How Hard Can It Be?
There’s a common misconception that manufacturing a medicine can be relatively straightforward – you initiate a series of automated steps and a product comes out. In reality, the process is incredibly complex, especially for a class of medicines called biologics. It’s a black box that is rarely explored outside the walls of companies like ours that make biologics.
Biologics, such as therapeutic antibodies, are made in living cells and are thousands of times larger and more complex than relatively simple molecules like aspirin.
The complexity of biologics inherently affects the complexity of the manufacturing process. Producing certain types of biologics can sometimes take up to 18 months, with different components of the molecule traveling over 18,000 miles to be properly assembled.
In addition, the fact that biologics are produced in living cells poses a number of interesting challenges. For example, no two living systems are exactly the same as they're prone to natural variation.
And therein lies the challenge. While we have the ability to use nature’s toolbox to make targeted, biologic medicines for some of the world’s most devastating diseases—from cancer to cystic fibrosis to heart disease—we have to constantly deal with nature's inherent variability.
It is this challenge that makes manufacturing biologic medicines such a fascinating and complex pursuit.
Producing a biologic can take up to 18 months with different components of the molecule traveling over 18,000 miles to be properly assembled.
The Process Defines the Product
Up to half of a regulatory application for a new biologic is focused on the manufacturing process. That’s because regulatory authorities like the U.S. Food and Drug Administration (FDA) or the European Medicines Agency (EMA) are not just licensing the product, but the exact manner in which it is manufactured. Different process conditions can result in different product characteristics. In other words, the process truly defines the product.
Here are the main steps involved:
- Cellular Programming - The first step in manufacturing biologics is genetic engineering. We introduce a sequence of DNA into the cell which acts as an instruction manual for the cells to create the intended biologic. We then use this single cell to generate thousands of identical copies called a “cell line.”
- Population Boom - To begin production, a small vial of a particular cell line is thawed and allowed to grow in a controlled environment for a few days. Our goal is to expand the cell population into the trillions. When the cells grow to sufficient numbers, they are transferred to large-scale production tanks and grown for approximately another two weeks.
- The Harvest - At this point we’re ready to harvest and purify the biologic we’ve created. We need to separate the biologic from cells, unwanted proteins, and other process-related impurities. Purification is a multi-step process and it varies from one biologic to another. By the end, we’ve purified our target biologic 1,000,000-fold. It is this level of purification that makes the biologic pure enough to be used as a medicine after processing. There are many places where this process can go wrong and each step needs to be exquisitely controlled and tested to ensure the consistency of the final molecule.
Let’s take a closer look at the cell culture step as an example of the complexity.
Creating Order Out of Chaos
In a single 12,000 liter bioreactor, more than 100 trillion cells are working side by side, acting as tiny factories to produce a biologic. This number is so large it’s hard to compare it to anything, but it’s more than 1,000 times as many cells as our entire galaxy has stars.
When dealing with numbers this large, even a little variability can create problems. But the reality is that not all of the cells are the same and not all of them can do the same thing every day. So how do we manage it?
It starts with rigorous control of the cells’ environment. The food for our cells has nearly 100 different starting materials; the way those raw ingredients are combined can make a huge difference. We also have to consider how the effects of oxygen, temperature, pressure, and other variables change as we scale up production. It’s often not simple multiplication—results at one end of the scale don’t necessarily predict results at the other.
Age is also important. Just like people, cells slow down as they get older. We need to find the sweet spot of productivity in the life cycle of our cells, which can be different depending on the biologic.
To create order in the face of all these challenges, our teams have developed an interconnected infrastructure, called platform technologies, that ensures consistency in the safety and quality for every biologic we make. We have also developed sophisticated technologies to help us analyze, characterize and ultimately control the quality of our biologic products. We are constantly working to make sure that our technology is state of the art. This ensures we can reliably supply our medicines in sufficient quality and quantity to patients around the world, from the moment we receive DNA from our researchers until the time we package medicines for use.
From DNA to IND
Given the inherent challenges in manufacturing, our work and processes start from the very beginning of a medicine’s journey towards regulatory approval – not towards the end. We are deeply involved with our teams in Genentech Research and Early Development (gRED) and Roche Pharma Research and Early Development (pRED) to help design and characterize multiple forms of the initial biologic and advance the right ones into clinical trials. We also work with Genentech Partnering on licensed molecules.
After FDA Approval
Manufacturing isn’t a static set of instructions, it’s a scientific process. As such, we are always looking for new ways to improve efficiency and plant productivity, shorten process times, and deliver the purest possible medicines to the people who need them as fast as possible. We need our biologics to be ready on Day 1, whether that means for a clinical trial or for a person who is waiting for it after it's first approved.
Only 5 years ago, it took us anywhere from 18-24 months to go from the genetic engineering stage to where we could file an Investigational New Drug (IND) application with the FDA to begin clinical trials. With rigorous manufacturing science, we have now been able to cut this time down to 15 months. Our new goal is to do it in less than a year, in order to start the clinical trials of promising investigational medicines as fast as possible.
The biotechnology revolution that started at Genentech has changed the entire landscape of medicine. Just 30 years ago, we struggled to produce even grams of antibodies every year. Today, we produce more than 10 metric tons of biologics annually – that’s nearly 20 percent of the world’s biologics.
We are now engineering new types of medicines that go beyond mimicking human proteins or antibodies. We are using protein engineering to make antibody-drug conjugates, bispecific antibodies, antibody-antibiotic conjugates, and antibody-cytokine fusions. Each one requires its own scientific exploration and manufacturing process.
Making biologics is far more complex than most people realize. But it’s also far more interesting. Every day we are working to produce some of the most advanced therapies in the history of medicine. And, as ever, our goal of putting patients first is what drives these innovations.