Pharma Focus Asia - Issue 23

Issue 23 2015

www.pharmafocusasia.com

R&D to Manufacturing

Riding the Wave of Innovation

Redesigning Drugs For better performance Innovation Challenges in Manufacturing

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Two pioneers in their respective fields collaborating to advance innovation in drug development.

Foreword

R&D to Manufacturing Evolution of disease treatments As they target new types of diseases in special-

Countries like US, Japan and EU5 (Germany,

ist areas such as oncology and diabetes, the

France, Italy, Spain and UK) will contribute more

pharma companies are investing in innovative

for growth in the coming future. Pharmerging

treatments to address these unmet clinical

markets (Brazil, India, Turkey, Mexico, Russia,

needs.

South Korea and China) will continue to show

According to IMS health, in 2014, the amount

increased growth.

spent on innovating new medicines is more that

Increasing burden of chronic diseases and

the amount spent on brands associated with

demand for speciality drugs and patent expir-

new generic entrants. The global spending on

ies continue to be challenges for the industry.

medicines was US$373.9 billion in 2014 and

At the same time, ensuring the accessibility of

is expected to reach US$1.3 trillion by 2018.

medicines and treatments for all the patients

Spending on specialty medicines increased

required through the universal health coverage

US$54 billion over the past five years, contribut-

will drive the industry. Future of the pharma-

ing 73 per cent of overall medicine spending

ceutical industry is expected to be moderate

growth in 2014. The emerging markets, biolog-

with a key role of speciality products dwelling

ics and generics markets are expected to see

into the market.

more spending.

Special thanks to Brian Smith, Dough Krafte,

Over the past decade, patent expiries of

Ricardo Cavazos, Patrick J Crowley, Luigi G

many small molecule drugs have restricted the

Martini, AsaGaasvik and Jan Lilja for their valu-

spending on traditional drugs and with new

able insights in this special issue on Pharma

diseases being affected, the R&D pipeline has

R&D and manufacturing.

shifted to speciality products. This transformation allowed ten new breakthrough therapies entered the market in 2014, designated by the FDA under the 2012 FDA Safety and Innovation Act and largest number of orphan drugs launched in 2014 including one drug for cancer treatment and nine ‘ultra-orphan’ drugs. This trend allows mid-sized pharmaceutical companies to compete with large pharmaceutical players.

Prasanthi Potluri Editor

www.pharmafocusasia.com

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Contents 05 Innovation Challenges in Manufacturing

Ricardo H Cavazos Cepeda, Chief of Staff and Chief Economist COFEPRIS (Comisi贸n Federal para la Protecci贸n contra Riesgos Sanitarios), The Mexican Health Regulator, Mexico

05

12 Future Trends in Ion Channel and Solute Transporter Drug Discovery

Douglas Krafte, Chief Scientific Officer, Icagen Inc., USA 20 Redesigning Drugs

For better performance

Patrick J Crowley, Founder and Owner, Callum Consultancy USA

Luigi G Martini, Professor & Chair, Pharmaceutical Innovation King's College London, UK

28 Competing on Alignment Brian D Smith, Principal Advisor, PragMedic, UK

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34 Modularisation in Biologics Manufacturing

Recent trends and developments

Jan Lilja, Director, Commercial Management KeyPlants AB, Sweden

AsaGaasvik, Sr Design Engineer, KeyPlants AB, Sweden

ParAlmhem, ModWave LLC, US

40 Books 42 Industry Reports 44 Research Insights 48 Projects in Progress

28 20

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Advisory Board

Editor Prasanthi Potluri Alan S Louie Research Director, Health Industry Insights an IDC Company, USA

Christopher-Paul Milne Director of Research, Tufts Center for the Study of Drug Development, Tufts University, USA

Douglas Meyer Senior Director, Aptuit Informatics Inc., USA

Frank Jaeger Regional Sales Manager, Metabolics, AbbVie, USA

Georg C Terstappen Director and Head of Biology, Neuroscience Discovery AbbVie Deutschland GmbH und Co. KG, Germany

Kenneth I Kaitin Director and Professor of Medicine, Tufts Center for the Study of Drug Development, Tufts University, USA

Laurence Flint Head Clinical Research Cough, Cold & Respiratory Disease Novartis Consumer Health, Inc., USA

Neil J Campbell President & CEO, Helomics Corporation HealthCare Royalty Partners University of Liverpool, UK

Editorial Team Grace Jones Sasidhar Pilli Art Director M A Hannan Product Manager Jeff Kenney Senior Product Associates Veronica Wilson Ben Johnson Product Associate Annie Jones Circulation Team Naveen M Sam Smith Subscriptions In-charge Vijay Kumar Gaddam IT Team Sitaram Y Jareena K Ranganayakulu V Head-Operations S V Nageswara Rao

Pharma Focus Asia is published by

In Association with

A member of

Phil Kaminsky Chair, Department of Industrial Engineering and Operations Research University of California, Berkeley, USA

Rustom Mody Senior Vice President and R&D Head Lupin Ltd., (Biotech Division), India

Sanjoy Ray Director, Strategic Alliances & Health Innovation Merck, US

Confederation of Indian Industry

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The products and services advertised are not endorsed by or connected with the publisher or its associates. The editorial opinions expressed in this publication are those of individual authors and not necessarily those of the publisher or of its associates.

Copies of Pharma Focus Asia can be purchased at the indicated cover prices. For bulk order reprints minimum order required is 500 copies, POA.

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Innovation Challenges in Manufacturing

Most firms in the pharmaceutical industry think globally to expand demand for their products.

There are ‘amenities’, from which firms leverage to launch a strategy to gain global market share. These amenities include the regulatory dimension which helps reassign resources within and outside the firm.

Ricardo H Cavazos Cepeda Chief of Staff and Chief Economist, COFEPRIS (Comisión Federal para la Protección contra Riesgos Sanitarios), The Mexican Health Regulator, Mexico

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R

egulatory agencies in charge of protecting the population against health risks have a large burden divided, mainly, between two large areas.

The first is a direct consequence of the mission, that is, to effectively protect the population against health risks across the diverse industrial sectors and activities which might generate risks. This implies that the State must guarantee the safety

of all the products used and consumed by the population. The second is an indirect consequence of the constant intervention of the regulatory agency in day to day trading activities of the economy as a whole. When this intervention by the regulatory agency distorts trade by generating additional transaction costs to economic agents, the normal flow of the market is disrupted and, hence, the growth rate of the economy is reduced.

In protecting against health risks, the pharmaceutical industry is a central concern for regulatory agencies across the globe for several reasons: it is one of the most fragmented industries in the world, and there is a considerable regulatory burden attached to the marketing authorization of a pharmaceutical product, and given the nature of the products any miscalculation can have dire consequences for the population.

Specifically, the production process of any single medicine now takes place in multiple countriesto usufruct the country´s comparative advantage.

However, from the regulatory perspective this new production scheme geared towards cost minimisation will create new challenges for regulatory authorities. In order to succeed in the mission the regulatory paradigm has to be updated.

In the past, when the supply chain was entirely located domestically it was relatively simple for regulators to establish traceability processes linking the diverse production units involved in the manufacturing activities. Nowadays, the production setup of firms requires constant and up-to-date communication between regulatory agencies as a consequence of the granularity in the necessary activities to place a finished pharmaceutical product at the point of sale ready for consumption.

In this context, reliance among regulatory agencies has become fundamental to reduce health risks for any country´s population. While the concept of reliance is not new, it is, however, controversial

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because it implies modifications to the regulatory framework, which sometimes is not easy to change, and to the internal operating procedures of regulatory agencies. The challenge is now about how to reach that equilibrium level of reliance which creates efficiencies for firms to increase market access without jeopardising the regulatory agency´s capacity to act swiftly when faced with situations that generate health risks for the population. The balance has to be achieved in such a manner that the internal operating procedures are strengthened while, simultaneously, flexibility is enhanced and trade is not hampered.

The concept of reliance has several degrees spanning simple communication among regulatory agencies at one end of the spectrum to complete mutual recognition of each other’s processes on the other. Unfortunately, there is not a one size fits all recipe to achieve the right balance and coordination needed for an appropriate and comfortable level of regulation with reliance. The longer it takes the regulatory agency to reach this desired state at the frontier; there will be opportunity costs that are to be realised not only for producers, but also for consumers. At the end of the day, those flexibilities that are not implemented may manifest themselves in diverse constraints, thus affecting the price of a product.

As regulatory agencies move towards risk-based models and regulators have more information about the multiple stages in the production chain they are able to discriminate among the diverse manufacturing activities which represent higher risk. This way they are better equipped to evaluate new manufacturing processes focusing on the identification of those links which possibly could generate a health risk. In this sense, alternative production activities which might be a source of cost savings are properly contextualised and the allocation of resources corresponds to the to the risk level presented by any activity.

Mexico´s experience could be an important case study on regulatory reform and administrative modernisation which has generated considerable benefits to all who could be classified as users of the regulatory agency. Starting from a serious problem of administrative impasse during 2009-2010 a bold modernisation plan was implemented with the objective of creating a world class regulatory agency operating under the best international regulatory practices. During the process of updating, the agency has been adjusting to new regulatory and production environments which required creative thinking and quick implementation of action plans. These strategies are geared towards achieving economic efficiencies swiftly without losing sight that protecting the population against health risks is the primal concern.

COFEPRIS regulates approximately 10 per cent of Mexico´s Gross Domestic Product, 12 per cent of the whole economy´s foreign trade, and 44 cents out of every peso that is spent by consumers in Mexico. Therefore, for a single agency COFEPRIS, the impact on economy is considerable. If we look at specific sectors that fall under the regulatory scope of COFEPRIS we find food and drug, medical devices, cosmetics, pesticides and agrochemicals, alcoholic beverages, tobacco, an interaction with the environment and climate change, and a number of other types of emergencies which might generate human health risks. Given the large set of regulatory activities and the evidence insufficient set of resources, regulatory reform was imminent and desirable to make the operation efficient and increase risk protection coverage.

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The modernisation plan consisted of four pillars which interacted with each other. The first two pillars were highly correlated as they consisted of having a solid regulatory agency operating with a robust process to grant marketing authorisations to products that are safe, efficacious, and of high quality. The third and four pillars were also highly correlated among themselves and they consisted of eliminating barriers to market entry and elevating the regulatory standards to adopt best international regulatory practices and harmonisation to eliminate unnecessary transactional costs for both Mexican product imports and exports.. It is clear that a health regulator´s first responsibility is not to drive the economy and sometimes it is portrayed as a necessary cost.

On the other hand, it is also true that due to the cross-sector influence it is desirable that regulators align industry´s incentives to reduce frictions to economic activity without foregoing the protection against risks. The outcome of doing this can only lead to transparency, legal certainty, and objectivity in day to day operations and will boost economic activity. Therefore, such alignment allows the regulator to transform itself from a necessary cost to a valuable asset.

That is, if harmonisation with best international practices can remove transaction costs without lowering protection against risks, a consequence of price reductions, then multiple objectives are accomplished simultaneously: 1) an increase in access to safe and efficacious products; 2) benefits to firms; and 3) savings to the consumer.

Mexico has accomplished the aforementioned benefits by relying on international best practices which have been scrutinised to avoid gaps. Moreover, they are constantly updated to account for innovation in manufacturing process.

In 2012, Mexico unilaterally decided to implement accelerated pathways for innovative products, new molecules, which have received marketing authorisation by reference regulatory agencies. This

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Nowadays, the production setup of firms requires constant and up-to-date communication between regulatory agencies as a consequence of the granularity in the necessary activities to place a finished pharmaceutical product at the point-of-sale ready for consumption.

accelerated pathway allows the Mexican consumer to be the beneficiary of the newest and best products which are now able to cure diseases that, in the past, were treated with products that were only able to provide temporary relief.

Recall, that economic research has found that the introduction of new medicines increases annual income by 0.75to 1 per cent yearly; they increase life expectancy, and increase the quality of life of the individual.

Another good example of how reliance may be able to produce extraordinary benefits is reliance on the Certificates for Good Manufacturing Practices issued by other health regulators. For industry, perhaps the most onerous process is obtaining a Certificate of Good Manufacturing Practices because depending on the scale of operations, the inspection may last from two weeks to over one month of going over procedures both administrative and at the field level.

There is a considerable economic cost attached to all these activities. However, these inspections are a necessary part of the marketing approval process. Moreover, as the number of pharmaceutical firms

has increased and the locations of their plants are different, it is imperative that these inspections be performed with the highest standards to guarantee the quality and safety of the products.

Mexico has been able to capitalise on opportunities related to Good Manufacturing Practices Certificates.

For instance, COFEPRIS has created information exchange mechanisms with certain health regulators to share and analyse the inspection dossier in order to determine whether another inspection by the domestic regulator is required. That is, based on the evidence that has already been generated and the improvements already performed in the facility, the health regulator can determine whether it is appropriate to issue documentation to the credit of that plant with a Certificate of Good Manufacturing Practices through reliance.

Other forms of reliance have to do with participation in international fora related to inspections such as World Health Organization (WHO) seminars on Quality Risk Management and the Pharmaceutical Inspection Cooperation Scheme (PICs). Mexico has been part ofthe accession process to this international cooperation scheme to update and raise the standards ofits regulation on pharmaceutical inspections, to engage in field training, and to exchange information about alerts and recalls. It is expected that once Mexico accedes, transaction costs to obtain Good Manufacturing Certificates may be reduced considerably.

The third example on reliance is exemplified by outreach activities performed by COFEPRIS. With the aid of Panamerican Health Organisation, Mexico has engaged in training activities through instruments that have allowed countries which do not have the same regulatory standards to implement rapid access pathways for generics which have been already approved by Mexico. There is then a multiplier effect, as COFEPRIS is able to authorise innovative products which later on can be quickly authorised

especially when the interaction of the health regulator with the economic flow is large, can certainly unlock efficiency benefits which can be exploited not only by firms, but more importantly by the consumer. The guiding principle in the regulatory reform plan implemented in COFEPRIS has always been to benefit the consumer by increasing access, while additionally generating opportunity areas to firms.

Fortunately, this plan has shown high payoffs both to consumers as retail prices have fallen on an average by 60 per cent for certain products, the growth rate of A u t h o r BIO

and found in countries located in Central and South America that do not have the same regulatory strength as COFEPRIS. This has a double objective; in the short run the supply of products increases immediately lowering domestic prices and in the long run, through training activities, the domestic regulator can strengthen its regulatory capacity and focus on necessary activities and rely on other regulators for activities which are not a priority as they build technical capacity.

These examples have put forth the benefits that reliance and increased knowledge of the production process may bring to a health regulator and the economy. Achieving the ¨right interaction¨ between the activities of the regulatory agency and the activities of the economic agents to maximise efficiency should be a priority. Going from a necessary cost to a valuable asset,

the industry has reached two digits, during the period 2011-2014 it has grown by 13.2 per cent, and exports have increased by 30 per cent during the same period. There are seven countries which rely, at varying degrees, on the marketing authorisations issued by Mexico thus expect this double digit growth rate for the industry and for exports to continue.

Disclaimer: The opinions stated in this article are the sole responsibility of the author and not of the COFEPRIS, the Mexican Ministry of Health, or the Mexican Federal Government.

Ricardo H Cavazos Cepeda is the Chief of Staff at the Federal Commission for the Protection against Sanitary Risks (COFEPRIS) since July of 2014. Before being Chief of Staff he was Director General of International Affairs from July 2011 to June 2014 in the same institution.

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MEDICAL FAIR ASIA 2016 Date: 31 Aug – 2 Sep, 2016 Venue: Marina Bay Sands, Singapore

• Region’s hallmark event for Asia’s medical and healthcare sector returns to Singapore for 11th edition • Exhibition well-positioned to meet the next wave of healthcare modernisation

Following on its successful growth path since its inception in 1997, the region’s most established platform for the medical and healthcare sectors— MEDICAL FAIR ASIA—will see its most impressive line-up ever of prominent medical and healthcare players from around the world from 31 Aug to 2 Sep 2016.

Reinforcing the global appeal and market relevance of the trade fair, MEDICAL FAIR ASIA 2016 is expected to attract strong participation from some 1,000 exhibitors from 45 countries including 20 national pavilions and country groups. This is a marked increase from 2014, which saw MEDICAL FAIR ASIA welcome a stellar list of 700 exhibitors from 38 countries. Visitor attendance is also expected to increase by 50 per cent from the last edition in 2014, with 15,000 trade visitors coming from across ASEAN and the Asia Pacific region.

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Co-located with MEDICAL MANUFACTURING ASIA 2016, a trade fair focusing on the medical technology and medical manufacturing sector and jointly organised

by Messe Düsseldorf Asia and the Singapore Precision Engineering & Technology Association (SPETA), the synergistic qualities of both trade fairs will present a comprehensive one-stop event for trade professionals sourcing for solutions across the value chain.

Focused on equipment and supplies for the hospital, diagnostic, pharmaceutical, medical and rehabilitation sectors, MEDICAL FAIR ASIA 2016 is well positioned to be the No.1 procurement stage for industry professionals to experience new and innovative technologies, solutions, products and services – many of which will be launched in Asia for the first time – but will also align its theme with current and future demographic trends, challenges and notably, the next wave of healthcare modernisation.

Spotlighting on digital healthcare at the 2016 event In the spotlight at MEDICAL FAIR ASIA 2016 will be a platform dedicated to Digital Healthcare. Global key leaders from the industry will showcase new disruptive digital healthcare solutions such as remote and wireless healthcare, IT platforms, wearable devices and smarter medicine, and healthcare analytics.

Industry experts will also be sharing their wealth of insights and expertise in this fast-growing area. By creating a platform for the exchange of the latest innovations and technologies, MEDICAL FAIR ASIA continues to raise the overall capabilities and spur the growth of the region’s medical and healthcare sectors to meet the changing demands in both the public and private sectors.

Driven by rapid urbanisation, increased population and increased longevity, the focus of medical and healthcare services within the region is turning to disease management and healthcare provision for the elderly, as well as preventive healthcare for the general population. Coupled with the launch of the ASEAN Economic Community (AEC) and the rise in affluence, the demand for quality medical services by both local and international patients within the region is rapidly increasing, opening up a wealth of opportunities.

As the region’s medical and healthcare sector continues on the robust growth, MEDICAL FAIR ASIA will continue to be the preferred strategic business platform for region’s medical and healthcare industries.

With exhibition spaces filling fast, interested exhibitors are encouraged to submit their space booking forms for MEDICAL FAIR ASIA 2016 at the earliest opportunity. For more information on the trade fair, please visit www.medicalfair-asia.com Press contact: Maria Wesson Tel: +65 6332 9651, Email: maria@mda.com.sg Exhibitor contact: Daphne Yeo Tel: +65 6332 9682, Email: daphne@mda.com.sg Organised by: Supported by:

Messe Düsseldorf Asia / Organiser of:

Held in:

Advertorial www.pharmafocusasia.com

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Future Trends in Ion Channel and Solute Transporter Drug Discovery Gene family members of the ion channel and solute transporter (SLC) families represent both historical targets of pharmaceutical significance and serve as exciting opportunities for current and future therapeutic development. The common property of ion movement for many of the SLCs lends itself to considering platforms used in ion channel research to enable early drug discovery. In addition, the convergence of advances in both genetic analysis and assay technology bodes well for the identification of the next generation of ion channel and transporter-based drugs in the near future.

Douglas Krafte, Chief Scientific Officer, Icagen Inc., USA

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I

on channels have been excellent drug discovery targets for decades with clinically meaningful drugs identified targeting sodium channels, including (e.g. lamotrigine), calcium channels (e.g. amlopdipine), GABA receptors (e.g. diazepam) and ATP-gated potassium channels (e.g. glipizide) and several others. However, new ion channel modulators have not been emerging at a rapid pace in the recent years, and some question

whether targeting the ion channel gene family has seen its best days. However, to paraphrase Mark Twain, the reports of the death of ion channel drug discovery are greatly exaggerated. In fact we appear to be on the precipice of a new generation of ion channel modulators where common and/or rare genetic variation can be leveraged to both design selective modulators and to select the most responsive patient populations, moving us closer to a period where precision medicine becomes the norm.

Current Research

Conceptually, designing variant-specific drugs are not new, with one of the best examples in the ion channel space being the corrector and potentiator drugs modulating Cystic Fibrosis Transmembrane Regulator (CFTR). The design paradigm was directed to attack the root of the problem and correct the specific defect causing the disease. Molecules have been identified that either rescue a CFTR trafficking variant, ⊗F508, which is not expressed on the plasma membrane in disease or potentiate the effect of the CFTR proteins that are present on the plasma membrane. The overall effect is to increase CFTR function and normalise fluid movement in the lung. In a variation on the same theme, we now see companies asking which patients will be most responsive to selective therapies.

One recent example illustrating this trend is found with the calcium channel gene family. In 2013, the Psychiatric Genomics Consortium published the results of an extensive human genetics study leading to identification of 108 loci strongly associated with schizophrenia (Ripke et al 2013). Among these loci, there were several calcium channels including the dihydropyridine-sensitive channel, CACNA1C. In drug discovery, the identification of a set of genetic loci at the start of the process is akin to tossing all the pieces of a jigsaw puzzle on the table to start assembling the final product. Getting to the final product involves understanding how the genetic association translates to action and how

In the SLC space, technical limitations are more of an issue, and the field has yet to see the development of a truly common technology platform that can be utilised to develop assays for a large number of SLC transporters.

the mechanism translates to disease (see Schubert et al 2014). An elegant step in this process is illustrated in the work of Yoshimizu et al.(2015) which generated iPSC-derived human neurons with wild type (wt), heterozygous and homozygous genotypes encoding wt CACNA1C or SNP rs1006737. The results indicated that the risk variant is associated with increased CACNA1C current density as well as mRNA expression. This suggests that a therapeutic approach to downregulate or inhibit these channels might be viable if one can design molecules with appropriate state-dependent and tissue distribution properties.

Similar examples exist in other therapeutic areas and diseases covering rare and/or common variants. Some examples include epilepsy (Epi4K 2013), pain (Waxman et al 2014), Atrial Fibrillation (Jabbari et al 2015) and perhaps oncology (Huang et al 2015). The genetic guidance of both target selection coupled with molecule design and/or patient stratification where the genotype biases towards a more drug response population should lead to new and exciting clinical development programs and better ion channel drugs in the near future.

In addition, the ion channel gene family and the solute carrier gene family are similar in some respects to the ion

channel family in which both families encode membrane proteins and functional activity often involves ion movement. In these cases the ion movement serves to be the energy source rather than having a direct effect on cell physiology. Certain SLC gene subfamilies have historically provided excellent drug discovery targets exemplified by the SLC12 family with diuretics and the SL6 family with monoamine reuptake inhibitors. More recently second line therapies for type 2 diabetes (T2DM) have been successfully developed and approved targeting SGLT2 in the SLC5 family as well. Despite these successes, however, the gene super family remains largely untapped with respect to drug candidates, in part owing to the diversity amongst the family which results in a lack of common assay platforms. In contrast, there is a wealth of emerging genetic data suggesting that SLC modulators could provide a large number of new drug discovery targets. Approximately 20 per cent of the reported mutations in SLC transporters have been associated with disease, and ~80 SLC transporters have been linked to monogenic disorders (Lin et al 2015). This association with monogenic disease is often a strong foundation from which to mount drug discovery programmes targeting rare diseases, but also more common disorders where the rare disease data inform the biology and provides confidence in target validation. In addition, GWAS studies are generating exciting potential opportunities studying common variants as exemplified by the recent lossof-function associations with SCL30A8 reported in type 2 diabetes. These data indicate that haploinsufficiency (i.e. only one functional copy of the gene is present) in man is protective against type 2 diabetes in patient populations who is otherwise at high risk to develop the disease (Flannick et al 2014). Based in part on these data, many pharmaceutical companies are already exploring programs to identify inhibitors of Zn transporters to support next generation development of T2DM therapeutics. www.pharmafocusasia.com

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Current Limitations

Future Research

Several unique challenges exist with SLC drug discovery. One is the fact that in many cells, there are often multiple subfamily members expressed in the same cell. This is a function of the role these proteins play in moving solutes necessary for normal metabolism and cell health amongst cellular compartments.

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Sorting out activities attributable to one subfamily member from another can be challenging, particularly since there is often little known about baseline function and properties. In addition, subcellular localisation is often important for the SLC family members to function properly, and activity of any one gene product can be restricted to a specific cellular compartment difficult to access with current assay methods. To address some of these challenges, groups are attempting to create background cell lines for recombinant expression whereby endogenous transporters that do not have detrimental effects on cell health, thereby limiting utility, are eliminated. In addition, cell free preparations such as proteoliposomes which inherently should have lower background in any assay format since they will not be contaminated by multiple transporters will allow specific investigation of the single transporter protein of therapeutic interest. Finally, assay technologies are also being developed including genetically encoded sensors targeting certain compartments and ligands or applying

A u t h o r BIO

The similarities between ion channel and SLC drug discovery perhaps diverge at this point, however. The technology platforms to pursue ion channel drug discovery have advanced significantly and assuming a high level of expertise in applying these technologies; common platforms exist which can be used to mount a modern ion channel drug discovery effort. In the SLC space, technical limitations are more of an issue, and the field has yet to see the development of truly common technology platform that can be utilised to develop assays for a large number of SLC transporters. One of the reasons this is important is that modern drug discovery efforts are facilitated by generating data using the same or similar assays to provide a greater understanding of relative structure-activity relationships across closely related gene family members. In many cases this information is essential to ensure appropriate on-target effects while avoiding off-target adverse events.

A recent broad perspective on the SLC field was published by Cesar-Razquin et al (2015). The authors highlighted 11 areas where they believe additional research and investment would be helpful in enabling SLC de-orphanisation (i.e. identifying the role and function of the protein) to better understand the potential landscape for drug discovery.

As noted above, however, there are a number of very interesting SLC targets for drug discovery today emerging from genetic studies. To fully capitalise on these new targets as well those arising from the next generation of discoveries, newer and more robust technology platforms are necessary to complement those already in existence.

different sensor methodology such as x-ray fluorescence, where subcellular distribution does not matter provided gene product specific signals for the solute of interest can be detected. Progress in these technology areas is likely to greatly facilitate identification of new SLC modulators. These molecules may then be used as tools to validate drug discovery targets and also as leads in novel SLC drug discovery programs.

Conclusions

More data, better technology and greater sophistication in applying both genetic validation and assay methodology bode well for the future of ion channel and SLC transporter based drug discovery efforts. There is no lack of good drug discovery opportunities in these gene families and the growing ability to apply the right drug to the right patient should mean more breakthroughs and better ion channel-based and SLC-based medicines in the coming years.

References are available at www.pharmafocusasia.com

Douglas Krafte is currently Chief Scientific Officer of Icagen Inc. He was formerly Executive Director & Site Head for the US arm of Pfizer’s Pain & Sensory Disorders Research Unit. Dr. Krafte has spent over 25 years in the pharma/biotech sector across multiple therapeutic areas in Icagen Inc., Pfizer, Aurora Biosciences, Boehringer-Ingelheim and Sterling Winthrop. Over the years he has gained extensive experience in managing and leading small molecule drug discovery teams that have successfully advanced multiple molecules to the clinic.

Dr. Krafte did his post-doctoral training at the California Institute of Technology in Molecular Neurobiology and received his MS/PhD in Physiology from the University of Rochester.

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Therapeutic Applications of Glycopeptides Glycoproteins and glycopeptides are an important class of biomolecules involved in a number of biological processes. The class of compounds having a carbohydrate moiety that is covalently linked to another chemical constituent is in general classified as glycoconjugates. Carbohydrate moieties (glycans) attached to cell surfaces, peptides and proteins play a crucial role in several important biological functions.

They are useful in detecting various pathways of complex diseases with the help of the glycopeptide probes. Glycopeptides are a group of molecules consisting of a carbohydrate moiety covalently bound to an oligopeptide or peptide composed of L- or D- amino acids. Chemically, glycopeptides are identified in two major groups namely N-linked and O-linked glycopeptides. Peptides and proteins can be glycosylated at various positions. In O-glycans, the hydroxyl moiety of serine or threonine is linked to sugars. N-Glycans contain sugars linked to the side-chain of asparagine. C-Glycans contain sugars linked to the indole moiety of tryptophan.

N-and O-glycosylation is a common modification that plays an important role in cellular recognition and other physiological and pathological processes, whereas C-glycosylation is only rarely observed(1).

positive bacterial infections. Vancomycin is popular as a last resort for multi-resistant infections by grampositive organisms. Vancomycin was isolated in 1953 and clinically used since1955. In 1958 it was approved to treat infections resistant to penicillin (staphylococci) by the FDA.

Fig-1: Vancomycin

The best examples for therapeutic applications of glycopeptides include effective antibiotics like vancomycin and telavancin. These glycopeptide antibiotics are used as main drugs to combat gram-

Bachem and GlyTech, Inc. Two pioneers in their respective fields collaborating to advance innovation in drug development.

Fig-2: Telavancin

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Advantages of Chemical Glycosylatation • Homogeneous products: chemical synthesis yields well-defined glycopeptides • Most chemically synthesized peptide drugs can be easily adapted to glycosylation • Competitive production costs

www.bachem.com Telavancin is an antibacterial lipo-glycopeptide derived from vancomycin and is used against complicated infections of the skin structure and for hospital-acquired bacterial pneumonia caused by Staphylococcus aureus.

Both vancomycin and telavancin are large rigid molecules. They inhibit the peptidoglycan synthesis during late-stage bacterial cell wall formation and have been in use as a last resort for bacterial infections.

Unique specific peptide combinations of (L-D-D) amino acids(2) are best fit for the sequences that are found in bacterial cell walls, hence these glycopeptides are selectively toxic. The glycopeptide antibiotic forms a complex with the bacterial cell wall peptide L-Lys-D-Ala-D-Ala stabilized by hydrogen bonding.

As a result, the glycopeptide complex inhibits the formation of the backbone glycan chains due to steric hindrance(3). This also inhibits the trans-peptidation step that provides rigidity to the bacterial cell wall. As a consequence non-alignment of the active sites of the enzymes involved in the bacterial cell wall synthesis

is possible thus making the acquisition of resistance to the glycopeptide antibiotics more difficult. The carbohydrate moiety in these antibiotics helps to improve pharmacokinetic properties, solubility and transport making it more bioavailable while at the same time modulating their toxicity(4).

In summary, glycopeptides have been proven to be best in class to treat gram-positive bacterial infections. Bachem has been pioneering partner for peptides and in collaboration with Glytech has the capacity to make glycopeptides in large scale, specifically N-glycans, with high purity.

About Bachem Bachem provides a full range of services to the pharma and biotech industries. It specializes in the development of innovative, efficient manufacturing processes and the reliable production of peptidebased active pharmaceutical ingredients. The group has a global reach with more experience and know-how than any other company in the industry.

Towards its customers, Bachem shows total commitment to quality, innovation and partnership.

Bachem. Pioneering Partner for Peptides References: 1. L.X. Wang and M.N. Amin, Chemical and chemoenzymatic synthesis of glycoproteins for deciphering functions, Chem. Biol.

21, 51-66 (2014).

2. H.R. Perkins, Specificity of combination between mucopeptide precursors and vancomycin or ristocetin, Biochem. J. 111, 195-205 (1969).

3. N.J. Economouet al., Structure of the complex between teicoplanin and a bacterial cell-wall peptide: use of a carrierprotein approach, ActaCrystallogr. D. Biol. Crystallogr. 69, 520-533 (2013).

4. V. Kren and T. Rezanka, Sweet antibiotics - the role of glycosidic residues in antibiotic and antitumor activity and their randomization, FEMS Microbiol. Rev. 32, 858-889 (2008).

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Redesigning Drugs For better performance When a compound progresses to a medicinal product the complexities of disease, drug action, and the diversity of patient response can mean that nuances of drug behavior may not be fully evident. However, new insights may emerge on more widespread use. These can provide ideas for new indications or better treatment of the existing indication.

Patrick J Crowley, Founder and Owner, Callum Consultancy, USA Luigi G Martini, Professor & Chair, Pharmaceutical Innovation, King's College London, UK

P

rograms to identify and evaluate novel therapeutic agents are expensive, take a long time and do not guarantee a successful outcome.

Proving safety and efficacy is difficult, complex and slow. Furthermore, even after efficacy and safety are demonstrated and the compound becomes a medicinal product the complexities of disease and of the drug action, allied with the diversity of patient response can mean that nuances of the new drug’s behaviour may not be fully evident. Consequently, most new edications are not perfect.

Recent restrictions and withdrawls of the Cox-2 Inhibitor drugs for arthritis exemplify how difficult it is to determine each and every facet of drug performance in clinical studies. Much greater patient experience may be required.

As a medication becomes widely used, new insights emerge on modes of action, side effects and patient response. At the

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same time, advances in molecular biology, receptor pharmacology and better understanding of the clinical condition may create possibilities for new indications or for better treatment of the existing indication by altering dosage regimen or by dosage form redesign.

Concurrently, technologies may emerge to enable more efficient, effective or convenient ways of delivering or even targeting the medication.

Possibilities exist, therefore, to redesign established drugs—usually by reformulation— so they are more effective, safer or more convenient for the patient.

have been moves to make detailed clinical trials data available in readily accessible databases. Such knowledge, allied to creative interpretation and linkage to other emerging facets of knowledge can be a rich source of opportunities for product redesign.

Information sourced in such ways may concern: • The drug • The clinical condition (“the disease”) • The patient • New technology and diagnostic techniques

General considerations

Development programs exploring safety and efficacy cannot possibly cover each and every permutation and combination of dose frequency and timing.

Information from widespread use may suggest other more suitable regimens.

The last decade or so has seen an explosive growth in Information Technology (IT), making data and information capture, analysis and dissemination widely available. More recently there

The drug

Table 1

The antibacterial amoxicillinclavulanate (Augmentin速) was administered three times daily when first commercialised, reflecting the rapid elimination rates of both the amoxicillin and clavulanate components. It proved to be a very effective therapy in communityacquired infections but three times daily dosage is less convenient (and may lead to reduced dosing compliance) than less frequent administration. Furthermore, diarrhoea was a frequent side effect, especially in children under two years of age.

This was attributable to the clavulanate component.

In vitro evidence that lower doses of clavulanate coupled with a shorter treatment period might be equally effective, prompted the development of formulations for twice daily dosage. Clinical trials in paediatrics indicated that the twice daily presentation was equally effective to that dosed three times and that the diarrhoea side effect was significantly less as illustrated in Table 1.

More detailed knowledge on metabolism, pharmacokinetics of the metabolites and possible impact on clinical behaviour is also likely to accumulate on widespread usage of the medicine. This may suggest that the dosage form could be redesigned.

An example concerns Niacin, utilised as a lipid lowering agent. Side effects (flushing and hepatotoxicity) are related to its metabolic pathways. Metabolism proceeds via two pathways viz. conju-

gation and amidation. If the amount ingested and absorbed saturates the amidation route (as would be expected from a rapidly releasing dosage form), the conjugation route dominates, resulting in a higher incidence of flushing.

Slower absorption can result in enhanced amidation and a relatively higher level of the metabolites associated with hepatotoxicity (Table 2).

Thus, dissolution rate from the dosage form can influence the metabolic profile and associated side effects. This knowledge allowed a formulation to be developed with drug release rate providing an appropriate metabolic balance to minimise side effects.

Drug-related improvements may also be stimulated by advances in separation sciences or purification techniques to provide a medication that may be more potent, has greater specificity or evinces fewer side effects. The Proton Pump

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Table 2

Inhibitor, omeprazole, used to treat gastric ulceration and related conditions is a racemic mixture. The single isomer esomeprazole has now largely replaced it because of better ulcer healing rates.

Purity-related improvements have also been recorded for biopharm products.

Recombinant human insulin reputedly has less side effects than porcine-derived material. Similar improvements have been recorded for recombinant human growth hormone. It has also been reported that a “new formulation” of ß interferon-1a is better tolerated and induces less antibody formation when treating multiple sclerosis.

The clinical condition Molecular biology

Knowledge of the aetiology of diseases is continually expanding. Two decades ago there was no evidence that gastric ulceration is caused by bacteria in the gastric mucosa. In 2005, the scientists who identified and elucidated the role of Helicobacter in gastric ulcers were awarded the Nobel Prize for Medicine.

Aspirin was used as an anti inflammatory and analgesic for almost a century, before its prostaglandin inhibition mechanism was elucidated and its beneficial effects at low dose as a platelet aggregation inhibitor established. Such findings have led to the use of antibiotic preparations, possibly in conjunction with proton pump inhibitors or other anti acid agents for treating gastric ulcers and of low dose aspirin as an anti-clotting agent.

Increased insight of molecular biology, whether of the disease or mechanism of drug action may also suggest a drug’s potential in related or even different clinical conditions. In such a context, the anti arthritic drug celcoxib (Celebrex)

is currently being evaluated for efficacy in colon cancer.

Time-related effects

Symptoms in some disease states can be manifested at different times of the day, or even seasons of the year. Seasonal effects can be environmental (e.g. Hay Fever or other allergic conditions are more acute at the height of the pollen season) but others can be more complex.

Time-associated effects include: • Asthma: Airways obstruction can be most severe early in the mornings • Rheumatoid Arthritis: Joint stiffness is usually most severe in the morning.

Conversely, pain from osteo-arthritis is more prominent in the evening • Cardiovascular incidents: Heart attacks occur frequently in the early morning. This may be related to the stresses to the cardiovascular system, caused by going from a prone to the upright position after waking up. It is important, therefore, that beta blockade or other cardioprotective effects are optimal at this crucial time

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• Hy p e r t e n s i o n : Blood pressure in normotensive subjects usually falls during sleep (“cardiovascular system rests”). However, in some hypertensives this does not happen. The increased incidence of nocturnal heart attacks at around 2 AM to 3 AM is ascribed to the cardiovascular system remaining under stress.

Awareness of such circadian effects can stimulate ideas for timing drug delivery to coincide with the chronotherapeutic requirements of the clinical condition.

The timing of the cardiovascular events listed above has led to the development of a medication of the calcium antagonist, verapamil that delays delivery of drug (the medicine being taken at bed time) until about 8 hours after dosing to cover the vulnerable early morning period. The drug is thereby delivered to the receptor at the time of greatest need.

Other examples of delivering drug “when required” concern theophylline and salbutamol. These drugs have relatively short half lives with concomitantly short durations of action. Formulation as delayed/sustained release formulations are calculated to provide adequate plasma levels to cover the vulnerable early-morning period. Sustained release theophylline also reduces its peak plasma level, thereby mitigating the effect of its low therapeutic index.

Figure 2

Seasonal effects, other than environmental or climatic ones are lesser known but endorphin levels are apparently greater during January/February and lowest in July/August. One could speculate as to whether this might mean that cancer therapy would be optimal at times when the patient might be more resilient to aggressive treatment.

Could vaccination be more effective if aligned with season-related levels of natural mediators? There is no evidence for such effects but such relationships might merit exploration.

Changed disease patterns Infectious diseases

Bacterial resistance to antibiotics is not new; it has always been a race between resistant organisms evolving better defence mechanisms and scientists finding novel antibacterials. However, few novel antibacterials have emerged in recent times and resistance by pathogenic bacteria is a major issue. The prevalence of methicillin-resistant S.aureus has been well-documented. Drug resistance by pseudomonas aeruginosa is also increasing. The problem is not confined to hospitals or Intensive Care Units.

Resistance in community-based infections is also a concern. Penicillinresistant

Streptomyces pneumonia are now prevalent in many countries. In the light of all these considerations it is necessary to consider new approaches to treating infections using existing drugs.

New treatment paradigms

The emergence of bacterial resistancecaused Craig W.A. and Andes.D to develop the “time above MIC” concept for antibacterial therapy. The principle is that if levels of some antibiotics are maintained above the minimum inhibitory concentration for a specific time (“T>MIC”), efficacy is enhanced.

Woodnut et al, working with resistant strains of Streptomyces pneumoniae confirmed this thesis for the broad spectrum antibiotic amoxicillin. They showed that the minimum “T>MIC” for amoxicillin was about 35% of the dosage interval (Figure 1).

Thus, if amoxicillin is administered twice daily, and serum levels exceed the inhibitory concentration for a minimum of 4.2 hours (35% of 12 hours) it is likely to be effective against penicillinresistant Streptomyces pneumonia.

This finding provided an opportunity for redesigning amoxicillin-containing dosage forms as findings in animal studies can be morereadily translated to clinical efficacy in patients as the bacterium

can be considered “the receptor” in both instances.

However, the rapid clearance rate of amoxicillin (half life of about 1 hour) militates against persistence in the biosystem. This, together with its limited “absorption window”, makes it difficult to formulate as a delayed or prolonged release formulation. This is because, although it is absorbed very well in the upper regions of the duodenum absorption becomes progressively less efficient in the jejunum and ileum and is almost non-existent in the colon (Figure 2).

Furthermore, “unabsorbed drug” could kill symbiotic bacteria in the colon, causing gastro-intestinal side effects because of overgrowth of resistant bacteria.

The formulation developed to provide sustained plasma levels utilised a novel approach, incorporating two salts of amoxicillin viz. the conventional trihydrate for “immediate release” and the sodium salt, co-formulated with citric acid as a release modifier to deliver a later dose. The plasma level profile is shown in Figure 3, with a “time above MIC” (4mcg/ml) that is almost 50% of the twice daily dosage interval.

This formulation was shown to be effective in Phase 3 clinical trials and is now a commercial product in the US and some European countries.

Prolonging drug in the biosystem for the requisite time to optimise bacterial kill rate is one example of changed paradigms providing more effective therapy. More recently, the concept of dosing “pulses” of drug that provide limited time and duration in the biosystem has also been propounded. The concept has been validated in vitro with antibiotics and antifungal agents but is also being suggested for other clinical conditions including antifungal and cancer therapy.

Not every drug will be suited to pulse dosing. Drugs with long half-lives will not be cleared quickly enough to get true pulse profiles. It is also likely to

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be difficult to deliver pulses orally; the gastro intestinal tract is too variable to facilitate such precise plasma profiling.

Pulse delivery is probably best suited to parenteral administration. Variables such as the frequency and amplitude of the pulses may be critical and need to be explored and defined. It might well be that different organisms or clinical conditions require different pulse profiles.

Programmable pump systems could be utilised to reliably deliver the requisite pulse profile.

Knee/hip joint replacement techniques have revolutionised the treatment of joint inflammatory disease.

Cardiac stents have had a similar impact in coronary bypass surgery. But they have also brought new challenges. Bacterial infections, localised at the replacement site are notoriously difficult to treat and frequently require further invasive surgery. Consequently, a need and associated opportunities exist for antiinfectives, embedded in the joint or stent material to be released slowly to evince a local antibacterial effect.

Chronic low dose therapy is also being considered for treating cancer.

Traditional chemotherapy usually involves giving the patient the highest dose they can tolerate to maximise tumor reduction. But such drugs are toxic, so dosing must be periodically halted for several weeks to allow the body to recover. It has been suggested that such “rest periods” can allow a tumor to rebuild the blood vessel network it needs to keep growing. So, researchers are experimenting with giving very low doses of cytotoxic drugs for extensive periods of time. Patients are spared the toxic side effects associated with high dosage, so treatment could be continuous and long term. This could help turn some cancers into chronic, manageable conditions. Promising results are being reported from clinical trials on cancers like brain tumors, non-Hodgkin’s lymphoma and breast and ovarian cancer. Prolonged administration of low doses will require more convenient,

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Figure 3

non-invasive modes of dosing than are now utilised with cytotoxic agents, again providing opportunities for developing new formulations or delivery systems.

The patient Demographics

Better diet, living conditions and healthcare programs mean that people are now living longer in many regions of the world. Consequently, diseases of old age have become more prominent.

For instance, the incidence of Benign Prostatic Hyperplasia (BPH) in males at age 60 is about 50%. By age 70 it rises to 70%-80% and by age 85 incidence is in the region of 85%.

Many of the elderly remain active, alert and independent because of their lifestyle, sensible dieting, and diligent use of medication, or, in many cases, several medications. Convenience can greatly affect compliance in chronic dosing scenarios. For instance, if all the medications could be incorporated in a single unit it would enhance convenience, compliance and consequently effectiveness. If such “multi-drug” medications could be designed to deliver each drug at

the right time and possibly the appropriate rate to reflect differences in clearance rates, or in other metabolic processes in the elderly, it could be enormously beneficial. A drug for insomnia might be designed to take effect quickly whereas a medication for emphysema might be released later from the dosage form. In addition to such chronotherapy-related delivery, a multi-medication unit might be designed to gradually release drug to avoid saturation of biosystems enzymes or pharmacological interactions. There are immense opportunities in geriatric medicine to provide more user-friendly and more effective medications.

Pharmacogenetics and pharmacogenomics

The DNA sequence of the human genome (the “physical map”) has been elucidated.

The functional aspects are also being progressively mapped and a stage may be reached where it is possible to predict many biological responses and susceptibility to particular diseases or enzyme deficiencies. Evidence is being accumulated that drug response may be influenced by individual genomic networks. This may provide greater insight on what medica-

tion might or might not be appropriate for specific individuals, leading to more focussed, more effective and safer pharmacotherapy. It might also stimulate demand for “personalised” medications, requiring greater flexibility in terms of dosage, possible rate of drug input (release rate from the dosage form) than is now thought necessary. Systems and technologies need to be developed to provide such flexibility but, when demand emerges, technologies, ideas and associated opportunities invariably follow.

Inhalation Delivery System for Insulin*

Paediatric medications

Medications are evaluated primarily in adults in the first instance because of ethical, regulatory and “informed consent” considerations. Traditionally, paediatric medicine has usually been an “add-on” to adult therapy. It is now accepted that the premise that plasma levels and kinetics established in adults evince the same effects (on a mg/kg basis) in paediatrics can be flawed. Children can differ from adults in metabolic and clearance capability (and such characteristics change more rapidly over time than with adults). Scaling down the dose, based on body mass considerations may be too simplistic. Paediatric-specific medications may be necessary.

Patient convenience

Adult dosage forms (usually a tablet or capsule) are often unsuitable for dosage to young children because of size and swallowing difficulties. A liquid product is preferable but palatability then becomes critical. Taste is usually a function of the level of drug in solution.

If concentration in the dissolved state exceeds the bitterness threshold there is little that can be done by simple formulation to improve matters. Sweeteners like sucrose can elevate the bitterness threshold to some extent but sucrose is now considered undesirable in medicinal products. Other techniques to mask poor taste (e.g. coating with polymeric materials) are generally of limited value.

Bioavailability may be compromised and in any case coated particles (because they are likely to be larger than drug

*Reproduced with permission from Pfizer Inc. Figure 4

particles) can have a gritty texture and may be broken by mastication, with the drug being “released” in the mouth and evincing the bitter taste.

More effective ways must, therefore, be used to improve palatability of liquid products. One approach is to utilise a form of the drug (e.g. different salt form), whose solubility is lower than the bitterness threshold. However, depression of solubility can affect absorption rate and bioavailability. In very general terms it is accepted that, when solubility exceeds about 1-2mg/ml absorption may not be an issue. This suggests that, where bitterness threshold is in this region, the use of an alternative salt offers possibilities for taste masking with no impact on bioavailability.

Technological innovation

Drug-device combinations Many useful systems have been developed to facilitate parenteral administration (particularly self-injection), diagnostic testing (e.g. blood glucose monitors) and for inhalation dosage. The search for a non-invasive way of delivering insulin has lasted a long time. Indeed, many despaired that

there would ever be a successful outcome.

The major barriers concerned insulin’s peptide structure, making oral delivery unreliable, if not impossible. The steep dose-response relationship and need for dose to reflect blood glucose levels were also considerable constraints. Persistence has paid off, however, and a system for insulin delivery by inhalation has now been tested in clinical trials and shown to be safe and effective. The product shown in Figure 4 is now commercially available.

Time will tell whether inhaled insulin becomes widely used and whether such delivery is appropriate for patients suffering from other conditions that cause breathing problems (emphysema and asthma). At the same time, other devices for inhalation delivery of insulin are being developed. It is the nature of such competition that each new product represents an incremental improvement over existing ones. Over time, such cumu -ative enhancements lead to significantimprovements.

Incremental improvements have also featured prominently in inhalation products for treating asthma. The first systems for delivery of dry powder were effective but required manipulation of drug (which was contained in a capsule) and device prior to dosage. In young children, this could be embarrassing for dosage while at school and on social and sporting occasions. Devices are now available that do not require cumbersome pre-dosing assembly so are more convenient and acceptable to the patient (Figure 5).

Drug-device combinations are likely to continue to offer great opportunities for innovative ways of drug delivery.

Novel diagnostic techniques are also likely to attain greater prominence in all patient groups. The Prostate-Specific Antigen test for early diagnosis of prostate cancer is now routine but there is great hope that similar diagnostic tests for autoimmune conditions, cancer, osteoarthritis and liver disease will become available over the next decade. It is conceivable that treatment paradigms

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Optimising absorption may involve using a different solid state form of the drug, altering the physical properties of the existing form, formulation with materials that enhance absorption, exploiting the physiology of the gastrointestinal (GI) tract or capitalising on pre-hepatic metabolic and transport systems. There is a wealth of literature to provide guidance on improving absorption. Hence, the topic is not reviewed in this article.

Multi-Dose Inhalation Delivery System for Asthama

Conclusions

Figure 5

Enhancing oral absorption

Medicinal agents are structurally designed for optimum specificity and “potency” in most cases. They can be highly lipophilic and poorly soluble as a consequence. Yet, a material must dissolve in aqueous media to be transported to the systemic circulation (while being sufficiently lipophilic to partition from the aqueous intestinal contents across the enterocytes lining the small intestine). It may be difficult to balance such competing features in a chemical structure. Consequently absorption may be sub-optimal, variable or dose-constrained, leading to plasma level variations causing unreliable therapeutic response or greater incidence of side effects. Local side effects are also possible, consequent to poor absorption. Gastrointestinal side effects during treatment with broad spec-

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trum antibiotics have been ascribed to unabsorbed antibiotic killing symbiotic bacteria and subsequent overgrowth of resistant flora.

Oral absorption enhancement has the potential to make the medication more reliable, by reducing the variability in plasma levels. Other potential advantages, if absorption enhancement were to be significant might be a lower dose, smaller dosage units and lower cost of goods for the medication.

A u t h o r BIO

for “early disease states”, identified by such techniques may differ from those applied to well-established disease states.

This too should lead to existing drugs finding new or slightly different uses that make them better medications.

Performance enhancement of medications is invariably driven by new biological insights that may relate to the patient, the disease condition or the drug. Generally, evidence from clinical trials is required to validate and support any claims for improvement. However, overall there is less risk of failure with such programs than with novel molecular entities. The compounds being evaluated for improvements will have been thoroughly evaluated for safety, so the risk of attrition because of toxic effects is low or maybe non-existent.

Better understanding of how drugswork and increased access to such knowledge makes it likely that such opportunities will continue to become available for providing better medicines so that patients receive improved treatments to make them feel better and live longer.

References are available at www.pharmafocusasia.com

Patrick Crowley is an expert in Dosage Form Development and Evaluation. He operates an independent Consultant to the pharmaceutical industry, specialising in dosage form design and evaluation, product registrations, biopharmaceutical products and patent litigation. He is a Visiting Professor at The School of Pharmacy, King's College, University of London, UK.

Luigi G Martini is Professor of Pharmaceutical Innovation at King’s College London where he is the UK’s first and only Industrial Pharmacist teaching practitioner providing an important link between Industry and Academia. His research interests include personalised medicine, drug delivery systems and medical device engineering.

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Competing on Alignment SWOT is both the most powerful and least understood strategic management tool. Used correctly, it translates the outputs of many other market analyses into a small number of key issues.

Brian D Smith Principal Advisor PragMedic, UK

T

he most powerful strategic management tool is also the most misunderstood

Consultants often use military analogies, comparing competitors to enemies and strategies to battle plans. This tradition arose in the early days of strategic planning in the 1950s, when many executives and writers had personal experience of military life. But for the life sciences sector it is a flawed analogy, neglecting both the role of customers and the reality of cooperation between rivals. Much closer are the parallels to biology, where success depends on achieving the best fit with the environment. The idea of “strategy as fit�

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emerged in the late 1960s and central to it was the SWOT (strengths, weaknesses, opportunities, threats) analysis, which almost every life science firm uses as part of its strategic planning.

Despite its widespread use, SWOT remains the most misunderstood and abused technique in the strategists’ toolkit. Academic research reveals that most SWOTs produce lists of meaning-

What are the implications of the external macro environment?

(SLEPT Analysis)

List of opportunities and threats arising from the external environment

What are the implications of the competitive situation?

(Porter's 5 Forces)

List of threats (rarely opportunities) arising from the competitive situation

What are the implications of the market structure?

(Segment analysis, sometimes market mapping in tiered markets)

List of opportunities and threats arising from market segmentation

Distinctive organisational strengths ( tested

by VRIO)

SWOT alignment to reveal key issues to be addressed by strategy

List of key issues that any choice of strategy must address

Distinctive organisational weaknesses (tested by MUDU)

Figure 1: SWOT as a processing tool

less, unverified factors that are of little practical use. This means that many firms are wasting valuable executive time doing useless SWOTS and are failing to realise the benefits of a powerful aid to strategy making. In my work, researching the evolution of competitive capabilities in the life sciences, I’ve observed the differences between firms that gain value from using SWOT and those that don’t.

Three practically useful lessons emerge from my work.

Lesson One: Everything in its place

SWOT is typically used independently from other tools but the effective use of SWOT involves using it as part of a process. Here, SWOT becomes a tool that makes sense of the outputs of other techniques, as shown in figure 1.

In the life science companies that I have observed, to use SWOT effectively, the practice was to feed the SWOT with the inputs from a wide range of other strategic management tools. Typically, market segmentation, Porter’s 5-forces,

Life Cycle Analysis and SLEPT (or PEST) were the most useful tools for clarifying factors external to the firm. When used correctly, those tools cover the whole gamut of factors that shape pharmaceutical and medical technology markets, from regulation and market access to technological developments and clinical practice. For factors within the firm, value-chain comparison, benchmarking, and market-mapping are useful. These reveal both tangible factors, such as product advantages and IPR, and important but less obvious factors, such as customer relationships and core competencies.

When used in this way as a processor of the outputs of other tools, SWOT classifies positive, internal factors as strengths and negative internal factors as weaknesses. Similarly, positive external factors are classed as opportunities and negative external factors as threats. Later in the process, these are aligned. But for now the critical difference to note between useful and useless SWOTs is that effective SWOTs don’t stand alone,

they use the outputs from all the other analyses.

Lesson Two: Garbage In, Garbage Out

Surprisingly, my work finds that most effective SWOTs are usually much shorter than those of less effective companies, which are characterised by repetition, overlap and contradiction. For example, life science companies are particularly prone to adding lots of technical and clinical factors into the SWOT that have little strategic relevance. Equally, they often overstate the importance of local or temporary changes in the market environment. In my research, I uncovered a novel filtering process that leading firms use to avoid this; whereas most firms dump their ideas into the SWOT, better firms sieve them, allowing only useful information into the SWOT. The mechanism of this filtering process is based on a body of research known as the Resource Based View of the firm. It is critically important to the

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A strength is only a strength if it is VRIO

A weakness is only a weakness if it is MUDU

Valuable: it can create value for the firm or the customer

Meaningful: it makes a significant difference to the customer or the firm

Rare: it is not shared with rivals

Uncommon: it is not shared with rivals

Inimitable: it is difficult or costly to copy

Difficult: it not easy or cheap to fix

Organisationally aligned: the firm is able to use the strength

Uncompensated: it is not counterbalanced by some other factor

Table 1: Filtering tests for Strengths and Weaknesses

success of SWOT and is shown in tables 1 and 2. Importantly, these filters are cumulative: a factor must pass all four tests to qualify as a genuine strength, weakness, opportunity or threat. When used well, this approach filters out the irrelevant noise in the environmental analysis and reduces the real, strategically relevant strengths and weaknesses to a small number of very important factors.

If the first two lessons are applied and SWOT is used as part of a process with filtered inputs, the result is four very succinct lists (strengths, weaknesses, opportunities, threats) with typically 5-10 factors in each. In life science

An opportunity is only an opportunity if it is CLAL

A threat is only a threat if it is USUL

Complementary: it does not prevent taking advantage of another, better, opportunity

Unmitigated: it is not removed or significantly reduced by some other external factor

Large: it is big enough to justify the costs of winning it

Significant: it is a large enough threat to make a significant impact on the firm

Accessible: it can be taken advantage of by the firm

Undefended: it is not removed or significantly reduced by some action the firm is already undertaking

Lasting; it lasts long enough to be taken advantage of

Lasting: it lasts long enough to have a significant impact on the company

Table 2: Filtering tests for Opportunities and Threats 30

SWOT is typically used independently from other tools but the effective use of SWOT involves using it as part of a process.

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markets, strengths and weaknesses usually include factors about the firm’s technology but also about capabilities in managing customer relationships.

The opportunities and threats include newly identified market segments and competitive activity but also factors arising from the payer environment.

Importantly, these four lists now contain everything that is strategically important and nothing that is not. Using these, the strategist can now extract real value and insight from the next and final stage of SWOT process.

Lesson Three: Analysis by alignment

In those life science companies who wasted time on fruitless SWOTs, it was typical to see large amounts of data analysis, a habit that is exacerbated by data availability and cheap processing power. By contrast, the more effective companies, whilst still valuing data, did less analysis and concentrated on aligning the factors that had emerged from their filters. This alignment process involves two sequential steps: • Looking for two sets of connectivity: those between strengths and opportunities and those between weaknesses and threats. • Identifying the critical success factors implied by that connectivity.

Firms that try to leap to lesson 3, without learning lessons one and two, waste resources on invalid SWOT analyses. Those that are more thorough usually find that the connections are obvious and clear. VRIO validated strengths almost always align obviously to CLAL validated opportunities as do MUDU validated weaknesses to USUL validated threats. As a small but useful practical tip, this first step of alignment is made easier when the connected factors are written in the left and right hand columns of a table, as exemplified in table 3.

Only when this first alignment step between internal and external factors is complete, can the second alignment

Strength

Key issue

Opportunity

We have superior clinical efficacy compared to our competitors

A strong strategy must leverage our clinical efficacy to exploit the clinically oriented segment

There is a segment of the market prioritises clinical efficacy over health economic outcomes

We have superior distribution strength in the secondary care channel

A strong strategy must focus on the secondary care channel

The secondary care channel contains a large proportion of clinically oriented customers

Our brand is well trusted in emerging markets relative to our competitors

A strong strategy must leverage our brand reputation to exploit emerging markets

Concerns about product quality and provenance strongly influence brand choice in emerging markets

Weakness

Key issue

Threat

We have a high price relative to less innovative competitors

A strong strategy must avoid wasting effort on price sensitive segments

There is an increasingly large market segment that is very price-sensitive

The resources we dedicate to brand building in emerging markets are much less than our competitors

A strong strategy must allocate greater resources to brand building in emerging markets

Increasingly crowded emerging markets mean that the brand is more important to customer choice than before

Our clinical data is more biased towards developed markets than that of our competitors

A strong strategy must allocate greater resources to generating emerging market clinical data

Emerging market customers increasingly expect local market clinical data

Table 3: An example SWOT for a Life Science Company

example of table 3. When observing what life science companies do in practice, it is noticeable that best practice always involves an iterative process, repeating the whole process from initial analysis,

A u t h o r BIO

step be executed. Effective firms ask themselves questions about what needs to happen for each strength to exploit its connected opportunity and for each weakness to be mitigated in the face of its connected threat. If the first alignment step has been done thoughtfully, the answers to these questions emerge as clear, unequivocal key issues that the strategy must address. As another practical tip, this second step is made easier when the key issues are written in the central column of the table, as in the

through filtering to alignment and identification of key issues, several times.

Ineffective practice was typified by rushing through the process and reluctance to reiterate, a habit that simply failed to cope with the complexity of typical pharmaceutical or medical technology markets.

Although table 3 is a simplified and disguised example, it illustrates the key features of an effective SWOT. Using only a small number of filtered inputs, the output of a useful SWOT is a limited number – typically 5 to 10 – of key issues. Despite and perhaps because of this succinctness, these key issues make it clear to the firm’s executives what they must do to align its internal strengths and weaknesses to the opportunities and threats arising from the market environment.

The difference between good and bad SWOT

Although the key issues that come out of SWOT do not dictate what the strategy should be, they help the strategist identify what really matters. Especially in complex, turbulent markets like those for pharmaceuticals and medical technology, this makes SWOT an important and arguably essential tool for senior executives. However, like any tool, it can do more harm than good if used badly. Used alone, without filtered inputs and without the alignment step, SWOT deserves the other meaning it is sometimes given: A Silly Waste Of Time. But used correctly, to process the outputs of other techniques, with carefully filtered inputs and a thoughtful, two-part alignment step, it is perhaps the single most useful tool available to the strategist.

Professor Brian D Smith is a world-recognised authority on competitive strategy in the pharmaceutical and medical technology sectors. He researches the evolution of the sector at the University of Hertfordshire, UK and SDA Bocconi, Italy. He welcomes comments and questions on brian.smith@pragmedic.com

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CPhI and P-MEC India 2015 to create regional knowledge and business hub Pre-connect congress launches in 2015 to increase information sharing and analysis at South Asia’s largest pharma event CPhI and P-MEC India (#cphiindia #pmecindia), organised by UBM India, will return to the Bombay Convention and Exhibition Centre, Mumbai, India from 1st to 3rd December 2015. The event hosts the key players in India’s pharma machinery, technology and ingredients sectors, and provides an unrivalled opportunity to gain a competitive advantage in this dynamic pharma economy.

India is fast emerging as the Globe’s key pharma region, with forward looking companies investing due to its unrivalled mix of high quality and low cost pharma solutions. Local knowledge, market information and meeting the right partners, are undoubtedly the crucial elements to success in this most fluvial and growing pharma sourcing economy.

This year, CPhI and P-MEC India will welcome more than 1,100 exhibitors from 25 countries and 32,000+ visitors from 97 countries. Driving the event’s growth is the pharma market in India, which will reach a staggering $45 billion USD by 2020 according to most analysts, with the cost of production and R&D nearly 60 per cent lower than in the USA and almost half that of Europe - allowing for maximum efficiency of Indian pharma companies. In fact, pharma in India accounts for over 10 per cent of global pharmaceutical production, holding over 60,000 generic brands, across 60 different therapeutic categories and manufacturing over 500 different APIs. Additionally, the Government of India has also unveiled ‘Pharma Vision 2020’, which has the ultimate goal of making India a global leader in end-to-end drug manufacturing.

Pre-connect congress For the first time in 2015, CPhI and P-MEC India will present the Pre-Connect Congress, taking place on 30th November 2015 at The ITC Maratha, Mumbai. This event brings together the industry and leverages the knowledge of leading experts to expand the vision and goals of the Indian Pharmaceutical Industry.

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At CPhI and P-MEC India, technical seminars will be held throughout the duration of the programme, as well as the UBM India Pharma Awards - celebrating excellence in the pharma industry from India, Asia and Europe through 10 different categories.

“CPhI & P-MEC India is the meeting place for all players in the pharmaceutical space. This is the only show of its kind in India and an invaluable chance to find new developments, meet new customer demands and be in touch with the leading pharmaceutical companies.” Harish Shah, Managing Director, Signet Chemical Corporation

About CPhI CPhI drives growth and innovation at every step of the global pharmaceutical supply chain from drug discovery to finished dosage. Through exhibitions, conferences and online communities, CPhI brings together more than 100,000 pharmaceutical professionals each year to network, identify business opportunities and expand the global market. CPhI hosts events in Europe, Korea, China, India, Japan, South East Asia, Turkey and Russia and co-locates with ICSE for contract services, P-MEC for machinery, equipment & technology, InnoPack for pharmaceutical packaging and BioPh for biopharma. CPhI provides an online buyer & supplier directory at CPhI-Online.com.

For more information visit: www.cphi.com About UBM India UBM India is India's leading exhibition organizer that provides the industry with platforms that bring together buyers and sellers from around the world, through a portfolio of exhibitions, content led conferences & seminars. UBM India hosts over 25 large scale exhibitions and 40 conferences across the country every year; thereby enabling trade across multiple industry verticals. A UBM Asia Company, UBM India has offices across Mumbai, New Delhi, Bangalore and Chennai.

UBM Asia is owned by UBM plc which is listed on the London Stock Exchange.UBM Asia is the leading exhibition organizer in Asia and the biggest commercial organizer in mainland China, India and Malaysia.

“Together – CPhI in its ninth year and P-MEC in its eighth year – provide the ideal regional platform for companies to learn, invest and do business with India’s high quality pharma solution providers. With the highest number of USFDA approved facilities outside of the US, India is now emerging as the Globe’s finished formulation economy and is set for a sustained period of growth. But with such a dynamic market, it is essential that pharma companies have a full view of the market opportunities and, just as crucially, the most up to date analysis to make the right investment choices.

With CPhI, P-MEC and now the pre-connect, we are centralizing knowledge and business together to increase collaborations and business opportunities.”

Chris Kilbee, Group Director Pharma at UBM EMEA.

For further details, please visit www.ubmindia.in For media enquiries, please contact: Mili Lalwani T: +91 22 61727139 E: mili.lalwani@ubm.com

The main sponsors of CPhI and P-MEC India 2015 are: Platinum Partners, Fette Compacting; Gold Partner, ACG Worldwide; and Silver Partner, Fabtech Technologies. Registration is free until November 27 and onsite registration is also possible for INR 500.

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Modularisation in Biologics Manufacturing Recent trends and developments The inherent risk in establishing biopharmaceutical production (product, process, timeline, capacity, regulatory and location) can be significantly mitigated by using a modular and standardised approach. Utilising a combination of standardisation, modularisation and use of modern process solutions such as single use equipment offers significant advantages over traditional design and construction.

Jan Lilja, Director, Commercial Management, KeyPlants AB, Sweden AsaGaasvik, Sr Design Engineer, KeyPlants AB, Sweden ParAlmhem, ModWave LLC, US

D

esign, construction and installation of complete modular production facilities for pharmaceuticals and biopharmaceuticals have in recent years been widely accepted.

According to Gilroy and Martini ‘modular construction’ of a pharmaceutical manufacturing facility refers to construction of all or part of a new or renovated facility built at a remote location, transported to the owner´s address and re-assembled on site. Modules consist of structural frames that are fit out with all mechanical, electrical and plumbing architectural elements – complete with all fixed process equipment. Modularisation considerably increases productivity, which is probably one of the most unpredictable aspects of a construction project. Besides bad weather conditions, conventional on-site construction labour productivity is plagued by high turn-over, changes, inexperienced contractor´s workers, and the challenges of working out of position.

In a modular facility project typically over 80per cent of all installations are performed and qualified in the supplier’s workshop instead leaving 20per cent or lest to be performed in the field.

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The pioneer in the construction of modular pharmaceutical facilities was Pharmadule AB, a Swedish company that is out of business since February 2011. Companies that offer modular facility construction include Biologics Modular, G-Con, Jacobs Engineering and Key Plants. Some traditional bioprocess equipment suppliers, e.g. GE Healthcare Life Sciences, Sartorius Stedim Biotech and Merck Millipore have begun to offer fully equipped modules for specific process steps.

Key Plants has developed an innovative approach to modular facility design and construction that is flexible, and cost efficient, while allowing for use of process equipment from any supplier.

This design provides greater flexibility in the layout and design of both upstream and downstream process areas. Modules can be installed and operated within an existing building or as a separate modular building as long as a suitable power source is available.

Introduction to the new generation facilities

In a recent discussion on next-generation manufacturing facilities, an author

argued that bio-manufacturing facilities can be divided into process, facility, and infrastructure components. Each plays a significant role in the success of a manufacturing enterprise. A failure or weakness in either will lead to poor product quality and/or inefficient manufacturing.

Improvements in manufacturing technologies and advancements in single use systems have clearly transformed bioprocesses. Hand-in-hand with those process improvements comes modular construction, which will become more and more common because modular alternatives can have smaller footprints than traditional facilities and be deployed rapidly in locations where clean-room and piping expertise may not be readily available.

Combined, modular technology and single-use technologies can reduce investment and operating costs, as well as the financial risk of building new biopharmaceutical manufacturing facilities.

Smaller, greener and more flexible facilities of the future that look to new technology solutions may also enable a key industry transition from fixed to variable cost structures to structures that

Current trends Market developments are increasing the demand for modular solutions, at the same time as technical advancements in pharmaceutical and biopharmaceutical processing are making modular alternatives even more feasible. These market and technical trends include (but are not limited to): • Increasing pressure to significantly reduce the time and cost to build manufacturing capacity– “How can we build in half the time, at half the cost, without compromising quality?”

• Needs/demands for local production in many markets that previously did not have this capacity or the necessary competences to build and sustain it • Increased capabilities and use of single use technologies in biopharmaceutical production – for drug substance as well as for formulation and filling • Developments in processes for OSD manufacturing, including continuous processing.

Table1

follow demand. Defining and understanding the business drivers, uncertainties, and risks associated with building and operating bio-manufacturing facilities is a key first step in the development of future generation manufacturing facilities.

Success of future facility design must be measured in terms of utilisation, flexibility, and efficiency while providing a platform that supports and facilitates the operational excellence required to reliably produce high quality product, while meeting an ever-evolving set of regulatory compliance guidance. As the industry looks to make the transition from current state to the future model, new enabling technologies can provide manufacturing platforms that meet the goals of being flexible with low capital unit operations changeovers, efficient movement to new markets, and a scaleout approach with smaller increments of capacity from highly productive processes to meet lower demand markets.

Operational excellence is the fundamental driver for producing high quality product and efficiently meeting all necessary regulatory requirements. The following questions could be the starting point for identifying the best facility options to satisfy product quality, operational excellence and regulatory compliance: • Does the facility provide an optimum environment (not to small not too large) to execute the process steps

• Based on the manufacturing requirements, does the facility incorporate and support optimal segregation strategies for separating the products and processes manufactured in the facility • Does the facility design facilitate the use of existing and future advanced process control technologies • Is the process train designed for reliable operation given the operational design basis • Does the facility meet current as well as likely future technology challenges in the Quality Target Product Profile established and thus will it be able to meet future regulatory expectations

• How can the impact of uncertainties and risks be minimised?

In order to answer these questions, a novel design platform was developed for biologics production. Several criteria were identified as essential in order to come up with the right answers, such as a modular design, utilisation of singleuse equipment, build on a well-known bio-process, and risk-based level of segregation.

A flexible layout is of importance especially for sites working with combinations of products, product classes, and host-cell types. The important issue is how we can combine single-use and stainless steel technologies to provide the most productive, cost-effective and regulatory risk-optimised process in a faster and more predictable way.

Basis for a standard design platform

The standardised drug substance manufacturing suite´s configurable modules have adequate space based on a MAb process on the basis of a CHO cell line and bioreactor train 1x 50 litre – 1x 200 litre – 1x 1000 litre, The downstream process consists of preparation of equipment, buffer preparation of buffer solutions, tangential filtration and concentration of the uterine culture fluid,

A platform layout was developed utilising six functional modules

Figure 1 Standard Platform Functional modules: material staging and dispensing, media and buffer preparation and storage, and upstream and downstream processing, along with sufficient space for all support functions and appropriate airlocks and corridors.

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and subsequent depth filtration of the concentrate, affinity chromatography, cation-exchange chromatography, anion exchange chromatography, concentrating tangential diafiltration and viral inactivation of the concentrated MAb obtaining the active pharmaceutical ingredient (API),formulation and sterile filtration of the API followed byaseptic filling in vials.

The estimated productivity of the cell line 4-6 g MAb from 1 liter of culture.

The total loss initially estimated in the upstream and downstream process is 70 per cent. The API has a concentration of monoclonal antibody (MAb) 10 mg / mL, titer concentration 5g. Annual output from 80 kg Mab, annual output approximately 50 batches(300 working days, batch duration 18 days including change-over time), 16,000 vials per batch, filled in 10 ml vials (100 mg/vial).Filled during three shifts.

The utilisation of single-use equipment is optimised for the process. This can be adjusted to the end user’s needs, and the level of stain less steel equipment increased to meet each application.

The standard facility is equipped with single use seed and production bioreactors. In addition all media and buffers were prepared using single use systems consisting of powder transfer bags, disposable bags with a disposable internal agitator, external mixing system, weighing station, and a disposable path (pump, tubing, filters, etc.) for transfer of the prepared media or buffer into a disposable bag system for storage. When necessary, buffers are prepared in concentrated solutions to accommodate the transport in disposable bags at a maximum volume of 500 L, which is a typical volume limitation for transport within the facility. In-line dilution skids were utilised at point of use for the concentrated buffers. Media is prepared at the start of each production batch. Similarly, buffers are prepared in advance and stored within the facility until used. A new batch of media or buffer is prepared for each production batch. For each of the chromatography

steps included in the purification process, 630 mm diameter columns packed to 200 mm bed heights are used, with each column being used for multiple cycles per batch. For the Protein A affinity column, five cycles per batch is required.

For the cation exchange column, three cycles per batch is used and for the anion exchange column, two cycles per batch is assumed. CIP/SIP for column packing is included.

Important to consider is the level of segregation based on regulatory requirements, product, closed/contained processing steps and user corporate standards.

Starting from an open design, it is possible to increase the segregation level by adding walls and airlocks, e.g. to divide cultivation and initial purification areas into two rooms. Also the media and buffer preparation and hold works in the same way. In order to choose the appropriate level for a certain product/ multi-product facility and the risk for cross-contamination or contamination from adventitious agents is to use a riskbased approach. Rios makes the same conclusion at a recent conference “One well-recognised challenge in multiproduct facilities is minimising or eliminating cross contamination. For that, industry and regulatory experts have advised manufacturers to take a risk-based approach. Such strategy can prove benefi-

Risk acceptance profile

Figure 2 36

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cial in flexible layouts in sites working with combinations of products, product classes, and host-cell types.”.

To further ensure segregation within the facility, the design includes multiple air handlers located on an upper level. The level of segregation is based on a risk assessment and includes the following: • Separate air handling zones • Segregated pre- and post viral processing • Closed process where possible (grade D) • Live organism containing areas separated from other areas • Open processing areas (seed lab, final purification and bulk filling) separate and in grade C (also with bio-safety cabinets) • Increased segregation in cell cultivation and purification areas possible with easy to erect clean-room panels according to product and risk (BSL, cross-contamination etc.).

ICH Q9 II.4: QRM for facilities, equipment and utilities recommend the use of a Risk Acceptance Profile (Figure 2). EMA 5.19 EU GMP Guide states that cross contamination should be avoided by appropriate technical or organisational measures.

In addition, separate processing areas are provided for downstream processing

Modular Bio Solutions,MAb Facility

Standard Modular Bio Solution

Figure 3

operations pre- and post-virus removal by nan-ofiltration. Wherever possible, fully closed and contained processing is used, generally within a Grade D environmental classification. Open processing areas, such as those required for innoculum preparation, final purification, and bulk filling are designed to be Grade C with specific open operations being performed in suitable bio-safety cabinets with laminar air flow.

The facility also includes suitable staging areas for raw materials, consumables, and equipment and appropriate locker rooms and airlocks for personnel changing and entry and exit from the facility. Media and buffer preparation areas are located in the centre of the facility to allow the most possible adjacencies to processing areas. Wherever possible, buffers are stored in closed containers in controlled but unclassified space to minimise the environmental burden and lower the overall HVAC requirements for the facility. The result of the design of the layout within the product processing area is a general U-shape design for the product flow being unidirectional from one end of the facility to the other. The facility includes a thorough and optimised equipment positioning in order to minimise the tubing or piping needed for product and material transfer.The tubing components are delivered gamma irradiated and can be connected by tube welding. The layout has one single access point for all production personnel and one exit point. Included in the bulk drug

substance area are also functionality such as Storages for raw material, consumables and equipment. The buffer and media preparation is centralised in order to minimise the adjacencies between the media hold bags and the process equipment respectively. In order to maximise the ease of transporting the different bags the largest hold bag is 500L. There is also included an in-line dilution skid for the buffer preparation for the Protein A Chromatography step to even further reduce the amounts of buffer that needs to be prepared and stored. In the Grade C area for Final Purification, an Aseptic Filling (Crystal® closed, pre-sterilised vial technology) L1 Robot Line has been placed, to meet a filling capacity of up to 600 vials/hour. Typical batch size around 5,000 vials, on a single shift basis.

The standard MAb manufacturing facility (Figure 3) has a total floor area of 1208 m2, including the mechanical space on the second floor.With the 1,000 liter bioreactor train, the process area is less than 740m2.The time schedule to build the facility is less than 12 months for the standard layout. The price for the ‘plug-and-play’ two storey facility described is estimated to be well in line with conventional clean-room installation. The facility may be connected to an existing building as well as being used in an indoor concept and built in an already existing building or a rapidly constructed shell.

In-door modules (Figure4) can be placed on a concrete slab in a building with pipe-racks and connections installed under, over or parallel to the modular process facility. HVAC and utility systems (mechanical areas) can be placed over or next to the modular building. An outdoor(Figure 5) modular building can be placed on foundation of concrete-pillars, a slab or on top of basement or building.

The main difference is the façade/roof system for the out-door building, which is insulated and weather proofed.

Clean-rooms are constructed utilising an integrated panel system for walls, ceilings, doors, windows etc. Walkable ceilings create mezzanine space with

In-door facility

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Out-door facility

Figure 5

The modular cost advantage–time is money

One key advantage of modular construction for biopharmaceutical facilities is the off-site construction of modules.

The benefits of this approach include enhanced quality control, reduced waste, reduced impact on current operations, and simplified site logistics. Transferring labour hours away from the construction site also reduces risk and overall cost for a facility construction project. Building multiple modular elements in parallel without,for example, weather impact,

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can reduce the construction schedule for a facility project by 50per cent. The ability to leverage factory acceptance testing (FAT) at a module construction facility will often significantly shorten the time for start-up and commissioning of a new facility. Once modules are delivered to the construction site, they are assembled into the complete facility so that final testing and qualification can be completed.

Jamesonhas discussed in detail the cost benefits of the Modular Facility Technology. Comparisons of project cost components were discussed to help potential users of this technology gain a better

Jan Lilja has over 28 years experience from Management in Lifescience companies in Europe/Asia/USA. Established Life-Science companies in 10 countries including 6 Asian J/Vs. Lilja has 10 years experience in Pharmadule (modular project execution turn-key) as Director responsible for biotech &pharma sales in Pharmerging Markets and previously Asia, strategic business planning, feasibility studies for pharma/med-tech start-ups, multinational strategic analysis and project co-ordination.

A u t h o r BIO

service access above the clean-rooms for AHUs and other utilities such as piping, electrical and ductwork distribution. It may also be used for electrical rooms and clean utility generation.

Support systems (electrical, piping, HVAC, etc.) will have the main distribution in the mezzanine. Each pre-fabricated module will have distribution integrated in the module with only one hook up point for the support systems.

This will create minimal hook-up installation and each module will work as a plug and play unit. Utilities have access points into process rooms either with ceiling panels lowered into the process room or integrated wall panels. Other systems included aredata communication – ethernet, grounding system, telecommunication, security system, air lock interlocks, fire alarm, etc. Sprinklers and alarm systems are installed according to local codes and requirements. Functional modules can be designed to incorporate any kind of process with automation as an integrated solution.

understanding of cost allocations and expected differences between a modular approach and a conventionally executed project. While this example indicated an initial 9per cent cost premium for the modular concept at the conceptual design phase, the risks involved with a conceptual design were quantified, which in turn shows that the modular approach is actually in the range of5per cent more cost effective. This comparison does not include consideration for the potential loss of sales revenue due to delays in market launch (every day of lost sales revenue will be substantial considering a per dose price of certain MAb products of around US$ 1,000). With the new standardized modular concepts, also the first cost of a modular alternative is typically competitive to conventional design and construction. Adding the lower risk in the project, and the shorter time to market, a modular project many times offers a significantly higher Net Present Value.

References are available at www.pharmafocusasia.com

Asa has over seventeen (17) years’ of experience working for the pharmaceutical and processindustry. She has focused on studies and projects involving process design, capacity planning, building design, site planning, estimating etc. Åsa possesses deep knowledge in process design in different processes for both pharmaceutical and process industry regarding various substances including containment and hazardous substances. Åsa also presents twelve (12) years of experience working with layouts for both conventional and modular facilities to accommodate good material and personal flow in process GMP facilities including SVP, OSD, API etc,.

ParAlmhem is the President of ModWave LLC, a solutions provider to the Pharmaceutical, Biopharmaceutical, Food and Process Industries, and of ModularPartners, a leading supplier of modular solutions to the Life Science Industries.Prior to his current engagements, Mr.Almhem was President of Pharmadule, Inc., the U.S. entity of Pharmadule AB of Sweden who was the pioneer supplier of high-techmodular production facilities to the Pharmaceutical and Biotech industries.

Almhem holds a Master of Science Degree in Applied Physics and Electrical Engineering from Linköping University, Sweden.

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39

Books

Practical Biotechnology: Methods and Protocols

The Future of Drug Discovery: Who Decides Which Diseases to Treat?

Author: S Janarthanan, S Vincent

Author: Jeffrey S Handen

Year of Publishing: 2015

Author: Tamas Bartfai, Graham V Lees

Year of Publishing: 2014

No. of Pages: 158

Year of Publishing: 2013

No. of Pages: 152

Description: The book helps undergraduate, postgraduate and research students to perform basic experiments in biotechnology. The laboratory protocols are simple to understand by students from different scientific backgrounds.

Each laboratory exercise contains an introductory unit, protocol and easy-to-follow instructions for reagent preparation. The methods and protocols given here aim to make students ready for independent research in biotechnology laboratories.

The protocols include

No. of Pages: 376

Description: In this book, contributors drawn from the executive ranks of clinical development practitioners and stakeholders—from biopharmaceutical companies, clinical research organizations, academia, the financial community, and the patient perspective—have all come together to provide their expertise and visions.

Their goal is to start a dialogue about ways to radically improve therapeutics development and get more and better medicines to the patients who need them, as fast as possible, in the most cost-efficient manner.

• DNA Isolation • Molecular Biology Methods • RNA Isolation • Useful Information for Molecular Biology Methods • Working with DNA • Preparation of Solutions

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Re-inventing Drug Development

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Description: This thought-provoking book is the first to: • provide an in-depth, broad perspective on the crisis in drug industry • expose the disconnect between what society needs and what the drug companies are working on • analyse and project over 10 years into the future • explain what it means for scientists and society • determine what is needed to be done to make sure that the industry responds to society's needs, remains commercially attractive and answers the question as to who decides which…Preparation of Solutions

Principles of Translational Science in Medicine: From Bench to Bedside Author: Martin Wehling Year of Publishing: 2015 No. of Pages: 364 Description: Principles of Translational Science in Medicine: From Bench to Bedside, Second Edition, provides an update on major achievements in the translation of research into medically relevant results and therapeutics.

The book presents a thorough discussion of biomarkers, early human trials, and networking models, and includes institutional and industrial support systems. It also covers algorithms that have influenced all major areas of biomedical research in recent years, resulting in an increasing numbers of new chemical/biological entities (NCEs or NBEs) as shown in FDA statistics.

The book is ideal for use as a guide for biomedical scientists to establish a systematic approach to translational medicine.

Knowledge Management in the Pharmaceutical Industry: Enhancing Research, Development and Manufacturing Performance Author: John Riddell, Elisabeth Goodman

Design and Analysis of Clinical Trials: Concepts and Methodologies (Wiley Series in Probability and Statistics) Author: Shein-Chung Chow, Jen-Pei Liu Year of Publishing: 2014

Year of Publishing: 2014

No. of Pages: 892

No. of Pages: 136

Description: In summary, this third edition is an impressive expansion beyond a remarkable second edition.

This book would be good reference for biostatisticians, clinical researchers, and pharmaceutical scientists in clinical research and development.

(Journal of Biopharmaceutical Statistics, 1 July 2014)

Description: This book demonstrates the critical importance of knowledge management and data sharing to translate the new vision of drug development into concrete actions.

This is a timely endeavor since more than ever therapeutic advances depend on integrative analysis of big data by scientists acquainted to the principles of collective intelligence.'Michel Goldman, Executive Director, Innovative Medicines Initiative (IMI)'This isn't just a book describing the theory of knowledge management, but rather an illustration of how it can be applied to the real, challenging world of the pharmaceutical industry. For those attempting to improve ways of working collaboratively in pharma, look here for some practical and pre-tested ideas, even if a formal KM strategy is already in place.' Alison Zartarian, AstraZeneca'With little published in this area, this book provides valuable, concrete evidence of the value of Knowledge Management (KM) to Pharma operations.

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Industry Reports Antisense RNAi Therapeutics Deals Value Approached $5.6 Billion in Landmark 2014, says GlobalData

Publication Date: September 2015

The deals market for antisense RNA interference (RNAi) therapeutics witnessed a record yearin 2014, with a total value of almost $5.6 billion across 59 transactions, by far the largest deal value ever seen in this space, according to research and consulting firm GlobalData.

volume will be in line with historical averages, although deal values will be significantly higher than pre-2014 levels,” the analyst concludes.

The company’s latest report* states that this figure is almost triple that of the previous year, with just over $1.9 billion raised from 62 deals in 2013, and almost double the previous high of approximately $2.9 billion from 58 transactions in 2010.

This report provides analysis on the antisense RNA interference (RNAi) therapeutics market, including current and future growth drivers and developments in clinical trials, deals, and pipeline investments. The report also assesses the competitive landscape and emerging strategies expected to influence current players’ positions in antisense RNAi therapy development and commercialization.

Adam Dion, MS, Senior Industry Analyst for GlobalData, says three mergers and acquisitions worth $1.2 billion, as well as record highs for licensing and capital raisings, helped to fuel deals in 2014.

Dion explains: “In particular, 2014 witnessed two very significant licensing deals when Celgene and Nogra Pharma struck a $1.5 billion agreement for Nogra’s GED-0301 to treat Crohn’s disease, and Genzyme and Alnylam signed a $775 million pact to co-develop Alnylam’s patisiran for transthyretin-mediated amyloidosis patients with familial amyloid polyneuropathy.

“The number and value of capital raisings in the antisense RNAi therapy field has been steadily increasing, with the past six years averaging about 40 deals at a combined value of just over $1.1 billion per year. This peaked in 2014, when capital raisings grew considerably by $600 million in 2013 to $1.9 billion last year, highlighted by a $500 million private placement from Isis Pharmaceuticals.”

GlobalData believes these developments provided a groundswell of support for future industry advancement and expects 2015 to register another strong year for capital raisings, given that 15 deals had already been struck by the end of July, for a total value of over $1.4 billion.

Dion continues: “The majority of the capital raised was from investment banks, such as JP Morgan, Deutsche Bank, and JMP Securities, for top RNAi therapeutics vendors, including Alnylam, Isis Pharmaceuticals, Moderna, and BioMarin.

*PharmaSphere: Emerging Biotechnologies – Antisense RNAi Therapeutics Market Analysis

This report was built using data and information sourced from proprietary databases, primary and secondary research, and in-house analysis conducted by GlobalData’s team of industry experts.

The report provides: • Market developments across the RNAi therapy field, including clinical trials, deals, and pipeline investments • Investment examined from both industry and financial communities • Clinical trials activity examined across phase of development, therapy area, and indication.

• This report offers a deep dive into the synergies behind partnering and acquisition activities • Deals examined across geography, entity type, company, financial advisor, phase of development, therapy area, indication, and mechanism of action • Pipeline profiles of 25 leading biotech companies developing RNAi therapeutics

Key Questions Answered • What are the drivers of the RNAi therapy field?

“Projecting forward, these numbers suggest that the deals

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• Who are the leading companies involved in the development of RNAi therapies?

emerging-biotechnologies-antisense-rnai-therapeuticsmarketanalysis/sample?companyid=vtk

• What are the major trends in RNAi clinical trials?

Disclaimer : All Rights Reserved.

No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form by any means, electronic, mechanical, photocopying, recording or otherwise, without the prior permission of the publisher, GlobalData.

• What specific therapeutic areas and indications are receiving the most clinical research?

• What specific business development activities are taking place in terms of partnerships or mergers and acquisitions (M&As)?

Link to the Report: http://store.globaldata.com/market-reports/ pharmaceuticals-andhealthcare/pharmasphere-emergingbiotechnologies-antisense-rnai-therapeutics-marketanalysis/ highlights?companyid=vtk#.Vi8UQtIrLDc

The facts of this report are believed to be correct at the time of publication but cannot be guaranteed. Please note that the findings, conclusions and recommendations that GlobalData delivers will be based on information gathered in good faith from both primary and secondary sources, whose accuracy we are not always in a position to guarantee. As such GlobalData can accept no liability whatever for actions taken based on any information that may subsequently prove to be incorrect.

Free sample Pages Link: http://store.globaldata.com/ market-reports/pharmaceuticals-andhealthcare/pharmasphere-

Antisense RNAi Therapeutics Deals Value Approached $5.6 Billion in Landmark 2014, says GlobalData © GlobalData. This report is a licensed product and is not to be copied, reproduced, shared or resold in any form.

• Has investor confidence been restored in the antisense/ RNAi therapy field?

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43

Research Insights Geographic and Temporal Trends in the Molecular Epidemiology and Genetic Mechanisms of Transmitted HIV-1 Drug Resistance: An Individual-Patient- and SequenceLevel Meta-Analysis Abstract

Authors:

Background Regional and subtype-specific mutational patterns of HIV-1 transmitted drug resistance (TDR) are essential for informing first-line antiretroviral (ARV) therapy guidelines and designing diagnostic assays for use in regions where standard genotypic resistance testing is not affordable. We sought to understand the molecular epidemiology of TDR and to identify the HIV-1 drug-resistance mutations responsible for TDR in different regions and virus subtypes.

Methods and Findings We reviewed all GenBank submissions of HIV-1 reverse transcriptase sequences with or without protease and identified 287 studies published between March 1, 2000, and December 31, 2013, with more than 25 recently or chronically infected ARV-naïve individuals. These studies comprised 50,870 individuals from 111 countries. Each set of study sequences was analyzed for phylogenetic clustering and the presence of 93 surveillance drug-resistance mutations (SDRMs). The median overall TDR prevalence in sub-Saharan Africa (SSA), south/southeast Asia (SSEA), upper-income Asian countries, Latin America/Caribbean, Europe, and North America was 2.8%, 2.9%, 5.6%, 7.6%, 9.4%, and 11.5%, respectively. In SSA, there was a yearly 1.09-fold (95% CI: 1.05–1.14) increase in odds of TDR since national ARV scale-up attributable to an increase in non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance. The odds of NNRTI-associated TDR also increased in Latin America/ Caribbean (odds ratio [OR] = 1.16; 95% CI: 1.06–1.25), North America (OR = 1.19; 95% CI: 1.12–1.26), Europe (OR = 1.07; 95% CI: 1.01–1.13), and upper-income Asian countries (OR = 1.33; 95% CI: 1.12–1.55). In SSEA, there was no significant change in the odds of TDR since national ARV scale-up (OR = 0.97; 95% CI: 0.92–1.02). An analysis limited to sequences with mixtures at less than 0.5% of their nucleotide positions—a proxy for recent infection—yielded

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Soo-Yon Rhee , Jose Luis Blanco, Michael R. Jordan, Jonathan Taylor, Philippe Lemey, Vici Varghese, Raph L. Hamers, Silvia Bertagnolio, Tobias F. Rinke de Wit, Avelin F. Aghokeng, Jan Albert, Radko Avi, Santiago Avila-Rios, Pascal O. Bessong, James I. Brooks, Charles A. B. Boucher, Zabrina L. Brumme, Michael P. Busch, Hermann Bussmann, Marie-Laure Chaix, Bum Sik Chin, Toni T. D’Aquin, Cillian F. De Gascun, Anne Derache, Diane Descamps, Alaka K. Deshpande, Cyrille F. Djoko, Susan H. Eshleman, Herve Fleury, Pierre Frange, Seiichiro Fujisaki, P. Richard Harrigan, Junko Hattori, Africa Holguin, Gillian M. Hunt, Hiroshi Ichimura, Pontiano Kaleebu, David Katzenstein, Sasisopin Kiertiburanakul, Jerome H. Kim, Sung Soon Kim, Yanpeng Li,Irja Lutsar, Lynn Morris, Nicaise Ndembi, Kee Peng NG, Ramesh S. Paranjape, Martine Peeters, Mario Poljak, Matt A. Price, Manon L. Ragonnet-Cronin, Gustavo ReyesTerán, Morgane Rolland, Sunee Sirivichayakul, Davey M. Smith, Marcelo A. Soares, Vincent V. Soriano, Deogratius Ssemwanga, Maja Stanojevic, Mariane A. Stefani, Wataru Sugiura, Somnuek Sungkanuparph, Amilcar Tanuri, Kok Keng Tee, Hong-Ha M. Truong, David A. M. C. van de Vijver, Nicole Vidal, Chunfu Yang, Rongge Yang, Gonzalo Yebra, John P. A. Ioannidis, Anne-Mieke Vandamme, Robert W. Shafer

trends comparable to those obtained using the complete dataset. Four NNRTI SDRMs—K101E, K103N, Y181C, and G190A—accounted for >80% of NNRTI-associated TDR in all regions and subtypes. Sixteen nucleoside reverse transcriptase inhibitor (NRTI) SDRMs accounted for >69% of NRTI-associated TDR in all regions and subtypes. In SSA and SSEA, 89% of NNRTI SDRMs were associated with

high-level resistance to nevirapine or efavirenz, whereas only 27% of NRTI SDRMs were associated with high-level resistance to zidovudine, lamivudine, tenofovir, or abacavir.

Of 763 viruses with TDR in SSA and SSEA, 725 (95%) were genetically dissimilar; 38 (5%) formed 19 sequence pairs.

Inherent limitations of this study are that some cohorts may not represent the broader regional population and that studies were heterogeneous with respect to duration of infection prior to sampling.

Conclusions Most TDR strains in SSA and SSEA arose independently, suggesting that ARV regimens with a high genetic barrier to resistance combined with improved patient adherence may mitigate TDR increases by reducing the generation of new ARV-resistant strains. A small number of NNRTIresistance mutations were responsible for most cases of high-level resistance, suggesting that inexpensive pointmutation assays to detect these mutations may be useful for pre-therapy screening in regions with high levels of TDR. In the context of a public health approach to ARV therapy, a reliable point-of-care genotypic resistance test could identify which patients should receive standard first-line therapy and which should receive a protease-inhibitorcontaining regimen.

Citation: Rhee S-Y, Blanco JL, Jordan MR, Taylor J, Lemey P, Varghese V, et al. (2015) Geographic and Temporal Trends in the Molecular Epidemiology and Genetic Mechanisms of Transmitted HIV-1 Drug Resistance: An Individual-Patientand Sequence-Level Meta-Analysis. PLoS Med 12(4): e1001810. doi:10.1371/journal.pmed.1001810 Academic Editor: Andrew Carr, St. Vincent's Hospital, AUSTRALIA Received: July 17, 2014; Accepted: February 27, 2015; Published: April 7, 2015 This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication Data Availability: This is a combined study of previously published studies with sequence data available in GenBank. The studies and the sequence data included can be accessed on the web site: http://hivdb.stanford. edu/surveillance/map/.

Funding: SYR, VV, and RWS were supported in part from NIH grant R01 AI068581. SYR and RWS were supported in part from an Bill & Melinda Gates Foundation grant.

MRJ is supported by CFAR grant 1P30A142853. No funding bodies had any role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: JHK and MR are employees of the Walter Reed Army Institute of Research, however, the views expressed herein are those of the authors and do not represent the official views of the Departments of the Army or Defense. DD has received honoraria and travel grants from Viiv Healthcare, Janssen-Cilag, Gilead-Sciences, MSD and BMS for participation to advisory boards and international conferences. SHE collaborates on research studies with investigators from Abbott Laboratories (distributor of the ViroSeq HIV-1 Genotyping System). Abbott Laboratories has provided reagents and performed testing for some collaborative studies. PF has received paid employment for educational presentation (Bristol-Myers Squibb, JanssenCilag), travel grants and honoraria for speaking or participation at meetings (Bristol-Myers Squibb, MSD, Gilead, Astellas). WS has received honoraria for speaking from Viiv, MSD, Janssen and Torii. PRH has received grants from, served as an ad hoc advisor to, or spoke at various events sponsored by: Pfizer, Glaxo-Smith Kline, Abbott, Merck, Tobira Therapeutics, Virco and Quest Diagnostics. MAP was supported in part from the United States Agency for International Development (USAID), however, the contents are the responsibility of the authors and do not necessarily reflect the views of USAID or the United States Government.

SB is a staff member of the World Health Organization and the contents are the responsibility of the authors and do not necessarily reflect the views of the World Health Organization. JPAI is a member of the Editorial Board of PLOS Medicine. All other authors have declared that no competing interests exist.

Abbreviations: ARV, antiretroviral; CPR, Calibrated Population Resistance; FSU, former Soviet Union; HIVDB, HIV Drug Resistance Database; IQR, interquartile range; LMIC, low- and middle-income country; MCMC, Markov chain Monte Carlo; NNRTI, non-nucleoside reverse transcriptase inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; OR, odds ratio; PI, protease inhibitor; RT, reverse transcriptase; SDRM, surveillance drug-resistance mutation; SSA, sub-Saharan Africa; SSEA, south/southeast Asia; TAM, thymidine-analog mutation; TDR, transmitted drug resistance

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Research Insights The Impact of a One-Dose versus Two-Dose Oral Cholera Vaccine Regimen in Outbreak Settings: A Modeling Study

Abstract

Authors:

Background In 2013, a stockpile of oral cholera vaccine (OCV) was created for use in outbreak response, but vaccine availability remains severely limited. Innovative strategies are needed to maximize the health impact and minimize the logistical barriers to using available vaccine. Here we ask under what conditions the use of one dose rather than the internationally licensed two-dose protocol may do both.

Andrew S. Azman, Francisco J. Luquero, Iza Ciglenecki, Rebecca F. Grais, David A. Sack, Justin Lessler

in past epidemics are based on severely limited singledose efficacy data and may not fully capture uncertainty due to imperfect surveillance data and uncertainty about the transmission dynamics of cholera in each setting.

Methods and Findings Using mathematical models we determined the minimum relative single-dose efficacy (MRSE) at which singledose reactive campaigns are expected to be as or more effective than two-dose campaigns with the same amount of vaccine. Average one- and two-dose OCV effectiveness was estimated from published literature and compared to the MRSE. Results were applied to recent outbreaks in Haiti, Zimbabwe, and Guinea using stochastic simulations to illustrate the potential impact of one- and two-dose campaigns. At the start of an epidemic, a single dose must be 35%–56% as efficacious as two doses to avert the same number of cases with a fixed amount of vaccine (i.e., MRSE between 35% and 56%). This threshold decreases as vaccination is delayed. Short-term OCV effectiveness is estimated to be 77% (95% CI 57%–88%) for two doses and 44% (95% CI −27% to 76%) for one dose. This results in a one-dose relative efficacy estimate of 57% (interquartile range 13%–88%), which is above conservative MRSE estimates. Using our best estimates of one- and two-dose efficacy, we projected that a single-dose reactive campaign could have prevented 70,584 (95% prediction interval [PI] 55,943–86,205) cases in Zimbabwe, 78,317 (95% PI 57,435–100,150) in Port-au-Prince, Haiti, and 2,826 (95% PI 2,490–3,170) cases in Conakry, Guinea: 1.1 to 1.2 times as many as a two-dose campaign. While extensive sensitivity analyses were performed, our projections of cases averted

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Conclusions Reactive vaccination campaigns using a single dose of OCV may avert more cases and deaths than a standard two-dose campaign when vaccine supplies are limited, while at the same time reducing logistical complexity. These findings should motivate consideration of the trade-offs between one- and two-dose campaigns in resource-constrained settings, though further field efficacy data are needed and should be a priority in any one-dose campaign.

Citation: Azman AS, Luquero FJ, Ciglenecki I, Grais RF, Sack DA, Lessler J (2015) The Impact of a One-Dose versus Two-Dose Oral Cholera Vaccine Regimen in Outbreak Settings: A Modeling Study. PLoS Med 12(8): e1001867. doi:10.1371/journal.pmed.1001867 Academic Editor: Mirjam E. E. Kretzschmar, The National Institute for Public Health and the Environment, NETHERLANDS Received: September 9, 2014; Accepted: July 15, 2015; Published: August 25, 2015 Copyright: © 2015 Azman et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use,

distribution, and reproduction in any medium, provided the original author and source are credited Data Availability: The authors confirm that all data underlying the findings and source code needed to reproduce the main results are available without restriction. Code and data can be found at https://github. com/HopkinsIDD/singledose-ocv or by contacting the corresponding author directly.

Funding: JL, ASA, FJL, and DAS’s work were supported by the Bill & Melinda Gates Foundation (OPP1089243 and

the DOVE project, OPP153556). JL is recipient of a K22 grant from the National Institute of Allergy and Infectious Disease (K22AI92150). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

Abbreviations: MRSE, minimum relative single-dose efficacy; OCV, oral cholera vaccine; PI, prediction interval; RSE, relative single-dose efficacy.

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Projects in Progress 1. Athenex Plans Two New Pharma Manufacturing Plants in China Introduction: Buffalo, USA-based Athenex, formerly known as Kinex Pharmaceuticals has announced that it has entered into a definitive agreement with the Banan District in Chongqing, China, to build two new pharmaceutical manufacturing plants on Banan sites.

According to the agreement, Banan District of China’s Chongqing province will fund the land and construction of the two manufacturing plants and Athenex will equip the facilities.

Features: The capital investment by China government is expected to be US$200 million for two plants. The first 400,000 squarefoot plant will manufacture finished goods and distribute and the second 120,000 square-foot plant will produce active pharmaceutical ingredients. Athenex will invest US$75 million on equipment.

Athenex will employ nearly 500 workers at the two factories and work on the plants is expected to begin in early next year.

Mr. Flint Besecker, Athenex Board Director and Chief Operating Officer commented, “The existing plant from our recent acquisition of Polymed/Taihao located in Chongqing, China is capacity constrained. The new API plant will be approximately five times larger and add significant capacity.

This expansion is an important next step in assembling a world-class global pharmaceutical supply chain in the oncology area and will complement our U.S. based manufacturing strategy.”

Athenex is the specialty cancer-drug startup headquartered in Buffalo.

Specifications:

Company Name : Athenex, until recently known as Kinex Pharmaceuticals Location

: China

Type

: Manufacturing Facility

Estimated Cost

: US$275 million

Operations Starts : Early 2016

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2. Chugai to Build New Antibody API Manufacturing Plant Introduction: Japan-based Chugai Pharmaceutical Co., Ltd. has revealed its plans to construct a new plant at its Ukima Plant (Kita-ku, Tokyo) site to increase its capacity to manufacture antibody API and to meet the demand of initial commercial products in the future.

Features The new plant is intended to manufacture antibody active pharmaceutical ingredients (API) capable of high-mix low-volume production for late-stage investigational drugs and initial commercial products.

Capital investment into new plant is expected to be 37.2 billion yen (US$312.6 million) and with this capital investment, six 6,000 L bioreactor tanks will be newly installed which sums up to the existing tanks and makes the total capacity to 49,000 L bioreactor tanks.

3. Oxford Pharmaceuticals Starts Building New Generic Drug Plant in Birmingham, Alabama Introduction: British-based, Oxford Pharmaceuticals has started construction of a new generic drug manufacturing plant on 23.4 acres of land at the Jefferson Metropolitan Park-Lakeshore in Birmingham, Jefferson County, state of Alabama.

Features: The new US$29.4 million plant will produce package and research generic drugs.

The new 120,000-square-foot plant will initially employ 61 and the figure is expected to increase to 200 in next 10 years.

The plant is expected to be operational in the third quarter of 2016.

Specifications: Construction of the new plant is expected to start in January 2016 and operations at the new plant are scheduled for June 2019.

Company Name

: Oxford Pharmaceuticals

Location

: Birmingham, Alabama

Type : New generic drug manufacturing plant Estimated Cost

Specifications: [Overview of the Ukima Plant] 1. Plant Location: 5-5-1 Ukima, Kita-ku, Tokyo

: US$29.4 million

Operations Starts : Third quarter of 2016

2. Site Area: 23,636 m2 3. Total Floor Area: 45,780 m2 (Includes the total floor area of the new plant) 4. Business Activities: Production of antibody API, manufacturing of injection products, manufacturing of investigational drugs for clinical studies [Overview of new Antibody API Production Plant at Ukima Plant] 1. Start of Construction : January 2016 2. Completion of Construction : December, 2017 3. Total Investment

: 37.2 billion yen

4. Completion of Building

: July, 2018

5. Start of Operation

: June, 2019

6. Construction Area

: 4,066 m2

7. Total Floor Area

: 26,634 m2

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49

Projects in Progress 4. Novo Nordisk to Build US$225m Plant in Denmark Introduction: Bovo Nordisk has started its work on building a new US$225 million facility at its existing site in kalundborg, Denmark. The new facility will spread into 7,500 sq m area.

Features: The new facility is intended to manufacture the finished Active Pharmaceutical Ingredient (API) for NovoSeven and haemophilia drugs from the raw materials shipped.

The new facility is expected to create 100 new production and engineering jobs in Kalundborg.

The new facility is expected to be operational by 2020.

5. Aurobindo Pharma to Construct Three Plants in Andhra Pradesh and Telangana, India Introduction: Hyderabad-based Aurobindo Pharma has announced its plans to build three new formulation plants in Andhra Pradesh and Telangana, India over next 12 months.

Features: The US$150 million (INR900 crore) project includes an oral solid finished dose facility in Naidupet (Andhra Pradesh), oral finished dose facility for European markets in Visakhapatnam (Andhra Pradesh) and a new semi-synthetic penicillin plant near Hyderabad.

The new plants will partly go live in 2015-16 and will become fully operational in 2016-17.

Specifications:

Company Name : Novo Nordisk Location

: kalundborg, Denmark

Type : New haemophilia drugs manufacturing plant Estimated Cost

: US$225 million

Operations Starts : 2020

Specifications: Company Name

: Aurobindo Pharma

Location : Andhra Pradesh and Telangana, India Type

: New formulation plants

Estimated Cost

: US$150 million

Operations Starts : 2016 - 17

6. China's ShangPharma Plans to Construct Biologics Plant in Qidong Introduction: China-based Shang Pharma has planned to construct a biologics plant in Qidong.

ShangPharma and the Qidong Biopharma Industrial zone have decided to spend US$60 million on a two-piece project. The project includes both a biologics manufacturing facility, as well as a preclinical research facility.

Features: The project includes a 500-liter, single-use mammalian cell culture train for clinical phase supply and two 2,000-

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liter trains for commercial manufacturing. The new plant will also have fill-and-finish operations.

The new plant will be operated by ShangPharma's China Gateway Biologics CMO division. The new plant is expected to be fully operational by 2018.

Specifications:

Company Name : Location : Type : Estimated Cost : Operations Starts :

Shang Pharma Qidong Biologics Plants US$60 million 2018

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51

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Company........................................................ Page No. Bachem......................................................... IFC 18 & 19 www.bachem.com Bio Clean...................................................................... 07 www.bioclean.com Bosch........................................................................... 03 www.bosch.com CPHI & P-MEC 2016...................................... 17, 32 & 33 www.cphi.com/pmec Global Data.................................................................. 27 www.globaldata.com Himss Asia Pacific 2016........................................ 14 &15 www.himssasiapac.org Laboratoria Smeets...................................................... 47 www.labosmeets.be Medical Fair Asia 2016.................................. IBC 10 & 11 www.medicalfair-asia.com Prior Clave.................................................................... 43 www.priorclave.co.uk Rotronic........................................................................ 09 www.rotronic.ch World Courier............................................................OBC www.worldcourier.com

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