A case study of nondelamination glass dissolution resulting in visible particles: implications for neutral pH formulations.

Visible particles were unexpectedly observed in a neutral-pH placebo formulation stored in glass vials but were not observed in the same formulation composition that contained protein. The particles were identified as silica gel (SiO2 ) and polysorbate 20, suggesting dissolution of the glass vial. Time course studies were performed to assess the effect of variables such as pH, excipients, storage temperature, and duration on particle formation. Data suggest that glass dissolution occurred during the storage in the liquid state, as shown by increased Si levels in solution. Upon freezing, the samples underwent freeze concentration and likely became supersaturated, which resulted in the appearance of visible silica particles upon thawing. The glass degradation described here is unique and differs from the more commonly reported delamination, defined by the presence of reflective, shard-like glass flakes in solution that are often termed lamellae. This case study underscores the importance of an early assessment (during formulation development) of potential incompatibility of the formulation with the primary container.

Impact of Uncontrolled vs Controlled Rate Freeze-Thaw Technologies on Process Performance and Product Quality.

Most biomolecules, owing to their marginal stability in liquid state, susceptibility to microbial growth, and tendency to foam upon storage/shipment in the liquid state, often require an alternate method of long-term storage. Cryopreservation is preferred, as it addresses most of these issues associated with liquid storage. However, the stability of the protein in the frozen state depends on the methodology of freezing/thawing and physico-chemical characteristics of the protein. A systematic study was undertaken to understand and evaluate the impact of freezing/thawing method on the process performance and product quality attributes using two freezing methods-conventional freezing in walk-in freezers and thawing in cold rooms using carboys as an uncontrolled rate method, and Celsius/CryoFin™ technologies as a controlled rate method. To assess the impact of freeze-thaw cycles on product quality, two types of proteins, a fusion protein and a peptibody (peptide fused to the Fc portion of the antibody), were used, employing appropriate stability-indicating assays. The results demonstrate superior process performance by the controlled rate freeze-thaw technology, both in terms of process times and cryoconcentration, compared to uncontrolled rate freeze thaw technology. Product impact studies indicate that the peptibody is sensitive to the method of freeze-thaw while the fusion protein is not and those that are sensitive to uncontrolled rate freeze-thaw processes can be effectively protected by controlled rate freeze-thaw technologies such as Celsius.