Deciding Where to Outsource in Biopharma Development and Manufacturing

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Every year, new and innovative drug products and technologies emerge, changing the landscape of biopharma and the treatments that are possible. This can be credited—in part—to the capabilities and flexibility provided by outsourcing.

“Drug developers are reshaping modern medicine by bringing possibility to reality. They are transforming how diseases are combated by bringing new curative treatments to the forefront. Emerging and virtual companies that are driving the future pipeline heavily rely on external development partners—but not just for hard-to-make products. Even more established companies are contracting with CDMOs [contract development and manufacturing organizations] to gain access to capacity and specific capabilities,” says Dirk Lange, head of life science services, MilliporeSigma, the Life Science business of Merck KGaA, Darmstadt, Germany.

As the biopharma industry continues to outsource tasks within analytics, development, and manufacturing, one question continues to arise: what should be outsourced vs. performed in-house? Moreover, should the industry outsource more and, if so, where? Prior to establishing what should or shouldn’t be outsourced, it should first be determined exactly what is being outsourced.

Where the industry is outsourcing

“In cell and gene therapy [CGT], many of the CMC [chemistry, manufacturing, and control] tasks are outsourced including process development, analytical development, testing, manufacturing, and fill/finish. Outsourcing can occur really at any point in a therapy’s life cycle up and through commercial production,” says Audrey Greenberg, co-founder and chief business officer, Center for Breakthrough Medicines.

CGTs, specifically, have challenges that require costly and difficult-to-procure consumables, equipment, space, and talent, explains Greenberg, which might further encourage a company to consider outsourcing clinical through commercial manufacturing processes. Hanna Lesch, PhD, chief technology officer, Exothera, adds that the level of outsourcing will depend on the size and type of biopharma company.

“Big companies have the resources to perform development and manufacturing, but they might need support with specific tasks, like dedicated analytical assays or process optimization studies,” says Lesch. “Small companies—which represent the majority of the advanced biotherapeutic developers right now—have very limited internal development and manufacturing capacity and expertise; so, they tend to outsource process development, process scale-up, and manufacturing (including analytics).”

Similarly, Sigma Mostafa, senior vice president and site head, KBI Biopharma, expresses that what is outsourced usually depends on the size of a given company, adding that the overall level of outsourcing has recently increased.

“The smaller biopharma companies usually outsource most of their activities from early development to manufacturing and rely on partners for early and late phase activities,” says Mostafa. “Larger pharmaceutical companies tend to manage their early development work in-house and then ‘tech transfer’ the process to a CDMO for manufacturing.”

According to Hanns-Christian Mahler, chief enablement officer and board member, ten23 health, outsourcing has been traditionally more focused on manufacturing. Mahler adds that development is increasingly being outsourced as well.

Determining where to outsource more

Early-stage candidate selection, scaled-down, and at-scale process characterization studies, according to Mostafa, should be outsourced more. Candidate selection is when it’s determined which molecule best matches the target profile for efficacy, pharmacology, and manufacturability. Mostafa explains that biopharma companies usually consider three to six molecules at this stage with a focus on predicting clinical outcomes—regardless of the manufacturability of a molecule.

“Typically, this early-stage candidate selection process is not outsourced but doing so can bring benefits, such as offering a broader set of analytics and a more representative cell line and process,” says Mostafa. “By using a stably transfected cell line instead of a transiently transfected one, we can identify potential productivity and product quality challenges. An extensive array of analytical methods can be utilized to determine whether any candidates have aggregation, deamidation, oxidation, isomerization, or peptide bond cleavage issues. Surface hydrophobicity and conformational stability evaluation are the other services that CDMOs can provide.”

Meanwhile, scaled-down and at-scale process characterization studies, according to Mostafa, are rarely outsourced. These studies require nine to 12 months to complete and are resource intensive, and CDMOs can potentially perform these studies with greater efficiency.

Other internal tasks to consider outsourcing, according to Lesch, are CMC studies and regulatory review.

“CMC is a particularly complex area, and the increasing regulatory requirements placed upon advanced therapy medicinal products makes this an area where service providers can provide the latest expertise,” says Lesch.

Greenberg, on the other hand, points out that recent market movements have resulted in finances as another deciding factor for what to outsource.

“Customers strapped for capital should consider outsourcing activities from process development, manufacturing, fill/finish, primary and secondary packaging, analytical development, testing, and regulatory support during IND [investigational new drug application]/BLA [biologics license application] filings,” says Greenberg—adding that it will come down to what is best for the process, and where some companies might benefit from an entirely outsourced approach, others may only require 50% outsourced efforts.

“Overall, outsourcing is a much more efficient use of capital for the industry, as it prevents building something from scratch that involves learning curves, which can create a backlog inventory of products, materials, and consumables as well as underutilized space and talent,” says Greenberg.

Meanwhile, Lange emphasizes the advantages of outsourcing to a CDMO, which offers end-to-end services, as this can help to integrate activities, reduce interfaces, and create better alignment between teams. For sterile manufacturing, for example, companies should consider working with a CDMO that is already equipped with formulation development, primary packaging selection, and manufacturing process design space, rather than working with various partners, according to Mahler.

What should be performed in-house

There are a lot of differing opinions regarding which analytical, development, and/or manufacturing tasks—if any—should be performed in-house instead of outsourcing. What it often comes down to is existing capabilities in a company’s facility/facilities, whether the maintenance is sustainable, in-house talent, and bandwidth (among other reasons). According to Mahler, it’s all about balancing risk and cost.

Mostafa adds: “Any analytical methods that are subject to interpretation, such as specific cell-based assays, are not ideal activities for outsourcing. Any activity that would be significantly more efficient in-house, such as narrowing down the candidate pool from hundreds to <10, should also be done in-house. If the process is extremely long compared to standard process duration, then considering the cost of the additional suite time, manufacturing in-house may make the most sense.”

Greenberg further points out that biopharma companies, especially those in the CGT space, should consider outsourcing as soon as possible in a drug’s life cycle to adhere to GMP-grade materials, methods, processes, and testing as part of forward process integration activities. This avoids delays and regulatory issues down the road that may further delay approval.

Potential pain points for frequent outsourcing

When selecting and working with partners, one fact many companies drive home is the importance of good communication and trust. However, after having worked on a given biomolecule or product for many years, it can be difficult for a company to bring in a third party and hand over the reins.

“Innovator companies are rightly concerned with maintaining not only the intellectual property, but also clarity and control in their process,” says Greenberg. “These products are the result of years, if not decades, of work, and it can be hard to trust and share with a new party. This is what makes choosing the right outsourcing partner so critical.”

Lange also highlights the importance of trust. CDMOs should be transparent and engage with the client in decision-making, which builds trust in the partnership.

“Clients need to be engaged in decision-making to ensure the CDMO’s programs meet the client’s scientific and regulatory goals, timelines, and budgets. Therefore, engaging in co-development with a flexible, collaborative, and client-centric CDMO is key to ensuring success,” says Lange.

Similarly, Mahler believes a fear of a loss of control can be a challenge for certain companies. Though this will depend on the collaboration model.

There are other potential challenges, one of those is being reliant on another party’s capacity and timelines, adds Lesch. Another is the potential time investment during the tech transfer phase of the in-house process to the service providers platform, which might take more time than expected.

“[Biopharma companies] may have developed a platform process with a standard set of assays since they have a molecular structure that can use the same analytics across their pipeline and feel those processes and analytics cannot be replicated in a CDMO,” says Mostafa.

The most popular tasks to outsource in biopharma

Depending on where a company sits in the supply chain (upstream through downstream), different tasks will, of course, be more top-of-mind for outsourcing. The experts interviewed by BioPharm Internationalshare the following as some of the most popular tasks to outsource:

• Development. “The activities outsourced are dependent on different factors, such as modality, capabilities of the customers, and phase of the molecule,” says Lange. “In general, we do see more outsourcing in the early phases. This is mainly driven by the rise of emerging biotechs since they are predominantly driving the development of new molecules.”
• Process development and release assays. “It’s quite common to outsource process development if the outsourcer is looking for the right technology for manufacturing. It is usually prompted by a need to improve upstream unit operations, like the selection of transfection/infection strategy or the type of bioreactor,” says Lesch. “During manufacturing, it’s common to outsource specific release assays; for example, assays to detect adventitious viruses or sequencing undesired DNA/RNA portions which can be complex to establish and are thus outsourced.”
• Viral vector manufacturing, testing, and analytics. “Viral vector manufacturing seems to be the most outsourced task,” says Greenberg. “Testing and analytics remain strong outsourced activities. And we are also seeing a growing interest in newer or re-emerging modalities, such as mRNA, exosomes, and plasmids.”
• Replication. “As a general approach, anything closer to manufacturing, anything that's just replicating something done in-house, is more frequently outsourced,” says Mostafa. “For instance, in case of a re-supply run: a clinical trial has already started, and a process is in place. Outsourcing involves transferring the process to another site (CDMO) and having the CDMO be responsible for the manufacturing.”

Large molecule outsourcing trends

Large molecules are no longer limited to monoclonal antibodies (mAbs) and have become more diverse, says Mahler, adding that this encompasses therapeutic proteins, oligonucleotides, and CGTs. More expertise is required for increasingly diverse molecules.

Thus, with more biomolecules to pursue, it would be no surprise to learn that outsourcing in general is a trend, specifically for complex molecules and recombinant proteins (not just novel modalities), according to Lange.

“The next generation of mAbs or fusion proteins are more complex, and we see the share of projects in this space increasing,” says Lange. “This is not limited to the development and manufacturing space, since these complex constructs require extensive analytical characterization and advanced formulation capabilities in order to navigate their way to treat patients safely.”

Other trends, according to Lange, include a larger number of smaller, refined indications, and not only in the rare disease arena—courtesy of increased capabilities, specifically in diagnostics. Furthermore, single-use technologies continue to gain traction.

“[T]he technology landscape keeps evolving, since manufacturing templates are driving efficiency in the manufacturing process,” says Lange. “For example, today’s cell culture titers allow for smaller manufacturing scales. This creates a shift towards single-use manufacturing services. Today, single-use manufacturing trains can support the entire life cycle from clinical to commercial volumes of many assets.”

Yet another trend that has formed roots is outsourcing at a “one-stop-shop” provider.

“[S]mall companies are looking for a CDMO that can provide end-to-end services, from plasmid constructs to fill/finish within quality and regulatory standards,” says Lesch. “This allows them to reduce the number of interactions with external partners and optimize costs while saving time.”

Looking ahead

What does this look like going forward? Like most industries, the pandemic has made lasting effects in biopharma, including the need (and, therefore, trend) to outsource. This is often due to resources, capital, expertise, and time constraints, according to Greenberg.

“Outsourcing is here to stay,” says Mostafa. “The CDMO industry has been flourishing over the past decade.”

“We are still navigating a pandemic where supply chain constraints have challenged business models. There does not seem to be any easing up of current market landscape; so, I believe we will see the outsourcing trend continue because of cash, time, and resource constraints,” says Greenberg. “It is critical to have partners you can trust and who provide the transparency and the flexibility to work with you based on the program needs. In the end it is about doing whatever it takes to bring these innovative therapies to the patients who need them the most—and we have all acknowledged, you cannot do this alone.”

“Biopharma is an exciting space to be in,” says Lange. “The rise of novel modalities and the second generation of biologics will open endless opportunities to improve the life of patients. We as a CDMO/CTO [contract testing organization] have a crucial role to play on this quest, as we can help accelerate the time to market and bring therapies to patients faster.”

Whatever a company chooses to outsource, evaluate whether that potential partner has the proper experience, capabilities, and lead times to determine whether it’s a good fit all around. Be clear in your needs and expectations and find a partner you can trust.

About the author

Meg Rivers is a senior editor for Pharmaceutical Technology, Pharmaceutical Technology Europe, and BioPharm International.

Article details

BioPharm International
Vol. 35, No. 8
August 2022
Pages: 10–14

Citation

When referring to this article, please cite it as M. Rivers, "Deciding Where to Outsource in Biopharma Development and Manufacturing," BioPharm International 35 (8) 10–14 (2022).