November 11, 2022 PAO-10-022-CL-09
The sterile fill-finish market has markedly evolved in the wake of the COVID-19 pandemic. The very high demand for fill-finish of the mRNA vaccines against the SARS-CoV-2 virus caused upheaval in the sector, with many drug makers losing their production slots at contract development and manufacturing organizations (CDMOs). A few outsourcing partners — like PCI Pharma Services — elected not to pursue COVID-19 commercial sterile manufacturing projects but rather to provide capacity, not only to existing clients but to biopharma companies with non-COVID-related sterile fill-finish development and manufacturing projects.
The pandemic also highlighted the challenges associated with fragmented and diverse supply chains for different parts of the drug manufacturing process. Companies were often having their APIs manufactured in one country, purchasing excipients from suppliers in another country, and then relying on CDMOs in yet another location for final product formulation and filling. There is consequently increased interest in accessing end-to-end solutions from local outsourcing partners and raw material suppliers to streamline supply chains, reduce costs and lead times, and mitigate risk.
The greater demand for fill-finish services is not only attributed to COVID-19-related products but also to the general growth of the biologics sector. At PCI Pharma Services, for instance, more than 50% of our fill-finish projects are large biomolecules. The increased industry demand has resulted in capacity shortages, not only for fill-finish activities but also for the production of excipients and various other consumables used in the fill-finish process.
Another trend is the growing need for lyophilization services; many biologics are not stable in aqueous solutions and benefit from lyophilization (freeze-drying) with respect to stability and ease of storage and transportation. There is also a growing preference for prefilled syringes (PFS), owing to their ease of administration and greater convenience for patients and caregivers, as this type of device ensures that the patient receives the correct dose. In addition, PFS do not need to be overfilled, reducing the product losses that must be accepted with traditional vials. With increasing demand and the persistence of supply chain challenges, just-in-time procurement models are no longer applicable; manufacturers must be very proactive in stocking these materials to ensure that sufficient supplies are readily available for any given sterile fill-finish development or manufacturing project.
For a similar reason, the interest in robotic sterile fill-finish (SFF) systems is increasing, because robotic systems greatly reduce line loss compared with what is observed in traditional sterile filling operations. Robotic systems also enable filling of smaller quantities in prefilled syringes for early-phase clinical trials, helping save valuable and limited API and reducing costs. As a result of robotic sterile filling platforms being able to pivot between vials, prefilled syringes (PFS), and cartridges for auto-injectors, biopharma companies no longer need to only use vials for early-stage development studies and then switch to a PFS device as the program advances though clinical trials. Access to PFS solutions earlier in development enables the collection of stability data to support regulatory filings and creates additional value for those small biotechs looking toward the future and possible acquisition by a big pharma company.
Robotic systems comprise filling lines installed within isolators. Ready-to-use (RTU) components (e.g., vials, syringes, caps, stoppers) come pre-sterilized and are preloaded into the robotic system. After decontamination of the preloaded isolator using vaporous hydrogen peroxide, the robotic system is ready for the sterile filling operation. All processing of the vials/syringes, filling, capping, and stoppering are performed by the validated automated system without any human intervention. As a result, there is less risk of operator error and cross-contamination. Overall, the fill-finish process is completed rapidly and more accurately with greater sterility and quality assurance, maximizing patient safety.
While the use of robotic platforms for SFF operations is relatively new, demand surged during the COVID-19 pandemic, as these systems provide a reasonably rapid means of adding SFF capacity. The rate at which new systems have come online has consequently increased over the last two years. Of course, these robotic technologies have limitations with respect to the maximum batch size and are not suited for products that require filling tens of thousands of vials. The smaller batch sizes combined with quicker changeovers, however, make robotic SFF systems ideally suited for use by CDMOs to provide a flexible, speed-to-patient aseptic manufacturing solution.
Clearly, one of the biggest determiners of the appropriateness of robotic SFF is batch size. Another is the configuration of the trays that hold the vials or syringes within the isolator. Not all configurations are appropriate for all vials, syringes, or cartridges.
Additionally, robotic SFF systems are ideally suited for early-stage projects, particularly phase I, II, and smaller phase III studies. Generally, the vial/syringe configuration has not yet been established for these early-phase programs, thus allowing more flexibility to fit projects into robotic SFF systems.
The limited configurations of robotic SFF platforms are beneficial with respect to overcoming supply chain concerns. With only a certain number of configurations possible from a vial and cap standpoint, there are few consumables that must be maintained in inventory. Pre-ordering consumables, including caps, vials, stoppers, and syringes, therefore becomes simpler.
In response to the evolving biologic industry landscape and as part of PCI Pharma Services’ global strategy to increase our sterile fill-finish capabilities and help alleviate the worldwide capacity shortage for sterile drug manufacturing and packaging, we continue to invest and grow our service offering through acquisition and investment in state-of-the-art technology and our people.
To that end, PCI acquired LSNE, a CDMO differentiated by its high-quality GMP aseptic fill-finish and lyophilization capabilities, at the end of 2021 and subsequently invested in state-of-the-art robotic aseptic filling platforms. We purchased two leading-edge Cytiva Microcell Vial Filler units for clinical-scale manufacture, one located in San Diego, California, and one in Melbourne, Australia, and installed a large-scale Cytiva SA25 Aseptic Filling Workstation at the San Diego facility. As a result of these strategic investments, PCI is able to deliver a seamless, end-to-end robotic SFF solution for large molecule, pre-formulated biologics, including monoclonal antibodies, fusion proteins, and bispecific antibodies from small to larger scale, supporting our clients through their drug product life cycle toward commercialization. The additional capacity, agility, and shorter changeover times that can be realized with the robotic SFF systems typically mean that prospective clients do not have a long lead-time before there is an opening in the sterile manufacturing schedule at either our San Diego or Melbourne facility.
The automated, gloveless robotic aseptic filling process is carried out within a confined isolator space, meaning only so many vials/syringes and press-fit caps can be processed at any one time. Preloading, decontamination, filling, capping, and unloading takes between 90 minutes to two hours; therefore, the output of filled vials/syringes produced in a shift or a working day is determined by vial/syringe size, fill volume, and product characteristics. Even with these limitations, a batch size of approximately 20,000 2-mL vials can be achieved using the Cytiva SA25 system. In the Microcell Vial Filler units, 300 vials can be loaded at one time, but the changeover cycle is shorter, leading to a maximum batch size of about 1,800–2,100 2R vials, depending on the fill volume. The fast changeover and agility of these technologies make them suitable for the production of both personalized medicine batches and clinical trial supplies, delivering true speed to patients.
Operation of the robotic aseptic platforms is controlled by an easy-to-use human-machine interface. Once the components and process parameters are loaded into the system, the process is initiated by pressing a start button, with the rest of the process proceeding via robotic filling with no human intervention. PCI leveraged the expertise of our legacy LSNE colleagues when installing, qualifying, validating, and programming the actual filling operations, reducing the time needed to get the platforms operational and ready for our clients’ sterile fill-finish programs.
The robotic platforms at PCI’s San Diego and Australian facilities focus on providing a scalable speed-to-patient solution supporting early-phase projects that involve smaller-scale filling operations from a few thousand up to 20,000 vials. As clients progress to later-phase trials and ultimately commercialization, they can be transitioned to the larger-scale operations within our global sterile manufacturing and lyophilization network. This transition is seamless, with dedicated project management teams across sites, and, as PCI has a global quality system, there is harmonization across operating standards.
The ability to provide end-to-end support for SFF drug product manufacturing together with specialist biologic packaging provides significant benefits to clients. Not only can PCI provide assistance with the selection of an appropriate primary packaging configuration and container closure solution, but, with our wealth of experience, we can also assist clients in evaluating and understanding their long-term fill-finish needs, as well as their timeline and regulatory pathway. Working with our clients, we then help develop a plan to realize that long-term vision, clearly outlining the integrated solutions that PCI will provide from early-phase clinical stages through commercial manufacturing, eliminating the need for transfer of operations from one CDMO to another. With this in mind, cost and time efficiencies can be significant.
Furthermore, the robotic SFF services offered by PCI can be readily integrated with our biotech centers of excellence for labeling and packaging operations. Again, this integration eliminates the need to transfer the product to another outsourcing partner, mitigating supply chain risk while saving more time and costs. As soon as the filling process is completed, sterility is confirmed, and the batch is QA approved, the filled vials / syringes can move directly into labeling and placement into kits or cartons for shipment to clinical sites. This capability further compresses the timeline associated with the filling process, reducing the time needed to get clinical studies initiated.
Across the PCI Pharma Services network — and independent of the investment in the new robotic SFF technology — the company is investing approximately $200 million to expand capacity at the Bedford, New Hampshire site in the United States and at our EU facility in Leon, Spain. These investments reflect the outlook and the market opportunity that the company envisages for the future of sterile fill-finish. PCI not only wants to meet the growing demand for SFF services, but as a leading global CDMO aims to exceed customer expectations. Everything we do is underpinned by a quality framework, incorporating expertise and innovation to ensure regulatory compliance and complete peace of mind. We are regarded as a true end-to-end solution provider by our global client base, delivering flexibility and excellence in all that we do to accelerate the development and commercialization of novel medicines.
Mark Shepanski is the Vice President of Global Program Management at PCI Pharma Services and has been with the organization for eight years. He is a quality and operations professional with over 23 years of management experience in the pharmaceutical clinical packaging and diagnostic medical device industries. His strong scientific background, coupled with key project management skills, has allowed him to establish a track record of delivering exceptional customer service, measurable results, and significant quality improvements to products and processes. Mark graduated from Penn State University with a bachelor of science in biology, vertebrate physiology.
.svg)