Abbott Laboratories is to spend a85m and expand its pharmaceutical manufacturing facility in Sligo (Ireland), saying that would help the company to ensure its supply of compounds in biopharmaceutical areas like virology and nephrology. The investment, which will result in the creation of up to 175 jobs, is supported by the country’s investment promotion agency IDA Ireland. The expansion will be completed in 2014, bringing total employment at the site to 300. Azita Saleki-Gerhardt, president of global pharmaceutical operations at Abbott, said the company has had a presence in Ireland for more than 65 years, and that Sligo is an important part of its pharmaceutical manufacturing network. In total, Abbott runs eight manufacturing facilities in Ireland.
Outsourcing is one of the biggest global trends in the biopharmaceutical industry. It is taking more and more specific know-how to master the challenges posed by manufacturing of biologics, which include rising price and cost...
Outsourcing is one of the biggest global trends in the biopharmaceutical industry. It is taking more and more specific know-how to master the challenges posed by manufacturing of biologics, which include rising price and cost pressures, the need for high flexibility, and the ever-shifting (and in most cases
growing) regulatory requirements for biomanufacturing. This article will give you an overview of how a contract manufacturing organisation (CMO) with many years of experience in manufacturing several classes of biopharmaceuticals is positioning itself to face these challenges.
In the maturing biopharmaceutical industry today, there is increasing competition to innovative pipelines from me-too products, biobetters and biosimilars. The pressure on the cost of goods (COG) is therefore increasing. And to reduce COG, each manufacturing facility needs to meet the specific requirements for a new project regarding the technical instrumentation even before the project enters its initial stages. This will reduce investment and later depreciation, which impact negatively on costs. At the same time, it is important to be able to maintain as much flexibility as possible in order to comply with upcoming regulatory requirements. Thus CMOs need to invest constantly in the development and establishment of new manufacturing technologies and the necessary equipment.
Implementation of new
At Richter-Helm, the investment in new technology does not focus only on adding new (greater) manufacturing scales, although this is often a first reaction to COG pressure. Many firms consider
decreasing costs by increasing scale. But a good alternative to simple scale-up is the implementation of new process technologies that can achieve higher yields, while at the same time improving quality or process robustness – at least for certain processing steps. Over the past few years, the biomanufacturing industry has made substantial improvements in expression and fermentation technologies. In terms of microbial production, innovative E. coli expression systems combined with high density fermentation regimes can lead to yields up to 20g of the target protein per litre of fermentation broth – as was recently accomplished by Richter-Helm for a fusion protein process. In addition to high product yields, in many cases it is also important to find the appropriate expression system for high-quality products that show no or only low expression rates in E. coli. In these cases, the use of other bacterial expression hosts such as Bacillus or Pseudomonas strains can help. Pichia pastoris technology is another option for dealing with even more complex proteins such as enzymes or antibody fragments. A multipurpose facility for manufacturing biopharmaceuticals therefore needs to be equipped to take advantage of all these expression systems in order to be able to reduce upfront investment costs from the outset. New expression systems lead to high primary product yields, and these need to be dealt with in purification processes. Thus optimisation of the downstream processes is also necessary. A recent study showed that the implementation of EBA technology can reduce total process cost by up to 56%. Other new purification technologies that can be implemented include multicolumn counter current solvent gradient purification (MCSGP), which reduces the loss of product in chromatography steps. An ongoing trend in biopharmaceutical product development is the covalent modification of proteins by chemical or enzymatic cross linking (e.g. PEGylation, HESylation, Polyasialation) to increase the half-life of those products in humans. These technologies therefore need to be accessible in a multipurpose facility as well.
Expert project management
Of course, all of the technologies mentioned above also need to be scalable. For a CMO to offer customers the option of going from bench to market with a single manufacturer, it is important to offer more than one scale. For instance, at Richter-Helm three different manufacturing scales are available (lab, pilot, large) to implement each project at the best matching scale while limiting costs for large equipment or a higher number of batches (Fig. 1). But a CMO does not only need sufficient technical capabilities to serve the future needs of its customers. Professional project execution is also a major success factor. It is extremely important for a CMO to be prepared for the fact that different customers have different requirements, as they range from small start-ups to big pharma. The project approach, for example regarding the regulatory consultancy required, will be extremely dependent on the customer’s situation (Fig. 2). Project management that ensures close collaboration and communication between all parties is becoming increasingly important, driven by the trend towards long-lasting partnerships and strategic alliances between developers and manufacturers.D
References  Kaiser et al., Steigerung von Qualität und Ausbeute in der Wirkstoffproduktion; Laborwelt 11 (3), 18-22, 2010  May, Pohlmeyer; Improving Process Economy with Expanded-Bed Adsorption Technology, BioProcess International, January 2011
Contact Dr. Kai Pohlmeyer Dr.-Ing. Philipp Göpel Richter-Helm BioTec GmbH & Co. KG Nordkanalstrasse 28 20097 Hamburg, Germany Tel.: +49 40 2375-0 firstname.lastname@example.org email@example.com www.richter-helm-biotec.eu
Brussels – The European Commission has launched the biggest ever call for proposals to fund European research and innovation and said that it will continue to foster health research on the continent. The European Commissioner for...
Brussels – The European Commission has launched the biggest ever call for proposals to fund European research and innovation and said that it will continue to foster health research on the continent. The European Commissioner for Research, Innovation and Science Máire Geoghegan-Quinn presented the EUR7bn FP7 funding scheme aimed to foster innovation through research at the end of July. As one of the key areas, Health is being funded with EUR656m. “We are issuing the largest-ever invitation to researchers and innovators to compete for EU funding,” said Geoghegan-Quinn.
Sussex/Brussels – British experts warn that hospitals in the country’s National Health Service (NHS) are risking being taken to court for carrying out genetic tests based on techniques patented by private companies. Lawsuits...
Sussex/Brussels – British experts warn that hospitals in the country’s National Health Service (NHS) are risking being taken to court for carrying out genetic tests based on techniques patented by private companies. Lawsuits involving intellectual property in DNA diagnostics are still largely confined to the US, but Michael Hopkins, an expert in the field from Sussex University, says that court cases are becoming more and more certain. “As time goes on, it’s more likely that a company will become hungry enough to want to pursue a hospital because they are infringing a test in a valued market,” he says. Hospitals currently employ patented DNA-based patents with the tacit approval of the authorities – for example to develop tests for relatively rare diseases like cystic fibrosis. Unlike in the US, genes are under certain circumstances generally patentable in Europe.
A Our recent contribution in this column (No. 1-2, Vol. 10, 2011) focused on the end of Swiss-type medical use claims in the EPO. According to the EPO decision G2/08, the traditional Swiss-type medical use claim (“Use of...
A Our recent contribution in this column (No. 1-2, Vol. 10, 2011) focused on the end of Swiss-type medical use claims in the EPO. According to the EPO decision G2/08, the traditional Swiss-type medical use claim (“Use of substance X in the preparation of a medicament for the treatment of disease Y”), will no longer be allowed in applications filed on or after January 29, 2011. Claims filed today in the EPO, and directed to further medical uses, must thus be drafted in the new form provided by Art. 54(5) EPC: “Substance X for use in a method of treating disease Y.” The ultimate value of a claim granted in the EPO is often first determined when this claim is enforced in national courts of EPC contracting states. It therefore remains to be seen how these courts will interpret the new claim form allowed in the EPO. Will national courts interpret the new purpose-limited product claim in the same way as the previous Swiss-type form (this was the EPO’s intention)? Or will they interpret it differently? Or will the new form be admissible at all? At least in Switzerland, it is questionable whether the new form of the claim in the EPO complies with Swiss patent law. Like Art. 54(5) EPC, Art. 7d of the Swiss Patent Act (SPA) relates to the novelty of second/further medical uses. Both the EPC and SPA provide for the patentability of a substance for which a first medical use is known, for any specific (further) use in a surgical, therapeutic or diagnostics method otherwise excluded from patentability. But where the EPC stops there, the SPA continues on to specify that such purpose-limited substance protection is allowable “... provided they [i.e. substances or mixtures thereof] are only intended for the use in the manufacture of a medicament for the purposes [of the excluded methods].” For second medical use protection, the SPA thus requires an element of intention for the manufacture of a medicament which is lacking in the EPC. The danger of course is that claims are allowed in the EPO which do not fulfill national (e.g. Swiss) requirements, potentially jeopardizing the enforceability of such claims in the EPC contracting state (Switzerland). To minimise this danger, we recommend pursuing both kinds of medical use claims in parallel for as long as possible: traditional Swiss-type and the newer purpose-restricted product format. This will still be possible for a while, since the traditional Swiss-type claim will still be allowed for EP patents granted and EP applications pending before January 29, 2011. We are indebted to Dr. André Escher of the IGE in Bern for his informative commentary on this topic, published in sic!, 7-8, 2010, 548 (www.sic-online.ch).
Parma – The European Food Safety Authority has reached a first major milestone in its work on health claims. With the publication of its 6th and final series of evaluation results, the authority finished the scientific assessment...
Parma – The European Food Safety Authority has reached a first major milestone in its work on health claims. With the publication of its 6th and final series of evaluation results, the authority finished the scientific assessment of what are known as ”general function” claims. Since October 2008, the EFSA's NDA panel has reviewed 2,758 food-related general function health claims to determine whether they were backed up by scientific evidence. Based on the results of those assessments, the European Commission is due to present a list on the matter by the end of the year clarifying for consumers whether food products claiming to have a beneficial impact on health actually have such effects. Unconfirmed health claims may not be printed on food products half a year after the list has been published. In its last 35 so-called §13.1 evaluations, the EFSA confirmed positive health effects for walnuts on blood vessel function, of certain fatty acids on heart function, and an antioxidative effect for the polyphenols found in olive oil. However, scientists and food companies said the evaluation process and criteria had not been transparent enough at any stage of the assessment process (see EuroBiotechNews 3-4/2011). The EFSA reacted to that criticism in mid-August by announcing plans to open a help desk to give food companies support and feedback on submitting dossiers for the assessment of health claims
“EFSA’s work on general function health claims has highlighted the importance of constructive dialogue between risk assessors, scientists, decisionmakers and stakeholders, and has contributed to our thinking on the future shape of our organisation,” said EFSA executive director Catherine Geslain-Lanéelle. The plans appear similar to services just established by EU drug authority EMA, which also offers support to companies seeking product
Brussels – As this ‘Heard in Brussels’ is being written, the ‘Heard’ element of my column is fairly ironic, as all you can hear in Brussels in August is the sound of tumbleweeds blowing down empty streets as politicians and their...
Brussels – As this ‘Heard in Brussels’ is being written, the ‘Heard’ element of my column is fairly ironic, as all you can hear in Brussels in August is the sound of tumbleweeds blowing down empty streets as politicians and their minions head off to their châteaux in the south … Now is the time of year to get all that work done that has piled up in your in-box, and this August is no different. We have Europe’s 2010 Survey on R&D Investment Business Trends just published, and in the midst of an epic global recession, it delivers good reading and key warning points for biotechnology spending in Europe. R&D funding didn't collapse as much as feared in Europe, and cautious increases are forecast for 2011. BUT, the percentage of spending is miniscule compared to the rest of the world. Many new young highly-innovative markets are being fuelled by greater economic growth than in Europe. At the same time, the established giants are having to reorder themselves and squeeze maximum revenue from reduced spend.
Still a long way to go
The perennial issue of access to the right skills has been an important positive aspect for Europe. We have brilliant people in science and in business, and as investors and companies over the years have learned, it is the people that create success – the technology is secondary. Europe needs to continue growing great business managers for science, and get ruthless with those that stifle a technology with their inability to develop it as a business or product. A great technology is not chained to its inventor or the inventing organisation, especially if it's come from publicly-funded research. It belongs to the taxpayer. The issue of IPR was negative for EVERYBODY in the R&D survey, and this is ridiculous – it is so fixable within Europe, and a perfect example of how fragmented the EU chooses to make itself. There is no excuse whatsoever for the continued delay in a European patent. It remains a serious barrier to technology-driven economic growth. A big ‘well done’ for Germany as well, the only European country to feature in the top three for R&D investment outside a company’s home country. France and the UK in particular should be wondering why they don’t feature more strongly. If Europe is to deliver on its innovation potential, it should be much more attractive to R&D investment from abroad. Finally and very positively, the greatest demand for collaboration was with other companies. B2B research partnerships have featured strongly in the last 12 months for the European Biotechnology Network, and the rewards are being felt in the shape of strong results across all biotech sectors. Time to return to roaming the empty streets of Brussels. But in just a few more weeks they'll have filled again – and I will have cleared my in-box.
In the ongoing biofuel debate, probably the only viewpoint every participant shares is that fossil fuels will one day run out, and that a viable alternative needs to be found. In the early days of biofuel production, worldwide...
In the ongoing biofuel debate, probably the only viewpoint every participant shares is that fossil fuels will one day run out, and that a viable alternative needs to be found. In the early days of biofuel production, worldwide acreage dedicated to raising biofuel crops was negligible. With the greening of societies in the industrialised world, the terms “renewable” and “sustainable” at times seemed interchangeable. But then increasing numbers of farmers began growing crops for fuel, and attitudes changed. Suddenly, the biofuels that were supposed to dramatically reduce carbon dioxide emissions were responsible for stealing food from the plates of the world’s hungry, as well as the destruction of wetlands and rain forests. Now the European Commission has taken the next controversial step, and set up a system for certifying sustainable biofuels.
The seven approved sustainability schemes (http://ec.europa.eu/energy/renewables/biofuels/sustainability_schemes_en.htm) that were agreed in mid-June have two primary goals. The Commission says biofuels must deliver “substantial reductions in greenhouse gas emissions” and “should not come from forests, wetlands and nature protection areas.” At this stage, “substantial” has been defined by the Commission as “at least 35% compared to fossil fuels, rising to 50% in 2017 and to 60%, for biofuels from new plants, in 2018.” The responsible Commissioner Günther Oettinger calls the scheme “the most stringent in the world, (with) the highest environmental standards.” The Commission is also encouraging industry, governments and NGOs to set up what it calls “voluntary schemes“ to certify biofuel sustainability – and has attempted to explain the standards these schemes must meet to gain EU recognition. That’s a welcome advance for producers and distributors, who until now have had little regulatory data to help them make informed choices on what kinds of biofuel would ultimately be considered acceptable to both governments and consumers.
Before the ink is dry
While industry representatives were cautiously optimistic about the attempts to provide clarity, NGOs immediately went on the offensive. They have already sued the Commission for a lack of transparency and a failure to consult on whether the certification schemes violate the Aarhus Convention, which guarantees citizens and organisations the right to participate in environmental decisions, as well as access to the information for effective participation. One important issue is that of “indirect land use change” (iLUC), a parameter that seeks to define the indirect effects of biofuel impact, such as the amount of rain forest that is destroyed each year in order to provide farmland for biofuel-crop agriculture. The lawyer association and plaintiff ClientEarth continues to accuse the Commission of “withholding time-sensitive and critical environmental information necessary for meaningful public participation in the
review.” The Commission has said it will re-examine iLUC issues in September.
The future of biofuel production
Second and third-generation biofuels promise to be less divisive when it comes to social issues. But although few would deny that the concept needs work, the seven seals certification model is the Commission’s first really earnest attempt to differentiate between “renewable” and “sustainable”.
In June, the European Commission presented the first EU certification schemes designed to certify that biofuels marketed in the EU are produced from sustainable resources. The approval of these voluntary schemes is excellent news...
The seven voluntary certification schemes approved thus far have been introduced to support the implementation of sustainability criteria for biofuels, a requirement of the EU’s Renewable Energy Directive (RED). The schemes provide a practical implementation of the mandatory sustainability criteria, and ensure that only sustainable biofuels will contribute towards the RED target of 10% renewable energy in transport by 2020. The approval of the first batch of EU certification schemes should help address growing concerns associated with biofuels, and they have the advantage of providing certification that is applicable across the whole European market. Industry has indicated a willingness to demonstrate compliance with the RED sustainability criteria, and the new schemes now make this possible. EU approval is also very important for Member States, which have been waiting to clarify the implementation of certification procedures before embarking on additional efforts to incorporate biofuels. The absence of certification schemes is one reason why growth in European biofuels consumption lost momentum last year. The certification schemes position Europe as a global front-runner in promoting sustainable biofuels. This will hopefully provide a boost for top-performing products, including advanced biofuels. However, we should not underestimate the efforts required for industry to implement the sustainability criteria. The approval is clearly a step in the right direction, but it won’t solve all of the sustainability issues. Regulatory issues also still need to be clarified. The debate surrounding indirect Land Use Change (iLUC) has generated a lot of uncertainty, and has delayed investments in advanced biofuels plants. Forming a coherent policy on iLUC is challenging, because its effects are hard to quantify. But to end the market uncertainty, the European Commission must come to a conclusion soon. Any decision should be both easily implementable and stable. It should also promote the best performing biofuels available and the fast deployment of advanced biofuels. Only when this regulatory gap is closed will Europe start to reap the benefits sustainable biofuels can bring. Europe should also be looking at the role advanced biofuels can play beyond the transport fuel sector. Biocomponents are the only sustainable alternative to fossil fuels in the production of chemicals, plastics or textiles. Advanced biofuels deployment is therefore a first step towards a sustainable bio-based society.
The pharmaceutical industry and regulatory authorities are facing new challenges in the development of new drugs that have complex interdependencies. Even at the early stage of process development, a number of detailed parameters...
The pharmaceutical industry and regulatory authorities are facing new challenges in the development of new drugs that have complex interdependencies. Even at the early stage of process development, a number of detailed parameters have to be captured and large amounts of data must be analysed systematically. The following provides some insights into the more notable advantages of using process-integrated data management in tandem with parallel bioreactor systems.
A decade ago, the typical bioreactor fermentation process generally involved less than 15 process parameters, most of which were manually defined. Ten years on, bioreactor systems can easily capture more than 40 parameters automatically. This translates into more work for both the pharmaceutical industry and regulatory authorities when it comes to analysing and interpreting data. A good example is the development and manufacture of monoclonal antibodies. The A-Mab study demonstrates how the “Quality by Design” (QbD) concept can be implemented (see below). It also reveals that improved product understanding – as well as a precise knowledge of the critical quality characteristics of the target product – are essential requirements for the development of modern pharmaceuticals. The identification of these characteristics and monitoring them during the manufacturing process is an important requirement in the US Food and Drug Administration’s process analytical technology initiative (PAT). This requires defining, among other things, a large number of cultivation process parameters found in the bioreactor. These critical process parameters (CPP) are systematically defined with methods such as design of experiment (DoE). DoE ensures efficient planning of the experiments that are to be carried out, and helps to identify interdependencies between the individual factors. Parallel bioreactor systems are ideal for use in process development in accordance with PAT (see Fig. 1). They support the DoE approach, enable the integration of external laboratory analysis and feature powerful and flexible integration management.
Expanded bioreactor analysis
The typical parameters that are captured in a bioreactor when cultivating bacteria, animal or human cells include temperature, pH, dissolved oxygen and the actual values of key actuators such as pumps, stirrers or gassing conditions. In addition, data such as viable cell density and nutrient or metabolite concentrations are determined with external analysis equipment using primarily manual methods. When integrating externally-determined data into the bioprocess or long-term archive, manual or analogue data transmission from laboratory equipment to the bioreactor control system is increasingly being replaced by network connections and standards like “OLE for process control” (OPC). The DASGIP Control 4.0 OPC Software for example collects the data from an integrated autosampler and analytical equipment, then visualises and saves it together with the primary process data in its built-in data historian. That means the analysis data is available within the control process – particularly for process development – and can be used in monitoring and process control for operations such as the online feedback control of analytes or metabolites.
Integration of autosamplers
and analysis equipment
At the University of Delaware, Babatunde A. Ogunnaike and his team combined an autosampler from Nova Biomedical with a DASGIP Parallel Bioreactor System. This approach established the foundation for effective real-time online control of glycosylation patterns on monoclonal antibodies (mAbs) produced with Chinese hamster ovary cells (Fig. 2). For establishing base regulatory control of key process variables known to effect glycosylation, the researchers designed a bioreactor system with nutrient control and cellular metabolite monitoring in addition to the common bioreactor measurements. Within this system, parameters including pH, glucose, glutamate, glutamine, lactate, Na+, K+, and NH4+ were measured using a Bioprofile 100+ bioanalyzer with an autosampler that was integrated with the DASGIP Parallel Bioreactor Control Software via OPC. The validated bioreactor-analyser system allowed for closed loop control of glucose concentrations in the media, leading to improved quality and yield of the target product. A multi-scale model using process variables (glucose and glutamine media concentrations, DO, pH, temperature and agitation rate) to predict glycosylation patterns is currently under development, and will be used as the basis of a model for predictive control strategy of glycosylation.
Data and information management
The measured process data, profiles and recipes for each reactor are stored by control modules. Additional information must frequently be incorporated to conduct enhanced analyses; for example, for comparing individual approaches from a parallel cultivation or with existing process runs. The type of organism used within the process, the composition of the culture media, nutrient supplements and defined set points or feeding strategies all flow into the analysis, as do analysis results such as product yield or living cell density. This supplemental information is often saved separately and administered individually by each user. However, this particular information is also the key to any targeted information retrieval – also known as “data-mining”. Software properties like the DASGIP information management option, combined with the integrated archive system, ensure that all of the process-relevant information is collected, stored in a central database and intuitively available to the user based on self-defined criteria. Through targeted queries of historical and current data, the process data can be compared in various ways, and thus enables a comprehensive process analysis. Besides OPC, connectivity opens integration into supervisory control systems and corporate histories. This allows for data access not only across different workplaces, but also between different sites.
Handling maximum complexity
Strict regulations for the processing of biopharmaceuticals has lead to the need for detailed control of operational processes and comprehensive information management for the large amount of data generated through bioprocesses. When working with parallel bioreactors, automating processes by integrating autosamplers and analysers – and combining that with intelligent data management – ensures that the resulting data will conform to PAT. D
References  CMC Biotech Working Group (2009): A-Mab: a Case Study in Bioprocess Development, Version 2.1. www.ispe.org/PQLI_A_Mab_Case_Study_Version_2.1.pdf  Rix K and Grolms M (2010) BioPharm International Suppl June, p. 22-28  Huether CM and Schneider F (2009) BioTech International Feb/Mar, 6-10.
Contact Claudia M. Huether DASGIP AG Rudolf-Schulten-Str. 5, 52428 Jülich, Germany Tel./ Fax: +49-2461-980-121/ - 100 firstname.lastname@example.org, www.dasgip.com
Cambridge (UK) – Muscarinic receptor agonists like pilocarpine demonstrably boost amounts of secreted saliva, and are therefore promising agents for the treatment of xerostomia (dry mouth), a common discomfort following cancer...
Cambridge (UK) – Muscarinic receptor agonists like pilocarpine demonstrably boost amounts of secreted saliva, and are therefore promising agents for the treatment of xerostomia (dry mouth), a common discomfort following cancer therapy of patients with head and neck cancer. In July, British Acacia Pharma Ltd initiated a Phase II efficacy study in advanced cancer patients of APD515, an new oromucosal formulation of a marketed muscarinic receptor agonist. In the course of the trial, the 30 patients will either receive a placebo or a daily oromucosal 15mg administration of APD515 over 7 days, followed by a washout week, and then the reverse of what they received in week one during the third week. Patients will grade their symptoms before and after treatment, and their salivary flow will be measured. Acacia expects results of the trial in Q4/2011.
7th Berlin Conference on IP in Life Sciences: Big Data, Big Drugs
The health care industry faces significant transformation, driven by a boom in knowledge within biomedical sciences and breakthrough technologies such as gene sequencing. The management of "big data“ will change the understanding of diseases, development of drugs and treatment of patients. more