Lyophilized Drug Product Cake Appearance: What Is Acceptable?

Patel, Sajal M.; Nail, Steven L.; Pikal, Michael J.; Geidobler, Raimund; Winter, Gerhard; Hawe, Andrea; Davagnino, Juan; Gupta, Shailaja Rambhatla

doi:10.1016/j.xphs.2017.03.014

Cited by 160 publications

(102 citation statements)

References 33 publications

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“…To prevent this defect product temperature can be kept lower in drying step and cycle optimization should be done with trial-and-error method. However, this defect does not significantly alter product characteristics [25].…”

Section: Shrinkage and Crackingmentioning

confidence: 90%

“…Shrinkage and cracking may also be affected by fill volume. Higher cracking was seen in 10R vials than 2R vials with constant fill volume [25]. Srivalli Telikepalli studied that shipping stress can play a major role in breakage of the cake [27].…”

Section: Shrinkage and Crackingmentioning

confidence: 99%

“…The cake is detached from the walls and bottom of the vial when the unfrozen water in the frozen matrix dries and creates stress which results in shrinkage or cracking of the cake (Fig 4 A). The cake gets separated from the bottom when inverted due to release of stress [25]. However, there is an opposite relation between shrinkage and cracking.…”

Section: Shrinkage and Crackingmentioning

confidence: 99%

“…Melt back defect is observed due to the improper formulation and processing parameters. This defect is not accepted because it directly affects the quality and appearance of the final freeze dried product (Fig 4 C) [25]. It can be eliminated by formulation and freeze drying cycle optimization using suitable design of experiment.…”

Section: Melt Backmentioning

confidence: 99%

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An overview of lyophilization: troubleshooting the challenges and pharmaceutical applications

2019

Lett Appl NanoBioSci

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Although, lyophilization is well known technique for drying, recently its applications in pharmaceutical field is tremendously increased. The quality product with low moisture content, higher solubility and easy reconstitution lead to wide spread applications of the process. The formulation is frozen, followed by sublimation and desorption to yield dry powder ready for reconstitution. This technique is critical, therefore optimization of many parameters is mandatory to get quality product. The improper insight of parameters like freezing temperature, drying temperature, vacuum, fill volume, etc. may result into collapse, melt back, blow out, shrinkage of the cake which directly affects product reconstitution time, moisture content, assay, and ultimately the stability of the final product. In this review, the challenges experienced in development of freeze drying cycle and its appropriate remedies are discussed at a length. Additionally pharmaceutical applications with the regulatory concerns are also reviewed.

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Section: Shrinkage and Crackingmentioning

confidence: 90%

Section: Shrinkage and Crackingmentioning

confidence: 99%

Section: Shrinkage and Crackingmentioning

confidence: 99%

Section: Melt Backmentioning

confidence: 99%

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An overview of lyophilization: troubleshooting the challenges and pharmaceutical applications

2019

Lett Appl NanoBioSci

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“…4 Solution wetting the inner vial surface when handling the vials during loading the liquid-filled product units into the freeze dryer leads to fogging. 5 Wetting of the inner surface can also appear without significant vial movement. Fogging is often considered a cosmetic defect.…”

Section: Introductionmentioning

confidence: 99%

Method to Predict Glass Vial Fogging in Lyophilized Drug Products

Langer

Mahler

Koulov

et al. 2020

Journal of Pharmaceutical Sciences

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a b s t r a c tGlass fogging is a phenomenon occurring in lyophilized drug products and can be described as a thin product layer deposited on the inner surface of the glass container, in the area not covered by the lyo cake itself. It is often considered a cosmetic defect; however, the loss of container closure integrity is a potential consequence of the fogging's expansion to the vial neck region, making this a potential critical defect. Thus, a method for predicting the extent of vial fogging before the actual freeze-drying is of particular interest for the pharmaceutical industry. For that reason, we evaluated a simple method ("simulated fogging") applicable to drug product formulations in a specific container closure system. Two different vial types with different surface hydrophilicity were tested using 3 model protein formulations, comparing the simulated fogging test and the degree of fogging after actual lyophilization. The simulated fogging method could predict fogging and showed a correlation to fogging in lyophilized drug product glass vials. We observed that all formulations showed fogging in the hydrophilic vials. By contrast, hydrophobic vials prevented fogging, however, interestingly with remaining defects of so-called droplet formation. Other than extent of fogging, no additional differences of lyophilized cake properties or other product quality attributes were observed between products using the different glass vial types tested.

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Future Directions

Alexeenko

Topp

2020

Drying Technologies for Biotechnology and Pharmaceutical Applications

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Lyophilized Drug Product Cake Appearance: What Is Acceptable?

Cited by 160 publications

References 33 publications

An overview of lyophilization: troubleshooting the challenges and pharmaceutical applications

An overview of lyophilization: troubleshooting the challenges and pharmaceutical applications

Method to Predict Glass Vial Fogging in Lyophilized Drug Products

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