Jennifer Markarian is a contributing editor for 

Jennifer Markarian

Traceability of the raw materials used in pharmaceutical and biopharmaceutical manufacturing is a crucial part of quality management. Digital tools offer time savings, better compliance, and greater efficiency for all aspects of raw materials qualification and handling.

Raw material quality begins with raw material suppliers, and supplier and material qualification are crucial steps for any drug manufacturing process. Quality management systems (QMS) can be useful here, says Patrick Nieuwenhuizen, senior manager and consultant at PharmaLex.

PharmaLex introduced a digital tool in November 2020 to help companies perform risk assessments of excipient interactions in the final drug product, which are required by Europe’s 

 Volume 4, Part III guidelines (1). “The SmartRisk tool prompts the user with a series of questions to help organize the assessment,” explains Nieuwenhuizen. He notes that the commercially available, cloud-based system complies with US 

 Annex 11 (3), including data integrity protection.

“Having a robust quality management system with procedures and processes for raw material traceability and management supports consistency and reliability throughout the supply chain,” adds Jessica Cansler, senior quality management specialist for Nutrition & Health, North America, at BASF. “Adhering to appropriate quality standards, as well as establishing a program based on risk and application will help ensure the appropriate level of review of raw materials.”

BASF’s Virtual Pharma Assistants, introduced in 2019, are digital tools for pharmaceutical development. “ZoomLab allows formulators to predict their next starting formulation for a pharmaceutical product; RegXcellence untangles the complexity of the compliance process via instant access to regulatory and quality documentation; and MyProductWorld helps customers find the optimal excipient or API solution for their next formulation challenge,” says Valerie Van Hulle, global strategic marketing manager, Pharma Solutions, at BASF. The company continues to update the online tools, she reports.

Quality systems should not be separated in “silos” from other operations, suggests Matt Lowe, chief product officer at MasterControl, which released a new version of its life sciences QMS software on Feb. 3, 2020. “Gaining greater visibility is the first step toward ensuring traceability. Connecting your QMS with other systems and stakeholders helps provide the necessary visibility and transparency to extend a culture of quality not only across your organization, but also your supplier network. With the technology that we have today, any company should be considering a digital QMS and connecting systems in a paperless environment.”

Digitalization for raw materials handling can take many forms—from online certificates of analysis (CoAs) to electronic batch records (EBR). While the trend is toward digitalization, companies in the pharma industry are at various stages in the process, with some completely manual, others completely automated and paperless, and others in between.

Automated systems for raw materials records remove the double verification required in manual paperwork. “The system virtually does the verification for you as it can act as a ‘pass or fail’ whereby the system is working for you instead of you working for the system, which is a time savings and results in better compliance,” adds Nieuwenhuizen.

“It does take effort and time to implement digital systems,” Nieuwenhuizen cautions. He notes one example in which a company implemented a complex vendor management system that required a dedicated project team. The result, however, was the ability to link materials management and ordering with EBR, which also helped manage stock levels. Nieuwenhuizen notes that when implementing digital systems, it can be challenging and potentially counterproductive to translate manual workflows directly into digital workflows. “It may be better to embrace a new way of working and look first at how the digital tools are designed to be used,” he suggests. “The software suppliers have the knowledge about the benefits of the tool, and they can be a resource.”

Integrating digitalized systems within a company eliminates data silos, in which data are stored in separate, unconnected digital systems. An integrated platform makes all the data in an organization accessible so that data can be analyzed to identify trends and make data-based business decisions, notes Lowe. For example, he says, if raw materials supplier data were integrated with other quality and manufacturing data, a manufacturer would have another tool to help better identify the root cause of a deviation.

Integrating QMS and laboratory inventory management systems (LIMS) is beneficial, adds Nieuwenhuizen. “Inventory control systems help with QMS. Quality control of materials can be linked to LIMS for intake, quarantine of problem batches, and release or rejection of material. An important aspect is that it gives you full traceability by batch number,” says Nieuwenhuizen. LIMS can then be interfaced to inventory control systems and to vendor management.

Inventory management and supply-chain visibility software can help with managing complex supply chains. “There are more platforms seen in the industry to alert when there is a possible supply disruption in an area due to natural disasters and other issues in the region or sourcing company,” notes Cansler.

A CDMO uses a digital platform to make real-time inventory, production, distribution, and shipping information readily accessible to its biopharmaceutical clients. Read the article 

Although data interfaces between raw materials suppliers and drug manufacturers are not yet widespread, there is a move toward sharing information so that parties can make informed decisions more quickly. Data security and confidentiality, however, are important. “Use of password protection and user vetting helps maintain confidentiality,” says Cansler. “Confidentiality can be further addressed by allowing visibility only one level up and down; [users would need to] request authorization to further review the transparency beyond their one level capability.”

Connecting supply chain management systems and QMS also improves efficiency of the supplier audit process, adds Lowe. “Manufacturing organizations need to be able to securely track and store supplier audit information, reports, deviations, supplier corrective action requests (SCARs), and more while making it easy to find suppliers that meet audit requirements.” He notes that digital audit tools within quality systems connected to supplier information allowed remote audits to take place during the COVID-19 pandemic’s travel restrictions. “A digital system can even allow you to invite suppliers to participate in tasks relevant to them, providing a secure, online collaboration space and restricted access to suppliers for collaboration and concurrent engineering efforts. For many companies, having this technology has impacted their business continuity. If there is something good that comes from COVID-19, it’s that it has illustrated the need for digitization to maintain business operations and has spurred companies to make the digital transition.”

While more companies are now embracing these well-established digital tools and systems, new data analysis tools are also being increasingly used. “Machine learning (ML) and artificial intelligence (AI) are tools that some companies are already taking advantage of, and I would expect this will be the big trend in the coming years,” suggests Lowe. “Integrating [supplier, quality, and manufacturing] systems to share information and using AI/ML and natural language processing to analyze that data will be a game-changer for companies.”

 “Guidelines of 19 March 2015 on the Formalised Risk Assessment for Ascertaining the Appropriate Good Manufacturing Practice for Excipients of Medicinal Products for Human Use,” (Brussels, 2015). 
2.

 “Computerised Systems,” (Brussels, 2011).

Jennifer Markarian is manufacturing editor for 

Volume 45, No. 3
March 2021
Pages: 42–43

When referring to this article, please cite it as J. Markarian, “Digital Tools Enhance Raw Material Traceability," 

Articles

Integrated, paperless data systems can improve efficiency and quality.

Digital Tools Enhance Raw Material Traceability

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 

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

Optimizing Bioprocessing Equipment to Speed Development and Increase Capacity


Supplement: Partnering for Bio/Pharma Success
February 2021
Pages: s16–s18

When referring to this article, please cite it as J. Markarian, “Equipment Suppliers and CDMOs Advance Process Development,” Partnering for Bio/Pharma Success Supplement (February 2021).

Equipment Suppliers and CDMOs Advance Process Development

The cold chain is of crucial importance for the distribution of COVID-19 vaccines, and the industry—from pharmaceutical companies to dry ice suppliers—has been gearing up to support the effort. A key to success is tracking the vaccines as they move through the supply chain to ensure that they are delivered on-time and remain under appropriate storage conditions. 

 interviewed Mahesh Veerina, CEO of Cloudleaf, whose digital visibility software is being used for this purpose, about trends in tracking vaccines through the supply chain, including the use of Internet of Things (IoT)-based sensors for real-time monitoring of cold-chain distribution. 

Podcasts

Pharmaceutical Technology interviewed Cloudleaf about trends in tracking vaccines through the supply chain.

Trends in Vaccine Tracking

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.

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 iCON 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.

 spoke with Tania Pereira Chilima, Deputy CTO at Univercells Technologies about their technology and how it can be used in viral vector manufacturing, which is needed for production of some of the COVID-19 vaccine candidates. Read the interview: 

Intensified Process Offers Cost-Effective Viral Vector 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.”

1. 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.


Vol. 44, No. 12
December 2020
Pages: 32–34, 46

When referring to this article, please cite it as J. Markarian, “Modular Processes and Facilities Enable Flexible Vaccine Manufacturing,” 

The COVID-19 pandemic has accelerated the need for modular designs to rapidly expand vaccine production capacity.

Modular Processes and Facilities Enable Flexible Vaccine Manufacturing

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.

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