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Lyophilization Biotech Processes. [David M. Fetterolf Lyophilization David M. Fetterolf “Biotech Processes” discusses fundamental information three stages of process validation: process defini- about biotechnology manufacturing useful to practitio- tion, process qualification, and continued process ners in validation and compliance. Reader comments, verification. questions, and suggestions are needed to make this column a useful resource for daily work applications. INTRODUCTION The key objective for this column: Useful information. Lyophilization, more commonly known as “freeze-dry- Contact column coordinator David Fetterolf at dfet- ing,” is a means of dehydration (desiccation) used in the [email protected] or journal coordinating edi- food, chemicals, pharmaceutical, and biotechnology tor Susan Haigney at [email protected] with industries. In all cases, lyophilization is used to improve comments or suggestions for future discussion topics. the stability of a perishable product or make the product easier to store or transport. In the biotechnology indus- KEY POINTS try, lyophilization is used as a final processing step for The following key points are discussed in this article: purified active pharmaceutical ingredients (APIs) or drug • Lyophilization, or freeze-drying, is used to remove products to stabilize the protein for long-term storage. moisture by sublimation Freeze-drying is a process that removes water by first • Products are lyophilized to increase shelf life freezing the material within a lyophilizer. The ambient • Freeze-dried products are reconstituted with water pressure is then reduced and the temperature is slowly at time of use increased within the lyophilization chamber to allow • Lyophilization processes are based on the physi- frozen water to sublimate (i.e., move from the solid phase cal properties of water, as described by the phase directly to gas). Many food products (e.g., coffee, fruits, diagram vegetables, meats, and ice cream) can be freeze-dried and • Sublimation is effected by control of product tem- subsequently stored at room temperature. The resulting perature and pressure within the lyophilization product generally retains its original shape and is much equipment lighter and easier to carry. For example, hikers frequently • There are four major steps to the lyophilization pack freeze-dried food to reduce weight in their packs. process: formulation/filling, freezing, primary The freeze-dried products are easily reconstituted with drying, and secondary drying water. Freeze-drying is also used to preserve museum • The major components of a lyophilizer are the artifacts, remove moisture, and prevent degradation and chamber, condenser, and vacuum pump. mold growth. Similarly, in the biotechnology industry, • Freeze-drying is ancient technology, but lyophi- protein products, antibodies, oligonucleotides, and vac- lizers have only been around for approximately cines are lyophilized to increase the shelf life by reduc- 100 years ing the risk of degradation during storage. Again, these • Lyophilizers are qualified by typical installation products are much lighter and take up much less space, qualification (IQ), operational qualification (OQ), which make them easier to store and ship. The end user and performance qualification (PQ) protocols. (i.e., doctor, patient, downstream manufacturer, etc.) Lyophilization processes are qualified by the simply reconstitutes the freeze-dried powder prior to For more Author ABOUT THE AUTHOR information, David M. Fetterolf is a consultant with BioTechLogic, Inc. He provides manufacturing and CMC go to support for clients with biopharmaceutical products from development through commercial launch. gxpandjvt.com/bios [David can be reached by e-mail at [email protected]. 18 JOURNAL OF VALIDATION TECHNOLOGY [WINTER 2010] ivthome.com David M. Fetterolf, Coordinator. Figure 1: Phase diagram for water. injection or other use. This article discusses the funda- mental principles behind lyophilization and the specific stages of the lyophilization cycle. It also briefly describes the types of equipment used in lyophilization and the types of validation studies that are typically performed for this unit operation. PHASE DIAGRAMS The principles of lyophilization are based on the physical properties of water that are illustrated by the phase dia- gram for water. A phase diagram for a substance describes the solid, liquid, and gaseous states of a substance as a function of temperature and pressure. In the lyophiliza- tion process, the temperature and pressure conditions within the lyophilizer are controlled to enable the sub- limation of water and its removal from the dosage form. Water is removed from the dosage form as a gas. Figure 1 provides the phase diagram for water. As previously stated, the phase diagram for a sub- stance provides information on its state as a function and pressure enable sublimation. In sublimation, frozen of temperature and pressure. In Figure 1, temperature water is converted directly to water vapor gas, avoiding the is on the x-axis, with values ranging from below 0°C to water liquid state. The following provides an example of a above 100°C. Pressure is on the y-axis, with values from lyophilization process for a product dissolved in water. The an absolute vacuum (0 mm Hg or 0 microns) to beyond process begins at ambient temperature and pressure and 760 mm Hg, or atmospheric pressure (760,000 microns). proceeds with changes to each paramater, as follows: The three states of water are indicated: solid (ice), liquid • Atmospheric pressure and room temperature. Prod- (water), and gas (water vapor). The lines between each uct in solution is aseptically filled into vials. Water phase represent equilibrium conditions. The following is in the liquid state. are phases of water at specific pressures as temperature • Atmospheric pressure and temperature lowered to is increased, as described in Figure 1: -10°C. Product freezes to ice. • Pressure 760 mm Hg or atmospheric pressure (1 • Pressure is reduced to approximately 4 mm Hg and atm). We know water freezes, and ice thaws, at temperature remains below 0°C. Product remains 0°C. Between 0°C and 100°C, water is liquid. At as solid ice. 100 °C, water boils and water vapor condenses. • Pressure maintained at 4 mm Hg and temperature • Pressure 380 mm Hg, or midway down the pres- increased to 20°C or higher. Water begins to sublime sure scale. As temperature increases, ice melts directly into the gaseous state. Transition to the liquid at slightly above 0°C. As temperature increases state does not occur at this pressure and temperature. further, water boils at approximately 82°C. Water continues to sublime until all ice has subli- • Pressure 4.58 mm Hg. As temperature increases mated. This is termed “primary drying.” to 0.0098°C, ice, water, and water vapor exist in • Temperature is continually increased until all adsorbed equilibrium. This is known as the triple point moisture is eliminated. Pressure may or may not be of water. increased. This is termed “secondary drying.” • Pressure below 4.58 mm Hg. As temperature increases, solid ice converts directly to water vapor These conditions enable the dosage form to maintain gas. Liquid water does not exist at these pressure its integrity without losses due to boiling. There is no and temperature conditions. liquid state in the sublimation process. Figure 2 shows the stepwise description of the example lyophilization Water Phase Diagram And The process described previously. As you can see, the steps Lyophilization Process form a curve around the triple point, thus avoiding the The various steps in lyophilization can be plotted on the liquid state of water. water phase diagram to understand how temperature gxpandjvt.com JOURNAL OF VALIDATION TECHNOLOGY [WINTER 2010] 19 Biotech Processes. Figure 2: Example lyophilization process. as unfolding, during lyophilization. Commonly used stabilizers for biologics are sugars and glycols. At the end of the lyophilization process, biotech drug products resemble a fluffy white powder, or “cake.” Because the aesthetics of the cake sometimes play an important role in product marketability, bulking agents are often added to make the cake appear fluffier. Bulk- ing agents can also help to prevent “collapse” of the drug product, which can occur if the product is heated too rapidly during the drying stages. These bulking agents are not intended to change the chemical proper- ties of the product. Some examples of bulking agents typically used in the biopharmaceutical industry are mannitol, dextran, and polyethylene glycol. Once the product is in the proper form and all excipi- ents are added, the last step prior to placing the material into the lyophilizer is filling the product into the proper container. For biotechnology products, the containers are usually glass vials, which come in a variety of shapes, LYOPHILIZATION PROCESS FOR sizes, and colors. Although not always, vials are typically BIOPHARMACEUTICAL PRODUCTS used if no further processing is needed. Once the product There are four major stages in the lyophilization process is filled into the vials, each vial is partially stoppered (i.e., for biopharmaceutical products, as follows: not fully pushed into place) such that the vial is vented • Formulation/filling so water vapor can escape during lyophilization. Other • Freezing types of containers such as trays can be used to lyophi- • Primary drying lize large quantities of product. Trays are typically used • Secondary
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