CASE STUDY 1
The first case study describes the implementation of LEAN in a large-scale cell-culture facility, with three independent manufacturing
lines using 3,000-L and 10,000-L bioreactors. The facility is used to produce clinical active pharmaceutical ingredient (API)
material, primarily for Phase 2 and Phase 3 trials, of various biopharmaceuticals in development. Several product-to-product
changeovers are performed every year in each line, resulting in a significant "loss" of total plant capacity. This facility
also hosts technical development activities, in laboratories adjacent to the clinical manufacturing lines.
Objectives and Results
Following the LEAN assessment, several specific projects were defined to increase the throughput rate, decrease throughput
time, and enhance the "right first time" level. In this article, we have focused on the first two metrics.
Throughput Rate. There are obviously numerous factors that can influence the throughput rate. For this specific facility, changeover activities
were identified as having a major impact on this metric, leading to the following objectives:
- Accelerate batch-to-batch changeover.
- Accelerate product-to-product changeover.
Table 1 summarizes the baseline, practical vision, and achieved values for these two types of changeover activities. Under
the baseline conditions, about 27% of the total yearly plant capacity was lost as a result of changeover activities. If we
could achieve our practical vision target, we could reduce this capacity loss to <10%. At the end of the project, we were
able to show that we could perform batch-to-batch and product-to-product changeovers in 0.55 day, corresponding to less than
3% of the yearly plant capacity. It should be noted, however, that in reality, before one can achieve such fast changeovers
in a sustainable fashion, the duration of each batch must be perfectly synchronized with the timing of inoculum preparation
of the next one. This requires reproducible and robust cell-culture processes.
Table 1. Summary of the changeover acceleration project (case study 1).
To achieve this result, each individual task performed during changeovers was evaluated, focusing on possibilities and consequences
to shorten them, cancel them, or schedule them differently (details not shown). Each beneficial change was then allocated
to one of the four following categories:
- low risk (regulatory, business, etc.), no investment
- low risk, low investment
- high risk, low investment
- high risk, high investment.
The combination of the first two categories was found to bring the most significant improvement in the changeover time and
thus led to the changeover time of 0.55 day. In brief, the main changes were:
- radical optimization of cleaning-in-place and steaming-in-place operations
- acceleration of several testing procedures
- acceleration of probe calibration.
The third and fourth categories were not retained, because they brought only modest additional improvement while bearing significant
As a result of this shorter changeover time and of streamlined maintenance activities (mostly performed in "hidden time,"
not shown), the proportion of the yearly plant capacity available for production was raised from 68.4% to 94.9% (Figure 2).
Throughput time can be defined in different ways depending on the scope of activities. For clinical manufacturing, we defined it as the cycle
time, i.e., the total time to produce the first clinical batch, starting with technical transfer activities from the process
development group. As the first LEAN milestones, the following specific projects were started:
- Minimize the lead time for the first supply of raw materials at the beginning of each campaign.
- Accelerate technology transfer activities.
The discussion below focuses on the second project.
Specifically, the goal was to reduce the generation of batch record templates and operations instructions from 14 days to
7 days with the same manpower. For this purpose, a second objective was set to reduce the total size of documents (i.e., some
intermediate transfer protocols, the process description, the batch record templates) significantly. Table 2 summarizes the
baseline, practical vision, and achieved values, showing that both objectives were met.
Table 2. Summary of the technology transfer acceleration project (case study 1).
Several improvements at different levels were implemented to achieve this result. In brief, these were:
- using generic templates
- eliminating wastes: redundant information and information not relevant to the process was systematically removed. Information
constant in all projects was systematically incorporated into standard operating procedures (SOPs). Intermediate transfer
protocols were eliminated.
- organizing regular face-to-face meetings among representatives of the development, production, QC, and QA departments.
- stringent monitoring of timelines, to maintain the "drumbeat."
In addition to a 50% reduction in time and a 25% reduction in document size, we have identified other business benefits, which
are more difficult to quantify, such as: clearer responsibilities during technology transfers, better transfer of know-how
from development to clinical manufacturing, earlier involvement of QA, with critical issues addressed sooner, and clearer
adherence to timelines.