GAINING EFFICIENCY THROUGH PROCESS DEVELOPMENT LIFE CYCLE STAGED PLANNING
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:
Technical feasibility stage: In this initial stage, the key technical hurdles are assessed and possible solutions identified. This is a problem-definition
stage that determines whether the overall program (i.e., the process and product targets) is feasible and what the development
path should be. The draft TPPP is refined based on the technical feasibility stage assessment to guide the development stage.
Critical thinking at this stage guides the use of resources and directs efforts to address the right question. More time is
spent on this stage during earlier phases of development than during late-stage development programs when further product
and process experience has been gained.
Development stage: In this stage, unit operations that would achieve the TPPP are defined, potential hurdles to scale-up are determined, and
technology transfer is facilitated. Because each process is linked to the manufacturing plant's capabilities, the facility
fit is assessed early to allow delivery of long-lead equipment and raw materials and to confirm the production schedule and
supply-chain plans. Analytical procedures are developed to support PD and product characterization. The development plan for
the given clinical phase is finalized.
Optimization stage: In this stage, the process operational parameters and test procedures for assay qualification are finalized. With finalized
actual PPPs, a process description is drafted. Critical process parameters and ranges are drafted. There is less optimization
during early stages than during late stages.
Process confirmation and assay qualification stage: In this stage, the PPP is demonstrated by running the process intended for technology transfer. This stage establishes technology
transfer readiness at all clinical development phases. Assays are ready to be validated.
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.