Case Studies in Pharmaceutical Project Management

Effective project management is an invaluable competency in a successful outsourcing relationship. Catalent Pharma Solutions, SAFC, and Neuland Laboratories, offer examples of successful project management, respectively in blow/fill/seal operations, viral-product manufacturing, and real-time project management in API manufacturing.

Project management underpins successful relationships between contract technology and service providers and their sponsor companies. As pharmaceutical companies increase their level of outsourcing, it becomes increasingly important for contract technology and service providers to provide not only the technical capabilities needed to execute a given project, but the management skills to deliver a project on time, to specifications, and with the necessary communication to prevent or mitigate project delays. To illustrate the importance of project management in outsourcing, several industry members provided case studies on how to coordinate, organize, and implement a successful project. Participating in this technical forum on project management are Norman Weichbrodt, strategic account manager at Catalent Pharma Solutions; Nick Johnson, marketing manager at SAFC; and Saharsh Rao Davuluri, president of contract research at Neuland Laboratories.

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Blow/fill/seal manufacturing

Norman Weichbrodt, strategic account manager at Catalent Pharma Solutions

Catalent Pharma Solutions is a provider of drug and biologic development services, delivery technologies, and supply solutions. Effective project management is the cornerstone of being a complete provider of services ranging from development of new products to technical transfer of existing products. Building the proper project team and employing the correct methodology for handling a complex project is the foundation on which success is achieved.

In July 2010, Catalent was approached by a major pharmaceutical customer to transfer an ophthalmic product approved for sale in Europe to Catalent's blow/fill/seal (BFS) manufacturing site in Woodstock, Illinois. The successful technical transfer of the manufacturing process for this product would potentially lead, following FDA approval of the product already made in the European facility, to approval of the drug for manufacture and sale in the United States.

Project scope. The actual scope of this project was much larger for the Woodstock facility than a simple technical transfer. The project required the following:

• A complete renovation of a formulation and filling suite, including a new separate air-handling system

• Designing, building, and qualifying an automated formulation skid

• Upgrading an existing BFS filling machine to match the capacity requirements for the product

• Designing, building, and qualifying new vial molding and filling systems to duplicate the existing European design

• Qualifying the room, formulation skid, BFS machine, and secondary packaging to produce stability and process-validation batches to support the customer's submission and approval timeline

• Developing and approving the required documentation for supply-chain, manufacturing, and quality assurance functions to meet the production timeline

• Analytical-method transfer for chemistry and microbial testing

• Complete process-validation protocols, test plans, and final reports to meet the submission timeline.

Cross-functional teams. To manage a project of this scope, the Catalent New Product Development (NPD) group and the site-management team agreed to form a group of cross-functional resources. The team members served as the primary representative of their functional area for the project and were assigned for the duration of the project. The project team consisted of a project manager from NPD, an engineering project manager, a development scientist, an operations specialist, a validation specialist, a quality-assurance product specialist, a technical writer, and various contract resources as required. A strategic account manager had overall responsibility for the project team. The establishment and use of an expanded core project team of cross-functional resources was a new approach for Catalent's Woodstock facility, but the scope and timeline for this project and the Catalent goal of meeting customer needs required an innovative solution.

The project was divided into six major activities: the room, the formulation skid, the BFS machine, method transfer, secondary packaging, and documentation. The NPD project manager was the owner of the overall project timeline. Each major activity was included in a Microsoft project schedule and maintained by the project manager. The engineering project manager handled all activities involving the renovation of the filling suite, making use of contractors from design through construction and qualification. He also participated in the design and construction of the formulation skid, primarily focusing on the software development. The development scientist and the operations specialist focused on the design of the formulation skid and the interface of the skid with the BFS machine to ensure the system had the proper design and controls to replicate the process already being used in Europe. The validation specialist developed the installatoin qualification, operational qualification), and product qualification protocols and had oversight of all factory acceptance testing (FAT) and site-acceptance (SAT) activities. The technical writer and the quality-assurance product specialist worked with the NPD project manager to manage the change-control process for the project and to complete all the required documentation, including material specifications, standard operating procedures, and manufacturing batch records. The NPD Project manager also provided oversight of the analytical method transfer, development of secondary packaging materials, and the documentation of project activities.

Technology transfer. The technology-transfer process was initiated by creating a comparability document that detailed every aspect of the manufacturing process. The process used in the European manufacture was listed step by step in the document with Catalent's suggestions and capabilities side by side. A final agreement for each step was included and served as the approved path forward. The specifications for in-process testing at each stage of the formulation as well as finished-product specifications were included in the document. The formulation process required bulk sterilization of a multicomponent polymer base with a relatively tight viscosity range. Two APIs were combined in a second part of the formulation and transferred to the polymer solution by sterile filtration. Of course, the entire formulation skid required steam sterilization of the product path through the BFS machine and maintenance of the sterile boundaries for the product during the entire filling process. Electronic documentation of all temperatures, times, and controls for each process step also were also required.

Communication. The NPD project manager and the strategic account manager facilitated weekly calls with the original equipment manufacturers of the formulation and BFS equipment as well as construction meetings during that phase of the project. Weekly calls were held with the customer representatives who were in liaison with the project team. A standard methodology was used to ensure that the meetings had a structured agenda and minutes issued for review in a timely fashion. A joint Project Steering Committee was formed, which was comprised of customer senior leadership members, Woodstock site leadership members, and Catalent business-development members.

Project Steering Committee meetings were held every three weeks during the course of the project. A formal presentation was made at each meeting to discuss progress toward major milestones in the project plan. Strategic decisions were discussed and developed through the Project Steering Committee meetings, and the decisions were ultimately made by the joint project team. This management design reduced the cycle time for critical decision-making between the customer and Catalent.

Figure 1 (Catalent): A blow/fill/seal suite at Catalent’s Woodstock, Illinois, facility. (FIGURES 1-3 (CATALENT) ARE COURTESY OF THE AUTHOR)

An example of such decision making was approval of a change to the SAT/FAT strategy originally planned for the formulation skid. The formulation skid is a fully automated two-tank system with over 100 control and process valves that are actuated in approximately 20 sequences. When the software development lagged behind the construction of the hardware, the opportunity arose to do a mechanical FAT, ship the formulation skid to the Woodstock site, complete the installation and mechanical troubleshooting of the skid and wait for the software to complete the qualification as a SAT. This decision saved as much as six weeks in the project schedule and enabled Catalent to meet the customer's timeline for stability and process-validation manufacturing. It also resulted in a formulation system that is part of a robust technical transfer process from the customer through the NPD group to Catalent's commercial manufacturing team.

Execution. To date, all of the engineering, stability, and process-validation batches have met the in-process and final-product test specifications. With nine batches produced, there have been no out-of-specification results for bulk or final product. In addition, no human error deviations have occurred in the formulation and filling of these batches.

Figures 1–3 (Catalent) show the facility upgrade and project equipment after installation.

Figure 2 (Catalent): A blow/fill/seal cavity fill machine at Catalent’s Woodstock, Illinois, facility.

In summary, Catalent did not employ new or groundbreaking methodology for this project. However, supplying the proper structure and resources for a project team is the crucial first step in meeting a customer's timeline and supplying the customer with quality product, reliably supplied.

Figure 3 (Catalent): A fully automated formulation skid at Catalent’s Woodstock, Illinois, facility.

Viral product manufacturing

Nick Johnson, marketing manager at SAFC

This case study in project management involved the partnership between SAFC and Oncolytics Biotech, a biotechnology company headquartered in Calgary, Canada, which has developed a novel cancer treatment, Reolysin, based on a modified wild-type reovirus expressed in suspension-adapted human embryonic kidney cells (HEK 293). In 2007, Oncolytics partnered with SAFC's Carlsbad, California, site as part of the commercialization process for Reolysin. After officially announcing SAFC as the contract manufacturer for the project in early 2011, Oncolytics announced in November 2011 that validation studies were underway. Now in Phase III clinical trials, SAFC and Oncolytics have worked as partners to manage this project from the initial phases of identifying how to make the technology work through to making the consistent batches required for licensure. The current goal is to obtain a successful regulatory approval for Reolysin.

Project challenges. The production of the modified reovirus presented a significant manufacturing challenge. Not only was it going to be the first time for this type of product to be made on such a large scale, it also involved transferring technology from a contract development organization (CDO) in Canada to the SAFC site in Carlsbad. At the beginning of the project, there were four partners in different locations, including Oncolytics, its CDO, SAFC, and SAFC Biosciences in St Louis, which developed the novel media used in the production process.

SAFC Carlsbad already was filling the bulk product for clinical trials out of a product that was being made at another CMO in the United Kingdom. As the product progressed into later-stage clinical trials, the production was ramped up and transferred to Carlsbad, at first on a 40-L scale, and up to the present 100-L batches. The technology transfer was a whole new ballgame in terms of scale and complexity and required a new project team to be formed. On the SAFC side, this included a director of operations plus senior managers in manufacturing, quality assurance, quality control, and project management. Business-development support was also brought in when new scopes of work and new contracts needed to be worked out and finalized.

Despite the disparate locations, the communication between the teams in the different sites worked well with routine weekly conference calls and many coordinating activities carried out electronically. Some face-to-face meetings were essential, including the manufacturing representative and project manager visiting the CDO to address process scale-up. A week also was spent with all partners, including the CDO, watching the process and filming it so that it could later be used for operator training in Carlsbad.

The whole process took quite some time with many technical challenges, leading to a stop–start of operations from late 2008 through to 2009. By the end of 2009, however, sufficient clinical material had been made to continue with the trials, so there was less urgency from that perspective. Once the 100-L scale was reached, one or two batches were made per year until the program was ready to initiate process validation batches. Now that the product has advanced to conformance batches, three to six batches will be made per year.

Tracking progress.From a production standpoint, Gantt charts (i.e. charts used to show the project's schedule) are used for all SAFC projects. They are mapped out further than just a single department and include everything that might affect the timeline from the vendor through to the customer. The anticipated timings were all shared with the customer as well as the troubleshooting of possible technology-transfer issues that the technical team mapped. The team was tasked to look through historical data from the previous partnership to identify where there were areas for improvement and to help resolve issues quickly with input from both the SAFC team and the CDO. Specifically, SAFC Biosciences also helped by developing a custom growth media that increased the viral productivity and eased the purification process.

When SAFC inherited the contract, it already contained the required specifications that were used as an ultimate metric for success. The new goal became making and purifying the product to the required level for a commercial launch. After a number of changes to the process on the CDO's side and a few creative manufacturing approaches from SAFC, these specifications were exceeded and brought the project to the current point. Oncolytics is now in a position where accessing materials for its clinical needs is no longer a constraint, and the project has advanced into process validation in anticipation of commercial launch.

Issue resolution. One issue the team faced was the presence of an impurity that prevented the product from meeting specifications. The teams were brought together, and all the possibilities that might have led to the impurity were considered. From there, action items were distributed to the teams for them to pursue, including the review of historical data. This approach was successful as by the time of the next team meeting, the problem had been pinpointed. By adapting the process for the next batch slightly, a solution was found allowing the product to met specifications and the issue was resolved.

A key factor in the overall project's success was the customer relationship. In addition to the customer having a very good project manager, the relationship was developed based on trust and a common goal. Another key factor was ensuring that we had the resources needed to move the project forward. When the program moved into the process-validation phase, a second project manager was added to increase bandwidth. The way all parties worked together allowed the manufacturing to enter into conformance batches within a relatively short period of time with only a limited number of clinical batches having been completed.

Real-time project management

Saharsh Rao Davuluri, president of contract research at Neuland Laboratories

On-time execution of API project development is a challenge for manufacturers. Neuland Laboratories has designed its GuarD project-management system around the principles of critical chain project management (CCPM), a concept developed by Eliyahu Goldratt, a prominent management consultant, who introduced the theory of constraints business model. Unlike other project-management systems, CCPM emphasizes flexible start dates and shared project resources. CCPM also uses buffers as a shared project resource rather than an individual task resource, thus enabling the overall project to be completed on time without requiring the individual tasks to be completed on time.

Process and organization. Neuland is an API and contract manufacturer based in Hyderabad, India. Almost 80% of the company's products are sold into the US and European markets, and these product must meet strict regulatory standards. In a typical year, Neuland scientists complete 30–40 projects ranging from complete API development, production of starting materials, and development of alternate processes for new molecular or chemical entities, as well as a variety of contract-manufacturing assignments for pharmaceutical ingredients and peptides. Depending on their complexity, projects may require process chemistry, analytical chemistry, technology transfer, production, developmental quality assurance, supply-chain management, regulatory affairs support, and project-management services.

Figure 1: (Neuland). A screenshot illustrating how a project’s progress can be tracked and how a user can participate directly through the GuarD web portal. (FIGURE 1 (NEULAND) IS COURTESY OF THE AUTHOR)

Organizational framework and real-time monitoring. Under GuarD's CCPM approach, each project is broken down into its basic tasks by a cross-functional team. The project has a designated team leader, usually an experienced scientist from the process-chemistry department, and a project manager responsible for managing timelines and communications. The team leader is the technical head of the project and responsible for overall execution.

Once the project has been divided into the basic tasks and sub-tasks, the details are transferred to a Microsoft project software template. This ensures that all the dependencies, resource requirements, and tentative start and end dates are recorded. The project is not considered "live" until the cross-functional team signs off on the detailed project plan. The finalized project document is uploaded to a web portal, and managers update respective tasks and sub-tasks as the project progresses. Managers can make qualitative updates detailing how tasks are proceeding, or quantitative updates to help respective task managers track how long a task will take to complete. Teams are encouraged to make at least one status update per day.

The ability to make both qualitative and quantitative updates in the GuarD project-management system is highly useful. Personnel in downstream operations, and more importantly the client, get an accurate picture of progress upstream and can plan accordingly. Neuland's customers also can track a project's progress and participate directly through the GuarD web portal.

Benefits. A key advantage of the GuarD system is that its detail and interactive nature make it easier to promptly identify and manage delays at any step, thereby facilitating on-time completion. For example, when the process-chemistry department requires more time to complete their tasks, the project manager is immediately aware of the situation and can work with all task managers to identify opportunities downstream to recover that time. Although it is important for the project manager to investigate the reasons for the delay, the immediate focus is on finding ways to deliver a quality project on time. Solutions might include running additional shifts or vessels or staggering batches. In most cases, customers are invited to join these discussions and contribute to the solution based on their experience and priorities.

Neuland's project-management system helps its clients in several ways. It provides a platform of almost 100% transparency, providing more insight than weekly calls or project reports. A smart phone app will soon allow customers to access their projects real-time. It also enables higher on-time completion rates. Although the GuarD approach cannot promise 100% on-time completion, it has enabled Neuland to make considerable progress towards this goal.

Customer trends: biopharmaceutical companies