What is acceptable appearance in Lyophilized products-II

Dried Product Between Vial and Stopper

During the manufacturing of the lyophilized products, while filling bulk solutions into vials, splashing may occur. Sometimes while manual loading of the tray with filled vials may leave a few droplets of bulk solution around the neck of the vial and even on the stopper. After completion of Lyophilization, If we observe, in these vials at the bottom cake may be intact and elegant. But at the top, but there are chances of freeze-dried product at the neck of the vial or between vial and stopper.

Dried product between vial and stopper

Product Sticking to stopper and neck of vial

Impact: This is a critical defect as the container closure integrity failure may occur resulting in comprise of sterility of the drug product. Also, due to the product adhering to the stopper, there are chances of low deliverable doses. Hence the vials shall be rejected. 

Mitigation: Avoid the solution of Splashing over the neck walls of the vial. Use Siliconized vials / Rubber stoppers if possible. Using larger wide neck vials and stoppers.

Cracked cake and cake shrinkage

Cake shrinkage refers to the apparent loss of cake volume typically by the cake pulling away from the walls and perhaps the bottom of the vial. Often, inverting the vial causes the cake to come loose from contact with the vial. 

Cake shrinkage

Cracked Cake

Shrinkage may be the first manifestation of collapse. However, most cake shrinkage is not associated with collapse. 

Mitigation: For the development scientist, it is important to ensure that cake shrinkage is not associated with collapse. This can be done easily by trial cycles at a range of conditions to be sure that collapse is not contributing to cake shrinkage. Thermal analysis of the frozen formulation and the dried cake (e.g., differential scanning calorimetry, freeze-drying microscopy), online process analytical technology methods (e.g., manometric temperature measurement, thermocouples), or offline characterization methods (e.g., X-ray powder diffraction, residual moisture, SSA) can help to distinguish between unintended collapse or unavoidable shrinkage.

Impact: Both cake shrinkage and cracked cake should not be considered defects, because the underlying physics has to do only with the mechanical properties of the cake, which are dependent on the formulation and primary container. Neither visual attribute has ever been shown to have any impact on CQAs of freeze-dried products.

Reference and more information:

http://dx.doi.org/10.1016/j.xphs.2017.03.014