Vendor Versus Center of Excellence

What type of CDMO is the right fit for you?

When it comes to outsourcing, there is often confusion about the type of partner that is most appropriate for a project. In our previous article, we discussed the difference between a CRO, CMO and CDMO. In this article, we would like to zoom in on the different type of CDMOs in the field of biopharmaceutical contracting.

Different types of CDMOs

The term CDMO is becoming fashionable. More and more CMOs are adding the D for development to highlight that they have more to offer than manufacturing biopharmaceuticals. However, there is a great variety in CDMOs in terms of capabilities and expertise. For example, many of the large CDMOs apply a business model focused at late-stage and commercial manufacturing.

As a result, larger CDMOs tend to offer process development services only to those companies who are willing to sign for late-stage manufacturing, which is where most of their profit is generated.  On the other hand, there are CDMOs whose primary focus is on process development rather than manufacturing. They perform GMP manufacturing only for the processes they have developed and know better than anyone.

The most notable difference in CDMOs is that between what we call a ‘vendor CDMO’ and a ‘Center of Excellence (CoE) CDMO’.

Vendor CDMO

Vendor CDMOs focus on operational excellence, meaning they’ve optimized one or more standardized processes and, as a result, are able to keep the prices for their services below market average. These companies must apply economies of scale to keep their costs and, subsequently, their prices low. This requires heavy spending on facilities and equipment to achieve efficiencies.

Projects that are an excellent fit for vendor CDMOs are those that fit their standard processes. Typically, these projects are strongly defined by nature, and commodity based. The production of a master cell bank is an example of such a project. In general, making a cell bank is very straightforward. Outsourcing such a program to a vendor CDMO is an outstanding way to cut expenses, without too much risk.

Vendor CDMOs are able to handle large volumes of such projects, because they have optimized every step of the process. Their staff is trained to repeat the same step over and over again very accurately. But what if your program doesn’t fit the platforms of these CDMOs?

Center of Excellence CDMO

When you have a unique project, requiring a company to provide knowledge to make it a success, a CoE type of CDMO would be a better fit for you. CoE CDMOs provide leadership in a certain focus area, share best practices, perform research, and provide support. Many CoE CDMOs offer consultancy services next to their process development and manufacturing capabilities.

The business model of a CoE is based on creating long-term partnerships with their customers, to whom they offer tailored services. Because this model requires hiring a highly educated and experienced staff, requires a higher level of customer intimacy, and attracts more high-risk projects, prices tend to be above the market average. In return, the customer can expect a higher level of quality, flexibility and customer service than a vendor CDMO could provide.

Product development for a new viral vector-based product typically requires a custom-developed manufacturing process. In particular, scaling up viral vector production for clinical manufacturing requires specific know-how that can only be gained from years of experience in the field.  For this reason, partnering with a CoE CDMO that specializes in viral vectors is often the wisest choice to de-risk and accelerate such programs.

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. Interested to learn more about what we can do to help your product development moving forward?

How the Netherlands became a key player for vaccine development

The Netherlands has a long history in the life sciences industry. Especially in the field of vaccine development and manufacturing, this small country has always played a significant role. Lately, the rich history proved a fertile ground for developing and manufacturing a wide variety of SARS-CoV-2 vaccines.

The website Invest in Holland has written an interesting article on how the Dutch became such a prominent player for vaccine development. Gerard Schouw, Director of the Association Innovative Medicines, states in the article:

“The Dutch life sciences & health sector has been at the innovative forefront of Europe for many years. The Netherlands has a lot to offer due to its central location in Europe and successful history of public-private partnerships.”

Role of Batavia in vaccine development

We, at Batavia, are proud to play our part in the development of new and innovative vaccines. In the recent years, we have announced partnerships for the development of vaccines against viruses like: SARS-CoV-2, polio, Marburg, Lassa, rota, measles, and rubella.

In each project, we strive to improve the affordability and availability of these life-saving medical countermeasures. For example, with our  HIP-Vax®  platform for low-cost, highly intensified manufacturing, we are able to bring the Cost of Goods of vaccine manufacturing well below <$1.00 per dose and reduce the time from bench to clinic to 9 months. This timeline is including the biosafety testing. These benefits are the result of significant reductions in the manufacturing footprint, increased cell density and less process steps.

With our extensive bioprocessing knowhow, we will continue to expand our footprint in the vaccine development sector until all those in need have access to vaccines.

Link  to full article

How to work with a CDMO for viral vectors: 5 steps to success

How to work with a CDMO for viral vectors: 5 steps to success

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Viral vector technologies are at the heart of many promising new therapies, such as vaccines, gene therapies, immune-oncology therapies and other advanced therapy medicinal products (ATMPs). In this rapidly evolving and competitive landscape, there is little scope for error or inefficiency in the development process.

A contract manufacturing and development organization (CDMO) specializing in viral vector products can be a lifeline for process development and CMC managers, who bear the lion’s share of responsibility for ensuring their company’s innovations make it from bench to bench clinic as quickly and efficiently as possible. Outsourcing to a CDMO is one of the best ways to de-risk and accelerate viral vector projects—provided it is carefully planned and managed. So how do you engage effectively with a CDMO and make the most of this vital relationship? Here are 5 steps to a successful collaboration.

1. Start early

In viral vector product development, the seeds of success—or failure—are sown early. In particular, there are many challenges and pitfalls when taking a product from proof-of-concept to the first clinical trials. The decisions you make at this stage can have major consequences regarding the overall capability, reliability, quality and cost-efficiency of your process.

By reaching out to a CDMO in the early stages of development, you can benefit from the full range of their experience, capabilities and services. This usually starts with a comprehensive evaluation. For example, how scalable is your current process? Is your cell line suitable for GMP manufacturing? Do you have the appropriate analytical methods for in-process and release testing?

A CDMO with a strong track record in viral vector development and process engineering should be able to evaluate your project from every angle—scientific, technical, operational, cost and regulatory. An early assessment will maximize the number of design options available and ensure that strategic gaps, issues, and potential stumbling blocks are spotted early, before they become problematic.

2. Be clear about what you need and want from a CDMO

The first step to getting what you want from a CDMO partnership is knowing what you want. This may sound trivial, but it is surprising how often companies reach out to a CDMO with a request for proposal (RFP) before having a clear idea about precisely what they need to get out of the partnership and how they prefer to collaborate.

Before engaging with a CDMO, it is a good idea to run a gap analysis to assess your in-house capabilities and identify any gaps you think need filling regarding skills, expertise and resources. Consider also the more intangible qualities that make for a good working relationship. Intangible qualities could be your preferred communication style, the importance of compatible values, and the degree of responsiveness, flexibility and support you expect from a potential partner.

3. Find the right fit

With your general needs and preferences in mind, you will be better positioned to research potential CDMOs, articulate your needs, and effectively interview candidates. At the same time, it is vital to remain open-minded in your initial discussions with CDMOs. In many cases, they will be able to spot gaps or needs that weren’t identified in your gap analysis.

Some of the key topics to explore with potential CDMOs include:

  • Range of services and competencies. Does the CDMO have the right capabilities to cover all of your needs, from virus and cell banking to regulatory sign-off and support for manufacturing handover?
  • Track record in viral vector process development and clinical manufacturing. How extensive is the range of viral vectors they have successfully manufactured? Will your vector system be new to them?
  • Flexibility to tailor their approach and processes to meet your vector-specific requirements.
  • Equipment and facilities. Are they appropriate for your current and future needs?
  • Regulatory history and experience with IND/IMPD dossier submissions. Can the CDMO prepare and provide all the necessary information for filing? Do they offer support in completing the CMC section?
  • Project and program management capabilities. How experienced are they at managing complex viral vector development projects? Would you be able to trust them to drive your project forward while you focus on the high-level strategy and manage your in-house team?
  • Capacity and willingness to support you at every stage of the project. Importantly, how will the CDMO prioritize your project against existing work or the needs of larger clients?

Before you make your final selection, arrange some face-to-face time with the leadership team. If possible, an on-site meeting will help you assess the culture. During such a meeting you can get a sense of what it would be like to work together. Do they listen? Are they open and easy to get along with? Do you feel comfortable working together? Is this a company you can trust to deliver?

4. Align and organize

Once you have found a good match, proactive engagement is key to ensuring your project gets off to a good start. This includes putting the right mechanisms in place to keep the momentum going. Together with the CDMO, organize an on-site kick-off meeting to align on project vision and scope. Key milestones, priorities and ways of working can be established during the meeting. Ensure roles and responsibilities are clearly defined from the start so there is ownership when problems arise. Along the way, note how quickly the CDMO gets up to speed and takes action on your requests. If they are slow to respond in the signing of documents, for example, or to address your questions and concerns, this could be an early warning sign.

5. Maintain strong lines of communication

Lastly, never underestimate the importance of transparency and regular communication throughout your project. Establishing a schedule of communication and sticking to it will help you build strong connections and establish trust. Your CDMO should also be willing and available to participate in more impromptu discussions to work out any issues as soon as they arise. The more proactive you are about ensuring the lines of communication are open, the better able you will be to build a productive and lasting partnership.

Partnering with a CDMO can make a world of difference for your project. To discover how, talk to one of our experts. They will be happy to discuss your needs and perform a free review of your current process.


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

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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.

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.

What is a 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 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.

What are the benefits of creating a Product Development Plan 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 – gives 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 – 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 – comprise 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 the 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.



Guide To Viral Vector Production: From Bench to Bedside. Faster.

Guide To Viral Vector Production: From Bench to Bedside. Faster.

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Viral vector technologies are taking center stage in the development of novel vaccines and therapies to combat a wide spectrum of human diseases. Efficient development of safe, cost-effective, and robust methods for viral vector manufacture is therefore of vital importance for patients to benefit from these potentially life changing new medicines.

Can I use my cell line for clinical production? What is the quickest route to clinical trials? How can we effectively de-risk and accelerate viral vector development? These are just a few of the many questions we address in this go-to resource for anyone navigating the complexities of viral vector process development, scale-up, and cGMP manufacturing.

Viral vector technologies

The use of viral vectors in vaccines and targeted therapies is revolutionizing the way we tackle some of nature’s most intractable human diseases and infectious pathogens. From rare diseases to cancer to COVID-19: viral vectors are becoming indispensible weapons in the armory of drug modalities?

What are viral vectors

Viral vectors are viruses that have been engineered in the lab to efficiently infect target cells and deliver a genetic payload. These properties make them highly attractive for a wide variety of clinical applications.

When genetically engineered with the code for an immunogenic antigen, viral vectors essentially hijack the cell’s own machinery to produce large amounts of the antigen, which is then effectively presented to the host immune system. This makes them an attractive platform for development of novel prophylactic and therapeutic viral vector vaccines.

Viral vectors also offer tremendous promise for the development of novel cell and gene therapies. An estimated 70% of gene therapy trials worldwide involve the use of viral vectors.

The scope of viral vector technology further extends to the development of oncolytic viruses, a rapidly evolving class of anticancer agents that are tailored to specifically target cancer cells for destruction, working in combination with the patient’s immune system.

Viral vector vaccines 

The rising global threat of infectious diseases and cancers has been a major driver in the evolution of next-generation vaccines.


Milestones in preventative and therapeutic viral vector vaccines



Viral vector technologies in particular have emerged as an enabling platform for vaccine development. Notably, the technology gave rise to the first FDA-approved vaccine for Ebola virus in late 2019, and in December 2020 the first viral vector vaccines for SARS-CoV-2 / COVID-19 were granted emergency use authorization (EUA) less than a year after the genetic sequence for SARS-CoV-2 was shared.

Milestones like these, underpinned by significant progress in addressing safety and scale-up challenges over the past few years, are paving the way to more widespread adoption of viral vectors in vaccine development.


Table 1. Human clinical trials in progress with viral vectored vaccines1,2

Virus Vector Phase I Clinical Trial
Adenoviruses (Ad)
ChAd3 (Chimpanzee adenovirus) Ebola Zaire, Hepatitis C, Ebola Sudan, Ebola Marburg
ChAdOx (Chimpanzee adenovirus) Tuberculosis, Chikungunya, MERS-CoV
Ad5 (Adenovirus type 5) Cystic fibrosis, HIV, Ebola Zaire
VXA (Replication-deficient Ad5) Respiratory syncytial virus, Norovirus, Influenza
rAd26 (Recombinant Ad 26) HIV, Ebola Zaire
Ad35 Tuberculosis, HIV
Ad4 HIV, Anthrax
VEE Replicon (Venezuelan equine encephalitis) CMV
Measles Virus (MeV)
Measles virus COVID-19
MVA (Modified vaccinia virus Ankara) Ebola, HIV, Hepatitis C, MERS-CoV
FPV (Fowlpox vector) HIV
ALVAC (canarypox vector) HIV
Vesicular Stomatitis Virus (VSV)

Replication-competent VSV



Lassa virus

Virus Vector Phase II Clinical Trial
ChAdOx1 Malaria, SARS-CoV-2
MVA CMV, Tuberculosis


Gene and cell therapies 

According to the Alliance for Regenerative Medicine, at the end of 2020 there were 1,220 ongoing regenerative medicine and advanced gene and cell therapy trials worldwide.3 Of these, 152 were in phase 3 clinical trials, in line with EMA and FDA predictions that by 2025 the annual rate of cell and gene therapy approvals will reach 10-20 per year.

Valued at $4.4 billion in 2020, the global gene and cell therapy market is projected to reach $15.48 billion by 2025 at a growth rate of 28.7%.4 Viral vectors are playing a central role in this rapidly expanding market.

Although in vivo gene therapies have had their ups and downs recently, there are over 400 viral vector gene therapy assets in preclinical and clinical phases of development.5 The vast majority of these utilize adenovirus, adeno-associated virus (AAV), and lentivirus vectors.

While cancer is by far the predominant disease area, viral vector gene and cell therapies are under investigation for a wide variety of other indications including cardiovascular and monogenic disorders, as well as metabolic, inflammatory, neurological and ocular diseases.

In late 2020, two new viral vector-based therapies gained regulatory approval: Libmeldy (Orchard Therapeutics), approved by the European Medical Agency for treatment of metachromatic leukodystrophy (MLD), and Tecartus (Kite), the first CAR-T treatment approved by the FDA for relapsed or refractory mantle cell lymphoma. This was followed in February 2021 by FDA approval of Breyanzi, a lentiviral vector-based CAR-T therapy for relapsed or refractory Large B-cell Lymphoma.

Viral vectors in gene therapy trials globally


Data source: Gene Therapy Clinical Trials Worldwide database, The Journal of Gene Medicine, John Wileys and Sons LTD.   

Oncolytic viruses 

Targeted eradication of cancer cells using oncolytic viruses is another exciting and constantly evolving application area for viral vector technologies.

Oncolytic viruses are able to selectively infect, replicate in and lyse cancer cells and/or deliver a genetic payload, leaving healthy cells untouched. In addition to directly mediating cell death, virus-induced lysis of the target cell can activate cytotoxic T cells. This wakes up the immune system to actively seek out and destroy tumor cells.

Many different virus families and subfamilies have been investigated for use in oncolytic therapies, including: adenovirus, coxsackievirus, herpes simplex, vaccinia, measles, reovirus and parvovirus. This diversity presents a potential manufacturing challenge in terms of the breadth of manufacturing strategies and capabilities required.

Roadmap for viral vector process development 

While global markets for viral vector vaccines and therapies continue to expand, the journey from bench to clinic is rarely straightforward. Strategic end-to-end planning of the entire process development journey is an important first step to avoid common development and scale-up pitfalls, mitigate risks across the development program, and identify the most cost-effective strategies for each stage of development.


Viral vector process development road map



Common roadblocks in viral vector production

While the promise of viral vector-based vaccines and therapies is great, so too are the development risks. This is largely because of the complexities of working with viral particles and living cells, including the challenges of scaling up production for clinical manufacture. At the same time, rigorous safety standards must be met to ensure products are safe for patients and the environment.

The bottom line is that many potentially life-changing viral vector products never make it to market. It is not uncommon to invest considerable resources in viral vector development, only to discover at a late stage that the production process is not sufficiently scalable, robust or cost-effective to be commercially viable. As these statistics from the vaccine industry illustrate, the price of failure is high:


The high cost of failure in vaccine development


5 frequently reported challenges in viral vector manufacturing 

Recent business surveys10 have identified some of the main problems respondents mention when asked about the difficulties they face in viral vector manufacturing. These include:

  1. Complexity of working with viral particles and living cells
  2. Scaling up manufacturing processes
  3. Gaps in process engineering and regulatory expertise
  4. Temperature sensitivity and related storage and logistics challenges
  5. High capital investments required to establish and maintain production facilities

To address issues like these and de-risk development, many viral vector product developers are turning to contract manufacturing and development organizations (CDMOs) that have the track record, specialized expertise, and facilities needed to bypass these issues.

Foundations and guiding principles for success 

Designing for quality, manufacturability, compliance and cost-efficiency are key foundations for success when developing any commercial product. This becomes all the more important when manufacturing viral vectors, which are especially complex, difficult to handle, and subject to stringent regulatory oversight.

Batavia’s guiding principles in viral vector process development


At Batavia Biosciences, we follow three guiding principles in viral vector process development:

  • Right first timeGetting process development right the first time around starts with a thorough understanding of the expected commercial manufacturing process.  This means ensuring that all raw materials, equipment and process architecture will allow seamless extrapolation to commercial scales. This is supported by Design of Experiment (DoE) approaches, scale-down models, assay platforms, and cost modeling tools that enable timely data-driven decision-making at every stage of the process.
  • Cost-efficiencyA cost-efficient manufacturing process is vital to ensuring you meet the Cost of Goods (CoG) requirements for your product. This includes fine-tuning upstream and downstream processes to maximize viral yield in bioreactors and obtain high recovery from purification steps.
  • Bullet-proof documentationRobust documentation is essential at every stage of development: from establishing a sound development roadmap, to submitting an IND or IMPD dossier that will hold up to regulatory scrutiny, to ensuring that QA release and technology transfers happen without a hitch. Batavia’s expert QA team provides vital support throughout the entire development cycle. 

Step by step: troubleshooting process development

Process evaluation and design 

The starting point for clinical process development is usually a thorough evaluation of the current process for vector production. Raw materials, including plasmids, virus seeds, cell lines, media and supplements, are assessed for cGMP compliance and suitability for clinical manufacture, as well as ability to achieve the target product profile (TPP).

Both the upstream and downstream processes are assessed for overall design, scalability and anticipated CoG. Time constraints and investment milestones are also factored into the mix to map out the most phase-appropriate and cost-efficient strategies. In addition, critical supply chains and any necessary licensing for raw materials or technology IP needs to be secured.

Batavia Biosciences has a strong track record in cGMP process development for clinical manufacturing of viral vectors. Our experts can evaluate your project from every angle – scientific, technical, operational, financial and regulatory. An early assessment will maximize the number of design options available and ensure that strategic gaps, issues, and potential stumbling blocks are spotted early, before they become problematic.

Cell line selection:  Can I use my cell line for clinical production? 

One of the most crucial steps in the evaluation phase is ensuring that a suitable cell line has been selected.

Some of the questions asked at this stage include:

  • Does the cell line comply with cGMP requirements? For example, is the history of the cell line known? Has it been properly tested for purity and viral safety?
  • Is a cGMP-produced master cell bank (MCB) available?
  • How robust does the cell line need to be to tolerate upstream processing
  • Does the cell line support viral stability and yields?
  • Does it make sense to switch from an adherent to a suspension format?

HEK293 cells and their derivatives are a common choice for clinical manufacture of AAV, adenovirus and lentivirus vectors. Vero cell lines are also widely used, particular for production of measles and VSV vectors.

Cell and virus banking

Once an appropriate cell line has been chosen, the MCB can be established. To do this, the cells are expanded under cGMP conditions and quality tested to demonstrate identity, purity and viral safety. From the MCB, working cell banks (WCB) can be generated. These are the banks that will be used for expansion to support production of the final product, without the chance of depleting the MCB.

Similarly, a robust, traceable and regulatory-compliant master virus seed (MVS) must be established using the MCB or WCB. Once tested to confirm viral identity, purity and stability, the MVS gives rise to the working virus seed (WVS) used in the production process.

Upstream process (USP) 

Cell cultures are inherently heterogeneous, sensitive to mechanical and environmental disturbances, and susceptible to contamination. Factors such as these mean that the USP portion of viral vector manufacturing is particularly challenging to develop, optimize and control. 

During USP development, many parameters need to be investigated to identify the critical process parameters. These must then be optimized to find the “sweet spot” for a robust, reproducible and cost-efficient design. 

Upstream processing steps


Given the large number of USP variables, the numbers of experimental conditions and replicates that need to be tested can quickly become unmanageable or require too much time and materials. Design of Experiments (DoE) provides a systematic way to maximize the information gained about the test system, while limiting the number of experiments. It can also uncover hidden relationships between variables that can have profound effects on process outcomes. In a nutshell, DoE approaches can enable you to more quickly hone in on the most optimal system and process settings. This significantly shortens the development cycle and reduces experimental costs.

Batavia Biosciences combines DoE with its proprietary SCOUT® platform to facilitate high-throughput cell culture in mini bioreactors that closely mimic what happens at clinical production scales. Not only does this reduce the amount of time and materials required for testing, it also allows parallel development of both upstream and downstream processes.

Downstream process (DSP) 

One of the many challenges of DSP development is that processing needs are highly product-specific and dependent on the type of vector produced and USP choices. This means that the nature and order of processing steps can vary widely, there are no standardized solutions for vectors, and it can be difficult to develop both USP and DSP in parallel.

Despite product-specific variations, there are certain commonalities in downstream workflows, usually starting with clarification of the harvest to remove large impurities like cell debris. This is typically followed by tangential flow filtration (TFF) to concentrate the virus and transfer it to the appropriate buffer. 

If depth filtration is used, it is sometimes possible to streamline DSP by combining particle purification with removal of impurities such as host-cell or plasmid-derived nucleic acids. A number of chromatography steps may be needed to remove any remaining impurities. If the viral vector particle size is not prohibitive, a sterile filtration step is performed after formulating in the final buffer. Otherwise, aseptic process validation may be a necessity.


Downstream processing steps


Analytical methods and assay development

Success of viral vector process development and manufacturing strongly depends on having suitable analytical assays for a variety of different purposes:

  • Qualification of MCB and MVS
  • Materials testing and control
  • Process development 
  • Monitoring and QC during manufacturing 
  • Quality assurance and release testing 


To develop the appropriate assays product release, the process must first be well characterized. This means being able to generate representative material. Assays intended for release testing must then be qualified for phase 1/2 clinical trials.  Regulatory guidelines such as those issued by the ICH and FDA for chemistry, manufacturing and control (CMC) require demonstration of suitable testing for key critical quality attributes relating to: identity, potency, purity, safety and stability.

Batavia uses state-of-the-art assay technologies, and supports analytical assay development and implementation to support the entire development and manufacturing cycle. Examples of the types of analytical assays that may be implemented during viral vector development are shown in Table 2.


Table 2. Analytical Assays in viral vector development

What can be tested Example Assay
Genetic identity Genome sequencing (NGS) PCR
Identity PCR
Protein identity SDS-PAGE
Western blot (immunoblot)
Physical viral titer ELISA
Optical density (A260/280)
Functional viral titer Plaque-forming assay
Fluorescence foci assay
TCID50 (end point dilution assay)
Residual testing ELISA (benzonase, BSA)
Host cell-related impurities Host cell DNA/RNA: Picogreen, qPCR
Host cell proteins: ELISA
General impurities HPLC
Sterility Standard sterility tests (EP 2.6.1, USP71)
Endotoxin LAL method (EP 2.6.14, USP85)
Mycoplasma qPCR (EP2,6,7)
Mycobacterium Culture medium method (EP 2.6.2)
Environmental monitoring Environmental monitoring during production
Adventitious viruses (human, bovine, porcine) qPCR 
Adventitious agents In vivo and in vitro cellular assays
pH Potentiometry
Appearance Check for visible particles
Osmolality Osmometry
Aggregate formation HPLC
Stability indicating TCID50
Western blot

*Assays in these categories may be outsourced

How to accelerate the journey to clinical trials

In the high-stakes arena of viral vector vaccines and therapies, companies are under increasing pressure from changing market forces, competitors, investors and other stakeholders to get products to market as quickly as possible. At the same time, quality needs to be assured and program risks minimized.

Finding the quickest route to clinical trials requires considerable experience and know-how across a wide range of disciplines. While there are no one-size-fits-all solutions, our experts at Batavia have found that there are 3 actions in particular that can help drive a swift and successful transition from bench to clinic.


1. Use in silico cost modeling
When looking for opportunities to streamline processes and accelerate development it is crucial to be able to quickly understand the cost implications of any proposed changes. Without this insight, what seems like a timesaving measure could instead lead to costly delays. In silico cost modeling of production processes can help you make well-informed decisions at every stage of development, saving considerable time and resources.

2. Combine DoE with scale-down analysis
To develop a robust and reliable manufacturing process, extensive experimentation is needed to identify and optimize all the critical quality attributes that can impact on process performance, yield and cost. Due to the complexity of viral vectors and cell culture systems, the number of parameter combinations that need to be tested in parallel can still run into the hundreds, even with a DoE approach.

In many cases, running so many experiments would simply not be feasible or cost-efficient without miniaturization. To overcome this problem, it is possible to use scale-down platforms that faithfully mimic full-scale process steps—both upstream and downstream.

Batavia Bioscience achieves this with its proprietary SCOUT® platform, which integrates mini bioreactors for high-throughput cell culture with high-throughput purification technology and matching analytical capabilities.

DoE methodology paired with scale-down models is becoming an indispensible tool for viral vector process development. Using this approach it is possible to develop a representative process that can be used to generate enough material for phase 1 clinical trials without having to wait until the full scale process has been implemented. This saves considerable development time and cost.

3. Partner to mitigate the risks
Companies venturing into development of viral vector products for the first time often have a deep understanding of the biotechnology but more limited expertise and resources in other crucial aspects of development and manufacturing, such as process engineering, cleanroom operations, cGMP manufacture and regulatory affairs.

This introduces significant risk into the program, and raises a red flag for venture capitalists and other potential investors. On top of that, in-house development and manufacture may require significant capital investment in specialized equipment and regulatory-compliant facilities. For less experienced players, there is also a high risk of failing to secure regulatory approval for phase 1 clinical trials, due to problems in completing the CMC section of the IND or IMPD dossier.

What is the best way to mitigate these risks and speed the journey from bench to clinic? In many cases, a CDMO partnership is the answer. 

If you are considering partnering with a CDMO to accelerate your development journey, our blog provides some top tips to ensure you make the most of this important relationship: How to work with a CDMO for viral vectors: 5 steps to success.

Common abbreviations and terms

(Contract Development and Manufacturing Organization) – A company that provides development and manufacturing services on a contract basis.

(Current Good Manufacturing Practice) – Refers to the Current Good Manufacturing Practice regulations issued by the United States Food and Drug Administration. cGMP regulations aim to assure the identity, strength, quality and purity of drug products by requiring that manufacturers to adequately control manufacturing operations. The “c” of cGMP stands for “current”, signifying the requirement for companies to use up-to-date technologies and systems that are fully compliant with the latest regulations.

(Chemistry, Manufacturing and Controls) – The body of information that defines product characteristics, manufacturing processes and product testing to ensure the safety, efficacy and batch consistency of pharmaceutical products.

(Cost of Goods) – In manufacturing, the abbreviation CoG is often used to refer to the cost of goods manufactured, comprising the total direct manufacturing cost of a product, including materials, labor and factory overhead.

(Critical Process Parameter)  A key variable in pharmaceutical manufacturing affecting the production process. CPPs impact critical quality attributes (CQA) and should therefore be controlled within a proven acceptable range to ensure the drug product meets its quality specifications.

(Critical Quality Attribute) – Any physical, chemical, biological or microbiological property or characteristic that must be maintained within a defined range, limit or distribution in order to ensure a product’s quality.

(Design of Experiments) – A systematic method of determining cause-and-effect relationships between factors affecting a process and the output of that process.

(Drug Product) – A specific drug in dosage form.

(Drug Substance) – An active ingredient that is intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the structure or any function of the human body, but does not include intermediates used in the synthesis of such ingredient.

(Downstream Processing) – Describes the steps in biopharmaceutical manufacturing required to purify the desired ingredient, from the production harvest up to purified Drug Substance Bulk.

(Investigational Medicinal Product) – A pharmaceutical drug or active substance or placebo being tested or used as a reference in a clinical trial.

(Investigational Medicinal Product Dossier) – A document that must be submitted to regulatory authorities in the European Union in order to gain approval for use of an IMP in clinical trials.

(Investigational New Drug) – A drug that has not been approved by the US FDA, but is under investigation for use in human clinical trials. An IND application must be submitted to the FDA to obtain authorization to administer an IND or biological product to humans in a clinical trial.

(Master Cell Bank) – A bank of a cell substrate from which all subsequent cell banks will be derived. The MCB represents a collection of cells of uniform composition derived from a single source prepared under defined culture conditions.

(Master Virus Seed) – A viral seed of a selected vaccine virus, from which all future vaccine production will be derived—either directly or via Working Virus Seeds.

Scale-down model
– A scaled down or miniaturized model that mimics a larger scale unit operation in the manufacturing process. Scale-down models are developed and used to support process development studies. Models should account for scale effects and be representative of the proposed commercial process. A scientifically justified model can enable a prediction of quality, and can be used to support the extrapolation of operating conditions across multiple scales and equipment.

– A scale-down model using a miniaturized production and purification platform to rapidly develop multivariate processes. The SCOUT® technology provides for an effective tool for “Design-of-Experiments” (DoE) approaches.

– The SIDUS® platform combines biological materials (cell lines and vector systems) with in-depth experience and complete protocol systems for manufacturing viral vector-based vaccine, oncolytic and gene therapy products.

(Upstream Processing) – The entire process from early cell isolation and cultivation, to cell banking and culture expansion of the cells, and production of the desired biological substance until final harvest.

(Working Cell Bank) – A cell bank derived by propagation of cells from MCB under defined conditions and used to initiate host cell cultures required for virus production on a lot-by-lot basis.

(Working Virus Seed) – A viral seed derived by propagation of virus from the MVS under defined conditions and used to initiate production virus production lot-by-lot.



Vrba SM et al. Development and applications of viral vectored vaccines to combat zoonotic and emerging public health threats. Vaccines (Basel) (2020) 8(4):680.

2 database. US National Library of Medicine, NIH,

3 Alliance for Regenerative Medicine. (2021). 2020: Growth & Resilience in Regenerative Medicine. Annual Report.

4 Gene Therapy accounts for a major portion of the cell and gene therapy market and it is expected to have the most growth. The Business Research Company, Intrado GlobeNewswire, 23 February 2021,

5 Capra E et al. (17 May 2021). Gene-therapy innovation: Unlocking the promise of viral vectors. McKinsey & Company web post. Retrieved from

6 D’amore T and Yang Y-P. Advances and Challenges in Vaccine Development and Manufacture. BioProcess International (2019) Volume 17, September issue.

7  This is how much it costs to develop a vaccine. The Cost of Things. MarketWatch, 1 October

8  Pronker ES et al. Risk in vaccine research and development quantified. PLOS One (2013) 8(3): e57755.

9  Gouglas D, et al. Estimating the cost of vaccine development against epidemic infectious diseases: a cost minimisation study. The Lancet (2018) 6(12): E1386-1396.

10 Viral Vectors, Non-Viral Vectors and Gene Therapy Manufacturing Market (3rd and 4th Editions)Roots Analysis.


Biotech startups – understanding the ecosystem for success

Biotech startups – understanding the ecosystem for success

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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.


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