Monday, January 9, 2012

How To Make Biologics

Drugs used in modern medicine are manufactured with mammalian cell culture.

Why Mammalian Cells?

Humans have been making therapeutic biological molecules utilizing fermentation since Alexander Fleming sneezed into a Petri dish and discovered penicillin. But complex biological molecules, like antibodies, cannot be produced by microbes because microbes cannot do post-translational processing. Post-translational what?

Basically when our bodies construct a human protein from the things we eat, our cells will "sign" the newly created protein with a carbohydrate. This "signature" not only helps the protein fold, but also helps our bodies recognize the protein as self-made. Microbes do not have the machinery to do this post-translational glycosolation such that proteins made by them simply unfold and lose their therapeutic value.

What is Cell Culture?

Cell Culture refers to the cultivation of (typically mammalian) cells. The reason companies use mammalian cells is because the active pharmaceutical ingredient (API) in drugs are complex molecules that cannot be made with chemical synthesis and also needs post-translational processing. To make the API, firms genetically engineer cells to secrete the complex molecule. Cell culture is the art/science/process of growing mammalian cells in at a large-scale so the purified API can be sold.

Inoculum/Seed Cultures

The first of two parts in cell culture is growing a sufficient amount of cells.  You'll hear people say, "scale biomass" when referring to "seed" or "inoculum" cultures. Note: we've assumed the cells have been engineered and are stable. The goal is to get as many cells in as short a time as possible - i.e. get fast growing cells. To do this, you get some cells and put it in a large volume of nutrients at growth-promoting pH (somewhere near 7) and temperature (between 30 to 40 degC). The cells will grow, consuming nutrients and secrete metabolic waste (CO2 and lactic acid etc). To keep the cells growing, you must replenish their nutrients or remove the waste.  Companies do this by transferring the cells to a larger bioreactor;  the classic "solution to pollution is dilution."

Production Cultures

The second and final part in a cell culture cultivation is having the cells secrete the API. After all, your sales comes from the API, not the cells themselves. The cells get their final transfer into a bioreactor with nutrients that encourage the secretion of API. The bioreactor is typically called the "production bioreactor" and the nutritious fluid is typically called "production media." After the cells produce the API, the cells are typically discarded while the API is "harvested" for purification - a.k.a. "downstream processing".

One Unit Operation

Many in the downstream world (Rob Caren) like to take pot-shots at cell culture scientists and engineers and ask, "How hard can this be? There's just one unit operation, right?" Sure. But on a large-scale, very few things in cell culture are well understood, which is why armies of chemical engineers are hired to do multivariate data analysis on cell culture.

So in addition to providing this brief primer on mammalian cell culture, the reason I'm putting this out there is that the ultimate goal of the data acquisition is to enable multivariate analysis that confers process understanding. This is something that Zymergi engineers, given our first-hand experience supporting large-scale cell culture processes, are able to do.

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