Top biopharma companies are starting to focus on complex generics as the simple generics market is becoming increasingly congested.

Examples of complex generics are:

1. Products with complex active ingredients, formulations, routes of delivery, dosage forms.
2. Complex drug-device combination products.

Each of these requires a higher level of expertise than is required for simple generics development, deeper understanding of the regulatory, quality and safety requirements, and a sophisticated go-to-market strategy. This blog focuses on fermentation technology which is used to produce many complex generics.

This blog is part a full whitepaper on complex generics.

The Background

The fermentation segment is a key part of a pharma company’s portfolio. APIs obtained by fermentation can be used in several therapeutic areas, including:

• Antibiotics
• Anti-fungal drugs
• Anti-cancer drugs
• Cholesterol-lowering drugs
• Immunosuppressants
• Special drugs, including those used against Parkinson‘s disease, dementia, hemochromatosis

Besides fermentation-based APIs production, fermentation technology also supports biocatalytic development through enzyme fermentation.

The Challenges of Fermentation

• Robustness issues: Fermentation involves dealing with living organisms, as well as raw materials that come from agriculture. It is not always easy to predict how these will react. For example, one batch of raw materials can be very different from another batch. A drug manufacturer therefore needs to be fully equipped to deal with problems associated with robustness.
• A lengthy process: The entire fermentation process is extremely long from beginning to end, much longer than with synthetic APIs. This is true both in terms of development and lead time.
• High-complex compounds: Fermentation is not a simple process – the right expertise is needed and the right equipment. Due to this, fermentation-based APIs can be complicated and expensive to produce.
• Sterile facilities: Under no circumstances can a fermentation facility become unsterile. If contaminant microorganisms enter the bioreactor, there will be undesired competition for the nutrients, leading to poor yield. Keeping large fermenters sterile is no easy feat.

Capabilities Needed for Successful Fermentation

A high level of expertise is needed for an API to be successfully fermented. For example, the Teva api sites in Europe have a long history in pharmaceutical purpose fermentations, with over 60 years of practice in this field.

Synthetic products require mainly expertize in engineering sciences and chemistry. However, for APIs obtained by fermentation, the biology aspect is crucial, especially microbiology.

And when developing even more specialized fermentation-based APIs, other disciplines are needed aside from basic biology. These include; molecular biology, computer science, process control, bioinformatics, statistics, robotics, and so on.

To remain competitive, a drug manufacturer has to use the best available equipment to get the best productivity. At Teva api, the Biotechnological R&D microbiological Lab has a Biolog Phenotype microarray system to characterize the microorganisms in a high throughput and automated manner.

The molecular biological Laboratory has DNA isolator robot, to facilitate the parallel separation of cellular components and NanoDrop a special spectrophotometer, which is able to handle very small volumes.

Fermentation & the Teva api Advantage

Fermentation-based APIs are an important part of Teva api’s portfolio. In fact, many of Teva api’s top products are fermentation-based APIs. An example of such a top product is Mupirocin, an antibiotic used to treat certain skin infections which is on the World Health Organization’s List of Essential Medicines.

These microorganism originated drugs are produced in our EU sites. The R&D team deals with new product development and lifecycle management as well.

In products that are already commercial in Teva api, they are able to improve the producer strain by classical and molecular biological tools as well.

The commercial product strain developments make a significant contribution to the competitiveness of the APIs, because a large reduction in raw material costs can be achieved by these activities — approximately 20-50%.

Recombinant Tools

New methods are continuously and successfully being implemented in the field of biotechnology.

An example of this is the application of recombinant tools, where we have the capability to introduce foreign genes to cells. This is also beneficial from enzyme technological point of view.

These recombinant hosts are able to produce efficient and environmental friendly enzymes to replace certain ineffective synthetic production steps. The internal enzyme preparation has a great advantage, because its cost is 70-95% lower than the commercial ones.

Certain enzymes also aren’t available at all commercially. Our R&D Center of Excellence has the capability to screen, select, produce, purify and finally apply the different biocatalysts.

Our latest achievement in this field was the successful evolution of transaminases, which in essence means that despite the lack of specific enzymes on the market, we were able to develop such enzymes that perform these specific reactions by enzyme-engineering with high activity and perfect enantioselectivity.

High Throughput Screening (HTS) platform contributed substantially to the success of enzyme development. Colony Picker Robot and Pipetting Robots facilitated the fast and effective screening of the mutated protein candidates.

This equipment has been recently complemented with an up-to-date RapiFire MS device, which expedites the sample analysis in a way never seen before.