Study Tour France




From May 11th till May 17th, a delegation of eleven post-graduate students in bio(proces) technology and one analytical biochemist of the Kluyver Laboratory of Delft University of Technology commited themselves to visit five companies and one school of industry throughout France. The journey itself, which comes down to 3,300 km on the road, was a big experience already and asked much endurance of the participants. In fact, all twelve (sometimes stubborn) individuals integrated well with each other and contributed perfectly to the group spirit till the end of the study tour.

Not surprisingly, the participants got the opportunity more than once to utilise their Frence. Thanks to the spontaneous translation of French conversations by Hugo Billiet and Ahd Hamidi, everybody learned matters about the R&D, which is needed to explore new applications in environmental, food and pharmaceutical bio(proces)technology. Paul van Mierlo was the main representative of the Dutch delegation during the visits, since he had arranged all visits in advance. The visits went smootly as planned and were interesting for both the guests and the hosts thanks to Paul and last but not least the representatives of the visited sited.

This booklet reports on the various visits, which would never have been possible without the financial support of the sponsors who are listed in the back. The following pages, including beautiful (group)pictures, will enforce the nice memories of the participants and will give an impression of the study tour to every interested reader in general.

The organisation,

Nathalie Penders, Paul van Mierlo, Tony Flameling, William Arts

List of participants

Group picture at Courvoisier
From left to right and top to bottom: Herman Krab, Nathalie Penders
Sander Worst, Hugo Billiet, Pieter Nelisse, Mr Lavergne (employee of Courvoisier), Ahd Hamidi, Suping Wang, Linda Jacobs, Paul van Mierlo
Koen Meesters, Tony Flameling
And last but not least William Arts, he took the picture


Program of the week

Monday: INRA Lille
Tuesday: Diosynth France and Degrémont
Wednesday: Courvoisier
Thursday: Pasteur Mérieux Connaught
Friday: Ecole nationale d'industrie laitière et de biotechnologies



Monday May 12

INRA, Villeneuve d'Ascq
Institut National de la Recherche Agronomique

9.45Welcome by Mister De Pessemier
10.00 - 10.40General presentation about INRA Lille by Mister Maingonnat, Director of the Laboratory
10:40 - 11.00Presentation from the members of Delft
11.00 - 12.00Visit to the LGPTA and the experimental pilot hall
12:00 - 13.00Lunch and departure to Paris

Laboratoire de Génie des Procédés et Technologie Alimentaires

INRA is the French equivalent of the Dutch institute ATO/DLO and exerts R&D in different fields related to agriculture. INRA is mainly financed by the ministry of research, by itself, by contractual financing, and the ministry of agriculture. INRA employs about 3,900 researchers, 3,900 technicians, and 800 administrators at 22 centres that are spread over France.
The quality of natural resources for agricultural production, such as soil, water, and climate, is one of the interests of INRA. Improved knowledge concerning the major bio-geochemical cycles or the production of polluting gases may lead to better awareness of changes in the quality of natural resources. Another interest of INRA is the biology and molecular biology of cultivated species. Structural information on genes of e.g. farm animals can be related to population biology, physiology, and behavioural sciences to select for animals with certain characteristics. Economists and sociologists of INRA examine the agricultural effects of public and industrial policies on regional, national, and international levels. Furthermore, investigations are spent on the nutritional requirements and the behaviour of consumers.
One of INRA's centres, called 'Laboratoire de Génie des Procédés et Technologie Alimentaires', aims to improve knowledge and technology in food transformation and preservation area. This area is important, since nowadays over 70 % of agricultural produce is processed. This centre offers scientific and technical expertise in food process engineering and microbiology. Most of its R&D is confidential, but is described below briefly.
One project deals with thermal treatment of complex fluids on pilot scale. Many food industries, like e.g. soup and marmalade producing industries, have to process complex fluids in such a way that the food product obtains specified (gel) characteristics. Since product characteristics can be a strong function of temperature, the effects of thermal treatment have to be implicated in the process design of a new production facility. In order to make rational choices for certain equipments, like tubes, evaporators, and batch reactors, effects of local heating on fluid characteristics in these equipments have to be investigated. Instead of testing the heating of fluids that are actual food products, it is more elegant to test the heating of model fluids like guar gum. Once it is known how measurements on a model fluid can be translated to heating effects on actual fluids, model fluids may offer a relatively cheap and general way to perform pilot scale R&D on food processing.
Another project is concerned with the development of microfiltration systems for beer clarification. Crossflow microfiltration of beer gives membrane fouling and cleaning problems on large scale. Small sugars can already foul membranes in some cases. Scanning electron microscopy and rheologic models are applied to investigate the structure of fouling particles. Such information is used to optimise membrane modules used for crossflow microfiltration.
Adhesion forces in tubes and walls of processing equipments are sometimes high enough for bacteria or bacterial rests to adhere firmly. In order to safeguard the sterility of food products, test methods have to be available for the assessment of closed equipment cleanability and sanitation. Besides, relevant micro-organisms involved in spoilage, such as Clostridium, Bacillus, Pseudomonas, Pectinatus, are studied in different types of equipments to model growth, survival, destruction, and physiological responses to sublethal injury and stress. In addition influences of processing and storage conditions, the composition of the food matrix, and microbial interactions are taken into account to improve predictions concerning spoilage of food products.

Tuesday May 13

Diosynth France, Eragny-sur-Epte

9.45 - 11.30Welcome and presentations by Mr Morellet, Mr Olivie and Mr Texier
11.30 - 12.30Tour round the factory
12.30 - 13.00Lunch
13.00Departure to Degrémont

Diosynth France
Usine Saint Charles

The AKZO NOBEL group consists of approximate 70,000 employees; which are divided over 35 Business Units (BU's) throughout the world. Diosynth France develops and manufactures biochemical substances and fine chemical molecules mainly for Pharma industries, like Organon. While most R&D is located in Oss, Diosyth France is mainly involved in production of Bulk Pharmaceuticals and Fine Chemicals like insulin, glucagon, hyaluronic acid, Super Oxide Dismutase (SOD) and nandrolon sulphate. Other Diosynth sites are located in the USA, Mexico, Brazil and India. The plant Usine Saint Charles comprises of DIOSYNTH and ORGANON, of which the organisations are interconnected via the services department. At the location, ORGANON currently comprises of 159 employees, while 27 people of DIOSYNTH work in the Factory, and 27 in Services. The surface of the plant is about 25 acres, of which 7 are build. The main productions of pharmaceutical raw materials come from either animal origin or chemical intermediates. The origin of extraction and purification of insulin is the porc pancreas. Activities of DIOSYNTH are based on long experienced know-how and cover basic technology, purification steps and finished goods. Unit operations, Quality control, Quality assurance, Raw and Waste materials management are topics of intensive innovations and control.

Unit operations: For the large-scale yield of 100 gram of pure insulin out of 1000 kg porc pancreas, laborious extractions, purifications, crystallisations and enzymatic treatments are necessary. Therefore, optimisation of for instance cryogenic breaking, gel permeation columns, industrial columns, multipurpose reactor vessels is constantly maintained and controlled.

Quality control and quality assurance & Raw and Waste materials management: Constant quality level is a must. The whole factory team is devoted to quality in order to comply with standards. The quality control laboratory performs all analyses on (incoming) raw materials, intermediates and finished goods. Therefore, the total control of supplying, warehousing and waste products is based on a long-standing experience enhanced by specially adapted facilities as: cold storage, drying, solvent recovering, waste treatment and maintaining a laboratory dedicated to environmental problems. Waste water (20,000 equivalent inhabitants) treatment includes the classical nitrification/denitrification steps.
Altogether, DIOSYNTH France is a dynamic company, of which the facilities and the production from raw materials to final pure product and waste water is constantly optimised and controlled. The equipment is especially adapted to extraction and purification of biochemicals. It's experienced staff is able to adapt quickly to new projects and developments and is constantly involved in quality.

Degrémont, CIRSEE Le Pecq/CERDEG Croissy

15.00 - 15.30Welcome and a presentation about CIRSEE
15.30 - 16.00Visit to the laboratory of CIRSEE
16.00 - 17.00Presentation about CERDEG by Mister Haubry
17.00 - 17.30Presentation about the post graduate studies
17.30 - 18.30Visit of the pilot hall of CERDEG
18.30Departure to Poitiers

Traiter l'eau, proteger l'environnement

Degrémont is a company specialised in water treatment. It has a global network comprising 32 subsidiaries and 17 offices. Two of the departments of Degrémont are CIRSEE and CERDEG

CIRSEE (300 researchers and technicians, 214 MFF budget)
CIRSEE stands for Centre International de Reserche sur l'Eau et Environnement. It is active in analysis, research, technical assistance and training. The full circle of water usage is investigated; from the withdrawal, via treatment and transport to the consumer, and from there, via sewer, waste water treatment and discharge, back to the environment. Many efforts are in characterisation of water qualities in the circle and in the reuse of water within the circle. One of the main activities of CIRSEE is analysis of water samples. Here the water and environmental specialists not only carry out the analysis of water samples, but also help to choose analysis strategies, provide advice on treatment adaptations, and so on. The second main activity consists of research on drinking water, waste water treatment and other wastes. Especially membrane techniques like micro filtration, ultra filtration, reverse osmosis and membrane bioreactors are investigated. Application of the investigated is an emergency drinking water treatment plant based on ultra filtration. It is built in a container (so it can easily be transported) and has a capacity of 55 m3 per hour.

CERDEG stands for Centre d'Etudes et de Recherche Degrémont. If lab-scale investigations at CIRSEE or elsewhere in the organisation are successful, the pilot-scale experiments can be done here. The hall is situated above one of the main sewers of the city and therefor real sewage is available for experiments. Apart from sewage, well water, Seine river water and drinking water is available for experiments.

Wednesday May 14

Courvoisier - Le Cognac de Napoléon, Jarnac

11.00Welcome by Mr Lavergne
11.00 - 12.00Visit of the Napoleon Museum and the Courvoisier diaporama
12.00 - 13.00Lunch
13.00 - 15.00Visit of the Jubert distillery at Chateau Neuf and tasting of some fine 70% spirits
15.00 - 16.00Visit to the warehouses
16.00 - 17.00Visit to the Courvoisier Laboratory
17.00 - 17.30Final speeches and departure to Clermont-Ferrand

Le cognac de Napoléon

The cognac distillery Courvoisier started 200 years ago in Paris. When Napoleon asked Courvoisier to become cognac supplier of the imperial court, the distillery was situated in Jarnac, in the Cognac area. From 1869 Courvoisier was named "Official Purveyor to the Court of Napoleon III". Their logo, that can still be found on the label, is Napoleon with his right hand under his jacket. This was the moment that the great imperium of this cognac fabric started. At the begining of this century there were no more inheritants of the Courvoisier family left. The distillery was sold to an Englishman. It became part of the Iran Walker group. Since 1986 it is part of Allied Domecq (English/Spanish). Nowadays, 98% of the Courvoisier cognac is exported, the main part to Asia.
In the Courvoisier museum one can find very old bottles of cognac, the oldest dating from 1789. The bottles are conserved standing, not lying as with wine. This is because of the high alcohol percentage, that would dissolve the cork. Anyway the cork has to be replaced every 10 year. Apart from the cognac, Courvoisier also manufactures its one bottles. Cognac bottles have a typical design, which distinguishes it from other drinks. In the past however, cognac was bottled in 'wine bottles'. The museum keeps some belongings of Napoleon, like his hat, sward, bed and clothes, which remind on the time it all started. Also there is cognac with prices varying from 100 to 20,000 Francs.
Cognac is a protected name (appellacion controlé). That means that only grapes grown in a specific part of France can be made into real cognac. The cognac area is situated around the city Cognac. The ground consists of a lot of sand and is very suitable for growing a specific white grape race (Ugni Blanc) that gives excellent cognac, but very bad wine. The roots grow as deep as 15 meters into the ground in order to reach the ground water. In the cognac area there is 8,000 Ha grape fields, and there are 50,000 wine farmers. Courvoisier buys its wine from different farmers, spread over the four best parts of the area, Grand Champagne, Petite Champagne, Borderies and Fins Bois. Harvest takes place in October. The grapes are collected with machines. They are pressed and the juice is fermented in barrels during 10-12 hours. The alcohol percentage of this wine is about 10%.
The distillation process starts in October and ends in March. During this time the wine is distilled and the "wine spirit" or "eau-de-vie" is collected. The distillation process is performed with "Alembics Charentais" of approximately 6 m3 . The alembics have a very typical shape. The red copper alembic resembles the roof of a mosque. Placed on top of the roof is an exhaust pipe with the distinguished shape of a Swan's neck. The first distillation gives the "Brouillis" at 27-30% alc./vol., and lasts about 10 hours. The second, the "Bonne Chauffre" at 68-72% alc./vol., lasts about 12 hours. The potstills are heated with an open flame. Most process control is done manually. Especially the cutting of the different fractions of the distillations is an art, based on the long experience of the operators.
After distillation the "spirits" are aged in oak barrels. The ageing period has a minimal period of 4 years, depending on it's quality. The spirit is traditionally stored in oak barrels in big warehouses. During the ageing period the aroma of the oak gradually attaches to the spirit. This aroma is very specific for cognac. The alcohol percentage decreases from 70% to some 50% due to the evaporation of the alcohol. It is said that the angels take there share. Besides angels also a particular fungi benefits from the evaporating alcohol. Every cognac warehouse is covered with a black layer of micro-organisms and one can smell the scent of alcohol in the narrow streets near the ageing houses. Inside the warehouse, you can smell the cognac so well that it seems like you are drinking it, although our guide, being born in this area, declared that she did not smell it anymore.
When the ageing is completed "The Master" (there is only one) starts his elaborating task of tasting and blending the different spirits into a cognac. After blending the cognac is put to sleep for at least a year. Then the cognac is ready for bottling and can be sold to the consumer.
The quality of the Courvoisieur cognac is carefully monitored in the Courvoisier laboratory. With HPLC the fingerprint of every batch of spirit and cognac is determined. The technology is also used to track fraud sale of fake Courvoisier cognac. Sometimes unsatisfied customers return there purchased cognac because there is deficit in taste. In all cases the customer is provided a new bottle. Like all companies that have a very special trade mark to protect, Courvoisier treats it's customers and it's visitors with the upmost respect.

Thursday May 15

Pasteur Mérieux Connaught, Marcy l'Etoile

12.30 - 14.00Lunch
14.00 - 14.30General presentation by Ms Gosselin
14.30 - 15.30Presentation about the newly built vaccine factory by Mr
15.30 - 17.00Tour around the production sight

Pasteur Mérieux Connaught

Pasteur Mérieux Connaught (PMC) is one of the world leaders in world health. Each year, more than 1 billion doses of vaccines are sold to immunise 400 million people around the world.
Pasteur Mérieux Connaught teams work in close co-operation with World Health Organisation (WHO) and UNICEF, for whom it is the leading supplier of vaccines.
PMC employs more than 5000 people world-wide. Half of the manpower is involved in the four manufacturing operations at Marcy l'Etoile and Val de Reuil in France, in Toronto, Canada and Swiftwater, Pennsylvania in The United States.
The main objective of PMC is to produce preventive and therapeutic vaccines in the areas of infectious diseases and cancers.
Depending on the nature of individual vaccines, the preparation of active ingredients requires a wide diversity of technologies. These differences are dictated by the types of micro- organisms needed to produce a vaccine and their specific culture conditions. Purification processes must be adapted to each antigen. Large capacity fermentation, purification using ultra-centrifugation, and process chromatography techniques are implemented.
The distribution of vaccines is ensured by the facilities in the majority of the countries, or through distribution agreements.

History: The microbiology was born in the 19th century thanks to Louis Pasteur, who demonstrated that infections are linked to micro-organisms.
In 1880, Pasteur demonstrated that infectious diseases, such as streptococcus and pneumococcus, could be prevented by injecting attenuated microbes.
The first human vaccine he created was against rabies, that has been successfully used on the young Joseph Meister. The Institut Pasteur was built in 1888 in Marnes-la-Coquette, France.
Pasteur worked early in his career with the chemist Marcel Mérieux who established the Institut Mérieux Biologique in Lyon in 1897. He manufactured tuberculin and produced therapeutic serums for tetanus and diphtheria. Charles Mérieux succeeded his father in 1937. He worked mainly in the veterinary field and has been succeeded by his son Alain Mérieux in 1967 who made the institute a multinational industrial capacity. In 1968, Rhône-Poulenc acquired a 51% share of the institute, which in 1985 formed an alliance with Institut Pasteur Production.
After the acquisition of Connaught Laboratories in 1989, Pasteur Mérieux Connaught became the world leader in vaccines.
Connaught Laboratories was established before the first World War at the University of Toronto, Canada. The founder was Dr. John FitzGerald who began with the production of tetanus and diphtheria equine-based serums. Connaught has extended its scope with the acquisition of a US affiliate in 1978, and has regularly increased its range of vaccines, which includes rabies and influenza vaccines. In the course of the time Connaught has become one of the most advanced companies in the field of immunological research and development.

Structure: Pasteur Mérieux Connaught has three geographical divisions: Europe, North America and International.
In Europe through Pasteur Merieux Merck Sharp and Dome, a joint venture with the pharmaceuticals group Merck and Co, headquarted in the USA.
In North America, the group has 70 cent of the vaccine market in Canada and over 20 per cent in United States. The activities in these countries are primarily aimed at preventing childhood diseases.
International, it is active on every continent. For example it has a partnership agreement with Shenzhen Kangtai Biologicals in China.

Research: The research program is being carried out by 900 researchers. Pasteur Mérieux Connaught concentrate on four areas of research:
Development of new vaccines targeting a broad range of infectious diseases, particularly childhood respiratory infections. The resurgence of diseases such as tuberculosis and an increased number of antibiotic-resistant bacteria require the development of new preventive responses as rapidly as possible.
Optimisation of existing vaccines, for example influenza vaccine and to simplification of the vaccination process through the development of new administration routes and new combinations of vaccines or by reducing the number of injections. And develop new vaccine vectors to stimulate more effective immune responses. The first pentavalent vaccine has been licensed in 1993. This vaccine is effective against five infantile diseases (diphtheria, tetanus, whooping cough, poliomyelitis and Haemophilus B infections responsible for meningitis and septicaemia).
20% of the research activity is devoted to discovering a vaccine against AIDS. Produce several candidate vaccines to be tested in efficacy trials starting in 1998. There are several projects carried out in association with a number of partners including the World Health Organisation (WHO), and the National Institute of Allergy and Infectious Diseases (NIAID) in the United States.
Open a new perspectives in the treatment of chronic infectious diseases and certain cancers, through immunotherapy. Treating infectious diseases once they have developed by stimulating the immune system. Pasteur Mérieux Connaught is able to envision the treatment of some cancers by stimulating immune responses at different stages of the disease's development, in the absence of micro-organisms.

Alliances: To meet both the needs of preventive medicine on a world-wide scale and current economic dictates a system of strategic alliances is needed. Pasteur Mérieux Connaught has built an international network of collaborators, through partnerships with universities and close links with fast-expanding biotechnology companies.
In France, Institut Pasteur and Agence National de Recherches sur le SIDA (AIDS)
In North America, national Institutes of Health, numerous biotechnology companies and universities.
In Asia, Bangkok Mahidol university in research projects on dengue fever and national Serums and Vaccines Institute.

Future perspectives: Meet more stringent economic demands while providing effective responses for the vaccination needs.
Pursue an ongoing strategy of innovation through major research and development programs.
Establish new links with partners and broaden its geographical presence and extend the product ranges.
Improve the cost-effectiveness of the production processes in order to promote preventive medicine that is accessible to the greatest possible number of people.

Friday May 16

ENILBIO, Poligny
Ecole nationale d'industrie laitière et de biotechnologies

14.00 - 18.00Visit of the biotechnology laboratory, the dairy technology hall, the general food technology hall and the cheese laboratory.

Ecole nationale d'industrie laitière et de biotechnologies

In this tertiary level type of school, comparable to the Dutch >Hogeschool=: the students have fulfilled a basic secondary school after their high school. Four departments can be distinguished among which biotechnology, dairy technology, general food technology and a cheese laboratory. Before these departments are described, a brief introduction to the French educational system ENILBIO is given.

ENILBIO educational system
The goal of the ENILBIO educational system is to satisfy the following four prerequisites:

1 mission of formation
After finishing secondary school students earn a degree called baccalaureate. Student then enter in an educational system which is comparable to the Dutch HTS. Before ending this, they enter ENILBIO in their last year to do some practical work in the field of food technology.
2 applied research
Students perform applied research in teams of four guided by one supervisor. They are confronted with all production methods described beneath.
3 international collaboration
Exchange of students takes place with many countries, among which Canada, Australia, Argentina and several European countries.
4 local animation
Students who participate in the ENILBIO course live on the school premises. In high esteem of the school students should be at their ease. Therefore they are introduced in local life, sports and habits.

This department only meets education purposes: students are introduced in laboratory techniques and analyses which are applied in food technology.
The students are expected to do e.g. lactic acid fermentations, protease production and the fermentation of alcoholic liquors, such as apple cider and wine. Research focuses on temperature, pH, stirrer speed and pO. This is done in (10 L) fermenters which are inoculated with the right yeast to start immediate production.
Analyses of fermentation broths are mainly focused on biomass and activity measurements. Biomass measurement is done by dry weight and optical density determination, activity by RNA activity (fluorescence techniques), ATP-metry (enzymatic) and HPLC.

Dairy technology
This is the department where money is earned due to milk, cheese, butter and yoghurt production. Teams of four students and one supervisor do the work.
First, the milk pasteurisation and skimming takes place. The amount of milk treated is 8,000 L/h. From the cream butter is made twice per week. From the skimmed milk, cheese is produced by lactic acid bacteria. Afterwards the cheese is cut in cubes, whey is removed, the cheeses are pressed in the right shape (1 bar), and cheese maturation takes place: e.g. Morbier and Raclet cheese are produced here.
To produce the yoghurt, two types of bacteria are used: Streptomyces thermophilis and Lactobacillus bulgaricus. Stabilised fruit is added to the yoghurt, to produce different types.

General food technology
Many different types of meat and milk products are processed in this department. The main purpose of this department is to do research with various food handling methods. This is done by students, who may be assisted by people from industry. A part of the department may be used and hired solely by people from industry for use of specialised equipment. Examples of processing methods concern meat shaping, chocolate handling, baking methods, heat treatment and ice cream production.

Cheese laboratory
In this department cheese technology for education and applied research is performed. Research focuses on standardisation of milk for cheese, and studying of cheese yield. Cheese coagulation is researched by measurement of metal migration and pH-temperature relationships. The basis for research is the final product. The reason behind this is reversed engineering, meaning that from the quality and composition the production method can be derived.


List of sponsors

Akzo Nobel N.V.
Hoogewerf Fonds
HWZ Milieu
Royal Gist-brocades N.V.
Stichting Universiteitsfonds Delft
Unilever Research Laboratorium



The organisers wish to thank the sponsors, listed on the previous page, who financially contributed to the study tour.
Furthermore, Professor Karel Luyben, the scientific director of the institute 'Biotechnological Sciences Delft-Leiden' (BSDL), and Professor Gijs van Dedem deserve acknowledgement for their advice and for important letters during the organisation.
Linda Jacobs and Tony Flameling (organiser himself) performed a study at Gist-brocades in order to increase the budget of the participants and Rob van der Lans assisted them with the writing of their report. Without these kind contributions the study tour would probably not have been held as far away as in France.
Hoping that other study tours will follow, the organisers would like to thank all participants and the French people for their enthusiasm.