When you take a pill for high blood pressure, you expect every tablet to be exactly the same. That’s because small-molecule drugs are made in a lab using chemical reactions - like baking cookies from the same recipe. But when you get a biologic drug - say, for rheumatoid arthritis or Crohn’s disease - what you’re getting isn’t a single molecule. It’s a complex soup of millions of slightly different versions of the same protein. And that’s normal. It’s not a mistake. It’s biology.
Why biologics aren’t like generics
People often think biosimilars are just like generic drugs. They’re not. A generic version of aspirin is chemically identical to the brand name. Every molecule is the same. Biosimilars? They’re highly similar, but not identical. That’s because biologics are made inside living cells - yeast, hamster ovary cells, bacteria - not in a beaker. These cells don’t follow a perfect script. They make small changes as they build the protein. Sometimes they add extra sugar molecules. Sometimes they tweak an amino acid. These tiny differences are called lot-to-lot variability.The U.S. Food and Drug Administration (FDA) says this variation is inherent. Even the original brand-name biologic has it. Every batch, or lot, of Humira or Enbrel contains millions of slightly different versions of the same antibody. That’s why a biosimilar doesn’t have to be identical - it just has to be similar enough to work the same way and be just as safe.
What causes these differences?
It all comes down to how biologics are made. The process starts with a single cell. That cell is grown in a bioreactor, fed nutrients, and coaxed into producing the therapeutic protein. But living systems are messy. Temperature shifts. Nutrient levels change. Even the pH of the solution can nudge the cell to make a slightly different version of the protein. These changes lead to what scientists call post-translational modifications - mainly glycosylation (adding sugar chains), oxidation, or deamidation (chemical changes to amino acids).These aren’t defects. They’re expected. In fact, the FDA says these variations are part of what makes biologics work. Some of these small changes might even help the drug bind better to its target. The key isn’t eliminating variation - it’s controlling it. Manufacturers must show that their process keeps those variations within a narrow, safe range - and that the range for their biosimilar matches the reference product.
How regulators ensure safety
The FDA doesn’t just look at one batch. They examine dozens. A biosimilar applicant must submit hundreds of analytical tests comparing their product to the original. These tests look at molecular weight, shape, charge, sugar patterns, and more. They use advanced tools like mass spectrometry and capillary electrophoresis to detect differences as small as one part in a million.Then comes the big question: Does any of this variation affect how the drug works in the body? That’s where functional assays come in. Does the biosimilar bind to the same target? Does it trigger the same immune response? Does it last as long in the bloodstream? If the answer is yes across multiple tests - and if clinical trials show no meaningful difference in safety or effectiveness - the FDA approves it.
For a biosimilar to be labeled interchangeable, the bar is higher. The company must prove that switching back and forth between the reference product and the biosimilar doesn’t increase risk or reduce effectiveness. That means running studies where patients alternate between the two drugs over months. As of May 2024, 12 biosimilars in the U.S. have interchangeable status - meaning pharmacists can swap them without needing a doctor’s OK.
What this means for labs and testing
Lot-to-lot variability isn’t just a problem for drugmakers. It’s a headache for labs too. When a hospital changes the reagent lot for a blood test - say, to measure HbA1c for diabetes - the new lot might give slightly different results. A 0.5% shift might not sound like much, but for a patient whose HbA1c is hovering at 7.0%, that could mean a misclassification from “well-controlled” to “poorly controlled.”Lab directors report that 78% of them see lot-to-lot variation as a significant challenge. Why? Because quality control materials don’t always behave the same way as real patient samples. A control sample might look fine with the new lot, but patient results could drift. That’s why labs run verification studies using 20 or more patient samples, often with duplicate tests. They track results over time using moving averages - a method first used in the 1960s and still the gold standard today.
Smaller labs struggle the most. Verifying a new reagent lot can take up to 20% of a technician’s time each quarter. For a busy lab, that’s hours diverted from other critical work. But skipping verification? That’s risky. Undetected variation can lead to misdiagnoses, incorrect dosing, or unnecessary treatment changes.
Why this matters for patients
If you’re on a biologic - whether it’s the original or a biosimilar - you might wonder: What if my next refill is a different lot? Should I be worried?The short answer: No. The system is built to handle this. Every lot - whether it’s the original drug or a biosimilar - goes through the same strict controls. The FDA requires manufacturers to prove that their product performs consistently across all lots. Clinicians have been switching patients between lots of the same biologic for decades without seeing safety issues.
But there’s a catch. If you’re on an interchangeable biosimilar, you can be switched at the pharmacy without your doctor’s involvement. That’s by design. It’s meant to lower costs. But if you’ve been stable on one product for years, some doctors still prefer to keep you on the same one - just to minimize any potential disruption, even if the science says it’s safe.
Patients should know: Biosimilars aren’t cheaper because they’re lower quality. They’re cheaper because they don’t need to repeat every single clinical trial the original drug went through. The science behind them is just as rigorous - just more focused on proving similarity, not starting from scratch.
The bigger picture: Where this is all headed
The biosimilars market is growing fast. In 2023, it was worth $10.6 billion. By 2028, it’s expected to hit $35.8 billion. More than 32% of all biologic prescriptions in the U.S. are now filled with biosimilars. That’s saving billions in healthcare costs.As biologics get more complex - think antibody-drug conjugates, cell therapies, gene therapies - lot-to-lot variability will only become more important. These next-generation drugs are even harder to manufacture. But the tools are getting better. New analytics can detect changes we couldn’t see five years ago. Regulatory agencies are adapting their guidance to keep pace.
The future isn’t about eliminating variation. It’s about understanding it, measuring it, and managing it. The goal isn’t perfection - it’s predictability. Patients deserve consistent outcomes, whether they’re taking the original biologic or a biosimilar. And thanks to decades of science and regulation, they’re getting it.