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Fallet C.,TU Braunschweig | Fallet C.,NNE Pharmaplan | Rohe P.,TU Braunschweig | Rohe P.,Jülich Research Center | Franco-Lara E.,TU Braunschweig
Biotechnology and Bioengineering | Year: 2010

The synthesis and secretion of the industrial relevant compatible solutes ectoine and hydroxyectoine using the halophile bacterium Chromohalobacter salexigens were studied and optimized. For this purpose, a cascade of two continuously operated bioreactors was used. In the first bioreactor, cells were grown under constant hyperosmotic conditions and thermal stress driving the cells to accumulate large amounts of ectoines. To enhance the overall productivity, high cell densities up to 61 g L -1 were achieved using a cross-flow ultrafiltration connected to the first bioreactor. In the coupled second bioreactor the concentrated cell broth was subjected to an osmotic and thermal down-shock by addition of fresh distilled water. Under these conditions, the cells are forced to secrete the accumulated intracellular ectoines into the medium to avoid bursting. The cultivation conditions in the first bioreactor were optimized with respect to growth temperature and medium salinity to reach the highest synthesis (productivity); the second bioreactor was optimized using a multi-objective approach to attain maximal ectoine secretion with simultaneous minimization of cell death and product dilution caused by the osmotic and thermal down-shock. Depending on the cultivation conditions, intracellular ectoine and hydroxyectoine contents up to 540 and 400 mg per g cell dry weight, respectively, were attained. With a maximum specific growth rate of 0.3 h -1 in defined medium, productivities of approximately 2.1 g L -1 h -1 secreted ectoines in continuous operation were reached. © 2010 Wiley Periodicals, Inc.

von Stosch M.,New University of Lisbon | Davy S.,NNE Pharmaplan | Francois K.,Siemens AG | Galvanauskas V.,Kaunas University of Technology | And 7 more authors.
Biotechnology Journal | Year: 2014

This report highlights the drivers, challenges, and enablers of the hybrid modeling applications in biopharmaceutical industry. It is a summary of an expert panel discussion of European academics and industrialists with relevant scientific and engineering backgrounds. Hybrid modeling is viewed in its broader sense, namely as the integration of different knowledge sources in form of parametric and nonparametric models into a hybrid semi-parametric model, for instance the integration of fundamental and data-driven models. A brief description of the current state-of-the-art and industrial uptake of the methodology is provided. The report concludes with a number of recommendations to facilitate further developments and a wider industrial application of this modeling approach. These recommendations are limited to further exploiting the benefits of this methodology within process analytical technology (PAT) applications in biopharmaceutical industry. This report highlights the drivers, challenges and enablers of the hybrid modelling applications in the biopharmaceutical industry. It is a summary of an expert panel discussion of European academics and industrialists. A brief description of the current state-of-the-art and industrial uptake of the methodology is followed by a number of recommendations to facilitate further developments and a wider industrial application of this modelling approach. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Gremiakova T.A.,NNE Pharmaplan | Thomas A.,NNE Pharmaplan | Guldager N.,NNE Pharmaplan | Hermansen K.,NNE Pharmaplan
Russian Journal of Biopharmaceuticals | Year: 2013

Lessons learned from 2009 pandemic flu gave evidence that key issues in pandemic flu vaccine production are shortage of time, scalability, speed and biosafety of production. Developing of new universal flu vaccine preparations, alternative technological production platforms and new process equipment to overcome drawbacks of existing are the main trends for future vaccine production. Ideally, future vaccine manufacturing facilities would handle multiproduct campaigns and include a range of safe and profitable production and process platforms and technologies. It's time for business to reconsider their business production model.

Beregovykh V.V.,Moscow State University | Spitskiy O.R.,NNE Pharmaplan
Vestnik Rossiiskoi Akademii Meditsinskikh Nauk | Year: 2014

Risk-based approach is used for examination of impact of different factors on quality of medicinal products in technology transfer. A general diagram is offered for risk analysis execution in technology transfer from pharmaceutical development to production. When transferring technology to fullscale commercial production it is necessary to investigate and simulate production process application beforehand in new real conditions. The manufacturing process is the core factor for risk analysis having the most impact on quality attributes of a medicinal product. Further important factors are linked to materials and products to be handled and manufacturing environmental conditions such as premises, equipment and personnel. Usage of risk-based approach in designing of multipurpose production facility of medicinal products is shown where quantitative risk analysis tool RAMM (Risk Analysis and Mitigation Matrix) was applied. © 2014 Annals of the Russian academy of medical sciences.

Mauricio-Iglesias M.,Technical University of Denmark | Johansen K.,NNE Pharmaplan | Jrgensen S.B.,Technical University of Denmark | Sin G.,Technical University of Denmark
11AIChE - 2011 AIChE Annual Meeting, Conference Proceedings | Year: 2011

In order to increase efficiency in resources and energy allocation and reduce capital costs, chemical processes tend to use more heat and mass integration, which increase interactions, and fewer surge vessels that could dampen disturbances. As a consequence, interactions between process units become more important, which has to be considered and managed properly in the design of the control layer for the process operation. One particular area where process operation optimization and control challenges frequently are observed is separation systems. In particular for distillation processes, strategies for heat recovery have been extensively implemented in industrial processes during the last decades. Operation (including start-up and shut-down) and control of, heat-integrated systems become formidable challenges if not problematic since higher-order dynamics occur where different time-scale phenomena interact. Furthermore, if the dynamic state of the process does not lie close to the designed state, the amount of energy wasted increases, questioning the economics of the implementation of heat integration. On the other hand, literature deals extensively with classic distillation columns whereas much less has been investigated on dynamics of heat integrated distillation systems and the significance of developing a proper plantwide control strategy to ensure optimal and stable operation. Classic control strategies may be unsuitable for such complex systems and, more importantly, the design and operating conditions of the process may lead to a hardly controllable process. The goal of this work is to present a systematic and process engineering oriented methodology for the assessment, troubleshooting and improvement of existing operation and control strategies for distillation systems. The operation and control strategy is assessed stepwise following a top-down and bottom-up approach (Skogestad 2003) according to the following steps: (i) reviewing control objectives & strategy; (ii) the model development &control degrees of freedom analysis strategy; (iii) reviewing and generating pairing of control and manipulated variables and obtaining the subsequent fine-tuning parameters; (iv) finally, evaluation of the new proposed strategy. Particular attention was given to the analysis of existing operating conditions of the process and how their modification can lead to a more easily controllable system. To this end, the driving force concept -a powerful and relatively simple graphical method (Bek-Pedersen et al. 2010), is used that provides optimal operating set-points insensitive to disturbances and require minimum energy for the separation (Hamid et al. 2010). The application of the methodology was highlighted using a real industrial case problem, for which a dynamic model for heat-integrated distillation systems is developed and used to analyze and solve operational and control problems for solvent recovery in a pharmaceutical industry. The system studied in the industrial case is composed of two distillation columns in series (operated at 3.5 and 1.5 bar respectively) for recovery of ethanol (light key) from a liquid mixture, modeled as pseudo-binary (water is the heavy key). Heat recovery is carried out both backward (from the two bottoms flow to the feed) and forward (from the first condenser to the second reboiler). Finally, based on a numerical model of the system and using the methodology described above three solutions were generated for improving its control: i) a fine tuning of the existing control strategy, therefore suitable for immediate implementation; ii) a new control strategy considering improved pairings of variables in the existing plant; and iii) a new control structure, including sensors and actuators for long term modification of the system. Benefits of each alternative remedies have been evaluated and benchmarked against each other.

Johnsson O.,Lund University | Sahlin D.,Novozymes AS | Linde J.,NNE Pharmaplan | Liden G.,Lund University | Hagglund T.,Lund University
Control Engineering Practice | Year: 2015

In this study a modified mid-ranging strategy is proposed where the controller for the secondary manipulated variable uses its own output as its setpoint, possibly with an offset and/or re-scaling. This modification allows the manipulated variables to increase in unison so that the mid-ranging advantage of utilizing the fast dynamics of the primary controller to regulate the process can be achieved also in non-stationary processes, while not adding complexity to the controller. The proposed control strategy has been implemented in pilot-scale (500. l) industrial bioprocesses where it is used to control the dissolved oxygen level by manipulating agitator speed and aeration rate. The controller is demonstrated to perform well in these, outperforming a reference controller which has previously been shown to give satisfactory control performance. It is also shown in similar experiments that the strategy can easily be adapted to control dissolved oxygen in bioprocesses where the feed rate is controlled using an extremum-seeking controller. The proposed strategy is generally applicable to non-stationary processes where a mid-ranging approach is suitable. © 2015 Elsevier Ltd.

Beregovykh V.V.,Moscow State University | Spitskiy O.R.,NNE Pharmaplan
Vestnik Rossiiskoi Akademii Meditsinskikh Nauk | Year: 2013

Innovation development of pharmaceutical industry is close connected to knowledge transfer going to each subsequent life cycle phase of medicinal product. Formal regulation of technology and knowledge transfer is essential for achievement high quality during production of medicines designed during development phase. Conceptual tools, approaches and requirements are considered that are necessary for knowledge and technology transfer across all the life cycle phases of medicines. They are based on scientific knowledge of medicinal products and take into account both international and Russian regulations in the area of development, production and distribution of medicines. Importance of taking into consideration all aspects related to quality of medicines in all steps of technology transfer is shown. An approach is described for technology transfer organization for Russian pharmaceutical manufacturers based on international guides in this area.

PubMed | Lundbeck and NNE Pharmaplan
Type: | Journal: European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences | Year: 2016

Due to the complexity and difficulties associated with the mechanistic modeling of roller compaction process for scale-up, an innovative equipment approach is to keep roll diameter fixed between scales and instead vary the roll width. Assuming a fixed gap and roll force, this approach should create similar conditions for the nip regions of the two compactor scales, and thus result in a scale-reproducible ribbon porosity. In the present work a non-destructive laser-based technique was used to measure the ribbon porosity at-line with high precision and high accuracy as confirmed by an initial comparison to a well-established volume displacement oil intrusion method. The ribbon porosity was found to be scale-independent when comparing the average porosity of a group of ribbon samples (n=12) from small-scale (Mini-Pactor) to large-scale (Macro-Pactor). A higher standard deviation of ribbons fragment porosities from the large-scale roller compactor was attributed to minor variations in powder densification across the roll width. With the intention to reproduce ribbon porosity from one scale to the other, process settings of roll force and gap size applied to the Mini-Pactor (and identified during formulation development) were therefore directly transferrable to subsequent commercial scale production on the Macro-Pactor. This creates a better link between formulation development and tech transfer and decreases the number of batches needed to establish the parameter settings of the commercial process.

News Article | February 26, 2015

Christophe Boulanger, Managing Director, NNE Pharmaplan India,in an interview with Usha Sharma, speaks about the company’s future plans for the Indian market How long you have been associated with the Indian pharma market and what have been your learning experiences? NNE Pharmaplan is a business partner to the pharmaceutical and biotech industries and is one of the leading engineering and consulting companies within the field. NNE Pharmaplan started its operations in 1996 in India and has been providing engineering consulting services to the pharma and biotech sector over the past 18 years. Personally, I have been associated with the global pharma industry for more than 20 years now. During the past eight years, I have been involved in various global positions within NNE Pharmaplan which has given me insights into the Indian pharma industry. The Indian pharma market, along with the markets of China, Brazil and Russia, will spearhead growth in the pharma industry in the coming years. The Indian market has some unique characteristics: First, branded generics dominate, making up for 70 to 80 per cent of the retail market. Second, local players have enjoyed a dominant position driven by formulation development capabilities and early investments. Third, price levels are low, driven by intense competition. However, the industry will need to strengthen three sets of commercial capabilities: marketing excellence, sales force excellence and commercial operations. In addition, players will need to put in place two enablers: strengthen the organisation to be able to sustain performance and manage rising complexity; and collaborate with stakeholders within and outside the industry to drive access and shape the market. NNE Pharmaplan is aligning itself to cater to these requirements and help the industry players to strengthen their operations by providing first-class consulting services driven by technology leadership. Tell us about the company’s ongoing activities and the major projects which it is working on? In India, we focus on vaccines, OSD and injectables as well as the latest trends and technologies such as single-use systems. To support this, we have established a consulting department focused on high-level business support, which is headed by Aeby Thomas. Aeby comes with a rich global experience in production and consulting, and has been with NNE Pharmaplan for more than seven years. Supporting him, we have local experts in India. At the same time, we are also utilising our global consulting department to look into critical domains such as containment, oncology and continuous processing. Our focus has always been to create value for our customers across the world. We strive to deliver a similar experience for our customers irrespective of where they choose to work with us. Our goal is to increase the quality of our deliveries while focusing on our core of pharma and biotech customers. We are currently engaged in the following domains in India: Unfortunately, I cannot share the precise customer and project details with you due to confidentiality agreements. There have been regulatory compliance issues with many Indian manufacturing facilities. How critical are these challenges? What steps do you follow to overcome these issues? It’s important to note that many Indian companies understand and adhere to current good manufacturing practices (cGMPs). The problems encountered by FDA investigators in India are similar to those seen around the world in manufacturing. These include inadequate or poor quality systems implementation, data integrity issues, inadequate validation of various processes used in manufacturing or testing and product adulteration or contamination. While some Indian companies operate state-of-the-art facilities and meet cGMPs, others do encounter problems and operational challenges. Not only is quality critical to public health, but also the basis of the public’s confidence in pharma. Overcoming these issues requires a willingness to change and a pro-active approach to looking into other high technology industries, investigate their practices and adopt these selectively so as to achieve the goals of transparency, traceability and therefore quality. When designing facilities, we have our GMP experts review the layout of the facility. Our GMP experts are up-to-date with latest guidelines and regulations laid down by FDA which helps us to design facilities in accordance with current guidelines. NNE Pharmaplan has devised internal tools called ‘Our model and our Wiki’ which are global platforms for sharing knowledge about latest trends and technological solutions available across the globe and for sharing best practises within the organisation. If a customer wants to check whether their facility is in compliance with latest guidelines, NNE Pharmaplan can provide GMP review and assessment studies and make a review report with recommendations of corrective actions. Why should multinational pharma companies invest in India? Particularly in the Asia-Pacific region, which market do you feel have a huge business potential and why? India is expected to rank amongst the top three pharma markets in terms of incremental growth by 2020. Within APAC, NNE Pharmaplan has offices in India, Malaysia and China and we have the required muscle to support even the biggest and most complex projects in this region. However, I still believe that India has an advantage in these markets, primarily due to the following reasons: Workforce: India possesses a skillful workforce with high managerial and technical competences. Cost-effective chemical synthesis: The track record for development, particularly in the area of improved cost-beneficial chemical synthesis for various drug molecules is excellent. Legal and financial framework: India is a democratic country with a solid legal framework and strong financial markets. There is already an established international industry and business community. Globalisation: The country is committed to a free market economy and globalisation, which is constantly increasing. Approval time for new facilities has been drastically reduced. India’s cost of production is significantly lower than that of the US and almost half of that of Europe. What will the consultant keep in mind while setting up new units? NNE Pharmaplan keeps in mind the following things while designing for new facilities: How many people are associated with the group and out of them how many are technical experts? NNE Pharmaplan has a resource pool of 2,000 resources at more than 25 locations around the world. The resources are divided into two categories: operational and non-operational. The operational resources are the technical resources that are involved in designing and engineering consultancy for pharma and biotech domains. Around 80 per cent of our employees are billable/ operational. They are supported by 20 per cent non-billable/non-operational employees involved in IT, HR, sales etc. NNE Pharmaplan also has a pool of senior technology partners (STP) who are high level technical specialists within their own respective fields. We currently have STPs within vaccines, sterile and aseptic fill and finish, regulatory compliance, OSD, biopharmaceuticals, medical devices and drug delivery systems. Most of our STPs are technology leaders within their domains and work to provide innovative solutions to our customers globally. Tell us about the company’s future plans. NNE Pharmaplan has set out on a journey to build long-term relationships with strategic customers based on a role as trusted advisor. We believe that we can deliver the right solutions through deep insight and understanding of our customers’ challenges and opportunities. So to say, our New Year’s resolution is to be more focused on our key customers, understand their pains, deliver customised solutions, move towards focused pharma engineering, attract the right talent and distinguishing ourselves from other players on the market by providing high value for our customers. We are on the right path of sustainable growth and we are entering the new year with a good pipeline.

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