What is acceptable appearance in Lyophilized products-I

Hello folks, 

Working with lyophilized products is always interesting. If lyo cycle went well and everything goes fine then no issues. But, Lyophilization is more tricky when unexpected variations happened during lyo cycle. This results in different kinds of issues majorly, related to appearance of product. 

Normally, after lyophilization the resulting product may be an intact cake or powder or some kind of flakes depending on the type and concentration of ingredients in the formulation. During visual inspection, there will be collection of acceptable appearance vials along with  separation of vials with defects. So, it is important to determine which cake is acceptable and which is not. Sajal patel et.al have published a wonderful article about what is an acceptable cake after lyophilization and what is not acceptable. 

Let us have a look at few cakes with issues.

After lyophilization, drug products are subjected to visual inspection. These visual inspection parameters include cake appearance, extraneous particulate matter, and assessment of minor, major, and critical defects of the lyophilized drug product. The appearance of an ideal lyophilized cake should be uniform and elegant without any defects and should have adequate mechanical strength to avoid cake disruption during handling and distribution. 

Collapsed cake:

This is the most common defect found in lyophilized product. This may or may not be a critical defect. Also, the collapse is crumbling of lyophilized cake. This may be partial or complete. 

Left vial: Complete collapse, Centre vial: Partial collapse, Right vial: No Collapse.

Reason : Most of the time, Collapse may occur during primary drying when product temperature exceeds the collapse temperature (Tc) of formulation. 

Impact: Increased residual solvent content (If organic solvents are part of formulation), increased reconstitution time. Some studies indicating, it is just cosmetic issue and there is nothing to do with stability of drug product. 

What to do: The impact of collapse on critical quality attributes shall be evaluated and the decision shall be taken as per the impact on CQA. 

Sometimes, the collapse may not necessarily at the initial stages of drug product but may also occur at the storage during stability particularly at high temperatures. This is attributed due to the glass transition temperature  is near to the product storage temperature.

various degrees of cake collapse during storage under stressed conditions.

 

How to avoid Collapse: Just keep the product temperature below collapse temperature or glass temperature of the product during primary drying. 

Melt back: 

Not to mean it as a synonym of collapse. Many opinions on melt back as either melting of frozen matrix during the freeze-drying process or collapse. But actually melt back is the presence of ice at the starting of secondary drying. it means the removal of ice during primary drying is not complete. During the secondary drying, the remaining ice is not removed. When the process is finished, the ice will melts and wet the product. Sometimes melt back could also be a form of collapsed cake.

Melt back from Right to left on the order of proportion

Ice crystals after primary drying

Reason & impact: Meltback usually indicates poor formulation and process understanding and, hence, product with meltback is rejected.

Rectification: The process should be modified by setting longer primary drying time to ensure complete removal of ice from the cakes without increasing the primary drying temperature.

Product Blow out : 

It is some part of partially dried or completely dried product coming out of the vial during either primary drying or secondary drying. Sometimes the product may stick to the stopper also. It is also called as product ejection. 

Blow out of product during primary drying

Blown out product 

Ejected product deposited on stopper region 

Reason: It is more common in formulations containing organic solvents such as t-butanol or ethanol, as well as in formulations containing a very low level of total dissolved solids, resulting in a poorly cohesive cake (i.e., a more fragile cake).

Impact: Product ejection is generally indicated by solid material in the “shoulder” and neck area of the vial. It should be considered as a critical defect because the solid material is likely also present between the sealing surfaces of the vial and the closure, which would compromise the sterility assurance of the product (container closure integrity failure) and the deliverable dose, thereby endangering the patient.

Rectification: By optimizing the primary drying duration and decreasing the vacuum of the primary drying step. Increasing the concentration of dissolved solids can be considered.  Using higher capacity vial. By combination of two or more before said practices the blow out can be avoided.