TECHNIQUES FOR FRACTIONATION, ISOLATION AND ... Emilien Georges Pascal FOLZER aus Mulhouse, Frankreich

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    TECHNIQUES FOR FRACTIONATION, ISOLATION AND

    CHARACTERIZATION OF SUBVISIBLE AND SUBMICRON

    PARTICLES IN BIOPHARMACEUTICAL PREPARATIONS

    Inauguraldissertation zur

    Erlangung der Würde eines Doktors der Philosophie vorgelegt der

    Philosophisch-Naturwissenschaftlichen Fakultät der Universität Basel

    von

    Emilien Georges Pascal FOLZER

    aus Mulhouse, Frankreich

    Basel, 2016

    Originaldokument gespeichert auf dem Dokumentenserver der Universität Basel edoc.unibas.ch

  • Genehmigt von der Philosophisch-Naturwissenschaftlichen Fakultät

    auf Antrag von

    Prof. Dr. Jörg Huwyler (Faculty representative), Dr. Atanas Koulov und Prof. Dr. Wolfgang Friess

    Basel, 13. Oktober 2015

    Dean of Faculty: Prof. Dr. Jörg Schibler

  • LABOR OMNIA VINCIT IMPROBUS.

    Harte Arbeit siegt über alles.

    Virgile, Géorgiques.

    FÜR MEINE ELTERN

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    ACKNOWLEDGEMENTS

    My first “huge thank you” is for Prof. Jörg Huwyler, my PhD supervisor from the university

    Basel. I would like to express my deepest gratitude to Jörg for the possibility to carry out my

    PhD in his research group and for his encouraging support that always motivated me. Thanks

    a lot for keeping up the good spirit in the group; I always felt as a part of the team although

    my regular work place was at Hoffmann-La Roche. Many thanks to Christina Erb, Maya

    Schnell and Carola Seuret who organized the different team events and administrative paper

    work.

    I want to deeply thank Roland Schmidt and Atanas Koulov (Hoffmann-La Roche, Basel), my

    successive line managers during the PhD, for their continuous enthusiasm and interest in my

    work, for the scientific input and advice over the last years. I would also like to thank Prof. Dr.

    Wolfgang Friess from Ludwig-Maximilians-University Munich for taking time and kindly

    being co-referee of this thesis.

    The opportunity to carry out my PhD in Late-Stage Pharmaceutical & Processing

    Development (Hoffmann-La Roche, Basel) came from PD Dr. Hanns-Christian Mahler. I am

    most deeply indebted to him for his outstanding and reliable support in every phase of the

    project. I enjoyed talking and exchanging scientific information concerning my project with

    him. It was my pleasure working with him and I am very grateful for all his valuable and

    honest advice (scientifically but also personally). Many thanks for the “always-good-

    comments” and corrections of the different chapters included into this thesis.

    Many thanks are expressed to all the colleagues belonging to Hanns-Christians organization.

    First, I want to deeply thank the different lab mates that I had during my time in lab 244

    building 72: Caroline Hilbert, Andrea Allmendinger, Anacelia Rios, Dominik Ditter and Tarik

    Khan for the fantastic time, for the fruitful discussions, for the shared lunch-times, for the

    jokes and for the pleasant atmosphere. I would also like to say thank you to Tarik for the help

    and time on determining IgG titer for the in vivo experiments that were carried out for this

    thesis. Then, I would like to thank the different lab members (PTDE-P) that made my time

    inside Roche very enjoyable; special thanks to Stefanie, Severine, Monika, Jason, Mirushe,

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    Fabian, Tatjana, Roger, Rania, Vanessa W., Raphaela, Jenny, Jennifer, Anita, Kevin, Gerd,

    Claude, Vincent, Petteri, Tobias W., Sulabh, Andrea K., Carole and all the others. Adeline,

    Vanessa H., Constanze, Martin, Thomas and Eva-Maria are acknowledged because they

    helped me to order chemicals, HPLC-columns or other materials. I want to thank the lab-

    heads that gave me precious advice and took time for me beside their regular project work.

    Especially, I would like to thank: Claudia Müller, Karin Schoenhammer, Ulla Grauschopf,

    Sylvia Kiese, Astrid Pappenberger, Carmen Lema-Martinez, Robert Müller, Stefan Fisher,

    Kishore Ravuri, Heiko Nalenz, Pierre Goldbach, Michael Adler and Felix Heise.

    To my colleagues from Penzberg, where I could spend 2 months to learn mass spectrometric

    methods and analyze my samples, I want to say a huge thank you, especially to Jana Gassner,

    Lea Bonnington, Dietmar Reusch, Michaela Hook, Marco Thomann, Ingo Lindner, Nadine

    Floeser, Elisabeth Schirmer, Anna-Katharina Heidenreich, Ulrich Gilles, Nadja Alt, Monika

    Gerl, Tobias Kailich, Markus Haberger, Martina Suessmair, Susanne Eltner, Britta Peter,

    Maria Maier, Manuel Schott, Christian Goesswald, Sebastian Malik and Andreas Adler. The

    team of Patrick Bulau - Katrin Bomans, Katharina Diepold, Sadia Golschan, Ayse Koyuncu,

    Sabine Fuchs and Michelle Yegres - is kindly acknowledged for the scientific explanations, the

    precious help and for the wonderful time in lab 110 building 433. Juergen Fichtl and Bernd

    Maier are deeply acknowledged for their help using the Orbitrap systems and computer

    software in order to find out cross-linked species in stressed samples.

    Beat Ernst, Guy Zielinski, Susanne Elmer and Daniel Fishlock are acknowledged for their help

    during synthesis and analysis of reference material of chemically cross-linked amino acids.

    Eric Kusznir and Arne Rufer are acknowledged for their AUC expertise.

    I would like to thank our collaboration partners: Juliana Bessa, Antonio Iglesias, Herman

    Beck, Thomas Bückel, Anja Langenkamp, John Wang, Jun Liu, Tom Patapoff, Valerie

    Quarmby, Volker Schnaible and Björn Boll for the shared immunogenicity work. From the

    Joint Particle Lab, I thank Valerie Kempf, Rita Gruebel, Fabian Stump, Johanna Karbe, Lena

    Josse and Thierry Da Cunha for the nice working atmosphere. From the analytical

    department, I would also like to express my gratitude to Christof Finkler for welcoming me

    into his department to continue my PhD studies. I really appreciated working, learning and

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    talking with qualified and experienced scientists like Stefan Marty and Cécile Avenal. Special

    thanks to Alexia Schumacher for her good mood, the breaks and funny chat sessions on the

    messenger.

    From the university research group, I would like to thank all the members especially Urs

    Dutaler, Isabel Meister, Daniel Preisig, Maxim Puchkov, Rainer Alles, Tanja Stirniman,

    Veronika Eberle, Sandro Sieber, Leonie Hattler, Helen Kettiger, Philip Grossen, Marine

    Camblin, Fabiola Porta, Gabriella Québatte and Le-Ha Dieu. All colleagues from Jörg’s group

    are kindly acknowledged for their welcoming and integrative attitude and for sharing good

    time during the supervision of the pharmaceutical technology practical courses.

    I would like to say a big thank you for the fantastic time that I spent with all the different

    people that I could met during Blind-date-lunches; Adeline, Paola, Shijun, Margot, Richard,

    Christine and Caroline. Specials thanks to Kristina, that always made me laugh and forget

    work during our lunch times.

    I want to thank my friends from sport (handball, running, swimming): Axel, David, Mika,

    Titi, Christophe, Malik, Tom, Stéphane, Jean-Claude and all the others. Around 1400 trips by

    train to go and come back from the lab gave me the chance to meet amazing people; all of

    them contributed to my happiness and good mood during the PhD. Thanks to Liliane,

    Corine, Yves, Geogette, Jérome, Josée, Marc, Catherine, Kiersten, Jean-Claude, Thierry, Gilles,

    Claude, Philippe and Malhom for the pleasant discussions and exchanges in the train or on

    the SNCF-platform (waiting trains that were late!). I also would like to thank my closest

    friends Louise, Céline, Yannick, Florian, Paméla, Mathieu, Maroussia, Stéphane and Julia:

    thank you for our precious friendship.

    Many thanks go to my new colleagues from the Parenteral Production (Hoffmann-La Roche,

    Basel) who made me feel welcome as a part of the team since my first day, beginning of May

    2015. Therefore I would like to thank Jörn, Regula, James, Elin, Christian, Jonas, Zoran,

    Alexia, Michael, Ute, Silke, Roman, Lisa, Theresa, Didier, Sieglinde, Sabina, Livia, Theresa,

    Claudia, Lara, Yvonne, Annika, Marcel, Walter, Antonietta, Tobias, Olivera, Jean-Pierre,

    Mike, Achim, Jörg, Alice, Flavia, Didier, Andreas, Juri, Christophe, Adrian, Joanna, Gueler,

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    Cristina, Samantha, Elisabeth and all the others for the pleasant working atmosphere and all

    the good moments that we shared until now.

    Finally, and most important I want to thank my wonderful family and especially my parents

    (Pascal and Madeleine) and my grandmother for their love, their encouragement, and support

    throughout my entire study-time.

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    SUMMARY

    Therapeutic proteins have assumed a key role in the treatment of various diseases such as

    cancer, inflammation, viral infections, metabolic disorders and diseases of the central nervous

    system.1 However, physical and chemical instability present a challenge in the development of

    protein therapeutics. Physical (e.g. unfolding, de