In this white paper, we consider the key characteristics of a typical CGT capital project, the project lifecycle and the critical role of project management in delivering project success, which will generally include the following:

• Preparation and delivery of a defined project scope according to user requirements, regulatory expectations and quality standards
• Tracking and delivery of execution to cost and schedule goals
• Assuring safety standards are adhered to during construction and operation
• Licensure readiness (regarding GMP, building safety, EHS and other regulations)
• Ensuring visibility and satisfaction for project stakeholders.

Characteristics of a CGT Capital Project Manufacturing processes in the CGT industry require informed consideration; while not all requirements for these processes are unique, when specific unit operations are performed in sequence, the combination may pose distinct challenges. The aforementioned characteristics include:

• Products may be
• o Autologous, intended for a single patient, with small batch size and scaled-out manufacturing requiring multiple workstations, clean room suites and stringent logistics and tracking to support parallel supply for multiple patients
• o Autologous, intended for a single patient, with small batch size and scaled-out manufacturing requiring multiple workstations, clean room suites and stringent logistics and tracking to support parallel supply for multiple patients o Allogeneic, manufactured to supply multiple patients from each batch, where processes can be scaled-up but are still clean room-based.
• Low volume, small batch numbers.
• Predominance of costly Grade C (ISO8) and Grade B (ISO7) clean room space; Biosafety Level (BSL) 1 and BSL2 biocontainment measures.
• Segregation of processes /unit operations handling different cell types and virus material
• Aseptic production operations, necessary in most cases because CGT products cannot be sterile filtered; aseptic filling of final Drug Product is generally manual for earlier stage candidate assets (driven by batch size and COGS) and performed on a small volume of material
• Immature process equipment and manufacturing platforms, manual workflows, limited closed processing or process integration
• Significant reliance on proprietary process equipment
• Reliance on single use equipment and components, need for pre-prepared bought-in reagents, use of freeze-thaw and cryopreservation techniques, generation of significant biologically-contaminated waste streams.
• Careful control of flows of people, materials, samples, product and waste to, within and away from production suites to avoid cross-contamination, driven by substantial manual movements of items.
• A high degree of flexibility is expected in the design of CGT facilities in order to adapt for improved processes, greater automation, evolution of regulatory requirements and multi-modal and potentially multi-product manufacturing, as technology and scientific knowledge increase over time
• Complex and well-characterized testing requirements, with many and varied analytical testing requirements which may be fulfilled either internally or externally.

In common with other biologics manufacturing, CGT production suites are supported by areas for material and component preparation, fill/ finish, product storage including cryopreservation, personnel gowning and QC analytical labs. Additionally, these facilities require warehousing, offices, utilities and other amenities within a building shell.

CGT capital projects deliver facilities that are highly regulated by FDA and other agencies with often first-to-market products, lack of regulatory precedents and unique processing and product handling requirements. Therefore, the design, construction and testing of the facility and equipment must be fully compliant to support phaseappropriate manufacturing and potentially future licensure, with the company’s quality team playing a critical role in risk assessments, audits, and thorough reviews throughout the development lifecycle. The project manager must keep in mind that the consequences of noncompliance are significant, including forced shutdowns, product recalls, company reputational damage, financial penalties and, most critically, an interruption to supply of a potentially life-saving medicinal product.

The nature of CGT projects means that they can be vulnerable to schedule delays caused by long lead times for delivery of specialized equipment, design changes due to ongoing process development, and lack of skilled people possessing critical, nuanced CGT experience. At the same time, on-time project completion will invariably be critical to the clinical development, licensure and/or launch of a new therapy. Regulatory, CMC and clinical development strategies must be clearly defined and aligned to inform the delivery of the capital project, with key milestones and supporting compliance resources properly identified. Therefore, risk assessment and management are critical aspects of the project manager’s remit to secure and protect the schedule, identify and mitigate risks and review the living risk register at regular intervals.

Phases of the CGT Capital Project Lifecycle
The four main phases of the project lifecycle can be summarized as Plan, Design, Build and Validate Test (see below).

Plan: In the Plan phase, the CGT company will evaluate the need for capital investment, carefully identify the business drivers for the project to initiate and proceed, and consider alternatives such as contract manufacturing rather than creation or expansion of in-house capacity. Build vs Buy analysis and quantitative modeling of capacity as these relate to projected demand should be appropriately undertaken and analyzed as part of business case planning, to evaluate options, optimize the requirements and identify risks associated with the project. In this phase, project management is primarily focused on effectively supporting the high-level decision-making process, providing accurate information in a timely fashion to senior leadership and using external consulting support where needed for specialist tasks such as financial modeling or the generation of a feasibility study. The project manager should be assigned as early as possible and remain with the project through all subsequent phases for continuity.

Design: Once the decision has been approved to proceed with the capital project, the Design phase can begin. CGT facility design is a specialized activity that requires the right architectural-engineering

firm with experience in the design of facilities of this nature. Usually, a concept design phase is executed first, delivering an initial project scope, cost and schedule within ten to twelve weeks to confirm that assumptions made in the Plan phase are accurate. The project manager will ensure that the design firm works alongside the CGT company’s specialists in a collaborative way, with the goals of capturing key project requirements, defining risks and developing a concept design to meet those needs. This will be an iterative process depending on the design solutions identified, their associated costs and timeline for delivery. Once the concept design is approved, the project team will continue into basic and detailed design phases aimed at fully defining the project scope including process equipment, clean rooms and supporting areas such as mechanical spaces, offices and warehouses. The project manager will coordinate additional funding requests as the project proceeds, and ensure regular reporting of progress, both technical and financial to the steering team responsible for oversight of the project and further upward to senior stakeholders as necessary.

Build:
While the Design phase is being completed, preparations for the Build phase can start, including procurement of the various goods and services needed to construct the facility. Construction of the building shell may commence before all of the detailed design is complete, with fit out of clean rooms within the shell continuing later in the project lifecycle. By this time, a large number of organizations will be involved in delivering the project, including civil engineers, equipment suppliers, clean room fabricators, mechanical and electrical contractors and others, usually coordinated by a construction management firm. The CGT project management is focused on safe, efficient, coordinated working between the construction site and other locations such as the design office where members of the project team are located. The project management team must continually monitor the schedule, risks and project spend to ensure these key metrics remain on track. It may also be necessary to accommodate changes to the project scope, cost or schedule, especially where a CGT process is still in development and manufacturing changes might be required.

Validate:
As construction comes to an end with all equipment and systems installed, the final Validate phase of the project can proceed. This phase is aimed at commissioning and qualifying manufacturing equipment, facilities, systems and utilities. It is critical to confirm that all elements of the new facility have been installed appropriately and operate in accordance with specified, pre-defined criteria. A team of commissioning agents may be hired in to work alongside the company’s manufacturing staff, to start up the facility and its equipment, gaining familiarity with the new systems that will be routinely operated after project handover. The project manager coordinates progress during the Validate phase, obtains resources and ensures that a logical sequence of start-up activities is planned and executed. Modifications may be required to successfully complete all qualification and validation tasks. Once completed, the capital project is finished, and the facility is handed over and available for beneficial operation. In addition to the main capital project, there will usually be several supporting operational projects to be executed in parallel, which are key to the successful start-up of the new facility. For example, recruitment of the staff needed to operate the new facility, training, technology transfer from a sending unit, regulatory activities to achieve licensure, supply chain management for raw materials and single use components, contracts for external analytical testing, set up of maintenance and calibration contracts etc. The project manager plays a key role in coordinating these supporting projects to align with the delivery of both the new facility and the overall program delivery strategy.

Managing High-Performing Project Teams
A CGT project relies on the effective contribution of many team members. The project manager must ensure that the team is resourced, supported and coordinated effectively. The project team will include the CGT company’s representatives for the different disciplines involved, such as Process Development, Manufacturing, Quality, Facilities and Engineering. External to the CGT company will be a number of key consultants, suppliers and contractors. The project team structure should be designed to maximize team collaboration, avoid silo working and ensure good communication between parallel work streams. A strong communication strategy with regular reporting, team meetings and progress tracking are vital. The design and construction organizations should bring strong project management, communication and leadership skills to the team - and these resources should be leveraged as part of the overall project organizational structure by the CGT company’s project management team.

Additional project stakeholders will include senior management from the CGT company and from key suppliers such as the design and construction management firms. Steering meetings provide a regular strategic-level overview of project progress and an opportunity to escalate any issues that require senior team decision making or resolution.

Overall, the project manager must ensure that the team and wider stakeholder representatives are aligned on the project objectives and coordinated in their work activities. Well-executed projects maintain focus on critical success factors by achieving and maintaining close alignment and communication across a broad team of experts.

Conclusion
The project manager plays a crucial role in delivering CGT capital projects and must focus on the technical, regulatory and commercial aspects of the project to achieve success, working with a diverse set of project team members to coordinate multiple activities across the project lifecycle. Dark Horse Consulting Group offers a range of project and program management services for CGT projects of all types, with deep experience in the planning, design, construction, qualification and operation of CGT facilities.