Engineering excellence: Scaling up antibiotic production

Up to 250,000 litres capacity per tank, up to 400 tonnes of active ingredients per month. Scales that rarely occur in fermentation for the manufacture of pharmaceutical products: In order to enable the supplier-independent production of an antibiotic, Virchow Petrochemicals built a huge plant in India for the in-house cultivation of Penicillin G. Bürkert contributed its industry expertise from the very beginning. With optimised valve design and automated processes, the active ingredient manufacturer was able to maximise yield and reduce costs without compromising process reliability and sterility.

From small to (very) large

Virchow Petrochemicals manufactures Penicillin G (benzylpenicillin), GCLE and cephalosporin to supply medication mainly to India. Initially, the production of Penicillin G was tested in a pilot plant. Following the successful operation of the prototype, the scale-up followed just a few years later: 400 tonnes of benzylpenicillin are to be produced per month with the new production plant in the final stage. In the beginning it will be 200 tonnes per month. “No one in India has ever installed a plant of this size before,” explains Vamshidhar Reddy Kallem, Managing Director of Virchow Petrochemicals.

Highest production quality

Stable and economical production processes with a high yield were required for the plant. To this end, Virchow Petrochemicals compared the solutions of numerous equipment suppliers.

The decision was ultimately made in favour of Bürkert. However, it was not only the product quality and the recommendation of the pilot plant manufacturer, who also relies on Bürkert, that were decisive. The broad product portfolio, which includes standard diaphragm valves, custom-made hygienic block solutions, flow and level measurement devices as well as pneumatic valve islands for process automation, also contributed to the decision.

Local fermentation expertise

However, the most important argument for the active ingredient manufacturer was Bürkert’s in-depth technical knowledge in the field of fermentation processes: “We received full support on site from day one. Bürkert also helped us with the complete process planning and the piping and instrumentation diagram. The know-how of the experienced experts extends far beyond valve technology and also includes other applications such as automation. In a project of this dimension, it is extremely helpful to have a local team of experts available on site who are always on hand,” Mr. Reddy confirms the decision.

Rapid realisation

Only two and a half years passed from the initial planning to the acceptance of the huge production plant, which is located around 90 kilometres from the Indian city of Hyderabad. Impressively fast for a plant of this size, as the Managing Director emphasises. The plant is home to eight seed fermenters, nine tanks for pre-fermentation and nine main fermentation tanks. The tanks have a capacity of 30,000, 150,000 and 250,000 litres and are up to 18 metres high. “We built the tanks directly on site. Transporting them would have been impossible due to their immense size,” explains Vamshidhar Reddy Kallem.

From cultures to powder

The entire production process for a batch takes around ten days: once the Penicillin G cultures have been prepared in the laboratory, the inoculum is dosed into the cultivation fermenters. Here the cultures grow for around 30 hours in a controlled environment. Preparation for production begins in the following pre-fermenter tanks. Enzymes are added and the cultures multiply here for around 80 hours. In the final step, the end product is produced in the main fermenter tanks. The cultures remain here for 100 hours in a controlled environment. The end product then undergoes a filtration, extraction, crystallisation and drying process and is converted into pure Penicillin G powder. This is then transported to the API plant where the cephalosporins are produced.

Consistently reliable production

Any interruption in the fermentation process would be disastrous: “Fermentation is a very sensitive process, and when it comes to plants of this size, we are particularly careful to ensure that no batches are lost. A reliable energy supply is therefore essential for all process steps,” says the Managing Director. To ensure consistently stable processes, Virchow Petrochemicals has set up its own power supply, which includes a 14 MW gas turbine and a photovoltaic System with a capacity of 11 MW. Diesel generators are used as a backup. “But at least as important for reliable production as a continuous power supply are stable production conditions during fermentation. And this is where Bürkert comes in,” adds Vamshidhar Reddy Kallem.

Welcome to the showroom!

Bürkert solutions can be found in all stages of the fermentation process. Particularly outstanding are the 75 FLOWave flowmeters of type 8098, which are used in line sizes with ½ inch and 1 inch for measurement of phenylacetic acid for pH correction as well as for measuring sucrose solutions. The compact size and low weight of the flow meters allowed them to be installed flexibly and easily. Devices that can be fully integrated into the Siemens environment also proved to be very helpful in setting up the plant: “The communication interfaces provided by Bürkert saved us a lot of work in developing and setting up the automation,” the Managing Director of Virchow Petrochemicals is pleased to report. 

Also used in the sucrose solution supply are type 8802 diaphragm control valves and type 3233 manual diaphragm valves. These are also utilised in the ammonia dosing line, where they are supplemented with type 8756 mass flow controllers and type 2031 diaphragm valves. Over 2,000 pneumatic diaphragm valves ensure efficient and safe processes during media transfer between the tanks. “The flow rate is around 40% higher compared to solutions from other manufacturers, which leads to a significant increase in production capacity,” explains Santosh Antony, Area Sales Manager India at Bürkert. In the overall plant, more than 70 specially developed hygienic valve blocks with minimal dead space are used, with valve body sizes ranging from 6 to 12 inches.

In addition, 400 type 2671 butterfly valves with type 8791 side control positioners and integrated diagnostic functions for Valve monitoring reliably regulate the flow. Over 20 type 8007 gas flow meters supply the sparger in the fermenter with the necessary air via large pipes with diameters of 4, 8 or 10 inches. The filling level in the fermenters is precisely determined using over 40 contactless type 8139 radar level meters. CIP/SIP-compatible type 8802 globe valves with excellent chemical and temperature resistance ensure reliable cleaning after fermentation.

Clear commitment

The demand for Penicillin G continues to grow. Virchow Petrochemicals is already thinking about further production plants. “We got to know Bürkert as a trustworthy, competent and reliable partner who accompanied us on an eye-level throughout the project. The first project of this size in India brought numerous challenges with it. Thanks to the great Team effort, we were able to overcome all hurdles. That is why Bürkert is also our partner of choice for the next plants. We are in good hands here,” the Managing Director is convinced. By the way: With the modern Systemhaus in Pune, Bürkert offers its customers in India extensive local production capacities and engineering expertise.

What does it take to manufacture pharmaceutical active ingredients at large scale? Watch now!