Jennifer Markarian is manufacturing reporter for Pharmaceutical Technology.

Jennifer Markarian

Many bio/pharmaceutical companies have started digital transformation projects in various parts of their companies, including manufacturing. Modern manufacturing technologies that enhance product quality and process efficiency embrace moving away from manual and paper-based processes to automated collection of digitized data that can be employed in process analytics and used to help improve overall process control. 

 spoke with Tiffany Barnes, global technical solution consultant in the Life Sciences Group for Honeywell Process Solutions, about trends and best practices in digitalization of bio/pharmaceutical processes and facilities.

 What trends do you see in digitalization of biopharma processes and facilities?

 Digitalization of biopharma processes/facilities is an interesting topic because traditionally, once a facility underwent a preapproval inspection, the goal was to keep it running as long as possible without making changes (other than like-for-like maintenance). Unfortunately, this conventional approach left facilities frozen in time for fear of having to rework and revalidate. Only more recently are we seeing that the regulators are recognizing these unintended consequences. As an example, FDA has stated that they are committed to supporting and enabling pharmaceutical innovation and modernization because they firmly believe that embedded in that transformation are benefits to both industry and patients (1). And in part because of this support, we are slowly seeing cutting-edge and forward-thinking organizations begin to digitally transform their enterprise. As more organizations become a part of this transformation and their stale documents become actionable data, we see a large uptick in data integrity and a downtick in human error. What this change translates to are organizations which can begin to quantify improvements in product quality, product yield, and acceleration of new product introductions—all while maintaining regulatory compliance.

 What trends do you see in using machine learning or artificial intelligence (AI) and real-time monitoring of biopharmaceutical processes?

 We are seeing a significant jump in investment and capabilities in this space. A consistent goal for facilities with biopharmaceutical processes is faster delivery of medical therapies to customers. In order to accomplish this result, these process facilities need to remain audit-ready and maintain compliance across the enterprise. This is where data analysis platforms play an important role. Advanced analytics, AI, and machine learning can minimize regulatory risk, increase operational efficiencies, and deliver products to customers faster while reducing rejections and waste of products. Advanced AI predictive models can predict equipment failures; advanced analytics coupled with AI and the Industrial Internet of Things (IIoT) can provide deeper root-cause-analysis; and consolidating compliance-related manufacturing data from disparate siloed systems enables faster lot release and increased inspection readiness.

 What do you see as trends in modularization in biopharmaceutical manufacturing facilities? How do modular builds affect automation and process control?

 As the need for speed and agility has become increasingly critical, the life-sciences industry has seen a rise in modular facilities. Modularization is the enabler for facilities to serve as multi-purpose and multi-product facilities, which is particularly important for biopharmaceutical facilities that produce personalized medicine in areas such as cell and gene therapy. The flexibility of the modular approach enables life-science [drug] manufacturers to quickly change the formulations of the products they manufacture and introduce new products quicker than ever before.

As it pertains to automation and process control, solution providers must also incorporate modularity and flexibility throughout their process architectures, which means that change is also needed in the automation and process control industry. If solution providers can simplify their control system design, implementation, and lifecycle management, then new technologies can deliver the infrastructure for modular engineering that capitalizes on the flexibility inherent to modular manufacturing.

 What are the primary challenges for automation of modular processes?

 In general, traditional automation did not support modular processes as effectively. It is the modular processes and need for agility that have been pushing the automation providers to become more flexible in their solution architecture. For example, the days of tightly bound physical relationships between controllers and input-output (IO) devices are becoming a thing of the past. Realistically, automation solution providers must break free of those legacy constraints, begin looking at their existing technologies, and make significant investments in solutions that intrinsically support modular engineering. There has been a significant step change with new innovations in cloud computing, technologies that decouple control from the physical platform, and the use of simulation environments with virtual systems. These advancements are also critical in supporting the biopharmaceutical industry as a whole as they adopt workflows that heavily leverage contract manufacturing organizations who often need to supply different products for their clients. Automation solutions that are leveraging these technologies are on the path to building a necessary foundation to implement modular engineering strategies that meet ever-changing sector demands.

 What options are available for automation of modular processes?

 There are two main approaches for implementing automation solutions for modular processes. One is the traditional approach, where there is a one-to-one relationship between IO and controllers. Another is decoupling control from the physical platform.

The traditional approach is not conducive for modular facilities that require agility. The rigid architecture reduces engineering flexibility and increases overall cost as hardware is often fixed. An automation solution that has the capability to decouple the controls from the physical thrives in a highly adaptive environment. This approach would usually require an information technology infrastructure to support a data center or virtualization technology where controls and IO can move effortlessly. This [approach] brings elasticity to the control system architecture by enabling manufacturers to change the IO footprint when adding or moving equipment. In effect, IO becomes an extension of the equipment that can be managed independently of the control system infrastructure.

 What are the concerns with data integrity and security when connecting equipment via the IIoT, and how can these concerns be addressed? What are the primary concerns for data security/data integrity for modular processes in particular?

 As the industry heads into digital transformation, inevitably there is an increase in connectivity across the enterprise. With respect to an IIoT device, data can exist in motion, at rest, and in process. When data integrity is compromised, this not only means that an IIoT device cannot operate correctly, but it can also mean that the device is now open to being exploited as a potential launching point for other attacks within the enterprise. Modular process managers must be cognizant of these risks because there is a potential for more touchpoints and insertion opportunities. Traditionally, security has been viewed as a cost center but, in reality, it is a competitive advantage as systems remain up and running and unplanned downtime is eliminated. Facilities need to manage the risk that comes up at different stages in the cybersecurity lifecycle. To do so, security must come to the forefront and organizations must apply the right technology and best practices at both the device and platform level.

 Can you comment on what the biopharma industry could learn/adopt from other industries regarding these technologies?

 There is a lot to be gained in the biopharma industry by both learning and adopting processes and best practices for IIoT and cybersecurity from other industries. Refineries, chemical plants, and other automated industries have a long history of mitigating safety and security risks. Often, risk in those industries can result in devastating human loss in addition to the impact on production. Over the years, those industries have found that security and safety are tightly integrated with more than just technology—that people and the work process contribute to the overall data integrity of the facility. Therefore, though there are many lessons learned, one of the important concepts that the biopharma industry should adopt is an integrated safety and security approach that includes what other industries refer to as layers of protection. This comprehensive approach begins with understanding pertinent regulations and standards and how they affect the various layers of protection. Then it looks to incorporate the work process and practices that make use of and maintain the technology as well as the people that interact with the technology and work practices. Looking at how to maintain data integrity holistically is key to formulating successful safety and security philosophies.

Digital Transformation and Manufacturing Modernization


Vol. 44, No. 11
November 2020
Pages: 54–56

When referring to this article, please cite it as J. Markarian, “Adopting Digitalization in Biopharma Facilities,” 

Articles

Consider modular automation and cybersecurity when modernizing manufacturing processes.

Adopting Digitalization in Biopharma Facilities

	As the biopharmaceutical industry races ahead with development of vaccines and therapeutics to address the COVID-19 pandemic, experts have acknowledged that building up adequate capacity for fill/finish and ensuring the supply of materials for primary packaging containers are crucial requirements. In an unprecedented compression of manufacturing timelines and with significant investment from government and non-profit sources, commercial fill/finish manufacturing capacity is being built at-risk, while drug development and clinical trials are ongoing. 

	“A vaccine will only be effective if we can make and distribute adequate supply,” John Shiver, senior vice-president of Vaccines Global R&D at Sanofi pointed out in a March 23, 2020 post (1). He expressed confidence that industry is up to the task, saying, “If we can develop a safe and effective vaccine, the global pharmaceutical industry has the capacity to make and deliver it. [Sanofi] has the established capacity and infrastructure to make up to 600 million doses in two existing facilities based in New York and Pennsylvania, without compromising the supply of vaccines for other illnesses, including influenza. Other companies have similar capacity.” Furthermore, he noted, “Fighting an emerging pandemic is an enormous undertaking requiring the entire pharmaceutical ‘ecosystem’ to come together at pace and at a scale that are both extraordinary.”

	Contract development and manufacturing organizations (CDMOs) are crucial components of this ecosystem for handling the expected surge of capacity needed for vaccines against COVID-19, and several have announced manufacturing agreements and capacity expansions.

	Catalent, for example, has announced manufacturing agreements with COVID-19 vaccine candidate developers including Johnson & Johnson’s Janssen (2), Moderna (3), and AstraZeneca (4) to provide fill/finish capabilities. Catalent says it is working with more than 40 customers on COVID-related antivirals, vaccines, diagnostics, and treatments for symptoms and effects of COVID-19 (5). At the Catalent Biologics business unit’s facility in Bloomington, IN, the company reported that the scale-up in production would include the use of two new high-speed machines, including an Optima vial filling line and a Dividella NeoTOP 1604 top-load cartoner (2). The company is rapidly scaling segregated manufacturing capacity at the Bloomington facility to support dedicated production of Johnson & Johnson’s investigational vaccine candidate and plans to hire approximately 300 additional employees “to meet operational readiness and 24x7 manufacturing schedules by January 2021” (2).

	The Bloomington facility is also being prepared to provide vial filling and packaging capacity for Moderna’s mRNA-based COVID-19 vaccine candidate (mRNA-1273). Barrier isolator technology will be used for filling. The capacity and the staff for commercial-scale production expect to produce an initial 100 million doses of the vaccine candidate for the US market starting in the third quarter of 2020, and the companies are discussing fill/finish capacity for continued production of hundreds of millions of additional doses (3).

	Catalent Biologics facility in Anagni, Italy is being prepared for commercial-scale vial filling and packaging for AstraZeneca and the University of Oxford’s adenovirus vector based COVID-19 vaccine candidate, AZD1222. The facility will be able to supply hundreds of millions of doses of the vaccine candidate from August 2020, and potentially through to March 2022 should the product be approved by regulatory agencies, Catalent reported (4). 

	One of the funding sources for COVID-19 countermeasures is the US government, which is building a network of manufacturing partnerships through programs including Operation Warp Speed, which is a partnership among components of the Department of Defense (DoD) and the Department of Health and Human Services (HHS), including the Centers for Disease Control and Prevention (CDC), FDA, the National Institutes of Health (NIH), and the Biomedical Advanced Research and Development Authority (BARDA) (6). In addition to contracts with Johnson & Johnson, AstraZeneca, and Moderna, in June 2020 HHS contracted with Emergent BioSolutions for manufacturing capacity, including an investment of approximately $85.5 million for the rapid expansion of the company’s viral and non-viral CDMO fill/finish capacity for vaccine and therapeutic manufacturing (7).

	Operation Warp Speed is also investing in US domestic capacity for glass vials, with $204 million going to Corning to expand capacity for its Valor Glass vials, and for two more unconventional container types-$143 million to SiO2 Materials Science to increase capacity to produce the company’s glass-coated plastic containers and a $138 million contract with ApiJect to produce prefilled syringes using the blow-fill-seal process for plastic containers (6). 

	These announcements illustrate a piece of the global puzzle and the drive to increase capacity for the anticipated billions of doses of vaccine that will be produced, once approved.

	1.  Sanofi, “Sanofi Mobilizes to Develop a Vaccine against COVID-19,” 

	2.  Catalent, “Catalent Signs Agreement with Johnson & Johnson to be US Manufacturing Partner for Lead COVID-19 Vaccine Candidate,” Press Release, April 29, 2020.

	3.  Catalent, “Moderna and Catalent Announce Collaboration for Fill-Finish Manufacturing of Moderna’s COVID-19 Vaccine Candidate,” Press Release, June 25, 2020. 

	4.  Catalent, “Catalent Signs Agreement with AstraZeneca to Manufacture COVID-19 Vaccine Candidate,” Press Release, June 15, 2020.

	5.  Catalent, “Catalent COVID-19 Response,” 

	6.  HHS, “Fact Sheet: Explaining Operation Warp Speed,” 

	7.  HHS, “HHS Adds $628 Million to Contract with Emergent BioSolutions to Secure CDMO Manufacturing Capacity for Operation Warp Speed,” Press Release, June 1, 2020.

Filling and packaging of primary containers is a crucial piece of COVID-19 vaccine and therapeutic production.

Industry Builds Fill/Finish Capacity for Pandemic Response

	When the COVID-19 pandemic struck, pharmaceutical manufacturing continued as a highly essential industry, but companies were suddenly faced with the challenge of many employees working remotely and the need to ensure that operators working in-person have a healthy workplace.

	“Operational teams had to become instantly virtual, which increases risks,” says Andreas Eschbach, CEO of Eschbach, which focuses on software for plant process management. He notes that operations teams need solutions to make informed decisions confidently and to reduce the stress of vastly changing work conditions and procedures. “Helping the workforce confidently collaborate and communicate electronically using digital tools is of utmost importance to maintain productivity and cohesiveness among manufacturing teams now working remotely or socially distanced,” says Eschbach. Digital monitoring of adverse events in production, quality, and safety, for example, can ensure that managers have up-to-date information for effective decision-making among remotely dispersed teams, he explains. As another example, the company’s interactive product suite provides digital shift handovers to improve communication among manufacturing team members, even with social distancing. 

	Pharma manufacturing companies have been evaluating what needs to be done to minimize the risk that workers in the facility are exposed to the novel coronavirus. Cleanrooms are already low risk with strict controls on air quality, cleaning, and control of the movement of people and materials, but non-classified areas and non-production areas might need new approaches. 

	“In addition to current thoughts on people, product, and material flows and how to adapt to the post COVID-19 era, we are also exploring new and novel approaches to protecting all areas of the facilities we design, beginning with how people initially enter the property and facility, including maintaining safe working distances, long-before they get near (or into) the production areas,” says Dave Watrous, vice-president, Advanced Technologies and Life Sciences at Fluor Corporation. Changes include adjusting designs of heating, ventilation, and air-conditioning (HVAC) systems and related air-cleaning technologies for non-production environments, as well as increasing cleaning and limiting human interactions. “There is a balance between automation, cost, and levels of effective protection in non-production areas,” notes Watrous. 

	HVAC systems serving classified spaces are considered very low risk because they use extensive filtration and are designed and validated to manage contamination, but HVAC systems serving non-classified and non-good manufacturing practice (GMP) areas are designed differently and should be evaluated, says Keith Beattie, director at life-science specialist Energy Efficiency Consultancy EECO2, which has put together a document about managing risk in pharmaceutical HVAC systems (1). The document points to building readiness guidance from the England-based Chartered Institution of Building Services Engineers (CIBSE) (2) and ASHRAE, the American Society of Heating, Refrigerating and Air-Conditioning Engineers (3). A risk assessment should “account for all direct and indirect consequences of modifying HVAC systems with respect to a hazard that is not fully understood at this time, rather than following blanket recommendations, which may not be suited to a specific system or space type,” the EECO2 document cautions (1). For example, increasing airflow may be beneficial for some areas, but doing so in an area that adjoins a GMP or pressurized space could disrupt the pressure balance. EECO2 has developed a risk assessment tool that can be used to assess HVAC system risk and recommend appropriate and practical mitigation actions.

	Computational fluid dynamics (CFD) analysis is one way to visualize and evaluate airflow. CFD can be used to model the airflow inside a room or cleanroom to evaluate air movement and find solutions to any problems with the HVAC distribution, adds Curt Firestine, senior mechanical engineer at CRB. He notes that Grade C and higher cleanrooms typically have ceiling high-efficiency particulate air (HEPA) filters, low-wall returns, and high air-change rates. “But in lower classification cleanrooms (Grade-D or ISO-9) and in unclassified support rooms, we often see ceiling supply and [ceiling] returns for HVAC systems. These areas operate at lower air-change rates, which are typically less than 15. This combination of ceiling supply and return air devices without low-wall returns does not sweep the room. … Airflow does not get down to the occupants,” explains Firestine. Additional concerns include the number of people in the room and how closely together they are working, as well as what level of gowning they are using, Firestine noted in a 

 on facility design (4). Solutions might include increasing air-change rates, using low-wall returns or exhaust registers, improving HVAC system filtration, or increasing gowning and facemasks for workers.

	While CFD can visualize airflow, other simulation tools can be used to visualize the movement of people and materials in an operation. “Process simulation techniques [can] determine how operations could be improved while distancing employees inside the room,” says Firestine. Another problem might be that, with reduced numbers of operators, getting materials in and out may become an issue, Firestine noted in the webcast (4). “CRB has utilized simulation tools successfully to demonstrate manufacturing process improvements including personnel and material flow changes,” he says. 

	There has been a long-term trend toward automation in pharmaceutical production, which may accelerate due to the pandemic, notes Watrous. He says there is a rising demand for automation in non-production areas, such as warehousing and building management systems, as well. “We are already designing several post COVID-19 facilities that have less non-production space, meaning it will include more automation but spread throughout a smaller footprint,” says Watrous.

	Remote monitoring tools that allow manufacturers to evaluate machine health without entering the cleanroom have been becoming more widely used in pharmaceutical manufacturing (5), and this trend has been accelerated by the travel restrictions caused by the pandemic. 

	“Our customers are telling us that machine health and remote collaboration matter more than ever to them, and they want to expand their deployment of digital solutions in these challenging times,” said Saar Yoskovitz, CEO of Augury, in a May 2020 press release announcing its machine health monitoring tools could be installed by users in new facilities even when access is restricted, with remote guidance from Augury personnel (6).

	Although automation and remote monitoring tools can reduce some of the human interactions with the process in the cleanroom or the lab, expertise will still be needed. “While automation looks like a good solution to workplace congestion, the infrastructure and support required to maintain automation is not insignificant,” suggests Bikash Chatterjee, chief operations and science officer at Pharmatech Associates. “The lab may begin large deployments of automated solutions to run high volume assays, [for example]. However, anyone who has ever developed and implemented these systems knows they do require care to remain productive and effective.”

	“There is no doubt the workplace will look very different post-COVID-19,” concludes Chatterjee. He predicts that remote work will continue, virtual collaboration solutions will be prevalent, the use of data management solutions will expand as the need to remotely evaluate data increases, and manufacturing automation will continue to increase.  

	1.     EECO2, “COVID-19: Managing Risk in Pharmaceutical HVAC Systems,” rev. 2 

	2.     CIBSE, “Emerging from Lockdown,” 

	3.     ASHRAE, “ASHRAE Epidemic Task Force Building Readiness,” 

, “Strategies for Designing Adaptable, Resilient Bio/Pharma Facilities,” 

	5.     J. Markarian, “Optimizing Machine Health,” 

	6.     Augury, “Augury Delivers New Features and Services to Keep Machines and People Healthier and More Productive in Critical Industrial Facilities,” Press Release, May 6, 2020.

Manufacturers are adapting with virtual work, remote monitoring, and re-evaluation of facility design to ensure worker safety.

Responding to COVID-19 in Pharma Facility Design and Operation

	US bio/pharmaceutical manufacturers are working urgently to not only develop vaccines and treatments for COVID-19 but to ensure that the manufacturing capacity to produce them is available once they are approved. Preparing capacity before a drug is even in clinical trials is a significant departure from standard practice and carries the risk of investing capital in equipment and facilities for a drug that might not become commercial, but the pressing need for treatments and vaccines for the novel coronavirus is driving new ways of planning for manufacturing capacity. 

	The US government is taking on some of this financial risk through “Operation Warp Speed (OWS),” which is a public-private partnership to accelerate the development, manufacturing, and distribution of COVID-19 vaccines, therapeutics, and diagnostics, the Department of Health and Human Services (HHS) 

 that named leaders and advisors for the effort. The US government program will provide funding, and in return, companies will be expected to donate a portion of the product that is developed. 

	Approximately eight vaccine candidates are expected to be chosen to go through early-stage small clinical trials, and three to five candidates will proceed to larger-scale trials. HHS said that in the OWS vaccine development plan, “the manufacturing capacity developed will be used, to the extent practicable, for whatever vaccine is eventually successful, regardless of which firms have developed the capacity.” The government is also making plans for the infrastructure for packaging and distributing an eventual vaccine, including cold-chain storage and a supply of glass vials. 

	Biopharmaceutical companies are rushing to create capacity for COVID-19 vaccines both internally and through partnerships with contract development and manufacturing organizations (CDMOs). The past few weeks have brought multiple announcements of partnerships and scale-up plans.

 positive interim Phase I data from its clinical trial of its mRNA vaccine candidate (mRNA-1273) against the novel coronavirus, which had received a Fast Track designation from FDA on May 12. The company continues to move as quickly as possible through testing and is concurrently investing to scale up manufacturing at its facilities and at facilities at its contract development and manufacturing (CDMO) partner, Lonza. Funding from HHS’ Biomedical Advanced Research and Development Authority (BARDA) supported trial planning and will support trial execution as well as manufacturing scaleup, Moderna noted in the press release.

	Pfizer, which is co-developing an mRNA vaccine with BioNTech SE, is gearing up for potential production at three US facilities: St. Louis, MO for critical raw material manufacturing; Andover, MA for drug substance manufacturing; and Kalamazoo, MI for formulation and fill, the company said in a 

. Preparations include ordering materials, planning for two parallel supply chains, modifying facilities for the vaccine candidates and reprioritizing capacity, and hiring and training staff. Production could also occur at its site in Puurs, Belgium, and more sites could be selected. BioNTech is manufacturing vaccines for the clinical trials at its GMP-certified mRNA manufacturing facilities in Mainz and Idar-Oberstein, Germany, and plans to increase capacity further. Participants in initial clinical trials were dosed in Germany and the US, the companies 

announced manufacturing agreements with Emergent BioSolutions

 for J&J’s lead investigational vaccine candidate for COVID-19. The vaccine will be developed and manufactured using the AdVac viral vector technology and PER.C6 cell line from the Janssen Pharmaceutical Companies of Johnson & Johnson, which the company says allows rapid manufacturing scale-up. J&J 

 that it was preparing for clinical vaccine production at its Netherlands facility for initiating Phase 1 human clinical studies of its vaccine candidate in September 2020, and that it was planning to increase capacity globally to be able to supply more than one billion doses. Catalent 

 that its Biologics business unit would prepare for large-scale commercial manufacturing at its facility in Bloomington, IN. The company said it planned to hire approximately 300 additional employees at the site for this program starting in July 2020 to meet operational readiness and 24×7 manufacturing schedules by January 2021. And 

, CDMO Vibalogics, which specializes in virotherapy products and has a GMP-manufacturing facility in Cuxhaven, Germany, said that it had been contracted to manufacture multiple batches of Janssen’s vaccine for clinical trials.

	Novavax is moving forward with clinical development of its COVID-19 vaccine candidate, with funding by the Coalition for Epidemic Preparedness Innovations (CEPI) (a consortium created in 2017 with funding from multiple countries and the Bill and Melinda Gates Foundation) that will be used for clinical trials, process development, and manufacturing. In a 

, CEPI noted the importance of investing now in manufacturing, even while vaccines are still in development. 

	CEPI has also funded Inovio’s investigational DNA vaccine (INO-4800). Inovio 

 that it was expanding its manufacturing partnership with German CMO Richter-Helm BioLogics to support large-scale manufacturing of DNA plasmids. Inovio’s vaccine is in Phase 1 clinical testing in the US, and the company plans to manufacture one million doses by the end of 2020.

	Catalent is also manufacturing the drug substance for human clinical trials and potential commercial manufacture of Arcturus Therapeutics’ COVID-19 mRNA vaccine candidate (LUNAR-COV19), Catalent 

	UK-based AstraZeneca and the University of Oxford announced a development and manufacturing partnership 

. AstraZeneca will manufacture the recombinant adenovirus vaccine (ChAdOx1) developed by the University of Oxford’s Jenner Institute and Oxford Vaccine Group. According to a May 18, 2020 article in 

, AstraZeneca will make 30 million doses for the UK by September and 100 million doses by the end of 2020.

	Packaging and aseptic filling capacity are also crucial for vaccine manufacture. Injectable vaccines are traditionally packaged in glass vials, and a supply of vials is crucial. The possibility of using polymeric prefilled syringes that could be made using the blow-fill-seal (BFS) process, which produces the containers and fills them in one step, is being considered. 

 the launch of a new public-private partnership for Rapid Aseptic Packaging of Injectable Drugs (RAPID) to investigate the possibility of using BFS for vaccines in prefilled syringes and to build a network of facilities that could be called upon as surge capacity for fill/finish operations. According to HHS, BFS is used for sterile medicines, including oral rotavirus vaccines. RAPID is being led by ApiJect Systems America, a public benefit corporation based in Stamford, CT. 

 that it had been awarded an HHS-DOD contract to accelerate the project. RAPID USA’s Project Jumpstart will stockpile needle hubs for the prefilled syringes and contract with BFS facilities to prepare capacity to enable production before the end of 2020, with the capability to manufacture a minimum of 30 million prefilled syringes per month. Additional networks of facilities are being planned for 2021.

	In addition to preparing for rapid vaccine scale-up, manufacturers are expanding production of therapeutics that are being tested as treatments for patients with COVID-19. Gilead Sciences’ investigational antiviral remdesivir received emergency use authorization from FDA for the treatment of COVID-19 on 

, and the company planned to rapidly scale-up production. Gilead 

 it would also increase capacity by working with manufacturing partners. A partnership with Mylan, for example, was announced on 

	Multiple suppliers have also been ramping up capacity for hydroxychloroquine (HCQ) and related products that are being used as investigational treatments for COVID-19. In late March, Bayer, Novartis, Mylan, and Teva 

 donations and ramp-up of supply.  CDMO AMRI 

, that it was increasing capacity for HCQ API at its Rensselaer, NY, manufacturing facility. On May 11, 2020, UK-based CDMO Sterling Pharma Solutions 

 that it would manufacture HCQ API and had entered a partnership with Durham, NC-based Accord Healthcare to manufacture the finished drug product.

	CytoDyn’s leronlimab, a novel CCR5 antagonist with the potential for multiple therapeutic indications, received an emergency investigational new drug (EIND) authorization from FDA and is in clinical trials. On May 5, 2020, CDMO Ajinomoto Bio-Pharma Services 

 that it would manufacture the drug for the trials. 

	Designing facilities for the future and for the “new normal”

	As manufacturers consider how to rapidly scale up capacity for drugs to combat the global pandemic, new technologies for facility and process design and new ways of planning and executing facility construction may play a role. In addition-at least until a successful vaccine is widely available-companies need to consider how to keep their manufacturing workforce healthy by using engineering controls and new work practices. On Tuesday, May 26, the 

editors will host a webcast with facility design experts to discuss these topics. 

 for the “Editors’ Series: Strategies for Designing Adaptable, Resilient Bio/Pharma Facilities.”

US manufacturers focus on preparing capacity while vaccines and treatments for COVID-19 are being developed and tested.

Preparing to Meet Manufacturing Needs During a Pandemic

Microneedle array patches (MAPs) have been in development as an alternative to injections for delivering vaccines and other drugs. Microneedle patches differ from transdermal patches that deliver medicine through the outermost layer of the skin (the stratum corneum), because the microneedles pierce the stratum corneum and deliver the drug into the epidermis or upper part of the dermis, but not deep enough to cause pain. Microneedle technologies include solid microneedles coated with the drug, hollow microneedles filled with a liquid drug, and dissolvable microneedles with the drug embedded in a soluble material.

	Microneedle patches have been studied in a clinical trial for delivering a flu vaccine (1) and in preclinical trials for delivering inactivated rotavirus vaccine (IRV) and co-administration of IRV and inactivated poliovirus vaccine (2). Recently, MAPs are being investigated for a vaccine to fight COVID-19 (3). The University of Pittsburgh Medical Center (UPMC) announced in an April 2, 2020 press release that its scientists had developed a potential vaccine against SARS-CoV-2 that would be delivered through a MAP (3). The fingertip-sized patch uses 400 microneedles that deliver the spike protein pieces into the skin, where the needles, which are made of sugar and the protein pieces, dissolve. Noting that scalability is crucial for vaccines intended for protection from pandemics, UPMC said that the process to make and purify the protein for the vaccine is scalable, and that mass-producing the microneedle array involves spinning the protein-sugar mixture into a mold using a centrifuge. Advantages of the vaccine, dubbed PittCoVacc, are that (like other MAPs) it does not require a cold chain for storage and that it maintains its potency after being sterilized with gamma radiation. The researchers are in the processing of submitting an investigational new drug application to FDA. 

	PATH, a nonprofit, global health organization has been investigating transdermal drug delivery patches for more than 10 years and is in the middle of a four-year initiative, through its Microarray Patch (MAP) Center of Excellence, to accelerate development for global health needs, such as vaccines and essential medicines, in low- and middle-income countries. The group says that developing scalable, automated, good manufacturing practice (GMP) processes is crucial for success (4). 

	“Although microneedle arrays are being used commercially in some cosmetic applications in Asia, the technology is not yet commercial for vaccines. Optimization of equipment and manufacturing processes is crucial for producing these systems in the large quantities and reasonable costs needed for clinical studies and vaccination campaigns,” adds Stefan Bernsau, sales director for Needle Technology at Harro Höfliger (HH), which develops and manufactures various types of production and packaging equipment for pharmaceutical companies, the medical device industry, and other industries. The company is working with various organizations and partners to develop microneedle array patch (MAP) technology, and in January 2020, Harro Höfliger and PATH hosted a workshop on MAP manufacturing attended by MAP developers and representatives from the World Health Organization, UNICEF, the Bill & Melinda Gates Foundation, and the Gavi Vaccine Alliance. 

 spoke with Bernsau about some of the considerations for MAP manufacturing. 

 What are some of the advantages of using MAPs for vaccines? 

 Vaccine delivery faces several challenges that can be addressed with MAP technology. A significant issue is that low- and middle-income countries often do not have a clear cold chain, which is necessary for transport and storage of liquid, injectable vaccines. MAPs do not require a cold chain. Another concern is that a significant number of people have a fear of regular injection needles and the associated pain. Microneedles in a patch form eliminate the pain. In addition, MAPs can be administered without skilled healthcare workers, by trained workers or potentially by self-administration. This advantage is beneficial for developing countries that lack skilled healthcare providers. Recently, it is also being thought of as a benefit for all countries for use in pandemics, where patients could potentially have the vaccine delivered for self-administration, thus avoiding the need for people to go to doctors’ offices or hospitals. 

 What are the biggest challenges in microneedle patch manufacturing and what are some best practices for addressing these challenges?

 Companies developing products at the laboratory scale are looking at issues such as dosing (either by coating or filling) and drying. At the commercial scale, however, automation is crucial for obtaining output at an appropriate cost, with a reasonable total cost of ownership. As a machine manufacturer, we want to join in the development process as early as possible so that we can provide input to developers for how to optimize the process for commercial automation. 

	One of the constraints for vaccine manufacturing is that most cannot be terminally sterilized, therefore they must be produced in a sterile environment. One of the keys for sterile production is material flow through the processing line: raw materials must be brought into the machine; various automated steps are performed; then the product must be taken out of machine. Sterile environments can include isolators or various types of barrier technology, depending on the cleanroom setup. 

	Dosing of the API, either into the hollow mold or as a coating, must be done in a combination of high precision and with high output. These are very small doses, and different dosing technologies are used to obtain the specific tolerances needed for a particular process. There are some new developments in the market for dosing. VAXXAS, for example, has developed their own high-speed and high-precision dosing technology that is similar to ink-jet printing technology. As another example, scraper technology can be a solution for dissolvable microneedles, depending on the viscosity and the physical characteristics of the liquid or the vaccine.

	For the automation of the lines, we use dedicated servo-driven units because the parts being handled are so small-the whole array may be about the size of a penny, for example. Robotic arms can cause turbulence in the airflow, which can be a problem regarding the aseptic requirements of such small, precise units. Another proven technology is a so-called ‘walking beam,’ which uses pick-and-place handling for small and delicate parts inside an isolator.

 What are some best practices for inspection of MAPs after manufacturing? 

 Several quality attributes need to be inspected, particularly that the required amount of drug is there (either coated or filled). Inspection of microneedles is more difficult than syringe inspection because of the small size of the microneedles. Cameras are used to view the top and side. Other critical pieces are the light source, appropriate software, and hardware for fast computing speed. A best practice is 100% inspection of each part, but a challenge is the speed and an eventual reflectance of image acquisition to accomplish this. 

 What are the requirements for packaging of microneedle patches? 

 To a large degree the microneedles are fragile; they are typically packaged in an applicator, with a rigid container to protect the needles. The patch must also be packaged in a sterile environment. After primary packaging, it must also be packaged for transportation. An advantage of MAPs is that temperature is not as much of an issue, compared to traditional liquid vaccines, because the MAPs vaccine is dry. 

Do you foresee in-country, for-country production with MAP technology? 

 It is far too early to know whether production in developing countries is feasible, because the initial investment in these lines is high and a lot of technical knowledge and skill are needed to run these lines. However, some organizations are looking at this possibility, and the current pandemic may cause more governments globally to think about in-country production. 

	1. NIH, “Researchers Develop Microneedle Patch for Flu Vaccination,” Press Release, June 27, 2017.
	2. Micron Biomedical, “Micron Receives Additional Funding from the CDC for Collaboration on the Development of a Microneedle Patch for IRV-IPV Co-administration,” Press Release, Aug. 27, 2018
	3. UPMC, “COVID-19 Vaccine Candidate Shows Promise,” Press Release, April 2, 2020.
	4. J. Markarian,


	Vol. 44, No. 5
	May 2020
	Pages: 31–32

	When referring to this article, please cite it as J. Markarian, “Manufacturing Microneedle Array Patches for Vaccine Delivery,” 

Equipment and process optimization must be considered for scaling up these developmental technologies to commercial production.

Manufacturing Microneedle Array Patches for Vaccine Delivery

	The level of automation in the bio/pharma industry varies and continues to evolve. Many are investing in Industry 4.0 concepts such as digitalization and automation to improve manufacturing efficiency, quality, and capacity. According to Amos Dor, general manager of the Applied Materials’ Automation Products Group, one such capability for improving operations is advanced analytics, which takes manufacturing data and provides insights into how the process and equipment are holistically performing.  Analytics-combined with advanced scheduling solutions-can be used to minimize downtime and identify additional capacity within existing manufacturing constraints, says Dor. To further examine current trends in pharmaceutical manufacturing, 

spoke with Dor and with Amy Doucette, manager for the Americas for Applied Materials’ Automation Products Group, Pharma Solutions. 

What are some ways to address the problem of how a lack of manufacturing capacity or quality impacts drug shortages? 

We see that the pharmaceutical industry is investing in digitalization of their manufacturing facilities. They are trying to extract value from the data being collected on the plant floor by using machine learning and advanced analytics to gain insight into how their process and equipment are holistically performing. For example, our advanced analytics and control solution applies analytics to automate business processes end-to-end to increase quality and productivity in pharmaceutical manufacturing.  

	In addition, the ability to integrate directly to the plant floor enables an advanced scheduling digital twin with optimization algorithms and expert rules to manage the plant, ensuring schedules are realistic and optimal for the next schedule horizon.

How are digital twins being used in pharmaceutical manufacturing? 

Pharma is taking a phased approach to implementing digital twins. Some companies are starting in the quality control (QC) lab because QC is integral to ensuring that products are released on time. Others are taking initial snapshots of one manufacturing line and eventually building out to the entire manufacturing facility and its supply chain. 

	Digital twins allow scenario planning, using our scheduling solution, to go through different scenarios for how a company can debottleneck a process. Sometimes the process can be optimized by simply changing the schedule, and other times adding equipment or operators should be evaluated. Using these solutions, the workforce can work smarter to increase productivity and quality by increasing yields, reducing variability, minimizing downtime, and identifying capacity within existing manufacturing constraints.

What are some of the key lessons pharma can learn from other industries-such as semiconductor manufacturing-on modernizing manufacturing?  

As James Moyne from Applied Materials and co-authors wrote in 2017, the semiconductor industry, which operates at higher process capabilities and overall equipment effectiveness than the pharmaceutical industry, can serve as a role model. Semiconductor chip manufacturing has used advanced sensing and diagnostics, advanced process control, and robotics and automation, as well as advanced dispatching and scheduling, to achieve profitable productivity and quality (1).

	Looking at the BioPhorum Operations Group (BPOG) plant maturity model (2), many pharmaceutical manufacturers are moving from digital silos (Level 2) to a connected plant (Level 3). The goal is a predictive plant (Level 4) and eventually progressing to an adaptive plant (Level 5). The semiconductor industry has been on this journey longer. In the pharma industry, we are working to help companies connect the silos. We have an agnostic platform that sits above the automation system and integrates with manufacturing execution systems (MES) and enterprise resource planning (ERP) systems. We are working with internal Applied Materials groups, equipment manufacturers, and sensor companies to enable a modular “plant in a box” that integrates predictive analytics with other layers of automation, such as inspection, MES, and ERP.

	1.    S. Romero-Torres, J. Moyne, and M. Kidambi, 

Development of a Digital Plant Maturity Model to Aid Transformation in Biopharmaceutical Manufacturing

Analyzing process and equipment data provides insights that can improve quality and productivity of pharmaceutical manufacturing.