Trends, technologies and interest in Continous Processing

by  Dr Margit Holzer, Scientific Director, Ulysse Consult

Minimizing operational costs and capital expenditures is a considerable challenge for production in the Biopharmaceutical industry.  Many different contributions have to be taken into account when calculating these costs – capital investment, materials, consumables, labour, utilities, waste handling together with development, scale up, qualification and validation time and costs, etc – all add up to make production expensive.

One way to address this issue is to switch processes from batch ones to continuous ones; which are well established in other industries like food processing.  When switching, the entire physical processing installation could be shrunk: necessary clean rooms, utilities, tank farms, processing and other equipment can often be reduced by half and operating costs for production, cleaning, analyses can be reduced significantly.

In 2007, Novasep published a cost study showing that a switch from batch to continuous downstream processing of Monoclonal Antibodies could reduce operational costs by 69% – a huge reduction and a very promising way to achieve a more economical production chain.

The question is then: how can one convert current batch processes into continuous ones?  Related challenges include issues of quality and process control and the need for further process understanding and characterization. However, modern technologies using the approach of Process Analytical Technologies (PAT) for  in-line/at-line/on-line controls allow getting the adequate level of information on process performance as well as a tighter control of product quality during development, scale up and production. A more structured & scientific approach of process characterization and design facilitated by using process simulation tools is equally desirable both for batch and continuous process, for  developers and for regulatory bodies.

Switching a batch chromatography step to a continuous process has been challenging during many years.  The main reasons were/are:

  • the chromatographic process needs to be robust and integrate cleaning steps,
  • the equipment (including that required for process monitoring/control strategy) needs to be extremely reliable, cleanable and easy to handle & maintained,
  • it must be possible to qualify and validate the equipment, the software, the process and the cleaning to meet regulatory standards,
  • the “where is my batch syndrome”: while the batch size is perceived as naturally defined in a discontinuous process, it requires definition with continuous processes. Let us notice that these definitions have already been accepted by authorities for several  APIs.

Last but not least, regulatory bodies like the FDA support the implementation of continuous manufacturing using a science and risk-based approach because this can result in an improvement of critical quality attributes, more process control, less product holding time and processing in steady state conditions.

The EMA and FDA assess QbD

“The European Medicines Agency (EMA) and the United States Food Drug Administration (US FDA) have published a joint question and answer document that outlines the conclusions of their first parallel assessment of quality-by-design (QbD) elements of marketing-authorisation applications.

Quality-by-design is a science- and risk-based approach to pharmaceutical development and manufacturing that was introduced a few years ago in international guidelines intended for the pharmaceutical industry. QbD involves the use of statistical, analytical and risk-assessment methods to design and develop pharmaceutical compounds and manufacturing processes to ensure the quality of the manufactured product.

. . .

The objective of this parallel assessment is to share knowledge, facilitate a consistent implementation of the international guidelines on the implementation of the QbD concept (International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) guidelines Q8, Q9, Q10 and Q11) and promote the availability of pharmaceutical products of consistent quality throughout the European Union and the US.”

At BioProduction this year we have a dedicated QbD track:
QbD: Development through to Biomanufacturing

At this year’s event we have case studies highlighting the successful implementation of QbD; advice on how to get your QbD programme passed by the regulators; and the implementation of QbD for upstream processing.

Our QbD speakers include:

  • Dr Mark Uden, Head of Biopharm Process Research, The Biopharm R&D Unit, GlaxoSmithKline, UK
  • Dr Patrick Gammell, Principal Development Scientist, Pfizer, Ireland
  • Dr Alex Eon-Duval, Project Coordinator, Biotech Process Sciences, Merck Serono SA, Switzerland
  • Dr Brij Patel, Deputy Manager and Assessor, MHRA, UK

For more information about BioProduction 2013 and what you can learn from our QbD expert speakers, visit our website

The First Biosimilar Antibody Therapeutic is Approved by the EMA

bioprod no background guest blog

This week’s BioProduction blog post is by Professor Roy Jefferis, Division of Immunity and Infection, University of Birmingham, UK

“The EMA has approved the biosimilar Remsima for all indications for which the innovator product Remicade (Infliximab) is approved. Approval by the EMA is seen as a landmark event as I understand some biosimilar programmes have been progressed slowly, partly due to uncertainty and/or lack of confidence in regulatory approval pathways. Importantly, approval for Remsima demonstrates that the EMA has confidence in its ability to evaluate the comparability of biosimilar antibody products. The successful development and approval of Remsima, following EMA guidelines, may act as an incentive for the biosimilar “industry” and establishment of definitive FDA guidelines.

The EMA website announcement includes the following statement:

“Remsima is a biological medicinal product similar to the reference product Remicade (infliximab) authorised in the European Union since 13 August 1999. Studies have shown Remsima to have a comparable quality, safety and efficacy profile to Remicade (infliximab). A pharmacovigilance plan for Remsima will be implemented as part of the marketing authorisation.”

http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/002576/smops/Positive/human_smop_000532.jsp&mid=WC0b01ac058001d127

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM291128.pdf

To find out more about Roy’s presentation at BioProduction this year, please visit our website

The Value of Small Scale Studies

mic image

BioProduction recently caught up with Brij Patel, Deputy Manager and Assessor, MHRA to find out more about his upcoming talk at this year’s event and what attendees can take away from his session

BioProduction (BP): Could you give us a brief overview of your key research interestes?

Brij Patel (Brij): Originally, my research experience stems from work with vaccines and drug delivery technology. I still remain interested in vaccines and biotech products, but now from a regulatory perspective (where I have had considerable experience as a regulatory evaluator for biological products on both MHRA and EMA applications).

BP: What can industry gain from this?

Brij: The ultimate aim is to attain regulatory approval – as fast and as efficiently as possible. My previous regulatory experience would provide an insight into how regulators assess risks and solutions.

BP: And what work will you be presenting at BioProduction this year?

Brij: EU regulators have now come across a number of QbD applications for biological products. There is obviously a “disconnect” between industry and regulators. I would like to present a reflection on regulatory experience with biological QbD

BP: What will our delegates gain by attending your presentation and session? What is the message you would like them to leave with?

Brij: Some of the key issues include agreement on risk assessments, the value of small scale studies, and regulatory flexibility. Communication (appropriate detail, at the right times, FTF meetings) is critical in order to persuade the regulator when deviating from the usual

BP: How will the industry look in 2-3 years? What challenges will still remain/would have been overcome?

Brij: QbD principles will be built into most programmes. The issue will be how to get ROI

BP: What did you want to be when you were young?

Brij: Useful

For more information about Brij’s talk and all of our other presentations, please visit our website or download the brochure

 

Dinosaurs Can Evolve: Examples of Bioprocess Legacies in Action

“Barring fire, major eartherquakes, or volcanic catastrophe, concrete is good for centuries – the Pantheon has been in continuous use since 126AD. The long expected life and high initial cost of biomanufacturing buildings and equipment builds legacy into the system from the start. And the imperatives of launching a new biotechnology industry in the 1980s led to the building of many facilities within a few years to product the first wave of recombinant DNA products.”
(The Dinosaurs Can Evolve – Some Examples of Bioprocess Legacies in Action by Ellen M. Martin)

CHO expression is a legacy in several senses. In use since the 1980s, CHO systems today produce four of the top five blockbuster biologic products and remain the most common cell expression technology (making – 70% of biologics). How did CHO cells hold on to that dominance for a quarter of a century despite the hundreds of alternative expression systems that have emerged? Many alternative expression companies were founded with the expectation of beating the cost of CHO production, only to find the bar rising higher than when they were funded. The industry is partial to CHO, so we keep inventing new ways to get continual improvement out of CHO systems.

Download more information and other examples of bioprocess legacies for both upstream and downstream: The Dinosaurs Can Evolve by Ellen M. Martin

Included in Track 1 and 2 of BioProduction 2013 are talks that will address a mixture of CHO and alternative expression systems. Mark Ellis from UCB Celltech will talk about their experiences of using E. coli periplasmic expression of Fab’ fragments whilst Dr Gavin Davey from Trinity College Dublin, will talk about controlling N- and O- linked glycosylation in CHO cells.

Please visit the website for more information

What Can Industry Gain from Bioprocessing Using Animal Host Cells?

interview

An insight from Dr. Hermann Katinger,
em.Univ.Prof., Boku Wien, CSO Polymun Scientific

We recently had a chance to discuss with Dr. Katinger about his upcoming presentation at this year’s BioProduction.

BioProduction (BP): Can you please give us a brief overview of your key research interests

Dr. Katinger (Dr.K): For 4 decades I have been involved in R&D of bioprocessing using animal host cells for the production of a wide number of glycoproteins. Basically I have a particular interest in advances of immunological research and the molecular mechanism of biological communication.

BP: What can industry gain from this?

Dr.K: New perspectives for innovative biopharmaceuticals

BP: And what work will you be presenting at the 2013 BioProduction conference?

Dr.K: I shall present a case study concerning the manufacture of a CHO recombinant natural human IgM antibody for further clinical exploitation. This IgM was originally established from blood of a healthy person and is recognising several malignant cancer cells

BP: What will delegates gain by attending your presentation and session? What is the message you would like them to leave with?

Dr.K: IgM antibodies represent extremely large and complex glycoproteins which are not very easy to produce. I want to show how we establish a manufacturing platform and create awareness that natural IgMs might have potentials to avoid or treat cancer

BP: What is the No.1 challenge facing the bioprocessing industry at the moment?

Dr.K: Stagnation of innovation of therapeutics to improve treatment of cancer, neurodegenerative diseases and chronically inflammatory diseases

BP: What was the last “breakthrough” technology you either bought or used?

Dr.K: I think it was the introduction of purification of proteins with affinity ligands

BP: How will the industry look in 2-3 years? What challenges will still remain/would have been overcome?

Dr.K: I wish that personalised medicine will develop to become more of a reality than at present. Biomarker research and epigenetics would serve as promoters

BP: What other sessions/talks are you interested in attending at this year’s event?

Dr.K: My focus will be on downstream processing

BP: Are there any articles that you would recommend the audience follow that relates to your area?

Dr.K: Publications reviewing research on innate immunity

BP: And finally, on a lighter note, what did you want to be when you were young?

Dr.K: Champion in downhill ski-racing

images
Thanks to Dr. Katinger for his insights into bioprocessing and recombinant antibodies – for more speaker insights and industry articles, please visit the website