The recent trend towards the “one-stop-shop” CMO that provide services from development to commercialization may not be all it’s chalked up to be. Particularly with large molecule drugs, it is becoming apparent that the best way to differentiate in the world of CMOs is to differentiate, by being specific.

When considering the size and complexity of biologics relative to small molecule drugs (SMD), the type of expertise required to develop and manufacture protein-based drugs, versus SMDs is not the same. On a simplistic level, SMDs are manufactured by following a tightly controlled chemical recipe. They have a well-defined structure and can be chemically synthesized. Scale-up to manufacturing is often a matter of upsizing that recipe. Biologic production, in comparison, is considered more of an art that requires a high level of experience and a keen eye to understand and fine-tune these highly complex and intricate processes. 

Because there are so many steps in the biologics manufacturing process that can influence the purity, potency, clinical efficacy, and safety of the finished product, extensive experience across multidisciplinary fields is essential. Biochemical and industrial engineering interact with molecular and cell biology, biochemistry, protein chemistry and regulatory affairs. All are significant components requiring very specific people and expertise, which, in an early stage biotech situation may not be available.

In today’s cost consideration climate, both commercialization scale-ups and even larger biotechs are considering the “Go/No-Go” question around a move to contract manufacturing. The expensive and highly specialized expertise required with biologics, coupled with the tightly controlled processes in a GMP facility create a sense of justifiable caution around the ability to identify CMO partners who can deliver.

Specialties within Specialties
The recent period of CMO consolidation, much of it driven by mergers and acquisitions, has created a push towards the “one-stop-shop” model for outsourced manufacturing. Many of these larger organizations do offer a wide range of services across multiple disciplines, and this can feel like a positive, with acres of cleanroom space and lots of equipment visible on a tour. However, consumers of large molecule CMO services need to be especially wary of going to a “one-stop-shop.” As many in the field know, the ability to provide quality services across a wide range of biotech processes is a lot trickier than it would seem.

After all, if you can make one type of biologic, does it not follow that you should be able to make them all? Among large molecule processes for example, some biologics are manufactured using mammalian expression systems (predominantly CHO cells) while others use microbial expression systems (predominantly E. Coli). Can a one-stop-shop model provide both?

On paper, perhaps. But not according to the scientists who work on either side of this peptide/protein experience bench. The two types of experience are quite different. Understanding of the quality, regulatory and process considerations, for both upstream and downstream manufacturing will be critical to meeting production timelines. For example, a very different set of expertise would be required to operate a microbial fermenter than to operate a CHO cell bioreactor.

Consider it a specialized understanding, critical in an already specialized field. 

Is Their Business “Your Business?”
Because the majority of work in the large molecule field is CHO cell  (mammalian expression) for antibody or antibody fragments, typically larger “one-stop-shop” CMOs will be very skilled in that area. But if a biopharmaceutical client comes to that large CMO with a microbial process for peptides or smaller proteins, while the CMO would be generally capable, it is simply not their normal business case. Their expertise and overall knowledge could be somewhat limited because that type of microbial process would not constitute a large portion of their manufacturing runs and thus attention and staff may be diluted. The analytical procedures, the qualification of those procedures, the chemistry and the equipment, testing and knowledge required are just different enough to matter.

For processes with peptide chains in the 30-100 amino acid range for example, your team should be seeking peptide experience from a CMO, because a CMO that handles mammalian processes as a large percentage of their business might lack the necessary microbial expertise. In contrast to mammalian expression systems, peptides or small proteins produced in microbial expression systems can be either intracellular or engineering to be secreted into the conditioned medium. Intracellular products can be soluble or insoluble (inclusion bodies), requiring vastly different upstream processes.  Harvest, clarification, cell lysis, solubilization and refolding of even small proteins produced in microbial expression systems is a challenge and the many scientists and engineers who are lifelong biologics people may simply not have this particular level of understanding and expertise. Only dedicated teams, with years working in peptides will be able to understand the nuances of how to scale a microbial process, how to run it, even how to write it up properly for regulatory submission. After all, doing something many times before makes it much easier to do again.

So, how does this translate into locating a qualified CMO partner? Ask the CMOs being interviewed: What percent of their time and resources are dedicated to your specific process needs?

Ability to Make Targeted Investments in Your Niche
One other advantage of the niche CMOs is that because they specialize, they have the correct equipment and unit processes, and investments will continue to be made in equipment that suits the niche they have chosen. Being niched yields advantages from a resource allocation standpoint, which is obviously to the client’s advantage.  

For example, in the case of a recombinant manufacturing process for therapeutically relevant peptides, by focusing on microbial expression, as opposed to mammalian cell, a CMO can have the benefit of investing in facilities and equipment targeted specifically for that process. They would have the knowledge to precisely run and properly scale those processes. 

The basic unit operations from a high level are the same: cell production, fermentation, harvest/clarification, purification, and characterization. But there is a difference in the equipment and technology choices that are available for “large protein versus peptide” and then it is all about experience in determining how to handle problems that inevitably arise. 

Looking for large-scale reversed-phase chromatography? This requires solvent handling and safety measures such as explosion proof cleanroom suites. Who needs that? Well, no one, unless they are dealing with peptides in the 30-100 amino acid range; that is then precisely the type of technology that is often needed to purify them.  Only a CMO that has expertise in peptide purification would have a place for such a technology. 

How about the harvest of the fermentation?  For CHO cells, separating the cells from the product is fairly straightforward. But for E. Coli and other microbial systems, this step can present different challenges. In the best case, the E. coli secrete the peptide/protein of interest into the medium—this greatly facilitates downstream purification. But it is often the case that the protein is expressed as insoluble inclusion bodies that must be solubilized and refolded. These are particularly challenging aspects of microbial production, and the development of optimal expression systems can go a long way to minimizing subsequent harvest and purification challenges. The analytical equipment differs greatly as well, with most peptides analyzed by RP-HPLC, while larger protein biologics often require specialized equipment. 

The point is, that even within biologics, there is a huge difference in the equipment needed to make smaller proteins versus large proteins. As a biotech that is looking to outsource manufacturing of your therapeutic products, make sure the CMO that you choose is committed to the process that you need. This sort of specialized process understanding can mean the difference between success and failure.   

Ability to Attract Expert Employees in Your Area of Specialty
The specialty knowledge of how to run those unit operations and how to properly scale them, how to accurately evaluate how they perform, and in the previous example of microbial purification equipment, how to design the in-process controls to demonstrate that each step is performing properly are all reasons why biotech customers need to be very choosy about where they outsource their manufacturing. 

While many clients understand what they are looking for in terms of technology and equipment, it is easy to be taken in by the “we have it all” mentality which in reality, may translate into a dilution of the precise experience that client needs.  

The same goes for the staffing required for different types of processes. You want CMO teams who have lived your process challenges during their careers, not teams who need to learn your process. The subtle differences in peptide versus protein mentioned above, will give rise to issues that a CMO team (that is learning on the job) has not faced before. When you “go specialty”, you have so many more people who deeply understand the potential roadblocks, and that expertise can predict and prevent those roadblocks in the first place. This may be especially important when evaluating a downstream purification process from both the production and analytical standpoint, understanding the limitations on both sides, comparing chromatograms, and implementing the best process to yield the purest product possible.

Consider the Soft Traits
Smaller niche CMOs tend to possess those traits that are a bit hard to pin down, like nimbleness, agility and responsiveness, and because these traits translate into faster timelines and general ease of working relationship, they become important considerations when seeking a CMO partner. 

Intuitively, it is easy to understand why this is true. Nimbleness and timeline sensitivity are possible only if a team deeply understands the process. Their responsiveness will naturally be quicker if their problem solving is based on hundreds more situations where those problems have been seen and solved. If a CMO team is somewhat familiar but not deeply familiar with scale-up challenges in, for example, large molecule microbial processes, timeline could suffer as alternatives are tested, discarded and tried again. Can they effectively evaluate scale-up issues for each upstream and downstream unit operation and instantly make accurate suggestions? These early suggestions can save immeasurable time to running a successful first GMP run. To respond to questions such as “How soon can we start?” and “How fast can we go?” the more deeply trained teams will be the most nimble and responsive. 

Niche Experience and Regulatory Experience
Typically, securing Phase III API supply and subsequent future commercial manufacturing involves years of preparation and planning. In contrast, the decision to conduct early phase clinical studies can happen overnight, leaving API supply as the limiting factor in the overall timeline.

More often than not a client comes to a CMO with a process they’ve worked hard to scale, but sometimes that’s almost too late, because they may have made decisions that impact licensing and regulatory approvals. Look for a CMO who has seen EMA and FDA through their facilities as a matter of course. Ask how many times those regulatory agencies have visited and ask for the results. If they have the years of experience in your niche, positive answers should be forthcoming. Choose a CMO that has strong CMC expertise, one that can provide technical and written support for regulatory filings.

A large conglomerate CMO might be more likely to have the client conform to their existing equipment flow or processes. A small nimble niche CMO can be more flexible to work with and can understand where the holes are in a an early commercialization project and be a little more creative in getting the correct information from a regulatory standpoint, in parallel with getting ready for manufacturing runs.  

Considering the complexity of large molecule manufacturing, look for a niche specialty partner when considering your CMO options. It often yields a partnership with deeper experience to solve your problems and in that process, may offer a higher level of open communication, less bureaucracy, and an agile approach to handling issues as they arise. 

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Dr. Paul Shields, vice president of operations at Enteris BioPharma since 2013, brings more than 24 years of experience in the biopharmaceutical industry, focusing on Chemistry, Manufacturing and Controls (CMC) for a variety of products.
Dr. Shields previously served as the vice president, manufacturing operations for Unigene Laboratories where he managed commercial CMC operations for recombinant active ingredients, and clinical and commercial supplies of nasal spray and solid dose products. Prior to that, he served as Unigene’s director of plant operations. Dr. Shields holds a Ph.D. in biochemistry from the University of Pennsylvania and a B.S. in chemical engineering from the University of Michigan.

Angelo P. Consalvo is a director of manufacturing at Enteris BioPharma. With over 30 years experience, Angelo has been responsible for development of viable manufacturing processes for recombinant peptides and proteins originating from mammalian and microbial expression systems. He served as director of recombinant process development at Unigene Laboratories from 2009-2013. In 2013 he joined Enteris BioPharma, where he is heading up the recently launched contract manufacturing business for products produced exclusively in microbial expression systems. Angelo can be reached at aconsalvo@enterisbiopharma.com