SubscribeMajor Danish insulin factory upscaled using Modular Engineering principles at all levels.
How could anyone double the production capacity of a high-tech insulin factory in six months after just a seven-day shutdown period? And triple it after 16 months, with only nine more days of shutdown? This was the challenge that NNE, a Danish engineering company, took on when Novo Nordisk asked us to upscale their primary insulin recovery facility in 2000. NNE has many years’ experience in engineering solutions for the pharmaceutical industry and had designed and built the factory for Novo Nordisk 15 years earlier.
The need to upscale was prompted by escalation in demand for analogue insulin products, due largely to Novo Nordisk’s entry into the US market. Novo Nordisk’s long-term solution was to build a new factory. However, as the new facility would not be ready for market production until about 2003, the capacity of the existing factory had to be increased as fast as possible. To keep pace with demand, the upscaling project was implemented in two phases: a six-month phase that doubled capacity followed by a 12-month phase to triple capacity. The same number of staff was to be used for both phases.
The constant flow of liquid throughout the system makes continuous bulk production a difficult process to upscale. Units cannot be withdrawn from the system during the upscaling process without shutting down the entire factory for a period. We had to think along new lines and decided to apply modular engineering principles, a departure from traditional upscaling methods that enabled us to implement the large-scale project as planned with minimum shutdown time.
Modular Engineering – a way of thinking
Modular Engineering is usually associated with planning new facilities and basing construction on smaller units or modules. The modules can be assembled and pre-tested off-site, an advantage that improves efficiency at all project stages. Although the present project was not the construction of a new plant, the solution involved modularization in every detail from processing, CIP units and utilities to documentation, qualification and validation. If two different processing units could theoretically be made identical, we modified their design to make them the same. We then copied the design and applied it to the required number of modules of this type, in other words ‘reused’ it. By thinking first in terms of modularization and then describing and streamlining production using pre-defined modules, we simplified the upscaling process by exploiting the ‘copy effect’ inherent in Modular Engineering.
We did not limit modularization to process-related units, but used it for other aspects of the production environment: design specifications, P&I diagrams, validation documentation, requirement descriptions, test specifications and software – the modular principle was applied to the planning and design of every component. The advantages of this approach are clear: once one module is in place, the same design can be replicated for all modules of the same type. And as design and documentation processes are notoriously complex and time-consuming, it is obvious that the modular approach significantly improves efficiency and thus minimizes the shutdown period so critical to production and budget management. Based on the same interface and design, Modular Engineering offers the additional side-benefits of a more uniform user interface and simpler maintenance.
A summary of the advantages of Modular Engineering:
- Reduces project completion time
- Minimizes shutdown time
- Reduces the number of tests
- Reduces the number of requirements, design, documentation and qualification.
A redesigned factory
To achieve the greatest capacity increase in the shortest possible time, the individual upscaling solutions were designed in-house at the factory. We copied equipment or installed larger equipment wherever we could. If new regulatory requirements or the physical layout of the factory ruled out this solution, we fell back on the third option of process optimization to increase production capacity. Processes were optimized using new improved process parameters developed by Novo Nordisk Pilot Plant and by increasing the level of automation at selected critical points throughout the project. Bottlenecks and waiting times were thus minimized and production equipment used more efficiently. The design was based on Modular Engineering principles regardless of the method used for a given unit.
Basically, the project involved the extensive re-design of an entire factory. All processing units and practically all utility systems were affected, because almost everything tends to become too small during an upscaling project of this magnitude. By the time we had finished, the factory had made the transition from conventional design documentation to one based entirely on modular assembly, with the option of future duplication at all levels.
No component is too small for modularization
The following is an example of how the modular principle can be applied in practice. Instead of producing one type of heat exchanger for centrifuges and another for columns, we made it a rule to use the same type of heat exchanger, identical in all respects – mechanical construction, components and design – for both processing units. Thinking in terms of modules means you can never ‘think too small’ because in theory, all components can be reused, provided they are based on the modular principle from the outset.
Two upscaling methods
In principle, we used two different methods, each reflecting an aspect of the upscaling methods of Modular Engineering:
- Duplication
- Cut and paste
Duplication is the most widely used Modular Engineering method. Duplication serves to increase capacity by duplicating a specific module a certain number of times. The first step is to re-design the unit so it can function as an independent module and then duplicate it. Individual modules may vary in size and complexity, and each separate module may contain other, smaller modules. In addition to processing units, associated equipment and piping can also be modularized.
We increased production capacity from two to five columns by duplicating the columns, pool tanks and piping by a factor of three. If the modules are correctly designed, the method offers the added advantage of eliminating in-process dependencies. All the modules have been provided with their own heat exchanger, additional feed pipes and their own delivery pipes. Each unit is thus less dependent on the others and the whole process is less vulnerable. It should be noted, however, that the duplication method requires complex application software for the process control system. Nonetheless, generally speaking, another bonus of these sophisticated systems is that they have potential for further process optimization.
Cut and paste means removing an entire unit and replacing it with a number of exact replicas elsewhere in the factory. For this project, we had to use the method when lack of space prevented us from duplicating the unit in the original location, or when the time-consuming development work associated with applying for regulatory approval of large equipment made upscaling impossible.
Transferring a unit to a new location and subsequently duplicating it usually requires a long shutdown time. Instead, we built the new copies in the new location so they were completely ready before the existing unit was removed. The advantage was a significant drop in shutdown time. The fact that the design was finalized and in place at the start of the project, was another important advantage. There was no need to discuss minor modifications, and because the units were exact replicas, all the software and design features of the original unit could be repeated in the new copies. This not only minimized shutdown time but the overall project completion period as well. The only disadvantage of the cut-and-paste method is the relatively high cost, because the original unit cannot be reused.
Close cooperation, flat structure and teamwork
At NNE, we use the term ‘Fast Track Engineering’ for projects of this scale with an ultra-tight schedule. The success of this type of project depends on more than process expertise. It pushes the organization and staff of both NNE and the client to the limit. We opted for a flat structure with one project manager, four coordinators and about 60 associated engineers. The coordinators were responsible for machinery, electrical installations, automation and validation/qualification. I was the project coordinator for automation. The client appointed a project manager and five project assistants with offices in the same building as NNE’s project group.
We worked so closely with the client that it was sometimes hard to tell us apart. We had well-defined assignments but shared a common goal. It is not always easy to generate this type of team spirit, which builds on the kind of mutual respect that can only be developed over time. Many companies are in fact surprised by how demanding these projects are for the client. Detailed functional requirements have to be drawn up and a qualified project team appointed to ensure that the client’s organization is geared to the adjustment process. Although the staff members are specially selected for the project team, they still have to be an integral part of the whole project and the company itself. Weekly meetings with key personnel ensured close communication and dialogue at managerial level. During shutdown periods, we could contact them at a few hours’ or even minutes’ notice to get the go-ahead for the next step and thus avoid unnecessary delay.
Last, proper management of ongoing production was essential, as it was the area most directly affected by the project. We made sure the NNE project group and the production team worked together closely on a daily basis throughout the project in order to resolve technical problems ad hoc without disrupting overall planning.
Interdisciplinary focus and team spirit bring out the best
To optimize the advantages of modularization, the various experts involved in the project must have insight into each other’s jobs and ideas, regardless of profession or trade. In turn, the organization must have a multidisciplinary structure. In practice, this meant that the 20 key engineers and four coordinators worked in the same open-plan office, with the coordinators’ desks grouped together. The noise level occasionally scaled new heights, but as we could not avoid seeing and hearing what was going on all around us, we also had the chance to exchange good ideas on the spot. The project environment was multidisciplinary at all levels because process rather than profession organized the project. This meant that people working on the same part of the project sat together regardless of discipline. This encouraged the development of modular systems, and we avoided many of the communication errors that can otherwise easily arise when so many different professions have to work together.
Team spirit and delegating responsibility were other key words for the project. All changes had to be made simultaneously because no unit could be taken out of the process and modified individually. Meticulous coordination of all activities to meet the tight time schedule was therefore crucial. Everyone had to be willing to accept and take on a great deal of responsibility, including during shutdown periods when work pressure peaked.
Focus on information, time and competence
The high level of information in the key group had a positive impact on the entire project. As time was a greater concern than money, we took the opportunity to celebrate milestones and other special occasions along the way. Together, this meant that we managed to create an environment that people enjoyed working in despite the time pressure. It also inspired them to do their best, and we were able to compensate them accordingly.
The overall focus on time rather than money was a key success factor. This overarching principle allowed each engineer to concentrate on his area of expertise – with time and the technical solution as the most important criteria for success. Our phase-oriented approach was another essential parameter for success, enabling us to exploit NNE’s core competence in the various project phases. At times we could assign NNE specialists to the project on a temporary basis and thus gain the full benefit of NNE’s broad spectrum of expertise.
Prefabrication minimizes shutdown time
An underlying principle of the modular approach is the fabrication and pre-Installation Qualification testing of equipment off-site so that existing equipment can be used for on-site production until the last minute. In this project, the equipment was mechanically tested off-site as far as possible, and all software subjected to a proving system that simulated functionality and tested major qualification aspects before installation. When everything was ready for shutdown, the module underwent final on-site installation, testing and validation. All the corresponding modules were subsequently set up very quickly; since full testing had been carried out on one module, the remaining modules only needed installation testing and limited functional testing.
Security of supply and risk analysis
We prepared a risk analysis specifying what could go wrong and what we would do in such cases. Recovery is part of the bulk supply chain in insulin production. Without any stockpiles, if our shutdown dragged on longer than expected, it would affect not only the factory we were rebuilding but also the next facility in the supply chain. It was thus essential to address potential supply issues by producing sufficient stocks to prevent the supply chain from suffering if production had to shut down longer than expected. We also prepared fallback plans for critical modifications so that old equipment could be reinstalled if necessary. Finally, we defined a series of points of no return, that is, places where old equipment could not be reused after modifications had been made. In these cases, we asked for the client’s full acceptance before continuing.
Before shutdown, we drew up a detailed hourly activity schedule for everyone involved. The critical issue here was not the timing but the duration of the shutdown period. Twice, we had to postpone shutdown for a few days: once because of an electricians’ strike and once because the agreed conditions for shutdown were not yet in place.
Daily routines and shutdown
How can a project of this nature be implemented while production is in full swing? Maintenance was the responsibility of the project support group, which held meetings every morning with production chemists to evaluate the events of the past 24 hours and make sure the necessary maintenance was done without affecting project progress. This precaution ensured that production could continue, with the possibility of fixing minor problems that were causing production delays. Key personnel held weekly meetings to monitor project finances and overall progress, and to clarify any modifications arising from the morning evaluation meeting.
Only a handful of key personnel were dedicated to the qualification process. Six weeks prior to shutdown, they called in a team of external test engineers for the job. During the six-week period, they learned about cGMP practices and factory processes. While this added to the cost of the project, it was well worth the extra expense because qualification was completed quickly without involving project engineers, who could thus devote themselves 100% to dealing with unforeseen problems and deviations. The qualification process was also simplified as the protocols for all identical equipment could be reused, thanks to the modular technique.
To optimize the shutdown period, we held a review meeting for each section after installation testing, which released the section for the performance test. After functional testing, a second review meeting was held before the section could be released for production. At these review meetings, users, quality assurance and project engineers prepared a preliminary approval authorizing the start of production while the report was being written. All in all, this procedure significantly minimized the duration of the shutdown period.
Lessons learned
We came very close to meeting our goal by completing the project in 16 months with an upscaling factor of 2.8. A further shutdown period proved necessary to achieve the target factor of 3. After six months’ production, the factory was shut down according to the original concept and using basically the same project team. The result was an upscaling factor greater than 3.
We have learned several lessons from the project:
- Owing to time constraints, it is important and crucial to reduce the number of scope changes; agreeing to too many minor changes causes delays.
- The number of staff involved in preparing specifications should be limited to avoid inconsistencies and time-consuming discussions.
- Communication is a key word: everyone must know what is going on and why.
- It is important to work closely with and motivate the Quality Assurance team – they set the documentation standards and have to approve everything.
- A post-tuning period for the factory must be expected. Further optimization more than compensates for the extra time spent.
The total cost of the project amounted to approximately USD 30 millions. Could we have achieved the same capacity increase for less? That is a hard question to answer, but one thing is for sure: in the final analysis, any saving would have resulted in a higher overall cost in the form of a longer shutdown period. The pros and cons – time against money – have to be weighed before embarking on each individual project. The main lesson learned from this particular project is that it is possible to upscale a factory in a very short period of time – with Modular Engineering as the key tool.