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
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.