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Pharma Innovations

28-31 January 2015, Mumbai , India

PHARMA BIO WORLD R.N.I. No.: MAHENG/2002/8502 Chairman

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FEATURES 10

Recent Innovations in Therapeutic Recombinant Protein – Dr Madhusudan Dabhole

Oral Solid Dosage Form Excipients Market Set to Grow – Nikola Matic

Nebulisers: Understanding the Regulatory Framework and Testing Requirements – Mark Copley

Bio Derived Medicines and Biosimilars: A Consensus Statement – Dr Anil Kumar Sharma, Dr Harish S

Integrated Solutions for the Delivery of Biologics – Graham Reynolds

Innovating to Meet Sector-Driven Demands – John Folkers

26 54

How to Ready Your Organisation for an FDA Inspection – Ellen Leinfuss, Noreen Muscat

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Budget 2014-15: Ticks n’ Crosses on Pharma Priority Boxes – Mahesh Kallayil

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Press Release

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Biotech News

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Recent Innovations in Therapeutic Recombinant Protein Therapeutic recombinant proteins are one of the most important and rapidly growing segments of the biopharmaceutical market. The emerging business of therauptic Proteins, since 1980, have witnessed a paradigm shift with enhanced efficacy, greater safety, and reduced immunogenicity comes from the conjunction of clinical, scientific, technological and commercial drivers that have identified unmet needs. Since the first protein therapeutics were approved two decades ago, the field has seen a transition from the development of naturally occurring proteins to design of molecules engineered for optimal target recognition, pharmacokinetics, bio distribution, and therapeutic function.

Dr Madhusudan P Dabhole Group Manager – Bioprocess Richcore Life Sciences Ltd 10 eJuly 2014

herapeutic proteins can be grouped into molecular types that include: antibody-based drugs, anticoagulants, blood factors, bone morphogenetic proteins, engineered protein scaffolds, enzymes, Fc fusion proteins, growth factors, hormones, interferons, interleukins, and thrombolytic. Recombinant proteins are produced in bacteria, yeast, filamentous fungi, insect cells, mammalian cells, transgenic animals, and transgenic plants. Overall, 39 per cent of recombinant proteins are made by E. coli, 35 per cent by CHO cells, 15 per cent by yeasts, 10 per cent by other mammalian systems. The first human protein therapeutic derived from recombinant DNA technology was human insulin (Humulin) created at Genentech , developed by Eli Lilly, and approved by the US Food and Drug Administration (FDA) in 1982. The first therapeutic application of an r-protein produced in mammalian cells was approved in 1986 (human tissue plasminogen activator, tPA, Genentech). Recombinant Protein drugs have changed the landscape for the treatment of many diseases, including many types of cancer and rheumatic conditions. Moreover, the recombinant protein market has grown at an annual average rate of 35 per cent since 2001, indicating a financially sound future for the biopharmaceutical industry. Antibody-based drugs are the largest and fastest growing class of protein therapeutics with 24 marketed antibody drugs in the USA and over 240 more in clinical development. Antibody-based drugs contributed USD 38 billion of USD 99 billion in world-wide sales for protein biopharmaceuticals in 2009. Moreover, 5 of the 10 top-selling protein therapeutics in 2009 were antibodies, namely, infliximab (Remicade), bevacizumab (Avastin), rituximab (Rituxan and MabThera), adalimumab (Humira) and trastuzumab (Herceptin). Existing mAb therapies are based on ‘cocktails’ of molecules containing sin¬gle- or double-site cell binding fragments

allow the formation of dimers, chains and cycles. Currently, mammalian cell line development technologies used by biopharmaceutical industries are based on either the methotrexate (MTX) amplification technology or the glutamine synthetase (GS) system. The main strategies that have been adopted for the creation of second generation Protein products include reformulation, pegylation and other forms of modification, or the creation of analogues with different amino acid structures. Most of these drugs are aimed at being longer lasting in the body and having improved pharmacokinetics (PK), while still having similar pharmacodynamics (PD) as the first generation molecules. Achieving this aim can lead to highly advantageous properties such as a lower frequency of administration and improved patient compliance. Examples of highly commercially successful products include Amgen’s Aranesp (an analogue of EPO) and Roche’s Pegasys (pegylated interferon alpha). The major challenges facing recombinant protein production are to reduce the production cost, improve the productivity both in upstream and downstream and obtain high titer while maintaining the quality of the products. The global biopharmaceutical industry is currently worth over USD 116 billion and should exceed USD 167 billion in 2015, says IMARC. Geographically, North America represents the largest market, as majority of the key players are domiciled in United States and thus many new drugs first are introduced in these regions. In 2010, the Department of Pharmaceuticals (DoP) of the Government of India (GOI) set the nation’s biopharmaceutical industry (BioPharma) a goal: to become a leading global producer of affordable “biopharmaceutical” products by 2020. Industry experts estimate that it could be worth US USD 319 billion by 2020. Pharma Bio World

Global Therapeutic Protein Market

Recent Innovations Scientists searched for proteins from 17 bodily organs, including the frontal cortex of the brain, the retina in the eye, ovaries, testes and more. In addition, the scientists analysed six types of cells found in the blood and seven samples taken from organs in human fetuses. The team identified proteins made by 17,294 genes. 2,535 of those genes made proteins that have never been described by science before. 193 of those genes werenâ&#x20AC;&#x2122;t previously predicted to be protein-making genes at all. The efforts included 72 scientists from six countries: the US, India, Canada, Chile, the UK and Hong Kong. The second team, made up of 22 scientists from different institutes in Germany, found similar, although not exactly the same, numbers. The German team found proteins made from 18,097 genes. Those genes made 86,771 different proteins. Now that the proteins in humans are mapped, it will create a platform for understanding genetic links to human diseases. Bioinformatics will bridge the gap in evaluation of data between the protein function and expression in human diseased states. In the near future, protein therapy for novel diseases will be created by combining MAbs and genes. According to Garcia & Calantone, the essence of innovation can best be described as: â&#x20AC;&#x153;an iterative process initiated by the perception of a new market 12 eJuly 2014

opportunity for a technology-based invention which leads to development, manufacturing, and marketing tasks aspiring commercial success of the inventionâ&#x20AC;?. So the stage is set for scientists across the world who has initiated the study to work on the protein disorders by aligning the protein function and characterisation from different organs and tissues. In Mammalian cells, the culture media has an important impact on both the yield and quality of recombinant proteins. Mammalian cells require a combination of both nutritive (eg, sugars and amino acids) and nonnutritive (eg, trace metals, vitamins and co-factors) components to support cell growth and protein production. Continous feeding and intermittent feeding of carbon source at a specific interval is critical for protein synthesis. In addition, the media environment has been shown to affect protein glycosylation, which is an important aspect of protein quality and influences its efficacy as a therapeutic. The efficacy of recombinant glycoproteins as a human therapeutic is strongly dependent on their carbohydrate structures, or glycosylation. Glycosylation has been implicated in bioactivity, receptor binding, and susceptibility to proteolysis, immunogenicity and in vivo clearance rate. It is known that two mammalian cell lines cannot be considered similar as proteins are virtually very difficult to be copied. Protein Modifications changes such as acetylation,

methylation, glycosylation, hydroxylation, phosphorylation and sulphation may reduce biological activity and cause an intrinsic molecular heterogeneity which is difficult to control. Furthermore, the structural complexity of protein concentrates the final product influenced by many variables, such as the use of an expression system such as bacterial, yeast and mammalian cells, growth conditions, purification processes, formulation, storage and transportation. The process related impurities may increase the severity of an immune response to a protein product. Bottom-Up mathematical modeling approach provides cellular responses to different stimuli, but has limitations due to low peptide recovery. Top-down Mass Spectrometry is becoming a powerful technology for comprehensive analysis of protein modifications. Top-down approach enables identification and analyses of an entire cellular network for characterisation of the recombinant protein mutants and is applied together with evolution and mutagenesis experiments. For mammalian cell culture, Process improvement requires and integrated approach that can be achieved through optimisation of bioreactor physicochemical environment. Optimisation of culture conditions needs to balance cell growth with antibody production. The most common approach to developing a feed medium uses concentrated basal media without salts (to avoid high osmolality). Certain key feeding components (eg, phosphate) have also been identified. During medium preparation, pH and temperature may need to be adjusted to completely dissolve some low-solubility components. To optimise a feeding strategy, consideration should be given to nutrient consumption, by-product accumulation, and the balance between growth and production. Studies indicated that byproducts, such as lactate and ammonia, could be minimised by maintaining low glucose and glutamine concentrations through frequent feeding. In the breakthrough that provided the details of large scale proteomic analysis of 6164 grouped proteins complemented by the genomic data of CHO cells, the codon Pharma Bio World

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bias of CHO cells, distinct from humans has been deciphered. The accessibility of methods in the analysis of metabolites in CHO cells with combined data from genomics, transcriptomics, proteomics and metabolomics now can identify novel genes that affect the growth and protein production rate of CHO cells. The success of novel protein therauptic and rise of antibody based drugs have led to research on engineering protein scaffolds which are in the early stages of study and clinical development. High cell density fermentation is a major bio-process engineering consideration for enhancing the overall yield of recombinant proteins in E. coli. The development and design of fermentation process and fermenter itself play a key role for achieving productivity and robustness at scale up. Increasing aeration rate, feeding O 2- rich air, decreasing temperature, gas holdup in media, tip speed, increasing partial pressure of the culture vessel are some of the methods employed to maintain aerobic condition during cell growth. One of the significant technologies developed for microbial growth and expression of recombinant proteins is the use of Tender Coconut Water (TCW) as Animal Origin Free (AOF) growth media by C-CAMP, DBT India. The dynamics of scale for each protein production will differ based on rate of the synthesis of protein in the cell, oxygen availability, feeding strategy, carbon source utilisation, operating fermentation parameters and metabolic load. Generally, proteins that are larger than 100 kD are expressed in a eukaryotic system while those smaller than 30 kD are expressed in a prokaryotic system. The future of single use bioreactors for recombinant protein production will witness a complete revolution with respect to processing and application on a prodigious platform which will involve production of high volume, high value products with high yields as compared to low volume high value products. The major challenge in single use bioreactor is the usage of Pharma grade 14 eJuly 2014

polymers which needs validated analytical methods for leachables and extractables. It is important to bring the flexibility in biopharma operations and analytics with platform technologies. Platform analytical technologies can simplify timely acquisition and reproduction of technology from clients, which otherwise can pose a risk of substantial project delays. Cost is another factor which will have to be optimised during recombinant protein production from R&D scale level. The set-up of a large number of libraries of Clone from bacteria, yeast and CHO cells are in developmental stage which will be available for commercial production of recombinant proteins. Hansenula Polymorpha is looked upon as one of the promising candidates for insulin and Hepatitis B Vaccine production. In yeast cells, the formation of the disulphide bonds is efficient; however, the proteolytic digestion of proinsulin is not possible. In this case, proinsulin is produced and the purified proinsulin is digested in vitro with trypsin. Hepatitis B virus cannot be propagated in vitro; therefore HBs-Ag is produced by heterologous expression in yeasts (Saccharomyces cerevisiae, Hansenula anomala, Pichia pastoris). According to its genome sequence, 8 genotypes (A-H) have been identified. The newly described G genotype has been isolated in the USA and France, while the H genotype originates from South and Central-America. The active immunisation is generally based on HBsantigens. (SHBs, MHBs, LHBs, HBc-Ag, or combination of HBs and HBc antigens are also used.) . With FDA approving the first inhaling insulin powder which will be available by 2015, the insulin business has scaled new heights with new innovations being introduced periodically. Scientists are working on to identify the effect of Host Cell Protein during recombinant protein production. Identification and elimination of toxic molecules due to contamination and absence of prion proteins is another area of concern which is being addressed on a global platform. Case Western Reserve University researchers published findings

that point to a promising discovery for the treatment and prevention of prion diseases, rare neurodegenerative disorders that are always fatal. The researchers discovered that recombinant human prion protein stops the propagation of prions, the infectious pathogens that cause the diseases. Scientists across the world are in the process of developing recombinant fusion protein markers and phage proteins for serological diagnosis of human infectious diseases and contaminants. Recombinant phage protein technique is a novel technology on Vidas as phage proteins bind efficiently to the receptor and exhibit an extraordinary stability. A tail fibre phage protein is used for detection of contaminants. New peptide phage display libraries allows gathering all the information regarding a patient’s antibodies for mapping the human response to the recent diseases and allergies in just one step. Proteomics technology is being applied in the field of protein identification and quantification at all stages of the development from cell line expression to protein production. The use of Proteomics has led to development of a robust process optimisation to achieve recombinant protein for clinical phases so as to obtain faster regulatory clearances. Biosidus is involved in a groundbreaking initiative in the field of biodiversity known as the White Genome Project, which aims at the isolation, identification and characterisation of Antarctic bacterial strains for further sequencing of the complete genome. In collaboration with the Argentine Dirección Nacional del Antártico, research is being conducted at the isolation and characterization of certain microorganisms from the Antarctic territory that are particularly adapted to extreme temperature and have isolated and identified a novel species, Bizionia argentinesis and have sequenced its full genome. Current investigation is focused on the identification and characterisation of genes coding for “cold active enzymes” for industrial processes, particularly in the field of food processing. Pharma Bio World

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Frost & Sullivan recognised MicroProtein Technologies for Technology Innovation for the development of its proprietary MPTxpress technology that provides a cost-effective production method for pharmaceutically and diagnostically relevant recombinant proteins, along with the highest percentage of yield in the industry. MPTxpress has achieved these objectives and has the potential to become the standard production protocol for bacterial expression in this USD 2 billion market. The platform uses a solid media to produce higher yields of the total soluble protein. In addition to significantly reducing procedural steps for obtaining and extracting purified protein, the solid media platform is biodegradable. This makes it the first completely green recombinant biologics production process in the industry and it leaves behind a considerably lower carbon footprint.

by USFDA. Rixubis [Coagulation Factor IX (Recombinant) Fusion protein] is for use in people with hemophilia B who are 16 years of age and older for the control and prevention of bleeding episodes, perioperative (period extending from the time of hospitalisation for surgery to the time of discharge) management, and routine use to prevent or reduce the frequency of bleeding episodes (prophylaxis). An inherited blood clotting disorder mainly affecting males, Hemophilia B is caused by mutations in the Factor IX gene and leads to deficiency of Factor IX.

Recombinant CBD (cellulose binding domains) produced by E coli and Pichia Pastoris are gaining importance as affinity tags, scaffolds and for purification of Hematopoietic stem cells. Hematopoietic stem cells (HSCs) are the only type of stem cells that have been routinely used to treat patients with blood cancers and disorders of the blood and immune systems by HSC transplantation (HSCT). The difficulty to the development of novel treatments using HSCs is the lack of HSC source of sufficient purity and yield. As a result, effort has been devoted on HSC purification using recombinant CBD and ex vivo expansion which will create stem cell bio factories for the treatment of human diseases.

Synthetic biology is a new emerging field bringing engineers and biologist to design and construct biomolecular network pathways for pharmaceutical applications. Artemisinic acid, as a precursor towards the biosynthesis of artemisinin, an important antimalarial drug, was successfully transferred into E. coli and S. cerevisiae. The plant derived kaempferol and quercetin were heterologously synthesised in E. coli. Synthetic biology is being applied to create several artificial biological systems like synthetic gene network â&#x20AC;&#x201C; the gene toggle switch for producing cheaper drugs. The challenges are clear and range from host design to producing non - natural chimeric recombinant proteins.

Genetically engineered protein polymers with specific monomer sequence and polymer length has provided opportunities for the utility of these polymers in drug delivery. The development of elastin-like, silk-like, and silk-elastin like protein polymers has led to the study in gene delivery systems and tissue engineering. The first recombinant protein coagulation factor IX that is specifically indicated for routine use in preventing bleeding episodes (prophylaxis) has been approved 16 eJuly 2014

HIV associated Tuberculosis vaccine is in the mid stage of clinical trials as we move into 2020. There is an urgent need to develop an innovative tuberculosis vaccine with immunogenicity that can be administered to HIV patients.

Quality by Design (QbD) is a new system towards the progress of recombinant therapeutic protein that upholds a better understanding of the product and its manufacturing process. Quality features observed in biopharmaceutical proteins include product-related impurities and substances, process-related impurities and contaminants are evaluated each for their impact on biological activity, immunogenicity, and toxicity. The impact of structural characteristics on the therapeutic proteins is to reduce immunogenicity by controlling critical quality attributes of proteins.

Worldwide, there are more than 500 biologic products in various stages of clinical trials and pre-registration. New Biotech clusters may soon emerge that are able to reap the benefits afforded by the development of several types of recombinant proteins. The success in future therapeutic protein markets will require tractability, vision and the ability to develop affordable biologics for patients and physicians. Regulatory Framework The similar biologic drug products are usually referred to as similar biotherapeutic product (SBPs) by WHO, biosimilars by European Medicines Agency (EMA) of the European Union (EU), follow-on biologics (FOBs) by the US FDA, and subsequent-entry biologics (SEBs) by Health Canada. In some cases, the term â&#x20AC;&#x153;biosimilarâ&#x20AC;? has been used in an inappropriate way, and therefore it is important to review differences in definitions of biosimilar products in different regions. WHO defines SBP as a bio therapeutic product, which is similar in terms of quality, safety and efficacy to an already licensed reference bio therapeutic product. India is creating a framework to introduce single window clearances for project and approvals. Government of India is on the path to abridge the procedures for import and export biologics. The Regional Committee on Genetic Manipulation (RCGM) committee along with Department of Biotechnology (DBT) meets once every month to evaluate projects on biologics who should approve the projects within specified timeframe by planning to meet twice monthly. The RCGM and DBT have the preeminent biosafety and pollution control norms which the biotech sectors needs to follow stringently. In India, the Guidelines on Similar Biologics were prepared by CDSCO and DBT laid down the regulatory pathway for similar biologic claiming to be similar to an already authorised reference biologic. CDSCO is the national regulatory authority in India that evaluates safety, efficacy and quality of drugs in the country. Pharma Bio World

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There are three Competent Authorities involved in approval process namely: 1) R e v i e w C o m m i t t e e o n G e n e t i c Manipulation (RCGM)/IBSC under Department of Biotechnology (DBT), Ministry of Science and Technology. 2) Genetic Engineering Appraisal Committee (GEAC) under the Ministry of Environment and Forests (MoEF) and 3) C e n t r a l D r u g s S t a n d a r d C o n t r o l Organisation (CDSCO) under Ministry of Health & Family Welfare. The Biotech industries manufacturing recombinant products will have to provide 1) Gene sequence, vectors and promotor of the selected strain. 2) Three batches of reproducible fermentation data at pilot scale. 3) Consistent Specific protein yield. 4) Overall productivity is reproducible and scalable. 5) Steps involved in purification of protein. 6) Batch size for protein purification. 7) Consistency of recovery in 3 consecutive batches of purification from 3 independent batches of fermentation. 8) Determination of primary and higher order structure of the product. 9) The target amino acid sequence of the similar biologic should be confirmed and is expected to be the same as for the reference biologic. 10) In cases, where post translational modifications are taking place, these modifications need to be identified and quantified. 11) In case any significant differences are found, these should be scientifically justified and critically examined in preclinical studies and clinical trials. 12) Biological assays will be required to characterise the activity and establish the products mechanism of action and clinical effects (in units of activity). 13) Assays should be calibrated against an international or national reference standard, where available and appropriate. If no such standards are available, an internal reference standard must be established as per the ICH guidelines. If 18 eJuly 2014

the methods of bioassay(s) are documented in the specification, test(s) can be conducted accordingly. 14) Evaluation by characterisation (antibody or antibody-derived product); comparison to reference biologic with respect to specificity, affinity, binding strength and Fc function; and evaluation by animal studies. The clinical development of recombinant proteins is commonly divided into three phases (ie, phases I, II, and III). Each phase is more complex, time-consuming, and resource-intensive than the preceding one. In India, Clinical drug trials including biologics, post new rules in 2014, have medical ethics committee to be registered with DCGI which reviews the clinical phases stringently. With new virus strains being introduced for recombinant vaccines production, DBT will have to review the Biosafety norms and frame stringent guidelines for manufacturing and purification of the product. Industry–Academia Partnership A large number of students work towards s p e c i a l i s e d s k i l l s i n M i c r o b i o l o g y, Biotechnology, Biochemistry and Genetic Engineering in and around the world. Continous developments are seen across in research journals of which less than 1 per cent gets translated to commercial success. The economic significance demonstrates the importance of universityindustry partnerships to biotech. It has been observed that the Biotech courses taught in the academic orientation are practically diverse from the industrial requirement. Few biotech industries like Biocon have entered into agreement with Universities to set up a course with industrial outlook for aspiring candidates. Association of Biotechnology Led Enterprises (ABLE) facilitates strong industry - academia interactions to explore opportunities for collaborative research and technology transfer as well as human resource development through various platforms of engagement. The biotech industries should

take the initiative to set up a research projects in colleges across the country which can transfer the technology from the lab scale to the manufacturing scale. The value addition created by the industry academia interaction is unparalleled as the industry will benefit from tangible assessment created through insights and industry ready employees. Biotechnology Industry Research Assistance Council (BIRAC) a Public Sector Section 25 “Not-for-Profit Company” of Government of India, registered under India Companies Act 1956, has been set up as Department of Biotechnology’s interface agency, which serves as a single window for the emerging biotech industries. It was incorporated on 20th March, 2012. .BIRAC has been set up as a separate body for supporting product innovation and pr ov i di ng r equi r ed i nf r a s t r u c t u r e and services at different stages of the value chain for promoting innovation and product development. Entrepreneurs are looking for a magic bug which will initiate producing the product and reach the market instantly. This has created the gap in understanding for manufacturing biological products which needs incubation at various stages for research, clinical trials, manufacturing and validation. Further, these biological products should be affordable to a common man. Medicines have become an integral part of human life and to combat the deadly diseases, both existing and new arrivals, scientists will have to develop a roadmap for the next 50 years. The traditional pharmaceutical manufacturers will have to focus and invest now for these future biologic blockbuster products. It will be a challenge to bring the Innovation, instead of renovation, to obtain pure, safe, high efficacy, cost effective and high yielding recombinant human therapeutic proteins with quality to market. As Charles Darwin rightly said “Survival of the fittest”. Contact: madhusudan.d@richcoreindia.com Pharma Bio World

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Oral Solid Dosage Form Excipients Market Set to Grow This article examines complex combination of factors that are driving the market of specialty excipients for OSDF.

mong various pharmaceutical drugs dosage forms oral solid dosage forms (OSDFs) are the most common and preferred methods of drug delivery outperformed in growth only by injectables. Oral administration is a natural means of consumption and is best for chronic drug therapy. The manufacturing of OSDF compared to other dosage forms is positively impacting the price of pharmaceutical products. As the global growth in the pharmaceutical market is forecast to perform well, with the estimated by IMS Health 3.3 per cent increase in 2013 and with the AsiaPacific region being the fastest growing pharmaceutical market in the world; consequently, the OSDF excipients market is also growing sustainably, historically exhibiting a robust increase. This market, valued at nearly USD 2.3 billion in the United States, Europe, India, and China combined, is driven by a complex range of factors. The OSDF excipients market is shaped by several macro and micro trends, macro drivers being for instance rising incomes and willingness to spend more on healthcare in emerging markets such as China and India and aging population with its growing demand for pharmaceuticals in major markets like the United States and Europe. Due to this growing demand, the major markets will continue to flourish; however, it is worth noting that emerging markets will outpace major markets. Driven by growth from India and China, the mean consumption of OSDF excipients is expected to increase at a healthy pace of 7.4 per cent per year until 2018.

Nikola Matic

Industry Manager - Chemicals & Materials Practice, Kline & Company 20 eJuly 2014

Another vital macroeconomic factor transformed across regions is the effect that the GDP will have on growth. In emerging markets, GDP is expected

to grow at a pace much greater than the major markets of the United States and Europe. The emerging markets are expecting a combined double digit average growth with India, while seeing a slowdown in growth, but still leading the way at nearly 12 per cent, a higher rate than the other markets. Meanwhile, major markets are seeing a slower, more stable growth rate. The United States and Europe are expected to see a growth rate around 4 per cent. Nonetheless, we can expect to see GDP positively impact the growth in all regions. In terms of consumption of specialty excipients for OSDF pharmaceuticals, although the major markets of Europe and the United States have similar volume to the emerging markets of India and China, which currently stand at approximately 100,000 tons per region, the market values vary from one region to another. This is due to the different types of excipients used based on the geography. While mature markets are dominated by functional and usually more expensive excipients, emerging markets are looking to use cheaper alternatives. Within binders and fillers, whereas more expensive excipients dominate in Europe, China, and India are dominated by cheaper native starches. Within specialty disintegrants, higherpriced X-PVP and CCS are the leading mature markets while the less expensive SSG is still a widely used disintegrant in India and China. The highly functional excipients in major markets have influenced todayâ&#x20AC;&#x2122;s market value which shows major markets holding strong at 75 per cent; despite the continued growth in emerging markets, the higher functionality and better quality of the more expensive excipients are influencing the market share. The Pharma Bio World

of excipients in both, emerging markets.

competitive advantage that cheaper excipients have is that they can get close to the service ability of higher functional products at a fraction of the cost; as a result, allow the emerging markets to develop generic quality products and effectively compete in the global market. The added properties of some excipients allow more functional finished products, for instance, offering sustained-release of the active ingredient. Excipients vary greatly in price from USD 1.00 to USD 40.00 per kilo, and emerging markets are dominated by cheaper alternatives. GDP growth and prices are not the only factors affecting the excipients market, as the consumption of OSDF excipients is driven by three different levels of drivers and restraints. The consumption of excipients is primarily driven by the global growth of the pharmaceutical industry itself. This is the first of the three levels, and its key drivers include aging populations in mature markets and economic growth in emerging markets. These macro drivers are continuing to drive demand 24 eJuly 2014

for pharmaceuticals. The second level consists of the factors affecting OSDFs in particular. For their easy use and manufacturing, OSDFs are favored over other dosage forms, which again positively affect the market of OSDF excipients. The third level affecting growth consists of the trends shaping the OSDF excipients market internally. It notably includes the larger growth of excipients used in tablets due to the

mature

and

It is important to know how all levels interact to understand the current and future excipients market development, notably as certain facets create important market opportunities. For instance, excipients such as povidone are seeing consumption increase significantly in some regions. Meanwhile, formulated coatings are seeing growth across all regions; while co processed excipients, MCC, and povidone are expected to see double-digit growth. The reason why some of these excipients are seeing increased consumption is due to the fact that they are offering additional properties. For instance, povidone can be used to enhance the solubility of the active ingredients, a predicament within the industry for many years. As a result of this breakthrough, these highly functional excipients will drive the OSDF excipients market into a bright and prosperous future. Aging populations and growing wealth in markets across the world will only help transform this market into a promising and successful market

The competitive advantage that cheaper excipients have is that they can get close to the service ability of higher functional products at a fraction of the cost; as a result, allow the emerging markets to develop generic quality products and effectively compete in the global market. increased instances where tablets are preferred to capsules; another example is the expansion of orally disintegrating tablets (ODTs),a successful subsegment within OSDFs, which also benefit specific excipients. Finally, the growth of functional excipients which allow controlled-release and sustainedrelease of active ingredients within a pharmaceutical product is also a micro-factor reshaping the consumption

showing signs of stable and positive growth potential. All excipients are going to see growth; some more so than others. The growing need for higher functionality and higher performing disintegrants, alongside the increased preference of OSDF consumption are among many factors that will allow global markets to prosper into the foreseeable future. Contact: vera.sandarova@klinegroup.com Pharma Bio World

Nebulisers: Understanding the Regulatory Framework and Testing Requirements Nebulisers are a popular choice for inhaled drug delivery, most especially for those with poor coordination or lung function, such as geriatric or paediatric patients. In countries such as China, they represent as much as 36 per cent of the market share for orally inhaled products1. In this article, author provides an introduction to nebulisers, focusing on the regulatory guidance that governs their development, and the tests required to characterise performance.

ebulisers are used routinely for inhaled drug delivery both in hospitals and at home. Once loaded, a nebuliser continuously aerosolises a liquid formulation which the patient inhales by breathing through a face mask or mouthpiece. This means that nebulisers, unlike other orally inhaled products (OIPs), do not require the coordination of inhalation with device actuation, making them especially suitable for those with poor coordination or lung function, such as geriatric or paediatric patients. They are also useful for delivering high drug doses over long periods of time. However, because of the mode of action of a nebuliser the amount of drug received by the patient is dictated by their breathing profile.

Here we examine how nebulisers work and how this governs the way in which they are tested. A review of regulatory guidance and of the pharmacopoeia monographs relating to nebulisers, which were revised in 2012 2,3, supports a detailed discussion of the specific requirements for dose delivery testing and aerodynamic particle size distribution (APSD) measurement for this important class of OIPs. How do Nebulisers Work?

Mark Copley

Sales Director Copley Scientific 26 eJuly 2014

Drugs destined for delivery via a nebuliser are formulated as therapeutic solutions or suspensions, which are generally loaded into the nebuliser from a nebule. The nebuliser actively atomises the liquid to form a cloud of respirable droplets using one of a number of different atomisation technologies. Jet actuated systems, for example, use compressed air to achieve atomisation while ultrasonic nebulisers aerosolise formulations by transmitting vibrations from a piezoelectric crystal through the formulation reservoir. These vibrations create a series of waves from which droplets separate to form a respirable

mist. Ultrasonic devices need an electricity supply, which can be a limitation in certain instances, while jet based nebulizers rely on the availability of a compressed air source. Both technologies result in nebulisers that can be quite bulky, and that consequently lack the portability and convenience associated with conventional inhalers. Furthermore, in the case of jet nebulisers, these can be quite noisy due to the need for an associated compressor. The more recent development of mesh technology has brought portable, silent, battery operated nebulisers to the m a r k e t p l a c e . W i t h a m e s h n e b u l i z e r, droplets are produced by pushing the formulation through a static or vibrating plate, mesh or membrane, using either a vibrating piezoelectric crystal, as in ultrasonic devices, or a vibrating metal head. This technology leads to a very tightly controlled droplet size distribution, offering improved drug delivery characteristics. However, it shares with other nebuliser technology the disadvantage of being costly compared with alternative OIPs. In use, nebulisers, unlike metered dose inhalers (MDIs) or dry powder inhalers (DPIs), do not deliver a pre-metered dose. Rather nebulisers continuously produce a steady stream of aerosolized droplets, which in some devices is moderated by breath actuation or breath enhancement mechanisms 4. The amount of drug that the patient receives is, therefore, dependent on how effectively the repetitive tidal breathing cycle of the patient draws this aerosol into the lungs, and the duration that the device is used for. A Revised Regulatory Framework Traditionally health care practitioners and hospitals purchased nebulisers and used them with a range of different formulations. Pharma Bio World

Breathing Simulator Specification for Nebuliser Characterisation Tests Adult

Neonatal

Infant

Child

Total Volume

500 ml

25 ml

50 ml

155 ml

Frequency

15 cycles/min

40 cycles/min

30 cycles/min

125 cycles/min

Waveform

Sinusoidal

I/E Ratio

1:1

1:3

1:2

Table 1: The breathing profiles defined for delivered dose testing for nebulisers.

The regulatory framework classified nebulisers as stand alone medical devices leaving the choice of formulation/nebuliser combination as the responsibility of the prescribing clinician. In line with this classification nebulisers were tested in accordance with the European Committee for Standardisation (CEN) Standard for Respiratory Therapy Equipment EN 13544-1 5. However, in 2006, new regulatory guidance was issued by the European Medicines Agency (EMEA) and Health Canada 6. This guidance reflected the dependency of safe nebuliser use on the selected formulation/ device combination. Inter-brand variability is a known issue with regard to nebuliser performance, but the physical properties of a formulation also impact the droplet size delivered by any individual device. The revised regulatory framework harmonised nebuliser testing with testing for other OIPs, which are consistently treated as combination (device/formulation) products, and is now supported by two new harmonised monographs Ph. Eur. 2.9.44 and USP 1601 2,3. These came into force in January 2012 and August 2012 and specify tests for assessing dose delivery and for APSD measurement. The new monographs provide more comprehensive methods for evaluating nebuliser performance than the standards that predate them, and make use of the most up-to-date testing equipment. However, the preceding standards remain in place. Adherence to the revised regulations and pharmacopoeial methods is consistent with the requirements of EN 13544-1, but there is also a standard from the International 28 eJuly 2014

Standards Organisation (ISO) to consider 7, which incorporates, in most cases, the requirements of its European counterpart. Delivered Dose Testing Delivered dose testing is carried out to determine the total amount of drug that the patient might be expected to receive during a treatment period. Two discrete metrics are defined and measured: the active substance delivery rate and the total active substance delivered. Reflecting the mode of operation of nebulisers, delivered dose testing is carried out using well-defined breathing profiles for specific patient types (see Table 1). The defined profiles for child, infant and neonate patients are based on significantly smaller volumes, higher breathing frequencies and different inhalation/exhalation ratios. These are derived from published clinical work and further harmonised with breathing profiles used in a Canadian Standard for the testing of MDIs with spacers and Valved Holding Chambers (VHCs) 8 . Breathing simulators are used to reliably apply these test conditions. To measure active substance delivery rate the output from the nebuliser is captured on a filter, under appropriate test conditions, over a specified time (typically 60 seconds). Longer test times are applied to provide sufficient mass (greater than the limit of quantification) for reliable analysis, where delivery rates are low. Replacing the filter and continuing the test until nebulisation stops, because the reservoir is empty, enables calculation of the second metric – total active substance delivered. This is the total mass collected during steps 1 and 2 of the test.

Breathing simulators, exemplified by the BRS Breathing Simulator range from Copley Scientific, have been specifically developed to streamline nebuliser testing in line with the revised monographs. Such systems enable the user to vary: WLGDO YROXPH IUHTXHQF\ WHVW GXUDWLRQ LQKDODWLRQ H[KDODWLRQ UDWLR to easily and accurately apply the test conditions specified for different patient groups. Measuring Delivered Droplet Size For all OIPs, APSD is measured to infer information about the likely deposition site of the delivered drug, in vivo. Generally speaking a particle size range of < 5 microns is taken as being optimal for pulmonary deposition. Cascade impaction is the preferred method for APSD measurement because of its ability to provide wellresolved, drug specific particle size data in the size range of interest. Furthermore cascade impaction determines aerodynamic particle size, as opposed to geometric particle size; an intuitively representative metric for OIP characterisation. During cascade impaction testing, sample laden air is drawn through a series of stages each of which has a defined number of nozzles, manufactured to a closely specified diameter. With increasing stage number, total nozzle area decreases, leading to a progressive increase in particle velocity. At each stage, particles with sufficient inertia impact on a collection surface beneath the stage, while those with less inertia remain entrained in the Pharma Bio World

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simulators that enable application of the test conditions set out in the monographs is now met by systems that have been brought to market specifically to meet this need. All the elements required for safe, accurate, and effective nebuliser testing are now securely in place to support on-going development.

The BRS1100 (Copley Scientific) breathing simulator is capable of applying all of the breathing profiles detailed in the new monographs for nebulisers, during routine delivered dose testing.

air stream and flow to the next stage. In this way the sample is size fractionated; chemical (or gravimetric) analysis of the amount of drug collected on each surface then allows full characterisation of the inhaled dose 9 . Cascade impactors are precision instruments that operate under constant flow rate. The new pharmacopoeial monographs specify a flow rate of 15 L/min – the mid-inhalation flow rate of an adult – as does EN 13544-1. However, at the time of publication of the CEN standard no cascade impactors were commercially available with calibrated performance at 15L/min and so a Marple 298X cascade impactor was typically used, despite a 2 L/min calibrated flow rate (resulting in the need for partial sampling of the aerosol) and capacity limitations. This situation changed in 2004 when the Next Generation Impactor (NGI) was calibrated at this flow rate 10 . The new monographs reflect the suitability of the NGI for nebuliser testing, not least due to the high capacity of its collection cups, and focus specifically on its use. Test methods directly address, for example, the issue of the high thermal mass of the NGI which is recognised as having the potential to impact the accuracy of the reported APSD, by causing droplet evaporation, under ambient test conditions 11 . Cooling of the NGI prior to testing (especially for drug in solution) is therefore specified unless method development has indicated that this is unnecessary. 30 eJuly 2014

In Conclusion The regulatory framework and pharmacopoeia monographs for nebulisers have changed considerably over the last decade. All OIPs now share a harmonised approach to testing based on the characterisation of a specific formulation/ device. Furthermore, the tests specified for nebuliser testing now robustly scope their performance for specific patient groups. Nebulisers are an important class of OIPs for the treatment of paediatric patients and there is now an established testing approach to characterise their performance for such applications.

The NGI has calibrated performance at 15 L/ min and high capacity collection cups making it particularly suitable for the characterisation of nebulisers.

The revisions to nebuliser testing have capitalised on recent advances in inhaler testing equipment and prompted further development. The focus on the NGI for APSD measurement, for example, reflects the instrument’s suitability for this application which is underpinned by calibrated performance at 15 L/min. The need for flexible, cost-efficient breathing

References 1) Ying Li et al. ‘Addressing China’s Growing Need for Inhaled Drugs: Development Strategies for Marketing, Distribution, and Regulation’ Respiratory Drug Delivery 2014. 2) Ph. Eur. Chapter 2.9.44 Preparations for nebulisation: Characterisation. 3) USP 1601 Products for nebulization: Characterization. 4) Copley, M. ‘Nebuliser testing: Exploring the implications of new regulatory guidance for testing nebulizers’ Inhalation, Oct 2008. 5) CEN 13544-1:2007+A1:2009 6) CPMP (2006) ‘Guideline on the Pharmaceutical Quality of Inhalation and Nasal Products’ to be read in conjunction with – CPMP (2004) ‘Points to consider on the Requirements for Clinical Documentation for Orally Inhaled Products (OIP)’. 7) ISO 27427:2013 ‘Anaesthetic and respiratory equipment – nebulizing systems and components’ 8) J. Jauernig et al. Recommendation on the Adoption of Breathing Patterns for Infants and Small Children in General Chapter 2.9.44. Preparations for Nebulisation. Pharmeuropa Scientific Notes, 2008, pp. 73-74. 9) Copley, M. ‘Understanding cascade impaction and its importance for inhaler testing’ White paper available for download at: http:// w w w. c o p l e y s c i e n t i f i c . c o m / d o c u m e n t s / w w / Understanding%20Cascade%20Impaction%20 White%20Paper.pdf 1 0 ) V. M a r p l e e t a l . ‘ N e x t G e n e r a t i o n Pharmaceutical Impactor: A new impactor for pharmaceutical inhaler testing. Part III. Extension of Archival Calibration to 15 L/min’ Journal of Aerosol Medicine, Volume 17, Number 4, 2004, pp. 335-343. 11) J. Dennis et al. ‘Cooling the NGI – an Approach to Size a Nebulised Aerosol more Accurately’ Pharmeuropa Scientific Notes, 2008, pp. 1-4.

Contact: ellen.chesterman@kapleronline.com Pharma Bio World

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Bio Derived Medicines and Biosimilars: A Consensus Statement Bio Derived Medicines or biologics are widely used in the management of several diseases such as diabetes, certain types of cancers and immunologic conditions. This is true for India as well, which has one of the largest populations of people living with diabetes with numbers estimated to be more than 60 million and this is expected to reach a mammoth 100 million by the year 2030.

Dr Anil Kumar Sharma M/S Natural Solutions

Dr Harish S

ICBio Clinical Research Pvt Ltd 32 eJuly 2014

here has been a tremendous growth in the availability of Bio Derived Medicines over the past couple of decades. The Indian biotechnology industry has also gained considerable momentum, which has triggered the growth of several National Research Laboratories employing thousands of scientists. his has in turn triggered a spurt in the number of college level educational and training institutes offering degrees and diplomas in biotechnology, bioinformatics and the biological sciences, producing nearly 5 l a k h s t u d e n t s a n n u a l l y. G i v e n t h i s backdrop, biotechnology is certainly the next big frontier for the Indian economy. However, this exploding scenario can put immense pressure on the healthcare regulators to facilitate the growth of biosimilar products without suitably modifying the procedure for approval and marketing of these products, which still rely on the standards set for chemical generic copies. While the government has taken a welcome step toward addressing this anomaly and released a draft robust guideline on biosimilars; this has still not been notified as a law. In the absence of such guidance, India has standards, which are more lax than most countries in the world as a result of which there has been a spurt of introductions of several versions of a biologic product all claiming to be “biosimilar” to the innovator product. The purpose of this article is to present a consensus statement on this issue and also introduce the practicing clinicians to the various issues and complexities presented by biopharmaceutical products or biologics especially by the biosimilar versions as these have a direct impact on the disease outcome. It also provides guidance on the standards needed and the reasons for

the same so that the clinician is suitably educated and consequently empowered to make appropriate decisions on behalf of the patient. It also aims to ensure that Indian patients are protected with similar standards of medicinal quality as patients in the rest of the world and as envisaged by the World Health Organization (WHO). Bio Derived Medicines And Biosimilars Biologics can be broadly defined as those medicines produced using a living system or genetically modified organism. They are different from traditional chemical medicines 1 in many ways. Size is one of the most obvious distinctions: the molecules of a biologic are much larger, have far more complex spatial structures and are much more diverse (“heterogeneous”) than the chemical molecules which make up classical drugs. The conditions in which biologics are produced largely define the final product. Each biotech company uses unique cell lines and as a consequence develops its own unique manufacturing process (See Figure 1 on the next page). 2 The manufacturing process defines the product quality and safety profile; it is vital to precisely control the whole manufacturing process in order to obtain consistent results and to guarantee the safety and efficacy of the end product. Variations at any stage in the manufacturing process can impact on the product’s clinical profile and raise the safety concerns. Biosimilars can never be identical copies of the originator molecules, even when they have demonstrated comparable physicochemical and biological properties to a reference product using currently available tests. For non glycosylated products such as hum an i ns ul i n, phar m ac ok i ne t i c ( P K ) Pharma Bio World

Figure 1: Expression systems used for manufacture of approved drugs

and pharmacodynamic (PD) differences are most probably caused by differences in formulation, while for glycosylated products (Eg, epoetin), the glycosylation pattern is probably the major source of PK/PD variations. 3 A d d i t i o n a l l y, c o m p a r e d t o c h e m i c a l drugs, proteins are relatively unstable, introducing additional challenges in their storage, formulation and delivery. he criticality of the manufacturing process can be emphasised with the example of the increased incidence of pure red cell aplasia (PRCA) in patients being treated with erythropoietin (EPO). Extensive investigation revealed that most likely change in excipient and manufacturing process may have caused the incidence of PRCA. No matter what the ultimate cause or causes of PRCA may be, the foregoing demonstrated the potential for immunogenicity from even slight changes in any facet of the manufacturing process for a biotechnology-derived protein product. 4,5 Biosimilar medicines are follow-on versions of original biopharmaceutical medicines (innovator products). Biosimilar medicines are intended to have the same mechanism of action as the original biopharmaceutical medicines, and are designed to treat the same diseases a s t h e i n n o v a t o r ’s p r o d u c t . T h e r e i s a considerable debate surrounding the definition, licensing and marketing of biosimilar medicines. The crux of 36 eJuly 2014

this debate rests on the differentiation between biosimilar medicines and traditional generic copies of chemical medicines. Generic copies of traditional chemical medicines are identical in the molecular structure and are approved for use in humans based on a strict definition of “sameness”, usually based on bioequivalence studies. However, due to the size, complexity of structure and sensitivity to manufacturing processes, a corresponding definition cannot be e s ta b l i s h ed f or bi os i m i l ar m edi c i nes . As a result, biosimilar products can merely meet a “similarity” standard for approval. he ability or lack thereof to scientifically develop and manufacture identical generics compared to similar biosimilars necessitates other regulatory safeguards to ensure product safety and efficacy. 6 Complex Issues Thus, the manufacture and use of Bio Derived Medicines and so called biosimilar products raise several new questions in evaluation and comparability of different products. his also raises new challenges for the practicing clinician who is neither trained nor equipped with enough knowledge to perform this task while prescribing these products.The important issues that need to be addressed include: Manufacture: Small changes in the manufacture of biopharmaceutical medicinal products can dramatically affect the safety and efficacy of

the therapeutic molecule. The very nature of a biologic means it is practically impossible for two different manufacturers to manufacture two identical biopharmaceutical active substances if non identical host expression systems, processes and equivalent technologies are used. 1 This has to be demonstrated in an extensive comparability Programme which not only includes a clinical programme but also several nonclinical parameters. Quality and immunogenicity: A product that claims to be a biosimilar should d e m o n s t r a t e s i m i l a r i t y f o r q u a l i t y, safety and efficacy with the reference innovator product. It should also be noted that biologicals being proteins have the inherent potential to evoke immune reactions. he potential to evoke immune reactions can differ from product to product and rare effects can be detected and assessed only when large numbers of patients have been ex pos ed t o t he pr od u c t . T h e immunogenicity profile of a biosimilar product must also be shown to be similar to the reference product. 7 6XEVWLWXWLRQ DQG LQWHUFKDQJHDELOLW\ Unlike chemical drugs, biosimilar medicines can be “similar” but not “identical” to the innovator reference products. Substitution of the innovator product with a biosimilar product can have clinical consequences as p a t i e n t s c o u l d r e s p o n d d i ff e r e n t l y to the two products. For example, one of the major concerns while switching between various brands of insulin products is the issue of hypoglycemia and the development of antibodies. 8 Thus, certain regulators like the European Medical Agencies (EMA) and the authorities in France, G e r m a n y, G r e e c e , I t a l y, S l o v e n i a , Spain, Sweden and UK do not permit s u b s t i t u t i o n o r i n t e r c h a n g e a b i l i t y. Indian Insulin Technique Guidelines 2012 also do not permit interchange .9 Pharma Bio World

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he major reason for this being that, in case of any adverse reaction the cause needs to easily sourced which may not be the case where there has been frequent swapping between the different versions of the biologic product. 10 Â&#x2021; 7KH 86 )RRG DQG 'UXJ $GPLQLVWUDWLRQ permits interchangeability only if the developer of the biosimilar has conclusively demonstrated that it can be expected to produce the same clinical result in any given patient and that the risk associated with alternating or switching between the two products is not greater than that involved in continuing to use the reference product. Â&#x2021; (IILFDF\ YDULDWLRQV %HVLGHV VDIHW\ RI D biosimilar product, data suggests that the efficacy can also be a concern. (IILFDF\ RI D YDULHW\ RI (32 ELRVLPLODUV from different manufacturers was tested using a mouse bioassay, and the measured in vivo activity varied from 71 per cent to 226 per cent, with five samples failing to meet their own specifications. 11 Â&#x2021; 5 H J X O D W R U \ V W D Q G D U G V : K L O H L W L V reasonable to permit the generic versions of product to have an abbreviated pathway toward regulatory approval as compared to the innovator product due to the inherent economic advantages they offer, it is important that pathway is more stringent than that permitted for chemical generics. 7R HQVXUH WKH HIILFDF\ DQG VDIHW\ RI biosimilar products, these products should only be approved following the submission of appropriate data generated with the biosimilar drug. 7KLV GDWD VKRXOG LQFOXGH H[WHQVLYH preclinical tests, quality testing, immunogenicity profiles, robust and adequately powered clinical efficacy studies versus the innovator products and finally an extensive post marketing safety evaluation to ensure that 38 eJuly 2014

adequate patient numbers have been exposed to this products. 7 Â&#x2021; ,QGLD $OWKRXJK WKH &HQWUDO 'UXJV 6 W D Q G D U G & R Q W U R O 2 U J D Q L V D W L R Q &'6&2 KDV UHOHDVHG GUDIW JXLGHOLQHV governing biosimilars, this has not yet EHHQ QRWLILHG DV D ODZ $V D UHVXOW WKHVH drugs are still governed by laws framed for chemical entities. 12

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Â&#x2021; 'LIIHUHQFHV EHWZHHQ WKH WZR PHGLFLQHV LQ WHUPV RI WKHLU LPSXULW\ 3URILOH Â&#x2021; 6WDELOLW\ GDWD RI WKH DFWLYH VXEVWDQFH and of the medicine to be Marketed. Â&#x2021; 7 K H S U R F H V V X V H G I R U S U R G X F L Q J the final medicinal product was Not Regulatory Standards for Biosimilar adequately validated. Products Â&#x2021; 7KH WHVW XVHG LQ WKH VWXG\ WR LQYHVWLJDWH the potential for the medicine to trigger Europe 10 an immunological response was not 7KH OHYHO RI GDWD UHTXLUHG IRU D SURGXFW sufficiently validated. claiming to be a biosimilar is substantially Â&#x2021; (XURSHDQ PHGLFDO DJHQFLHV UHIXVDO less than that required for an original ( X U R S H D Q S X E O L F D V V H V V P H Q W E L R O R J L F D O S U R G X F W 6 L Q F H W K H 5HSRUWV DYDLODEOH (XURSHDQ 8QLRQ (8 KDV FUHDWHG D OHJDO and science-based regulatory pathway to 0DUYHO /LIH 6FLHQFHV 8. ZLWKGUHZ LWV enable the development and marketing of (8 PDUNHWLQJ DXWKRULVDWLRQ DSSOLFDWLRQ ELRVLPLODUV 7KH (8 UHJXODWRU\ DSSURYDO 0$$ IRU ELRVLPLODU KXPDQ LQVXOLQ ,QVXOLQ process includes guidelines containing +XPDQ 5DSLG 0DUYHO QHXWUDO SURWDPLQH details of clinical, nonclinical and quality +DJHGRUQ LQVXOLQ ,QVXOLQ +XPDQ /RQJ r e q u i r e m e n t s f o r b i o s i m i l a r p r o t e i n 0DUYHO DQG SUHPL[ ,QVXOLQ +XPDQ WKHUDSHXWLFV 7KHVH JXLGDQFH GRFXPHQWV 0L[ 0DUYHO LQ 'HFHPEHU 7KH r e f l e c t t h e d i s t i n c t d e v e l o p m e n t a n d UHDVRQV IRU UHMHFWLRQ E\ WKH &RPPLWWHH IRU manufacturing challenges of biosimilars. 0HGLFLQDO 3URGXFWV IRU KXPDQ XVH ZHUH 7 K H \ K D Y H D O V R U H O H D V H G L Q G L Y L G X D O DV IROORZV guidelines pertinent to specific biological Â&#x2021; ,W ZDV QRW SRVVLEOH WR FRQFOXGH WKDW products, eg, insulin, human growth WKH SXULW\ RI WKH 0DUYHO /LIH 6FLHQFH hormone, granulocyte colony-stimulation products were comparable to the IDFWRU (32 LQWHUIHURQ DQG KHSDULQ 13 reference product. Â&#x2021; 2WKHU LQIRUPDWLRQ RQ NH\ VHFWLRQV ZDV 7KH (8ÂśV ELRVLPLODU DSSURYDO SDWKZD\ considered incomplete, unclear and requires a biosimilar manufacturer to inadequately presented. demonstrate similarity for quality, safety Â&#x2021; 7KH HIILFDF\ &ODPS VWXG\ GLG QRW and efficacy with a reference product demonstrate equivalent blood glucoseDOUHDG\ OLFHQVHG LQ WKH (8 6SHFLILFDOO\ lowering effect to that of the reference the biosimilar must demonstrate, through SURGXFW +XPXOLQ ,Q DGGLWLRQ HIILFDF\ clinical studies in which the biosimilar + E $ 1 c D Q G V D I W \ G D W D V K R Z H G is directly compared with the reference consistent trends in favor of the product, that it has no significant clinical reference product. differences with the reference product. Â&#x2021; 7KH 0$$ ODFNHG LQIRUPDWLRQ DERXW production procedures, and processes 7KHUH KDYH EHHQ VHYHUDO FDVHV ZKHUH had not been validated. applications for a biosimilar product h a s b e e n g i v e n a n e g a t i v e o p i n i o n 4 ,Q 1RYHPEHU 0DUYHO /LIH 6FLHQFHV >$OSKHRQ LQWHUIHURQ DOSKD %LIHURQH[ 8. DJDLQ ZLWKGUHZ WKHLU DSSOLFDWLRQ DQG Pharma Bio World

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With our extensive knowledge and experience in the power transmission arena, we continuously innovate and launch new products, aimed at meeting the varied application needs of our customers. Our line of products for the Chemical & Pharmaceutical sector manufactured at our Chennai production facility in India, applying state-of-the-art technology, ensuring superior quality standards and matching the best cost/performance ratio. While the AS Series is most dependable and performing solution for all in-line drive applications featuring unsurpassed Quality to Price ratio, the light-weight F Series ensures rugged and effective operations. Compact, and yet extremely powerful, are the units of the 300 series planetary drives that make them the ideal choice for all the severe duty applications where shock loadings and impacts are more the rule than the exception. The newly launched ACTIVE VFDs is a complete series to compact and flexible solution drives that are versatile and extremely easy to use featuring control for high performance and unbeatable advantages in their scalability. Welcome to the world of Bonfiglioli! Bonfiglioli Transmission PVT ltd. Survey No. 528/1, Perambakkam Road, Mannur Village, Sriperambudur Taluk, Chennai - 602 105, India * \Ê³ £Ê{{ÊÈÇ£äÎnÓxÊUÊ >Ý\Ê³ £Ê{{ÊÈÇ£äÎ Ê salesindia.ins@bonfiglioli.com

in their withdrawal letter they mentioned that they took the decision to withdraw the products so as to give it time to repeat and submit bioequivalence (PK and PD) data on each Clamp study in order to comply with the planned new EMA guideline on biosimilar insulin.

(INNs) served as a useful tool in worldwide pharmacovigilance, for biologicals they should not be relied upon as the only means of product identification or as an indicator of SURGXFW LQWHUFKDQJHDELOLW\Â´ ,W VWDWHV that prescriptions of biologics should not be based on INN but on a unique name, for example the trade name. 15

generally do not apply. Biosimilars, like other biological products, require effective regulatory oversight for the management of their potential risks and in order to maximise their benefits Â&#x2021; 7KH :+2 DOVR VWDWHV ÂłDOWKRXJK International Non-pro prietary Names

Efficacy variations

Comparative PK/PD and pivotal studies

Regulatory standards

Strict adherence to applicable guidelines such as those from the WHO

Substitution and interchangeability

Not recommended unless following advice from the healthcare professional.

0 H G L F L Q D O 3 U R G X F W V Â´ D S S U R D F K D V proposed by the WHO, based on the comparability exercise, will then have to be followed (Table 1).

The following approaches could be considered: Â&#x2021; 7KH :+2 JXLGHOLQH RQ ELRVLPLODUV provides a practical and good guidance World Health Organisation 14 for approving and regulating the standards of these products for WHO has come with a comprehensive A description of other guidelines from developing countries such as India. and practical guideline on evaluation of other countries is beyond the scope of Â&#x2021; $ O O E L R O R J L F D O S U R G X F W V V K R X O G E H this article but suffice to say that countries similar biotherapeutic products (SBPs) FRQVLGHUHG DV ÂłQHZÂ´ GUXJV LQ RUGHU in October 2009. The WHO opines that such as USA, Australia, Malaysia, Turkey, to ensure that they come under the the clinical experience and established Taiwan, Japan, Israel, Canada, Korea, purview of the central drugs standard Singapore and South Africa, essentially safety profile of the originator products control organisation (CDSCO). his should contribute to the development follow the above principle while framing would ensure that uniform standards of SBPs. The WHO guidelines provide their guidelines. are followed by all manufacturers and globally acceptable principles for licensing the standards would not be dependent biological products that are claimed to be A Proposed Approach on the location of the manufacturing similar to a biological products of assured plant or the quality and knowledge of The standard generic approach (for oral quality, safety and efficacy that have been the local drug inspectors. formulations it means the demonstration of licensed based on a full licensing dossier. bioequivalence with a reference medicinal Â&#x2021; $ V S U R S R V H G E \ W K H : + 2 W K H prescriptions of biologics should not Among the key principles proposed by product by appropriate bioavailability be based on their generic name but studies) is normally applied to chemicallythe WHO are: on a unique name, for example the Â&#x2021; 7 K H G H Y H O R S P H Q W R I D E L R V L P L O D U derived medicinal products. Due to the trade name. Product labeling should complexity of biological/biotechnologyinvolves stepwise comparability be transparent and clear, summarizing d e r i v e d p r o d u c t s , t h e s a m e g e n e r i c exercises starting with comparison clinical data submitted for approval, of the quality characteristics of the approach is scientifically not appropriate enabl i ng pr es c r i ber and p a t i e n t t o IRU WKHVH SURGXFWV 7KH Âł6LPLODU %LRORJLFDO biosimilar and the reference product Â&#x2021; 7KH EDVLV IRU OLFHQVLQJ D SURGXFW DV D Sr. biosimilar depends on its demonstrated Issues with biosimilars Approaches toward biosimilars No. similarity to a suitable reference product i n q u a l i t y, n o n c l i n i c a l a n d c l i n i c a l Manufacturing cell lines, quality, P r o v i n g c o m p a r a t i v e p h y s i c o c h e m i c a l 1 impurities, potency similarity parameters. If relevant differences are found in the quality, nonclinical or Comparative preclinical and clinicalstudies as per guidelines clinical studies, the product will not Comparative immunogenicity studies as per likely qualify as a biosimilar. 2 Safety and immunogenicity guidelines for 12 months with Â&#x2021; %LRVLPLODUV DUH QRW ÂłJHQHULF PHGLFLQHVÂ´ 6 months of comparative period. Prescription and many characteristics associated by trade name with the authorisation process

40 eJuly 2014

Table 1: Biosimilars: Issues and approaches Abbreviations: WHO, World Health Organization; PK, Pharmacokinetics; PD, Pharmacodynamics

Pharma Bio World

Ad Template 01.indd 33

30-10-2013 15:05:02

make informed decision on the use of product. Automatic substitution of biosimilar products for originator products is not appropriate. Â&#x2021; ,Q FDVH RI SURGXFWV VXFK DV LQVXOLQ switching between products should be DYRLGHG ,W VKRXOG EH UHFRJQLVHG WKDW response to insulin manufactured by different manufacturers and methods can be unique and they are not identical HYHQ LI QDPHG VLPLODUO\ 7KXV WKH e ff i c a c y o f t h e p r o d u c t a s w e l l a s incidence of hypoglycemia could vary between products implying that these products are not interchangeable. Regarding substitution the EMA recommends that any decision to treat a patient with a reference product or biosimilar medicine should be taken only following advice from a health professional. 16 $GGLWLRQDOO\ LQ FDVH RI LQVXOLQ WKHUH LV DOVR D WHQGHQF\ WR induce antibodies which could have an impact on the efficacy of the product and in such a situation if the products have been frequently switched the source of the antibody would not be easily traced 10 Â&#x2021; ,QVXOLQV DUH DOVR FRPSOLFDWHG E\ WKH fact that the delivery device raises another level of complexity as they are unique and have been tested with particular brands of insulin. 3 Conclusion Bio Derived Medicines have revolutionised the management of several diseases VXFK DV GLDEHWHV FDQFHU DQG VHYHUDO LPPXQRORJLF FRQGLWLRQV ,QGLD LV ZHOO poised to exploit this growth due to its inherent strength in pharmaceutical manufacturing. While this needs to be H[SORLWHG LW LV DOVR LPSRUWDQW WR HQVXUH that the patientâ&#x20AC;&#x2122;s safety is not sacrificed DW WKH DOWDU RI FRPPHUFH ,W VKRXOG EH recognised that biologics are different from other chemicals and thus need to have different standards than their 42 eJuly 2014

chemical brethren. These standards have been well laid down by the WHO and ,QGLD VKRXOG DW D PLQLPXP IROORZ WKHVH standards. This would ensure that the ,QGLDQ SDWLHQW LV SURWHFWHG ZLWK D VLPLODU standard as patients in other parts of the world.

w w w. e u r o p a b i o . o r g / H e a l t h c a r e / H C _ FA Q -biosimilars.htm. [Accessed December, 2012]. 9. Kalra S, Balhara YP, Baruah MP, et al. Forum for injection techniques, India: the irst Indian recommendations for best practice in insulin injection technique. Indian J Endocrinol Metab. 2012; 16(6):876-85. 10. Strohl WR, Knight DM. Discovery and

The clinician should recognise these differences and also appreciate the impact that these can have on the patientâ&#x20AC;&#x2122;s safety. While prescribing these medications the physician should take care of prescribing them by their brand names and also educate the patients especially in case of products such as insulin that they are not interchangeable and any decision to do so should only be done by the physician. This would also ensure that the physician retains his traditional role as the principle decision maker in disease management.

development of biopharmaceuticals: current issues. Curr Opin Biotechnol. 2009; 20(6): 668- 72. 11. Schellekens H. Biosimilar epoetins: how similar are they? Eur J Hosp Pharm. 2004; 3:43-7. 12. CDSCO. (2012). CDSCO guidelines on similar biologics. [online]. Available from www. cdsco.nic.in/ [Accessed December, 2012]. 13. EMA Biosimilar guidelines. (2005). [online]. Available from www.ema. europa.eu/ema/index. jsp. [Accessed December, 2012]. 14. W o r l d H e a l t h O r g a n i z a t i o n . ( 2 0 0 9 ) . Guidelines on evaluation of similar

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What a physician needs to know. Internet J

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2. Walsh G. Biopharmaceutical benchmarks

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2010. Nat Biotechnol. 2010; 28(9):917-24.

Biosimilar Products. Geneva; 2006.

3. K r Ă¤ m e r I , S a u e r T. h e n e w w o r l d o f

16. E M A . ( 2 0 11 ) . Q u e s t i o n s a n d a n s w e r s

biosimilars: what diabetologists need to know

on biosimilar medicines (similar biological

about biosimilar insulins. Br J Diabetes Vasc

medicinal products). [Online]. Available from

Dis. 2010; 10(4):163-71.

www.ema. europa.eu/docs/en_GB/document_

4. McKoy JM, Stonecash RE, Cournoyer D,

library/Medicine_QA/2009/12/ WC500020062.

et al. Epoetin-associated pure red cell aplasia:

pdf. [Accessed December, 2012].

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Transfusion. 2008; 48(8):1754-62.

of insulin antibodies on the metabolic action

5. Kuhlmann M, Marre M. Lessons learned

of inhaled and subcutaneous insulin: a

from biosimilar epoetins and insulins. Br J

prospective Randomized pharmacodynamic

Diabetes Vasc Dis. 2010; 10:90-7.

study. Diabetes Care. 2005; 28(9):2161- 9.

6. Heinemann L, Hompesch M. Biosimilar

18. E u r o p e a n M e d i c i n e s A g e n c y. ( 2 0 0 6 ) .

insulins: How similar is similar? J Diabetes Sci

Guidance on similar medicinal products

Technol. 2011; 5(3):741-54.

containing recombinant human soluble insulin.

7. Owens DR, Landgraf W, Schmidt A, et al. he

[ O n l i n e ] . Av a i l a b l e f r o m h t t p : / / w w w. e m a .

emergence of biosimilar insulin preparations-a

europa.eu/docs/en_GB/ document_library/

cause for concern? Diabetes Technol her. 2012;

Scientific_guideline/2009/09/WC500003957.

14(11):989-96.

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8. EuropaBio, Frequently Asked Questions, Biosimilars. [Online]. Available from

Contact: dranil1965@gmail.com Pharma Bio World

Integrated Solutions for the Delivery of Biologics Biologics are some of the most promising drugs in the pharmaceutical industry pipeline. Over the past several years, there has been a steady rise in biologic drugs used to treat chronic conditions such as diabetes, rheumatoid arthritis and autoimmune diseases because of their ability to offer patients better long-term outcomes and fewer side-effects than traditional, chemical-based therapies. This article gives an outlook of the growing trends in integrated delivery system of biologic medicines.

Graham Reynolds

Vice President, Marketing and Innovation West Pharmaceutical Services, Inc. 44 eJuly 2014

ore than 907 biotechnology medicines were in development as of 2013 – nearly 30 percent of all drugs in the pipeline. 1In addition, injectable biologic drugs are being developed for conditions previously treated by non-injectable means, such as asthma and cholesterol-related conditions. When these drugs reach the market, it is likely that the majority will be presented to patients in a self-injectable format, enabling patients to regularly administer their own medication a t h o m e , r a t h e r t h a n i n t h e d o c t o r ’s office. As chronic conditions continue to rise, and more patients take on the responsibility of administering their own injectable medication, it is increasingly important that delivery and administration systems are designed with the patient in mind. Delivering biologics can be quite different from delivering traditional small molecule drugs. Typically large in size, biologic molecules may require a higher concentration of the drug product for efficacy. In addition, biologic molecules tend to be sensitive to products commonly found in traditional glass prefillable syringe systems, such as metal ions and silicone oil, substances that may impact the drug product’s efficacy and a delivery system’s performance. Trends toward self-injection and home care have also increased the demand for products that are easily injected by patients or caregivers with a prefilled syringe or by incorporating the syringe into a disposable auto-injector. In the coming years, many biologic medications, including Humira and Enbrel, will be coming off patent, resulting in a rise in demands for comparable delivery systems that will facilitate biosimilars approval while differentiating the drug and through incremental improvements to the delivery system. As pharmaceutical companies create and clinically test large-molecule antibodies for new therapeutics that may require larger

doses given over a longer period of time, packaging and delivery challenges can arise. Designing a Successful Integrated Delivery System Successful partnerships between drug manufacturers and drug packaging and device companies can help facilitate the creation of innovative, effective delivery systems for biologics. Research and development for a biologic drug product can typically last as long at 15 years and cost as much as USD 1.2 billion. 2But often the delivery system is considered only during the final stages of development. If the drug product cannot be effectively stored or reacts chemically with the containment materials, or if the system does not function well with a high-viscosity drug or is not a good fit for the intended audience, issues may arise that can be costly for the manufacturer to correct. Early collaboration during the lengthy development stages can result in a delivery system that meets the needs of both the drug and the patient. Since a drug product cannot be effective if the patient does not adhere to therapeutic recommendations, easy to use, safe and effective integrated delivery systems are an essential part of any drug product. A successful integrated delivery system should combine the following key elements: 1) T h e d r u g : A b i o l o g i c d r u g p r o d u c t must provide effective treatment in an appropriate form that enables effective administration with an optimum delivery rate and frequency. 2) A primary containment system: The drug must be held in a container that maintains effectiveness, safety and optimum quality over a period of time. 3) A d e l i v e r y d e v i c e o r s y s t e m : T h e drug should be compatible with the containment system and designed to enhance the drug delivery experience for the patient or caregiver. Pharma Bio World

Above all, a delivery device needs to consider the needs of the patient, caregiver and healthcare professional. Devices should be designed with the clinical benefit in mind, as well as the ease-of-use and ability to help patients adhere to a treatment schedule. Biopharmaceutical companies can design and develop an integrated system that can help bring these elements of effective delivery system together sooner by collaborating with a packaging and device partner early in the development process. This will help to ensure that the biologic drug product reaches the market in a delivery system that not only helps to protect the drug product’s efficacy, but will also help a patient adhere to treatment during any part of the therapeutic lifecycle. Sophisticated Technology for Integrated Delivery Systems Drug delivery technology has recently evolved to keep pace with the emerging biologic pipeline. With many biologics requiring high dose volumes delivered over longer periods of time, it’s important that the delivery device be capable of effectively and safely containing and delivering large doses of the drug product in a w a y t h a t i s e a s y fo r p a ti e n ts to use while withstanding increased dimensional forces. A novel material used for drug vials and prefillable syringes, Daikyo Crystal Zenith is an alternative to glass for drug delivery devices. Crystal Zenith is a cyclic olefin polymer that can be molded into a variety of shapes and designs. This unique property enables biologic delivery systems with larger fill volumes and tighter dimensional tolerance to be used while still remaining compatible with established filling technologies. One of the brightest areas in biologic delivery device design is wearable t e c h n o l o g y. W e a r a b l e d r u g d e l i v e r y systems can aid patients with self48 eJuly 2014

administration and compliance to a therapeutic regimen. For example, the SmartDose electronic wearable injector* is a single use, subcutaneous, preprogrammable electronic injection system that adheres to the skin and can deliver the drug over time. It features a drug containment system based on a Daikyo Crystal Zenith cartridge and Flurotec barrier film-coated plunger and is designed specifically to hold high-volume doses of sensitive biologics. Wearable delivery devices such as the SmartDose injector often feature easy to use interfaces, audio and other electronic indicators that help guide patients through the delivery process and help to aid patient adherence and caregiver monitoring. Patient Needs Inform Device Design To create an effective delivery system, the patient use cycle must be considered. From initial diagnosis of a disease or condition to long-term adherence, the patient passes through a variety of emotional and physical phases. Human factors testing can help establish the emotional and physical needs of patients at each stage of their therapeutic journey. For example, upon initial diagnosis, a patient may be frightened and unsure of the delivery mechanism, and may require guidance from a healthcare professional to deliver the prescribed dose. Delivery systems for a person at this stage should be designed to ease that burden of fear by being simple to use and intuitive in design. It should also provide clear indications that the dose has been delivered successfully. As the patient learns to cope with the condition, other factors such as accessibility and portability may rise in importance. Auto-injectors, pen devices or cartridge-based systems may offer patients highly desired convenience. Patients who must be on long-term therapies often find their own level of comfort through varying degrees of drug delivery control. Many may be comfortable determining their own rate or

angle of injection with a prefilled syringe system, while others prefer the speed and simplicity of an auto-injector. There is no “one-size-fits-all” device or system for patients suffering from chronic conditions, so a variety of choices for self-injection may soon become normal for many biologic therapies. Early stage planning for such choices can help pharmaceutical companies select materials for containment that can be used for multiple options. Changing a device can be easier than changing the primary containment for a drug, so an understanding of how to create a platform of devices around a single drug container is essential. Early collaborations between pharmaceutical manufacturers and packaging experts can help to create a platform of delivery options for patients. While the drug development journey may be long and expensive, the patient journey can last a lifetime. To ensure adherence and brand loyalty throughout that journey, biologics manufacturers should consider the drug delivery device design as early as possible. By working with an integrated packaging and delivery system partner from research and development stages through commercialisation and beyond, the biopharmaceutical manufacturer can present patients with options that encourage adherence for as long as the patient requires medication. References 1)PhRMA, “2013 Report: Medicines in Development – Biologics,” http://www.phrma. org/sites/default/files/pdf/biologics2013.pdf, accessed on April 4, 2014. 2)PhRMA slide pack “Biopharmaceuticals in Perspective” * F o r i n v e s t i g a t i o n a l u s e o n l y b y We s t ’s pharmaceutical and biotechnology development partners.

Contact: Alok.Chandorkar@westpharma.com Pharma Bio World

Innovating to Meet Sector-Driven Demands This article highlights some of the innovation processes employed by packaging equipment suppliers, including printing and marking companies, to ensure their solutions address the evolving needs of the pharmaceutical packaging community.

ccording to the International Federation of Pharmaceutical Manufacturers & Associations, global spending on Pharmaceutical Research and Development was almost USD 135 billion USD in 2011. It is hard to think of that sum and not be in awe of the contribution by hundreds of thousands of pharmaceutical researchers working to solve arguably the most challenging maladies facing the world community. But often overlooked in the discussion of Pharmaceutical research is the recognition of a similarly dedicated group of Pharmaceutical packaging engineers and suppliers working diligently to bring products safely and securely to market. Pharmaceutical packaging operations are undeniably getting more complicated. The enactment of country and regional level regulations pertaining to serialisation including the FDA Drug Quality and Security Act and EU Falsified Medicines Directive will require more sophistication at the packaging line to control the physical movement of product but also the corresponding flow of packaging and supply chain data. Packaging equipment suppliers, including printing and marking companies, are working diligently to ensure their solutions address the evolving needs of the Pharmaceutical packaging community. Building on a Culture of Quality

John Folkers

&KLHI 7HFKQRORJ\ 2IÂżFHU Videojet Technologies 50 eJuly 2014

Application specific innovation most often builds on organisational core competencies to deliver the functionality necessary for a given industry sector. By default, that targeted innovation requires a strong foundation in product planning, research and development, and manufacturing execution to deliver high quality to the customer. As an example, strong process discipline pertaining to the creation of Market Requirements Documents (MRDs) ensures customer needs are communicated

i n c l e a r, p r e c i s e t e r m s t o p r o d u c t development teams. Other examples include toll-gate development processes to enforce Technology Readiness Levels and proven development tools such as Design for Reliability (DfR) to ensure failure modes are addressed well in advance of prototype development. High performance innovation teams rely upon these building blocks, recognising that process discipline and process maturity in all steps of the new product development process can then be leveraged for applicationspecific development. Understanding Customer Objectives In some industry sectors, innovation is defined as providing solutions that customers do not yet recognise they need. In Pharmaceutical packaging, however, innovation is substantially focused on delivering to a set of known functional requirements. Yet, to execute applicationspecific development well, the R&D process needs to move beyond an understanding of what the customer is trying to accomplish to include both; 1) how the customer processes are structured, and; 2) how the technology provider can improve customersâ&#x20AC;&#x2122; intended outcomes and processes. Solutions must be engineered based on a deep understanding of customer needs and operational challenges. It is this 360-degree approach to R&D that differentiates companies that focus on customer-driven innovation versus product-focused innovation. In the world of packaging, the inline printer is a critically important component of the packaging process â&#x20AC;&#x201C; it sits on the critical path. This process, executed well, can yield meaningful customer improvements beyond the core printer functionality. Targeted innovation, by definition, is more narrowly focused yet still needs to recognise Pharma Bio World

the inherent workflow variation from one customer to the next in a given sector. Given the interest in serialisation, variable data handling at the printer provides an illustrative example. Some customers will require their printers to accept buffered data with a set of commands to check and control buffer levels as well as various exception handling conditions including buffer overflow conditions, loss of printer communications, and power interruption situations. Other customers will execute their serialisation schemes in a “printonce” or un-buffered mode with a range of command options to accommodate data transmission and data over-write as well as exception handling such as data absence. The investment to understand these workflow variants yields many of the necessary insights to deliver the needed solutions. Product-in-Place Observation Listening to customers and doing quantitative analyses are great tools for gathering VOC insights. But a third component that really brings a holistic perspective is real life observation of products in use. Observations at customer sites by qualified engineering and technical specialists can yield surprising insights about product performance and usage. This team must be comprised of very technically minded and experienced people that can meet with customers, know what questions to ask and who really understand technical details. This VOC expertise is a critical component for not only avoiding problems later in the development process, b u t m o r e i m p o r t a n t l y, f o r u n c o v e r i n g opportunities to help customers. For example, site observations may uncover packaging line set-up and changeover processes interacting with multiple human machine interfaces (HMIs) on a given line. This simple observation may spur creative discussion and debate about the value of consolidating operator interaction to a more limited set of HMIs, and the resulting specifications to operate a printer or other device in a master-follower arrangement. 52 eJuly 2014

Prioritisation of Needs A well-functioning innovation engine rigorously prioritises the product attributes to provide clarity to the development teams. However, this raises the obvious question of how to best prioritise the customer insights and data collected from on-site observations. While a given packaging application and related solution m a y r e q u i r e a d i ff e r e n t a p p r o a c h t o prioritisation, it is important not to lose sight of broader programme objectives. Targeted innovation is ultimately driven by the recognition that general purpose solutions are either insufficient or poorly adapted to meet the sector’s application needs. While MRDs require the extensive observation discussed above, an appreciation for the customer’s broader mission can help frame the prioritisation discussion and ensure other customer requirements are not lost in the shuffle. Pharmaceutical packaging places a great emphasis on both process and output q u a l i t y, p e r h a p s t o a g r e a t e r d e g r e e than other packaging operations. An appreciation of these customer goals can lead to engaged customer discussions regarding the relative priority of solution functionality. In the printing and marking industry, topics such as the hard and soft costs of poor quality can lead to informative discussions ranging from print quality and the implications of different substrates and inks to the potential for coding errors from incorrect data entry and opportunities to minimise risks. Getting it Right: Testing for Success & Reliability Finally, the last step in any development process should always include rigorous testing procedures. Proper testing should incorporate the same holistic approach that informs the R&D process as a whole. Best-in-class development incorporates elements of a stage gate development process to continually challenge whether the R&D process is delivering to the

customers’ requirements. Quantitative technical testing performed by real application experts is a critical early-stage step to check solution performance in a manner consistent with customer use and customer environments. Typically on-site customer evaluations, where new products are installed at select customer locations, are another vital stage in customer-driven innovation. It’s vitally important to conduct customer trials as early in the process as possible. Not only does this act as further concept validation, but allows for iterative improvements relative to product design and uptime. The final stage of testing should be done to evaluate product reliability and determine the product lifecycle in a replicated customer environment, mimicking real world circumstances across a variety of intended applications. During these rounds of testing, issues should be recorded and ranked by severity. A rigorous toll-gate process dictates that all issues need to be addressed and cleared before a new product can move forward to the next stage of development. This methodical testing is yet another element of having a culture that promotes a consistent drive toward improvement. Summary Regardless of the specific innovation drivers, technology suppliers can be well-served by keeping the customer at the center of their R&D efforts. Best-inclass companies use customer-driven innovation to avoid the trap of viewing the technology development in itself as the objective. Rather, by following the disciplined approach inherent in customerdriven innovation, the repeated customer touch points throughout the innovation process ensure the solution stays true to the customer’s needs. Contact: sli@abipr.com Pharma Bio World

How to Ready Your Organisation for an FDA Inspection The US Food and Drug Administration continues to increase the number and depth of its inspection of Pharmaceutical, Biologic and Medical Device facilities, especially outside the US. Since 2009, the number of foreign drug inspections have steadily increased, with 40 per cent of the total (almost 1,000) planned for 2015. Equally important, FDA has emphasised its intent to focus on “high-risk” facilities and companies for enforcement of compliance with quality regulations.

DA inspections of manufacturing facilities are serious and violations can have devastating consequences. In the past year, FDA inspections have led to product recalls or Warning Letters for drugs manufactured in countries ranging from India to Ireland, Canada and the US. For some manufacturers, nonconformities discovered during FDA inspections have resulted in product bans, loss of trust and record-setting fines. Although the greatest attention is typically paid to events involving “major” nonconformities, since they can result in withdrawals of essential certificates or trigger shipment holds, companies have discovered that several “minor” nonconformities inthe same area can produce the same, serious results and alert inspectors to potentialproblems at the company’s other facilities. An inspection effectively gives regulators an “open door” to a plant’s operations, peopleand compliance program. In 2013, FDA published draft guidance intended to keepthe doors open. FDA’s Guidance for Industry: Circumstances that Constitute Delaying, Denying, Limiting, or Refusing a Drug Inspection put the regulated community on notice that the agency would not tolerate any interference in its effort to ensure the quality of medical products destined for the US market.

Ellen Leinfuss

Life Science Practice Leader UL EduNeering

Noreen Muscat

Sr Consultant, Advisory Services UL EduNeering 54 eJuly 2014

FDA isn’t fooling around. Multiple actions have been identified as being potential violations of the Guidance. Among them are delays or refusal in scheduling an inspection and preventing an investigator access to an area of the facility even though it is operational and within the authority of FDA to inspect. FDA calls out specific actions it considers to be in violation, including limiting access to facilities or manufacturing processes, l i m i t i n g p h o t o g r a p h y, l i m i t i n g a c c e s s to or copying of records and limiting or preventing the collection of samples.

FDA’s Focus on Foreign Drug Inspections: Since 2009, FDA has increased its focus on inspections and enforcement. It has hired more inspectors and is shifting its attention to companies importing drugs into the US. The shift in the number of foreign inspections reflects the agency’s risk-based regulatory approach.

Clearly, refusing to allow entry to FDA investigators is beggingfor trouble but the agency considers “refusal” toinclude passive behaviors and non-actions such as not answering calls from the investigator and barring the investigator from entering the facility or certain areas within the facility. It is essential that all employees, subcontractors, agents and third-party entities understand the seriousness of an FDA inspection, how to prepare for an inspection and how to behave during an inspection. The Training Component The vast majority of regulated companies are committed to producing quality products and complying with regulatory requirements. Part of that commitment involves providing inspectors with the information they need to document compliance. In most cases the “information” is in written form, such as SOPs, training records and reports to regulators. During an FDA inspection, this type of information may be requested and must be provided. A separate category of information, however, comes from individuals who are being questioned by the FDA inspector. Pharma Bio World

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Preparing for an Inspection Preparation is critical to any inspection (or internal audit). That preparation should include the following: sĂ? Designation of the team to work directly with the FDA, including a main company contact and escort, backup contacts and scribes.

An audit effectively gives regulators an open door to your plantâ&#x20AC;&#x2122;s operations, people and compliance programme. Itâ&#x20AC;&#x2122;s important that everyone in the organisation understand how serious the audit is, what can go wrong, and what the consequences can be.

sĂ? Preparation of a meeting/interview room for the inspector. sĂ? Preparation of an operational room (including resources) for document and interview request. sĂ? Preparation of your opening presentation. Critical components of the presentation are: Â&#x2021; Company overview including organisation chart; Â&#x2021; Brief bios of executive management and senior staff expected to be involved in the audit; Â&#x2021; Product types, production volume, and facility plan; Â&#x2021; Promotional/sales brochures and materials; Â&#x2021; Hours of operation (and working hours if shifts are used); Â&#x2021; Draft agenda. sĂ? Ensuring Compliance Â&#x2021; Up to date company and device listing and registration. Â&#x2021; Operation within the scope of any QMS certification. Â&#x2021; Completion of CAPA from any previous inspection. Â&#x2021; Product complaint/adverse event/recall documentation is current and complete. Â&#x2021; Electronic signatures/software validation is documented. Â&#x2021; Check accuracy of authorised Representative Agreement, if applicable. Â&#x2021; Identify any major suppliers the inspector may decide to include in the inspection. Â&#x2021; Check that all training and qualifications on SOPs/Policies are current. Train employees, suppliers and agents how to behave during an FDA audit. A review of recent warning letters and 483s will help you identify issues and trends and will point to key issues for preparation, such as: Corrective and Preventive Actions (CAPA):Ă?$URINGĂ?THEĂ?AUDIT Ă?EXPECTĂ?TOĂ?BEĂ?ASKEDĂ?FORĂ? THEĂ?CURRENTĂ?STATUSĂ?OFĂ?ANYĂ?CORRECTIVEĂ?ACTIONĂ?PLANĂ?nĂ?ANDĂ?EXPECTĂ?AĂ?SEVEREĂ?RESPONSEĂ?IFĂ?THEĂ? #!0!Ă?PRODUCEDĂ?AFTERĂ?THEĂ?LASTĂ?AUDITĂ?HASĂ?NOTĂ?BEENĂ?COMPLETEDĂ?ORĂ?PROPERLYĂ?DOCUMENTED Internal Audits: 4HEĂ?&$!Ă?PLACESĂ?PARTICULARĂ?EMPHASISĂ?ONĂ?THEĂ?STATUSĂ?OFĂ?ANĂ?INTERNALĂ?AUDITĂ? AND Ă?ASĂ?WITHĂ?THEĂ?#!0! Ă?ONĂ?THEĂ?STATUSĂ?OFĂ?RECTIFYINGĂ?ISSUESĂ?IDENTIFIEDĂ?INĂ?THEĂ?AUDIT Quality Records: 2ECORDKEEPINGĂ?ANDĂ?DOCUMENTĂ?STORAGEĂ?AREĂ?BASICĂ?REGULATORYĂ?REQUIREMENTSĂ? ANDĂ?CANĂ?TRIGGERĂ?WARNINGĂ?LETTERS Ă?%NSUREĂ?THATĂ?RECORDSĂ?AREĂ?COMPLETE Ă?ACCURATE Ă?CURRENTĂ?ANDĂ? PROPERLYĂ?STORED Adverse events, medical device reporting, recalls: %FFECTIVEĂ?DOCUMENTĂ?MANAGEMENTĂ? ISĂ?ESPECIALLYĂ?IMPORTANTĂ?INĂ?THESEĂ?HEAVILYĂ?SCRUTINISEDĂ?AREAS Control Measures: Inspectors will scrutinise the control measures implemented in the facility including production and process controls, document controls and design controls.

56 eJuly 2014

In most cases, specialised training is warranted to teach relevant personnel how t o behav e dur i ng an i ns p e c t i o n . Companies should conduct this specialised training as a matter of course but it deserves reinforcement as an inspection date approaches. Ending the Inspection An FDA inspection ends with the opportunity for a company to work directly with the inspector on any observation or nonconforming issue. Listen carefully to the auditorâ&#x20AC;&#x2122;s report. You may already have resolved some issues identified by the inspector during the audit and be planning a corrective action plan for any remaining issues. When you are assured that you have all relevant information about the auditorâ&#x20AC;&#x2122;s findings, agree to the corrective action plan deadline and escort the inspector from the facility. After the inspector leaves, your work should move into high gear. Conduct a debriefing of the audit with the senior management group, identify action items and the individuals who are responsible for completing each item, and set a timetable for follow-up meetings with the same group to review intermediate progress on those action items. A formal CAPA programme should be created based on the findings from the inspection. Ensure that all nonconformities are included in the CAPA programme. Maintain careful oversight to ensure that you meet the timeline agreed to with the inspector. Pharma Bio World

There are a number of points worth reinforcing to employees: Do not attempt to hide anything the inspector requests – but neither should you offer information that has not been requested. Simply answer the inspector’s questions. Don’t “fill in the silence.” Simply remain silent until the inspector asks another question. If you don’t know the answer to an auditor’s question, offer to find someone who does know the answer. Don’t try to “wing it.” Every auditor is different. Some prefer to work in a designated meeting room, requesting necessary materials and individuals to interview. In such cases, assign someone to find requested materials and individuals. Other auditors prefer to stay on the move throughout the facility, watching employees work and unexpectedly asking questions of individuals on the shop floor. Inspectors have the right to see virtually anything in the facility. Be professional. An FDA inspector isn’t a friend or buddy visiting the plant. All employees – including senior managers and officers – should remember that an FDA inspector is an experienced professional with a job to do. Make sure everyone knows how to access SOPs and other corporate policies quickly and with minimum fuss. Remember: it doesn’t matter where an SOP is “supposed” to be; what matters is where it is. Make sure all staff know where to locate the SOP and understand its purpose. Increasingly, FDA is asking individual floor staff to explain the SOP and why it is important. Craft your response letter to FDA, fully answering any issues raised by the audit. If a corrective action is completed by the time your response is finalised, provide objective evidence of its completion. Two points about FDA’s expectations and your response deserve special mention. First, FDA will expect to see evidence that any training required by your corrective action plan is effective. Make sure that you have provided and documented all training required by the CAPA – but go the extra step and provide evidence (through testing or competency assessments, for example) that the training has been effective. Second, FDA will expect you to identify and address the root cause of any nonconformity – not just the individual n o n c o n f o r m i t y. N o n c o n f o r m i t y a t one facility may suggest a systemic compliance issue to the inspector.

In all cases, it is essential to fix the system that led to the problem rather than simply applying a bandage to a single wound. FDA inspectors are trained to “connect the dots.” They know that minor issues often signal larger, systemic problems. The companies that understand that approach and integrate it into their own quality and compliance programmes are most likely to catch small nonconformities before they become major problems leading t o Wa r n i n g L e t t e r s , r e c a l l s o r e v e n product bans. Contact: kavita.mehrotra@ul.com

products, personnel and compliance. Unfortunately, too many companies fail to gain an equal amount of broad-based information, such as the regulatory agency’s evolving\ approach to inspections and compliance, and specific information about the inspector’s observations at your facility. Those observations should guide the way you respond to any nonconformities or concerns the inspector may have.

Gaining Value from Inspections

Consider, for example, a potential problem area the investigator has noted in one area of your facility. You could ignore the problem, hoping that it won’t be serious enough to be written up. Or, at the end of the day, you could ask the inspector about any problem area, then fix it – even if it means working through the night. There is no substitute for being able to say on the following day, “That problem you mentioned yesterday – we have worked hard to address it quickly. This is what we did and I’d like to make sure we addressed the issue in the right way.”

An inspector will work hard to gain as much information as possible about your facility,

great deal of information can be gleaned from an FDA inspection and put to

60 eJuly 2014

good use in improving your quality and compliance programmes. If SOPs are not easily accessible, move them; if new hires are unaware of proper procedures, retrain them; if facility housekeeping is inadequate, increase attention to it; if records are not up to date, update them.

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news features

Budget 2014-15: Ticks n’ Crosses on Pharma Priority Boxes Pharma Bio World round ups reaction from pharma-biotech stalwarts on the new union budget.

ith the dawn of new government in centre, raised were the hopes of pharmaceutical industry. Like other industry counterparts, pharma pundits too were keen to know the changes new union budget about to bring. Since the election manifesto of Modi lead government had promises for pharma industry, it was quite obvious that all eyes were on the budget box and its offers to the industry. “There are a lot of expectations from the budget,” said Arjun Handa, MD & CEO, Claris Lifesciences. “But it would be prudent to expect long term measures with minimal populist measures. Focus to boost manufacturing with a control on inflation and increase in investments in infra and FDI might show up as one of the pillars of the budget. We would expect the budget to increase allocations for healthcare and pharmaceutical industry with some sops to drive India to being a research driven country,” added Handa. Pawan Chaudhary, CMD, Venus Remedies opined that the government should give impetus to R&D through incentive-linked funding and there should be more clarity on guidelines on expenditure liable for weighted average deduction under section 35(2) AB of the Income Tax Act. “Essentially speaking, we expect this budget to push for a new era of accelerated reforms. We hope the budget supports the industry by giving incentives to exporters like exemption under section 80HHC,” he added. Finally, when the much anticipated general budget of the newly-elected government is out, the finance minister although walking a tight rope on the fiscal front, has tried addressing several issues raised by the Indian Pharma Industry.

62 eJuly 2014

“The issues around the pharmaceuticals sector are more policy related, with tax measures forming only part of the solution. While the support of the Government toward macro issues like skill development and bridging the infrastructure gap are fairly commendable, issues directly related to the pharma industry were fleetingly mentioned,” comments Utkarsh Palnitkar, Partner, Head of Advisory, Head - Life Sciences, KPMG in India. “The promise of central assistance to strengthen drug laboratories and research should assist research in the country. However, the clarity around the role of the CDSCO and CDRI and the current regulatory ambiguities were much desired, today. Initiatives around developing clusters for biotech and promoting global partnerships to strengthen generic engineering and biotech will also help the biotech sector in the country. The Free Drug Service and Free Diagnosis Service were mentioned as priority were not substantiated enough from a procurement perspective, leaving behind ambiguity around execution. In a nutshell, the budget did leave much to be desired in terms of answering the many questions that all the pharma industry stakeholders have in mind,” Palnitkar adds. Dr Habil Khorakiwala, Founder Chairman and Group CEO, Wockhardt feels the government has done a commendable job with the Union budget considering that it been in office barely for six weeks. “Even though the Finance Minister has not had too much time to develop the budget, he has managed to lay out a directional road map for achieving a higher rate of growth, reigning in inflation and curbing the fiscal deficit to a reasonable level over the next few years. While, the Finance Minister announced some key measures Pharma Bio World

news features to enhance governmental participation in healthcare over the next few years, nothing major was announced with respect to the pharmaceutical industry, which is a little disappointing,” points out Dr Khorakiwala. Dr Rajiv Modi, Chairman and Managing Director, Cadila Pharmaceuticals Ltd welcomed the budget as a positive step towards nation building. According to him, “Decision to set up new drug testing laboratories and strengthening the 31 existing State laboratories is a noteworthy step which will provide assistance to the States’ Drug Regulatory and Food Regulatory Systems.”

of clinical trials being done in the country slowing down dramatically. Withdrawing the exemption on service tax for clinical trials will act as a further disincentive to doing clinical research in India. Given the fact that a sixth of the world’s population lives in India and we have the highest disease burden in the world, we need to foster an environment and ecosystem that encourages clinical research. The ultimate impact of a slowdown in clinical research is on patients, for many of whom participation in a clinical trial is their only hope of survival or a better quality of life,” Thatte continues.

experts are seems to be ignoring these as minor hiccups from a new government, considering the magnitude of the ‘Good Days’ that the budget offer. “The budget has drawn some broad strokes on the canvas showing the governments intent in the coming years. Overall this was a positive budget considering the fact that this government has been in power for about a month only,” notes Arjun Handa. The new budget elicits mixed reaction from the pharma-biotech industry.

Budget 2014 -15 Suneela Thatte, President Indian Society for Clinical Research thinks that withdrawal of service tax exemption on clinical trials sends a wrong signal to the global community on the Government of India’s commitment to promoting research for better healthcare. “The clinical research industry in India has, over the last couple of years, already been challenged by a difficult and unpredictable regulatory environment with the number 64 eJuly 2014

“Further, this will also impact Indian companies who have an innovation agenda and work with CROs as the withdrawal of the service tax exemption will make the process of drug development even more expensive and act as a deterrent to the culture of research and innovation that needs to be encouraged in the domestic industry,” explains Thatte. As with any budget, this budget too has its flaws. But most of the industry

Although the budget has initiated some key measures to stimulate the investment climate, revive growth and create a sustainable growth model for pharma-biotech industry, some policies might not seem so reasonable. To see how much successful this budget will be into implementation, we need to wait for few more months. - Compiled by Mahesh Kallayil Pharma Bio World

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marketing initiative

Facilitating Efficient Equipment Cleaning Equipment design and cleaning procedures both play a role in thorough sterilization and cleaning.

terilization or sanitization is usually applied to kill bacteria in a system. In addition, equipment is cleaned to remove residues from the previous batch of product, and subsequently flushed to remove the cleaning liquids. To ensure that sterilization and cleaning are efficient and safe, it is not enough to develop the appropriate procedures. Selecting the right manufacturing equipment further improves cost efficiency, as well as patient safety.

Considerations in Equipment Selection The chosen equipment must minimize the risk of contamination due to inappropriate product-contact surfaces. Machines should not introduce airborne particles and dust into the environment, nor should they entail the risk that oil or other substances required for their operation will contaminate the product. If an operator cannot contact all equipment surfaces adequately, he or she simply cannot clean them. To facilitate efficient cleaning, equipment must be designed with this principle in mind. The time, temperature

action, chemicals, and (TACT) circle originally

developed by Sinner in 1960 shows the cleaning effects that these parameters generate on the equipment surface (see Figure 1). The circle shows the extent to which time, plus at least one more parameter, clean residues from a surface. If one parameter is increased, the others may be reduced. For example, if one dips oneâ&#x20AC;&#x2122;s greasy hands in water, they will not become clean. If one puts them into a soap bath, they will become clean, but only after a long time. If one raises the temperature of the soap bath, however, oneâ&#x20AC;&#x2122;s hands will become clean more quickly. But if one also rubs oneâ&#x20AC;&#x2122;s hands together, they will become clean even more quickly. The residue and the product-contact surface determine the size, or the impact, needed for the cleaning process. The most suitable type of chemicals and the appropriate temperature are decided according to the residue. High surface action enables the chemicals and temperature to work more efficiently, which makes it possible to reduce both of these parameters, as well as the cleaning time.Because the action is often built into the equipment design, selecting the right equipment can reduce the cost and increase the cleanability of a system.

Figure 1: The time, action, chemistry and temperature circle

66 eJuly 2014

Cleaning action on the equipment surface is achieved by generating high velocity or flow of cleaning fluids on all product-contact surfaces. This technique distributes the chemicals and temperature better than low velocity does. Increased velocity also generates high turbulence and shear force on the surface, which ensures that the chemicals and temperatures reach deep into the residues and dissolve or detach them safely and efficiently. Testing TACT Parameters To test the influence of the TACT parameters, the author designed a tankcleaning test incorporating two tankcleaning devices that generated different amounts of action. A static spray ball typically generates a wall shear stress of 2---5 Pa (i.e., falling filmstress, depending on liquid temperature). A rotating jet head typically generates a wall shear stress of 40---1000 Pa (i.e., jet impingement, depending on jet pattern mesh). To clean the tank sufficiently, two static spray balls operated for 48 min at a flow rate of 20 m3/h and a system pressure of 2.5 bar. One rotating jet head, however, achieved better resultswhen it operated for 14 min at a flow rate of 6 m3/h and a system pressure of 5.0 bar (see Figures 2 and 3 and Table 1). The test showed that the theory of the TACT circle works in practice. To clean a certain residue from a certain surface, the parameters in the TACT circle can be adjusted for cost optimization (see Figure 3). With increased action, it was possible to reduce the time, the amount of chemicals, and the heating energy and still achieve an equal or better result. High shear forces can remove residues Pharma Bio World

marketing initiative Parameters

Two static spray balls

Time

48 minutes

One rotating jet head 14 minutes

Action (i.e., wall shear stress) 3 Pa

50 Pa

Amount of cleaning liquid

16,000 liters

1,400 liters

Heating energy

913 kw

73 kw

Table I: Parameters of two cleaning operations

Figure 2: A tank cleaned with (a) two static spray balls and (b) one rotating jet head

Figure 3. TACT circles for 8a) two static spray balls and (b) one rotating jet heat.

from most surfaces by themselves without chemicals or high temperatures. This technique can reduce the risk of contamination from cleaning chemicals and dramatically reduce cleaning costs. Equipment design pitfalls Strong cleaning action on all product contact surfaces minimizes the risks of contamination and of system malfunction and also enables cost efficient cleaning. Common design pitfalls, however, impair equipment cleanability. Dead legs, pockets and crevices, air pockets, and improper equipment surfaces are pitfalls too often seen in the pharmaceutical industry. 68 eJuly 2014

Dead legs. It is widely understood that dead legs should be avoided or minimized in a system (see Figure 4). Some guidance states that the length to diameter (L/D) measurement for dead legs should not be more than 2, and, in some cases, not more than 3. The relation between the main-pipe velocity and the L/D measurement, however, is often overlooked. High main-pipe velocity makes the turbulence go deeper into the dead leg, and if the turbulence or action is strong enough, it will remove the residues at the bottom of the dead leg. In a 1997 article, Haga et al. presented results from tests with various

velocities in the main pipe in various L/D measurements 1 . They found that for an L/D of 6, it is possible to clean the residue adequately if the main-pipe velocity is higher than 1.5 m/s. They also found that for an L/D of 3, it is impossible to remove the residue if the main pipe velocity is lower than 0.7 m/s (see Figure 5). Pockets and crevices. No rule of thumb governs the depth of pockets and crevices. Figure 6 shows a typical crevice found in pharmaceutical systems. Many guidances state that crevices should be avoided or eliminated when possible, a statement that seems weak considering that a crevice could be likened to a dead leg with an L/D measurement of 50-100, compared with the normal 2-3. Following Haga et al., it would be impossible to achieve the velocity required to clean the bottom of a crevice. Thus, pockets and crevices should not exist in pharmaceutical systems because they will always pose a major contamination risk. Air pockets. Air pockets may be described as upside-down dead legs or crevices (see Figure 7). Although residues do not collect in an air pocket, they stick to its surface. It is difficult to evacuate the air from these pockets during the cleaning process, which means that the cleaning liquid will not reach the top of the air pocket and, accordingly, will not

Figure 4. Dead leg.

Pharma Bio World

marketing initiative

Figure 5: Velocity and length/diameter measurement.

Figure 6: A hard-to-clean pocket can be created between two metal parts and an O-ring seal.

Figure 7: Typical air pocket

the bacteria are too large to get trapped DQG FRVW HIILFLHQW FOHDQLQJ 7KH PRUH clean it. Air pockets, therefore, must be between the surface imperfections. In FOHDQLQJ DFWLRQ LV DSSOLHG RQ DOO SURGXFW another study, however, Riedewald contact surfaces, the easier, safer, and eliminated, or they will introduce a high showed that when bacteria accumulate TXLFNHU V\VWHP FOHDQLQJ ZLOO EH risk of contamination. in a biofilm, adherence and cleanability - Per-Ă&#x2026;ke Ohlsson, Global Manager depend on the surface finish 3 . It is hard Alfa Lavalâ&#x20AC;&#x2122;s Market Unit Pharma & Personal Care Surface finish. Surface finish is often for biofilm to attach to a smooth surface, considered a measurement of hygienic and thus it is easy to detach them from References design. The maxim is that the smoother such a surface. The same is true for other the surface, the more hygienic and sticky residues. A study at the Institute of easy to clean. But this principle is, in Technology in Kolding, Denmark, tested 1) R. Haga et al., Pharm. Eng. 17 (5), fact, open to debate. A 2003 study by the cleanability of surfaces spiked with a 8-21 (1997). Hilbert et al. tested the adherence of yogurt solution that had been ovendried 4 . 2) L.R. Hilbert et al., Int. Biodeterior. bacteria to several surfaces and the This study clearly showed that a surface Biodegradation 52 (3), 175-185 (2003). cleanability of these surfaces 2 . The with a low Ra value was easier to clean 3) F. Riedewald, PDA J. Pharm. Sci. Technol. VXUIDFHV IURP Č?P HOHFWUR SROLVKHG than one with a high Ra value. The 60 (3), 164-171 (2006). WR Č?P PHFKDQLFDOO\ SROLVKHG tested surfaces ranged from Ra 0.15 to 4) D. Bagge-Rawn, Microbial Adhesion and showed no differences in adherence or Č?P (OHFWURSROLVKHG VXUIDFHV DOVR Biofilm Formation in the Food Processing cleanability. The main reason was the were easier to clean than mechanically Industry (Technical University of Denmark, relatively large size of the individual polished surfaces, which, in turn, are Kolding, Denmark, 2007). bacteria compared with the small size easier to clean than pickled surfaces. of the surface imperfections. As long as (TXLSPHQW GHVLJQHG FRUUHFWO\ ZLOO DYRLG (This article is being reprinted with permission WKH VXUIDFH ILQLVK LV EHORZ 5D Č?P, the above pitfalls, thus facilitating safe from Pharmaceutical Engineering)

72 eJuly 2014

Pharma Bio World

Ad Template 01.indd 17

23-11-2013 21:37:59

marketing initiative

In vitro Anti-hypertensive Activity of HYPERCUM

ypertension or high blood pressure is one of the most preventable causes of premature morbidity and mortality world-wide. Hypertension is an elevated pressure of the blood in the arteries. Hypertension results from two major factors, which can be present independently or together. The heart pumps blood with excessive force or the body’s smaller blood vessels (known as the arterioles) narrow, so that blood flow exerts more pressure against the vessels’ walls. Hypertension is considered when the blood pressure reading greater than or equal to 140 mm Hg (systolic) or greater than or equal to 90 mm Hg (diastolic). Hypertension is a major risk factor for stroke (ischaemic and haemorrhagic), myocardial infarction, heart failure, chronic kidney disease, peripheral vascular disease, cognitive decline and premature death. Untreated hypertension is associated a progressive rise in blood pressure, often culminating in a treatment resistant state due to associated vascular and renal damage (August,2004;WHO 2012) Surprisingly, despite education programs and the numerous drugs that can be employed by physicians to normalize high blood pressure, this ‘silent killer’ is still active. Even though people are more aware of their hypertension and control rates have improved, only 30% of hypertensive patients are controlled. Moreover, the global picture of hypertensive patients is changing. Obesity (currently associated with hypertension) and aging are on the rise and will likely contribute to more hypertension. Therefore, research on new drug targets that could be employed to obtain well-tolerated treatments and that could simultaneously act on different cardiovascular risk factors in particular groups of patients is still a challenge (Monassier, 2006). However, an ethnobotanical survey has revealed that herbs are commonly used in the treatment of hypertension as they are

74 eJuly 2014

safe. Hence the present study focuses on a poly herbal formulation (HYPERCUM) in treating hypertension. To understand the mechanism of action of HYPERCUM an in vitro study on rat precontracted aorta with endothelium and without endothelium is performed to assess the vasodialatory property. Objective of the study To investigate the antihypertensive activity of HYPERCUM in rats using in vitro model. In vitro – Vasodilatation model using thoracic rat aorta preparation. Product details HYPERCUM – An Ayurvedic Proprietary medicine from NATURAL SOLUTIONS. It is a polyherbal formulation containing the following medicinal plantsMaterials and methods Test substance: HYPERCUM proprietary product of Natural Solutions Identification: White powder Total number used: 12 male rats Animals Experimental study was carried out using adult male Wistar albino rats weighing between 200–250 g. The animals were procured from Sree venkateshwara enterprises, Bangalore. The animals were housed in polypropylene cages and were maintained clean and hygiene. Animals were acclimatized in a room 12–12 h dark-light cycle, maintained at temperature 25±2ºC and humidity 50±5%. The rats were fed with commercial pellet rat feed (M/s Pranava agro industries Sangli, Maharastra.) and water ad libitum. The study was approved from the Institutional Animal Ethics Committee, Siddaganga College of Pharmacy, Tumkur, Bangalore, Karnataka.

In vitro model: A most common contributory to the pathogenesis hypertension is endothelial dysfunction. The imbalance between vasodilator agents (nitric oxide (NO), endotheliumdependent hyperpolarizing factor (EDHF)) and vasoconstrictor agents (endothelin, thromboxane A2, endoperoxides) released from endothelial cells as well as an increase in free radical production appear to be the most important cause of endothelial dysfunction in hypertension. NO released from vascular endothelium mediating vascular smooth muscle cell relaxation plays a key role in the maintenance of vascular tone. Other possible causes of systemic vasoconstriction in NO-deficient are enhancements of sympathetic nerve Sl.No.

Name of the Plant

5DXYRO¿D VHUSHQWLQD

Nardostachys jatamanshi

Allium sativam

Ocimum sanctum

Curcumin longa

(PEOLFD RI¿FLQDOLV

Azadirachta indica

Trigonella foenum graecum

=LQJLEHU RI¿FLQDOH

10.

Tribulus terrestris

11.

Withania somnifera

12.

Pueraria tuberosa

13.

Terminalia arjuna

14.

Centella asiatica

15.

Menthe arvensis marsh mint

16.

Foeniculum vulgare

17.

Andrographis paniculate

18.

Cichorium intybus

19.

Myrtus caryophyllus

20.

Cuminum cyminum

21.

Aloe indica

Dosage: For human use 3 g at night or as directed by the physician with half tea spoon of water.

Pharma Bio World

marketing initiative a muscarinic analogue) was added to the bath to assess 1. Aorta with endothelial layer 06 endothelium integrity. 2. Aorta without endothelial layer 06 • The relaxant effect of Hypercum on 10-4 M Phenylephrine pre-contracted Dosage: For human use 3 g at night or as directed by the physician with half tea spoon of water. aortic rings was examined. When activation, alterations of the reninconcentrations( 1mg, 2mg, 3mg/ml ). contraction had reached a steadyangiotensin system, and an increase in • The effect of Hypercum was evaluated state after about 10 min (considered oxidative stress markers. It has been as the percentage of relaxation of the as 100%, and was defined as control), suggested that superoxide production is Phenylephrine induced contraction. Hypercum was added at different raised and suppressed NO availability concentrations( 1mg, 2mg, 3mg/ml ). leads to endothelial dysfunction and Aorta without endothelial layer: Testing • The effect of Hypercum was evaluated finally hypertension (Belmokhtar et al., on denuded aorta. as the percentage of relaxation of the 2009; Pakdeecho et al., 2011). Phenylephrine induced contraction. • The endothelium was removed Methodology mechanically by gently rubbing the Statistical analysis lumen of the artery with plastic tubing. All drugs and chemicals used for the • The absence of CCh-induced Results are expressed as the percentage experiment were obtained from Sigma relaxation indicated that the vessel reduction in aortic ring tension from laboratory and Nice chemicals. was successfully denuded. phenylephrine precontracted aorta. • Rats will be anaesthetized and • The aortic rings was stabilized with a the thoracic aorta was removed near maximal contraction induced by Results and placed in Krebs–Henseleit 10-4 M Phenylephrine in normal KHS. solution (KHS). • When the steady contraction was Aorta with endothelial layer: In the present • An aortic ring of about 2–3 mm in reached, 1 μ M carbachol (CCh: study to asses direct vasorelaxant effect, length was suspended between two stainless steel hooks in 20ml waterTreatment Concentration Tension (grams) % Response jacketed bath containing KHS Phenylephrine 0.1μmr 0.714±0.070 ---• The tissue bath solution was Carbachol 1 μM 0.022±0.011 96.91 maintained at 37ºC and gassed with SHC-649 1mg/ml 0.650±0.675 3.97 95% O2, 5% CO2 (pH 7.4). The SHC-649 2mg/ml 0.615±.0662 9.77 isometric contraction was recorded via a force- displacement transducer SHC-649 3mg/ml 0.021±0.010 99.50 (AD instrument) Table-1.Relaxant effect of carbachol (CCh, 1 µM) and SHC-649 on aortic rings pre-contracted Sl. No

Experiment details

Animals used

by Phenylephrine (Phe,10-4 M) with endothelium.

Aorta with endothelial layer: The aortic rings was stabilized with a near maximal contraction induced by 10-4 M Phenylephrine in normal KHS. • When the steady contraction was reached, 1 μ M carbachol (CCh: a muscarinic analogue) was added to the bath to assess endothelium integrity. • The relaxant effect of Hypercum on 10-4 M Phenylephrine pre-contracted aortic rings was examined. When contraction had reached a steadystate after about 10 min (considered as 100%, and was defined as control), Hypercum was added at different 76 July 2014

Fig-1: % Relaxantion of SHC-649 on rat aortic rings pre-contracted by Phenylephrine (Phe, 10-4M) with endothelium

Pharma Bio World

marketing initiative

Fig-2: Graph of Relaxant effect of carbachol (CCh, 1 ÎźM) and SHC-649 on aortic rings pre-contracted by Phenylephrine (Phe,10-4 M) with endothelium.

rats isolated thoracic aorta with intact HQGRWKHOLXP ZDV SUHFRQWUDFWHG ZLWK VLQJOH FRQFHQWUDWLRQ RI 3KHQ\OHSKULQH 3KH 0 $IWHU HTXLOLEUDWLRQ WKH SUHVHQFH RI D IXQFWLRQDO HQGRWKHOLXP ZDV DVVHVVHG RQ WKH EDVLV RI UHOD[DWLRQ HYRNHG E\ WKH HQGRWKHOLXP Âą GHSHQGHQW GLODWRU FDUEDFKRO Č?0 LQ DRUWD ULQJV precontracted with phenylephrine (10 0 &DUEDFKRO RQ LQWDFW HQGRWKHOLXP DRUWD LQGXFHG UHOD[DWLRQ RQ WKH phenylephrine-induced contracted aorta. +\SHUFXP DW PJ PO PJ PO DQG PJ PO RQ LQWDFW HQGRWKHOLXP DRUWD LQGXFHG DQG UHOD[DWLRQ respectively on phenylephrine-induced precontracted aorta. Results are shown LQ WDEOH )LJXUH DQG Aorta without endothelial layer: Rats isolated thoracic aorta without or denuded HQGRWKHOLXP ZDV SUHFRQWUDFWHG ZLWK VLQJOH FRQFHQWUDWLRQ RI 3KHQ\OHSKULQH 3KH 0 $IWHU HTXLOLEUDWLRQ WKH SUHVHQFH RI D IXQFWLRQDO HQGRWKHOLXP Treatment

Concentration

Phenylephrine

Č?PU

Fig-3 % Relaxation effect of SHC-649 on rat aortic rings pre-contracted by Phenylephrine (Phe, 10-4M) without endothelium.

ZDV DVVHVVHG RQ WKH EDVLV RI UHOD[DWLRQ HYRNHG E\ WKH HQGRWKHOLXP Âą GHSHQGHQW GLODWRU FDUEDFKRO Č?0 LQ DRUWD ULQJV SUHFRQWUDFWHG ZLWK SKHQ\OHSKULQH 0 &DUEDFKRO RQ ZLWKRXW HQGRWKHOLXP DRUWD GLG QRW LQGXFHG DQ\ UHOD[DWLRQ RQ WKH SKHQ\OHSKULQH LQGXFHG contracted aorta. +\SHUFXP DW PJ PO PJ PO DQG PJ PO RQ GHQXGHG HQGRWKHOLXP DRUWD Fig-4. Graph of Relaxant effect of SHC-649 induced 2.82%, 35.27% and 98.76 % on aortic rings pre-contracted by Phenylephrine (Phe,10-4 M) without endothelium. UHOD[DWLRQ UHVSHFWLYHO\ RQ SKHQ\OHSKULQH induced precontracted aorta. Results are References VKRZQ LQ WDEOH )LJXUH DQG $OO WKH PHQWLRQHG FRQFHQWUDWLRQV DUH WKH 1) August, P. 2004. Overview: mechanisms of ILQDO FRQFHQWUDWLRQV SUHVHQW ZLWKLQ WKH hypertension:cells, hormones, and the kidney. tissue bath. J American Society of Nephrology 15: 1971Conclusion +<3(5&80 KDV SRWHQW YDVRGLDODWRU\ property. Tension (grams) 0.567Âą0.046

% Response ----

Carbachol

Č?0

Nil

SHC-649

PJ PO

0.551Âą0.044

2.821

SHC-649

PJ PO

0.367Âą0.047

35.27

SHC-649

PJ PO

0.007Âą0.001

98.765

Table-2 Relaxant effect of SHC-649 on aortic rings pre-contracted by Phenylephrine (Phe,10-4 M) without endothelium.

78 eJuly 2014

1973. 2) Belmokhtar M,et al., Antihypertensive and endothelium-dependent vasodilator effects of aqueous extract of Cistus ladaniferus. Biochemical and Biophysical Research Communications 389; 2009:145â&#x20AC;&#x201C;149. 3) Monassier L, Combe R, Fertak LE. Mouse models of hypertension. Drug 4) Pakdeechot P,et al,. Mentha cordifolia extract inhibits the development of hypertension in L-NAME-induced hypertensive rats. Journal of Medicinal Plants Research Vol. 5(7), pp. 11751183, 4 April, 2011. 5) World Health Organization and International Society of Hypertension 2012. Pharma Bio World

False-positive identification becomes easy in Microbial Sampling • False-Positive Identification : Reduces investigation costs through the use of the BioCapt’s radial slit design. The inlets of the Impactor Head are precision cut to ensure laminar flow, thus maximizing collection and biological efficiencies in accordance with ISO 14698-1. • Makes the Job Easier : The MiniCapt Mobile Microbial Air Sampler simplifies the job of microbial air sampling by applying modern data management capabilities that save time and reduce operator error in air sampling data. The sampler incorporates a capacitive touchscreen, allowing easy use with gloves without the need for a stylus. • Reduced Errors : Intuitive user interface that is icondriven with multiple levels of security and allow the use of pre-configured recipes to avoid possible sampling errors. • Does Not Contaminate : Cleanroom does not get contaminated through the use of a unique HEPAfiltered exhaust. The autoclavable BioCapt® Microbial Impactor and sanitizable enclosure are ideally suited for aseptic environments.

MiniCapt®

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For further information, please contact us:

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marketing initiative

Use of High Efficiency Mist Cooling System as a Superior Alternative to Conventional Cooling Towers

ater Cooling has played an important role in all types of Process industries & Power Plants since its inception. Efficiency of a Process industry largely depends on availability of designed cold water temperature through-out the year, but mainly in summer & monsoon. During these months when humidity is high, cooling tower fails to achieve desired cold water temperature which results in lower efficiency of plant. Now it is time’s need to find new solution to get desired cold water temperature throughout year.

The ultimate Mist creation technology is the best alternative to conventional cooling towers. This advanced mist creation system can achieve an approach of 1 to 2 0C to WBT as against 5 to 6 0C approach for conventional cooling tower. Hence guaranteed cold water temperature of around 30 0C could be obtained throughout the year in our tropical climate. Also the spraying head is equivalent to the height of cooling towers thus requiring same pumping power. As mist creation system does not require fans for cooling it saves huge amount of power. Also, as there are no moving parts involved in Mist creation system the maintenance cost is negligible and system runs trouble free. This article will review basic type of cooling systems utilized in process/power plants and other industries. It will also explain why new mist creation system is superior than conventional cooling towers. In Process / Chemical Plants, product vapour generated in the process is condensed in a Heat exchanger and is recovered back. The condensation of steam / Vapour requires a cooling medium. In early days 80 eJuly 2014

Open Pond Design

this was achieved by using water from a river, a pond or seawater. The cold water is pumped through a heat exchanger and the warm water is discharged back to the water source. This is called ONCE THROUGH cooling system. A once through system is an open loop system. The necessity to reduce the huge amount of water gave birth to the idea of closed loop system. Thus the WET COOLING system came into effect.

Louver Type MCS

mechanical draft cooling towers, where the air flow is accomplished by fans.

In a wet cooling system, water is circulated to condense the steam in the same type of heat exchanger that is used in the once The Principle cooling device used in an through cooling. The warm water, instead Induced /forced draft cooling tower are of being returned to the water source, is Fans which run at the top of Cooling Tower cooled in a cooling tower using air as the (CT). Air enters through side louvers and cooling medium. Only the water carried escapes from the top. Water enters at the away due to evaporation, drift and blow- top and trickles down while getting cooled down needs to be replenished by make-up by air draft. water. Thus requirement of water quantity A correctly designed induced draft CT is vastly reduced. can give an approach of 4 to 6°C to wet bulb temperature with a temp. drop of Wet Cooling Systems 10°C. Even a very highly efficient CT can not give an approach less than 4°C to 1) Wet Cooling Tower System WBT. Moreover, if ambient temperature We will first consider the Wet Cooling or humidity levels rise, efficiency of Tower System. The wet cooling tower system is based on the principle of CT reduces. evaporation. The heated water coming out of the surface condenser is cooled Let’s consider this through in example as it flows through a cooling tower, : For a Chemical Plant , an induced draft where air is forced through the tower by cooling tower is designed to maintain either mechanical or natural draft.Now a Cold water temperature of 32°C at a days, mostly, all wet cooling towers are WBT of 28°C with an approach of 4°C. Pharma Bio World

marketing initiative

GRAPH A & B: Results from a chemical unit in Andhra Pradesh.

Cooling Tower performs as desired during winter, early summer months. But during peak summer / Monsoon , efficiency of cooling tower reduces as humidity rises & its approach to WBT reaches beyond 6°C from design 4°C. Thus due to this rise in Cold Water temperature, these industries always experience loss in production by at least 5 to 7%. These losses do not occur in winter months. This means that the plant will operate at a reduced efficiency for almost 5 to 6 months in a year. (Kindly refer graph A&B) Also due to use of Fans, CT consumes a lot of power. It is observed that the efficiency of CT reduces over a period of time due to ware and tear of moving parts, Fills, Fins etc. which invites heavy maintenance. Hence there is an urgent demand from the industry for a water-cooling system, which will operate with high efficiency even in adverse climatic conditions and maintain cold water temperature in closed vicinity to WBT. 2) Mist Cooling System MREPL has come out with a solution by designing MIST COOLING SYSTEM which is a high efficiency system, which 82 eJuly 2014

ensures an approach of 1°C to prevailing wet bulb temperature with a Temp. drop of 12 to 15°C even in adverse climatic conditions. In tropical conditions, worst wet bulb temperature even at coastal applications is maximum 30.5°C. Hence MCS will always maintain Cold Water of around 31°C±1°C throughout the year. No other cooling system can operate with such efficiency and it makes cooling tower/ spray pond systems obsolete. Salient Features System

Mist

Cooling

1) Cold Water Temperature: Mist Cooling System ensures an approach of 1°C to WBT with a temperature drop of 12°C to 15°C. 2) Energy Savings (Please refer diagrams Plan A & B): Due to increase in ǻ7, water quantity required at the process side is much less. MCS requires water pressure equivalent to the height of cooling tower as shown in the following diagrams. Hence, considerable amount of energy is saved on circulation water pumping. Also, MCS does not require any fans for cooling. Thus, a huge amount of energy is saved on circulation and cooling.

3) Process Benefits: Mist Cooling System will supply cold water at a temperature very close to WBT (Approach of 2°C) as against an approach of 6 to 7°C in cooling tower. This will reduce the product vapour losses in shell & tube heat exchangers. This will ensure that your plant operates at an enhanced yield in summer and monsoon also. This also means that your plant can operate at its FULL LOAD throughout the year. 4) Maintenance: MCS has no moving parts. Also the material used in the mist cooling system is special grade saran polymer, a highly non-corrosive material having a life of more than 20-25 years. This makes MCS absolutely maintenance free. As against this, cooling towers require a heavy maintenance in form of replacement of louvers, fan blades, clamps etc. every year. 5) Chokeless Design: MCS operates with a chokeless design. Size of smallest opening in MCS is more than one inch (25 MM) in diameter. Hence chances of particles choking the system are minimum. 6)Various Designs of MCS to Suit Site Conditions: A) Open Pond Mcs: Here, MCS ensures Pharma Bio World

marketing initiative reduces the plot size by 60% of open pond design. MCS ensures an approach RI & WR :%7 ZLWK D ǻ7 RI WR & Drift loss comes down to 0.002% and also space requirement reduces considerably. C) Table Top Design To Prevent Algae Formation: Latest table top design of MCS pond does not allow formation of water level inside the pond and all water passes to suction pit which is covered from top thus minimizing chances of algae formation. D) MCS Design For Working In Dusty Environment: Unique suction pit design does not allow dust to pass to the inlet of circulation pumps. Dust is drained from drain valve while only clear water passes to circulation water pumps.

Circulation Water Cycle in Cooling Tower Plan A

7) System Flexibility (Capacity Turn Down Ratio): We offer MCS with individual line isolation valve. MCS is the only system, which gives you such a high flexibility in operation.

Circulation Water Cycle in MCS Plan B

Advantages of MCS over Cooling Towers Description

MCS

Approach to WBT

4 to 6 C

1 to 2 C

Temperature Drop

8 to 10 C

12 to 150C

Circulation Water Quantity

1.2 times MCS

80% of CT

Power Consumption

Requires Fans which consume power.

Nil (No fans required)

Equipment + Civil Cost

125% Higher than MCS

80% of CT

Maintenance Cost

High

Very low-Practically Nil

Drift & Evaporation Losses

Same

Area

Less

More (2 to 5 times CT area depending on Capacity)

COMPARISON TABLE OF MCS & COOLING TOWER SYSTEMS Note: As capacity (Flow, M3/Hr) through MCS increases, ratio of area required between MCS and CT reduces.

DQ DSSURDFK RI & WR :%7 ZLWK D ǻ7 RI 12 to 15°C. Water loss due to drift is 0.1 to 0.25% depending on wind load. 84 eJuly 2014

B) Louver Type Mcs: Here MCS pond is closed from sides, up to a height of 6 mtrs. by louver type cover sheeting. This

8) Make-Up Water Requirement: Due to latest Louver Type design, drift loss through MCS is reduced to 0.002% while maintaining an approach of around 2°C to wet bulb temperature. Hence, Overall make-up water quantity required is approximately same as compared to cooling towers. 9) The Pay Back Period of the MCS will be Less Than One Year Only. The author is Mr Makarand A Chitale, Director (Technical), Mist Ressonance Engineering Pvt Ltd. Contact Details : Mist Ressonance Engineering Pvt Ltd. ‘Anandi’ 1304-1/7 Shukrawar Peth Bajirao Road, Pune- 411 002 Tel : 020-24472726/24471184 Email : mistcool@vsnl.com mistcreation@gmail.com Website: www.mistcreation.com Pharma Bio World

marketing initiative

Company Profile: Joyam Engineers & Consultants Pvt Ltd

OYAM is a group of company manufacturing various vacuum related products and now it is the only company in India manufacturing entire range of Vacuum Products.

Mr. Anil Mankad , the Director of JOYAM Engineer & Consultants has worked in the field of vacuum technology for more than 25 years , and also has a solid technical background from one of the pioneers in India in vacuum products manufacturing company SLM Maneklal (Sulzer Brothers) for more than 15 years.

Due to this, JOYAM products are performing so well that most of the leading companies in the related field and consultants are offering preference to JOYAM products. Also in a span of last 15 years, JOYAM has done lost of research and development for the improvement of products to save on power and energy like saving in water quantity and pressure. All this is done without any collaboration and technical assistance but with expertise in the vacuum products technology and past experience and with the guidance and assistance of their valued customers. All JOYAM vacuum products are designed as per Indian ambient condition, and hence they perform their best without any problems for long time with entire satisfaction to end –users

1) JOYAM started its operation by manufacturing the spares for the SLM Maneklal make Vacuum Pump and also repairing and maintaining the The product range of JOYAM includes: imported pumps of companies like SIHI, NASH & SIEMENS. JOYAM started 1) Single Stage Water-Ring Vacuum Pumps developing the Single Stage Liquid (Lr Series) :Our Single stage water-ring Ring Vacuum Pump both Mono – Block vacuum pump, develop maximum vacuum & Coupled ranging from 1 Hp to 50 Hp. up to 710 mm of hg and capacity ranges Now JOYAM is developing the Single from 25 m3/hr to 2500 m 3/hr are very widely Stage Liquid Ring Vacuum Pump up to used in various application and its design is based on most proven SLM design. 100 Hp. 2) After gaining the experience from this activities, JOYAM ventured into the development of Two Stage Liquid Ring Vacuum Pump, which are more efficient machine, Now the company is manufacturing Two Stage Liquid Ring Vacuum Pump up to 50 Hp, The machines are running successfully 3) JOYAM is manufacturing the Mechanical Vacuum Booster system, a combination of Roots Blower and Water ring Vacuum Pump or Oil – seal Vacuum Pump as per the requirement. This is why all the vacuum products manufactured by JOYAM are with complete technical expertise and also with knowledge of Process Industry, where Vacuum Pump or System is a heart of the process. 88 eJuly 2014

2) Two Stage Water-Ring Vacuum Pumps (Ts Series): Similarly, now our Two stage water-ring vacuum pumps are of better design, having advantage of higher capacity at high vacuum and its also consume lower quantity of water at low pressure. As our design is based on a latest technology, it is getting more popular. Two –stage Vacuum Pump develop maximum vacuum of 720 mm of Hg. and capacity ranges from 80 m 3/ hr to 1500 m 3/hr. 3) Low Vacuum Water-Ring Vacuum Pump (Lrv Series: LOW Vacuum Water-Ring Vacuum Pumps work with double suction and double discharge, They develop high capacity at low vacuum. They develop maximum vacuum of 680 mm of hg* and capacity ranges from 90 m3/hr to 1300 m3/hr. 4)Monoblock Vacuum Pump (Mv Series): Mono –Block Vacuum Pumps are compact,

easy to assemble, easy to install and simple design with smooth operation. They develop Maximum Vacuum of 680 and 700 mm of hg* and capacity varies from 14 m3/ hr to 330 m 3/hr. 5)Oil Sealed High Vacuum Pump (Lm Series): Oil Sealed High Vacuum Pumps develop maximum vacuum up to 0.05 mm of hg. in single stage pump and 0.005 mm of hg. in two stage pumps and capacity ranges from 3 m3/hr. 6)Twin Lobe Rotary Blower & Mechanical Booster System: Twin Lobe Rotary Blower, having capacity of 10 m 3/hr to 22,000 m 3/ hr and developing pressure from 100 mbar to 1000 mbar. These twin lobe blowers are also converted into a booster system, a combination of watering vacuum pumps or with oil sealed high vacuum pump vacuum ranges from 5 mm to 0.005 mm hg. 7) Steam Jet Ejector Systems: Apart from manufacturing of various vacuum pumps, we are the leading supplier of steam jet ejector systems, combination with –ring vacuum pump and our new designed multistage multi-nozzle ejector systems are getting more popular this days as it consume less steam quantity, we can offer a suitable system as per the customer requirement . 8) Dry Screw Vacuum Pumps: We have tied up with Twain firm and have started our Research and development for the Dry screw vacuum pump, it would be shortly introduce with all new range . New Product Addition New Product Shortly Induce Within Couple of Months. Joyam has got expertise in the field of vacuum technology and hence can solve all the vacuum related problems and can size indigenous vacuum pump or system to match vacuum and process for better yield. Pharma Bio World

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press release Merck Millipore Opens First-of-its-kind Kiran Mazumdar-Shaw Awarded the Solid Dose Formulation Lab in India ‘2014 Global Economy Prize’ Merck Millipore (India), the life sciences tools division of Merck KGaA of Darmstadt, Germany, launched its new Process Solutions Formulation Lab in India, its first outside of Europe. The Lab, which is part of a larger laboratory complex, is strategically located at Nerul, Navi Mumbai, with easy accessibility from the major pharmaceutical manufacturing centers at Ahmedabad, Goa and Hyderabad. The facilities at the lab are built to provide services and application assistance to the pharmaceutical industry for classical pharmaceutical clients working on solid dose formulations. The objective of setting up the Lab is primarily to assist clients, using advanced excipients from the Merck Millipore portfolio, with preformulation studies. Additionally, it will offer the possibility of inviting clients for hands-on training sessions and demonstrations of new technologies in Solid Dose Formulation. The Formulation Lab is expected to engage in a continuous exchange of technologies and experts from Merck Millipore sites across the world to bring the latest developments in excipients and technology to formulation scientists in India.

Pharma EXPO Serves Growing Medical Device Industry The global medical device industry has grown significantly over the last five years, and it is projected to reach approximately $302 billion by 2017 with a compound annual growth rate (CAGR) of 6.1 percent (2011-2017) (Global Medical Device Industry 2012-2017, Lucintel). To serve this growing industry,Pharma EXPO 2014 (Nov. 2-5; McCormick Place, Chicago), co-located with PACK EXPO International, will provide solutions medical device manufacturers can use to enhance efficiency, speed and time to market, and to ensure regulatory compliance.

Kiran MazumdarShaw, CMD Biocon

Kiran Mazumdar-Shaw, Chairperson and Managing Director of Biocon Ltd, Asia’s leading Biopharmaceutical Company, has been awarded the Kiel Institute’s most coveted ‘2014 Global Economy Prize’ for Business during the 100th anniversary celebrations of the Institute held in Kiel, Germany on Sunday, June 22.

The Kiel Institute for the World Economy is an international center for research in global economic affairs, economic policy consulting and economic education. This prestigious award, established in 2005 by the Kiel Institute, is bestowed upon individuals who have been pioneers in finding solutions to global economic problems by strongly influencing and implementing economic or trade systems based on individual initiative and responsibility. Mazumdar-Shaw is the first Indian woman and the fourth Indian to be conferred this prize. Previous honorees include Amartya Sen, Nobel laureate in Economics (2007); Baba N Kalyani, Chairman of the Kalyani Group (2009); and Sunil Bharti Mittal, Chairman of the Bharti Group (2009).

New Entrants to Spur Chronic Lymphocytic Leukemia Treatment Market The introduction of several new drugs will accelerate growth in the Chronic Lymphocytic Leukemia (CLL) treatment market, from USD 1.4 billion in 2013 to USD 3.3 billion by 2018 across six major markets (6MM: the US, France, Germany, Italy, Spain and the UK), according to a new report from research and consulting firm GlobalData.

Pharma EXPO, produced by PMMI, The Association for Packaging and Processing Technologies, in collaboration with the International Society for Pharmaceutical Engineering (ISPE), will draw more than 2,000 exhibitors and over 50,000 attendees. Sideby-side, the events will be the largest resource for processing and packaging innovation in North America this year.

The company’s latest report states that this impressive revenue increase, at a Compound Annual Growth Rate (CAGR) of 18.8 per cent, will occur as numerous premium-priced therapies for CLL patients with high unmet needs are set to enter the market during the forecast period.

Along with being the largest resource for pharmaceutical processing and packaging technologies, Pharma EXPO will serve as a destination for comprehensive educational programming and a cross-pollination of ideas between the pharmaceutical and other manufacturing industries.

GlobalData forecasts that Imbruvica and idelalisib, set for launch in the US and EU in 2014, will have total combined sales of USD 2 billion in 2018, thus capturing more than 60 per cent of the total CLL market by the end of the forecast period.

90 eJuly 2014

Pharma Bio World

press release India to Emerge as Global Hub for CPC Launches AseptiQuik Connectors Biotech Research: Dr K Vijay Raghavan for Indiaâ&#x20AC;&#x2122;s Biopharmaceutical Industry India through its Department of Biotechnology of the Ministry of Science and Technology reiterated its commitment and focus on Biotechnology sector and provided glimpses of its blueprint of vision 2025 at BIO 2014 held in San Diego. Dr K Vijay Raghavan, Secretary, Department of Biotechnology led a strong 75 member delegation to the convention representing members from various private and public sector companies along with key government departments. Commenting during the convention, Dr K Vijay Raghavan said, â&#x20AC;&#x153;India with its research capabilities and scientific community is well positioned to take the next step in its journey towards emerging as the global hub for biotech research and business excellence and Indian government is committed to provide all necessary support.â&#x20AC;? He further added, â&#x20AC;&#x153;Indian biotech sector industry has been averaging an above average growth of 20 per cent for the past decade but wants to step it up to 30 per cent per annum to ensure that the sector reaches its target of ` 100 Billion in revenue by 2025 and the same can be achieved through partnerships and focus on research.â&#x20AC;?

Cresset Introduces Forge V10.3 Cresset, innovative provider of computational chemistry software and services, announces the release of Forge V10.3. This major new release includes significant enhancements to the science, visualization, and integration of Forge, the computational workbench for ligand-based drug design, including significant enhancements to Activity Miner. â&#x20AC;&#x153;Activity Miner has been a huge hit since its release as part of Forge last year,â&#x20AC;? says Dr Tim Cheeseright, Director of Products at Cresset. â&#x20AC;&#x153;Customers have found it invaluable for finding and understanding critical activity cliffs in the SAR landscape. In response to customer requests we have now added selectivity cliffs â&#x20AC;&#x201C; the use of multiple activity parameters to look for changes that disproportionately change one activity relative to another.â&#x20AC;? â&#x20AC;&#x153;Even though independent tests show that our performance is one of the best, we have still made improvements,â&#x20AC;? says Dr Mark Mackey, CSO at Cresset. â&#x20AC;&#x153;Forge V10.3 includes improved conformation hunt settings that give significantly fewer, lower energy conformations, enabling you to find the correct alignments even more reliably.â&#x20AC;? 92 eJuly 2014

CPC (Colder Products Company), the leader in connections solutions, has announced the availability in India of the companyâ&#x20AC;&#x2122;s line of solutions for biopharmaceutical manufacturers seeking a robust sterile connector for single-use processing. AseptiQuik Connectors are a reliable, easy-to-use solution and the connectorâ&#x20AC;&#x2122;s intuitive â&#x20AC;&#x153;Click, Pull, Twistâ&#x20AC;? design reduces complexity and the risk of operator error. AseptiQuik Connectors deliver quick, easy and reliable connections for Indian manufacturers using single-use systems and enable sterile media transfer, even in non-sterile environments. The intuitive three-step process enables operators to quickly connect two single-use assemblies: an audible CLICK confirms the initial connection, PULL tabs allow simultaneous membrane removal and a simple TWIST of the integrated lock ring provides secure final assembly. Extensive validation testing completed on post gamma and autoclave sterilised connectors confirms that external organisms are prevented from entering the flow path before, during or after connection. Testing includes functional performance, biocompatibility and three types of microbial ingress tests. CPC has also unveiled its AseptiQuik S AseptiQuik X large-format connectors, biopharmaceutical manufacturers a full line connectors with flow configurations ranging 1-inch.

small-format and offering Indian of robust, sterile from 1/8 inch to

First Ever Dengue Vaccine Candidate to Show Efficacy Against Dengue Fever Sanofi Pasteur, the vaccines division of Sanofi, announced the publication in The Lancet of the detailed results of its first landmark phase III dengue vaccine efficacy study conducted in five countries in Asia. Results show overall efficacy against symptomatic dengue of 56.5 per cent in children aged 2 to 14 years old after a three-dose vaccination schedule. Importantly, DQDO\VHV VKRZ DQ Â&#x2021; SHU FHQW UHGXFWLRQ RI GHQJXH haemorrhagic fever, the severe form of dengue, according to the WHO criteria. The study also showed a clinically important reduction in the risk of hospitalisation due to dengue by 67 per cent during the study. The favorable vaccine safety profile observed during the 25 month follow up of the phase III study in Asia is consistent with the safety profile documented in other studies (phase I, II, IIb). Pharma Bio World

press release Avantor Introduces High-Purity Acid DSM Sinochem Bags Golden Peacock Line for Trace Metal Testing Environment Management Award 2014 Avantor Performance Materials, a global manufacturer of performance materials and chemicals, has launched a new grade of high-purity laboratory acids optimised for trace metal analysis and designed to meet the needs of customers in environmental, food, quality control and other testing applications. Marketed under the company’s renowned J T Baker brand, the new BAKER INSTRA-ANALYZED Plus acids product line features a selection of widely used acids specially formulated to enable more accurate trace metal analysis in the very low parts per billion (ppb) range (most from 0.1-1ppb). BAKER INSTRA-ANALYZED Plus acids offer customers upgraded capability from Avantor’s popular BAKER INSTRA-ANALYZED acid line products, which have been trusted in laboratory testing for over 25 years. The new line of high-purity acids is produced under strict protocols, quality tested for up to 64 key trace metals such as iron and lead to ensure purity, and packaged in environmentally friendly recyclable HDPE bottles. With its new BAKER INSTRA-ANALYZED Plus acids and other existing BAKER INSTRA-ANALYZED, ULTREX II, and BAKER ANALYZED ACS grade acids, Avantor offers customers a complete solution for trace metal analysis across many laboratory applications.

BMS India Appoints New Country Head

DSM Sinochem Pharmaceuticals’ Toansa facility has been awarded the “Special Recommendation” Golden Peacock Environment Management Award 2014 for its contribution and efforts towards green chemistry and environmental compliance by the Institute of Directors at a gala awards evening in Delhi. The plant is located in Toansa, Punjab, India. The Golden Peacock Awards were introduced by the Institute of Directors India in 1991 and are now regarded as a benchmark of corporate excellence. The award was declared by the Awards Jury under the Chairmanship of Justice P N Bhagwati, former Chief Justice of India and Co-Chairmanship of Justice (Dr) Arijit Pasayat, former Judge, Supreme Court of India & former Chairman, Competition Appellate Tribunal of India & Authority for Advance Ruling (Customs, Central Excise & Service Tax). Lt Gen J S Ahluwalia, PVSM (retd), President, Institute of Directors, Rana Kapoor, Chairman & Managing Director, Yes Bank and S Chakraborty, Chief Executive, Innovative Financial Advisors were present during the award ceremony to present the awards together with Atul Chaturvedi, IAS, Chairman, Public Enterprises Selection Board.

Bristol-Myers Squibb India Pvt Ltd has announced that Jitendra Tyagi has been appointed BMS India country head effective July 22, 2014. He will report to Michael Norman, General Manager – Middle East, Africa and India.

Innovative Pre-filled Pen Injector for Adults with Type 2 Diabetes

Jitendra Tyagi has successfully performed diverse commercial roles at BMS India in the past few years. He is known for his ability to think strategically, resolve complex business challenges and connect and collaborate.”

An innovative technology promises to improve treatment for diabetes patients. Product design and development firm Cambridge Consultants has worked with AstraZeneca to develop BYDUREON Pen (exenatide extended-release for injectable suspension) 2 mg – which received US Food and Drug Administration (FDA) approval in February.

Jitendra Tyagi brings a broad range of experience to his role. He joined BMS in 2010 as Director- MRCEI. In the last few years he performed diverse commercial roles in India such as Business Unit Head, Market Research, Market Access, Key Accounts, Business Excellence and Patient Support Programme. He was the Project Leader who ensured a smooth transition of the diabetes business as well as employees to Astra Zeneca India. In his most recent role in BMS, he led the Critical Care and Cardiovascular Business Unit, where he also managed efficiently the alliance with Pfizer. 94 eJuly 2014

BYDUREON is the first once-weekly medicine as an adjunct to diet and exercise to improve glycaemic control in adults with type 2 diabetes. The BYDUREON Pen is a pre-filled, single-use pen injector – eliminating the need for the patient to transfer the medication between a vial and syringe during the self-injection process. The exenatide microspheres and diluent are housed in separate chambers within the pen device and only mixed at the time of injection. Pharma Bio World

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press release Wacker Honors Researchers for Producing Complex Proteins Wacker Chemie AG has presented the “Alexander Wacker Innovation Award” to Dr Tobias Daßler, Dr Carsten Bornhövd and Dr Günter Wich for their pioneering work on WACKER’s proprietary ESETEC secretion system. The researchers were honored for their fundamental analysis of the Ecoli-based production system for pharmaceutical proteins and for making enhancements which enable even highly complex molecules such as antibody fragments to be produced cost-effectively and efficiently. This year’s €10,000 innovation award focused on basic research. Developed and patented by WACKER, the ESETEC secretion sys-tem affords a way of producing pharmaceutical proteins cost-effectively and efficiently inside microbes. The prizewinning team conducted a detailed analysis of the Escherichia coli-based technology and developed new cell lines by making selected genetic modifications. As a result, antibody fragments can now be produced in high yields and be secreted into the culture medium in active form.

West Pharmaceutical Expands Presence in Asia West Pharmaceutical Services, Inc has dedicated its manufacturing plant in the Sri City Special Economic Zone (SEZ), where the company will expand its growing primary packaging for injectable medicines business. “West is experiencing a very exciting period of growth and business expansion in Asia and we are proud to open our first facility in India,” said Donald E. Morel, Jr., West’s Chairman and Chief Executive Officer. “With more and more pharmaceutical customers establishing operations in India, our new plant will help West meet market demand and further establishes the company’s presence in this growing and dynamic market. “On behalf of West’s Board of Directors, I would like to thank the many representatives of the Indian government for their support throughout the planning process. This new facility in Sri City will allow West to continue to satisfy the needs of our customers, who are serving a growing number of patients in India and the Asia Pacific region.” In June 2012, West signed a 99-year lease on 72,800 square meters (approximately 783,600 square feet) of land in Sri City. 96 eJuly 2014

Sri City offers the advantages of a metropolitan location and was selected primarily on the suitability of land, availability of utilities, labor suitability, logistics and quality of life.

Password-Protected FTP Access Management from B&R All B&R controllers have an FTP server on board as a standard feature. A protection mechanism with integrated user name and password management now makes accessing this server even more secure – without sacrificing ease of operation. Whether it’s to perform maintenance, supply a machine with new recipes or load a new function module, direct access to the controller is becoming increasingly important throughout the entire life cycle of production equipment. Developers of automation applications must maintain a high level of security when preparing the functions involved, while also ensuring that they are simple to learn and easy to operate. B&R draws on methods that have proven themselves in the realm of IT to help machine and system developers implement access security. User authentication is managed with user names and passwords. Management of user data and assigned rights is integrated in Automation Studio. This data is stored on the runtime system in encrypted form to ensure seamless security. User management for FTP access to B&R systems allows an unlimited number of users to be assigned access rights. At runtime, up to eight different users can access the controller at the same time via FTP.

New Software Updates for Avacta’s Optim Instruments Avacta Analytical has released a number of software updates for its innovative Optim series of biophysical characterisation instruments. Designed to reduce the time and cost of therapeutic protein preformulation studies, the compact and robust Optim instruments can probe multiple protein stability indicating parameters at high speed using ultra-low sample volumes. The latest software updates have been developed to streamline this process, offering faster, more flexible operation and analysis. Optim Client v2.1 instrument control software offers a number of exciting new features to simplify and accelerate research workflows, increasing measurement flexibility and allowing users to define custom experimental parameters. Pharma Bio World

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pharma news Cipla to Expand Global Footprint

Actavis Buys Furiex Pharmaceuticals

Cipla Limited, a global healthcare company, has announced in collaboration with the UK Government, its intention to make investments of up to 100 million pound in its UK subsidiary over the next few years.

Actavis plc announced that its subsidiary Forest Laboratories, LLC has successfully completed its acquisition of Furiex Pharmaceuticals, Inc in an all-cash transaction valued at approximately USD 1.1 billion, and up to approximately USD 360 million in a Contingent Value Right (CVR) that may be payable based on the status of eluxadoline, Furiex’s lead product, as a controlled drug following approval.

Said The Right Honourable George Osborne, Chancellor of the Exchequer, Her Majesty’s Government of the United Kingdom: “I am happy to be able to announce that Indian pharmaceutical company Cipla will invest up to £100 million in the UK. The investment will fund the launch of a range of drugs in the areas of respiratory, oncology and antiretroviral medicines as well as research and development, clinical trials and further expansion internationally and in the UK. Cipla is one this decision attractiveness in Cipla’s long

of India’s leading pharmaceutical firms and shows the UK’s international strength and in this sector as well as its growing importance term strategy” said the Chancellor.

AcelRx and Grünenthal Seek EU Marketing Authorisation for ZALVISO AcelRx Pharmaceuticals, Inc and Grünenthal Group have announced that Grünenthal has submitted a Marketing Authorisation Application (MAA) to the European Medicines Authority for ZALVISO for the management of moderate to severe acute pain in adult patients in a medically supervised environment. ZALVISO is a drug-device combination product utilising the opioid agonist sufentanil formulated in a proprietary sublingual tablet formulation and delivered through a preprogrammed, non-invasive proprietary delivery device. AcelRx and Grünenthal entered into license and supply agreements for ZALVISO in the EU, Australia and certain other countries in December 2013. Under the terms of the license agreement, AcelRx will receive a cash payment of USD 5 million for the MAA submission. AcelRx is eligible to receive an additional USD15 million milestone payment upon the approval of the MAA. After approval by EMA, AcelRx is eligible to receive approximately USD 200 million in additional milestone payments, based upon successful regulatory and product development efforts and net sales target achievements. Grünenthal will also make tiered royalty, supply and trademark fee payments in the mid-teens up to the twenty percent range, on net sales of ZALVISO in the Grünenthal territory. 98 eJuly 2014

In connection with the close of the Furiex acquisition, Actavis further announced that it has closed the transaction related to the sale of Furiex’s royalties on alogliptin and Priligy to Royalty Pharma for approximately USD 415 million.

Glenmark Generics’ Telmisartan Tablet Gets Final ANDA Approval Glenmark Generics Inc, USA a subsidiary of Glenmark Generics Limited has been granted final abbreviated new drug approval (ANDA) from the United States Food and Drug Administration (US FDA) for Telmisartan Tablets. Glenmark will commence distribution of the product immediately. Telmisartan Tablets are Glenmark’s generic version of Boehringer Ingelheim’s Micardis. Telmisartan is indicated for the treatment of hypertension. The approval is for the 20mg, 40mg and 80mg tablets. For the 12 month period ending March 2014, Telmisartan garnered annual sales of USD 250 Million according to IMS Health.

Isis Gets USD 1 Million from GSK for Advancing ISIS-TTR Isis Pharmaceuticals, Inc has earned a USD 1 million milestone payment from GlaxoSmithKline (GSK) related to the advancement of the Phase 2/3 study of ISIS-TTR in patients with familial amyloid polyneuropathy (FAP). Including this milestone payment, Isis has generated USD 27 million in upfront and milestone payments for advancing ISIS-TTR. This USD 1 million milestone payment is the fifth of the nearly USD 58 million in milestone payments Isis is eligible to earn as the Phase 2/3 study progresses. In addition, if GSK elects to exercise its option to exclusively license the ISIS-TTR programme, Isis is eligible to receive a license fee, regulatory and sales milestone payments and double-digit royalties on sales of ISIS-TTR. Pharma Bio World

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pharma news The Cooper Companies to Acquire Sauflon Pharmaceuticals Ltd The Cooper Companies, Inc has entered into definitive agreements to acquire Sauflon Pharmaceuticals Ltd, a European manufacturer and distributor of soft contact lenses and solutions, in a transaction valued at approximately USD 1.2 billion. Sauflon forecasts revenue of approximately USD 210 million for its fiscal year ending October 31, 2014, up approximately 22 per cent year-over-year. The transaction is subject to regulatory approval and is anticipated to close prior to fiscal year end, October 31, 2014. Excluding one-time charges and deal-related amortisation, the transaction is expected to be accretive to earnings per share in fiscal 2015. The acquisition will be financed with off-shore cash and credit facilities.

GSK Submits EU Regulatory Application for RTS,S GSK has submitted a regulatory application to the European Medicines Agency (EMA) for its malaria vaccine candidate, RTS,S. The submission will follow the Article 58 procedure, which allows the EMA to assess the quality, safety and efficacy of a candidate vaccine, or medicine, manufactured in a European Union (EU) member state, for a disease recognised by the World Health Organization (WHO) as of major public health interest, but intended exclusively for use outside the EU. This assessment is done by the EMA in collaboration with the WHO, and requires products to meet the same standards as vaccines or medicines intended for use in the EU. Eligibility for the application was granted by the CHMP after agreement from WHO that RTS,S met criteria for such an evaluation. RTS,S is intended exclusively for use against the Plasmodium falciparum malaria parasite, which is most prevalent in subSaharan Africa (SSA). Around 90 per cent of estimated deaths from malaria occur in SSA, and 77 per cent of these are in children under the age of 5.

Diplomat to Market Zydelig Diplomat, the nation’s largest independent specialty pharmacy, announced today that it has been selected as a provider of Zydelig tablets. Zydelig was approved by the US Food and Drug 100 eJuly 2014

Administration on July 23, 2014 for the treatment of three B-cell blood cancers. Zydelig is indicated for the treatment of relapsed follicular B-Cell non-Hodgkin lymphoma (FL), small lymphocytic lymphoma, and in combination with rituximab for patients with relapsed chronic lymphocytic leukemia (CLL). Over 200,000 patients in the US are living with FL, SLL or CLL which are slow-growing incurable blood cancers that can lead to life-threatening complications such as anemia, serious infection and bone marrow failure.

Auxilium to Get USD10 Million from Asahi Kasei Auxilium Pharmaceuticals, Inc has announced that the company will receive a USD 10 million regulatory milestone payment from its partner Asahi Kasei Pharma Corporation (Asahi Kasei). The payment is due because of the successful submission of a regulatory application to the Japanese Pharmaceutical and Medical Device Agency (PMDA) for Xiaflex (collagenase clostridium histolyticum) for the treatment of Dupuytren’s contracture (DC) The review by PMDA is expected to be completed by mid-2015. Xiaflex is a biologic approved in the US, EU, Canada and Australia for the treatment of adult DC patients with a palpable cord and, in the US for the treatment of adult men with Peyronie’s disease (PD) with a palpable plaque and curvature deformity of at least 30 degrees at the start of therapy. Under the agreement, Asahi Kasei was granted the exclusive right to commercialise Xiaflex for the treatment of DC and PD in Japan upon receipt of applicable regulatory approvals.

Xellia Buys Fresenius Kabi’s Drug Plant Xellia Pharmaceuticals, a specialty pharmaceutical company focusing on providing important anti-infective treatments against serious and often life-threatening infections, has acquired Fresenius Kabi’s dedicated lyophilized (freeze-dried) vial manufacturing facility in Raleigh, North Carolina. The deal includes a continuous manufacturing and supply agreement with Fresenius Kabi USA. Financial details are not disclosed. The manufacturing site is located close to the world famous Research Triangle Parkand is Xellia’s first facility in the US, significantly expanding the Company’s manufacturing capacity for injectable pharmaceutical products. Xellia intends to retain all ~80 staff currently employed at the site and will continue to manufacture certain products at the site for Fresenius Kabi. In the future, Xellia plans to employ more staff as it expands the site further. Pharma Bio World

biotech news Eurofins Acquires ViraCor-IBT Laboratories Eurofins Scientific, the global leader in bio-analytical testing, and one of the world leaders in genomic services, announced the successful closing of the transaction to acquire 100 per cent of ViraCor-IBT Laboratories, Inc. (VIBT) following thorough review and approval from relevant regulatory bodies. As communicated on May 9, Eurofins signed an agreement to acquire VIBT for USD 255m in cash. VIBT is a premier esoteric reference laboratory serving 550 institutional clients and over 4,000 affiliated clinicians as well as 12 leading pharmaceutical companies across the US. The company is expected to generate revenues in excess of USD 80m and EBITDA of USD 25m for the calendar year 2014. Eurofins assumes no debt from the acquisition of VIBT. Furthermore, no site consolidations or restructuring costs are foreseen as a result of this acquisition. Based on VIBT’s historic and projected profitability, the transaction should be immediately margin accretive for Eurofins.

CMC Biologics, Portola Pharma Sign Supply Pact CMC Biologics, Inc, a global leader in process development and contract manufacturing, has entered in to a Commercial Supply Agreement with Portola Pharmaceuticals, a biopharmaceutical company for the development of andexanet alfa, a potential first-in class Factor Xa inhibitor antidote in phase 3 ANNEXA (Andexanet Alfa a Novel Antidote to the Anticoagulant Effects of fXA Inhibitors) studies. Andexanet alfa is designed to reverse the anticoagulation activity of Factor Xa inhibitor-treated patients who are experiencing a major bleeding episode or who require emergency surgery. Under this agreement, Portola will expand its manufacturing commitment at CMC Biologics to include commercial supply for a Biologics License Applications (BLA) filing, which is expected at the end of 2015, and initial product launch in the United States.

Genentech to Buy Seragon Pharma Genentech, a leading biotechnology company, has entered into a definitive agreement to acquire Seragon Pharmaceuticals, Inc. (Seragon), a privately held biotechnology company based in San Diego, California. With this acquisition, Genentech obtains rights to Seragon’s entire portfolio of investigational next-generation 102 eJuly 2014

oral selective estrogen receptor degraders (SERDs) for the potential treatment of hormone receptor-positive breast cancer. Under the terms of the agreement, Genentech will make an upfront cash payment of USD 725 million, plus additional contingent payments of up to USD 1 billion based on achievement of certain predetermined milestones. The closing of the transaction is subject to customary closing conditions, including clearance under the Hart-Scott-Rodino Antitrust Improvements Act. The transaction is expected to close in the third quarter of 2014. Once the transaction is completed, Seragon’s portfolio will be integrated into Genentech Research and Early Development.

OU Grants Kosher Certification to Pfizer Elelyso Pfizer Inc, announced that the Orthodox Union (OU) has granted kosher certification to Elelyso (taliglucerase alfa) for injection, an enzyme replacement therapy (ERT) for the long-term treatment of adults with a confirmed diagnosis of Type 1 Gaucher disease. Elelyso is the first prescription medication to be certified kosher by the OU, a milestone for the brand which was approved by the US Food and Drug Administration (US FDA) in May 2012. Elelyso is an FDA-approved plant-based treatment option for Type 1 adult Gaucher patients that, in addition, meets the stringent standards of kosher regulation and inspections. The OU, the most recognised certifier of kosher products worldwide, inspected the Protalix Biotherapeutics manufacturing facility in Israel in which Elelyso is produced to ensure that the treatment met all applicable qualifications. The criteria were met due to Protalix’s innovative and proprietary manufacturing system which uses genetically engineered carrot cells grown in a simple solution of water, plant extracts, sugar, and a mixture of vitamins and minerals to produce Elelyso.

Amgen’s BiTE Gets Breakthrough Therapy Designation The US Food and Drug Administration (US FDA) has granted Breakthrough Therapy Designation to Amgen’s investigational bispecific T cell engager (BiTE) antibody blinatumomab, for adults with Philadelphia-negative (Ph-) relapsed/refractory B-precursor acute lymphoblastic leukaemia (ALL), a rapidly progressing cancer of the blood and bone marrow1. The Breakthrough Therapy Designation was based on the results of a Phase 2 trial of 189 adult patients with Ph- relapsed/refractory B-precursor ALL treated with blinatumomab. Pharma Bio World

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Vertical Pressure Leaf Filter SAP Filter Pvt Ltd has made a mark in manufacturing and exporting a spectrum of filtration equipment. Its product range is renowned for its quality and durability. SAP Filter Pvt Ltd offers vertical pressure leaf filter for filtration of liquids with solid content up to 5 to 7 per cent and finds application in edible oil, chemicals, and food and pharma industries in areas up to 100 m 2 with dry or wet cake discharge. SAP make vertical pressure leaf filter equipped with SS filter element assembled on a filtrate collecting manifold and enclosed in a hermetic steel casing with a pneumatically operated vibrator for shaking of the filter cake. For more information, please contact: SAP Filter Pvt Ltd Plot No: A-5, Sector-1, The Vasai Taluka Indl Co-op Estate Ltd, Goraipada, Vasai (E), Dist: Thane, Maharashtra 401 208 Tel: 0250-2458982, 3208273, 2023040 | Fax: 91-0250-2458982 E-mail: info@sapfilter.com / sales @sapfilter.com

Particle Sizer The new ANALYSETTE 28 ImageSizer is the ideal instrument for analysis of particle shape and size of dry, freeflowing powders and bulk solids in a measuring range from 20 μm to 20 mm. Via the optical analysis of particle shape and particle size, damaged particles, contaminates, agglomerates or oversized or undersized particles are identified accurately and fast, and can be viewed as single images. At the same time, the instrument offers a fast and efficient particle size measurement. The measuring time, depending on the sample quantity, is below 5 minutes and the result is available immediately. This makes the ANALYSETTE 28 ImageSizer the perfect measuring instrument for the easy quality control, as well as for research and for laboratory tasks – and it is the fast alternative to sieving. For more information, please contact: FRITSCH GmbH Milling and Sizing Industriestrasse 8 , 55743 Idar-Oberstein, Germany Tel: +49 67 84 70 146 | Fax: +49 67 84 70 11 E-mail: koehler@fritsch.de

High-purity Lab Acids for Trace Metal Testing Avantor Performance Materials offers a new grade of high-purity laboratory acids optimized for trace metal analysis and designed to meet the needs of customers in environmental, food, quality control and other testing applications. Marketed under the company’s renowned J T Baker brand, the new BAKER INSTRA-ANALYZED Plus acids product line features a selection of widely used acids specially formulated to enable more accurate trace metal analysis in the very low parts per billion (ppb) range (most from 0.1-1ppb). BAKER INSTRA-ANALYZED Plus acids offer customers upgraded capability from Avantor’s popular BAKER INSTRA-ANALYZED acid line products. The new line of high-purity acids is produced under strict protocols, quality tested for up to 64 key trace metals such as iron and lead to ensure purity, and packaged in environmentally-friendly recyclable HDPE bottles. With its new BAKER INSTRA-ANALYZED Plus acids and other existing BAKER INSTRA-ANALYZED, ULTREX II, and BAKER ANALYZED ACS grade acids, Avantor offers customers a complete solution for trace metal analysis across many laboratory applications. For more information, please contact: Avantor Performance Materials, Inc 3477 Corporate Parkway, Suite #200 Center Valley, PA 18034, U.S.A. Tel: 1-610-573-2600 | Fax: 1-610-573-2610 E-mail: info@avantormaterials.com

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Bio-Energy Engineering Working like Bees for making your Energy Independent...

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ǀĂƉŽƌĂƟŽŶ Θ ƌǇŝŶŐ ^ŽůƵƟŽŶƐ tĂƚĞƌ DĂŶĂŐĞŵĞŶƚ Θ ^ŽůƵƟŽŶƐ ĞƌŽ >ŝƋƵŝĚ ŝƐĐŚĂƌŐĞ͘ ; > Ϳ WƌĞĐŝƐĞ WƌŽĐĞƐƐ ĞƋƵŝƉŵĞŶƚƐ dƵƌŶŬĞǇ ^ŽůƵƟŽŶ ĨŽƌ ŝŽͲ&ƵĞůƐ WůĂŶƚ ŝŽ ĞŐƌĂĚĂďůĞ tĂƐƚĞ ƚŽ ŝŽŐĂƐ WůĂŶƚ ŶĞƌŐǇ DĂŶĂŐĞŵĞŶƚ &ŝƌĞ ,ǇĚƌĂŶƚ ^ǇƐƚĞŵ WƌŽĐĞƐƐ ƵƚŽŵĂƟŽŶ ,ĞĂƚ ǆĐŚĂŶŐĞƌƐ Θ ŝƐƟůůĂƟŽŶ ^ǇƐƚĞŵ dƵƌŶŬĞǇ ^ŽůƵƟŽŶ ĨŽƌ ^ƚĂƌĐŚ Θ ^ƚĂƌĐŚ ĞƌŝǀĂƟǀĞƐ WůĂŶƚ

ZĞƌĞŐŝƐƚĞƌĞĚ KĸĐĞ ͗ 7-B, Ghaisas L/O, Surendra Nagar, Nagpur – 440 015, Maharashtra, India ƌĂŶĐŚ KĸĐĞ͗ C-23, Swami Samarth Society, Sus Road, Pashan, Pune 411 021, Maharashtra, India DŽďŝůĞ ͗ 09960400959 / 09823765467 | ŵĂŝů͗ sales@bee.net.in| tĞď͗ www.bee.net.in

Horizontal Pressure Leaf Filter SAP Filter Pvt Ltd has made a mark in manufacturing and exporting a spectrum of filtration equipment. Its product range is renowned for its quality and durability. SAP Filter Pvt Ltd offers horizontal pressure leaf filter for filtration of liquids with higher solid content in edible oil, food, chemical, and pharma, and molten sulphur industries in areas from 2 m 2 up to 200 m 2 with dry or wet cake discharge. Opening and closing of filter is by hydraulically operated bayonet clamp ring. Both shell and bundle retraction is available. Material of construction includes SS, carbon steel, carbon steel with PP, PVDF, rubber lining. For more information, please contact: SAP Filter Pvt Ltd Plot No: A-5, Sector-1, The Vasai Taluka Indl Co-op Estate Ltd, Goraipada, Vasai (E), Dist: Thane, Maharashtra 401 208 Tel: 0250-2458982, 3208273, 2023040 | Fax: 91-0250-2458982 E-mail: info@sapfilter.com / sales @sapfilter.com

Humidity Chamber Mack Pharmatech Pvt Ltd offers humidity chamber in temperature range 20 to 60 oC, humidity range 40% RH to 95% RH with accuracy of Âą0.2Â°C and Âą2.0% RH and uniformity Âą1.0Â°C and Âą3.0% RH. Test is suitable for 25Â°C and 60% RH, 30Â°C and 65% RH, 40Â°C and 75% RH, and 30Â°C and 75% RH. Features PLC-based control system; 21 CFR software; HMI (touch screen display); standby refrigeration system; standby humidity system; imported hygroflex sensor; 4+4 scanner; GSM technology; hooter system; full view glass door; bullet feet leveling legs; tray spacing every Â˝â&#x20AC;&#x153; adjustable. etc. For more information, please contact: Mack Pharmatech Pvt Ltd B-48, Malegaon MIDC, Sinnar Dist: Nashik, Maharashtra 422 113 Telefax: 91-02551-230877 E-mail: sales@mackpharmatech.com

Disposal Transfer Tools Tecan has introduced an innovative new consumable device offering increased throughput and capacity for Freedom EVO workstations. The patent pending Disposable Transfer Tool is designed for use with Tecanâ&#x20AC;&#x2122;s Nested LiHa disposable tips, and offers fully automated handling of empty tip trays without the need for a gripper. Nested LiHa disposable tips offer increased worktable capacity IRU WLS VWRUDJH DOORZLQJ ILYH WUD\V RI Č?O WLSV WR EH VWDFNHG RQ D VLQJOH 6/$6 IRUPDW FDUULHU position. Until now, this solution has only been available for instruments equipped with a Robotic Manipulator Arm or a MultiChannel Arm gripper option to remove empty tip trays. Tecan has overcome this by developing an innovative consumable device â&#x20AC;&#x201C; the Disposable Transfer Tool â&#x20AC;&#x201C; that allows the Freedom EVOâ&#x20AC;&#x2122;s Liquid Handling (LiHa) or Air LiHa Arm to pick up and dispose of empty trays. Implementation of the Disposable Transfer Tool is designed to be as easy as possible using Freedom EVOware (v2.6 SP1 onwards). The only additional hardware required is a 16-position Transfer Tool Holder, which can be quickly and easily filled by hand prior to beginning a series of runs. This elegant solution is particularly suited to smaller Freedom EVO workstations-where workdeck space is limited. It also offers benefits for larger systems, allowing the gripper to perform other operations while the LiHa Arm disposes of empty trays, improving productivity and functionality for high throughput applications. For more information, please contact: Tecan Trading AG Seestrasse 103, CH-8708 MĂ¤nnedorf, Switzerland Tel +41 (0)44 922 81 11 Fax +41 (0)44 922 81 12 E-mail: info@tecan.com

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Dew Point Sensor CS Instrument, Germany offers dew point sensor FA400 required for aluminium smelter, steel plant, pharma industry and health care for continuous monitoring with local digital display. Dew point sensor FA400 has 3 different ranges - refrigeration, adsorption and membrane dryer. FA400 has digital integrated display, extremely precise long term stability with quick response time, output 4-20 mA analogue output and also PC connection with SDI interface with standard measuring chamber up to 16 bar with special optional features up to 350 bar. Output signal via software or DS400 dew point set possible to show engineering unit %RH, Ctd, g/m 3, mg/m 3, ppm V/V. The user can define alarm to optimize and achieve better air quality and threshold value adjustable via keypad for alarm relay max 60 V DC and 0.5 A. For more information, please contact: AV Measurement & Control (India) Plot No: P46/1, 102 Sonata Comml Complex MIDC, Dombivli (E), Dist: Thane, Maharashtra 421203 Tel: 0251-2424418, 6458885 E-mail: vadnerkar@avmacindia.com | sheeja@avmacindia.com

Walk-in Humdiity Chamber Mack Pharmatech Pvt Ltd offers walkin humidity chamber in temperature range 20 to 60oC, humidity range 40% RH to 95% RH with accuracy of ±0.2°C and ±2.0% RH and uniformity ±1.0°C and ±3.0% RH. Test is suitable for 25°C and 60% RH, 30°C and 65% RH, 40°C and 75% RH, and 30°C and 75% RH. Features PLC-based control system; 21 CFR software; HMI (touch screen display); standby refrigeration system; standby humidity system; imported hygroflex sensor; 8+8 scanner; GSM technology; hooter system; full view glass door; etc. For more information, please contact: Mack Pharmatech Pvt Ltd B-48, Malegaon MIDC, Sinnar Dist: Nashik, Maharashtra 422 113 Telefax: 91-02551-230877 E-mail: sales@mackpharmatech.com

Easy-to-Use AseptiQuik Connectors CPC (Colder Products Company), offers line of solutions for biopharma manufacturers seeking a robust sterile connector for single-use processing. AseptiQuik Connectors are a reliable, easy-touse solution and the connector’s intuitive “Click, Pull, Twist” design reduces complexity and the risk of operator error. AseptiQuik Connectors deliver quick, easy and reliable connections for Indian manufacturers using single-use systems and enable sterile media transfer, even in non-sterile environments. The intuitive three-step process enables operators to quickly connect two single-use assemblies: an audible CLICK confirms the initial connection, PULL tabs allow simultaneous membrane removal and a simple TWIST of the integrated lock ring provides secure final assembly.Extensive validation testing completed on post gamma and autoclave sterilized connectors confirms that external organisms are prevented from entering the flow path before, during or after connection. Testing includes functional performance, biocompatibility and three types of microbial ingress tests. CPC has also unveiled its AseptiQuik S small-format and AseptiQuik X large-format connectors, offering Indian biopharma manufacturers a full line of robust, sterile connectors with flow configurations ranging from 1/8 inch to 1-inch. For more information, please contact: Dover India Pvt Ltd (Colder Products Co) Bagmane & Laurel, Block C, Level 2, Baagmane Tech Park, C V Ramanagar, Bengaluru, Karnataka 560 093 Tel: 080-40689689 E-mail: pavan.urs@cpcworldwide.com

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Energy Saving SS Centrifugal Pump NeoMag is a powerful and reliable energy-saving, SS centrifugal pump with magnetic coupling. (This is the best alternative to conventional seals). As compared to centrifugal pumps with mechanical seals, the NeoMag is a maintenance-free solution. Loss of production due to leakages/maintenance in system can be avoided. Main advantages whilst being hermetically sealed are no power losses, no additional heat generation in system, good chemical stability, competitive price level and increased efficiency. (tested and calculated energy saving up to 30%). resulting in increased efficiency factor >70%. Finds application in chemicals, process engineering, pharma, biotech, petrochem and water management. For more information, please contact: BEDA Flow Systems Pvt Ltd W-7 Sector XI, Noida Uttar Pradesh 201 301 Tel: 0120-432 99-90 E-mail: info@bedaflow.com

Computational Workbench Forge V10.3 includes significant enhancements to the science, visualization, and integration of Forge, the computational workbench for ligand-based drug design, including significant enhancements to Activity Miner - for finding and understanding critical activity cliffs in the SAR landscape. Cresset have now added selectivity cliffs – the use of multiple activity parameters to look for changes that disproportionately change one activity relative to another. Forge V10.3 includes improved conformation hunt settings that give significantly fewer, lower energy conformations, enabling you to find the correct alignments even more reliably. For more information, please contact: Cresset New Cambridge House, Bassingbourn Road Litlington, Cambridgeshire SG8 0SS, U.K. Tel: +44 (0)1223 858890 | Fax: +44 (0)1223 853667 E-mail: sue@cresset-group.com

CLARiTY Laser Controller The new CLARiTY Laser Controller offers an innovative line set-up wizard to aid maintenance and production staff during both initial line set-up and during product changeovers. The interface provides a visual representation of the laser on the packaging line, eliminating trial and error by configuring the print job to match the required production set-up. In addition to minimizing planned downtime, the CLARiTY Laser Controller offers tools to address the root causes of unplanned downtime. The on-board diagnostics tool presents instant fault information in a logical way with a drilldown option to enable the identification of the most frequent causes of printer faults. To address manufacturers’ needs to eliminate sources of poor quality, the CLARiTY Laser Controller offers on-board Code Assurance. Predefined coding rules can be easily established during set-up that limit the operator’s choices to an allowable range, helping eliminate errors and the resulting impact to quality. With the addition of the CLARiTY Laser Controller, Videojet now offers a common controller interface for all of its main primary and secondary packaging printers. For more information, please contact: Videojet India Unit 101/102, Rupa Solitaire Building No: A-1, Sector-1 Millennium Business Park, Mahape, Navi Mumbai 400 710 E-mail: marketing.india@videojet.com

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New Dual-View Atomic Spectrometer Agilent 5100 Inductively Coupled Plasma –Optical Emission Spectrometer (ICP-OES) enables customers to run samples using less gas. It is ideal for pharma testing and industrial applications. While conventional dualview systems require up to four sequential measurements per sample, the Agilent 5100 requires only one, thanks to its innovative Dichroic Spectral Combiner and Synchronous Vertical Dual-view technologies. Customers will be able take the guesswork out of method development with intuitive ICP Expert software and Dichroic Spectral Combiner technology. The Agilent 5100 is available in three configurations, all featuring a robust vertical torch: Synchronous Vertical Dual View (SVDV); Vertical Dual View (VDV) and Radial View (RV). For more information, please contact: Agilent Technologies Inc 5301 Stevens Creek Blvd Santa Clara, CA 95051 U.S.A E-mail: susan_berg1@agilent.com

Decorated Packaging Photorealistic printing and more legible product information are some of the advantages of the newly launched Brilliance tube packaging from Sanner GmbH. Combined with proven Sanner desiccant closures, the tubes are best suited for effervescent tablets, but also work with conventional or coated tablets and other solid pharma products. The advantage of in-mould labeling (IML) technology is that packaging production and decoration are combined into a single process. Printed labels are placed in the mould and the liquid plastic is injected. The temperature of the plastic causes the label to fully bond with the tube. Additionally, the geometry of the tube base ensures that the tubes can be easily packaged in standard commercial sales trays. For more information, please contact: Sanner GmbH Schillerstraße 76 64625 Bensheim, Germany Tel. +49(0)6251 938-0 | Fax: +49(0)6251 74672 E-mail: info@sanner.de

Innovative Tablet Weight Control Romaco Kilian offer in-line Continuous Weight Control (CWC) that allows the continuous and in-line weighing of a tablet being produced without destroying it. The scale is integrated into the tablet chute. The weighed tablet is then returned into the good channel using compressed air. There is no need for tablet sampling in order to check the weight and therefore there is no product loss, especially for companies that use expensive raw materials. This fully automatic system measures one tablet per turn of the rotor with an accuracy of 0.1 milligrams. The CWC system is fully integrated in the PLC and touch panel. It can be supplied as an option for all models in the KTP 420X and KTP 720X Series and will in future also be available as a retrofit kit. The Romaco Kilian KTP 420X is a versatile, high speed tablet press that compresses up to 360,000 tablets an hour absolutely reliably. It is ideal for the production of mono-layer, bi-layer or core tablets (Tab-in-Tab), and it can also be used to compress poorly flowing materials. The wear-free torque motor, extremely durable compression rollers and wearfree patented lower punch brake magnets underlie the very low Total Cost of Ownership (TCO). The likewise patented punch bellows protect the tablets from lubricants. Due to the hermetic separation of the compaction and service areas, no product or oil gets into the machine compartment of the press. The optimised hygienic design permits quick and easy cleaning. Operating and maintenance staff additionally profit from the reduction in press noise. In response to customer feedback, the machine’s Windows 7 based GUI was developed with swipe functionality that makes the new KTP 420X even more user friendly. For more information, please contact: Romaco Group Am Heegwald 11 76227 Karlsruhe, Germany Tel: +49 (0) 721 4804 0 | Fax: +49 (0) 721 4804 225 E-mail: susanne.silva@romaco.com

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Laboratory Stirrers Fluidyme offers laboratory stirrers to meet various stirring, homogenizing operations in laboratories and small formulations in chemical, pharma industries, etc. The stirrers are compact, sturdy and perfect for continuous operation. The stirrers are fitted with 1/4, 1/8, 1/12, 1/20 HP AC/DC universal motors with quick shaft interchangeability and speed variation by transformer speed regulator. Stirrers with PMDC motor for wide range of mixing applications provided with digital RPM indicator. These stirrers have high torque at low speeds, accurate speed control and continuous duty. For stirring high viscosity liquids effectively stirrers with AC/DC motor and gear box gives high torque at relatively low speeds. The motor is fitted on chrome-plated guide bar. The height and angle of the stirrer can be adjusted according to the requirement. The base is rigid made of CI casting.

pH STAT Titration pH STAT titration predicts the response to any reaction involving production or consumption of protons, hydroxyl ions or inorganic carbon chemical species. It is a technique which maintains a constant pH throughout the reaction as hydrogen ions are released or consumed during the process. In case of any deviation in pH from set pH, the value is quickly compensated by titrant addition. The speed and volume of reagent addition can be controlled to match the reaction rate. The acidity determination of an enzyme or monitoring release kinetics of antacid requires a titrator capable of adjusting pre-defined pH value and maintains it over a period of time. Synthesis lab task differ from titrations. Typical synthesis requires maintaining constant pH value over a period of time. Predefined volume of reagent has to be added to the solution in the given time. Spectralab’s AT-38C pH STAT offers programmable titrations and automatic documentation of titration data. It comes with provision to control reagent flow rate with respect to time. The whole reaction has to be carried out at a control temp, which can be maintained by Spectralab’ MCS-150, a peltier based device.

For more information, please contact:

Fluidyme Process Flow Technologies E-2/4, Popular Prestige Off Highway Bridge Warje, Pune, Maharashtra 411 058 E-mail: fluidyme@vsnl.net.

Spectralab Instruments Pvt Ltd W-446, Rabale MIDC Navi Mumbai 400 701 Tel: 022-27644030, 27644031, 27644032, 27644033, 27644034 E-mail: marketing@spectralab.biz

Hot Water Systems HRS hot water system is the most compact hot water generation system. It provides highly efficient solution to instantaneous hot water generation using energy efficient heat exchangers (Funke Brazed or Gasketed plate heat exchanger or Ecoflux corrugated tube heat exchanger). It can also be installed with storage (buffer) vessel for semi-instantaneous applications and in conjunction with solar-based hot water systems. A hot water system not only heats the water to a desired temperature using low pressure steam but also maintains the required temperature of water with better temperature control using automation and control. It finds application in pharma – single fluid heating and cooling systems, food, HVAC, hospitals, hotel, textile and breweries. Hot water generation is instantaneously available for fluctuating process loads and urgent demands. System designed with heat exchangers with very high heat transfer rates and efficiency. Inexpensive solution in terms of initial capital costs, installations, operation and maintenance cost. Ensures accurate temperatures for hot water required for the most heat sensitive processes. For more information, please contact: HRS Process Systems Ltd 201/202 Karan Salene, 861 Bhandarkar Institute Road Pune, Maharashtra 411 004 Tel: 020-25663581, 66047894, 66047895 | Fax: 91-020-25663583 E-mail: ShambhaviKarnik@hrsasia.co.in / info@hrsasia.in

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New Lab Software for Complex Samples Agilent Technologies Inc offers an enhanced version of OpenLAB CDS: Peak Explorer for single-click peak integration and intelligent reporting. These newly added features boost sample throughput for petrochemical, chemical and other industry laboratories processing large numbers of complex samples. Complex samples containing hundreds of peaks often require time-consuming data review and manual integration. Peak Explorer is a new OpenLAB CDS data visualization module that speeds review of complex chromatographic data. It enables users to browse multiple sample runs containing multiple peaks—including entire sequences—rapidly, in one data review window.Using patented OpenLAB CDS Data Analysis peak integration software, users can manually integrate peaks with a single mouse-click. As there are no changes to the integration algorithm, historic results can be compared. OpenLAB CDS intelligent reporting features intuitive drag-and-drop chromatography reporting, making it easy to create reports without transferring data to other software, such as Microsoft Excel.Intelligent reporting is expanded to provide even more ways to tailor reports to specific laboratory workflows. Now included is support for all types of calibration curves, and new options for report formatting, annotating chromatograms, defining tables and fields, creating charts and importing data from other applications. A software maintenance agreement entitles all customers to these enhancements at no additional cost. For more information, please contact: Agilent Technologies Inc 5301 Stevens Creek Blvd Santa Clara, CA 95051 U.S.A. E-mail: susan_berg1@agilent.com

Diode Array UV Dissolution System Agilent Technologies Inc offers the Cary 8454 UV Dissolution System, which incorporates new Cary 8454 UV-Vis Spectrophotometer technology and enables researchers to sample the entire UV spectrum for fast, efficient diode array analysis. The 8454 UV Dissolution System is available in several scalable solutions to support both online and offline dissolution analysis. The 8454 UV Dissolution System is an ideal solution for both single and multicomponent products. The system is available in three configurations to support a variety of laboratory needs: multicellbased single apparatus for dedicated flow-cell lines, eliminating cross-contamination and supporting simultaneous or sequential UV analysis; valve-based single apparatus for sequential sampling, offering the most economical option with use of a single-flow cell line; and valve-based multi-apparatus, enhancing the productivity of up to four apparatus and supporting the testing of large amounts of samples. The 8454 system uses Agilent’s UV-ChemStation Dissolution Software, which seamlessly integrates with OpenLAB ECM. To complete an entire dissolution test and UV analysis, the UV-ChemStation software controls the spectrophotometer as well as Agilent and legacy Varian and VanKel dissolution apparatus, all in a 21 CFR Part 11-compliant environment. For more information, please contact: Agilent Technologies Inc 5301 Stevens Creek Blvd Santa Clara, CA 95051 U.S.A. E-mail: susan_berg1@agilent.com

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Direct Access to the Controller All B&R controllers have an FTP server on board as a standard feature. A protection mechanism with integrated user name and password management now makes accessing this server even more secure. B&R draws on methods that have proven themselves in the realm of IT to help machine and system developers implement access security. User authentication is managed with user names and passwords. Management of user data and assigned rights is integrated in Automation Studio. This data is stored on the runtime system in encrypted form to ensure seamless security. User management for FTP access to B&R systems allows an unlimited number of users to be assigned access rights. At runtime, up to eight different users can access the controller at the same time via FTP. FTP access that is as secure as it is versatile is one of the many ways that B&R systems allow machine and system operators to react quickly and flexibly to new requirements.

SK180E: Intelligent IP69K Drives NORD DRIVESYSTEMS supplies efficient drive units in applications that need to be regularly cleaned with highpressure steam jets. Developed for strict hygiene requirements and featuring IP66/ IP69K ingress protection, smooth-surface motors with an integrated frequency inverter are available for the 0.37..1.1 kW performance range. Sensor data can be directly communicated to the drives. In conveyor applications, light barriers can be used for contact-free or gapless accumulation. The drives tolerate high temp fluctuations and are suitable for ambient temp from -25 to +50°C. The Type SK 180E inverter comes in a rugged die-cast aluminum housing that absorbs impacts up to 7 J. Due to class C1 radio interference suppression and a discharge current decidedly below market average, SK 180E drives can even be operated on standard domestic power sockets. The NORD-developed treatment is compliant with FDA Title 21 CFR 175.300 requirements.

For more information, please contact:

B&R Industrial Automation Pvt Ltd 8, Tara Heights, Mumbai-Pune Road Wakdewadi, Pune, Maharashtra 411 003 Tel: 020-41478-999 | Fax: 91-020-41478-998 Email: shyam.padwal@br-automation.com

Getriebebau NORD GmbH & Co KG Getriebebau-Nord-Straße 1 22941 Bargteheide/Hamburg, Germany Tel: +49 45 32 / 2 89 -0 | Fax: +49 45 32 / 2 89 -22 53 E-mail: Joerg.Niermann@nord.com

Thermal Inkjet Printer Markem-Imaje offers the 1050 integrated thermal inkjet printer. It produces high resolution serialized data and complex 1D and 2D barcodes on fast-moving production lines in the food, pharma and other industries. It is also designed to excel at case coding in dusty, humid or corrosive environments. The 1050’s high-speed accuracy is due to the precision control of 600 separate ink nozzles, allowing variable dpi from 1 to 600 for optimal printing. The flexible printhead can print codes from 12.7 mm up to 50.8 mm high. The 1050 features ink cartridges that combine the printhead and ink, which means no moving parts. It is free from hassle, with snap-in and -out cartridges, allowing operators to maintain the 1050 with minimal line interruption and keeping availability high.The 1050 utilizes the same easy-to-use 7” touch-screen user interface with intuitive WYSIWYG as other Markem-Imaje products. It is fully compatible with Markem-Imaje’s powerful CoLOS coding software as an option for network control of all Markem-Imaje printers. For more information, please contact: Markem-Imaje H-23, Sector-63, Gautam Budh Nagar Noida, Uttar Pradesh 201301 Tel: 0120-4099500 | Fax: 91-0120-4099555 E-mail: salesindia@markem-imaje.com

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events diary

Pharmabiotika 2014 - Bonsai Meet Date: 26 th August 2014 Venue: Hitex Exhibition Centre, Hyderabad Pharmabiotika is a significant event that contributes significantly in the development of the pharma industry. This is a leading event that helps the professionals and experts to connect and interact with each other and to significantly contribute in the growth and expansion of the sector. It presents an ideal opportunity and platform for the professionals to discuss about the latest developments of the industry and also presents them with a great scope to share and exchange their valuable experiences and to develop their knowledge. Contact: Human Crayon Management Services Pvt Ltd C-28, Sector-4, Noida - 201301, India Tel: +91-120-6528801, +91-11-65378800 Email: info@crayon4.com Web : www.pharmabiotika.com

Pharmac India 2014

Frost & Sullivan’s 6 th Annual India Healthcare Excellence Awards 2014 Date: 19 th September 2014 Venue: Taj Lands End, Mumbai Frost & Sullivan’s Annual India Healthcare Excellence Awards programme recognises companies for their superior planning, leadership, strategy, growth, innovation, integration, marketing, and financial performance. The award categories span across various healthcare segments such as Pharmaceuticals and Biotechnology, Medical Technologies, Healthcare Delivery Services and Special Awards. Contact: Akshata Mahtre, Ranjani Shanker Tel: +91-22-66072029 Mobile: +91-9884872658 Email: akshatam@frost.com; ranjanis@frost.com

BioPharma India Convention Date: 18 th -19 th November 2014

Date: 11th -13 th September 2014

Venue: Hyatt Regency, Mumbai

Venue: Mahatma Mandir Exhibition Centre, Gandhinagar, Gujarat

BioPharma India Convention is a perfect platform for pharma and medical professionals to understand the biopharmaceutical sector in depth. The conference will highlight the new opportunities available in Indian biopharmaceutical sector. The conference is scheduled at the Grand Hyatt, Mumbai. Topics of the conference will be drug discovery and clinical trails to manufacturing. Professionals will get an opportunity to meet more than 80 speakers, 800 decision makers and 500 products. Be a part of this conference to know the latest developments in pharmaceutical sector and build business rapport with associates.

Pharmac India is 5 th International Pharma Machinery, Equipment, Bulk Drugs, API, Pharma Lab, Pharma Pack & Material Exhibition in India. It has successfully brought together manufacturers and buyers on a common platform and contributed substantially towards the growth of the industry. Pharmac India 2014 is jointly organised by Orbit Exhibitions Pvt Ltd & Indian Drug Manufacturers’ Association(IDMA-GSB). Contact: Ramesh Vartak 303, 3 rd Floor, Raindrops Building Opp. Yes bank CG Road Ahmedabad - 380009, Gujarat Mobile: +91 93216 53011 Email: ramesh.v@orbitexhibitions.com 116 eJuly 2014

Contact: Rebecca Koh Terrapinn Pte Ltd, 1 Harbourfront Place, #18-01 Harbourfront Tower 1, Singapore 098633 Tel: +65 6322 2725 | Fax: +65 6271 2035 Email: rebecca.koh@terrapinn.com Pharma Bio World

bookshelf Leading Pharmaceutical Innovation: Trends and Drivers for Growth in the Pharmaceutical Industry [Hardcover] Authors: Oliver Gassmann, Gerrit Reepmeyer, Maximilian von Zedtwitz Price: USD 58.79 No of Pages: 186 pages About the Book: Pharmaceutical giants have been doubling their investments in drug development, only to see new drug approvals to remain constant for the past decade. This book investigates and highlights a set of proactive strategies, aimed at generating sustainable competitive advantage for its protagonists based on value-generating business practices. We focus on three sources of pharmaceutical innovation: new management methods in the drug development pipeline, new technologies as enablers for cutting-edge R&D, and new forms of internationalisation, such as outside-in innovation in the early phases of R&D.

Innovation in the Biopharmaceutical Industry [Paperback] Editors: Rifat A Atun, Desmond Sheridan Price: USD 81.70 No of Pages: 150 pages About the Book: Innovation is at the heart of all advances and has the capacity to solve problems facing humanity. Societies which have turned away from innovation and technological development have failed in their ability to support their populations. Understanding the nature of innovation in the life sciences and in particular healthcare, how it operates, what enables and hinders it is therefore of great importance to meeting the challenges ahead. This book, originally and concurrently published in the International Journal of Innovation Management, Vol. 11, No. 2, 2007, offers the latest research and insights concerning innovation in the biopharmaceutical industry.R&D, and new forms of internationalisation, such as outside-in innovation in the early phases of R&D.

Pharma Packaging Innovations (Paperback) Author: Sandeep Kumar Goyal Price: USD 44.10 No of Pages: 124 pages About the Book: : This publication comes after the success of Ideas & Opportunities 2013 held on 19th July 2013 in India. Various innovations were presented during the one day workshop by the expert consulting team of Sanex Packaging Connections Pvt Ltd popularly known as Team PackagingConnections. Idea behind this is to bring the innovations to wider group of professionals to meet the mission of packaging knowledge sharing and that too cost effectively. This publication will further fill the project pipelines of companies and improve the standards of packaging.

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Pharma Bio World

R.N.I. No.: MAHENG/2002/08502. Date of Publication: 26th of every month. Postal Registration No: MH/MR/SOUTH-284/2014-16 Posted at Patrika Channel Sorting Office, Mumbai 400001, on 26th & 27th of every month. Total Pages:- 120