Impact of Pharmaceutical Processing on Glass Vial Fogging in Lyophilized Products

Glass vial fogging, the deposition of a thin layer of product on the inner surface of glass vials above the lyophilized cake, is a common challenge in freeze-dried drug products. While typically considered a cosmetic defect, fogging around the vial shoulder and neck can potentially impact container closure integrity and reject rates during inspection. This study looks at how different processing conditions, such as vial pre-treatment, changes to the lyophilization cycle, and filling conditions, affect how much fogging there is in lyophilized products.

Understanding Vial Fogging:

• Definition: Vial fogging is the phenomenon observed post-lyophilization where the drug product creeps along the inner vial surface, resulting in a haze of dried powder within the vial.
• Cosmetic Concern: The presence of vial fogging diminishes the cosmetic appeal of the drug product, making it barely acceptable for commercial distribution.

Research into the root causes of fogging in the manufacturing process of a lyophilized monoclonal antibody drug product was done as part of development studies.

Factors Influencing Vial Fogging

• Filling Process: Drug product creeping occurs during the filling process, contributing to vial fogging post-lyophilization.
• Glass History: Previous processing of the vial, including cleaning and sterilization methods, can influence fogging.
• Glass Quality and Inner Surface: The quality of the glass and its inner surface, as well as its history in terms of processing, play significant roles in vial fogging.
• Container Material: Different materials used for vial construction, such as glass or plastic, may exhibit varying levels of fogging.
• Formulation Excipients: The inclusion of formulation excipients, such as surfactants, affects glass fogging to varying degrees.
• Inner Surface Condition: The condition of the inner surface of the vial, including scratches or imperfections, can contribute to fogging.
• Hydrophilicity/Hydrophobicity: The level of hydrophilicity or hydrophobicity of the inner vial surface affects fogging control.
• Environmental Factors: Temperature and humidity conditions during manufacturing and storage can influence the occurrence of fogging.
• Handling and Transportation: Rough handling or improper transportation of vials can exacerbate fogging due to physical agitation.
• Processing Conditions: Post-filling processing steps, such as depyrogenation and lyophilization parameters, can impact fogging levels.

Key Findings and Solutions

• Hydrophilicity/Hydrophobicity of the Inner Vial Surface: The primary factor influencing fogging control is the hydrophilicity/hydrophobicity of the inner vial surface.
• Effectiveness of Glass Types: While Duran vials didn’t reliably improve fogging levels, hydrophobic containers proved effective in reducing fogging and enhancing cosmetic appearance.
• Depyrogenation Treatment: Varying depyrogenation treatment conditions did not satisfactorily eliminate the fogging effect.
• Impact of Processing Conditions: Post-filling processing conditions of the vial strongly influence fogging reduction, although complete elimination may not be achieved.

Methods

A fogging score was used to evaluate the degree of fogging in glass vials, and analytical techniques were used to investigate the causes influencing it. Additionally, a dye-based method studied solution uptake (Marangoni flow) post-filling. Various vial types were utilized, and different pre-treatment conditions, including washing, foiling, and depyrogenation, were applied.

Results: Lab-scale results indicated measurable improvement in fogging with the addition of an annealing step in the lyophilization cycle. Pre-freeze isothermal holding of vials at 5 °C showed a reduction in fogging, while increased freezing time had no effect. While vial pre-treatment conditions had no effect on fogging in vials, they were crucial factors in determining fogging for Type 1 vials. Investigation of headspace relative humidity indicated conditions conducive to the formation of a hydration film, a precursor to Marangoni flow.

What is marangoni flow?

Marangoni flow, also known as the Marangoni effect, is a phenomenon in fluid dynamics where there is a mass or momentum transfer along the surface of a liquid due to gradients in surface tension. The name of this effect comes from Italian physicist Carlo Marangoni, who first noticed it in the 19th century.

Understanding Surface Tension

The ability of a liquid to withstand outside forces is known as surface tension. The cohesive forces between the liquid molecules are the cause of it. When there are differences in surface tension across a liquid surface, it creates a gradient, leading to the movement of liquid.

History

This phenomenon, known as the ‘tears of wine,’ was first noticed by physicist James Thomson, who was the brother of Lord Kelvin. It’s named after Italian physicist Carlo Marangoni, who researched it for his doctoral thesis at the University of Pavia and shared his findings in 1865. A comprehensive explanation of this effect was later provided by J. Willard Gibbs in his work ‘On the Equilibrium of Heterogeneous Substances’ between 1875 and 1878.”

Tears of Wine

• Wine exhibits a phenomenon known as “tears of wine.“
• This effect occurs due to the lower surface tension and higher volatility of alcohol compared to water.
• The alcohol in the wine raises the surface of the glass, reducing the surface energy.
• As alcohol evaporates, the remaining liquid has a higher surface tension, pulling it up the glass.
• Eventually, the weight of the liquid exceeds the force, causing it to drip back down the glass.
• You can demonstrate this effect by spreading water on a surface and adding an alcohol drop, which will cause the liquid to rush away from the alcohol drop.

Summary :Tears of wine” happen when alcohol evaporates from wine, leaving liquid with higher surface tension. This causes the wine to climb up the glass before eventually dripping back down.

Example and application 

• Stabilizing soap films: The Marangoni effect stabilizes soap films.
• Behavior of Convection Cells: Convection cells, known as Bénard cells, also exhibit the Marangoni effect.
• Silicon Wafer Drying: The Marangoni effect is utilized for drying silicon wafers in the manufacturing of integrated circuits.It prevents liquid spots on the wafer surface, which could cause oxidation and damage components.

Self-Assembly of Nanoparticles

• It has been proven possible to generate nanotubes and self-assemble nanoparticles into ordered arrays using the Marangoni effect.
• Spreading alcohol-containing nanoparticles on a surface and then blowing humid air over it causes the nanoparticles to form ordered structures.

Manipulation of Particles

• The Marangoni effect is utilized in manipulating particles, especially at small scales.
• Locally heating the air-water interface induces controlled thermo-capillary convection, which permits manipulation of floating objects and self-assembly.

Applications in Welding and Crystal Growth

• The Marangoni effect is important in fields such as welding, crystal growth, and the electron beam melting of metals.

Discussion:

The study aimed to comprehensively evaluate and understand the influence of process parameters on the severity of Marangoni flow-induced glass vial fogging. Results highlighted the complex interplay of processing conditions on fogging extent, with annealing showing a time-dependent decrease in fogging. However, extended freezing did not significantly affect fogging. Pre-freeze isothermal hold, though promising, yielded inconclusive results at short times for viable commercial implementation.

Conclusion:

Different processing conditions have an impact on glass vial fogging in lyophilized drug products. Annealing of frozen products demonstrated a time-dependent decrease in fogging severity, while extended freezing had minimal impact. The study emphasizes the importance of understanding and optimizing processing parameters to mitigate fogging and ensure aesthetically acceptable drug products.

These are some key FAQs about pharmaceutical vial fogging.