the technology. But a typical design engineering team for a complete system, you may have a couple of different electrical engineers, mechanical engineering for the instrumentation or equipment and consumables. Those are very different. Typically the software, you have some kind of firmware as well.
And then if you're following a software life cycle development effort, you'd want your software quality assurance on the team as well. And I would recommend, if you have a multi-domain system to have a system engineer to integrate all those domains and then depending on the technology, you may have some specialty disciplines as well. And then with that you would have the support team of the typical business practice and business operations.
And one of the things about the House of Quality document, you start that early on in the process. It's almost an agreement with everybody: your support team and the design engineering team. So that marketing and sales, manufacturing, everybody's involved, and they can see what the product needs to do. And that's the time to bring up any concerns, and get those addressed early on. So Richard.
Design Management and Testing
Richard Grant: Terrific. So we've set up the teams. We've got everything going. How do we manage the design chaos that ensues? We've got a range of different tools. Obviously, you're prioritizing features and functionality and managing the risk that we talked about earlier.
I'll talk to Agile a little bit here. Traditionally, in a waterfall style product development, you get your mechanical and electronic challenges sorted early and you've got parts coming in. But the software doesn't come until near the end of the project. And so there's this mad rush to get things working and to find mechanical and electrical difficulties that can't be found until those subsystems or full systems are exercised with the software.
So the benefits that Agile brings to software is you can break things down into epics and stories and use cases. And you can actually get small parts of the software performing operationally, and they can be used to exercise subassemblies or components earlier on, and that gives you the ability to draw out issues that you may have with your other designs before you get to the final product.
So then, we move on to the concept of the minimum viable product. So that's a basic version of the product, relatively cheap and fast to build. But it has all of the key functions that you want in your product. And if you've been exercising different modules of that early on, you can get this working product to early adopter customers or even to market faster than you would a traditional product development. And therefore, you've got the ability to move things, you can do testing. You can make sure it works and you get it out there and get feedback from the market quite early. So that helps you with system integration. Resource leveling is all just a matter of juggling to get in a product development process.
So we could then move on to testing. So you've got your minimum viable product. How do you know it works? We've talked about having those subsystems working early, doing the engineering characterization of performance. You've obviously got the requirements document. And we talked about briefly the traceability matrix to measure how we meet the requirements. So you've got predetermined acceptance criteria.
You're obviously working with the standards that apply in the industry you're doing and that you're wanting to get into. And you've developed some test methods and they help you validate your equipment and consumables. It's important to be measuring statistically valid samples and including obscure corner cases for performance. We certainly found that at Fluidigm in low cell flow, low volume of cells, and you're off in a corner of the performance spectrum of the acoustics there. So there's a real effort in resolving your test program, testing enough items, testing them in strange enough situations that may occur that you've got real confidence in the technology.
You need to put effort into usability testing. So, Michael talked earlier about ease of use. How quickly does it take to load a consumable? Is that measured as a requirement? Can you comply with that? When the user is setting up the software, is it unambiguous? Is there a workflow through that that is quick and easy to use? So there are times you can put on that that will give you a solid measurement of how easy your system is to use, and that's certainly becoming a competitive item in the marketplace.
Reliability testing, a particular bugbear in mind, begin early and continue. Don't let your prototypes sit idle in the lab if they can be doing useful repetitive functions that tell you how it's going to work in the long term. Begin your subsystem integration testing as early as you have modules for that. You've got a process for managing design changes. Look at where those changes fit and how they impact your testing program. And then we move to the end in manufacturing process validations and getting your equipment installed at users places, and making sure that it fits their tests, and what they expect of their product.
I'll throw back to Michael.
Regulatory Pathways and Compliance
Michael Kinzie: So regulatory pathway, so bioprocessing manufacturing equipment are not medical devices. But we often get this question: is my product a medical device? And it really does depend on the intended use you have or plan to have for your product. And then think about what marketing claims you are planning to make. If you are making any claims about the cure, treatment, mitigation, prevention of a disease condition, then you are most likely a medical device. And that leads you down the road of complying with 21 CFR 820 for the FDA and/or ISO 13485 as applicable as well, and they're both well defined regulatory standards and the expectations are well outlined.
Bioprocessing manufacturing equipment are cGMP systems, or will be used in the manufacturing of cells for therapeutic use. So you can use GAMP 5 as well. It's a very good standard to follow. The systems have 3 distinct components or domains: the hardware, electrical, mechanical instrumentation or equipment, software and consumables. And realize that each of these domains, they have a different approach to even the design effort. But the quality assurance, risk management, usability and reliability, they all have to integrate. So the domains have interfaces to manage. And I'd recommend doing so with requirements.
Richard Grant: So we've got a cGMP product. We're manufacturing biologicals. What path do we take? We've got 2 paths here. There's the sponsor's path and the equipment developer's path. So the sponsor wants to work out that their therapy is producible and will have a positive impact on the patient, so they want to get the clinical trials as soon as possible. That sort of conflicts with an extensive and in-depth product development program from the tool provider's perspective.
And they can address that need for haste and also availability of product by going down a research use only equipment path. So this enables you to take the phased approach to implementing cGMP at your customers by providing them a device and consumable you're making lower levels of claims on. So your work as a technical developer is reduced because you've got claims for this early product that are less than the claims that you'll have for the cGMP product.
And to compensate for that, the customer will then be able to use your equipment and consumables in their phase one therapy production, and they compensate for the fact that you might not have electronic batch records enabled in your equipment by using their well defined manual written procedures and documentation and controlling all that stuff there.
It doesn't detract from the fact that you need to continue to develop your products as a technology provider to comply with the CFRs for drug production and finished pharmaceuticals that 21 CFR 210 and 211. But you can phase that in through the development of your equipment and consumables.
Both the sponsor and the technical provider should be using a quality by design process. So they type requirements in, they specify what they're doing, they do their design work, they verify. So a standard, high quality design of a product, process or a piece of equipment. It's a very similar process on those things. And as a technology provider, your product should enable your sponsor to demonstrate fitness for use so they can put their quality target product profile together, and they can get product that indicates that off your equipment. They need to identify their CQAs. Your equipment has to produce product that demonstrates those under testing.
And a final note here is anything that's going to be deployed into the European market needs to be CE marked. That's effectively a mandatory electrical safety standard for equipment deployed in Europe. It's a self assessment program, but it needs to be calculated into a development program and complied with, and there are similar electrical safety standards applied to the American market, and tested by firms like Underwriters Laboratory, and so forth.
So I'll pass back onto myself. So we've got a product. We've got a technical product that we're deploying into a cell therapy process, and you will have heard a lot about drug master files. What is it? Do you need one?
A master file is a voluntary submission of information to the FDA, and it's a way that your sponsor can be confident that the FDA has reviewed what your device and consumable will do, and that they don't need to disclose to them in extensive detail confidential and proprietary information. You disclose it to the FDA, goes on file there. The FDA will not review that file until it's referenced in an IND by a drug sponsor.
But it will be there. So as an equipment and consumable developer, it is one way of documenting your technology and putting it out there and getting the FDA to be ready to approve it. That doesn't require you to disclose all of your confidential information to multiple different potential clients along the journey to getting your product to market. So it does create an initial documentation load and ongoing maintenance. But it is one way of handling the how do I keep my proprietary information close to my chest?
So I'll pass on.
Key Challenges and Lessons Learned
Michael Kinzie: So some key challenges. Avoid the eleventh hour syndrome, if possible. Realities of early phase product development. I mean, there is a sticker shock. If you think about it, you really will have low volume product requirements for your customer. Your customer will have those low volume product requirement needs because you think about the time it takes for a clinical trial, and what we found often, that results in a high quote from suppliers, especially for consumables. And so another way of saying that: low volumes result in high cost of goods sold.
You typically don't realize volume discounts until after launch. And you're talking into the hundreds of thousands to millions of consumables as an example. And the other shock is that most of the early manufactured product goes to testing. So your customer may need 5 or 10, but you may need, depending on what the sampling plan is for performance testing, you may need in the 100 to 300 units.
So that just to let you know Dark Horse, we do have a database of contract engineering groups who we've worked with in the past and whose business models do support these early low volume needs. And there's also the one stop shop, if you will, where the product development is done at the contract engineering group. They transfer it to their manufacturing, and then they will be able to scale and commercialize with you for your product.
Dark Horseが提供できるもう一つの価値は、貴社の製品に対する公平な評価です。当社には細胞・遺伝子治療の専門的なオペレーターやエンジニアが在籍しており、貴社の製品を実際にテスト運用することが可能です。いわば「試運転」を代行することで、顧客が初期段階で遭遇しがちな回避可能な問題を未然に防ぎます。また、すでに製品が現場に導入されている場合でも、ユーザーやエンジニアリングの観点から、顧客がどのように製品を使用し、どのような体験をしているかを現地で評価し、そのフィードバックを貴社に提供いたします。
マイケル・キンジー： プロトタイピングから得られる教訓についてお話しします。プロトタイピングの設計段階では、タマネギをイメージしてください。皮をむくように、次々と新しい発見や学びが得られます。ですから、設計上のリスクが高い技術的要素をターゲットにして、可能な限り迅速に進めてください。これにより、素早い学習が可能になります。そして、継続的にフィードバックを得ながら、特定したキーオピニオンリーダーや、VOC（顧客の声）調査を行った潜在顧客と連携を続けてください。
次に、「動作する」ことの定義についてです。当たり前のように聞こえるかもしれませんが、実はそうではありません。特に、最小限の実行可能な製品（MVP）として「十分な品質」を定義する場合、さまざまな要素が絡んできます。「何をもって十分とするのか？」を考える必要があります。どのくらいの期間、あるいは何サイクル動作すればよいのか、どのような条件下で、システムの信頼性はどの程度か。こうした「動作する」ことの定義に、しっかりと時間を割いてください。細胞培養を例に挙げると、これは24時間365日のプロセスであり、細胞は休んでくれません。複雑なシステムには、問題が発生する可能性が数多く潜んでいるのです。
もう一つの重要な点は、製品の設計と製造プロセスを徹底的に検証することです。コストがかかることは承知していますが、投資する価値は十分にあります。有効なプロトタイプが完成したら、意図的に検証を行ってください。「本当に実現可能か？」を問い、少数ではなく多数の試作機を製造する計画を立てます。もちろん、その大半は廃棄することになるでしょう。しかし、欠陥は後になってからよりも、早い段階で見つける方がはるかに良いのです。顧客に見つけられる前に、自ら欠陥を発見することが重要です。
一例を挙げましょう。私がテルモBCTで「COBE Spectra」の製品エンジニアを務めていた際、上司の計算によると、私たちは2,000万キット以上の成分採血キットの製造を支えてきました。この消耗品は非常に複雑で、200以上の手作業による組み立て工程があり、約90の部品で構成され、45秒ごとに完成品がラインから流れてくるというものでした。それでも製品には欠陥が発生しました。数は多くありませんでしたが、それらにはサポートが必要でした。
製品開発における設計変更のコストは、開発初期なら「1セント」ですが、製造段階では「10セント」、そして商用化後に現場で問題が発覚すれば「数ドル」かかることを認識してください。すべては相対的なものです。CAPA（是正処置・予防処置）による予防的措置に時間を割くことを強く推奨します。医薬品や生物学的製剤においては、Subpart J, Section 211.192がCAPAに該当します。設計段階で欠陥を排除しておくことは、将来的に製造現場で継続的な是正処置に追われるよりも、はるかに効率的です。
試験方法の開発とバリデーションには、設計そのものと同じくらいの時間がかかることがあります。設計が完了してから「さて、どうやってテストしようか？」と考えるような状況には陥らないでください。それでは遅すぎます。適合性を証明するための公的な規格が存在しない場合、試験方法を独自に開発する必要が出てくる可能性が高いからです。これには時間と労力がかかります。適切なバリデーションを行い、正しい試験方法であることを確認してください。リチャード、お願いします。
リチャード・グラント： まとめに入ります。バイオプロセス機器の開発を成功させるための鍵は、マデリンが先ほどのプロジェクト計画で触れたように、18〜24ヶ月のプロジェクト期間を見込むことだと考えています。もし、すでに実証済みの科学的応用から始めるのであればの話です。「細胞処理の新しいアイデアがある。うまくいけば24ヶ月以内に機器と消耗品を市場に出せる」といった不確実な前提ではありません。マイケルと私は、18〜24ヶ月で市場投入を実現した製品を数多く見てきました。それらに共通しているのは、実証済みの科学的応用をベンチスケールのプロセスに落とし込んでいるという点です。
では、何をすべきでしょうか。顧客自身が理解している以上に、顧客のことを理解しなければなりません。先ほどマイケルと話していたのですが、ヘンリー・フォードが市場調査をした際、人々は「もっと速い馬が欲しい」と言いました。しかし、彼は自動車の必要性を導き出しました。顧客が欲しがっていたものではなく、顧客が本当に必要としていたものを提供したのです。
貴社の製品が市場のニーズを満たし、競合製品よりも優れていること、できれば性能が高く、かつ安価であることを証明しなければなりません。昨今は特に低コスト化が求められています。治療にかかる製品コストを抑えるという圧力は確実に存在します。しかし、コストだけでなく、パフォーマンスの面でも確固たる根拠を持つ必要があります。
要件定義は製品の基盤です。これほど強調してもしすぎることはありません。要件定義書は「生きている文書」ですが、それでも正しく作成する必要があります。明確でなければなりません。マイケルが言ったように、要件定義書は必要な長さであるべきで、それ以上でも以下でもいけません。要件そのものも、的確かつ測定可能である必要があります。
まずはリスクの高い設計課題から着手してください。製品の存続に関わるような、科学的に未検証の要素は、初期段階のテストで重点的に扱う必要があります。テストから得られる学びを最大化しましょう。「早く失敗し、頻繁に失敗する」ことが大切です。自信があることではなく、懸念があることをテストしてください。これらのプロセスすべてが、最小限の実行可能な製品（MVP）を定義する助けとなります。
MVPを世に出し、実際に動作させ、テストを行い、顧客に使ってもらいましょう。もし顧客がプロトタイプを返品してくるようなら、それは実行可能な製品とは言えません。顧客が手放したくないと思うような製品にするために、さらに努力が必要です。顧客が製品に満足していれば、手元に置いておくためにあらゆる理由を見つけてくれるはずです。もし顧客が簡単に返品してくるようなら、何かがうまくいっていない証拠です。
規制当局への承認ルートを選択してください。先ほど議論した通り、RUO（研究用）からcGMP（医薬品適正製造基準）承認を目指すのであれば、開発の初期段階から明確な戦略を立てる必要があります。
最後に、パートナーの選定は慎重に行ってください。すべてを自社内で行うことは不可能です。スキルセットや特定のエンジニアリング分野が不足することもあるでしょう。助けてくれる専門家を見つけてください。彼らと信頼関係を築き、二人三脚で協力して製品を市場に送り出し、市場のニーズを満たしていきましょう。
ありがとうございました。以上で終了です、マデリン。
質疑応答
マデリン・サン・オンジ： 残り15分ほどとなりましたので、質疑応答に移ります。まだ質問を投稿されていない方は、ZoomのQ&A機能をご利用ください。
先ほど少し触れた内容に関連する質問から始めたいと思います。まずリチャードさん、次にマイケルさんにお聞きします。細胞・遺伝子治療のツールや技術に新規参入する企業が直面する最大の課題は何でしょうか。細胞・遺伝子治療がこれほどまでに難しい理由は何なのか、また、新規参入企業が製品開発の過程で特に注意すべき最大のハードルは何だとお考えですか。
リチャード・グラント： そうですね。クライアントの誰もが最初に口にするのは「私の細胞は特別だ」「私のプロセスは他とは違う」という言葉です。そのため、装置をカスタマイズしたいと考えるわけです。先ほども述べたように、彼らが使用している装置の多くは科学研究用のものであり、彼らが必要とする作業に特化して設計されていない場合があります。そこで私が多くの現場で採用してきたアプローチは、プロセス開発段階では柔軟性を持たせつつ、製造段階ではGMPモードに固定できるような装置を設計することです。
その他の課題としては、市場での認知度が挙げられます。スタートアップ企業の場合、既存の技術を置き換えて自社製品をどう差別化するかが重要です。臨床試験で他社の装置を排除して自社製品を採用してもらうには、圧倒的な優位性が必要です。他社の臨床試験で使われている装置を入れ替えるには、膨大な作業とプロセスへのコミットメントが伴うからです。
一方で、新しい技術であれば臨床試験に採用されやすいという側面もありますが、まだ試験が始まっていない段階であれば、製品が市場に出るまでに長い年月とリスクを負うことになります。この点はよく検討しなければなりません。また、マイケルさんが先ほど触れたように、消耗品の製造については、初期の生産量は少なく、使い捨て技術の複雑さは高いため、製造パートナーを見つけるのが困難です。
こうしたメーカーからの供給は、これまで断続的で品質も安定していませんでした。これも課題です。使い捨て製品の製造で利益を上げられる企業を見つけるのは容易ではありません。また、自家細胞から他家細胞へと移行する中で、使い捨て製品を用いたバッチサイズが大きくなれば、使い捨て消耗品の需要量自体は減少していくでしょう。これも市場にとって新たな課題となります。
マイケルさんにバトンを渡す前に、最後にもう一つ。ビジネスモデルについてです。どのようなビジネスモデルを構築するつもりでしょうか。市場から冷ややかな目で見られているモデルもいくつか存在します。技術をどのように収益化し、かつ顧客を遠ざけないような方法をどう実現するのか。マイケルさん、いかがでしょうか。
マイケル・キンジー： リチャードさん、補足させていただきます。リチャードさんがおっしゃったように、顧客は皆「自分の細胞は特別だ」と考え、独自の培養方法を持っています。その顧客だけでなく、同じように考えている他のすべての顧客にも対応できるシステムをどう設計するかが鍵です。つまり、システムは10通りの異なるニーズに応えられなければならないのです。
また、タイミングも重要です。非臨床試験の段階であれば、スポンサーである顧客がIND申請やCMCセクションにその技術を組み込むのは比較的容易です。しかし、そこから治療薬として承認されるまでには、おそらく10年かかります。一方で、開発の後期段階であれば、比較試験（コンパラビリティ試験）という大きな壁があり、多大な労力を要します。市場参入の障壁は非常に現実的なものであり、それを認識しておく必要があります。
マデリン・セント・オンジ： お二人ともありがとうございます。他にもいくつか質問が来ています。リチャードさんが触れたマーケティング、商業化、ビジネスモデルに関する質問です。顧客に対してどのようなアプローチを確立すべきでしょうか。この質問はビジネスモデルだけでなく、開発初期のパートナーシップについても言及しているようです。ベストプラクティスとして何が推奨されますか。
リチャード・グラント： 非常に良い質問ですね。答えは一つではありません。ご存知の通り、治療プロセスのわずか一工程に自社の技術を組み込むために、まるで「長男を人質に取る」ような法外な対価を要求する企業も存在します。これでは導入のハードルが高すぎます。そうした企業がこれまで成功してきたのは、他に代替手段がなかったからです。しかし、今後製品が増えるにつれ、顧客は技術プロバイダーに対してより現実的な要求をするようになるでしょう。
技術プロバイダー側も、製品の商業化においてより妥当な姿勢を示す必要があります。最終的なスポンサーと技術プロバイダーの間で、どのような道筋をたどるべきか対話を持つべきです。ロイヤリティ方式にするのか、あるいは初期費用のみにするのか。装置のコスト、消耗品のコスト、そして生産量が増えるにつれてコストがどう下がっていくのか。これらは対話によって決めるべきです。エンジニアは開発プロセスにおける消耗品や装置のコスト限界を提示できます。それをもとに、自社にとって最適なビジネスモデルを導き出す必要があります。顧客がどれだけ購入する意思があるか、どのような支払い方法を望んでいるか、どのような財務条件であれば納得できるか。こうした対話を早期に始めることが、長期的な成功には不可欠です。
マデリン・セント・オンジ： ありがとうございます。もう一つ質問です。これはマイケルさんにお聞きしたいのですが、患者までの距離によって装置の要件は変わるのでしょうか。例えば、他家細胞治療製品において、マスターセルバンクに近い段階と、患者に近い段階とでは、要件の考え方はどう変わりますか。
マイケル・キンジー： 要件に関して言えば、大きな違いはないと考えています。システムは本来果たすべき役割を果たす必要があり、その要件がすべてを定義します。ここで重要なのはリスクベースのアプローチです。患者に近い段階であれば、スポンサーである顧客が患者の安全性と有効性を確保するために提供できる緩和策は限られてきます。例えば、上流工程で白血球アフェレーシスパックを扱う場合、充填・仕上げ工程に至るまでに多くのプロセスを経ます。しかし、アフェレーシス装置に接続して患者から採取するその工程の要件は非常に厳格であり、安全性も極めて高いレベルが求められます。
顧客の製造プロセスを考慮し、自社のシステムがその中でどのような役割を果たすのかを考える必要があります。どの工程や段階に組み込まれるのか。また、下流工程に複数の洗浄ステップがある場合、そこで不純物が混入しても、患者への投与前に除去される可能性があるのか。つまり、リスクベースのアプローチで考えることが重要です。
リチャード・グラント： そうですね。補足すると、システムの要件を策定する際には、その装置がどこで運用されるのかを把握しておく必要があります。細胞処理プロセスには時間的な制約が多く存在します。「この工程は50分以内に完了しなければならない」「DMSOを使用するため、10分以内に除去する必要がある」といった要件は、技術がどこで使われ、どのような細胞や試薬が使用されるかを想定して策定されます。つまり、装置の設置場所や用途に合わせて要件をカスタマイズするということです。要件定義の段階でその点を理解し、技術の導入環境に最適化させることが不可欠です。
マイケル・キンジー： それが「意図された使用目的（インテンデッド・ユース）」につながります。もし顧客が設計意図とは異なる使い方をした場合、医療機器の分野では「適応外使用（オフラベル使用）」とみなされます。誤った使用や意図された用途から逸脱した運用が行われた場合、保証請求などに対して、メーカー側には正当性を主張する根拠が生まれます。
マデリン・サン・オンジュ： ありがとうございます。最後にいくつか質問をさせていただきます。2部構成の質問です。1つ目は、新しい装置や製品開発のための資金調達は大きな課題であるという点です。小規模な企業の場合、投資家が細胞・遺伝子治療装置の市場機会を十分に理解していないことがあります。何かアドバイスはありますか？初期段階のクライアントを支援する際、私たちがまず整理をお手伝いするのはピッチデッキ（事業計画書）です。先ほども触れましたが、解決しようとしている課題を明確にすることが重要です。非常に優れた技術であっても、「解決策はあるが、解決すべき課題が不明確」というケースをよく目にします。特定のプロセスや単位操作をどのように改善できるのか、その裏付けとなるデータが初期段階であってもあれば、それを提示して説得力のあるストーリーを描くことが極めて重要です。
もう1点、過去1年半の経済状況を考えると、細胞・遺伝子治療分野に投資している投資家は、現在ではかなり洗練されており、この分野に精通している傾向があります。そのため、やはりストーリーをしっかりと練り上げる必要があり、彼らは専門的な議論を求めてきます。もし現在やり取りしている投資家がそうでない場合は、細胞・遺伝子治療分野で現在活発に活動しており、あなたの提案を理解できる投資家を探すのが一つの手かもしれません。マイケルやリチャード、何か付け加えることはありますか？
リチャード・グラント： そうですね。ロブやアンソニー・デイヴィスとこの件について議論したことがありますが、彼らは医薬品製造に特化した投資家というよりは、市場の動向に敏感なベンチャーキャピタリストとつながりを持っています。市場を理解し、投資意欲のある層は確実に存在します。この分野に精通した経験豊富な投資家は存在するため、そうした層にアプローチする道はあります。ピッチデッキを洗練させれば、可能性は広がるはずです。
マイケル・キンジー： その技術が新規であり、既存の市場製品よりも優れていることを証明できれば、説得力は増すでしょう。ただし、投資家が求める18〜24ヶ月という投資回収期間の目標は、技術に対する深い理解がなければ現実的ではないかもしれません。しかし、その投資がコスト削減や、より優れた治療法の提供につながるものであれば話は別です。現在は希少疾患が中心で患者数は比較的少ないですが、鎌状赤血球症のように米国だけでも10万人以上の患者がいるケースもあります。さらにパーキンソン病のように、米国で100万人、世界で1,000万人という患者数を抱える疾患もあり、高齢化に伴いその数は増加しています。そうした将来を見据えた展望こそが、ピッチデッキをより魅力的なものにするはずです。
マデリン・サン・オンジュ： 最後にもう一つ、寄せられた質問にお答えします。「細胞株樹立装置において、cGMPは関連しますか？」という質問です。
リチャード・グラント： 良い質問ですね。質問の続きには「すべてのプロセスは、当初はGMP準拠ではなかった」とありました。これは、細胞製造プロセスで使用されるヒト血清アルブミンなどの成分にも当てはまります。これらは開発当初、cGMP要件下にはありませんでした。業界では、ウシ血清アルブミンをGMP準拠のヒト血清アルブミンに置き換えることで対応しています。もし過去に非GMP装置で細胞株を樹立したとしても、最終的にはその細胞株をGMP対応にする必要があるでしょう。
では、どうすればよいのでしょうか。純粋で汚染のない細胞株であれば、いずれ誰かが「これはGMPプロセスで使用可能だ」と判断する時が来ます。つまり、ある時点で劇的な変更を行うのではなく、進化の過程で対応していくのが現実的でしょう。非常に鋭い質問ですね。
マイケル・キンジー： FDAのガイダンスの多くは「これが現在の我々の考えである」という言葉で始まります。つまり、知見が深まるにつれて変更される可能性があるということです。初期には有効だった手法でも、安全性や有効性に問題が見つかれば見直されます。cGMPはこれまで様々な業界で機能してきた実績があります。規制の動向を先取りし続けることも、この分野では重要な戦略の一つです。
閉会の挨拶
オリバー・ボール： お時間の都合上、ここで締めくくらせていただきます。非常に活発な質疑応答で、すべてのご質問にお答えしきれなかったのが心残りですが、個別の質問がございましたら、お気軽にお問い合わせください。直接お話しさせていただきます。
リチャード・グラント： そうですね。未回答のご質問については、後ほど回答をまとめてお送りすることも可能です。
オリバー・ボール： 承知いたしました。それでは最後に、本ウェビナーのオンデマンド配信についてお知らせします。後日、弊社ウェブサイトにてアーカイブを公開し、アクセス方法をメールでお送りしますので、ぜひ同僚の皆様と共有してください。本日はご参加いただきありがとうございました。今後も「Unbridled Excellence」ウェビナーを順次開催予定ですので、ぜひご期待ください。ありがとうございました。
リチャード・グラント： 皆さん、ありがとうございました。