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Small Batch Size Lyophilization: A current trend in the biopharmaceutical industry

Updated: Jun 7, 2020

Patient centered manufacturing instead of a bulk approach is trending in the biopharmaceutical industry. Notably in the fields of oncology, immunology and neurology, biologics are in high demand and their contribution is still growing. To ensure flexibility, time, and cost-effective aseptic fill/finish manufacturing at high quality, new machinery with high automation and control is being developed. Lyophilization is often required to achieve adequate stability of the biopharmaceutical. Consequently, it is necessary to include lyophilization as part of the fill/finish process in these new flexible units which come with different vial handling compared to standard equipment using robots, disposables, ready-to-use materials, and racks.

Lyophilization is a time consuming and critical step. One challenge in lyophilization is the inhomogeneous heat transfer across a shelf and related edge vial effect. During lyophilization energy can be transferred through direct contact, specifically between vial and shelf, radiation, and gas conduction.

Nests with vials filled with the liquid formulation are one approach utilized in flexible automated production for transfer into the freeze dryer. This represents both challenges and opportunities which must be thoroughly understood. It is necessary to evaluate heat and mass transfer mechanisms to ensure high quality manufacturing. Especially for transfer and scale-up, understanding of energy transfer is essential to achieve adequate quality of biopharmaceutical products.

Heat transfer for sublimation in vials nested in a rack system is dominated by direct contact between vial and shelf and radiation coming from the rack itself. Heat transfer through direct contact is limited to contact between vial and shelf. Contribution of direct contact is higher and radiation effect from the chamber wall is less than in the standard configuration. Separated corner vials without a rack have a shorter primary drying time as they lack the radiation shielding provided by the rack. With increasing pressure, the difference in sublimation rates between corner and center vials in the rack decrease due to a higher contribution of gas conduction, leading to a reduced edge-vial-effect.

Lyophilization in the rack vial system enables a homogeneous drying with a reduced edge-vial-effect and shielding against radiation from surrounding components, e.g., the chamber wall. Due to the separation effect of the rack, direct shelf contact contributes approx. 40% to the overall energy transfer to the product during primary drying. Hence overall the rack is a flexible, robust tool for small batch production, which ensures a controlled heat transfer resulting in a uniform product.

Original article: "energy transfer in vials nested in a rack system during lyophilization"

Pharmaceutics 2020, 12, 61

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