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 2

Introduction

The second case study describes the implementation of LEAN in a large-scale commercial cell-culture facility, with six 14,500-L bioreactors. At the time of the LEAN project, the facility was used for one monoclonal antibody product only, with ample capacity to meet market demand. However, the facility was intended to be used for large-scale clinical manufacturing campaigns, too, and eventually for commercial manufacturing of additional products. There were thus strong incentives to improve capacity utilization.

Objectives and Results

Besides the throughput time, throughput rate, and failure rate, two metrics have been added to the scope the LEAN project: production yield and the "overall asset effectiveness", i.e., a measurement of the part of the plant capacity which effectively can be used for manufacturing activities. Only the first metric is discussed below.


Figure 3
Throughput Time. In this example, the definition of throughput time was different from the one used in case study 1. It was defined, for each batch, as the time from the start of upstream processing until release by QA. Figure 3a shows the activities included in the throughput time, along with average duration values. Batch record review and deviation handling obviously start in parallel with the manufacturing steps. Mycoplasma testing of pre-harvest samples is shown here because it is the assay with the longest lead time. To achieve the practical vision (Figure 3b), the goal was to reduce primarily the batch-record review, deviation handling process, and release activities. Some minor improvements were also targeted in upstream and downstream processing, with the condition that they would not have regulatory relevance.

At the end of the LEAN project, a throughput time of 74 days was achieved, not including mycoplasma testing. With this assay, which was contracted out and could not be significantly shortened, the average throughput time was 81 days (Figure 3c).

To achieve this result, the measures below were implemented. None had any regulatory impact. Their variety highlights one of the main characteristics of our LEAN approach compared with "traditional" improvement initiatives, i.e., a very systematic and comprehensive evaluation of all the possible ways to eliminate "waste."

  • improved planning, in particular improved timing of inoculum transfers
  • accelerated downstream processing operations by removing non-added-value steps, and shrinking CIP-steps (a 56% reduction)
  • streamlined in-process control activities
  • simplified batch record templates (50% shorter)
  • streamlined batch record review process (training of personnel and removal of non-added-value steps)
  • reduced number of deviations four-fold
  • streamlined deviation-handling process (by removing non-added-value steps).

The overall business impact was an initial 20% reduction in the API production cost. Further improvements can be realized with a higher capacity utilization of the plant. Furthermore, with the increase in the throughput rate from one batch per week to two batches per week, no headcount increase was needed.

Both LEAN projects (case studies 1 and 2) are being continued through a second wave of projects, such as the reduction of deviations, the reduction of unplanned maintenance activities, and the improvement of QC testing activities.

HOW TO CREATE A LEAN CULTURE

Personnel Qualification


Table 3. LEAN qualification level of a manufacturing site: target as a function of time
To ensure that LEAN is not treated as a simple one-time project in the various manufacturing sites and that instead a real culture of continuous improvement is developed, as foreseen by the TPS, we have first developed an ambitious personnel qualification program. We have three different levels of qualification (bronze, silver, and gold) and each consists of a theoretical part (technical tools, including Six Sigma) and a practical one. The pillar of the first level is a so-called "LEAN game," where LEAN principles can be tested on a simple mechanical assembly of plastic pieces. The higher levels include the execution of a specific LEAN project. One of these three qualification levels is attributed to each position in the plant and the goal is that eventually all employees will have gained the qualification level corresponding to their position. This operational excellence target is set to be achieved typically in five years, as illustrated in Table 3. The achievement level is regularly monitored as a KPI.

A new flat and cross-functional process-oriented organization


Figure 4
Orienting the organization around LEAN processes is a critical element to sustain operational excellence and a culture of continuous improvement. For this purpose, we have modified the organizational structure of our manufacturing facilities by introducing a flat and cross-functional "process-oriented organization" (POO), with only three hierarchical layers from the site head to the operator level. The main principle is the incorporation—ideally with physical co-location—in one process unit (PU), of all the functions (e.g., manufacturing, QA, QC, maintenance) needed to operate one or a set of manufacturing lines (Figure 4). The traditional silo-based departments or functions, with a "chain of command" hierarchy and a slow flow of information and general lack of flexibility, are eliminated. The POO culture is based on empowerment, self direction, innovation, flexibility, and customer focus. The main advantages are better support of the processes and thus the products. Problems are solved faster by multifunctional teams. Ideas for process improvements are also implemented quickly. Team members have the opportunity to continually learn new skills and broaden their responsibility.

For the successful implementation of a sustainable POO structure and culture, with the necessary new leadership skills, a multi-year change-management plan is needed, with the adequate level of training. A description of such a plan is beyond the scope of this article.


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