Fill finish is clearly a critical step in the biopharmaceutical manufacturing process.
Single-use filling needles manufactured from either polyether ether ketone (PEEK) or stainless steel have kept pace with advances in manufacturing, and proven themselves across a broad range of filling applications from liquid injectable pharmaceuticals to biologics and vaccines. This versatility is not their only advantage. As part of an autoclavable or gamma irradiated single-use fluid path, sterilization of single-use needles is simple. A completely disposable polymeric solution, however, removes the obvious cost and time associated with cleaning validation and as such is an attractive alternative to stainless steel. The potential for vial damage due to needle strikes is also significantly reduced thanks to the inherent flexibility of polymeric materials. However, the challenge, as with any needle within a biopharmaceutical filling process, is in reducing the potential for a needle to clog or drip and cause costly interruptions that can so easily derail the most well controlled of filling processes
So, why do filling needles clog or drip and how can we effectively reduce these effects? These questions can be answered when we take a closer look at needle design, needle size and the physical attributes of a final formulation.
How Needle Internal Diameter Size Can Affect Final Fill Performance
Fill volume requirements that have tight tolerances will shape an initial decision on the size of needle selected. Needle internal diameter, will influence dosing accuracy and precision. The size of the needle should also be determined by assessing the characteristics of the liquid and the desired filling speed. It is also important to assess the inner diameter of the container neck to eliminate potential for spillage and to provide sufficient space for air to be expelled as the liquid fills the container. Smaller, low diameter needles may also be used to restrict the filling speed to maintain the filling accuracy and to avoid any drip formation.
Consideration for Needle Size and Formulation Viscosity
Clogging is generally observed towards the end of a long fill run or after a fill interruption, due to drying of a fluid, at or close to the tip of the needle. This results in complete or partial needle blockage. With smaller needle sizes, the chance of a needle clogging close to the needle tip are higher, especially in the case of process interruptions or if there is a requirement for lengthy hold times during filling. The clogging can be attributed to water evaporation – the fluid rapidly establishes a viscous film at the drying front that can easily become elastic, thicken, or solidify. This drying-induced needle blockage is typically seen with high concentration/high viscosity formulations containing high molecular weight species (polymer, proteins, mAbs, etc.) Pumping viscous solutions like these through small–diameter tubing and small diameter needles can generate shearing and other effects that can also degrade protein-based formulations.
Experiments confirm that it takes longer for a larger needle to clog when compared with a smaller needle. The reality is that when optimizing needle size, fill volume and viscosity of formulation should be taken into consideration.
Factors to Reduce Dripping and Clogging: Suck Back Optimization and Material Hydrophobicity
Optimization of pump settings to adjust the level of fluid retraction in the needle lumen is observed to affect the rate of formulation drying. Without optimization, this ‘suck back’ can lead to a deviation in filling accuracy, product loss and extended interruption time during a filling operation. One way to minimize this is to lower the viscosity of a high concentration drug product by carefully selecting the formulation excipients. Process capability of large-scale batches is shown to improve with optimized suck back control.
It has also been shown that the material of the needle tip plays a dominant role in slowing down formulation drying and needle clogging, due to surface interactions between the liquid and the needle material. Needles manufactured from hydrophobic materials allow the liquid plug to form away from the needle tip, which slows down formulation drying rates. Even if the liquid is not sufficiently sucked back (i.e., leaving a drop at the needle tip), the dried mass can be easily dislodged at the tip of the hydrophobic needle, preventing clogging.
How Velocity of Liquid Flow Affects the Drip Formation
It is clear that an inconsistent velocity profile will impact volumetric accuracy across a batch during filling. However, The experiments have shown a direct link between fluid flow velocity and droplet formation. The slower the fluid flow, the higher the risk of droplet formation and the larger the droplet size. It is also true that increasing the flow of an outer boundary layer close to the needle surface, whilst keeping the inner layer flow rate constant, will cause the droplet size to reduce. It can therefore be reasonably assumed that reducing surface roughness of the bore will reduce the thickness of the boundary layer. This will allow an increase in fluid velocity in these regions, and thus reduce the risk of droplet formation.
The Trend Towards High Concentration/High Viscosity Formulations
Monoclonal antibodies (mAbs), as an example, are typically given as intravenous infusions, but subcutaneous administration is fast becoming the preferred alternative, especially for patients with chronic diseases who require frequent dosing of the mAb over their lifetime. When developing mAb formulations for subcutaneous administration, volume and viscosity are crucial considerations. Because the subcutaneous space limits the volume that can be delivered, mAb formulations tend to be developed as highly concentrated solutions, often in the range of hundreds of mg/mL, which consequently give rise to high viscosities. Additionally, various salts, sugars and other excipients may also contribute in increasing the viscosity of a final formulation.
Viscosity increases exponentially with increase in concentration. Highly concentrated protein solutions can have viscosity levels that present special challenges in drug product fill-finish operations. Selecting tubing with a different Shore hardness, internal/external diameter, and final configuration all play their part in managing viscosity effects.
The Importance of Needle Construction
Good needle design and construction can provide rigidity while strictly controlling lumen diameter, wall thickness, surface smoothness, and shaft straightness. Filling needles typically plunge into the primary container and start filling close to the bottom of the primary container, while gradually rising to the top at the end of the dose cycle. Therefore, needle straightness during such operation is essential to avoid any contact with the container. Filling needles were traditionally made from stainless steel but in recent years reinforced high performance plastics such as polyether ether ketone (PEEK) have shown to be identical, if not more accurate and consistent, in target dosing volume.
In summary, when comparing candidate filling needle performances, end users should assess the following aspects with their drug product: filling accuracy, tendency to drip, tendency for drug product dry out on the needle tip, and straightness when filling desired target container.
Mihir Kumar Patel
Application Specialist, Single Use Technologies
Pall Life Sciences