Bioprocess development and manufacturing are often perceived as sources of potential high-stakes problems, frequently cited as contributing to program failures. However, this view is usually misguided. Failures attributed to CMC (Chemistry, Manufacturing, and Controls) are often the result of a lack of understanding of the job's requirements and an inability to assess risk effectively. 

Bringing in individuals who understand these risks, whether through direct hires or consultants, is crucial, especially for small biotechs. Even large, siloed companies can lose sight of this, hindering their ability to plan for and mitigate potential issues.

This concept is discussed in greater detail with Mark Melville in an episode of the Smart Biotech Scientist Podcast, hosted by David Brühlmann, founder of Brühlmann Consulting.

A Career Forged in Bioprocess Development

Mark's journey into biotech wasn't a planned trajectory. After three years in a postdoctoral fellowship, dissatisfied with the demands of academia, particularly the lack of work-life balance exemplified by a colleague who divorced due to excessive dedication to a textbook, Mark sought alternatives.

In 2001, he discovered the then-unknown field of bioprocess development through professional networks. His first role in the industry began in 2002 at Wyeth, a decision he has never regretted. Like many in the biotech space, Mark's path to his current role was unforeseen, highlighting how often careers in this field unfold without a predetermined plan.

Core Challenges in Bioprocess Development and Biologics Manufacturing

The bioprocessing industry faces both technical challenges and organizational hurdles. While new modalities constantly introduce technical complexities beyond monoclonal antibodies, a significant challenge, especially for small biotechs, is a lack of understanding of what's required for a successful development and manufacturing program. This stems from the fact that CMC experts don't typically find small biotechs.

The main challenge, therefore, revolves around communication. Effectively conveying program needs and functional requirements to key stakeholders and external vendors is a continuous learning process. As companies grow, such as Mark's current company, which has expanded to approximately 100 people, the challenge of communication constantly evolves.

Unique Dynamics of Small vs. Large Biotechs

Working at a small biotech presents distinct challenges and advantages compared to a larger organization:

• Speed: Small biotechs face the constant pressure to move fast due to limited revenue and significant cash burn from CMC activities. However, this need for speed is also a considerable advantage. Decision-making is significantly faster with minimal hierarchy and fewer committees, enabling quick responses to crises, program shifts, or delays.
• Transparency: Small organizations benefit from direct lines of communication across all departments, which may even consist of a single person. Constant interaction with partners in quality, regulatory, clinical operations, and supply chain allows for rapid execution.
• Wearing Different Hats: In smaller companies, individuals often take on responsibilities outside their core function, such as participating in site initiation visits for clinical sites. While challenging, this presents unique opportunities for career expansion and exposure to adjacent areas, such as quality or regulatory, making individuals more attractive as their careers develop.
• Culture: Small biotechs typically have less "BS", meaning less time for politics and departmental competition for resources. The environment demands a strong focus on completing the task. While large companies can have good cultures, small companies must be nimble, fast, and focused on their work. Additionally, small biotechs often offer a closer connection to patients, providing a direct and inspiring view of the product's impact.
• Decision-Making: At its core, decision-making in small biotechs is primarily driven by cost and time constraints, due to limited resources and the urgent need to achieve goals quickly to maintain solvency. The impact on value generation (e.g., ability to raise capital, stock price) is also a significant factor, unlike in larger, more established companies.

Ensuring decisions align with long-term goals is relatively easy in a small company due to inherent transparency. Direct lines to the CEO and other C-level executives keep company-wide objectives at the forefront of all discussions, fostering a collective effort towards shared goals rather than siloed departmental objectives.

But more often than not, what I've seen is that these failures that are assigned to CMC are really more a function of lack of understanding of what the job actually is and what's required in order for a program to succeed in this area.

Strategic Prioritization in Resource-Limited Environments

In smaller companies with limited resources, strategic decision-making and prioritization are essential. Transparency across departments and a constant awareness of long-term company goals are key to prioritizing competing needs effectively. Priorities are adjusted based on the overall company priority and what is best for patients.

A historical example illustrates this: in a previous company that made biosimilar products, a critical decision was made to proceed with a product despite discovering a point mutation in a small fraction of the protein. This decision, driven by the need to get to the clinic quickly, was risky but defensible to regulatory agencies. Simultaneously, a backup strategy to knock out the mutated gene was developed, a decision driven by CMC expertise and the ability to assess risk. This proved crucial when regulatory agencies, while agreeing the product was safe, deemed it not a biosimilar due to the mutation.

Advantages and Disadvantages of Outsourcing Development and Manufacturing

Outsourcing offers distinct advantages and disadvantages:

• Advantage - Flexibility to Change Vendors: If a vendor is underperforming, it is possible, though not easy or cheap, to change service providers. This option is not available with internal departments in a large company.
• Advantage - Access to Specialized Expertise: Especially in today's landscape with diverse molecular modalities (small molecules, antibodies, cell therapies, etc.), it's impractical for a small biotech to house all expertise internally. Outsourcing allows companies to work with the best vendors for specific purposes or types of molecules.
• Disadvantage - Loss of Control: Outsourcing inherently means losing some control over the process.
• Disadvantage - Time Loss: There's a time sacrifice as new experiments or programs require setting up contracts, negotiating terms, and waiting for resources to be assigned.
• Disadvantage - Misaligned Goals: Vendor goals (such as profit-making and managing multiple customers) may not always align fully with a single company's objectives.

Ensuring Quality Control and Regulatory Compliance with External Vendors

Maintaining quality control and regulatory compliance when outsourcing heavily relies on a "triumvirate" of functions: CMC, Quality (QA), and Regulatory.

• Quality Organization: For external vendors, companies rely on their quality organization (whether contracted or in-house) to establish well-crafted quality agreements. These agreements provide initial evaluation and oversight, while robust maintenance and audit plans ensure ongoing compliance and facilitate information sharing regarding regulatory inspections.
• Regulatory Group Alignment: Regulatory groups must be aligned with the work performed by CMC and Quality. The primary interaction point for compliance with external vendors is with the quality team.
• Outsourcing Quality vs. Keeping it In-House: Small biotechs often start by outsourcing quality, utilizing contractors, and purchasing basic quality system SOPs. However, as companies grow, especially with broad pipelines and multiple clinical programs, having an internal quality group becomes essential. Quality, when done correctly, is a "best friend," preventing future headaches and saving companies from mistakes. Once resources allow, internal quality is advocated for, as it provides constant oversight and proactive problem-solving.

Criteria for Selecting External Service Providers

Vendor selection involves numerous criteria, often managed through exhaustive spreadsheets. 

While specific needs vary by company stage, some constants remain crucial:

• Cost: Always an important consideration, with negotiation being ideal but not always possible for small companies.
• Regulatory History: Assessing a vendor's inspection history and the types of products they've made is key. Vendors with commercial experience are preferred due to their greater exposure to regulatory agencies.
• Long-Term Program Needs: Even in the early stages of development, consider whether a vendor can take the product to the commercial market. This helps avoid making a program unattractive to potential acquirers.
• Company "Vibe" and Communication Style: This is perhaps the most important, albeit subjective, criterion. Assessing how a vendor communicates, their approach to program management, and the level of direct access to project teams is crucial. The interaction style should align with what is needed from the partnership.

A lesson that I took from one of my first small biotech jobs is quality done right is your best friend. Many people look at quality organizations as "Oh, no, not another SOP. But when you do quality right, it saves you so many headaches down the line.

Establishing and Maintaining Strong Vendor Relationships

The success of outsourced projects often hinges on the strength of relationships. Mark emphasizes approaching the relationship as a collaboration rather than just a service provider arrangement.

• Collaborative Approach: Small biotechs, lacking significant financial leverage, must rely on collaboration. Building internal teams with SMEs (Subject Matter Experts) who contribute to scientific discussions and problem-solving, rather than just dictating, fosters a collaborative environment.
• Leveraging Vendor Expertise: Engaging vendors as scientific partners who contribute their expertise adds significant value beyond just "paying for hands." Scientists working on programs enjoy being challenged and engaged, which leads to greater effort and improved problem-solving.
• Transparency and Alignment: Being transparent about program details, even beyond what's strictly necessary for execution, invests vendors in the project. This increased understanding enables vendors to anticipate needs and make decisions more closely aligned with the company's goals, rather than merely adhering to the contract. This collaborative dynamic fosters more proactive problem-solving and yields better outcomes.

Advice for Aspiring Biotech Scientists and Key Takeaways

Mark offers young biotech scientists specific advice: begin your career in a large company. He believes this is crucial for gaining essential hands-on bench experience, providing a foundational understanding of the work's practicalities and difficulties, which is vital for effectively managing outsourced projects and navigating challenges.

Final Remarks

Ultimately, it's essential to reiterate that bioprocess development is a dynamic and intricate form of process science. While the initial entry into this field might seem accessible, true mastery demands not just theoretical understanding but also years of dedicated effort, continuous learning, and the accumulation of a wealth of practical knowledge. 

It is far from a straightforward endeavor; excelling in this complex and constantly evolving discipline requires a unique blend of scientific rigor, adaptability, and an unwavering commitment to navigating its inherent challenges. The journey to becoming proficient in bioprocess development is a demanding yet highly rewarding one, essential for bringing life-changing therapeutics to patients.

About Mark Melville

Mark has been in the biotech industry for more than 20 years, dedicating all that time to the bioprocess sciences. Mark began his career in large companies, working at Wyeth and Pfizer before transitioning to smaller, startup companies. For the past 12 years, he has operated in a virtual setting, overseeing all development and manufacturing outsourcing.


Connect with Mark Melville on LinkedIn. 

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.  

Hear It From The Horse’s Mouth

Want to listen to the full interview? Go to Smart Biotech Scientist Podcast. 

Want to hear more? Do visit the podcast page and check out other episodes. 
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