Peptides in stable form: Ice-cold dried

Freeze-drying for sensitive molecules

Biopharmaceuticals are often unstable liquids and therefore have poor shelf life. This includes the raw materials, such as peptides and olionucleides, which are necessary for the production of important biopharmaceutical drugs. Freeze-drying is one way to bring these sensitive molecules into a stable form. OPTIMA pharma GmbH in Gladenbach, Germany develops and produces these special systems suitable for these active pharmaceutical ingredients.

Frozen, pressurized, heated: This sounds like torture. While in fact, they are actually a daily routine in the manufacturing process for biopharma­ceuticals and many other drugs, providing a gentle method to remove excess water. The result is the required active ingredient in form of a fine powdery substance.

Freeze-drying, known also as lyophilization, is preferred by the pharma­ceutical industry to convert antibiotics, hormones, antibodies, RNA-based vaccines, and many other pharmaceutical drugs into a storable, solid powder form.

“Most patients receive these drugs in liquid form rather than tablets; since the sensitive molecules are not particularly stable in liquid form. They can change in structure and thus lose their effectiveness,” explains Stephan Reuter, Managing Director of Optima Pharma GmbH, Gladenbach, Hesse. The company specializes in the development and production of freeze-drying systems.

Important for you
  • mRNA-based pharmaceuticals are versatile therapeutics with a growing number of application prospects and become more interesting and gain in popularity.
  • Peptide and oligonucleotides are less stable in liquid-form than freeze-dried.
  • The freeze-drying process requires considerable expertise and the systems have to be designed according to peptide and oligonucleotide requirements.
  • Our expertise: Modular freeze-dryer design that is configured to customer process specifications – from laboratory to commercial production.
Gentle evaporation of frozen water

What makes freeze-drying a gentle process? A key aspect is the frozen water that evaporates under vacuum (sublimation) while the temperature is gently increased again. Ideally, only the required product remains, in the form of a fine powder. Another way of extracting a dissolved substance from water is familiar to anyone who cooks: boiling water until it has evaporated. However, this latter approach is anything but gentle. The problem here is that the product will be irreversibly damaged by sustained high temperatures. In addition, not only water will disappear but the required product might change to a gaseous state and is thus lost. “Freeze-drying, on the other hand, is a safe method and proven for converting even sensitive biopharmaceuticals into a stable and storable product,” Reuter says.

Biopharmaceuticals: freeze-drying is preferred

Due to factors like the Coronavirus pandemic, as well as the growing number of biological pharmaceuticals and their transport, demand for freeze-drying continues to increase. Optima Pharma has doubled its production area in Gladenbach, where the freeze-drying equipment is manufactured, and the number of employees has almost doubled since 2014. The company’s export share is more than 85%. With an average growth rate of 7-10%, the company can look optimistically to the future.

Reuter is confident that this positive trend will continue. “Already, about one-fifth of the top 100 pharmaceuticals are freeze-dried, and for bio­logics it’s already almost half,” Reuter says. As an engineer, Reuter has two decades of professional and management experience in the pharmaceutical industry, which provides many insights. He foresees methods for continuous product development. “The demand for freeze drying has also increased the requirements for the lyophilization process itself. As a result, we develop innovative, sustainable and visionary solutions for these needs.”

Peptides are promising pharmaceutical drug candidates

The freeze-drying of peptides, in particular, requires complex production processes and special expertise. Peptides are small proteins, i.e. protein molecules. They consist of several amino acids linked by peptide bonds. Peptides have numerous functions – some act as messenger substances in plants, and others as hormones in the human body. Due to their properties, there are numerous potential applications for these small proteins in molecular biology, immunology and (bio) medicine. Peptides offer a new opportunity for cancer patients, the chance for future individualized vaccines– and thus a promising strategy for an effective therapy. “Peptides are highly effective, and they exhibit high selectivity and specificity with regard to their biological targets,” Reuter explains. “Peptides thus offer a promising prospect for novel drug designs and are of great value.”

FD-CS freeze dryer
Freeze-drying converts unstable macromolecules into a stable state
The fine art of freeze-drying

Due to their great versatility, freeze-drying equipment must be de­signed to meet the needs of peptide production, the final stage that involves solid-liquid separation. “The freeze-dried product they call freeze-drying “cake”, is obtained at our customer’s facility in containers that resemble baking trays,” Reuter says. TThe final stable peptides are then available in milligrams to kilograms as a fine powder and used as active ingredients for the production of various pharmaceuticals.

“There is no off-the-shelf freeze-dryer that completes all requirements. We have to adapt the equipment to the particular pharmaceutical product, according to customer’s requirements and on-site conditions. This is our expertise as a special equipment manufacturer,” Reuter says.

The company is also involved in a promising new area of development: controlled nucleation. The focus is the freezing process that is difficult to control, especially for highly purified products. An irregular freezing process has a corresponding effect on the ice structure. However, con­trolled nucleation is a process that solves this problem: Additional pressure is created in the system and released quickly, resulting in forming very homogeneous ice crystals, while at the same time, accelerating the drying process.


Shorter process times reduce the material consumption – and, above all save energy.

“Despite the benefits offered by freeze-drying, it is, unfortunately, also a very energy-intensive process, and correspondingly costly,” explains Reuter. “After all, the stainless steel systems, which can weigh up to 30 tons, must first be sterilized with steam up to 130 °Celsius, cooled to freezing temperatures down to minus 70 °Celsius, placed under vacuum and then reheated to 130 °Celsius again, to start the process. This is the only way to achieve the desired temperatures inside,” Reuter adds. “As a result, drug manufacturers are often reluctant to consider this technology for their products.”

However, refrigeration technology and new high-performance cooling agents, yield significant savings: Using a dedicated refrigeration system lowers energy consumption. In addition, new innovative cooling agents also save 10 to 20% in energy. Considering the savings from shorter process times, freeze-drying systems today consume up 25% less energy than before these measures were implemented.

Phase diagram with transitions of the states of aggregation using the example of water
Phase diagram with transitions of the aggregate states using water as an example: Representation of the sublimation and melting process.
Focus on medical trends

Optima Pharma is also working to establish alternative cooling agents and to create more sustainable and environmentally friendly techno­logies (see article on pages 24 to 29). New trends in the pharmaceutical industry are an additional reason for new developments. For example, personalized medicine, mRNA and cell and gene technologies.

“These changes influence the production facilities of drug manufacturers, which require fewer large systems, but rather produce marginal and with smaller equipment,” Reuter says. “Analogous to batch sizes, biopharma­ceutical drug companies tend to install smaller freeze-dryers, and often multiple freeze-dryers at the same time. Even hospital pharmacies are interested in our systems.” As a result, the footprint per freeze-dryer or the number of units is a key factor.

Today’s freeze-drying process has become much more energy-efficient and more diverse than it was just a few years ago. Optima Pharma has made it a priority to keep an eye on evolving industry trends and to develop new process technologies accordingly – thus making an important contribution to innovative, high-quality pharmaceuticals.

Stephan Reuter, Managing Director at Optima Pharma
Stephan Reuter, Managing Director of OPTIMA pharma GmbH
We have to adapt the equipment to the particular pharmaceutical product, the customer's requirements and on site conditions. This is our expertise as a special equipment manufacturer.
Stephan Reuter, Managing Director of OPTIMA pharma GmbH
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