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A new production plant for APIs and their precursors has been in operation at Boehringer Ingelheim’s largest research and development facility since December 2014.

Process automation

Taking the long view

A new production plant for pharmaceutical active pharmaceutical ingredients (APIs) and their precursors has been in operation at Boehringer Ingelheim’s largest research and development facility in Biberach, Germany, since December 2014. The technical center, known as Technikum K 62, is the result of an intensive project successfully implemented across multiple phases.

The quantities of pharmaceutical APIs required to develop new drugs to the licensing stage are rising steadily. In early research phases, just a few milligrams of a substance are often sufficient. For more advanced toxicological and pharmaceutical testing, quantity requirements rapidly increase to tens or hundreds of kilograms.

The largest research and development facility within Boehringer Ingelheim’s global network, in the town of Biberach in southwest Germany, is where most of the corporation’s in-house development is carried out.

New innovative technical center

In 2011, to be able to provide adequate quantities of newly developed drugs for clinical studies and the continually increasing numbers of patients they involve, Boehringer Ingelheim began planning a new technical center, with an investment budget of some €50 million, to replace the existing building. The new pilot plant was planned to produce pharmaceutical APIs in quantities from 10 to 100 kg. The project team put forward a number of additional ideas to extend the facility’s service life over the long term in a project presentation at the Siemens Competence Center Pharma in Karlsruhe, Germany. These included the virtualization of client and server applications and the use of Profinet for both the plant bus and fieldbus.

Three-level plant design

In contrast to those of a mass-production facility, the technical center’s operations are characterized by continually changing synthesis reactions, products, and processing methods. So the plant design did not focus on optimizing the production processes of specific APIs; rather, the installed equipment had to offer maximum flexibility in order to produce a wide variety of different APIs and intermediate products.

The plant design incorporated three production levels: two reactor levels and an isolation area. The top reactor level also needed to incorporate hydration reactors. The entire planning process was implemented in line with cGMP (current Good Manufacturing Practice). To interlink the reactors as flexibly as possible, the reactor rooms were arranged in a cascade configuration. The physical separation of production areas enables the simultaneous, contamination-free production of multiple APIs.

The original system design was continuously enhanced throughout the project by Siemens Solution Partner on/off engineering gmbh and by Siemens itself, adapting the system to the needs and wishes of the operator. The project team presented Simatic Batch, Profinet, Scalance, and Maintenance Station based on the functions of the latest version of Simatic PCS 7 and answered customer questions in the course of meetings. Implementation of the project by on/off ­engineering gmbh began in late 2012.

Implementation with the latest products

The high degree of flexibility provided by on/off allowed for some adaptations during implementation of the systems, so as to incorporate the latest products from the Siemens portfolio as appropriate. For example, the originally planned Simatic S7-400 CPUs, types 414-3 and 414-H, were replaced on short notice with the new Simatic PCS 7 CPU 410-5H controller.

Operators were impressed by the extensive but integrated hardware package, with high-end memory, communication, and computing performance, as well as scalability. A total of 11 new controllers were deployed, including two configured as a redundant ­automation system. Complemented by additional Simatic PCS 7 components including redundant Batch, OS, maintenance, and engineering servers; two engineering clients; a Process Historian server; and a total of 26 Batch–client–licensed OS clients, the overall ­system won over the operator right from the initial partial acceptance testing, thanks to its wide-ranging options and, above all, its usability.

The new Boehringer Ingelheim facility for the production of pharmaceutical agents is adapted to the operator’s needs

Configuration in a virtual environment

Implementing the complete system in a virtual environment posed a particular challenge and represents a highlight of the project. Five ESXi hosts were deployed for the purpose, with an additional one on cold standby. This project represents the first time that this configuration has been implemented in a Simatic PCS 7 environment. The technical expertise and experience of on/off engineering gmbh were beneficial in achieving this. A redundant fieldbus was implemented to boost availability based on MRP (Media Redundancy Protocol) and system redundancy. The Advanced Engineering System was used to implement high-quality programs in a timely and cost-effective manner. Use of the Advanced Process Library in conjunction with qualified control module type (CMT) modules from on/off ensured a high level of standardization as well as cGMP-compliant implementation. The operator was provided with a step-by-step introduction to the extensive possibilities offered by the system. This included, for example, the implementation of a manual level for direct control of the batch phases from the visualization unit. The benefits in terms of day-to-day operations and the reproducibility of workflows were already ­apparent to the operator in this phase.

Successful together

The new technical center has been up and running since December 2014. The 2,700-square-meter site houses synthesis labs, where processes are transferred from laboratory to pilot plant scale, and the complex pilot plants in which the newly developed pharmaceutical APIs are produced.

For all the project stakeholders – the customer, the Solution Partner, and the system supplier – the aim was quite simple: to complete the project successfully together. And that worked very well. On completion of the project, Siemens provided Boehringer Ingelheim with a support contact from Simatic Systems Support Process Automation beyond the standard level of service in order to ensure ongoing assistance in all technical matters. Another key factor in the project’s success was the increasingly strong collaboration between the project team and the head office during the period from January to October 2013. During that time, the team monitored specific issues within the project and drew up an action plan. This resulted in detailed specifications for the configuration of the ESXi servers as a visualization platform and for on-site support for the initial installation of all software components. Simatic Batch workshops are held to answer specific questions, assess the experience gained to date, and agree on further optimization measures.

The Technikum K 62 facility in Biberach, Germany, offers more than 2,700 square meters of floor space.

 

Not least, on/off and Siemens also help minimize risk in connection with the adoption of new functionality. For example, before the commissioning, the operator wanted to update to Simatic PCS 7 Version 8.1 in order to selectively load individual continuous function chart (CFC) diagrams. Thanks to detailed update planning ­involving all stakeholders, this aim was achieved.

Investment in the future

At the launch, Dr. Fridtjof Traulsen, head of corporate division development, asserted, “Regulatory requirements relating to the development and licensing of innovative pharmaceuticals are continually increasing. The new technical center will assure supplies of APIs  to the preclinical development stages and clinical studies over the years ahead.” Professor Dr. Andreas Barner, the former chairman of the board of managing directors of Boehringer Ingelheim, said in summary, “The new technical center is an investment in the future for Boehringer Ingelheim.”

Picture credits: Boehringer Ingelheim