Developing a Better Process is Only the Start

Researchers must show grit to get a pharmaceutical plant to adopt a novel approach

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This Month’s Puzzler

We manufacture astaxanthin by fermentation and decided to switch from spray-drying to freeze-drying or lyophilization because freeze-dried astaxanthin is 41% more active than the spray-dried version and can be stored without refrigeration.

A block flow diagram developed by project engineering summarizes the proposed design (see figure); the process involves sterilization, low-temperature drying in a turbo tray dryer followed by freezing and drying in a series of tray dryers ending with a belt dryer.

The design has evoked a lot of criticism. Production complains it’s too complicated and will make it hard to keep the product sterile. Corporate management says we can do away with the sterilization because the freezing process will eliminate bugs. The construction manager argues that maintaining a vacuum between the dryers and even in the dryers themselves will be tough: he suggests going with multiple batch dryers instead. Research counters that the continuous dryers will produce a more-consistent product, even more so than the spray dryers, which are batch. Our safety manager is concerned about dust in the belt dryer. What do you think of the design?

Kudos For Research

I have to applaud the research team for taking a bold step in developing a process that saves the company significant money that is pure profit. In addition, research is taking a nontraditional step for the pharmaceutical industry.

Research’s suggested process should produce quality product and minimize or eliminate the current practice of quality by repeated analysis. This will have substantial impact on the total operation and profitability of the company.

However, to get to that point, research will have to do significant selling, hold hands and demonstrate their concepts will work. They will have to test their concept using commercial versions of their equipment. They will have to guide their colleagues every step of the way and answer every question posed. In addition, after the process has been commercialized, they will have to train, stay in touch with and assist operations until it has mastered the process. All this is not going to be easy but is the only way to take the company to the chosen innovative path.

From my experience, I suggest that research and corporate should consider the following:

1. Show operations how the concept works in the laboratory or at a pilot plant.
2. Design, demonstrate and construct a process that does not pose any issues raised by the construction manager. Address every eventuality from the get-go.
3. Train operations and develop answers to every possible challenge.
One of the hang ups that construction and operations have is their lack of familiarity with continuous processes in pharmaceuticals. They are used to batch processes. Continuous drying is alien to them. But a win will be a win for all. I wish you lots of luck as the journey will be a game changer.
Girish Malhotra, president
EPCOT International, Pepper Pike, Ohio

Use A Bench Test For Buy-In

If the process works, the possibilities are endless. Imagine eliminating refrigeration systems for bio-products while also producing a more-active product. On the negative side, production is concerned because they don’t understand how all the wheels and levers work. Maintenance is trying to figure out what new hassles they’ll face.

The fly in the soup is that dryers can’t be easily bench-tested. Fortunately, you’ve still got a spray dryer to fill in while the new process is built and tested. Because this hasn’t been done before, the prototype should be as small as possible but still large enough to handle the fermenter load. Fortunately, Astaxanthin has a fermentation cycle of 10 days so there is time for testing.

As for each of your questions: 1) No, freezing is not a substitute for sterilization; 2) vacuum maintenance is tricky; 3) dust control in dryers is always a fire risk; and 4) batch drying is always easier.

Cells are hardly ever killed by freezing. This idea was tried a century ago with worm-ridden meat and hundreds were infected. Sterilization is a delicate matter. You may find that cell activity goes down significantly. This is an area for future optimization: lower the temperature as much as possible to reduce refrigeration costs and to save cell activity. In autoclaves for steam sterilization, time and temperature are inversely related: reducing the temperature lengthens the required dwell time.

Another idea to reduce operating costs is to recover some heat from the first dryer and re-use it during the freeze-drying after refrigeration. In addition, the Freon chillers could be optimized to improve efficiency and cut costs. Some heat could be recovered from the vent refrigeration systems as well. The margins are very low based on studies I’ve looked at.

Vacuum leaks will plague this process. For that reason, the dryer equipment must be over-sized a little to compensate for leaks in other dryers. Freeze-drying works by replacing vacuum for heat to reduce the thermal stress the product goes through during the drying process. The best approach is to isolate sections to avoid one leak from affecting the entire process. A good placement of vacuum pressure transmitters also will help.

Watch out for dust build-up. Dust control is mainly a problem at the end of a process. You may find it necessary to put the belt dryer at the end under pressure to prevent dust from accumulating around the belt. Pressurizing would allow the use of an N2 blanket of a few millimeters of water column to prevent a flammable dust mixture from igniting and allow dust collection to function.

Astaxanthin is a highly combustible dust. We had several fires with a spray dryer but the dryer wasn’t set up very well and there was poor housekeeping. Dust and powder accumulated and auto-ignited in dryer ducts.

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