The fill/finish operations for biotherapeutics is a critical, but often overlooked hurdle in the production process for these products, especially for early phase clinical evaluation. From a processing perspective the products are complex and fragile however terminal sterilization is not an option. All products need to be sterilized by point of fill filtration, which from a regulatory perspective is a challenge in itself.

From an operational perspective the products are often highly potent, hugely expensive and complex to produce for early phase studies, plus only very small amounts of material are available. In some cases only 1L of drug substance may have been produced at costs in excess of $500,000. One impact of this is that losses incurred during the filling operation need to be kept to an absolute minimum, not least to ensure that sufficient filled drug product is available to support planned clinical studies.

It is therefore essential that the approach taken by fill/finish facilities to produce the drug product addresses these issues and seeks to reduce process losses to an absolute minimum while retaining regulatory compliance with regards to testing and quality assurance for these operations.

In 2009, a state-of-the-art facility in Matfors, Sweden was approved by the regulatory authorities for provision of fill/finish services for clinical and commercial supply, meeting the rigorous sterility requirements in accordance with aseptic manufacturing procedures. It was designed to perform in-line 0.22μm sterile filtration integrated in a fully disposable system to fill either vials (0.5–100mL) or pre-filled syringes (0.5–3mL).

During the five years the automatic fill line has been operational, not a single vial or syringe has been contaminated in the annual validation programs, which emphasizes the filling lines excellent design. This facility approach was, from the onset, designed around the use of single use filling systems, to enhance operational flexibility, while retaining the highest levels of regulatory compliance. Figure 1 shows an overview of the fill/finish set up including classification of surroundings.

Shortly after a successful validation of the fill line, regular manufacture of a commercial small-molecule API was running in the facility. For this low cost API, no special regards were taken to minimize drug product losses and the system was both flushed and the filter integrity tested with the bulk solution. In total, up to 1L of bulk was used and discarded for these purposes. In 2011 the facility was acquired by Cobra Biologics, a leading CMO for proteins, plasmid DNA and viruses production, and the requests for fill/finish of biopharmaceuticals increased accordingly.

Many of the products generated by Cobra are for early phase clinical evaluation and as such are often products in relatively small quantities of 20% of the production batch, which is clearly not acceptable. To better accommodate these high-value, small-volume fillings, a project was initiated to modify the existing fill process with the aim of minimizing product losses (Figure 1). What follows is an overview of fill/finish line design and a summary of improvements leading to reduced fill volume losses.

Objectives

The initial project focused on a detailed assessment of the equipment and filling procedures; here a number of challenges and constraints for the reduction of system volume losses were identified. In order to minimize re-validation work and staff re-qualification, and hence costs, major design changes were excluded in the first instance. Therefore the project sought to use the existing disposable system design and with only minor changes; smaller fill bags and tubing with smaller diameter, to enable the desired volume loss reduction. With these constraints at hand and by comparing the design and capabilities of the fill/finish suite at the time of approval with current expectations on a successful small-volume, high-value fill, the goals were set for the project.

At the start of 2009:
• Matfors pioneers the field of disposable technology;
• Custumers required automatic aseptic filling of large volume of low-cost drug substance; and
• Manufacturing losses: ≈ 1L.

Goals today:
• Adapting existing automatic fill/finish systems;
• Adopting disposable solutions to custumer-specific needs: small volume of high-cost drug substance;
• Improving working procedures; and
• Manufacturing losses: ≤100mL.

Method and results

The entire fill process including staff, equipment and process flow was carefully mapped and key target points during both filtration and filling to be addressed were identified.

Key target points during filtration:
• Saturation of filter;
• Remaining substance in compounding bag; and
• Loss during filtration.

Key target points during filling
• Losses due to filling weight adjustment;
• Losses during set up of the filling tubes;
• Loss of fluid due to failing check weights at end of filling; and
• Loss of fluid trapped in the tubes and bag (line losses).

In a series of experiments, various modifications to address the above key points were evaluated. As a start, smaller sized formulation and filling bags were installed as well as tubing with smaller diameter and a sterile filter with a smaller filter area. By working with the staff to determine the best way to practically handle the bags and tubing the first steps were taken to minimize the line losses in terms of incomplete emptying of those (Figure 1).

By using just one of two fill needles available in the line, the number of fill weight controls was reduced to half. To address the issue of losing drug product solution when saturating/rinsing the sterile filter before the fill, a procedure where first water for injection and then buffer of an appropriate composition was used to flush the filter was developed. How far into the fill correct fill weight controls could be obtained was also challenged to make sure as much as possible of the drug product solution was filled before the weight control failed.

To verify the effect of the modifications three test runs were performed; the first with water and the other two with buffer. Between 1.0L and 1.5L of water or buffer was sterile filtered into the 10L filling bag and then filled into around 400 vials, size 10mL, with a fill volume of 3 mL per vial. The total loss of drug product solution could in all runs be reduced to less than 100g of solution, compared to up to 1L loss with the un-optimized methodology.

Conclusion and Outlook

Successful improvement of the fill process, based on a commercially available filling equipment and tubing sets, resulted in a more than 10-fold decrease in product waste. This was achieved by careful mapping of the fill process followed by small changes in the working procedures and the choice of disposables. Having optimized the filtration process, Cobra’s on-going project will be to further minimize volume losses, enhancing customer product yields, by thorough review of drug product sampling and validation procedures.