Drips and clogs: Overcome sterile filling needle challenges

Fill-finish is a critical step in biopharmaceutical manufacturing. Issues such as needle clogging or dripping can affect product quality, dosing accuracy, process efficiency, and product loss.

This article reviews why filling needles drip or clog during sterile fill-finish operations, and how needle size, material selection, liquid flow, formulation viscosity, and suck-back settings can help reduce these risks.

Single-use filling needles manufactured from either polyether ether ketone (PEEK) or stainless steel have kept pace with advances in biomanufacturing 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. While both PEEK and stainless steel single-use needles are available, PEEK needles offer a fully disposable alternative to conventional reusable stainless steel needles, eliminating the cost and time associated with cleaning validation. The potential for vial damage due to needle strikes is also significantly reduced thanks to the inherent flexibility of polymeric materials, such as PEEK. 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 easily derail the most well controlled filling processes.

Why filling needles drip or clog

Dripping and clogging are influenced by three key factors: needle design, needle size, and the physical attributes of the drug product formulation. Understanding these variables helps teams improve fill-finish efficiency, reduce interruptions, and minimize product loss.

How needle internal diameter size can affect final fill performance

Fill volume requirements with tight tolerances will shape your initial decision on what size needle to select. 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, helping 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 during process interruptions or when lengthy hold times are required during filling. The clogging can be attributed to water evaporation—the fluid rapidly forms 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 (such as polymers, proteins, and mAbs). Pumping viscous solutions through small-diameter tubing and needles can also generate shearing and other effects that may degrade protein-based formulations (1-5).

Experiments confirm that larger needles take longer to clog compared with smaller needles. When optimizing needle selection for fill-finish processes, it is therefore important to consider needle size alongside fill volume and formulation viscosity (6,7).

Factors to reduce dripping and clogging: suck-back optimization and material hydrophobicity

Optimizing pump settings to adjust the level of fluid retraction in the needle lumen is known to affect the rate of formulation drying. Without proper 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 these effects is to lower the viscosity of a high-concentration drug product by carefully selecting the formulation excipients. Process capability in large-scale batches has been shown to improve with optimized suck-back control.

It has also been shown that the material of the needle tip plays a key role in slowing formulation drying and needle clogging, due to surface interactions between the liquid and the needle material.

Needles made from hydrophobic materials cause the liquid plug to form away from the tip, which slows formulation drying. Even when the liquid is not fully drawn back—leaving a small droplet at the tip—the dried residue can be more easily dislodged from the hydrophobic needle surface, reducing the risk of clogging (8).

How velocity of liquid flow affects the drip formation

An inconsistent flow velocity can reduce dosing accuracy and increase the risk of droplet formation during filling. However, experiments show 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 in the outer boundary layer close to the needle surface, while keeping the inner layer flow rate constant, will cause the droplet size to reduce. It can therefore be reasonably assumed that reducing the surface roughness of the bore will reduce the thickness of the boundary layer. This will allow a higher fluid velocity in these regions and thus reduce the risk of droplet formation.

The trend towards high-concentration, high-viscosity formulations

Monoclonal antibodies (mAbs), for example, are typically administered 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 delivery, volume and viscosity are crucial considerations. Because the subcutaneous space limits the volume that can be delivered, mAb formulations are often developed as highly concentrated solutions, often in the range of hundreds of mg/mL, which results in high viscosities. In addition, various salts, sugars, and other excipients can further increase the viscosity of the final formulation (drug product) (1-4).

Viscosity increases exponentially with concentration. Highly concentrated protein solutions can therefore present special challenges in drug product fill-finish operations. Selecting tubing with appropriate Shore hardness, internal and external diameter, and final configuration can help manage viscosity-related 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, gradually rising to the top at the end of the dose cycle. Therefore, needle straightness during 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 deliver equal, if not more accurate and consistent, target dosing volume.

In summary, when comparing filling needle performances, manufacturers should assess the following aspects with their drug product: filling accuracy, tendency to drip, tendency for drug product to  dry out on the needle tip, and straightness when filling desired target container (9).

Our aim is to provide a wide range of internal diameters of filling needles manufactured from GMP-specified materials and designed to minimize clogging interruptions during the final fill process. Our Allegro™ single-use filling needles meet these criteria and are single-use and ready-to-use, a pre-requisite for integration into single-use systems.

Learn more about Allegro single-use filling needles.