How to Turn An Innovative Drug Candidate into a Commercial Success – The Product Development Plan Explained

How to Turn An Innovative Drug Candidate into a Commercial Success – The Product Development Plan Explained

Without doubt, biotech startups and smaller pharmaceutical companies have become the major drivers of innovation in the pharmaceutical industry. In 2020, 63% of approved new therapeutic drugs in Europe and the US came from small-to-medium enterprises. Yet for every success, there are countless tales of defeat. How do investors and executive managers bridge the gap between identifying a promising drug candidate and turning out a commercially successful product? While there is no simple answer to this question, one thing is certain: behind every successful new drug, there is a well-crafted product development plan (PDP). In this article, we explore why and how to use this pivotal tool to formulate a winning drug development strategy.

What is a Product Development Plan (PDP)?

The PDP is a strategic document that creates a detailed and comprehensive picture of the development strategy. It serves as a step-by-step guide to arrive at the envisioned drug product. For each stage of the development process, the PDP clarifies the major goals and critical success factors, specifying how success will be measured and what needs to be done to mitigate any risks.

A well-designed PDP not only increases the chances of success, it also plays an important role in helping the program teams reduce cost of goods, maximize efficiency and shorten time to market.

The PDP: Where Opportunity Meets Reality

Bringing a beneficial new drug or therapy to patients is an exciting opportunity and a worthy goal, but not without significant risks. For the best chance of success, it is imperative to start out with a realistic understanding of what lies ahead, and a solid plan of how to arrive at an end product that is not only marketable but will give a healthy return on investment.

Even with sound science and technology as the starting point, turning a lead candidate into a commercially viable drug is no easy feat. It is a multidisciplinary effort that requires extensive planning and coordination, as well as a clear vision of the end goal.

As we saw previously, partnering with more experienced industry players who have been there before and know what to expect is one way that smaller biotech companies can improve their chances of success. Another is to make sure there is a sound product development plan (PDP) in place from the start.

The News No CEO Wants to Hear

Imagine having spent several years and several million investor dollars to get a drug candidate successfully through phase 1 clinical trials, only to learn that your manufacturing process is not suitable for commercial scale production or that the COGS is too high.

Or perhaps your new gene therapy turns out to be the next Zolgensma, with a price tag of over $2M per patient. Will the benefit to patients justify the price of your product? Will insurers agree to cover it? If not, it may mean going back to the drawing board to rework the formulation or the manufacturing process.

What if you had to tell stakeholders that there would be a massive delay in bringing your product to the market because you did not correctly anticipate pivotal next steps and investments?

All of these scenarios are catastrophic for any company, but in particular for smaller companies that pursue a product strategy rather than a technology platform strategy.

For companies relying on Big Pharma partnerships, Menzo Havenga, President & CEO of Batavia Biosciences offers these additional words of caution:

“If at the heart of your company strategy a big pharma partner is imperative, then please note that they will take a meticulous look at the manufacturing process underlying your Phase I clinical data. Should there be any risk that the process cannot be scaled to final commercial volume, they may find the return on investment disappointing.”

Scenarios like this happen far more often than you might think, especially when developing complex biological products or advanced therapeutics, where there may be no established manufacturing or commercialization paradigms, and the path to regulatory approval is uncertain.

Where does it all go wrong? More often than not, the cause of costly delays and roadblocks can be traced back to inadequate planning or failure to fully appreciate the commercial aspects of the program and their implications in product development.

What is the Role of the PDP and Who Will Use It?

Given that a typical drug can take over a decade and more than $2 billion to develop, business leaders need to be fully aware upfront, before spending money, of what they’re getting themselves, their teams and their stakeholders into. The PDP lays everything out on the table from the start, so that the chance of success can be accurately assessed. This starts with being brutally honest about capabilities, weaknesses and deficits, as well as any challenges and risks they face.

As the program unfolds, executive management, potential partners and investors need to be presented with all the relevant facts and information required to decide whether the investment is a viable one, and whether all the criteria have been met to progress to the next stage gate.

In addition, teams executing on the plan will need to have clear guidance on strategy and know what steps to take at every stage of the development process in order to gather the right information and achieve the end goals. They will need to follow the metrics to success, understand what contingency plans are in place, and know when to act on them should things go wrong. A good PDP helps ensure timely action so that there is a smooth transition between phases. In particular, it helps your teams understand how any proposed changes will impact the program as a whole, so that they can make mission-critical decisions without delay.

On this point, Christopher Yallop, COO of Batavia Biosciences comments:

“As any cyclist knows, if you are on your bike and looking only at the tarmac you will not see the bus coming around the corner! It’s imperative when developing a drug that you see the road ahead and steer when needed. That’s where the PDP is essential.”

Finally, Program leaders must of course have sight of the big picture to be able to delegate responsibilities and coordinate the activities of all the relevant teams—including finance, marketing, non-clinical and clinical development, quality assurance, and regulatory affairs. They can refer to the plan to check whether teams are on track to meet important milestones and deliver to specification and within budget.

The PDP is the central command station that makes all of this possible.

The Benefits of Creating a PDP for Your Drug Candidate?

A PDP should meticulously map out the journey of a drug candidate, from early-stage research through commercialization. By charting the course, it paves the way for smoother navigation, optimal resource allocation, and informed decision-making.

A PDP is more than just a roadmap – it’s a strategic compass guiding drug developers to achieve the desired outcomes efficiently. Here are some compelling reasons to consider crafting a PDP for your drug candidate.

  1. Provides clear guidance at each stage
  2. Serves as a reality check
  3. Facilitates communication
  4. Improves alignment
  5. Drives agility and sound decision-making
  6. Increases efficiency

What Should Be in the Product Development Plan?

In practice, the PDP is not one strategy, but many. The key to creating a well-integrated program is to ensure that the PDP encompasses all stages and aspects of the drug development program. While the structure and content may vary, most drug development plans include these components:

Executive Summary

A high-level overview of the drug product and target patient, the market position, as well as a summary of the financial figures and projections needed to support investment and stage gate decisions.

Marketing Strategy and Business Case

This section focuses in more detail on the commercial aspects of the program, plotting the strategy for achieving the necessary market penetration and expected return on investment. Intellectual property and trademark strategy – plays a crucial role in maintaining competitive advantage, ensuring protection in major markets, and responding quickly to any changes in the IP landscape.

Target Product Profile (TPP)

Often described as the backbone of the PDP, the TPP details the target product attributes needed to obtain regulatory approval and to satisfy commercial goals; these specifications are crucial in determining what can be claimed on the product label, and they also drive the design and evidence gathering strategies for other critical program elements.

Detailed Roadmaps

Comprising of the ‘meat and bones’ of the PDP, laying out the most effective strategies for non-clinical and clinical development, CMC, manufacturing, regulatory affairs, and quality assurance, project organization, planning and budget considerations.

How to Get it Right First Time

Having a PDP in place as early as possible lays a solid foundation for success, but only if it has the right structure and content. To see what a typical PDP looks like, request our free PDP template, which you can access after completing the form below. In the next and final article of this series, we’ll discuss how to put together the most effective PDP for your drug development program.

Biotech Startups – Understanding The Ecosystem For Success

Biotechnology is in the midst of a great era of innovation, with an ever-expanding toolbox of drug modalities spawning development of exciting new vaccines, medicines and therapies. Today’s ecosystem for innovation in drug development looks quite different compared to ten or twenty years ago, with many more symbiotic relationships between venture capital (VC)-backed pharma and small biotech startups working to diffuse risk across the development lifecycle.

On the upside, the appetite for investment in the life science industry is big and getting bigger.  According to Silicon Valley Bank’s 2020 annual report, biopharma investment hit record highs for the fourth straight year in a row, in terms of both the number of deals and the dollars invested.  Especially encouraging for biotech startups was the significant increase in Series A funding in 2020 compared to 2019.  Into 2021 the venture capital outlook continues to look bright, with PitchBook predicting that this year “Biotech and pharma VC deal activity will likely exceed $20B for the second consecutive year.”

Big fish, little fish – finding a niche in the funding ecosystem

On a more sobering note, even as VC-backed innovation flourishes, the competition for early stage funding among biotech companies is fierce, with much of the investment dollars going into the hands of fewer but more well-connected players—the big fish, if you will.

“What we’ve really seen lagging now is seed money for new founders who don’t have a track record for having started successful companies in the past and don’t have a very strong extensive network of people in funding and in company development,” says Craig Kaneski, an associate in patents and innovations at the law firm Wilson Sonsini. Speaking in a September 2020 webinar on navigating the life science funding landscape, Kaneski elaborated: “We’ve observed that some deals are deemed more for founders that are very experienced and have strong track records, [including] a good track record with VCs.”

So the big question is – what about those little fish – the biotech startups who have great ideas, but whose founders haven’t been lucky enough, or in the game long enough, to have the same track record and connections as the big players?  How do they find their niche in the ecosystem?

Big Pharma as a resource for biotech startups

A common perception is that funding and support from a large pharmaceutical company only becomes relevant for biotech startups when their product is in the latter stages of development—that is to say, after the development project has been significantly ‘de-risked’ by the startup company.  But a recent analysis of how large pharma impacts biotechnology startup success turns this thinking on its head.

In their study published in Nature Biotechnology, analysts from two venture capital firms in the Netherlands trawled GlobalData’s Pharma database to identify all deals between large pharma and biotechnology startups over the 15-year period from 2004-2019. They then looked to see whether there was a link between startup success rate and having an established connection with a pharmaceutical company.  In this case, they defined success as being listed on public markets (IPO), acquired (majority or 100%), or having had a drug approved during the period in question.

Remarkably, they found that the startup success rate increased from 18% to 37% when a large pharma investor was on board. This connection also increased both the size of success (from a median of $138M to $332M market capitalization) and the acquisition value (from $136M to $377M).  Counter to the prevailing dogma, they found that success rates were boosted for startups that partnered not just at the clinical stage, but also earlier—during preclinical development. They concluded that large pharma partnerships are advantageous throughout the startup lifecycle—from the preclinical stage through exit by acquisition or IPO.

What are the reasons for this positive effect?  In the early stages of development, the authors suggest that access to the pharma partner’s intellectual property (IP) may play a significant role.  They speculate that the pharma partner essentially de-risks the IP before outlicensing it to the startup, which could effectively give them an edge over competitors.

They also highlight what is perhaps an even more important factor: that a large pharma partner can provide ongoing support—in terms of both resources and specific expertise that entrepreneurs may be lacking—for example, in GMP clinical development, regulatory interactions and large-scale manufacturing.

Partnering to build credibility

Another expert panelist in the life science funding landscape webinar we mentioned earlier, Cynthia (Cyndi) Green, commented on how difficult it can be for startups to succeed in the competitive biopharmaceutical space:

“On the therapeutic side of things, which is really where I’ve spent most of my time, therapeutics and vaccines, it’s tough,” says Green.  “We’re looking to invest in early stage, and when something doesn’t have clinical data yet—and a lot of times definitely doesn’t have efficacy data—it’s a hard sell and it’s a lot of risk.”

As Managing Director of Connecticut Innovations, the state’s strategic venture capital arm, Green has had a wealth of experience supporting the growth of innovative biotech companies. From what she’s seen, surviving in this competitive landscape has a lot to do with giving potential partners and investors confidence that you know what you’re doing.  She highlights the importance of having access to specialized expertise—either in-house or through partnerships—in any areas that are unfamiliar:

“If you are a new entrepreneur, try to get somebody on your team, at least as an advisor, that’s ‘been there done that’ and has credibility…[Investors] have to have faith in the [startup’s] team and their ability to find the correct advisors, to take help, and to do well with your money.”

The rise of Center of Excellence CDMOs

By definition, being an innovative biotech startup means breaking new ground. Working with a new drug modality—for example, a novel type of viral vector—may call for completely new development and manufacturing strategies.  This frequently requires entrepreneurs to venture into unfamiliar territory, especially in areas such as production scale-up, regulatory compliance and cost-of-goods estimation.

In such cases, a specialized contract development and manufacturing organization (CDMO) is another valuable resource that can give new startups an edge.  With years of experience and expertise in scale-up and manufacture of complex biological products, a CDMO can help teams avoid common pitfalls and find the quickest route to the next development milestone.

In particular, there’s a new breed of CDMO emerging, called a Center of Excellence CDMO (CoE CDMO). CoE CDMOs go beyond service provision. They provide leadership in their particular areas of focus, share best practices, and are able to offer more tailored solutions. Importantly, they aim to create long-term partnerships with their customers, which means they can often provide more comprehensive support and guidance across the development cycle.

If Green is right, having a CoE-CDMO on your side may be just the sort of knowledgeable expert you need to boost credibility with potential VC and pharma investors, and get your innovative product into the clinic sooner.

Looking for more insights on this topic? Don’t miss our next article, where we take a closer look at the elements of a successful Product Development Plan and how you can use one to build credibility with potential investors and partners.

Adenoviral Vector Platform: Past & Current Challenges

Adenoviral Vector Platform: Past & Current Challenges

Adenoviruses have been explored for gene therapy purposes for many decades. They are DNA viruses, with a double-stranded DNA genome of around 26-45 kilobases. Adenoviruses have been isolated from a broad range of species giving the  adenovirus family  an impressively wide host range. Adenoviruses typically cause mild infections which are self-limiting and as such, an adenovirus infection usually does not present with clinical symptoms. In addition, the vector can efficiently infect both resting and dividing cells and does not integrate into the host genome which avoids stable genetic modification.

The adenoviral replication cycle is tightly controlled by the expression of E1 proteins, providing an opportunity to generate replication deficient adenoviral vectors by deleting the E1 protein from the viral genome and producing so-called E1-deleted viruses in cell lines stably expressing the E1 protein. In addition, insertion of foreign DNA expressing one or more desired proteins under the control of heterologous promoters located in the former E1 region has been successful. As a consequence, high expression of desired proteins in target cells can now readily be achieved using E1-deleted vectors.

Adenoviral vectors are used in some of the most high-profile clinical trials in the field of gene therapy and have been approved as vaccine carriers to battle COVID-19 and Ebola. As with all vectors, their road to success has been paved with challenges.

Challenges in development adenoviruses as vectors

One of the first challenges in the development of adenoviruses as vectors was the rise of replication competent adenoviruses in product preparations. Here, E1 containing (and thus replication competent) vector particles were found to be present in product batches. This was considered a major safety issue as replication of recombinant adenoviral vectors in host cells had the potential to lead to tumor formation. The ultimate design of new packaging cell lines e.g. PER.C6 cells, void of any DNA sequence overlap between the vector and the E1 sequences present in the packaging cell line could successfully prevent the formation of replication competent particles in product preps.

Another challenge in the development of adenoviral vectors was the pre-existing immunity to many adenoviruses in humans. Here, owing to the widespread prevalence of wild-type adenoviruses in nature, as well as the vast numbers of serotypes circulating in humans, there is a substantial chance that the host will have encountered the adenovirus previously and therefore possesses pre-existing immunity against the virus. In such instances, and depending on the route of administration, the host immune system may clear the vector product before it has had a chance to infect target cells and express the desired protein(s) thus severely limiting product efficacy. To circumvent pre-existing immunity, researchers turned to rare human serotypes and serotypes from non-human origin. To date, there are many different adenoviral vectors available to circumvent pre-existing immunity. Available vectors are either selected from rare human serotypes, non-human primates or alternative species like dogs or goats.

Successfully avoiding host pre-existing immunity has helped to re-position adenoviral vectors as important tools in future gene editing and vaccine product development. Here the human Ad26 vector from Janssen Vaccines and the Chimpanzee derived vector from Oxford have taken dominant roles in building safe and effective vaccines against SARS-CoV-2, the cause of COVID-19 disease. Mass vaccination campaigns using these vectors have now revealed another challenge and that is the induction of severe clotting in humans at extreme low frequency. Around the globe researchers are currently working to understand the basic scientific principles of this rare phenomenon. It can be expected that a thorough understanding of the underlying pathway(s) of adenoviral vector mediated clotting will be elucidated soon, most likely resulting in further modifications to the adenoviral vector backbone.

Current uses of adenoviral vectors

The adenoviral vector represents one of the most studied vector systems currently available to researchers and product developers. The wealth of knowledge and available databases on vector development, manufacturing, pre-clinical data and clinical data is unprecedented. The thorough R&D scrutiny of adenoviral vectors have provided tools and methods for assessing both safety and efficacy prior to conducting clinical trials and have proven extremely robust. This is one of the biggest strengths of the adenoviral vector platform. In addition, the adenoviral vector system represents by far the most mature vector platform when it comes to manufacturing. This is mainly due to the fact that several vectors have been approved as products on the market. Vector production trains, purification methods and testing/release protocols have been thoroughly scrutinized and completely streamlined. The latter has resulted in a thorough understanding of the volumetric output of the vector platform in relation to the cost of goods (COG) of manufacturing. Such analyses have shown that the adenoviral vector platform is extremely competitive on pricing compared to any other vector platform currently being researched.

Many of the factors outlined above have significantly contributed to the rapid response by both AstraZeneca and Janssen in the deployment of their adenoviral vector based COVID vaccines for emergency use. Here, plug-and-play vector platforms and a well-known and established regulatory path have been crucial for rapid deployment.

This is why the adenoviral vector platform is as sought after as ever. Indeed, adenoviral vectors are the vector of choice for many different vaccine strategies including HIV, Zika, malaria and tuberculosis to name but a few. In all of these programs currently being pursued, pre-clinical studies have demonstrated effective protection against disease. In addition, these studies have proven that adenoviral vector-based vaccines provide long term and durable protection, avoiding the need for repeat vaccination. The latter is crucial in the logistics of vaccine deployment especially in developing countries. There is no doubt that many new vaccines using the adenoviral vector platform will make it to market.

When it comes to gene therapies, adenoviral vectors have been very successful where localization of the treatment is required. The ability to modify the fiber protein and inject the adeno vector locally means that genetic therapies can be closely confined to specific regions of the body. Genetic therapies for treating the eyes as well as targeting specific tumors have been well established using adenoviral vectors. Another popular use is in ex-vivo therapies where for instance veins are removed and treated with adeno vectors before being returned to the body (vein grafting). Here, adenoviral vector therapies have a highly promising preclinical success rate and have demonstrated the ability of local gene transfer confined to the tissue of interest.

Adenovirus vector manufacturing

Despite the broad tissue tropism of the adenovirus family, the vast majority of them grow on an engineered cell line called HEK293. This is a commercially available cell line that can be used in the research lab as well as the production hall. While there are different cell lines that can be used to produce different adenovirus serotypes, the fact that most will grow in HEK293 offers a great advantage. The prevalence of HEK293 cells in the development of adenoviral vectors means that from a regulatory standpoint, they are much less risky than novel cell lines with no track record.

Adenoviral vectors are also amenable to genetic modification. It is common and relatively straight forward to change the fiber proteins on the surface of an adenovirus. Such a change can have significant effects on the tissue tropism, helping to guide the virus to specific tissues in order to deliver its payload. This is a very useful feature for treatment and can also help determine the administration route. This provides the adenoviral vector platform with high flexibility when it comes to therapeutic options. This feature is especially useful for developing oncolytic therapy where an adeno vector can be engineered to specifically target tumor cells or even specifically replicate in tumor cells.

In conclusion, the  impressive track record of adenoviral vectors  coupled to the platform flexibility and versatility in developing new vectors make them an important and extremely relevant tool for developing therapies and vaccines.

How to devise a drug development plan that actually works

A well-crafted  product development plan (PDP)  can play a pivotal role in the development and commercialization of a new drug product, but creating one takes time, commitment, and a lot of hard work. After all that effort, will your PDP be the magic bullet that builds investor confidence and steers you on the path to success—or will it end up being filed away and forgotten? We tapped into the wisdom of Batavia’s president and CEO, Menzo Havenga, for his advice on how to create an effective PDP.  True to form, he had some refreshing insights that turn conventional thinking on its head.

Start With The End Goal and Work Backwards

Perhaps the piece of advice that comes least naturally to those who are new to commercial drug development is the suggestion to work from the finish line backwards. Especially in cases where a drug candidate is coming out of an academic setting, the development strategy tends to focus first on the technical and scientific aspects, because this is the entrepreneur’s comfort zone.

“This can get you into a lot of hot water when constructing a product development plan,” says Havenga. “Instead of thinking from the bottom up, emerging biotech companies need to learn to plan from the top down, starting with the commercial drivers, and drilling down from there. Otherwise, they risk developing a product that fails to satisfy regulators, is not cost-effective to produce, or that no one will buy.”

For example, you might start by asking what is the ultimate business goal – will you out-license to a partner or take it all the way through to product launch?  If it’s the latter, then in what countries will you launch first? What are the main market assumptions and the competitive landscape in those regions? What do these imply for the target product profile and the clinical development strategy? What does that mean for the manufacturing process?  And so forth.  By working backwards from the end, you have the distinct advantage of being able to answer any question from any stakeholder along the way.

As a manufacturing partner, this is typically where we help our clients to create value immediately, by challenging them to think that way.

Lay All Your Cards On The Table

In the enthusiasm to secure financial backing and move forward with development partners, another common temptation is to put a positive spin on everything you communicate.  When it comes to a drug development plan, however, it’s important to do the  exact opposite.  Now is the time to ruthlessly expose every potential threat, obstacle, risk and weakness you can possibly identify. Only then can you get the experts thinking about these problems and formulating strategies to address them.

For example, if you suspect you may have to swap out an animal-origin product for a more expensive non-animal derived alternative, schedule in some detailed cost modelling as early as possible.  Far better to spend the extra time and research dollars upfront to find a technical work-around, than to have difficult conversations down the road on regulatory compliance or how your drug is going to cost $1M per dose.

Involve The Experts Early

Commercial drug development is a multidisciplinary undertaking, which means that to create an all-encompassing PDP that reflects reality, you will need to gather input from all of the relevant functions.  While it may seem expedient for one leader or manager to work up the first draft of the PDP before pulling in the experts to review it, involving those experts from the start creates a shared sense of ownership and helps the author avoid imposing his or her own views and bias on the process. In the end this can save a lot of time, because you are more likely to get it right the first time.

Honesty also comes into play again here, as companies need to admit to themselves when they need outside help in areas where they have less experience. It’s also important to recognize that all of the components of the PDP are interdependent, so if there is expertise lacking in one element, it will have knock-on effects on the others.

“After all, if you aren’t well versed in commercial manufacturing,” says Havenga, “how can you advise on the chemical manufacturing and controls (CMC) strategy?  And if you cannot advise on the CMC, how can you propose a suitable process development plan?”

The bottom line is that the earlier you can reach out and get input from experts—both internal and external—the more time you’ll save and the less risk there is that you will overlook something critical.

Increasingly, biotech companies are seeking the help of specialized  “center of excellence” CDMOs  at the early stages of drug development to bypass the steep learning curve and accelerate strategic planning.

Batavia Bioscience is one such CDMO that offers strategic planning services and will work with clients to co-develop a sound PDP.

What Does the PDP Development Process Look Like?

Developing an effective drug development strategy is an intensive process that can’t be rushed.  When a client turns to Batavia for help in creating a PDP, they set aside a full 5 days for the workshop. This ensures there is ample time to cover the entire process comprehensively and dig deep into areas of ambiguity or concern.

“The whole experience can be very enlightening,” says Havenga. “As our subject matter experts drill down into the specifics, we almost inevitably uncover areas that need more thought. It’s very rewarding to see how together we can then find practical solutions to serious obstacles.”

Ready to Kick-Start Your Drug Development Strategy?

Batavia Biosciences is a Center of Excellence for viral vaccine and viral vector development with extensive experience in the field of infectious diseases and oncology. If the prospect of putting together an effective PDP is making your head spin, reach out and talk to one of our experts.  We’re here to help you succeed.

GMP Viral Vector and Viral Vaccine Production: Is Outsourcing to a CDMO the Answer For Your project?

Developing a successful viral vaccine or viral vector for use in a clinical setting is notoriously challenging. Unforeseen  pitfalls and roadblocks in process development and scale-up  can lead to costly delays. Worse still, a poorly developed process can be difficult to control. This can adversely impact many factors, including production costs, yield, and even efficacy of the final product. Given the complexity, significant time investment, and high risk inherent in developing viral vaccines, viral vectors and other virus-based products such as oncolytic viruses and cell or gene therapies, outsourcing some or all of the development process is often a wise choice to de-risk your project, shorten the development cycle, and improve the final outcome. Is outsourcing right for your project? Here are some key considerations to help you decide.

CRO, CMO, CDMO – What’s the difference?

When it comes to outsourcing, there is often some confusion over which type of partner is most appropriate.  While the answer depends on your specific needs, goals and in-house capabilities, there are 3 main outsourcing options:

Contract Research Organization (CRO)

A CRO facilitates the research and discovery phase of product development. This may be the right choice for companies looking for help with ideation and proof-of-concept, but a CRO typically will not have the dedicated resources and expertise to help with GMP scale-up for clinical trials and commercial manufacturing.

Contract Manufacturing Organization (CMO)

As the name suggests, a CMO focuses primarily on manufacturing, and is typically used later in development and for larger scale manufacturing projects. Many CMOs will have a fully developed and well-controlled process or platform for manufacturing, which they can adapt to fit incoming projects, but which may be less flexible in terms of development capabilities.

Contract Development Manufacturing Organization (CDMO)

A CDMO offers both development and manufacturing services, providing the expertise, support, equipment and facilities needed to take your process from proof-of-concept to clinical-scale production and beyond. This effectively bridges the gap between what CROs and CMOs can offer. Collaborating with a CDMO has the advantage that the people who develop your process will also implement it in GMP, eliminating the need for additional technology transfer.

Navigating the Complexities of Development and Scale-up

Since process development is where many common pitfalls are encountered, a specialist CDMO is often the best choice for a start-up or small-to-medium enterprise looking to get a new vaccine, viral vector-based product or therapy to clinical trials as soon as possible, with the least amount of risk.

From definition of your process development strategy through to product release, there are countless scientific, technical, and operational aspects that need to be carefully planned, coordinated and controlled to ensure a successful outcome (Figure 1). This is where experience in process development will make a great difference—and consequently, it is often where collaboration with a CDMO can add the most value, compared to developing the process on your own.

Factors to consider in viral particle process development and optimization
Figure 1: Considerations in process development and optimization of viruses and viral vector-based products. (TPP: target product profile; QP: Qualified Person)

When deciding whether or not to outsource to a CDMO, here are some of the key development steps and related factors to consider:

Process Development Strategy

Planning is everything. As we touched on in the previous article, the myriad decisions you make at the start of your project lay the foundations for success—or failure. While this is true for any project, forward planning is especially critical in viral vector production due to the complexity of viral particles, the interdependencies of various processing steps, and the constraints imposed by GMP compliance. For businesses new to viral vector and viral vaccine production, or those seeking to accelerate development cost-efficiently, an experienced CDMO will be an invaluable resource. They will assess your current process, taking your target product profile (TPP) into account, and help you map out a plan to progress smoothly through the development process.

GMP Compliance and Regulatory.

 The manufacturer’s release of a biological product for its use in clinical trials is highly product-specific. It makes a big difference whether a monoclonal antibody or a viral vector has been manufactured. How much experience does your team have with developing a GMP-compliant process? Do you have an in-house expert with the requisite knowledge and awareness of regulatory requirements specific to viral vaccines and vector-based products?

As you scale up production of viruses and virus-based products intended for clinical use, regulatory requirements become more stringent, and there are many different aspects that need to be considered to ensure the final process will be compatible with GMP manufacturing. As we saw in the previous article about viral vector development and scale up, failure to account for later stage regulatory requirements in the early development phases is a common source of project delays and failures. For example, it is not uncommon for clients to be unaware of, or unable to document, the origin of the cell line used for proof-of-concept studies, yet this knowledge is essential for a GMP compliant process.

A specialized CDMO can spot potential GMP compliance issues like this before they become problematic, and ensure that your entire process is designed for compliance from the start.

Culture System Definition and Optimization

Regardless of your application, the production cell line and viral seed you are working with not only need to be GMP compliant, they also need to be productive, genetically stable, and robust to various upstream and downstream processing steps.

A CDMO specialized in development and production of viral vaccines, viral vectors and other virus-derived products has experience with optimal growth of the mammalian cell types commonly used for manufacturing, such as Vero (for viruses such as measles, polio and VSV) and HEK293 (for viruses such as AAV, adeno and lenti). Moreover, they may be able to recommend and help you access cell variants that have been genetically engineered or further optimized for stability and high yield of viral particles.

If needed, they may also be able to engineer the viral genome to tailor it to your requirements—for example, to ensure high expression of genes of interest. Once the culture system has been chosen, they can kickstart the development process with pre-developed SOPs and tailor them to the specific requirements of your target product.

Scaling Adherent Cultures

Scale-up of adherent cell cultures is a key undertaking where a CDMO’s input can significantly reduce risk and development time. In the vast majority of cases, viral vectors and other virus-based technologies are initially developed in an adherent cell line, and typically these cells are propagated in T-flasks or roller bottles. While this provides a convenient and familiar format for research and pre-clinical studies, it is generally not compatible with large-scale production.

Is a fixed-bed bioreactor the way forward? If so, which type is most appropriate? Would 3D culture on microcarriers or switching to a suspension cell type give better results?

A CDMO can help guide you through this decision process quickly, and then implement and optimize the solution as efficiently as possible. They are likely to have the equipment and facilities needed for scaled-down design optimization and scaled-up production, as well as having familiarity with cutting edge technological advances, such as new types of bioreactors, biomimetic and temperature-responsive growth substrates, and much more.

Recovery & Purification

The characteristics and performance of viruses can be highly sensitive to process changes. Just as scale-up of upstream bioprocessing requires careful planning and consideration, so do the solutions implemented downstream.

Conventional lab-scale methods such as cell lysis by freeze-thawing and ultracentrifugation for purification become impractical and costly at larger scales. Recovery and purification steps need to be appropriate to produce the amount of material needed at each phase, and upfront design is essential to avoid process changes later on that could potentially alter the properties of the product or the purification yields.

Can your process be appropriately scaled-down for screening and optimization DoE (Design of Experiments)? Is your virus compatible with a final sterile purification step, or will you need an aseptic process? Which chromatography technology is right for your specific vector?

Anticipating and effectively addressing critical questions like these requires years of experience and expert process knowledge.

Getting it right from the start

In this article, we have highlighted just a few of the many challenges and decision points that need to be tackled during development of viral vaccines, viral vectors and other virus-based products, such as oncolytic viruses and targeted cell or gene therapies.

While CDMOs vary considerably in terms of their areas of specialization, as well as the breadth and depth of their offering, with the right outsourcing partner, it is possible to bypass many development risks and fast-track your product through the development process.

Do Fixed-Bed Bioreactors Provide A Solution to Viral Vector Shortages?

Written by expert: Yang, Bioprocess Scientist

In 2017, the New York Times wrote an article to report the critical shortage in the global viral vector manufacturing capacity.

Next to the shortage of experienced manufacturing organizations capable of producing viral vectors, the high costs to produce this material is a main challenge for patients awaiting a viral vector treatment. Novartis was the first company to market a viral vector-based gene therapy. They charge $475,000 for a one-time treatment per patient. Given the production issues, we expect that novel gene therapy products will be launched at comparable market prices. The production costs are high due to:

  1. the high dose needed for the treatment of a patient
  2. the low viral vector production yields obtained in current manufacturing campaigns

Therefore, there is an urgent demand to scale-up the manufacturing. This way sufficient product for the patients in a phase 1 clinical study can be produced. Additionally, we need a breakthrough innovation to improve the viral vector yield in current production processes. The yield is a major factor for the high cost of goods. A recent development which promises higher vector yields, is the rise of novel fixed-bed bioreactors. Herewith, I would like to guide you through some of my team’s experiences with this equipment for virus manufacturing.

The Challenge For Viral Vector Production

Most protein-based biopharmaceuticals are produced using suspension mammalian cell cultures. In contrast, most viral vectors are produced using adherent cells. Adherent cells will only proliferate and produce the desired product when attached to a surface. Therefore,  traditionally static systems, such as T-flasks, Cell Stacks, Roller Bottles, or Cell Factories, were used. Unfortunately, such systems are very labor intensive, require a large footprint, and only allow very limited in-process control. The biggest issue, however, is the fact that these systems only allow increased production capacity through out-scaling instead of up-scaling.

The first scale-up alternative was the microcarrier system. In the 1970’s, van Wezel et al. developed this technology. The advantage of this system is that cells are grown on beads. These beads are suspended in a tank and agitated, providing a homogeneous environment and the possibility to scale-up. Therefore, this technology provides similar characteristics to suspension cells. Nowadays, several viral vaccines are produced using a microcarrier system. There are, however, a few downsides to this system. Expert know-how and experience is absolutely required to avoid reduced cell growth. This is particularly true for production at larger scales. Reduced cell growth has been a common observation in microcarrier-based processes because of the agitation needed to keep the microcarriers in suspension. In addition, separating the virus product from the microcarriers upon harvest requires an extra step. Each extra step has the potential to reduce the overall yield of the viral product.

Fixed-Bed Bioreactors For Viral Vectors

The second scale-up alternative is the use of fixed-bed bioreactors. Fixed-bed bioreactors are two-phase systems in which the medium flows continuously through a stationary bed made of a porous polymer. Because the matrix on which the cells are growing is fixed, the cells have to endure substantially less shear stress, while process parameters such as pH and dissolved oxygen can still be tightly controlled. This set-up generally allows for high cell densities in a small-footprint bioreactor and easy recovery of the viral vector product.

Our process development data

My team at Batavia uses both the scale-X™ and iCELLis® fixed-bed bioreactors. We gathered a wealth of data on both systems. For example, the scale-X bioreactors have been successfully used for the Sabin poliovirus strains (PV1, PV2, PV3) production. As a direct comparison of our results in the scale-X bioreactor with the microcarrier production process described in literature, an average yield increase of 178% (in DU/cm2) was achieved for the 3 serotypes of poliovirus.3 In addition, the scale-X bioreactor was implemented for production of the VSV vector in our Lassa and Marburg vaccine programs.

Using iCELLis® bioreactors, lentiviral vectors have been successfully produced in our lab. We corroborate the conclusions of Valkema et al. that iCELLis® bioreactor based processes are much easier to be scaled up and use significantly less floorspace compared to the T-flask based production process.

Overall, our working experience with fixed-bed bioreactors is very positive, because it provides smooth scale-up, is less labor intensive, and we are able to reach very high cell densities. These high cell densities benefit transfection efficiency and product yield. We therefore believe that these systems may substantially contribute in overcoming viral vector manufacturing cost.

Batavia Biosciences offers a broad range of  process development and  manufacturing services for all major classes of biopharmaceuticals. We are dedicated to help bring biopharmaceuticals to the market at higher speed, with reduced costs, and with a higher success rate. Batavia Biosciences has vast experience in developing and manufacturing vector vaccines, gene therapy vectors and oncolytic vectors. Our team of experienced scientists and technicians are well equipped to take on any challenge associated with viral vector development.

Low-cost viral vector manufacturing

High-throughput screening for viral vectors

Viral vector manufacturing

Thermostable viral envelope protein formulation

Maximizing protein expression