Fill–Finish Operations for Advanced Therapies: Emerging Equipment Options and Facility Considerations

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Because of their proximity to final-product administration, formulation and fill–finish (FFF) operations are critical, high-value steps within all biomanufacturing processes. The stakes are especially high for cell and gene therapies (CGTs). As is the case with monoclonal antibodies (mAbs) and related drug modalities, CGTs are too sensitive to undergo terminal sterilization in final containers. Yet therapeutic cells and viral vectors for in vivo gene delivery are too large to pass through the kinds of filters that are designed to ensure sterility for mAb drug products. Compounding those difficulties are the relatively small scales at which CGTs are manufactured and the number of manual interventions associated with small-batch processing — not to mention the logistical difficulties of vein-to-vein time for autologous cell therapies (CTs) and the cryogenic storage requirements for most cellular products.

Help is on the way for mitigating such difficulties. Peter Walters (fellow of advanced therapies) and Todd Vaughn (fellow of aseptic and sterile products) of facility design and engineering firm CRB explained to me that biomanufacturing-equipment vendors have begun over the past decade to offer automated filling solutions that are designed to address the small-batch requirements of many CTs while eliminating manual steps. This past September, I corresponded with Walters and Vaughn about distinctive aspects of CT FFF — and about how emerging equipment options could facilitate such operations. Below are their combined responses.

Walters has 20 years of experience in pharmaceutical process and facility design, with particular expertise in equipment and process design for multiprocess facilities predicated on maximum flexibility and optimized logistics. Vaughn has over 20 years of experience in pharmaceutical process design. He is an expert in aseptic processes, hazardous-compound containment, risk mitigation, and regulatory compliance.

Foundations for Formulating and Filling Cell Therapies

How do drug-product formulation requirements differ between CTs and recombinant proteins? How do such differences influence subsequent filling and packaging steps? Most CT products are cryogenically frozen for storage and shipping, so formulation steps must incorporate a cryopreservant — typically dimethylsulfoxide (DMSO) — to help protect cell integrity and viability throughout freezing. However, DMSO deteriorates cells, so manufacturers have placed rigid restrictions on how much time can elapse (typically <1 hour) between formulation and filling, inspection, labeling, and initiation of freezing. Those factors can become a serious burden for (relatively) large-batch products such as allogeneic CTs. Drug sponsors might need to pursue strategies such as sublotting of FFF to accommodate time and logistical constraints.

CTs that are not frozen instead are shipped “fresh” in refrigerated shippers. Products in that state have short shelf lives and must go through rapid inspection, labeling, packaging, and shipping to reach patients quickly. Expiration for such products can range from a few days to <10 hours.

How would you characterize the evolution of FFF processes for CTs over the past 10–20 years? CTs began primarily as small-batch processes framed around single patients. Given the scale of operations and the lack of suitable equipment technologies, early processes largely involved open, manual steps performed inside of biosafety cabinets (BSCs) located in highly classified cleanroom environments. FFF steps were no exception. Because most CTs were administered through infusion, nearly all of them were filled into sealable intravenous (IV) bags.

As both the therapies and their associated technologies have progressed, a slight shift has occurred in filling applications. Processes for autologous CTs (single-patient scale) now can leverage commercially available closed and automated formulation and filling equipment. One major benefit of filling into IV bags is that they can be filled using complete, presterilized tubing manifolds such that filling is fully closed and performed without high-cost isolators.

Following the successes of autologous and patient-scale applications, developers of next-generation CTs now seek to leverage allogeneic cell lines, many of which can be scaled up to multipatient batch sizes. Such therapies have followed similar technology pathways as gene therapies based on viral vectors, with drug developers leaning toward small, commercially available solutions. Clinical-scale applications for CGTs often leverage BSCs with foot-operated vial or bag fillers and closing machines, whereas commercially focused processes tend to leverage isolated vial-filling lines with automated solutions and presterilized, ready-to-use (RTU) components.

In the future, filling of critical in-process materials (typically used to produce gene-modified CTs) could shift toward small-volume, weldable bag filling to support subsequent manufacturing processes more effectively. Over time, commercial applications are likely to grow for closed bag-filling systems as well as for automated, isolator-based filling systems in both gloved and gloveless formats.

A Focus on Facilities and Equipment

How does the need for small-batch processing influence FFF needs in terms of facility design and equipment selection? Small batches (e.g., for single patients) typically involve manual fills performed in BSCs. Such processes necessitate a grade B and/or ISO 7 cleanroom and tight control of gowning, operations, and procedures for material movement and decontamination. The critical-zone environment carries higher requirements for air-quality control and monitoring — e.g., a grade A and/or ISO 5 environment within a BSC. Highly trained personnel must be employed in container filling and handling.

The extremely small batch sizes of ultrahigh-value CGT products can complicate automated-system design. Hold-up volumes and system fluidics can affect formulation and dosing accuracy, not to mention product yields.

One notable benefit is that similarities in CGT scales and processing needs have encouraged vendors to provide a number of new offerings to support the advanced-therapies market. Such systems can help substantially, if not provide entirely off-the-shelf solutions. Moreover, low fill-container counts per batch operation have made RTU components an attractive option, reducing requirements associated with good manufacturing practice (GMP)–grade washers, autoclaves, and preparatory areas.

How effective are currently available filling systems for small-batch processing, and what needs remain? Small-scale technologies required to manufacture personalized medicines suffer from fluidics challenges. Some therapies require extremely small volumetric additions, possibly in the single-digit milliliter range. It is difficult to build in the performance capability needed to add formulation solutions, mix, and fill such small volumes without incurring costly losses to yield and quality. Thus, equipment in the small-batch CGT space often comes at the cost of flexibility in terms of vendors, container types, container counts, and sample sizes. However, large-scale CGT operations have found success in using either off-the-shelf vendor options with automated filling systems in isolators or semicustomized filling options.

How can a manufacturer ensure that a filling system is compatible with its needs? You can prepare best by understanding your container types, closure sizes, and batch counts as well as the degree of uncertainty and change surrounding those aspects. Use those considerations to identify a filling solution that can accommodate your container needs. Work with equipment vendors to understand filling-system requirements such that your facility is equipped not only to accommodate space and infrastructure needs, but also to provide supporting functions (e.g., for parts washing, sterilization, and room classification). Troubles can arise when stakeholders — manufacturers, equipment vendors, and facility design/construction teams — make assumptions or communicate poorly about project requirements. Once a manufacturer selects an equipment vendor, system requirements should be communicated to the facilities team prior to design completion so that all requirements can be accounted for, preventing later need for renovation.

The Nuts and Bolts of CGT Filling

What are some key considerations for FFF components? Final-use requirements are critical factors. Drug products based on viral vectors typically are filled into vials for ease of freezing and transport. Raw materials for genetically modified CTs usually are thawed, pooled, and transferred into bags that can be welded onto CT manufacturing platforms. Those steps can represent tremendous manufacturing burdens at large scales for multipatient populations.

Due to the off-the-shelf nature of technologies that support the CGT FFF submarket, many drug sponsors put off considering or defining the details of their filling technologies and containers for too long. Such details can be critical to product integrity and quality, and off-the-shelf filling equipment might not support all FFF components. In fact, many systems will corner you into specific groupings of container types, sizes, and closures. Understand your product requirements and target-container needs before beginning your search for an appropriate filling solution, and consider lead times for such systems to ensure that you are not already behind for when you will need your equipment to be operational.

What sterilization requirements come with CGT FFF operations? How do such requirements influence facility operations? Leveraging presterilized RTU components can be more cost-effective than maintaining validated sets of facility equipment used for fill–finish components, which would need to be washed and sterilized before each batch. Thus, RTU components can simplify user preparation while making most of the sterilization validation the component vendors’ responsibility.

If operations use all presterilized components —including formulation components, component-handling parts, and environmental monitoring (EM) heads — then a facility can operate without a GMP-grade washer and autoclave associated with filling. That would help to save space and capital expenditure (CapEx). A product’s final delivery device and closure will play a role in whether a filling system requires autoclave sterilization. For many CGT facilities, manufacturing processes do not require clean steam for areas outside of drug-product operations, so autoclave removal would eliminate clean-steam requirements altogether. Most CGT operations require little to no water for injection (WFI) for manufacturing raw materials; removal of clean-steam requirements would allow facilities to source WFI from membrane-based systems or remove such systems entirely. Either outcome would provide significant site savings for mechanical, electrical, and plumbing (MEP) infrastructure; improve environmental sustainability; and move companies toward electricity-based infrastructure.

Taking Nothing for Granted in CGT FFF

What advice regarding FFF operations do you give to early-stage CGT companies as they scale up and establish their own filling processes? What kinds of things should they know about their products and/or facilities as they prepare to make the commercial leap? Do not take for granted the complexity of filling processes just because vendors offer off-the-shelf solutions. Sponsors still have many details to hammer out before engaging filling-equipment vendors. For the best chance at success, sponsors must work out their container types and closures, sizes, and counts. You also should identify factors that require flexibility as you continue to develop their respective processes toward commercialization. All of that identification should happen before surveying the marketplace for filling solutions. Sponsors that do not have answers to such design questions can try to leverage how other companies have progressed, but doing so comes with risks. Your predecessors will have had different business drivers and priorities. Purchasing a filling solution before understanding a CGT delivery system normally is a waste of time and capital.

What aspects of CGT FFF merit more attention than they usually receive? Adjacent to the topic of drug-product filling are the needs surrounding in-process aseptic filling, which often involves the same equipment options and regulatory requirements. Materials such as sterile media components, viral vectors, and plasmids often must be added to a CGT process using aseptic conditions because of quality and yield concerns. Such materials have their own manufacturing needs and platforms, and they often need to be aliquoted aseptically into specific containers, sometimes in batch-specific quantities and timeframes. As a result, some of those fill counts will be low, and the cost of many traditional fill–finish offerings becomes cost-prohibitive compared with that for a manual operation within a BSC. Equipment vendors need to continue pushing isolator and filling technologies toward modularization and cost commoditization to accommodate the CGT FFF submarket.

Brian Gazaille is managing editor of BioProcess International, part of Informa Connect Life Sciences; [email protected]. Peter Walters is a fellow of advanced therapies, and Todd Vaughn is a fellow of aseptic and sterile products, both at CRB.