Shepherding a new large-molecule drug or biosimilar from early-stage clinical development to market is a long and complex process that famously takes many years and costs millions to billions of dollars. Emerging biotech and small pharmaceutical companies know that success hinges on navigating this process quickly. However, a wide variety of hurdles appear from the very beginning, requiring biopharma executives to make anticipatory decisions critical to the outcome of the project, and often, the fate of both product and company.
The key to success is understanding that while the fastest path is often tempting, the right path is to ensure product quality and viability while expediting the development timeline. And sometimes, predicting which path will be most successful for your molecule requires serious strategic thinking and experience in areas ranging from finance to cell line and process development, to technology and regulatory planning (see Figure 1).
Finding a collaborator to perform contract development and manufacturing services for large molecules can save a less-experienced developer time, expense and anxiety. An expert partner can bring many capabilities to the table, including:

• Full process development from DNA to manufacture and release of GMP clinical batches;
• High quality products, services and testing—and the latest technologies;
• Global footprint;
• Experience with the constraints and challenges you may face;
• Expert consultation for technical assistance at each stage of the biopharmaceutical development process and strategic recommendations beyond the basic choice of products and technologies;
• Assistance with scale-up and commercial-scale production—everything from designing, equipping and starting up new commercial production facilities to process scale-up, tech transfer and validation;
• Ability to provide a single point of contact to help simplify and accelerate the process.

Wisely side-stepping early clinical pitfalls while bearing in mind the unique aspects of the project at hand will allow your company to advance your molecule as quickly as possible while enhancing product quality, process efficiency and patient safety.
Plan your business strategy
While working to create value and moving quickly to access the market, plan your business strategy. The financial health and viability of your molecule are often directly related to how fast you can demonstrate its merits, and thereby raise funds. From a business point of view, the key is to navigate the earliest phases of clinical development quickly while creating value for your molecule. There are three possible strategies to help you extract this value.

1.  Out-license your molecule to generate revenue before approval. This is usually done toward the end of Phase II and may include just one molecule, or your entire portfolio, to generate the cash needed to fund other clinical development programs.
2.  Outsource production of your molecule to an external manufacturer. The immediate benefit is reducing capital expenditures while maintaining rights to the molecule, though you may reduce profit margin and have less control of the process.
3.  Build your own facility. This approach is costly and typically only makes sense when commercializing multiple molecules to mitigate risk. The financial success of the facility will depend on long-term market visibility: low visibility makes infrastructure investments riskier. Designing for flexibility through the right technology choices can help to mitigate risk by enabling a multi-product facility.

Whether your drug is a new molecular entity (NME) or a biosimilar must factor into the choice of business model. An NME has no initial specifications except those emerging from the preclinical proof of concept. Often these are incomplete, requiring the development of a quality and regulatory framework. Developing a technical understanding of product and process impurities that may be generated through process development and manufacturing will help you anticipate what regulatory agencies might ask.

Development of a biosimilar requires a deep understanding of the original molecule and comparisons to demonstrate biosimilarity to the originator. Therefore, creating the analytical package requires serious heavy lifting. More than 10 batches of the original molecule must be analyzed to define the range of acceptable analytical results and the specification to which the biosimilar must conform.
Success through Phase III will hinge on demonstrating that the new molecule is close enough to the original molecule. This is complex work already, but the challenge is multiplied by the need for speed. Speed is THE key to be first to market and provides short term exclusivity. Biosimilar developers have to weigh the return on investment and strategic implications of building a facility versus outsourcing production.

One final aspect of business strategy is to target the right market. Choosing your local or global target market will depend on market size, regulatory considerations and reimbursement. Assess localities carefully. Where should you file your drug first for the fastest market access? Are there enough doctors, adequate infrastructure and a suitable patient pool to conduct the clinical trials there? Will the government or local insurance payers pay for your drug? These are all critical issues to consider before committing to a location. Once the selection is made, be sure to plan for all the necessary regulatory filings at the beginning to avoid costly oversights.

Be sure your clone can go the distance
When developing a cell line for your new molecule, you must identify the best clone, demonstrate proof of concept and satisfy regulators through appropriate testing. When outsourcing cell line development, choose a provider capable of producing high-quality clinical material.

Select the right host
The cell line you choose must be able to produce the biologic of interest. Your clone must produce high quality protein molecules at high titers. Some providers offer proprietary, high-producing cell lines requiring less development time than non-proprietary cell lines. But always keep risk versus cost in mind. A host cell line may come with strings attached. Find out the cost of a license, the expected productivity and the line’s track record in market approvals before you make your selection.

Bank it
Cell banking ensures robustness over development—you will always have access to your clone as it was in the beginning. Cell bank establishment takes 28-30 days, is the first GMP activity and enables the required safety testing.

Demonstrate genetic stability
While high productivity is critical, you need to make sure that your clone is genetically stable so it will continue to produce high titers of the intended molecule. After 60 generations (60 to 120 days of reproduction) with stable productivity and protein quality, the clone is empirically considered stable. To document stability, the cell line must be re-characterized via DNA sequencing and copy number determination. A reliable supply of a stable clone is the solid foundation you need to continue development.

Administer tough love
Bioreactors are rough. Perform robustness studies to determine whether your cells will physically be able to survive the shearing forces and perform as expected in commercial bioprocessing. Subject cells to the same aeration rate, agitation and shear forces they will experience in the scaled-up environment. By ensuring that productivity and product quality are maintained, you will avoid the heartache of having to start from scratch because of cells that are too delicate for the bioreactor.

Choose efficiency and viability over speed
Process efficiency and viability should be addressed during the early clinical stages. Often, they are not: companies focus on speed, move forward with imperfect processes and encounter manufacturing and economic problems down the road. Problems run the gamut—inefficient production making the drug too expensive; products and technologies not scalable or compatible with quality and regulatory requirements; poor analytical package or weak product characterization lowers the perceived value of the drug. In developing your process, take a long view to ensure the product will be commercially viable.

Ensure the process is efficient and viable
A viable process is one that is robust and helps you achieve favorable economics of the project and the product. It can be tested by the reproducibility in scale-up, tech transfer to other operation sites and implementation. An efficient process is one that has few wasteful steps and has optimized multi-work area capacity utilization.

Optimize upstream process
Upstream optimization is key to increasing productivity and reducing production cost per gram. This involves media selection, feed selection and optimization of culture conditions. It is a balance and you have to consider the clone, media, feed and culture conditions all together.

Consider expected cost of end-product
A poorly developed process could result in a product that is too expensive to produce, negatively impacting commercial success. Consider these factors that have economic impact early on: the cost of raw materials, upstream titers, downstream efficiency, dose per patient and the urgency of market need. Determine the optimal yield for your process, realizing that it may not be the maximal yield.

Technology: friend or foe?

Technology is another early choice that can make a developer’s life easy or unpleasant when the time comes to scale up for commercial production. The flexible factory is trendy for a reason and single-use is, by definition, flexible.

Through many years of process development and cGMP drug manufacturing, the industry has learned the value of single-use technologies for simplifying operations, saving time and cost, improving operator safety and reducing the risk of cross-contamination (see Figure 2). We have even calculated the cost savings single-use implementation can achieve across various process steps, for customer use.

The benefits of single-use tools include:

• For prepacked columns: No packing time, no solvent exposure.
• For disposable mixers for viral inactivation: No cleaning (or cleaning check), sterilization or spare parts.
• For platforms: Quick and easy set up and reconfiguration of mobile suites for a variety of processes; rapid equipment turnover between batches; less tubing preparation, with sterile connectors/tube welders; fewer mistakes through closed, aseptic processes with sterile, pre-constructed, disposable assemblies that reduce contamination risk; elimination of clean in place/steam in place processes and associated chemical, energy and time requirements; safer operation; ease of connecting all processing steps; and common software, from process development through manufacturing.

A single-use bioprocessing setup with mobile units is very different from a fixed setup. A single-use system is pared down for maximal efficiency. On the other hand, a fixed setup features lots of piping with no flexibility. There are many intermediate activities and checks for setup, requiring a complex validation process and many more full-time equivalents (FTEs) to operate.

Scalability and ease of use are key
The use of a bioreactor with proven scalability is a way to ensure success through clinical development. It’s important to have a strategy in mind when you select your equipment. Once the top media and feed candidates are selected from high throughput screening, you should be able to scale up from a small, laboratory scale bioreactor to a medium sized non-GMP toxicology or GMP clinical batch and finally, to a large GMP Phase III batch easily. Alternatively, a development template may allow you to skip the engineering run and scale up directly from the laboratory batch to the large GMP batch, which saves a lot of time and cost.

Evaluation for ease of use is also part of ensuring that your final process is as efficient as possible. Single-use systems are the essence of simplicity and are generally much easier to use than standard systems. Operators require less training than they do with stainless steel equipment because the equipment is much simpler, has less piping and few or no spare parts. “Flexware” assemblies are pre-configured for quick and easy installation. Operations are mostly automatic. Employing single-use systems can help scale-up go smoothly.

Mitigating risk and gaining regulatory approval
As with everything above, thinking about patient safety and regulations early on will avoid problems later in the course of drug development. Consider the following guidelines.

Patient safety is what regulations are all about
Patient safety is the main driver of risk assessment. Start early in clinical development. Obtain deep knowledge of your product early on to anticipate potential safety issues. Check for both contaminants and toxic product isoforms. Prevent cross contamination by implementing logical product, personnel and waste flows. Implement appropriate risk mitigation strategies as needed.

Document product quality and process robustness as you go
From the start, plan how you are going to demonstrate product quality and process robustness. Develop supporting analytics in parallel with your process and begin collecting data early in development. Focus on establishing critical quality attributes. When you do finally administer your drug to an actual patient, monitor the patient closely.

Think of your filing strategy as global and connect with authorities early
Most customers think about filing their molecules locally first, then globally. But if a product is successful, eventually, global registration will be necessary. Since regulatory bodies’ requirements vary and may pertain to any point along the development pathway, developing a good technical understanding of what the various regulatory agencies expect in terms of process development, validation, viral validation, analysis, facility inspections and so on is a must. For instance, if you file in the EU, one GMP batch is sufficient for Phase I; in China, investigative new drug (IND) filing requires three.

Of the main regulatory agencies—the Federal Drug Administration (FDA), the European Medicines Agency (EMA) and the International Conference on Harmonisation (ICH)—be aware that ICH is becoming the world basis for all countries. Engage in discussions with regulatory authorities both upfront and regularly throughout development to understand requirements, validate your approach, correct faulty assumptions, remain on-target and avoid inconvenient surprises. Make sure any contract manufacturing organization (CMO) you engage demonstrates regulatory expertise, supplies helpful documentation and can support local and international regulatory requirements for the duration of the project.

Fast, but smart, early development begets success
Early, careful planning in all areas of development is the key to bringing a molecule from bench to bedside successfully. As a biopharma executive in a competitive landscape, you must focus on speed. However, in certain critical steps, such as process development, thoroughness is more important; final product quality, process efficiency and patient safety are critical. In the end, the fastest process may not be the most financially viable. Care in commercial strategizing, technology selection and early attention to regulatory requirements will prevent setbacks later on.

Many companies lack the expertise and resources to navigate the business planning, cell line development, process development, technological challenges or regulatory and risk assessment needed for early-stage clinical development. Engaging a proven service provider to help prevent missteps and find the best development pathway can make commercial success a reality.

If you plan to outsource, ask questions. Some partners can provide time-saving process templates based on previous projects, offer expert assistance and top quality processes at every step of the way or even complete the entire project for you, from start to finish. Experience matters, so ask what the last 10 process development problems they tackled were—and what solutions they found.

It’s your molecule—don’t let just anyone handle it. 

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Christian Cattaruzza is Director of Strategy and Marketing Development for BioReliance End-to-End Solutions, at MilliporeSigma. He leads the strategy and marketing for a portfolio of services including process development, cGMP clinical manufacturing, quality and regulatory support, training, commercial facilities design, engineering and build-up as well as production equipment supply and process technical transfer activities.