Why biosimilars aren’t just generic drugs

When you think of a generic drug, you probably picture a small pill that looks different from the brand-name version but does the same thing. That’s straightforward. But biosimilars? They’re not like that at all. A biosimilar is a biologic drug - a large, complex molecule made inside living cells - that’s designed to be as close as possible to an already-approved reference biologic. Think of it like trying to recreate a handmade Swiss watch using only photos of the original, without ever seeing the tooling or knowing the exact sequence of steps the original maker used. That’s the reality of biosimilar manufacturing.

Unlike small-molecule generics, where chemists can replicate the exact same chemical structure using predictable reactions, biosimilars are built by living cells - usually Chinese hamster ovary (CHO) cells or bacteria - that produce proteins with tiny, unpredictable variations. These aren’t just minor differences. They can affect how the drug works in your body. A single change in sugar attachments (glycans) on a protein can alter how long it lasts in your bloodstream or whether your immune system reacts to it. That’s why saying a biosimilar is "similar" isn’t just marketing. It’s a scientific and manufacturing feat.

The "process defines the product" problem

The biggest hurdle in making biosimilars is this: the process defines the product. That means the way you grow the cells, feed them, control the temperature, and purify the final molecule all determine what the drug ends up being. Even if two companies use the same gene sequence to make the same protein, if one uses a different type of culture media or runs its bioreactor at 37.2°C instead of 36.8°C, the final product can be measurably different.

Developers don’t get access to the originator’s exact manufacturing recipe. They have to reverse-engineer it by testing hundreds of variables. One study showed that over 150 critical quality attributes (CQAs) need to be matched - from protein folding to charge variants to glycosylation patterns. Each one has to fall within a narrow range to prove biosimilarity. This isn’t guesswork. It’s high-stakes detective work with millions of dollars on the line.

Glycosylation: The silent game-changer

One of the most difficult things to control is glycosylation - the sugar chains attached to the protein. These aren’t just decorations. They’re functional. A change in just one sugar molecule can make the drug clear from your body faster, reduce its ability to bind to target cells, or trigger unwanted immune responses.

These sugars are added by the cell’s own machinery, which responds to tiny changes in its environment. Even switching from one batch of fetal bovine serum to another can shift glycosylation patterns. Manufacturers have to test dozens of media formulations, oxygen levels, pH buffers, and feeding schedules to get the same glycan profile as the reference product. It’s like trying to bake the same cake using different ovens, flour brands, and humidity levels - and having to prove every slice tastes exactly the same.

Scaling up: Bigger tanks, bigger problems

Getting a biosimilar to work in a 5-liter lab bioreactor is one thing. Getting it to work in a 2,000-liter commercial tank is another. At larger scales, mixing isn’t uniform. Oxygen doesn’t distribute evenly. Temperature gradients form. Cells in one corner get more nutrients than those in another. These differences can lead to inconsistent protein quality batch after batch.

Companies have to spend years optimizing conditions for scale-up. They test agitation speeds, sparging rates, and feeding strategies to make sure cells in a big tank "feel" the same as cells in a small one. Many smaller manufacturers can’t afford the capital investment to build these large-scale facilities. That’s why most biosimilars today come from just a handful of big players with global manufacturing networks.

Supply chain and cold chain nightmares

Biosimilars are fragile. They can degrade if exposed to heat, light, or even vibration. That’s why they need a tight cold chain - constant refrigeration from the factory to the hospital. One broken refrigerated truck, one mislabeled storage unit, and an entire batch can be ruined. These aren’t cheap drugs. A single batch can cost over $1 million to produce. Losing it isn’t just a financial hit - it can cause drug shortages.

Even the containers matter. Traditional stainless steel tanks require cleaning and sterilization between batches, which takes time and introduces contamination risk. That’s why more manufacturers are switching to single-use bioreactors - plastic bags that come pre-sterilized and are thrown away after use. They cut cleaning time by 70%, reduce contamination risk, and let companies switch between products faster. But they’re expensive, and sourcing them reliably is a challenge in itself.

Regulatory maze: One country, different rules

Getting a biosimilar approved isn’t a single step. It’s a multi-phase marathon. You need to show analytical similarity - proving your molecule matches the reference in structure and function. Then you need preclinical data - animal studies to show it behaves the same. Finally, you need clinical trials - usually a pharmacokinetic study and sometimes an efficacy or safety trial.

The problem? Each country has different expectations. The FDA in the U.S. might accept a single PK study. The EMA in Europe might require an additional clinical trial. India’s regulators have their own guidelines. And all of them demand access to state-of-the-art labs with mass spectrometers, NMR machines, and high-resolution chromatography systems. Few companies have the expertise - or the budget - to meet all these requirements across multiple markets.

Technology is helping - but it’s not a magic fix

There’s hope. New tools are making biosimilar manufacturing more predictable. Process analytical technology (PAT) lets manufacturers monitor critical parameters in real time - like pH, dissolved oxygen, and cell density - and adjust on the fly. Artificial intelligence is being used to predict how changes in feed composition will affect glycosylation before a single batch is run. Automation reduces human error in filling and packaging.

Continuous manufacturing - where the process runs nonstop instead of in batches - is also gaining traction. It reduces variability and can cut production time by half. But these technologies require deep expertise and big investments. Only companies with strong R&D budgets and regulatory experience can implement them effectively.

Why this matters for patients

Biosimilars are meant to lower the cost of life-saving biologics - drugs for cancer, autoimmune diseases, and rare conditions that can cost over $100,000 a year. The global biosimilars market is expected to hit $58 billion by 2030. But if manufacturing is too complex, too slow, or too risky, prices won’t drop as much as they should. Supply shortages can still happen. Patients might wait longer. Doctors might hesitate to switch.

The real win isn’t just having more biosimilars on the market. It’s having reliable, consistent, affordable ones - made by manufacturers who understand that every cell, every sugar, every temperature setting matters.

What’s next?

The next wave of biosimilars will include even more complex molecules - bispecific antibodies, antibody-drug conjugates, fusion proteins. These require extra purification steps, refolding, and precise conjugation chemistry. Each adds another layer of risk. The companies that will win are the ones who treat biosimilar manufacturing not as a cost-cutting exercise, but as a science-driven, precision engineering challenge.

For now, the bar remains high. Only those who can master the invisible variables - the glycosylation, the scale-up, the cold chain, the regulatory shifts - will survive. And that’s why, despite the hype, true biosimilar success is still rare.