Lyophilization

Defects-

a) Freezing stage-
1. Puffing - Top part of cake separate from lower part, sometimes rising to the shoulder of vial.

This typically happens as a result of incomplete freezing prior to pulling a chamber vacuum for primary drying phase.

It is important to allow adequate time for freezing (and temperature conditioning) before pulling chamber vacuum.

b) Primary drying stage-
1. Meltback - Usually occurs as a result of eutectic melting of crystalline components of the formulation (eg- Glycine or mannitol).

The frozen part of the plug melts and dissolves the dry portion of the plug, leaving (at its worst) a concentrated solution in the bottom of the vial.

The problem is avoided by staying below Tg (and so below eutectic temperature of crystalline components).

A similar product appearance will result if vacuum is lost before primary drying is complete, or if secondary drying is begun prematurely.

2. Collapse - Product affected by collapse is not just aesthetically unacceptable, there may also be impact on any protein active, with conformational changes affecting stability.

Tc is usually slightly higher than the Tg.

If the self temperature is too high during primary drying, the rate of ice sublimation will exceed the rate at which the sublimed ice can penetrate the dried layer of the plug above it.

The result will be an increase in product temperature above what is usually referred to as the 'collapse temperature' Tc, resulting in loss of structure of the plug or collapse.

3. Skin formation and meltback - Sometimes impermeable skin forms on the top of the product (this is usually formulation problem rather than a lyophilization cycle problem).

If temperature within the plug rises too high it will melt beneath the skin.