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Cynthia A. Challener, PhD, is a contributing editor to BioPharm International.
Experience, communication, collaboration, transparency, planning, and prioritization contribute to success.
Technology transfer of bioprocesses, while common in the biopharmaceutical industry, can be complex and present numerous challenges. Projects with accelerated development timelines that also involve multiple contract service providers have the potential to magnify the difficulties. Both contract manufacturing organizations (CMOs)/contract development and manufacturing organizations (CDMOs) and sponsor companies can facilitate the process using pragmatic approaches that mitigate risks and ensure cooperation between all parties involved.
When transferring a bioprocess to a CDMO, manufacturers often face multiple challenges that can include meeting the material demands of their clinical or commercial strategy and achieving aggressive timelines. These constraints must be met while accommodating the facility fit and scale-up needs determined by both the established process and the CDMO’s platform, equipment, and capabilities, according to Frank V. Ritacco, director of scientific and technical affairs for pharma services at Patheon, part of Thermo Fisher Scientific.
Abel Hastings, director of process sciences at Fujifilm Diosynth Biotechnologies, adds there are some themes that often slow the progression of sponsor projects, including materials challenges, specification ambiguity, and challenges with historical change management. “The implications of an ill-selected material can linger and hinder manufacturability. Once selected, materials dogma can be difficult to unpick because of the fear of the unknown,” he notes.
With respect to specifications, Fujifilm splits them into two general categories: safety/efficacy and manufacturability. It is important, according to Hastings, to convey the known safety/efficacy limits as early as possible and communicate what events might cause specifications to change. “As a CDMO, our primary goal is often to adjust the process design to reliably meet these specifications, and knowing the status of specifications up front helps us guide our clients,” he explains.
Issues can arise, however, if sponsors establish specifications that are rooted in manufacturability too early and then the process performance changes in the development stage or when moving a program from one site to another. Establishing expectations for process performance with limited data can, Hastings says, often over-constrain the development team, leading them to necessarily forego improvements in order to achieve a manufacturability specification.
Change management during process development, meanwhile, can challenge both sponsors and CDMOs as they work to expedite processes. “In this day and age of accelerated processes and ever-changing team members, capturing rationale for change becomes increasingly important to guard against knowledge loss as team members leave a company and to help guide development in an unemotional manner,” Hastings asserts.
While commercial processes typically have robust quality and change-control systems, earlier-phase projects can often change quickly and with limited traceability. “We recommend taking a balanced approach in order to capture pertinent information while not hindering development,” comments Hastings. Some sponsors use iterative risk assessments or failure mode and effects analysis tools to quickly capture changes and build catalogs of development and lifecycle changes. “This approach allows the user to both convey historical details and to project forward-looking risks in order to steer development in a planned way,” Hastings observes.
The overall challenge in tech transfer is to ensure that the sponsor’s process will be reproduced in a similar, robust, and compliant way. Manufacturing product in the quality and quantity in the defined timeframe are indicators of a successful transfer of the manufacturing process to the CMO/CDMO, according to Andrew Bulpin, head of process solutions at MilliporeSigma. “This overall challenge,” he says, “is mainly linked to the process itself, but it also relates to the capacity to transfer the process knowledge built for several years to the CMO/CDMO that will be integrated to ensure a successful tech transfer.”
It often also varies depending on the development phase of the bioprocess being transferred. Sponsor companies’ early-phase programs are typically challenged by transferring processes that do not fit into their external partners’ platform operations, according to Emily Schirmer, senior director of process development at Catalent Biologics. “Those partners that can offer a high level of flexibility and unit operation expertise are more successful in accommodating unique or non-traditional processes,” she remarks.
In addition, as programs progress through clinical stages, process transfer becomes more difficult because there is less inherent flexibility allowed and process changes or adaptations become more challenging to justify, Schirmer adds. Bulpin agrees that the process parameters in Phase I or II can be slightly adapted or adjusted to ensure a successful tech transfer, while in Phase III the process is more locked with defined critical process parameters, critical raw materials, and designated critical quality attributes (CQAs). Thus, any changes in Phase III should be assessed, justified and, if necessary, validated.
Adding in a scale-up element when transferring a process increases the overall risk for project success and comparability. “It is difficult to discern the differences observed from facility to facility and any disparities that can be observed on scale up independently,” Schirmer says. “These risks,” she notes, “can be minimized by having a good depth of knowledge of the facility’s specific equipment and well-established scaling models.”
Variations in equipment and material handling at facilities can complicate the tech transfer process, agrees Bulpin. “If the target facility uses different equipment, the raw materials must be compatible with that equipment,” he explains. In addition, to ensure a successful scale up, it is critical that raw materials are available at large scale and equipment capacity is evaluated. “The scale-up strategy of the CMO/CDMO, as well as its expertise in various process types, molecules, and innovative process methods-including perfusion, precipitation, and single-pass tangential flow filtration-is also key,” asserts Bulpin.
For cell-culture processes in particular, scale up can be challenging because scaling to larger volume is not linear, and multiple engineering parameters must be optimized to match process performance developed at the bench scale and confirmed at pilot to manufacturing scales of 2000 L and beyond, according to Ritacco. Harvest and downstream purification processes also need to be scaled up to match product quality and impurity profiles, and sometimes adapted to address differences in product titer and impurity profiles observed at larger scale.
Even if projects don’t involve scale-up, generally they still require a thorough investigation of which parameters need adjustment to fit best within the CMO/CDMO facility and equipment constraints without impacting specifications, Hastings observes. “In our view, scale changes and facility-fit adjustments are not complications but rather just part of what we do,” he says.
Many new biologic drug candidates are awarded some form of accelerated approval designation. While accelerated approval designations may allow a faster path to the clinic or to commercial approval for breakthrough therapies, the time it takes to develop a bioprocess that will be robust, scalable, and reproducibly deliver target product quality remains significant, according to Ritacco. “Fast-tracking the timeline and schedule without compromising product quality and patient safety is an additional challenge,” Bulpin says.
While some product development steps can be reduced, Bulpin insists that risk analysis and decision justifications should not be underestimated. “Sufficient understanding of the process is necessary to ensure control of operating parameters to consistently deliver safe and efficacious product to patients, and achieving this on an accelerated timeline requires a skilled team leveraging well-established processes and methods, as well as past experience to streamline development and avoid pitfalls,” adds Ritacco.
It is also extremely important for sponsor companies to work with a partner who has extensive experience with tech transfer and scale up into commercial launch, according to Schirmer. “A typical program with an external partner is designed to have a process-acquisition phase, which includes a paper transfer followed by establishing the process at a small scale. Then the scale up occurs within the facility infrastructure. These scale-up activities can, however, be minimized by performing the process acquisition at the manufacturing scale to meet accelerated timelines,” she says.
Fujifilm often observes three particular challenges with accelerated programs: prioritization, collaboration and communication, and planning. Most sponsors with accelerated designations greatly reduce timelines, Hastings says, by focusing on refining their processes to reliably achieve CQAs, often at a cost to the yield. “The most successful projects have a cross-functional team that is clear on their priorities and what success looks like. Ensuring all members of the team work together to settle on the right balance of yield and CQA reliability will ensure teams aren’t derailed by conflicting priorities,” observes Hastings.
One problem Hastings has observed, however, is that as teams turn attention to accelerating development timelines, they have a tendency to unintentionally reduce the circle of communication. “The most successful teams, however, enlarge their circle to engage all functional areas, allowing everyone to be part of the process of building the best balance of speed, reliability, and risk,” he asserts.
Planning for an accelerated designation project, meanwhile, requires a balance of creativity, dedication, and pragmatism, according to Hastings. “Teams need to be able to challenge their platform expectations to strike a balance to improve timelines. This planning cannot be done once, but rather needs to evolve as the scientific understanding of the process grows and teams need to be aware that any new data might require an adjustment to the project plan,” he adds.
For many projects, it is necessary to transfer a bioprocess from one CMO/CDMO to another. Regardless of the reason, it is essential that everyone involved does not overlook the complexities associated with leveraging previous data and maintaining technical continuity, according to Hastings.
To proactively address this issue, Fujifilm identifies new, unique, or difficult (NUD) elements, such as process-specific factors that depend on equipment idiosyncrasies that may not be fully evident to a sponsor while the process is running at a CDMO. “When a process is moved from one CDMO to another, the receiving site rarely has access to complete equipment-specific details, which can make interpretation of previously generated data challenging and incur risk,” Hastings says.
“At Fujifilm, we work hard to identify NUDs as early as possible and then categorize them as equipment-specific versus equipment-agnostic. This approach allows us to suggest studies that may improve facility fit,” he adds.
Differences in equipment throughout the process, as well as differences in scale, require optimization of multiple engineering parameters to match process performance in cell-culture, harvest, and downstream purification processes between facilities, Ritacco agrees. He also points out that analytical methods have to be transferred, established, qualified, and ultimately validated to assure consistency in analytical results between manufacturers.
Hastings also notes that some processes include historical elements that are difficult to translate into and out of batch records. “In some cases, sponsors deal with this issue by maintaining some of the same staff throughout transfers to minimize the chances that so-called tribal knowledge is lost,” he observes.
Transparency between all team members, adds Schirmer, can actually be the catalyst to a successful development, scale up, and tech transfer of a drug with an accelerated approval designation. “Whether the process technology transfer occurs between the sponsor company and the external partner, or between two external partners, the importance of transparency is the same. Communication is also critical. If all parties are aligned and understand the path forward, it is much more likely that the transfer will be a success,” she comments.
The general constraints are the same for any tech transfer process, including those between outsourcing providers, although the confidentiality becomes more marked and the training process can be slightly different. “The aim remains the same,” Bulpin says. “In addition, any process, analytical, equipment, raw material, and/or regulatory gaps should be listed and mitigated to meet specifications and ensure a successful tech transfer.”
Technology transfer introduces additional risk to the development and commercialization of biopharmaceuticals, so minimizing risk is fundamental to successful technology transfer of bioprocesses.
A clear project plan with milestones that are mutually agreed upon sets the stage for a successful program, Schirmer observes. “Risks should be identified at the onset of the project and continuously re-evaluated to determine effectiveness of mitigations and any additional risks,” she says. In addition, risk assessments should be backed by scientific reasoning and process data.
The main strategy, according to Bulpin, is to consider tech transfer-with or without scale up-as an entire project with dedicated subject matter experts, communication flow, clear responsibilities, and planning. Dedicating one individual to the management of one CMO/CDMO group helps with this approach, except for quality assurance and regulatory topics, which Bulpin says should be managed globally to ensure process compliance.
The preparation and review of thorough process descriptions, facility fit, and tech transfer documentation, with appropriate quality review and oversight, go a long way toward achieving a successful tech transfer, adds Ritacco. The experience and expertise of the teams involved is also critical. “A highly skilled and experienced team will anticipate potential challenges and leverage their deep understanding of bioprocess development, tech transfer, and manufacturing to achieve the desired process performance and product quality in a new facility, even when the timeline may be challenging,” he asserts.
It is also important, according to Hastings, for everyone involved in a tech transfer project to recognize up-front that priorities may change during the development cycle for biologics with accelerated approval designations. Risk-based tools can be used to segment process characterization into two or more phases and to design the process to prioritize CQAs over yield. “Using this approach, it is possible for sponsors to start their process performance qualification (PPQ) in parallel with some process characterization work, thereby shortening the timeline from clinical manufacturing to PPQ,” Hastings observes.
On the other hand, it can result in post-approval yield fluctuation, which makes business-planning difficult. Fujifilm sees this issue as an opportunity to move through a natural transition point. “Purposefully pivoting from biologic license application-enabling activities to business-enabling process improvements at the optimum time will allow programs to benefit from both accelerated PPQ and long-term commercial pay-back,” he concludes.
Vol. 33, No. 4
When referring to this article, please cite it as C. Challener, “Ensuring Smooth Tech Transfer of Bioprocess Operations,” BioPharm International 33 (4) 2020.