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The manufacturing process, which influences a drug's safety and efficacy, is particularly critical for drugs administered through injection, and personnel must closely supervise lyophilization to ensure product quality.
Regulators and manufacturers have worked to ensure that enough influenza A (H1N1) vaccine will be available for patients. Debate has focused on whether Merck’s (Whitehouse Station, NJ) human papillomavirus vaccine is beneficial for boys as well as girls. These developments have kept biological drugs in the public consciousness. Biological drugs are largely administered through injections and often must be lyophilized to increase their stability, temperature tolerance, and shelf life. The manufacturing process, which influences a drug’s safety and efficacy, is particularly critical for drugs administered through injection, and personnel must closely supervise lyophilization to ensure product quality.
One factor that manufacturers must monitor during lyophilization is supercooling, which occurs when a product’s temperature falls below its actual freezing point. Supercooling tends to lead to the formation of small ice crystals in the formulation, resulting in a dense ice matrix, says Brian Bucur, associate director of lyophilization and sterilization at Ben Venue Laboratories (Bedford, OH). A highly dense ice matrix can impede the release of sublimed moisture from the formulation and thus lengthen the time needed for primary drying. Supercooling also can result in inconsistent drying, which can cause heterogeneity in the finished product, adds Bucur.
The manufacturer’s choice of freezing method influences the freezing rate, which, in turn, affects the degree of supercooling. Rapid freezing generally increases the risk of supercooling. “It is important to make sure that the first ice crystals nucleate to facilitate consistent and thorough product freezing,” says Bucur. “Slow freezing of the product in a well-developed cycle will allow the ice crystals to nucleate and cause the desired ice to form consistently. This normally minimizes the risk of supercooling,” he adds.
Shelf freezing (i.e., freezing a product in a lyophilizer rather than in a separate unit) entails the least risk of supercooling, notes Jameel Feroz, principal scientist at Amgen (Thousand Oaks, CA). Consistent and controlled shelf-temperature ramps during the freezing process can lower the risk of supercooling within a lyophilization chamber.
Yet shelf freezing might not be the only way to reduce supercooling. “Fast freezing using liquid nitrogen may help bypass supercooling altogether, provided that an amorphous structure is acceptable for the resultant product,” says Mark Williams, senior research and development group leader at Hospira (Lake Forest, IL). An annealing step can further reduce product variability from vial to vial, he adds.
Variation in vial thickness also can affect the extent of supercooling within a batch, even when the vials are within specifications. Tubing glass vials or ampuls are preferable because they have thinner, more consistent bottom thickness than molded containers, which enables the product to be cooled and heated uniformly through the lyophilization shelves, says Bucur. The bottom thickness of molded vials tends to vary more, and this variation can increase the risk of supercooling.
When scaling up the lyophilization process, supercooling must be controlled to achieve consistent process and product profiles. “The desired outcome is uniformly dried product across a batch,” says Bucur. Minimizing the extent of supercooling in any batch size can contribute to consistent drying.
It is difficult to model the scale-up of lyophilization because the process contains a high number of variables. The rates of cooling, supercooling, and freezing depend not only on the programmed rate of temperature decrease, but also on chamber size, the flow of thermal fluid, the smoothness of the lyophilizer shelves, and thermal-transfer rates from the shelf to the vial bottoms and from the vial bottoms to the rest of the vials, says Michael Akers, senior director for pharmaceutical research and development at Baxter BioPharma Solutions (Bloomington, IN) and member of Pharmaceutical Technology’s editorial advisory board.
Mathematical modeling helps to predict drying rates based on variables such as temperature, pressure, and vial thickness. “Modeling can give you targets, but cannot give you dependable and actual final parameters for a well-designed cycle,” says Akers. Optimal drying cycles are based on actual experimentation.
A design-space approach to experimentation that explores key process parameters may offer the best approach to scale-up, says Williams. Ultimately, scale-up is restricted by the performance capabilities of the manufacturing lyophilizer, which may not be able to reproduce the cooling rate that was experimentally determined as optimal with a pilot unit. “Therefore, it is important to develop a process that can be reproduced by the lyophilizers that will be used for final manufacturing,” says Williams.
Scientific understanding of the chemical, physical, and thermal aspects of lyophilization has improved over time, thus bringing manufacturers greater control over the process. This understanding, combined with mathematical modeling and practical experience, can help personnel predict and control the extent of supercooling. Today, it is easier for drugmakers to develop optimal lyophilization processes that yield uniform batches of safe biological drugs that have the desired characteristics.