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INTERVIEW 10

“Outdoor air quality is likely to deteriorate even more…” Mr. Pradeep Randhawa, Managing Director Mann+Hummel India

FEATURES 13

Healthcare 2019: What the future holds for the Pharma Industry

Cold chain management for sensitive goods

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Driving cost excellence and productivity in pharmaceutical operations through Digital and Advanced Analytics

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interview

“Outdoor air quality is likely to deteriorate even more…”

Good air quality is critical be it indoor or outdoor. The pharmaceutical industr y is regularly exposed to dust, raw materials and other hazardous materials. A l l o f t h e s e e l e m e n t s c a n l e av e c o n t a m i n a n t s i n t h e i r wa ke a n d t h r e a te n t h e h e a l t h a n d s a fet y o f staf f and patients. But, there are also solutions to minimize the impact of these unwanted par ticles, as explained by Mr. Pradeep Randhawa, Managing Director - Mann+Hummel India, in this inter view with PharmaBio World.

Could you give us a brief background of M+H? Mann+Hummel is a leading global expert for filtration solutions. Established in 1941, the company is headquartered in Ludwigsburg, Germany, and develops solutions for automotive, industrial applications, clean air in metropolitan areas and buildings and interior spaces. In 2018 the group achieved sales of approximately 4B euros, with more than 20,000 employees in more than 80 locations around the world. Who are the other major players in this sector apart from M+H? There are many MNCs who are part of this specialized field like Camfil, Pall, 10 ◄ February 2019

Cummins, IQ Air, Emerson, Honeywell, Philips, etc. What are the typical impurities found in ambient air and which of those are highly detrimental to human health? PM, TVOCs & CO 2 are the major constituents of air impurities that are harmful. Particulate matter (PM): Also known as fine dust, refers to the size of particles in units of µm. The risk for humans is eye, nose, and throat irritation, breathing difficulties, lung irritation, asthma, weakened immune system, increased risk of stroke and heart disease.

• Human hair is around 70 µm, and can be caught in the nose. • PM10: Enters the upper lungs • PM2.5: Penetrates the lungs deeply and can enter the bloodstream • PM1: Enters the bloodstream To t a l Vo l a t i l e O r g a n i c C o m p o u n d s (TVOCs): The risk for humans is irritation of the eyes and mucous membranes, damage to the liver and kidneys, allergic skin reactions, respiratory issues, probable carcinogen • VOC: organic chemicals emitted by solids or liquids, e.g. hydrocarbons, alcohols and organic acids. Pharma Bio World

interview • Formaldehyde - a type of VOC used in building materials and many everyday products.

engineering innovation and a deep commitment to the well-being of our customers.

Carbon Dioxide (CO 2 ): The World Health Organization recommends 1000 parts per million (ppm) as an acceptable limit, and healthy range is around 600 – 800 ppm. Elevated levels of CO 2 affect cognitive ability, productivity and encourage mold and bacteria growth, which is harmful for respiratory health. Additionally, it can cause drowsiness and extreme amounts can cause even death.

Our solution comprise of 3 key components: 1. Air Quality Monitors: we have a range of professional grade, 3 rd party accredited monitors which make accurate, real time data visible to the facilities managers and occupiers. 2. HVAC filters: a comprehensive range of HVAC filters which we recommend based on your air quality data, ensuring that filtration needs are right-sized and cost-effective. 3. Digital Platform: this feature meshes actual usage data, air quality data and filter performance data to provide notifications on filter change requirements and energy recommendations.

Do you see the air quality deteriorating further in the coming years or will we see a decline in air pollution due to improved industrial processes, efficient commuting via electric vehicles, innovative transportation modes like drones, etc? It is still early days for EVs and even more so for drones, not just in India, but globally. Air pollution is an outcome of what planners call a ‘wicked problem’, a highly complex issue linked inextricably with other economic and social drivers. Demand for EVs is growing, but still not enough to bring down the costs for the man on the street – who might be better served with mass transportation or other alternative last-mile options. Hence, air quality will likely deteriorate even more, before we see people demanding for better air outdoors, and controlling their quality of air indoors. Currently the level of awareness and corresponding action is still fairly low. W h a t a r e t h e i n d u s t r i a l H VA C products provided by M+H? ‘OurAir’ by Mann+Hummel provide clean air solutions for indoor spaces that combine cutting-edge IOT technologies, world-leading filtration expertise, Pharma Bio World

What is the USP of your products? Our approach to better air is end-toend, data-driven, and optimised to the customer’s needs. Solutions are seamless and integrated, resulting in a trusted clean air ecosystem. This is a differentiated offering from what is currently available in the market, where the products and services are standalone. Globally, ‘OurAir’ is the only one that provides a complete intelligent HVAC filtration solution, from knowing your air quality, improving it and finally being able to manage it. What is the ‘Know-ImproveManage’ approach? Our ‘Know-Improve-Manage’ approach helps our customers make smarter choices for better air. A) Know: We have a range of professional grade air quality monitors, certified by a 3 rd party in terms of data veracity, to help establish the level of airborne contaminants in your indoor space. The air quality monitors measure the top 5 most common parameters (PM2.5, PM10, CO 2 , TVOCs, Temp and

Relative Humidity) and this information is displayed on the ‘OurAir’ App or Web Portal. B) Improve: We have a range of filtration solutions for industrial and commercial applications, and these are based on the intelligence and actionable insights derived from the air quality monitors. C) Manage: ‘OurAir ’ digital platform enables you to manage the air quality across multiple sites and assets. The air quality data is presented in real time on the App and Web Portal, and provides guidance on selecting the best filters for your operating environment, so you can ensure the efficiency of your air delivery system and the safety of your building occupants. The outcome that we want to achieve is that you can understand and take control of the air quality in your facility, ensuring the air quality required for sensitive manufacturing. Which are the sectors that require stringent air quality control? For sensitive manufacturing processes, semiconductor, pharmaceutical industries require high standards of air quality; as well as hospitals and schools will have higher requirements. Could you elaborate a bit more about the kind of solutions provided by M+H to the pharma/ biotech industry? We currently provide air filtration solutions to our clients in pharma/biotech; these include high performance filters like HEPA, ULPA filters, for tackling particle and chemical contamination. Cleanrooms are extensively used in a variety of industries especially in R&D and sensitive manufacturing like the semiconductor and pharmaceutical industries. In order to maximise yield and protect the workforce in pharmaceutical and research facilities, HEPA & ULPA filters are used February 2019 ► 11

interview in cleanroom and containment rooms for supply, recirculation and exhaust air. Mann+Hummel’s range of products for this area is second to none, including the industry renowned ULPA and HEPA filters. In the emerging industries of genetic research, nanotechnology and other pathogen free environments, these air filters continue to ensure that maximum protection and maximum yield can go hand-in-hand. Manufacturers of cleanair booths, benches and cabinets for the pharmaceutical industry and biological research industries know that their company’s reputation is only as good as the ultra filters that they put into their equipment. A filter failure is, as far as their customers are concerned, a failed system. Because we produce dependable, tested, high efficiency air filters, our customers return time after time. Who are your major global pharma/biotech clients? GSK, Novartis, Pfizer, AstraZeneca, Bayer. Any Indian clients from the pharma/biotech sector? We are currently building our presence in India and Asia. Lately, the process automation sector is abuzz with digitization, AI, IoT, etc. What role does IoT play in your HVAC solutions? IOT, in essence, connect things (i.e. smart things with sensing and actuating capabilities) to the internet, and enables these things to be controlled from anywhere, at any time. The power of IOT is that now the HVAC system, which connects AHUs to indoor spaces via ductwork, can be controlled to provide c o o l a i r, v e n t i l a t i o n , a n d c o n t r o l t h e quality of the air based on the needs of the occupants in that space. Through IOT, we are able to know the indoor air quality, provide recommendation on the types of 12 ◄ February 2019

filtration required, and ultimately be able to provide filter management solutions and even new business models through data. Our digital platform provide real-time data through our user-friendly dashboard and domain specific visualization for asset management purposes. Our APIs supports integration to end-to-end security for sensor data and device management. It pushes out alerts and actionable insights through the data collected, and provides recommendations through our patented eco16 program, where it finds a sweet spot where the filtration system is supply a safe level of air quality but at the lowest possible energy demand. How significant are sensors in IoT especially with reference to your intelligent solutions? Sensing needs are the basis of IOT, as these are the data-collection end nodes that send information about the ‘thing’ it is sensing and reporting on, the behavior of the person operating this ‘thing’, i.e. usage data and trends, as well as the larger environment or context which it exists in. In our case, the sensors will detect the air quality in terms of key parameters e.g. temperature, relative humidity, particulate matter and carbon dioxide. It can also report on its own health, so you would know if there is power going to the sensor, or if the sensor requires a recalibration.

How long has M+H been in India? Mann+Hummel India, a 100% subsidiary of Mann+Hummel GmbH started production of filtration components in India in 2006. Today, we supply products to the OEMs in the automotive (cars, trucks) and industrial sectors (compressors), apart from the construction industry. Does the company have any manufacturing/R&D facilities in India? The India corporate headquarters is located in Bangalore. The company has two manufacturing units in India - one in Tumkur, Karnataka and the other in Bawal, Haryana. What are the areas of research being pursued at the India centre/ German centre? We are interested in areas that are related to air pollution in general, both indoor and outdoor. A recent development is the fine dust eater, which brings the concept of IOT-enabled filtration solution to outdoors, to tackle traffic-related air pollution.

Our professional grade and awardwinning air quality sensors comes with industrial protocols and backhaul WAN technologies. Our air quality sensors and the data provided are certified by a wellregarded certification system ‘RESET’, the only one globally that provides certification of devices and real-time data, providing the assurance that the air quality is indeed better in operations, and not just at design and construction stage. Pharma Bio World

Healthcare 2019: What the future holds for the Pharma Industry

edicines continue to form the mainstay of treatment methods for most medical conditions known today, despite some speculations that chemicals in the human body may be self-regulated via nanobots in the future. But that future is still 50 years away. At present, healthcare is still learning to cope with the possibilities of precision medicine and artificial intelligence. The domestic pharmaceuticals market is said to be the worldâ&#x20AC;&#x2122;s third largest in terms of volume and thirteenth largest by value. Implying that one out of every three tablets available anywhere in the world has been produced by an Indian company. The sector was valued at USD 33 billion in 2017; and by September 2018, the market had grown by 9.7% to tally almost USD 18 billion. The US makes up for 40% of all generic medicine demand from India, while

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its pharma workforce boasts of great representation in new drug applications and drug master files applications in the country. Healthcare has seen a clear shift toward patient centrality and quality enhancement while pharmaceuticals are moving towards niche products. There are several new areas, which modern pharma employees need to have knowledge of and train themselves to remain relevant and have a sustainable role in tomorrowâ&#x20AC;&#x2122;s industry. Biosimilars and rare diseases One of the most exciting opportunities forIndian pharma has developed in the nascent field of biosimilars based on biologics. Biologics are medicines made from living microorganisms found in plant and animal cells. Biosimilars are simply generic versions of popular biologics. Indian companies are already in the race to

create these generic versions of biosimilars. No wonder, the market has been growing at a CAGR of 30% year-on-year since 2008. The second largest engagement in pharma is the market for rare diseases which requires specialized medicines with a larger net price to cost value. Today, this industry makes up about 17% of the sector. Treatment of non-communicable diseases such as diabetes, inflammation and cancer has seen greater adoption of biologic drugs and improvements as the manufacturability of peptides has fueled new growth in this field. In the future, gene therapy and gene editing through manipulation of RNA will shape the future of the entire pharmaceutical sector. Precision medicine and microchips lined with human tissue Mixing living human tissue with microchips has also shown huge potential to

February 2019 â&#x2013;ş 13

revolutionize drug development, disease modeling and customized medicine. Bio printing of human tissues and organs using a liquid matrix bioink that enables life and growth of human cells has shown great promise in healthcare. However, it is believed that 3D printing for drugs can radically alter the face of drug manufacturing, delivery and distribution across remote geographies. Precision medicine is a technique that combines clinical and molecular inputs to comprehend the underlying basis of disease. This input can be obtained in the form of information collected through genome sequencing reading disease tendencies and risks through associated biomarkers in DNA. Side effects can be minimized by accurate dosages suited to genetic markers in the individual and thus targeted therapies can be developed along those lines. Mobile health platforms Another immense pharma phenomenon taking place is the increasing reliance 14 â&#x2014;&#x201E; February 2019

on mobile health technology to conduct clinical research. Smartphones with powerful microprocessors can employ advanced sensors to monitor bodily indices and take biometric readings. Wearable devices with embedded technologies are also being used to gather such data and track heart rates, stress and sleep patterns, temperature, glucose levels, blood oxygen, and many others that could be relayed across always-connected interfaces to doctors and clinicians who can then expand the scope of drug trials to larger cohorts and resultantly draw more representative and accurate health outcomes. Nanotechnology in healthcare Nanotechnology has progressed to particles that relay information once ingested to physicians through mobile applications. It might soon be possible to remote control these particles to carry out certain acts in the body such as performing surgeries or seeking out and destroying cancer cells.

Artificial Intelligence and pharmaceutical management Artificial Intelligence combined with Big Data Analysis enables computer systems to sift quickly through massive amounts of patient data and discover and correlate previously unknown variables and diseases. The system can modify its recommendations based on the learning and continuous inputs it receives in the course of a live monitored therapy program. This process reduces costs for the patient and makes the process of consultation more convenient and non-intrusive. These and many other exciting changes await the pharmaceutical industry practitioner.

(Dr. Pankaj Gupta, IIHMR University, Jaipur)

Pharma Bio World

Cold chain management for sensitive goods Packaging, route planning and risk analysis ensure safe conditions during transportation of delicate drugs. Drugs are sensitive goods to transport, which can be subject to irreversible damage if they are stored or transported at temperatures outside the tolerated range. If the temperature falls below or rises above the specified range the quality of drugs requiring refrigeration can be seriously affected and they may cease to be effective. This article therefore describes how transport conditions during the transportation of drugs can be optimised through suitable packaging, individualised process design, the analysis and assessment of potential risks and close collaboration between the sender and the freight carrier.

owadays drugs are transported over long distances both over land and by air. In addition to choosing the right packaging and correct cooling system, the transport process must ensure that the drugs reach the patient without having suffered any loss of quality as a result of the negative effects of inappropriate temperatures.

of Guideline 937 under the heading ‘Good Distribution Practices for Pharmaceutical Products’ (GDP), the WHO stipulates the storage conditions to be complied during transportation and the permitted deviations2. The US Pharmacopeia (USP)

also demands temperature control and monitoring during transportation3. In the EU, the 1994 ‘Guidelines on Good Distribution Practice of Medicinal Products for Human Use’ apply. These guidelines likewise require that for drugs which need

During transportation drugs are subject to the same provisions with regard to maintaining a specified temperature range as applicable during storage. Drugs requiring refrigeration – medication which must be stored at temperatures between 2 °C and 8 °C - can either be transported using a controlled active cooling system or an uncontrolled passive cooling system. By active cooling system we mean the use of refrigeration units in appropriately equipped vehicles or active air freight cargo containers. Passive cooling systems involve the use of insulated cool boxes in which cool packs are packed along with the goods to be transported in order to cool them. Requirements in respect of the transportation of drugs Legislation requires proof that medical products incur no damage as a result of storage or transportation1. In Annexure 5

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Figure 1: IATA Standard Time and Temperature Sensitive Label. February 2019 ► 15

essential to ensure that the specified temperature range for that drug is maintained throughout the whole period from production to delivery to the patient.

to be stored at a specific temperature, suitable conditions are to be maintained during transport4. However, since there have been considerable changes in transport and logistics since 1994, the European Commission has issued new draft guidelines (EU Commission Guidelines on Good Distribution Practice of Medicinal Products for Human Use). These new guidelines take into account the general advances in the practices employed in storage and transportation, as well as the ‘Directive 2011/62/EU’ on combatting counterfeit drugs, and will replace the 1994 guidelines in the coming months. The above brief summary of the legal requirements shows that there are differences between the conditions for the storage and transportation of drugs set out in the GDP (Good Distribution Practice) guidelines issued by the authorities in different countries. These include quality assurance requirements which must be taken into account by both the pharmaceutical companies and their logistics partners during the storage and transportation of drugs. The fact that the GDP guidelines are not harmonized globally adds to the complexity of transporting drugs. For example, American legislation requires temperature monitoring, which is not required in the existing EU guidelines. Exceeding or falling below the specified temperature range for a particular product during transportation can have a decisive effect on the quality of the drug, even if these limits are exceeded only briefly. 16 ◄ February 2019

A practical example will demonstrate exactly how problematic that can be. Let us take the example of a passive transport packaging being used to transport goods requiring refrigeration (temperature range 2 °C to 8 °C), and is stocked with frozen cool packs. If the goods are being transported in December and are leaving winter temperatures in Europe to arrive in summer temperatures in South America, the risk of the goods warming up on reaching the destination airport is factored in, and the level of cooling required is therefore often exaggerated. By contrast, the risk of the goods freezing at the departure airport is barely considered. As a result of the excessive level of cooling, the temperature of the drugs briefly falls below 0 °C. Being frozen, even if only briefly, can cause irreparable damage to the drugs and cause lasting changes to its characteristics. This entails the risk that the safety of the drugs may be reduced and can endanger the patients, e.g. by reducing the shelf life, making the drugs less effective or because of toxic by-products created during degradation. It is therefore

Process analysis and risk assessment As the above example demonstrates, the choice of appropriate packaging for transportation is not sufficient to ensure that the drugs continue to be safe. It is necessary to analyse the whole transport process and to assess the potential risks for each individual stage of the process with regard to drug safety. When drugs requiring refrigeration is transported in packaging with passive cooling systems, it is usual to apply one packaging solution for general consignments to all destinations worldwide. This packaging is aimed at catering for every extreme circumstance. In practice, this means using large packing cases with thick insulation, special foil on the outside and many cool packs, which have often been cooled to different temperatures prior to packing. These standard packagings have a poor internal – external volume ratio, are heavy and therefore result in increased transportation costs. A first step towards reducing transportation costs, whilst at the same time reducing the risk of quality problems arising as a result of transportation is to select suitably adapted packaging, i.e. packaging

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Identification) technology enables the temperature to be measured and recorded throughout the transportation period. Thus, it is possible to check immediately upon arrival at intermediate points or at the destination, whether the temperature range has been exceeded during transportation, thereby making it possible to react quickly. In this context, the IATA Time and Temperature Sensitive Label (Fig. 1), the use of which has been compulsory for the transportation of drugs requiring refrigeration since 1st July 20126, has improved handling of goods in transit. It contains all the information that those involved in the process need in order to deal correctly with drugs which require refrigeration. It is internationally recognised and hence is understood correctly at all interim points along the transport route. which meets the demands of the drugs and the route. In order to be able to assess the risks faced by drugs requiring refrigeration whilst in transit, it is necessary to analyse every stage in the transport process. A detailed analysis is a vital prerequisite if the whole transport process is to be organized in such a way that the temperature requirements can be maintained during transportation of the medicinal products along with reduced cost of transportation. Ideally, the sender (i.e. the pharmaceutical company), and the logistics service provider should collaborate closely in the process analysis and risk assessment. Whilst the pharmaceutical company has the relevant knowledge with regard to its product, the logistics service provider can add its expertise regarding the transport aspects. Together, both parties should conduct the process analysis, which shall include the study and documentation of the individual sections of the route, as well as the procedures and protocols to Pharma Bio World

be followed by every party involved in the logistics operation (handling agent, airline company, etc). On the basis of this process analysis, a suitable route and the packaging are to be determined. This results in individualised transport routes that have taken into account all the relevant factors like the seasons in the departure and arrival airports, the quality of the handling agents, the logistics, the airport, etc. In order to comply with the legal requirements in force in the relevant country of dispatch, and in order to be able to react quickly, if the temperature is not kept within the specified limits, both parties should ensure temperature monitoring. For example, the guidelines set by the American health authority, the FDA, require temperature monitoring throughout the whole transport process5. The measuring equipment for this can be attached either on the inside or the outside of the package. Measuring equipment using RFID (Radio Frequency

When pharmaceutical companies and logistics service providers work together to conduct the process analysis, they should start by answering the following questions: • What kind of transported?

drugs

are

• What storage and transportation conditions apply for these drugs? • What are the absolute temperature limits for these drugs? Do these • limits also apply for the packaging? • What kind of packaging is to be chosen? Is the packaging suitable for • the job? Based on what temperature profile was this type of packaging • selected? • Is the most important information clearly displayed in a form that is • easily understood on the outside of the cooling packaging? Once the answers to these questions have been arrived at, the next step is to establish and document the process with all parties involved in it. For this, the process documentation is broken down into the following points: February 2019 ► 17

of drugs that require refrigeration, thereby ensuring the quality and safety of the drugs. References 1. Arzneimittel und Wirkstoffherstellungsverordnung (AMWHV); Section7 - Lagerung und Transport. 2. WHO; Expert Committee on Specifications for Pharmaceuticals Preparations Technical Report Series 937 (Annex 5 - Good Distribution Practices for Pharmaceutical Products); 2006. • • • • • • •

preliminary phase, handling at the airport, interim storage, loading, main phase (flight), unloading, separating the package components, customs clearance and preparing • the goods for collection. In some cases the next phase, i.e. delivery to the patient, is also considered. The risk analysis is conducted based on the process documentation. In short, all potential sources of errors are analysed and assessed. For this, one should attempt to take as objective a viewpoint as possible, and the process should be undertaken by all the parties involved. The FMEA (Failure Mode and Effects Analysis) model is a suitable method for analysing and assessing potential risks. The risk analysis should be undertaken for every stage in the whole process and should consider every risk that could endanger the quality of the drug as well as list the likelihood of that risk becoming real. Once the process has been set out in detail and all risks assessed, the plan for monitoring the temperature is to be drawn up. Depending upon the country and the legal requirements in force in that 18 ◄ February 2019

country, this may entail comprehensive monitoring or random sampling.

3. US Pharmacopeia (USP); Chapter 34; 1079. 4. European Union; Guidelines for Good Distribution

The recorded temperature data should provide the following information on

Practice of Medicinal Products for Human Use

- whether the specified temperature range has been maintained throughout the entire transportation period; - whether the temperature rose above or fell below the tolerated range and what caused this; - whether the anticipated risks were successfully eliminated; whether - the process requires adaptation, and - whether the packaging used is suitable for transportation.

Communities (No. C 63/4); 1st March 1994.

Ultimately, the temperature monitoring data determines whether the drugs are to be released in the market at their destination.

(94/C 63/03); Official Journal of the European

5. Lucas, T. I., Bishara, R. H., and Seevers, R. H.; A Stability Program for the Distribution of Drug Products; Pharmaceutical Technology; July 2004; 68-73. 6. IATA Time and Temperature Sensitive Label to Become Mandatory from 1 July 2012; www.iata.org; June 2012.

(Source: HGP AG)

Conclusion When it comes to the effects of transportation on drug safety, it is not only the correct choice of packaging which is decisive, but also the design of the transportation procedure and route based on risk analysis and assessment. Individualised transport protocol design, the choice of packaging, sensible planning of transport routes and close collaboration between pharmaceutical companies and logistics service providers enable optimisation of the transportation Pharma Bio World

insights

Driving cost excellence and productivity in pharmaceutical operations through Digital and Advanced Analytics Cost excellence in production and raw material procurement used to be a source of competitive advantage among pharmaceutical companies. Today, it is a necessity for survival in the industry, primarily due to the constant margin pressures that pharmaceutical companies face. While traditional cost excellence and productivity levers have helped pharma companies capture profits, maintaining and increasing margins in the future will require newer ways of driving cost excellence. This paper shares how Digital and Advanced Analytics (DnA) can play a central role in achieving greater cost excellence. It shares examples of how some pharma companies have already started using DnA across different spend bases. It also proposes a step-by-step approach companies can consider when going digital. The need for pharma operations to embrace Digital and Advanced Analytics Pharmaceutical company margins are under pressure from various factors. Incumbents and new players have increased competition, the complexity of portfolios is creating production inefficiencies, buyers are consolidating and quality costs are rising. While the revenues of several pharma companies have remained flat (or grown minimally), their costs have significantly increased, pressuring overall margins and impacting the bottom line of pharma companies. Between 2013 and 2017, EBITA margins have declined for nine of the worldâ&#x20AC;&#x2122;s top 10 Gx pharma companies. This has forced pharmaceutical companies to undertake large-scale cost reduction and productivity improvement initiatives However, these do not enable companies to capture all opportunities for better productivity and cost excellence. DnA can help in this scenario, and has already been effectively deployed in other industries. The limitations of traditional levers Most pharma companies have so far resorted to traditional levers and Pharma Bio World

methodologies for better productivity, such as Alternate Vendor Development (AVD), negotiation, trial-based yield improvement and six sigma-based throughput improvement. These traditional levers have helped weather headwinds to some extent by capturing the optimization opportunities within easy reach. But, given prevailing market realities, it is critical for pharma companies to capture all opportunities for best-in-class productivity. The traditional levers and methodologies have some limitations which restrict pharma companies from achieving cost excellence and market leadership. They do not enable pharma companies to recognize patterns and predict trends The pharma industry often experiences dynamic changes at both the consumer and the supplier end. An inability to predict these changes can lead to sudden increase in costs. For example, when demand predictions are inaccurate, they can compromise supply chain agility, pushing up inventory costs or causing a loss of sales due to supply shortages. Pharma companies collect and maintain a large amount of data related to manufacturing, quality and procurement

to comply with quality and regulatory requirements. But this data is not typically used to drive productivity and cost excellence initiatives. These data sources include Batch Manufacturing Records (BMR), raw material specification information and IP/FG (In-process/ Finished Goods) test reports to name a few. Manual and Excel-based processing/ analytics on such large data sets are either inadequate or time consuming. They lack the ability to manage complex and fragmented spend bases Large pharma companies, which may procure thousands or sometimes tens of thousands of SKUs (including bulk drugs, packaging materials, etc.) annually, rarely negotiate for 30 to 40 percent of their tail spends, leaving them unmanaged. This tail spend is highly fragmented, has a complex distribution network with many suppliers and, in many cases, unclear accountability within the procurement team. Applying traditional levers such as negotiation, AVD and yield improvement through continuous improvement programs does not yield adequate returns on investment since they need resource commitments over a long period of time February 2019 â&#x2013;ş 19

insights e.g., manpower to carry out negotiations, expense on account of lab testing samples for change in QC material SKUs, internal management bandwidth for approvals on all small ticket vendor/specification changes.

marketing campaigns customized for over 15,000 customer personas. The bank created a 360-degree view of all the customers using data related to customer demographics, cross-channel interactions, transactions and marketing.

They have been unable to improve execution Despite coming up with great ideas and design, the sustainability of new initiatives remains a concern in many productivity improvement programs undertaken by pharmaceutical companies. Sustaining and implementing such a program is often person-dependent, requiring manual interventions along critical processes like the “procure to pay” cycle. In addition, large-scale capability-building initiatives to drive transformations are timeconsuming, non-standardized, often restricted to classrooms, and do not follow adult learning principles.

In the automotive industry, a newly appointed CEO of an elite automotive organization set out to determine the causes of delays in bringing the current car to the market. The goal was to reduce time to market by five percent, with each week saved worth GBP 3 million. Analytics models identified all the factors involved in the new product development process, including bill of materials and engineering deliverables. The company used insights from the AA model to create an action plan targeting release phases of components and reducing engineering churn. The solution cut time to market by 10 percent (over-delivering by 100 percent), six to nine months ahead of the expected delivery time and reduced design and engineering costs by 11 percent.

How DnA has been deployed in other industries Embracing DnA could help to address these challenges, as industries like telecom, transportation, financial services and automotive manufacturing have demonstrated. Digitization in these sectors was propelled by the availability of rich data streams, the introduction of new technologies, and a clearly defined opportunity or business case. The financial services industry was one of the earliest adopters of advanced analytics (AA) and digital and has benefitted greatly from it. For instance, a leading retail bank increased its net income by 3 to 5 percent, reducing customer churn by 20 to 40 percent using AA. Advanced modelling techniques helped the bank to identify the top 50 drivers of customer attrition, build real-time predictive models to map the likelihood of attrition through the customer journey for the drivers, and design interventions to prevent attrition. In the second phase of the transformation, the bank tripled the customers’ likelihood of making purchases through advanced 20 ◄ February 2019

Such Digital and Analytics (DnA) applications can be successfully applied to the challenges previously highlighted for pharma companies. The next section provides an end-to-end view of the potential applications of DnA, and shares use cases to drive the next wave of cost optimization initiatives. DnA can enhance profitability for pharma companies Technology-related trends such as advancements in analytics, sensors and automation, and the movement of nontraditional players into pharma are likely to facilitate the adoption of DnA in the pharmaceutical industry over the next five years. Our analysis suggests DnA led approach can deliver savings of 8 to 10% on the cost base, as an additional wave of cost Nexcellence for pharmaceutical companies. Various use cases illustrate the potential of DnA applications when applied to pharma companies.

How DnA applications can help The use of DnA can help to address the three challenges that the traditional approach has not been able to overcome. Improve predictive and prescriptive ability The application of machine learning (ML) algorithms—like classification and regression algorithms, and unsupervised learning algorithms—to specific pharma operations has shown tremendous cost reduction outcomes, identifying specific variables or input parameters which impact performance. Some successful ML-based use cases include demand projection algorithms, predictive API yield improvement tool, predictive and prescriptive inventory/sales loss optimization model and Natural Language Processing or NLP-based applications to identify optimization opportunities in MRO spend (Maintenance, Repair and Operations). DnA tools can be applied across the entire value chains of procurement, manufacturing, supply chain, quality and manpower. For example, analyzing all production and utility condition parameters based on three to six months of historical data can help uncover relationships between these parameters and energy consumption. The output could be prescriptive actionable insights on parameters driving seasonal variations, “areas and periods” during the day/night/ year with mismanagement of energy usage, etc. Manage complexity and coverage Accessing the long-tail spend in fragmented spend bases, through DnA applications like NLP, fuzzy logic, optical character recognition (to convert physical documents to machine readable formats) broaden savings potential by another 30 to 40 percent. For example, both packaging and repairs/consumables categories have smallticket items with a long tail which typically form 30 to 40 percent of the spend base and are not covered through traditional levers of cost optimization. Most of these items are Pharma Bio World

insights Exhibit 1

Potential use cases of Digital and Advanced Analytics for cost excellence in pharma companies Non-exhaustive

Spend category

Direct raw material (e.g., Intermediates/ KSMs, APIs, Excipients)

Packaging material and manufacturing consumables

Predictive and prescriptive applications

▪

Advanced Analytics – led yield variability reduction

▪

Automated spend analytics to provide prescriptive recommendations

▪

Incremental impact from DnA led approach (as % of costbase addressed)

▪

Automated clean sheeting of raw materials to uncover ‘should-cost’ of complex materials

8–10%

Natural Language Processing to prescribe volume consolidation and arbitrage opportunities

▪

Optical character recognition to automatically read specs from physical spec sheets/documents

3–4%

Supervised learning algorithms to prescribe PTPK rates for all routes and modes of transportation

▪

Advance analytics based application parameters impacting energy consumption

▪

Proactively manage attrition by n=1 employeelevel predictive algorithms

▪

Advanced Analytics – based application to predict stock outs/ inventory build up and suggest proactive actions

▪

Advance Analytics based optimization in OOS and deviation range

▪ Logistics

▪ Energy and utilities

▪ Manpower

Supply chain

Quality

Applications to manage complexity and coverage

Applications to accelerate execution excellence

Rule-based algorithms to optimize utilization and backhaul opportunities for containers and trucks

Smart digital dashboards based energy monitoring to identify leakages and provide recommendations Automated optimized manning in plant operations (production, quality and support functions) based on 'demand' outlook Digital S&OP for dynamic planning and shorter lead time

▪

Cloud-based intelligent project management tools

▪

Remote digital gamified capability building

▪

e-RFX/ e-auction: web based automated RFQ engine

▪

Robotic process automation, AI-based contract adherence

8–10%

6–8%

10–12%

10–15%

6–8%

often overlooked, while the top spend items operations to new-age companies with 7AIDriving cost excellence and productivity in pharmaceutical operations through Digital and Advanced Analytics led abilities for network efficiency. are repeatedly addressed. Advanced Analytics can also be used to address complex spend bases, e.g., logistics with complex networks. Pharma companies could either take the active management route by building intelligent internal platforms to sift through complex networks and suggest the best possible routes, along with backhaul opportunities, or entirely outsource the logistics Pharma Bio World

Accelerate and support execution excellence DnA interventions can make execution and implementation activities personindependent and system-driven, plug leakages in execution and slash the implementation timeline across the procure to pay cycle. This will help to bridge the gap between savings targeted versus realized due to poor execution.

Web-based automation tools like eRFX (automated RFQs sent to vendors) and program management tools like McKinsey’s WAVE tool can track milestone deadlines and alert activity owners, preventing slippages and delays. Another leak in the procure to pay cycle is contract management and execution. Tools using ML algorithms can automatically build out contracts and automate repetitive tasks. Blockchain technology can create and track changes across multiple copies of a contract distributed among multiple stakeholders. Finally, contract analytics can monitor adherence Band issue alerts or reminders if the terms are not followed. Building the capabilities of the “doers” is a key enabler for implementing and sustaining any transformation effort. Digital solutions can now deliver standardized learning content at scale in an engaging manner, while allowing the on-demand consumption of knowledge and training. For example, McKinsey’s proprietary tool, Ninja, is a gamified learning and capability building tool with specific modules directed towards procurement, manufacturing, quality and sales. Ninja delivers learning in “micro-bursts”, which are short bursts of questions and relevant knowledge nuggets, delivered to the workmen or the sales force on their mobile devices, enabling on-field learning. It follows a gamified approach with leader-boards that allow players to challenge each other on quizzes, weekly and monthly recommendations on topics, making learning fun and engaging. Applying DnA in pharma companies DnA use cases can be applied across the spend bases of pharma companies in pursuit of cost excellence (Exhibit 1). Case example 1: Improving direct material productivity in manufacturing APIs Large variability in yield while manufacturing APIs is a daily problem for pharma companies. It occurs due to a multitude of factors, sometimes involving February 2019 ► 21

based on the input data (like the rate of increase in temperature to rate of increase in pressure delta T/delta P). The input data and new features were put through an AA engine which ran multiple supervised algorithms like CART and Random Forest to make sense of the problem. The algorithms were then customized to ensure that they fit the requirements of the organization. Upon implementing the recommended results, the pharmaco observed a 10 to 12 percent improvement in yield per product.

insights over 200 variables, such as temperature, pressure and raw material properties. Even a small reduction in variability while manufacturing large-volume APIs could improve the bottomline. Traditional methods used spread sheet-based analytics to identify high-quartile yield batches, study batch parameters and generate ideas. This is limited by the hypothesis-based thinking of experts and shopfloor operators which rules out some non-obvious parameters that could be impacting the product yield. A large Gx pharmaco recently reduced API yield variability by about 80 percent, using an AA model that identified attributes with high correlation to the batch yield, with the allowed ranges (Exhibit 2). First, the input data was stripped of inconsistent and out-of-bound 8 datasets. Multiple parameters from the dataset were combined to create specific features based on the input data (like the rate of increase in temperature to rate of increase in pressure delta T/delta P). The input data and new features were put through an AA engine which ran multiple supervised algorithms like CART and Random Forest to make sense of the problem. The algorithms were then customized to ensure that they fit the requirements of the organization. Upon implementing the recommended results, the pharmaco observed a 10 to 12 percent improvement in yield per product. Case example 2: Clustering fragmented SKU data using NLP to optimize procurement spends On several occasions, pharma companies lack clean data or standardized procurementprocesses for MRO and consumables like gloves, shoe covers, lab equipment, labconsumables, other safety equipment, etc. Handling these SKU categories can become difficult, particularly when unique material codes are not defined due to highly fragmented SKUs. Driving procurement efficiencies in these categories can become extremely cumbersome using traditional levers like 22 ◄ February 2019

Exhibit 2

API yield improvement: Leveraging insights from historical data to predict optimum parameter ranges for future batches Situation

DnA application implemented

Impact observed

▪ Leading pharma company

▪ Developed a data lake from

▪ Yield improvement potential

with ~100 APIs manufactured across multiple sites

▪ 6–10% yield variation on average across the top APIs

▪ Cost competitiveness was critical to maintain and improve market share

10+ data sources creating 300+ variables for each API stage, e.g., BMR, LIMS, SCADA systems

▪ Created a customized

of 10–12% per product achieved on adjusting the identified critical process parameters to recommended ranges

algorithm (iterative T-test followed by multiple regression) to help identify the relationship between parameter and yield

What is distinctive about this approach?

▪ Ability to precisely identify and prescribe the parameters and value ranges which influence product yield ▪ Ease of implementation, recommendations can be directly implemented on the shop floor, without needing a pilot/validation batch (since recommendations are 'within' the BMR range)

consolidating vendors, plugging price a pharmaceutical company to identify Driving cost excellence and productivity in pharmaceutical operations through Digital and Advanced Analytics arbitrage leakages and harmonizing savings of 12 to 13 percent (Exhibit 3). specifications across plants. Case example 3: Inventory optimization A DnA-led approach involves reading through increased visibility on the endtext data and creating clusters based to-end value chain on keywords to identify unique Supply chains at pharma companies are material SKUs. NLP techniques becoming complex due to the growing eliminate spelling mistakes, and number of SKUs, increasing customers and cluster the data using New Detection distribution reach. Manual spreadsheetAlgorithm (NDA) and semantic based Supply Chain Analytics is no clustering algorithms. The output of longer capable of balancing all the three an NLP algorithm is a clear set of objectives of an efficient supply chain: unique materials and clusters on which low inventory, zero stock-outs and limited procurement efficiency levers can be distribution costs. applied systematically. A rule-based centralized digital engine ensures that every material is ordered according to the latest and lowest company-wide price, leading to consolidation and harmonization across the organization. In addition, domain expertisetize is employed to generate a businessspecific taxonomy of keywords using relevant terms and topics. This helps to categorize items for a far more efficient analysis. Using such techniques in a procurement spend optimization program enabled

AA algorithms now allow companies to predict over stocking and stockouts, helping them to minimize supply chain costs. Automotive companies and auto component manufacturers are already ahead on this curve. Even within the pharmaceutical industry, numerous companies have already adopted a predictive and agile supply chain. A Gx pharma company recently put in place a predictive, prescriptive and descriptive supply chain algorithm which helped reduce inventory by about 15 percent while reducing stockouts by about 60 percent in a span of just 12 months (Exhibit 4). Pharma Bio World

price, leading to consolidation and harmonization across the organization. In addition, domain expertisetize is employed to generate a business-specific taxonomy of keywords using relevant terms and topics. This helps to categorize items for a far more efficient analysis. Using such techniques in a procurement spend optimization program enabled a pharmaceutical company to identify savings of 12 to 13 percent (Exhibit 3).

insights

on the DnA transformation journey. Commonly stated reasons include an MRO & Consumables: Converting millions of purchase line items to a few logical procurement categories inability to mobilize large capex for digital equipment and applications, and the lack DnA application Situation implemented Impact observed of availability of “electronic data”. Such reasons are often driven by the lack of ▪ Mid-sized pharma company ▪ Reads text data and creates ▪ 12–13% savings identified a comprehensive understanding of what with highly fragmented clusters based on keywords for across repairs and Case example 3: Inventory optimizationDnA through visibility the end-to-end hasincreased to offer. Mostondigital use cases repairs and consumables identification of unique material consumables spend-base value chain have very limited capex outlays, often purchase ▪ Techniques used for tagging Supply▪ chains Helped at topharma optimizecompanies the are becoming complex due to the growing number with less than one year for payback, and ▪ No unique material codes raw data are Natural Language inventory with the right of SKUs, increasing customers and distribution reach. Manual spreadsheet-based Supply resulting in the inability to Processing, Stemming and material at the right place the lack of electronic data can be easily Chain Analytics is no longer capable of balancing all the three objectives of an efficient consolidate vendors, spot Semantic tagging circumvented with acosts. one-time effort of supply chain: low inventory, zero stock-outs and limited distribution price arbitrage losses and ▪ Taxonomy created after collecting and converting manual data to get volume discounts extensive client involvement, AA algorithms now allow companies to predict over stocking and stockouts, helping them electronic form. Exhibit 3

▪ Inventory at multiple sites

validation and syndication

What is distinctive about this approach?

to minimize supply chain costs. Automotive companies and auto component manufacturers are already ahead on this curve. Even within the pharmaceutical industry, numerous Organizations need not begin their DnA companies have already adopted a predictive and agile supply chain.

transformation journeys with a big bang but can make the journey step by step. (or addressed only in part) due to fragmentation supply chain algorithm which helped reduce inventory by about 15 percent while reducing Adopting DnA involves planning the ▪ It gives procurement managers visibility on the nature of spends and possibleby synergies across stockouts about 60 percent in a span of just 12 months (Exhibit 4). transformation in phases and creating manufacturing sites ▪ It presents the opportunity to comprehensively address a categoryAwhich was previously Gx pharma companydeprioritized recently put in place a predictive, prescriptive and descriptive

Case example 4: Improving the cost Exhibit 4 9 cost excellence and productivity in pharmaceutical operations through Digital and Advanced Analytics of quality Driving by optimizing instances of Inventory Optimization: Solving a highly complex cost element through increased visibility on the end-toend value chain Out-Of-Specification (OOS) Though not a direct P&L line item, DnA application Situation implemented Impact observed the Cost of Poor Quality (COPQ) can have huge implications on productivity ▪ Highly complex Gx supply ▪ Machine learning helps Sustained impact and cost efficiency. From decreased chain with 1000s of SKUs, develop a “self-correcting” ▪ Service level increased from productivity due to unresolved OOS to multiple DCs across the planning and faster S&OP 91.4% to 99% even as sales country and several plants batch rejections, COPQ impacts the ▪ Predictive Analytics answers grew by 15% per year ▪ Lack of supporting “What will happen?” profitability and often the reputation of ▪ Supporting 5–6% of sales infrastructure, in the form of ▪ Prescriptive Analytics through better demand a pharma company. In case of major fragmented IT systems answers “so-what?” planning deviations, pharma companies start ▪ Descriptive Analytics answers performing a root-cause analysis. “What has happened?” However, manual analysis limits the amount of data that can be processed. This leads to the use of hypotheses and What is distinctive about this approach? prioritization based on the 80–20 rule, ▪ Helps to proactively identify and avoid stockouts/overstocking without any manual intervention which may cause managers to overlook ▪ “Self-correcting” to ensure continuous improvement in the “quality” of output and recommendations some not-so-obvious parameters driving the deviation. A pharmaceutical client implemented an an ecosystem of enablers within the ﬁrm to AA models can overcome this by sifting AA-based OOS and deviation resolution effect change. Leading companies that have through entire sets of data from multiple model. The Case orchestrated successful digital pharma company achieved an of quality example 4: Improving the cost by optimizing instances of transformations Out-Ofsources spanning longer periods of time average of Specification 35 percent (OOS) reduction in OOS have done so in three phases. They started Though not direct P&L line the Cost of Poor Quality (COPQ) can have huge these up to predict the cause of the deviations. within 1.5 months with speciﬁ c use cases, followed of adeploying theitem, model on productivity decreased productivity For example, using the data binary and helped implications with anFrom end-to-end overhaul of adue function (the bring a critical productand ofcost theefficiency. to unresolved OOS to batch rejections, COPQ impacts the profitability and often the partition algorithm (dividing data sets company back lighthouse approach), and then scaled up the to the market (Exhibit 5). into two distinct subsets and identifying changes across theDigital enterprise. Driving cost excellence and productivity in pharmaceutical operations through and Advanced Analytics 10 parameters driving the difference) The path to embracing DnA successfully can help identify the range of process Several myths abound regarding why Phase 1: A use case–led solution to a parameters impacting the deviations. pharma companies have not yet embarked specific problem statement—Building Pharma Bio World

February 2019 ► 23

and identifying parameters driving the difference) can help identify the range of process parameters impacting the deviations. A pharmaceutical client implemented an AA-based OOS and deviation resolution model. The pharma company achieved an average of 35 percent reduction in OOS within 1.5 months of deploying the model and helped bring a critical product of the company back to the market (Exhibit 5).

insights Exhibit 5

Quality: Advance Analytics helped reduce overall OOS instances by 35% for a formulation product

Situation

DnA application implemented

Impact observed

▪ A leading Gx player was

▪ Collected data for 2+ years,

▪ 97% accuracy in model

facing issues in manufacturing a critical product

including digital data from central systems, manual data and external data

– Large number of valid

▪ Multivariate model to predict

OOSs and OOTs were found in critical parameter test

– Delayed launch in multiple countries

– Internal team working to find CAPA with for 4 months

FPM built using all the RM test results and process variables

▪ 11 variables found to contribute to FPM outcome: 8 raw material variables, 3 manufacturing process variables

prediction

▪ Resumed batch manufacturing within 3 weeks of implementing modeling recommendations

▪ 35% reduction in OOS instances and product could be launched on-time in critical markets

What is distinctive about this approach?

▪ Efficient combination of all data sources to arrive at the right insights; no need to develop or capture new datasets; can leverage available data from an existing digitized process

▪ High accuracy in ability to predict the source of issues; short lead-time for implementation, faster resolution leading to lower loss of sale/profitability

momentum in the organization early on Phase 3: Enterprise-wide transformations is critical. Pharma companies launch across several functions - This phase a highimpact use case which is limited focuses on transforming the entire Driving cost excellence and productivity in pharmaceutical operations through Advanced into Digital one and that usesAnalytics DnA on11 in scope (restricted to a specific unit or organization process). Examples of use cases include a large scale. The firm deploys several cross-functional use cases to transform procurement optimization of tail spends the organization. Examples include data among APIs/ntermediates/MROs, yield and analytics–driven sales excellence, improvement initiatives for a set of one operational excellence and procurement to five APIs in a manufacturing block, and excellence programs, undertaken OOS reduction efforts in a set of one to simultaneously. This phase requires five formulations at a formulation site. rapidly building the foundations including the organizational setup and modernizing Phase 2: A “lighthouse-focused” end-tothe technological infrastructure and end implementation of DnA use cases operating model. For this, the organization across one function or area—The main needs to mobilize substantial resources, objective of this phase is to create an investments and time. To be successful, inspiration and innovation hub for the organizations embarking on digital organization. Pharma companies launch transformations require a set of key multiple use cases or projects within a enablers. A new McKinsey Global Survey function to demonstrate the full potential on digital transformations reveals five key of a given technology. Examples include dimensions that increase the chances improving operational efficiency (e.g., of a successful digital transformation. manufacturing andquality throughput), Consistent focus from leadership: Nearly strengthening of quality levels across 70 percent of all respondents say their a network, and optimizing opex organizations’ top teams changed during across the units or blocks of a the transformation leading to failure of implementation. The right people need to manufacturing location. 24 ◄ February 2019

be identified to lead the change, and they must see the implementation through till the end. New workforce capabilities: As organizations progress through the phases of a digital transformation, they will need to nurture a workforce with specific capabilities through initiatives like creating an Advanced Analytics Centre of Excellence. Feedback mechanisms: Organizations need to reinforce new behaviours through formal mechanisms, to support organizational change. These include establishing Bpractices like soliciting employee feedback on digitization. A digital upgrade: Organizations need to implement digital tools to make information more accessible, upgrade to digital selfserve technology and modify standard operating procedures to include new digital technologies. Frequent communication: Leadership in the organization must communicate the “change story” (reason for change, and how it ties in with overall priorities) in a clear and relatable manner across the organization. With use cases demonstrating tangible and sustainable on-ground impact, the time is right for pharma companies to embrace DnA. Early movers will have an advantage with the opportunity to differentiate themselves from the competition through a best-in-class cost structure. This could set them on the path to higher profitability and growth. (Sasikanth Dola - McKinsey & Co.)

Pharma Bio World

insights

Trends And Waves On The Biopharma Horizon The biopharmaceutical industry has a reputation of being averse to change. This is likely because traditional approaches to drug development have withstood the test of time, delivering safe and effective drugs for decades. Yet, new market dynamics, such as growing competition from biosimilars and niche drugs targeting smaller patient populations, are reshaping how drugs are produced and sold. The saying ‘If it isn’t broke, don’t fix it’ no longer suffices in a market focused more on efficiency and flexibility in manufacturing. Instead, these qualities have become the foundation of managing demand uncertainty and appropriately preparing for a wide range of possible launch outcomes. To achieve more control within a set design space and to mitigate costly risks requires a combination of process intensification, proper facility utilization, and successful technology transfer. Therefore, the time has come to look outside the comfort zones and explore alternative processes and technologies to achieve the industry’s goals. Exploring a scaleout, rather than scale-up, paradigm allows manufacturers to increase volume to fit the market needs and deliver quality drugs to patients faster than ever before.

he launch of many innovative biologic drugs is creating exciting new opportunities for patient care. As these novel medicines become a larger part of the industry’s portfolio, it is critical we secure a supply chain and manufacturing processes that produce drugs in a reliable, cost-effective way. Modern technologies can help achieve this by increasing facility flexibility and process intensification, which reduces facility size and costs with resulting decreases in manufacturing costs and financial risk. We now have a toolbox for the future that allows us to bring many different types of molecules to the market quickly and efficiently. Biopharma market dynamics Over the last 20 years, a combination of biopharmaceutical proteins, plasma products, and vaccines has driven the value of the world biopharmaceutical market from $11 billion to $230 billion1. A major factor in this tremendous growth is monoclonal antibodies. Many of the Pharma Bio World

monoclonal antibody therapies first approved in the ’90s are now the targets for the first wave of antibody biosimilars. These ‘follow-on biologics’ are expected to be a key factor in the growth of the global market over the next 10 to 15 years. Biosimilars are nothing new. In fact, biosimilar versions of erythropoietin (EPO) and growth hormone have been around in Europe and emerging markets for more than 10 years. However, what is capturing people’s attention are the first biosimilar approvals for the U.S. market and the rate at which biosimilars are emerging for many of the industry’s highest-revenue monoclonal antibody drugs. For example, there are currently 27 different projects in progress aimed at creating a biosimilar for Enbrel, a firstgeneration monoclonal antibody and topselling biopharmaceutical in 2016. When looking at other top-selling molecules from that year, there are currently at least 112 biosimilar projects spread over seven different molecules (as outlined

in the chart below)2. This emphasizes how competitive the biosimilar market is predicted to become. Look to Remsima as an example of a biosimilar’s potential for market success. Korean drugmaker Celltrion introduced Remsima as the world’s first biosimilar referencing Remicade in Europe in 2014. By the end of 2016, Celltrion reported it had taken away nearly 40 percent of the original drug’s European sales for that year3. In the United States, biosimilar adoption has been slower due to regulatory hurdles and a lack of interchangeability harmonization. Nonetheless, there is good evidence from Europe that, under more streamlined conditions, biosimilars can be adopted very quickly. Also, the manufacturing processes used to make biosimilars can be much more efficient than the legacy processes employed to make the originator drugs. This, in addition to other factors such as lower February 2019 ► 25

drugs are increasingly targeting smaller patient populations. This means that many of the biologic drugs coming onto the market over the next few years will be manufactured in lower volumes. Yet, there will be more of them. This, combined with the growth of biosimilars, makes for a strong pipeline of biopharmaceuticals for

insights

certainty in how we configure and develop manufacturing capacity. We must determine a way to construct capacity that ensures we can effectively manage this very dynamic environment moving forward. In terms of capacity uncertainty, three major factors can affect the type of capacity you build and when and where you build it:

API

Reference Therapeutic 2016 revenue Company product area [$ M]

Infliximab

Remicade™ Janssen

Autoimmune diseases

8057

Celltrion/Hospira (Korea, EU, USA, Brazil, Japan, Russia), Nippon Kayaku (Japan), Ranbaxy/Epirus (India), Samsung Bioepis (EU, USA, Korea)

Bevacizumab

Avastin™

Roche

Bowel, breast & colon cancer

6681

Biocad (Russia), Hetero/Lupin (India), Reliance Life Sciences (India)

Etanercept

Enbrel

Amgen/ Pfizer

Arthritis Psoriasis

9265

Sandoz (EU), Samsung Bioepis (EU, USA)

Trastuzumab

Herceptin™ Roche

Cancer

6680

Celltrion (Korea), Shanghai CP Gujian (China), Shanghai Henlius (China), Biocad (Russia), Biocon/Mylan (India)

Adalimumab

Humira™

AbbVie

Autoimmune diseases

16 524

Amgen (EU, USA), Torrent Pharmaceuticals (India), Zydus Cadila (India)

Rituximab

Rituxan™

Roche

Cancer, autoimmune diseases

7190

Celltrion/Hospira (Korea, EU), Sandoz (EU), DRL, Hetero, Intas, Zenotech (India), Probiomed (Mexico), Biocad (Russia)

Insulin Glargine

Lantus™

Sanofi

Diabetes

6324

Biocon (India, Japan), EMA submitted Nov 2016, Wockhardt (India), Eli Lilly / Boehringer Ingelheim (EU, USA, Japan, Australia), Samsung Bioepis / Merck (EU)

60 721

112

Total

# of biosimilar projects

clinical and R&D costs, contribute to drug conjugates (ADCs), bi-specific antibodies, and gene and CAR T-cell cost savings that allow biosimilar Preparing for the future: visions and insights for biomanufacturing manufacturers to price their drugs more therapies. For gene and cell therapies, an additional challenge is how to efficiently aggressively. manufacture drugs intended for individual The pace of therapeutic and molecular patients, which involves a more complex innovation is also paving a new path and ‘personalized’ supply chain. for the future of biopharmaceuticals. A key driving point in the expansion of As our understanding of disease biology breakthrough therapeutic modalities is the becomes more refined, drugs are development of cancer immunotherapies, increasingly targeting smaller patient such as Keytruda and Opdivo. There are populations. This means that many of the a large number of global clinical trials biologic drugs coming onto the market over around the development of these exciting the next few years will be manufactured in new drugs. However, their high cost is lower volumes. Yet, there will be more of giving healthcare systems pause as to them. This, combined with the growth of whether these types of therapies could biosimilars, makes for a strong pipeline ever be affordable for large populations. of biopharmaceuticals for the future. As There is also a great deal of molecular a result, by 2022, biopharmaceuticals are innovation, such as the rise in antibody- expected to make up about half of the top-

8overall of 28

26 ◄ February 2019

Biosimilar approvals, companies

selling 100 products and about 30 percent of the prescription drug market4. The top 10 is likely to include more small molecule drugs, which are staging a comeback in the industry. As the dynamic biopharma market continues to evolve, there are significant challenges that needs to be overcome in order to deliver these therapies to patients. How can we manage the key risks of a burgeoning market? The innovation shaping the industry is creating a lot of excitement and buzz; nonetheless, it also creates a substantial amount of uncertainty in how we configure and develop manufacturing capacity. We must determine a way to construct capacity that ensures we can effectively manage this very dynamic environment moving forward. In terms of capacity Pharma Bio World

insights uncertainty, three major factors can affect

• building too little capacity can result in

To overcome these challenges, you need

terial and variation) without impacting quality.that You iche drugs for patient pop-and when robust processes batch (i.e., processes missedprocess market Opportunity the smaller type of capacity you build tolerate to the greatest possibleas • manufacturing capacity is often and built reliability you build it: n areas suchand aswhere immune-oncology, must also have transparency with yourextent supplier, raw material and process variation) before regulatory approval increased competition among well as delivery at a high level of consistency. Finally, appropriate 1. Market fragmentation - Niche drugs • a product may not be approved, leaving without impacting batch quality. You must e same profit makes alsocan havesignificantly transparency andimpact reliability with capacity unused. for pool. smallerThis patient populations, choice an of manufacturing technology the your supplier, as well as delivery at a high intense areasyour such as immunes you may not be focus sureonwho time and capital risks of building manufacturing infrastructure. With these factors in mind, a manufacturer level of consistency. Finally, appropriate oncology, and more biosimilars mean many will exist by the time you go increased competition among companies must ensure it has the appropriate choice of manufacturing technology petition alsocompeting puts supply chains for the same profit pool. This manufacturing capacity and can secure can significantly impact the time and capital risks of building manufacturing st make suremakes we do not planning comprocapacity difficult, as you enough of the raw material supply chain infrastructure. Scale up or scale out? maythe not market. be sure who your competitors to meet the demands of this rapidly haste to reach will be or how many will exist by the growing environment. The challenge is The breakdown of the cost of goods forupmanufacturing an antiScale or scale out? you go to market. This intense made more complex because of some t part of thetime overall pharmaceuThe breakdown of the cost of goods for bodyunique shown below important insights into managing features of provides biopharmaceutical competition also puts supply chains manufacturing an antibody shown below cted to takeunder place in emerging manufacturing, such as: pressure, and we must make sure the costs and risks of manufacturing. Theimportant variable costs, such provides insights into managing sh to manufacture their markets we do not in compromise process quality in the costs and risks of manufacturing. The as cell culture media, chromatography resins, disposables, and • the complexity of the biopharmaceutical our haste to reach the market. ecurity it creates and because this variable costs, such as cell culture media, drug and are manufacturing process, consumables, a relatively smallchromatography part of theresins, equation. Yet, and the disposables, uring is seen2.asGlobalization a key component - A significant part where the process defines the nature are a up relatively part fixed costs for the necessities that consumables, keep a facility and small running, he cost of building and operating of the overall pharmaceutical market and quality of the end drug of the equation. Yet, the fixed costs for electricity, and maintaining GMP qualification, growth environment is predicted to take place such in • as processes that security, are consequently less-developed the necessities that keep a facility up and emerging markets. Many countries wish difficult expensive to change for and 60 to 70 percent offoran antibody’s of goods. running, such ascost electricity, security,This and type and size of capacity we build account to manufacture in their markets because regulatory reasons maintaining GMP qualification, account for percentage also includes the cost of depreciation. Most of these t markets. of the healthcare security it creates • supply chains with unique raw 60 to 70 percent of an antibody’s cost of fixed costs have to be of whether or not materials, which are maintained often natural irrespective and because this type of high-tech goods. This percentage also includes the ntity of biopharmaceuticals we products and single-sourced cost of depreciation. Most of these fixed manufacturing is seen as a key component the drug is being manufactured (or in what quantity) (Fig 1). economic development. onsiderably.of There will be more The cost of • costly manufacturing infrastructure with costs have to be maintained irrespective long construction lead times of whether or not the drug is being building and operating manufacturing nt of material required will be less capacity in a less-developed environment many cases, creates it mayquestions even be around about the type and size of capacity we build in and el. This is in stark contrast to anaround those different markets. number of relatively large-volume sks to consider: 3. Demand - The physical quantity of biopharmaceuticals we need to deliver

d capacity based on expected is changing considerably.deThere will be more processes where the able manufacturing economics amount of

material required will be less than 500 kilograms and, in many cases, it may can result in missed market even be around the 100 to 200 kilogram level. This is in stark contrast to an industry founded on a small number often built ofbefore regulatory relatively large-volume processes. Other demand risks to consider:

• building too much unused roved, leaving capacity unused.

capacity based on expected demand can lead to unfavorable manufacturing economics

nufacturer must ensure it has the city and can secure enough of the Pharma Bio World t the demands of this rapidly grows made more complex because of

Fixed cost Upstream Downstream Depreciation

Figure 1: Nearly 70 percent of the cost of goods for manufacturing an antibody can be attributed fixed costs for facilityof maintenance andgoods depreciation. Fig to1:the Nearly 70 percent the cost of for manufacturing

an antibody can be attributed to the fixed costs for facility maintenance and depreciation. February 2019 ► 27

Host cell choice Integration strategy Clone selection:

Figure 2: Considerations at different steps in process development

Up pr str oc ea es m s

- Stability - Titer

am tre s ns s w oce Do pr

Process-related impurities Product-related impurities Virus clearance Aggregates

e in ll l

- Protease or PTM sites - Aggregation prone regions - Oligomerization

Codon optimization Modification of:

M o de lec sig ule n

insights

Media & Feed selection Cell behavior: - Viability - Productivity

Product attributes Fig 1: Considerations at different steps in process development

manufactured (or in what quantity) (Fig 1). and cleaning time. The introduction of Two of the biopharmaceutical market’s technology is eliminating When youRoutes haveto increasing this type costcellsingle-use biggest Samsung and Amgen, The(SUT) end goal is to create a robust andplayers, reproducible good manachieved. titersofinclude line engineering, and time-consuming cleaning and structure, the inmost wayrequires to costly demonstrate the two extremes growing cells higherresourceful densities (which higher levels of ufacturing practice (GMP)-ready process that meets the criteria in the nutrients and oxygen), and changes processes, such as moving changeover costs for and delivering more theindustry manufacture economically is in through overall yield, achieves critical quality and to choosing whenattributes, it comes from batch to continuous perfusion processes. creates a final downstream processing specification ready process intensification. This allows you productive manufacturing time. capacity and technology.to In 2015, scale up for production. to The drive batches of material final as step,many downstream processing, is harvesting the proteins Samsung BioLogics announced the feel such they have commercial certainty, construction of its third manufacturing through your facility as possible and to Some and removing any processand product-related impurities, as host cell protein, DNA, protein A, fragments, and Applying based on product demand, and,bioinformatics: as a result, continuously improve throughput. Yet to aggregates, plant in Songdo, Incheon, in South undesired isoforms. Assessing product properties benefit, you must be able to sell these continue to build capacity at large scale. Korea. The facility, where commercial In silico bioinformatics mitigate the risks allow of process developers to analyze biobatches. Additional batches of an antibody However, a desire to production is expected to begin in 2020, logic molecules and predict how they will act in given situations. produced or an extra 1 percent yield over determining manufacturing capacity before at this stagethe mean the molecule can ‘pureThe application of “smart bioprocessing” Screening and modifications will make company the largest a year could be worth tens of millions of a drug hits the market and less overall play’ biologics contract manufacturer in The drivers of manufacturing therapeutic are upstream for capital risk have increased dollars in sales in Western markets.proteins If appetite productivity, protein quality, and overall cost. The aim of smart biyou can find a way to make your facility focus on building smaller facilities. This the world. The $750 million, 180 000-liter oprocessing is to use bioinformatics, lab-scale processing, and ancapacity plant is expected to manufacture more efficient, can potentially approach is often based on the benefits of Bioinformatics: alytics to createyou better process designs delay that can be verified before kilograms of biological product each Assess 4500 physicochemical investments in upnew facilities meet SUT and they are scaled to clinical trial andtocommercial-scale production. process intensification technologies product properties year5. On the other end of the spectrum increased demand that range from tens to to maximize output from the smallest The smart bioprocessing approach is modular and iterative (Fig is the Amgen facility recently built in hundreds of millions of dollars. possible 2). Analysis after each step provides more information thatfacility can footprint. Combining those be fed into the next step, and steps can be repeated refine the typesto of technology with new approaches Singapore, which adopted a flexible, Verification: Small-scale analytics: Process intensification is driven by many entire production process. to constructing manufacturing capacity, modular design6. It has a footprint of Test and evaluate the Explore thermal square feetand(75 percent technological trends. In particular, the particularly the design and rapid deployment only 120 000 The aim with “smart bioprocessing” is to front-load the critical process iteratively mechanical stability last 10 years have seen as tenfold increase of as modular-type analytics steps and solve many issues up front possible be-facilities, is changing the way smaller than a conventional facility), in fore the moving efficiency of cell culture, allowing which can be rapidly reconfigured. In into the small-scale and design steps. initial weOnce thinkthe about the overall scale paradigm. thesmall-scale use of smaller bioreactors. Purification production begins, the developers can look for issues contrast to Samsung’s use of 15 000-liter in the production or purification process and find ways to solve Design: processes are similarly shrinking as new Amgen’s facility uses Rather than scaling up to increase output, bioreactors, them before moving up to are a larger scale. Bytogathering theoretical chromatography resins adopted Develop process steps 2000-liter bioreactors that accommodate for example, by increasing bioreactor and experimental information as early as possible and then ironmatch the increasingly efficient upstream. volume, a manufacturer instead scales single-use bags. This setup allows ing out problems at a small scale, it is possible to verify that the Many efforts are underway to larger-scale make out to bioprocessing easily switch by rapidly building smaller facilities operators process works before committing to production. Fig 2: The smart approach among manufacturing more continuous, for to increase drug output as demand equipment to make different products. example, by reducing time-consuming increases. This reduces capital risks in the 12 of 28 for the future: visions and insights for biomanufacturing hold steps Preparing in processes. Better equipment early stages and allows a more dynamic So how do you know which type you design is leading to reduced maintenance matching of capacity to demand. should build? The answer is dependent on 28 ◄ February 2019

Pharma Bio World

cessing”

Assessing product properties In silico bioinformatics allow process developers to analyze biologic molecules and predict how they will act in given situations. Screening and modifications at this stage mean the molecule can

e upstream of smart bising, and anerified before ale production.

erative (Fig on that can to refine the

Bioinformatics: Assess physicochemical product properties

Verification:

Small-scale analytics:

Test and evaluate the

Explore thermal and

he critical process iteratively mechanical stability possible beOnce the initial ook for issues ys to solve Design: g theoretical Develop process steps nd then ironrify that the Figure 3: The smart bioprocessing approach oduction. Fig 2: The smart bioprocessing approach

acturing

the amount of risk you are willing to take. If you believe you have commercial certainty for your product and expect to need large amounts of material, most likely to supply a global market, building a large, conventional infrastructure can give excellent economics, albeit with a large up-front capital investment. If, on the other hand, you are targeting fragmented markets, niche products, and regional supply, then building a smaller, often SUT-based infrastructure is worth serious consideration. Some questions to consider are: What size of demand are you manufacturing for? What’s your market like? What is your confidence about being able to deliver to market? Make sure you consider the technology progress that has been made with titers, continuous processing, and SUT. With new technology and facility types, you can build your facility much more quickly than you could in the past. This allows you to make crucial decisions later when you have a better idea about the success of your product in clinical trials and the demand you will potentially face when you go to market. The scaleout, rather than the scale-up, paradigm is becoming a credible way to deliver Pharma Bio World

more volume to the market, as our ability to build manufacturing infrastructure accelerates through modular and singleuse technologies and increased focus on process intensification. Reinventing smart bioprocessing As biopharma companies develop growing numbers of biologic therapeutics and drug budgets are squeezed worldwide, there is an increasing pressure on manufacturers to find more efficient and effective production processes. To reach this goal, Rentschler Biopharma, an independent and family-owned contract manufacturing organization (CMO) based in Laupheim, Germany, is using an approach it calls ‘smart bioprocessing’ to create scalable manufacturing processes rapidly and efficiently. Manufacturing biologic drugs: Upstream and downstream Monoclonal antibodies have become one of the most commonlmanufactured complex biologic molecules by CMOs. There are also growing demands for hard-to-produce biologics, including fusion proteins, bispecific antibodies, and antibody-drug conjugates to meet specific

insights therapeutic needs. In this burgeoning area of complex molecules, cost-effective manufacturing is critically important. This is particularly true for cost-sensitive applications such as biosimilars and for molecules used to treat rare and orphan indications, where market size is limited. Small companies and startups with financial constraints also look for lower-cost support to be able to move rapidly through proof-of-concept studies to support deals. To ensure that their manufacturing methods are as efficient and cost-effective as possible, CMOs look to optimize production and purification using platform processes, continuous processing, and process intensification. Many factors need to be considered when developing a manufacturing process, particularly for a complex biologic (Fig 2). The first step in development is molecule design. This includes adapting the building blocks of the molecule — for instance, to improve the glycosylation sites or using protein engineering to enforce heterodimerization of bispecific antibodies. The next step involves the generation of the cell line, which begins with a choice of the mammalian host, such as hamster, mouse, or human cells. The decision depends on the type of protein to be produced, as these hosts differ in their ability to generate glycosylation. The DNA coding for the target protein must then be integrated into the cell genome, and recombinant cells are selected primarily according to expression levels, a process that traditionally takes around 18 weeks. Rentschler Biopharma has developed a process that uses site-directed integration in Chinese hamster ovary (CHO) cells to speed up the transfection process. This, along with fluorescence-activated cell sorting (FACS), halves the cell line development timeline, cutting it to around nine weeks. One key factor in the economics of protein manufacturing is the level of protein produced (titer). In the February 2019 ► 29

insights Applying bioinformatics: Assessing product properties In silico bioinformatics allow process developers to analyze biologic molecules and predict how they will act in given situations. Screening and modifications at this stage mean the molecule can be optimized to refine post-translational modifications (PTMs) or to eliminate protein aggregation and therefore increase yield. Examples of physicochemical properties that can be predicted using bioinformatics: • Isoelectric point (pI) • Charge distribution and hydrophobicity • Aggregation-prone regions • PTM sites • Protease sites • Immunogenicity early days of protein manufacturing in the 1990s, 0.1 g per liter was an acceptable level. Current commercial manufacturing capacities are more commonlyb around 5 g per liter, though levels of 10 g per liter or more can be achieved. Routes to increasing titers include cell line engineering, growing cells in higher densities (which requires higher levels of nutrients and oxygen), and changes in processes, such as moving from batch to continuous perfusion processes. The final step, downstream processing, is harvesting the proteins and removing any process- and product-related impurities, such as host cell protein, DNA, protein A, fragments, aggregates, and undesired isoforms. The application of ‘smart bioprocessing’ The drivers of manufacturing therapeutic proteins are upstream productivity, protein quality, and overall cost. The aim of smart bioprocessing is to use bioinformatics, lab-scale processing, and analytics to create better process designs that can be verified before they are scaled up to clinical trial and commercial-scale production. 30 ◄ February 2019

The smart bioprocessing approach is modular and iterative (Fig 3). Analysis after each step provides more information that can be fed into the next step, and steps can be repeated to refine the entire production process. The aim with ‘smart bioprocessing’ is to front-load the critical analytics steps and solve as many issues up front as possible before moving into the small-scale and design steps. Once the initial small-scale production begins, the developers can look for issues in the production or purification process and find ways to solve them before moving up to a larger scale. By gathering theoretical and experimental information as early as possible and then ironing out problems at a small scale, it is possible to verify that the process works before committing to larger-scale production. The end goal is to create a robust and reproducible good manufacturing practice (GMP)-ready process that meets the criteria for overall yield, achieves the critical quality attributes, and creates a final downstream processing specification ready to scale up for production.

Companies will need training and expertise to make the most of bioinformatics and in silico screening, but the hurdles for this are much lower than they have ever been, with resources and applications available online or alternatively as desktop solutions. In that context, it is important to remain aware of security and confidentiality issues. Small-scale analytics: Exploring stability Once the physicochemical molecular properties are assessed using bioinformatics and the product is expressed in a cell line, explorative capture studies follow. The preliminarily purified protein is then evaluated for its stability at different temperatures and how it copes with the steps used in virus removal/inactivation, which include low pH, or the use of organic solvents, and detergents. It is also important to look at the mechanical stability of the protein during stirring, agitation, and shaking, as these will be part of the normal production and purification steps. This practical combination of analytics steps allows confirmation that in silico predictions work in the real world. Pharma Bio World

insights possible to suit the molecule. In the future, it would be more efficient for CMOs to work with companies at an earlier stage to collaborate over the optimization of the biologic or even help to design the molecule from the beginning.

Design: Process development The process design stage includes putting together a lab-scale bioreactor and looking at increasing the level of expression of the protein to as high a titer as possible. However, besides expression levels, product quality must also be considered. Several variables can be changed and evaluated in the bioreactor to improve the yield, including: • Cell culture mode — batch, fed-batch, or continuous perfusion • Length of culture time • Cell density • Oxygen levels • Media type • Nutrient levels and feeding strategy • Temperature The process development steps are iterative, with the process developers working at a small scale and modifying these variables individually. Analysis of the protein’s quantity, purity, and quality attributes shows the impact on the final process, and each change brings an optimized design a step closer. Pharma Bio World

Verification: Testing and evaluation The final test is confirming the feasibility of the process, including confirming the purification steps and finalizing the downstream specification. For this, the proteins must reach the appropriate purity and quality targets, and the process must be GMP-ready and economically viable. Achieving the benefits of smart bioprocessing A modular approach to molecule optimization and process development will save money, time, and effort. An ideal manufacturing development process would begin at the stage of molecule design to create a molecule that is optimized, for example, with low propensity for aggregation, high stability, and high expression. However, particularly for CMOs developing a manufacturing process on behalf of a client, this is not always possible. Pharmaceutical companies using this approach begin the process much earlier, which saves time and costs in manufacturing. Yet, CMOs often enter an existing process and then have to refine the process as tightly as

Overall, the aim of smart bioprocessing is to use bioinformatics, lab-scale processing, and analytics to create better process designs that can be verified before they are scaled up to clinical trial and commercialscale production. Companies should start by carrying out as much analysis in silico as possible up front to identify potential problems and eliminate them by redesigning the biologic, if possible. Then, they would verify the predictions from the in silico analysis in small-scale studies. It is crucial to identify the challenges properly either by in silico or experimental approaches to be able to react accordingly in the process design. References 1. Jagschies, G. et al; Biopharmaceutical Processing: Development, Design, and Implementation of Manufacturing Processes; Elsevier; 2017 2. Generics and Biosimilars Initiative (GaBi online); http://www. gabionline. net/Biosimilars 3. The Investor; Celltrion’s Remsima will take away half of J&J’s original drug share in US market: CEO; h t t p : / / w w w. t h e i n v e s t o r. c o . k r / v i e w. php?ud=20170419000819 4. EvaluatePharma; World Preview 2017, Outlook to 2022; http://info. evaluategroup.com/rs/607-YGS-364/ images/WP17.pdf FiercePharma, Samsung Biologics 5. nears finish line with massive biologics manufacturing project; https://www. fiercepharma. com/manufacturing/ samsung-nears-finish-line-massivebiologics-manufacturing-project 6. Amgen Science; The Next Generation of Biotech Manufacturing; https://www. amgenscience.com/next-generationbiotech- manufacturing/ (Source: GEHLS) February 2019 ► 31

research

Rational Use of Drugs and Irrational Drug Combinations Irrational use of medicines is a global phenomenon. Rational use of drugs may be defined as: Patients receive medications appropriate to their clinical needs, in doses that meet their own individual requirements, for an adequate period of time, and the lowest cost to them and their community. Overuse, polypharmacy and incorrect use of drugs are the most common problems of drug use today. Irrational use of drugs may result due to various reasons at various levels including the prescribing errors and over the counter drugs. Irrational use of medicines may lead to serious negative health and economic consequences. Many irrational drug combinations are available in the Indian market. Proper implementation of rational use of drugs will improve the quality of life and result in better community healthcare.

he Alma-Ata declaration, during the International Conference on Primary Health Care in 1978, reaffirms that health is a fundamental human right and the attainment of the highest possible level of health is a most important worldwide social goal. 1 Medicines are an integral part of the health care system and modern health care is unthinkable without the availability of necessary medicines. They not only save lives and promote health, but prevent epidemics and diseases too. Medications are undoubtedly one of the weapons of mankind to fight disease and illness. Accessibility to medication is a fundamental right of every person. 2 Ever since the accessibility of modern medicine increased all over the world, increasing incidents of its misuse in the form of overprescribing, multi-drug prescribing, use of unnecessary expensive drugs, selfmedication and overuse of antibiotics and injections have started. Thus, medications are starting to be misused. Irrational drug use is a global phenomenon now. Medically inappropriate, ineffective 32 ◄ February 2019

and economically inefficient use of drugs occur all over the world. The scenario in developing countries is the worst. According to the reports of NRHM India, irrational drug use is a widely pervasive, irrational practice of medicine and is a matter of serious concern, especially for a developing country like India. 3, 4 Definition The concept of rational drug use is age old, as evident by the statement made by the Alexandrian physician, Herophilus, in 300 B.C that “Medicines are nothing in themselves, but are the very hands of god if employed with reason & prudence” 5 In simplest words rational use means “patient receiving appropriate drug to clinical needs, in adequate dose for the sufficient duration and at the lowest cost possible.” As per the WHO (1985), the definition of rational use of medicines – “Patients receive medications appropriate to their clinical needs, in doses that meet their own individual requirements, for an adequate period of time, and at the lowest cost to them and their community.” 6,7

In addition to above definition, which is from the angle of medical therapeutic view, rational use of drugs can also be viewed from the consumers` perspectives. What is rational in a medical sense may not be rational for the consumer and vice versa. For the consumer, the rationality of using a drug is based on the (re) interpretation of its value for daily life, influenced by cultural perceptions and economic conditions. 8 In India, therefore it can be a complex one with multiple cultures, religions, dialects and castes. For example, in North-east India, as Malaria is endemic in nature, people may buy and keep a few antimalarial tablets to be consumed whenever bouts of malarial attack comes, never bothering to complete the whole course of the medicine. Or, as most part of north eastern India is tough

Pharma Bio World

research 1. Lack of information: Unlike many developed countries we donâ&#x20AC;&#x2122;t have regular facilities, which provide us with up to date, unbiased information on the currently used drugs. The majority of our practitioners rely on medical representatives. There are differences between pharmaceutical companies and the drug regulatory authorities in the interpretation of the data related to indications and safety of drugs.

hilly terrain, people may prefer to spend money on analgesic tablets, and particularly injections to relieve their misery and to be able to carry on their normal works of earning livelihood, while good food and rest would have been better for their health. Therefore, in understanding the actual meaning of rational use of drugs, both perspectives may need to be considered. However, the present overview on rational use of drugs shall be restricted to the medical perspective only. The problem of irrational use As per WHO, irrational or non-rational use is the use of medicines in a way that is not compliant with rational use as defined above. It was reported that worldwide, more than 50% of all medicines are prescribed, dispensed, or sold inappropriately, while 50% of patients fail to take them correctly. Moreover, about one-third of the worldâ&#x20AC;&#x2122;s population lacks access to essential medicines. Common examples of irrational medicine use are: Overuse of drugs and injections: occurs as a consequence of overprescribing as well as overconsumption. It concerns particularly the use and prescription of Pharma Bio World

antibiotics, antidiarrhoeals, painkillers, injections and cough and cold preparations. Injections have long had a special connotation as particularly powerful and fast acting medicines. Multi-drug use or polypharmacy: The number of drugs per prescription is often more than needed, with an average of 2.4 up to ten drugs, while generally one or two drugs would have sufficed. Multi-drug use is also common among consumers who purchase their drugs (over the counter drugs). Incorrect drug use: involves the wrong drug for a specific condition (e.g. antibiotics or antidiarrhoeals for childhood diarrhoea), drugs of doubtful efficacy (e.g. antimotility agents for diarrhoea), or use of drugs in the wrong dosage (which is often the case with antibiotics, ORS and antimalarials). Incorrect drug use occurs in the sense of incorrect prescribing as well as inappropriate use by consumer

2. Faulty and inadequate training and education of medical graduates: Lack of proper clinical training regarding writing a prescription during training period, dependency on diagnostic aids, rather than clinical diagnosis, is increasing day by day in doctors. 3. Poor communication between health professional and patient: Medical practitioners and other health professional giving less time to the patient and not explaining some basic information about the use of drugs 4. Lack of diagnostic facilities/Uncertainty of diagnosis: Correct diagnosis is an important step towards rational drug therapy. Doctors posted in remote areas have to face a lot of difficulty in arriving at a precise diagnosis due to non-availability of diagnostic facilities. This promotes poly-pharmacy. 5. Demand from the patient: To satisfy the patient expectations and demand of quick relief, clinicians prescribe

Reason for irrational use of drugs There are several reasons which may contribute to irrational use of drugs in our country: February 2019 â&#x2013;ş 33

research Risk of infection; due to improper use of injections. Injection-related disorders are abscesses, polio, hepatitis and AIDS. 14 Waste of resources; reduced availability of other vital drugs and increased cost. The WHO says that antimicrobial resistance is one of the world’s most serious public health problems worldwide. According to WHO, a major reason for the irrational use of medicines is due to the fact that more than 50% of all medicines are prescribed, dispensed or sold inappropriately and 50% of patients fail to take them correctly. The consequence of this is seen directly with the misuse of antibiotics. The WHO model list of essential medicines contains only about two dozen approved drug combinations, whereas in India, there are innumerable examples of irrational drug combinations, which are available and can be bought without necessarily giving a prescription.

drugs for every single complaint. Also, there is a belief that ‘every ill has a pill’. All these increase the tendency of polypharmacy. 6. Defective drug supply system and ineffective drug regulation: Absence of well-organized drug regulatory authority and presence of large numbers of drugs in the market leads to irrational use of drugs. 7. Promotional activities of pharmaceutical industries: The lucrative promotional programmes of the various pharmaceutical industries influence the drug prescribing. 34 ◄ February 2019

Impact of irrational use of drugs Some of the public health and economic consequences of irrational use of drugs are: Adverse, possibly lethal effects; due to misuse or inappropriate use of drugs in self-medication. 10 Limited efficacy; in the case of undertherapeutic dosage of antibiotics, tuberculosis or leprosy drugs. Antibiotic resistance; due to widespread overuse of antibiotics, as well as their use in under-therapeutic dosage. 11,12 Drug dependence; due to daily use of painkillers and tranquilizers. 13

Conclusion The issue of rational use of medicines has been debated since decades along with the essential medicine (EM) concept. Most of the economically developed and some developing countries have a medicine policy and their essential medicine list is regularly updated .15 Publication of EM list by Govt. of India in 2003 was a major step towards implementation of rational use of medicines. As of now, India has started to adopt policies of generic use, teaching and training the EM concept at the undergraduate level, pharmacovigilance programs and prescription audits, all contributing to the greater goal of rational use of medicines. On its proper implementation, it would be very helpful to reduce morbidity and mortality rates associated with drug use. It also will improve the allocation of resources Pharma Bio World

research Zimbabwe; European Journal of Clinical Pharmacology; 1988; 34(10); pp 87–90. 13. Grand le A, Sri-Ngernyuang L and Streefland PH; Enhancing appropriate drug use: The promotion of herbal medicine promotion; Social Science and Medicine; 1993; 36(8); pp 1023–35. 14. Wyatt HV; The popularity of injections in the third world: Origins and consequences for poliomyelitis; Social Science and Medicine; 1984; 19(9); pp 911–5

leading to better availability of necessary drugs with proper costing. Overall, patients will benefit via decreased risk of unwanted effects such as adverse drug reactions and drug resistance. Promoting the rational use of medicines would definitely help mankind to fight diseases and illnesses for a better tomorrow. References 1. Declaration of Alma Ata (1978). Available from: http://www.who.int/hpr/NPH/docs/ declaration_almaata.pdf 2. Kar SS, Pradhan HS, Mohanta GP; Concept of essential medicines and rational use in public health; Indian Journal of Community Medicine; 2010; 35(1); pp 10-13 3. Tripathi KD; Aspects of Pharmacotherapy: Clinical pharmacology and Drug Development; Essentials of medical pharmacology; Jaypee Brothers Medical Publishers (p) ltd; pp 68 4. WHO; Promoting Rational Drug Use under NRHM; 2002 . 5. Ambwani S, Mathur AK; Rational drug Use; Health Administrator Vol 29, No.1; pp 5-7 Pharma Bio World

6. WHO Policy Perspectives on Medicine - Promoting rational use of medicines:

15. Thawani V; Rational use of medicines: Achievements and challenges; Indian Journal of Pharmacology; 2010: 42(2); pp 63-64

core components; 2002 7. WHO Model Formulary, WHO press; 2004

(DK Brahma, MD Marak, & JB Wahlang Department of Pharmacology, NEIGRIHMS)

8. Grand AL, Hogerzeil HV, and HaaijerRuskamp FM; Intervention research in rational use of drugs: A review. Health Policy and Planning; 14(2); pp 89– 102; Oxford University Press; 1999 9. Shivhare SC, Kunjwani HK, Manikrao AM, Bondre AV; Drugs Hazards and Rational Use of Drugs: A Review; J. Chem. Pharm. Res.; 2010; 2(1); pp106-112 10. Rhashid HU, Chowdhury SAR and Islam N; Patterns of antibiotic use in two teaching hospitals; Tropical Doctor 1986; 16(4); pp 152–4. 11.Kunin CM; The responsibility of the infectious disease community for the optimal use of antimicrobial agents; Journal of Infectious Diseases; 1985; 151(3); pp 388–98. 12. Taylor HG, Stein CM and Jongeling G; Drug use before hospital admission in February 2019 ► 35

research

Therapy Induced Disorders – A Review Iatrogenic infection is complex because it has so many causes, including chance, negligence, medical error, and interactions of prescription drugs. Nosocomial infections, another leading cause of iatrogenic illness, are those that occur during hospitalization or through treatment in another health care setting. Vectors for infection in these facilities include vomit, blood, urine, and feces. Some microorganisms can be spread through the air. Postsurgical patients are particularly vulnerable to hospital-acquired infection. Illnesses can be transmitted by health care providers who neglect proper methods of sanitation.

atrogenic disease is the result of diagnostic and therapeutic procedures undertaken on a patient. With the multitude of drugs prescribed to a single patient adverse drug reactions are bound to occur. The Physician should take suitable steps to detect and manage them. Iatrogenic (of a disease or symptoms) induced in a patient by the treatment or comments of a physician.

Chambers English Dictionary One of the basic principles in treatment stated by Hippocrates is ‘First do no harm’. Stories of medical remedies causing more harm than good have been recorded from time immemorial. An iatrogenic disorder occurs when the deleterious effects of the therapeutic or diagnostic regimen causes pathology independent of the condition for which the regimen is advised. It would be impossible to provide the benefits of modern medicine if reasonable steps in diagnosis and treatment were withheld because of possible risks 1. Diagnostic procedures (mechanical and radiological), therapeutic regimen (drugs, surgery, other invasive procedures), hospitalization and treating doctor himself can bring about iatrogenic disorders.

Adverse effects of diagnostic procedures Mechanical procedures 36 ◄ February 2019

Diagnostic aspiration of fluids may lead to hemorrhage, secondary infection, etc. Rapid pleural or peritoneal fluid aspiration and needle biopsies may lead to shock and even death. Endoscopic procedure may cause perforation of hollow viscus. Diagnostic radiology Reactions to contrast media injected intravenously or intra-arterially may be mild, moderate or severe, and some are potentially fatal. Intravascular contrast media may have a nephrotoxic reaction. Cerebral angiography may cause transient or permanent neurological deficits. Radioisotopes are safe except in pregnant mothers or in newborn 2.

Adverse effects of therapeutic regimen

Adverse drug reactions (ADR) ADR is defined by World Health Organization as any response for a drug which is noxious, unintended and which occurs at doses normally used for prophylaxis, diagnosis and therapy of disease 3. ADR can be classified as predictable (side effects, toxicity, superinfection, drug interactions) and unpredictable (intolerance, idiosyncrasy, allergy or pseudo allergy) 4. When fewer than 6 different drugs are given in hospitalized patients, the probability of an adverse reaction is about 5%, but if more than 15 drugs are given, the probability is more than 20%. Of the patients admitted

to a general hospital, 2 to 5% are due to ADR and fatality in patients with ADR varies from 2-12%. ADR occurs in the elderly more frequently 5. To overcome the inadequacies in the WHO definition, new definition for adverse drug reaction is ‘an appreciably harmful or unpleasant reaction, resulting from an interaction related to the use of a medicinal product, which predicts hazard from future administration and warrants prevention or specific treatment or alteration of the dosage regimen or withdrawal of the product’. They are classified into six types; dose related (Augmented), non-dose-related (Bizarre), dose related and time-related (Chronic), time-related (Delayed), withdrawal (End of use), and failure of therapy (Failure) 6. Anaphylaxis Penicillin and other Beta-lactum antibiotics and various types of vaccines and sera, and human insulin, are the most common agents that cause anaphylaxis. Aspirin and other nonsteroidal anti-inflammatory agents (NSAIDs) cause non-IgE mediated anaphylactoid reactions 7.

Drug induced cutaneous manifestations Some of the cutaneous manifestations are8: 1) Alopaecia: Cytotoxic agents Pharma Bio World

research Drugs that cause thrombocytopaenia 12 Alpha-methyldopa, carbimazole, chloramphenicol, cyclosporins, phenylbutazone, quinine, quinidine, rifampicin, sulphonamides, etc.

2) 3) 4) 5) 6) 7)

Erythema multiforme: Exanthematous eruptions: Exfoliative dermatitis: Fixed drug eruptions: Photosensitivity: Toxic epidermal necrolysis:

Chlorpropamide, Sulphonamides Allopurinol, Anti-convulsants Streptomycin Barbiturates, Tetracyclines Griseofulvin, Indomethacin Barbiturates, Sulphonamides

Drug induced haematological disorders

Megaloblastic Anaemia (MA) Oral contraceptives, phenytoin, phenobarbitone and primidone cause MA due to folic acid deficiency, colchicines, neomycin, paramino salicylic acid (PAS) due to vitamin B12 deficiency and 6-ercaptopurine, 5 flurouracil, hydroxy-urea, acyclovir and zidovudine by interfering with DNA metabolism 9. Hemolytic anemia Drugs causing haemolysis by direct action are phenacetin, PAS, sulphonamides; by immune mechanism are aminopyrine, chlorpromazine, quinine and tetracycline; and in G-6 PD deficient patients, antimalarials (primaquine) and antibiotics (nitrofurantoin) 10. Aplastic anaemia Drugs that regularly produce bone marrow depression: busulphan, cyclophosphamide, chlorambucil, vinblastine, and 6 mercaptopurine. Drugs which rarely produce bone marrow depression: chloramphenicol, penicillamine, sulphonamides, isoniazid, NSAIDSs, analgin, thiouracil, anticonvulsants, antidiabetics, cimetidine, tranquilizers, etc 11. Drugs producing Neutropenia 12 Analgesics and NSAIDs: Anticonvulsants: Antithyroid drugs: Phenothiazines: Antiarrhythmic: Pharma Bio World

Indomethcin, Phenacetin, Acetaminophen, Phenylbutazone and Aminopyrine Phenytoin, Carbamazepine Thiouracil, Methimazole Chlorpromazine Quinidine

Hazards of blood transfusion 13 Complications occur in 2 percent of blood transfusions. a) Immunological reaction: Allergicanaphylaxis, fever, haemolysis, noncardiac pulmonary oedema. b) Non immunological: Circulatory overload, thrombophlebitis and embolism, bacterial contamination, transmission of diseases like malaria, hepatitis, syphilis and AIDS and transfusion siderosis in multiple transfusion.

Drug induced gastro-intestinal diseases 5,7 Oral lesions 1) Lichen planus like lesions: methyldopa, chloroquine and propranolol. 2) Lupus erythematosus like lesions: hydralazine 3) Acid peptic disease: acetyl salicylic acid, NSAIDs, corticosteroids, etc. 4) Pancreatitis: azathioprine, glucocorticoids and oral contraceptives. 5) Malabsorption: broad-spectrum antibiotics, cholestyramine and neomycin. Hepatic damage Drug induced liver injury is a potential complication of nearly every medication because liver metabolizes virtually all drugs. Acute (acetaminophen, halothane) and chronic (nitrofurantoin, methyldopa) hepatocellular injury, veno occlusive disease (cyclophosphamide) and hepatocellular carcinoma (sex and anabolic hormones) can all occur. There are many new drugs like glyburide, ketoconazole, lisinopril, lovastatin, ticlopidine etc. which were also associated with hepatotoxic reactions. Among causes of fulminant hepatic failure certain drugs like halothane, acetaminophen, phenytoin and alpha methyldopa account for 20-50% of cases. 14 February 2019 â&#x2013;ş 37

research Respiratory disorders due to drugs 5,15

38 â&#x2014;&#x201E; February 2019

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Methysergide, Hydralazine, Methyldopa.

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7. Retroperitoneal fibrosis

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NSAIDs, Thiazides.

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6. Chronic tubulointerstitial disease

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5. Isolated proteinuria with nephritic syndrome heroin, Captopril, NSAIDs, IFN- alpha, D-penicillamine.

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Syndrome of drug-induced kidney disease Common risk factors which precipitate adverse effects include old age, volume-depleted state, preexisting renal dysfunction and co-existing use of other nephrotoxins. Syndrome Drugs 1. Pre-renal failure/functional renal NSAIDs, ACE-inhibitors, Diuretics, Interleukin-2, Amphotericin-B. 2. Acute tubular necrosis Aminoglycosides, Rifampicin, NSAIDs, Cyclosporine, Cisplatin 3. Acute Interstitial nephritis Penicillins, NSAIDs, Allopurinol, Thiazides, Sulfonamides. 4. Thrombotic microangiopathy/hemolytic uremic syndrome Mitomycin-C,Cyclosporine, Quinine, Cocaine, Clopidogrel.

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Analgesic Nephropathy: Heavy and prolonged consumption of compound analgesic preparations particularly those containing phenacetin can cause chronic renal failure. This analgesic nephropathy is part of a broader analgesic syndrome, which includes hypertension, peptic ulcer, anaemia and recurrent headache.

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Renal disorders caused by drugs 16 The kidney is the main excretory organ of the body and hence affected by most drugs. 1) Directly toxic to the tubular cells: paracetamol, amphotericin B, cisplatin, sulphonamides etc. 2) Function as an antigen or as a hapten and the resulting antigen antibody reaction damages renal interstitium and leads to acute interstitial nephritis: penicillins, cephalosporins, NSAIDs, anticoagulants, captopril etc. 3) R enal failure by reducing renal blood flow: noradrenaline and dopamine in high doses. NSAIDs indirectly affect renal blood flow by inhibiting production of prostaglandins.

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Drug induced cardiovascular diseases Drug reactions may lead to exacerbation of angina (alpha blockers), arrhythmias (digitals, beta-adrenergic agents, tricyclic anti-depressants and quinine), cardiomyopathy (daunorubicin, emetine and lithium), hypo or hypertension (glucocorticoids and sympathomimetics), pericardial disease (emetine, procainamide and minoxidil), and Torsades de pointes (sparfloxacin) 5.

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Example of drug Beta-Blockers, Adenosine, NSAIDS ACE inhibitors Oral contraceptives, Reserpine,Guanithidine Contrast media, Methadone, Interleukin 2 Fenfluramine Anticancer agents, Acyclovir, Amiodarone Hydralazine, Methysergide Oral contraceptives

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Type of reaction 1) Airway obstruction (Bronchospasm) 2) Cough 3) Nasal congestion 4) Pulmonary oedema 5) Pulmonary hypertension 6) Pulmonary infiltration 7) Pleural disease 8) Pulmonary thromboembolism

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Dear Readers, Launched by Chemtech Foundation in 1992, Pharma Bio World (PBW) features contents from Pharmaceutical and Biotechnology industries. PBW provides in-depth information on business practices, latest trends, technologies, research & innovation and processes across the entire industry pipeline. Each monthly edition of PBW covers a separate area of pharma and biotech industry and includes articles from a range of peers, consultants and commentators, interview with industry experts, Market research analyzing industry trends, News Features, News Updates, Product Trends, Events Diary and Bookshelf. Target readers for PBW are Drug manufacturers, Intermediates, Pharma machinery/equipment manufacturers and suppliers, Pharma packaging firms, Research institutes, Academic institutes, Biotechnology firms, Consultants and Government bodies. You are most welcome to share editorial content with us such as technical articles, case studies and product write-ups. The length of the article should not exceed 1500 words with maximum three illustrations, images, graphs, charts etc. All the images should be high-resolution (300 DPI) and attached separately in JPEG or JPG format. Have a look at our editorial calendar on our website www.pharmabioworld.com. To know more about Chemtech Foundation, Jasubhai Media and other publications and events, please visit our website â&#x20AC;&#x201C; www. chemtechonline.com Thank you, Regards, Thomas Antony Editor Jasubhai Media Pvt Ltd Tel: +91-22-40373636 E-mail: thomas_antony@jasubhai.com

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research B) Withdrawal phenomenon: A new clinical syndrome unrelated to the original disease Antihypertensive drugs: Sudden stoppage of clonidine and alpha methyldopa cause syndrome resembling pheochromocytoma. Beta-blockers: Sudden stopping of the drug in coronary artery disease may cause infarction, aggravation of angina or rhythm disorders. Corticosteroids: Withdrawal accidents are seen after prolonged treatment, unrelated to the dose and duration of treatment and relapse of basic disease even in an aggravated form.

Neurological manifestations 17 1. Aseptic meningitis Intravenous immunoglobulin 2. Extra pyramidal lesions Haloperidol, Methyl dopa, Phenothiazine 3. Peripheral neuropathy Isoniazid, Metronidazole, Nitrofurantoin, Amiodarone, Vaccines. 4. Pseudomotor Cerebri or intracranial hypertension Amiodarone, Glucocorticoids, Oral contraceptives 5. Convulsions Amphetamine, Analeptics,Phenothiazine 6. Stroke Oral contraceptives 7. Encephalitis and Guillain-Barre syndrome A nti-rabies vaccination (purified chick embryo cell) 8. Myopathy Statins

Neuroleptic Malignant Syndrome: Rigidity, hyperthermia, altered mental status resembling catatonia, labile blood pressure and autonomic dysfunction characterize one of the serious complications of neuroleptic agents like Haloperidol 18. Drug induced psychiatric syndromes 5 1) Delirium or Confusional state Anticholinergics, Glucocorticoids, Phenothiazines Betablockers,Glucocorticoids, Nifedipine 2) Depression 3) Drowsiness Antihistamines Beta blockers, Levodopa, Narcotics 4) Hallucination 5) Hypomania, Mania Glucocorticoids Sympathomimetics Amphetamines 6) Paranoid states Drug induced musculoskeletal/rheumatic disorders 19 Disorder Drug 1. Arthralgia Fluorides, growth hormone, Penicillin, Quinolones (in children), Sulphonamides 2. Hyper-uricaemia and Gout Cytotoxic drugs, Cyclosporine, Salicylates Ethambutol, Levodopa, Nicotinic acid, Phenytoin, Diuretics. 3. Mylagia/Myositis Amphotericin B, Chloroquine,Cimetidine, Clofibrate, Colchicines,Cyclosporines, Gemfibrozil, Lovastatin, Levodopa, Penicillamine, Phenytoin, Rifampicin,Vincristine,Zidovudine 4. Osteoporosis 5. Scleroderma like disorder

Anticonvulsants, Corticosteroids, Heparin, Methotrexate. Bleomycin, INH, Penicillamine, Silicon Breast implants.

Adverse reactions due to sudden stoppage of drug Sudden stoppage of drugs can cause 20: A) Rebound phenomenon: Relapse with or without exacerbation of the basic disease Pharma Bio World

Barbiturates: Sudden stoppage in epileptic patients can induce status epilepticus. When used to induce sleep, sudden stoppage can cause acute insomnia, confusion, agitation, hallucinations and convulsions. Drugs producing malignant diseases 21 1. Leukemia - Anti cancer agent, rarely Chloramphenicol and(esp. acute myeloid leukemia) Phenylbutazone 2. Cancer of breast and endometrium - Estrogens, Tamoxifen 3. Cancer of vagina - Diethyl stilbesterol 4. Liver cancer - Anabolic steroids, Oral contraceptives Drug nutrient interaction Drugs may decrease nutrient absorption, increase urinary excretion, directly compete with or antagonize the nutrient from a carrier protein and interfere with the synthesis of an enzyme or coenzyme essential for the metabolism of the nutrient 22 . Drug induced fever Drug fever constitutes one percent of all fevers of unknown origin. Any drug can cause fever (antihistamines, barbiturates, iodides, penicillins, phenytoin, propylthiouracil, b-lactum antibiotics etc). A history of allergy, skin rash or eosinophilia is often absent in cases of drug fever23 February 2019 â&#x2013;ş 39

research Adverse reactions following immunization24 1) Inherent vaccine induced (a) Mild and common local reaction, fever (b) Moderately severe and uncommon – Suppurativelymphadenitis (BCG vaccination) (c) Severe and rare - Encephalopathy and hypersensitive reactions (paralytic polio following oral polio vaccine). 2)ProgrammaticerrorsSeptic – Toxic shock syndrome and abscess. Interaction between indigenous and prescription drugs Use of indigenous drugs is neither inquired in the drug history nor are the patients advised to avoid such an indiscriminate concurrent use of drugs. Sometimes these factors lead to either a therapeutic failure or a drug interaction or an accentuation of the unknown toxicities of the chemical prescription drugs25. Ophthalmological complications5 1. Busulphan Cataract 2. Chloroquine Corneal opacities 3. Digitalis Colour vision alteration 4. Sympathomimetics Glaucoma 5. Quinine Optic neuritis 6. Chloroquine Retinopathy Radiation hazards5 1. Acute and chronic progressive radiation injuries 2. Pneumonitis 3. Glomerulosclerosis and chronic interstitial nephropathy 4. Enteritis and cystitis 5. Venoocclusive disease of liver 6. Bone marrow depression 7. Malignancy Hazards of hospitalization The prevalence of hospital-acquired infections is around 10%. Urinary tract infections and respiratory infections are the commonest. There is increased chance of infections associated with diagnostic and therapeutic procedures and with antibiotic resistant bacterial flora26. Physician as the cause of the disease The harm that a physician can do is not limited to the imprudent use of medicine or procedure, but may include unjustified remarks and misinterpretation of investigational data. The physician should be aware of the properties of drugs that he prescribes and their potential dangers. Ignorance of the possibility of a 40 ◄ February 2019

reaction is a clear evidence of negligence. The physician should warn the patient of the likely side effects1,27. The list of drugs given in this article is in no way complete and only examples are given. Readers should look up the references to have more details. Drugs affecting the fetus or breastfed babies are not discussed. References 1. The practice of medicine: Iatrogenic disorders; Fauci SAS, Braunwald E, Kasper DL and Hauser SL (editors); Harrison’s Priniciples of Internal Medicine, McGraw Hill; 2001; 3. 2. Sutton D, Gregson R; Arteriography and interventional angiography; Textbook of radiology and Imaging; Churchill Livingstone; 1998; 681. 3. WHO; International drug monitoring: The role of national centers; Tech Rep Ser; WHO; 1972; 498. 4. Kishore K, Nagarkar KM; Adverse drug reaction; Hospital Today; 1996; 35-41. 5. Wood AJJ; Adverse Reactions to Drugs; Fauci SAS, Braunwald E, Kasper DL, Hauser SL (editors); Harrison’s Principles of Internal Medicine; McGraw Hill; 2001; 430-8. 6. Edwards IR, Aronson JK; Adverse drug reactions: Definitions, Diagnosis and Management; The Lancet; 2002; 356:12559. 7. Marquarit DL; Anaphylaxis and Drug Reactions; Stein JH (editor); Internal Medicine; Little Brown; 1998; 1193. 8. Hood AF; Cutaneous Manifestations of Drug Reactions; Stein JH (editor); Internal Medicine; Little Brown; 1998; 1312-6,1402. Hereditary Hemolytic 9. Agarwal MB; Anaemia; Shah SN (editor); API Text Book of Medicine; 2003; 939-44. 10. Nayak J; Megaloblastic Anaemia; Shah SN (editor); API Text Book of Medicine; 2003; 934-8. 11. Velu N; Bone Marrow Facture Status; Shah SN (editor); API Text Book of Medicine; 2003; 963-6. 12. Bichile SK; Neutropenia (granulocytopenia, agranulocytosis); Shah SN (editor); API Text Book of Medicine; 2003; 967-8. 13. Kamath SA; Blood Transfusions; Shah SN (editor); API Text Book of Medicine; 2003; 980-2. 14. Sherlock S, Dooley J; Drugs and the Liver; Sherlock S (editor); Diseases of Liver

and Biliary System; Blackwell Scientific Publications; 2002; 335. 15. Dowdeswell IRG; Pleural Diseases; Stein JH (editor); Internal Medicine: Little Brown; 1998; 505-10. 16. Jacob CK; Drugs, Toxins and the Kidney; Shah SN (editor); API Text Book of Medicine; 2003; 668-72 17. Wadia RS, Dalal PM; Drug induced neuromuscular disorders; J Assoc Physicians India; 1994; 42(7):537-9. 18. Aminoff MJ; Parkinson’s disease and other Extra Pyramidal Disorders: Neuroleptic Malignant Syndrome; Fauci SAS, Braunwald E, Kasper DL Hauser SL (editors); Harrison’s Principles of Internal Medicine; McGraw Hill; 2001; 2405. 19. Joshi VR, Balakrishnan C; Drug induced Rheumatic Disorders; J Assoc Physicians India; 1994; 42(1):805-8. 20. Wahi S, Wahi PL; Adverse reactions on stoppage of drugs.; J Assoc Physicians India, 1986; 34:205-8. 21. Advani SH; Basic consideration of oncology; Shah SN (editor); API Text Book of Medicine; 2003; 987-90. 22. Weser E Young EA; Nutrition in Internal Medicine: Drug Nutrient Interaction; Stein JH (editor); Internal Medicine; Little Brown; 1998; 2099-112. 23. Tauber MG; Fever of unknown Origin - Drug fever; Stein JH (editor); Internal Medicine; Little Brown; 1998; 1378. 24. Adverse Events Following Immunization, CSSM Review; 1994; 231-5. 25. Rai J; A potential for interactions between indigenous and prescription drugs; Shah SN (editor) API Text Book of Medicine; 2003; 164-6. 26. Mandal BK, Dunbar EM, Mayon White RJ; Hospital Acquired infection; Mandal (editor); Infectious Disease; Blackwell Science; 1996; 26. 27. Sarangi MP, Maini A, Sharma GK; Drug and Product Liability; Ind J Clinical Practice; 1995; 5(9):94-6. (Lt Gen NR Krishnan, PHS (Retd), GKNM Hospital, Tamil Nadu & Brig AS Kasthuri, VSM (Retd), Vydehi Institute of Medical Sciences and Research Center, Bangalore.)

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research

Vaccine production via mammalian cell culture systems Mammalian cell culture systems are starting to dominate the production of vaccines for viral diseases such as rabies. Making use of existing biopharma infrastructure, these advances might even spell the end for the use of hens’ eggs in future vaccine development.

oday, the rapidly expanding demand for vaccine products for viral diseases such as rabies has necessitated the development of more sophisticated production techniques based around cell culture systems. This article reviews vaccine production strategies, with a focus on rabies, looking specifically at the use of the Vero cell line – used worldwide and approved by the US Food and Drug Administration – as well as media technology and the bioreactor options available. Growing Demand Viral diseases, including rabies, are worldwide challenges for the international biomedical community. The World Health Organization (WHO) notes that over 32,000 rabies-related deaths were reported in 1998, while annual deaths worldwide from the virus grew to 55,000 by 2006 1,2.

vaccination was put on a sound scientific footing. Demand for vaccine products has continued to increase ever since, prompting the advances in production technology that we see today. Viral Cultivation The expanding vaccine requirements have led to techniques for growing large quantities of antigenic proteins. Traditionally, viruses have been grown in embryonated hens’ eggs, but numerous shortcomings compromise their utility. These include a bottleneck in the availability of high-quality, pathogen-free eggs, as well as low titers of emerging viruses 3). A major concern is that, when viruses are cultivated through extended passages in hens’ eggs, there is an evolutionary

process in the amnion or allantoic cavity of the egg, resulting in the selection of a virus subpopulation, antigenically and biochemically distinct from the original inoculum 4 . Because of these and other factors, permanent cell lines are coming to dominate the field as an alternative method. Mammalian cell culture systems provide much shorter lead times; a more controlled production process that takes advantage of closed-system bioreactors; a reduced risk of microbial contamination; and the opportunity to cultivate viral stocks without significant egg passage-dependent antigenic changes 5 . These systems provide a flexible and scalable platform that can make use of existing biopharma infrastructure for vaccine production,

Rabies is often transmitted to humans from infected domestic animals. Dogs infected with rabies can become extremely aggressive and attacks on humans are widespread, especially in certain Asian countries where using unleashed dogs for home security is common. It is spread through the saliva of infected animals and bites can be fatal. Since the 18th century, vaccination has proven to be the most successful – and perhaps the only – route to the total elimination of viral diseases such as rabies. From the early work of pioneers such as Jenner and Pasteur, Pharma Bio World

Figure 1: Fluorescent image of confluent Vero cells; DAPI-stained nuclei appear blue, and actin filaments stained with rhodamine-conjugated phalloidin appear red February 2019 ► 41

research serum-free media has become routine for Vero cell cultivation. Comparable results were observed with a commercial serumfree medium MDSS2N (AXCEVIRVeroTM by Axcell Biotechnologies). Rabies Strategies The Brazilian group led by FrazattiGallina has been active in the field of rabies vaccine production 13. Using Vero cells adhered to microcarriers, and cultivated in a bioreactor with serumfree medium, they generated an effective rabies vaccine. With the aid of tangential filtration, they purified the rabies virus by chromatography and inactivated it using beta-propiolactone. and could replace egg-based vaccines in the foreseeable future 6 . Cell Line Options In the past few years, several continuous cell lines have been approved by regulatory authorities for virus production. These include the Spodoptera frugiperda insect cell line from Protein Sciences 7 , Madin-Darby canine kidney (MDCK), the PER.C6 cell line, designed for growth to high densities 8 , and the widely used Vero line.

Media Alternatives There is a variety of different Vero isolates available from commercial suppliers, but all are quite similar, and their nutritional needs are comparable 10. The search for the ideal mammalian cell culture medium began in the 1950s, with the holy grail being an economical, protein-free, serumfree medium that would provide strong growth support and have the property of scalability to large volumes, up to thousands of litres, while coming in at an affordable price.

It is important to note that certain cell lines may provide an environment favouring selection of viral subpopulations, and these types may be inappropriate for vaccine production. In light of this, various lines of investigation support the Vero cell line as the candidate of choice for viral vaccine production, including:

Serum provides a protective function to cultured cells, and binds toxins and other contaminating materials. As such, serum-free media must be extremely carefully formulated 11. Albumin can be substituted for serum, but it may impede the downstream steps of purification 12.

• Efficiency of primary virus isolation and replication to high-infectivity titers • Genetic stability of the haemagglutinin molecule, while maintaining the antigenic properties of human-derived viruses • Similarities in the pattern of protein synthesis and morphological changes between virus-infected Vero and MDCK cells 9

Chen et al tested five different serumfree media, combined with Cytodex 1 microcarriers 12. The following were evaluated: OptiPro SFM (Invitrogen), VPSFM (Invitrogen), EX-CELL Vero SFM (SAFC Biosciences), Provero-1 (Lonza) and HyQ SFM4MegaVir (HyClone). EXCELL Vero SFM gave one of the highest cell densities, demonstrating that the use of

42 ◄ February 2019

Their protocol states that 350cm 2 T-flasks were harvested and inoculated into a 3.7-litre CelliGen bioreactor, at a proportion of 16 cells per microcarrier (Cytodex 3-GE), yielding an initial seeding of 2.5×105 cell/ml. The cells were grown in serum-free MDSS2 medium. The serum-free VP-SFM medium, according to the manufacturer, was developed for Vero, BHK-21 and Chinese hamster ovary cell growth. This medium drives the adherence of the Vero cells to the microcarriers. After four days of cultivation in VP-SFM medium, the cells were infected with Pasteur vaccins (PV) strain rabies virus (multiplicity of infection = 0.08). The harvests of the culture supernatant were carried out three days after the virus inoculation and four times thereafter at 24-hour intervals. During

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research The process used for ChengDa was developed by Aycardi 17 . A single bioreactor was capable of producing one million doses of rabies vaccine per year. The method uses ultra-high-density microcarrier cell cultures adapted to a 30-litre CelliGen bioreactor equipped with a patented cell lift impeller, specifically configured for a perfusion system to feed the growth media into the bioreactor. A specially designed decanting column was used to prevent perfusion loss of microcarrier and keep the cells in high concentration. The system delivers high oxygen transfer, high nutrient level and low shear stress, allowing cell growth of up to 1.2x107 million cells/ml under continuous perfusion for up to 20 days. this period, culture conditions were maintained at 60rpm at a pH of 7.15 and 5 per cent dissolved oxygen. Only the temperature varied, from 36.5ºC in the cellular growth phase of the culture to 34ºC after virus inoculation. In the course of the programme, seven batches of virus suspensions were produced in the bioreactor (16 litre per cycle) at a mean viral titer of 104. FFD50/0.05ml. The effectiveness of the preparation was demonstrated by immunising mice with three doses of the new vaccine, and comparing it with the commercial Verorab and human diploid cell rabies vaccine. Mean titers of neutralizing antibodies of 10.3-34.6, 6.54 and 9.36 IU/ml were found, respectively. The choice of the serum-free medium was fortunate. In this case, the amount of contaminating DNA was very low and tolerable – less than 22.8pg per dose of vaccine. The authors argue that this protocol is especially applicable in the developing world, where rabies is a constant hazard and a major public health problem. Pharma Bio World

Increasing Yield Yu et al sought methods to increase yield in Vero cell culture systems over that obtained using roller bottles 14. In a recent review, they summarized the production technology developed over the course of the last seven years. They have adopted the 30-litre BioFlo 4500 fermentor/bioreactor. The cells were cultivated in media containing 10 per cent serum, first grown as a monolayer, and when the cell density reached 1.01.2×106 cells/ml, they were transferred to the bioreactor containing 25g/litre of Cytodex-1 for perfusion culture. The virus preparations, also cultured in roller bottles, were infected with the PV2061 virus strain, harvested and transferred to the bioreactors. Purified Vaccine Wang et al have described a purified Vero cell rabies vaccine that has been widely produced in China, referred to as ChengDa (Liaoning ChengDa Biological) 15,16. It is grown on a Vero cell line utilizing the PV2061 strain, inactivated with beta-propiolactone, lyophilised, and reconstituted in 0.5ml of physiological saline. It fulfils WHO recommendations for potency.

Important Step The combination of advances reviewed here provides strong support for the use of cell culture systems for virus production of vaccines. The fact that Vero cells have been approved for clinical products represents an important step on the road to technologies that do not rely upon hens’ eggs for generation of adequate quantities of viruses. Advances in culture media enable the elimination of serum, thus driving the rapid and efficient purification of proteins. The use of carrier beads adds to the efficiency of culture technology, allowing greatly increased cell densities to be reached. Improvements in bioreactor design, combined with these various technological advances, results in a greatly improved and more functional production train. References 1. World survey of rabies number 34 (for the year 1998), WHO, 2000. Visit: www.who.int/emc/diseases/ zoo/wsr98/html version/wsr 98 index.html February 2019 ► 43

research 14.Yu P et al, Production and evaluation of a chromatographically purified Vero cell rabies vaccine in China using microcarrier technology, Hum Vaccine Immunother 8(9): pp1230-1235, 2012 15.Wang C et al, Promising rabies vaccine for postexposure prophylaxis in developing countries, a purified Vero cell vaccine produced in China, Clin and Vaccine Immuno 17(4): p688, 2010 16.www.bariconsultants.com/projects. html 17. Aycardi E, Producing human rabies vaccines at low cost, Genetic Engineering News 22(8), 5th April 2002

(Source: DASGIP AG)

2. Kaur M, Rai A and Bhatnagar R, Rabies DNA vaccine: no impact of MHC class I and class II targeting sequences on immune response and protection against lethal challenge, Vaccine 27(15): pp2,128-2,137, 2009 3. Genzel Y and Reichl U, Continuous cell lines as a production system for influenza vaccines, Expert Rev Vaccines 8(12): pp1,681-1,692, 2009 4. Oxford JS et al, Serological studies with influenza A(H1N1) viruses cultivated in eggs or in a canine kidney cell line, Bull World Health Organ 65(2): pp181187, 1987 5. Doroshenko A and Halperin SA, Trivalent MDCK cell culture-derived influenza vaccine, Optaflu (Novartis Vaccines), Expert Rev Vaccines 8: pp679-688, 2009 6. Montomoli E et al, Cell culture-derived influenza vaccines from Vero cells: a new horizon for vaccine production, Expert Rev Vaccines 11(5): pp58794, 2012 44 â&#x2014;&#x201E; February 2019

7. www.proteinsciences.com/BEVS.htm 8.

www.crucell.com/Technology%20%20 Cell%20Technology

9. Govorkova EA et al, African green monkey kidney (Vero) cells provide an alternative host cell system for influenza A and B viruses, J Virol 70(8): pp5,519-5,524, 1996 10.Ammerman NC, Beier-Sexton M and Azad AF, Growth and maintenance of Vero cell lines, Current Protocols in Microbiology, Appendix 4E, November 2008 11. Chen A et al, Serum-free microcarrier based production of replication deficient influenza vaccine candidate virus lacking NS1 using Vero cells, BMC Biotechnol, 11th August 2011 12. www.invitria.com/cell-cultureproductsservices/serum-albumin.html 13.Frazatti-Gallina NM et al, Vero-cell rabies vaccine produced using serumfree medium, Vaccine 23(4): pp511517, 2004 Pharma Bio World

marketing initiatives

Making water safe through quick detection of Legionella

egionellosis is a collective term for diseases caused by legionella bacteria including the most serious Legionnaires’ disease, as well as the similar but less serious conditions of Pontiac fever and Lochgoilhead fever. Legionnaires’ disease is a potentially fatal form of pneumonia and everyone is susceptible to infection. The risk increases with age but some people are at higher risk including: • people over 45 years of age • smokers and heavy drinkers suffering from chronic • people respiratory or kidney disease • diabetes, lung and heart disease • anyone with an impaired immune system

The bacterium Legionella pneumophila and related bacteria are common in natural water sources such as rivers, lakes and reservoirs, but usually in low numbers. They may also be found in purpose-built water systems such as cooling towers, evaporative condensers, hot and cold water systems and spa pools. If conditions are favourable, the bacteria may grow increasing the risks of Legionnaires’ disease and it is therefore important to control the risks by introducing appropriate measures. Where does it come from? Legionella bacteria are widespread in natural water systems, e.g. rivers and

ponds. However, the conditions are rarely right for people to catch the disease from these sources. Outbreaks of the illness occur from exposure to legionella growing in purpose-built systems where water is maintained at a temperature high enough to encourage growth, e.g. cooling towers, evaporative condensers, hot and cold water systems and spa pools used in all sorts of premises (work and domestic). How do people get it? People contract Legionnaires’ disease by inhaling small droplets of water (aerosols), suspended in the air, containing the bacteria. Certain conditions increase the risk from legionella if: • the water temperature in all or some parts of the system may be between 20-45°C, which is suitable for growth • it is possible for breathable water droplets to be created and dispersed e.g. aerosol created by a cooling tower, or water outlets • water is stored and/or re-circulated • there are deposits that can support bacterial growth providing a source of nutrients for the organism e.g. rust, sludge, scale, organic matter and biofilms Cases of Legionnaires’ disease are often the result of infections caught within the country itself, but a number of cases also occur while travelling abroad.

Thus, legionella bacterial infection can be caught from any water source that produces spray or aerosols. Some common sources of infection include showers, pools, spas, hot tubs, air conditioning systems, cooling towers and even ice machines. These high-risk areas and units need to be properly cleaned and managed or else microorganisms will quickly multiply. Cooling towers are of particular concern as they have the ability to spread deadly Legionella bacteria over long distances. In warm climates, water temperature is harder to control and can provide the heatloving legionella bacteria with optimal conditions for rapid growth. Stagnant water in the pipes of empty rooms can also encourage the growth of scale, sludge and amoeba which protects the legionella bacterium and provides the bug with nutrients, thus accelerating its growth and spread. At present, everyone depends on the lab culture method for the legionella test, which takes 2-3 weeks to give results and confirm whether the location is legionella free or not. But, while waiting for the test results there are chances of the affected area turning into a dangerous zone. Therefore, tests that give reliable results quickly and consistently are preferred by the industrial and healthcare sectors and also recommended by the authorities. In India, IPL Technology offers the latest detection technology that can provide accurate details about the presence of legionella in less than an hour.

(Source: IPL Technology Pvt. Ltd.)

Pharma Bio World

February 2019 ► 45

marketing initiatives

Radio-Opaque Silicone Tube

owadays, silicone based biocompatible polymers are used to produce catheters and other devices that are inserted into the body for interventional procedures. The inserted parts are commonly filled with substances opaque to x-rays, thereby rendering the devices visible under fluoroscopy or x-ray imaging. These fillers or radiopacifiers are based on typically dense metal or metallic salt powders that affect the energy attenuation of photons in an x-ray beam as it passes through matter, reducing the intensity of the photons by absorbing or deflecting them. Because these materials exhibit a higher attenuation coefficient than soft tissue or bone, they appear lighter on a fluoroscope or x-ray film. This visibility helps to accurately position the device in the affected area. Image contrast and sharpness can be varied by the type and amount of radiopacifier used. Device design is also a factor; a higher loading of radiopaque material, for instance, is needed for thin-wall catheter tubing than for products with thicker walls. Generally, compounds should contain only the amount of additives absolutely required for the application, since overloading can result in the loss of the polymerâ&#x20AC;&#x2122;s mechanical properties. Blending together several radiopaque materials can produce better results than using only one type in the solution. Among the most widely used radio pacifiers for medical devices are barium sulfate, bismuth compounds, and tungsten - metals that are excellent absorbers of x-rays. Selection of the correct fillers in the proper amount requires a thorough understanding of 46 â&#x2014;&#x201E; February 2019

attenuation and how it is affected by various radiopaque compounds. X-rays belong to the electromagnetic radiation family, having a range of wavelengths. Diagnostic x-rays fall near the shorter-wavelength end of the spectrum, measuring between 1 angstrom and 0.1 angstrom. X-rays are produced from the conversion of energy that results when fast-moving electrons from the element of an x-ray tube interact with a tungsten anode or target. The kinetic energy of the electrons increases as voltage, expressed as peak kilovoltage (kVp), is increased. The intensity of an x-ray beam is determined by the number of photons in the beam and the energy of the photons, which is expressed as kiloelectronvolts (keV).

COMMON RADIOPACIFIERS Barium Sulfate Barium sulfate (BaSO4) was the first radiopaque material to be widely compounded in medical formulations

and is the most common filler used with medical-grade polymers. It is a nontoxic filler having specific gravity of 4.5. Patients are often asked to swallow a solution of barium sulfate before an examination of their digestive tract. It is an inexpensive material and its white color can be changed with the addition of colorants. Use of higher doses, beyond the normal doses recommended for X-ray imaging during interventional procedures, might destroy base polymer physical properties. With elastomers, barium sulfate mixes better than do tungsten or bismuth compounds. Bismuth Considerably more expensive than barium, bismuth trioxide (Bi2O3), which is yellow in color, has a specific gravity of 8.9. Since bismuth produces a brighter, sharper, higher-contrast image on an x-ray film or fluoroscope than does barium, it is commonly used whenever a high level of radiopacity is required. Compared with barium, higher loadings are also possible: even a 60% bismuth compound can maintain the same base polymer mechanical properties as a

Figure 1: Characteristics of X-ray generation Pharma Bio World

marketing initiatives high attenuation coefficient. A loading of 60% tungsten has approximately the same volume ratio as a 40% bismuth compound. Devices can be made highly radiopaque with relatively low loadings of tungsten, enabling good mechanical properties to be maintained. Because of its density, tungsten is typically selected as a filler for very-thin-walled devices. Tungsten is black in color, which cannot be changed with colorants. It is abrasive and can cause accelerated wear in extruders and other processing equipment. Devices filled with high loadings of tungsten will exhibit surface roughness. Because the material invites oxidation in the presence of oxygen and heat and is highly flammable, care should be taken while drying it.

Figure 2: Medical x-ray image 40% barium sulfate compound. A 20% bismuth loading by weight equals 3% by volume; a 40% loading by weight equals 7.6% by volume. Bismuth is sensitive to compounding and must be treated gently, with low-shear mixing recommended for optimum results. Because of their high

levels of radiopacity, bismuth fillers have grown in popularity. Tungsten A fine metal powder with a specific gravity of 19.35, tungsten (W) is more than twice as dense as bismuth and can provide a

Figure 3: Radiopaque catheter for interventional procedure Pharma Bio World

Medical devices used in diagnostic radiology must be easily seen on x-ray film and fluoroscopes in order for medical practitioners to precisely position them inside the body during critical procedures. The type and amount of radiopaque filler compounded with the silicone elastomer in the manufacture of these devices determines how they appear during radiological and interventional procedures.

(Ami Polymer Pvt. Ltd. research@amipolymer.com www.amipolymer.com) February 2019 â&#x2013;ş 47

marketing initiatives

Solid Dosage: Technologies to tablet effervescent products

ableting effervescent products is a complex process. Yet, with the right technology, these tablets can be produced just as rapidly and safely as regular oral solid dosage forms. Romaco Kilian has the perfect solution for compressing effervescent formulations with maximum efficiency. Children are particularly fond of effervescent products because, quite simply, theyâ&#x20AC;&#x2122;re fizzy. As such, the beverage and confectionery sectors offer an enormous variety of products, as does the pharmaceutical industry, such as pain relievers, cough syrups or medications for the gastrointestinal tract. A broad array of nutraceuticals is also available, often in several different flavours. The administration of water-soluble drugs is particularly recommended for children, the elderly or patients with swallowing difficulties or a sensitive stomach.

single-sided rotary press is consequently equipped with three separate compression stations. The first compression roller simply tamps the powder. Next, the tablets are precompressed; in the third step, they are converted into finished products in the main compression unit. The use of Kilian 28/41 tooling simultaneously extends the dwell time, meaning that harder tablets can be made because there is more overall time for deaeration. This stops the tablets from bursting during subsequent processing steps. Smoother than ever Effervescent powders are hygroscopic and demonstrate poor flow properties. As such,

the fill shoes and paddles of the tablet press must be designed to accommodate efficient filling and uniform distribution within the die. The powder can also be lubricated with magnesium stearate to prevent the product from sticking to the tooling. An external lubricant supply system sprays the punch tips and the die walls during the production process. This has the advantage that the lubricant no longer has to be mixed into the product beforehand. Much less material is required for external lubrication and harder tablets can be achieved as a result, which improves the overall quality of the end product. Whatâ&#x20AC;&#x2122;s more, external lubrication protects both the product and the machine

Tablets with complex demands Effervescent tablets offer many consumer benefits; but, manufacturing and processing these hygroscopic products inevitably presents a number of complicated hurdles to overcome. By their very nature, effervescent tablets react extremely vigorously with air, light and moisture. In addition, many of the active pharmaceutical ingredients (APIs) and vitamins processed in effervescent formulations are readily affected by heat. Furthermore, effervescent tablets tend to be friable and susceptible to breakage. All these factors must be considered when tableting effervescent powders. The Romaco Kilian KTP 590X tablet press is tailor made for these kinds of applications. Gentle compression Effervescent tablets are naturally prone to unwanted air pockets and capping, which is why the tableting process takes place in three steps. The Kilian KTP 590X 48 â&#x2014;&#x201E; February 2019

Figure 1: The Kilian KTP 590X singlesided rotary press is equipped with three separate compression stations Pharma Bio World

marketing initiatives Fast off the mark If effervescent tablets are to be manufactured efficiently, it is vital to optimise the retooling and cleaning times. The number of productcontact parts in the tablet presses has been systematically reduced by Kilian for this very purpose. Furthermore, the die-table, tablet chute and fill shoe can be swung right out for easy access to all components. Format changes can be completed without any additional tools. At the same time, the start-up dosing control based on the filling parameters shortens the run-in times and avoids material loss. The OEE (overall equipment effectiveness) of the tablet press can be significantly improved under these conditions. Depending on the formulation, the Kilian KTP 590X achieves an output of up to 290,000 effervescent tablets an hour with mono or bilayer formats; the singlesided rotary press manages a maximum hourly output of 511,200 tablets.

Figure 2: The die-table, tablet chute and fill shoe can be swung right out for easy access to all components by reducing the tablet ejection force. Effervescent tablets that are lubricated using an external system have a smoother surface, contain less magnesium stearate and dissolve in water without leaving a greasy film, much to the delight of the consumer. Cool machines Extremely low temperatures are essential to process temperature-sensitive medications. The process temperature of the tablet presses in Romaco Kilian’s KTP X series is therefore kept at a constant level — below 30 °C. To reduce heat input, the compression rollers are fitted with smooth-running bearings and the fill shoe gear is mounted externally. A special cooling ring, situated underneath the die table, acts as a thermal barrier. Additionally, the low temperature in the service area is maintained by the torque drive’s efficient cooling system. The brake magnets also play a crucial Pharma Bio World

role here by eliminating frictional heat and protecting the material. Thus, there’s no need to install an additional cooling unit when tableting temperature-sensitive products.

Clean performance Manufacturing effervescent tablets is an extremely dusty affair. Hygienic design is all the more important to keep unwanted dust formation in check. The compaction, retooling and service areas of the KTP 590X are strictly separated for precisely this reason. This prevents tablet dust from entering the machine compartment or, in

Figure 3: Brake magnets play a crucial role by eliminating frictional heat and protecting the product February 2019 ► 49

www.pharmabioworld.com

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Figure 4: Kilian’s hygiene concept ensures reliable processing and reduces the risk of cross-contamination to a minimum the opposite direction, machine oil from contaminating the product. A patented punch bellows surrounds the upper and lower punches and protects the tablets from impairments in the form of black spots. The closed system, made from an elastic synthetic material, is ventilated by means of holes in the die table. The press’s fill shoe and tablet chute are fully washable and easy to clean. The concentration of particles in the production environment is greatly reduced by the dust-tight tablet chute. In short, Kilian’s hygiene concept ensures reliable processing and reduces the risk of cross-contamination to a minimum. Safe processing Once the effervescent tablets have been compressed, they must be further processed according to the specific application. Owing to their chemical and physical properties, effervescents are not stored in a buffer container but transferred directly to downstream packaging machines. A special transfer station developed by Romaco conveys the fragile tablets from the press to the primary packaging unit. The tablets are fed from the press scraper directly to a 50 ◄ February 2019

high-speed Kilian conveyor belt. Tailbacks of tablets at the press discharge area are prevented by acceleration, so that the products are removed and separated gently. This enables selective sampling before the tablets are distributed by a rotary table to the primary packaging machine’s conveyor belt. On their way to this machine, they pass via two more stations for dust aspiration and breakage elimination. Effervescent tablets are normally packed in strips or tubes. The Romaco Siebler brand includes both heatsealing machines and tube fillers. Together with Kilian presses, these two product lines form a functional unit to manufacture and package effervescent tablets. Romaco’s effervescent portfolio is optimally complemented by Promatic cartoners and case packers.

(Peter Heyn Romaco Kilian GmbH)

Each monthly edition of PBW covers a separate area of pharma and biotech industry and includes articles from a range of peers, consultants and commentators, interview with industry experts, Market research analyzing industry trends, News Features, News Updates, Product Trends, Events Diary and Bookshelf. Target readers for PBW are Drug manufacturers, Intermediates, Pharma machinery/equipment manufacturers and suppliers, Pharma packaging firms, Research institutes, Academic institutes, Biotechnology firms, Consultants and Government bodies. You are most welcome to share editorial content with us such as technical articles, case studies and product write-ups. The length of the article should not exceed 1500 words with maximum three illustrations, images, graphs, charts etc. All the images should be high-resolution (300 DPI) and attached separately in JPEG or JPG format. Have a look at our editorial calendar on our website www.pharmabioworld.com. To know more about Chemtech Foundation, Jasubhai Media and other publications and events, please visit our website – www. chemtechonline.com Thank you, Regards, Thomas Antony Editor Jasubhai Media Pvt Ltd Tel: +91-22-40373636 E-mail: thomas_antony@jasubhai.com

Pharma Bio World

news, events, etc Health for Life Capital II, World Leading Microbiome-focused Fund Announces its First Close Seventure Partners, one of Europe’s leaders in financing innovation and a world-leader in life science microbiome investment, recently announced that it has completed the first closing of its second dedicated fund focused on the microbiome, and health, nutrition and digital/connected health sectors, Health for Life Capital II (HFL II), with a target for the final close of over €200 million. Health for Life Capital first fund (HFL) attracted strategic investments from prestigious organizations including Danone, Novartis, Lesaffre, Tornier, Unigrains and Bel. The new fund has attracted cornerstone investors from this first fund, as well as new strategic industry partners including a US based global food ingredient provider (to be disclosed), alongside financial institutional Limited Partners and entrepreneurial investors. “We are proud to be trusted by prestigious industry champions as Danone, Novartis, our new US global food ingredient provider, Lesaffre, Bel, Unigrains etc. In addition, the close cooperation we have established will boost the financial performances of the fund. Our industry partners display strong innovative oriented strategy. They are world leaders and pioneers in supporting innovative food and health concepts” commented Isabelle de Cremoux, CEO and Managing Partner of Seventure Partners, who led the fund raising. Building on its successful investment strategy ‘beyond the pill’, Seventure’s latest fund will keep its core focus on the microbiome, including platforms, drugs, nutritional solutions, diagnostics and biomarkers, as well as opportunistic investments in digital therapeutics, connected health, digital nutritional advice, personalised nutrition, precision medicine and food technologies. Seventure was ground-breaking when it launched HFL in 2014, becoming an acknowledged leader in its field by anticipating the microbiome revolution in the health and nutrition sectors. It has invested in an innovative portfolio of twenty companies at the forefront of their fields, such as Enterome, Vedanta Biosciences, MaaT Pharma, Eligo Bioscience, LNC Therapeutics, TargEDys, A-Mansia Biotech, BiomX, Microbiotica, Anaeropharma, NeurIMM, Siolta Therapeutics, DayTwo, Zipongo, Mdoloris Medical Systems, MycoTechnology and others. It achieved its first transactional exit with the trade sale of Cambrooke in 2017. HFL II will seek to invest in a similar number of companies, with a global focus, spanning Europe, North America, Israel, and opportunistically Asia. HFL II has already committed to its first two investments, Axial Biotherapeutics in the US and Galecto Biotech in Denmark. Isabelle de Cremoux, CEO and Managing Partner of Seventure Partners, said: “The significant interest we have attracted for our new fund is a testament to the exceptional experience the Seventure team has within the exciting field of the microbiome, and the exponential growth in our understanding of the interplay of the microbiome as well as nutrition and food on health, both for treating and preventing diseases and also maintaining people healthy at all ages from new-borns to elderly”. “Research and investment in the microbiome was at its infancy when we launched our first fund in 2014. Fast-forward to 2019 and, alongside digital health, precision medicine and personalized nutrition, the

Pharma Bio World

microbiome has exploded and is one of the hottest areas for healthcare and nutrition investment.” “HFL has already been approached by numerous pharma, diagnostics and food ingredient companies as well as financial investors. As we work towards our imminent final close of Health for Life Capital II™, we welcome discussions with investors with a like-minded passion for funding innovation at the intersection of microbiome, and health, nutrition and digital health sectors.” The microbiome, which consists in all the micro-organisms that reside in and on the human body, is an exciting and fast-developing new field at the interface of pharmaceuticals and nutrition, offering abundant opportunities for developing new medicines. The composition and functionality of the bacterial ecosystem forming a large part of the microbiome, in the gut and elsewhere, has been linked to various health conditions, among which allergies, gastrointestinal ailments, Crohn disease, obesity, diabetes, autism, Parkinson, depression, acne, psoriasis or cancer. There are approximately 10 times more bacteria than human cells in the body, and over a hundred times more bacterial genes than human ones. The multitude of biological processes and indications affected by the bacterial ecosystem within the human microbiome, makes its balance critical to health. Understanding and maintaining and adequate balance of species within this complex ecosystem is an important goal for future medical progress, especially in the area of preventing and treating chronic diseases. In Life sciences, the main areas of focus include ‘classic’ approaches such as biotechnology and pharmaceuticals, diagnostic and medtech, industrial biotechnology, as well as ‘beyond the pill’ approaches such as microbiomelinked innovations, nutrition, foodtech, digital/connected health and personalized medicine. Seventure Partners successfully launched Health for Life Capital which invests in Life sciences (health, nutrition, digital/ connected health, etc) with a core focus on the microbiome revolution and its applications in human health, nutrition and food. The €160m first fund launched in 2014 has invested in 20 companies at the forefront of their fields, such as Enterome, Vedanta Biosciences, MaaT Pharma, Eligo Bioscience, LNC Therapeutics, TargEDys, A-Mansia Biotech, BiomX, Microbiotica, Anaeropharma, NeurIMM, Siolta Therapeutics, DayTwo, Zipongo, Mdoloris Medical Systems, MycoTechnology, etc. In January 2019 it launched second fund Health for Life Capital II with a target fund size of over €200m. Health for Life Capital funds have attracted strategic investments from prestigious organizations including Danone, Novartis, Lesaffre, Bel, Tereos, Tornier, Unigrains and more recently a US based global food ingredient provider (to be disclosed), as well as entrepreneurs and financial institutions. Seventure Partners launched Health for Life Capital™, the first venture capital fund focused mainly on investments “beyond the pill” in the microbiome and nutrition space. Europe is the primary focus of the fund, but it also invests in North America, Asia and Israel. The €160m first fund and the €200m second fund attracted strategic investments from prestigious organisations including Danone, Novartis, a US based global food ingredient provider (to be disclosed), Lesaffre, Tornier, Tereos, Unigrains and Bel, as well as financial institutions and entrepreneurs. Health for Life Capital™ is managed by Seventure Partners’ Life sciences team. February 2019 ► 51

news, events, etc Lonza’s New Spheroid-Forming Human IDT expands free next-day delivery Hepatocytes Facilitate Improved In Vitro service As an advocate for researchers in the genomics age, Integrated Liver Model Systems Lonza has further expanded its hepatocytes portfolio characterization with the addition of Verified for Spheroids Human Hepatocytes, which are pre-screened for their ability to promote rapid spheroid formation in cell culture. Researchers working in toxicology, disease modeling and DMPK studies can now feel more confident in the performance of Lonza’s hepatocytes in their spheroid and other 3-dimensional (3D) culture platforms. Physiologically relevant in vitro liver model systems play a crucial role in the success of toxicology, disease modeling and DMPK studies. Conventional 2-dimensional (2D) hepatocyte cultures offer good short-term models, but they tend to rapidly lose typical hepatocyte functionality, which makes them unsuitable for longer-term studies. To address this challenge, self-assembling liver spheroids generated from primary human hepatocytes (PHH) are increasingly employed. These spheroids exhibit in vivo-like cell organization, improve the predictability of known clinical liver toxicants and preserve the viability and functionality of the hepatocytes. However, not all currently available hepatocyte donor batches are capable of forming spheroids in culture. “Using spheroids as in vitro liver model systems requires researchers to carefully select donors and thoroughly examine hepatocyte lots in advance,” said Erica Chamberlin, Technical Specialist at Lonza. “With our Verified for Spheroids Human Hepatocytes, we take on this burden on behalf of our customers, enabling them to focus on what matters most – their science.” During the SOT Annual Meeting, Dr. Magdalene Stosik, Senior Scientist at Lonza, will present the results of a study whereby Lonza analyzed and optimized the formation, culture and performance of PHH in different spheroid culture systems. The study also compared metabolic function and viability of the spheroids over 28 days in culture. Primary human hepatocyte spheroids were rapidly generated that exhibited the ability to support liver metabolic function during long-term exposure and repeated dosing toxicology studies. Lonza is an integrated solutions provider that creates value along the healthcare continuum. Through its pharma & biotech segment and the specialty ingredients segment businesses, the company harnesses science and technology to serve markets along this continuum. Lonza focuses on creating a healthy environment, promoting a healthier lifestyle and preventing illness through consumers' preventive healthcare, as well as improving patient healthcare by supporting their customers to deliver innovative medicines that help treat or even cure severe diseases. Founded in 1897 in the Swiss Alps, Lonza today is a well-respected global company with more than 100 sites and offices and approximately 15,500 full-time employees worldwide. The company generated sales of CHF 5.5 billion in 2018 with a core EBITDA of CHF 1.5 billion. 52 ◄ February 2019

DNA Technologies (IDT) is expanding its courier zones to ensure that the highest-fidelity oligos are available in less time and at the same price, to more customers. UK scientists based in Cambridge, Oxford, and London—both inside and out of the M25 orbital—can now benefit from IDT’s free next-day delivery service, enabling projects to be started and finished sooner. IDT is widely recognized as a leading manufacturer of nucleic acid products and genomics solutions. All of its single-stranded and duplexed DNA sequences are produced with industryleading coupling efficiencies, resulting in higher quality DNA products. Specialized platforms allow the company to deliver the purest primers for PCR, dual-labelled probes for qPCR, indexed adapters and fusion primers for sequencing, as well as a variety of advanced and custom products. Researchers can be assured of oligo integrity thanks to electrospray ionization (ESI) mass spectrometry traces, supplied free with every order – providing the utmost confidence in quality and consistency. “IDT is committed to helping researchers accelerate discovery”, commented Rik Leyssens, General Manager at IDT’s EMEA facility in Leuven. “From January 7th, our customers in the UK can now receive and use IDT oligos the day after ordering. Many of our customers in Belgium and parts of the United States, who already benefit from our the next-day service have commented that our ability to deliver so rapidly has enabled them to do more, in less time.” Orders placed from within the courier zones before 5pm will be delivered the next day at no additional cost, enabling researchers to generate consistently reliable data with IDT’s unmatched oligo quality. In addition, scientist can take advantage of an offer to receive ten free 25 nmol DNA oligos by visiting a landing page for a promotional code. IDT develops, manufactures, and markets nucleic acid products for the life sciences industry in the areas of academic and commercial research, agriculture, medical diagnostics, and pharmaceutical development. IDT has developed proprietary technologies for genomics applications such as next generation sequencing, CRISPR genome editing, qPCR, and RNA interference. Through its GMP services, IDT manufactures products used in diagnostic tests for many forms of cancer and most inherited and infectious diseases. IDT is widely recognized as the industry leader in custom nucleic acid manufacture, serving over 100,000 life sciences researchers and producing over 65,000 nucleic acids daily. IDT has its manufacturing headquarters in Coralville, Iowa, USA, with additional manufacturing sites in San Diego, California, USA; Leuven, Belgium; and Singapore. Pharma Bio World

news, events, etc OGT to open new Cytocell facility in Cambridge, UK Oxford Gene Technology (OGT), the molecular genetics company, has announced that it is expanding its Cytocell operations with a move to a new facility in Cambridge, UK. Cytocell, OGT’s fluorescence in situ hybridisation (FISH) probe brand, will be moving into the significantly larger facility on the prestigious Cambridge Science Park, due to expansion of the organisation, current sales volumes and predicted sales growth. In addition to investing in OGT by expanding Cytocell’s operational footprint, OGT’s parent company, Sysmex, is demonstrating its confidence in the UK by establishing the new premises. OGT’s Cytocell brand provides the largest range of high-quality, reliable, and cost-effective FISH probes on the market and is well known for its comprehensive range, exceptional customer support, service and expertise. Over recent months, OGT has been expanding the direct sales of Cytocell products in Europe and Asia. Staff numbers across the organisation are increasing and a larger space is needed for manufacturing and logistics facilities to match the increased volume of product manufacture and shipment. The new facility will have approximately three times the floor space of the current premises and capabilities to deliver a significant increase in output as the business continues to grow. OGT also plans to create a training and demonstration facility in the new premises to host its customers. John Anson, CEO of OGT commented, ‘We’re delighted to announce the investment in, and expansion of, our Cytocell operations by Sysmex. Sysmex is committed to growing our business and aligning our commercial synergies. In addition, Sysmex is demonstrating its confidence in the UK’s strong traditional base in Life Sciences. Our ever-growing cooperation with Sysmex delivers the benefits of being part of a larger organisation to our customers, providing them with enhanced services and support.’ In addition to investing in OGT’s Cytocell brand, Sysmex is considering creating a global R&D facility at the premises to evaluate new technologies and pursue collaborations with key opinion leaders, resulting in delivery of innovative new products to the market. Kenji Tsujimoto Executive Vice President of Technology Strategy at Sysmex Corp. added, ‘Our acquisition of OGT has been, and continues to be, extremely successful. We are very much aligned in our goals and our synergies make for an excellent collaboration. This significant investment in the company is testament to our confidence and desire to further develop OGT’s brands alongside our portfolios’. OGT anticipates the new facility to be fully operational by May 2019. Oxford Gene Technology (OGT) provides world-class genetics research solutions to leading clinical and academic research institutions. Founded by Professor Sir Edwin Southern, and with customers in over 60 countries worldwide, OGT has a strong reputation and increasing share in the large and growing genomic medicine market. The Company’s Cytocell®, CytoSure™ and SureSeq™ range of fluorescence in situ hybridisation (FISH), microarray and next generation sequencing (NGS) products deliver high-quality genetic analysis, enabling accurate identification and confirmation of the causative variation underlying genetic disease. OGT was acquired by Sysmex Corporation (Sysmex), a Japanese in vitro diagnostic company in June 2017. The acquisition of OGT expands Sysmex’s life science business and reinforces its initiatives towards personalised medicine. Pharma Bio World

Sysmex Corporation is a world leader in clinical laboratory systemisation and solutions, including laboratory diagnostics, laboratory automation and clinical information systems. Serving customers for more than 50 years, Sysmex focuses on technological leadership in diagnostic science and information tools that make a difference in the health of people worldwide. The company is also exploring emerging opportunities in the life science field. Its R&D efforts focus on the development of high-value-added testing and diagnostic technologies that are innovative, original and optimise individual health. Sysmex also seeks to leverage its state-of-the-art technologies for cell, gene and protein analysis. The company, headquartered in Kobe, Japan, has subsidiaries in North America, Latin America, Europe, the Middle East, Africa, China and Asia Pacific and employs more than 8,000 employees worldwide.

‘Maya’, Abbott’s AI based personal assistant for its sales force Abbott, in association with SmartBots AI, has successfully launched an innovative new virtual assistant to support and engage their pan-India sales force — and her name is Maya. As a global healthcare company, Abbott has taken a leadership role in implementing digital solutions across all stakeholders, including patients, doctors and employees, through the adoption of integrated technology solutions. In early 2018, Abbott became first in the Indian Pharmaceutical Industry to deploy an AI assistant for its field force. Abbott’s Pharmaceuticals Division initiated a pilot by getting around 3,000 sales employees to start engaging with Maya for their day to day queries. Maya acts as a personal assistant to the employee, providing sales operations support and keeping them ready for the day, providing access to contextual information at their fingertips. She is their virtual assistant while they are in the field meeting doctors. With Maya handling the nitty-gritties of querying and fetching information from enterprise applications, an employee can focus on the crucial aspects of his role and leave the spadework to Maya. Moreover, Maya is a BOT with a personality. Developed by SmartBots AI, and powered by Amazon’s LeX technology, she uses a voice or chat interface to communicate with employees in simple natural language, and provides them the assistance they need. She acts as a facilitator, helping employees to tap into an enterprise knowledge base (like SalesForce or Tableau) through familiar, easy-to-use communication channels. The results of this pilot study have been encouraging. Since launch, Maya has addressed close to 12,000 queries. Currently, 32% of the monthly queries raised by Abbott reps are now being answered by Maya with a 74% success rate. Medical representatives can also check their execution parameters, expense reimbursement status, plan for the day and leave balance on Maya leading to increased satisfaction. 69% of the field force rate Maya as helpful. Having tested Maya’s capabilities with the Sales team, Abbott has deployed this virtual assistant to more than 8,000 employees and plans to use the SmartBots AI platform to build bots for several other departments. February 2019 ► 53

news, events, etc Supreme Court Exempts Saridon from Dr. Reddy's Laboratories announces the List of Banned FDCs the re-launch of its Buprenorphine and The Supreme Court of India has ruled in favor of Saridon, a heritage Naloxone Sublingual Film after favorable brand from the healthcare product portfolio of Piramal Enterprises Limited (PEL), exempting its formulation from the list of banned FDCs ruling in patent litigation (Fixed Dose Combinations).

In September 2018, PEL had been awarded a stay order from the Supreme Court on the ban, which allowed it to continue manufacturing, distribution and sale of the FDC. Saridon, amongst the most trusted heritage analgesic brands in India, enjoys strong customer allegiance globally. Commenting on the Supreme Court ruling, Nandini Piramal, Executive Director, Piramal Enterprises Limited said, “We are pleased with the Supreme Court ruling, as it is an affirmation to our commitment to provide effective and safe healthcare solutions that address unique needs of Indian consumers. We were confident that the law would prevail in our favour. Saridon is a heritage brand trusted by customers for the last 50 years in India. This exemption from the banned list of FDCs validates our intent to serve our customers with the highest levels of integrity. We continue to expand our healthcare product portfolio with an aim to be amongst the top three OTC (over the-counter) product companies in India by 2020.” As per a recent study by A.C. Neilson, the addressable analgesic market is ~INR 6,450 crores, of which the analgesic tablet market is ~INR 2,050 crores (as of December, 2018). Saridon is amongst India’s most widely distributed analgesic tablets with a strong distribution network across 9 lakh outlets in India. The popularity of the brand is widespread with 31 tablets being sold every second (Source: A.C. Nielsen Retail Audit Dec 2017 – “Every second, 31 Saridon tablets are sold in India”). Saridon continues to be amongst the most trusted heritage brands in India, that enjoys strong customer allegiance globally. PEL’s India Consumer Products portfolio comprises 18 brands with offerings spanning across multiple categories. It aims to be among the top three over the-counter (OTC) product companies in India by 2020. Over the last two years, the business has invested significantly in various growth levers. The Company’s strategy of expanding the product portfolio and distribution network has worked well and the Consumer Products business is evolving into a strong player in India’s OTC market. PEL is one of India’s large diversified companies, with a presence in Financial Services, Pharmaceuticals and Healthcare Insights & Analytics. PEL’s consolidated revenues were over US$1.6 billion in FY2018, with ~46% of revenues generated from outside India. In Pharma, through an end-to-end manufacturing capabilities across 13 global facilities and a large global distribution network to over 100 countries, PEL sells a portfolio of niche differentiated pharma products and provides an entire pool of pharma services (including in the areas of injectable, HPAPI etc.). The Company is also strengthening its presence in the Consumer Product segment in India. PEL’s Healthcare Insights & Analytics business is the premier provider of healthcare analytics, data & insight products and services to the world’s leading pharma, biotech and medical technology companies and enables them to take informed business decisions. 54 ◄ February 2019

Dr. Reddy’s Laboratories Ltd. recently announced the re-launch of its Buprenorphine and Naloxone Sublingual Film, 2 mg/0.5 mg, 4 mg/1 mg, 8 mg/2 mg, and 12 mg/3 mg, a therapeutic equivalent generic version of Suboxone® (buprenorphine and naloxone) sublingual film, in the United States market. The re-launch comes on the heels of a favorable decision issued by the United States Court of Appeals for the Federal Circuit concluding that Indivior had not shown that it is likely to succeed on its claim that Dr. Reddy’s product infringes U.S. Patent No. 9,931,305. The Federal Circuit’s decision vacates the District Court’s preliminary injunction that had prohibited Dr. Reddy’s from selling its generic version of Suboxone® (buprenorphine and naloxone) sublingual film. The Federal Circuit’s decision went into effective yesterday. As a result of the Federal Circuit’s ruling, Dr. Reddy’s has resumed shipping of the product. “We are pleased with the decision of the appellate court in Dr. Reddy’s favor, vacating the preliminary injunction that had prevented Dr. Reddy’s from continuing to market this important drug to the public,” explains Marc Kikuchi, Chief Executive Officer, North America Generics. “Dr. Reddy’s is committed to providing affordable treatment options for opioid use disorder and addiction. We look forward to helping patients and our communities in the United States who are impacted by the opioid epidemic.” In June 2018, the U.S. Food and Drug Administration (USFDA) approved Dr. Reddy’s Buprenorphine and Naloxone Sublingual Film, in four strengths including 2 mg/0.5 mg, 4 mg/1 mg, 8 mg/2 mg, and 12 mg/3 mg, for sale in the U.S. market. The product was launched immediately after approval, with sales and commercialization activities halted as a result of a court-imposed temporary restraining order (TRO) and preliminary injunction against Dr. Reddy’s. The TRO and preliminary injunction did not prohibit commercial manufacturing of the product. Dr. Reddy’s Laboratories Ltd. is an integrated pharmaceutical company, committed to providing affordable and innovative medicines for healthier lives. Through its three businesses Pharmaceutical Services & Active Ingredients, Global Generics and Proprietary Products – Dr. Reddy’s offers a portfolio of products and services including APIs, custom pharmaceutical services, generics, biosimilars and differentiated formulations. Its major therapeutic areas of focus are gastrointestinal, cardiovascular, diabetology, oncology, pain management and dermatology. Dr. Reddy’s operates in markets across the globe. Our major markets include – USA, India, Russia & CIS countries, and Europe. Pharma Bio World

events diary       

   

Date: 4-6 December, 2019 Venue: HITEX Exhibition Centre, Hyderbad

Date: 19 – 21 September, 2019 Venue: HITEX, Hyderabad

BioPharma World Expo 2019 is the best platform for both Indian and international manufacturers/service providers/ startups connected with pharma machinery, CR AMS, CROs/CMOs, packaging, logistics, exports, APIs, generics, biotech, regulatory affairs, etc . It offers a unique opportunity to meet, network and establish business partnerships. The concurrent conference tracks would highlight latest technological developments, market trends, investment opportunities and challenges facing the industry. The technical sessions would cover pharmaceutical technology, biosimilars, green chemistry, compliance, etc.

The laboratory and analytical market is growing at an exponential rate due to the recent investment plans initiated by the government; which is furthermore complemented by the industry bodies to capitalize on the growth projection. More and more pharma and R&D projects have been commenced leading to increased demand for laboratory and analytical instruments. In order to capitalize on this growth opportunity, Messe Muenchen India is organizing the 13 th edition of India Lab Expo, the leading trade fairs for laboratory technology, analysis, biotechnology and diagnostics at Hyderabad.

 Jasubhai Media Taj Building, 210, Dr. D.N. Road, Fort, Mumbai - 400 001 Tel: 91-22- 40373636 Email: amrita_patil@jasubhai.com

 Messe Muenchen India Pvt. Ltd. INIZIO 507 & 508, Cardinal Gracias Road, Opp. P&G building, Chakala, Andheri (E), Mumbai - 400 099, India. Tel : +91-22-42554710 Email: info@mm-india.in

 

   

Date: 10 – 12 April, 2019 Venue: Helipad Ground, Gandhinagar

Date: 19-21 April 2019 Venue: Parade Ground, Chandigarh

iPHEX is an exhibition that brings together the drugs, pharmaceutical and healthcare industry- all under one roof. It is one of the largest showcase of Indian pharmaceutical products and technologies to a global audience. The show will offer the industry majors from India and all across the world a great platform to connect and do business. iPHEX provides visitors and exhibitors with an opportunity to meet new and existing customers actively looking for new suppliers, or looking to assess the current progress of existing projects.

PharmaTech Expo 2019 & LabTech Expo 2019 is an exhibition related to pharma and packaging machinery in addition to analytical and lab equipment. This year the focus is on pharma manufacturing and processing technology, pharmaceutical services, formulations, nutraceuticals and ayurveda. There is a strong local and global opportunity in North India for the manufacture of pharmaceutical & biotechnology products, cosmetics and ayurvedic items. According to industry estimates there are approximately 3000+ manufacturing units in nearby states adjacent to Chandigarh (i.e. Himachal Pradesh, Haryana, Uttrakhand, Punjab, Delhi etc.). The strong growth prospects of the pharmaceutical exports segment and increasing demand from the domestic market is bound to further fuel growth in the pharmaceutical machinery sector, which will be present in large numbers at the show as exhibitors along with other segments of the pharma and biotech industry.

 Pharmexcil 101, Aditya Trade Centre, Ameerpet, Hyderabad - 500038 Tel: +91-40-23735462 Email: sales@iphex-india.com

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Contact: PharmaTechnologyIndex.Com Pvt. Ltd. 302, Shails Mall, C G Road, Ahmedabad – 380009 Tel: +91-79-40306340 Email: expo@pharmatechnologyindex.com

February 2019 ► 55

Microdosing Machine The Romaco Macofar MicroMaxX 18 microdosing machine processes pharma powders with different flow properties as well as freeze-dried products and sterile liquids. The system is equipped with a dual dosing disc which allows multiple dosing into the same vial; alternatively, the product can be filled in two separate process steps. Furthermore, even very small product quantities right down to 25 mg can be dosed precisely. Thanks to an innovative in-line weighing system, 100 per cent weight control is now possible for the first time. The machine achieves a max filling speed of 12,000 vials per hour. Up to 18,000 vials an hour are possible in the version with statistical weight control. The Romaco Macofar MicroMaxX 18 can be supplied in different containment designs. Automated processes ensure reliable operation and meet the high cGMP requirements for dosing sterile powders and liquids. 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

Pressure Boosting Hydro-pneumatic System Pressure Boosting Hydro-Pneumatic (HYPN) system is a conventional pumping system converted into an automated pumping system. Kirloskar Brothers Ltd’s (KBL’s) HYPN system is an intelligent water supply solution ideally designed for high-rise buildings and commercial complexes that can serve the changing water demand at constant pressure. A HYPN system maintains a constant temperature and helps eliminate unnecessary functioning of pumps in case of zero flow. Also, the performance of HYPN system is controlled, smooth and facilitates energy and water optimization. KBL’s energy-efficient HYPN system requires low maintenance and its customized configuration and design ensures its long life, making it one of the most cost-effective pressure-boosting systems globally. For more information, please contact: KSB Pumps Ltd Mumbai Pune Road Pune, Maharashtra 411 018 Tel: 020-27101231, Fax: 91-020-27426000 E-mail: Yagnesh.Buch@ksb.com

Calorimeters Parr Instrument offers bomb calorimeters and acid digestion bombs to meet the needs of today’s research and fuel testing laboratories for testing of variety of solids and liquid fuels (coal, coke, petrol, diesel and other alternate fuels), minerals, feeds, foodstuff, animal and human nutrition, combustible waste/materials and many more applications. Parr 6000 Series calorimeters feature high degree of automation with touch screen operation, Linux operating system with fifth generation microprocessor control. Parr 6000 Series has many models employing removable as well as fixed bomb and bucket designs. Removable bomb calorimeters are the most acceptable type of calorimeters. In this type of calorimeters the bomb and bucket are removed from the calorimeter for loading the sample and filling the bucket with the carefully measured amount of water which absorbs the energy released in the combustion. These types of calorimeters meet BIS Standards. For more information, please contact: Orbit Technologies Pvt Ltd B-50 Indl Estate, Sanath Nagar Hyderabad, Telangana 500 018 Tel: 040-67216354 E-mail: orbit@orbitindia.com

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Double-sided Rotary Press The tablet presses in the Romaco Kilian K Series are specially tailored to the needs of the Asian market. The K 720 double-sided rotary press was configured by Romaco Kilian for the production of mono and bi-layer tablets and can be switched flexibly between the two operating modes. This high speed press has a max output of 1,000,000 tablets per hour. The technology is used both in the pharma industry and in the non-pharma sector, and is particularly suited for compressing effervescent tablets, nutraceuticals and drug store items. The systematic reduction of product loss was a top priority when Romaco Kilian developed the K Series. Amongst other features, this is achieved by means of product scrapers, which are in constant contact with the die table surface due to magnetic force. Targeted measures to improve the Kilian K 720â&#x20AC;&#x2122;s productivity, availability and quality have simultaneously increased its overall equipment effectiveness. External fill shoe gears enable a lower process temperature, which is an advantage with temperature sensitive products. Patented bellows result in higher product quality by preventing so-called black spots on the tablets. Punch brake magnets, likewise patented, ensure constant braking forces and a small standard deviation of the tablet weight. The hermetic separation of the tablet press process area from the changeover and service areas moreover restricts cleaning to a minimum and extends the production time of the Romaco Kilian K 720 rotary press. 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

Wireless Transmission of Safety Data The openSAFETY safety bus protocol can now be transmitted via UDP using the black channel principle. This facilitates the use of wireless transmission technologies for safety communication. openSAFETY can be configured flexibly, making it particularly well suited for wireless data transmission. One application of wireless transmission for safety data is to communicate between fixed base stations and moving system components. This principle is used in warehouse logistics and baggage transport systems, for example. The user can configure openSAFETY with latencies of up to 2.5 seconds. This prevents low bandwidth or brief transmission interruptions from triggering unwanted safety reactions or stopping the machine. Wireless safety communication allows self-driving units to switch safety zones without interruption. The transition from one zone to the next is seamless. This means that the units can be used flexibly and are always safe within the network. To provide comprehensive diagnostics, openSAFETY also has error counters and other diagnostic functions. 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 E-mail: pooja.patil@br-automation.com

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February 2019 â&#x2013;ş 57

TwinCAT IoT Communicator The TwinCAT IoT Communicator makes it easy for PLCs to communicate with mobile devices by connecting the TwinCAT controller directly and securely to a messaging service through TLS encryption. For smartphone and tablet users, the associated IoT Communicator App ensures that process data can be represented on all mobile devices in a clear overview. Alarms are sent to the device as push messages. The TwinCAT 3 IoT Communicator exchanges data using a publish/subscribe mechanism. Since no special firewall settings are needed, integration into an existing IT network is easy. Information is exchanged via a message broker that uses the standardised MQTT protocol and acts as a central messaging service in a cloud or local network. A high level of communication security is guaranteed by proven TLS encryption (up to Version 1.2). Transmitted process data can be displayed on mobile devices using the IoT Communicator App, which is available for both Android and iOS operating systems. The IoT Communicator App also incorporates an integrated QR code scanner to facilitate entry of access data for communication between the broker and individual users. The TwinCAT IoT Communicator simplifies the transmission of push messages. It offers a number of advantages over conventional e-mail and SMS messages by visualizing live data, variables and status values. This makes the IoT Communicator an ideal addition to the related TwinCAT IoT and TwinCAT Analytics software products. For more information, please contact:

BECKHOFF Automation Pvt Ltd Suite 4, Level 6, Muttha Towers Don Bosco Marg, Yerwada, Pune, Maharashtra 411 006 Tel: 020-40004802, Fax: 91-020-40004999 E-mail: a.phatak@beckhoff.com

Push-through Strips Together with Huhtamaki, the film and foil specialist, Romaco Siebler will premiere a push-through strip packaging for pharmaceuticals. The tablets can be removed simply by pressing them out of the pockets in the four-sided sealed foil pack. This innovative push-through strip thus combines the excellent barrier properties of strip packaging with the opening mechanism of blister formats. In direct comparison with cold formed aluminium blisters, the push-through strip scores with its lower consumption of packaging material. The thinner foil of the heat-sealed strips enables cost savings here. The new push-through strips are manufactured either from a multilayer laminated PET-PE-Al-PE/Surlyn foil or from a transparent barrier foil. The material does not tear and can therefore be regarded as child resistant. Thanks to the targeted perforation of the upper polyester layer, the pack can be opened simply by pressing the tablet out of the laminated foil with the thumb. The push-through strips are also senior friendly and as such a good alternative to tear-open strip packaging or aluminium-aluminium blisters. Huhtamaki has a patent pending for the manufacturing process used for this special foil. Romaco’s new push-through strips can be supplied either in the standard rectangular format or as so-called design strips. A Siebler HM 1-350 heat-sealing machine equipped with a special die-cutter is used to manufacture special formats. The continuous cutting station supports both round strip formats and heart, petal or even star-shaped ones. The Siebler HM 1-350 achieves a max output of 800 design strips per minute. The production of push-through strips in a heat-sealing process expands Romaco’s portfolio in the area of air, light and moisture-tight unit dose packaging. 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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bookshelf Drug-Induced Diseases: Prevention, Detection, and Management Authors : Dr. James E. Tisdale (Editor) & Douglas A Miller (Editor) Price : $225 Pages : 1400 Publisher : American Society of Health System Now in its third edition, this comprehensive guide provides a detailed overview of diseases that result from drug therapy, arming healthcare professionals with critical knowledge to protect the health and welfare of their patients. This important reference includes information on Bleeding Disorders, Teratogenicity, and Oral Manifestations of Systemically Administered Drugs. It also contains comprehensive coverage of scores of drug-induced diseases, in addition to information pertaining to the contribution of genetic polymorphisms to specific drug-induced diseases and much more. The book is the must-have resource for pharmacists, physicians, nurses, and pharmacy students alike.

Stockley’s Drug Interactions: A Source Book of Interactions, Their Mechanisms, Clinical Importance and Management Author : Claire L. Preston (Editor) Price : $285 Pages : 1840 Publisher : Pharmaceutical Press Stockley’s Drug Interactions remains the world’s most comprehensive and authoritative international reference book on drug interactions. Based upon thousands of published papers and reports it: Covers interactions between therapeutic drugs, proprietary medicines, herbal medicines, foods, drinks, and drugs of abuse; Contains in-depth yet concise monographs in an easy-to-read format; Provides comprehensive details of the clinical evidence for the interactions under discussion, an assessment of their clinical importance, and clear guidance on managing the interaction in practice; Has a brief summary of the interaction in each monograph – perfect for the busy healthcare professional; Is fully referenced throughout; contains almost 4500 monographs; Is global in coverage – inclusion of drugs used worldwide has been added in the 11th edition apart from over 350 new monographs; Many existing monographs have been reviewed, revalidated, and updated; A comprehensive update and restructure of the chapter on Antidiabetic drugs, in-line with published literature; Addition of new advice regarding the concurrent use of aliskiren, ACE inhibitors, and angiotensin-II receptor antagonists; An updated list of drugs that have a risk of prolonging the QT interval; The addition of new drugs, including apixaban, apremilast, dolutegravir, lomitapide, mirabegron, the NS5A inhibitors (daclatasvir, ledipasvir, ombitasvir), the NS5B inhibitors (dasabuvir, sofosbuvir), the sodiumglucose co-transporter-2 inhibitors (canagliflozin, dapagliflozin, empagliflozin), and telavancin. In short, the voluminous information is thorough, concise, clinically relevant, and referenced to the primary literature.

Vaccine Development and Manufacturing Authors : Emily P. Wen, Ronald Ellis & Narahari S. Pujar (Editors) Price : $125 Pages : 456 Publisher : Wiley Vaccine Manufacturing and Production is an invaluable reference on how to produce a vaccine - from beginning to end - addressing all classes of vaccines from a processing, production, and regulatory viewpoint. It will provide comprehensive information on the various fields involved in the production of vaccines, from fermentation, purification, formulation, to regulatory filing and facility designs. In recent years, there have been tremendous advances in all aspects of vaccine manufacturing. Improved technology and growth media have been developed for the production of cell culture with high cell density or fermentation. Vaccine Manufacturing and Production will serve as a reference on all aspects of vaccine production by providing an in-depth description of the available technologies for making different types of vaccines and the current thinking in facility designs and supply issues. This book will provide insight to the issues scientists face when producing a vaccine, the steps that are involved, and will serve as a reference tool regarding state-of-the-art vaccine manufacturing technologies and facility set-up. Pharma Bio World

February 2019 ► 59

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