Jennifer Markarian is a contributing editor for 

Jennifer Markarian

The speed at which the industry has been moving vaccines and treatments for the COVID-19 pandemic into trials and commercial production is unprecedented, and contract development and manufacturing organizations (CDMOs) are playing an important role in quickly adding capacity for clinical trial and commercial manufacturing. Lessons learned during the pandemic may also benefit manufacturing for clinical trials in general, as companies implement best practices for speeding up tech transfer processes.

Ron Chantung, associate director of Drug Substance Manufacturing at global CDMO Ajinomoto Bio-Pharma Services (Aji Bio-Pharma), notes, “While there is always a constant influx of drug products to the market, since the start of the pandemic, the speed and the number of vaccines, therapeutics, and candidates that have entered in clinical development has been extraordinary, making CDMOs and their capacity for manufacturing these products in high demand.”

Aji Bio-Pharma entered a manufacturing agreement in May 2020 with CytoDyn, a late-stage biotechnology company developing leronlimab, a monoclonal antibody CCR5 antagonist, for multiple therapeutic indications, including a clinical trial for patients with severe-to-critical COVID-19 indications (1). CDMO Cascade Chemistry is also providing clinical trial materials for COVID-19; in June 2020, Cascade was selected to manufacture the API for clinical trials of an investigational therapy from Renibus Therapeutics, RBT-9 (stannous protoporphyrin), an antiviral with organ-protective attributes that received Fast Track designation from FDA and is being tested in high-risk COVID-19 patients (2). CDMO Purysis says it is supplying companies conducting COVID-19 research, whether by manufacturing repurposed antiviral compounds that do not have readily available good manufacturing practice (GMP) supply chains or by development and manufacturing of novel small molecule therapeutics for investigative new drug applications.

This article was first published in the December 2020 issue of 

 spoke with Chantung; Scott Mohler, director of Business Development at Cascade Chemistry; and Joshua Hoerner, Chief Innovation Officer at Purisys, about how CDMOs involved in clinical trial materials’ manufacturing are responding to the current environment and what can be done to speed their clients’ projects.

 How has the COVID-19 pandemic affected clinical trials materials manufacturing and packaging, and what do you see as key industry trends and challenges?

 The global pandemic has presented challenges to clinical trials in general, limiting the availability of trial slots and, in some cases, delaying trials for indications other than COVID-19. Securing raw materials for clinical trials, such as those aimed at evaluating therapies for COVID-19, can be especially difficult where the synthetic route is not fully mapped out, particularly for companies operating in the early biotech space where demonstrating proof-of-concept is vital to secure further funding.

 Timing is a major challenge. It seems every year the desired timelines from clients grow shorter while the chemistry gets more complex. Having enough process research and development time to fully understand a process before it reaches the manufacturing space is essential. However, in many cases, synthetic routes have not been fully mapped out, and this means additional work is frequently required. With COVID-19 trials, the time pressure is even greater.

The biggest trend we have seen is an overall lack of capacity in the API industry. We have had to rapidly expand our current GMP space as well as adding a second shift and weekend shifts to continue to meet demand. We doubled our GMP capacity in spring 2020 with new manufacturing space. Our new facility construction will continue through fall 2021 when we will more than double our GMP capacity again as well as quadrupling our maximum batch size.

 In unparalleled ways, COVID-19 has altered the landscape of how CDMOs provide for clinical trials. After months of seeing disruption to clinical trials from travel restrictions and site closures to interrupted supply chains, we are now starting to see that trend slowly reverse.

One interesting development that we have been keeping an eye on is the supply and demand for cold-chain shipments. With countries imposing travel restrictions due to COVID-19, which may therefore present challenges within shipping lanes, re-assessing validated shipping containers has become a priority to ensure the biologic’s quality attributes maintain stability in transit. CDMOs need to gauge their internal capacity of temperature storage units, form strategic partnerships with logistics companies, and potentially offer validated temperature storage of clinical trial material.

In response to this ever-changing environment, it is more important than ever for CDMOs to ensure they are proactive with how they plan, resource, and execute programs with their customers, rather than reacting to the larger challenges they are facing with supply chain and general product development.

Beyond monitoring stock and working closely with outside suppliers, we have found that providing customers options to select from in stock, preferred components and excipients from GMP-audited and qualified vendors helps reduce variables and speeds up the manufacturing timeline. Additionally, utilizing an existing library of packaging and labeling components and employing existing validated shipping configurations and preferred couriers can help drug sponsors overcome any logistical hurdles to clinical trials.

 Can you comment on any technology developments or best practices that are helping to speed up processes?

 One aspect is the limitations placed on travel and onsite visitors at a CDMO. Organizations are becoming creative in hosting virtual, video audits to maintain the regulatory and quality commitments to agencies and clients, as well as showcase capabilities to prospective business partners. The ability to observe the manufacturing process is something that varies among CDMOs. A virtual and online site visit and audit experience helps ensure customers are meeting their quality obligations for selecting or maintaining a qualified vendor. Through the use of secure document sharing platforms, remote viewing systems, and virtual site tours, clients can be assured they will be able to perform a thorough review of facilities and quality systems and have connections with the subject matter experts and remote access to live action activities to meet their program requirements and quality standards.

For example, we are offering personalized, secure remote viewing platform for clients to monitor their filling process through our secure portal. This provides the sponsor with the ability to monitor the operations in real time and to stay connected to their product even when they cannot be physically present. In addition, procedures are in place to host remote audits via technology platforms that support live, interactive conversation and interviews with subject matter experts, guided walk-through of operational areas, and the ability to securely review documents and data.

 Virtual audits and video teleconferencing have helped maintain communication with clients and their quality teams during the COVID-19 pandemic. The faster things go, the more important frequent communications are. For instance, quality groups need to be in constant communication, while technical teams need to be emailing and calling ad hoc as well as having regular update meetings. To ensure projects continue to run to time, it is vital that upper management and business development have the ability to check in constantly.

 Modeling and simulation tools have been extremely valuable to reduce the amount of work required for scale-up; for example, engineering technologies such as Scale-up Systems’ Dynochem can model solvent swaps, drying, distillation, off-gassing, and many other fundamental elements of synthetic and chemical processes. Small-scale reaction calorimetry tools are helpful to determine the safest process to scale up. Automating unit operations like lyophilization can reduce the need for manual intervention.

What are some best practices for tech transfer in clinical trial manufacturing?

 Some program details tend to have a bigger impact on the timeline for a client’s tech transfer and clinical program design. We have found that performing compendial methods verifications in parallel with manufacturing activities and working concurrently on batch documentation reviewing supports a quicker release. Performing risk assessments early in clinical development can help fast-track the clinical process and expedite the path to filing.

Other efficient tools for speeding up time to release include working from templated batch documentation to quickly generate a master batch record, utilizing an existing library of packaging and labeling components, and employing existing validated shipping configurations and preferred couriers.

Concurrent and in-parallel reviews and method verifications, minimized analytical transfer scope, and satellite identification samples for bulk drug substance lots sent back to the drug substance manufacturer can decrease the cost and time associated with method transfer. Additionally, early and regular collaboration with an experienced regulatory team can help expedite regulatory submissions, clinical filings, and commercial launches.

Taking all this into account, Ajinomoto Bio-Pharma Services launched the AJILITY platform. AJILITY is designed for novel therapeutics/vaccines and existing drug products with a new indications that can be used in COVID-19 trials, FDA Emergency Use Authorizations (EUAs), or other programs, providing enhanced flexibility by leveraging our existing, streamlined project configurations. The goal of the AJILITY platform is to minimize variables during tech transfer, manufacturing, and shipping processes and rely on our regulatory expertise to navigate traditional production hurdles to quickly get therapies to clinics.

While the pandemic has presented a unique opportunity for our customers to capitalize on Ajinomoto Bio-Pharma Services’ regulatory and manufacturing expertise with our AJILITY integrated drug product manufacturing platform, it will be available beyond the pandemic, for any therapeutic program that needs flexible and responsive support for expediting your lifesaving therapeutic to the clinic.

 In tech transfer, what are typically the rate-limiting steps, and how can these be optimized?

 Too often, the provided information is unclear or is delivered only gradually in installments, which can lead to wasted time and resource where process R&D work is repeated unnecessarily, for example, where research performed to improve a synthesis has already proven to be ineffective. Having a robust analytical package is also critical. All involved teams should understand what analytical is available, what has been used previously, what its limitations are, and how these factors can impact not only the process R&D that has already been carried out, but also that which still needs to be performed.

 Tech transfer for an early phase chemical process can occur relatively quickly provided a strong technical package is available. Where key technical or scientific information is missing, it is important that any gaps are filled to de-risk implementation of the technology. Effective de-risking strategies include running multifactorial design of experiments versus one variable-at-a-time studies, using modeling and simulation, and ensuring you have a robust, complementary analytical technology package. In terms of manufacturing compliance, it is important that any necessary environmental permitting is in place; government permitting can take time, especially when working with larger quantities of solvents or reagents.

 Tech transfer activities for bringing a new product or process into the facility are usually rate limited by analytical method transfers, process transfer, process development, availability of components, and formulation specifics. Especially in early-stage novel therapeutics, there are often gaps between the state of the methods for in-process control and product analysis and what is suitable for current good manufacturing practice (CGMP) operations.

Sound technical transfer at a CDMO is founded by aligning equipment, materials, and quality with its clients. Expertise within the technical transfer staff is a key building block. Experienced staff coupled with a sound training program, quality-by-design philosophies, and clear planning (including roles and responsibilities between the client and organization) play an active role in optimizing technical transfer. In addition, harmonizing documentation from technical transfer to GMP production to bridge a seamless transition to the manufacturing team, employing a repertoire of scalable and industry standard equipment, and executing parallel operations all blend to accelerate a client’s timeline to the clinic.

 What new technologies in facilities and equipment benefit the tech transfer process or clinical trial material manufacturing? 

 Innovator companies use modeling and simulation tools that are typically supported by a strong technical core expertise and provide line of sight to scale-up and implementation in a given facility’s equipment train. Low bioburden capabilities are also beneficial; any drug delivered in a parenteral format—whether that be intravenously, intramuscularly, occularly, or topically—may be subject to higher sterility requirements. Additionally, further environmental controls can be advantageous, for example controls to prevent light, heat, moisture, and oxygen-sensitive chemical degradation. Lastly, broad milling capabilities are key, because small-molecule particle size requirements can vary considerably depending on the delivery technology.

 The technical transfer piece of clinical trial material manufacturing benefits from high-throughput screening equipment. A CDMO can clearly demonstrate its nimbleness as a business partner via a timeline- and results-driven process development team.

Systems geared toward wide vetting of critical process variables, such as media formulations, cell growth optimization, and resins to capture and polish biologics, are cost effective and time sensitive for the client. For CGMP production of clinical trial materials, a well-known model of single-use equipment returns to the forefront in light of the COVID-19 pandemic. Faster delivery of biologics and reduced validation time through single-use technology plays into a client’s budget, safety, expediency, reproducibility, and quality interests. Flexible, multi-purpose fill lines also provide a benefit by providing various filling options and multiple set ups. Finally, in-house, on-site packaging and labeling systems that are compliant with the Drug Supply Chain Security Act help support clinical success.

Aji Bio-Pharma, “Ajinomoto Bio-Pharma Services Announces Manufacturing Partnership with CytoDyn for Drug Product Used in COVID-19 Clinical Trials,” Press Release, May 5, 2020.

Cascade Chemistry, “Cascade Chemistry Selected to Produce Active Pharmaceutical Ingredient for Clinical Trial Supplies of COVID-19 Investigational Drug RBT-9,” Press Release, June 16, 2020.

Vol. 32, No. 12
December 2020
Pages: 37–40

When referring to this article, please cite it as J. Markarian, “Manufacturing Materials for Clinical Trials,” Pharmaceutical Technology Europe 32 (12) 2020.

Articles

CDMOs strive for flexible, adaptable processes and fast tech transfer for manufacturing investigational drug products, including COVID-19 treatments and vaccines. 

Manufacturing Materials for Clinical Trials 

The COVID-19 pandemic has accelerated demand for quickly expanding capacity for manufacturing vaccines, including the facilities for viral vector production and for fill/finish. This capacity crunch is exacerbated because the industry was already capacity constrained before the pandemic began.

Running additional production campaigns in existing plants and adapting existing, suitable buildings for additional current good manufacturing practice (CGMP) lines are two avenues being taken for expanding fill/finish and existing virus- and vector-based vaccine processes, says Stefan Kappeler, technology manager of the global business unit, Biopharma & Life Sciences, at Exyte. For new vaccine platforms, such as mRNA vaccines, however, he says, “The short-term CGMP-compliant production is more difficult, as a completely new production and release process has to be designed and validated for the commercial scale, and then checked and approved by the national authorities.”

These new types of vaccines require new technologies and processes that have to be built from the ground up, and accomplished rapidly without interruption, adds Maik Jornitz, president and CEO of G-CON Manufacturing.

“Manufacturing capacity is the biggest hurdle for producing COVID-19 therapies right now. Companies with frontline options are scrambling to design and order equipment while in parallel designing and building the facility production space,” says Peter Walters, director of advanced therapy medicinal products (ATMP) at CRB. “Many of these therapies are based on pivoting process platforms, so development is being performed in parallel with design and construction of the facility, which makes flexible adaptable spaces so critical right now.”

Modular and prefabricated cleanrooms for manufacturing, which have been promoted for several years for the benefits of fast delivery and flexible capacity, stand ready to meet these needs. Modular process equipment is also finding use.

An established benefit of modular facilities is that they are constructed off-site and then delivered to the site where they will be put into use. Off-site construction has been shown to be particularly valuable under the limits imposed by the pandemic, says Jornitz.

“In an on-site construction, there may be a multitude of delays due to the limited headcount being allowed on-site, if at all. Off-site construction is not affected, because it is considered an essential business and has not stopped or slowed down since the start of the pandemic. As soon as the states opened travel, G-CON shipped four projects [of its prefabricated cleanroom PODs],” Jornitz reports. “The off-site prequalification also helps, as we can shorten the time and resources needed on-site, again to create the lowest headcount density needed and therefore lowest risk.”

The drive to produce COVID-19 vaccines and treatments has led to much faster building of cleanroom infrastructures and entire facilities than in the past, says Jornitz. “Delivery times of three to six months instead of years became the new normal, and this new normal will stay,” he predicts. He believes these short timelines are not unrealistic. “Any application could be predesigned to abbreviate the design timelines and can be prefabricated to stock to be much faster in the construction of the cleanroom infrastructure,” says Jornitz. G-CON introduced six standard cleanroom PODs that enabled them to shorten the delivery timeline further; these structures can be mass produced and then delivered from stock. Jornitz notes that, in addition to fast delivery, the industry requires reliable delivery timelines and robust cost budgets. “Too often we see a time and cost overrun, which puts any planning in jeopardy and cause a tremendous stress on project management. With off-site prefabrication, we avoid these overruns,” he notes. 

Walters agrees that a key benefit of modular facilities is faster time to production compared to other construction models. “Use of fully modular cleanrooms allows a large bulk of the critical technical facility to be constructed in parallel with the remaining facility, creating a more compressed overall facility timeline,” he explains.

CRB’s SlateXpace was introduced in September 2020 as a “suite-based” modular facility design for cell and gene therapy. “SlateXpace is a templated production cleanroom platform to address the growing need for flexible multi-modal capability,” says Walters. “The platform has a pre-engineered design to accommodate changes in processing technology and processing platforms, while also providing consistent and easily scalable design. One big benefit of templated design is that it can provide greater cost predictability and certainty up front, with a more predictable and consistent construction schedule, both of which greatly help in early facility planning.”

Standardization of modular facilities allows replication, which is a faster route to operational availability either at the same manufacturing site or a different location, adds Kappeler. An additional benefit of facility replication is production consistency across a site or different locations. He notes that, in addition, Exyte’s ExyCell prefabricated cleanrooms have been designed to be flexible and configurable, so that the modular units can follow the optimized process flow.

Flexible capacity to address market needs

Flexibility is another benefit of modular designs that allows companies to quickly add capacity to meet demand.

“One lesson from the current pandemic is the greater emphasis on security of supply and national independence. Modular systems enable the manufacturer to produce regionally on the required scale and thus to react flexibly to the current situation and local requirements,” says Kappeler. When vaccine manufacturing capacity is not in high demand, the facilities can be used instead for viral vectors for the ATMP sector, to combat neglected communicable diseases, or for animal vaccines. “At Exyte, we strive for a high degree of layout flexibility, process adaptability, and design standardization in plant design in order to convert and expand existing manufacturing capacities for new purposes,” he concludes.

“Designing in flexibility is paramount for the current manufacturing industry,” agrees Walters. “The ability to accommodate new processing technologies or swap to different processing platforms without a dramatic schedule-breaking renovation is where the industry needs to be headed to adapt to and accommodate the ever-changing and evolving product pipeline demands.”

Whether capacity constructed for COVID vaccines will be needed for short or longer term is unknown, says Jornitz, but the facilities can be used for other production if it is designed with containment, segregation and repurpose in mind. “Podular infrastructures have the benefit of being mobile, autonomous, and built for segregation. These units can either be used for other applications, moved to a different location where capacity is needed, or broken down to smaller segments for totally different needs. Repurposing cleanroom infrastructures is part of the total cost ownership value,” explains Jornitz.

The industry is moving toward the use of turnkey, predesigned facility platforms, says Jornitz. “Today, most of these facilities are piecemeal and at the end everybody hopes it will work, but it really all depends on the experience and capabilities of the project management,” he says. Moving to turnkey facilities reduces the dependence on project management and allows more predictability. G-CON and IPS partnered to offer the 

CON turnkey modular facility platform solution for biomanufacturing, and Jornitz says it can be used for vaccine production. “It is a complete package, tying together the facility, utilities, cleanroom infrastructure, equipment, and automation,” explains Jornitz. G-CON also partnered with Pall to offer a viral vector manufacturing platform with process equipment from Pall inside a G-CON POD cleanroom. The platform is offered in four scales, from process development through CGMP clinical and commercial manufacturing.

In May 2020, Exyte and Univercells Technologies announced a partnership to deploy modular, standardized facilities for manufacturing vaccines (1). Univercells’ NevoLine vaccine manufacturing platform is an intensified process that uses continuous/semi-continuous process equipment with automation, and the small manufacturing footprint can be housed inside the ExyCell cleanroom. The facilities can be commissioned quickly, regardless of location, says Kappeler.

“Univercells’ process … allows an unprecedented reduction in the necessary scale and the required floor space. We see these developments as fundamental for future vaccine facilities, as they enable a significant downsizing of the plant design and a reduction in complexity regarding the provision of utilities or the biosafety level requirements for building and installations,” explains Kappeler.

The COVID-19 pandemic has put a spotlight on the need to be able to respond quickly and be better prepared for the next time. In the future, although some of the more traditional, large-scale processes for vaccine manufacturing may not see dramatic change, cell-based vaccines will have smaller, more flexible footprints with more single-use process technologies, suggests Jornitz. “We see a strong pull for in-country/for country manufacturing sites [that] are ultimately smaller and still meeting the capacity needs. COVID showed that dependency on supplies from other countries could jeopardize the fulfillment of healthcare needs in one’s own country. These types of facilities will see a higher utilization even with seasonal vaccine needs and could potentially be used for multi-product purposes,” he predicts.

“Companies need to have a way to pivot spaces between different production platforms without having to gut them and renovate every time,” says Walters. “Leveraging the flexibility of single-use technologies, equipment can be rearranged within flexible production spaces to allow for shifting to production of different products. Companies having more facility spaces with this level of flexibility in mind may just help set the stage for a more rapid industry response to the next global shortage.”

Exyte, “Exyte and Univercells Technologies Combine Forces for Rapid Deployment of Vaccine Production Plants in the Wake of the COVID-19 Pandemic,” Press Release, May 14, 2020.

Modular building and process designs allow faster time to market for COVID-19 vaccines and treatments.

Flexible Facilities Speed Production

The bio/pharmaceutical industry has been talking about Industry 4.0 and digitalization for many years, and commercial use of automation and data analysis tools has been making progress. The sudden pandemic-related travel and business restrictions, however, have driven more rapid adoption of technologies such as 

 modeling, digital twins, remote acceptance testing, virtual and augmented reality tools, and other digital solutions.

Bikash Chatterjee, CEO of Pharmatech Associates, points out that the pandemic situation is driving the pharma industry to adopt the tools it has been talking about for more than a decade. Pamela Docherty, Life Sciences industry manager at Siemens, adds that her company saw an immediate uptake of digital tools when R&D personnel were restricted from accessing their laboratories, and that 

 modeling tools allowed them to continue their experiments virtually. 

When travel shut down, equipment suppliers introduced remote factory acceptance testing (FAT). IMA, for example, instituted virtual FATs in which customers could witness by video as the IMA engineers performed tests (1). Companies supplying virtual and augmented reality tools were able to step in to provide solutions. Apprentice.io, for example, deployed its smart glasses and Tandem technology platform to pharma manufacturers and their suppliers; the tools facilitated tech transfer, facility tours, and acceptance testing (2). API manufacturer Cambrex noted that digital tools allowed employees to operate remotely and internal and external audits to continue for both client and regulatory audits (3).

Digital tools will continue to benefit pharma manufacturing operations after the pandemic restrictions are in the past. On Nov. 11, 2020, 

 will host a panel discussion on digitalization that looks at using real-time monitoring and artificial intelligence to optimize manufacturing operations. Chatterjee and Docherty will be part of the panel, along with Amos Dor, general manager of the Pharma Team in the Automation Products Group at Applied Materials, and Bob Lenich, global life sciences director at Emerson. To listen to the discussion, 

www.pharmtech.com/view/ima-introduces-digital-platform-remote-fat

www.pharmtech.com/view/augmented-reality-kits-deployed-wake-travel-bans

Automation and tools for remote monitoring are finding increased use as pharmaceutical manufacturing adapts to pandemic restrictions. 

Pandemic Drives Digitalization in Bio/Pharma Manufacturing

As the industry gears up for the expectation of high demand for COVID-19 vaccine containers, suppliers of traditional glass vials are increasing capacity, and suppliers of alternative primary packaging materials are offering potential solutions as well. Honeywell recently introduced its Aclar Edge polymer bottles and vials for pharmaceutical packaging that are made from polychlorotrifluoroethylene (PCTFE). The compay says the containers can eliminate the risk of breakage found with glass containers; the containers are also 75% lighter than their glass counterparts, which reduces transportation costs (1). The containers meet the requirements of the compendia pharmacopeia for extractables, elemental impurities, and biological reactivity and are classified as Medical Grade Class VI, says Kori Anderson, general manager for Honeywell Healthcare Packaging

 spoke with Anderson about designing containers for vaccines.

 What are the key requirements for vaccine containers?

 Vaccine packaging must ensure suitability, safety, protection, compatibility, and performance. The primary package must be tested and validated to ensure container closure integrity, sterility, drug stability, and manufacturing feasibility. Materials of construction need to demonstrate low to no levels of detectable extractables, leachables, particulates, bacterial endotoxins, impurities, degradation products, volatile and involatile organics, and free ions to avoid adverse interaction that may react with the drug product and render the product unstable or ineffective. Materials of construction must not create changes in pH of the drug product and must meet stringent biocompatibility safety standards through appropriate compendia testing.

Vaccine vials must establish and maintain appropriate moisture and oxygen barrier levels to ensure against drug product degradation or loss of potency or efficacy. Since many vials are stored and transported in cold-chain environments, the vials must be tested in accordance with the recommended storage and transportation environmental conditions to ensure container closure integrity, stability, and functional performance are maintained throughout the distribution lifecycle of the product. Distribution testing should be mapped to include temperature excursions to demonstrate the robustness of the packaging system to maintain drug stability and container closure integrity. Vials must not exhibit any surface characteristics that may cause the proteins or other active ingredients to bind to the walls of the container. They need to exhibit a high level of clarity in order to permit inspection the product for visible particulates and cross-contamination.

www.pharmtech.com/view/industry-builds-fillfinish-capacity-pandemic-response

www.pharmtech.com/view/expanding-options-for-vaccine-packaging

 What do you see as the key challenges for distributing vaccines on a global scale?

 There are many variables that need to be addressed, including general shipping and freight issues with temperature control to ensure the stability and efficacy of vaccines. The sheer numbers for the COVID-19 vaccine could stress the supply chain to the max. It’s important for pharmaceutical companies to develop a back-up plan. We see Aclar Edge as a solution to alleviate those constraints.

 What are the requirements for filling equipment and automated inspection equipment using this container type?

 Vials must be evaluated for manufacturing feasibility and demonstrate resilient performance with high-speed packaging lines. Vials must demonstrate robust mechanical and physical strength to avoid jamming and impact damage during unpacking, collating, conveying, filling, capping, labeling, shipping, and distribution. PCTFE vials exhibit excellent physical properties, which prevent breakage during filling and capping as well as during transportation testing.

Automated inspecting equipment differs based on several factors, but any equipment that is compatible with plastic containers should also be compatible with Aclar Edge. Since the exterior is PET [polyethylene terephthalate], any labels used on PET bottles should work well with Aclar Edge bottles and vials. We have not performed testing specifically for automated inspecting equipment for Aclar Edge, but the containers have been run by one of our lead customers working on glass alternatives, with no major issues on their commercial lines.

Polymeric containers offer an alternative to glass.

Considering Materials for Vaccine Containers

The biopharmaceutical industry is working at unprecedented speed to develop and manufacture vaccines for the COVID-19 pandemic. Among the challenges of a pandemic is the need to scale up to billions of doses, at a larger scale than typically needed for vaccines, from raw materials all the way through to the materials for the containers for fill/finish.

Collaborative efforts to make a safe and effective vaccine against the novel coronavirus, SARS-CoV-2, are underway around the world. The timeline to develop, produce, and distribute an approved vaccine is being dramatically compressed, and companies are scaling up manufacturing “at risk,” making the vaccines before they have been approved. While pharmaceutical companies are bearing some of the risk, these efforts are being extensively funded by governments as well as non-profit organizations, such as the Coalition for Epidemic Preparedness Innovations (CEPI) foundation and Gavi, the Vaccine Alliance (GAVI). In the United States, the federal government’s Operation Warp Speed program—a partnership among the US Department of Health and Human Services (HHS), the Department of Defense (DoD), and others—is investing in vaccine development and manufacturing, fill/finish capacity, and in capacity for supply of vials, needles, and prefilled syringes. As of August 5, 2020, more than $6.5 billion had been designated to flow through HHS’s Biomedical Advanced Research and Development Authority (BARDA) for countermeasures and $3 billion for National Institute of Health (NIH) research (1).

Production of the billions of doses needed will require manufacturing at multiple sites, and innovators and contract development and manufacturing organizations (CDMOs) are partnering to come up with all the capacity that will be needed globally. Manufacturers know that it is not only the equipment, facilities, and raw materials—although these are necessary and require planning ahead—but also the knowledge and the expertise to run the process. Technology transfer is, thus, a crucial piece.

Consultants at McKinsey note that tech transfer time for vaccines normally can take 18 to more than 30 months, with transfers to external sites taking even longer. They predict, however, that by employing best practices, the time can be shortened to 8–11 months, or even six months with regulatory flexibility (2). Indeed, the tech transfer process is already well underway at CDMOs.

Everyone is working at “pandemic speed,” says Andre Goerke, head of the planning and value chain management business unit at Lonza; Goerke also is the global project lead for Lonza’s efforts to make the active ingredient for Moderna’s mRNA vaccine. The overarching challenge is to do what needs to be done in this accelerated timeline, but the team is unified in making it happen, he explains. “So far, the most significant asset has been the excellent integration of the Lonza and Moderna teams into a single group working for a common target,” says Goerke.

Having adequate raw materials, building and staffing the facilities, and tech transfer are all keys to success. Flexible, modular facility designs allow manufacturers to adapt and move quickly. Goerke says Lonza’s Ibex facilities “have been set up with exactly this challenge in mind, to allow adaptation to manufacture different kinds of products. Adaptability allows us to cut construction time considerably compared to standard builds and gives the flexibility to install a broad range of manufacturing technology. In addition, we can plug into existing infrastructure, including services (gas, water, waste, etc.) as well as analytics and quality labs.”

Emergent BioSolutions says that its flexible CDMO capacity deployment model can respond quickly to demand fluctuations. The company’s Bayview multi-suite facility in Baltimore, MD is designated by the US HHS as a Center for Innovation in Advanced Development and Manufacturing (CIADM) and is designed to leverage single-use technologies to manufacture product in large quantities during public health emergencies. The CIADM can accommodate various types of vaccine platforms that can be manufactured in parallel. Four independent suites allow products or customers to move in and out quickly, explains Dino Muzzin, senior vice-president of manufacturing operations at Emergent BioSolutions. Platform-based equipment at the facility allows flexibility and facilitates tech transfer, noted Richard W. Welch, vice-president of development services at Emergent BioSolutions, in a presentation at BIO (3). Additionally, the company is adding new capacity at its Rockville, MD, and Canton, MA sites and expediting an expansion of its Camden facility in Baltimore, MD.

Several types of vaccines are being developed and tested in the hopes that at least one, but possibly multiple vaccines and of different types, will be approved. The industry is counting on the advantages of “platform” technologies, with development and manufacturing processes that can use the same or similar systems and equipment, tailored for different vaccines. Such platforms allow more rapid development and scale up and, even prior to the current pandemic, were predicted to be useful for responding to an outbreak caused by a new pathogen.

Nucleic acid-based vaccines—based on messenger ribonucleic acid (mRNA) or on deoxyribonucleic acid (DNA)—are examples of platform technologies. Moderna, Pfizer/BioNTech, CureVac, CanSinoBio, and others are making progress using mRNA platforms, with mRNA formulated in a lipid nanoparticle delivery vehicle. Inovio and others are working on DNA-based vaccines. Although nucleic acid vaccines have been tested in clinical trials, for Zika and Middle East respiratory syndrome (MERS), for example, none have yet been approved for use.

Moderna’s vaccine candidate, mRNA-1273, is encapsulated in lipid nanoparticles, and it has progressed to Phase III clinical trials. Moderna is building up manufacturing capacity, partly through its CDMO partner, Lonza, which is adding manufacturing lines in New Hampshire and in Visp, Switzerland. In an interview in late July, Goerke reported that tech transfer for the first step of the process has started as planned, and that preparation was well underway at the Portsmouth, NH facilities, with batches for the first of three process steps (the mRNA step) to be produced in July 2020. “Fit-out of our Visp facility is ongoing. We envisage the start of operations in Visp by the end of 2020,” said Goerke.

“Lonza aims to replicate the facility, equipment, and data management principles developed by Moderna,” adds David Callaert, head of global strategic growth investments and engineering at Lonza. “We plan to further strengthen and pragmatically ensure reliable supply through intense collaboration with the technical teams of Moderna. The aim is to achieve short processing times with high throughput. Going digital and maximizing the use of disposable equipment are some of the key components necessary to achieve these goals.”

Another CDMO partner of Moderna, CordenPharma, will manufacture large-scale volumes of Moderna’s proprietary lipids needed to make the lipid nanoparticle excipients. A challenge is the need to quickly scale-up by a factor of several hundred times the initial scale, says Matthieu Giraud, director, global peptides, lipids and carbohydrates platform at CordenPharma International. “We have to optimize the process for large-scale manufacturing and, at the same time, transfer to our larger assets. In addition, the scales are so incredibly large that we have to leverage our entire CordenPharma network to ensure a sustainable supply chain,” he explains.

The company’s facilities in France, Switzerland, and the US are working on the project; at CordenPharma Colorado, unique high-pressure chromatography systems usually used for manufacturing peptides have been reallocated for purifying lipids. Although making Moderna’s proprietary lipid at large scale is new, Giraud notes that CordenPharma has a long history of large-scale production of standard lipids using its platform technology. CordenPharma’s sister company, Weylchem Innotec, has been able to provide key raw materials for lipid production, Giraud adds.

Quality of the lipids is crucial because of the high proportion of lipids in relation to the mRNA. “The quality of the lipids is known to affect the encapsulation efficiency, liposome internalization by cells, and efflux rate of encapsulated therapeutic agents, all of which have implications for drug delivery and formulation shelf life. It is essential to create a very well-controlled process when manufacturing lipids,” says Giraud.

CordenPharma is on track to meet Moderna’s aggressive timeline, and manufacturing has started at three sites, says Giraud. He points to close collaboration between the company’s facilities, and he says that a rigorous risk management process identified gaps early on, so that risks could be mitigated.

Pfizer and BioNTech are also making progress on their lipid nanoparticle mRNA-based vaccine candidate, BNT162; initial results from Phase I/II studies are positive, and the companies are planning a global Phase IIb/III trial (4). Acuitas Therapeutics is providing lipid nanoparticles for the vaccine. If the trials go well, Pfizer and BioNTech plan to seek regulatory approval or authorization as soon as October. Pfizer says it expects to manufacture 100 million doses by the end of 2020 and approximately 1.3 billion doses by the end of 2021. The US government placed an order for 100 million doses, and the UK government signed an agreement for 30 million doses, both pending regulatory authorization or approval (5). Pfizer says it is building inventory of existing products now to make room for vaccine production later. Additionally, according to a Reuters report, Pfizer plans to shift some of its existing drug manufacturing to CDMO partners so that it can prepare for manufacturing the vaccine candidate at three facilities in the US and one in Belgium (6).

CureVac in Germany is also working on an mRNA vaccine, CVnCoV, and Phase I clinical trials began in June 2020 in Germany and Belgium. The company has a proprietary RNAoptimizer platform, which includes an end-to-end, good manufacturing practice (GMP) manufacturing process designed for mRNA-based drugs. The company is expanding its GMP facility and completing construction of its fourth production site in Tübingen, Germany. The company said the facility has the capacity to potentially supply several hundred million doses per year, depending on the human dose defined in the clinical trials (7).

In addition to its large-scale production facilities, CureVac is developing a small-scale, portable manufacturing “facility” it calls The RNA Printer, which it envisions could be transported to outbreak regions or placed in hospitals. In early 2019, CEPI and CureVac announced a partnership to advance the automated equipment that can produce several grams of lipid nanoparticle-formulated mRNA, which could potentially be more than 100,000 doses, in a few weeks (8).

A challenge for distribution of mRNA-based vaccines is the need to keep them frozen. Inovio’s DNA-plasmid vaccine candidate, INO-4800, however, is stable at room temperature for more than a year and does not require being frozen in transport or storage, the company reports (9). Inovio announced positive interim Phase I results at the end of June and had hopes to begin Phase II/III over the summer. The company has a proprietary delivery device, the Cellectra 3PSP, that delivers the DNA-plasmid vaccine directly into the skin. The US DoD provided funding for large-scale manufacturing of the device, and Inovio says it has produced initial quantities at its San Diego, CA, facility and demonstrated that the manufacturing process could be transferred to contract manufacturers (10). An earlier version of the Cellectra has been used in clinical trials of Inovio’s DNA medicines.

Viral vector vaccines are another platform, which uses a live, attenuated virus as a vector or delivery vehicle for an antigen’s genetic code. A benefit of this type of platform is that the viral vectors are made with a standardized manufacturing process independent of the active part of the vaccine, noted CDMO Cobra Biologics (11).

Vaccines made with this type of platform from Merck, Johnson & Johnson, and CanSino Biologics have approvals for Ebola, and these companies are using their respective platforms for vaccine candidates against the novel coronavirus. China’s CanSinoBio’s viral vector vaccine for Ebola has been approved by China’s regulatory agency; the company’s vaccine candidate for the novel coronavirus uses adenovirus 5 (Ad5) and, as of August 9, 2020, was preparing to begin Phase III trials. Merck’s Ebola vaccine, approved by FDA in December 2019, uses an engineered vesicular stomatitis virus (VSV) as the viral vector; Merck currently is working on a VSV-based COVID-19 vaccine. In addition, Themis, which was acquired by Merck in June, has a platform technology that uses a measles vaccine vector.

The Janssen Pharmaceutical Companies of Johnson & Johnson (J&J) received European marketing authorization for their two-dose viral vector vaccine for Ebola on July 1, 2020 (12). The first dose of this approved vaccine uses Janssen’s AdVac viral vector platform, based on adenoviruses that are genetically modified, so they are non-replicating in humans. The AdVac platform is being used for the company’s investigational SARS-CoV-2 vaccine, Ad26.COV2-S, recombinant, which moved into Phase I/IIa first-in-human clinical trials in late July. J&J’s goal is to manufacture more than one billion doses, and it is scaling up manufacturing capacity globally. On August 5, 2020, the company announced that the US government, through BARDA, is committing more than $1 billion for large-scale US manufacturing and delivery of the vaccine following FDA approval or authorization (13). The company said its partnership with CDMO Emergent BioSolutions for drug substance, announced in April 2020, was “the first in a series of prospective global collaboration agreements designed to accelerate manufacturing” (14).

The University of Oxford and AstraZeneca’s novel coronavirus vaccine candidate (AZD1222) uses a recombinant adenovirus viral vector platform that has been used in experimental vaccines for Ebola and MERS. Phase II/III trials have started in the United Kingdom, Brazil, and South Africa, and are planned for the US, with more than $1 billion from BARDA for development, production, and delivery planned for fall 2020 (15). AstraZeneca has committed, so far, to more than two billion doses, in supply agreements with the UK, the US, Europe’s Inclusive Vaccines Alliance, the Coalition for Epidemic Preparedness, Gavi the Vaccine Alliance, and the Serum Institute of India (16).

Preparations for large-scale viral vector manufacturing capacity were picking up speed late in 2019 as the biopharmaceutical industry was beginning to address shortages due to the rapidly growing demand for viral vectors from the pipeline for cell and gene therapies and viral vaccines. Modular facilities and single-use systems are seen as one way to build capacity more quickly (17).

While vaccines based on mRNA, DNA, or viral vectors are still new, recombinant DNA vaccines made in cell-based bioprocesses are another technology that offers the potential for rapid scaleup and have been in use on the market for several years. For example, the Flublok Quadrivalent influenza vaccine, initially approved by FDA in 2013 and acquired by Sanofi Pasteur in 2018, uses a recombinant DNA technology that combines the target DNA sequence in a plasmid with a baculovirus (BV) DNA, which produces antigens in a host cell; the antigens are then collected and purified to be formulated in the vaccine. These cell-based processes are more easily controlled and scaled than the traditional egg-based influenza vaccine production method, thus the recombinant DNA technology had been recognized for its potential as a response to a pandemic.

In December 2019, Sanofi entered an agreement with BARDA to increase its domestic pandemic influenza vaccine production capabilities in Swiftwater, PA. And now Sanofi’s platform is being put to use for the COVID-19 pandemic; Sanofi and GlaxoSmithKline (GSK) are partnering to produce a vaccine candidate using Sanofi’s S-protein COVID-19 antigen and GSK’s adjuvant technology.

Novavax’ recombinant nanoparticle vaccine platform uses recombinant BV to infect Sf9 insect cells, which express the antigens that are then purified as multimeric nanoparticles. Although the company does not yet have an approved drug, the platform is used to make the company’s seasonal influenza vaccine candidate, NanoFlu, which received FDA fast track designation in January 2020. The platform is being used to make the company’s NVX-CoV2373 COVID-19 vaccine candidate, which is a stable, prefusion protein with Novavax’ proprietary Matrix M adjuvant.

Novavax received more than $1.6 billion from BARDA to manufacture NVX-CoV2373 and to stockpile raw materials needed for the Matrix M adjuvant (18). The company is working with Emergent Bio to manufacture both its NanoFlu seasonal influenza candidate and its COVID-19 candidate at Emergent’s Bayview, MD, facility.

Novavax also announced a manufacturing partnership with CDMO Fujifilm Diosynth Biotechnologies (FDB) to make the bulk drug substance for NVX-CoV2373, and FDB’s site in Morrisville, NC, began production in July (19). AGC Biologics was contracted to manufacture the Matrix M adjuvant to expand Novavax’ capacity.

China’s Sinovac is using an even more traditional technology of an inactivated vaccine for its novel coronavirus candidate, CoronaVac. The company is conducting Phase II trials in China and has been approved for Phase III clinical trials, which will be conducted in Brazil and Bangladesh. The company is building a commercial vaccine production plant that is expected to manufacture up to 100 million doses annually (20).

The importance of fill/finish for vaccines is well known, and the supply chain is ramping up capacity for materials (including injection needles and the glass for vials) and for filling. CDMO capacity will be crucial in this stage, as well. Companies expanding capacity for fill/finish include Thermo Fisher Scientific; Emergent Bio, which received fundingfrom BARDA and is working with four vaccine innovator companies; and Catalent, which is ramping up to support Janssen, Moderna, AstraZeneca, and others (21).

While the world waits for the results of the clinical trials for vaccines to prevent COVID-19 and, hopefully, regulatory approval or authorization of one or more successful candidates, pharmaceutical manufacturers are moving ahead with manufacturing at commercial scale, while also preparing to adapt to changes that arise, as development is also still being completed. The vaccine fill/finish line will, if all goes well, be the beginning of the end of the global pandemic

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

C. O’Sullivan, P. Rutten, and C. Schatz, “Why Tech Transfer may be Critical to Beating COVID-19,” 

R. Welch, “Solutions for Rapid Development and Manufacturing Responses to COVID-19 and Other Public Health Threats,” Presentation at BIO (June 2020).

Pfizer, “Pfizer and BioNTech Announce an Agreement with US Government for up to 600 Million Doses of MRNA-based Vaccine Candidate Against SARS-CoV-2,” Press Release, July 22, 2020.

Pfizer, “Pfizer and BioNTech Announce Agreement with the United Kingdom of MRNA-based for 30 Million Doses Vaccine Candidate Against SARS-CoV-2,” Press Release, July 20, 2020.

Reuters, “Pfizer to Outsource Some Drug Production, Focus on Coronavirus Vaccine,” May 8, 2020.

CureVac, “Germany: EIB and European Commission Provide CureVac with a €75 million Financing for Vaccine Development and Expansion of Manufacturing,” Press Release, July 6, 2020.

CureVac, “CEPI Awards US$34M Contract to CureVac to Advance The RNA Printer—a Disruptive, Transportable Mrna Vaccine Manufacturing Platform That Can Rapidly Combat Multiple Diseases,” Press Release, Feb. 27, 2019.

Inovio, “INOVIO Announces Positive Interim Phase 1 Data For INO-4800 Vaccine for COVID-19,” Press Release, June 30, 2020.

Inovio, “INOVIO Receives $71 Million Contract from US Department of Defense to Scale Up Manufacture of CELLECTRA 3PSP Smart Device and Procurement of CELLECTRA 2000 for COVID-19 DNA Vaccine,” Press Release, June 23, 2020.

Cobra Biologics, “Blog: COVID-19 Vaccine Hopes and Hurdles,” 

Johnson & Johnson, “Johnson & Johnson Announces European Commission Approval for Janssen’s Preventive Ebola Vaccine,” Press Release, July 1, 2020.

Johnson & Johnson, “Johnson & Johnson Announces Agreement with U.S. Government for 100 Million Doses of Investigational COVID-19 Vaccine,” Press Release, Aug. 5, 2020.

Johnson & Johnson “Johnson & Johnson Announces Collaboration to Expand Manufacturing Capabilities For its COVID-19 Vaccine Candidate in Support of the Company’s Goal to Supply More Than One Billion Vaccine Doses Globally,” Press Release, April 23, 2020.

AstraZeneca, “AstraZeneca Advances Response to Global COVID-19 Challenge as It Receives First Commitments for Oxford’s Potential New Vaccine,” Press Release, May 21, 2020.

AstraZeneca, “COVID-19 Vaccine AZD1222 Showed Robust Immune Responses in All Participants in Phase I/II Trial,” Press Release, July 20, 2020.

Novavax, “Novavax and FUJIFILM Diosynth Biotechnologies Initiate Large Scale Manufacturing of COVID-19 Vaccine Candidate,” Press Release, July 23, 2020.

Sinovac, “Sinovac Secures $15 Million in Funding to Accelerate COVID-19 Vaccine Development,” Press Release, May 22, 2020.

PharmTech Outsourcing Resources Supplement

Jennifer Markarian is manufacturing editor, 


Vol. 44, No. 9
September 2020
Pages: 16–20

When referring to this article, please cite it as J. Markarian, “Preparing Pandemic Vaccine Capacity,” 

Rapid scale-up to billions of doses requires collaborative, all-out efforts by innovators, their manufacturing partners, and the entire supply chain. 

Preparing Pandemic Vaccine Capacity

Designing and then manufacturing a drug–device combination product is a complex process that must take into consideration variables in manufacturing the drug delivery device, such as an inhaler or an autoinjector, as well as interactions between the drug and the device. Phillips-Medisize, a Molex company, has both clinical and commercial manufacturing facilities for drug–device combination products, and the company is expanding its Global Innovation and Development site in Struer, Denmark by adding a dedicated unit for manufacturing development. 

 spoke with the company’s experts: Justin Westendorf, product development manager; Bryan Moris, director of Global Pre-Production Quality; and Chris Conger, director of Connected Health Device Technology, about some of the best practices in manufacturing drug–device combination products.

 What are some of the best practices in moving from clinical manufacturing to commercial manufacturing of a drug–device combination product?

 During the design development process, there must be a good partnership and engagement between the device development team, formulation development team, clinical team, and the regulatory team. When scaling from building 500 units to 10,000 units to 10 million units, the device design can often undergo significant evolutionary changes. All stakeholders need to be aligned on which areas are allowed to change (such as assembly features) and which areas have to be locked down early (such as drug contacting features), as well as when features must be locked down to protect the integrity of the data being generated throughout the device development lifecycle.

It’s important to point out that there are perspective differences between a commercial manufacturing team and a product development team. When building products in commercial manufacturing, devices are built with the expectation that if the components and assemblies are produced to specification, then the performance requirements of the device will be met for the intended use population. In product development, however, the need for product may come before the design or manufacturing processes are well established or controlled. There are more nuances associated with ensuring the design and the drug formulation will successfully work together in these early builds.

For instance, there may not be time or value in performing process validation for early builds when the design is still evolving. This situation requires a flexible but compliant quality management system to work with stakeholders on a risk-based approach to controlling early device builds. In addition, how users will use the product must be assessed. This means getting device samples into users’ hands to study how they interact with them in the context of specific environments. If it’s determined that there are points of confusion that could lead to use errors and harm, regardless of drug performance, the design team will need to make adjustments to the design. By the time a product gets to commercial manufacturing, all of these types of questions have been answered by a robust design development process.

 What are some of the concerns for choosing materials for the device in a drug–device product? Do you need to evaluate potential interactions between the device and the user or between the drug and device?

 Physical interaction with a user is one concern. It’s important to understand the intended use and use environment and make sure you’ve identified how the user will interact with the product. You should consider which product components may interact with the user’s hands, skin, mouth, nasal passages and other areas of the body. Materials need to be assessed for the potential risks they may pose to the user.

Drug interaction also must be considered—especially for inhalers, where you have very small, often organic, charged molecules that are flowing through a pathway that’s typically plastic and may also be charged. These types of interactions can have an impact on how—and how much—of the drug exits the device. It’s also important to understand the chemical interactions to make sure nothing from the components could leach into the drug or change its chemistry.

Manufacturing is also a consideration. Every component will be manufactured via some means (e.g., machining, injection molding) and likely be assembled using some technology (e.g., adhesive, laser welding). A key variable in material selection is the compatibility between the material, the desired manufacturing method, and assembly to other components in the device.

Early in the design development process, you identify candidate materials. But then you must use tools and evaluation techniques to gain confidence in those candidate materials. It’s here you may realize you need to make a material change, perhaps because structural performance is lacking or clinical performance is falling short, or it could be you’re simply having a hard time making a device component with that material.

‘Material selection’ isn’t an event that happens, but rather a maturing of the design and better understanding of the materials and how they interact with the drug and the patient and how suitable they are for the intended manufacturing processes. This understanding improves as you progress through later stages of the development and verification testing process to reach a point where you’ve demonstrated the component materials meet performance and manufacturing requirements.

 What are some best practices for quality assurance (QA)/quality control (QC) of drug-delivery device manufacturing? What are some of the factors that need to be tested that are unique to a drug delivery device?

 When it comes to drug delivery devices or combination products, it’s really about control—control of the product and control of the components going into it. A high level of control is required, but that can mean many different things. It could refer to additional levels of training or processes and procedures that are well-vetted to ensure control over the drug itself, whether it needs to be filled into a container or in containers that are already prefilled.

A high degree of control is paramount when going from clinical manufacturing to commercial manufacturing. Designing processes and having conversations up-front based on best practices for controlling the device and the drug, from both a clinical and volume manufacturing standpoint, are important. For example, if you’re working with different dosages, you want to ensure a unique vial labeling or color-coding system exists to help minimize the potential for a mix up.

You also need to ensure a fool-proof shift from labor-intense, detailed, and manual clinical processes to automated commercial processes. The process must be carefully designed from the beginning, so that when it does ramp up and a product goes to many global commercial sites, you’re set up for success. Because, ultimately, you’re designing a product for commercialization.

The fact is, there will be variations in the production of the device—from device development to the manufacturing process to final refinements in commercial manufacturing. That’s why it’s important to uncover, on the front end, where variation can occur and how that variation might impact drug delivery performance. Then it’s crucial to take that a step further by characterizing how the variation that’s expected in commercial manufacturing will impact drug delivery performance. Skipping this characterization step can negatively impact the investment around, and commercial success of, the device.

 What are some of the risks for a drug delivery device that should be considered in manufacturing?

 The biggest risk to commercial manufacturing is the investment and effort—or lack thereof—made in design development and the manufacturing development that should occur in parallel to development. If you spend time focusing on de-risking the technology piece, but not much time finding sources of manufacturing variation and de-risking them during design development, you’re passing residual risk into the commercial environment, where a combination of variations in manufacturing processes is unavoidable.

There can be an investment impact, especially pertaining to schedule and price. When collaborating with customers to construct a design development proposal, it’s therefore important to understand their approach to risk-based decisions and what they consider important. Some are more willing than others to accept a certain amount of residual risk and deal with those potential repercussions in commercial manufacturing, in favor of speedier outcomes. So, it comes down to collaboration and building a strategy together to determine how much time and effort will be spent identifying user, technology, and manufacturing risks. Both parties will need to decide on either a ‘fast’ approach, in which the customer agrees to accept transferring more risk, or a more thorough approach that draws risk down further during design and development, even if that takes more time.

 What are some considerations for designing and manufacturing a drug delivery device that is connected to the Internet?

 For connected drug delivery devices, you introduce design and manufacturing techniques beyond what are needed for a typical mechanical device. Two additional considerations require significant attention in the design process: validation of the software that goes into the device and managing the cybersecurity of the device.

Validation is typically done against the ISO standard, IEC 62304 (1), which encompasses the process of managing software development through the entire lifecycle, from the beginning of development through the end of the market life of the device. Our development and management processes conform to this standard, which tells us how to develop the device, how to document the development, and how to test it and validate the device so that it meets all requirements.

Device cybersecurity requires as much attention as validation. Once a device is connected, the potential for malicious remote device intervention remains a threat. For this reason, FDA has issued detailed guidance on how to approach device security, which includes taking a risk-based approach to both the software and hardware of the device (2). Risk assessments should be conducted to determine what could go wrong or where vulnerabilities exist, and then correlated to how serious the consequence is of each identified risk. If it’s determined to be a serious risk, the mitigation you must enact to prevent the risk becomes significant. On the other hand, if the potential risk is not very high, the effort to mitigate is much less significant.

1. ISO, IEC 62304:2006, Medical device software—Software life cycle processes (May 2006).
2. FDA, “Cybersecurity,” 

www.fda.gov/medical-devices/digital-health/

Jennifer Markarian is manufacturing editor, Pharmaceutical Technology.

Pharmaceutical Technology
Vol. 44, No. 9
September 2020
Pages: 33–35

When referring to this article, please cite it as J. Markarian, “Manufacturing Drug–Device Combination Products,” 

A device manufacturing process must be carefully designed in the early stages of development to ensure success in commercial manufacturing. 