With nearly two-thirds of the early-development pipeline coming from small and emerging biopharma, there is a great need to accelerate programs into clinical trials and secure additional funding. At the same time, companies are seeking to de-risk manufacturing operations. Robotic gloveless isolator sterile fill-finish (SFF) systems address both of these needs. In discussion with Pharma’s Almanac Editor in Chief David Alvaro, Ph.D., three technical experts from PCI Pharma Services explain how the company supports the accelerated timelines of its client partners as they commence early-phase clinical trials with immediately available robotic SFF capacity at their clinical manufacturing and packaging facility in the United States.

David Alvaro (DA): Can you explain how early-phase development is changing and what impact those changes are having today?

Jerome Detreille (JD): It is well known that on a global basis nearly two-thirds of the early-phase development pipeline is coming from small, emerging, and virtual biotech companies. In addition, there are emerging classes of biomolecules that have huge potential to change disease treatment, including monoclonal antibodies, bispecific proteins, peptides and siRNA therapeutics, and other oligonucleotides. These pipelines are typically platformized through the delivery technology, with the same types of formulations applied to different siRNA, mRNA, or polypeptide drug substances. A screening approach is also often used, allowing for replication on a regular basis of similar types of molecules, which may further enhance the firepower needed to support larger programs by conducting many phase I studies in different indications. This is a big change from the traditional approach of developing one molecule at a time for a single indication.

From the perspective of a biopharma startup, reaching the first-in-human milestone is critical. Investment release often aligns to key milestones within the development cycle. Often, virtual companies will stay in the preclinical stage for a long time, as they secure the appropriate funding; then, as soon as they have this funding, they need to reach that milestone as quickly as possible to be able to move to the next funding round. With uncertainty in macroeconomics affecting the biopharma market, the funding process has become more complex, even for companies with lead candidates backed by good early data, funding is more difficult to obtain than in the past, and there is an increasing trend toward demonstrating longer-term security of supply chain. The cost of money has increased, and the selection process is much longer. This in turn is placing even more pressure on developers to reach the next funding round and avoid delays in the development process.

Derek Truninger (DT): I would reemphasize that the financial landscape shift is quite impactful for early startups and small, phase I companies. It is difficult to get funding, and obtaining good clinical data is paramount to attracting investors. Underlying this issue is a trend toward formulation of products as injectables. Therefore, as a CDMO, we support our clients in de-risking manufacturing processes to avoid failed batches and aligning to their objectives of obtaining clinical data rapidly.

DA: What else can you tell me about the shift to prefilled syringes, auto-injectors, and similar delivery solutions and how drug developers are managing that move?

JD: Historically, the earliest that companies were incorporating auto-injectors into their clinical pipeline was when they were entering phase III — sometimes not even until phase IV. When a product was commercialized, if it was successful, conversion to prefilled syringes for use within an auto-injector would be used as a life cycle management solution. Today, some of these discussions are taking place as early as phase II.

The benefits of prefilled syringes are clear. One of the biggest drivers in the movement to prefilled syringe technology is the desire to make products easier to use to support patient self-administration, which is a growing trend itself. Prefilled syringe dosage forms also eliminate the waste caused by overfilling vials, which can be as high as 15–25%. This is not the case with a prefilled syringe format, as the design, components (including stopper), and functionality improve dosing control, thereby significantly saving valuable drug product.

In terms of auto-injectors, in recent years, there has been a rapid growth in the use of this drug delivery device, again driven by the increasing adoption of self-administration devices across various therapeutic areas, for allergies and lifestyle and chronic diseases, such as psoriasis, diabetes, multiple sclerosis, and rheumatoid arthritis. Biopharmaceutical companies are actively incorporating auto-injector drug delivery technology into their product portfolios, recognizing the competitive advantage these devices offer in terms of differentiation and patient satisfaction with greater convenience, accuracy, and control over their treatment regimens.

As the demand for biologic therapies continues to grow, advanced drug delivery solutions, such as prefilled syringes and auto-injectors, are emerging as key drug delivery mechanisms for enhancing patient adherence, reducing healthcare costs, and improving overall treatment outcomes.

DA: Is phase II the optimum time for those discussions, or would even earlier be better?

JD: Phase II is a good time, particularly for drug developers who have access to a CDMO like PCI Pharma Services who — with a global network of experts across sterile drug product development and manufacturing, packaging design, assembly, regulatory, and quality — can provide guidance at critical time points to develop an optimum patient-centric drug–device combination product.

DT: I agree. I wouldn’t want to see clients heading into self-administration in phase I because at that point you really do not have sufficient patient data. For a drug in a vial format, doses are administered by physicians; at that point the emphasis should be on ensuring that the study design is properly followed. Once good clinical data have been generated, a decision can be made regarding whether the ultimate format should be a vial, prefilled syringe, or auto-injector. If it is the latter, the growing number of products being introduced in auto-injectors is beginning to impact lead times for components. Waiting until phase III or commercialization is not recommended because thousands or hundreds of thousands of units will be needed, which can add 12–13 months to the timeline.

Peter Kim (PK): In my prior experience and since joining PCI, I have seen clients having discussions during early development about potential downstream issues going into phase III and running their PPQ (process performance qualification) batches. These discussions often revolve around the choice between open or closed RABS (restricted access barrier systems) for filling in a non-sterile environment — the conventional filling lines outside of an isolator system.

During FDA inspections, it has become evident that the agency is shifting away from endorsing open/closed RABS. While achieving sterility assurance is feasible, it comes with associated costs.

Isolator technology stands out for ensuring sterility, and clients frequently express the wish to have an isolator system in place as early as phase I and II to seamlessly carry through the entire drug life cycle. In addition, preparing the delivery format and filling technology earlier can prove advantageous.

Use of robotics in sterile fill-finish (SFF) manufacturing de-risks the SFF process for high-value molecules. Scalable integrated solutions with a strategic contract manufacturing partner with robotic SFF capabilities add even more value.

DA: Can you highlight the range of benefits that robotic SFF technology offers?

PK: Robotic aseptic processing is an established, fully automated gloveless sterile filling technology that complies with Annex 1 and FDA guidelines for aseptic processing. With no operator intervention and a robot performing the processes in a validated, recipe-driven system utilizing single-use parts, pre-sterilized flow paths, and RTU (ready-to-use) containers, multiple sources of risk are eliminated, including potential cross-contamination, human error, electro-mechanical filling and closure activity failures, environmental control failures, cleaning and set-up errors, and product loss.

Using press-fit vial closures with integrated rubber stoppers not only reduces particle risk but also simplifies the manufacturing process, with the press-fit closures being a one-step application that presses on top of the vials, versus the traditional two-step process of stoppering and aluminum crimp capping. Similarly, the use of dynamic peristaltic pumps ensures accurate fill volumes and reduced shear stress and thus reduces concerns over aggregation. All this combined means that our clients are able to move more rapidly through the clinical stages and provide safe, life-changing therapies to patients.

Furthermore, the FDA cites gloveless isolators as key to streamlining the CMC (chemistry, manufacturing, and controls) development process. For these reasons, robotic SFF is ideal for clinical drug product manufacturing.

JD: Robotic SFF occurs in a gloveless isolator, so there is no human intervention, and customers are always interested in ways to de-risk manufacturing processes. Most of the APIs we work with are very expensive, beyond the manufacturing costs themselves, since they are sometimes very rare and only produced in very small quantities with long lead times. With a closed isolator and robotics implemented and thus no human intervention, the risk is drastically reduced compared with fully human-driven, manual filling operations. It is possible to limit losses to around 50 mL for an entire batch with these robotics systems, which can have a significant impact, and not just on cost; it can also increase the number of doses available to patients.

DA: What are the key considerations for the effective use of robotic SFF platforms?

JD: A primary consideration is having access to enough of the drug substance, which is critical for early-phase projects when API availability is often limited. The characteristics of the drug substance and formulated product must be considered when selecting the delivery format. Some products are better suited for filling in vials than prefilled syringes, for instance. Scalability, cleaning requirements, and cross-contamination control are other factors that must be taken into account.

DA: How do you see robotic SFF changing in the near term?

JD: There are currently only a few companies manufacturing these robotic filling systems for the marketplace: major players include Cytiva, SKAN, and groninger. While PCI Pharma Services has only been involved with robotic SFF for a couple of years, I would recommend it for any and all clinical programs. The isolator is simply the right way to fill sterile products.

DT: I would add, if you do a quick internet search on where aseptic processing is headed, the results will include how regulatory bodies are pressing for the industry to move to isolator technology over the next few years. With access to solutions that meet small- to large-scale needs, the fully robotic isolator is the technology of the future.

DA: Are clients fully aware of the benefits of robotic SFF? Is having this capability a real differentiator for PCI Pharma Services?

PK: To start, timelines are hugely important to clients of PCI Pharma Services. In addition, early in phase I or even phase 0, drug substances often are very difficult to obtain, so yield optimization is equally important. Everybody is looking to maximize the number of units they get from a batch. In this context, the low line loss on robotic SFF systems becomes incredibly advantageous. Clients value the minimal operator hours required to run these systems, as well as the assurance that an aseptic core is maintained during the filling process. All those benefits are multiplied when they work with a CDMO like PCI Pharma Services with an integrated offering that can get those fill-finish activities completed and vials or prefilled syringes labeled, kitted, packed, and ready for distribution all from a single site because that further compresses the timeline and helps clients get their first patient data faster.

DA: How appropriate are robotic SFF systems for multi-product facilities?

PK: In a multi-product facility, robotic isolator platforms are ideal for sterile filling, as the components that come in contact with the product are single-use, including even the needle used to do the filling. These components are used only for one particular batch and then discarded. As a result, there are no residues or any types of product extractables that could be carried over and contaminate the next batch.

In addition, cleaning requirements for robotic SFF systems tend to be less invasive than traditional filling operations. The isolators have a built-in VHP (vaporized hydrogen peroxide) cycle for decontamination of the chamber. Before that step, limited manual cleaning is performed — a 70% isopropyl alcohol solution is used to wipe down the surfaces. After VHP decontamination, the equipment can be set up for the specific format and size needed for the next run. No clean-in-place or steam-in-place steps are required.

Robotic technologies are designed for maximum flexibility while maintaining high aseptic processing rates. Meeting the needs to fill many different products and process multiple projects with minimal changeover time between batches provides ultimate savings in time, allowing us to better support clients who have urgent drug product supply needs.

DA: What robotic SFF systems does PCI Pharma Services currently have in place?

JD: Complementing our global sterile fill-finish and lyophilization manufacturing capabilities across North America and Europe, PCI has invested in two state-of-the-art robotic technology platforms at our San Diego, California, facility. 

Utilizing the latest advancements of the Cytiva Microcell and SA25 technologies, we deliver flexible aseptic fill-finish solutions for both small- and larger-scale production runs across a variety of dosage forms, including vials, prefilled syringes, and cartridges for use in auto-injectors.

The Microcell platform in San Diego offers fully automated, gloveless filling, performed through closed robotic isolator technology that provides both small batch flexibility and standardized manufacturing. The fast changeover and agility of the technology makes it suitable for the production of both personalized medicine batches and early-phase clinical trial supplies, delivering true speed to patients. Superior drug product quality is assured through advanced automation, removing the need for operator intervention during the filling process and limiting product contact. Importantly, the Microcell technology can fill up to 1,200 vials per batch with fill volumes ranging from 1.0 mL to 50 mL.

Providing a scalable aseptic solution in support of clients progressing through the clinical life cycle toward commercialization, the SA25 Aseptic Filling Workstation is a larger-scale, gloveless, isolator-based filling technology offering small- and large-scale batch production of up to 20,000 units, supporting fill volumes from 0.2 mL to 50 mL. It provides flexible manufacturing solutions with the ability to fill multiple delivery device formats, including vials, syringes, and cartridges, through an aseptic process.

For both the Microcell and SA25 technologies, precise, programmable robotic functions cover all aspects of the fill process, including isolator leakage tests, VHP sterilization of the container closures, filling into the container closure system (CCS) of choice, capping, and batch delivery. They are also compatible with RTU containers and closures, removing the container and closure preparation stage, aiding speed of delivery of a quality and sterility-assured drug product.

At PCI Pharma Services, clients have immediate access to our robotic SFF capacity. In addition, packaging, labeling, and distribution activities are also located at the San Diego site. Pack labeling can also be done under quarantine if needed to further compress timelines. The combination of these capabilities provides clients the shortest route to getting their candidates into patients.

As we discussed earlier, our customers really want to hit the clinical milestone as quickly as possible for the next round of funding. Our robotic SFF capability is a unique solution because typically, on a larger, standard line used for commercial production, clinical projects are fit into the schedule around those commercial runs, which can extend the timeline significantly. At PCI, our equipment is dedicated to clinical production, and clients can expect a quick turnaround.

DA: Can you share more about PCI’s clinical packaging sites?

DT: PCI Pharma Services has a network of clinical sites throughout North America, Canada, Europe, the UK, and Australia. From a clinical packaging perspective, PCI offers global reach. With the robotic SFF capability in San Diego, PCI is a true end-to-end CDMO supporting clients from first-in-human trials all the way through phase III and into commercialization.

It is also important to note that the San Diego clinical manufacturing and packaging site ties directly into the wider PCI sterile manufacturing network, which was established with the acquisition of Lyophilization Services of New England (LSNE) in 2021. The acquisition was a key step for PCI, as LSNE expanded the breadth of our services as a global, integrated CDMO, building on our expertise in specialty manufacturing, clinical trial supply, and commercial pharmaceutical packaging.   PCI now offers integrated large and small molecule solutions for clinical and commercial clients, including global manufacturing capabilities in complex formulations, high-potency compounds, sterile fill-finish, and lyophilization.

DA: Is there interest in adding additional sites in the future to access other global regions?

DT: As more new biologically derived therapies are discovered, the need for specialized sterile fill-finish manufacturing and innovative packaging capabilities and capacities will continue to increase.

To meet these growing capacity needs of the industry, PCI is continuing to invest and provide strategic manufacturing and packaging solutions for our client partners. With a $100 million investment, we will enhance our integrated development to commercialization sterile fill-finish offering with a new 50,000-ft² multi-product commercial scale facility at our Bedford, New Hampshire, campus. Meeting global requirements, including Annex 1, the new facility will provide increased capacity using state-of-the-art isolator technology, including high-speed, large-volume sterile vial filling and lyophilization with twin 400-ft² freeze dryers.

Supporting the downstream supply chain and growing biologic market needs for specialized packaging for injectable drug–device combination products, we are also investing $150 million in a new 200,000-ft² facility at our Rockford, Illinois, site. This new facility will support the assembly and packaging of vials, prefilled syringes, auto-injectors, and pen-cartridges, such as those for oncology, CNS, and vaccines.

With both manufacturing and packaging facilities to be operational by Q4 2024, capacity reservation is available immediately to our clients, helping them strategically plan their product outsourcing with a single integrated CDMO. As a leading global CDMO through innovative integrated solutions, we aim to reduce time to market and de-risk our clients’ supply chain, delivering true flexibility and excellence in all that we do to accelerate the development and commercialization of life-changing therapies.

DA: How you see the introduction of robotic SFF capabilities aligning with PCI’s long-term vision and mission?

DT: At PCI, ensuring that life-changing medicines reach those who need them most is our highest priority. As a truly integrated global CDMO, we are manufacturing, packaging, and supply chain experts, harnessing our experience and expertise to deliver a seamless solution to customers with the ultimate aim of improving the lives of patients.

Robotic SFF ties directly into our core commitment to support clients of all sizes as quickly, efficiently, and effectively as possible. It helps us de-risk sterile manufacturing while also making it possible to provide the highest-quality products. In that sense, robotic SFF complements what PCI Pharma Services has been doing all along, with the added benefit of further differentiating us from the competition. We are not just well positioned to meet the growing demand that is being driven by market trends and regulatory expectations but ahead of the curve.

JD: I agree wholeheartedly. PCI is a leading global CDMO providing integrated end-to-end drug development, manufacturing, and packaging solutions. We have the expert core services expected from a CDMO, but we also address the challenges that customers face when going from preclinical to clinical as much as possible and as early as possible. To do that, we are making significant, strategic investments, and the installation of robotic SFF lines is a part of that effort. We are also investing in other aspects of early-stage formulation development and expanding our in-house analytical support services to provide true end-to-end solutions to streamline and de-risk our customers supply chain and ultimately deliver life-changing therapies to patients.