Many types of cake appearance flaws can indicate missteps in the manufacturing pipeline.
by Susan Thompson, Technical Director at VxP Pharma
While lyophilized drug products are typically not intended for consumer display, the composition of their final cakes can still play a major role in their success or failure in the marketplace. In fact, some flaws in cake appearance actually can have clinical impacts; for example, product caught between the vial and stopper may indicate compromised sterility, as well as inconsistent doses between vials.
In addition to clinical hazards like these, non-uniform cakes can result in serious concern on the end user’s part. When cake appearance fails to align with the description on the packaging, clinics and other users may well lodge complaints with the manufacturer, expressing worry about poor-quality manufacturing (whether this is actually the case or not). Indeed, inspectors in certain markets closely examine the cake appearance of every product they plan to purchase. In these cases, non-uniform or otherwise flawed cakes may inhibit regulatory approval, or even prevent access to those markets altogether.
For all these reasons, the formulation and final appearance of lyophilized cakes is far more than just a cosmetic issue. All the following issues with cake formation may indicate significant issues with the formulation or good manufacturing practices (GMP) somewhere in the manufacturing pipeline, and are deserving of careful analysis.
Uneven distribution or settling of the lyophilized cake may point back to issues in the drying phase, or problems with the cake formulation.
During the primary drying phase, lyophilized cake powder may sometimes be partially “blown out” of the vial. This may happen due to melting, but a more common cause is an issue with the cake’s formulation, resulting in a cake matrix that lacks the cohesion to withstand the force of escaping water vapor. This is particularly common with formulations containing organic solvents or low levels of total dissolve solids. It should be considered a serious issue, as partially ejected cake matter can compromise the vial’s seal.
Dried product can also accumulate between the vial and stopper if droplets are left around the stopper’s neck during initial filling. This residual material then solidifies throughout the freeze-drying process, compromising the integrity of the seal as it expands and contracts in response to shifts in temperature and dryness. Since dried product between the vial and stopper poses a serious risk to product integrity, any vials presenting this issue will have to be discarded.
After a cake is removed from the lyophilizer, it may have separated from the vial’s inner wall and risen slightly off the bottom of the vial. The exact physics of this process remain largely unstudied, but it may be related to the pressure of water vapor that rises upward during primary and/or secondary drying. Lifting tends to occur most commonly when the cake’s mass is low. It may or may not be indicative of a seal breach, but it may indicate that the drying stages should be more closely monitored, or that the formulation should be slightly modified to increase its mass.
Bubbles, rings, meltback, and other residue inside the vial may indicate flaws in freezing and/or drying.
When a small amount of eutectic melting occurs during the drying stage, the solution becomes saturated with air, resulting in the formation of small air bubbles within the concentrate during freezing. These air bubbles may then expand, rising to the surface of the solution; and if the formulation’s chemical properties cause them to remain structurally stable during drying, they may give the cake a “puffed” appearance. The pharmacological impact of cake puffing (if any) is not well-studied; however, entire batches of puffed cakes may be indicative of a mechanical problem.
Some cakes, on the other hand, may appear “shrunk,” having pulled away from the walls and bottom of their vials. This appears to be correlated with an abnormally high amount of unfrozen water during the freezing stages, which evaporates during the drying stages, contracting the volume of the cake. When the vials and handled, the structural stress within the cakes causes them to crack.
If some of the solution fails to drip all the way down to the bottom of the vial before freezing is complete, or the vials are excessively agitated after filling, they may display the distinctive “lyo ring” of residue after drying. While the lyo ring (or minor dried splashes on the vials’ inside walls) may not impact product quality, it may be indicative of poor handling, or inadequate control of the fill/finish stage.
Another potential problem in the drying phase is “meltback,” a somewhat vague term that typically refers to the formation of ice around the beginning of the secondary drying period. This issue can have several causes, including loading issues, or lack of even contact between the vial and the heating element, resulting in uneven heat transfer. In some cases, meltback may also indicate an issue with the formulation itself.
Lyophilized cakes that are slanted, cracked, or otherwise physically damaged may be indicative of issues with the loading or transportation processes.
Many other cake malformations can result from a wide variety of mechanical issues at various stages of the manufacturing process. One of the simplest and most common issues is slanting: cakes come to rest at an angle within their vials. This typically occurs when some vials within a cluster lose contact with the shelf. It can create serious problems with product stability, however, as slanted cakes may dry with higher residual moisture then their non-slanted counterparts.
In some cases, a film may form on the interior surfaces of vials. While this “fog” might at first glance appear to be related to excess water vapor or improper drying conditions, it more frequently results from agitation of the vials’ contents as they are loaded into the lyophilizer. Because fogging can lead to buildup of residue around the seal of the vial, it is a cause for serious concern, and must be addressed by taking handling vials more gently during loading.
Breaking, chipping and dusting of cakes are also typically indicative of problems with handling; particularly if the product that emerges directly from the lyophilizer appears uniform and evenly settled. Transportation stresses frequently fragment cakes, causing them to arrive at their destinations with dust or chips that were not present at the manufacturing facility. Although minor dusting and chipping may not impact product quality, distributors should be cautioned to avoid unnecessary agitation during transport.
In all these cases, although unusual appearance of cakes may not in itself indicate compromised product quality, the causes of such alterations bear closer investigation. Even if the product’s efficacy remains fundamentally unaltered, batches of vials caked with interior residue or dust, or containing cracked or fragmented cakes, are likely to spark concern (and complaints) from end users. Thus, most unusual cake appearances should be treated as unacceptable, and as indicative of flaws in the manufacturing process that must be isolated and addressed.
In addition to being an author and speaker, Susan Thompson serves as the Technical Director of Indianapolis based VxP Pharma.