A history of lyophilization in pharmaceutical applications: control and monitoring, accuracy, and reproducibility continue to define the lyophilization process, thus enhancing product aesthetics, stability, and reconstitution

A history of lyophilization in pharmaceutical applications: control and monitoring, accuracy, and reproducibility continue to define the lyophilization process, thus enhancing product aesthetics, stability, and reconstitution
Feb, 2004
by Timothy Smith
Pharmaceutical Technology
FindArticles
Nearly 70 years ago, lyophilization began to change the way scientists developed food products and drugs. Since then, the use of lyophilization has resolved several problems in the food and pharmaceutical industries. However, from a process point of view, lyophilization also has created some challenges.
Application history
Early uses of freeze-drying involved the naturally occurring processes of freezing and dehydration. For example, residents of the Andes recognized the phenomenon and used it to preserve vegetables. Other references cite the industrial application of freeze-drying in the 1920s, forecasting it as a means of preserving grain crops and other foods on a large scale. The basic process has been used at least since the 1930s for commercial purposes. Several theoretical applications also have been recognized, including military purposes for the development of offensive weapons as an adjunct mechanism for delivering stable, viable microorganisms or chemicals as well as its use in field medical treatment.
Many liquid drug formulations are not adequately stable. Although some liquids may be adequately stable when refrigerated, frozen, or protected from other environmental influences, these precautions have an undesirable effect on practicality and economy. Some developmental parenterals are evaluated as frozen liquids during initial toxicological and clinical development. However, the continuation of these products into large-scale studies or to the commercial market in this form is a rare occurrence.
Lyophilization is nearly always investigated as an alternative to a frozen product for extended clinical trials and for commercialization. The process can reduce or eliminate the need for difficult storage and handling arrangements and may provide a pathway to a drug product with a favorable shelf life.
During World War II, lyophilization substantially improved the stability of life saving plasma, plasma supplements, and therapeutic agents and facilitated their handling in remote military fields. During this era, lyophilized antibiotics became available as well.
In addition to its role in making injectable drugs feasible, lyophilization has been used to find alternatives to dry-powder-filled products that have undesirable processing and drug product characteristics. Although powder-filled products are less expensive to produce, their manufacture can involve challenges in processing safety (powder control), uniformity (blending), aesthetics, inspectability, reconstitutability, stability (residual moisture and solvent control), and particulate control. Industry and regulatory scientists realized that these characteristics could be controlled or overcome with the development of lyophilized forms of injectable drug products. The instrumental particle-measurement test described in the US Pharmacopeia beginning in the 1980s was one of the parenteral-release criteria that made the powder filling processes more challenging and, in some cases, undoubtedly triggered the development of lyophilized alternatives.
Technological developments
The first lyophilizers were laboratory-scale units with simple cooling and condensing capabilities, often fabricated from glass tubing and flasks. Initial lyophilization feasibility studies sometimes are still carried out using similar, basic equipment--often with simple dry-ice and alcohol baths and minimal control over temperature and pressure. Development and production-scale dry-ice and alcohol refrigeration systems with direct circulation or heat exchangers were still being used at some manufacturing companies during the 1980s.
This dry-ice and alcohol process involved considerable manual operator intervention. Various methods were used to combine dry ice and alcohol, including a process in which large blocks of dry ice were loaded into a tower above an alcohol reservoir and then descended into the reservoir as the dry ice dissipated. In some cases, chilled alcohol was circulated through lyophilizer shelves and condensers. In other instances, chilled alcohol was used to refrigerate a fluid such as silicone oil, trichloroethylene, or Lexsol, which then was circulated through the system.
The combination of carbon dioxide from the dry ice and alcohol vapors in the loading area presented a challenging environment for operators. Now, most parenteral developers and manufacturers either outsource or carry out in-house feasibility studies, development work, and commercial production in lyophilizers with automated controls and data acquisition capabilities.
In the past, commercial lyophilization systems for parenteral products were fitted with basic controls for pressure and for shelf and condenser refrigeration. These units were expected to be rugged, cleanable, and capable of logging analog data on a chart recorder or printer at regular intervals. Operator intervention was required frequently for making critical adjustments and to start or stop the cycle. Chambers and shelves required sanitization or sterilization capabilities. The sterilization of external condensers was not always a standard industry process. Lyophilization systems with these basic features were used successfully for years in the development of food and drug products.
Environmental concerns pushed the industry toward the use of non-ozone-depleting refrigerants for mechanical systems. In most cases these replacement refrigerants, although more expensive, were phased in successfully without a significant effect on existing lyophilization systems or cycles. Liquid-nitrogen systems also were developed and implemented as a means of reducing end-user reliance on lyophilizer refrigerants. Although they were somewhat more difficult to control, liquid-nitrogen-chilled heat exchangers and circulating systems offered rapid ramping to low temperatures--a characteristic that is desirable for some food and drug products. The thermal expansion and contraction characteristics of materials used in chambers, valves, pump parts, and other components are critical with the more common lyophilization systems but must be capable of bearing additional stress with liquid nitrogen and superlow-temperature mechanical refrigeration systems.
Current technology
Lyophilization advancements have been numerous and broad in scope. Although the process remains much the same, many aspects have changed. Most current production operations use rugged mechanical lyophilization equipment with advanced data acquisition and control systems. Some lyophilizers used in large-scale routine production of a relatively specific range of product sizes are engineered with robotic loading and unloading equipment.
The unique requirements of new molecular entities, advanced formulation techniques and equipment, special handling needs of controlled delivery dosage forms, and new excipient options have been met with improvements in lyophilization technology and the evaluation of thermal characteristics during formulation development.
As with any other technology, improvements in technological capabilities are followed by an increase in expectations. Control and monitoring precision, accuracy, and reproducibility as well as product aesthetics, stability, and reconstitution characteristics remain critical factors in the evolution of lyophilization and the development and production of human and veterinary drugs.
Timothy Smith is director of product and process development at Ben Venue Laboratories. Inc. (Bedford, OH), tel. 440.232. 3320, fax 440.439.6398, phansbury@cle.boehringeringelheim.com.
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