Pharma Bio World January 2019

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INTERVIEW 10

“Drug products will continue to become more advanced and personalized…”

Mr.Sanjeev Taneja, President & Managing Director, Evonik India

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8 ◄ January 2019

Pharma Bio World

interview

“Drug products will continue to become more advanced and personalized…”

Evonik is one of the world’s leading specialists for advanced drug delivery and their Eudragit portfolio of functional polymers is arguably the world’s most trusted brand for drug products that have specific functionality requirements. As an industry leader for functional excipients with best-in-class services, Evonik is collaborating with leading pharmaceutical companies for initial feasibility and screening studies to evaluate and identify the most attractive opportunities. Mr.Sanjeev Taneja, President & Managing Director, Evonik India tells us more in this detailed interview with PharmaBio World.

Could you give us a brief profile of Evonik?

Evonik is a world leader in specialty chemicals based out of Germany and active in over 100 countries around the world with more than 36,000 employees. In fiscal 2017, the company generated sales of €14.4 billion and an operating profit (adjusted EBITDA) of €2.36 billion. Our specialty chemicals operations are divided into three chemical manufacturing segments - Nutrition & Care, Resource Efficiency and Performance Materials.

Since we are a pharma cum biotech magazine, our readers would be very much interested in knowing more about the products & services covered under the healthcare business line of Evonik?

The healthcare business line of Evonik serves more than 1,000 pharmaceutical, medical device and nutraceutical companies worldwide. As a global partner for advanced drug delivery, we provide pharmaceutical customers with a broad portfolio of functional excipients for oral solid dosage forms and specialty parenterals together with formulation development and manufacturing services.

We are also one of the world’s largest CMOs 10 ◄ January 2019

for APIs and intermediates, and a leading supplier of amino acids and ingredients for pharmaceuticals, cell culture and nutraceutical applications.

Which are Evonik’s well-known brands in the performance polymer category?

The Eudragit® portfolio of functional polymers has been providing pharmaceutical companies with flexibility and reliability for the immediate, delayed and sustained release of their oral solid dosage forms for more than 60 years. Our polymers can be used either individually or in combination to match virtually any target release profile, are easy to handle and are compatible with all relevant process technologies.

What core competencies make ‘Evonik Healthcare’ an attractive partner for development services?

Evonik is one of the world’s leading specialists for advanced drug delivery. We have extensive technical expertise and a strong commercial track record in the development of complex oral solid dosage forms such as multiparticulates and matrix tablets. Our global network of formulation and application laboratories

regularly support customer projects from initial feasibility to the clinical and commercial scaleup of the finished dosage form.

What can you tell us about ‘Eudragit’?

Eudragit ® is arguably the world’s most trusted brand for drug products that have specific functionality requirements. With more than 20 polymers that have secured worldwide monograph acceptance and been reliably used with various types of oral solid dosage forms for many decades, Eudragit helps customers release the true value of their APIs. We regularly help customers overcome specific formulation challenges.

For immediate release, this can include taste or odor masking, swallowability improvement and light, moisture or oxygen protection.

For enteric or sustained release, areas of speciality include high-precision colonic delivery, improved intestinal absorption and the protection of acid sensitive APIs. What solutions do you provide to the challenges of bioavailability enhancement?

We routinely work with customers to increase bioavailability and address poor solubility. We are highly specialized in solid dispersions, Pharma Bio World

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interview API and silica technologies, with well-defined flexible processes in place for hot melt extrusion and spray drying. Our polymers also have robust thermoplastic properties with high thermostability and miscibility. We also provide customers with predictive systems to select the best carrier excipient and process parameters, with various downstreaming options in place to improve dosage forms and speed to market.

Where do you think the future of drug delivery is headed?

Drug products will continue to become more advanced and personalized, with pharmaceutical customers increasingly seeking innovative formulation solutions to enable, enhance or differentiate their originator products from the competition, or achieve equivalence for approved brands.

This will require long-term collaborations with partners such as Evonik that have the strength, expertise and flexibility to reduce project risk, accelerate speed to market and improve global supply security.

Do you see a future in personalized medicine and implants?

Yes. We see strong trend in all major markets.

The convergence of 3D printing technologies with formulation technologies for oral solid dosage forms is expected to create significant opportunities for pharmaceutical companies to pioneer next-generation therapeutic solutions.

We believe that the pharmaceutical market has only begun to scratch the surface of what’s possible. We expect significant breakthroughs over the next decade in the development of personalized medicines for various chronic and rare diseases that will transform the costeffectiveness of patient care.

How do you see 3D printing evolving and your contribution in terms of products and services offered for this technology?

As an industry leader for functional excipients with best-in-class services, we are collaborating with customers for initial feasibility and screening studies to evaluate and identify the most attractive 3D-printing opportunities. In addition to our formulation 12 ◄ January 2019

and application services, it also helps that Eudragit ® has accumulated more than 10 years of published data with 3D-printed drugs.

Many of our polymers are ideal for use with all applicable process technologies for 3D printing including melt extrusion. Evonik is a world leader and pioneer in the production of high performance polymer powders, which allow for the industrial production of high-tech components using 3D printing technologies.

Polyamide 12-based powders Vestosint® are apt for the pharmaceutical industry due to their high quality and processing capabilities.

The property profile of each powder is perfectly matched to the respective 3D printing technology such as Selective Laser Sintering (SLS), High Speed Sintering (HSS), Multi Jet Fusion (MJF) or Binder Jetting. Evonik has become the first company in the world to develop a polymer filament based on PEEK (polyether ether ketone) in implant-grade quality for use as a 3D printing material for implants. This high-performance material can be used in fused filament fabrication (FFF) technology and is expected to enable additive production of three-dimensional plastic parts for medical implants in the human body. In addition, Evonik has also opened up ‘Asia Research Hub’ in Singapore, to internationalise and enhance its research efforts into the areas of additive manufacturing, smart materials and tissue engineering.

What is Evonik’s vision with reference to the global pharma industry?

Evonik will continue to serve as a strategic partner in the development of advanced oral solid dosage forms and specialized parenterals. Our R&D pipeline continues to reflect the unmet and emerging needs of customers that require advanced functionality solutions. By leveraging our existing core competencies, we look forward to help customers improve patient care, reduce healthcare costs and improve drug brand competitiveness.

How long has Evonik been in India and how significant is your presence in India both in specialty chemicals and pharmaceuticals?

Evonik stared with a sales office in India in late 90’s with its predecessor companies. Since

then we are continuously growing. Today, with the head office being located in Mumbai, Evonik has 3 production sites, 2 R & D centers and 8 application technology labs across India.

The production of precipitated silica, mainly for industrial applications like tyre, mechanical rubber goods, is carried out at Insilco Ltd. site in Gajraula whereas silica for consumer applications - oral, food, pharma, etc. - are produced at the Jhagadia site in Gujarat.

We also have a range of Catalysts - Oils and Fats Hydrogenation Catalysts, Activated Metal Catalysts and Precious Metal Catalysts. These catalysts grades are produced at the Evonik Catalysts India site in Dombivli, Maharashtra.

Evonik has been serving the needs of pharmaceutical companies in India for more than 30 years. Over that time, we have attained a strong track record for technical expertise, production quality and regulatory reliability. Our health care business line has a specialized R&D center in India [Research Center India (RCI)], that has been playing the role of a solution provider to the pharmaceutical and nutraceutical industry by developing new formulations and technologies. With an ever growing demand due to the vast size of the Indian market and fast paced industrialization, it will be our endeavor to continuously cater to an increasing number of industrial applications in paints and c oatings , a u to mo b ile s , construction, renewable energy, etc and consumer applications such as personal care, household care, pharmaceuticals, food & beverages.

What are the specific government policies that you would like to be implemented for the growth of the specialty chemicals and the pharma industry in India?

Evonik supports government initiatives that seek to improve the quality and supply security of drug products. We look forward to continue to support local pharmaceutical companies, regulatory agencies and other healthcare providers to ensure that Indians have consistent access to high-quality medicines.

Pharma Bio World

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Double Impact: QbD + PAT

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t is rare these days to discuss the future of pharmaceutical manufacturing without using the terms quality by design (QbD) and process analytical technologies (PAT). Both of these concepts provide means for establishing an in depth understanding of a manufacturing process, which exceeds the traditional approach of process validation and testing of samples taken from the batch. So what do these terms mean?

The basic principle behind QbD is that quality should be built into a product with an understanding of the product and process by which it is developed and manufactured along with a knowledge of the risks involved in manufacturing the product and how best to mitigate those risks. QbD has been embraced by the regulatory agencies as a ‘best practice’

14 ◄ January 2019

for pharmaceutical product development, and FDA and EMA have recently published the conclusions of their first parallel assessment of QbD elements of marketing-authorization applications 1. An important aspect of QbD is understanding and controlling the manufacturing process for the product. Defining the critical process parameters (CPPs) (e.g., air flow, temperature, rotor speed, spray rate) and then monitoring these parameters during manufacture is a standard practice in pharmaceutical manufacture.

In addition to monitoring process parameters, a relatively new trend in pharmaceutical manufacturing is the real-time measurement of critical quality attributes (CQAs) during processing, using analytical techniques generally used in a quality control (QC) laboratory, hence the term ‘process analytical

technologies’ or PAT. In particular, the use of spectroscopic technologies for in situ determination of material characteristics is fast becoming a standard feature in pharmaceutical processing 2. Examples include the determination of drug content uniformity during powder blending 3 and tablet manufacture 4,5, drug-laying during pellet coating6 and even in the processing of biopharmaceuticals 7.

PAT systems can enable continuous monitoring of product characteristics throughout processing. Consequently, the influence of changing process parameters on product characteristics can be rapidly assessed-building up an understanding of what process parameters will provide product of acceptable quality. This mapping of the relationship between process inputs and CQAs can be described as defining the

Pharma Bio World

‘design space’ for a process and is an important contributing element to QbD.

a regulatory compliance perspective, but also for sound financial reasons.

6. P. Avalle et al., Eur J Pharm Biopharm 87 (2) 244-251 (2014).

If we can define the design space and are then able to monitor the CPPs and CQAs of the product in real-time, can we abandon QC testing of product samples for confirmation of acceptable product quality? Yes, we can, in principle. Realtime release is certainly achievable and acceptable by the regulatory agencies who have issued guidelines on the subject 8, 9 . The benefits of real-time release are to a large extent self-evident:

A marriage made in heaven? Well, QbD and PAT certainly complement each other

7. J. Gomes, V.R. Chopda, and A.S. Rathore, J Chem Technol Biotechnol 90 (4) 583-589 (2015).

• Confidence in product quality • Significant cost saving as no final product testing required • Reduced time from manufacture to product release It can, therefore, be seen that adopting QbD and PAT principles for new product development makes sense not only from 16 ◄ January 2019

and the likelihood is that the partnership References

8. EMA, “ Guideline on Real Time Release Testing,” EMA/CHMP/QWP/811210/2009Rev1 (London, Mar. 2012).

1. EMA, ‘EMA-FDA pilot program for parallel assessment of Quality by Design applications: lessons learnt and Q&A resulting from the first parallel assessment,’ EMA/430501/2013 (London, Aug. 2013).

9. FDA, Guidance for Industry: Submission of Documentation in Applications for Parametric Release of Human and Veterinary Drug Products Terminally Sterilized by Moist Heat Processes (Rockville, MD, Feb. 2010).

has a very promising future.

2 T. De Beer et al., Int J Pharm 417 (1-2) 32-47 (2011).

3. C. Corredor et al., J Pharm Innov 10: 47–55 (2015).

4. K. Jarvinen et al., Eur J Pharm Sci 48: 680-688 (2013).

5. P.R. Wahl et al., Eur J Pharm Biopharm 87 (2) 271-278 (2014).

(Source: JPS)

Pharma Bio World

A Tonic For Indo-China Relations China’s expertise and massive market for medicine coupled with India’s cost-effective quality formulations could be a match made in heaven.

I

ndia takes great pride in its reputation as ‘pharmacy to the world.’ Today, India exports drugs to almost every major market in the world except China. India has established itself as a key source of cheap generic drugs and contributes almost 20 percent of the world’s non-branded formulations, maintaining a big lead over China. Exports account for nearly 60 percent of India’s total pharmaceutical revenues, and India’s total pharmaceutical market (domestic and exports) is estimated to be over US$30 billion.

However, India is far from self-sufficient and imports nearly 92 percent of all raw materials (also known as active pharmaceutical ingredients, i.e. APIs or intermediaries, which Indian manufacturers process, mix, and make into formulations that are sold as finished medication), of which China supplies as much as 80 percent.

Manufacturing companies have tried and failed to match the price of Chinese raw materials, and several API units in India have gone out of business in the past few years. One could argue that China is as dependent on India to unload these raw materials, but the reality is that it is easier to find other markets than to create a manufacturing base.

In 1991, China contributed 0.4 percent of India’s bulk drug imports, and in 2018, this figure had grown to 80 percent by volume. This is a clear evidence of the surging growth in the Chinese API manufacturing as well as India’s failure to keep up. India has, however, made up in terms of finished formulations, and India’s total pharma exports in 2018 were valued at around US$17 billion, compared to China’s US$10 billion plus.

High dependence on imported intermediates has remained on the government’s radar for a while, and in 2013, a committee was formed under then Health Secretary VM Katoch to recommend ways to reduce India’s dependence on imported APIs. The Katoch Committee submitted a report in 2015, but its recommendations are still under consideration.

Bonding Over Drugs On the positive side, imports from China almost singlehandedly sustain the Indian pharma industry. If not for the cheap raw material, it would have been unlikely for India to become a leader in generics. Chinese players have also pressured Indian

API manufacturers to keep their prices competitive. India’s trade relationship with countries like the United States depends heavily on the pharmaceutical sector. In 2018, for instance, India exported around US$6 billion worth of pharmaceutical products to the United States, which constituted over 11 percent of India’s total exports of goods to the U.S. Since India is not yet equipped to manufacture raw material at this volume, Chinese APIs have been supporting the sales. India’s cost of production of drugs is almost half that of Europe, and this is only possible because China’s cost of API is almost a fourth of the cost in India.

Better access to medicine is high on India’s agenda, and lower costs of medicines have led to a higher penetration of healthcare. Recognizing past success in terms of dominating the global generics market and reducing out-of-pocket expenditures with affordable medication, the government of India has further strengthened its resolve to promote generics via ‘Pradhan Mantri Bhartiya Jan Aushadhi Scheme’ (Prime Minister’s Indian Public Medicine Scheme). The scheme works

Dreams Of Self-Sufficiency In an extremely ambitious move under its Pharma Vision 2020, India aimed to become a global leader in end-to-end production of pharmaceuticals. The year 2015 was designated the ‘Year of Active Pharmaceutical Ingredients’ by the government under its ‘Make in India’ program. While this was supported by policy such as exemption of customs duties on certain bulk drugs, these are still baby steps towards achieving that aim.

18 ◄ January 2019

Pharma Bio World

Rocky Road Ahead Among the recommendations of the Katoch Committee are pertinent ideas such as pharma hubs or parks where support is given for API production, investment in R&D, effluent treatment and patents. Already, a pharma hub is being developed in Hyderabad, and others are being planned across the country. Industry experts feel that India has the capacity, but regulatory support is needed to encourage Indian players to make intermediates.

through special stores that sell only generic medicines to the public. Already more than 850 such outlets are operating across the country and the government plans to expand this program several fold to ensure quality medicines for all at affordable prices. In India, where disease rates are among the highest in the world and the economic divide between the rich and the poor is gaping, the future of public health depends greatly on the success of initiatives like these.

The availability of raw material has also made it possible for India’s pharmaceutical industry to flourish. Of more than 10,000 drug manufacturers in India, about 77 percent make only formulations and depend on external sources for API. The Indian market is price sensitive. As long as raw materials meet the requisite quality standards, companies will buy from the cheapest available intermediary since there is no difference in quality. The im-

20 ◄ January 2019

pressive growth of India’s pharmaceutical industry has been propelled by formulation manufacturers, who in turn rely on China’s exceptional ability to process raw materials at low prices.

Time for Some Checks At the same time, India depends on Chinese resources for many essential drugs, including amoxicillin, ampicillin, ciprofloxacin (antibiotics), paracetamol (analgesic), and metformin (a diabetes drug).

Penicillin, the drug that started the antibiotic revolution and remains a key treatment, is no longer produced domestically, but imported almost entirely from China.

The government has imposed some checks on imports. For instance, every pharmaceutical ingredient being imported into India must be pre-registered. This has helped keep track of not only quality and adherence to standards, but also the volume being imported. To help the few remaining API manufacturers in India, anti-dumping duties have been imposed on some products that are made indigenously such as Vitamin A, C and Ceftriaxone Sodium Sterile. However, since this anti-dumping duty is imposed only on these specified items, formulation manufacturers have found ways to circumvent these duties by importing the precursor form of the intermediate (for instance, importing crude Ceftriaxone Sodium and sterilizing it in India).

Needless to say, it is important for India to diversify sources of resources to safeguard its exports, and for China to diversify its market, the country must overcome supply and market risks and ensure that no single player (or country) maintains a monopoly or the power to control prices.

Presently, China imports finished drugs from Western countries, and since Indian drugs already meet the high quality standards prescribed by the United States, they would also meet Chinese standards. This could help balance the trade gap, and also open another market for India, while reducing China’s cost of end drugs.

With Donald Trump’s call to ‘manufacture in the United States’ (along with a promise to drastically cut regulations and approval processes) expected to adversely impact India’s pharmaceutical exports, it is an important time for India and China to acknowledge their respective strategic advantages and work together to collectively become more powerful global players. With China’s API expertise and huge market for finished medicines, and India’s cost-effective but quality formulations, each country offers something to the other.

(Source: CI Dialogue)

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Combating AMR with phages Afflictive bacteria have been the scourge of man but what is the bacterium’s worst nightmare?

E

ffective antibiotics have been one of the pillars allowing us to live longer, live healthier, and benefit from modern medicine. Unless we take significant actions to improve efforts to prevent infections and also change how we produce, prescribe and use antibiotics, the world will lose more and more of these global public health goods.

Based on current trends, the implications of AMR are bound to be devastating.

Antimicrobial Resistance (AMR) which includes Antibiotic Resistance (AR), occurs when microorganisms (bacteria, fungi and parasites) adapt to the drug that is attempting to attack it and continue to multiply in its presence.

Since the discovery of the first antibiotic penicillin - in 1928, subsequent antibiotic discoveries moved at a rapid pace, particularly from the 1940s to 1980s. Some notable discoveries include cephalosporins - a class of antibiotics structurally related to penicillin - in 1948, carbapenems in 1976 and fluoroquinolones - antibiotics used to treat urinary tract infections - in

1980.

Athough antibiotics have transformed modern medicine and have saved millions of lives over the years, their overuse has been a main driver of antibiotic resistance. During the last 75 years, bacteria have shown the ability to become resistant to every antibiotic that has been developed. And the more antibiotics are used, the more quickly bacteria develop resistance.

The use of antibiotics at any time in any setting puts biological pressure on bacteria that promotes the development of resistance. When antibiotics are needed to prevent or treat disease, they should always be used. But research has shown that as much as 50% of the time, antibiotics are prescribed when they are not needed or they are misused (for example, a patient is given the wrong dose). This inappropriate use of antibiotics unnecessarily promotes

antibiotic resistance. One of many reasons why antibiotic use is so high is that there is a poor understanding of the differences between bacteria, viruses and other pathogens, and of the proper use and value of antibiotics. Antibiotics are very often prescribed for no useful purpose. Too many antibiotics are prescribed for viral infections such as colds, flu and diarrhea.

Surgery (elective and from trauma), cancer treatment (surgery and immunosuppressive therapy), intensive care, transplant surgery, even simple wound management would all become much riskier if we cannot use antibiotics to prevent infections, or treat infections if they occurred. Similarly, we now take it for granted that many infections are treatable with antibiotics, such as tonsillitis, gonorrhea and bacterial pneumonia. But some of these are now becoming untreatable. Excessive and incorrect use of antibiotics in foodproducing animals has also been a key player in drug resistance, since resistant bacteria can be transmitted to humans through the food we eat.

Antibiotics have saved countless lives throughout their long history in medicine but they are not without problems. Besides the looming terror of resistance, the use of antibiotics brings other concerns.

For instance, although they destroy the bacteria that are causing disease, they also indiscriminately kill other species

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products around the world. However, the antimicrobial properties of honey have not been fully exploited by modern medicine as its mechanisms of action are not yet known.

Microbiologists and pharmacologists are also focusing on environments where well-known antibiotic producers like Streptomyces can be found. And now preliminary trials have found that bacteriophages — viruses that infect bacteria — might be a viable replacement for antibiotics in the future. These ubiquitous viruses are found wherever bacteria exist and they are a bacterium’s worst nightmare. It is estimated there are more than 1031 bacteriophages on the planet, more than every other organism on Earth, including bacteria, combined. of bacteria. It is becoming ever clearer that our gut bacteria are an essential part of our health, and destroying them in huge numbers will have negative consequences. Antibiotics can also cause gastrointestinal distress - often because of the mass culling of bacteria. For these reasons, the hunt for alternatives to antibiotics is heating up.

Each year, drug-resistant infections kill around 7, 00,000 people worldwide, and by 2050, antibiotic resistant superbugs could end up killing around 10 million people, apart from increasing global healthcare costs by more than $1 trillion per year, according to recent research. A World Bank report analysing the economic threats of AMR also suggests a decline of 3.8% of world’s annual GDP by 2050. In developing and tropical countries like India, Pakistan, Bangladesh, etc, the problem

of antibiotic resistance is even more crucial as these countries bear a huge burden of infectious diseases as well. No wonder the World Health Organisation (WHO) describes the problem as one of the biggest threats to global health, food security, and development today.

The search for replacement antibiotics to combat multi-resistance has prompted researchers to explore new sources, including folk medicines - a field of study known as ethnopharmacology. A case in point is honey which has long been acknowledged for its antimicrobial properties. Traditional remedies containing honey were used in the topical treatment of wounds by diverse ancient civilisations. Manuka honey derived from nectar collected by honey bees foraging on the manuka tree in New Zealand is included in modern licensed wound-care

Although using a virus to fight off bacteria within our bodies might appear to be a risky idea, bacteriophages only attack bacteria, leaving human cells untouched. Also, they are highly specific to certain bacterial strains, meaning that there is no widespread cull of all species — neither good nor bad. Using viruses that infect only specific types of bacteria spares the many good bacteria in the gut, which are linked to numerous long-term beneficial health outcomes.

It has been shown in recent trials that bacteriophage treatment has no apparent side effects, at least with short-term use. Also, the potential uses for bacteriophage treatments go beyond gastrointestinal complaints. For instance, scientists are now exploring the use of bacteriophages in supplements to help restore balance in the microbiome of people with metabolic syndrome. These individuals typically have altered gut bacteria populations due to ongoing inflammation.

There may be a role for bacteriophages in developing countries where a significant number of people experience nutritional deficiencies due to chronic diarrhea.

Interestingly, bacteriophages were used as antibacterial agents in the 1920s and ‘30s in the United States. One main reason that they fell out of favour was the advent of antibiotics, which were much easier to manufacture, store, and prescribe. But with the threat of antibiotic resistance rearing its head, a shift back toward bacteriophages might well be on the cards.

(Source: PBW)

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insights

Patient Centric Pharma: Putting the patient at the helm The pharmaceutical industry is in the midst of radical change, with a growing shift in emphasis from products to patients. A half-century old business model based on blockbuster drugs, incremental innovation, and physician preferences, has been turned upside down and patients are in charge. Continuing pressure on the old model and the business benefits of adopting a new model of patient engagement will undoubtedly accelerate the drive towards a patient-centred focus. However, new strategies and new organisational structures won’t be enough. Top leaders will not only be tasked with developing innovative, patient-centred models, they will also need to achieve enterprise-wide culture change and introduce the new leadership competencies this new model requires. Genuine patient-centric focus means understanding patients’ experiences of their condition - what the individual patient values and needs, as well as what is most likely to result in positive healthcare outcomes. Therefore, pharma will need to integrate new skills and abilities into their business model.

P

harma has traditionally been a sales-focused industry, where organisations and individuals are rewarded for profits over patient outcomes.

However, pharma need only look to the recent public outcry over drug price hikes to realise that being too focused on financial benefits won’t serve anyone in the long run; structuring a business around aggressively chasing targets and encouraging the wrong behaviours is no longer effective or sustainable. The wider industry is placing itself at similar risk if it loses focus on its primary customer patients. The biggest misconception of pharma’s business model is that what’s right for the patient and what’s right for the shareholder are fundamentally at odds. In fact, the reverse is true. When the patients’ needs are our primary priority, business flourishes. Leaders are increasingly aware of the need to place greater focus on putting the patient at the centre of what pharma organisations do. By improving

26 ◄ January 2019

patient engagement and incorporating the patient voice into the design of products and services, a patient-centred focus is bound to improve patient outcomes.

In the last few years, pharma has witnessed the beginning of a revolution, and this revolution has a rallying cry - ‘Patient Centricity’. Suddenly, it seems that all the actors in the healthcare system have woken up to the fact that patients deserve to be central to the healthcare and technological decisions that affect them. One would think that patients have been in the centre of medicines since Hippocrates of Cos stated almost 2500 years ago that their diseases have natural causes and that the course of the disease can be influenced by medicines. However, for many hundred years, the science of developing medicines has been driven by an authoritative approach to experimentation with patients as

subjects rather than genuine participants in these technological developments.

Even quite recently, many medicines were developed purely through the championship of one expert, with the science at the centre of the innovation and with limited consideration of the needs and wants of the patients, and thus, the overall outcome.

Only after disastrous adverse events caused by some therapies marketed in the

Pharma Bio World

insights decision makers were already pursuing another course. The principle of Evidence Based Medicine (EBM) had become the vehicle by which patients would truly benefit. Only evidence with the highest epistemological strength (i.e., coming from meta-analyses, systematic reviews, and randomized controlled trials) should yield strong recommendations in guidelines.

Also, regulatory authorities strengthened their evidence requirements from the viewpoint of EBM for market authorization.

Hence, pharmaceutical companies adapted their development process to yield the quality data appropriate for supporting product authorization and adoption to standard practice. However, this push for better evidence still left out the patient.

It was the scientists and experts who determined which evidence to use, often resulting in measures that meant little to the daily life of a person with a disease. nineteen-fifties such as thalomide or animal cell therapy, regulatory requirements were introduced which made safety data, risk evaluation and pharmacovigilance processes an important part of medicines development. In addition, prescription laws were introduced or intensified to protect patients from uncontrolled overuse.

It became important for the healthcare system and pharmaceutical companies to better understand prescribers’ behaviours and needs. To prevent failures in the market, interactions with prescribers began to happen throughout the clinical development - but where was the patient in this?

fuelled by anger at the seeming lack of progress in releasing the new anti-virals to patients in need, and fuelled by the lack of a patient voice in the decision-making processes.

Although this action in 1988 should have sounded an alarm for including the patients in decisions; scientists, clinicians and

Whilst pharmaceutical companies were grappling with the concept of patient relevance, patients themselves were becoming much more connected, informed and assertive. Today, patients and caregivers network, collaborate, and have become organized. They have learnt how decisions are made. Patient organizations have fought against decisions which were

Perhaps, the genesis of the modern patient-centric movement can be traced back, when patients first started to fight against a system which locked them out of the decision process, to October 11, 1988 when a large group of activists laid siege to the FDA offices in Washington DC. They fought against the mechanisms that were being used to approve new medicines against HIV. This rise of activism was Pharma Bio World

January 2019 â–ş 27

insights

made without them but which, in their view, have an impact on their health. Therefore, regulatory and HTA (Health Technology Assessment) agencies have started to include patients or citizens perspectives into their decisions and in some cases as partners in their assessment of new technologies.

A few stumbling blocks have appeared along the way towards participatory decision making or Patient and Public Involvement (PPI); one of the most important being the communication between the different stakeholders (researchers, doctors, patients, health activists and citizens).

Industry players have struggled to determine the best way to engage patients, and many barriers exist, but there is a new determination to overcome them. A range of training initiatives for patients and citizens have been developed by patient organisations to disseminate the basics of good research and clinical practices as well as decision making in healthcare.

Online training and guidance (e.g., EULAR) or certification courses (e.g. EUPATI) are available for those patients who want to become more engaged in research and 28 â—„ January 2019

healthcare decisions. Now finally it is time for the pharmaceutical research and development community to conduct their research with the patients as partners in this scientific journey. The concept of patient centricity needs to become action, not just words. To become truly patient centric the patient perspective needs to percolate the innovation chain throughout the research and development process.

What can go wrong without involving patients actively? There are many examples of therapeutics which were developed with good intentions but wrong assumptions about patient needs, behaviours or tolerance for clinical trial settings. The discontinuation of the inhaled insulin product Exubera, marketed

by Pfizer is one such example. Many elements combined to dampen the uptake of this new form of insulin; the inhaler device was large, and there were patient concerns about the predictability of the dose of insulin that would be provided.

Despite successful clinical programs that convinced regulators of its efficacy and safety, payers and some patients were less convinced.

So, the insights from patients can be critical for the successful adoption of innovations.

Patient advocates representing different disease areas and different geographies want to see a higher involvement of patients in the entire process of clinical research and in any research with impact on clinical decision making, listing or reimbursement decisions.

Empowered patients in advanced countries have learned to speak the fully differentiated language of innovation and refuse to be treated only as subjects of research. It is about time for the global pharma industry to listen, learn and take action. Patients should motivate and inspire pharma executives every day. They should not accept the status quo. A patient-centred culture fosters innovation, encourages independent thinking, collaboration and rewards diversity of thought. It nurtures risktaking, creativity and inclusive behavior which leads to new ideas and solutions.

But to achieve maximum results, pharma companies need to nurture a culture that also welcomes disruption in the name of delivering medicines and solutions that make a difference to patients. Creating a culture that delivers the best the industry can offer to patients and society is a goal worthy of pursuit.

(Source: PBW)

Pharma Bio World

insights

Patient-Centric Pharma – A Radical New Business Model The clock cannot be turned back on patient empowerment; but what can change is how pharma responds. For some, it has already proved to be an opportunity to differentiate and edge ahead. What is clear is that there is no single blueprint for success and that the evolving landscape continues to offer plenty of opportunities for competitive advantage.

Some will inevitably be left behind as the world moves on. But for those that genuinely engage with patients, there is much to gain.

A

s governments and healthcare providers rapidly move towards a health system that focuses on outcomes rather than products and services, pharmaceutical companies are feeling their way towards a new business model: patient-centricity. This shift of emphasis from products to patients represents a radical departure for the pharma industry, upending a half-centuryold business model based on blockbuster drugs, incremental innovation, and physician preferences.

Continuing pressure on the old model and the business benefits of adopting the new model will accelerate the drive towards patient-centricity, but new strategies and new organizational structures will not be enough. Top leaders will not only have to develop innovative patient-centered models, they will also need to achieve enterprise-wide culture change and introduce the new leadership competencies patient-centricity requires.

Today’s increasing emphasis on patient outcomes is being driven by a confluence of powerful forces. Aging populations and increases in chronic diseases have put new strains on healthcare systems.

Policy makers and payers seek to control costs by requiring evidence of value and comparative effectiveness, compelling healthcare providers to focus on patient impact. At the same time, the technologydriven ability to leverage health data is Pharma Bio World

enabling providers to make better and faster diagnoses as well as more informed treatment decisions. Consumers, too, are playing a major role in this revolution.

They now arrive in physicians’ offices armed with information, and their insistence on taking a more active role in their treatment is transforming healthcare from a provider-dominated marketplace to a consumer-centered system.

To provide the kind of value increasingly being required by governments, payers and patients, pharmaceutical companies will need to genuinely commit to putting the patient at the center. ‘Patient-centric’ cannot simply be a marketing buzzword.

Pharma companies must walk the talk – or else risk reputational damage.

Nor should patient-centricity be confused with patient engagement and its emphasis on patient compliance. Genuine patientcentricity means understanding the patient’s experience of his or her condition – what the individual patient values and needs and what is most likely to result in a positive healthcare outcome in that context.

The insights gained by listening to the voice of the patient can be applied at every stage of a pharma company’s efforts, from drug discovery to winning regulatory approval to post-market disease management. As a result, the company will be able to bring drugs to market that better reflect patient needs (and may increase reimbursement and price, as well as prescribed volume for

precisely that reason), better align with the reward-for-outcomes that governments and payers insist upon, and help patients and providers achieve better outcomes.

Making the transition will be far from easy, requiring concurrent changes in strategy, structure and culture. Of these three, culture change is likely to present the greatest challenge to pharmaceutical companies. In the absence of culture change, new strategies and structures are unlikely to achieve the transformation at the requisite speed. Further, the shift from a product-driven approach to a patientcentric approach requires deep and lasting change in the habits, attitudes, beliefs, values and all of the other assumptions that collectively add up to ‘the way we do things around here.’ Because pharma’s traditional business model has been successful for decades and in place for so long, the culture associated with it is deeply entrenched and particularly resistant to

January 2019 ► 29

insights

such sweeping change. Moreover, cultural transformation must be pursued on three levels concurrently: the personal, the team, and the organizational. It is a daunting challenge. To meet that cultural challenge, companies can start by taking care to do these three things as they develop patient-centered strategies and the requisite organizational structures: • Build culture change into business model innovation.

• Lead culture change from the top.

• Understand the competencies required of patient-centric leaders.

By adhering to these principles a company can achieve the culture change that is essential for success, not only enabling the entire organization to walk the talk of patient-centricity but equipping it to do so for the long term.

Building culture change into business model innovation A number of pharmaceutical companies have taken tentative steps towards patient-centricity. A few have made great strides. Denmark-based Leo Pharma 30 ◄ January 2019

operates in more than 100 countries and focuses on dermatologic and thrombotic conditions. Leo is hastening its transformation to patient-centricity by experimenting and testing multiple new business models across the organization in such areas as patient services, payer engagement, pharmacy engagement, and more. The aim is to leverage the company’s understanding of patients and engage them to ‘co-create’ care solutions and future business models.

that new business models will have to accommodate some common themes.

Similarly, UCB, the Belgium-based multinational specializing in treatment for severe disorders of the immune and central nervous systems, has put patientcentricity at the heart of its values and has appointed a Chief Patient Affairs Officer to accelerate the transformation.

New partnerships To be a valuable part of the holistic delivery of treatment, pharma companies

A shift from brand to disease Payers, providers, and patients focus on disease areas, not brands. Pharma companies of course often specialize in one or more therapeutic areas, but scientific concentration on branded drugs for such areas is a much narrower focus than holistic treatment of a condition, especially if it is chronic.

New business models, with their accompanying value propositions, organizational structures, and profit formulas will of course differ from company to company – there is no onesize-fits-all. However, the changing healthcare landscape does suggest Pharma Bio World

insights

will have to find new ways of collaborating with payers, providers, and patients. For example, the wealth of data that pharma companies accumulate about patient populations could be brought to bear in cooperation with caregivers to add value in previously unimagined ways. In fact, the global healthcare system invests around $10B in health IT annually. Further, pharma companies will need to partner with newcomers in the healthcare market, such as IT, food and technology companies.

New reward structures As the criterion of success becomes optimal patient outcomes, pharma companies will need to forge workable reward structures for their role in achieving those results.

Those common themes suggest dramatically different ways of doing things – whatever the specifics of a particular patient-centric business model. The company will need to build new capabilities, change customer-facing roles, and alter the structure of the organization. These changes in strategy and structure, if they are to succeed and to be sustainable, must be accompanied by culture change – a conscious, enterprise-wide effort to instill a shared focus on the patient.

Further, the ultimate intent of a new business model is to disrupt and eventually supplant the existing business model. As Clayton Christensen, author of ‘The Innovator’s

Dilemma’ and other groundbreaking work on ‘disruptive innovation,’ has observed, such transformations are particularly difficult for large, well established companies. As a company makes the transition to the new model, it must continue to execute on the existing product-based model, allocating resources for both efforts simultaneously and gradually shifting the center of gravity over time. Often, however, the new model is overwhelmed by the sheer cultural inertia of the old ways of doing things, especially in the early days when the new model has not yet produced tangible financial results.

Culture change can happen by design or by default – and the default will usually be to the old culture, resulting in a failure to deliver on the new value proposition and subversion of the new organizational structure.

Driving culture change from the top

• Change the collective culture by creating genuine individual change.

• Build pace, momentum, and engagement across the whole organization.

• Ensure sustainability of the new culture by aligning practices and policies with the desired change.

Driving culture change from the top

The change starts from the top, with the CEO assuming the role of a de facto ‘Chief The change starts from the top, with the CEO assuming Experience Officer’ to drive innovation and the role of a de facto ‘Chief Experience Officer’ to drive transformation, while continuing to execute innovation and transformation, while continuing to on current business imperatives and preserving on execute current business imperatives and what is relevant from the existing business model. To keep preserving what is relevant from the existing the balance from tipping back in favor of the existing business model. keeppatient-centric the balance from model, the CEO canTo organize leadership to drive the in agenda entire value chain, the tipping back favorthrough of thetheexisting model, traditional boundaries of R&D, Regulatory CEOtranscending can organize patient-centric leadership Affairs, Sales & Marketing, and Payer and Provider and to drive thetheagenda entire value enlarging outlook ofthrough the peoplethe within those old chain, transcending traditional boundaries boundaries.

For example, given the broader definition of of stakeholders to include patients, providers, payers, R&D, Regulatory Affairs, Sales & Marketing, and governments, Sales & Marketing will need to how it and allocates Payerits resources, and Provider and enlarging targets “customers,” and incents its the personnel. outlook Similarly, of theR&D people within those the old will need to think beyond molecule to the vastly greater possibilities that a patientboundaries. For example, given the broader centric approach opens up. definition of stakeholders to include patients, Patient-centric leadership could consist of a Chief Patient providers, payers, and governments, Sales Officer (CPO) or the like, or a group of leaders – a kind & Marketing will need to rethink on how it of “P-suite” to stand outside of the commercial function allocates resources, targetsa unified ‘customers,’ and driveits culture change by sending message behalf of the patient/consumer than a diluted and on incentivises its personnel.rather Similarly, R&D and conflicted message restricted by capabilities, domain will and need to think beyond the molecule to capital (fig 1). But regardless of how this leadership the vastly greater possibilities thatif ait ispatientis structured, it will need to do four things to successfully createopens a culture up. that enables new strategic, centric approach operating, and organizational models to flourish:

• Provide purposeful leadershipcould that models Patient-centric leadership consist

of the culture from the top down. a Chief Patient Officer (CPO) or the like, • Change the collective culture by creating or a group of leaders – a kind of ‘P-suite’ genuine individual change. to stand outside of the commercial • Build pace, momentum, and engagement function drive culture change by acrossand the whole organization.

•

Ensure sustainability of the new culture by aligning practices and policies with the desired change.

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sending a unified message on behalf of the patient/consumer rather than a diluted and conflicted message restricted by capabilities, domain and capital (Figure 1). But, regardless of how this leadership is structured, it will need to do four things if it is to successfully create a culture that enables new strategic, operating, and organizational models to flourish: • Provide purposeful leadership that models the culture from the top down.

CEO Chief Experience Officer Culture

P-SUITE Patient Centric Leaders Process & Ideas

TRADITIONAL FUNCTIONS R&D

Regulatory

Medical Affairs

Market Access

Innovation Unmet Needs

Patient Insight

Patient Figure 1: Patient-centric leadership figure 1

Patient-centric leadership

January 2019 ► 31

Heidrick & Struggles | Senn Delaney 5

insights First, people watch what their leaders do and emulate them. Individually and collectively, leaders, through all of their actions, become role models for change – or not. And that includes not just the leaders in the C-suite or the ‘P-suite’ but the top leaders throughout the organization.

If the leaders do not personally own the change, nobody will. Further, employees are increasingly motivated by the mission of the companies for which they work.

Leaders who genuinely live the credo of patient-centricity can significantly increase employee engagement, which is widely known to drive productivity.

Second, culture in its essence is composed of individuals and their fundamental assumptions and beliefs. If a new culture is to take deep root and endure, each of those individuals – from the leader through all levels of the organization – must embrace it. Genuine and lasting personal change occurs only when people powerfully experience different ways of doing things and succeeds at them. It has been found that the most effective way to make a lasting impression on individuals about the value of the desired personal changes is by providing them with insights as to why the change is beneficial. Through focused engagement and personal and team coaching, individuals who have been driven by narrow customer-focused goals and metrics can personally experience the more holistic perspective that patientcentricity requires. Unless change occurs at this deep and individual level, the new business model is unlikely to take root in the organization.

Third, unless the organization can achieve a brisk pace, build momentum for change, and keep all employees engaged, it will remain stuck in its old ways or revert to them when the effort wanes. Everyone, enterprise-wide, must be continually engaged in a way that helps them shift their personal assumptions and align to a new way forward in terms of behavior, action, and results.

32 ◄ January 2019

Case Study: UCB

Parkinson’s Disease - More than shaking In 1817, an English doctor, James Parkinson, published his essay reporting six cases of paralysis agitans. His ‘Essay on the Shaking Palsy’ described the characteristic resting tremor, abnormal posture and gait, paralysis and diminished muscle strength, and the way that the disease, which was later named after him, progresses over time.

Almost two centuries later, most people, including those working in health care still think of Parkinson’s disease as primarily affecting the motor system, with shaking and disturbed movement being the main issues. For clinicians this conclusion is rather logical, since the motor disturbances are what really stand out during the brief and infrequent doctor visits. No wonder thus that (improvement of) motor symptoms have been the (only) standard used and reported in clinical studies and thus also for the development and approval of new medicines.

But when UCB started to listen much more deeply to the stories that are told by people actually living with Parkinson’s (and this includes both those having the disease as well as those caring for and living with the patient), a common theme soon emerged - the motor symptoms of Parkinson’s are not the hardest part of living with the disease. Direct observations throughout the day and night of people living with Parkinson’s confirmed that not only are there many non-motor symptoms, but these are both frequent and important. Unfortunately, these non-motor symptoms were seldom discussed, let alone measured, during routine clinical care, and they seemed to play little to no role in therapeutic and regulatory decision making.

Thus, the insights gained from the deep listening to patients revealed an important gap in the current understanding, assessment and management of Parkinson’s disease (PD). A disruptive intervention was clearly needed to raise general awareness and attention regarding the non-motor dimension of the disease.

Over the following (many) months, UCB continued to work with many patients to develop an easy assessment tool aimed at more adequately describing how someone living with PD is actually doing at a given moment in time. With the help of many patients and in partnership with the European Parkinson’s Disease Association (EPDA) this resulted in the development and validation of the Parkinson’s Well-Being Map™, a patient-centric and patient friendly self-assessment tool.

The tool is available for free online and can be used in both paper and electronic format. It helps enable a much better and more helpful discussion between patient and physician and also to track the fluctuating disease as well as the effect of different therapeutic options.

The tool has become a frequently used and well respected aid in the management of Parkinson’s disease. Importantly, the tool is also changing the perception of the disease itself by all stakeholders (patients, carers, researchers, regulators, payers), and this opens up new avenues for assessing and developing improved therapies.

As such, this tool, built upon patient insights provides a new solution to help improve the lives of people living with Parkinson’s disease.

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insights Fourth, to sustain change and create a culture that traverses all of the institution’s boundaries, many factors need to be aligned; institutional practices, systems, performance drivers, communications, and capabilities needed to drive towards the desired culture. Governance structures will need changing, as will decision-making processes. The same is true for daily rituals, such as meetings, team-based decision-making, and measurement.

Further, the organization should examine customer/consumer and supplier/partner touchpoints and, if necessary, adapt them to make the change real.

The degree to which each of these four principles is put into practice determines the degree to which the effort will succeed.

Omit any one of them – or apply them halfheartedly – and frustration and reversion to the old ways are likely to follow. Get them right and the conditions for a newly competitive, genuinely patient-centric organization can emerge.

Understanding the competencies required of patient-centric leaders

The patient-centric leadership structure may vary depending on the organization.

In some cases, the CEO may be the principal driver of the effort. In other companies, the best solution may lie in the appointment of a Chief Patient Officer – a single top executive charged with promoting and developing patientcentricity. Other organizations may create ‘P-suite’ that seeks to make a difference in the way things are done in each function.

Still other organizations may make patientcentricity part of the requirements for any leadership role. But regardless of the title these patient-centric leaders wear, they will need some specific competencies in five critical areas (Figure 2).

Relating to External Stakeholders Patients constitute the largest group of those external stakeholders. Leaders must understand how patients see the company and carefully consider how

the company interacts with them. Most importantly, patient-centric leaders must fully understand patient needs and be able to articulate those needs clearly and persuasively to the organization and be able to form partnerships with payers and care providers to drive better patient outcomes.

Strategic thinking Though patient-centric leaders might not be their companies’ chief strategists, they should be able to refine development figure 2 and commercialization strategies in Evaluating Patient-Centric ways that deliverfor greater demonstrable

Relating to external stakeholders

Driving Decision-Making Recognizing that success requires understanding how decision-making has Leaders changed in healthcare, and who is making

LEADERSHIP ATTRIBUTES FOR PATIENT-CENTRIC LEADERS

CRITICAL COMPETENCIES Facilitating culture change

value to patients. They will have to invest in understanding customers and their preferences, desires, and cultural attitudes in order to help design tailored products, services, and education strategies that genuinely differentiate the company from competitors. And they will have to continually make the patient’s experience a part of ongoing business reviews and strategy discussions.

Business Skills / Knowledge •

Develops a compelling patient engagement and advocacy vision and strategy

•

Demonstrates a clear understanding of marketplace dynamics and how broad trends shape the future

•

•

In-depth understanding of entire healthcare value chain. and divisions, commercial as well as scientific

•

Works to translate patient priorities into specific deliverables

Diversity of experience across grass-root healthcare

+

Personal Attributes Strategic thinking

Driving decision making

Monitoring execution

• •

Pioneer, entrepreneurial

• • •

Resilient, persistent

Intelligent – smart, quick and analytical

•

Facilitates change / ideas / creativity

• •

Can lead from front and back

Strong mentor Enthusiastic, self-motivating

+

Influencing Skills •

Conveys ideas persuasively and gains support for ideas and initiatives

•

Identifies, negotiates, and reconciles issues effectively

•

Operationally nimble, building strong and resilient relationships

Empathetic, curious, adventurous

•

Can ‘connect the dots’ – looks and sees, hears and listens

•

Engages in regular dialogue with key constituencies

•

Influences others without direct authority

•

Challenges status quo

Figure 2: Evaluation of patient-centric leaders Heidrick & Struggles | Senn Delaney 9

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insights the entire organization in a new direction against powerful cultural currents.

Identifying or securing leaders who possess all of the requisite skills and attributes is not easy, especially since few precedents for such roles exist in the industry. To this challenge, specialized human resource consulting agencies bring unparalleled capabilities in identifying the requisite leadership competencies and assessing talent. Their deeply consultative approach ensures that the best candidate for the demanding role emerges after careful assessment of internal candidates and comprehensive scanning of the external talent market. A well-designed talent management program – including recruitment, promotion, retention, and rewards – institutionalizes the qualities of leadership required to thrive in a new business model, offers people opportunities to develop those attributes, and creates a full pipeline of executives ready to take the company forward.

those decisions, patient-centric leaders will have to ensure that patient well-being drives internal decision-making as well.

Monitoring Execution Leaders will have to keep the key performance indicators of a positive, compassionate patient experience front and center in monitoring and measuring execution and make sure that ‘soft’ data isn’t crowded out by narrow financial criteria. To continually improve execution, they will have to dedicate and develop resources – from analysts that look specifically at satisfaction and experience data trends to social media experts who can help enhance the patient experience. Meanwhile, in-depth analysis of the economics of patient loyalty will enable everyone in the organization to understand the payoffs that investments in patient-centricity generate.

Facilitating Culture Change As change agents for patient-centricity, leaders should be able to help diagnose the 34 ◄ January 2019

current culture and define a direction to a new one that is infused with a passion for patient care. They must be adept at breaking down organizational silos that are barriers to patient care – especially where people are clear about their own roles but not about overlapping and ambiguous territories. And they must be able to help other leaders infuse the patient perspective in their teams.

Success in these diverse activities requires a demanding combination of business skills, personal attributes, and influencing abilities. In business skills, leaders must balance a deep commercial acumen and experience with clinical sensitivity in order to help devise novel ways to deliver value. Desirable personal attributes include an entrepreneurial streak, resilience, enthusiasm, and the ability to lead effectively. Influencing and communication skills are particularly critical for a leader who has no authority over execution and is trying to help take

Similarly with culture change; proven culture-shaping methodology that engages people and measurably impacts both the spirit and performance of organizations can both hasten transformation and make it sustainable. Although the journey towards patient-centricity may be challenging, pharmaceutical companies that undertake it sooner rather than later will find themselves not only with more viable future options but also with unanticipated benefits such as greater agility, reinvigorated people, and increased scientific robustness. And organizations that undertake this journey during the profit phase are likely to get there much faster, differentiate themselves more decisively, and have far greater impact on the chief measure of value today - patient outcomes.

(Source: SD-H&S)

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insights

Patient Centricity v/s Pharmaceutical Companies Various health care bodies (regulatory, health technology assessment, academia, health care providers, scientific journals) request patient input in their decision-making processes. This represents a shift from disease-centered to patient-centered approaches to health care. What does this ‘patient centricity’ mean for the pharmaceutical industry? A panel of pharmaceutical industry representatives discussed the following key issues: Why the pharmaceutical industry needs to be part of the patient-centric movement; How the industry can become patient-centric; and What a patient-centric company actually does.

This paper is a summary of the panel’s point of view on these key questions. The industry’s role has been to develop the science and medicines for prevention or treatment of disease.

In response to changes in the current health care environment, the industry should focus its efforts on initiatives that will improve impact and value for patients and carers. True patient centricity requires a change in the industry’s cultural mindset, an increase in public trust, clearer roles and responsibilities within pharmaceutical organizations, openness to learn from others, and a framework to measure success. There are examples of industry engagement with patients throughout the drug discovery and development process. Patientreported outcomes are becoming increasingly important endpoints in trials; they capture information of relevance to patients, identify preferences, and better inform treatment decision making. Understanding the patient experience can improve disease management at critical points in the disease course. The future of patient centricity lies in coordinated efforts by and alignment of multiple health care stakeholders, which can only be achieved through collaborations and consortia, with the industry playing a key role.

T

oday, patients are more knowledgeable than ever before. The technological and scientific advances of recent years have enabled easy access to information; patients are online and can connect with peers, exchange experiences and knowledge in real time, take part in advocacy and patient support groups, and contribute to real-time data generation. 1,2 As a result, patients feel empowered and expect their voice to be heard. 3 Patients are increasingly being recognized as important stakeholders in the health care Pharma Bio World

dialogue: regulatory agencies (Food and Drug Administration [FDA] and European Medicines Agency [EMA]), academia, and health care providers are requesting patient input into their decision making. 4-7 In 2014, the British Medical Journal launched a ‘Partnering With Patients’ initiative that requires clinical trials publications to include the patient perspective by having patients as authors, peer-reviewers, guest editors, and contributors to the journal. 8 Moreover, decisions about medicine reimbursement are becoming increasingly dependent on the demonstrated value of medicines to

patients. Therefore, payers are seeking evidence in the form of patient-reported outcomes (PROs) and are involving patients in health-technology assessments (HTAs).9,10 This shift in the social landscape is accompanied by increased pressure on health care costs, 11 with tension arising between the desire to act in the best interests of individual patients (individualized care) and taking into account the larger economic considerations. This disconnect is limited not only to the pharmaceutical industry but January 2019 ► 35

insights Is patient centricity feasible from a commercial standpoint? It is accepted that pharmaceutical companies need to make profit. It is how they get and use that profit that is important, and this must be aligned with any assertion of patient centricity. If the vision is directed at providing value to patients and carers, companies must be seen to be breaking out of the cycle of ‘recover costs of R&D - make profit - invest in new drugs - make more profit.’ This commitment, in turn, will help to generate credibility with external stakeholders (patients, regulatory, media, etc).

How Can the Pharmaceutical Industry Become Patient - Centric in a Modern Business Environment? also exists for health care providers and health care payers.

Patient Centricity — An Appropriate Response to Shifts in the Social and Economic Environment?

Patient centricity can be simply defined as integrated measures for listening to and partnering with patients, and placing patient well-being at the core of all initiatives. In essence, it represents a holistic approach to disease management. Although many agree that patient centricity is a concept to be embraced, there is still little published guidance and, in practice, significant variability 12 exists in its implementation by the pharmaceutical industry. Why is patient centricity coming to the fore today? Is it a reaction to the changing environment of a world in which patients are ever more connected and informed, or is it the realization of an ethical responsibility across the health care system? Is it realistic for a company operating in a commercial environment to place patients at the heart of everything that it does?

question: why are we doing this? 13 As in any organization, establishing the purpose and vision first will determine the subsequent plan and actions (how and what) and create alignment among employees towards a common cause. 13 Historically, the pharmaceutical industry’s role has been to develop the science and medicines for prevention or treatment of disease.

Patient centricity involves the patient in this scientific process. In essence, this is an innovative mindset whereby the industry is challenged to engage and collaborate with patients when deciding the best course of action. Therefore, patient-centric initiatives should start with a simple question: how can we make a difference for patients?

Shifting the cultural mindset Patient centricity demands a shift in cultural mindset within the pharmaceutical industry.

At the highest level, it involves listening to and partnering with the patient, and understanding the patient perspective, rather than simply inserting patient views into the established process. Only then can patient-centered outcomes truly be the core of the strategy.

This change in mindset requires leadership from the top and drives the need to redefine core strategy, organizational structure and processes, and capabilities to focus on transparency and value for the patient. A shift from a disease-centered to a patient-

Why Does the Pharmaceutical Industry Need to Be Part of the Patient-Centric Movement?

Transformation into a patient-centric organization requires an answer to this key 36 ◄ January 2019

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insights Table 1. Examples of Initiatives at GSK Aimed at Building Trust With Patients and Physicians.

Engagement with patients can only be possible if there is credibility: Change in marketing practices: In 2011, GSK eliminated prescription sale targets in the US and introduced a new incentive model for sales and marketing practices based on value and feedback from prescribers; external speakers/convention travel support was discontinued (2016).

Clinical transparency: Since 2013 GSK has committed to promote transparency of clinical research and is a leading example in the pharmaceutical industry - it was the first company to grant access to anonymized patient data; the All trials campaign (2013) commits to publishing all trial data; the GSK patient-level data access site has become a multisponsored portal (2014). centered strategy, and from a product-led to a patient-led development process, requires a change in outlook. A corresponding change in organizational model is also needed, with medical affairs, market access, regulatory, pharmacovigilance, and commercial teams at global and regional levels all collaborating with a common goal — to capture patient perspectives and insights and to respond to their needs. If patient centricity is to be the responsibility of everyone in a pharmaceutical company, key development and performance indicators (and possibly remuneration structures) should be adapted to reflect this change in mindset. These performance indicators could include the proportion of product strategies that are based on true patient input, the number of patients involved, patient feedback based on ratings of patients’ involvement (eg, how engaged/involved/satisfied they feel), number of study protocol revisions implemented as a consequence of patient input,14 the relevance of new product profiles Pharma Bio World

to the self-identified needs of the patients, and improving the information available to patients and prescribing physicians on the risks and benefits of a treatment, so that better decisions for the patient can be made.

Building trust One thing is clear: if the call is patient centricity, then the pharmaceutical industry has to be earnest about making it happen, not just using it as a means to seem more patient oriented. Indeed, the starting point of placing the patient at the heart of health care initiatives is trust. The industry has started to address questions about past behavior and public perception, and this positive intent, direction, and action is a vital component of rebuilding the industry’s reputation and forming the foundation for new trusted partnerships.

Trust between the pharmaceutical industry and the public can be built through clear communication about medicines’ riskbenefit profiles and a transparent drug development process. In this context, the relationships between patients, industry, and health care practitioners are essential to building credibility: ‘trust your doctor, trust the medicine, and trust the data.’

One way for pharmaceutical companies to build trust is to collaborate on the development of new patient-centered endpoints. In the context of the Critical Path Institute Patient-Reported Outcome Consortium 15, 10 diseased-focused working groups composed of representatives of pharmaceutical companies and government/regulatory agencies (FDA, EMA, and the National Institutes of Health [NIH]) have been collaborating to share data and develop standardized PRO endpoint measures. This precompetitive initiative aims to standardize PRO endpoint measures in order to facilitate comparisons and efficiencies in regulatory and payer decision making. A unified industry approach to collaboration with the appropriate parties is the key to the adoption of patient centricity across the

industry, and to improving credibility. In addition, many pharmaceutical companies have transparency initiatives; for example, GlaxoSmithKline has several transparency initiatives aimed at building trust (Table 1). 16,17 Table 2. Example of Patient-Led Value Strategy at the biopharmaceutical company UCB. Replacement of ‘brand strategy’ with ‘patient strategy’ is not enough. This process should start with the patient (rather than the commercial product) foremost in mind. Long-term strategy should be based on understanding of the patient journey and critical points (breakpoints) in the course of the disease. Typical breakpoints for potential involvement include diagnosis, new symptom development, relapse, start of a new medication, and emergent adverse events.

As an example, UCB has a medication for Parkinson disease: • Patients with Parkinson disease need to take their medication at the same time each day as their motor function can be very sensitive to changes in this rhythm • If these patients are hospitalized for a different reason, the hospital rarely has the medication for control of motor symptoms readily available; intake is delayed, the patient’s condition deteriorates, and they spend 2-3 days longer in the hospital than if appropriate medication were readily available.

• Understanding this scenario helped UCB to implement relevant solutions in collaboration with treating hospitals, ensuring these medications were available; this in turn led to a decrease in hospitalization duration for patients with Parkinson disease.

• Thus, insights into breakpoints in the disease can help to provide better outcomes for patients.

January 2019 ► 37

insights

Learning from others and collaboration Creating a patient-centric culture requires an understanding of its implications for information flow, decision-making processes, and institutional habits. To achieve this, the pharmaceutical industry cold gain insights from organizations that already have experience with patient interaction. For example, the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) has a patient-centered special interest working group18; the Medical Device Innovation Consortium (MDIC) is a partnership between public and private stakeholders in the medical device industry19; the European Patients’ Academy on Therapeutic Innovation (EUPATI) is a collaboration between 33 different patient organizations, universities, and pharmaceutical companies across Europe; the International Federation of Pharmaceutical Manufacturers & Associations (IFPMA)20 brings together regional/national patient associations and research-based biopharmaceutical companies. Furthermore, there is an ongoing collaboration between the FDA and EMA on patient involvement, that is, the FDA/EMA Patient Engagement Cluster, which enables the agencies to share best practices for patient selection and training throughout drug regulatory life cycles. The Patient Engagement Cluster focuses on cancer treatment and orphan drugs, among other topics.21,22 Multiple groups, including regulatory bodies (EMA), the National Institute for Health and Care Excellence (NICE), 23 different HTA groups,24,25 and others26,27 38 ◄ January 2019

have already established frameworks for patient engagement. For instance, there is a Consensus Framework for Ethical Collaboration28 that helps guide interactions between patients, pharmaceutical companies, and health care professionals. The Interest Group on Patient and Citizen Involvement of Health Technology Assessment international (HTAi) has developed a set of values and quality standards for involving patients in HTA.24 Furthermore, the MDIC has also established a framework for introducing patient preference information into regulatory risk-benefit assessments, specifically on medical devices.19 The lessons learned by these collaborations and consortia will help pharmaceutical companies reduce barriers to patient engagement.29 What are the challenges?

Several challenges exist that need to be overcome before the pharmaceutical industry can adopt the patient centricity concept. 7,10,30 Challenges to address include skepticism about commercial success; lack of process standardization as it relates to involving lay people in a highly regulated environment; lack of sufficient sharing of practices and lessons learned across the industry; lack of understanding of, and respect for, qualitative research methods that often form the foundation of patient centricity research; lack of alignment and measurements of collective progress; internal habits of going back to established information sources (“let’s just ask the clinicians”); compliance frameworks and the perception that direct engagement of industry with patients is inappropriate or unauthorized; and last but not the least, the conflict of responsibilities: the perception that industry should not be the party that engages with patients.

Most of these challenges concern the pharmaceutical industry as a whole and can only be solved in a collaborative fashion, as discussed above. Some solutions are beginning to emerge, highlighting the need to share and learn from each other’s experiences. For instance, a compliance

framework has already been developed and is available to guide direct engagement with patients by industry. 31

What Does a Patient-Centric Company Actually Do? Pharmaceutical companies are at different stages along the patient-centric journey. The following section aims to highlight patientcentric initiatives taken by pharmaceutical companies that have adopted patient centricity as a strategy.

Moving from a brand focus to a patientvalue focus A shift in the industry environment and patient empowerment is dictating a change in how health care solutions are designed.

Patient expectations and needs can differ considerably from the aims and objectives of health care providers, at both the policy and delivery levels. In fact, to be accepted by patients, the patient experience should be the key driver for the development of solutions (eg, medicines, devices, information, support programs, apps). A better understanding of patient experience at critical points (breakpoints) in the course of the disease will help to determine breakpoints that would benefit from pharmaceutical industry input (Table 2).

Roundtable discussions involving patients, or ‘patient value tables’, can be used to validate patient needs and understand the solutions patients seek, or assess the effects of solutions already in place.

UCB has involved patients in all internal meetings since 2002 and uses patient value discussions between patients, health care providers, regulators, and payers.

AstraZeneca engages with patients through research and therapeutic area collaborations using online patient platforms and networks (Table 3).

Essentially, capturing information about the patient journey and gaining an understanding of patient needs will help to develop a true patient-led strategy within the industry and design solutions that treat the patient and not just the disease.

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Figure 1. Patient involvement through drug discovery and development (FoTP - focus on the patient; PROs - patient-reported outcomes).

January 2019 ► 39

Figure 1. Patient involvement through drug discovery and development. FoTP, focus on the patient; PROs, patient-reported outcomes.

Pa�ent input on governance decisions at lifecycle transi�on points

Key enabler: Pa�ent access via strategic partnerships with pa�ent advocacy groups

Pa�ents on advisory commi�ees, contribu�ng to benefit-risk assessment Protocol input on study design: pa�ent views on poten�al barriers for study par�cipa�on; feedback on endpoints

Pa�ent preference assessment

Pa�ent input on pa�ent counseling informa�on, package inserts, med. guides, instruc�ons, devices

Informed consent

Inform pa�ent recruitment & pa�ent engagement plans

Greater disease area understanding, especially earlier in discovery and development: eg unmet need, current treatment, effec�veness/subpopula�ons

Protocol input

Pa�ent feedback on PRO messages/labels

Plain-language summaries

Pa�ents in med. vision workshops End-of-trial ques�onnaire

Disease area understanding

FoTP seminars

PRO measure valida�on and implementa�on Exit interviews

Device design PRO measure development

Epidemiology, observa�onal studies, and pa�ent registries

Phase IV Registra�on and launch Phase III Phase IIB Phase IIA Phase I Preclinical evalua�on Lead op�miza�on Lead discovery Target valida�on

Registra�on Commit to medicine development Commit to phase III Commit to file and launch Commit to candidate First �me in human Commit to target

Opportunity for greater pa�ent involvement Area of recent pa�ent involvement

Involving patients in research and development Another approach to patient centricity is promoting patient nvolvement throughout the drug discovery and development process (Figure 1) 5,32,33. Patient advisory groups already provide input on unmet needs, protocol design, trial conduct, data interpretation and dissemination, risk-benefit discussions, risk management plans (risk evaluation and mitigation strategies), and the interpretation of value of treatment relevant to conversations with payers. However, the degree of input from patients, the frameworks used to gain input, and the implications of their input are not consistent across the industry. Patient engagement in research and development is expected to provide benefits at various stages of the drug development process, which 464include

Area of established pa�ent involvement

• AstraZeneca has a focus group to internally facilitate patient centricity (PaCe): According to AstraZeneca (‘put the patients first’), patient centricity is the open and sustained engagement of the patient to respectfully and compassionately achieve the best experience and outcome for that person and their family; in this conceptual model, patient insights drive innovative solutions that in turn create positive effects for the patient.

• The PaCe approach engages with patients through several research and therapeutic areas; collaboration with PatientsLikeMe; more than 30,000 patients are now connected with AstraZeneca research projects.

• AstraZeneca is also setting up disease-specific networks and patient / carer networks (eg, Patient Expert Network) to advise the development/ brand teams on the co-creation of patient solutions.

Postmarke�ng surveillance

Table 3. AstraZeneca’s Approach to Patient Centricity.

insights -

identification of unmet patient needs, enabling better-informed decisionmaking about target choices and the required asset profiles for go/no go decisions; - study designs and endpoints that are more relevant to patients, which in turn improves recruitment and retention and provides regulatory and reimbursement decision makers with clear patientrelevant evidence; - shorter trial cycle time, so medicines can move more quickly to regulatory submission; - a greater range of products that are of greater value to more patients; - improved patient adherence to drug regimens, leading to improved outcomes for patients; and - a growing body of evidence of patient preferences and unmet needs that will help focus future research.

There is emerging evidence supporting the value associated with patient engagement in theinformation drug developmentabout and discovery ity to provide process.33,34 Considerable progress has nt to patients.

But already beenwhat made ininformathis direction, led by Clinical Trials Transformation Initiative35 A patient the would want to know, and a number of concrete examples of symptoms/side-effects?

How will engagement between pharmaceutical e to do? companies and patients.36,37 However, the from degree patients’ of input from perpatients, the it versus risk frameworks used to gain input, and the e it highlights the value of are treatimplications of their input not consistent 12 across the industry.

Therefore, the industry measures as “any report of the as a whole should aim to standardize and ndition thatincrease comes directly from patient involvement in research development as a priority by if its goal is tion of the and patient’s response patient centricity.

it highlights the value of treatment. The FDA defines PRO measures as ‘any report of the status of a patient’s health condition that comes directly from the patient, without interpretation of the patient’s response by a clinician or anyone else.’ 38 As only patients can report how they feel and function, this generates a need to define endpoints that are important and relevant to patients. 39,40 PRO assessments are increasingly becoming the primary trusted evidence for all stakeholders, including payers, regulators, and patients.

The use of PRO measures in the industry began many years ago, as health-related quality-of-life instruments included in clinical trials. Although many expert centers develop and validate PRO tools, there remains a gap between ensuring that adequate patient input has been sought at the beginning of the development of the tools (eg, truly reflecting the patients’ experience of a disease) and the experts’

Patient-centered drug development is expected to change the way the pharmaceutical industry operates. PRO tools and measures are ideally developed in a precompetitive collaborative way, to set standards across all medicines. 15,42,43 A standardized approach will provide easier, more straightforward assessment by all key stakeholders, including regulators (FDA38 and EMA44), patients, prescribers, payers, and everyone who reviews the data.

Expert Patients

Regulators (FDA, EMA), HTA bodies, NICE,45 and consortia46 all seek to involve educated patients as advisors (expert patients) in drug development, evaluation, and regulation.47 Expert patients have in-depth understanding of the disease context, and in most cases they function on patient advisory panels to provide 465 insights relevant to the patient journey.

The pharmaceutical industry needs to understand the conflicts of interest as

As only patients can report how generates aStandardizing need to define PROs endThe industry has a responsibility d relevant to patients.39,40 PROto provide information about medicines that will be Figure 2: Conceptual framework to achieve patient centricity in the pharmaceutical industry. becomingrelevant the primary trusted to patients. But what information are patients looking for?

A patient would perceived by other in health players, view 2.of How the patient Forcan Figure patientexperience. centricity be achieved thecare pharmas, including payers, regulators,

a recent(conceptual report showed low and such as PROs, want to know, What can I expect in termsceutical of example, regulatorypatient-reported bodies or HTA groups, industry framework). variable rates of patient involvement in in order to address them when involving symptoms/side-effects? How will I feel? and outcomes. the development of PRO measures, with expert patients or know when to step What will I be able to do? many es in the industry began only 6.7% of patients involved in all stages away. Currently, there are very few expert ed quality-of-life instruments Measuring treatment benefit versus risk from (item development, item testing, item patients across a small number of wellpatients’ perspectives important because selection). 41 Although many expert iscenters represented diseases. A need exists to

O tools, there remains a gap 40 ◄ January 2019 quate patient input has been the development of the tools

Concluding Remarks

Bringing patient centricity to life—role of the pharmaceutical Pharma Bio World industry Bringing patient centricity to life requires a vision shared by

insights expand the pool of expert patients across a wide range of diseases.

Concluding Remarks Bringing patient centricity to life - role of the pharmaceutical industry Bringing patient centricity to life requires a vision shared by all stakeholders. The key steps the industry needs to take in order to make this happen are (1) change the mindset — make patient centricity a company-wide and industry-wide vision; (2) collaborate — involve patients and other health care stakeholders to develop patient-centric solutions; (3) share the learning — challenge the status quo, record the experience, learn from it, and share it in order that the industry may get better at being truly patient-centric. Therefore, it is necessary to publish case studies of what is working well in order to keep the discussion alive and advance the collective learning.

In summary, a transformation into a patientcentric organization requires defining the answers to the following key questions: Why are we doing this? How should we do it? and What are the results we aim to achieve? (Figure 2). Historically, the pharmaceutical industry’s role has been to develop the science and medicines for prevention or treatment of disease. Patient centricity is an innovative mindset whereby the pharma industry is challenged to engage and collaborate with patients to get critical input for determining the best strategy to improve patient outcomes. This change from a brand focus to a patient-value focus requires leadership from the top and drives the need to redefine strategy, organizational structure and processes, and capabilities to focus on transparency, credibility, and value for the patient.

The industry is a major stakeholder in making patient centricity a reality, but cannot bring this about alone, or set the agenda. Equally, however, neither can medical professionals, Pharma Bio World

government, or policy makers. How and with whom to partner is the key challenge. The future of patient centricity lies in coordinated efforts and alignment of multiple healthcare stakeholders. Patient centricity can be achieved only through collaborations and consortia that include all health care stakeholders, in which the pharmaceutical industry has a key role.

References

1. PatientsLikeMe. patientslikeme.com.

11. Deloitte. 2015 Global health care outlook: Common goals, competing priorities. http:// www2.deloitte.com/content/dam/Deloitte/ global/Documents/Life-Sciences-HealthCare/gx-lshc-2015-health-care-outlookglobal.pdf.

12. Smith SK, Selig W, Harker M, et al. Patient engagement practices in clinical research among patient groups, industry, and academia in the United States: A survey.

PLoS One. 2015;10:e0140232.

https://www

13.

Sinek S. Start with why. https://www. startwithwhy.com.

2. Engaged patients. http://engagedpatients.org.

14.Getz KA. Establishing return-on-investment expectations for patient-centric initiatives.

Ther Innov Regul Sci. 2015;49:745-749.

3. Muller B. Patient 3.0: The centre of drug development. Amyotroph Lateral Scler Frontotemporal Degener. 2015; 16(suppl 1):62.

4. US Food and Drug Administration. Patient Engagement Advisory Committee. http:// w w w. f d a . g o v / A d v i s o r y C o m m i t t e e s / CommitteesMeetingMaterials/ PatientEngagementAdvisoryCommittee.

Critical Path Institute. Patient-Reported 15.

Outcome Consortium. https://c-path.org/ programs/pro.

16.GlaxoSmithKline. Data transparency. http:// www.gsk.com/en-gb/behind-the-science/ innovation/data-transparency.

5. Perfetto EM, Burke L, Oehrlein EM, Epstein RS. Patient-focused drug development: A new direction for collaboration. Med Care.

2015;53:9-17.

17.GlaxoSmithKline.

Interactions with prescribers. http://www.gsk.com/en-gb/ healthcare-professionals/interactionswithprescribers.

6.

European Medicines Agency (EMA).

Incorporating patients’ views during evaluation of benefit-risk by the EMA Scientific Committees. http://www.ema. europa.eu/docs/en_GB/document_library/ Other/2014/09/WC500173508.pdf.

18.International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Patient Engagement in Research Working Group. http://www.ispor.org/sigs/patientcentered/ pc_engagementinresearch.aspx.

7. Hoos A, Anderson J, Boutin M, et al.

Partnering with patients in the development and lifecycle of medicines: A call for action.

Ther Innov Regul Sci. 2015;49:929-939.

8. British Medical Journal. Patient partnership: partnering with patients. http://www.bmj. com/campaign/patient-partnership.

9. Berglas S, Jutai L, MacKean G, Weeks L. Patients’ perspectives can be integrated in health technology assessments: An exploratory analysis of CADTH Common Drug Review. Res Involvement Engagement. 2016;2:21.

10.

Muhlbacher AC. Patient-centric HTA: Different strokes for different folks. Expert Rev Pharmacoecon Outcomes Res. 2015;15:591-597.

19.

Medical Device Innovation Consortium (MDIC). Medical Device Innovation Consortium (MDIC) patient-centered benefit-risk project report: A framework for incorporating information on patient preferences regarding benefit and risk into regulatory assessments of new medical technology. http://mdic.org/wpcontent/uploads/2015/05/MDIC_PCBR_ Framework_Web.pdf.

20. International Federation of Pharmaceutical Manufacturers & Associations (IFPMA).

Putting patients first: five global healthcare organizations sign Consensus Framework for Ethical Collaboration. http://www.ifpma. org/resource-centre/puttingpatients-firstfive-global-healthcare-organizationssign-consensus-framework-for-ethicalcollaboration.

January 2019 ► 41

insights 21. US Food and Drug Administration and European Medicines Agency Patient Engagement Cluster. http://www.fda. gov/forpatients/patient engagement/ ucm507907.htm.

22. New FDA/EMA rare diseases and patient engagement clusters underway. http:// blogs.fda.gov/fdavoice/index.php/2016/10/ newfdaema-rare-diseases-and-patientengagement-clusters-underway.

31. Dewulf L. Patient engagement by pharma— why and how? A framework for compliant patient engagement. Ther Innov Regul Sci. 2015;49:9-16.

Hunter NL, O’Callaghan KM, Califf RM. 32.

Engaging patients across the spectrum of medical product development: View from the US Food and Drug Administration.

JAMA. 2015;314:2499-2500.

23.National Institute for Health and Care Excellence (NICE). Guide to the methods of technology appraisal. https://www.nice.org. uk/process/pmg9/chapter/foreword.

33.

Domecq JP, Prutsky G, Elraiyah T, et al. Patient engagement in research: A systematic review. BMC Health Serv Res. 2014;14:89.

24. Health Technology Assessment international (HTAi) Interest Sub-Group for Patient/Citizen Involvement. Values and quality standards for patient involvement in HTA. http://www.htai.org/fileadmin/HTAi_ Files/ISG/PatientInvolvement/v2_files/Info/ PCISG-Info-PosterValuesandStandards30-Jun14.pdf.

34. Brett J, Staniszewska S, Mockford C, et al. Mapping the impact of patient and public involvement on health and social care research: A systematic review. Health Expect. 2014;17:637-650.

25.

Kleme J, Pohjanoksa-Ma¨ntyla¨ M, Airaksinen M, et al. Patient perspective in health technology assessment of pharmaceuticals in Finland. Int J Technol Assess Health Care. 2014;30:306-311.

26. European Patients’ Academy on Therapeutic Innovation (EUPATI). Patient involvement in the HTA decision making process. https://www.eupati.eu/health-technologyassessment/patient-involvement-in-the-htadecision-making-process.

27. Institut fu¨ r Qualita¨t und Wirtschaftlichkeit im Gesundheitswesen (IQWiG) [Institute for Quality and Efficiency in Health care].

Involvement of people affected in the dossier assessment. https://www.iqwig. de/download/Involvement_of_people_ affected_dossier_assessment.pdf.

28. Fralick M. Putting patients first in the age of pharma. CMAJ. 2014;186:253.

29. Forsythe LP, Ellis LE, Edmundson L, et al. Patient and stakeholder engagement in the PCORI pilot projects: Description and lessons learned. J Gen Intern Med. 2016;31:13-21.

EyeForPharma. Patient-centered culture 30. by design. http://www.janssen.com/ emea/sites/www_janssen_com_emea/ files/2792_07jan16_pccultures_ whitepaper_v13.pdf.

42 ◄ January 2019

Clinical Trials Transformation Initiative.

35. https://www.ctticlinicaltrials. org.

36.AstraZeneca.

AstraZeneca and PatientsLikeMe announce global research collaboration. https://www. astrazeneca.com/media-centre/pressreleases/2015/astrazeneca-patientslikemeresearchoncology-diabetes-lupusrespiratory-disease-13042015.html.

37.GlaxoSmithKline. Engaging on patient engagement. http://gskmorethanmedicine. com/blog/2013/02/engaging-onpatientengagement.html.

US Food and Drug Administration.

38.

Guidance for industry. Patient-reported outcome measures: Use in medical product development to support labelling claims. http://www.fda.gov / ucm/groups/fdagovpublic/@fdagov-drugs-gen/documents/docu ment/ucm193282.pdf.

39. Patrick DL, Burke L. Focusing on the patient in drug development and research. ISPOR Connections. 2013;19:5-8.

42. Banerjee AK, Okun S, Edwards IR, et al.

Patient-reported outcome measures in safety event reporting: PROSPER Consortium guidance. Drug Saf. 2013;36:1129-1149.

43. Robbins DA, Curro FA, Fox CH. Defining patient-centricity: Opportunities, challenges, and implications for clinical care and research. Ther Innov Regul Sci. 2013;47:349-355.

44. European Medicines Agency (EMA).

Incorporating patients’ views during evaluation of benefit-risk by the EMA Scientific Committees. http://www.ema. europa.eu/docs/en_GB/document_library/ Other/2014/09/WC500173508.pdf.

45. National Institute for Health and Care Excellence (NICE). Hints and tips when preparing to be a patient expert. https:// www.ni ce.org.uk/Media/Default/About NICECommunities/Public-invol vement/ Developing-NICE-guidance/Hints-TipsPatient-Experts.pdf.

46.European Patients’ Academy onTherapeutic Innovation (EUPATI). Expert training course for patients and patient representatives on the medicines research&development process. http://www.patientsaca demy.eu/ index.php/en/edu.

47. O’Neill N, Mitchell G, Twycross A. The expert patient. Evid Based Nurs. 2016;19:41-42.

(D. du Plessis - GSK, J.K. Sake - UCB, K. Halling - AZ, J. Morgan - AG, A. Georgieva – EM, and N. Bertelsen – NBC)

40. Patient-Centered Outcomes Research Institute (PCORI). http:// www.pcori.org.

41.

Wiering B, de Boer D, Delnoij D. Patient involvement in the development of patient-reported outcome measures: A scopingreview. Health Expect.2017;20:11-23.

Pharma Bio World

research

Patient-Centric Drug Design For Better Patient Compliance As humans live longer, the likelihood of illness and disease will increase. This shift will result in more and more prescriptions being administered. The pharmaceutical industry must anticipate issues with adherence early in the development stage, and engage stakeholders to properly assess and create solutions that will be conducive to patient compliance. The outcome is healthier patients, enhanced patient satisfaction, and improved bottom lines for pharmaceutical companies.

T

he Tufts Center for the Study of Drug Development (CSDD) estimates the cost of bringing a drug to market at $1.4 billion.1 Time and opportunity costs nearly double that figure, to $2.6 billion, and sponsors spend an additional $312 million on post-approval R&D. This represents a 145% increase over CSDD’s 2003 estimate.

Pharmaceutical innovators worldwide are always in search of solutions to improve clinical outcomes, medication delivery profiles, patient adherence and treatment efficacy. The top challenges facing the pharmaceutical industry are: formulation, drug delivery, lengthy development cycles and high costs.2 Soaring drug development costs resulting from the greater complexity of clinical trials, a renewed focus on chronic and degenerative diseases, and the need for comparative drug effectiveness data, have all contributed to a greater need to look at the science behind drug delivery and make a concerted effort to improve drug delivery and patient compliance.3 Currently, approximately 70% of new chemical entities fall into the Biopharmaceutics Classification System (BCS) classification 2,4 where poor solubility is the major hurdle preventing complete bioavailability. BCS categorizes APIs according to solubility and permeability, which are key attributes related to drug development.5 Safety, efficacy, and stability remain perennial challenges for BCS category 2 molecules.

Each solid-state form of an API has unique physicochemical properties that can have a profound impact on bioavailability, stability, and manufacturability. Identification of the optimal solid-state form for development relies on several factors: Pharma Bio World

• A clear understanding of the target attributes of the API and drug product • Design and execution of an appropriate screen to produce solid-state forms of importance • Detailed evaluation of relevant solid-state forms • Assessment of the risk-benefit profile of the candidate solid-state forms against the target attributes.

Solid-form screening services from specialized CDMOs address all of these objectives and also provide stable crystalline forms for the selected compounds.

Factors not addressed in early development phases often surface during clinical stages, where high attrition rates contribute disproportionately to development costs.

Approximately 60% of molecules in Phase I are promoted to Phase II. The Phase II to Phase III success rate is 36%; 56% of Phase III drugs are eventually approved. Combined, these failure rates translate to just one approval for every 12 molecules entering human studies.6 Addressing these concerns early in development, through scientifically rigorous and data-driven design and development strategies is crucial to overcoming the innate shortcomings of many therapeutic molecules.

A single approach cannot solve all these challenges, nor do existing resources permit application of all potential solutions to every potential drug. A rational strategy involves examination of the API’s physicochemical and biopharmaceutical characteristics, and carefully selecting

technologies that are a good fit. In silico screening is a technique that can help narrow down options without consuming drug material. In addition, early formulation studies with high throughput and rapid screening techniques based on a minimum amount of API can streamline development and lower overall costs.

These tools, combined with a rational approach to molecule form selection and formulation selection, could help reduce the number of molecules that fail during early development.

An efficient approach should include: • High throughput screening for drug form and formulation •

Collaborative, development

inter-disciplinary

drug

• Early drug delivery feasibility studies •

Selection of technologies

proven

drug

delivery

Developability

The Developability Classification System (DCS)7 is an improvement on BCS, but with emphasis on the ability to be able to incorporate the molecule into a drug delivery system. DCS focuses on key early product development issues that need to be overcome to improve absorption.z A preponderance of drugs fall into DCS quadrant II, with poor solubility but adequate permeability. Quadrant II may be further subdivided into categories for which molecules are either dissolution rate-limited in the gastrointestinal tract (classification IIa) or solubility-limited (IIb), as delineated by the Solubility-Limited Absorbable Dose Rule (see diagonal line in the graph of Fig. 1).

January 2019 ► 43

research market image and packaging, prior approval inspections, and business considerations.

Communication with the FDA is critical for expedited programs to succeed. Moreover drug quality may not be compromised for speed, and all development activities must occur at the same level as for nonexpedited products.

Figure 1.

Very Early Development The utilization of early in silico analytical assessment helps to predict a molecule’s DCS classification, and to help determine whether a molecule’s bioavailability will be solubility- or permeability-limited.

Figure 1

For molecules falling under the IIa classifi -cation, the dose is expected to dissolve completely during the ~3 hour transit through the small intestine – provided that more of the undissolved molecule dissolves to replace it. Molecules in the IIB quadrant do not completely dissolve within the available time. This is of particular importance in doseescalation studies where the second and subsequent dose will never dissolve and the end point of the study cannot be reached.

treating rare or life-threatening diseases, or that alleviate unmet medical needs. Taking full advantage of accelerated regulatory timelines involves adopting a structured development approach at the very earliest stages.

DCS Classification provides insight into appropriate early-development technologies for overcoming pK and pD issues - DCS I molecules are typically formulated as conventional solid dosage forms. Molecules in categories IIa often exist in micronized form or as solutions. Molecules in the IIb category require lipid-based solutions or amorphous solid dispersions. Molecules under category III are challenging, and often benefit from permeation enhancements which can provide a pathway for an intravenous to oral delivery conversion, resulting in enhanced therapies for patients. Molecules in category IV are extremely challenging, often requiring individualized treatment.

Some of the development and analytical services required for accelerated development are:

Accelerated Development Programs

Accelerated regulatory pathways, including Fast Track and Breakthrough designations, shorten the approval process for drugs for 44 ◄ January 2019

Many sponsors of NCEs lack the internal support and infrastructure for some or all of the development activities needed to take full advantage of expedited designations.

• Analytical development, release and stability testing • Pre-formulation development

and

validation, formulation

Early development should focus on understanding the extent to which drugs enter the bloodstream and the properties that enable this. Solubility screening for these characteristics typically occurs during early development. Also key is understanding the drug’s solubility / stability in simulated biological fluids, which approximates performance in the GI tract. Rapid stability screening helps developers understand the drug’s decomposition characteristics in simulated biological systems, and provides clues regarding appropriate delivery vehicles.

Understanding these factors through solid state analytical tools is a proven strategy.

Microscopy and x-ray powder diffraction are used typically to characterize a drug particle’s morphology and crystallinity.

Calorimetry measures melting onset and heat of fusion, which provide indications of

• Clinical trial manufacturing, supply, packaging, labeling, and distribution support • Scale-up, registration and validation batch manufacture

process

• Commercial manufacturing Companies seeking expedited pathways must assure that other development activities support their program. Considerations include analytical method validation, drug substance performance and process qualifications, Pharma Bio World

research • Deliver provides vials of material to be used in an animal pK study and recommends a path to first-in-man studies to provide exposure and dose escalation.

Parallel Drug Development

Due to their physicochemical liabilities, many molecules enter Phase I studies with little knowledge of their solubility, resulting in a suboptimal formulation and poor bioavailability.

thermal stability and the overall quality of the solid state dosage form. Absorption provides information on the hygroscopicity.

Drug discovery focuses primarily on activity in specific assays and often selects only one molecule from related structures to move forward. Since discovery may have identified several candidates with comparable activity, the process for evaluating the developability of candidate drug is far easier if the delivery platform is known in advance. But without concrete developability assessments, candidates may be selected by activity alone. Therefore, early analytical data could help guide discovery strategies toward candidates with an appropriate balance of activity, solubility, permeability and stability.

Newly developed formulation screening and development technologies identify appropriate formulations for early-phase molecules through a three-step approach: • Assess involves understanding the molecule’s physicochemical properties with an eye towards formulation. During this stage, the solubility limited absorbable dose (SLAD) model and in silico DCS classification are used to create an early formulation screening protocol for evaluating technologies that overcome the molecule’s limitations.

• Enhance applies parallel screening of appropriate delivery technologies depending on the molecule’s DCS category and any other considerations evolving from the data or from a customer’s preferred strategy.

Pharma Bio World

Large pharmaceutical companies are equipped to conduct parallel formulation screening. But resources such as automated liquid handling, solid metering, automation expertise, and robotics software programming lie outside the capabilities of small or even average-sized drug sponsors.

Moreover, study material is often scarce during early development. Without sophisticated screening resources, companies are limited in the number and types of tests that are practically available. These limitations apply to physicochemical analyses, biochemical assays, and small animal experiments.

By accurately handling very small quantities of a compound per test, high-throughput screening allows drug developers to investigate as many dosage forms and formulations as are appropriate for a compound’s DCS category. The deeper the formulation testing advances, the more likely a drug will fulfill the patientcentric goals of the development program. This is where expertise in interpreting data and extrapolating it to scale becomes critical by combining miniaturization of analysis methods without foregoing the power of experiment.

In theory, parallel screening considers all reasonable and available dosage forms, but most sponsors may have already decided on oral, injection, topical, or inhalation delivery. Given, say, the preference for an oral dosage form, the next decision is how the molecule is processed to overcome potential bioavailability issues.

Depending on the delivery vehicle, this might entail grinding, micronizing, or nanosizing. Molecules in DCS categories II, III and IV may also require solubility and/or permeation enhancers.

Many development partners claim extensive dosage form and delivery capabilities, but few can carry projects through to approval.

Switching service providers entails substantial costs and delays associated with technology transfer. Note that some discovery companies are only interested in ‘proof of principle’ compounds that they can sell or license to a larger developer. In these instances, having conducted thorough, preliminary development work will make the product more attractive to potential buyers, but cannot guarantee that the technology can be reproduced in another facility.

Macromolecules Developing peptide and protein drugs presents unique challenges. Delivery of biologicals is limited by the molecule’s degradation in the gastrointestinal tract. Bioavailability is in many cases too low to achieve therapeutic systemic concentrations. Traditionally these medicines are delivered by injection or infusion, which raises compliance issues, particularly for biologics requiring frequent administration.

Confidence in experimental results is greater at large scale than at smaller scale, but the beauty of small-scale HTS is the ability to conduct many more studies to broaden the development picture. Developers may not know as accurately the results of any one test, but they may cover a broader design space. HTS is a very early piece of the development continuum that guides decision-making on which molecules to develop further.

January 2019 ► 45

research

Bio delivery platforms are typically based on technologies similar to those successfully employed for marketed largemolecule drugs. By overcoming adverse stability and permeability issues, oral delivery of some peptides and proteins can be achieved. Targeted delivery of drugs can be enabled via prevention of gastric proteolysis of API, and also through enteric coating which improves permeability of high molecular weight compounds. Additional modifications can improve API absorption in the small intestine, while permeation enhancers improve transport through the tight junctions of the lumen.

The latest preformulation and formulation screening protocols help determine the suitability of peptides and proteins for oral delivery. After shortlisting of the macromolecules, those unsuited to oral delivery can be transformed into self-administered drug products with improved compliance.

Technology enhancements can make freeze-dried oral solid dosage forms disperse instantly in the mouth while the pharmacokinetics can be enhanced through pre-gastric absorption. Such drug features / qualities improve patient compliance due to the drug’s quick dissolving properties and elimination of the need for water for drug delivery.

Conclusion

Pharmaceutical development is costly, lengthy, and fraught with uncertainty. The 46 ◄ January 2019

sheer number and breadth of competencies involved lies beyond the capability of many drug sponsors. Molecules falling into the DCs quadrant II, particularly IIb, present persistent challenges for formulation and, eventually, for drug delivery. When conducted early on, developability assessments can pay rich dividends by promoting ‘fast to human, fast to fail.’ Similarly, formulation testing to improve bioavailability of poorly soluble/ permeable molecules can guide every facet of mid- to late-stage development by providing close approximations of what would be expected to be the final, approved drug product. Together, these activities comprise a structured, rational approach based on proven, industry leading expertise in solving complex bioavailability challenges.

Since the components of best-in-class early development fall outside the expertise of many small to mid-sized companies, drug discovery companies should consider a development partner whose success depends on their success, and which can take a project from the discovery stage through commercialization.

5. U.S. Food and Drug Administration; The biopharmaceutics classification system (BCS) guidance; Accessed at: http://1. usa.gov/1U2yxL5.

6. Tufts Center for the Study of Drug Development, Briefing delivered; Nov. 18, 2014; Accessed at: http://csdd.tufts. edu/files/uploads/Tufts_CSDD_briefing_ on_RD_cost_study_-_Nov_18,_2014.pdf; [ibid].

7. J. Butler; The optimal use of biorelevant media and sample modeling; Controlled Release Society; 2008.

8.

Presentation: The optimal use of biorelevant media and simple modeling for the prediction of in-vivo oral behavior; James Butler – GlaxoSmithKline; Accessed at: http://www.apsgb.co.uk/ Events/PastEvents/20110609/James%20 Butler.pdf.

(Source: Compare Networks)

References 1. Tufts Center for the Study of Drug Development, Briefing delivered; Nov. 18, 2014; Accessed at http://csdd.tufts.edu/files/uploads/Tufts_ CSDD_briefing_on_RD_cost_study_-_ Nov_18,_2014.pdf 2. Finding optimal form; The Medicine Maker; Accessed at: http://bit.ly/1U2CQpF. 3. Mullin R; Costs to develop new pharmaceutical drug now exceeds $2.5 billion; Chemical & Engineering News; November 24, 2014; Accessed at: http:// bit.ly/1U2zfrx.

4. Bioavailability and solubility: A demand for enhanced technologies & materials is spurring innovation; Drug Development & Delivery; Accessed at: http://bit. ly/1U2BxXI. Pharma Bio World

research

Patient-Centric Optimal Dosage Forms The increasing complexity of compounds in the discovery pipeline means that many small molecule drugs are facing the challenge of lower bioavailability. This may often be combined with other technical or clinical formulation challenges, such as complex release profiles, the desire to simplify complex regimens with combination drugs and customised dosage forms for specific patient populations and indications. Decisions taken during the drug substance and drug product design process can have a major impact on patient outcomes. These include improved adherence to the regimen, reduced side-effects and fewer instances of discontinuation of compliance.

O

ptimizing pharmaceutical formulations offers numerous benefits that help differentiate products by delivery route, dosage form, improvements in safety and efficacy, and most importantly, to meet patient needs.

Thus the ‘patient voice’ becomes a value driver during the early-stages of formulation development rather than an after-thought in late-stage formulation development.

There are many factors and options to consider during early drug formulation and dosage form development. A scientifically based approach which focuses on the drug’s ability to treat diseases through enhancements in bioavailability and to better address patient-specific needs such as ease of administration, food effects, and less frequent dosing, is the ultimate goal for a patient-centric approach to formulation development. Fortunately, there are many products, technologies, and insights available to make the drug development journey a more cost-effective and efficient process.

strategies employed during the drug development process based on the target product profile (disease state, physiology, route of administration, etc.) and properties of the drug. Currently three of the most widely used strategies for improving dosage forms are particle size reduction, amorphous solid dispersion, and lipid based technologies.

Particle Size Reduction is a technology used for small molecule drugs in various types of dosage forms. It’s beneficial in improving an API (active pharmaceutical ingredient) content uniformity for commercial tablet manufacturing, suspension stability and/or texture of oral, topical, or ocular formulations, and is still a conventional technology for enhancing the oral and pulmonary bioavailability of small molecules.

Hot Melt Extrusion (HME) is another technology that is proving to be very valuable to the pharmaceutical industry due to its ability to generate physically stable and processable solid dispersions of amorphous APIs. Relative to crystalline APIs, amorphous solid dispersions improve bioavailability in more than 80 percent of cases where it is employed.

HME processing systems disperse APIs in the polymer matrix at the molecular level to form solid dispersions or solid solutions.

Lipid-based formulation technologies can be employed to solve complex formulation and development challenges, including improvement of solubility, permeability, or both to enhance bioavailability.

Even with the advanced technologies available today for drug development there are still challenges to be overcome. Drugs with poor solubility, or poor permeability, or both, leading to poor bioavailability can be developed into effective medicines for large and diverse populations, and enhance patient compliance. There are multiple formulation Pharma Bio World

January 2019 ► 47

research Each of these enabling technologies can be employed to improve the bioavailability of many poorly soluble drugs, and in the case of lipid-based formulations, poorly permeable drugs as well. Advancing these challenging drugs through development to the market is critical to provide options for patients with unmet medical needs to have their illnesses treated.

Class III - low permeability, high solubility The absorption is limited by the permeation rate but the drug is solvated very quickly.

The Drug Classification System (DCS) provides insight into appropriate early development technologies that may be employed to overcome PK (pharmacokinetic) issues in enhancing drug solubility, adsorption, and permeability in the gastrointestinal tract.

For example, DCS I molecules are typically presented as conventional solid dosage forms. Molecules in categories DCS IIa may be formulated with micronized or nanosized active pharmaceutical ingredients (APIs).

Molecules in the DCS IIb category require lipid-based formulations or amorphous solid dispersions as solubility-enhancing technologies, sometimes along with particle size reduction for those cases where the API is dispersed (or suspended) as solid particulates in a lipid-based suspension or solid dispersion HME, for effective formulation development of a poorly soluble drug.

Particle Size Reduction - A Straightforward Solution for Oral Bioavailability Enhancement

Most APIs (70%) in current development fall into DCS quadrant II1, with poor solubility but acceptable permeability.

Quadrant II may be further subdivided into categories for which molecules are either dissolution rate limited in the gastrointestinal tract (classification IA) or solubility-limited (IIB), as delineated by the Solubility-Limited Absorbable Dose Rule.

Class IV - low permeability, low solubility Those compounds have a poor bioavailability. Usually they are not well absorbed over the intestinal mucosa and a high variability is expected.

For molecules falling under the DCS IIA classification, the dose is expected to dissolve completely during the ~3 hour transit through the small intestine provided the drug particle size is less than the calculated target particle size based on the Drug Classification System.

Particle size reduction works by increasing the surface area of the drug that is exposed to fluids in the gastrointestinal tract, thereby increasing the dissolution rate of the drug.

Drugs that dissolve rapidly are naturally more quickly absorbed. However particle size reduction does not affect a drug’s intrinsic solubility. Numerous drugs’ oral bioavailability have been improved by micronizing or wetmilling (nanosizing). These include DCS category IIa drugs (nitrendipine, carvedilol),

and category IIb drugs that lay close to the Solubility-Limited Absorbable Dose Rule line.

In looking at the patient-centric approach to formulation development, the particle size of the drug is critical when understanding the effect of food consumption on bioavailability of the drug compound.

Danocrine, which treats pelvic pain and infertility in women, shows a six-fold food effect (fed vs. fasting), which was eliminated by formulating the drug as a nanocrystalline suspension. 1 Drugs in the DSC IIa classification, with poor solubility but adequate permeability, tend to have a higher AUC and Cmax when administered with food. The positive impact of nanoparticle formulations is believed to arise due to increased contact area between nanosized drug particles and biological membranes. 2 By reducing food effects, nanosizing also enhances dose tolerance, compliance, safety and efficacy. 3 Tricor from Abbvie Inc. is an example of a drug for which particle size engineering provided differentiation and follow-on approvals. Tricor-1, a non-micronized product approved in 2001 for lowering triglycerides, had a substantial food effect.

The DCS groups drugs in these categories: Class I - high permeability, high solubility These compounds are well absorbed and their absorption rate is usually higher than excretion.

Class II - high permeability, low solubility The bioavailability of these products is limited by their solvation rate. A correlation between the in vivo bioavailability and the in vitro solvation can be found.

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research dose uniformity even for drugs dosed at microgram levels.

This was followed by FDA approval in 2003 of Tricor-2, a micronized, lower-dose formulation also with a food effect, for the broader indication of lowering low-density lipoprotein. The third iteration of this drug, the nanomilled Tricor-3 approved in 2004, did not show a food effect.

Lipid-based Formulation Encapsulated in Soft Capsules - An Oral Delivery Option for Enhanced Bioavailability

Softgels are an ideal option to deliver lipid-based formulations developed for improving bioavailability and better patient compliance. Through the use of material sparing techniques, feasibility studies can be performed to develop prototype lipid fill formulations when API quantities are scarce. Laboratory-scale encapsulation of these fills provides small batches of soft capsules that can be used for in-vitro testing as well as in-vivo animal PK studies.

Lipid-based formulations in soft capsules are readily scalable from laboratoryscale to pilot-scale to production-scale thereby allowing for reduction in overall product development cycle times.4 One of the fastest growing segments of the pharmaceutical industry is the development of highly potent drug products.5 Unlike tablets that involve powder generating production steps, lipid-based formulations which are liquid or semisolid in nature, followed by their encapsulation in soft capsules, do not present issues such as dust generation, and as a result the risks of employee exposure and product cross-contamination are minimized. Lipid formulations in soft capsules are often the delivery option of choice for highpotency APIs, not only for the safety and contamination concerns mentioned previously, but for also achieving excellent Pharma Bio World

More recently it has been shown that lipidbased formulations and enteric coated soft capsules enable the oral delivery of peptides and proteins. By using lipidbased formulations, whose end products of digestion serve as permeation enhancers to open up tight junctions between cells, enteric coated soft capsules offer an excellent means of delivering these lipid formulations containing peptides and proteins to their site of absorption.

Importantly, this technology protects the API from degradation while providing high local concentrations of intact API and permeation enhancer to maximize the potential for absorption Conventional soft capsules use gelatin as the film-forming polymer in the capsule shell, which can successfully be used for a wide range of API’s and lipid-based formulations.

However, there are instances, where a gelatin-based soft capsule cannot be used for some fill formulations due to resulting physical instability. Examples include fill formulations that have a melting point higher than gelatin, fills that are highly alkaline in nature, and fills containing certain surfactants or low to medium chain free fatty acids. The use of plantderived polysaccharides in place of gelatin allows the encapsulation of these types of challenging fill formulations. Hot filling of lipid-based formulations that are semisolid at room temperature and require heating to higher temperatures for flow into soft capsules during encapsulation have enabled the filling of semi-solid formulations for extended release of poorly soluble compounds thereby optimizing drug product pharmacokinetics and potentially reducing dosing frequency.

Hot Melt Extrusion: Enhancing Bioavailability to Create Stable and Versatile Dosage Forms

Hot melt extrusion (HME) technology is the process of formulating an API within a polymer by applying heat and shear stress utilizing a twin screw extruder to create an

amorphous solid dispersion. It is a solventless continuous manufacturing technology that offers a lot of flexibility with the use of excipients and in-line process analytical tools to achieve the desired drug loading with good physical stability. Melt extrusion process technology may also allow for high drug loading which reduces pill burden and enhances patient compliance.

The melt extruded solid dispersions provides increased bioavailability, product differentiation, and shortens time-to-market.

HME covers a wide variety of extrusion processing technologies such as melt extrusion, wet, dry and melt granulation.

The extruded materials can be processed to generate final dosage forms such as tablets (Fixed-dose combinations, complex tablets, multi-layer), capsules (fixed-dose combinations, powder-filled, bead-filled) and stick packs.

Melt-extruded solid dispersions consists of several formulation components apart from API itself. It may include carrier polymer, plasticizer and solubilizer. The early phase preformulation assessment of API’s molecular, chemical and physical properties will help in rapid prototyping of early formulations. These formulations can be then scaled-up to provide clinical supplies for phase I and beyond.

The twin screw extrusion technology enables the interplay of the product and process variables to develop formulations for mid and late stage clinical supplies. Understanding and measuring the impact of equipment & process variables such as extruder type, screw configuration, die design, screw speed, feed rate, barrel temperatures on the product quality attributes such as physical and chemical stability, dissolution at an early stage will lead to technically sound scale-up process required to support midand late stage clinical phase supplies.

Recently, there are many products that are being developed utilizing twin screw melt extrusion technology to offer the clinical advantage of bioavailability enhancement to January 2019 â–ş 49

research consider development timelines, the ‘fourth dimension’ of drug development.

the patients. There are few products on the market with twin screw melt extrusion that have used the enabling advantage of this technology. Merck’s Noxafil tablet and Abbvie’s Kaletra tablet are excellent examples of utilizing melt extrusion technology for improving the therapeutic efficacy of the product.

Noxafil Advantage Merck reformulated the oral suspension of antifungal drug, posaconazole to develop melt-extruded amorphous solid dispersion tablet of Pocaconazole. The new tablet Noxafil with enhanced solubility and bioavailability also demonstrated consistent pharmacokinetics and several other advantages over the marketed oral suspension of Posaconazole. In addition, the bioavailability of posaconazole with the new melt-extruded tablet formulation did not appear to be significantly affected by food or the concomitant use of medications that raise gastric pH or speed gastric motility. Currently available as 100 mg tablets and approved for dosing as a 300 mg twice-daily on the first day and 300 mg once-daily dose thereafter, features the posaconazole API, mixed with the pH-sensitive polymer hypromellose acetate succinate (HPMCAS) via hotmelt extrusion technology. The melt extrusion process technology helped to maintain the amorphous state of the drug, preventing crystallization and improved the drug’s solubility, thus improving the bioavailability of the drug.

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Kaletra Advantage Abbvie’s Kaletra tablets for treatment of HIV (lopinavir and ritonavir) also use amorphous dispersion technology in order to achieve advantages in terms of dosing regimen and bioavailability enhancement. Abbvie used hot melt extrusion technology to reformulate the existing soft gelatin capsules, to improve pill burden, pharmacokinetic variability, and product stability.

Hot melt extrusion appears to have overcome the poor solubility and negligible oral bioavailability of previous experimental solid formulations of lopinavir/ritonavir.

In addition, and more importantly, the reformulated tablets require fewer doses to be taken each day, do not require refrigeration, and do not need to be taken with food.

Conclusion

Incorporating the ‘patient’s voice’ during drug development is a relatively new strategy. Factors contributing to patientcentric drug development include scientific expertise (e.g. greater understanding of PK/PD), pharmacogenomics, and the realization that few diseases are adequately addressed by a one-sizefits-all approach to dosing, dosage form, and formulation. Companies seeking development partners must keep in mind that without these three factors, tailoring new drugs in a patient-centric manner is a matter of hit or miss. Sponsors should also

Sponsors also need to ask these few questions to their development partners: Does the contract development company possess these capabilities during preclinical stages, in clinical phases 1 through 3, and through product commercialization? Can it apply lessons learned during one stage to subsequent development stages? These questions become critically important to the successful pursuit of patient-centric drug development for DCS category IIa and IIb compounds, and for more accessible category I and more challenging category IV molecules as well.

References 1. Merisko-Liversidge E et al; Nanosizing: A formulation approach for poorly-watersoluble compounds; Eur. J. Pharm. Sci.; 18 (2) (2003) 113–120.

2. Kakran M et al; Overcoming the challenge of poor drug solubility; Pharmaceutical Engineering; July/August 2012; vol. 32, no. 4.

3. Junghanns J et al; Nanocrystal technology, drug delivery, and clinical applications; Int’l J Nanomedicine; 2008; Vol. 3, no. 3; pp 295-309.

4. Fulper D; Softgels: Overcoming formulation challenges and winning customer acceptance; Tablets & Capsules; March 2016.

5. Siew A; Liquid encapsulation for HPAPIs; Pharmaceutical Technology; 40 (1); 2016.

6. Catalent Pharma Solutions; Technology profile: OptiGel Bio technology: Meeting formulation and delivery challenges for macromolecular drugs; (ebook) From Molecule to Dose Form: Bioavailability Toolkit to Fast Track Development; Accessed at: http://bit.ly/25zviSI.

(Source: CPS) Pharma Bio World

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Pediatric Centric Drug Design Historically, only a small fraction of all marketed drugs have had clinical trials performed in pediatric patients and a majority of marketed drugs were not labeled for use in pediatric patients.

Accordingly, many drugs were administered to children in an off-label fashion without adequate understanding of appropriate dose, safety, or efficacy. The first initiative took place in 1994 when the Pediatric Labeling Rule was issued, requiring drug manufacturers to survey existing data and to determine whether those data are sufficient to support additional pediatric use information in the drug’s labeling. Under the Pediatric Labeling Rule, if a manufacturer determines that existing data permit modification of the label’s pediatric use information, the manufacturer must submit a supplemental new drug application (NDA) to FDA seeking approval of the label change. The Pediatric Labeling Rule allowed the labeling of drugs for pediatric use based on extrapolation of efficacy in the adult population and additional pharmacokinetics, pharmacodynamics, and safety studies in pediatric patients, but only if the course of the disease and the response to the drug were known to be similar in children compared to adults. Although this rule was designed to improve pediatric labeling, it resulted in only a small number of well-designed and well-conducted studies. Since the approach under the Pediatric Labeling Rule was entirely voluntary, it did not substantially increase the number of products with adequate pediatric labeling.

O

ver the past decade, regulatory legislations for drug development in pediatric patients were passed worldwide, dramatically increasing the number of drugs tested in and labeled for children. Both, the Food and Drug Administration (FDA) in the United States (U.S.), and the European Medicines Agency (EMA) in the European Union (E.U.), established approaches that have been successful in generating important new information about the safety and efficacy of drugs used by children. Transparency and accountability of pediatric drug development has improved and the amount and quality of pediatric information has increased by an elevated number of clinical trials in children in recent years.

The progress has been achieved by combining requirements for pediatric drug development with incentives for the pharmaceutical industry to (at least partly) cover the additional investment for testing drugs in children. There was and still is Pharma Bio World

effort needed to harmonize the regulatory framework for pediatric drug development, but as of today pharmaceutical companies are still facing the problem that the regulatory requirements differ between FDA and EMA and that the development of a new drug in the pediatric population has to be in line with requirements from both authorities. Enforced by the authorities - in particular the EMA pediatric aspects have to be integrated early in the development process of a new drug and the general strategy has to be part of the overall development program.

Drug development for pediatric patients is accompanied by various challenges for pharmaceutical companies. Clinical studies in children are different from studies in adults and the planning and conduct of a pediatric study needs special attention since the patient population is more vulnerable. Practical and ethical considerations are prominent and the latter receives particular attention in the regulatory guidance documents. As a consequence, the main challenges are

to define the first dose in children, to find appropriate sampling strategies, to choose the right methods for data collection and analysis, to generate knowledge about safety, efficacy, pharmacokinetics, and pharmacodynamics of a drug in children, and ultimately to determine the right dose and dosing regimen.

To comply with regulatory requirements and to optimize pediatric drug development - in terms of ethical, operational, and scientific aspects - pharmaceutical companies have to develop new and appropriate strategies

January 2019 â–ş 51

research Most issues in pediatric drug development arise from the fact that drugs are traditionally developed for adults and not children. However, many improvements in pediatric drug development have occurred during the last 15 years.

for clinical studies in children. Modeling and Simulation (M&S) techniques are beneficial tools for optimization of the design, increasing the knowledge gained from pediatric studies.

Since several regulatory guidance documents refer explicitly to M&S methodology, there is a clear regulatory basis and a need for using M&S in pediatric drug development.

Towards a Renaissance of Pediatric Pharmaceutical Development Successful drug delivery to pediatric patients depends on overcoming basic differences between children and adults.

Pharmacokinetic and pharmacodynamic differences can make developing drugs very challenging for young patients. One can think of pediatric medicines as one of the last uncharted frontiers in patient-centric drug development.

Oral dosage forms, the preferred administration route, may not always be palatable or available in doses appropriate for children. Thus, pills and tablets are often manipulated in ways that are not ideal for delivering safe, effective, and consistent doses. Compounding pharmacies can help but their results are not always reproducible.

Parents often resort to dividing doses, crushing and dissolving them in liquids, and administering drugs in quantities that have not been adequately tested.

Alternative delivery vehicles are similarly problematic. Rectal dosage forms provide consistent dosing but are not patientfriendly. Younger children in particular have problems with nebulization masks that do not fit their face properly or cause them distress. Achieving reliably metered therapeutic dosages is complicated when small gaps exist between the mask and the patient’s face. 1 52 ◄ January 2019

Development-Stage Incentives Several regulatory changes have resulted in the recent development of close to 600 drugs supported by new pediatric studies. For example, the US has: • Best Pharmaceuticals for Children Act (BCPA) - The 2002 law established a program for pediatric drug development, provided mechanisms for studying on- and off-patent drugs in children, and offered an additional 6 months of exclusivity for on-patent pediatric drugs.

• Pediatric Research Equity Act (PREA) Passed in 2003, PREA requires sponsors to test new drugs in children under certain circumstances. Testing must occur with the same drug and for the same indication for which the drug was approved in adults.

BCPA and PREA have a sound scientific basis. The occurrence of suicidal thoughts in children taking the antidepressant Paxil was not uncovered until FDA ordered sponsor GSK to conduct pediatric studies. The result was an FDA warning, in 2008, for prescribers to consider the risks of prescribing Paxil to patients younger than 18.

Delivery Hurdles Many shortcomings of pediatric-administered medicines arise from less-than-perfect dosage forms and delivery mechanisms.

Improvements in these areas could be achieved with minimal regulatory risk.

Unpleasant taste is a perennial issue for many drugs administered to children. Clindamycin, an antibiotic for treating Gram positive and anaerobic infections, has a particularly bitter taste and unpleasant smell. Dosing is frequent and of long duration. Moreover the drug is available only as a dilute suspension requiring large administration volumes, which for young patients amplifies its negatives and complicates administration of therapeutic doses. Other antibiotics routinely administered to pediatric patients have similar issues.

Sabril (vigabatrin; Lundbeck LLC), which is prescribed for infantile seizures, is a classic case of a drug that has not been ideally formulated for its intended patient population. Sabril is available as a 500 mg tablet or a 500 mg packet. The tablet is too large for very young children to swallow.

Parents must suspend the packet contents in relatively large volumes of water, which introduces issues previously mentioned. It also requires caregivers to perform a multistep process in order to mix and measure the prescribed dose. 4

Before BCPA and PREA were enacted, as many as 80 percent of drugs prescribed to children were untested in that patient population. By 2008 between 50 and 60 percent of such medications had been studied at some level in children.

Nevertheless, children have been described as the ‘orphans’ of drug development.2 A bioavailability classification system (BCS) is not yet available for classifying the suitability of biopharmaceuticals for pediatric administration. However, preliminary investigations suggest that such a system may be available within a few years.3 Pharma Bio World

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Infant acetaminophen, available in several liquid formulations, comes with no directions for parents. While a dosing syringe is provided, there is no indicated dose for the age-group for which this product is intended.

Other important medications commonly prescribed for children also require liquid compounding. These include Lamotrigine, Topiramate, Tacrolimus, Metronidazole, Lansoprazole, Spironolactone, and many others. As always, compounding carries inherent risks in preparation and administration such as inadequate shaking and errors in calculations and measurements.

Measuring volumes of liquid pediatric medicines is critical for delivery of safe, effective doses.5 Available metering devices include cups, syringes, droppers, and vials, and the ubiquitous teaspoon. Only 12.8% of pediatric oral prescription liquid products come with measuring devices, and pharmacists only occasionally provide them. Even when available, the devices’

inherent inconsistencies can result in under-or over-dosing. 6

attractive alternative dosage form for these pediatric-relevant products.

Improvement on the Way? Thanks to regulatory and market incentives, more drug developers than ever are tapping into the potentially lucrative and medical need-fulfilling pediatric drug market.

Conclusion Even with dedicated development programs, pediatric drugs present numerous obstacles.

Pharmacokinetic and pharmacodynamic studies performed within ideal clinical settings may not reflect real-world results.

Additionally, dosage form and delivery platforms require close consideration in children. Industry and regulators recognize these facts, and are working harder than ever to introduce safer, more effective pediatric medicines to address specific patient-centric issues.

The Michigan Pediatric Safety Collaboration was founded to address the lack of standardization for oral compounded liquid pediatric medicines. The state-wide, FDAfunded pilot program maintains a database of more than 100 recipes for pharmacies to refer to, ensuring consistency in compounded formulations in the state.

Drug developers are doing their part as well.

The benzodiazepine Midazolam, for example, was approved as a rectal formulation in 1997 but presented the usual problems. The drug is administered to children who are experiencing seizures. An intranasal form of Midazolam, delivered through an atomization mister, was found to be as effective as the rectal dose and much easier to administer, however a commercially available product is still needed.

For drugs most suitable for administration by tablet or capsule, orally disintegrating tablets have shown benefit. Lansoprazole, prednisolone, and ondansetron are now available in this format, providing an

References 1. Lin H. et al; Respiratory Care; 2007; 52(8); pp 1021-26.

2. Grant B; Are the kids alright?; The Scientist; March 2012.

3. Shawana R; Pediatric biopharmaceutical classification system: Using ageappropriate initial gastric volume; AAPS J; 2016, May; 18(3); pp 728-36.

4. How to give Sabril to your baby. Accessed at: http://sabril.net/infants/giving_sabril/ 5. Sobhani P et al; Ann Pharmacother.; 2008; 42; pp 46-52.

6. Johnson A, Meyers R; Evaluation of measuring devices packaged with prescription oral liquid medications; J Pediatr Pharmacol Ther; 2016, Jan-Feb; 21(1); pp 75–80.

7. Holsti M et al; Intranasal midazolam vs rectal diazepam for the home treatment of acute seizures in pediatric patients with epilepsy; Arch Pediatr Adolesc Med; 2010, Aug; 164(8); pp 747-53.

(Source: Group)

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Pharmacy Advocacy

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provides all-embracing & cost-effective glass-lined equipment solutions

I

n this modern age, science and technology has a tremendous and awe-inspiring impact on our lives. The constantly changing and swiftly moving world urges us to strive for excellence and accuracy with minimum amount of risk. Today, the times are more challenging, motivating and full of big opportunities than ever in the course of human history.

and an impassioned team of management and production professionals. The company is on a successful mission to provide timely delivery of all-embracing and costeffective glass-lined equipment solutions and products; consequently, pushing every boundaries along the way to reach beyond customer expectations and give unrivalled and absolute customer satisfaction.

Shining like a rising sun in the vast and clear sky, Suryamani Glassed-Steel Equipment Pvt Ltd (SGEPL), has no secrets to its triumph. It is solely the outcome of its outstanding efforts, constant perseverance and commendable endeavours. Through sheer hard work and infinite fervour, the young company is poised to create a popular brand name for itself. Just like its name, ‘Suryamani’ is a precious gem in the invaluable and exquisite treasure chest of the glassed-lined steel industry.

As location is one of the most crucial factors for efficient and convenient transportation, the 32,000m 2 of vast and advanced manufacturing facility of the company is suitably and perfectly situated near one of the most foremost and easily accessible highways, which is also a key transportation nerve of the nation National Highway 64 - connecting the metro city Ahmedabad and smart city Vadodara.

Although the company was established recently in the year 2018, the seed of Suryamani was sown when Sunil A Patel, our founder and leader, started his entrepreneurial journey at the age of 33 years unaided amidst fierce national and international competition. Just like any ardent and target-oriented person, Sunil A Patel faced many obstacles and difficulties on his way. Armed with just a unique idea and an unending passion, taking single step at a time, with sheer diligence and tenacity, he made this company a strong global competitor. With truly motivational and passionate aspiration, he is undoubtedly the torchbearer for all the representatives of the Suryamani Glassed-Steel family.

With its modernistic and leadingedge technology that meets international code requirements, and a proficient and sharp team with unmatched experience, Suryamani is able to provide effective solutions and products of unquestionable quality and reliability. The company has dedicatedly allotted 15,000 m 2 out of its 32,000 m 2 to various units, such as, fabrication, assembly, material testing, dispatch and R&D.

Suryamani Glassed-Steel Equipment Pvt Ltd embodies a distinctly competent group of engineers, zestful and adroit technologists, 54 â—„ January 2019

GMP/cGMP requirements. Even in the most extreme conditions of high temperature or highly corrosive acids and bases, the company ensures zero errors and full safety of its glassed-lined steel products.

Being technologically advanced has not made Suryamani any less ignorant about the protection of the environment nor have they eschewed their central values of honesty, integrity and moral responsibility.

It fervently believes in the sustainability

Suryamani not only manufactures first-rate and peerless glassedsteel products, but also offers permanent and reliable corrosion solutions for various chemical, pharmaceutical, dye, agro, food and beverage industries, especially those companies having stringent Pharma Bio World

marketing initiatives

of the planet, as it is the only thing which all of humankind have in common. Hence, the company always strives to make our planet, a greener and healthier place for all of us to live peacefully. Towards this end, all its units are environmental friendly and the processes are green oriented. Suryamani’s deep understanding of the ecological impact of industrial processes can be gauged by its use of raw materials with superlative quality in order to ensure a safe and healthy environment.

The company truly considers the safety of its employees as a pivotal and fundamental responsibility. It has prudently implemented all the necessary measures to meet the industrial safety standards thus ensuring a secured workplace protected from all kinds of unsafe working conditions, equipment failure or other such dangerous accidents at the manufacturing facility. Over the course of time, the progress and growth of Suryamani has been akin to an enormous banyan tree with branches spread out, but roots still fixed to its essential and core values. The company has been consistently striving to provide up-to-the-mark products through overall quality management, product modifications and enhancements, which has resulted in tremendous customer loyalty unmatched in the industry.

Suryamani regards total customer satisfaction as the epitome of success in business. According to the firm, ‘A satisfied Pharma Bio World

customer is the best business strategy of all time’. This credo has stood them in good stead when the markets are presently a bit unsteady. Suryamani’s ardent team of production, maintenance, troubleshooting and training professionals makes it a onestop solution for all corrosion problems related to industrial processes. The company management’s intense focus on customer satisfaction and technological expertise has ensured a long-term healthy and beneficial relationship with their varied customers.

and out-of-the-box ideas and innovations in the glass-lined steel industry via ingenious applications of top-level technology and equipment coupled with a talented and avid workforce imbibed with revolutionary skills and capabilities to vanquish multiple and tough corrosion problems in the chemical and pharmaceutical industries. The fledgling giant aims to reach all across the world with its finest offerings and remarkable customer service in order to provide all-encompassing solutions to SMEs and MNCs alike.

Suryamani has become a pre-eminent and an outstanding brand in the glassedsteel segment through their ingenious, innovative and creative approach, in addition to providing quality, safety and reliability. The company had commenced a gigantic journey in the glassed-lined steel industry about a year back and it has now rapidly grown to be a distinguished, eminent and noteworthy brand name, both nationally and internationally.

This is merely the beginning of a long and successful story of the Suryamani family as it tenaciously seeks to accomplish and conquer new horizons via best in class technology and ultimate customer satisfaction. There is still a lot more to come for its ever-growing and loyal list of stakeholders be it clients, suppliers, service providers, employees, etc. Suryamani’s future plans promises to bring novel, unique

For details contact: Vivek Mishra CEO Suryamani Glassed-Steel Equipment Pvt Ltd, National Highway No. 64, Gutal Crossing, Gutal, Nadiad, Gujarat 387 370, India.

Mobile: +91-85111 13758 / 90815 72435 E-mail: info@suryamani.in / ceo@suryamani.in Website: www.suryamani.in January 2019 ► 55

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Fluid transfer solutions for corrosive solvents in pharma industry

S

olvents play a key role in pharma and biotech industries as it mainly provides a reaction medium in the manufacturing process. They are ideal for extraction and purification purposes.

Further, solvents play its role as helpers in the formulation of many pharma products such as penicillin, aspirin, cough syrup, and topical ointments.

There exists 3 major classes of solvents that are employed in the pharmaceutical industry: a) Class1: Human carcinogen and environmental hazard. Most harmful. b) Class2: Non-genotoxic animal carcinogen.

These are less harmful than class 1. c) Class 3: Low toxic potential to human and no health-based exposure limit is needed.

The Class 1 solvents include benzene, carbon tetrachloride, dichloroethane, etc and are mostly avoided unless their requirement is strongly justified.

Class 2 solvents include acetonitrile, chlorobenzene, chloroform, ethylene glycol, toluene, methanol, etc and their usage must be limited by means of

Property

Relative comparison

Temperature

Silicone > Fluoropolymer > Thermoplastics > EPDM > Neoprene

Chemical Resistance

Fluoropolymer > Hypalon > Thermoplastic > Nitrile > Silicone

Transparency

Fluoropolymer (FEP) > Silicone

Weatherability

Fluoropolymer > EPDM > Silicone > Neoprene

Cost

Fluoropolymer > Hypalon > Silicone > Thermoplastic > Nitrile > EPDM

concentration prescribed by the Q3C guidelines. Class 3 solvents include acetone, butanol, ethanol, formic acid, etc. It includes no solvent that is a human health hazard at levels normally used in the pharmaceutical industry.

In extraction, liquid-liquid separation and other applications, several alcohols, ketones, halogenated solvents, amide, ethers, nitriles are used. Depending upon the conditions (temperature, pressure, and humidity) required for the transfer of the solution at a certain rate, specific tubing and hoses are used. These tubing and hoses are made up of different resistant materials (metals, plastics and

elastomers). Each of these materials have their own characteristic benefits and cost differentials. Elastomers typically include silicone rubber, neoprene, EPDM, NBR, hypalon apart from fluoropolymers and thermoplastic based elastomers. These different elastomers are chosen based on the properties and concentration of the corrosive chemicals being transferred via the tubing/hoses.

The non-polar, chemically inert, high service temperature, hydrophobic nature of a fluoropolymer surface provides noninteractive containment for pharmaceutical and biotechnological process fluid streams. These attributes promise reduced production costs and lower downtime for regulatory compliance procedures, operations and maintenance activities.

It is essential to choose the right material when the process involves transfer of fluids safely within time limits as dictated by the process design. Most industrial processes are designed according to 3 basic parameters in order of importance - safety first, quality next and then productivity enhancement.

Fig.1 - Increasing use of fluoropolymers in various industries. (Source: Grand View Research) 56 â—„ January 2019

(Ami Polymer Pvt Ltd. research@amipolymer.com www.amipolymer.com) Pharma Bio World

marketing initiatives

Industry 4.0 in the pharmaceutical industry From sensors and software to analytics, the new wave of process automation and solutions are opening up new potentials in terms of transparency, quality, safety and efficiency. Industry 4.0 is bound to be a game changer for most sectors and especially the pharmaceutical industry wherein complex processes must be adhered to, and stringent requirements upheld. But, digitization needs a holistic approach and is not a sequential, single-handed project.

H

umans, machines, processes and IT – In short, everything and everyone would be connected in the factory of the future. Intelligent manufacturing is the answer to a rapidly changing market environment. Products are becoming more individualized, production processes more complex, and batches smaller. Manufacturers can address these challenges by reorienting their production, ensuring that it can quickly and continuously adapt to changing requirements. The basis for the digital transformation lies in the smart use of the virtually boundless amounts of available data.

Pharma - A special case Compared to many other industries, pharmaceutical production has more demanding regulations. Changes to production mean changes to the machines, processes and ultimately the product itself. To ensure consistently high product quality, authorities like the U.S. FDA and the EU Commission issue strict guidelines, such as those on Good Manufacturing Practice (GMP). Accordingly, companies have their fair share of reservations when it comes to implementing new and untried technologies.

Nevertheless, many pharmaceutical companies have already taken the first Pharma Bio World

step towards digitization and are now engaged in its implementation. A case in point is serialization based on Track and Trace applications which are an intrinsic part of holistic packaging solutions. To adhere to all relevant legal guidelines, it is not enough to simply print a data matrix code on the folding carton. A holistic serialization and aggregation solution should include the connection between machines and software, ensuring that the entire process can be managed, and the data is constantly available. Only this way manufacturers and distributors alike can have a clear overview of all the process steps – while simultaneously achieving the connectivity that is the hallmark of Industry 4.0.

Getting started step by step The implementation of a serialization solution alone represents a huge challenge. However, in the next step, pharmaceutical companies face obstacles of a very different kind. While Track and Trace applications focus on the packaging, other instruments directly affect the production or filling process. Accordingly, pharmaceutical manufacturers have especially high demands when it comes to Industry 4.0 solutions. They need the security of knowing that a given solution can be or has already been successfully implemented in the market.

Digitization projects can influence many processes and components. Hence, no single party can or should try to implement them alone. Instead, digitization is about bundling the respective expertise and experience on a cross-project basis. This can include participating in nationwide initiatives. Above all, machine providers, software manufacturers and process experts need to work together closely to reap the maximum benefits of Industry 4.0 for their customers. This does not mean they have to replace their entire machine setup or abandon their current production philosophy. A step-by-step approach is often the more sensible alternative.

Making use of existing competencies The first step is to make the existing data visible. For this purpose, an introductory solution like Bosch’s Pharma i 4.0 Starter Edition is a good fit. The package offers machine operators key functions for condition monitoring, event tracking and measuring Overall Equipment Effectiveness (OEE) on their PC or mobile device, including a complete audit trail for all user interactions. No matter whether anomalies or unexpected downtimes occur in the ongoing production, employees can access exactly the information they need, whenever and wherever they like, greatly simplifying their day-to-day work.

The data gathered by the software can be January 2019 ► 57

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subsequently analyzed and used as the basis for targeted process optimizations.

This also includes historical data, which can be compared to real-time data and offers valuable insights into the development of central parameters, such as the OEE within a certain timeframe.

data exchange. Adding further features, for instance the generation of Electronic Batch Records (EBR), is also possible.

Here, too, all process steps are subject to strict regulations concerning electronic signatures, GMP-compliant processes and long-term data archiving.

To make this possible, Bosch works with a software partner who has already installed numerous solutions in the field – including the pharmaceutical industry – and applies the software according to the respective customer’s specific situation and needs. Thanks to the use of open standards, incorporating machines and lines from different brands does not mean reinventing the wheel.

OPC-UA and the machine programming language PackML are primarily used as the standard for communication and

Finding buried treasure Once the data is available, the real challenge consists in identifying previously overlooked information and new potential for optimization. With the help of data analytics or data mining, huge amounts of data are assessed for effects and correlations using statistical methods. Usually, the data from two production batches is sufficient to draw initial conclusions. Yet the more data is evaluated, the more details come to light.

The only equipment needed are sensors

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to gather the data, which can also be found on the majority of older machines, and the right tool for analyzing the data.

The most important aspect, however, is the combination of extensive process expertise and IT know-how.

A real-world example: A pharmaceutical manufacturer suddenly had an ‘out of specification’ (OOS) batch. The data analysis revealed that a certain valve was responsible for the problem. Yet the valve had been ruled out in advance, as it was assumed to have no effect on product quality. The deeper correlations were analyzed, and a previously undetected causal chain became apparent. The analysis ultimately determined that the valve provided indirect evidence of an incorrect gas flow in the system, which would never have been detected Pharma Bio World

marketing initiatives

otherwise. The problem was then easily solved by recalibrating the system.

From vision to reality In the near future, such recalibrations could be even more easier, thanks to Augmented Reality and Virtual Reality (AR/VR). For example, AR applications can guide employees through the process step by step, and be used to display calibration instructions and spare parts. This can considerably accelerate the process – without the need for lengthy training. When more complex processes are involved that make training essential, it no longer has to take place in a classroom or on the shop floor. VR applications produce 3D simulations of machines, which can be used under highly realistic conditions in virtual training sessions. Trainers can follow the simulation live and add helpful instructions as needed, while operators can practice safely and without stress, since any errors they make will have no direct consequences or interrupt the ongoing process.

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Admittedly, some of these Industry 4.0 applications are still in an early stage of development. Nonetheless, the digital future is within our grasp, as essential devices like sensors are getting smaller and smaller, and components are becoming more affordable. To gradually make the vision of a connected pharmaceutical industry a reality in dayto-day production, strong partnerships are called for. After all, the challenges posed by digitization can only be successfully and sustainably overcome if machine manufacturers, software developers, process experts, and employees on the shop floor work hand in hand.

[Bosch Packaging Technology – (Pharma product division) is one of the leading providers of process technology and packaging solutions for the pharmaceutical industry. The portfolio includes single units, complete lines and integrated systems for the manufacturing and processing of liquid and solid pharmaceuticals. It also includes process technology, primary packaging, inspection technology for different

application fields and packaging types.

Secondary packaging with qualification and validation, software solutions for track and trace, and technical customer services are also available. The following product brands are part of the Bosch portfolio for the pharmaceutical industry: Hüttlin, Klenzaids, Moeller&Devicon, Pharmatec, SBM Schoeller-Bleckmann Medizintechnik, Sigpack and Valicare.]

(Dr. Christian Hanisch Bosch Packaging Technology)

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news, events, etc Pathios Therapeutics and Sygnature Discovery sign a strategic and innovative partnership to develop first in class therapies in autoimmune disease and immuno-oncology Pathios Therapeutics, an innovative biotech company focused on the development of first in class therapies for autoimmune diseases and immuno-oncology and Sygnature Discovery recently announced a strategic partnership to accelerate Pathios’ drug discovery and development programmes.

As part of the agreement, Pathios and Sygnature will collaborate on an integrated drug discovery programme against a novel G Protein-Coupled Receptor (GPCR) target. Specifically, Sygnature are providing their industry leading expertise in GPCR bioscience and medicinal chemistry to expand Pathios’ current hit-to-lead programme. Sygnature are also deploying their computational chemistry, library design and synthesis and medium throughput screening capability to broaden Pathios’ hit finding. As part of this agreement, Sygnature will receive equity in addition to fees.

Pathios Therapeutics brings together cutting-edge European science and a leading drug discovery and development team to modulate the activity of GPR65, a pH sensing GPCR. This drug target is characteristic of certain T helper 17 (Th17) cell populations which have been shown to contribute significantly to the pathology of autoimmune conditions, such as ankylosing spondylitis and psoriatic arthritis. In addition, recently published studies have demonstrated GPR65 drives tumour associated macrophages (TAM) to adopt a phenotype that supports cancer immune evasion.

Tom McCarthy, Executive Chairman and Co-founder of Pathios Therapeutics Limited, commented: "We founded Pathios to build on emerging science that demonstrated GPR65 sits at the nexus of autoimmune disease and immuno-oncology as this receptor links pathology caused by a low pH environment. The ultimate aim is to block the pathological process that GPR65 initiates without interfering with the physiological role of this receptor. In addition to developing potent and selective drugs to modulate GPR65, we are continuing to broaden the understanding of the fundamental biological processes that link to GPR65’s effects in Th17 cells, TAMs and other cell types.

Our team has worked closely with Sygnature in the past and know they have the deep experience, expertise and state-of-the-art drug discovery and development infrastructure to drive our programme forward. I’m delighted on this rare occasion Sygnature also chose to invest in Pathios and expand our GPR65 drug discovery efforts while we explore Series A funding opportunities".

Simon Hirst, CEO of Sygnature, added: "We are extremely pleased to take this exceptional opportunity to partner with, and invest in Pathios on their drug discovery projects. Based on our diligence activities, we are excited about the potential for GPR65 modulation to be central to new treatments for autoimmune disease and a critical mechanism of action in next generation immuno-oncology drugs targeting the tumour microenvironment. We are excited to have the opportunity to work with Tom and the rest of Pathios’ tremendously talented team again and contribute 60 ◄ January 2019

to the potential positive impact their therapeutics will have on patients’ lives".

Launched in 2017, Pathios is a drug discovery and development company focused on translating innovative science into new medicines. Pathios was founded by a team of experienced biotech and pharmaceutical industry professionals, entrepreneurs and clinicians, led by Chairman Tom McCarthy. The Company is initially focused on the development of modulators of the G protein-coupled receptor GPR65.

Sygnature Discovery is a leading independent integrated drug discovery and pre-clinical services company. Private equity-backed since 2017, it operates fully-enabled research facilities in Nottingham and Alderley Park, UK, housing over 200 research scientists (over 80% with PhDs). These experienced drug hunters possess all the professional skills and knowhow required to undertake the most demanding of research programmes and drive them from target validation through hit identification, hit-tolead and lead optimisation to pre-clinical development candidate. Since 2011, the firm has delivered 14 drug candidates to clients which have subsequently entered the clinic (Phases I, II and III). In 2017, Sygnature Discovery received the prestigious Queen’s Award for Enterprise for International Trade.

Alborada Drug Discovery Institute identifies advanced Huntington’s leads using BioAscent’s Compound Cloud library BioAscent Discovery Limited’s unique on-demand compound library, Compound Cloud, has been used by the Alborada Drug Discovery Institute for virtual screening and to progress promising leads against a novel Huntington’s disease target. The Alborada Drug Discovery Institute, established by Alzheimer’s Research UK, is developing new approaches to slow or halt the progress of the diseases that cause dementia. The Institute’s primary focus is to explore mechanisms associated with the misfolded, aggregated proteins which characterise most neurodegenerative diseases.

The institute has an advanced drug discovery program seeking to develop inhibitors of the PI5P4 kinases. Lead academic scientist Professor David Rubinsztein has previously used genetic studies to show that blocking these enzymes upregulates autophagy, a natural cellular protein clearance mechanism which is capable of digesting and removing neurotoxic proteins. In cell models, blocking the activity of the enzymes reduced the effects of Huntington’s disease.

Based on these findings, Alborada drug discovery team obtained compounds from a variety of sources in order to proceed with a deeper drug discovery program. Approaches employed included fragment screening, diversity screening and virtual screening. The virtual screening used BioAscent’s on-demand Compound Cloud service which provided quick access to a library of over 125,000 lead-like and drug-like IP-free compounds.

The institute undertook a Virtual Screening approach to select potential hits from Compound Cloud, downloading the structures of the 31,000 kinase inhibitor subset of the library, and selecting potential hits via a number of computational methods (filtering based on substructures, docking approaches using a literature crystal structure

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news, events, etc and pharmacophore approaches based on known ligands of similar targets). Based on their structures, the resulting compounds were assigned to 960 clusters.

Compound Cloud users can download structures of all 125,000 compounds (or pre-filtered subsets thereof), analyse structures and select only those compounds of interest, and have them delivered as liquid samples in the quantity, format and plate layout of their choosing (including near-assay ready plates). It represents an extremely costeffective way of accessing either ready-made or customised libraries in the quantities required for a screening program. BioAscent’s integrated drug discovery team also use the library in the drug discovery programs that it carries out for its customers.

mRNA-Seq kits are the first of the company’s NGS kits to be available for the NGS DreamPrep.

Tecan is a leading global provider of laboratory instruments and solutions in biopharmaceuticals, forensics and clinical diagnostics. The company specializes in the development, production and distribution of automated workflow solutions for laboratories in the life sciences sector. Its clients include pharmaceutical and biotechnology companies, university research departments, forensic and diagnostic laboratories.

US Patent Office Grants the 100th Patent to Immatics Underpinning the Company’s Leading Role in the Field of Innovative Tecan launches NGS DreamPrep delivering Immunotherapies unprecedented speed and accuracy for Immatics, a leading company in the field of cancer immunotherapy, recently announced that the United States Patent and Trademark automated library preparation Office has issued the 100th patent to the company.

Tecan recently announced the launch of NGS DreamPrep, a fullyautomated approach to next-generation sequencing (NGS) library preparation for research use. This groundbreaking new approach offers quality controlled, sequencing-ready NGS libraries in just a matter of hours, with minimal manual interaction and no sample loss.

This is a significant achievement for the company and demonstrates the breadth of Immatics’ innovation power and the quality of its science.

Immatics’ strong patent portfolio enables the company to develop its pipeline of cancer immunotherapies, to protect Immatics’ innovations and to safeguard the company’s technology investments.

NGS DreamPrep is a full walkaway solution that combines the Tecan Fluent liquid handler and Infinite plate reader, together with Celero DNA-Seq and Universal Plus mRNA-Seq library preparation kits – an optimized solution that brings significant improvements in speed, flexibility, accuracy and precision.

Immatics’ 100th patent (US Patent No 10,143,731) is directed against a peptide target discovered using the Company’s XPRESIDENT technology. The peptides identified by XPRESIDENT are presented by human leucocyte antigen (HLA) receptors on the surface of cells and are central to developing a range of novel powerful immunotherapies.

NGS experiments are time-consuming, expensive and generate vast quantities of data. This makes it particularly important that they are based on high-quality libraries that will yield valuable results. With NGS DreamPrep, quantification, normalization and pooling of samples can all be achieved in significantly shorter timelines compared to other methods that use qPCR or capillary electrophoresis. Importantly, this is the first library preparation method to incorporate a QC step, which takes just five minutes, ensuring the generation of highly reproducible libraries that are ready to sequence.

Since its inception, Immatics has put a key focus on the development of its Intellectual Property estate, in order to protect their technology innovations in the highly competitive field of Immunotherapy development. Immatics’ patenting strategy ensures broad protection of the company’s products, technologies and methods while still meeting the patentability requirements in a fast-paced environment.

Dr Klaus Lun, Executive Vice President Head of the Life Sciences Business Division, Tecan said: "Next-generation sequencing continues to revolutionize genomic research. Previously, the technique relied on libraries being quantified and normalized using methods that were timeconsuming and subject to variability. NGS DreamPrep enables users to easily transform samples into high quality, ready-to-use libraries."

NGS DreamPrep brings together Tecan’s technical expertise in chemistry and protocol development together with unsurpassed engineering know-how of automation and detection instrumentation to ensure an optimized approach. All elements have been designed to work hand-in-hand and researchers benefit from having a single contact point plus dedicated Tecan application support.

The Tecan Group acquired US-based NuGEN Technologies, Inc., now named Tecan Genomics, in August 2018 to further expand Tecan's dedicated solutions offering into the new market segment of NGS reagents and kits, making the company the one-stop-shop for genomic sample preparation solutions. The Celero DNA-Seq and Universal Plus Pharma Bio World

Immatics is a clinical-stage biopharmaceutical company active in the discovery and development of T-cell redirecting immunotherapies for the treatment of cancer. The company’s transformative product candidates are - best in class - Adoptive Cell Therapies and TCER Bispecific TCR molecules. These products are directed against tumor targets that have been identified and validated by Immatics’ proprietary XPRESIDENT technology. XPRESIDENT is the most sensitive, unbiased and high-throughput technology capable of identifying targets in virtually any type of cancer and any HLA type. Together with Immatics’ powerful TCR discovery technology XCEPTOR, these two platforms allow a full range of cancer therapies to be developed.

Immatics’ pipeline includes T-cell therapy programs based on the proprietary ACTolog, ACTengine and ACTallo approaches, which are developed in collaboration through Immatics US with University of Texas MD Anderson Cancer Center and co-funded by the Cancer Prevention and Research Institute of Texas (CPRIT), and several bispecific TCR and antibody molecules.

Operating from Tuebingen, Munich and Houston, the company has recognized that novel, better and safer targets are the key to developing future cancer immunotherapies and it continues to focus on delivering the power of T cells to cancer patients.

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news, events, etc Lonza and AllCells Join Forces for Global BioAsia 2019 to promote innovation in Life Commercialization of Hematopoietic Science and Healthcare sectors through Primary Cells ‘Startup Stage’ Lonza and AllCells have entered into a private label partnership for the manufacture and global commercialization of an extensive range of hematopoietic primary cells. This partnership expands Lonza’s broad offering of hematopoietic cell lines and enables cell biologists to easily access a wide selection of high-quality cells to boost their scientific research.

Under the new agreement, the entire AllCells research portfolio of products will bear the Lonza branding and will allow scientists on a global scale to further their research across an array of applications, including drug discovery, toxicity testing, cell therapy and personalized medicine.

Hematopoietic primary cells play a vital role in advancing in vitro research as they closely reflect in vivo morphology, metabolism and growth characteristics. However, obtaining those cells requires researchers to find a variety of donors and perform a series of tedious cell isolations.

“With this partnership, we aim to enable straightforward access to a wealth of viable, ready-to-use hematopoietic cells, such as mobilized peripheral blood progenitor cells,” said Mary Riley, Director of Discovery Solutions at Lonza. “All researchers will need to do is thaw and culture, while also being able to take advantage of Lonza’s strong after-sales technical support.”

BioAsia, Asia’s largest Life-sciences and healthcare forum will feature a dedicated platform called the ‘Startups Stage’ in its 16th Edition of the event to be held at Hyderabad from February 25 – 27, 2019.

This platform, Startups Stage, will enable entrepreneurs working on solutions for the pharma, bio-tech, life sciences, health-tech or medtech sectors to showcase their innovation to a global audience. BioAsia has the reputation of being a globally sought-after annual forum due to its diverse attendance of healthcare leaders from over 50 countries regularly. The marquee event has witnessed a prestigious participant history including the likes of several Nobel Prize winners including the likes of Dr’s Kurt Wuthrich, Ada Yonath, Harald zur Hausen, Barry Marshall, Martin J Evans, several Lasker Awardees and eminent industry leaders like Dr. Paul Stoffels (Vice Chairman and CSO, J&J), Dr. Vas Narasimhan (CEO, Novartis), Dr. Patrick Vallance (President R&D, GSK), Dr. Seth Berkley (CEO, GAVI), Dr. Freida Lewis Hall (EVP and CMO, Pfizer), Dr. Mark Caulfield (Chief Scientist, Genomics England), Shri Pankaj Patel (Chairman, Zydus Cadila), Mr. Satish Reddy (Chairman, Dr. Reddy’s Laboratories), Ms. Kiran Majumdar Shaw (CMD, Biocon), among others.

Founded in 1897 in the Swiss Alps, Lonza today has 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.

The participating startups will get an opportunity to showcase their solutions at the ‘International Tradeshow Exhibition’, network with global industry delegates, seek mentorship from eminent thought leaders, seek partnership avenues with companies and pitch to leading venture and M&A investors. Notable healthcare investors like Mr. Kris Gopalakrishnan (Axilor), Mr. Sanjiv Kaul (ChrysCapital), Mr. Pranay Adhvaryu (Lighthouse Canton), Mr. Mahadevan (Mahad) Narayanamoni (TPG), Mr. Jinesh Shah (Omnivore) and representatives from Norwest Venture Partners, RoundGlass Partners, Abraaj, Shunwei Capital, 3one4 Capital, Kae Capital, Kalaari, Patni Family Office, Ivy Cap Ventures, among many others shall be actively interacting with the participating startups exploring funding opportunities. Dr. Renu Swarup (Secretary, Department of Biotechnology), Government of India who has been instrumental in accelerating the growth of biotech sector in the country will interact with the Start-ups in the Start-up Stage. M&A teams from companies like Zydus Cadila, Dr. Reddy’s Laboratories, Alkem Laboratories, etc. will also participate in the event. In last 4 years, BioAsia provided an opportunity to around 150 Startups which benefitted by networking with industry experts along with their feedback and investors community to explore their funding requirements.

AllCells is a leading biotechnology company dedicated to providing researchers and biomanufacturing organizations with high quality primary cells that enable drug discovery, preclinical development, and manufacturing of cell therapies. Leveraging its expertise in hematopoietic and immune cell isolation and characterization together with bi-coastal on-site hematologic tissue clinical collection operations, AllCells maintains a large repository of donor profiles that can be qualified for various biomedical applications. Freshly collected tissue is immediately processed in contiguous manufacturing facilities to produce purified cell types having unparalleled quality and consistency. Cells are shipped worldwide, or fresh cells can be immediately utilized in fee-for-service cell-based assays custom designed according to customer criteria.

The startups will also get an unmatched opportunity to request exclusive one-to-one meetings with the participating delegates and be a part of the ‘Disruptors Roundtable’. The Disruptors Roundtable will be chaired by industry luminaries for a focused interaction with startups to provide insights and guidance on several emerging healthcare challenges. The likes of Mr. Satish Reddy, Chairman of Dr. Reddy’s Laboratories will be a part of the Disruptor’s Roundtable for startups.

The Startup Stage will also feature several activities and workshops conducted by industry experts on emerging trends healthcare globally.

The top 5 startups participating in the Start-up stage will get a chance to pitch their innovation to the global conference audience. Interested Startups can visit BioAsia 2019 website for free registration.

Don Klabunde, CEO at AllCells, added: “By leveraging our customization expertise, speed and flexibility to manufacture hematopoietic cells of superior viability and quality, and with Lonza's extensive reach, we will improve the availability of highly purified cells from different tissue sources to enhance a variety of research needs.”

Lonza is an integrated solutions provider that creates value along the healthcare continuum through niche pharma and biotech services as well as specialty ingredients. The firm 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.

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news, events, etc Cipla receives final approval for generic Meril’s price exemption request for version of Pfizer’s Depo-Provera biodegradable stent under review (Medroxyprogesterone Injectable, Meril Life Sciences Pvt. Ltd’s request for exemption from price caps for its first locally-made biodegradable cardiac scaffold, a naturally 150mg/mL) dissolving stent that clears blockages in arteries, has been sent to an Cipla Limited has recently received final approval for its Abbreviated New Drug Application (ANDA) for Medroxyprogesterone Injectable, 150mg/ mL from the United States Food and Drug Administration (US FDA).

Cipla’s Medroxyprogesterone Injectable, 150mg/mL is AB-rated generic therapeutic equivalent version of Pfizer’s Depo-Provera. It is a progestin indicated only for the prevention of pregnancy. According to IQVIA (IMS Health), Depo-Provera and its generic equivalents had US sales of approximately $159M for the 12-month period ending November 2018.

Depo-Provera is an injectable form of contraception. Each injection protects the user from pregnancy for 3 months. It works by inhibiting the hormones that are needed for the release of eggs from the ovaries. The drug also helps to stop the growth of cells outside the uterus in case of endometriosis.

Interestingly, Depo-Provera is also used in the treatment of certain types of cancer including cancer of the breast, kidney and endometrium (lining of the uterus), but is not considered as a cure for cancer. Its mode of action is through inhibition of the growth of these types of cancer cells.

Established in 1935, Cipla is a global pharmaceutical company focused on agile and sustainable growth, complex generics, and deepening portfolio in emerging and regulated markets. Its paradigm-changing offer of a triple anti-retroviral therapy in HIV/AIDS at less than a dollar a day in Africa in 2001 is widely acknowledged as having contributed to bringing inclusiveness, accessibility and affordability to the centre of the movement.

Aurobindo voluntarily recalls amlodipine/ valsartan from US markets Aurobindo Pharma recently announced a voluntary, consumerlevel recall of several lots of amlodipine/valsartan, valsartan/ hydrochlorothiazide (HCTZ), and valsartan tablets due to the detection of trace amounts of an unexpected impurity, identified as n-nitrosodiethylamine (NDEA), found in the finished drug product.

NDEA is a substance that occurs naturally in certain foods, drinking water, air pollution, and industrial processes, and has been classified as a probable human carcinogen as per International Agency for Research on Cancer classification. Aurobindo Pharma has declared that it has not received any reports of adverse events as yet, related to this recall. The recalled products were distributed nationwide.

Valsartan is used to control high blood pressure and for the treatment of heart failure. In combination with HCTZ or amlodipine, it is used for the treatment of high blood pressure. Patients taking amlodipine/ valsartan combination tablets, valsartan/HCTZ combination tablets, or valsartan tablets have been advised to continue taking their medication and to contact their pharmacist or physician for advice on alternative treatment as the risk of harm to a patient’s health may be higher if the treatment is stopped immediately without any alternative treatment.

Patients have been advised to contact their healthcare provider if they have experienced any problems that may be related to using the recalled valsartan-containing product. Existing inventory of the recalled product are being quarantined.

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expert panel for review. India’s price regulator, National Pharmaceutical Pricing Authority (NPPA), which took up the exemption claim at its 21 January meeting, has not accepted the proposal and has sent it for a re-examination. The exemption, if granted, would be valid for five years.

Meril based in Gujarat’s Vapi, has been trying to seek an exemption under para 32 of the Drug Price Control Orders (DPCO) that says the price cap won’t apply if a new drug developed through a unique, indigenous process, is patented under the Indian Patents Act and is not produced elsewhere.

NPPA verified the company’s submissions and decided that the matter be sent to an expert body for re-examination. “After detailed deliberations, the authority decided to refer the case to multi-disciplinary committee of experts, which after co-opting suitable experts shall make recommendation to the authority," said the minutes of the meeting. In February 2017, the government capped the price of stents, a mesh tube placed in arteries to improve blood flow, forcing manufacturers to cut prices by up to 85%. Since then, many foreign stent makers withdrew their high-end devices from India, and have been pressing to create a new category of stents with advanced features.

A committee was earlier set up to examine creation of a new category.

Stent makers and importers like Boston Scientific India Pvt. Ltd, Abbott Healthcare Pvt. Ltd, India Medtronic Pvt. Ltd and Meril Life Sciences Pvt. Ltd have made representations before the committee on 25 January last year urging that by creating a new category, quality and innovation would be rewarded and the segment kept viable. However, the eight-member government sub-committee of experts that considered stent makers’ arguments said there were ‘no grounds’ to create a new category.

The NPPA in a meeting on 28 June also discussed the processes developed by drug makers. “The authority noted that companies have produced documents showing that patents have been granted under Indian Patents Act, 1970 for producing the new drugs in the country by a new process developed through indigenous research and development and companies have also produced documents showing approval of such new drugs from DCGI," according to the minutes of the meeting.

The company says its stents are made of biodegradable material, and are an alternative to the traditional metal stents. The stents developed by Meril are known as MeRes100. However, the year they were granted approval by the Drug Controller General of India (DCGI) — in 2017 — was also when the prices of stents were slashed by the price regulator. This prompted Meril to hold back from launching its stents in the local market. Civil society groups, are concerned about the safety of the Meril product. “We do not believe that there is evidence to support any therapeutic advantage of this stent, given the limitations of the single arm clinical trial. Abbott’s BVS (bioresorbable vascular scaffold) that introduced the technology on which Meril’s stent is premised was found to be associated with higher risk of major adverse cardiac events and subsequently withdrawn globally. Therefore, it is our position that a price exemption for a risky, inadequately tested technology is unwarranted and the application should be rejected," said Malini Aisola, co-convener, All India Drugs Action Network (AIDAN).

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

 

Date: 20 – 23 February, 2019 Venue: Bombay Exhibition Centre, Mumbai

Date: 25 – 27 February, 2019 Venue: Hyderabad International Convention Centre (HICC), 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.

Biotechnology being an emerging industry, game-changing strategies and relevant application of the knowledgeintelligence resource pool, drive the process of growth.

BioAsia 2019 seeks to enhance, enrich and encourage newer innovations, path-breaking discoveries and effective solutions in the industry by offering a vibrant global platform for convergence of the key stakeholders - Biotech & Biopharma Companies, research institutions, investors, service providers, policy makers, regulators and analysts.

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

 BioAsia Secretariat 301, Gayathri Nest, Telecom Nagar, Gachibowli, Hyderabad - 500032 Telangana, India.

Tel: +91-9100061598 / +91-9177749651 Email: info@bioasia.in

  

   

Date: 16 – 17 April, 2019 Venue: Bombay Exhibition Centre, Mumbai

Date: 16 – 18 July, 2019 Venue: Pragati Maidan, New Delhi

Analytica Anacon India is one of the biggest show in laboratory technology and analysis in India. This is a trade fair that showcases the entire range of lab equipment and instruments including chromatographs, spectroscopes, microscopes, etc apart from lab furniture and other peripherals. The new feature of this year’s event in Mumbai is the introduction of pharma machinery pavilion organized by Indian Pharma Machinery Manufacturers Association (IPMMA). This pavilion will feature pharma machinery and equipment manufacturers from processing, packaging, cleanroom, filling, water treatment, environmental control to name a few.

Indian Pharma Expo (IPE) will provide an opportunity for the participating companies to display their products & services to the gamut of visitors, globally from pharma and healthcare industries. The 3-day expo will bring together eminent personalities from various sectors of pharma, nonpharma and healthcare industries. IPE is one stop juncture to all those who are planning to expand their business through various channels of franchise and distribution; as well as wholesalers and hospital purchase personnel who seek to buy bulk products at concessional rates.

Contact: 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

 CIMS Medica Boomerang, Unit No. 403 B1 Wing 4th floor, Chandivali Farm Road, Chandivali, Andheri (East), Mumbai - 400 072. India Tel: +91-22-66122612 / 627 Email: ipe@cims.co.in

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M-Series Mixer Seals

QB Series Pusher Seals

In chemical, pharmaceutical, food and oil refinery process plants, diverse systems are employed for agitating, blending and mixing products.

Mixers, agitators, reactors, filter dryers, and other specialty equipment should ideally be low maintenance as well as safe, in order to protect the environment and the workplace.

The mechanical seal design in such situations must provide excellent performance in the application, allowing for axial and radial shaft movements. Flowserve is focused specifically to provide the best mixer sealing solutions. The standard M-Series of double mechanical seals are built on a chassis that allows the conversion from one design philosophy to another. There are three distinct designs within this family of seals. A liquid lubricated, a dry contacting, and a dry non-contacting seal.

For more information, please contact: Flowserve India Controls Pvt. Ltd. S.F. Nos. 136/3 & 137, Myleripalayam road.

Myleripalayam Post, Othakkalmandapam Coimbatore - 641 032. Tamil Nadu. INDIA Tel: +91 422 661 2001, Fax: +91 422 661 2002 Website: www.flowserve.com

Pusher seal designs run the gamut from simple, low duty devices to very high duty, extremely sophisticated engineered solutions. Besides general services, pusher seals are often selected for light hydrocarbons, high pressures and high-speed applications because of their inherently greater strength and damping characteristics compared to bellow seals. Flowserve QB Series seals are balanced pusher seals available in single and dual seal configurations used for sealing environmentally-restricted products and meeting the most stringent regulations. It has high balance seal face design for low emissions. These faces are designed to suppress flashing and minimize heat generation in hydrocarbon applications.

For more information, please contact: Flowserve India Controls Pvt. Ltd. S.F. Nos. 136/3 & 137, Myleripalayam road.

Myleripalayam Post, Othakkalmandapam Coimbatore - 641 032. Tamil Nadu. INDIA Tel: +91 422 661 2001, Fax: +91 422 661 2002 Website: www.flowserve.com

Worcester Series WK 74 Tube Bore Clean Valves The performance of the WK 74 Tube Bore Clean Valves is based on a combination of high standard specifications. Worcester Series WK 74 clean valves operate dependably in the pharmaceutical, biotech, food, cosmetic, paint, chemical and semi-conductor industries where microbes, media deposits, mineral impurities and cross-contamination can threaten the quality of the product. The high-purity design, high vacuum rating, high cycle life and high pressure/temperature rating of these valves make them ideal for applications ranging from sterile steam to nutrient inlets to high-purity water.

For more information, please contact: Flowserve India Controls Pvt. Ltd. S.F. Nos. 136/3 & 137, Myleripalayam road.

Myleripalayam Post, Othakkalmandapam Coimbatore - 641 032. Tamil Nadu. INDIA Tel: +91 422 661 2001 Fax: +91 422 661 2002 Website: www.flowserve.com

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January 2019 ► 65

BulkTite Powder and Bulk Solids Seal Designed for rotating equipment handling powder and bulk solids, BulkTite seals are ideal for chemical, power, food processing, pharmaceutical and general industries. Leveraging proven air bearing technology, BulkTite seals provide improved sealing performance by eliminating the shortcomings of conventional seals such as packing, lip seals and bushings. With non-wearing, non-damaging and low maintenance features, BulkTite seals economically extend the continuous operation of rotating equipment such as screw conveyors, rotary airlocks, mixers, clinker grinders, and delumpers.

For more information, please contact:

Flowserve India Controls Pvt. Ltd. S.F. Nos. 136/3 & 137, Myleripalayam road.

Myleripalayam Post, Othakkalmandapam Coimbatore - 641 032. Tamil Nadu. INDIA Tel: +91 422 661 2001 Fax: +91 422 661 2002 Website: www.flowserve.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-PEAl-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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Triple Shaft Mixer

Foot Valves

Ross Process Equipment offer dual and triple shaft designs to meet the specific requirements of each customer. The economical dual shaft design includes a two-wing anchor agitator and a conventional high speed disperser. This combination is ideal for straight forward mixing and dispersion applications. The triple shaft design extends the operating range by adding either a high shear rotorstator mixer or a second high speed disperser. The addition of a high shear rotor-stator mixer adds the capability of emulsifying and homogenizing products that require higher shear to reduce the size of the particles being mixed.

For more information, please contact:

Ross Process Equipment Pvt Ltd Plot No: D-233/3, Chakan Indl Area Phase II, Village: Bhamboli, Tal: Khed Dist: Pune, Maharashtra 410 501 Tel: 02135-628400, 628401, 628402, 628403 E-mail: mail@rossmixers

CRI energy-efficient frictionless foot valves and reflux valves are basically swing type non-return valves. Foot valves are available in screwed type construction and reflux valves have threaded portions at both the ends. They are specially designed to give an unrestricted smooth flow of water and thus to reduce the frictional losses to a minimum. The CRI frictionless foot valve has ‘K’ value less than 0.8 and ‘K’ value for reflux valves are less than 0.5. Thereby it reduces additional load on prime mover and also gives more discharge. Foot valve is placed at the lower end of the suction pipe of a centrifugal end suction pumpset to retain water in the pumpset casing and suction pipe to keep the pumpset always in prime condition.

For more information, please contact: CRI Pumps Pvt Ltd 7/46-1 Keeranatham Road Saravanampatty Coimbatore, Tamil Nadu 641 035 Tel: 0422-3027000, Fax: 91-0422-3027005 E-mail: corp@cripumps.com

Electromagnetic Flow Meter Process Control Devices offers a Series of digital flow meters. Designed to measure the flow rate of liquids flowing through the closed pipe. The electromagnetic flow meter is volumetric flow meter having no obstruction as there are no moving parts. Hence, pressure drop is negligible. The performance is independent of density, viscosity, temperature and pressure of the flowing liquid. The magnetic flow meter is calibrated using water and can measure the flow of other conductive fluids, with no further correction. This is a special feature that other type of flow meters does not have.

Electromagnetic flow meters work on the principle of Faraday’s Law of electromagnetic induction. According to the law, when a conductive liquid cut the magnetic field, voltage induces. Further, that voltage signal is sensed by the electrode which is mounted on the wall of the flow tube. That induced voltage signal is processed by the electronic transmitter to determine the flow. The generation of voltage is directly proportional to the velocity of the fluid

For more information, please contact: Process Control Devices Plot No: 22, Rautara Indl Estate B/s Hanuman Hotel, Shil-Mahape Road Shilphata, Thane, Maharashtra 400 612 E-mail: sales@pcd-flowmeter.com / sales.pcdpl@gmail.com

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Mercury in Steel Thermometer

Gas Filled Thermometer

Mercury in steel thermometer, ZM Series from Adarsh Industries are the most accurate/fast response instruments with accuracy of ±1% FSD, available in dial sizes 4”, 6”, 8” and 10” dial. They are available as both Rigid Stem Type and Capillary Type and ranges from - 38 to max 600oC.

For more information, please contact:

Adarsh Industries 307 Shankala Indl Estate Gogatewadi, Off Aarey Road Goregaon (E), Mumbai 400 063 Tel: 022-29275496 Fax: 91-022-29275558 E-mail: sales@adarshpressuregauge.com

Gas filled thermometers ZG Series have nitrogen as filling media.

This makes it possible to use it for hygienic applications also. They are available in dial sizes 4”, 6”, 8” and 10” and as both Rigid Stem Type and Capillary Type. It ranges from -50 to max 600 o C.

For more information, please contact:

Adarsh Industries 307 Shankala Indl Estate, Gogatewadi, Off Aarey Road Goregaon (E), Mumbai 400 063 Tel: 022-29275496 Fax: 91-022-29275558 E-mail: sales@adarshpressuregauge.com

Telescopic Sliding Doors Telescopic sliding doors are space saving technology, suitable where there is less back run space/less door parking space to open the door.

Ideal for large/extra-large opening and partial opening can also be easily achieved. Specially designed high grade multiple tracks at the top holds the door firmly.

Telescopic sliding doors come with high performance dual type top and bottom rollers for a smooth operation of the door. requirement.

Various types of standard and economical ranges of panels are available to suit your structural

At each end-track stopper is placed to absorb any impact and to hold the door in the open or closed position. Specially designed multiple top tracks ensure the smooth, easy operation of the door and bottom guide track avoids oscillation of the door.

Telescopic sliding doors can be constructed with vertical EPDM rubber seal.

A total safety system, sliding doors are designed to meet all operational and safety needs.

Telescopic sliding doors can be provided with in-built pass doors for pedestrian access.

For more information, please contact: Avians Innovations Technology Pvt Ltd Gat No: 60/61, Dehu-Moshi Road, Chikhali Pune, Maharashtra 412 114 Tel: 020-71400600 Fax: 91-020-71400654

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Mass Flow Controller Coriolis mass flow meters are highly appreciated for their accuracy and independence of fluid properties. The direct Coriolis mass flow measuring principle is generally used for higher flow rates. Moreover, mini CORLFLOW instruments have an integrated PID-controller and a batch counter to control the fluid flow.

Features direct flow measurement, independent of fluid properties; fast response time; high accuracy, excellent repeatability; additional density and temperature output; compact design (same footprint as CORI-FLOW M50 Series); excellent price/performance ratio.

For more information, please contact: Toshniwal Hyvac Pvt Ltd 267 Kilpauk Garden Road Chennai 600 010 Tel: 044-26448558, 26448983 Fax: 91-044-26441820 E-mail: sales@toshniwal.net

Future-oriented Packaging Concepts The desiccant specialist will, amongst others, offers its drop-in solutions for moisture-sensitive pharmaceuticals. The AdPack desiccant sachets made of Tyvek offer an ideal combination of moisture protection, breathability and durability.

The desiccant capsules AdCap combine the advantages of conventional desiccant capsules and canisters. They make sure that moisture or odours are optimally adsorbed right after filling. According to demands, they are available with silica gel, molecular sieves, activated carbon or combinations. Sanner offers the broadest portfolio of plastic tubes and closures for effervescent tablets worldwide.

For more information, please contact: Commha Consulting GmbH & Co KG PoststraĂ&#x;e 48 , 69115 Heidelberg Germany Tel: +49 (0) 6221 18779-27 E-mail: sanner@commhaconsulting.com

Glass-lined Steel Tanks GLS tanks are glass-lined steel tanks, also known as glass-fused-to-steel-tanks. The reason of fusing glass with steel is to enhance the properties of latter. Single steel is vulnerable to environmental conditions, hence the fusing is required. After fusing the steel with glass, the strength increases, the acceptable bracket of pH value for alkaline solutions widens and the resistance of abrasion inflates.

The tank panels are lined inside and outside with the glass enamel. The enamel is a solid, smooth and shiny cover of silicate. It is fused in a special furnace having a temperature range from 780 to 900 oC. The steel rounded (cylinder) shell of the tank is built from two layer glass fused sheet coated on both the sides. The sheets are attached with special high grade bolts and sealed by constantly flexible sealants.

The connecting material and shell accessories are equipped by the surface treatment. The glass fused tanks can be used to store fluid or loose material. The tanks are also a fundamental building element of environrnental technological facilities such as waste water treatment and biogas stations.

Rostfrei follows EEA (Europenan Enamel Authority) quality standards. The spark test for each panel is conducted according to EN 14430:2004. For Mohs Hardness and Chemical Resistance, Rostfrei follows EN 15771 and EN ISO 28706 respectively.

For more information, please contact: Ketav Consultant Plot No: 21, 25, 26, 27, 28, Block No: 518 Village Juna Babalpura Patia Dahegam-Modasa Road Tal: Dahegam, Dist: Gandhinagar Gujarat 382 305 E-mail: ketavconsultant@rediffmail.com

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Dryers Drying system is generally the last, but a very important section of the zero liquid discharge setput. In most cases, it succeeds the multiple-effect evaporator where it is employed for converting the liquid effluents/concentrates into dry powder or thick paste. In other cases, dryers are used for drying wet solids in crystalline/amorphous forms to dry powder/flakes/ moisture content. Selection of the dryer depends on the specific application and the duty conditions. Energy consumption per unit production is an important consideration. A dust collection system on the exhaust air from the dryer is a must for the protection of the environment. Liquids and slurries are dried using SST Dryer (Scraped Surface Dryer) or Spray Dryer. Solids from the crystalisers/ filters after the MEE are dried using a paddle dryer or continuous fluid bed dryer (static or vibratory type). In cases, where the condenser from effluent evaporation is to be totally avoided, a spray dryer is used.

For more information, please contact: SS Techno Ltd 502 Mayfair Towers 1 Wakdewadi, Shivajinagar Pune, Maharashtra 411 005 Tel: 020-66524431, 66524432 E-mail: marketing@sstechno.com

Blister Line Romaco’s new Noack NBL 400 blister line was specifically designed to meet the needs of the Asian pharma markets. With an output of 400 blisters and up to 300 cartons per minute, this durable line is ideal for medium batch sizes. An integrated solution comprised of a blister machine with rotary sealing and a continuous motion cartoner, it is very easy to use. Machine operators require no specialist technical know-how to work on the blister packaging line and carry out product and format changes. The robust Noack NBL 400 is also recommended as an entry level model for contract packers and pharma manufacturers seeking to expand their business. Nearly all format parts of the Noack 921 blister machine are also compatible with Romaco’s new Noack NBL 400 blister line. Here, too, the new blister technology convinces with outstanding versatility and excellent value for money. Regarding product feeding, the Noack NBL 400 allows very flexible configurations. Tablets and capsules with different specifications can be placed in the blister cavities either individually or using a brush-box feeder. The products can also be fed manually, which is mainly an advantage with sample packs or with very small or clinical batches. The NBL 400 from Romaco Noack is capable of processing any standard thermoformable laminate and can also be employed in the manufacture of aluminium-aluminium blisters. Romaco trusts in BlisterMagic, its innovative software solution, to design the cavity geometries and develop individual packaging layouts. This innovative tool provides a very quick and easy route to customise blister packaging. Users of the Noack NBL 400 blister packaging line also profit from Romaco’s expert support when it comes to packaging designs.

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 Comprehensive Quality by Design for Pharmaceutical Product Development and Manufacture Authors: Gintaras V. Reklaitis, Christine Seymour & Salvador García-Munoz (Editors) Price: $98.00 Pages: 416 Publisher: Wiley-AIChE The book provides a broad view of Quality by Design (QbD) and shows how QbD concepts and analysis facilitate the development and manufacture of high quality products. QbD is seen as a framework for building process understanding, for implementing robust and effective manufacturing processes and provides the underpinnings for a science-based regulation of the pharmaceutical industry. Edited by three renowned researchers in the field, Comprehensive Quality by Design for Pharmaceutical Product Development and Manufacture, guides pharmaceutical engineers and scientists involved in product and process development, as well as teachers, on how to utilize QbD practices and applications effectively while complying with government regulations. The material is divided into three main sections - the first six chapters address the role of key technologies, including process modeling, process analytical technology, automated process control and statistical methodology in supporting QbD and establishing the associated design space. The second section consisting of seven chapters present a range of thoroughly developed case studies in which the tools and methodologies discussed in the first section are used to support specific drug substance and drug-product QbD related developments. The last section discusses the needs for integrated tools and reviews the status of information technology tools available for systematic data and knowledge management to support QbD and related activities.

‘Comprehensive Quality by Design for Pharmaceutical Product Development and Manufacture’ is an ideal book for practitioners, researchers, and graduate students involved in the development, research, or studying of a new drug and its associated manufacturing process.

How to Overcome the Antibiotic Crisis: Facts, Challenges, Technologies and Future Perspectives Authors: Marc Stadler & Petra Dersch (Editors) Price: $161 Pages: 496 Publisher: Springer This volume focuses on antibiotics research, a field of topical significance for human health due to the worrying increase of nosocomial infections caused by multi-resistant bacteria. It covers several basic aspects, such as the evolution of antibiotic resistance and the influence of antibiotics on the gut microbiota, and addresses the search for novel pathogenicity blockers as well as historical aspects of antibiotics. Further topics include applied aspects, such as drug discovery based on biodiversity and genome mining, optimization of lead structures by medicinal chemistry, total synthesis and drug delivery technologies. Moreover, the development of vaccines as a valid alternative therapeutic approach is outlined, while the importance of epidemiological studies on important bacterial pathogens, the problems arising from the excessive use of antibiotics in animal breeding, and the development of innovative technologies for diagnosing the ‘bad bugs’ are discussed in detail. Accordingly, the book will appeal to researchers and clinicians alike.

The reality of pharmaceutical care-based medication therapy management: Patients’, pharmacists’ and students’ perspectives

Authors: Djenane Ramalho de Oliveira Price: $68 Pages: 400 Publisher: Lambert Academic Publishing This book is the result of the author’s immersion in the world of pharmaceutical care practice, Medication Therapy Management (MTM) services, for one year. As part of her PhD thesis, Djenane Oliveira conducted field observation, in-depth interviews, focus groups, and analysis of documents in order to understand the practice as it is in the real world. Patients, pharmacists and pharmacy students narrated their experiences as they received, delivered and learned about pharmaceutical care practice. The text is a realistic and a comprehensive account of the process of building a new professional practice in a convoluted health care system. It illuminates the skills and knowledge required to be a patient-centered practitioner and provides invaluable guidance on how to better prepare students for this role. This volume should be read by pharmacists, pharmacy students, pharmacy educators, managers and decision makers in the health care system as it unveils what patients value and want from their providers, and what they need with regards to their medications. This cutting-edge text is a must-read for individuals committed to meeting patients’ drug- related needs.

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January 2019 ► 71

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R.N.I. No.: MAHENG/2002/08502. Date of Publication: 26th of every month. Postal Registration No: MCS/207/2017-19 Posted at Patrika Channel Sorting Office, Mumbai 400001, on 27th of every month. Total Pages:- 74