Full Title:Biopharmaceutical Processing (Upstream)
Language of Instruction:English
Module Code:PHAR S8006
 
Credits: 7.5
Valid From:Semester 2 - 2018/19 ( February 2019 )
Module Delivered in 2 programme(s)
Module Description:The aim of this module is to provide the students with an in-depth knowledge of the upstream processing of biopharmaceuticals (both theoretical and practical topics pertaining to the development, sourcing and production of biopharmaceuticals).
Learning Outcomes:
On successful completion of this module the learner should be able to
  1. Choose appropriate host/vector systems and transfection technologies required for the production of particular recombinant proteins.
  2. Design facility lay-outs including details on the practices, equipment and materials required for the upstream processing of biopharmaceuticals.
  3. Evaluate how plasmid vectors can be generated/modified in vitro to facilitate high, and sustainable, production levels of recombinant biopharmaceuticals.
  4. Synthesise both the apoptosis process and approaches for its detection using online and offline methodologies.
  5. Create solutions to overcome the problems associated with bioreactor up-scaling.
  6. Apply practical competence in selected molecular and cell culture related techniques.
 

Module Content & Assessment

Indicative Content
COURSE CONTENT
n/a
A review of recombinant product generation and the industry
Detailed overview of gene requirements for expression of a recombinant gene, e.g. promotor, enhancer, selection, suppression, on/off on demand expression etc. Genetic manipulation of cells; expression vectors, transfection, selection, cloning, and characterisation. Recombinant E. coli and other recombinant prokaryotic systems. Yeast and fungal cell culture systems. Recombinant mammalian cell lines and hybridoma cell lines. Chinese Hamster Ovary (CHO) cells as expression systems. CHO genomics. Impact of temperature shifts and microRNAs on the CHO proteome. The arrival of biosimilar production and the challenges ahead for the blockbuster-drug producing companies.
Cell-culture facility design, cell culture & associated practices
Considerations for design of a cell culture facility incorporating equipment and protocols. Understand the generation and maintenance of master cell banks, and working cell banks; theory, practice and regulations, freezing/thawing cells, maintaining a cell line, characterisation of cells, sub-culture of cells, monitoring growth and viability. Growth media, serum-free media, media development will also be discussed. Types of culture systems: attached cells (cell factories, roller bottles, hollow fibre bioreactors), suspension cells (stirred tank, airlift and wave bioreactors) and hybrid systems. Single use/disposable bioreactors. Problems of scale up from laboratory to pilot plant to industrial scale, comparability and the use of small-scale models. Fed batch vs Perfusion/Continuous culturing. Cleaning and carryover calculations. Cleaning Validation.
Bioprocess practices
Process design/Flowchart overivew of upstream bioprocess. Cell metabolism and process monitoring, Warburg effect. Viral contamination of biprocessing facilities; Viral clearance and strategies to mitigate risk; Gassing strategies in bioreactors (Kla); real-time release testing in biopharmaceutical manufacturing. Process validation lifecycle approach and ongoing process verification; Lab models vs commercial considerations.
Post-translational modifications
Regulation of post-translational modifications of recombinant proteins and metabolic engineering to control glycosylation with a focus on fucosylation prevention of monoclonal antibodies. C-terminal lysine and clinical relevance.
Apoptosis overview, its detection and its prevention in cultures.
An overview of Apoptosis, with a view to extending the life cycle of cells in a batch environment to increase protein production. The use of online probes and offline techniques to detect apoposis will be discussed.
Advanced Molecular Biology approaches & recent trends
Targeted gene integration, gene knock-out and knock in approaches; small interfering RNA (siRNA) and short hairpin RNA (shRNA), various omics technologies; Dihydrofolate reductase based gene amplification and its advantages in recombinant gene expression, applications of restriction enzymes in building recombinant cell lines, ligations, transformations, transfection technologies. Methods to combat 'the position effect' to increase product titre (for example plasmid insertion elements such as S/MARs, Barrier elements, insulators sequences etc. in addition to various gene targeting methods).
LEARNING & TEACHING RESOURCES
n/a
Format of Lecture series
Lecture delivery will comprise a range of methodology including on-line movie animations, visual demonstrations, large diagrams for illustration purposes as well as information and slide handouts. Novel methods using smartphone web/app based quizzes will also be utilised. Course material and revision quizzes will be made readily available on a virtual learning environment (VLE) for student access. The combination of these methods will facilitate in re-enforcing the student’s understanding of some of the technical and mechanistic processes involved. Various aligned classroom assessment techniques will also be employed. These will sometimes include the background knowledge probe, the one minute paper, small group interaction and discussion, question & answer sessions, team presentations to class colleagues, pop-quizzes and open ended questioning. Access to course textbooks will be provided through the DkIT eBook service, which will allow students 24/7 access to suitable reading material. A range of self-assessment, self-reflection and peer learning exercises will be built in to deliveries of both lectures and practical sessions. Relevant publications in the field that complement the course will also be provided to the students. These will inform class discussions throughout the module.
Weekly Practical Sessions
Students will attend weekly practical sessions during the module to improve their practical knowledge and skill set. These practicals build on the laboratory experience gained over the previous three years of the students' time in college. In these sessions, topics will be delivered using various approaches, e.g., use of pre-practical videos combined with smartphone based quizzes, digital feedback approaches, delivery via instructor led 'dry' lab practical sessions covering theoretical examples/overviews/audiovisual content/demonstrations showing techniques in detail, via practical sessions at the National Institute for Bioprocessing Research and Training (NIBRT) at UCD in addition to 'wet' lab practical sessions in DkIT. Using instructor led demonstrations/audiovisual content/formative exercises, students will be gain an overview of the details in involved in growing, splitting, waking & freezing cells in culture in addition to aseptic technique and cell culture etiquette. Students will also learn about adherent vs suspension cells, media components, monitoring cell growth, generating master and working cell banks, reducing risks of contamination, detecting contamination (e.g. mycoplasma detection using PCR). As an exercise, students will design a cell culture facility, providing explanations for the layout design and the equipment included. In the DkIT 'wet' labs of the module, students will use antibodies to detect presence/absence of proteins in cell samples using ELISAs, use PCR as a detection tool to test for the presence/absence of specific target sequences in samples, build plasmids through ligations to contain a gene of interest and perform blue/white screening in E.coli to ensure gene of interest is cloned correctly (this builds the student's knowledge of plasmid generation ahead of our lecture series on transfection technology). At the NIBRT facility, students will perform two practical sessions. In session 1, students will thaw a vial of suspension Chinese Hamster Ovary (CHO) cells and inoculate shake flasks; perform a routine passage of cells using aseptic technique; count cells using automatic and manual methods; analyse CHO cell culture using Nova bioprofiler; analyse cells after trypan blue staining. In session 2 at NIBRT, students will either work with a disposable bioreactor or will set-up a 150L Bioreactor for SIP as follows - includes removing sprayballs, changing sparger, put elbows in place, calibrate probes etc; students will identify SIP protocol using P&ID; run pressure test and SIP of the 150L bioreactor; disassemble SIP equipment and prepare bioreactor for CIP by fitting spray balls etc. Where possible, a site-visit to a local industry plant is also performed/or guest speakers will be invited to DkIT. A video-based project is also performed to improve teamwork, communication skills while also stimulating creativity.
Video Project (Technology enhanced learning)
Students will work in teams of three and will have one week to record a digital high-definition 2-4 minute video explaining a scientific topic of relevance to a general audience. Its design engages the students with teamwork, brain storming, creativity, technology and also improves their science communication skills.
Virtual Learning Environment (VLE)
All lecture notes will be provided to the students through a VLE. This VLE will also be used for access to helpful YouTube video clips and peer reviewed publications of interest to the course. Students will have 24/7 access to the VLE allowing them to download and study at their own pace and in their own time. Screencast and Podcast tutorials will also be made available to the students to download and listen to in their own time. This will facilitate learning and understanding for all students, but in particular the international students who may not have English as their first language.
Formative Assessments
Throughout the semester, students will be provided with formative assessments both in lectures and in laboratory environments. These are designed to facilitate group work in problem solving situations. These assessments are built in to the lecture and practical components.
Keeping up-to-date with the Biopharmaceutical industry
Break throughs in the Biopharmaceutical field will be sent to the students on a regular basis. This will involve novel developments in the field in addition to postings on jobs/careers in the industry. This concept facilitates the students in preparing for life after college in the Biopharm industry.
ASSESSMENT STRATEGY
n/a
Continuous Assessment/Practicals
Students will participate in weekly laboratory-based practical sessions as outlined above. Students will perform formal written lab reports/practical class tests in addition to various formative skill tests throughout the module to improve their communication and practical abilities. During the module, the students will spend one day at the National Institute for Bioprocessing Research and Training (NIBRT) at University College Dublin. This day will expose the students to biopharmaceutical plant equipment and systems involved in Upstream Processing. Formative assessments will be performed during the practical sessions which will centre around group work and peer assisted learning. The summative practical assessments will be joined by a summative video project assessment. Students will work in teams of three and will have one week to record a digital high-definition 2-4 minute video clip explaining a scientific topic of relevance to a general audience. Its design engages the students with teamwork, brain storming, creativity, technology and also improves their science communication skills.
Assessment Breakdown%
Practical40.00%
End of Module Formal Examination60.00%

Full Time

No Course Work
No Project
Practical
Assessment Type Assessment Description Outcome addressed % of total Marks Out Of Pass Marks Assessment Date Duration
Practical/Skills Evaluation Students will participate in weekly laboratory-based practical sessions in which formative assessments will be performed in interactive group settings (e.g. problem based learning, competency skill-set tests, quizzes, protocol review exercises, worksheet completion etc.). Summative practical assessments will be submitted in addition to a relevant class test and team-based, science/technique based video project. 2,3,4,5,6 40.00 0 0 Every Week 180
End of Module Formal Examination
Assessment Type Assessment Description Outcome addressed % of total Marks Out Of Pass Marks Assessment Date Duration
Formal Exam End-of-Semester Final Examination 1,2,3,4,5 60.00 0 0 End-of-Semester 120

DKIT reserves the right to alter the nature and timings of assessment

 

Module Workload & Resources

Workload: Full Time
Workload Type Workload Description Hours Frequency Average Weekly Learner Workload
Lecture 3 x 1 hour lectures 3.00 Every Week 3.00
Practical 1 x 3 hour lab session 3.00 Every Week 3.00
Directed Reading Notes / Paper / Textbook reading 2.00 Every Week 2.00
Independent Study Self / group study 5.00 Every Week 5.00
Total Weekly Learner Workload 13.00
Total Weekly Contact Hours 6.00
This course has no Part Time workload.
Resources
Recommended Book Resources
  • Michael Butler 2007, Cell Culture and Upstream Processing, Taylor and Francis Group Available on the DkIT NetLibrary collection
  • Shijie Liu 2016, Bioprocess Engineering : Kinetics, Biosystems, Sustainability, and Reactor Design, 2 Ed., Elsevier
  • Walsh, G. 2013, Biopharmaceuticals: Biochemistry and biotechnology, 2nd Ed., J. Wiley and Sons
  • John M. Davis 2011, Animal Cell Culture: Essential Methods, 1 Ed., Wiley
  • Butler, M. 2004, Animal cell technology, 2nd Ed., BIOS Scientific,
  • William Whyte 2010, Cleanroom Technology: Fundamentals of Design, Testing and Operation, 2nd Ed., Wiley
  • John R. W. Masters 2000, Animal Cell Culture: A Practical Approach, 3 Ed., Oxford University Press
  • Roshni L. Dutton and Jeno M. Scharer 2007, Advanced technologies in biopharmaceutical processing, 1 Ed., Blackwell Pub
  • Glyn Stacey And John Davis 2007, Medicines from animal cell culture, Wiley
  • Pauline M. Doran 2012, Bioprocess Engineering Principles, 2 Ed., Academic Press
Supplementary Book Resources
  • Stefan Behme 2015, Manufacturing of Pharmaceutical Proteins, 2nd Ed., Wiley
  • Gerd Gellissen 2006, Production of recombinant proteins : novel microbial and eukaryotic expression systems, Wiley
  • Ganapathy Subramanian 2012, Biopharmaceutical Production Technology, Wiley
  • Elmar Heinzle, Arno P. Biwer, Charles L. Cooney. 2007, Development of sustainable bioprocesses : modeling and assessment, Wiley
  • Sadettin Ozturk & Wei-Shou Hu 2006, Cell Culture Technology for Pharmaceutical and Cell-Based Therapies (Biotechnology and Bioprocessing), Taylor and Francis Group
  • R. Ian Freshney 2011, Culture of Animal Cells: A Manual of Basic Technique and Specialized Applications, 6 Ed., Wiley-Blackwell
This module does not have any article/paper resources
Other Resources
  • Textbook collection online with DkIT: 'Access online textbooks through DkIT's eBook collection (go to DkiT library site to begin)'
  • website: Biopharm International
  • website: Science Break-throughs: www.breebio.com
  • website: American tissue culture collection http://www.atcc.com
  • website: European Directorate for the Quality of Medicines and Healthcare http://www.edqm.eu
  • website: European Medicines Agency http://www.ema.europa.eu/ema/
  • website: International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) http://www.ich.org/
  • website: HPRA http://www.hpra.ie/
  • website: 'U.S. Food and Drug Administration http://www.fda.gov'
  • website: The National Institute for Bioprocessing Research and Training (NIBRT): www.nibrt.ie
  • website: Bioconnect Ireland: www.biotechnologyireland.com

Module Delivered in

Programme Code Programme Semester Delivery
Dk_NLBIO_8 Bachelor of Science (Honours) in Biopharmaceutical Science (2019) 7 Mandatory
DK_NLBIA_8 Bachelor of Science (Honours) in Biopharmaceutical Science (add-on) (2019) 1 Mandatory