As efforts to develop COVID-19 vaccines continue, the advent of non-traditional dosage forms and packaging formats expands options for vaccine packaging. Two plastic-based formats, a blow-fill-seal (BFS) syringe and glass-coated plastic vials/syringes, offer the potential for fast scale-up and good economics.

Still, the challenge is formidable. If more than one dose is needed to confer immunity, approximately 650 million doses of COVID-19 vaccine will be needed for the US population alone, reports Jay Walker, chairman and CEO of ApiJect, a supplier of the patented BFS syringe.

ApiJect was awarded a contract from the US Department of Health and Human Services (HHS) and the Department of Defense (DoD), under the Defense Production Act, that is valued up to $138 million in May 2020 to accelerate the building of a US-based, high-speed, population-scale emergency drug injection capability with prefilled syringes from its subsidiary RAPID (Rapid Aseptic Packaging of Injectable Drugs) USA. The public/private effort, dubbed Project Jumpstart, is expected to supply 100 million prefilled syringes by the end of 2020 (1).

BFS technology is widely used for containers for ophthalmic products; the BFS syringe adds a needle hub. The prefilled syringe, made of pharmaceutical-grade low-density polyethylene, is under stability testing for several products. “We are racing forward at full speed and retrofitting current ophthalmic lines to [biosafety level] BSL-2 requirements,” says Walker. The next step is to build three, 350,000-ft2 greenfield facilities for vaccines to BSL-2 and current good manufacturing practices (CGMP), and add cold-chain requirements capable of producing 4 billion syringes/year. Together, the plants will house 30 BFS machines from Rommelag, each fitted with a needle-hub application module and integrated with an inline wrapper that applies foil-based outer wrap to provide barrier properties and protect product shelf life. Walker says, “We effectively need 20 machines to hit US population-scale capacity each month; the 30 lines provide redundancy,” he explains. He adds the lines should be operational by the third quarter of 2021 and “will work with the widest possible range of products . . . and be able to extremely quickly fill and finish almost any vaccine.” Because the lines have been designed to be flexible, it will be easy to switch from filling a BSL-2 product to a CGMP product.

“There’s a need for an ultra-low-cost, prefilled syringe,” says Walker, noting glass syringes are a 165-year-old technology. He adds, “Our goal is to provide vaccines in prefilled syringes and replace multi-dose vials. Ultimately, the RAPID facilities in the US will have enough capacity to serve needs beyond the US. But we also anticipate building plants outside the US once domestic facilities are completed.” 

Another promising non-traditional primary package with impressive scale-up potential is a patented glass-coated plastic container from SiO2 Materials Science, which has received a $143 million contract from the US government to scale up capacity to support the development of COVID-19 vaccines and therapeutics (2). Lawrence Ganti, chief business officer at SiO2 Materials Science, reports, “We have 16 pharma companies using our packaging platform. This includes three companies that have a COVID-19 vaccine candidate in development.” Moderna is testing mRNA-1273

 its COVID-19 vaccine candidate, in the glass-coated containers

The vaccine is given in two doses, a month apart, and Phase III trials began at the end of July 2020 (3).

In the production process for the containers, after medical-grade cyclic olefin copolymer or cyclic olefin polymer is injection stretch blowmolded, a thin (nanometers thick), glass-like barrier is applied via plasma-enhanced chemical vapor deposition (PECVD). “The SiO2 vials solve significant challenges in the commercialization of vaccines and biological drugs that presently cannot be solved by glass or plastic vials,” said Dr. Glenn Fredrickson, a materials scientist who helped develop the product (2). 

In the cleanroom manufacturing process, “We apply the PECVD right after the vials come out of the molding machine and … pass through our first automated inspection system,” explains Ganti. Since the coating is covalently bonded, it cannot delaminate. “The PECVD process creates a new hybrid material,” he explains. Testing internally and by outside labs has confirmed there is no separation.

The container technology was cleared by FDA in a 510k filing in 2016 and has been confirmed as equivalent to glass. The containers have passed 

 tests for glass equivalency tests for hydrolytic stability, surface durability, and container durability. “In addition, we are collecting troves of data,” says Ganti. “We capture more than 50 individual data points on each vial or syringe. We have also shared exhaustive stability data from many of our customers with FDA and have an outlined pathway for rapid regulatory filing.”

Efforts are already underway to triple production. “We have [capacity for] more than 40 million vials (any combination of sizes) and will have [capacity for] 120 million by the end of November [2020],” he reports. Turnaround time for new production lines is relatively short. He notes, “We need two months of lead time to get a new system built, validated, and online. Each system can make 40 million units.”

To maximize output, Moderna has augmented its fill/finish capabilities via partnerships with Lonza and Catalent for domestic production and ROVI for international needs. These partnerships could make it possible to deliver approximately 500 million doses in 2020 and up to 1 billion/year beginning in 2021 (3).

1. ApiJect, “ApiJect Awarded HHS-DOD Title 3, Defense Production Act (DPA) Contract,” Press Release, May 12, 2020.

2. SiO2 Materials Science, “SiO2 Materials Science Receives $143 Million Contract from US Government to Accelerate Capacity Scale-Up of Advanced Primary Packaging Platform for COVID-19 Vaccines and Therapeutics,” Press Release, June 8, 2020.

3. Moderna, “Moderna Announces Publication in The New England Journal of Medicine of Interim Results From Phase 1 Study of Its mRNA Vaccine Against COVID-19 (mRNA-1273),” Press Release, July 14, 2020.

Articles

Plastic primary packaging could help prevent supply chain shortages associated with high demand for COVID-19 vaccines.

Expanding Options for Vaccine Packaging 

Continuous manufacturing for oral solid-dosage (OSD) drugs continues to grow in acceptance as early adopters and equipment manufacturers refine their equipment and processes. With six small-molecule OSD drugs approved using continuous manufacturing—including both new products and existing products made in a batch process and now made in a continuous process—the precedent has been set for other companies to follow. By manufacturing in a new way, processors hope to reap benefits, such as faster development, a smaller equipment footprint, greater flexibility in manufacturing scale, tighter process control, and the potential for real-time release. The advanced process control with continuous monitoring used in continuous processes allows more consistent quality, which reduces waste and lowers operating costs.

“CM practitioners will need to have a more advanced level of process understanding to apply advanced quality measurement and control strategies. However, if carried out successfully, the payoff will be a flexible and robust drug supply chain that can be ramped up quickly in time of health crisis,” notes Professor Johannes Khinast, head of the Institute for Process and Particle Engineering in the Research Center Pharmaceutical Engineering (RCPE) at the Graz University of Technology in Austria.

“CM is a tremendous opportunity to advance drugs to the market at a much faster pace than traditional batch manufacturing and [enable] enhanced product quality based on enhanced process understanding and a richer data environment,” agrees Jose Luis Santos, head of Drug Product Continuous Manufacturing at contract development and manufacturing organization (CDMO) Hovione.

A challenge for continuous manufacturing is that the material handling and feeding into the process is critical, and there are two primary concerns: some of the APIs and excipients are poorly flowing powders and feeding very low levels of API can be difficult.

“We need to significantly increase the consideration of process interconnection and materials aspects when designing and operating a continuous processing facility,” says Khinast. “The unpredictability of in-process material behaviour is tough, since small changes in the formulation can have significant effects on the rheology, stickiness, segregation tendency, chargeability and other parameters.”

Accurate and consistent feeding is a challenge, along with low-rate feeding and containment designs for high potency ingredients, agrees Sharon Nowak, business development manager at Coperion K-Tron USA. “High accuracy loss-in-weight feeders are at the heart of most continuous processes. As the pharmaceutical industry implements these systems, more and more robust designs in weighing technologies, loss-in-weight feeder controls, modularity in design, and also overall cleanability are being demanded,” she explains. Nowak points out that the importance of the refill system to the loss-in-weight feeders is crucial, but sometimes overlooked, by process designers. “It is imperative that the feeder technology and refill system chosen are designed to include not only optimal performance, but also integrated to ensure the highest accuracy and consistency levels in feeder mass flow output,” she cautions.

“The primary challenge with poorly flowing powders is inconsistent filling of the screw pitch,” adds Sarang Oka, process development engineer at Hovione. “Vendors have experimented with various agitator and screw geometries to improve screw filling, and these have shown promising results. Some powders, such as certain grades of silica with very low bulk density and substantial electrostatic adhesion tendency, however, continue to pose a challenge. Another trick in the book is coprocessing the poorly flowing powder with a flow aid prior to introducing the powder to a feeder.”

Pretreating the API can be a solution if changing the feeder design doesn’t work, says Doug Hausner, senior manager, Continuous Manufacturing Business Development, Pharma Services, Thermo Fisher Scientific. “Silication is the most prevalent and easiest pretreatment, but there are a number of options and companies are coming to market with solutions,” he notes.

Although feeders have been designed to feed low levels of APIs, there is a limit. “There is a physical lower limit below which signal-to-noise ratios even for the most sophisticated load cells becomes too low for effective gravimetric control, and this handicaps our ability to feed below a certain flowrate,” says Oka. “A management strategy has been to preblend (in batch) the ingredient with low weight fraction in the formulation with another ingredient, and then feed the preblend at the combined, higher feedrate.”

Development, tech transfer, and digital twins

In theory, CM processes should not require scale-up; instead of larger equipment, the line can be run for a longer time. CM thus offers the potential for faster development and easier tech transfer, but practitioners are still working on achieving these benefits. 

Because development is conducted in the same equipment and the same scale, there is potential for faster development cycles, agrees Santos. He suggests, however, that development in CM is currently slowed by a steep learning curve at most companies.

Currently, tech transfer is often conducted between units that are similar or identical in size and other characteristics, notes Oka. “One can be very confident that experiments performed, and results obtained on a standalone loss-in-weight feeder will translate well when an identical feeder is used to feed the same material in the integrated process train,” says Oka. “The challenge arises when development is performed on equipment that is different from commercial equipment. We still do not have correlations that help us transfer processes between dissimilar pieces of equipment or process trains. Recommended practice for organizations who wish to build multiple lines is to develop identical lines, if there is desire to transfer products between lines.”

Digital twins are proving to be a valuable tool for development of continuous processes. These computer models of a process allow process developers to run experiments 

, allowing a greater number of experiments to be run more quickly and a better process understanding to be developed before evaluating process conditions on the actual equipment.

“People are pushing in the direction of digital twins to limit development time, because the software/control is often the rate limiting step in getting a system up and running, not the process development in a chemistry, manufacturing, and controls sense,” says Hausner. Digital twins also allow users to demonstrate the process on different production lines, such as when transferring to a different facility, he notes.

Running experiments off-line is particularly important for CM, because the process of cleaning between products is time-consuming. “Tools that help us minimize the use of the rig are incredibly important to us [because of the time for cleaning.] These tools could be very sophisticated models or simple tools based on engineering correlations that predict the performance of the product in the rig,” says Oka.

Digital twins have been commonly used to run 

 residence time distribution (RTD) experiments, says Oka. “These experiments can be done either at the unit operation level or at the full process train level. Thorough characterization of the RTD enables one to track evolution of disturbance through the rig, a crucial element of today’s control schemes. The underlying models, if well calibrated, also enable the practitioner to ‘dial-in’ and test a desirable RTD.” Other uses of digital twins include understanding the impact of material properties and process parameters on process performance and eventually product quality.

RCPE’s particle-simulation based approach is a digital twin of CM processes, developed in collaboration with pharmaceutical companies and equipment suppliers. “We believe that such digital twins are crucial for the future of continuous manufacturing, as this technology allows us to better process and visualize real-time data to enhance our ability to predict and control the process dynamics,” says Khinast. “Specifically, we can use digital twins to monitor and predict critical quality attributes and key performance indicators throughout the process line, while simultaneously feeding data back to optimize the process output in terms of quality and yield. … Digital twins have the potential to make continuous manufacturing faster, cheaper, and less error-prone.”

Khinast says that RCPE’s digital twin allows development of key processes, such as continuous powder blending, based on material properties that can be measured with small amounts of material. “Because this 

 approach is based on the fundamental physics, it is far more efficient, compared to the traditional trial-and-error approach, when you need to transfer the product and process to a different set of equipment,” he explains.

Simulations and modeling are also commonly used to identify bottlenecks and eliminate inefficiency in processes, explains Dave DiProspero, director of Pharmaceutical Process Technology at CRB. “A continuous manufacturer’s success, survival, and profitability depends heavily on process efficiency. During the times when equipment is being maintained, cleaned, turned over or idle work in progress awaiting upstream processes, efficiency is being reduced and profits are being lost,” says DiProspero. Modeling can be used to find efficiencies in areas such as personnel movement, travel distances from operation to warehouse, process loading and unloading times, and quality control holds. “Wherever and whenever a step in the process can provide for a time reduction, operational improvements are achieved,” he says.

Another aspect of facility design is the need for maximizing flexibility and capability to handle different products on the CM line. “One of the best practices for modern OSD facility design to address flow is to incorporate uniflow operations, with minimal path crossing or back tracking,” says DiProspero. “Ideally, process flow should run in a linear motion from raw materials in, to final drug product out. Placing the weigh/dispense unit operation close to the warehouse, with direct access, and combining unit operations (e.g., granulation/drying and blending/milling) are common today.”

In addition to optimizing the equipment and facilities, manufacturers need to develop the workforce for operating CM processes. Such teams are different from those that typically support batch solid dose manufacturing, says Santos. “Now the skill set should comprise a strong background as well on process modeling, automation, and control. PAT [process analytical technology] is now a mandatory role in the teams. The quality teams should either adjust themselves to embrace a new paradigm, or new focused teams should be put together,” he explains.

Training is becoming more available, compared to in the past when most had to figure things out for themselves, says Hausner. The United States Pharmacopeia, for example, is offering training and is also considering developing standards for CM. The International Society for Pharmaceutical Engineering (ISPE) is also discussing standards as related to standard capabilities and connectivity technology to allow systems integration, reports Hausner.

To read the full interview with experts at Hovione, go to 

www.pharmtech.com/view/gaining-experience-in-continuous-manufacturing

Early adopters and equipment manufacturers refine their equipment and processes, paving the way for broader use. 

Solid-Dose Continuous Manufacturing Presses On 

Continuous manufacturing (CM) of oral solid dosage drugs has benefits that include faster development, a smaller equipment footprint, greater flexibility in manufacturing scale, tighter process control (and, thus, improved quality), and the potential for real-time release. Contract development and manufacturing organization (CDMO) Hovione partnered with Vertex in 2016 to expand Hovione’s facility in East Windsor, NJ, with continuous manufacturing equipment to produce Vertex products. 

 spoke with CM team members at Hovione: Alexandra Adao, head of Quality Assurance Continuous Manufacturing; Sarang Oka, process development engineer; and Jose Luis Santos, head of Drug Product Continuous Manufacturing about their experiences with implementing CM.

 As CM processes for solid-dosage drugs are being commercialized, what benefits are being realized? What challenges are arising?

 CM is a tremendous opportunity to advance drugs to the market at a much faster pace than traditional batch manufacturing, and additionally enabling enhanced product quality based on enhanced process understanding and a richer data environment.

Investment is significant, not just in terms of the equipment itself, but also the software for integration, which should include a strong [process analytical technology] (PAT) framework; the facility to host the equipment; and all the utilities associated.

The teams to be put together may be much different from the standard teams that typically support batch solid dose manufacturing. Now the skill-set should comprise a strong background as well on process modeling, automation and control. PAT is now a mandatory role in the teams. The quality teams should either adjust themselves to embrace a new paradigm, or new focused teams should be put together.

Development is more difficult, and requires more sophisticated process understanding, including process modeling. Currently it’s probably not as rapid as batch development, given the steep learning curve for most companies. It is likely that development takes more time than batch for similar development phases, but it shows a clear potential to be much faster than batch in the full cycle of development of a drug, since development is conducted always in the same equipment and same scale.

Even if our experience is still limited, the numbers we have currently at Hovione in terms of equipment occupancy already surpass those from our typical batch processes. So, there is a significant opportunity to make much better use of the assets in continuous as compared to batch manufacturing.

 What are some of the challenges for feeding materials into the system, and what are some of the best practices that have been implemented?

 Two challenges in feeding that plagued the technology in its early days continue to persist at their core, namely, feeding at very low flowrates and feeding of poorly flowing powders that exhibit substantial electrostatic adhesion. Although substantial progress has been made in how the challenges are managed, there has been very little transformative change in technology of powder feeding. Loss in weight (LIW) screw feeding continues to be the dominant feeding technology. For example, a few years ago, an academic group prototyped the use of a salt-shaker type feeder for feeding at very low flowrates. The technology showed only limited success, and thus, in absence of any transformative digression from LIW screw feeding, we continue to be constrained by physical limitations of screw feeders.

As previously mentioned, we have, however, made substantial progress in how we manage the challenge when feeding poorly flowing powders or feeding at low flowrates. The primary challenge with poorly flowing powders is inconsistent filling of the screw pitch. Vendors have experimented with various agitator and screw geometries to improve screw filling, and these have shown promising results. Some powders, such as certain grades of silica with very low bulk density and substantial electrostatic adhesion tendency, however, continue to pose a challenge. Another trick in the book is coprocessing the poorly flowing powder with a flow aid prior to introducing the powder to a feeder. For example, poorly flowing active ingredients are preblended with silica to improve their flow properties prior to being fed via screw feeders. In terms of excipients, progress has been made to design and develop excipients that are well suited for processing in continuous manufacturing lines and don’t suffer from the aforementioned challenges.

In the case of feeding at low flowrates, we are largely constrained by physical limitations of the hardware. There is a physical lower limit below which signal-to-noise ratios even for the most sophisticated load cells becomes too low for effective gravimetric control, and this handicaps our ability to feed below a certain flowrate. A management strategy has been to preblend (in batch) the ingredient with low weight fraction in the formulation with another ingredient, and then feed the preblend at the combined, higher feedrate.

 What are some best practices for technical transfer or scale-up that are unique to or particularly important for CM processes?

 These are many advantages when developing products for continuous processes. Development is performed at scale, eliminating the need for performing rigorous scale-up studies as would be the case for batch processing. One can be very confident that experiments performed and results obtained on a standalone loss-in-weight feeder will translate well when an identical feeder is used to feed the same material in the integrated process train. Tech transfer is often performed between very similar (in size and other characteristics) or identical units. The challenge arises when development is performed on equipment that is different from commercial equipment. We still do not have correlations that help us transfer process between dissimilar pieces of equipment or process trains. Recommended practice for organizations who wish to build multiple lines is to develop identical lines, if there is desire to transfer products between lines.

Interestingly, since several unit operations in the batch paradigm are intrinsically continuous (such as roller compaction or tableting), practitioners have been able to rely on their current development practices built over decades of development knowledge. For example, the use of compaction models and compaction simulators to develop roller compaction or tableting processes in batch manufacturing have been applied to developing these unit operations for continuous processes. Practitioners have been able to directly transfer such best practices developed for the batch world and apply them to developing continuous processes. Of course, this is not possible in cases where the unit operation is different from a batch process, such as powder blending, and completely novel development frameworks have had to be built for these.

 How are process models/digital twins being used in CM process development/process control? What are the next steps for the near future?

 Serious effort is being made in the development of digital twins for continuous manufacturing process trains and individual unit operations, with the underlying modeling framework ranging from discrete element method (DEM) based, population balance models, or other empirical and semi-empirical approaches. A very popular application of digital twins has been to perform in-silico residence time distribution (RTD) experiments. These experiments can be done either at the unit operation level or at the full process train level. Thorough characterization of the RTD enables one to track evolution of disturbance through the rig, which is a crucial element of today’s control schemes. The underlying models, if well calibrated, also enable the practitioner to ‘dial-in’ and test a desirable RTD, all performed from the comfort of one’s desk. Applications also include understanding the impact of material properties and process parameters on process performance and eventually product quality. Some digital twins even predict product performance, that is, the performance of the drug within the body.

It is also important to mention the drivers for these efforts. The primary driver continues to remain circumventing the use of valuable early stage API. However, practitioners of the technology are beginning to realize that most CM rigs have large turnaround times for cleaning. Introducing the material into the rig for experimentation and ‘dirtying’ the rig is associated with the cost of the follow-up cleaning. This limitation is especially important to us, as a CMO, where this translates to a substantial opportunity cost. Tools that help us minimize the use of the rig are thus incredibly important to us. These could be very sophisticated models or simple tools based on engineering correlations that predict the performance of the product in the rig.

 Is real-time release happening? What roadblocks remain?

 Hovione has already introduced all the requirements to enable real-time release testing in the quality systems. There are some companies that have already successfully implemented it, and we are confident that we have in place all the conditions to also perform its implementation. 

There are some technically relevant aspects that enable the implementation of real-time release testing, namely the online and inline PAT capabilities and the design of automation control systems (e.g., equipment monitoring, material tracking). An appropriate control strategy that combines both capabilities is a key element for an adequate implementation of the real-time release in CM. At Hovione, the referred capabilities are already in place and system qualification was performed, taking also into consideration the requirements for real-time release testing.

An example of a potential challenge in the implementation of real-time release is dissolution testing. In order to enable real-time release, the use of model-based prediction of dissolution performance based on process parameters and critical quality attributes (CQAs) will be required, and consequently, an adequate model maintenance procedure needs to be in place. The model maintenance requires a parallel testing program to test the methods against the respective laboratory/regulatory methods. Therefore, in addition to the significant effort associated with the verification of the models during implementation, there is also an important effort associated with the model lifecycle.

As a CMO, we have been preparing ourselves to be able to accommodate this type of release, and we agree on its benefits, as it can provide an increase of quality assurance and reduce release time, with an overall benefit for the patients. 

Experts at Hovione describe progress being made in understanding how to optimize continuous processes for oral solid-dosage drug products. 

PharmTech Equipment and Processing Report eNewsletter 08-19-20

Expanding Options for Vaccine Packaging

Solid-Dose Continuous Manufacturing Presses On

Gaining Experience in Continuous Manufacturing