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Achieving multiproduct development within shortened timelines.
The pharmaceutical industry accounts for about $65 billion of annual expenditure in the US. Each day of product development costs approximately $1 million in expenses and at least $0.5 million in losses from not having yet commercialized that product. These costs are anticipated to nearly double between 2008 and 2012 because of the projected increase in the costs of human and material resources and of meeting regulatory expectations. As a result, improvements in process efficiency and delivery become of paramount importance for a viable business. Process development (PD), technological, and learning capabilities are even more critical for efficiency in commercializing complex biological products (1). In the current economic environment, additional pressure to increase efficiency arises from the need to advance multiple projects through the pipeline without increasing resources.
The development of chronic therapies for rare diseases proceeds differently than the typical pharmaceutical development paradigm. A two-cycle approach (see Figure 1) is used for clinical development of therapies for rare diseases, which includes a safety and dose-finding Phase I and II clinical study followed by a pivotal Phase III clinical trial. Unlike a typical three-phase clinical development program (a Phase I safety clinical study, a Phase II dose-finding study, and pivotal Phase III trials) where manufacturing process changes are typically introduced at the initiation of each phase, the contrived breakpoints of a two-cycle development model create a higher need to perform PD in advance so that a commercial process can be introduced into the pivotal trial within approximately three years instead of the more common five to six years. Process changes are more difficult to introduce as there are not multiple clinical programs by which clinical experience with the new process can be gained. Introducing postcommercial changes which might affect product quality are even more difficult because of the limited number of patients with these diseases in whom clinical comparability trials can be conducted. The low patient numbers often result in the manufacture of a small number of batches to supply clinical studies and market needs, leading to limited data at the time of commercialization and limited time for the manufacturing group to become experts. The shortened overall development timelines and the small quantities needed result in a greater reliance on development-scale studies to support manufacturing, stability programs, and specifications at the time of licensure.
Figure 1: Two-cycle development process used in development of enzyme replacement therapies for rare genetic diseases. The typical pharmaceutical product development consists of three clinical development phases: Phase I (safety), Phase II (dose-finding), and pivotal trial Phase III studies, providing time for three-cycle sequential process development and the implementation of manufacturing changes at the initiation of each phase. For rare diseases, the clinical development is often condensed to two phases as depicted in this figure: a safety and dose-finding combined Phase I and II followed by a dose verification and pivotal trial PII/III study. The shortened time and limited number of clinical studies results in two-cycle overlapping process development, where the commercial process is developed during tech transfer and implementation of the Phase I process, and requires rigorous front-loaded process development activities.
To manage the constraints and increase the efficiency of this two-cycle approach to product development of highly glycosylated proteins for rare diseases, the the following three steps were taken:
1. Technology platforms were developed that were linked to manufacturing capabilities and built on the knowledge gained with each enzyme replacement therapy (ERT) development. Developing process and analytical technology platforms for the highly glycosylated lysosomal enzymes transformed the initial trial-and-error development model to a more cost-effective strategy by establishing a small-scale model in the PD department to represent manufacturing scale.
2. A systematic and integrated approach to PD, called the PD life cycle, was applied to define the appropriate questions and issues to be addressed at the appropriate time within the clinical-development program. Starting the PD life cycle by determining the technical feasibility of product and process targets, followed by refining the targets and development plans based on the knowledge gained at each phase, enables the efficient use of resources and minimizes rework while improving the ability to handle multiple programs in a consistent manner.
3. Business processes were developed and applied for integrated PD planning, decision making, and communicating with stakeholders.
Through the use of the above mechanisms, knowledge gained from the commercialization of one product has increased the efficiency of development of the next product, resulting in continuous improvement. This article describes this three–pronged approach to ERT product development. These concepts can also be applied when developing other types of pharmaceutical products.
Two–cycle product development: Condensed clinical trials consisting of combined Phase I and II to assess safety, pharmacokinetics, and dose-dependent pharmacodynamics, and Phase III to assess efficacy, instead of discrete Phase I, Phase II, and Phase III clinical studies.
Product development phase: Clinical trials leading to commercialization of a new drug are typically classified into three phases, each requiring regulatory approval before proceeding to the next: Phase I assesses safety, tolerability, pharmacokinetics, pharmacodynamics, Phase II assesses safety and dose-ranging efficacy in a larger population, and Phase III assesses definitive efficacy of the drug.
PD life-cycle stage: Structured approach to PD consisting of four stages of defined studies to address the needs of the given product development phase and increase predictability of success at manufacturing scale. The stages are technical feasibility, development, optimization, and confirmation or qualification.
Target process and product profile (TPPP): Detailed, desirable targets for process (e.g., titer and yield to meet manufacturing capacity and supply demand needs) and for product (e.g., protein concentration, excipient, and product quality to meet the dose and administration route requirements for the given patient population). Upon completion of PD optimization, the final (actual) process and product profile (PPP) is defined.
Although process technology platforms have been established for manufacturing monoclonal antibodies over the past two decades, such benefit was not available for other protein products such as ERTs. This section summarizes the evolution and effect of PD platforms established for these complex enzymes to accommodate accelerated development. Such platforms allowed efficient PD and predictable scale-up performance.
Glycosylation is critical to targeting the cellular uptake of lysosomal enzymes and their localization into lysosomes, requiring the development of platform process technologies to generate such highly glycosylated proteins. One of the systems used for expressing these glycoproteins was a human cell line (2, 3). Expression in human cell lines required building knowledge to improve titer, to grow cells in suspension, to control critical attributes, and thereby to increase production yields and tighten process controls. The cell culture process changed from roller-bottle to bioreactor process, thus leading to increased yields and better process control. The bioreactor cell-culture process could be conducted in either batch or perfusion mode, depending on factors such as the stability of the enzymes in the culture media and the desired product output. Animal-derived serum or plant hydrolysate initially used in the cell-culture media was later replaced with chemically defined media to ensure consistent raw materials and control of the process. To this end, the cell lines were adapted from an attached line on roller bottles to suspension culture, first on microcarriers, and eventually free of any carriers. These combined changes were implemented over three years and consumed approximately 25 PD full-time equivalents to accomplish. Applying the cumulated process knowledge to build process platforms led to efficiency in development time and lower cost.
Simultaneous measures for standardizing PD were introduced during the past eight years. Rapid screening of chromatographic resins is now performed to more efficiently identify suitable resins and initial conditions. Although each process must be adapted to the unique features of each enzyme, a standard purification process flow has been established; for example, an initial capture step, one or more viral inactivation steps, chromatographic steps, and ultrafiltration or diafiltration steps. In the purification area, small-scale models were developed to systematically learn about the effect of upstream and downstream processes on product quality. To accommodate the large number of samples generated by the process groups, the analytical strategy had to be revised. A decision was made to invest in robotics. Robots were subsequently adapted to perform analytical methods, such as enzyme-linked immunosorbent assay and enzyme-activity assay determinations, at a throughput of approximately 2000 samples per week.
The organizational structure was changed to define a centralized unit dedicated to supporting PD testing, to remove the conflict between development and routine testing activities. Systems were defined to accommodate sample-in, data-out for multiple projects from multiple stakeholders. Such investment and restructuring allowed for an order of magnitude increase in the sample testing throughput (see Figure 2). Additional automation was introduced in the bioassay development to speed up analytical optimization while addressing the complexity and variability in such assays. The overall effect of the combined changes was a doubling of PD capacity for developing multiple complex enzymes at a time.
Figure 2: Outcome of organizational redesign to enable faster process development (PD). Sample throughput was increased by orders of magnitude by centralizing dedicated analytical resources to support process development and introducing robotics. These changes enabled development of multiple products in a systematic and more efficient manner. This organizational redesign freed up resources in cell culture and purification PD, allowing analysts to focus on process, and enhanced the efficiency of the analysts by not requiring them to divide their time between development and routine testing priorities.
A key component of enhanced PD effectiveness was the technical problem-solving approach that provided feedback about gaps between the desired and the actual performance at manufacturing scale. Basic knowledge about the process–product relationship was gained during a decade of developing ERTs, initially through trial and error, later through using previous knowledge to design small-scale or pilot-scale studies that would predict process performance and minimize rework at the manufacturing scale. Specifically, a large-scale development laboratory at pilot scale was built to verify the lab-scale studies before implementation at the manufacturing scale. Small-scale and pilot-scale studies to characterize the process and to define the design space, process parameters, and process ranges also provided more efficient and effective mechanisms to resolve manufacturing investigations.
Efficiency in PD can be gained by a standardized approach to studies that answers the right questions at the right time, taking into consideration the interdependencies between the different product development functions, including the four PD disciplines for biological products: cell culture PD, purification PD, analytical development, and pharmaceutical development. Although the general questions asked at each product development phase are similar for all projects, the specifics vary depending on the properties of the molecule and the development strategy. This standardized approach aims to optimize the output in terms of overall process/product development rather than optimizing each separate discipline.
Figure 3: Key elements of process-development (PD) life cycle. The four stages of PD life cycle are depicted on the top left insert, illustrating the exploratory nature of the technical feasibility stage and the increasing predictability of technical success through the other stages as knowledge is gained. The intent and outcomes of each stage are listed on the top half of the schematic. The bottom half depicts the clinical-phase dependent application of each PD life-cycle stage; the time spent in each stage is not drawn to scale (see Figure 4 for scaled timing). Technical feasibility stage is when the boundaries of development and its limitations are defined (square symbol), development stage is tied to the scope/resource/quality (triangle symbol), optimization stage renders the final conditions (star symbol), and confirmation and qualification stage is when successful implementation of the final process is demonstrated (check symbol). Process characterization and other biological license agreement-enabling studies are done in preparation for process validation and subsequent commercialization of the product.
Shire's PD department created a PD life cycle that structures development studies into stages according to the needs of each product development phase. Figure 3 depicts PD life-cycle stages with key purpose and deliverables. The cycle starts with a draft TPPP based on customer input to meet the development program's strategy. The exploratory stage of technical feasibility assesses the technical hurdles to achieve these targets. The technical hurdles may require refinement of the program's strategy, including changes to targets or timelines. The predictability of development success increases during progress through the subsequent stages of the PD life cycle because the process–product knowledge base is increased. The definitions of the PD life cycle stages are as follows:
In anticipation of product commercialization, process-robustness studies are conducted to finalize the design space, denoting readiness for process validation. Studies are then conducted toward submission of a license application, including such information as impurity clearance, photostability, and complete product characterization.
The PD life cycle is designed to guide the efforts and resources needed by asking specific questions from the four PD disciplines at each stage and by critically reviewing the outcomes as an integrated result before moving to the next stage. The questions asked from each discipline at each stage must relate to the other three disciplines. For example, proceeding from the development stage to the optimization stage for the cell-culture process requires demonstrating that the material can be purified by a prototype process and meet the targets for process yield and product quality. In this example, a "go" decision to proceed to the optimization stage for cell culture development discipline is not solely based on cell-culture performance, but rather is based on the integrated PD life cycle evaluation by purification and analytical disciplines, obviating potentially wasted efforts in cell-culture development if the material from cell culture does not meet the overall targets of the other two disciplines. The relative duration of each stage is depicted in Figure 4.
Figure 4: Relative durations of process development (PD) life-cycle stages. The length of time spent in the life-cycle stages varies depending on the development phase. Early on, more time is spent on technical feasibility. As process and product knowledge are gained at later clinical phases, more time is spent in optimization. The type of development work as part of the product life cycle may vary from full development (e.g., going from a serum-containing roller bottle process to an animal-free bioreactor process) to a narrower scope (e.g., manufacturing site change, scale change, additional drug product presentation). The total duration of a development program is dependent on the details of the program.
To better coordinate the generation and execution of an integrated development plan, a structured PD team (PDT) process was established. Each team consists of a representative from each of the four disciplines (i.e., cell culture, purification, analytical, and pharmaceutical development) and from manufacturing technical support. Each team has a leader and a project manager; these individuals are responsible for driving the planning, coordinating activities, and tracking execution against the goals. The team leader is responsible for driving decisions, mitigating problems, and representing the process develpment department at higher level teams, such as CMC teams. One PDT is designated to champion each development program. The teams are sponsored by PD management, who provide strategic input into the project plans, and align and prioritize resources across projects.
Figure 5 depicts the PDT process for planning, prioritization, execution, and communication. Based on the inputs from external and internal stakeholders, the PDTs develop an integrated PD life cycle plan for each project, including detailed milestones and success criteria for each stage. The plans, the status, and the decision points for all teams are reviewed and prioritized by PD department management as the plans are being executed by the line functions. Periodic review of status and risks facilitate timely cross-functional decision making, raise awareness of current program problems, and provide cross-functional learning. The deliverables are also communicated or provided to external stakeholders in the appropriate forums, who might then give additional input.
Figure 5: Process development (PD) team business process diagram. A structured business process allows for consistent planning, prioritizing, and delivery on multiple programs in a resource-constrained and time-limited business. The inputs into process development work (top box) come from a wide range of stakeholders (right tall box) and vary in scope from product development strategy to a specific request such as responding to a regulatory question. The inputs are organized into an integrated process development plan with key goals and milestones (beginning of cycle). The PD teams drive compilation of such goals and milestones and integrating them into a detailed plan through iterative coordination with line functions. Work is prioritized and resources allocated by management and executed by functions. The team updates are one of the outputs of the team, which are periodically reviewed for strategic guidance or realignment as needed. Data, recommendations, and materials are other team outputs that are provided to the stakeholders to complete the circle of product-development interdependencies.
The effectiveness of PD is enhanced by establishing team structures, optimizing business processes, developing clear expectations for roles and responsibilities, and committing the organization to build, train, and mentor strong teams as centers of excellence in product development.
PD can be the leverage in product development performance where the speed and effectiveness of learning from each program to develop and implement process technologies can shape the overall cost, timelines, and results of new product introductions. PD life cycle planning enables a disciplined approach to PD for a given product and facilitates learning across programs to minimize rework. Establishing an integrated approach among the four disciplines of PD to answer critical questions early in the development cycle ensures timely and appropriate adjustments to the overall program plan and better use of resources. The development and application of process platforms with small-scale models that are predictive of manufacturing-scale performance leads to cost effective product development. Establishing a business process that facilitates integrated planning and decision making is a precursor to well-coordinated execution. Overall, PD life cycle planning, combined with continuous business process improvements, allows for efficient delivery within the fast-to-market complex biological product development paradigm.
The evolution of process platforms has been a result of the efforts led by Yas Saotome, previous head of cell culture process development at Shire (currently at Alexion Pharmaceuticals) and David Nichols, head of purification process development. The analytical automation technologies were introduced by the immunoassay and bioassay group (Jeffrey vanDoren and Laura Trubiano, led by Brian Lentrichia). The authors acknowledge the inputs into the PD life cycle by Chun Zhang (current head of cell culture process development), David Nichols, PD project managers (Jennifer Puhlhorn and Jennifer Terew) and Walter Uchendu. The insights of Matt Croughan, Rathmann Professor at Kegg Graduate Institute, on the process development learning modes are highly appreciated.
Zahra Shahrokh is currently senior vice-president at Aurabiosciences, and Marcio Voloch is currently a biotechnology consultant.
Zahra Shahrokh* was senior director, pharmaceutical and analytical development, Stacy Price* is director, process development operations, and Marcio Voloch was vice-president, process development, all at Shire Human Genetic Therapies, Cambridge MA. *To whom correspondence should be addressed, email@example.com or firstname.lastname@example.org.
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2. J. Muenzer et al., Genet. Med. 8 (8), 465–473 2006.
3. Y.H. Xu, et al., PLoS ONE 5 (5) e10750, 2010.