Yingtai: Why Do Vials Break During the Lyophilization Process?
Vials are specialized containers used for lyophilized products.
Lyophilization Process:
During the lyophilization process, liquid first undergoes freezing at low temperatures to transform into a non-flowing state. Then, through primary drying at a higher temperature, water is removed via sublimation. Finally, during secondary drying at an even higher temperature, adsorbed and bound water is removed.
However, vial breakage can occur during the lyophilization process. Vial breakage during production not only leads to product loss but also presents significant challenges in cleaning and validation of lyophilization equipment due to the need to remove broken glass and leaked materials. There is also a risk of glass shards contaminating other "open" vials, and they may even damage the sealing ring of the drainage valve, affecting the vacuum integrity of the equipment.
Although the probability of this issue occurring is low, when it does happen, it is a major challenge in lyophilized product manufacturing.
The causes of vial breakage are complex and mainly fall into two categories:
1. The expansion force generated by the material inside the vial due to temperature changes and phase transitions.
2. The stress differences in the glass material of the vial caused by temperature gradients during the lyophilization process.
Part 1: Principles
Fractography is a common and effective method used to analyze 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 in the glass depends on factors such as container shape, glass thickness, and the type of force applied.
- Glass breaks only under tensile stress, and cracks propagate perpendicular to the direction of tensile stress.
- Therefore, the fracture pattern accurately reflects the type of force acting on the glass object and can be used for subsequent analysis of vial breakage causes.
Part 2: Observations
(1) Common Vial Fracture Patterns During Lyophilization
- Vertical cracks appear in the lower sidewall region of the outer glass surface.
- Sometimes, branching cracks can be observed above or below the initial crack point.
(2) Fracture Patterns Due to Internal Pressure (Expansion Force)
Experiment 1: Internal Pressure Test
Method:
- Fill the vial with water and gradually increase pressure until the vial breaks.
- Observation:
- Vial A: Broke under higher pressure.
- Vial B: Broke under lower pressure.
Experiment 2: Thermal Shock Test
Method:
- Heat the vial in an oven and then immerse it in a cold-water bath.
- Observation:
- (a) Cracks produced under a high temperature difference.
- (b) Cracks produced under a lower temperature difference.
A finite element analysis (FEA) was conducted to simulate the forces generated by the expansion of freezing water. The results (Figure 5) show that the outward expansion force produces nearly equal tensile stress on both the inner and outer surfaces of the glass.
Since the outer surface of vials is more likely to have defects (such as scratches from upstream processing), fractures typically originate from the outer surface. This result is consistent with the observed fracture patterns shown in Figure 2.
A diagnostic study of 51 vials that fractured during commercial lyophilization processes found that the tensile fracture stress ranged from 27.6 MPa to 69.0 MPa.
To reach 27.6 MPa of total fracture stress, a temperature difference of 125°C between the inner and outer vial surfaces is required.
For a fracture stress of 69.0 MPa, a temperature difference of 314°C is needed.
Since heating and cooling rates in lyophilization are relatively slow, it is almost impossible for such high temperature gradients to occur.
Conclusion
Based on the common vial fracture patterns observed in industrial production, experimental results, and the stress data required for temperature-induced glass fracture, it can be concluded that:
- Most vial breakages are primarily caused by the expansion force generated by the material inside the vial due to temperature changes and phase transitions.
- They are not mainly due to temperature gradients in the vial walls during the lyophilization process.
