Harvesting the Benefits of LEAN in Biopharmaceutical Manufacturing

ABSTRACT

The LEAN manufacturing and management model, developed from the Toyota Production System (TPS), has triggered major transformations in various manufacturing industries. Implementation in the field of biopharmaceuticals, however, has been limited to date. We believe that properly implementing LEAN in biopharmaceutical manufacturing can bring huge benefits, despite the complexity of biotechnology and the stringent regulatory requirements. In this article, we provide practical examples to highlight the areas where such benefits can be achieved. We also describe our qualification concept and the implementation of a new flat and crossfunctional process-oriented organization in manufacturing sites, in line with TPS principles, to ensure the development of a "LEAN" culture—a culture of continuous improvement.

LEAN can be defined as a manufacturing and management model that aims to reduce the time from customer order to delivery by eliminating sources of waste and by making the product flow through value-adding steps without interruption. It is derived from the Toyota Production System (TPS), which Toyota started developing in the 1950s. TPS has helped Toyota become the largest and one of the most profitable car manufacturers in the world. An excellent and comprehensive presentation of LEAN can be found in the literature.^1,2 LEAN has since been implemented in many manufacturing industries, where it has triggered major transformations. However, LEAN has often brought only limited benefits. The first reason is that LEAN often has been implemented in a superficial manner, with a focus on "just-in-time" objectives only, without being understood as an entire system that must permeate an organization's culture.¹ Furthermore, direct applications in the field of biopharmaceutical manufacturing have been quite limited to date because of concerns about the complexity of the associated technology and stringent regulatory requirements. A few nice examples, however, have been published recently.³

Hermann Horvath/Novartis AG

We believe that implementing LEAN the proper way in biopharmaceutical manufacturing can bring huge benefits and help the industry to deal with increasing pressure on development and manufacturing costs, as well as with challenges in compliance and quality.

In the first part of this article, we present two case studies in which LEAN principles have been applied successfully to large-scale biopharmaceutical manufacturing, using our radical methodology. In the second part, we describe our qualification strategy and the implementation of a new flat, process-oriented organization in manufacturing sites, to ensure optimal support of LEAN and the development of a culture of continuous improvement, as described by the TPS. We conclude with some additional opportunities for how LEAN can be applied more broadly in (bio)pharmaceutical companies, with great benefits.

OUR LEAN METHODOLOGY

There are many different ways of implementing LEAN across an organization. Our methodology has been shaped over several years of application in the field of chemical, fill–finish, and now recently biomanufacturing operations. Our approach combines LEAN and the Six Sigma tools into a unique framework. The benefits of such a combination have been recognized by others.⁴

1. The first step in our LEAN methodology is a two-day assessment workshop, starting with a simulation game to create a strong awareness of what can be achieved with LEAN.

2. After defining the exact scope of the project, we assess the efficiency of the corresponding process—typically the manufacturing step including quality control (QC) and batch release activities—by drawing a high level "value stream map." We use only three measurements: throughput time, i.e., the overall cycle time for the production and release of a single batch; the throughput rate, i.e., the number of batches that can be produced per unit of time; and the failure rate, or "right first time" level.

3. We then set the quantitative objectives of the project, using a radical approach. The team first defines the "blue sky vision" of the process, i.e., how it would look with none of the current constraints (e.g., regulatory, technological, organizational, economic, safety-related) (Figure 1). This blue sky vision corresponds to the ideal efficiency level. Then, only the constraints which cannot realistically be eliminated within the timeframe of the project are carefully added back. This approach leads to the "practical vision," which determines the LEAN objectives. Experience shows that the practical vision usually remains a very ambitious target with dramatic improvements compared to the current status (or "baseline"). In a few instances, it may even be equal to the blue sky vision. This approach has two main advantages over a traditional stepwise optimization process, where incremental improvements are made sequentially in different areas (e.g., technical, operational, organizational) or activities (e.g., manufacturing steps). First, with a clear vision of the end-stage, improvements typically are achieved faster and more dramatically. Second, the mental journey of going first to the ideal and theoretical situation, without claiming it as possible, turns out to be a very efficient way of circumventing the normal human resistance of team members during the assessment phase of a LEAN project.

Figure 1

4. In the second day of the workshop, the LEAN implementation plan is developed, systematically including the following key milestones:

a. selection and implementation of sensitive performance indicators

b. determination of a "drumbeat" for batch production (typically on an hourly basis)

c. overall equipment effectiveness (OEE) improvement at the identified bottleneck (usually the production bioreactor)

d. synchronization of quality assurance (QA) and QC activities with production (thus minimizing waiting time for samples and accelerating batch record reviews)

e. optimum sequencing of manufacturing activities

f. throughput time reduction through the elimination of non-added value tasks

g. implementation of a new process-oriented organization (see below).

Several different technical tools are used to support LEAN, not only during the assessment workshop, but also during the execution phase of the project, such as a process walk, value stream mapping, spaghetti diagrams, rhythm wheels, failure mode and effects analysis (FMEA), and Six Sigma. (A description of these tools is beyond the scope of this article.)

5. A multi-year implementation plan is then built from the above milestones, which typically are translated into specific sub-projects. Progress during the execution phase is monitored by a steering committee. Short and regular communication to all the stakeholders and personnel is also very important to support the LEAN transformation of the plant. Visualization of the LEAN key performance indicators (KPIs) through on-line display on various screens or information boards in the plant is also usually implemented, so that employees can quickly see and understand the improvements, as suggested by the TPS.

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 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 risks.

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).

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.

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.

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.

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.

Figure 3

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

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.

Table 3. LEAN qualification level of a manufacturing site: target as a function of time

A new flat and cross-functional process-oriented organization

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.

Figure 4

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.

A BROADER SCOPE, BEYOND MANUFACTURING

From LEAN Manufacturing to LEAN Enterprise

LEAN is not just about manufacturing. Its philosophy and principles can, and should, be applied to other business areas, to improve processes and teamwork by eliminating bureaucracy and silo thinking, leading to a so-called LEAN enterprise.² A few examples we are working on are mentioned below, to illustrate the potential of LEAN and the variety of fields where it can be applied.

A LEAN Supply Chain

"LEANing" the individual facilities for API production and fill–finish, i.e., the main elements of the supply chain process, does not ensure that the whole process works in a LEAN fashion unless the "linking" process has been addressed as well. We have therefore started to apply LEAN to the entire supply chain process, from the supply of raw materials to the delivery of packaged products to the customers in the various countries for specific brands. The main benefits observed are a greater transparency and significant lead-time compression and inventory reduction, leading to higher flexibility and cost savings.

LEAN Technical Development

The technical development of biopharmaceuticals traditionally involves several steps or process versions, which leads to non-value-adding steps such as multiple technology transfers and comparability studies. We have thus started to implement a LEAN roadmap for the technical development of biopharmaceuticals, through which site transfers and comparability studies—among other things—are minimized. The main benefits are lower resource requirements, lower risk of non-comparable materials between clinical phases, and higher flexibility to support any acceleration dictated by clinical trials.

Numerous other applications in non-technical fields include HR processes and the clinical trial process.

SUMMARY

In this article we have shown how our methodology, based on a radical, systematic and relentless approach, can bring significant improvements to manufacturing operations in the field of biopharmaceuticals, with impact on the following performance factors:

• throughput time

• throughput rate

• failure rate

• overall asset effectiveness and capacity utilization.

The main business outcomes are general cost avoidance, reduction of production cost and higher flexibility. Implementing LEAN should not be a one-time project. Instead, it should be executed in several steps and may take years until it is fully embedded in an organization. For this purpose, the right people qualification program and organization must be put in place. Our innovative flat, process-oriented organization can greatly contribute to the sustainability of LEAN through the development of a culture of continuous improvement.

Thibaud S. Stoll is the head of Global Biopharmaceutical Operations and Jean-François Guilland is the head of operational excellence in global biopharmaceutical operations, both at Novartis Pharma AG, Basel, Switzerland, +41 (0)61 324 39 68, thibaud.stoll@novartis.com

REFERENCES

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