High Throughput Process Development Tools at Novartis Pharma

High throughput tools and scale-down models are of increasing interest to the biopharmaceutical industry where they can be used to perform process research quickly and without the expense of running experiments at production or pilot-scales. Technologies are being developed and used to study both upstream processing and downstream processing steps and both will form sessions at BioProduction Europe 2015 (www.bio-production.com) to be held in Dublin in October.

One field of process research in which high throughput process development tools are particularly applicable is in the generation of process design spaces as part of process characterization activities. Process characterization studies are typically performed during late stage process development in order to develop robust process control strategies for process qualification and commercial manufacturing batches. Biopharmaceutical companies are increasingly adopting Quality by Design methodologies in order to characterize their bioprocesses. This ensures that when operating within their defined design space their manufactured products will have the necessary critical quality attributes for them to be safe and efficacious.

High Throughput Process Development Tools at Novartis Pharma

Jean Aucamp, novartis
Dr Jean Aucamp, Lab Head in Protein Processing at Novartis Pharma AG
says the following of Novartis’ use of high throughput techniques for developing chromatography steps, “High-throughput process development (HTPD) is an approach where experimentation can be parallelized and automated in order to investigate large process design spaces quickly. There are numerous ways to conduct chromatography studies in high-throughput mode. HTPD chromatography refers to protein purification studies performed using miniaturized chromatography columns and a liquid-handling work station. At Novartis this technology is used across all stages of development to support column purification studies and shorten project timelines”.

The challenge high throughput process development technologies present, however, is the extent to which they replicate the performance of the large-scale. If they poorly represent large-scale performance the design spaces generated could potentially be meaningless. Dr Aucamp says the following “It is well known that results obtained from chromatography studies performed in high-throughput mode do not compare directly to laboratory-scale data.” Novartis have conducted a series of fundamental studies looking at the discrepancy in process data between laboratory and high throughput technologies which will be presented at the BioProduction Europe Conference.

Describing the outcomes of the work Dr Aucamp said “A better understanding of the differences that lead to scale offsets was obtained. This understanding allowed the development of an approach where results from the different scales can be better related.”

Dr Aucamp’s presentation “Assessment and Implementation of HTPD Chromatography for Process Characterisation Studies” is scheduled for 5pm on 15th October as part of the Downstream Processing Track.

Have your say

To what extent has your organization implemented High Throughput Process Development? What are they key challenges you have experienced?

Dr Nick Hutchinson

Dr Nick Hutchinson

Join me at #Bioproduction15

Contact me at nick.hutchinson@parker.com

Dr Nick Hutchinson has a Masters and Doctorate in Biochemical Engineering from University College London, UK where he focused on laboratory tools for rapid bioprocess development and characterization. He then worked at Lonza Biologics in an R&D function investigating novel methods for large-scale antibody purification before moving to an operational role scaling-up and transferring manufacturing processes between Lonza sites in the UK, Spain and USA. Nick now works in Market Development at Parker domnick hunter where his focus is in bringing Parker’s strengths in Motion & Control to Bioprocessing. This will enable customers to improve the quality and deliverability of existing and future biopharmaceuticals.

Continuous Manufacturing within the Biopharmaceutical Industry

Continuous manufacturing is a key topic within the biopharmaceutical industry at the moment. The topic will be the focus of one of the five tracks at BioProduction 2015 which will be held in Dublin in October (www.bio-production.com).

Why then is continuous biomanufacturing attracting such a lot of attention at the moment? Despite much analysis the answer to this question is in fact not that simple.

Continuous Upstream Bioprocessing

Performing cell culture in a continuous fashion has always made sense when the biopharmaceutical being expressed was vulnerable to degradation within the environment of the bioreactor. Monoclonal antibodies which have historically been key drivers for growth within the industry and are usually relatively stable, but biopharmaceutical companies these days can have diverse pipelines which include other recombinant human proteins including enzymes which can have their quality reduced by prolong exposure to bioreactor conditions.

Another reason for implementing continuous upstream bioprocessing is that it allows higher cell concentrations and product titres to be achieved. In this way, the same amount of product can be manufactured in smaller bioreactors. Utilizing smaller bioreactors reduces the capital cost of the vessel itself but also enables the use of single-use bioreactor technology thereby saving money, time and complexity in the set-up of utilities required to run a stainless steel system. The burden of battling the laws of physics in scaling up to 15,000L or even 20,000L bioreactors becomes diminished although it can be argued it is replaced with the burden of battling the danger of microbial ingress leading to contaminations. Increasing production output of perfusion systems is typically achieved by increasing the number of bioreactors rather than increasing the size. This can allow operational flexibility, not only, as to when product is produced but where. In this way biomanufacturers can choose to produce biologics allow over the world and close to emerging markets as part of global supply chain networks.

Continuous Downstream Bioprocessing

A key driver for the operation of downstream processes in a continuous manner has been the significant increase in upstream product titres that have occurred over the past 15 years. This has created purification bottlenecks that must be addressed to ensure all the product synthesised can be purified. Continuous chromatography technology has come of age in recent years and is being promoted as a viable alternative to traditional batch methods. In industries in which continuous chromatography is more common it increases resin utilization, reduces down time and optimizes consumable costs including buffer components.

Integration of Upstream and Downstream Continuous Steps

Genzyme, in particular, have stressed that for the full potential of continuous bioprocessing to be realised continuous upstream and downstream operations must be effectively integrated. They achieved this by using hollow fibre filtration and the alternating tangential flow system to give a highly clarified filtrate that can feed a continuous operated capture chromatography step. This philosophy of coupling upstream and downstream steps will be the subject of a Knowledge Exchange Roundtable Discussion featuring Neha Shah of Genzyme and Massimo Morbidelli at the BioProduction 2015 event.

If you are simply considering whether continuous bioprocessing will suite your product, you are planning your approach or you are seeking to overcome challenges in the implementation, this is an event you must attend this autumn.

Dr Nick Hutchinson

Dr Nick Hutchinson

Join me at #Bioproduction15

Contact me at nick.hutchinson@parker.com

Dr Nick Hutchinson has a Masters and Doctorate in Biochemical Engineering from University College London, UK where he focused on laboratory tools for rapid bioprocess development and characterization. He then worked at Lonza Biologics in an R&D function investigating novel methods for large-scale antibody purification before moving to an operational role scaling-up and transferring manufacturing processes between Lonza sites in the UK, Spain and USA. Nick now works in Market Development at Parker domnick hunter where his focus is in bringing Parker’s strengths in Motion & Control to Bioprocessing. This will enable customers to improve the quality and deliverability of existing and future biopharmaceuticals.

BioProduction 2015 – 4 Conferences, 1 Forum, 1 Exhibition

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14-15 October 2015

Citywest Conference & Event Centre, Dublin, Ireland

www.bio-production.com

Benchmark technological developments and explore best practices in biomanufacturing

The Bio Pharmaceutical industry is making a capital investment of approximately $8 billion in new facilities in Ireland, most of which has come in the last 10 years, representing close to the biggest wave of investment in new BioTech facilities anywhere in the world.

Join us at BioProduction 2015 in Dublin this October to see why so much is being invested in this area and to network with leading players within this growing industry!

BioProduction 2015: Europe’s leading and largest event for a comprehensive update on all aspects of large scale biological manufacturing. Providing insights on the latest technologies, upstream/downstream processing, process analytics, the implementation of continuous manufacturing, facility design, flexibility facilities and single use systems to reduce inefficiencies during the bio manufacturing process.

4 Conferences – 1 Exhibition – 1 Congress

  • Conference 1: Continuous Manufacturing
  • Conference 2: Upstream Processing- Production, Development & Analytics
  • Conference 3: Manufacturing Strategy & Technology
  • Conference 4: Downstream Processing

250+ Industry Experts – 130+ Companies Represented – 10 Interactive Discussions

Global panel of senior level industry professionals companies including:

  • Sean McEwen, Vice President, Biologics Manufacturing, AbbVie, Ireland
  • Guy McDonnell, Director of Engineering & EHS, Pfizer, Ireland
  • Trent Carrier, Vice President, Vaccine Technology & Engineering, Takeda Vaccines, USA
  • Roman Necina, Vice President Process Science & Technical Operations, Baxalta, Austria
  • Thilo Henckel, Vice President Manufacturing, Roche Diagnostics GmbH, Germany
  • Lada Laenen, Senior Director; Allston Landing Manufacturing Science and Technologies Head, Genzyme Corporation, USA
  • Lars Dreesmann, Executive Director, Head of Clinical Supply & Transfer, Biopharma Bioprocess & Pharmaceutical Development, Boehringer Ingelheim, Germany
  • Ciaran Brady, Director, Biotech Technical Services/ Manufacturing Sciences, Eli Lilly and Company, Ireland
  • Joe Runner, Manufacturing Technical Specialist, Genentech, USA
  • Weibing Ding, Principal Scientist, Process Development, Amgen Inc., USA

For more information on the 2015 event please visit the event website at www.bio-production.com

Pause For Analysis – Cheryl Scott, Senior Technical Editor, BPI Magazine

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For over a decade, BioProcess International has considered analytical methods to be such an integral part of biopharmaceutical product and process development — across the board — that in our rotating thematic arrangement of issues (upstream, downstream, manufacturing, and the new bioexecutive theme in December) we never thought to include a separate “analytical” theme.  After all, production process development (the focus of our January, April, and September issues) involves cell-line engineering and characterization, media optimization studies, and methods validation. Downstream process development (February, May, and October) involves viral safety issues, chromatography optimization studies, and more validation work. With its focus more on product than process, our manufacturing theme (March, June, and November) has often encompassed preformulation/formulation work and product characterization as well as quality assurance and control.

When we looked at the evolving approaches to FDA’s quality by design (QbD) initiative, it all made sense to us. You can’t have any of those things without a strong analytical laboratory and documented understanding of process and product. The dawning biosimilars era underscores our case. The only way that such products can be offered to patients at lower prices than their corresponding originator drugs is if they can be made more efficiently, at less cost, without compromising quality, safety, or efficacy. So how will biosimilars manufacturers do that? They need to cut out expensive clinical trials, for one thing — and the only way to do so is through intense product characterization and comparison with originator samples. And brand new products such as antibody–drug conjugates are presenting greater characterization challenges too (we’ll be looking at those in depth with a fall 2014 supplement on the topic).

Once again, enter the analysts. Is it any wonder that we saw fit to start our “BPI Lab” series in January 2013? So far, I’ve covered some of the most vital technologies to biopharmaceutical laboratories under the auspices of that title:  LC–MS, PCR, spectroscopy, electrophoresis, and more. Later this year, I’ll be looking at calorimetry, light-scattering, and circular dichroism. These are just some of the critical technologies that you’ll see providing data in support of numerous presentations throughout this year’s BPI European Summit program. They’ll even take center stage in Conference 4. And in upcoming editions of BPI’s weekly e-newsletter series, analytical methods will be getting their own focus once a month.

It is true that as analytical methods increase in power, selectivity, and resolution, biopharmaceutical companies may find themselves in a vicious circle: the more you can find, the more you will find. For example, a biosimilar version of a product originally approved 20 years ago may seem to have contamination issues that the originator didn’t — because modern analytical technologies are able to identify contaminants that were not detectable before the turn of the century. In fact, the comparator samples may turn out to be even more contaminated, and perhaps biosimilars makers can document that as part if their own market-authorization application process. It all remains to be seen.

So the modern question becomes, “How much analysis is enough analysis?” Regulators around the world seem to be saying, “Keep looking. Keep up with advancing technology. Keep us in the loop.” QbD and the process analytical technology (PAT) that supports it seem to have arisen at least in part from the FDA’s, EMA’s, and others’ acknowledgment of the analytical advances we’ve seen over the past couple/few decades. But how much are the “watchmen” really able to keep up with this stuff, themselves? And who wants to be the first company to present (and explain, and justify) a new method in its product dossier?

It’s a sticky, tricky issue — and one that won’t be solved any time soon. But the kinds of discussion you’ll find at BPI Europe and in BPI itself are vital in moving us all toward some kind of solution(s) as the industry evolves and continues to mature. And I’m curious about your thoughts on this subject in general.

Regenerative medicine may allow us to regrow heart muscle

by Jennifer Ellis, Director of Marketing, LabRoots

Regenerative medicine may have just received a boost, by allowing scientists to transform skin cells into beating heart cells. This new method, devised by researchers at the Gladstone Institute, is more efficient, and, more importantly, allows for complete reprogramming of skin cells into heart cells for the regeneration of lost muscle in heart attack victims.

Heart disease is a leading cause of death around the world, contributing to an estimated 17 million deaths every year. Advances in medicine and treatments have improved survival rates of heart attack victims in recent years. However, with the growing rate of heart attack survivors comes an increase in the number of people living with heart failure. Heart failure is a chronic condition in which the heart cannot beat to full capacity, most likely due to muscle loss during a heart attack. The scientific and medical communities have now turned to cellular reprogramming as a potential treatment for heart failure, to regenerate the damaged heart muscle itself.

Typically, reprogramming of skin cells into heart cells is a complicated process, requiring the insertion of several genetic factors. Genetic manipulation of this sort directly reprograms the cell and can be very time-intensive.  Additionally, there have been issues with scaling the gene-based method into effective and applicable treatments, such as high cost and time, and having to individualize treatments instead of delivering bulk therapy. Now, a different approach has been discovered by Gladstone Investigator Sheng Ding, PhD, and team.

Instead of inserting various genetic factors, the team searched for small molecules in the skin cells of adult mice that when mixed in certain combinations could make the skin cells behave more like contracting heart cells. The researchers found a small molecule “cocktail”, called SPCF, made up of four compounds that almost completely reprogrammed the cells, causing contracting and twitching behaviours. By adding one genetic factor, Oct4, to the cocktail, the team was able to create a completely reprogrammed beating heart cell, similar in behaviour to the electrical signalling patterns normally seen in ventricular heart cells. These results offer a more efficient and less complicated approach for reprogramming, and could lead to a pharmaceutical-based process to regrow heart muscle.

Technology Transfer for Biopharmaceuticals

by by Richard Dennett, Director, Voisin Consulting Life Sciences

What is Technology Transfer?

Technology transfer happens at each pivotal stage of the product/process development lifecycle of a biopharmaceutical product – this can be, for example, from development into cGMP manufacture, for the purpose of licensing, and as a function of outsourcing contract manufacture.  At each of these stages it is essential to demonstrate that the process remains robust and that the product (which can be influenced by the process) pre- and post-transfer is comparable. To do this it is necessary to transfer the methods, materials, equipment, training and knowhow required to realize the transfer.  Whilst this may look easy when written in a couple of lines of a blog, in reality, and for the manufacture of biopharmaceuticals, this can be very complex and any fault in a single aspect of technology transfer can seriously impact the whole program.

How do you know that you’ve achieved technology transfer?

Key to this is meeting pre-determined acceptance criteria, such as:

  • Qualification that the analytical methods can be reproduced
  • Demonstration that the process can be operated in accordance with the manufacturing instruction
  • Comparability of the product – it is essential that the active product meets equivalent pre-and post-transfer specification – this can involve testing of general specifications through to in depth characterization of higher order physiochemical properties to highlight product integrity or product associated impurities

So what tips have you got for making a successful technology transfer?

  • ‘Buy-in’ – development, manufacturing and quality should be a focus of the technology transfer team and this should be replicated within the giving and receiving party.
  • Planning – plan ahead.  An emerging biotech may think that technology transfer will take a couple of weeks: a seasoned biotech knows that successful transfer can take up to several months.
  • Strong project management and communication is essential

What advice would you give anyone currently embarking on technology transfer?

Build up a solid understanding before you start and, if possible, gain access to someone who’s had experience of doing it before.

What are the trip hazards?

  • Not following the plan of what needs to be transferred, how this will be done and assignment the correct acceptance criteria.
  • Lack of proactive project management
  • Rushing into things

What is your experience with technology transfer?

During my career I’ve worked at the development/cGMP interface of projects, as a technology transfer manager in a contract manufacturing organization and now within regulatory CMC  – so I have had great opportunity to see technology transfer from all angles.

Tech transfer from a regulatory point of view is key for supporting comparability within the dossier submission and technology transfer protocols and reports may be scrutinized as part of the pre-approval inspections – therefore it’s serious stuff.

What are your key take home messages?

  • Treat technology transfer seriously
  • Take time
  • Gain buy in
  • Plan correctly
  • Make sure you know what you are transferring and how you will achieve acceptance of the transfer.
  • If it isn’t written down it never happened – quality documentation –  technology transfer protocols and reports are essential.

We heard that you’re a fan of paper aeroplanes? 

Yes, look out for these at BioProcess International.  I’m actually an amateur pilot and recently had a crash landing in the last plane I flew  – a 1930s designed ‘flying flea’ – technology transfer of the understanding of the flight characteristics was to blame –  paper aeroplanes are much safer!

2014 – Why is technology transfer important today and what added value does it hold?

Technology transfer is essential. Correct technology transfer can mean the difference between a successful or failed project.  Done correctly, technology transfer can build in product/process robustness and positively expedite your development program therefore reducing costs and time to market.