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Challenging task

Design, construction and start-up of a pilot plant for active pharmaceutical ingredients
Challenging task

The construction of a pilot plant constitutes an important milestone in the development cycle of a new active pharmaceutical ingredient. Pilot plants are used to gain the technological experience needed for the scale-up process and are required for producing sufficient quantities of the active pharmaceutical ingredient for clinical trials and other types of tests. As a result, even these testing facilities must comply with GMP regulations.

Uwe Welteroth, Dirk Steinhäuser, Hans-Otto Möckel, Steffen Kutscher

Since the development of a new active pharmaceutical ingredient (API) always represents an ambitious challenge for pharmaceutical companies, the issues related to design, engineering, construction and commissioning of the pilot plant, i.e. quality, costs and schedule, are priorities for upper management levels. Once all targets have been set, no deviation is acceptable. One of the most challenging tasks for the engineering contractor involved is to ensure a seamless interface between the pharmaceutical company’s researchers and the process design engineer. Transferring the process from laboratory apparatus to a technical pilot plant is always a very challenging task due to its experimental nature. The work therefore has a special atmosphere, since unforeseen events can never be totally ruled out.
The Novo Nordisk project started in March 2006. In the beginning, only the laboratory apparatus, a few written process documents and a rough project outline were available. The task was to scale up the apparatus to a pilot plant 16 times its size, which was to be integrated into an existing building. Both costs and hand-over dates had already been fixed and were compulsory. Linde-KCA-Dresden was contracted to manage and coordinate the design, engineering and implementation of this project. In addition to this, their responsibilities also included procurement and construction management as well as commissioning and qualification activities. Linde was also involved in cost and schedule control as well as in corresponding project reporting to Novo Nordisk management. In accordance with the project strategy that had been discussed and agreed at the beginning of the project, it was decided to split the work into technological and construction sections with the intention of creating an appropriate platform for subsequent contracting of local vendors as well as to facilitate concentration on the essentials of process design.
Design phase
The first step in the scale-up design was to gather the available process expertise, mainly by interviewing the researchers. The corresponding design documents, e.g. block flow diagrams, process flow and mass balances as well as process flow diagrams were prepared and enhanced on this basis. This design stage also comprised calculations of utility consumption, ideas for manual plant operation, handling and logistics as well as the development of a basic plant layout. Having clarified a number of design problems related to the specific design of certain reactors, it was decided that a special manufacturer of glass plants was to be involved in the project at an early stage. The technological section was therefore divided into the glass plant and the remaining steel/stainless steel utility systems. The challenge in developing the building layout was to find the space required for the pilot plant, the utility systems, the technical rooms (with hazardous and non-hazardous proof conditions) as well as the researchers‘ office, given the restricted conditions in the existing building. An optimal arrangement of the different areas was found. However, the storage of bulky solvent containers had to be moved outside the building while the solvent drums remained inside.
A creative atmosphere combined with openness and enthusiasm characterised the work, communication and decision-making by all participants in the project. The process information was collected by interviewing the researchers and then documented appropriately. The design documents formed the basis for comprehensive discussions of options and alternatives during several workshops. The automation concept, for example, was changed completely from a totally manually operated plant to a semi-automatic plant with very convenient process data acquisition and registration facilities. The estimation of costs for the entire project and the development of the project execution schedule, which had to meet prior requirements, completed the design phase. The documents from the design phase formed the basis for the management decision to continue the project.
Engineering phase
Having clarified all related technical and commercial details, a specialist manufacturer of glass plants was contracted and integrated in the remaining project implementation; this manufacturer engineered the appropriate parts of the process, developed the piping and instrumentation diagrams, the manufacturer vessel drawings and the 3D model with the isometric drawings of the glass pipes. Appropriate meetings, audits and reviews of the relevant engineering documents were held in order to ensure that the original process design ideas had been properly understood and realised in accordance with the specific glass expertise of the specialist manufacturer. Linde engineered the remaining steel/stainless steel utility systems. They developed the piping and instrumentation diagrams, prepared the technical specification for the heating and cooling unit as well as the data sheets of the vessels, pumps and other equipment which were then used for tender on a fixed price basis for appropriate costing.
The construction section was engineered by a local planning company, which performed the planning work necessary for the building packages (civil, steel construction, HVAC, piping and electrical installations as well as fire and gas detection etc.). These package plans were tendered to appropriate local vendors. Their fixed price bids also formed part of the costing. This costing was the basis for the final decision on the scope. The cost reduction required was ultimately achieved by including existing equipment (nutsch filter) and by performing the last process step (product drying) in another facility. The local planning company was also in charge of contacting the local authorities as well as all relevant Novo Nordisk departments, e. g. plant safety, fire etc.
Implementation phase
The equipment was purchased and the vendors were contracted on the basis of the agreed and confirmed engineering documents. The construction started with the required demolition works inside the building and with foundation works for the external solvent storage. The installation of the glass plant was a critical element of the construction schedule. The site therefore had to be cleared for such works as early as possible. The procurement of bulk materials and the piping installations for the steel/stainless steel utility systems were coordinated by the local planning company. The installation works were carried out on the basis of the Linde engineering documents – e.g. piping instrumentation diagrams, parts list and data sheets, etc. – and of simple 3D planning performed by the local company. The electrical installations were also based on partial operative planning.
Commissioning and qualification were planned and implemented by Novo Nordisk and Linde according to the highly formalised procedures required by Novo Nordisk. All commissioning and qualification work was done under strict supervision of their QA department. Initial technical experience was acquired after completion of the qualification; the heating and cooling behaviour of each reaction vessel was investigated in detail, and process controllers were optimised accordingly. Measurements were also registered and calibrated. Thanks to the combined efforts of all parties involved – Novo Nordisk researchers, local planners, vendors and contractors as well as Linde engineers –, the pilot plant was handed over on time and under budget to the end users to start performance qualification in August 2007.
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Novo Nordisk A/S
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