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Sanjay Konagurthu is senior director, Pharma Services Group at Thermo Fisher Scientific, Bend, Oregon.
Derek Gallo is director, global technology transfer at Thermo Fisher Scientific, Greenville, SC.
Successful technology transfer depends on the ability to anticipate risks and plan ahead.
Successful technology transfer is essential to enable biopharmaceutical clients to safeguard supply, improve distribution, and reduce program costs and risks. When a customer approaches a contract development and manufacturing organization (CDMO) to gain technology transfer support, it is important to confirm that the CDMO has a proven history and a robust project management and technical platform in place. This helps ensure the ability to understand and execute against the project requirements, mitigate risks, deliver the project on time, and right first time. There are several key tools and best practices that enable the team to plan and deliver successful results, including mechanisms to overcome obstacles that may arise. Table I provides a list of questions for a pharma company to ask a potential CDMO partner.
To ensure that the technology transfer is successful, the project leader will establish a cross-functional team comprising subject matter experts (SME) for each function. These functions should be matched at customer and CDMO locations where possible. It is important the team establishes a strong partnership and lines of communication such that key roles can work closely with their counterparts throughout the project.
Establishing a communication plan and understanding each other’s escalation channels is crucial at the project start. Early in the project, reaching a level of trust and transparency can take time. To help, both companies must share all relevant details available, including product requirements, history, drivers, and any other information that will help understand one another’s needs. Project kick-off is best handled face to face as the team starts their relationship. It is important to have frequent face-to-face working sessions to allow the team to accomplish deliverables, especially if a significant obstacle arises.
As part of the communication plan, the teams must align on tools to manage the project and operate from a single ‘source of truth.’ This helps ensure alignment on expectations, timing of key deliverables, and communication between the organizations.
Project kick-off, and the conversations leading up to this point, represents a critical period where information sharing begins, and the project could suffer a delay if key information is missed at the start. A pre-defined checklist can assist the team in collecting all relevant information, as well as drive harmonization, incorporate lessons learned from previous projects, and proactively collect key data.
As timelines are often compressed, it may be tempting to jump into project activities immediately. Experience shows, however, that taking time to understand both companies’ requirements pays dividends, ensuring that important factors are not overlooked. For example, there may be differences in procedures for ordering equipment or materials, or shipping and receiving materials; change control processes; and document approval processes. As the project progresses, alignment will also be needed on validation strategy, and testing and inspection requirements. If this alignment does not occur early in the project, the timeline can be negatively impacted.
At the outset, the two teams should agree on a governance model, such as a steering team, which may be one tier of seniority above the project team. This team will monitor key project milestones and risks that may arise and take action on items escalated as requiring a decision. Additionally, a global technical forum can help connect global SMEs and functional leaders with the project teams quickly should technical issues arise. This model provides access to global resources and diverse perspectives, offering an additional level of technical oversight, decision making authority, and ability to mobilize resources as required to advance the project. The model also enables trends to be understood and learnings to be shared across the network.
The use of team huddles and visual boards is another tool to help drive understanding, accountability, and efficient decision making as the team executes the project. Visual boards are beneficial to represent the process, assign resources and action items, and flag issues. Huddles are key to efficiently aligning the team and functional management on project-related matters, as well as to recognizing the team’s accomplishments.
The ultimate goal of technology transfer is to deliver the new medicine, at the highest quality, to the patients who need it, when they need it; therefore, the final process must be repeatable and well controlled. To minimize delays, the team must have a relentless focus on ‘right-first-time’ execution. Robust procedures, quality controls, and personnel training must be in place to enable the team to bring in each deliverable within the highest quality standards. A right-first-time mentality is essential as part of the team’s culture. This begins with risk management to track, identify, and mitigate any potential risks, with a focus on ‘what could go wrong?’
Several risk management tools are available for technology transfer, such as formal assessments typically performed on the safety, quality, and overall process; others are part of the lifecycle validation process to identify, understand, and control the process. One major component of a successful risk management program is the use of a ‘risk register’ tool to document and track potential risks, requiring an action plan for each risk identified.
A comprehensive launch readiness tool has proven key in identifying potential risks. A risk management tool may include as many as 200 questions across the ‘seven Ms’ of machines, materials, manpower, manufacturability, market, measurement, and mitigation (Figure 1). These questions examine what could go wrong and incorporate lessons learned from previous projects across the network. The tool is updated regularly throughout the project to help track any new risks that arise or are resolved. Each potential risk identified requires development of a mitigation plan with clear actions, timing, and owners. This tool is useful in keeping stakeholders and executive leadership updated throughout the project.
Stage-gate meetings (also known as milestone reviews) are necessary for the team to review relevant data, accomplishments, and risks. Typically, these meetings include steering team or company leadership representation, depending on expectations set at the project start. The stage-gate will determine whether the team is ready to proceed to the next phase of the project, or whether additional development work or process improvements are required.
As transferring a new process to the facility typically demands new equipment/technology, materials, and other requirements, the team should consider which aspects need particular attention. These may include a combination of additional hands-on training, clarity to batch record and procedure instructions, pre-execution readiness huddles, and additional on-the-floor technical support. It is important to share observations and learnings and ask for feedback from users of the new processes to ensure new requirements are well controlled. These controls must be incorporated into the final process.
Upon successful completion of the project, a final stage-gate meeting should be held to capture learnings and improvements prior to production turnover, including a ‘lessons learned’ meeting with participation from both companies. Learnings should be shared across the site and network and incorporated into future projects.
The technology transfer network should continuously evaluate the project management toolkit, helping optimize and enable successful technology transfers. This evaluation can be facilitated through a monthly forum and face-to-face workshops with the global technology transfer team. The team can pilot new initiatives and tools at their site before finalizing and standardizing across the network. Similarly, this global forum is key to leverage knowledge and resources to manage the overall project portfolio.
In addition to a robust project management toolkit, for a technology transfer to be successful, the principles of quality by design (QbD) should be used to ensure a robust understanding of the process and design principles.
For large production batches to run smoothly, drug formulators need to be mindful of a compound’s performance, stability, and manufacturability from the earliest stages, and throughout formulation and process development. While drug product development scientists typically work on formulation development and stability improvement in Phases I and II of clinical trials, manufacturability is not always a priority. Scale-up, however, may not be straightforward or predictable if process knowledge that is scale-independent has not been developed. This knowledge should guide equipment selection, link the critical process parameters (CPPs) to critical quality attributes (CQAs), and establish the design space (DS). Sound scientific/engineering principles and mechanistic models should be employed whenever possible for scale-up of pharmaceutical unit operations. In addition, a robust risk assessment program invoking QbD principles at each stage of development is crucial for successful scale-up and transfer.
Process scale-up of pharmaceutical unit operations and understanding through models should be developed whenever possible. Models that describe pharmaceutical unit operations can generally be based on empirical, semi-empirical, and mechanistic approaches.
Models describing formulations and unit operations should be developed early in the process to avoid a trial-and-error approach. Formulation models are critical to understand the interplay between drug and excipients and provide a fundamental basis for rational formulation design in line with QbD principles. Figure 2 is a molecular dynamics model showing the effect of drug loading on a spray dry dispersion.
Mechanistic models for understanding the thermodynamics of unit operations (e.g., spray drying) are essential to predict the operating ranges a priori to running the actual process. Thermodynamic modeling of the process allows for the calculation of critical parameters and predictive performance. For scale-up and technology transfer, the CPPs are converted to scale-independent variables. Figure 3 shows an example of the design space (DS) for a spray dried product leading to particles of a desired morphology and size. Figure 4 shows a design of experiment (DoE) conducted for ‘compound X’ to identify the critical process parameters and critical quality attributes as part of process optimization and scale-up.
Effective implementation of models avoids reliance on a trial-and-error approach and provides critical information throughout drug product development. This leads to a robust manufacturing pathway and a thorough understanding to identify the CPPs and their impact on the CQAs.
These examples demonstrate that having fundamental mechanistic models based on engineering principles in combination with targeted process DoEs result in critical process knowledge and understanding, which in turn supports scale-up and technology transfer.
Successful technology transfer depends on many factors, including the ability to anticipate risks and plan ahead, so that the team is prepared to deal with all possibilities, including unforeseen events. It is important to connect the dots across the various elements of launch readiness (e.g., machines, manpower, materials, manufacturability, measurement, market, and mitigation) through utilization of a comprehensive risk management process.
Tools such as a readiness checklist, stage gate, governance, and visual boards can be used to develop an in-depth understanding of the process upfront, day-to-day focus on project requirements, clear escalation channels, and controls in place to ensure progress into each phase of the project. QbD principles are used to ensure process understanding and knowledge aid in the scale-up and transfer from development to commercialization, with CQAs and CPPs that can be closely monitored and controlled.
Forming a partnership and communicating effectively and transparently between sending unit and receiving unit is key, as is promoting continuous improvement and learning.
Vol. 43, No. 4
When referring to this article, please cite it as D. Gallo and S. Konagurthu, "Technology Transfer: Best Practices in Operational Development," Pharmaceutical Technology 43 (4) 2019.