Whether you’re a budding scientist or a seasoned expert, you need insights to navigate the complex world of biotech scale-up. In this exclusive piece, our Founder David Brühlmann breaks down the scale-up process into nine steps for better efficiency.

With more accessible technological tools, the focus is now on creating reliable datasets to unlock the full potential of these innovations in biological research.

Like many scientists, I was once preparing for a technology transfer into a large-scale manufacturing facility. I was scared, filled with doubt, and overwhelmed by the immense challenges ahead. I wondered, “Will I be able to pull it off?”

Before deep diving into this week’s topic, let me share a personal experience.

A House of Cards About to Crumble

One day our boss told us: you’ll have the pleasure to do a quick and straightforward technology transfer. A piece of cake. We already produced clinical batches years ago, so what could go wrong? Little did we know, this journey would be everything but a piece of cake.

As I stood there, armed with the confidence of past successes, I gazed at the process before me. It was supposed to be a smooth ride, but the technology quality and regulatory requirements had advanced over the years. The once-believed-to-be robust process now looked like a fragile house of cards, ready to crumble at the slightest breeze.

Time was not on our side. We couldn’t afford to go back to the lab and mend the broken pieces. So, there we were, thrust into a whirlwind of chaos, an uncomfortable situation that felt like a tightrope walk without a safety net.

Desperation and determination intertwined as we attempted to patch things up on the large-scale facility, all the while hoping for the best. It was a risky gamble, a far cry from the ideal way to conduct a tech transfer. I learned the hard way what you should not do.

The Challenges of Technology Transfer

Tech transfers are tricky, and they have the potential to overwhelm even the most experienced experts and leaders.

What most biotech scientists get wrong about process development is that managing it is incredibly complex and daunting. If you’re working in a startup company and you’re deep down into managing your clinical studies, you may be tempted to put off process development and scale-up until later, thinking it is feasible.

But the truth is scaling up is not an afterthought.

If you put it off, it will greatly increase your risk of encountering major issues. These issues will delay your project. It will cost you money and it could even lead to failure.

So how do we make the process of scale-up truly rewarding? We distill the process down to nine essential steps for a smooth transition from laboratory to large-scale production. We have divided these nine steps into three phases.

Phase 1: Discern

The goal of the first phase is to move from limited process understanding to having an assessment of strengths and weaknesses.

Let’s dive right in with the first step of Phase 1:

1. Map the Process

You may be unsure if the process is scalable. So let’s map the entire process to recognize the strengths and gaps.

The purpose of this step is to gain a comprehensive understanding of your process. Identify its limitations, strengths, and any obvious gaps that might hinder scaling. Here’s what to focus on:

• Strengths of Process: What are the aspects of your process that are working well and can be leveraged during scale-up?
• Obvious Gaps: What are the clear weaknesses or challenges in your process that need to be addressed?
• Minimum Scale-Up Requirements: What are the essential criteria for successfully scaling up your process?
• Major Roadblocks: What potential obstacles or roadblocks do you foresee in the scaling process?
• Raw Material Supply: Do you have a secure and consistent supply of raw materials needed for production?
• Process-Related Impurities: Are there any impurities or by-products generated during your process that need to be controlled?

2. Assess the Molecule

What’s your knowledge about your molecule? In step 2, we are moving from limited physicochemical & biopharmaceutical knowledge to knowing if the molecule is fit for purpose.

In this step, we shift our focus to the molecule itself. We need to answer four critical questions:

• Is the molecule stable? Would the stability be compromised during scale-up?
• Is Your molecule efficacious?
• Is Your molecule safe?
• Is your molecule manufacturable: Can your molecule be reliably manufactured at the desired scale without compromising quality?

3. Evaluate Inhouse Expertise

What expertise can you find in-house? And what expertise can you readily rely on? Like in the first step, we are mapping it to know what we have and where to find it.

Now, let’s talk about expertise. In this step, we want to assess the knowledge and skills available within your organization. Here’s what we’ll cover:

• Expertise Readily Available Within the Team: What expertise do your team members bring to the table that can be immediately utilized for scaling?
• Available Expertise In-House: Are there experts in other departments, sections, or sites within your organization that you can tap into for support?
• Expertise Needed (and Not Available): Identify any critical expertise that is lacking but required for a successful scale-up.
• Availability of R&D, TT, and Manufacturing Staff: Do you have the necessary research and development, technology transfer, and manufacturing personnel available when needed?

The foundation of the above knowledge will set the stage for confident and successful scale-up in the subsequent phases of our masterclass.

Phase 2: Define

Our goal here is to move from having doubts about what must be improved to a clear picture of the production process fit for commercial supply.

In Phase 2, we will define and shape our path forward, leaving behind any doubts about what needs improvement.

4. Identify Scalable Process

Are you wondering what you need to improve to succeed in scale-up? Do you need to solve all weaknesses? In step 4, we address your doubts about what must be improved. At the end of this step, we want to know what a robust, cost-efficient, and automated process looks like.

In this step, our objective is to determine the requirements for establishing a scalable process that is robust, cost-effective, and automated. Here’s what we will explore:

• Suitable Technological Options for Large-Scale Production: What technologies can you leverage to ensure smooth production at a larger scale?
• Critical Quality Attributes: What are the key quality attributes that must be maintained during scale-up?
• In-Process Controls (IPCs): How can you implement controls at various stages of the process to ensure consistency and quality?
• Availability of Raw Materials: Do you have a secure and reliable supply of raw materials for large-scale production?
• Workflow Optimization Solutions: How can you optimize the workflow to minimize waste and maximize efficiency?
• Simple Automation Solutions: What automation options can simplify and streamline your production processes?
• Required Unit Operations for Future Batch Record Creation: What unit operations must be documented for future batch records?

5. Scout Technology

It may well be possible that you lack certain solutions. You may not have the right equipment or technology available. We’re now ready to identify suitable options to improve the process & molecule to bridge the remaining gaps.

In this step, we will bridge any remaining gaps by scouting technology and solutions:

• Suitable Technical Options to Bridge the Gaps: What technologies or solutions are available to fill the voids in your process?
• Minimal Viable Process: What is the minimal set of processes needed to achieve the desired outcome?
• Internal Production Capacities: Do you have the in-house capacity to implement the required changes and improvements?
• Analytical Expertise and Capabilities: What analytical methods and expertise are needed to support the proposed changes?

6. Mitigate Risks

Doing scale-ups is risky. Hence we want to manage the risks as much as we can. We do this by moving from being unaware of potential roadblocks to creating an action plan to prevent failure.

Now, let’s focus on risk mitigation:

• Potential Risks: What are the potential roadblocks or challenges that could derail your scale-up efforts?
• Gravity: How severe are these risks, and what is their potential impact?
• Likelihood: How likely are these risks to occur during the scale-up process?
• Risk Mitigation Actions: What specific actions can be taken to minimize or eliminate these risks?

We now know how the large-scale process should look, we have identified the necessary technology and analytical methods, and we are well aware of the major risks that may come our way. Armed with this knowledge, we are ready to move on to the last phase of our masterclass, where we will strategize and plan for a successful scale-up.

Phase 3: Develop

The goal here is to go from a lack of focus to driving the project forward with a winning strategy for successful scale-up.

In Phase 3, we take all the knowledge we have gathered and create a roadmap for success. Let’s begin with the first step:

7. Identify Partners

If you are working in a smaller company, you may think that you need to figure out everything yourself.

There’s a better way. Instead of asking “How?” ask “Who?”.

In this step, we will unlock the power of collaboration and teamwork:

• Brian Tracy's ABCDE Method: One effective way to prioritize tasks is by using the A: Must do, B: Should do, C: Nice to have, D: Delegate, E: Eliminate method. This method helps you focus on what matters and allocate time and energy efficiently. By categorizing tasks into different priority levels, you can ensure they focus on the most important and urgent tasks (A: Must do) first, followed by significant but less time-sensitive tasks (B: Should do). This method also helps identify tasks that are nice to have but not crucial (C: Nice to have), which can be addressed when time allows. Delegating tasks (D: Delegate) is also important, as it allows you to allocate responsibilities to others with the necessary expertise. Lastly, the E: Eliminate category encourages individuals to identify unnecessary tasks and remove them from their to-do list altogether.
• Gay Hendrick’s Zone of Genius Concept: Identify what you do best—your zone of genius—and capitalize on that skill set as much as possible.
• Key Qualities of a Good CDMO: It is important to have a clear understanding of the various qualities that make a Contract Development and Manufacturing Organization (CDMO) a valuable and reliable partner in the pharmaceutical industry. One of the key qualities is competency, which refers to the CDMO's ability to effectively and efficiently handle complex projects and deliver high-quality results. Another crucial quality is experience, as an experienced CDMO would have a deep understanding of the industry's regulations, standards, and best practices, ensuring that the projects are executed flawlessly. By partnering with a CDMO that possesses these qualities, pharmaceutical companies can greatly benefit from their expertise and achieve successful outcomes.
• How to Maximize the Benefits of Partnerships? Discover effective strategies for leveraging the unique strengths and expertise of your partners and qualified individuals. By harnessing their capabilities, you can greatly enhance and expedite your scale-up journey, paving the way for even greater success.

8. Manage Stakeholders

Most projects fail because the project leader gives zero attention to the interests and requirements of stakeholders.

In this step, we will ensure successful stakeholder management:

• Stakeholder Management: It is important to recognize that effective stakeholder management goes beyond simply managing tasks. It also involves understanding and addressing the expectations, needs, and requirements of all the parties involved or affected by the project. By actively engaging with stakeholders, gathering feedback, and fostering open communication, project managers can build stronger relationships and ensure that the project aligns with the interests and goals of all relevant stakeholders. This comprehensive approach to stakeholder management enhances collaboration, minimizes conflicts, and increases the likelihood of project success.
• Identifying and Analyzing Stakeholders: Systematically identify and analyze stakeholders, both internal and external, who have a vested interest in your project.
• Systematic Approach: In order to effectively meet the needs of stakeholders, it is crucial to develop a well-defined and organized approach. This includes the identification, classification, and active engagement of stakeholders. By implementing a systematic approach, you can ensure that all stakeholders are properly addressed and their requirements are thoroughly considered.

9. Create a Roadmap

Now we have all the elements to create a solid, step-by-step plan. In this step, all the previous elements come together. We are ready to create our ScaleEasy Roadmap.

In this final step, we will craft a comprehensive roadmap that will guide us to success by incorporating the following key aspects:

• Identifying the Desired Future State: Clearly define the vision of the future state and outline the necessary steps to transition from the current state to this desired future state.
• Step-by-Step Scale-Up Process: Elaborate on the specific steps involved in the scale-up process, ensuring a clear and structured approach. This will help streamline the implementation process and minimize any potential challenges.
• Establishing Detailed Timelines: Develop high-level timelines that provide a comprehensive overview of the project's duration and key milestones. This will enable effective planning and monitoring of progress throughout the implementation journey.
• Thorough Cost Analysis: Conduct a detailed analysis of the financial aspects, including budgeting and resource allocation. By carefully considering the costs involved, we can ensure efficient utilization of resources and avoid any financial constraints.
• Clearly Defined Project Deliverables: Clearly define the tangible outcomes and deliverables that are expected at each stage of the project. This will help set realistic expectations and ensure accountability for the successful completion of each milestone.
• Measurable Objectives and Success Metrics: Establish measurable objectives and success metrics that can be tracked throughout the implementation process. This will enable us to monitor progress, identify areas for improvement, and ensure alignment with our overall goals.

By incorporating these additional details into our roadmap, we can enhance its comprehensiveness and effectiveness in guiding us towards achieving our desired outcomes.

You have the power to change your tech-transfer narrative.

David Brühlmann is a strategic advisor who helps C-level biotech leaders reduce development and manufacturing costs to make life-saving therapies accessible to more patients worldwide.

He is also a biotech technology innovation coach, technology transfer leader, and host of the Smart Biotech Scientist podcast—the go-to podcast for biotech scientists who want to master biopharma CMC development and biomanufacturing.  

Want to hear more? Go to Smart Biotech Scientist Podcast for insights and resources from our guests on various topics. Do you wish to simplify your biologics drug development project? Contact Us