How Biologic Drugs Are Made


In recent years, a number of biologic drugs have become available to treat Crohn’s and Ulcerative Colitis: Remicade, Humira, Cimzia, etc. — with many more in development. What makes these drugs ‘biologic’ is the way in which they are produced. Warning: it’s a bit weird, and may be disturbing to some readers.

‘Biologics’ are different from most drugs, in that most drugs are made through basic chemistry. Making a drug like prednisone, for example, only requires the right chemicals, and the equipment to mix them properly. That’s because prednisone and similar drugs are relatively simple molecules.

Biologic drugs are based on very complicated molecules — usually antibodies. Antibodies are used by the immune system to attack invaders like viruses and bacteria. Biologic drugs create counterfeit antibodies to trick the immune system. When a drug’s generic name ends in ‘mab’, that stands for ‘monoclonal antibody’: so Remicade is infliximab; Humira is adulimumab; Entyvio is vedolizumab; and so on.

Remicade and Humira, for example, are antibodies against TNF — a molecule that is a normal part of a healthy immune system. In inflammatory disease, the body produces more TNF than it should; biologic drugs like Remicade fool the immune system into getting rid of some of its own TNF molecules. Entyvio is an antibody against a different immune system molecule, integrin α4β7, that is especially important in gut inflammation.

Antibodies are made by living cells — for example, the cells in your immune system. But to manufacture antibodies at commercial scale, your body’s immune cells aren’t sufficient. Instead, scientists have to identify appropriate cell lines that are ‘immortal’ or can be made immortal. Immortal in this sense only means that the cells will reproduce indefinitely, where most normal human cells will only reproduce so many times before they stop.

The only cells in your body that are immortal in this sense are cancer cells. Cells from tumors are an important source of cell lines for biotechnology. For example, in the book, The Immortal Life of Henrietta Lacks, the cells cultured from Ms. Lacks’s cancer tumor were ‘immortal’ in that they reproduced indefinitely. Some cells used in biologic manufacturing come from mouse (‘murine’) tumors.

Cells can also be made ‘immortal’ by changing their DNA to make them more like cancer cells. This is done by using a modified virus to introduce new DNA — that is, genetic engineering. This technique has been used to make cells from Chinese hamster ovaries and fetal human retina into useful biotech cell lines. Scientists are also developing ways to make biologic drugs using bacterial cells, like E. Coli.

The next step is changing the cells to make the appropriate antibody. In some cases, that means injecting the cells with the antibody target, and letting it make antibodies naturally. More likely, it involves further genetic engineering. Extra DNA is introduced to the cell, to try to get it to make the correct antibody. Because non-human cells make non-human antibodies (which the human immune system recognizes as foreign), those cell lines have to be designed to make partly or fully human antibodies.

Partly human antibodies are usually called ‘chimeric’ antibodies. Remicade (infliximab) is a chimeric antibody, made from mouse cells that have been engineered to make human-like antibodies. The resulting antibody is about 30% murine (mouse) and 70% human. The murine part is why people  develop allergic reactions to Remicade.

A lot like a mouse, really.
Cricetulus griseus, the Chinese hamster

Humira (adalimumab) is a fully human antibody, but it is made using Chinese hamster cells. In this case the researchers have been able to design a genetic sequence that makes a fully human antibody, without using any DNA from the hamster cell itself in the sequence. Because the product of that process looks like a regular human antibody, reactions to Humira are less common. The key point here is that even ‘fully human’ antibodies can be made by not-fully-human cells.

Once a cell line has been engineered, the researchers look for the cells that grow best and produce the most of the antibody. The best cells are chosen to be cloned — that is, allowed to reproduced identical copies — and put into ‘bioreactors’, stainless steel containers of about 3 to 6 liters. A bioreactor provides the right environment for the cells to grow and produce the desired antibody. Bioreactors have to maintain parameters like temperature, PH, dissolved oxygen, and many more, to make sure the cells have the best conditions for growth.

After the cells have been allowed to grow for a while — for Humira, that takes 15 days — the bioreactors are processed to purify the antibody. No live cells should make it into the finished product, unless something goes wrong. However, some DNA or DNA fragments will make it into the medicine, simply because they are too small to purify out. This DNA poses no real risk to the patient, in any case.

As you can imagine, all of the above techniques and steps are more expensive than plain chemistry, which is one of the reasons why biologic drugs are more expensive than most other medicines. But  biological drugs are a relatively new technology that allows researchers and manufacturers to create medicines with the potential to be far more effective at treating some diseases — especially autoimmune diseases — than previous methods allowed. And as the technology progresses, it should become less expensive and even safer.

The main source for this article was Li, Feng; et al. “Cell culture processes for monoclonal antibody production”. MAbs 2:5 (Sept – Oct. 2010). Available free here.

Other sources included:

“‘Designer’ Cells as Substrates for the Manufacture of Viral Vaccines”. FDA 2001,

Martinez, de Lagran, Z; Perez-Barrio, S; & Diaz-Perez, JL. “Adalimumab: la molecular y el proceso de obtencion”. [Adalimumab: the molecule and the manufacturing process] Actas Dermosfiliogr. 99 Suppl. 3 (Feb 2008). Available for free here.

European Medicines Agency. “Scientific Discussion” [Remicade].

European Medicines Agency. “Scientific Discussion” [Humira].

HeLa cells photo “HeLa cells stained with Hoechst 33258 stain” by TenOfAllTrades used and modified via Wikipedia.

Chinese Hamster photo “Chinesedsaffa” by Tristanspotter via Wikipedia:



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