A Single-Use, Clinical-Scale Filling System … Multiple Solutions
Product: Allegro™ Single-Use Mixers
In 2012, Merck & Co., Inc., a leading pharmaceutical company, commissioned the replacement of an existing syringe-filling machine in its clinical manufacturing facilities for finished drug products. They wanted to add a single-use filling wetted path to their West Point, PA, facility.
One of the biggest challenges the commissioned company would encounter would be replacing a cleanable filling line containing stainless steel needles. The replacement would ensure that an alternative system could satisfy all critical performance parameters established for an existing process. Upgrading the single-use technology was also important because the manufacturing facility had a diverse range of sterile products that would require a filling line capable of supporting those products, including multiple dosing technologies and other configurations.
The project required a special emphasis on defining primary user requirements for it covering a broad range of items, activities and procedures. After a competitive bidding process, Bausch+Ströbel, a German based company that specializes in machines used for the pharmaceutical industry, was selected for the job.
Bausch+Ströbel’s team of experts decided that the SFM 5110 filling machine would be the best fit to meet the facility’s needs. The SFM 5110 filling machine can process syringes, vials and cartridges using nests or tubs of final containers. Additionally, the machine is suitable for batch sizes produced in formulation and development laboratories.
Upon further review, Bausch+Ströbel recommended use of a surge vessel to maintain a constant pressure head on the peristaltic pumps. The company sought out Pall to collaborate on designing a single-use filling wetted path with a two-dimensional (2-D) surge bag. Pall has over 30 years of experience creating innovative solutions and adapting to changing market conditions. Their experience and expertise made them the perfect partner for the job.
Smooth Integration of Barrier Technology
A critical decision had to be made between installation of an isolator-based system or a RABS. However, the single-use system had to be installed in an existing cleanroom area rather than a new facility, a requirement that became an important consideration in selection of a suitable barrier system. Several factors were considered when the team assessed the requirements for physical and aerodynamic barriers to protect the filling line from contamination.
They had to make sure the technology satisfied regulatory requirements, standards and guidelines. The system had to support operational demands of clinical drug-product manufacturing. It was also important that the process followed the existing staffing model for maintenance. Additionally, the barrier technology had to work with existing infrastructure for sterilization. And the new process was required to be smoothly integrated into an existing cleanroom infrastructure.
After evaluating risks, including a review of the potential failure modes and effects for the new syringe filler and single-use wetted path, a passive RABS was chosen. The facility would benefit from its increased protection of drug products, as well as ease of installation into the existing cleanroom. This solution also provided cost advantages over an isolator-based line option because of reduced changeover time, simplified automation, smaller footprint and use of existing sterilization infrastructure.
After accessing the risks, it was determined that project was ready to move forward. The 2-D biocontainers were manufactured using co-extrusion of bag layers, a process that minimizes the potential for introduction of particulates. To guarantee container integrity, all biocontainers were submitted to a leak test based on pressure-decay measurement before they were assembled in single-use systems.
During validation of the biocontainer manufacturing process, significant tests were performed both before and after radiation sterilization to verify that container integrity was not affected by the sterilization process. Components underwent a robust validation for biocompatibility and extractables. The validated sterile fluid-path claim was based on ISO 11137 for radiation sterilization of medical devices.
Engineering drawings and bill of materials were approved by the customer, and formal change-control processes are in place. Finally, material use is controlled with SAP materials management logistics software from Sapphire Systems.
Creative by Design
The design was evaluated as part of the FAT for the syringe filler at Bausch+Ströbel’s Ilshofen facility in Germany during September 2013 with participation of a single-use systems expert from Pall. Some design modifications were proposed based on observations during that testing. Acceptable dose control and system fit–finish were demonstrated with water and a product surrogate. Finally, Merck product development scientists and manufacturing staff provided additional VoC feedback on the prototype design. Through careful consideration, the design was perfected and approved.
Control of particulates during single-use system manufacturing and in the application of those systems is a topic of special focus within the biopharmaceutical industry. In 2014, the Bio-Process Systems Alliance (BPSA) published specific guidelines and recommendations for testing, evaluation, and control of particulates for single-use process equipment. Those guidelines state, “The goal of suppliers, end users, regulators, and standards-setting organizations should be to minimize particulates in drug products without placing unnecessary expectations for minimal safety/ quality gains.”
The risk of particulate contamination is most significant when filling products downstream of final sterilizing filtration. To mitigate this risk, a flush or purge step can be included before filling begins, but that procedure was deemed impractical at pilot scale because of limited drug-product availability. Merck had chosen to discontinue two earlier projects on single-use systems during proof-of-concept testing in 2012 because elevated levels of particulates were identified in three other suppliers’ biocontainers during testing.
A 2012 team rinsed the inner biocontainer surfaces with water that had been filtered through a 0.2-µm MilliQ filter from MilliporeSigma. The resulting rinses passed through a one-inch membrane filter, which the team then examined using a stereo microscope. Collected fibers ranged from submillimeter to several millimeters in length.
Particulates can be eliminated by incorporating a clarifying filter downstream of the sterilizing filter, an option first incorporated into the prototype design. However, VoC feedback from product development teams recommended removal of that clarifying filter from the prototype because its inclusion would require additional studies for support. Therefore, a new study was conducted to evaluate particulate levels in a Pall Allegro 1-L biocontainer in support of removing the clarifying filter from the prototype design. The studies also included simulated production conditions.
To simulate flushing of particulates from the biocontainer assembly, we filled a 45-L bottle with polysorbate 80 solution with similar properties to finished drug product. To recover and identify any particulate matter, we pumped that solution through a particulate capsule filter into the 1-L biocontainer, then pumped 1-L aliquots through three analyzing membrane discs.
Only one to three fibers showed up in each test sample, indicating a dramatic improvement over results obtained in the 2012 projects. The detected fibers (polycarbonate, cellulose and polyethylene terephthalate) are common in the laboratory environment. The test results showed that the fibers did not originate from the biocontainer itself. Confirming the suitably low particle counts for the biocontainer justified the removal of the particulate filter from the prototype design. The single-use system design was finalized and it was time to evaluate its performance with an engineering batch.
Final Design and Implementation
In November 2014, the single-use system (supplied as a gamma-irradiated, double-bagged assembly) was tested in an engineering batch. Stress tests and a visual inspection of filled syringes were completed. Next, the team evaluated the particulate levels against historical process capability to ensure the clinical-scale filing system was truly fit for the challenge. Finally, after assessing the entire process, the manufacturing team was trained and facility was ready to go.
The final system design incorporates a Bausch+Ströbel SFM 5110 machine and a Pall single-use filling wetted path. The newly installed single-use filling system improved the filling dose control for sterile syringes thanks to Bausch+Ströbel’s SFM 5110 machine and a Pall single-use filling wetted path. Updating the single-use filling system enabled the manufacturing department to achieve a broader implementation of single-use technologies.
Approximately 7,500 syringes were filled with a relative standard deviation in dosing of 0.46%. Such dosing accuracy met requirements listed in the filling machine URS. No visible particulates were observed in manual visual inspection using normal production procedures without magnification. The implementation of the single-use filing system was a crucial upgrade to its manufacturing capabilities. The new system more than satisfied all the facility’s performance parameters. It also backed the company’s emerging collection of sterile products that require versatile filling lines capable of accommodating them. Best of all, Merck & Co., Inc., was able to meet all of their filling needs and the new system positioned them to maintain their status as an industry-leading manufacture for years to come.