Process development is moving at unprecedented speed as manufacturers race to produce COVID-19 vaccines and treatments and the products needed to make them, such as viral vectors, as well as keep up with the burgeoning cell and gene therapy sector. Optimizing single-use bioprocessing equipment, including both upstream and downstream equipment as well as consumables and starting materials, is a crucial piece of process development. Knowledge of the equipment, the process, and the product are paramount, and successful projects rely on experts embedded throughout the supply chain. Close cooperation between equipment suppliers and the users of the equipment is a key to success, as the industry seeks to address the expanding need for process development, manufacturing capacity, and training.

Inter-company collaboration spurs innovation and speed

At EMD Millipore, the Life Science business of Merck KGaA (operating as MilliporeSigma in the US and Canada), process development is provided through the company’s contract development and manufacturing organization (CDMO). The CMDO works closely with the other parts of the company’s business, including the consumable products businesses, such as filters and media, and the company’s bioprocessing equipment business, says Sébastien Ribault, vice-president and head of end-to-end CDMO Services, Process Solutions at Merck Life Science. As users of the equipment, the CDMO gives feedback to the equipment business.

“When we have an idea at the bench or in the manufacturing area, where we see we could manufacture faster, cheaper, with higher quality, or with fewer mistakes by users, we reach out to our equipment and product suppliers so that they can translate these ideas into new products,” says Ribault. He points to a 2000-L bioreactor that MilliporeSigma’s equipment business introduced in 2015 as an example. “The team members on this product included our head of process development who brought experience in scale-up and scale-down. Now we can scale up directly from 3-L bench-scale to 2000-L commercial scale. We can save two months by not having to do an engineering run at intermediate scale (100–500 L), and we optimize our use of good manufacturing practice (GMP) suites.”

Since 2020, EMD Millipore has been hard at work supporting developers of treatments for COVID-19. In one example, the CDMO worked with an innovator of an antibody that needed to speed the development process. “We reinvented the process development template and went from DNA to final drug substance in nine months, when a more typical timeframe is 15 months. We could do this because of the close connection between our process developers and the EMD Millipore equipment business,” says Ribault. The product is now moving through tech transfer to GMP production. “This new way of process development took into account expectations from regulators and also adapted to quality requirements. The use of pre-packed purification columns instead of manually assembled is one good example to speed up processes through the use of products that did not exist years ago. It is faster to implement, easier to use, and eliminates a sometimes-difficult packing step,” he says.

In the fast-growing cell and gene therapy area, projects are also moving quickly. “Clients want to get to first-in-human stages quickly,” says Ribault. “The process needs to be developed to allow rapid advancement to clinical stages that match with the regulatory framework that will be needed to move to GMP manufacturing.”

While cell and gene therapy has been more research-oriented, it now needs to move to a focus on robust, reproducible processes, says Ribault. “Here is where a connection between the equipment developers and the process developers is key to make a templated approach and create the equipment,” he notes. Automation is becoming a more visible part of cell and gene therapy processes. “For some, the importance of automation is that it eliminates the risk of error. For others, automation is key for gaining throughput and allowing the process to run continuously,” explains Ribault.

Equipment builder expands development resources

Cytiva has long offered its Fast Trak process development services to customers developing processes using the company’s bioprocessing equipment. The company’s seven Fast Trak centers—in Korea; Japan; Cambridge, UK; Uppsala, Sweden; Shanghai; Toronto; and Marlborough, MA—house processing equipment that can be used for training, development, and manufacturing. In December, Cytiva announced that it had expanded its services at several of the sites, so that all now offer process development, media and assay development, and contract development services. The expansion supports the cell and gene therapy industry and small to mid-sized biotech companies in particular.

“Start-up biotech companies that can’t yet afford space, labor, and time until they have clinical data are benefiting greatly from this initiative,” says Shannon Eaker, Cell and Gene Therapy’s FastTrak leader at Cytiva. He adds that large pharma companies with large product pipelines can also benefit from the company’s process development services. “Companies are looking to expand their pipelines. Starting with Cytiva’s platform processes, which have supported the cell therapy field for many years, Fast Trak saves customers time and money in doing the R&D work. Starting with Cytiva’s platform processes, which have supported the cell therapy field for many years, saves the customer time and money in doing the R&D work,” says Eaker. A key area of development is developing scalable processes that are flexible for multiple cell types and processes, such as both autologous and allogeneic therapies, notes Eaker.

Pall Biotech supplies single-use biopharmaceutical manufacturing equipment and also has a process development services team that designs processes and performs tech transfer to GMP manufacturing; the group has developed more than 30 viral vector-based processes in the past three years. In April 2020, Pall joined a consortium started by Oxford University and funded by the government of the United Kingdom (UK) to develop Oxford’s COVID-19 vaccine candidate based on its adenoviral vector vaccine platform. The consortium included the University of Oxford Jenner Institute, University of Oxford Clinical Biomanufacturing Facility, UK non-profit Vaccines Manufacturing and Innovation Centre, Pall Corporation, Oxford Biomedica, Cobra Biologics, and Halix. The group was joined in late April by AstraZeneca, when the company partnered with Oxford University’s vaccine developers and licensed the vaccine technology. As of early January 2021, the vaccine being marketed as COVID-19 Vaccine AstraZeneca (formerly AZD1222) was authorized for use in the UK, India, and others and was in the midst of a large Phase III clinical trials in the US.

The consortium members worked closely together to develop and enable manufacturing of the vaccine in record time, says Clive Glover, director of strategy at Pall Corporation and the lead on the vaccine project. He noted that Pall designed the commercial manufacturing process and installed the equipment at a contract manufacturing partner within two months, breaking Pall’s previous record of nine months.

One of the keys to this success was starting with a standard manufacturing process. Glover suggests that for viral vector-based therapeutics, such as this vaccine, 80% of the manufacturing process is standard—the same no matter what the product—and the remaining 20% needs to be tailored. “The process can vary in several ways,” explains Glover. “For example, on the upstream, each process will rely on different cell lines, each of which may have slightly different growth rates, which will drive different feeding strategies. On the downstream side, viral vector products will vary in their physical properties and so require optimization of each downstream step to affect stability and ability to be concentrated. Finally, different products will need to be put into different concentrations for administration to patients, [which] has to be customized to each process.”

With Pall’s standard manufacturing process and the University of Oxford’s research as starting points, the consortium collaborated to optimize the process. “Decisions around the process were data-driven, based on initial pilot scale runs done by the University of Oxford,” notes Glover. “This process was then recreated by the Pall team at our Process Development Services laboratory in Portsmouth, UK, and developed into a small-scale process. [The process] was designed as a scaled-down model of a commercial process, and it allowed us to determine the specific parameters that would work at larger scale. Following successful runs at the small scale, we then did commercial runs to ensure the process was fit for purpose, before transferring that process to the various contract manufacturing organizations (CMOs). It’s important to note that the whole time we were doing these scale-up runs, we were constantly collecting data that helped with filing of the CMC [chemistry, manufacturing, and controls] section for the regulatory authorities.”

Because rapid scale up to high volumes of commercial product were needed, AstraZeneca called on multiple CMOs for production. Glover notes that, through the consortium, the CMOs worked to each use as similar a process as possible, which simplified the supply chain for equipment and raw materials.

A challenge Pall faced was supplying equipment in the short time that was required to set up the manufacturing process. “We did this by working very closely with our manufacturing sites and manufacturing some units at risk in order to compress timelines,” says Glover.

Another challenge addressed by a team of 20 that Pall had dedicated to the project was tech transfer. “Ensuring that the process is well characterized is critical for a smooth tech transfer. Given that speed was critical in the case of COVID-19 vaccines, we sent Pall personnel who were involved in the process development onsite to the CMOs for their initial runs to make sure that everything went smoothly,” reports Glover.

In addition to the efforts of Pall personnel, keys to the record speed of process development included “a combination of ground-breaking innovation, secure funding streams, relentless effort from some of the greatest scientific minds on the planet and, crucially, a consortium-wide commitment to the principles of lean process development and production,” concludes Glover.

Although different ways of collaborating are being employed, the need for a growing body of experts with the knowledge and ability to move manufacturing processes into commercialization is crucial for all. The rapid growth of the cell and gene therapy industry, as well as biopharmaceutical manufacturing for COVID-19 vaccines and therapies, is creating a greater need for training and education as companies add staff who need to learn how to use the equipment.

For new therapeutics, equipment suppliers play a crucial role because of their detailed knowledge of process technologies. “Unlike more established therapeutics like monoclonal antibodies, with many of the novel therapeutics, such as viral vectors, there is not yet a critical mass of knowledge on how to design and run large-scale commercial processes,” notes Glover. “Over time, manufacturers will have much greater expertise on their specific therapeutic and manufacturing process, but even then, they [can benefit from] the depth of knowledge that we have as an equipment supplier. This [knowledge] is why we build long-term partnerships with customers in this space, because we can add real value to them throughout the whole process.”

Jennifer Markarian is manufacturing editor at 

Articles

Collaboration between equipment suppliers and users is leading to innovation and optimization in biopharmaceutical manufacturing.

Optimizing Bioprocessing Equipment to Speed Development and Increase Capacity

The pharmaceutical industry has been on the leading edge of anticounterfeiting and brand protection efforts for many years. “Anticounterfeit solutions are usually tailor-made according to the needs of the brand owner,” says Paavo Sillanpää, senior business manager, Pharma at UPM Raflatac.

A diverse strategy considering threat scenario and product is needed. “Most pharma companies have a multi-layered approach,” notes Joe Farrell, life sciences expert at Loftware. The most common physical solutions are tamper-evident labels and packaging materials, designs that prevent the placement of a counterfeit product into the original packaging, serialization, and overt and covert authentication methods such as holograms, invisible markers, and taggants.

“Ideally, multi-level security concepts should be used that are individually tailored to a specific use case, combining analog and digital features, which can be verified by different stakeholders within the supply chain,” says Gene Dul, president of Schreiner MediPharm US.

There is heightened interest in tools and technologies that go beyond the package to protect patients, such as on-dose solutions. In addition, says Peter Wong, chief operating officer at TruTag Technologies, “the industry is increasing its public awareness campaigns of the problem of fake and unsafe medicine in an effort to educate consumers about the dangers of unauthentic drug products.”

As a result, John Pitts, key account manager for Antares Vision, predicts an increased focus on consumer engagement. He notes, “Enabling the end consumer and the dispenser to authenticate their products is powerful on so many levels. It makes counterfeiting more difficult, provides vital and real-time data to the consumer, and can offer the manufacturer feedback.”

Labeling plays an important role in the fight against counterfeit products. As the passport for moving products through the global supply chain, it contains any track-and-trace or authentication information. “In the label business, we have seen an increased interest in various tamper-evident (TE) solutions and holograms,” reports Sillanpää. One new product from UPM Raflatac combines heat resistance, advanced adhesion, and conformability. Designed primarily for the European market where cartoned blister packaging is common, the heat-resistant TE label won’t shrink in heat tunnels used to produce multipacks. UPM Raflatac has also introduced sustainable TE labeling. It’s produced from Forest Film, which Sillanpää says is “the world’s first wood-based plastic labeling material.” Benefits include performance equivalent to traditional plastic film label materials and the ability to help pharmaceutical brands achieve sustainability goals.

Demand for more sustainable products extends to RFID and near-field communication (NFC) tags. Eco-friendly RFID and NFC tags from Identiv feature paper-based transponder inlays that reduce polyethylene terephthalate content, resulting in a repulpable substrate (1).

RFID technology is integral to the Cap-Lock plus RFID cap adapter and label combination from Schreiner MediPharm. The label-integrated RFID inlay provides digital proof of integrity and first-opening evidence for syringes as well as product authentication. Dul explains, “The adapter is placed on top of the syringe’s primary closure and interlinked with it to equalize the diameter differences of the syringe body and closure. The label wraps around the syringe body and cap adapter and—once opened—provides irreversible tamper evidence due to an integrated perforation.”

Magnetic ink is another potential anticounterfeiting tool. Technology from Inspectron relies on a proprietary reader, track-and-trace software, and magnetic ink, long used on checks to facilitate automated sorting. The magnetic ink is used to print a barcode, which is detectable even if it’s not visible to the eye. That means the code, which may be serialized, can be hidden on the inside of a carton or under a label and still be read. The current reader works from a distance of up to 2 mm, but units with longer read ranges are under development. “However, longer read ranges require bigger codes,” notes Nathalie Muller, head of Innovation at Inspectron. Although the first commercial application of the technology inkjets the codes on paper to enable identification of diverted product, Muller says, the permanent magnetic codes could be printed on plastic or glass containers and potentially support tasks like vial tracking. Also under development is a hybrid one- and two-dimensional barcode that would hold more data.

On-dose technology enables authentication at the product level. Edible microparticles coupled with the Smart Medicine solution from TruTag Technologies confirms product authenticity and can help boost patient adherence and outcomes. A new Pharma Mobile App allows patients to scan each dose with their smartphone, authenticate it, and record that it was taken. If desired, the record of the dose can be shared with healthcare providers. The system also can link to other product information.

In April 2020, FDA accepted molecular tagging technology from Applied DNA Sciences into its Emerging Technology Program (2). The company says that its technology is a multilayered platform that gives both the dose and the packaging an immutable identity for authentication.

On Nov. 30, 2020, AlpVision launched its Alpvision COVID-19 Initiative to protect COVID-19-related therapeutics and vaccines against counterfeiting. Under the program, AlpVision provides pharmaceutical companies and their suppliers with the tools to deploy its Cryptoglyph digital security feature on their packaging. Invisible to the human eye, the Cryptoglyph feature can be authenticated via smartphone. Adopting the technology does not change the production process or involve additional consumables. In addition, the smartphone applications connect to AlpVision’s Brand Monitoring System, a centralized server platform that enables real-time monitoring of product authentication activities. AlpVision plans to provide this service for free until the World Health Organization declares the pandemic has ended (3).

1. Indentiv, “Identiv Launches Eco-Friendly RFID, NFC Tags,” Press Release, Jan. 23, 2020.

2. ADNAS, “Applied DNA Accepted into US FDA’s Emerging Technology Program, Creating Pathway for Molecular Tagging of Pharmaceuticals and Packaging,” Press Release, Apr. 30, 2020.

3. AlpVision, “AlpVision to Offer Free of Charge Security Feature to ProtectCOVID-19 Relevant Medicines against Counterfeiting,” Press Release, Nov. 13, 2020.

Hallie Forcinio is packaging editor at Pharmaceutical Technology, 

Labeling, printing, and on-dose tagging technologies provide a multi-layered approach to anticounterfeiting for pharmaceuticals.

Counterfeiting Countermeasures

Equipment and Processing Report e-newsletter

PharmTech Equipment and Processing Report eNewsletter 02-17-21

Optimizing Bioprocessing Equipment to Speed Development and Increase Capacity

Counterfeiting Countermeasures