Lyophile collapse

D. E. Overcashier, T. W. Patapoff, and C. C. Hsu, Lyophilization of protein formulations in vials Investigation of the relationship between resistance to vapor flow during primary drying and small scale product collapse, J. Pharm. Sci., 88(7), 688 (1999). 

Because the objective of this process is the preservation of the lyophilized material, the presence of collapsed material is suspect. Collapse may simply be considered a cosmetic defect. When the collapsed material exhibits an increased reconstitution time or poor solubility, the presence of collapse becomes more than just a cosmetic defect. If, however, the collapsed material retains a higher amount of residual water, where this water becomes involved in degradation of the product through hydrolysis, then there is a more serious concern. The presence of a significant amount of residual water may promote degradation of the product, such that the assay falls outside of the compendial limits. There would also be a concern for the toxicity or an influence on the therapeutic effectiveness of the product. Both potential results should be considered during product development. 

Regardless of the freezing behavior of the formulated solution, it is essential to make sure that the temperature of the product is decreased below the temperature where complete solidification is observed. If this condition is not respected, the incompletely frozen interstitial phase will boil or induce pellet partial melting or collapse during lyophilization. 

Although pressure-controlled lyophilization brings significant advantages, a drawback of this technique is to risk promoting collapse in delicate formulations. This is because the assigned pressure modifies the course of sublimation and elevates product temperature in parts of the cycle where little evaporation would occur under maximum vacuum. 

Evaluation of the analytical data should demonstrate that the product consistently achieves its predicted levels of quality, activity, and purity. The visual inspection data should also be assessed, at least for lyophilization-related defects such as collapse or melt-back. 

In addition to the various physical techniques, a simple visual inspection of the formulation is conducted to determine if there are changes to the formulation. The human eye is extremely sensitive to many changes observed in protein formulations, and for this reason visual inspection is a valuable tool in the bag of techniques used to assess stability. For liquid formulations, the appearance of precipitates or a change in color of the formulation signifies trouble. For lyophilized formulations, the visual appearance of the lyophilized cake is an important characteristic of the formulation. Collapse or discoloration of the cake could indicate a compromised formulation. 

The amount of moisture sorbed by the lyophilized protein sample is directly related to the activity of DjO vapor phase (i.e., RH) to which the protein is exposed. To maintain constant RH throughout the experiment, solid-state amide HX is usually carried out inside a sealed desiccator. The desired RH can be easily maintained by using a suitable saturated salt solution [62]. Some commonly used salts and the resulting %RH are LiCl (11% RH), KCjH30 (23% RH), MgCl (33% RH), I C03 (43% RH), and NaCl (75% RH) [60]. The RH values correspond to the RH over aqueous solutions of these salts at room temperature the humidity over D O is assumed to be identical. To control the rate of moisture sorption and prevent powder collapse in formulations containing hygroscopic excipients... 

In addition to DSC, other instruments, such as differential thermal analysis (DTA) and electrical resistance analysis (ER), are also commonly used in determining the thermophysical properties of a lyophilized formulation, such as the glass transition temperature (T, the collapse temperature, etc. One of the examples using DTA and ER has been recently reported by... 

As described previously, lyophilizing a crystalline matrix type of formulation allows micro-collapse of the amorphous components. This allows primary drying to be performed at a relatively high product temperature without loss of the cake structure. The hypothesis we made is that the micro-collapse would not compromise product quality, particularly in stability. Here we discuss this issue and particularly a study that we performed to confirm the hypothesis. 

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