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

Cynthia A. Challener

In the latest Intergovernmental Panel on Climate Change report issued in August 2021, the organization stressed that while some impacts of climate change cannot be reversed, such as continued sea level rise, “strong and sustained reductions in emissions of carbon dioxide (CO

) and other greenhouse gases (GHGs) would limit climate change” going forward (1).

The pharmaceutical industry, like other manufacturing sectors, contributes to CO

 and GHG emissions and is aware of the need to increase the sustainability of its operations. The IQ Consortium’s Green Chemistry Working Group first met with FDA in 2012 to identify opportunities for promoting green chemistry (2).

The IQ Green Chemistry Working Group also adopted the Green Aspirational Level (GAL)—originally developed by Boerhinger Ingelheim (3,4)—as a standardized green efficiency goal for API manufacturing processes that factors in the complexity of the synthetic route; the consortium also developed a Green Scorecard to show the value-added impact of green chemistry and other improvements, including process simplification (5). Individual manufacturers are tackling the issue in many different ways.

This article was originally published on the 

Small-molecule API manufacturing, according to Scott Martin, general manager of W. R. Grace & Co.’s Fine Chemical Manufacturing Services (FCMS), is driven by continuous improvement. “Most companies have pursued continuous improvement programs for many years, and many like Grace FCMS have embedded sustainability into those programs,” he says. “The expectation of sustainable manufacturing and the sustainable use of resources is top of mind for everyone in the industry,” he adds.

More specifically, Martin notes that both increasing yields and increasing throughput by definition result in a reduced environmental footprint. In addition to these types of efforts, improvements are also being made with respect to sources of energy, with drug manufacturers pushing utilities to produce more renewable energy, he continues. “As we see it, being more sustainable and pursuing continuous improvement are not two separate issues,” he concludes

Many technologies for ensuring cleaner energy consumption, abating emissions, and improving waste management have already been developed and, thus, are easier to implement and have more acceptable payback periods, adds Brian Peutherer, health, safety, and environment director at Sterling Pharma Solutions. “For contract development and manufacturing organizations (CDMOs), these solutions are the easiest way to make a significant impact on the sustainability of products without actually impacting API design,” he notes.

Sterling, for instance, has invested in a bio plant to treat wastewater, an anaerobic digestion plant to generate energy from waste, and a combined heat and power plant that generates approximately 98% of the energy used at its headquarters in Northumberland, United Kingdom.

The concepts of green chemistry and sustainability, according to Jeff Song, vice president of chemical development in the United States for Boehringer Ingelheim (BI) Pharmaceuticals, have been broadly accepted in the pharma industry for the past 15 years. At BI, he says, these concepts are incorporated into daily work, leading to the routine development of greener API processes for all projects through innovative chemical research as well as new technologies.

To achieve true sustainability, though, Song emphasizes that other approaches than green chemistry principles should be considered, such as developing an effective waste management protocol at the end of the process. “Some modifications should be also made to the supply chain by replacing existing methods with greener chemicals and materials and by reducing chemical steps to convert commodity chemicals into value-added building blocks for API synthesis. While efforts have already begun within the industry to track the greenness of chemical processes at building-block suppliers, more work is needed,” he observes.

BI, adds Frederic Buono, the company’s senior associate director of chemical development in the US, looks to design the most direct synthetic approach with the least number of chemical steps using commodity chemicals as early as possible in the API development cycle. The commodity chemicals should have minimal cost, short methods of preparation, and wide availability. There is also a focus on process optimization to reduce waste generation and energy consumption by minimizing reaction concentration and avoiding extreme reactions condition (e.g., cryogenic temperatures).

As a member of the ACS Green Chemistry Institute Pharmaceutical Roundtable, BI researchers have also helped to develop tools to measure process performance with respect to sustainability and greenness, including the innovation Green Aspiration Level (iGAL) (6).

The petrochemical industry is vital to the pharmaceutical industry today as a supplier of key raw materials used for the production of most 

synthetic-chemistry-based pharmaceuticals. It also, however, accounts for a large percentage of the world’s energy consumption. According to 

Jing-Ke Weng, cofounder of Double Rainbow Biosciences, a professor of biology at the Massachusetts Institute of Technology, and a member of the Whitehead Institute

current small-molecule intermediate/API manufacturing almost entirely relies on unsustainable precursors.

“The growing need to quickly move away from fossil fuel amid the threat of climate change creates urgent demand for novel sustainable approaches to replace the current supply chain for small-molecule drug production. Other than sporadic uses of biocatalysts in specific steps of some pharmaceutical syntheses, truly sustainably produced synthetic small-molecule pharmaceuticals are very rare,” Weng asserts.

Synthetic biology that integrates metabolic engineering of various biological hosts (e.g., bacteria, fungi, and plant cells) and enzyme engineering, Weng believes, will be a major solution that will lead to the next green revolution in the way future small-molecule pharmaceuticals will be produced. “Several proof-of-principle studies have shown the feasibility of employing biochemistry instead of synthetic chemistry to produce complex drug-like molecules sustainably; however, we are still far from widely adopting this new approach as a new industry standard,” he comments.

The first step, Weng predicts, will be the gradual replacement of synthetic chemistry production processes for small-molecule intermediates/APIs with enzyme-catalyzed reactions, which he notes are usually efficient, highly selective, and occur under mild conditions.

 and GHG emissions, all drug developers and manufacturers need to seriously consider measures to improve sustainability throughout each phase of their industrial processes, according to Weng. “The pharmaceutical industry is due for a major overhaul in all aspects of its unit operations. Essentially, the pharmaceutical industry should be evaluating sustainable alternatives for all current exercises that rely on fossil fuel inputs,” he sates.

The optimal time to consider sustainability is before the construction of a manufacturing plant, and at the design phase of the synthetic route, as these are the stages at which the most efficient technologies and techniques can be incorporated,” Peuthererasserts. “Considering sustainability from the outset allows the opportunity to integrate sustainability into every stage of a molecule’s lifecycle,” he continues.

Buono agrees that sustainability should be considered throughout the API R&D process starting from medicinal chemistry all the way to commercialization, but with different emphasis for each. “In our opinion, one should strive to implement new synthetic routes (hence those with a much higher level of sustainability) starting with the first clinical batch or shortly thereafter to achieve a balance between the overall speed, sustainability, and attrition rate.”

From the point of view of CDMOs, the greater focus on sustainability in the pharmaceutical industry requires greater collaboration with customers at an earlier stage of project planning and development to incorporate sustainable manufacturing techniques into the API process design, according to Peutherer. “Relationships with supply chains are critical when considering the impact of manufacturing on the environment to ensure expectations are clear, and standards are maintained throughout the supply chain process. This safeguards against companies passing on their environmental burden to others,” he says.

The best time to consider optimal, sustainable production solutions is during the design of the synthetic route to an intermediate/API, notes Martin, because once these processes are validated, it is very challenging to introduce any changes, even if they offer significant improvements in productivity and sustainability.

In addition to identifying transformations that require minimal energy inputs, Martin also remarks that it is beneficial to choose solvents and other reagents that if not consumed in the process can be recycled or at least reused or repurposed in some way.

Companies should become more comfortable with using non-virgin, reclaimed solvents, Peutherer agrees. “Solvents often make up the bulk of materials used in API manufacturing and reducing their use can play a huge part in lowering a process’s costs, carbon footprint, and waste management requirements,” he observes. It is also important to consider other alternative raw materials used in production that have a lower environmental impact.

There are many opportunities to improve operations no matter what type of chemistry or chemical products are involved, according to Martin. He points to crystallization as one area that could use some attention. “Many small-molecule intermediates and APIs are solids and automatically purified via crystallization, which requires the use of solvents and often low temperatures. Under certain circumstances, distillation can be a more effective approach,” he explains.

There are, in fact, many opportunities to increase process greenness and sustainability by intensifying unit operations, Buono observes. For example, solvent volumes can be limited using a continuous extraction process, and aqueous/organic separation during work-up can be maximized using some separative commercial membrane units.

Flow chemistry is one of the technologies being employed to some extent in API manufacturing to increase sustainability, because, according to Song, the principles of green chemistry and green engineering are both leveraged in this manufacturing approach.

The versatility of the batch reactor has, until recently, meant any gains from continuous processing were previously unjustifiable, notes Peutherer. “With improving technology and techniques, however,” he notes, “continuous processing, especially in tandem with process intensification, can majorly impact on the inherent safety of a process and lower utility demands, as well as improving process specificity and reducing waste.”

Continuous flow technology, says Buono, can enhance heat and mass transfer by shortening process times with precise residence time control, which can lead to increased safety and reproducibility and thus afford product quality, all combined with easy scalability. “For these reasons, flow chemistry may offer a more sustainable technology for chemical synthesis compared to traditional batch chemistry,” he says.

In one example, BI developed a convergent, robust, and concise synthetic route which reduced the overall complexity (by eliminating a deprotection step) for an API that leverages a continuous flow-based Curtius rearrangement (the thermal decomposition of an acyl azide to an isocyanate with loss of nitrogen gas) (7). The overall process is 160% greener than the industrial average and 58% more efficient than the original batch process, according to Buono.

It is important to remember, though, notes Martin, that flow chemistry, while useful in some cases, is not applicable to all. Drugs produced in only small volumes, such as orphan cancer drugs, will likely not benefit from a continuous process because only limited quantities are required. In addition to lengthening development timelines for drugs where speed to market is essential, the upfront investment in the design of processes and equipment may not be easily recovered.

Digital technologies will play a crucial role in enabling greater sustainability of small-molecule API development and manufacturing. “We need to embrace digital technology to revolutionize the drug discovery process, and to adopt artificial intelligence and machine learning into our processes,” Song asserts. Doing so, he adds, is in concordance with Chemistry 4.0, which calls for the implementation of more digitalization and lab automation.

“To achieve these goals, collaboration across the industry is crucial,” says Song. “Pulling together expertise and insights from chemists, process engineers, theoretical chemists, IT specialists, and computer scientists will allow us to efficiently develop the digitalization solutions of the future for application to process development,” he concludes.

Ideally improvement of the sustainability of all drug manufacturing processes should be achieved; however, the pharma industry needs to establish a mechanism for addressing the shortcomings of older, existing processes for previously approved drugs.

“Altering existing processes is always challenging, but the urgency of available climate projections suggests the effort will be well worth it in the long run,” asserts Weng. “The near-term investment in sustainable solutions will push the industry towards more efficient API production processes while leaving a greatly reduced carbon footprint,” he adds.

In addition, Weng suggests that given the threat of global climate change, a failure to proactively embrace sustainable solutions may result in environmental regulatory agencies mandating sustainability targets for pharmaceutical manufacturers and other chemical industries.

Currently, it is extremely time-consuming and costly to implement changes due to the complex regulatory process that is involved. One possible solution, notes Martin, is to offer simpler regulatory pathways for certain types of changes related to sustainability improvements that do not affect the intermediate or API itself.

In cases where alterations to processes are a challenge, Peutherer says the best way to achieve a more sustainable outcome is through gains in ancillary aspects: cleaner energy generation, improved waste treatment options, pollution incident prevention, and carbon offsetting. This lowers the overall carbon footprint of the manufacturing.

Weng believes, though, that as sustainable means of small-molecule pharmaceutical development are expanded and tested to validate their performance against conventional synthetic chemistry-based approaches, industry peers and regulatory bodies must work together to embrace these solutions.

All drug manufacturers are faced with these challenges. Contract manufacturers such as Grace FCMS work with customers to push the adoption of more sustainable solutions as part of continuous improvement efforts. “It is a combined effort that includes increasing yields, using more sustainable raw materials, and more environmentally friendly packaging equipment to recycling and reuse of solvents and shipping containers, all with the goal of reducing the environmental footprint of small-molecule intermediate and API manufacturing,” Martin states.

“Sustainability,” Martin continues, “is now at the forefront. Most public companies have sustainability targets and hold regular discussions with suppliers regarding their sustainability expectations. Grace FCMS is therefore continually looking at ways to help customers reach their sustainability goals while ensuring continued supply of high-quality API product on time and in full.”

New changes will continue to be made and observed due to the enhanced awareness and continued innovation, agrees Song. “The power of machine learning and digitalization will quickly bring the most efficient synthetic pathways to chemists, not only for reaction design but also for process optimization,” he notes.

Improvements to be made across the industry can be implemented in two ways, according to Peutherer. “Firstly, gradual improvements in the processes that companies presently undertake or redesigning of operations (e.g., microwave versus traditional oven drying) will have cumulative impacts. Secondly, on a more process-specific level, implementation of environmental operation studies at the concept stage, and waste audits on longer-running processes, can bring tremendous benefits,” he explains.

In the near term, Peutherer expects the greatest gains to be made in areas not directly associated with processes, including utility consumption and waste prevention/treatment. “For example, at Sterling we treat waste on site and are currently building an ‘energy-from-waste’ plant as part of our strategy to reduce the company’s overall carbon footprint,” he comments. Longer term, Peutherer predicts wider application of the green chemistry principles and improvements in API design and manufacturing processes will have a major impact on the industry.

Progress that has been made to date should be recognized too, Song adds. He points to the growing development and adoption of flow chemistry for API synthesis, and recent advances in catalysis, particularly in biocatalysis and non-precious metal catalysis (copper, nickel and iron), that offer an improved ability to build complex molecules with much higher efficiencies but less waste. Interest is also resurging in the photochemistry and electrochemistry due to the inherently green nature of these technologies, especially when coupled with flow technology.

Double Rainbow, according to Weng, employs twounique sustainable technology platforms to produce sustainable therapeutics: rich glycosylation biochemistry in all domains of life to produce glycosylated drug products that harbor unique pharmacological activities but are too difficult to be made using conventional synthetic chemistry methods and bioengineered microbial systems to recreate valuable medicinal natural products that are traditionally sourced from fragile natural ecosystems.

“In the near term, we anticipate moving several of our promising early-stage sustainable therapeutic candidates to clinical trials. Longer-term, we believe our bioengineered therapeutics will emerge as a new class of therapeutic modalities that play important roles in the future of health care while contributing to the sustainability of our planet,” Weng concludes.

1. Intergovernmental Panel on Climate Change, “Climate Change Widespread, Rapid, and Intensifying–IPCC,” Press Release, Aug. 9, 2021.
2. IQ Consortium, “Green Chemistry Working Group,” 

, accessed Aug. 23, 2021.
3. F. Roschangar, et. al., 

, 281–285 (2017)
4. F. Roschangar, R. A. Sheldon, and C. H. Senanayake, 

, 752–768 (2015).
5. IQ Consortium, “Inspiring Sustainable Drug Manufacturing,” 

, accessed Aug. 23, 2021.
6. ACS, iGAL 2.0 Scorecard Calculator, 

accessed Sept. 19, 2021.
7. M. Marsini, F. Buono 

Cynthia A. Challener is a contributing editor to 

Articles

Drug makers are going beyond continuous improvement and green chemistry to increase the sustainability of small-molecule manufacturing.

Pharma Sets a Foundation for Greener API Manufacturing

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 

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.

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