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THE DRUG MANUFACTURING PROCESS 155
Figure 3.29. Photographic representation of a blow-fill-seal machine, which can be particularly useful in the aseptic filling of liquid products (refer to text for details). While used fairly extensively in facilities manufacturing some traditional parenteral products, this system has not yet found application in biopharmaceutical manufacture. This is due mainly to the fact that many biopharmaceutical preparations are sold not in liquid, but in freeze-dried format. Also, some proteins display a tendancy to adsorb onto plastic surfaces. Photo courtesy of Rommelag a.g., Switzerland
automated filling of sterile product into the container and its subsequent sealing. In this way operator intervention in the filling process is minimized.
Freeze-drying (lyophilization) refers to the removal of solvent directly from a solution while in the frozen state. Removal of water directly from (frozen) biopharmaceutical products via
lyophilization yields a powdered product, usually displaying a water content of the order of 3%. In general, removal of the solvent water from such products greatly reduces the likelihood of chemical/biological-mediated inactivation of the biopharmaceutical. Freeze-dried biopharma-ceutical products usually exhibit longer shelf-lives than products sold in solution. Freeze drying-is also recognized by the regulatory authorities as being a safe and acceptable method of preserving many parenteral products.
Freeze-drying is a relatively gentle way of removing water from proteins in solution. However, this process can promote the inactivation of some protein types and specific excipients (cryoprotectants) are usually added to the product in order to minimize such inactivation. Commonly used cryoprotectants include carbohydrates, such as glucose and sucrose; proteins, such as human serum albumin; and amino acids, such as lysine, arginine or glutamic acid. Alcohols/polyols have also found some application as cryoprotectants.
The freeze-drying process is initiated by the freezing of the biopharmaceutical product in its final product containers. As the temperature is decreased, ice crystals begin to form and grow. This results in an effective concentration of all the solutes present in the remaining liquid phase, including the protein and all added excipients, e.g. the concentration of salts may increase to levels as high as 3 M. Increased solute concentration alone can accelerate chemical reactions damaging to the protein product. In addition, such concentration effectively brings individual protein molecules into more intimate contact with each other, which can prompt protein-protein interactions and, hence, aggregation.
As the temperature drops still lower, some of the solutes present may also crystallize, thus being effectively removed from the solution. In some cases, individual buffer constituents can crystallize out of solution at different temperatures. This will dramatically alter the pH values of the remaining solution and, in this way, can lead to protein inactivation.
As the temperature is further lowered, the viscosity of the unfrozen solution increases dramatically until molecular mobility effectively ceases. This unfrozen solution will contain the protein, as well as some excipients and (at most) 50% water. As molecular mobility has
THE DRUG MANUFACTURING PROCESS 157
Figure 3.30. Photographic representation of (a) lab-scale, (b) pilot-scale and (c) industrial-scale freeze driers. Refer to text for details. Photo courtesy of Virtis, USA
effectively stopped, chemical reactivity also all but ceases. The consistency of this ‘solution’ is that of glass, and the temperature at which this is attained is called the glass transition temperature, Tg'. For most protein solutions, Tg' values reside between — 40°C and — 60°C. The primary aim of the initial stages of the freeze-drying process is to decrease the product temperature below that of its Tg' value as quickly as possible.
The next phase of the freeze-drying process entails the application of a vacuum to the system. When the vacuum is established, the temperature is increased, usually to temperatures slightly in excess of 0°C. This promotes sublimation of the crystalline water, leaving behind a powdered cake of dried material. Once satisfactory drying has been achieved, the product container is sealed.
The drying chamber of industrial-scale freeze-dryers usually opens into a clean room (Figure
3.27). This facilitates direct transfer of the product-containing vials into the chamber. Immediately prior to filling, rubber stoppers are usually partially inserted into the mouth of each vial in such a way as not to hinder the outward flow of water vapour during the freeze-drying process. The drying chamber normally contains several rows of shelves, each of which can accommodate several thousand vials (Figure 3.30). These shelves are wired to allow their electrical heating and cooling and their upward or downward movement. After the freeze-drying cycle is complete (which can take 3 days or more), the shelves are then moved upwards. As each shelf moves up, the partially-inserted rubber seals are inserted fully into the vial mouth as they come in contact with the base plate of the shelf immediately above them. After product recovery, the empty chamber is closed and is then heat-sterilized (using its own chamber-heating mechanism). The freeze-drier is then ready to accept its next load.