Yingtai: Causes of Vial Breakage During Lyophilization

Yingtai: Causes of Vial Breakage During Lyophilization  

Although vial breakage during lyophilization is rare, its occurrence not only leads to product loss but also poses significant challenges in cleaning up broken glass, sanitizing, and revalidating the lyophilizer. The shattered glass risks contaminating other "open" vials and may damage the drain valve seals, compromising the equipment's vacuum integrity. Some experts attribute lyophilization breakage to thermal stress, suggesting that modifying the vial's thermal properties can reduce such incidents. Today, we focus on the most common form of breakage, where the stress in the glass is caused by internal forces from product expansion during freezing, rather than thermal stress from processing temperatures.  

1. Principles  

- Fractography is a commonly used and effective method for investigating the causes of breakage in any glass product.  

- When force is applied to a glass object, the glass undergoes elastic deformation (strain), generating compressive stress and tensile stress.  

- The distribution of these stresses depends on the container's design, glass thickness variation, and the type of force applied.  

- Glass breaks only under tensile stress, with cracks propagating perpendicular to the direction of tensile stress distribution. Thus, crack patterns can precisely indicate the type of force acting on the glass, aiding in post-analysis of breakage causes.  

Experimental Methods  

1. Pressure Test:  

   - Vials were filled with water and pressurized, starting at low pressure and gradually increasing until breakage.  

     - a) Vials breaking at higher pressures exhibited extensive cracking.  

     - b) Vials breaking at lower pressures showed a simpler pattern: a single vertical crack with a circumferential crack at the base.  

2. Thermal Shock Test:  

   - Vials were heated in an oven and then immersed in a cold water bath.  

     - a) At higher temperature differentials, cracks were widespread across the sidewalls and base.  

     - b) At lower temperature differentials, a circumferential crack appeared around the base.  

2. Computer Simulation Stress Analysis  

- Horizontal force simulation replicated the expansion force generated by water freezing.  

- Finite element analysis (Figure 5) showed that outward expansion forces produced nearly equal tensile stresses on the inner and outer surfaces of the glass.  

- Since the outer surface is more likely to have defects (e.g., scratches from upstream handling), fractures predominantly originated there, consistent with Figure 2.  

- Analysis of 51 vials broken during commercial lyophilization revealed tensile fracture stresses ranging from 27.6 to 69.0 MPa.  

  - To achieve 27.6 MPa, a temperature differential of 125°C between the inner and outer surfaces is required.  

  - For 69.0 MPa, a differential of 314°C is needed.  

- Given the slow heating/cooling rates in lyophilization, such extreme temperature gradients are virtually impossible.  

Conclusion: The fracture patterns and stress levels indicate that the most common vial breakage during lyophilization is likely caused by **outward expansion of the frozen product**, not thermal gradients.