Lyophilization and Biologics Growth: Lyophilization accounts for over 60% of marketed biologics because water removal yields temperature-stable Drug Products that bypass cold chain management constraints.
Contamination Risk Mitigation via Single-Use Technology: Single-Use (SU) technologies paired with automation eliminate human intervention—the primary source of batch contamination—enabling continuous aseptic fill/finish in flexible ballroom settings.
Modular Workcells for Small-Volume Formulations: Personalized medicines and ophthalmics rely on modular robotic workcells (such as Versynta microBatch) to execute rapid, sub-two-hour batch changeovers in contained small-volume fill/finish runs.
Supply Chain Fragility: Generic sterile injectables remain highly vulnerable to severe market shortages because suppressed generic pricing limits capital investment in cGMP-compliant manufacturing infrastructure.
1. Overall Challenges and Innovation
1.1. Sterile injectable drug products can be prepared as single dose or multidose products in liquid form or as dry powders (e.g., freeze-dried, spray dried) that require reconstitution. Regardless of their final form, all sterile injectable drug substances and drug products must be manufactured under sterile conditions in pyrogen-free atmospheres. Where possible, terminal sterilization is performed on final packaged products. For drug substances/formulations that will degrade under terminal sterilization conditions, aseptic filtration and filling are implemented. Validation and supporting documentation, including for environmental monitoring (e.g., temperature, humidity, microbiological data) are essential.
1.2. The increasing complexity of drug substances formulated for parenteral administration; the growing use of lyophilization, sterile spray drying, and other means for producing more stable powdered injectable products; and the introduction of advanced delivery devices for self-administration are driving key trends in parenteral manufacturing. These trends include increased outsourcing, greater need for flexibility and speed, the growing adoption of single-use (SU) equipment for clinical and commercial manufacturing, and greater interest in completely contained manufacturing solutions (single-use equipment and ready-to-use components) and automation technologies that allow production of even potent, sterile injectables in a ballroom setting rather than complex cleanrooms.
2. Storage and Distribution
2.1. Sterile injectable drug products based on biologic drug substances often pose storage and handling challenges. Many biologics are unstable at room temperature, and some may degrade when exposed to light, oxygen, shock, pressure changes, and other atmospheric conditions.
2.2. Special packaging is required for these drug products. The most challenging and complex solutions are required to maintain constant temperatures as low as –70 °C or beyond during storage and distribution, a necessity for many next-generation vaccines and therapeutics.
2.3. Management of the cold chain is achieved through planning and due diligence, often via partnerships with clinical logistics organizations (CLOs) with the unique skill sets and regulatory, packaging, and other knowledge necessary to ensure on-time delivery of challenging sterile injectables of the highest quality.(1) Advances in active packaging systems that provide real-time data on location, temperature, pressure, and other conditions, and thus true supply chain visibility, also play a crucial role by enabling the close monitoring of vaccine and therapeutic doses as they are shipped around the world.(2)
2.4. For some temperature-sensitive sterile injectables, it is possible to avoid cold chain requirements through conversion of the liquid to a powder via lyophilization or freeze-drying. Once the water or other solvents are removed from the liquid drug product, the remaining solid is often stable and can be stored for extended periods at room temperature.
2.5. In fact, many drugs with sales above $1 billion are formulated as lyophilized products, and, for biologics in particular, more than 60% of marketed products are lyophilized.(3) With the number of biologic candidates in development growing at a steady pace, the market for lyophilized injectable drugs is expected to grow as well. One market research firm estimates that the global lyophilized injectable market is expanding at a CAGR of 5% to reach a value of $5 billion by 2031.(4)
2.6. Lyophilization is a complex technology that requires special skills and equipment, and there is only limited capacity available within the contract manufacturing market. Aseptic spray drying is an alternative for producing dry powders that are stable at room temperature for short periods and can be stored for long periods at 2–8 °C.(5) Regular spray drying has been used for many years for the production of APIs. “Smart” freeze-drying technologies utilizing self-programming cycles and moisture analysis have been introduced, but investments into lyophilization technology remain flat.
2.7. Aseptic spray drying is performed under sterile conditions and has been used for a few drugs approved in the United States and Europe, with the first being Raplixa in 2015. Currently, both biopharma companies and CDMOs are evaluating its use for novel vaccines and therapeutics. Several solutions are available on the market, including the Vitrified Ready to Inject Suspension (VitRIS™) technology from Nova Laboratories, the ImplaVax® solid dose formulation technology from Enesi Pharma, and the XeriJect® formulation technology from Xeris Biopharma.(5)
3. Rising Demand for Small-Volume Fill/Finish
3.1. Personalized sterile injectable medicines pose a set of challenges that are increasingly being managed with the use of robots and cobots and the move to fully automated processes that also leverage advanced digital technologies to reduce human errors and increase productivity.(6) The same is true for ophthalmic drugs, which are administered directly into the eye and thus require small-volume doses that require extremely high purity.(7)
3.2. Whether small molecules, peptides, proteins, or nucleic acids, personalized medicines are typically manufactured in small batches and are often highly potent, low-dose therapies that can’t be terminally sterilized.(8) They require specialized capabilities in contained, small-volume aseptic fill/finish, and, for CDMOs in particular, the ability to rapidly switch between products that vary widely in terms of formulations and delivery technology without risk of contamination or long changeover times.
3.3. In addition to vial/syringe/cartridge filling, aseptic continuous microencapsulation, precise hot melt extrusion, liposomal extrusion, and microfluidic capabilities can be essential for these products.(8) Fortunately, equipment manufacturers have recognized this need and introduced modular, automated filling lines to the fill/finish of complex parenteral drug products.
3.4. Examples include the VarioSys® aseptic fill line, which was developed for Evonik by Bausch + Ströbel,(8) and the GENiSYS R filling machine from Automated Systems of Tacoma (AST).(9) These types of modular systems can be integrated with isolator-barrier and automation technologies, enabling the aseptic fill/finish of both conventional and highly potent sterile injectables into various formats with minimal operator interaction with the product.
3.5. Closed, robotic “workcells” are another solution. They provide sterility assurance, containment, and process control in aseptic filling.(10) One example is a system being developed by Vetter and Syntegon Technology (formerly Bosch Packaging Technology). The Versynta microBatch is a cGMP-compliant, highly flexible, and fully automated production cell with a gloveless isolator, a limited footprint, and a complete batch-to-batch changeover of less than two hours that offers an output of 120–500 containers per hour.(11)(12) It won the Parenteral Drug Association (PDA) Drug Delivery Innovation Award in the "Partnership Innovation" category.(12)
4. Increasing Adoption of Single-Use Technologies
4.1. The speed at which COVID-19 vaccines were developed and commercial-scale processes implemented revealed the agility with which the biopharmaceutical industry can move when needed. Increased speed to market has become essential in recent years as competition in the marketplace becomes markedly greater. For potentially curative treatments, being first to market can be a requirement for success.
4.2. The growing need for speed is occurring at a time when injectable drug substance and finished product manufacturing has become more complex. The drug substances themselves, from next-generation antibodies to potent ADCs to cell and gene therapies, are more complex and wide-ranging. The shift in focus to orphan drugs and personalized medicines continues, leading to the need for small-volume manufacturing capabilities, but there is also growing demand for large-volume parenterals (LVPs). Recognition of the importance of patient-centric solutions and the ongoing move toward self-administration are both also leading to the introduction of novel delivery devices.
4.3. Many manufacturing facilities, particularly those run by CDMOs, are now multiproduct facilities supporting many different sterile injectable products of different potencies and with different manufacturing and final formulation requirements.
4.4. To enable rapid changeovers and simplify manufacturing processes, there has been a strong trend in recent years — which has gained further traction as a result of the COVID-19 pandemic — to leverage SU technologies, not only for R&D and clinical manufacturing, but for commercial production as well.
4.5. SU systems come presterilized and eliminate the need for cleaning and cleaning validation, saving time and money during setup and when changing from one product to another and reducing the risk of cross-contamination.(13)
4.6. Both fully disposable assemblies and SU solutions designed to seamlessly connect with existing stainless-steel equipment are available. One example of the latter is SU split butterfly valves for the transfer of sterile powders between unit operations within a plant or even between different facilities during tech transfer.(14)
4.7. One of the challenges with SU technologies has been the availability of downstream processing solutions for large-scale production.(13) Companies such as Pall, Sartorius, Cytiva, and Thermo Fisher Scientific, among others, have been working assiduously to address this gap, introducing, for example, preassembled and presterilized disposable filtration systems for large-scale bioprocessing that are easy to install and replace.
4.8. As with production capacity, flexibility is a key feature of effective SU systems. For instance, bioreactors that function efficiently and equally effectively at 20% and 80% capacity allow manufacturers to produce a wide range of batch sizes using a single piece of equipment.
4.9. When SU technology is combined with automation, sterility can be even further assured, because human interventions — the greatest source of contamination — are reduced. Properly prepared raw materials are introduced into the presterilized equipment, manufacturing operations are implemented in the closed system, and the final product is generated. For fully closed fill/finish operations conducted in SU systems, the product does not come into contact with operators at all.
4.10. In addition, SU technology in combination with automation is also an enabler of continuous processing, which is another important trend in biologics manufacturing that, once suitable process analytical technologies (PAT) are available for real-time monitoring and control of all aspects of upstream and downstream operations, could ultimately and dramatically improve productivity and quality while reducing cost.
4.11. It is worth noting, however, that for well-established products that have large-volume sales and require large numbers of batches to be produced annually, production in stainless-steel systems is still often the most appropriate approach.(13)
5. Growing Use of Automation
5.1. Automation is not only an enabler of continuous manufacturing; for forward-looking injectables manufacturers, it is a means of managing the increasing complexity of parenteral drug production.(15) In addition to reducing the risk of contamination, automated and closed systems increase the safety for operators and the environment when processing highly potent drugs. Elimination of repetitive motions performed by operators also increases efficiency, while the ability to collect and analyze large quantities of data enables measurable process improvements.
5.2. For filling operations, automated systems allow for more precise filling of syringes and other delivery devices. Automated technologies are even available to check the thickness and distribution of the silicone layer within glass syringes and to evaluate whether stoppers are gliding smoothly in autoinjectors.
5.3. The most advanced automated injectables manufacturing solutions provide better in-process control while still affording significant flexibility by leveraging reconfigurable robotic processing to accommodate different volumes and packaging requirements — all within smaller footprints.(16)
5.4. There is also a growing need for custom automation solutions, particularly for the fill/finish of the diverse and ever-expanding range of delivery solutions for injectable drug products. In addition to prefilled syringes, wearable devices — each with unique engineering requirements that demand tailored, automated solutions — are becoming increasingly popular.(16)
5.5. Similarly, autologous cell therapies have unique manufacturing requirements, with each batch associated with one individual patient. Effective automation of parallel processing solutions (scaling out vs. scaling up, which is done for autologous therapies) have been crucial to their success to date.(16) Automated, enclosed systems in which the entire manufacturing process can be performed within hospitals and clinics are one hoped-for solution to dramatically expand access to advanced cell therapies.
6. The Debate about Cleanrooms, Ballrooms, RABS, and Isolators
6.1. Drug manufacturers are expected by regulatory agencies to take a risk-based approach to ensuring quality and safety. There are strongly differing opinions, however, on what approaches to sterile injectable drug manufacturing present acceptable levels of risk.
6.2. Currently, the EU Good Manufacturing Practices (GMP) Annex 1 (sterile products) regulation is under industry review, with a new consultation draft published in 2020.(17) There is considerable disagreement as to whether the changes being proposed are significant enough. The new version still allows the use of restricted access barrier systems (RABS), which are better than production lines with no barriers but still allow direct operator interaction with the product and therefore do not provide the maximum possible level of contamination control that is afforded with isolators.
6.3. The continued acceptance of RABS may be due to the fact that, according to a 2020 International Society for Pharmaceutical Engineering (ISPE) survey, less than 30% of new installations are based on isolators, and RABS remain the predominant barrier system. Some in the industry consider RABS to be outdated and their use in aseptic processing to be a high-risk approach that should not be acceptable given that more advanced, risk-mitigating technologies are available and have been for several decades.(18)
6.4. The revised Annex 1, however, continues to support RABS used in combination with full aseptic garb, rigorous cleanroom design, intensive environmental monitoring, frequent aseptic process simulations, airflow visualization studies, and other indirect methods of evaluating performance that do not actually mitigate or control contamination.
6.5. By leveraging isolators, robotics, single-use systems, smart automated monitoring technologies that provide real-time data (including electronic batch records) accessible remotely, closed-vial filling, precise nondestructive weight checking (with automatic correction of filler specifications), and other proven or emerging technologies, aseptic processing can be carried out with no human intervention, offering the safest approach to the production of sterile injectable products.(18)(19)
6.6. The debate about RABS and isolators relates to another discussion: the use of a ballroom approach versus individual cleanrooms. First defined in the ISPE Baseline Guide Volume 6: Biopharmaceutical Manufacturing Facilities (2013), ballroom manufacturing involves production in a large open area using functionally closed systems and no fixed equipment.(20) This manufacturing approach leverages SU systems and advanced automation.
6.7. The idea behind the ballroom concept is to afford significant manufacturing flexibility with respect to specific processes, equipment, and scaling (up or out).(20) Ballrooms also carry lower initial investment and ongoing operating expenses compared with cleanrooms, and facilities with ballroom designs can have a smaller footprint and all the benefits that provides. Obviating the need for gowning reduces material (purchase and disposal) and labor costs. Closed SU systems facilitate rapid changeovers as well. Finally, the ballroom concept could be ideally suited for multimodal facilities that are producing many different types of sterile injectable products, from mAbs to viral vectors and cell therapies.(21)
6.8. These advantages have also been gained in a modified or “dancefloor” approach suitable for existing facilities with many adjacent smaller spaces.(20) These spaces can be joined with through-the-wall connections to maintain process closure and avoid the need for major structural modifications. Such a solution is attractive for CDMOs. The one challenge is the lack of standardized connectors (size, materials of construction) for joining closed systems from different vendors.
6.9. Some argued initially that the capital and operating cost savings would come at too high a price with respect to the need for more constrained, less flexible process and infrastructure elements for assuring appropriate process separation and minimization of cross-contamination risk. Concerns of scheduling needs (product changeovers and scaling activities, plus the need to be prepared for unanticipated changes) might limit the flexibility of the initial ballroom layout. To date, however, the concept is gaining adoption and severe mishaps have not been widely reported.(20)(22)
7. Drug Shortages
7.1. One of the key concerns with generic sterile injectables, is the high number of drug shortages that have occurred in the last 20 years.(23) The inability of generic drug manufacturers to charge sustainable prices is thought to be one of the key causes of these shortages.(24) Suppressed generic drug prices have resulted in a lack of investment in new generic products, a lack of resources to upgrade manufacturing facilities and thus comply with current good manufacturing practices (cGMPs) and maintain drug quality, and fewer players in the market.
7.2. Any disruption, such as the closure of a plant due to quality issues or natural disasters, can therefore lead to supply interruptions. Shortages have many negative consequences. Patients cannot access their needed medications, and in some cases no alternatives are available. The need to turn to other solutions can lead to reduced patient safety, poorer health outcomes, and higher costs.(25)
7.3. The generic sterile injectable drugs most often impacted by shortages are older products, including antibiotics, pediatric oncology medications, pain management drugs, emergency treatments such as the anti-anaphylaxis agent epinephrine, and parenteral nutrition components.
8. Supply Chain Fragility
8.1. Hurricane Helene, which struck the southeastern U.S. in late September 2024, caused significant flooding at Baxter International’s North Cove facility in Marion, North Carolina. This plant is a major producer of IV fluids and peritoneal dialysis solutions, supplying approximately 60% of the U.S. market. The flooding led to a temporary shutdown of the facility, resulting in nationwide shortages of these critical medical supplies.(26)
8.2. In response to the shortages, Baxter implemented several measures:
Importation of IV products: Baxter coordinated with the FDA to temporarily import IV solutions from its international facilities in Canada, China, Ireland, and the United Kingdom. The company planned to import nearly 18,000 tons of IV products by the end of the year, utilizing around 200 Boeing 747 flights to expedite delivery.(27)
Production resumption: Baxter aimed to restart production at the North Cove facility in phases, with the goal of reaching 90–100% of allocated customer volumes for certain IV products by the end of 2024. The company prioritized the resumption of its highest-demand IV fluids, initially supplying customers with about 40–60% of their normal orders.(26)
8.3. The IV fluid shortages prompted hospitals across the country to implement conservation protocols, such as postponing elective procedures and seeking alternative hydration methods for patients. The American Hospital Association (AHA) called on federal agencies to boost the supply of IV solutions to mitigate the impact on patient care.(28)
8.4. Other manufacturers also took steps to alleviate the shortages. B. Braun Medical increased production at its facilities in Irvine, California, and Daytona Beach, Florida, to help fill the supply gap.(29)
8.5. Additionally, Otsuka and ICU Medical formed a joint venture to bolster IV solution supply in North America, aiming to enhance supply chain resilience.(30)
8.6. The situation underscored the fragility of medical supply chains and the critical need for coordinated efforts among manufacturers, healthcare providers, and government agencies to ensure the availability of essential medical supplies during emergencies
9. Sustainability
9.1. Sustainability concerns are becoming increasingly common in the pharmaceutical industry, and the sterile injectables market is an active area of discussion, driven largely by the economics of waste. Any wasted final drug product is necessarily more costly than most other steps in the manufacturing value chain.
9.2. Significant waste is generated in single-use vials for products that are dosed on the basis of patient’s weight, because the drug must be filled to accommodate variable doses. The material leftover from one single-dose vial is discarded. The first, albeit small step in reducing this type of waste is to measure it. In 2017, the Centers for Medicare and Medicaid Services (CMS) mandated that healthcare providers track the amount of discarded drug products.(31)
9.3. In 2021, a committee investigated this topic and issued a list of recommendations that could lead to reduced waste.(32) In 2022, the Environmental Protection Agency (EPA) published a report that was focused again on the reduction of waste in the healthcare industry among many different facilities.(33)
9.4. Switching to polypropylene vials would also have a significant impact. One study estimated a switch to polypropylene would reduce primary energy consumption by 25% and respiratory inorganics by 32%.(34)
FAQs
What is the difference between RABS and isolator systems in sterile drug manufacturing?
An isolator system provides a fully sealed, closed processing environment that virtually eliminates human contamination risks during aseptic fill/finish. Conversely, a Restricted Access Barrier System (RABS) uses physical barriers with active airflow while still allowing direct operator interaction, making isolators the preferred gold-standard under updated regulatory frameworks like EU GMP Annex 1.
Why are biopharmaceuticals increasingly reliant on lyophilization?
Biopharmaceuticals rely on lyophilization because complex biologics frequently degrade when exposed to heat, ambient temperatures, light, or shear stress in liquid form. Freeze-drying converts unstable liquid drug substances into dry powders, extending shelf life and enabling room-temperature storage without continuous, ultra-low cold chain logistics.
How do robotic workcells improve small-batch fill/finish operations?
Robotic workcells improve small-batch fill/finish by eliminating manual operator touchpoints, reducing human error, and offering rapid changeovers between different container formats. These automated, gloveless systems maintain continuous sterility assurance and strict process control, making them ideal for high-potency personalized medicines and small-volume therapeutics.
What causes persistent shortages in generic sterile injectable medications?
Generic sterile injectable shortages stem primarily from suppressed generic drug pricing, which erodes profit margins and deters manufacturers from investing in modern cGMP facility upgrades. Consequently, unexpected plant closures, quality failures, or natural disaster supply chain disruptions create immediate, widespread market deficits.
How does ballroom manufacturing compare to traditional cleanroom layouts?
Ballroom manufacturing utilizes large, open operational areas filled with mobile, single-use equipment and closed system technologies rather than static, multi-room cleanrooms. This design drastically cuts initial facility capital expenditure, reduces gowning overhead, and accelerates batch-to-batch changeover times for high-mix CDMO facilities.
What role does aseptic spray drying play as an alternative to freeze-drying?
Aseptic spray drying serves as a rapid, scalable alternative to lyophilization for producing stable, sterile dry powders from liquid therapeutics. It enables temperature-sensitive biologics and vaccines to remain stable at room or refrigerated (2-8℃) temperatures while utilizing less equipment footprint than traditional freeze-dryers.
