In 2014 BioPlan Associates prepared a comprehensive white paper on the trends affecting biopharma sterile fill-finish.¹ Here, we refresh our research and review our projections and assess the industry’s future over the next 10 years. 

Contract manufacturing for sterile liquids experienced significant disruptions during the COVID pandemic, especially at large scale; this also impacted virtually all segments. Post-COVID, based on BioPlan’s 21st Annual Report of biomanufacturing,² the industry is returning to its pre-pandemic growth patterns, including nearing its historic 8-10% growth rate. This is driven by the underlying global demand for biologics over the past 25 years, economic growth in developing areas, and growth of advanced therapeutic areas.

Due to the complexity and risks of contamination, pharmaceutical innovators are increasingly outsourcing their fill-finish services to specialized contract manufacturing organizations (CMOs) with the necessary expertise, equipment, and facilities. For example, our annual report data has shown a consistent 5% annual reduction in the number of facilities doing all their manufacturing in-house.² CMOs offer an array of services and expertise often not available to drug innovators, including formulation, sterile filtration, aseptic filling, lyophilization (freeze-drying), terminal sterilization and packaging.

2024 global challenges in fill and finish CMO services

In our current research, the most cited critical factor affecting services for biomanufacturers and CMOs doing sterile liquid fills today is the availability of capacity. This is partially a hold-over response to pandemic-related capacity shortages. Capacity has, however, also been significantly impacted by high demand in some segments, such as shifts from Covid vaccine production, and demand for GLP-1 volumes. 

There continues to be dynamic tension in regions traditionally strong in small molecule fill/finish such as China that are seeing significant growth. But this growth may be potentially tempered by geo-political tensions and initiatives like the U.S. Biosecure Act.  

In some segments, the high capital investment required to enter sterile fill finish markets have restrained growth, especially in emerging regions. This is because sterile fill-finish facilities have substantial capital requirements, high continuous operating costs, and very expensive staffing needs, after initial setup. Staffing challenges have been a particular problem, as seen in our annual report, with up to 50% of facilities indicating hiring is a significant or severe challenge.  

Comparing 2014 and 2024 trends in sterile fill finish outsourced services 

In 2014, we contacted over 50 industry experts, facilities, and suppliers to discuss industry trends and problems in fill and finish operations. The industry was focused on ensuring quality, safety, and cost-efficiency were not compromised at this critical, late-stage manufacturing step. At the time, trends included the increased use of Restricted Access Barrier Systems (RABS), and Isolator technologies. The segment was also seeing more high-speed operations, and more use of single-use technologies, greater automation and tools to enable pre-filled syringes.  Lyophilization capacity was also an important component.  

Ten years ago, our findings showed there was sufficient biopharma capacity, even without adding shifts or additional equipment. In contrast, some small molecule fill and finish facilities reported constraints, and many were working near-capacity due to facility consolidation, regulatory actions, closures, and use of less efficient legacy equipment. This created bottlenecks that in some cases led to drug shortages at the hospital level. 

Critical factors and growth trends 10 years ago in 2014

• Increasing use of isolators—in sterile fill-finish processes some were already seeing isolators as indispensable. At the time, isolators were becoming more important but were seen as providing less flexible manufacturing options. 
• High-speed fillers were increasingly common.
• Trends toward automation, to reduce human involvement.
• More pre-filled syringe lines.
• Manual operations were rapidly becoming less common as use of RABS, and isolators increased.
• Increased IT infrastructure to track storage, temperature, waiting periods, process timeline, etc.
• Increasing demand for high potency F/F process.

Other considerations mentioned

• Glass vial fill and finish containers fully dominated the industry, but use of plastic containers, including pre-filled syringes, were increasing. However, concerns about extractables, leachables, and particulates were thought to inhibit growth.
• Sterility testing was seen as a big bottleneck.
• Analytics testing and formulation development needs were reported to not matter whether done in-house or externally sourced, as long as the need for speed remains central.
• Lyophilization was not a must-have, but with mRNA coming online, it opened the need for small scale processes (Lyophilization was mentioned as being important in around half of all biologics F/F).
• More CMOs were implementing smaller filling machines for syringes or vials, specifically for Phase I and II clinical study supply. 

2024 trends: the move from RABS to isolators

We reviewed current trends in the industry and determined the segment has succeeded in achieving many of the objectives it set over the past 10 years. One of the major changes involved the shift from traditional filling to the use of RABS, and from that, over the past 10 years, to the use of isolator technologies. 

Although CMOs are often first adopters for innovations, 10 years ago, many continued to see advantages in the use of traditional RABS over isolators due CMOs’ need for greater flexibility, and to the high costs associated with isolator lines. This has shifted, so that RABS-only lines are now primarily seen as effective for niche products, biosimilars, and other lower value products. 

Today, full isolation is generally considered necessary for a competitive fill-finish CMO. The complexity in manufacturing has made isolators in sterile fill-finish processes indispensable for contamination safeguards and to ensure the safety of both patients and operators. 

Although most CMOs are already moving toward adoption of isolators, the future may involve regulatory intervention. Jim Agalloco, president, Agalloco & Associates, Belle Mead, NJ, says, “RABS were an attempt to gain the advantages of isolators without having to change much. Isolators force facility disruptions such that an easy upgrade from manned clean rooms wasn’t possible. That was a key driver for RABS, to upgrade without having to rebuild everything. Their performance can approach that of isolators, but only when the installation is near-perfect. There aren’t many that good, and at the low end of capability they can be an expensive waste.” 

Agalloco says that there appears to be hesitation from the FDA and EMA to embrace isolators more fully. From his long experience and perspective, “clean rooms should ultimately be banned after some defined period. Regulators are not taking the bold steps needed to really improve the way sterile products are made.” 

Other trends seen in 2024 

Today, fill and finish CMOs have become more specialized, regionally focused (vs. 10 years ago, when CMOs were becoming larger through mergers and acquisitions). CMOs today are expected to have state-of-the-art fill-finish equipment, mostly to support clinical manufacturing.  

• Demand for flexible fill-finish manufacturing options vs. dedicated lines: A flexible filler is a single filling line capable of processing vials, syringes, and cartridges. These can decrease capital expenditures and facility footprint, while improving the product, change over, and reducing product loss. These are typically used at clinical scale.  
• Partnerships/specialists: Ten years ago, drug substance CDMOs were increasingly doing more fill and finish internally and were doing less sub-contracting to specialized CMOs. This trend continues today. However, many smaller CDMOs continue to seek best-in-class partnerships with quality fill-finish CMO specialists. CMOs specializing in niche areas, such as formulating and filling live viral sterile products, or for antibody-drug conjugates (ADCs) for clinical studies have emerged. There have been new CMOs entering on a global level. 
• Emerging regions: Fill and finish CMO facilities in India and China started over 10 years ago to focus on their domestic and lesser-regulated international segments including for biosimilars. This has continued today. Global regulatory agencies, however, continue to expect higher quality standards from developing regions if they are to enter major markets. 
• Switch to disposable systems: Those who have not already made the switch to single-use systems to reduce the need for extensive cleaning validations will be doing so in upcoming years. Bags and custom-built configurations, tubing and connectors are being standardized to the fluid path. Tubing lines for formulation and receiving vessels in the aseptic processing area are now becoming the norm, as is pre-sterilization using gamma irradiation.

Future fill and finish trends through 2034

We identified on-going and emerging trends in sterile liquid fill and finish over the next 10 years:

• More improvements and adoption of isolator technologies as they continue to automate and move down in scale.
• Increased automation throughout fill-finish, including automation in full isolator units to reduce certain operators, addressing ever-increasing regulatory requirements. Become more integral to building enterprise systems automation. Expect completely automated lines, i.e. completely removing the operator from the process; no glove ports or defined interventions at all.
• Improvements in single use/disposable fill and finish equipment
• Improved systems for protecting operators in high potency and ADC environments.
• Increasing pre-filled syringes used for biopharmaceutical fill and finish operations.
• Greater use of artificial intelligence, robotics, machine vision, pattern recognition (computer-based visual inspection), etc.
• Filling accuracy improvements to handle an increasing number of highly potent biopharmaceuticals, e.g., ADCs, including fine filling accuracy and 100% monitoring.
• Increasing prices as the quality of compliant parenteral manufacturing capacity improves. 

Fill-finish CMO market analysis

Based on multiple sources including BioPlan’s internal databases, external analysis and research reports, the growth rate for outsourced fill-finish services in 2024 is returning to its historical 8% annual rate. However, some regions are still emerging from pandemic disruptions and are not seeing this rate yet.  

Today, qualified fill-finish CMOs are seeing past the COVID disruptions and a return to normal growth trends, while continuing to meet expected demand. Although COVID expansions in vaccine and therapeutic capacity resulted in regional capacity gluts at large scale, clinical scale supply of capacity has generally been able to match demand. As the industry normalizes, even areas with temporary excess capacity such as in Western Europe are finding equilibrium as growth in demand for biologics and advanced therapies, and expansions in emerging regions continues. 

With more than half of clinical trial volumes being filled by CMOs, as pipelines progress, these projects will transition to larger volumes, and then to larger CMOs. This suggests the long-term growth prospects for this segment remain solid. 

Our research of suppliers and end-users’ expenditures on outsourced fill-finish services indicates a market size around $5.9 billion in 2024, and post-COVID, this will grow at 8% over the next 5 years. Of this total, biologics (large molecules) make up around two-thirds of the market value. The remainder is for small molecule chemical drugs, and other sterile injectables. 

In BioPlan’s research we identified nearly 220 fill-finish outsource suppliers globally. The market is fragmented with many smaller competitors. However, the top 15 major companies providing sterile fill-finish hold around 60% of the market share by revenue.

The global sterile fill-finish services market can be broken into:

• Vials (~30%)
• Sterile Ampoules (~25%)
• Prefilled Syringes (~20%)
• Cartridges and Other (~25%)

In North America there are as many as 40 relative newcomers to the fill-finish CMO segment, with most investing in the current filling and isolator technologies. Germany, Switzerland, and the UK are also major players, but some have reported lower growth rates, partially due to political instability, higher energy and labor costs. In China, which has the largest market segment in Asia, sterile fill finish services are expanding due to rising growth of biologics, especially biosimilars and to a growing pipeline of clinical scale biopharmaceuticals. Government investments, particularly in China, are helping expand domestic biopharmaceutical companies and driving demand.

Summary

The handling of sterile liquids in the pharmaceutical industry had, until recently, relied on relatively consistent techniques used over the past 100 years. Then, over the past 20 years, technological improvements and regulations have resulted in safety, technology, efficiency and product quality shifts. Part of this change has been driven by biologics where value can often be measured in $10s of thousands per dose. 

To maintain the rate of improvement, including the on-going shifts toward isolator units and greater automation, will require more cooperation from industry stakeholders. For example, collaborative sharing to identify ways to improve compatibility of automation platforms is going to be needed. Innovation has always been supplier-driven because only they have the expertise to advance. Without greater collaborations, improvements will take substantially longer.

References

1. Trends in Aseptic Bioprocessing Capacity for the Fill and Finish of Recombinant Biologics: An Analysis of US and European In-house Capacity and Capacity Utilization. December 2014, BioPlan Associates, Inc. Rockville, MD 20850 www.bioplanassociates.com
2. 21st Annual Report and Survey of Biopharmaceutical Manufacturing, BioPlan Associates, Inc. Rockville, MD 20850, www.bioplanassociates.com/21st

Eric Langer is managing partner of BioPlan Associates. He has over 30 years of experience in biotechnology and life sciences international marketing, management, market assessment, and publishing. He has held senior management and marketing positions at biopharmaceutical supply companies and is an experienced biotechnology strategist, marketing practitioner, publisher, and researcher.