Harvesting the Benefits of LEAN in Biopharmaceutical Manufacturing - Practical examples of how LEAN was implemented in Novartis's biopharmaceutical manufacturing operations, showing the results achiev

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Harvesting the Benefits of LEAN in Biopharmaceutical Manufacturing
Practical examples of how LEAN was implemented in Novartis's biopharmaceutical manufacturing operations, showing the results achieved.


BioPharm International
Volume 22, Issue 10

CASE STUDY 1

Introduction

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. Summary of the changeover acceleration project (case study 1).
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.

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 risks.


Figure 2
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. 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.


Table 2. Summary of the technology transfer acceleration project (case study 1).
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.

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.


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