Many factors are enhancing performance but creating cost pressures for today’s drug manufacturers, such as the added complexity of modern biologics and increased competition across the industry. Remaining ahead of the curve requires strategies that can improve efficiency while lowering costs, without compromising safety. A common approach is to outsource certain activities, such as engaging a CDMO (contract development and manufacturing organization), that can accelerate process development and manufacturing by leveraging additional capacity and expertise while also sharing risk. However, that is only possible if you find one with the capabilities and resources necessary to support your program and its long-term goals.
With a successful history in today’s industry, Teva Pharmaceuticals understands the benefits outsourcing can offer and the importance of finding the right partner, which is why it recently decided to work with Cytiva’s Fast Trak™ team for the rapid transfer and scale-up of one of Teva’s biologics manufacturing processes. The result of that partnership is evidence that a successful tech transfer is possible only with effective communication, diligent project management, and a wide range of technical and regulatory expertise.
A coordinated exchange of vital data
When the project with Cytiva began, Teva had already established a robust manufacturing process on a single-use platform and desired to work with an outsourcing partner that could scale it up. The goal was to establish consistent performance at scale-up when compared to the existing lower scale process, requiring process knowledge and experience with the cell type and expression system. A solid understanding and application of cGMP (current good manufacturing practice) knowledge is also critical when moving from a non-cGMP process because of the challenges with ensuring regulatory compliance in an industry where market and patient needs are constantly evolving. Properly performing the technology transfer process from initiation heavily depends on not only the technical team of the transferring company, but also that of the CDMO. These teams must work together in harmony to coordinate a seamless transfer of process and product knowledge as well as an alignment of project goals.
Sourav Kundu, vice president of biologics CMC at Teva, says Teva’s cross-functional team, led by process development, prepared for the transfer by creating batch records and a sampling plan and determining process parameter settings for operations. Experts in quality assurance, manufacturing, and quality control also offered input during this phase. While some information is more impactful than others, anything related to process data, operating parameters, analytics, hardware design, raw material, and analytical methods is vitally important. This data had to be analyzed by Cytiva for subtle details, as each molecule and its process can have its own unique challenges. A CDMO must also have a system and standard operating procedures (SOPs) in place for collection and storage of the data. At Cytiva, this information is captured in a technology transfer document for each respective aspect of the process, including upstream, downstream, and analytics. It is subsequently placed on a secured SharePoint platform for access by only specific team members, including those designated by the client.
Upon receiving the process information, Cytiva performed a gap analysis to identify any areas where additional data were needed to reduce risk. “Depending on the client’s experience and knowledge, they may not always provide the necessary information,” explains Patrick Guertin, global technical manager at Cytiva. “This can sometimes include the raw materials specifications, cell line safety testing, analytical methods, or even data thought to be irrelevant. However, in this particular case, Teva was knowledgeable in the space and planned ahead, so they provided us with an appropriate amount and type of information.” Transparency by a CDMO and properly managing expectations during this phase are important to ensure the client is aware of any added time or effort that may be required to achieve its goals, such as with titer or product concentration. Although some of the data from Teva was generated in platform technologies that differed from Cytiva’s single-use platform, Cytiva’s experience enabled them to interpret the data and apply it to the Cytiva system at a larger scale.
Overcoming challenges together
As with any scale-up, some adjustments to Teva’s process parameters were needed, such as addressing media solubility concerns when using Cytiva’s equipment for formulating media solution. Additional considerations were also given to the documentation as well as to sampling, testing, and batch record reviews where further harmonization (e.g., practice for raw material release) between Teva and Cytiva was needed. “Through a collaborative process with Cytiva’s SMEs, process parameters for the manufacturing bioreactor scale were developed,” says Dr. Kundu. “Some process parameters, especially the scale-dependent process parameters, needed to be further evaluated and adjusted (e.g., pCO2 control) during batch execution at Cytiva. This was done through open communication and leveraging the experience of the members of the technology transfer team.”
In addition, the team at Teva reviewed and assessed the impact of any process deviations systematically before disposition of any of the batches produced at Cytiva, and secured raw materials through Cytiva’s established procurement system. The bill of materials was also transferred to Cytiva, but some adjustments or equivalent chemical substitutions were required in order to comply with Cytiva’s quality system approved vendor list. “Any challenges encountered were overcome by using sound process knowledge, equipment knowledge from the Cytiva side, and through excellent collaboration,” explains Dr. Kundu. A dedicated project manager is also included in Cytiva’s tech transfers to organize the various teams and ensure frequent communication, both written and verbal. They are responsible for documentation communication, weekly prescheduled meetings as well as ad hoc meetings, and any ongoing support that is needed as the client continues on its development path after the transfer.
As the pharmaceutical industry continues its focus on improving process efficiency and quality in drug development and the manufacturing process, automation also serves as a key component in that effort. Automation can reduce errors, increase speed, and help achieve consistency and traceability, which can be especially valuable during the tech transfer process. For the project with Teva, Cytiva used the Figurate™ Wonderware control automation software for the Xcellerex™ XDR single-use bioreactor production process, and Figurate UNICORN™ control software for its WAVE™ seed train as well as its ÄKTA™ chromatography purification process. “This Figurate control automation software, which is inherent to our systems, helped support process robustness and consistency,” explains Guertin. At-scale engineering runs prior to cGMP are most often needed to confirm process performance. But in this case, because of operational efficiencies combined with expertise, Cytiva was able to skip those prerequisites and move directly into expediting the project forward. Once the development work was complete, the cell culture process was successfully transferred to Cytiva, and the process was scaled up to pilot scale.
Efficient tech transfers with the right partner
“An efficient technology transfer not only saves time and resources, it also increases the success of manufacturing, ensuring that life-saving medications can be developed and made available to the patients,” says Dr. Kundu. However, an efficient tech transfer is possible only with the right partner. Guertin says Cytiva’s capabilities in process development, clinical manufacturing, bioprocess hardware, automation, and facility structure allow it to assist a diverse array of clients that could benefit from Cytiva’s experience. The end goal may ultimately be to enable clients to produce on their own. This includes virtual biotechs and start-ups, as well as mid- to large-sized pharma companies.
“Our unique advantage is that we conduct process development and manufacture bulk drug substance in a single-use platform that we also produce,” Guertin explains. “So, if the client wants to establish their own development or manufacturing capabilities, we can transfer the process back to them in the same platform with batch documentation and process know-how.” These systems and tools help expedite the process, thereby shortening the timelines and reducing risk. This also enables Cytiva to deliver data to clients sooner in order to make a rational decision about whether the process and data are consistent with their expectations. Cytiva is able to overcome tech transfer challenges using decades of experience, which allows it to quickly translate a client’s process from different technologies and scale it to the Cytiva platform.
“When manufacturing is carried out at multiple locations, appropriate studies have to be carried out for establishing product comparability. In the end, the benefit of manufacturing the clinical supplies in Cytiva’s manufacturing facility and keeping the project on track outweighed the additional comparability work that had to be carried out later,” explains Dr. Kundu. “Overall, the decision to outsource has to be made by carefully weighing the risks and benefits. Due to internal drug substance manufacturing capacity constraints at the time and the business needs, it was a good decision [for Teva].”