DEFINITIONS

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.

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.

GAINING EFFICIENCY THROUGH TECHNOLOGY PLATFORMS

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.

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.