Biopharmaceutical products are subject to stability problems distinct from traditional sterile pharmaceutical processing and thus require more care in handling and preservation than do classical "small-molecule" drugs. Most biopharmaceutical formulations are aqueous, and protein products have limited stability in their liquid state.
Aqueous therapeutics, therefore, are often frozen and then thawed, freeze-dried to be rehydrated when needed, or encapsulated in liquid form without being touched by the atmosphere. The container that touches the product, the label, the patient instructions, the outside packaging, transportation to a variety of global climates, and the promotional materials are all part of filling and finishing a product as it gets ready for market.
All production lines must be approved by FDA (or regulatory bodies in other countries) before they can be used to manufacture drugs. The approval process involves documenting and demonstrating that the line functions as designed and within established criteria for cleanliness and sterility. The manufacturer is responsible for providing that documentation.Freeze-Thaw One of the most effective preservation techniques is freezing, but that and subsequent thawing stresses protein molecules. Processing time, temperature, solute distribution, pH, stratification, and the porosity of the recrystallization must all be controlled.
Some companies find freezing and thawing to be an essential manufacturing step. Freezing adds flexibility to the manufacturing process, particularly when multiple products are being made, and allows cost savings from pooling lots or batches. Vessel design is a critical feature of a successful freeze-thaw system so that the product doesn't have to be transferred between containers. Each additional thaw operation increases degradation.
Freezing. Sometimes a specially designed, jacketed, portable, stainless steel freeze-thaw vessel that can be cleaned or steamed in place is used for freezing, sized to the product batch. Some containers use heat transfer surfaces with fins, which divide the vessel volume into compartments to reduce the freeze-thaw time. As water crystallization occurs, product and excipient concentrations between the crystals of ice greatly increase, a process known as cryoconcentration. The goal is to solidify these non-crystalline areas within the frozen product. The quicker that occurs, the less the product will be damaged. Usually, freezing is conducted from the bottom up to keep the warmest point at the top for temperature testing. The same container in which the product is frozen can then be used to ship the frozen product to fill-and-finish facilities around the world.
The freezing process takes the product from the liquid state through multiphase solidification to a low-temperature solid. The drug must not change physicochemical characteristics nor lose bioactivity during freezing. Considerations in a freezing plan include minimizing freezing time, cryoconcentration, and convection; promoting dendritic ice growth; preventing mechanical stresses in the vessel; developing a sanitary design; and monitoring and validating the system.
Thawing. Thawing is required before further processing (final purification, dilution, filling) can take place. During thawing, a vessel jacket or internal heat exchanger warms the product. A strict temperature limit (determined by product stability studies in small containers) sets the rate of warming. The goal is to make it as rapid as possible while preventing product deterioration. Control considerations include avoiding overheating, achieving maximum convection in the liquid phase, encouraging recirculation, preventing molecular and microscopic interactions related to the formulation, analyzing the heat and mass transfer, and designing a unique mechanical system to meet the requirements of the therapeutic. As crystalline ice undergoes internal melting, and since it is less dense than water, the liquid advances into the solid and necessarily creates a negative pressure cavity whose surface may theoretically degrade a protein. As much as possible, the controls avoid internal melting.