Manufacturing Challenges for Biosimilars: Complex Production

When you think of a generic drug, you picture a small pill that’s chemically identical to the brand-name version. But biosimilars? They’re not that simple. These are complex, living medicines-large proteins made inside living cells-that must match a reference biologic almost exactly. The catch? You can’t just copy the recipe. Even tiny changes in how they’re made can change how they work in the body. That’s why manufacturing biosimilars is one of the hardest tasks in modern medicine.

The process defines the product

Unlike small-molecule generics, where chemists can recreate the exact same compound using predictable reactions, biosimilars are made by living cells. These cells-often Chinese hamster ovary cells-are fed nutrients, kept at precise temperatures, and gently stirred in giant bioreactors. As they grow, they produce the protein drug. But no two batches are ever exactly alike. The cells respond to tiny shifts in pH, oxygen levels, or even the type of sugar in the growth medium. And that’s where the real challenge begins.

The phrase “the process defines the product” isn’t just industry jargon-it’s the core truth behind biosimilar development. If you change how you feed the cells, how long you let them grow, or how you filter the final product, you change the molecule’s shape, charge, and structure. These changes might seem minor, but they can alter how the drug behaves in the body. One small difference in glycosylation-the sugar molecules attached to the protein-can make the drug clear from the bloodstream faster, reduce its ability to bind to target cells, or even trigger an immune response.

Imagine trying to recreate a signature dish from a Michelin-starred restaurant without ever seeing the kitchen, tasting the food, or knowing the chef’s techniques. That’s what biosimilar developers face. They have the final product in hand, but not the recipe. They must reverse-engineer thousands of subtle characteristics using advanced analytical tools to map the reference product’s “molecular fingerprint.” Only then can they design a manufacturing process that gets as close as humanly possible.

Glycosylation: the silent wildcard

Glycosylation is one of the most difficult aspects to control. These sugar chains stick out from the protein like branches on a tree. Their length, branching pattern, and composition vary based on culture conditions, cell line health, and even the time of year. A single change in glycosylation can turn a therapeutic protein into a less effective-or even dangerous-version of itself.

For example, if a monoclonal antibody used to treat cancer has too few sialic acid residues on its glycans, the immune system might attack it too quickly. Too many, and it might not bind tightly enough to cancer cells. The reference product has a specific glycosylation profile that’s been proven safe and effective over years of clinical use. The biosimilar must match it within strict limits-usually within 5% variability. But achieving that consistency across hundreds of batches, over years of production, is like trying to hit a moving target with your eyes closed.

To tackle this, manufacturers use high-resolution mass spectrometry, capillary electrophoresis, and other cutting-edge tools to analyze glycan structures down to the atomic level. But even with the best tech, it takes years of trial and error to fine-tune the process. One company spent nearly three years adjusting feed rates and dissolved oxygen levels just to stabilize glycosylation in a single biosimilar candidate.

Scaling up without losing control

Getting a biosimilar to work in a 10-liter lab bioreactor is one thing. Getting it to work in a 10,000-liter commercial tank is another. At small scale, you can control every variable with precision. At large scale, mixing becomes uneven. Oxygen doesn’t distribute evenly. Temperature gradients form. Cells in one corner get more nutrients than those in another. These physical differences change how the cells behave-and therefore, the protein they produce.

Manufacturers must map out how every parameter scales. Stirring speed? It can’t just be increased proportionally. Oxygen transfer rates change with tank geometry. Feeding strategies that worked in a 500-liter tank might cause cell death in a 5,000-liter one. Many companies have lost entire batches because they assumed a linear scale-up would work.

That’s why modern biosimilar plants use advanced modeling software and real-time sensors to monitor conditions. Process analytical technology (PAT) lets them track pH, dissolved oxygen, and metabolite levels as the batch runs. If something drifts, the system adjusts automatically. Still, it’s expensive. Building a facility with this level of monitoring can cost over $500 million.

The cold chain nightmare

Biosimilars don’t just need careful production-they need careful handling from the moment they’re made. Most are proteins, and proteins are fragile. Heat, vibration, light, even too much shaking can break them apart. That’s why the cold chain-the network of refrigerated storage and transport-is critical.

One biosimilar manufacturer lost $12 million in product last year because a refrigerated truck’s temperature sensor failed during a 48-hour transport. The batch was still within legal temperature limits, but the protein had degraded enough to fail quality tests. The company had to recall the entire shipment. That’s not rare. In fact, 1 in 6 biosimilar shipments experience some kind of cold chain issue.

To fix this, companies are switching to single-use containers and smart packaging with embedded temperature loggers. Some even use blockchain to track every step of the journey. But these solutions add cost-and complexity. Smaller manufacturers struggle to afford them, putting them at a disadvantage against big players.

Regulatory maze

Getting a biosimilar approved isn’t like getting a generic approved. The FDA and EMA don’t just want proof that it’s similar-they want proof that it’s as safe and effective as the original. That means extensive analytical data, animal studies, and sometimes even clinical trials.

The regulatory bar keeps rising. In 2023, the FDA updated its guidance to require more detailed comparisons of post-translational modifications, including glycosylation, deamidation, and oxidation. Developers now need to show they can control these variables consistently-not just in one batch, but across every batch they’ll ever make.

And it’s not just one agency. Each country has its own rules. The EU might accept a reduced clinical trial program if analytical data is strong. The FDA might demand a full head-to-head trial. China has its own pathway. Navigating this is like solving a different puzzle in every country.

Technology is changing the game

The industry is fighting back with new tools. Single-use bioreactors are replacing stainless steel tanks. They eliminate cleaning validation, reduce contamination risk, and let manufacturers switch between products faster. Automation is cutting human error-robots now handle filling and labeling in cleanrooms, reducing the chance of mistakes.

Artificial intelligence is helping too. Machine learning models analyze years of manufacturing data to predict which process changes will cause quality issues before they happen. One company reduced batch failures by 40% in two years by using AI to adjust feed strategies in real time.

Continuous manufacturing is the next frontier. Instead of making one batch at a time, some companies are moving toward a steady flow of production-like a pipeline. This reduces variability and improves consistency. But it’s still early. Only a handful of biosimilars are made this way today.

Who can afford to play?

The global biosimilars market is projected to hit $58 billion by 2030. But only a few dozen companies have the expertise, capital, and infrastructure to compete. The cost to develop and launch a single biosimilar? Often over $100 million. The time? At least seven years.

Smaller players are getting squeezed. Many lack the analytical labs, automation systems, or regulatory teams needed to keep up. Some are turning to partnerships-licensing technology from bigger firms or outsourcing production. Others are focusing on simpler biosimilars first, like insulin or growth hormones, before tackling complex ones like bispecific antibodies.

The ones who win? Those who treat manufacturing not as a cost center, but as the core of their product. They invest in process understanding, not just product testing. They build flexibility into their plants. They train their teams to think like scientists, not just operators.

What’s next?

The future of biosimilars lies in smarter processes, not just cheaper ones. As more complex biologics lose patent protection-like antibody-drug conjugates and fusion proteins-the manufacturing challenges will only grow. But so will the demand. Patients need affordable options. Health systems need cost savings.

The companies that succeed won’t be the ones with the biggest budgets. They’ll be the ones who truly understand that a biosimilar isn’t just a copy. It’s a re-creation. And re-creating a living molecule, perfectly, every time, is one of the most difficult feats in science.