Cynthia A. Challener is a contributing editor to Pharmaceutical Technology.

Cynthia A. Challener

Pharmaceutical glass, above all, should be inert to drug formulations and ensure the safe storage of medicines. While borosilicate Type I glass is the industry standard, shortages of some types of glass vials in recent years have been further exacerbated by the COVID-19 pandemic supply chain disruptions and need for high demand for glass containers for vaccines.

Manufacturers that implemented advanced supply-chain planning for fill/finish materials have weathered these challenging conditions so far, but difficulties are expected to continue for some time. Glass manufacturers are helping customers adjust to the situation with validation of alternative glass container solutions, including ready-to-use (RTU) molded glass products and strengthened aluminosilicate glass. Greater flexibility and collaboration across the supply chain have also surfaced as important factors for managing fill/finish material supply.

Drug products produced in glass vials and pre-filled syringes must be safe for the people who rely on the medicine they contain. That is the number-one priority for Curia (formerly AMRI), according to Jon Leisner, the company’s director of US procurement. “We take our responsibility seriously, to both our clients and the end-user, to provide sterile, quality, and compliant products,” he says.

For that reason, the most critical aspect of the glass used for pharmaceutical primary packaging needs to be as inert as possible so that it does not react with, add to, absorb, or allow external factors to change a drug product’s established safety, identity, strength, quality, or purity characteristics, explains Kevin McLean, quality and technical manager—Americas with SGD Pharma.

As such, notes Woocheol Chae, head of the drug product planning group at Samsung Biologics, the glass material must be chemically stable and not generate extractables or leachables (E&L), delaminate, or undergo other changes upon contact with the drug product. Minimizing E&L concentrations, adds Robert Schaut, scientific director of Corning Pharmaceutical Technologies, promotes the stability and purity of the drug product.

In addition, according to McLean, glass containers must protect their contents from the environment, and in some cases protect people from their contents, for example, from cytotoxic drug products.

In the United States, specific requirements for primary packaging as established by FDA are outlined in 21 Code of Federal Regulations Section 211.94. With respect to glass packaging, the global pharmacopoeias list three types of containers distinguished by their compositions and classified by their hydrolytic resistances—the extent to which 121 °C superheated water extracts alkali from the surface of the glass.

Type I borosilicate glass, for instance, has a long history of application and is the global standard for parenteral drugs due to its high hydrolytic resistance and ability to withstand extreme conditions, according to McLean. Type II and III are both soda-lime-silica glasses, but the former is treated on the inner surface to increase hydrolytic resistance.

Borosilicate glass primarily comprises silica and boric oxide and only contains small quantities of sodium. This composition, says Leisner, makes it resistant to heat and to enzymes. Its chemical inertness also makes it non-reactive with pharmaceutical products and reduces the risk of contamination, API degradation, and pH shifts.

All three types of glass must meet the container and closure system specifications of the United States Pharmacopeia and/or the European Pharmacopoeia, says Chae. The use of a colorant (mostly amber) is possible as a means for protecting the contents from exposure to light, he adds.

The COVID-19 vaccines placed additional performance requirements on the packaging system, according to Schaut. Key examples, he explains, include maintaining container-closure integrity below the elastomer’s transition temperature, maximizing filling-line throughput while minimizing particle contamination, ensuring mechanical robustness during freezing and transportation, delivering cosmetic quality to permit inspection of the contents, and serving as a functional barrier to contamination, gas, and light.

“The introduction of messenger RNA vaccines sets more specific needs beyond conventional glass vials, demanding either increased strength for optimal fill volumes in cold storage or a greater number of conventional glass vials with lower fill volumes,” Schaut continues. “These needs have created new challenges for fill/finish manufacturing and drug delivery that traditional pharmaceutical packaging is not able to address and is pushing the industry to move towards new, more advanced solutions to glass manufacturing,” he asserts.

Filling-line throughput has been particularly important for the COVID-19 vaccine due to the need to fill millions of vials as rapidly as possible. “There are many factors that limit the speed and efficiency of pharmaceutical filling machines, including dimensions and friction of the vial being processed,” notes Schaut.

Traditionally, Schaut observes, filling machines have been deliberately engineered with output constraints due to the physical interactions between the machine and conventional borosilicate glass vials. “Stress and friction generation on turn tables, tracks and trays, and particularly at junctions between intermittent and continuous motion can lead to glass breakage and human line interventions, which risks greater contamination of sterile environments,” he says.

Rapidly filling millions of vials with COVID-19 vaccines requires optimal filling efficiency and quality, which can be achieved in part using vials with a low coefficient-of-friction exterior surface, improved dimensional consistency, and strengthening to resist breakage, concludes Schaut.

The supply-chain for the production of tubular glass pharmaceutical-grade vials has been under stress for several years. Notably, the raw cane used to produce these vials was under strain due to changes in regulatory expectations in Asia, where there was demand movement from so-called low-borosilicate to mid- and high-borosilicate compositions, according to McLean.

The COVID-19 pandemic then placed an enormous global demand on the supply of tubular vials, creating concerns for global drug supply lines. “The supply/demand balance can be challenging to maintain when we are in a steady state, so the addition of a once-in-a-generation public health emergency has certainly put additional pressure on the marketplace,” says Leisner.

“The speed at which companies are required to move in order to address supply shortages is impacting every stage of the supply chain, from manufacturing to business processes to people,” Schaut adds.

Many of the large pharmaceutical companies, notes McLean, took a risk and placed orders for vials to package vaccines that were yet to be approved, locking in supply to meet the demand. “Ultimately, the supply-chain challenges for glass packaging materials observed over the last year are a result of a series of events, with a ripple effect across the industry,” he concludes.

An extended delivery period, which caused supply shortages, posed the biggest challenge over the last year, according to Chae. “Where it used to take 4–6 months to get a fill/finish material supply delivered is now extended to 12–20 months.” In particular, glass vials that are widely used for vaccines, such as 10R vials, were difficult to secure due to immediate increase in demand.

Despite such advanced planning by many, there has—and continues to be—a tremendous amount of pressure on the entire supply chain, according to Leisner. “Quite simply, demand has outstripped supply across the entire spectrum of fill/finish. It is not restricted to glassware. There have also been shortages of things [such as] plugs and stoppers, as well as all the consumables we need throughout the manufacturing process to fill and finish vials and pre-filled syringes, such as filters and filter bags,” he comments.

For companies that typically rely on tubular glass vials to package their therapeutics facing supply shortages, one option was to rapidly qualify other solutions, such as molded glass, as a backup or alternative. Molded glass can have some shortcomings compared to traditional glass, such as higher weight, non-uniform thickness, and reduced cosmetic quality, but does meet good manufacturing practice requirements.

“Forward-looking fill/finish operators continue to shore up their supply base and are thinking ahead. As vaccine administration is allowing the world to resume some degree of normal activity, COVID-19-driven demand remains high, and demand for other therapies that dropped during the pandemic is also rebounding. We are seeing more and more interest in molded glass as an alternative or back-up option to tubular glass given its global availability,” McLean observes.

It is not a simple solution, though. “The difficulty here is that the qualification and validation for alternate packaging can be extremely resource-intensive and can overwhelm smaller pharma companies,” says McLean.

Some have therefore turned to glass suppliers like SGD Pharma for regulatory support and to help with providing stability evidence and other needed data, according to McLean. “Many companies are seeking the expertise of their primary packaging partners to ensure approval and mitigate the risk of validations not being accepted. For instance, SGD Pharma is working with fill/finish organizations to provide support and information to help with the scientific justification of material changes,” he says.

There has also been growing interest in RTU glass vials in several pharmaceutical segments. RTU glass vials can be delivered pre-sterilized in optimized secondary packaging ready for fill and finish, skipping up-front washing and depyrogenation steps in an aseptic environment, allowing biotechs and drug manufacturers to speed up time-to-market, according to McLean.

“RTU technology has been around for a while, but only recently have we seen real interest, particularly in markets that require considerable flexibility in their operations, such as veterinary and biotech,” McLean says. For example, he points to the growing trend of personalized medicine as placing demand on innovative biotech companies for more flexible production capacity that can be supported by novel combinations of primary packaging.

To help meet that demand, SGD Pharma has introduced a number of RTU molded glass range extensions for fill/finish, including 50-mL vials in clear and amber glass in pre-sterilized tray secondary packaging and 20-mL vials in clear and amber glass in a nest-and-tub format.

“These new RTU primary and secondary packaging combinations developed in collaboration with Stevanato Group offer drug producers the flexibility they need to deliver innovative medicines to patients significantly faster because the drug master files (DMFs) are available,” McLean comments. “The nest-and-tub format, for instance, protects vials with no glass-to-glass contact and enables combi-line filling, the ideal option for smaller biotech companies looking for optimal flexibility,” he adds. In addition, biopharma manufacturers now have access to an integrated, flexible multiple filling line solution for different sources of primary packaging.

Catalent has not had any direct experience of significant supply shortages during the pandemic because the company honed in on addressing supply-chain needs, according to Melissa Buchanan, supply-chain director at the company’s Bloomington, Ind., site.

“To ensure minimal disruption, Catalent has tightly monitored its inventories, collaborated with supply-chain partners to protect critical supply needs, and committed additional resources to identify, navigate, and resolve potential supply-chain disruptions. This has included expanding safety stocks and extending the buying horizon to ensure sites have the necessary components to manufacture medicines, vaccines, and therapies for customers,” Buchanan remarks. Additionally, Catalent has developed improved business analytics to identify and track potential supply risks earlier, allowing more time to respond to challenges.

Similarly, Samsung Biologics benefited from resilient and flexible supply-chain-management operations, which ensured a stable supply by anticipating such disruptions and adopting proper contingency plans in advance, according to Chae.

The value of early supply-chain management

Even prior to the pandemic, it was important to have supply-chain strategies and contingency plans in place to support biopharma operations in the long-term and withstand market fluctuations and sudden material supply disruptions, Chae asserts.

With the COVID-19 pandemic, the industry has come to understand even more than ever before the value of early supply-chain management, according to McLean. “It may sound obvious, but successful drug manufacturers are those that manage their packaging supply with a proactive, rather than reactive, approach,” he states. Although there is an element of risk involved, he notes that securing supplies before product approval has huge benefits, particularly in situations such as the COVID-19 pandemic. The importance of having a backup packaging supplier has also been highlighted this year, McLean adds.

As a step to address the concerns over packaging supply uncovered during the pandemic, drug manufacturers are encouraged, says McLean, to start stability testing for alternative packaging materials before they experience shortages to mitigate risk and ensure business continuity in an uncertain climate.

Catalent, like many companies, found during the pandemic that the use of online and virtual tools, including improved data analysis for business-decision making, was vital to success. “These types of tools are helping identify and track potential supply risks earlier, allowing more time and better options to react,” Buchanan remarks.

For Leisner, the pandemic has underscored the need for greater flexibility. “The pandemic has shown that the drug-development and manufacturing industry needs to build more diversity and agility into its processes and place an emphasis on phase-appropriate quality practices,” he asserts. “COVID-19 may not be the last pandemic that we’ll face in our lifetime, so we need to learn from the last 18 months and start making changes now,” he adds.

A specific example of how to increase agility in supply chains, Leisner highlights, would be to qualify multiple options for alternative components in the DMF. “That way we could diversify, if needed, and minimize disruption to manufacturing,” he says.

As a pharmaceutical glass packaging company, SGD Pharma has already learned to leverage flexibility, particularly the flexibility of the molded glass production process and run size, according to McLean. “During production, we form vials directly from the glass furnace, rather than converting from tubular cane that originates from a furnace elsewhere. We can therefore produce hundreds of thousands of containers per day on a single line and, when necessary, stop that line short and move to production of another size or design. In this way we can be flexible in production and add capacity quickly when needed,” he explains.

The pandemic, believes Schaut, has also highlighted the demand for increased efficiency and speed in pharmaceutical packaging and vaccine production. “New glass coating technology and high-speed filling lines can help enable pharmaceutical companies and contract manufacturing organizations (CMOs) to ramp-up capacity and throughput based on demand,” he asserts.

A positive outcome of the COVID-19 pandemic has been increased collaboration across the biopharma supply chain. “The pandemic has required unprecedented cooperation between all partners involved, sharing information; working on various activities in parallel; and focus, dedication, and hard work by all the teams involved,” Buchanan states.

“We learned that collaboration is essential to meet demand and overcoming challenges quickly. Companies up and down the supply chain have been required to collaborate and find new solutions, be it material or technical, in order to meet the current need,” agrees Schaut. “Collaboration throughout the entire supply chain is essential to move quickly to implement solutions. From raw materials to fill/finish operations, companies are working together with an understanding that change is inevitable,” he says.

“Over the course of the last 18 months, Catalent has not only seen an increase in demand, but also an increase in collaboration and transparency across the industry, from innovators and other [contract development and manufacturing organizations] CDMOs, to suppliers and even regulators,” Buchanan continues. As a result of these new levels of collaboration, she notes that partners have been willing to make investments at-risk, allowing Catalent to bring more commercial capacity online, faster.

Along with greater willingness to consider other options, Leisner has observed a declining interest in single-source contracts, which he believes may become a thing of the past. “To get there, we will need to work in partnership across the ecosystem, and we all have a role to play,” he says. Fill/finish experts, for instance, need to help their customers understand the supply-and-demand risks of over-specification in regulatory documentation, while regulatory agencies could make re-opening DMFs easier by streamlining the current Resource- and time-intensive process.

McLean agrees that the inability of CMOs providing fill/finish services to make changes to primary packaging is an issue that should be addressed. “Primary packaging options for products validated on a contract manufacturer’s production lines are limited and therefore CMOs cannot respond quickly if changes are needed. Going forward, CMOs need to be included during validation of different container sizes and glass types,” he remarks.

Regulatory guidance as a navigational aid

Regulators are realizing, according to Schaut, that support for new materials such as aluminosilicate and strengthened vials, will help to curve supply shortages and meet increased capacity and safety needs.

FDA, for instance, is playing an important role in facilitating the industry’s ability to respond to the changing supply situation that has resulted directly and indirectly from the pandemic. “Through regulatory guidance issued in early 2021 (1), FDA is helping fill/finish operators navigate the qualification process for alternative glass vials and accelerate approvals,” McLean observes.

“The release of this guidance signaled FDA’s flexibility in permitting changes and substitutions between material types for primary packaging, as long as a strong risk-based analysis justifies the safety of doing so,” McLean explains.

It is important to remember that the industry is not out of the COVID-19 period yet, says Leisner. “Vaccines are still in high demand and, while certain countries are realizing higher vaccination rates, we anticipate continued global demand. The need for booster shots also remains unknown. Consequently, tightness in the market remains, and supply will likely not catch up with demand for some time to come,” he comments.

Corning Pharmaceutical Technologies believes that the global shortage of borosilicate glass tubing used in the production of pharmaceutical glass primary packaging will continue to cause a bottleneck for fill/finish materials. “The need for COVID-19 vaccines is expected to continue on an annual basis in the form of annual boosters, new variant vaccines, and multivalent vaccines. Any tubing used for COVID-19 must be pulled from other drug products, potentially impacting the availability of non-COVID-19 related treatments,” says Schaut.

In addition, while COVID-19 vaccine manufacturers are currently filling at 10–20 doses per vial, Schaut notes that plans are already in place to shift towards single-dose vials and pre-filled syringes. Aging capacity in the industry also presents a long-term challenge for fill/finish material producers and the pharmaceutical companies who ultimately receive the converted packaging, he adds.

Overall, Schaut concludes that COVID-19 vaccine material demand is not expected to wane in the near future, which could lead to extended lead times until capacity throughout the supply chain is brought online.

Capacity investment and new manufacturing technologies, such as high-volume manufacturing lines, are needed to help meet evolving industry needs, according to Schaut. Large vendors are making investments to increase capacity, which are expected to go into actual operation by mid to late 2022, says Chae. He expects that as demand for pharmaceuticals continues to increase, even if it is not related to COVID-19, the shortage of materials is likely to worsen in the short term.

Building in the additional capacity needed to meet the increased demand, both logistically and with regards to regulatory sign off, does not happen overnight; it is a multi-year process, adds Leisner. “As an industry, it will take time to create the additional capacity necessary to meet the COVID challenge while also protecting the supply of medicines to those who already depend on us,” he concludes.

Indeed, many announced borosilicate capacity investments are one to two years away, and most are slated for Asia and may not be available for the US market due to local demand, says Schaut. As the only American primary packaging pharmaceutical glass manufacturer, Corning is ready to assist by leveraging its North American manufacturing assets. “As previously announced, Corning and the US government have made significant investments in US manufacturing,” he says. The company is also expanding capacity around the world to support global supply chains, including a facility in Bengbu, China, which is slated to open ahead of schedule in in the third quarter of 2021.

Glass, of course, is not the only material that can be used as containers for parenteral pharmaceutical products. Plastic is an alternative that is receiving increasing consideration in light of the shortages of glass materials. “With the enhancements in plastic molding technology, plastics may potentially become an alternative solution to glass in the long run,” Chae observes. Developments are also being achieved in blow-fill-seal technology, which he predicts may eventually replace vials and syringes to some degree.

Leisner adds that, while its excellent safety profile means borosilicate glass is a well-established industry standard, it does have limitations in some settings. As a result, he notes that a steady migration to polymer syringes, which are free of heavy metals and tungsten, has already been underway in recent years.

One key takeaway from Leisner is the fact that there never is a one-size-fits-all solution in the world of fill/finish. Plastic has its place, but it can be easily scratched and is not suitable for oxygen-sensitive drugs, he notes. It is essential to select the most suitable material for each drug product, considering the end user, route of administration, and manufacturing requirements.

So what does the future hold for glass containers for parenteral drug products? McLean expects trends such as robust shipping to continue, with packaging innovators continuing their focus on glass vials that are resistant to breakages.

Innovators are creating new types of glass to overcome challenges associated with borosilicate, Leisner agrees. He notes that a relatively new-to-market glass has been designed to be break-resistant and to lower the risk of delamination by eliminating boron and sodium from the glass surface, which could increase the throughput on filling lines.

Chae points to aluminosilicate glass, which contains aluminum oxide and exhibits more tensile strength and resistance to high temperature and chemical corrosion. He also notes that new external surface-coating technology offers enhanced durability and productivity, while vials with built-in sensors facilitate process analysis.

“The introduction of strengthened aluminosilicate glass offers superior chemical durability, strength, and damage resistance as compared to traditional borosilicate vials. These qualities can help enable increased throughput and more reliable access to state-of-the-art medicines for patients, while maintaining a high level of quality assurance for pharmaceutical companies,” Schaut adds.

In addition, Schaut observes that advances in glass coating technology have enabled improved damage resistance, reduced particulate generation, and improved machinability leading to increased manufacturing capacity.

Going forward, Corning also believes that the industry will further adopt high-speed filling lines enabled by coated vial technology that can be used to help respond to rapid surges in demand for primary packaging, according to Schaut. “This technology is being adopted now, and we believe that it will become more and more prevalent as CMOs and pharmaceutical companies continue to expand capacity and upgrade existing lines,” he states.

Other trends outside of glass composition noted by McLean include growing interest in individual vial serialization with cradle-to-grave track and trace capabilities and the development of new RTU formats for larger capacity vials, which is of particular relevance to compounders, a once-again growing segment of the market.

“Compounding pharmacies have the ability to create drugs that were experiencing shortages, such as anesthetics, sedatives, muscle relaxants, and painkillers, and to combine multiple medications into a single solution to make them easier and cheaper to administer. Larger-size RTU vials will help compounding pharmacies manage sterility needs through the pandemic and beyond,” McLean states.

COVID-19 Container Closure System and Component Changes: Glass Vials and Stoppers, Guidance for Industr

Cynthia A. Challener, PhD, is a contributing editor to 

Articles

Alternative materials, as well as supply-chain planning, are essential to ensure a reliable supply for parenteral drug packaging.

Setting a Clear Strategy for Primary Packaging

Controlling the rate and/or site at which an API is released provides drug developers with new ways to create medicines that are kinder to patients, yet just as effective. Controlling the release of the API eliminates fluctuations in drug plasma levels, which typically leads to reduced side effects, and also allows for reduction of the number of doses required per day, according to Jessica Mueller-Albers, strategic marketing director for oral drug-delivery solutions at Evonik Health Care.

Ideal controlled-release products enable administration once-per-day for oral therapies and no less than once-per-week up to every six weeks for parenteral treatments, adds Sudhakar Garad, global head of pharmaceutical profiling at the Novartis Institutes for BioMedical Research. Controlled-release doses are also easy to swallow or administer, cost-effective, stable at room temperature for at least two years, and easy to pack and ship.

Other important properties, observes Mueller-Albers, include an excellent retardation effect at low polymer doses, very good tableting behavior, no ethanolic effect on the swelling properties of APIs to avoid dose dumping if a patient consumes alcohol, and thin polymer layers to ensure short processing and coating times.

Achieving these goals can be challenging given the evolving properties of APIs and the increasing desire to develop more targeted medicines. Fortunately, there is a wide range of controlled-release mechanisms available today.

Successful controlled-release formulations provide for drug release over a defined period of time at a specific rate and at targeted locations, such as the gastrointestinal (GI) tract, skin, muscle, etc., according to Simon Chen, vice president of Bora Pharmaceuticals.

The most important property when designing a controlled-release formulation, asserts Brad Beissner, development scientist II with Metrics Contract Services, is to ensure its robustness of API release, particularly for APIs with a narrow therapeutic range.

“A well-formulated controlled-release formulation is designed to release the drug in a reliable and consistent manner at a predefined release rate and at the optimum site of absorption for its activity,” says Anil Kane, global head of technical scientific affairs, Pharma Services, at Thermo Fisher Scientific. It is critical that the formulation is consistent in performance in global patient populations, age groups, and disease states.

Robustness with respect to consistency of manufacturing is also critically important for controlled-release formulations, according to Ron Vladyka, director of scientific services, oral and specialty delivery at Catalent. “The defining factor that progresses the dosage unit from a prototype to a commercially viable product is its ability to be repeatedly manufactured in a commercial setting,” he says.

Drug release must also be consistent, predictable, and reproducible across population profiles, according to Firouz Asgarzadeh, vice president of pharmaceutics at BioDuro. Predictable release profiles, he notes, make it easier to determine the number of doses required to maintain therapeutic levels of an API in the plasma of a patient and stay below toxic levels. Robust reproducibility across a large spectrum of patients regardless of intra-patient variability is necessary to avoid the need to personalize each drug for every patient, Asgarzadeh adds.

The release rate of the API in the appropriate location along the digestive tract must also be controlled in a precise and reproducible way to achieve optimal bioavailability of the drug after oral administration and ensure a reproducible clinical response, according to Torkel Gren, senior director, technology officer, and strategic investments leader with Recipharm. “To do so usually means that process parameters and excipient qualities must be very carefully and stringently controlled in terms of loading to ensure the desired release rate consistently across the batch and avoid variation during trials and beyond,” he observes.

In general, summarizes Tejas Gunjikar, application development and innovation leader for IFF’s Pharma Solutions business in South Asia, controlled-release formulations should provide the desired and consistent controlled drug release; should be scalable, stable, easy to administer; and should help reduce dosing frequency and side effects, factors that lead to improved therapeutic outcomes for patients. “Such formulations are generally most acceptable and achieve commercial success,” he asserts.

A controlled-release formulation and process, if not carefully designed, could likely result in inconsistent drug release, resulting in variability in therapeutic response, dose dumping, and/or quality rejects. Dose dumping can occur if the controlled-release mechanism does not work, potentially resulting in side effects or toxicity in cases where the drug has a small safety window, according to Kane. In addition, if the drug-product manufacturing process is not robust, quality rejects can result, including deviations, out-of-specifications, and batch rejects, all of which can lead to manufacturing and/or financial losses, he adds.

Building robustness into the drug product begins early in formulation development with the selection of robust excipients, according to Vladyka. “In general, the selection of excipients for controlled-release dosage forms is performed in conjunction with the quality target product profile and physical and chemical properties for the drug substance, but is governed by the technology being employed to manufacture the controlled-release units,” he says.

Additional refinement or selection of critical excipient properties may be needed to modulate the controlled or localized drug-substance release, such as further sizing of core beads for a layering process or the selection of specific lots of polymer based on functional group substitution values. In some cases, a combination of different polymers with different molecular-weight distributions, degrees of substitution, and other characteristics—all of which must be carefully controlled—are necessary to achieve the desired API release rate, notes Philippe Gorria, senior director of formulation development for Recipharm.

“Regardless, the impact of the excipients sets a firm foundation for the optimization and development of the drug product’s formulation and process, enabling the development of a robust product that can be reliably manufactured in a commercial environment,” Vladyka states.

Designing the controlled-release dosage form using the most appropriate mechanism or principle of drug release is key along with the choice, quality, and quantity of the critical functional excipients, Kane remarks.

The most preferred excipients for a successful controlled-release formulation deliver a high degree of reproducible performance and are safe for use for oral controlled release, states True Rogers, senior scientist in IFF’s Pharma Solutions business. Examples of such materials are cellulose derivatives including hydroxypropyl methylcellulose (HPMC), ethyl cellulose, cellulose acetate phthalate, etc., and synthetic excipients such as polyethylene oxides and polymethacrylates. Certain naturally derived excipients based on seaweeds and natural gums are also used, but to a lesser extent, according to Rogers.

Because 100% synthetic excipients demonstrate less batch-to-batch variation with greater degree of modulation and control, they are used more often to achieve robust controlled-release formulations, Asgarzadeh notes.

“Ultimately,” asserts Gorria, “controlled-release excipients must be suitable for the manufacturing process, suitable for controlling drug release, and available in a defined, reproducible quality.”

Although excipients are traditionally thought of as inactive ingredients, they do play functional roles in controlled-release formulations. It is therefore critical, stresses Asgarzadeh, to have an excellent understanding of the material science and structural properties of selected excipients to overcome the various challenges faced by formulators. “Wisely and judiciously selected excipients will facilitate achieving the desired release profile of a controlled-release drug product, which ultimately affects the targeted therapeutic effects of the drug to a patient,” he says.

Kane also stresses that while the selection of the excipients with the proper functionality and their corresponding levels in the drug-product formulation are critical to the controlled-release drug-product performance, a deeper understanding of how variability in the excipients can affect drug-product performance and the proposed control strategy is an important consideration as well.

Functional excipients that have a direct impact on the performance of the dosage unit and its robustness include polymers, pH-modifying agents, and surfactants, which are used to control and mitigate negative factors when combining multiple enabling and controlled-release technologies, according to Vladyka. He adds that suitable binary or ternary polymer mixtures can inhibit or delay recrystallization of an amorphous drug substance. In addition, the availability of various excipient types and grades enables optimization of the performance of the API in the controlled-release formulation and delivery system being developed.

Furthermore, according to Chen, different excipients can be used not only to help modify the release rates of APIs using the same release mechanism, but to modify the release rates of APIs produced using different manufacturing processes, such as coating, mixing, hot-melt extrusion (HME), spray drying, and more.

“An advantage of using versatile excipients or polymers from an experienced provider is that these can be applied to a broad range of drugs and used for different formulation approaches such as diffusion-based or matrix systems, as well as in different process technologies like granulation, coating, tableting, and HME,” Mueller-Albers agrees. She also notes that excipients with long track records that have been investigated in numerous 

 trials and used in marketed products provide a strong basis for successful 

For high-dose controlled release formulations, Garad notes that there are a few special excipients that play an important role in enabling higher API loadings.

It is important, though, that excipient suppliers thoroughly understand their manufacturing processes and provide quality-by-design (QbD) samples that represent the ranges observed for critical material attributes, such as polymer molecular weight, relative substitution levels, particle size, etc., Beissner asserts.

Formulators can be proactive, as well, Beissner says. For instance, for hydrophilic matrix tablets, having at least 25% by weight of the formulation, the rate-controlling polymer helps limit the effects of any naturally occurring raw material variations and ensures tablet-to-tablet release uniformity in the batch. Designing sustained-release coatings to a specific mg/cm2 coating thickness based on surface area of the substrate, meanwhile, makes scaling up the film-coating process easier and provides greater assurance of repeatable results.

Release technology drives excipient selection

Excipients used on controlled-release formulations are constituted of two main classes: matrix and reservoir systems. The mechanism that controls the release differs for both systems and by matrix solubility (hydrophilic or hydrophobic), explains Joao Marcos Cabral de Assis, global technical marketing manager for pharma solutions within BASF’s orals platform.

Excipients that can form thin films and tablet matrices are particularly applicable, according to Gorria, because they can control drug release by limiting drug dissolution and/or drug diffusion, or even through osmotic pumping effects. Sensitivity to pH will also impact excipient selection for drug formulations intended to target a specific location within the intestinal tract. Controlled-release formulations are typically achieved by utilizing high-molecular-weight, water-soluble polymers to form hydrophilic matrix tablets or by film coating using predominately water-insoluble polymers, according to Beissner.

The majority of controlled-release drugs are formulated in hydrophilic matrices that release APIs by drug diffusion and matrix erosion. Cellulosic polymers such as HPMC, hydroxypropyl cellulose, hydroxyethyl cellulose, and methylcellulose are the most common polymers used in extended-release formulations. Alginates, carbopol, and gelatin are less common examples of these materials.

Hydrophobic matrices release APIs through drug diffusion because the matrix is water-insoluble and does not erode. API solubility is consequently a critical factor for the success of these formulations, according to Assis. He points to carnauba wax, cetyl alcohol, hydrogenated castor oil, microcrystalline waxes, ethyl cellulose (EC), stearic acid, and polyvinyl acetate (PVAc) as examples of lipophilic matrices.

The selection of a hydrophilic or hydrophobic matrix such as pH-dependent or pH-independent polymethacrylate is mainly determined by the solubility of the drug because a potential self-retardation effect of the drug at higher pH will have an influence on the release kinetics, according to Mueller-Albers. The same is true for highly soluble drugs that may require strong retardation during stomach passage.

Soluble components are often added to lipophilic matrices and insoluble film coatings to act as pore formers to better adjust drug release. Typical pore formers are povidones (polyvinyl pyrrolidones [PVPs]), polyethylene glycol-polyvinyl acetate (PEG-PVAc) grafted copolymers, sugars, and PEGs.

Reservoir systems consist of a nucleus containing the drug, which can be multi-particulates or a single tablet coated with an insoluble film. Drug release in these systems, says Assis, is carried out exclusively by diffusion and is modulated through film layer thickness, permeability modifiers, and added core components that alter the water-attractiveness. The application is mainly served by insoluble film-forming excipients such as methacrylates, EC, and PVAc.

To choose the right excipient, Mueller-Albers recommends that formulators consider the nature of the API, such as its solubility, charge, etc.; the type and design of the dosage; the strength and duration of the retardation effect; the preferred manufacturing process (i.e., direct compression, granulation, coating, HME, spray drying, etc.); and whether there is a need for easy swallowability, such as for pediatric and geriatric patients.

A thorough understanding of the functionality and material properties of polymers is key to the successful design of controlled delivery, specifically for matrix and osmotic zero-order drug release, adds Kane. For instance, Chen comments that for delayed-release formulations, pH-dependent excipients such as methacrylate polymers will provide gastro-resistant functionality; EC would be the choice for pH-independent controlled release such as with multi-particulate drug-delivery systems (e.g., pellets within a capsule); HPMC would be the main choice for monolithic controlled-release delivery systems; and poly(DL-co-glycolide) (PLGA)-based polymers would be preferred for microspheric depot injection formulations.

As with most formulations, Beissner adds that drug solubility plays a major factor in excipient choice. “Lower-molecular-weight polymers are generally used to generate a more erosion-based drug-release profile for low-solubility drugs, while higher-molecular-weight polymers that swell more and afford a diffusion-based drug-release profile are paired with high-solubility drugs,” he explains. The rate of API release from a sustained-release coating is, meanwhile, modified by changing the ratio of the water-insoluble and water-soluble polymers in the formulation and the film coating thickness.

In addition, Gorria adds that for a hydrophilic matrix tablet, powder flow and compatibility will be important while for a product comprising coated pellets, the polymer must be sprayable and generate a strong thin film on each pellet. It also depends on whether API release will be restricted by slow dissolution, by forming a semipermeable membrane, or through a gel.

Other guiding factors can include anticipating the patient characteristics of the target population, such as in the case of pediatric formulations for which excipient options can be limited somewhat because of safety concerns and the availability of process equipment, according to Vladyka. “Available process equipment can dictate the type of excipients that will be used in the manufacturing process,” he explains.

For instance, Assis notes that for poorly compressible APIs, PVAc can provide the plastic deformation needed to increase the compressibility and allow for simple direct compression, saving process time and costs.

Similarly, EC coatings require large amounts of plasticizer to achieve the necessary film elasticity, which leads to formulation and process complexities, according to Assis. In addition, while some aqueous EC dispersions are available, they have long curing times and require high temperatures, thus most EC coating solutions require the use of organic solvents. PVAc-based coatings, he observes, as aqueous dispersion films, are attractive alternatives with high flexibility, pH-independent drug release, lower curing temperatures, and lower dose-dumping risk.

The formulation scientist faces several challenges when formulating a controlled-release drug product. These challenges, according to Gunjikar, are due to the properties of the drug, such as its solubility, dose, handling, processability, interactions with other components of the formulation, and the need for delivery to a site/region in the body at a predetermined rate; incomplete API release; and most importantly the ability to provide reproducible performance for consistently attaining the desired therapeutic outcome.

Mueller-Albers agrees that the main challenge to formulating controlled-release small-molecule drug products is that the properties of the API influence the release kinetics, and therefore, it is not so easy to find the right starting formulation.

In the formulation design of a controlled-release drug product, Kane adds that it is essential to evaluate the excipient variability on drug-product performance, and so it is critical to identify the most impactful material properties of the functional excipient such as a polymer (chain length, viscosity, swelling behaviour, etc). “This excipient variability understanding can then be combined with the knowledge of each of the API properties and the process parameters used to manufacture the drug product and to develop an appropriate control strategy that ensures consistent supply of safe and efficacious drug product,” he asserts.

“Formulator experience is crucial to address the challenges in controlled-release small-molecule drug products. For formulators who have limited experience with controlled-release dosage forms, partnering with a supplier that can provide the right excipient, technology, and process on a short timeline is essential. When formulators work under extreme time pressure, it is also important to have a platform solution that can be applied to several candidates,” Mueller-Albers says.

Close collaboration between formulators and ingredient providers during product development and scale-up could identify ingredients and properties that are critical not only to quality, but also to performance, agrees Gunjikar. “Defining both quality and performance design spaces leads to a more robust medicinal product,” he says. Industry-leading excipient vendors are an underutilized resource during the development of dosage forms, and their knowledge and experience with the application of excipients can be used to solve issues as they arise, Ron Vladyka, director of scientific services, oral and specialty delivery at Catalent, adds.

Most important is starting the initial formulation development of controlled-release dosage forms with knowledgeable partners, such as excipient suppliers, Mueller-Albers says. “Establishing such partnerships very early on can accelerate development because the right formulation and process parameters can be found more quickly. We have found that early exchange between an excipient manufacturer and formulator helps overcome challenges such as curing of aqueous controlled-release coatings by in-process curing solutions and avoiding alcohol dose-dumping by modulating formulations,” she explains.

Achieving IVIVC, zero-order release, and robustness

One of the biggest challenges for controlled-release formulations is to achieve IVIVC. “The relationship between an 

 response is especially important for controlled release oral formulations,” asserts Mueller-Albers. Through the successful development and application of an IVIVC, 

 drug performance can be predicted from its 

behavior. “The establishment of a meaningful IVIVC can provide a surrogate for bioequivalence studies, improve product quality, and reduce regulatory burden,” she adds.

Establishing this correlation can be difficult, however, due to absorption variations in the fed and fasted states for each patient and differences in intestinal tract transit, gut metabolism, etc., patient-to-patient, adds Assis.

Obtaining a zero-order release can also be considered a challenge for formulators. “Push-pull systems are an alternative for achieving this type of release, but the technologies required for their manufacture are so complex that most companies steer away from these systems,” notes Assis. Recently, though, he remarks that the use of a combination of functional hydrophobic matrix polymers (e.g., PVAc) blended in the appropriate proportion with a gastro-resistant polymer such as methacrylic acid and ethyl acrylate copolymer that acts as a pH-dependent pore former makes it possible to ensure linear release.

One challenge that continues to create issues for formulators is the difficulty in achieving targeted release of API in the lower intestine, according to Gorria.

Stability in various forms can also pose difficulties. For instance, changes in dissolution characteristics are often observed when the drug product is stored, notes Thorsten Cech, pharmaceutical technology application expert and manager of BASF’s European Pharma Application Lab. While curing can minimize these risks, this property remains a potential critical material attribute that requires thorough investigation during product development.

Ensuring the robustness of API release can be challenging as well due to the inherent variability of the polymers used in controlled-release applications, according to Beissner. “It is important that controlled-release formulations can withstand this lot-to-lot raw-material variability,” he says.

To ensure robust and reproducible release with minimal inter- and intra-patient variability over the intended extended period for controlled release, Asgarzadeh observes that the polymer excipients used in these formulations need to remain intact throughout the GI tract, efficiently facilitate API diffusion from the core of the drug product through the excipient membrane over time, release the drug predictably independent of patient diet, and provide release of the therapeutic level of the API without undergoing any physical transformation.

Formulating high-dose controlled-release drugs

Dose is the biggest challenge from Garad’s perspective. “In controlled-release formulations, the dose should be lower than that for conventional drug products so that it is possible to generate a formulation of a palatable size whether given orally or administered parenterally,” he observes. The final dosage form—a tablet or capsule, for instance—may be very large once you have combined several doses and added release controlling excipients, explains Gorria. Large tablets and capsules can be difficult to swallow for children and elderly patients with dysphagia, leading to reduced patient compliance and thus the effectiveness of the treatment.

For this reason, Garad notes that molecules with a narrow therapeutic window are typically not ideal candidates for controlled release. Very low-clearance molecules are not generally good candidates either, as they keep accumulating, which can lead to side effects.

APIs with very high or very low solubility create additional challenges because it is difficult to control their release profiles with excipients, according to Chen. For APIs with poor solubility, Vladyka remarks that there is a need to conjoin enabling technologies to increase the apparent solubility of the drug substance within a controlled release form. “In some cases,” he says, “these two technologies may not have compatible manufacturing processes and their selection could limit the preparation of controlled-release dosage forms.”

Specifically, Vladyka points to higher-energy-state techniques for improving drug substance solubility, which he notes may not be suitable for aqueous or organic solvent-controlled release processing because their use may cause re-crystallization of the drug substance and a decrease in solubility. Use of higher-energy-state APIs in drug reservoirs for diffusion-based drug release can potentially result in recrystallization of the API, which would change the release profile.

Despite these concerns, Cech points to the formation of amorphous solid dispersions (ASDs), particularly via hot-melt extrusion (HME), as an attractive solution for poorly soluble APIs. “HME has been shown to improve solubility and bioavailability and modulate release through the simultaneous introduction of controlled-release functionalities,” he explains. The controlled-release behavior can be achieved not only through careful selection of the polymer used to form the ASD, but also through optimization of porosity of the tablets produced from the compacted extrudates.

While it is possible to design a molecule to fit a controlled-release formulation, that is not usually feasible. The current practice, according to Garad, is to take an existing molecule and fit it into a controlled-release dosage form platform technology. “The key is to combine the right physicochemical properties with the right pharmacokinetic properties of the molecule and the right controlled-release technology and the ideal polymer,” he states.

Proactive identification of critical material attributes and their impact on drug release is essential, Cech adds. The interplay between these attributes and process variables (temperature, compression pressure, etc.) and material incompatibilities also needs to be studied.

“Depending on the API’s solubility and other physiochemical properties of the drug, different approaches can be used by formulators to ensure the likelihood of success and to achieve the expected drug-substance release. Considerations such as hydrophilic or hydrophobic matrices, film- and pore-formers, feasibility of the manufacturing process, and product stability can be part of QbD programs for systematic drug product development,” Cech observes.

Vladyka also highlights the importance of using knowledge and understanding about the drug product under development to guide the choice of approach and at what stage in the process to begin. A successful strategy takes a combination of deep formulation knowledge and empirical testing, adds Asgarzadeh.

Cech notes that using alternative methods to investigate processing such as determining the porosity flowability, compactability, and tabletability and subjecting non-optimized formulations to stability testing early on to select the most robust ones might be a good tactic to assure the quality and safety of final controlled-release drug products.

Information can be collected using pharmacokinetic modeling and solubility studies in various media including in simulated gastric fluids (to determine logP, dose, and solution stability). Formulation and process development can range from a broad multi-dosage form approach to a single technology, highly focused development plan.

Gren is in favor of investigating several formulation principles and excipient combinations to identify the most appropriate approach for the needs of a given project, and also says it is essential to determine the compatibility between all components of the future formulation to avoid degradation phenomena (polymer/polymer and/or polymer/drug substance).

Equally important, says Vladyka, is using high-quality excipients from industry-leading suppliers that have well-characterized quality attributes throughout the development lifecycle. Because excipients play a direct role in the controlled-release profile itself, Asgarzadeh adds that they should be selected based on prior experience and demonstrated properties that satisfy the needs of the API itself. “The ability to test excipients in efficient animal models increases the probability of identifying formulations that will succeed in the clinic by helping to determine which excipients work best both 

, providing relative prediction for human release profiles,” he says.

“As all drug substances are different, there is no one-size-fits-all solution,” Gren concludes. “Once a suitable prototype is identified, therefore, a design-of-experiment approach is useful in establishing a formulation and process parameter space that gives robust drug-release characteristics. Formulators can then be confident that they understand how the formulation will perform in a variety of real-world situations (several physiologic media), which allows them to refine the finished product to ensure consistent performance, regardless of real-world conditions,” he says.


Vol. 45, No. 9
September 2021
Pages: 16–22

When referring to this article, please cite it as C. Challener, “On Time Delivery: Challenges of Controlled-Release Formulations,” 

Consistency, robustness, and understanding of the API and controlled-release excipients are essential for successful drug dosing.

On Time Delivery: Challenges of Controlled-Release Formulations

Ensuring API quality is essential to the safety of drug products based on small-molecule
drug substances. That includes the quality of generic and branded APIs produced in-house or outsourced from contract manufacturers. The quality of raw materials, the quality culture and systems of API manufacturers, and other factors determine API quality.

Access to real-time or near-real-time supply-chain data through digitalization can help formulators of branded and generic drugs monitor the quality of materials across the entire supply chain and ultimately the APIs they use to produce their final drug products.

The benefits of an interoperable supply chain are extensive, and potential speed and efficiency gains across the value chain are tremendous, according to Valerie Van Hulle, global strategic marketing manager for digital at BASF. “The process becomes much more efficient, fast, and with real-time data access,” agrees Selwyn Lustman, senior vice-president of global sourcing and procurement at LGM Pharma.

Instead of waiting for emails, phone calls, and even paper mail, companies can instantly exchange quality and regulatory content, supply-chain data, and other critical data. This ability leads to better collaboration between suppliers and manufacturers and, ultimately, improved assurance of API quality, Van Hulle explains.

For instance, says Lustman, pre-shipment certificate-of-analysis (CoA) approval carried out within a day and digitalized documents reaching the forwarder before goods arrive at port so preclearance of goods can be reached are just two examples of the faster flow of information made possible with digitalization.

In addition to enabling companies to collect and analyze data in real time, allowing for decisions to be made quickly, Lustman also says that digitalization can facilitate traceability and transparency. That is achieved, Van Hulle says, by sharing data via electronic data interchanges (EDI), application programming interfaces, and other software.

“The receiving organization can embed [these] data directly into their own systems, supporting their internal processes and opening the door to big-data analytics,” observes Van Hulle. “When it comes to quality,” she notes, “such advances can help companies maintain a much higher level of transparency, traceability, and accuracy throughout the manufacturing and supply chain process.” Companies are also recognizing that data sharing methods allow for greater flexibility, she adds.

Connecting data across the supply chain creates a single source of truth, Van Hulle asserts. “Connectivity requires a common language, and essential content such as terms and application programming interface metrics would be spoken in a single language, eliminating the need to compare ‘apples and oranges’,” she asserts. This consistency would drive further efficiencies and boost the quality of data across the value chain.

API manufacturing digitalization is, however, still premature, and it is hard to say whether this process can fully be digitalized, according to Lina Cogan, senior director of global sourcing and procurement at LGM Pharma. Compared to other high-tech industries, the pharmaceutical industry has much work to do, Van Hulle agrees.

“While there are pockets of digital expertise (e.g., modeling, advanced analytics), digital solutions have not yet been broadly deployed,” says Van Hulle. Even leading API manufacturers still produce drug substances in a more “manual environment”, adds Cogan, with batch records handwritten most of the time and handled by operators on the spot who document each and every activity as required according to current good manufacturing practice (CGMP) regulations. “API manufacturers still work manually both in production and various labs and rely on their people to document each and every step to comply with GMP regulations and requirements,” she says.

Van Hulle does note, however, that organizations and people are quickly realizing the benefits of digitalization and understand that customers, regulatory authorities, and partners are demanding a greater level of connectivity. As an example, she points to BASF’s exploration of the use of both virtual and remote audits of API and excipient manufacturing sites, which was enabled through digitalization, and an essential innovation during the COVID-19 pandemic to ensure high quality supply.

Many processes in the supply chain have be digitalized over the past 10–15 years, Lustman adds. For instance, at LGM Pharma, purchase orders are sent digitally, and CoAs for pre-shipment approval are provided digitally, so clients can ensure that material meets their quality requirements before shipment. In addition, he notes that most shipping documents from contract manufacturers are sent digitally to clients, so they can be provided to forwarders and authorities for release of the goods from customs.

Another example of increasing importance for biologic drug substances and vaccines is the use of advanced digital trackers for cold-chain shipments, according to Lustman. The trackers provide downloadable data throughout shipment so drug manufacturers know their products are delivered in good conditions. In the past, data loggers had to be sent back to the manufacturer for downloading of the information, delaying the release of the API on the client side. The new technology allows more efficient release of goods via government agencies as well, he adds.

The fact that some suppliers and manufacturers have progressed with digitalization while others still operate manually makes sharing data across the pharma supply value chain difficult. “Some companies are leveraging cloud systems and have fully digitized their operations while others are still relying on paper records. It is extremely challenging to share data across systems that are not prepared to do so, let alone between different systems,” Van Hulle comments.

“If the pharmaceutical industry is to achieve real-time level data sharing, companies must first look at their end-to-end IT structures and ensure they are ready for an exchange,” Van Hulle asserts. Greater connectivity also requires the adoption of data-sharing standards. “Common standards could speed up the connectivity process and incentivize companies to invest in compatible electronic solutions,” she says. BASF is, for instance, exploring how ASTM and other existing standards can help make data sharing possible.

Some regulations may also need to change. One challenge to digitalization of supply-chain data that LGM Pharma has observed is the need for certain types of APIs, such as scheduled products, to have original documentation. “Original documents have to be sent from the client to the contract manufacturer, and only once government authorities approve them can shipments take place. This process can take several weeks,” Cogan explains.

Digitalization should not be done for the sake of “going digital” but with a focus on addressing pain points, according to Van Hulle. “There is an abundance of new technologies available to support supply chain digitalization. Attempting to implement every digital solution can be overwhelming and lead to less-than-impactful investments,” she observes.

Organizations should look at how digital solutions can alleviate their supply-chain challenges and address evolving customer demands that can be met through digitalization. “Ultimately,” Van Hulle concludes, “digitalization of the supply chain is a great answer to many of these challenges and the first step in a company’s digital transformation.”

Industry suppliers that have recently announced digital supply-chain solutions include PCI Services and MilliporeSigma.

The launch of its pci | bridge platform in the fall of 2020 was one of many initiatives that PCI has undertaken to incorporate digital transformation as core to its business strategy, according the company (1). The digital solution makes real-time information readily accessible to clients including inventory, production, distribution, and shipping data, presented in organized, customizable formats. The platform also features a document repository where electronic paperwork can be stored and accessed in one place and signatures secured on the platform.

MilliporeSigma’s eMERGE Program is a standardized platform solution for the exchange of data via an XML machine readable format based on an existing ASTM industry standard (ASTM E3077-17), including COAs and certificates of quality (2). It is compatible with existing process monitoring and analytics systems, enabling end users to integrate raw material data directly into their internal knowledge management systems and process analytical tools for improved monitoring and analysis of production performance, a better understanding of how raw materials impact processes and product variability, and a more efficient investigations process for out-of-specification situations.

1. PCI Services, “First-of-its-Kind Digital Platform to Provide Clients with Real-Time Supply Chain Data and Analytics,” Press Release, Sept. 28, 2020.
2. S. Wing, “Setting the Stage for Electronic Data Exchange,” MilliporeSigma White Paper, February 2021. 


Vol. 45, No. 8
August 2021
Pages: 22–23

When referring to this article, please cite it as C. Challener, “A Digital Supply Chain Helps Ensure API Quality,” 

Data sharing facilitates traceability, transparency, and accuracy while driving efficiencies and boosting quality of active pharmaceutical ingredients.

A Digital Supply Chain Helps Ensure API Quality

As the name implies, subunit vaccines are based on a portion of the infectious agent rather than leveraging the entire virus (killed or live-attenuated). A subunit vaccine usually contains a protein, a polysaccharide, or a combination of both. Because they contain only a portion of the pathogen, subunit vaccines typically have fewer side effects and can be given to a wider group of people, including those with compromised immune systems and chronic health conditions. They typically lack pathogen-associated molecular patterns, however, and thus tend to cause weaker immune responses, requiring the use of adjuvants and possibly booster doses.

The first recombinant protein vaccine was developed for hepatitis B, and many more have been approved since. Subunit vaccines formulated as virus-like particles (VLPs) and nanoparticles are also under development today.

Subunit vaccines work by exposing the body to a piece of a pathogen (virus, bacteria, parasite) that triggers an immune response, according to a spokesperson from Novavax. The company’s NVX-CoV2373 candidate vaccine against COVID-19, for example, uses an optimized version of the full-length spike (S) protein from SARS-CoV-2 as the subunit antigen. This antigen cannot cause disease but is delivered in a way that is read to be recognized and learned by the immune system.

In contrast, genetic vaccines (DNA or RNA vaccines) only take a small part of the viral genetic information that encodes the antigen triggering the immune response, notes Axel Erler, associate director of commercial development with Lonza. RNA vaccines, however, don’t generate a direct immune response, adds the Novavax spokesperson. Instead, they deliver a molecule that must be translated into the desired antigen, which is then recognized by the immune system.

This article was published online on June 21, 2021.

One advantage of subunit vaccines is that their manufacture is achieved using established recombinant technology that is widely distributed in the biopharma world, according to Yves Balmer, head of microbial development services at Lonza. “This technology offers a well-defined technical and regulatory landscape that is readily available and does not require the culture of virulent organisms and their subsequent attenuation/inactivation, which can create safety concerns,” he says.

In addition, Balmer notes that the recombinant production of subunit vaccines enables the selection of specific antigens that can be combined in a multivalent vaccine and generate a well-characterized product. Furthermore, production platforms for subunit vaccines are highly adaptable, with exactly the same procedures used to develop and manufacture variant-strain versions for use in scenarios of genetic drift, according to a spokesperson from Novavax.

One key advantage of subunit vaccines over genetic vaccines is their strong stability profile. Transport and storage can take place at regular refrigeration temperatures, and there is no need for ultra-cold freezers. “This feature enables the distribution of subunit vaccines in diverse global locations where -20 °C or -80 °C cold chains are unavailable,” Novavax’s spokesperson observes.

Such an ability is not an insignificant factor. “It is critical nowadays to set up resilient supply chains to be prepared for any disruptions such as COVID-19. In addition to having transparent and scenario-based forecasting in place to anticipate risk-based future global demand scenarios, managing cold-chain requirements regarding storage and transportation remains a key capability, especially considering the variety of temperature classes (i.e., cool-chain to deep-frozen, all the way down to liquid nitrogen temperatures),” comments Christian Rochel, head of supply chain for biologics at Lonza’s Visp, Switzerland facility.

Rochel adds that a focus on internal and external supply capabilities, including multi-site inventory management, remains an important factor to ensure full supply.

Unlike novel approaches and emerging technologies for vaccine development that can lead to regulatory challenges regarding demonstration of the safety and efficacy of such vaccine candidates, the development and regulatory pathways to commercialization for subunit vaccines are well established, according to Karen Magers, director of regulatory affairs at Lonza. “Vaccine regulators tend to be conservative, and there is a requirement for providing rigorous, supportive data based on the large intended populations for most vaccines, which often include children,” Magers says.

Protein subunit vaccines are an established technology, adds the Novavax spokesperson, and there are several approved subunit vaccine products on the market. Noteworthy for the company is the fact that a recombinant protein subunit vaccine manufactured using Sf9-derived insect cells, the approach used by Novavax for NVX-CoV2373, was approved in 2013. The investigational vaccine candidate being developed by Novavax, however, is also undergoing rigorous evaluation of its safety and efficacy, along with characterizing the company’s manufacturing processes.

One potential challenge for subunit vaccines is the need to use adjuvants in these formulations to achieve robust/broad immune responses. The issue arises, according to Magers, if a novel adjuvant is introduced. “Regulatory challenges can arise while establishing the safety profile of new adjuvants,” she remarks.

The time and money needed to develop subunit vaccines can pose additional challenges. While development timelines for these vaccines are shorter than those for vaccines based on whole pathogens, subunit vaccine development is still time-consuming. One key hurdle is determining the right antigen. Determining the best dose and adjuvant combinations can also take time, according to the spokesperson from Novavax.

In addition, many specific subunits have unique physicochemical properties, and a tailored process needs to be developed for each, starting at the level of the expression host then moving to process and analytical method development, says Balmer. “This process development for non-platform molecules requires expertise, time, and flexibility in the manufacturing facility,” he adds.

The cost of goods for subunit vaccines can be an issue as well. “Recombinant protein technology was initially developed for biopharmaceutical drugs, for which the cost of producing the drug substance was not a critical factor,” Balmer observes. In contrast, vaccines are expected to be affordable considering the need for wide implementation.

An approach to address both issues, Balmer notes, is to develop platform processes that would shorten the development timeline, pre-define the manufacturing facility, and reduce the cost. “An example is the production of VLPs in which the frame remains constant and only the antigenic part is target-specific,” he says. This standardized approach, however, is only successful if the antigenic portion remains limited so it does not impact the production process.

For its COVID-19 vaccine candidate, Novavax had a head start due to its recent experience developing vaccines for the original severe acute respiratory syndrome virus and its NanoFlu candidate for seasonal influenza, according to the company spokesperson. This experience combined with knowledge of the coronavirus’ spike protein and access to the company’s nanoparticle technology and proprietary Matrix-M adjuvant has helped to accelerate development ofNVX-CoV2373. Today, Novavax can begin testing a new vaccine candidate in the pre-clinical environment within weeks of identification of a variant of concern.

The concept of subunit vaccines has been around for decades. Several advances in technology have helped improve their development and manufacture. Magers points to progress in genomics for the identification of vaccine candidates and incorporation of three‐dimensional (3D) structure, domain organization, and dynamics of surface proteins analysis into vaccine design as aiding development efforts.

There have also been improvements in subunit vaccine formulation, according to Magers, such as the use of nanoparticles (e.g., ferritin) that self-assemble into microscopic particles that display a protein antigen and the introduction of novel adjuvants (e.g., CpG 1018 used in Heplisav-B, AS04 [monophosphoryl lipid A, MPL] used in Cervarix, and AS01B [MPL and QS-21] used in Shingrix).

Advances in technology are accelerating the development and manufacture of subunit vaccines, an established class of vaccines.