Manufacturing APIs is a complicated procedure and requires all sorts of different technologies to do it properly and to do it safely.

Here’s a brief overview of what types of APIs we’re developing and manufacturing at Teva api, and what technologies we use for them.

Chemically synthesized APIs

At Teva api we mainly produce chemically-synthesized products. This is where a few components are taken and put in a huge reactor to produce a liquid. It’s then made in to a ready powder, by filtering, crystalizing, and drying the product.

The last stage in the process is milling, where we break down the API to reach the particle size the customer needs. This last step is a critical parameter for formulation, particularly for oral doses such as capsules and tablets.

Biological processes

Teva api also uses biological processes to make APIs. This is where live cells are used – mainly microbial, fungi, and yeast. These are specific bacteria that are genetically modified in order to produce the APIs, and they require fermentation.

The fermentation process occurs in a huge vessel that is fully controlled – we need the yeast or bacteria to stay alive while the fermentation is happening, and then we need to remove it using same filtration process used by chemically-synthesized APIs.

What are high-potent APIs?

High-potent APIs are made in small concentrations with a very high efficacy. Just a few milligrams of the API can be used in a drug product and it will be very effective.

But producing these APIs can be hazardous and damage the health of the people making them. This means that all the manufacturing lines need to be adapted so that the workers aren’t exposed to the API. There cannot be any leakages or powder in the air.

APIs are classified in terms of how hazardous they are and how many milligrams of the product can be exposed at any given time. These products are made in a fully covered system so that the workers don’t inhale anything.

They wear protective gear and use glove boxes or isolators when dealing with high-potent APIs.

The reactor

The first step in making any sort of chemically-synthesized API, is the reaction. This is where we take raw materials and solvents and create the API. A reactor can contain hundreds or thousands of liters, depending on the scale of the API. The impellor mixes it all.

It’s a closed system so everything is fed from outside of the reactor. This is for a dual purpose – to keep the workers safe and to prevent the material from becoming contaminated.

The bio-reactor

From the outside, the bio-reactor looks similar to the reactor. The main difference is that everything in the bio-reactor is monitored extremely closely, simply for the reason that we’re dealing with live cells.

The microbe itself needs to be sustained until the fermentation stage is over. Therefore, the oxygen levels, temperature, pH are all measured throughout the process. If anything needs to be added, it’s done with an automatic feed into the reactor.

Filtration technology

Two main tools are then used to extract the API from the solution. These are the centrifuge – where the liquid is put into a big box and spins really fast until all of the liquid is extracted and the API is left, and the filter dryer – which instead uses compression to extract the API.

Filter dyers work very well with high-potent APIs and can be fully contained. The liquid that is extracted goes in to a separate vessel so that nothing is leaked. A filter dryer not only extracts the liquid, but also dries the API which is anyway the next step in the process.

Drying Technology

Each API has very strict specifications as to how much solvent can remain inside it. It’s therefore dried to meet the specifications.

If a small volume needs to be dried, a tray dryer is used. Air comes in and the solvents evaporate. It’s also a fully closed system.

Agitated vacuum dryers act by pulling out the air. It mixes the API while it does this, helping to have a more homogenous drying procedure. This is useful when drying hundreds of kilos together as it is effective in reaching all the product.

Other drying methods are less common but used in specific cases. For example, for amorphous polymorphs, spray dryers are used.

When the API is really heat sensitive and it cannot tolerate 40 or 50 degrees, it’s dried using a freezer dryer with a process called sublimation. The material itself is frozen to -40 or -50 degrees and it’s sublimated from ice to gas.

Milling

The last step in the process of making an API is milling. What’s left after the drying stage is an fairly big API. Particle size and conformity among batches are both extremely important to customers.

We decide on which technology to use depending on what size particle is needed. This could mean that gentle milling is used, which breaks down the particle a bit (this looks a lot like a kitchen mixer). Or, the size could be reduced with a knife which cuts the particle into small pieces (this looks like a food processer). When very small particles are needed –- below 10 microns for low solubility — we use multiple knives and a lot of energy to cut and break the particle. This is called micronization.

For more information about our technologies, processes, or specific APIs, please contact us.