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european INDUSTRIAL

PHARMACY FEATURES 4

FORMULATION AND DELIVERY OF CANNABINOIDS The poor solubility of cannabinoids led GW Pharmaceuticals to develop an oral spray delivery system. by Mark Rogerson

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PHARMACEUTICAL INDUSTRY’S PERSPECTIVE ON SWITCHES AND ITS RELATIONSHIP WITH THE PHARMACY/PHARMACIST Reclassifying a medicine is becoming more widely accepted but there are challenges of trust to consider. by Mafalda Martins

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SOCIAL MEDIA IN LIFE SCIENCES A powerful and ultimately essential marketing took to help small and large companies alike to build relationships with their customers. by Mary Canady

BACTERIAL BILE ACID MODIFICATION AND POTENTIAL PHARMACEUTICAL APPLICATIONS Manipulation of bacterial bile acid metabolism could lead to a number of opportunities in disease prevention and treatment. by Brian V Jones

NOVEL ZERO-SACCHARIDE ORALLY DISINTEGRATING TABLETS The saccharide mannitol is commonly used as an excipient in the formulation of orally disintegrating tablets. This study investigates some amino acids as possible non-saccharide alternatives. by Farhan AlHusban and Afzal R Mohammed REACHING THE TIPPING POINT: PHARMACEUTICALS OUT OF BALANCE This report by the international consultants, AT Kearney, argues that the traditional model of a global pharmaceutical industry will struggle to survive and will need to shift from being R&D-driven to market-driven. by Jonathan Anscombe and Michael Thomas

REGULARS 3

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EDITORIAL COMMENT

REGULATORY REVIEW

NEWS FROM THE EIPG

PHARMACEUTICAL FORUM DATES FOR YOUR DIARY

ISSUE 9 • JUNE 2011

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Associate Editors

european IND US TR I A L

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Belgium: Kristina Bindus, Bart de Greef Bulgaria: Valentina Belcheva

Issue 9 June 2011 ISSN 1759-202X

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EDITOR Joe Ridge, MRPharmS

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PRODUCTION Dave Johnson

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SUBSCRIPTIONS Jill Monk EDITORIAL BOARD Michael Anisfeld Michael Gamlen Linda Hakes John Jolley

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Cover photo: Cannabis sativa

e u rop ea n IN DU ST RI AL PHARMACY • Issue 9 June 2011


E D I TO R I A L C O M M E N T Dear Colleagues

I would like to welcome you all to the latest edition of the European Industrial Pharmacy Journal. The EIPG has had an extremely busy year which culminated in our General Assembly meeting held in Madrid. I would like to personally thank the Spanish Association, AEFI, and in particular Carmen Castanon and Emma Fernandez for coordinating such a great meeting.

under review in this latest offering as follows: 1. Formulation and delivery of cannabinoids 2. Switching from prescription to non- prescription medicines 3. Social media in life sciences 4. Pharmaceutical potential of bile acids 5. Reaching the tipping point: pharmaceuticals off-balance

I would also like to acknowledge the sterling support from the Bureau and from the rest of the Associations for making the EIPG the successful and influential body that it is. Of particular note is that our great friend and supporter Kiriasis Savvas has decided to stand down as the EIPG representative for Greece, a role which he has conducted so effectively for over 10 years. I and many of our members will miss you my friend and we wish you the very best for the future!

6. Novel orally disintegrating tablets

I also need to acknowledge the great work of the publishers Euromed and in particular Joe Ridge for producing such a high quality journal. I know of no other journal which covers such a diverse range of pharmacy subject matters ranging from drug delivery challenges to the latest changes in the regulation of drug products. Consider the articles

I would recommend reading the thought provoking commentary by Jonathan Anscombe and Michael Thomas which was based on the AT Kearney White paper on ‘Pharmaceuticals out of balance’ and which summarises the Three Tipping Points affecting the current Pharmaceutical and Healthcare business models.

No wonder the feedback that I receive is so positive for this Journal with many Industrial pharmacists finding the subject matter of great utility including the regular items of Regulatory Review and Pharmaceutical Forum. I know that the readership is broad and includes some pharmacists working in community and hospital who find the Journal a useful reference tool.

Due to the positive feedback, the EIPG and Euromed have decided to increase the Journal frequency from three to four times a year and at the same time to expand the circulation to all pharmaceutical practitioners working in industry. The Journal is also available as a download on our website www.eipg.eu and I would encourage you to direct your colleagues to the website if they do not receive the Journal direct. As always, we welcome ideas and suggestions for the Journal and please feel free to send your suggestions and feedback either to myself as President of the EIPG at Luigi.G.Martini@gsk.com or to the Executive Director Mrs Jane Nicholson at jane@nicholj.plus.com. Please enjoy this edition of the European Industrial Pharmacy Journal in the knowledge that more fascinating editions are to come!

Best wishes

Dr Gino Martini FRPharms EIPG President

gmp-review news free news service for gmp revıew subscribers Monthly news service will keep you up-to-date on new developments in GMP and associated regulations. gmp-review news will be sent by email only to current gmp revıew subscribers. Subscribers should contact subs@euromedcommunications.com to register e u ro pe an IN D US TR IA L PHARMACY • Issue 9 June 2011

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FORMULATION AND DELIVERY OF CANNABINOIDS by Mark Rogerson

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ankind has used cannabis for many years, but the potential for the use of cannabinoids as prescription medicines is often obscured by the use of cannabis as a recreational drug. In recent years the historical uses of cannabis have been re-examined. Preparations of cannabis have been administered by most of the routes commonly employed in the pharmaceutical industry. Pulmonary administration is the fastest way of producing pharmacological effects for THC, the principal psychoactive component of cannabis, and is virtually equivalent to intravenous administration. Smoking as a route of administration of a prescription medicine cannot be justified on ethical, medico-legal or safety grounds. The problem faced by a pharmaceutical company developing a cannabisbased medicine, is how to get enough of the therapeutic components of cannabis to the site of action without using smoking as a delivery device. While the pulmonary surface looks like an attractive target for the delivery of a medicine, in fact it is not well-suited to the delivery of cannabinoids. Firstly, the respiratory mucosa is very sensitive, to the extent that very few medicines have ever been approved for use via the pulmonary route, except for the treatment of pulmonary disease. The burden of demonstrating the safety of pulmonary medicines is very substantial and presents a significant challenge to the drug developer.

MARK ROGERSON is Press and PR Executive for GW Pharmaceuticals plc Porton Down Science Park, Salisbury, Wiltshire SP4 0JQ, UK email: mvlrog@aol.com www.gwpharm.com

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With particular regard to psychoactive medicines, there is the additional problem of abuse liability. Uptake of drug from the lungs is fast, with the result that the drug reaches the target quickly, thus maximising psychoactivity and abuse liability. When developing a medicine with central nervous system effects for chronic use, the lungs are not an appropriate site for delivery. Delivery sites for cannabinoids

Synthetic Ä9-tetrahydrocannabinol (THC) has been available as a prescription

medicine in the USA for more than two decades. Dronabinol (Marinol®) is available as soft gelatin capsules, which are taken orally. Once in the stomach the gelatin dissolves, releasing the drug. The dronabinol is formulated in sesame oil, forming an emulsion, which is then absorbed during passage through the gut. One of the disadvantages of dronabinol is that much of the active drug is metabolised during passage from the gut via the liver, with the consequence that only 10–20% of the administered dose reaches the general circulation1. Effects of the drug begin 30–60 minutes or longer after administration, and there is a high degree of between-subject variability. Another disadvantage of dronabinol is that considerable quantities of the psychoactive metabolite, 11-hydroxy-THC, are produced in the liver from metabolism of THC. Dronabinol has been approved for two medical indications; nausea and vomiting associated with cancer chemotherapy and as an appetite stimulant to treat HIV-AIDS wasting syndrome. Prior to the recent approval of Sativex® in Canada, Spain and the UK, dronabinol and the synthetic THC analogue, nabilone, are the only approved cannabinoids medicines available. There are several other areas that can be targeted for administration of a cannabisbased medicine. It is desirable to avoid the first pass effect due to hepatic metabolism of cannabinoids. The logical sites for drug delivery that may do this are the oropharyngeal,or sublingual/buccal mucosae, the respiratory tract and the distal rectum. Mucosae at these sites all have venous drainage directly into the vena cava and the right side of the heart. Cannabinoids absorbed at these sites are therefore not exposed to the liver during their first pass into the systemic circulation. Figure 1 shows that the concentration of THC absorbed by the oral route is an order of magnitude lower than that absorbed by either the smoked or intravenous route 2. The first problem encountered in the formulation of a cannabis-based medicine lies in the insolubility of cannabinoids in aqueous systems. For this reason the product developed by GW Pharmaceuticals concentrated on drug delivery to the oromucosal membranes. The oromucosal application of medication involved the development of an

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FORMULATION AND DELIVERY OF C ANNABINOIDS (Co nt.) oromucosal spray, whereby the material is dissolved in a solvent vehicle and applied directly to the mucosae as measured, discrete and cumulative fractions of the total daily dose.

Cannabis sativa

In the development of Sativex, GW Pharmaceuticals opted for the sublingual/buccal mucosa as the most appropriate way to deliver the medicine. Formulation of an oromucosal spray device

GW Pharmaceuticals have developed Sativex using a botanical source of cannabis rather than synthetic THC. Specific Cannabis plant varieties that express a high and uniform proportion of their cannabinoids as either THC or cannabidiol (CBD) are used to prepare a standardised cannabis extract. Milled, harvested cannabis is extracted using CO2 as the solvent; the resulting extract is then chilled in an alcoholic solution to remove waxy ballast from the extract (a process referred to as winterisation) to produce a partially purified liquid extract that can then be used to formulate the finished product which contains more or less equal quantities of THC and the nonpsychoactive cannabinoid, cannabidiol (CBD).

insufficient to give the required dose in a convenient volume, and there are good environmental and regulatory reasons to avoid propellants if possible. Consequently, a manually operated pump-action spray was chosen to deliver the product in metered doses. This allows patients to titrate gradually, up to a total daily dose that provides the optimum balance between effectiveness and tolerability. The total daily dose required varies between patients but remains very consistent for individual patients over time.

Although cannabis extract is soluble in a norfluorane/ethanol/propylene glycol vehicle, its solubility is

The pump-action spray device produces a lower velocity spray than powered devices and there is

Figure 1: Comparison of plasma concentration of THC from delivery by IV, smoked and oral routes (Adapted from Reference 2)

e u ro pe an IN D US TR IA L PHARMACY • Issue 9 June 2011

therefore less possibility of ‘bounceback’ of material. The pump-action spray is also preferred to other pressurised spray systems for the delivery of cannabinoids as it delivers a larger droplet size thus eliminating the possibility of inhalation into the lungs. For example, the mean aerodynamic particle size delivered by a pressurised system is generally between 5 and 10 microns while the particles delivered from a pumpaction spray are between 20 and 40 microns3. The oromucosal application of cannabinoids requires the transfer of the material from a hydrophilic vehicle to the cell membrane of the

Figure 2: Comparison of THC plasma concentration after delivery of THC to the sublingual or buccal mucosae by various delivery methods (data normalised to administration of 10mg THC)

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FORMULATION AND DELIVERY OF C ANNABINOIDS (Co nt.)

Cannabis plants being grown for pharmaceutical use.

sublingual or buccal mucosae. In consequence this results in slower absorption of the drug than via the respiratory route, although it has been shown that delivery by this route is fast enough for the patient to receive benefit, and slow enough to avoid undesirable CNS effects. During the development of Sativex, various delivery methods were tested for their appropriateness in the transfer of cannabinoids to the oromucosal membranes. Figure 2 shows the plasma concentrations of THC after application to the sublingual/buccal mucosae by three routes, a pump-action spray device, sublingual tablets and buccal tablets. The optimum dosage form chosen was the pump-action spray, whereby 100 microlitres of product is delivered at a time, containing 2.7mg THC and 2.5mg CBD, together with a number of other plant components. Cannabinoids could also be delivered to the systemic system and avoid the first pass effect via the distal rectum. Thus, enemas and suppositories may be useful in therapeutic areas that certain cannabinoids are able to treat4. However, for chronic administration of a medicine, the

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rectal route is not generally considered suitable. Similarly, the nasal mucosa could theoretically be used. The sensitivity of the nasal mucosa means that very few medicines for chronic use are administered by this route, and the nature of the solvent system used in the formulation of Sativex, with 50% ethanol and 50% propylene glycol, means that nasal delivery would be irritating to the patient. Future considerations

Although professional attitudes to the medical use of cannabis can be polarised, it was once a prescription medication of some repute. Historically, cannabis has been used to treat ailments as diverse as epilepsy, migraine, rheumatoid arthritis and dysmenorrhoea5. The use of cannabis as a prescription medicine continued until the middle of the twentieth century when social abuse caused the drug to be prohibited by legislation. But the role of cannabis as a prescription medicine is now being revisited. Cannabis-based medicines are being investigated for the treatment of various symptoms of

multiple sclerosis including spasticity, pain, lower urinary tract symptoms and sleep disturbance, rheumatoid arthritis, migraine, cancer pain and other neurological pains. Initial indications are that they are effective in patients not well served by available types of medications. These studies, predominantly involving the medicine Sativex, have resulted in the marketing authorisation of Sativex as a prescription medicine in the UK, Spain and Canada. The development of Sativex serves as a welcome reminder of the potential value of exploring the therapeutic properties of plants, using an approach that meets the aspirations of patients, of doctors and of regulatory authorities. REFERENCES 1. Iverson L L. The Science of Marijuana. 2000; Oxford: Oxford University Press. 2. Ohlsson A, Lindgren J-E, Wahlen A et al. Plasma delta-9-tetrahydrocannabinol concentrations and clinical effects after oral and intravenous administration and smoking. 1980; Clin Pharmacol Ther 28: 409–416. 3. UK Patent Application No. 0218930.6. 4. UK Patent Application No. 0126150.2. 5. Merck’s Manual. 1899; New York: Merck Publishers. Part 1, 26–27.

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PHARMACEUTICAL INDUSTRY’S PERSPECTIVE ON SWITCHES AND ITS RELATIONSHIP WITH THE PHARMACY/ PHARMACIST by Mafalda Martins

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switch is the regulatory process that converts a prescription medicine to a non-prescription status. The objective is to increase patient and consumer access to safe and effective medicines for minor self-treatable conditions, with or without the intervention of a healthcare professional1. Candidates for switch status come from the prescription territory. New drugs have a patent lifetime protection that when expired, allows them to become potential non-prescription medicines, but only if they are used for a condition that has easily recognized symptoms and have a high margin safety under conditions of wide availability. Regulatory authorities must evaluate the benefits of easier access against the potential harm from unsupervised or inappropriate use. In case of switch products the safety profile has been established through years of experience and use as a prescription medicine1. So, switches are usually driven by patent lifetime and some examples are: ♦ Non steroidal anti-inflamatory drugs

(NAIDs) such as ibuprofen ♦ H2 antagonists such as cimetidine and

ranitidine ♦ Antihistamines such as acrivastine,

cetirizine and loratadine ♦ Proton pump inhibitors such as

omeprazole MAFALDA MARTINS is Technical Manager at GlaxoSmithKline Consumer Healthcare, Alges, Portugal. Email: mafalda.d.martins@gsk.com

But switches can also be influenced by cost containment motives (dereimbursement) such as magnesium and calcium supplements, statins, some decongestants and cough medicine, etc.

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Factors influencing demand

On the other hand, patients and consumers, with an improved general knowledge and level of education, also demand switches for prescription medicines. Some factors influencing this demand are convenience (antacids, antihistaminies, antifungals), urgency (headache/migraine, cough & cold and emergency contraception), embarrassment (overactive bladder, alopecia, chlamydial infection, erectile dysfunction, emergency contraception, overweight) and efficacy (smoking cessation, weight management and behaviour management). In these cases, when patients are denied access to non-prescription medicines, they become silent sufferers. An example is described in a research project report by the Association of the European Self-Medication Industry (AESGP) about overactive bladder/urge incontinence sufferers2. This report concludes that patients with such conditions suffer in silence because they feel embarrassed even to inform their doctors. In fact, about 23% have never discussed the condition with their doctor and 31% of women with urge incontinence have not discussed their condition with anybody. Quality of life is negatively impacted by this condition and it is worrying that only a very small percentage of sufferers are diagnosed and treated with drugs (Figure 1). Overactive bladder is a good switch candidate from prescription to selfmedication because it can be selfdiagnosed and drugs commonly used for the treatment, such as oxybutynin and tolterodine, have shown adequate efficacy and safety profile for non-prescription use. Effect on healthcare systems

The World Health Organization (WHO), in their guideline on non-prescription medicines3 says that the reclassification of medicinal products from prescription to non-prescription is of great current interest in many countries and it has become widely accepted that selfmedication has an important place in the healthcare system. Years of safe experience in many countries and increased patient and

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PHARMACEUTICAL INDUSTRY’S PERSPECTIVE ON SWITCHES (Cont.) obtain time-critical products such as emergency hormonal contraception which needs to be taken early to be most effective1,4. Self-medication reduces resources on consultations and prescriptions for minor ailments that can be redirected to more pressing areas. Chronic diseases (cardiovascular diseases, cancer, chronic respiratory diseases and diabetes) are emerging as primary sources of disease burden in both developed and developing countries. The importance of these diseases is that they are preventable through appropriate self-care behaviours although current health systems are not generally prepared for disease prevention and self-care improvement. Figure 1. Silent suffers with overactive bladder.

consumer interest and knowledge about self-medication is a solid basis for switching prescription medicines to non prescription status, including self-treatment for longer term use in chronic conditions such as heart disease, stroke and diabetes1. Self-medication enables comprehensive patient and consumer interventions by using safe and effective medicines, which can help give people a sense of control over their individual health situation. It also drives patients to make lifestyle changes. Responsible self-medication gives people more choice and responsibility, but it is also necessary to ensure that they have the correct necessary information, usually provided through the packs and leaflets on non-prescription medicines. Information on the outer packaging allows consumers to easily make a choice about the appropriateness of the medicine for their needs at the point of sale. Additional information for consumers can be provided by booklets and website links. Advertising has an important role in

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communicating to the patient and consumer the existence of a condition and the appropriate treatment. Impact on public health

In future, prescription to nonprescription switches can help governments relieve pressures on healthcare systems, as patients and consumers can treat more of their everyday health conditions without the costs associated with the formal system. Switches can enable doctors to spend their time and attention on more important illnesses. Also, pharmacists can use their knowledge to recommend appropriate self-care actions and responsible use of non-prescription medicines, increasing pharmacy contribution to a better healthcare system. People can visit a pharmacy rather than wait for a doctor appointment. They can treat themselves for common conditions that have easily recognisable symptoms, such as cold sores and hay fever, reducing the time from the onset of symptoms to the treatment. They can more easily

Globally, of the 58 million deaths in 2005, approximately 35 million (60%) were the result of chronic diseases. In fact, common, modifiable risk factors underlie the major chronic diseases. These factors include tobacco use, obesity and high cholesterol levels. Switching some medicines to non-prescription status contributes to the control of these risk factors by empowering people to look after themselves through better self-care behaviours1. Switching prescription medicines to non-prescription status is also an opportunity to improve public health. Some conditions are important for switching, including appropriate regulatory and political support to harmonise the classification system for medicinal products and make switching procedures transparent. Although the industry is using EU procedures, such as Mutual Recognition and Decentralisation in Europe, most switches still use national procedures5. Switching under the European Medicines Agency’s (EMA) Centralized regulatory procedure was recently introduced in Europe. This was a new step to help switches and

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PHARMACEUTICAL INDUSTRY’S PERSPECTIVE ON SWITCHES (Cont.) thereby facilitate market access to non-prescription medicines through a pan-European license which allows a company to market in 27 countries. However, this procedure is limited to products originally approved through the centralised procedure. The experience of EMA’s Committee for Medicinal Products for Human Use (CHMP) with non-prescription medicines has so far been limited to only three products and more experience at the central level is needed for non-automatic switches, i.e. switches of products not originally approved through the centralised procedure5. First experiences

The first switch licensed under EMA’s centralized procedure was alli, indicated for weight loss in adults who are overweight with a BMI ≥286. Considering that obesity is a problem of epidemic proportions7 and that important health risks are related to obesity such as type 2 diabetes, hypertension, coronary heart disease and cholelithiasis (Figure 2), alli had the potential to contribute to the promotion of selfcare and the improvement of public health.

Figure 2. Relation between Body-Mass Index up to 30 and the Relative Risk of Type 2 Diabetes, Hypertension, Coronary Heart Disease, and Cholelithiasis.

interested consumers into wellprepared pharmacies”. Strategy imperatives included press releases (press launches; KOL engaged; 1,750 articles), internet (24 websites; >500k visits to EU sites; >1m page views on UK website), advertising (TV and print advertising; a consistent media strategy), visibility (85% distribution; available in pharmacies; consistent campaign) and endorsement (pharmacy training; “ambassador” pharmacies).

The alli switch was approved by the European Commission in 2009. alli was the first weight loss medicine approved without prescription, filling the gap in products available for weight loss treatment. As a nonprescription medicine, alli offered consumers the opportunity to have a weight loss product with the same access as medical devices or dietary supplements, and also the same clinical efficacy as prescription medicines, such as Xenical and Reductil.

♦ Trust patients and consumers to

The role of the pharmacist was important in alli’s centralised switch and the concept of “Pharmacist intervention” was introduced.

responsibly, accepting that direct communication with consumers is a key for responsible promotion.

alli’s marketing strategy was based also on the principle of “driving

Considering many of switch’s challenges, the challenge of trust is one of the most important: choose and use non-prescription medicines appropriately, provided they have all the information they need and if such information is simple, understandable and correct. ♦ Trust companies to promote

♦ Trust pharmacists to be first-line

healthcare professionals for less

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serious conditions, but ensure that relevant training is provided. ♦ Trust regulators to be open to

healthcare provision without prescription, but accept that safety concerns need to be addressed. All stakeholders must work in partnership to ensure optimum benefits from switching prescription medicines to non-prescription status. References 1. WSMT 2009. Switch – Prescription to nonprescription medicines switch 2. AESGP. Final report research project “Development of an information policy for medicinal products”, January 2002. Annex 2 – Overactive bladder – Urge incontinence case. 3. WHO. Guidelines for the Regulatory Assessment of Medicinal Products for use in Self-Medication. 4. AESGP. Study on the Economic and Public Health value of Self-Medication, January 2004. 5. AESGP Conference – Making the European Self-Care Industry More Competitive, London 19-20 January 2010 6. alli Summary of Product Characteristics. GlaxoSmithKline Consumer Healthcare. 7. European Conference on Counteracting Obesity: WHO; Istambul, 15-17 November 2006.

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SOCIAL MEDIA IN LIFE SCIENCES by Mary Canady

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n November 2009, the FDA held hearings to discuss how companies involved with regulated products should use social media. The meetings were effective in getting the dialogue started, but it became clear that social media communication guidelines would not be made available from some time. This outcome has led many to mistakenly believe that social media are stalled from the entire industry when in fact, many opportunities exist for companies in both nonregulated and regulated industries. What are social media?

Since the Internet’s inception, websites have continually evolved, becoming dynamic, interactive applications that allow users to exchange information with anyone in the world – be it friends, colleagues, or even companies. Unless you have been living in a cave over the last few years, you have likely heard about Facebook, LinkedIn, Twitter, and other applications. When used correctly, companies can leverage social media to build relationships for marketing, business development and corporate/investor relations. How is this relevant for biotech and life science?

At the core of our industry lies a wealth of information that must be shared and utilized to better understand the science behind our business and to use it to make greater progress. I encourage you to think beyond the specific applications and how to embrace a new way of thinking about how we communicate and gather information. There are so many ways our industry can benefit from using new media now.

Mary Canady, PhD is founder and president at Comprendia Consulting Group. Email: mcanady@comprendia.com Web: www.comprendia.com Twitter: twitter.com/comprendia

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Life science companies that sell non-FDA regulated products have no government imposed restrictions for utilizing social media. I have talked to many life science companies that are beginning to see the value of using tools such as blogs, twitter and Facebook to reach out to customers. While many of them are just getting started, my conversations with those who are implementing campaigns show that

they are impressed with the results they have seen so far. The benefits for life science companies in employing social media are clear – they strengthen their brand by developing stronger relations with their customers and gaining more feedback from them, as more lines of dialogue are opened. The rules of the new media mean less broadcasting (eg. traditional advertisements) and more engagement. Perhaps I am biased, as I am a strong proponent of social media, but I feel as though life science companies that don’t engage in social media run the risk of spending more marketing dollars for less effect, and at the same time becoming more out of touch with customer needs. Small companies. The great news with the social media is that smaller companies can do more. Previously, only companies with large advertising budgets could get exposure through print ads in life science publications. Today, a small company with a great product can build an engaging content-rich website and be found by search engines, sparking a lot of interest in so-called “inbound marketing” where emphasis is placed on leading visitors to a company’s website. They can thus extend their reach with a small budget. Social media tools allow creative small companies to carve a niche and to leverage the web and applications such as LinkedIn to grow their business. Small companies can also leverage thirdparty social media applications outside their websites. LinkedIn is a great tool for small companies, as individuals can develop a large personal network or create groups based on their company’s offering.

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S O C I A L M E D I A I N L I F E S C I E N C E S ( Co n t . ) When used correctly, LinkedIn can be a great source to generate leads. The information stored in LinkedIn, from user and company information to the way it connects professionals, has enormous potential to enable small companies and the industry to grow. Social media monitoring. Web content about life science, biotechnology and pharmaceutical companies is becoming more usergenerated because scientists and consumers can now easily share and discuss news and opinions openly. All companies, regardless of whether they are regulated, can benefit from monitoring the sentiment about their company and products. From free tools such as Google Alerts, to myriad specialized tools, companies can gain useful feedback from

Many websites are now dynamic, interactive applications that allow users to exchange information with anyone in the world, be it friends, colleagues, or even companies

customers that they can respond to or use for product development. Of course, larger brands such as pharmaceutical companies will find much more information as their customer base is significantly broader. I’m sure that many marketing professionals in pharma

companies are closely tracking social media sentiment about their products and brands, even though they might not yet have the regulatory guidance to take external actions. In summary, there are many ways in which social media are relevant to our industry now, and all evidence points to it gaining traction. I see it as a natural progression from the ways scientific companies have communicated with customers for decades. How different is a blog from a useful newsletter, or answering questions on Twitter from customer service calls? The biggest barriers I see are in companies that view social media as being strange, new and risky, rather than embracing them as a powerful and essential tool.

the key to gmp

gmp revıew gmp revıew is the first newsletter dedicated to the analysis of international pharmaceutical regulations and providing informed comment on good manufacturing practice. Researched and edited by an expert team, gmp revıew will provide you with a clear, practical guide to the often complex and jargon-ridden regulations that are continually being produced. See our website for details or call +44 (0)1428 752222

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BACTERIAL BILE ACID MODIFICATION AND POTENTIAL PHARMACEUTICAL APPLICATIONS by Brian V Jones Introduction

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odification of bile acids by gut bacteria has the potential to influence host physiology and risk of metabolic disease through effects on bile acid signalling, and may be involved in the pathogenesis of colorectal cancer via a range of mechanisms. We have recently examined the distribution, abundance, and function of bile salt hydrolase (BSH) activity (a key microbial enzyme involved in bacterial bile acid modification) in the human gut microbial ecosystem, and found this to be a specific function, which may be of pharmaceutical interest1. This article summarises current knowledge regarding the potential for microbial bile acid metabolism to influence human health and highlights possibilities for pharmaceutical intervention. Bile acids and their functions

DR BRIAN V JONES is Senior Lecturer in Microbiology at the Centre for Biomedical and Health Science Research, School of Pharmacy and Biomolecular Sciences at the University of Brighton, UK. Email: b.v.jones@brighton.ac.uk

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Bile acids (BA) are cholesterol derivatives synthesised in the liver and linked by amide bonds with either glycine or taurine to form conjugated bile acids (CBA). The formation of bile acids is the primary pathway for cholesterol elimination in humans and it is estimated the liver converts ~500 mg of cholesterol per day into BA2. The major bile acids in humans are cholic acid and chenodeoxycholic acid, which are conjugated to glycine or taurine. CBA constitute a major component of bile and facilitate the emulsification and absorption of dietary lipids from the small intestine through the formation of mixed micelles (for comprehensive reviews see references 2,3,4). BA are also efficiently reclaimed from the ileum through a combination of active transport and passive diffusion, and returned to the liver via the portal vein where they are reconstituted into the bile

acid pool and reused. This process is referred to as the enterohepatic circulation, and serves to reclaim and recycle BA in a highly efficient process2,3. However, around 400–800 mg of CBA per day still reach the colon and are largely lost in faeces, while a portion of reclaimed bile acids entering the portal vein are not sequestered by the liver on the first pass and instead enter the systemic circulation2,3. Bile acids lost through excretion in faeces are subsequently replaced though de novo synthesis of new BA in the liver, maintaining the overall size of the available BA pool. The physiological functions of BA are diverse and not limited to lipid absorption. As well as having an important digestive function, BA have also recently been highlighted as key signalling molecules involved in the regulation of various aspects of host physiology including triglyceride, cholesterol, and glucose homeostasis in addition to regulation of their own synthesis2,5. Bile acid signalling is thought to be controlled by the activation of two dedicated bile acid receptors, designated FXRα and TGR5, by various forms of bile acids (Figure 12,5). Because different types of bile acids have been found to activate these receptors to varying degrees, these insights have also illuminated the potential for perturbations in BA signalling to play a role in a range of metabolic diseases including obesity, diabetes (Type 2), and atherosclerosis. In addition to their digestive and signalling roles, CBA are also thought to be integral to the repression of bacterial growth in the small intestine through two distinct but overlapping mechanisms (Figure 15,6). In contrast to the distal colon, the microbial population in the small intestine is relatively low, and uncontrolled growth of micro-organisms in this section of the gastro-intestinal tract (GIT) can be damaging to health. CBA are thought to prevent overgrowth of bacteria in the small intestine, either through the direct antibacterial effects of CBA, the enhancement of mucosal defences, or the joint action of both mechanisms3,5,6. Due to the involvement of BA in a range of important physiological and

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BACTERIAL BILE ACID MODIFICATION (CONT. ) bile acid receptors, with microbial BA derivatives constituting some of the most potent agonists for receptors such as TGR52. Therefore, BSH activity and subsequent BA modification in this community could impact significantly on host physiology through disturbances of BA controlled endocrine functions and influence the risk of metabolic diseases1,2.

FXR α TGR5

Figure 1. Overview of physiological function associated with bile acids. Black arrows indicate functions directly associated with physical properties of bile acids, once secreted into the lumen of the intestine. Blue arrows indicate aspects of host physiology influenced or controlled by bile acid signalling pathways via the dedicated bile acid receptors FXRa and TGR5. For comprehensive reviews of functions of bile acids and bile acid signalling see references 2 and 5.

homeostatic processes, BA signalling pathways or other functions of BA have become attractive targets for pharmaceutical intervention in a range of human diseases. For excellent reviews of bile acid signalling and other functions see references 2 and 5. Bacterial bile acid modification and human metabolic disease

the de-conjugation of CBA to liberate free primary BA (deconjugated cholic acid or chenodeoxycholic acid) and amino acids3,4. Free primary BA are subsequently open to a wider pathway of BA modification encoded by the gut microbiota, which generates secondary and tertiary forms of BA through dehydroxylation, dehydrogenation and sulphation3,4.

The human gut harbours a complex and diverse microbial ecosystem collectively referred to as the gut microbiota, and members of this community are responsible for the transformation of endogenous bile acids to alternate forms. The initial “gateway” reaction in the bacterial metabolism of CBA is mediated by bile salt hydrolase, which catalyses

Free primary and secondary BA have been directly implicated in the pathogenesis of a range of human diseases8-13, and recent studies indicate that the mammalian gut microbiota can modulate host bile acid synthesis, which may influence host lipid metabolism14. Modified BA have also been shown to display altered binding characteristics for

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Bacterial bile acid modification and colorectal cancer

There is also much evidence implicating the products of microbial bile acid metabolism with the initiation and progression of colorectal cancer (CRC) through several mechanisms9-13. These include the carcinogenicity of free primary or secondary BA, the induction of pro-inflammatory, antiapoptotic pathways which facilitate the survival of malignant cells, and effects on cell proliferation and cancer cell invasion which may enhance disease progression. In contrast, some studies indicate a potential protective function against CRC for certain products of microbial bile acid modification, and BSH activity in particular has the potential to be either protective against this disease or involved in its pathogenesis. For comprehensive reviews of the role of bile acids in colorectal cancer see references 8 and 12. Overall, there is increasing evidence that the indigenous gut microbial population is a significant factor in the pathogenesis of CRC, and that this community mediates the effects of diet on colonic health11, 12. Increased fat intake has been consistently linked with CRC and leads to elevated levels of BA secretion. The influence of bile acids and microbial derivatives on expression of pro-inflammatory and anti-apoptotic pathways, coupled with the reported carcinogenicity of modified bile acids, highlights

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BACTERIAL BILE ACID MODIFICATION (CONT. ) microbial BA modification as a key function by which the human gut microbiota may integrate known risk factors, such as diet and inflammation, to direct CRC pathogenesis. Pharmaceutical potential

A greater understanding of microbial bile acid modification by the human gut microbiota, and the impact of this activity on the human host promises to uncover a range of pharmaceutical opportunities, and facilitate the development of strategies to manipulate or exploit the gut microbiota to enhance human health. For example, the potential for inter-individual variation in capacity for bile acid modification may have diagnostic value and facilitate the identification of individuals at greatest risk of acquiring diseases such as CRC1. Alternatively, the manipulation or inhibition of various stages of bacterial bile acid metabolism may lead to novel approaches to disease prophylaxis, or strategies to modulate aspects of BA signalling to improve features of host metabolism such as energy balance and regulation of fat storage. Paradoxically, there is also potential for aspects of microbial BA metabolism to be protective against CRC as well as important in its pathogenesis. BSH in particular has

the potential to be protective in this regard and, if so, enhancing this activity of the gut microbiota may be a viable strategy for pharmaceutical intervention. Understanding the mechanisms by which bacteria colonising the human gut overcome the toxic effects of bile and bile acids will also facilitate the rational design of better, more effective probiotics. Probiotics may also constitute a means to manipulate BA modification in this community. Since synthesis of new bile acids utilises cholesterol, there is significant scope for the development of novel cholesterol lowering probiotics which function though modulation of microbial bile acid metabolism in the gut microbiota, leading to increased synthesis of new bile acids. In contrast, the potential role of microbial BA modification in diseases such as CRC may make this an undesirable trait in probiotics, and in this context it is notable that many commercially available probiotic species exhibit BSH activity. Clearly, much fundamental information regarding the role of microbial BA metabolism in human health and disease is currently lacking, and significant study is still required before the pharmaceutical potential of this microbial activity may be realised. In particular, the

contribution of microbial BA transformations to the pathogenesis of diseases such as CRC should be clarified. A greater understanding of this promises to provide much insight into mechanisms of disease, and identify new targets and strategies for prophylaxis and diagnosis.

References 1. Jones BV, Begley M, Hill C, et al. Proceedings of the National Academy of Sciences USA, 2008; 105: 13580–13585. 2. Thomas C, Pellicciari R, Pruzanski M, et al. Nature Reviews Drug Discovery, 2008; 7: 678–693. 3. Ridlon JM, Kang D-J, Hylemon PB. Journal of Lipid Research, 2006; 47: 241–259. 4. Begley M, Gahan CGM, Hill C. FEMS Microbiology Reviews, 2004; 29: 625–691. 5. Hylemon PB, Zhou H, Pandak WM, et al. Journal of Lipid Research 2009; 50: 1509–1520. 6. Inagaki T, Moschetta A, Lee Y-K, et al. Proceedings of the National Academy of Sciences USA, 2006; 103: 3920–3925. 7. Hoffman AF and Eckmann L. Proceedings of the National Academy of Sciences USA, 2006; 103: 4333–4334. 8. Berr F, Kullak-Ublick GA, Paumgartner G, Münzing W, Hylemon PB. Gastroenterology 1996; 111: 1611–1620. 9. Bernstein H, Bernstein C, Payne CM, Dvorakova K, Garewal H. Mutation Research 2005; 589: 47–65. 10. Hill MJ. Mutation Research, 1990; 238: 313–320. 11. O’Keefe SJD. Current Opinion in Gastroenterology, 2008; 24: 51–58. 12. Huycke MM and Gaskins RH. Experimental Biology and Medicine, 2004; 229: 586–597. 13. Debruyne PR, Bruyneel EA, Li X, et al. Mutation Research, 2001; 480–81: 359–369. 14. Martin F-P, Dumas M-E, Wang Y, et al. Molecular Systems. Biology 2007; 3: 112.

gmp-review news free news service for gmp revıew subscribers Monthly news service will keep you up-to-date on new developments in GMP and associated regulations. gmp-review news will be sent by email only to current gmp revıew subscribers. Subscribers who wish to register should contact subs@euromedcommunications.com

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NOVEL ZEROSACCHARIDE ORALLY DISINTEGRATING TABLETS by Farhan AlHusban and Afzal R Mohammed

F

ormulations of orally disintegrating tablets (ODTs) were originally developed to address swallowing difficulties of conventional solid oral dosage forms (tablets and capsules) experienced by wide range of patients, especially children and the elderly. However, due to their convenience of administration (they do not require water), ease of swallowing and fast onset of action, ODTs have become appreciated and even preferred by other patient groups1. Moreover, for pharmaceutical companies, the development and formulation of drugs into ODTs allows extension of their patent life and ensures market exclusivity. In 2004, ODTs were the main driver for a significant growth in the market for oral drug delivery products which resulted in a turnover of $35 billion2. Currently, three main approaches are used to prepare ODTs, namely, direct compression, moulding and lyophilisation. ODTs prepared by lyophilisation have been considered the most successful in terms of sales value, sales volume and number of products available on the market3.

Farhan AlHusban PhD, is a researcher at the Medicines Research Unit, Aston Pharmacy School, Aston University, Birmingham, UK Afzal-Ur-Rahman Mohammed PhD, is a Lecturer in Pharmaceutics at the Aston Pharmacy School, Aston University, Birmingham, UK Tel: 0121 204 4183 email: a.u.r.mohammed@aston.ac.uk

Regardless of the preparation method, all ODT formulations in the market contain a high concentration of saccharides, with mannitol being one of the most commonly used. Extensive use of saccharides and polyols limits their application in delivering drugs for the treatment of long term chronic conditions and also for multiple dose medications, primarily due to limitations on daily intake of saccharides, especially for children, diabetic and obese patients. Therefore, replacement of saccharide in the lyophilised ODT formulation requires an excipient that fulfills stringent characteristics such as reasonable drying time, good stability during and after freeze-drying process as well as the formation of elegant tablets with short disintegration time, adequate mechanical

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properties and suitability for a wide patient population. Naturally occurring amino acids are prospective candidates because of their versatility in terms of physicochemical properties, high safety profile and availability. In the current study, the fundamental physicochemical properties of mannitol that contribute to its superiority in the lyophilised ODT formulation were investigated and compared with four naturally occurring amino acids, alanine, glycine, threonine and proline, to assess their potential as matrix-forming agents within the formulation. Thermal profiling

Thermal analysis of the frozen formulations is crucial in the development of lyophilised ODTs to optimise the freeze-drying process and to ensure the formation of intact tablets, as it determines the maximally tolerable product temperature during primary drying, known as thecollapse temperature. Differential scanning calorimetry (DSC) scans of formulations consisting of 5% gelatin (binder) and 5% mannitol, alanine, proline, glycine or threonine are presented in Figure 1. The results show that alanine and glycinebased formulations resemble mannitol by exhibiting a tendency to crystallise, while proline and threonine formulations retain their amorphous state with a glass transition temperature of -50.4°C and -35.4°C, respectively. The crystallisation behaviour of the excipient is critical in the formulation of lyophilised ODT as it limits the mobility of the molecules within the system and accordingly raises its collapse temperature, which allows freeze-drying at a higher temperature and consequently a shorter production cycle. In the case of amorphous excipient, lyophilisation of the frozen solution at a temperature 1 to 3°C higher than its glass transition results in physical damage to its structure (collapse). Mechanical properties

Successful ODT formulations must have enough mechanical strength to withstand the mechanical stresses during packaging, shipping and handling by patients.

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Heat Flow Endo Up (mW) –––– ––––

N OVEL ZERO-S ACCHARIDE ORAL LY DISINTEGRATING TABLETS (CONT. ) suitability in enhancing the mechanical properties of the resultant tablets.

34.87 30

Mannitol

25

Glycine

20

Alanine

15

Proline

10

Threonine

6.81

-64.49

-60

-55

Cr

Disintegration time

Cr Cr Tg Tg -50

-45

-40

-35

-30

-25

-20

-15

-10

-5 -2.30

Temperature (°C) Figure 1. Overlaid DSC heating curves of frozen gelatin stock solution (5%) with 5% of the excipient. Cr: crystallisation, Tg: glass transition temperature.

Disintegration time is the key issue in the development of ODT formulations. According to the US FDA industrial guidance, the stipulated disintegration time of ODTs should be less than 30 seconds, whereas the European Pharmcopoeia has set a limit of 3 minutes, both based upon the conventional disintegration apparatus. Despite this regulatory variation, it is generally agreed that a lower disintegration time improves the practicality and patient compliance of the ODT dosage form. At present, ODTs prepared by lyophilisation have the shortest disintegration time. This is due to their highly porous structures that allow fast diffusion of water (disintegrating medium) through a highly wettable matrix, which disintegrates/dissolves rapidly upon contact with saliva. Therefore, the wettability of the excipient plays a major role in determining the disintegration time of ODTs.

Figure 2. Representative profiles of contact angles of water with amino acids and mannitol as a function of time.

Measurement of hardness of lyophilised ODTs using the conventional tablet hardness tester is not a suitable method due to the spongy nature of the tablets that tend to deform rather than break in response to the applied force. Alternatively, texture analysers have been used extensively, where a combination of compression and shear forces are applied. Previous research from our laboratory has shown that a high concentration of mannitol (greater than 30% of the dried tablets) is

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required to enhance the mechanical properties of lyophilised ODTs4. Inclusion of a high concentration of amino acids in the formulation requires solubilisation of the added excipient within the binder solution. The solubility of the investigated amino acids (alanine, proline, glycine or threonine) was examined in 5% gelatin solution (binder). The results (data not shown) revealed that all the studied amino acids were completely soluble up to a concentration of 70% of the total solid materials, suggesting their

In this study, the wetting profiles of mannitol and the amino acid powders were analysed by measuring their contact angle using the Wilhelmy method, where a powder-coated glass slide was used as a measurement plate. The results (Figure 2) revealed that mannitol and the all thetested amino acids displayed zero contact angle (complete wetting). However, analysis of wetting time, the time taken for the complete wetting phase to finish and appear in the wettability profile as a sudden increase in the contact angle, showed differences for the different excipients (Figure 3). Compared to mannitol (wetting time of 23.5 ± 1.8s, n=3), proline, alanine and glycine exhibited shorter wetting times of 2.7 ± 0.4,

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N OVEL ZERO-S ACCHARIDE ORAL LY DISINTEGRATING TABLETS (CONT. ) amino acids displayed lower hygroscopic profiles than mannitol. While alanine and threonine absorbed minimal amount of moisture (less than 0.11%), proline and glycine showed a slightly higher uptake of 0.19 ± 0.02 and 0.30 ± 0.02%, respectively, further strengthening their application as replacements for the conventional saccharides within the ODT.

0.45

Moisture uptake %w/w

0.4 0.35 0.3 0.25 0.2 0.15 0.1

Summary

0.05 0 Mannitol

Alanine

Glycine

Threonine

Proline

Figure 3. The percentage of moisture uptake (w/w) of the freeze-dried powders. Table 1. Summary of the various physico chemical properties of amino acids when compared to mannitol. Thermal property

Mechanical property

Wettability uptake

Moisture

Alanine

✔ ✔

✔ ✔

Glycine

✔ ✔

✔ ✔

Threonine

✔ ✔

Proline

✔ ✔

✔ ✔

Amino acid

Key: ✔ similar to mannitol; ✔ ✔ Higher performance than mannitol; ✘ Poorer performance than mannitol

15.4 ± 1.1 and 19.8 ± 2.0s (n=3), respectively, whereas threonine had longer wetting time (34.2 ± 2.6s, n=3). Shorter wetting time translates into enhanced interaction between the material and water, resulting in a quicker disintegration of ODT. Moisture uptake

As explained above, the lyophilised ODTs consist of a high concentration of hydrophilic material with a porous anatomical architecture which results in high susceptibility to moisture uptake. This can in turn affect both the physical and chemical stability of the dosage form. Therefore, the hygroscopicity of the materials is another key criterion when

selecting an excipient for the formulation of lyophilised ODTs. The moisture uptake test was measured by keeping 1g of the freeze-dried powder in a lab desiccator along with saturated sodium chloride solution to generate 75% relative humidity at room temperature for 7 days. Figure 3 shows the percentage of weight gain due to moisture uptake of the freeze-dried mannitol and the four amino acids. The results indicated that all the tested powders absorbed a relatively small amount of moisture despite the high relative humidity (75%). The non-hygroscopic nature of mannitol is another crucial feature for its incorporation in ODT formulation. Interestingly, all the

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Mannitol is one of the most commonly used excipients in the formulation of lyophilised ODTs because of its crystallising behaviour in the frozen state, its non-hygroscopic nature, high aqueous solubility and fast wetting profile. Analysis of the properties of the amino acids has shown their suitability as matrix-forming agents as they exhibit all the essential properties required in the formulation of lyophilised ODTs (Table 1). Conclusions

Alanine and glycine showed great potential with a similar thermal and mechanical profile to that of mannitol, along with the added benefit of better wettability and lower moisture uptake. These amino acids provide an alternative choice in the formulation of lyophilized orally disintegrating tablets as they have added benefits when compared to mannitol and require no manipulation to the existing manufacturing protocols. References 1. Van Arnum P. Avancing ODT technology. Pharm. Technol. 2007; 31(10): 66–76. 2. Ghosh T, Pfister W. Drug delivery to the oral cavity: molecules to market. CRC Press 2005, Boca Raton, USA. 3. Muir I. Growing sales and new opportunities for oral fast dissolve. Oral delivery: when you find the holy grail. ONdrugDeliveryLtd 2007; 4-6. 4. Chandrasekhar R, Hassan Z, AlHusban F, Smith A, Mohammed A. The role of formulation excipients in the development of lyophilised fast-disintegrating tablets. European Journal of pharmaceutics and biopharmaceutics 2009; 72: 119–129.

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REACHING THE TIPPING POINT: PHARMACEUTICALS OUT OF BALANCE

by Jonathan Anscombe and Michael Thomas

T

here is a danger that the current pharmaceutical model may become irrelevant in the context of 21st century’s global healthcare needs. Healthcare is out of balance and, therefore, so is the pharmaceutical industry. The fortunes of the pharmaceutical industry are driven by the healthcare systems it serves – and virtually every healthcare system is restructuring. The same forces driving global healthcare reform are having a major impact on the pharmaceutical industry, which is at a tipping point – indeed, three interconnected tipping points – and that it will emerge in a much different form. These tipping points relate to what the industry sells, to whom, and how it must be organised. Tipping Point 1: From therapies to service models

The pharmaceutical sales model has always assumed that the prescribing doctor is the primary decision maker and that prescribing decisions are based solely on the doctor’s perception of patient need. This assumption has led to the current dual-track market-access model, in which sales and marketing focus on influencing doctors and pricing.

Jonathan Anscombe is a partner and co-head of AT Kearney’s pharmaceutical and healthcare practice in Europe. He is based in London email: jonathan.anscombe@ atkearney.com Michael Thomas is a principal in AT Kearney’s global pharmaceutical and healthcare practice. He is also based in London. email: michael.thomas@ atkearney.com

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However, the doctor is increasingly constrained or influenced by formularies, guidelines, IT systems and financial mechanisms. These mechanisms are driven by payers and regulators or by provider organisations responding to payer costs and political pressures. While the doctor-patient relationship is similar everywhere, the payer landscape is exceedingly complex, with priorities varying by country, locality and even ethnic group. In the pharmaceutical industry, the traditional view is that volume is not elastic to price. However, the growing influence of payers is changing this assumption.

Organisations such as the UK’s National Institute for Health and Clinical Excellence (NICE) define where a drug is used in the care pathway on the basis of clinical cost-effectiveness. Expensive drugs are often relegated to second-, third- or even fourth-line treatments even if they have high efficacy as a firstline treatment. There is also a trend towards changing the use of drugs from treatment to preventative use as they decline in cost. Over the past few years, there has been a dramatic change in what payers are looking to achieve with the effectiveness of the treatment pathway becoming more relevant than the costeffectiveness of a particular drug. Therefore, payers are far more interested in pathways than in drugs. Moreover, epidemiological shifts towards chronic diseases, the emergence of technologies that can turn diseases from terminal to chronic, and a growing sophistication in understanding what really drives health costs have expanded the concept of value to encompass its impact on the healthcare system. For payers seeking to address complex diseases, the availability of a marginally more effective, but much more expensive therapy, is far from compelling. The problem with many drugs is not their efficacy, but getting patients to take them as instructed. Compliance is poor even for life-threatening diseases such as cancer. What would be compelling for payers is a service model that enables therapies to be administered with high compliance and can be proven to result in fewer admissions. It would be even more compelling if this could be demonstrated in the payer’s specific care system and target population. Positioning a therapy in this context dramatically increases its value. Tipping Point 2: From rich niches to global mass markets

The US dominates the pharmaceutical industry. Prices are based on what the US market will bear and pricing policy seeks to defend this “list price” regardless of revenue impact in other countries. However, the US market is failing. Whether the new legislation for

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REACHING THE TIPPING POINT (Cont.) universal healthcare insurance turns out to be successful or not, mechanisms to limit access to medicines based on their cost effectiveness will inevitably spread. The likely outcome will be that the US pharmaceutical industry may well see revenues decline. Meanwhile, healthcare demand is shifting rapidly towards the developing world, with emerging markets experiencing a dramatic increase in diseases long common in developed countries. The developing world is today characterised by high levels of selfpay and rudimentary public health systems. However, most countries will develop some form of comprehensively funded healthcare system as soon as they can afford to do so. This scenario offers enticing but challenging opportunities for the global pharmaceutical industry. Emerging state-funded systems will need to develop cost-effective solutions to Western-style health problems, but they will not be prepared to pay Western-style prices. As the size of developing markets become too attractive to ignore, the pharmaceutical companies will need to drop their obsession with high-priced solutions and instead price in a way that maximises revenue over the drug’s life cycle and throughout the global portfolio. Low-cost mass-market solutions

There are signs that the pressures to create low-cost mass-market solutions are appearing in the pharmaceutical industry. Indian and Chinese biotech companies who once focused on treatments for local patients are becoming significant innovators on a global scale. Pharmaceutical companies need to view emerging markets in a new light – not just as an opportunity for lowering R&D costs or demonstrating market

commitment, but as a source of low-price, breakthrough innovation. If the global pharmaceutical industry does not respond to these challenges, then local companies surely will. Tipping Point 3: From integration to connection

The traditional model of a globally integrated pharmaceutical industry will struggle to survive. It will be too large, unwieldy and unfocused to connect with the payers, providers and potential partners in markets it seeks to serve. Successful pharmaceutical companies of the future will shift from being R&Ddriven to market-driven, and this will require a complete re-wiring of their organisations.

pharmas ❝of theSuccessful future will shift

on profitability. However, for mass market products, supply-chain costs become a key profit driver. We expect to see the further emergence and consolidation of highly efficient outsource manufacturers. Management of the contractual relationships with these providers will become a core competence of the truly connected pharmaceutical company – and a major driver of profitability. Shifts in distribution strategies will also accelerate. There is an increasing trend for healthcare systems to focus away from hospitals and towards home- and communitybased care. Thus, the current shift from wholesale distribution towards direct-to-pharmacy will shift again to direct-to-patient. Different types of companies

Given the complexity of healthcare systems and treatment pathways, the challenge for pharmaceutical companies is to decide on which therapy areas to focus. The current R&D-driven trend to specialise in specific therapy areas will accelerate further. This will require a very different kind of sales-andmarketing organisation. Virtually all pharmaceutical companies have dramatically reduced their traditional sales forces in favour of localised “market access” organisations and that trend will continue.

There are several different types of pharmaceutical companies, all with different competencies, that will operate in the space currently occupied by integrated pharmaceutical firms. Valuedelivery companies will focus on specific therapies in certain countries, and will gear value propositions in response to local market needs. Health innovation companies will develop and leverage technologies in as many applications as possible to gain a return on investment at a reasonable cost. Supply-chain companies will focus on optimising operating efficiencies. The truly connected pharmaceutical company will have to decide which of these functions it wishes to deliver, and which companies it needs to partner with to deliver other services.

The shift towards mass-market solutions introduces a dramatically different dynamic to the supply chain. When margins are 80% or more, working capital, manufacturing costs and distribution costs have little impact

This article is based on an AT Kearney White Paper on “Pharmaceuticals out of Balance”.

from being R&D driven to market-driven

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REGULATORY REVIEW

Review of developments in GMP and the regulation of Medicines March 2011 – June 2011

by Malcolm Holmes

Introduction The current review period has seen a number of actual/proposed changes in the regulation of medicines and regulatory guidance in both the EU and USA. Worryingly, it has also seen incidents related to the microbial contamination of IV fluids, potentially leading to the the deaths of a number patients in both the USA and India. United States of America

• Rules for the internet sale of medicines.

Suspension or withdrawal of a Certificate of Suitability (CEP) The EDQM has issued a revised policy document. Changes include:

• Greater transparency on the •

possibility for appeal against a decision taken by the EDQM The procedures applied when the holder asks to withdraw a CEP.

Retrospective review of Regulations FDA has announced this review via its blog. It is asking for submissions on how to improve existing regulations. It hopes to improve innovation by both itself and stakeholders.

GPS/DUNS information in CEP application forms These data for manufacturing site(s) must be included in the new/revised CEP application forms, in order to better identify the location of those sites

Formation of glass lamellae Following the recall of several drug products, FDA has issued an Advisory Note to drug manufacturers. The Advisory – identifies some contributory factors to this problem.

Refusal of information from third parties in reply to EDQM's request for information EDQM has noted that third parties (e.g. manufacturers of starting material or purchased intermediates) are requesting that information is kept confidential from the CEP holder/applicant. EDQM considers it necessary however that manufacturers of a final substance detain full information on the manufacture of a starting material or intermediate in order to suitably control the quality of the final substance.

Draft Guidance for Industry – NonPenicillin Beta-Lactam Risk Assessment: A CGMP Framework This guidance is intended to assist manufacturers in assessing whether separate facilities should be used based on the relative health risk of cross-reactivity. Europe

EU Directive on counterfeit medicines Amendments to Directive EC 2001/83/EC aimed at combating counterfeit medicines have been adopted and will have to be transferred into national law within two years. The amendments include:

• introduction of safety features • •

(serial numbers and/or tamperevident seals) more stringent rules for importation of APIs better controls of the supply chain (traders and wholesalers)

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EMA Q&A on computerised systems Topics covered include:

• Requirements for spreadsheets • Data security of databases • Risk management in the system lifecycle

• Use requirements as part of the

retrospective validation of legacy systems

• Revalidation of computerised systems

• Storage time of electronic data and documents

• Validation efforts for small devices

• Alternative controls in case a

system is not capable to generate printouts. Contamination of drug products arising from the preservative used on wooden pallets MHRA has published a notice relating to a recall of product following complaints of musty and mouldy odours. Source of the odour was trace amounts of 2, 4, 6tribromoanisole (TBA) in some bottles arising from a preservative used on wooden pallets used for distribution. Other such incidents in the USA (different company/products) led to recalls and an FDA Warning Letter. In this case, from exposure of packaging materials to TBA from wooden pallets. Comment: companies may be well advised to perform risk assessments/ take risk management action, wherever they make use of wooden pallets within the supply chain. International

Training Material on ICH Q8, Q9 & Q10 Following international workshops the Quality Implementation Working Group has published on the ICH website a consolidated training package on the above guidelines. Contaminated IV fluids implicated in deaths of patients in USA and India 9 people died in Alabama USA after receiving contaminated IV fluids from a US manufacturer. 13 women died in India after receiving contaminated IV fluids from an Indian manufacturer. For further information on these and other topics we suggest you refer to the websites of relevant regulatory bodies and to current and past editions of GMP Review News” published by “G Euromed Communications. To subscribe to this monthly news service contact info@euromed.com

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NEWS FROM THE EIPG General Assembly in Madrid

Presentation on Quality Regulation Update

The 2011 General Assembly of the European Industrial Pharmacists Group held in Madrid on 9/10th April was preceded on the Friday by a seminar for staff and students of the Faculty of Pharmacy of Alcalá University. The Dean, Dr Julio Álvarez-Builla, noted that pharmacy in Alcalá gives every encouragement to students to enter the pharmaceutical industry which he considers strategic in all modern societies. Everyone at Alcalá, including a group of postgraduate students studying industrial pharmacy, made the pharmacists from EIPG extremely welcome.

Michael Murray, ABPI, presented a European Quality Regulation Update. He discussed the industry views on the recent consultations of proposed amendments to Chapters 5 and 7of GMP guidance, the concept paper on storage conditions during transport and the QP declaration for APIs. Also, he described the status, key issues and timelines for implementation of the Falsified Medicines Directive.

During the seminar, several presentations were made on the future of the pharmaceutical industry, the future education and training of pharmacists and the challenges of the cold supply chain. Overheads from these presentations are on our website: www.eipg.eu under “media library”. Past year’s activities

The report on the year's activities showed EIPG to have had a busy year since the last General Assembly, particularly in its role as an active partner in consultations with the European Commission on educational matters and with the European Medicines Agency on technical guidelines. EIPG response to consultations on various chapters of the GMP Guide, the QP Declaration Template and the Professional Qualifications Directive can be found on our website: www.eipg.eu under “position papers”. An update to the EIPG guidelines on Good Distribution Practices has been published and a working group led by the Ordem dos Farmaceuticos, Portugal, is drafting a Code of Practice for Pharmacovigilance.

Enlargement of EIPG considered

A draft of the updated Statutes of EIPG was considered by the General Assembly, initially brought about by the proposal to update the membership of the Bureau but now having been extensively modernised. One of the proposals which elicited most discussion was whether the Member Associations should be restricted to Member States of the European Union or have a wider definition to include the European Economic Area, Accession countries, European countries which have a Mutual Recognition Agreement with the European Union in relation to conformity assessment of regulated medicinal products or

simply any country of “Europe”. Let us hear your opinions! Membership survey

The results of the recent Membership Survey were debated, including ways of improving our systems of lobbying in Europe. A list of pharmacists who are expert in specialist areas of industry is to be compiled from Member Associations to assist with responding to scientific issues. These areas would include: Production/Quality Assurance; R and D; Commercial/Sales and Marketing; Regulatory Affairs; Biotechnology products/Medical Devices; Counterfeits; Clinical Trials management; Wholesale Distribution; Pharmacy Education. Anyone interested in assisting with lobbying, please contact your national representative or mail to: jane@nicholj.plus.com Education working group

An education working group reviewed the report of Pharmine 1 and considered a submission to the Education, Audiovisual and Culture Executive Agency (EACEA) for a pilot to review specific advanced level competencies and how best these should be delivered ( for example, part-time distance learning in conjunction

Malta and Sweden re-elected Vice-Presidents The General Assembly re-elected Malta (Claude Farrugia, left) to the Bureau as VicePresident for Communications for the next three years and Sweden (Pär Tellner, right) as Vice-President for Education & Careers for a further year’s co-option to the Bureau.

e u ro pe an IN D US TR IA L PHARMACY • Issue 9 June 2011

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NEWS FROM THE EIPG (Co nt.) with an HEA) for pharmacists working in industry. National reports

National reports from Member Associations described various methods used to lower the prices of pharmaceuticals, in order to reduce health care budgets. Some members indicated the price reductions were considered so low that they were

[B*%B&OHDQ$LUB&5LQGG

22

unsustainable. Site closures and headcount cuts, particularly in the biotechnology industry were reported. However, it was not all doom and gloom. Italy marked the 50th anniversary of the founding of AFI with a national symposium attended by over 1,000 participants. During the year, AEFI has run 36 specialist courses in Spain attended by 1,753 participants.

Anyone looking for employment should note that there is a lack of pharmacists in all sectors in Germany and pharmaceutical companies are looking for pharmacists to fill various positions. Jane Nicholson, Executive Director EIPG, jane@nicholj.plus.com



e u rop ea n IN DU ST RI AL PHARMACY • Issue 9 June 2011


PHARMACEUTICAL FORUM The following questions and responses are a recent selection of those published on an open online discussion group www.pharmweb.net/gmp.html. The Forum serves as a means of exchanging views on international regulations affecting the pharmaceutical industry. Readers are invited to contribute to the Forum by sending their Q&As to www.pharmweb.net/gmp.html. Total Viable Count test

Q

If a product’s Pharmacopoeial monograph does not contain a “Total Viable Count” test, do we need to conduct it at all? In brief, what is the significance of the test for a nonsterile product? Can it be substitute for a Bacterial Endotoxin Test (BET)?

Response 1 – To perform or not to perform a Total

Viable Count test totally depends on the risk and extent of contamination/bioburden. It is always recommended to monitor bioburden to check/monitor the process controls. Usually, preservatives are added to non-sterile drugs to prevent an increase in microbial load, but every preservative has its own capacity/limitations to control the load, after that it will not work and the product is exposed to extreme risk. In answer to the second question – “No”, BET and Total Viable Count are different tests for different purposes, and cannot be substituted.

Response 2 – The microbial limit tests are designed to perform the qualitative and quantitative estimations of specific viable micro-organisms present in pharmaceutical dosage forms, which include tests for Total Viable Count (bacteria and fungi) and specified microbial species (Escherichia coli, Salmonella, Pseudomonas aeruginosa and Staphylococcus aureus).

Although adequate care is taken to exclude microorganisms during manufacturing by incorporating preservatives, it again depends upon the efficacy of the preservative in the long term. Therefore, a test should be performed to establish that the formulation has not been contaminated inadvertently by any undesirable microbial flora and hence safe to be consumed by humans. BET is a different analytical tool to determine pyroburden in pharmaceuticals and hence cannot be used as an alternative to TVC.

Response 3 – Preservatives should be used to deal with possible user contamination in non-sterile products and also in sterile products intended to be used on more than one occasion. It is not GMP to include them to cover manufacturing defects or lack of control on raw materials. e u ro pe an IN D US TR IA L PHARMACY • Issue 9 June 2011

Expiry and re-test dates

Q

I understand that the expiry date of the finished product cannot be beyond the date of expiry marked on the Active Pharmaceutical Ingredient/s. However, some APIs do not have “Expiry Dates”, rather they have “Retest Dates”. How many retests would be acceptable in such cases? Also, I am told in some countries the API can be used for preparing formulations until the “Expiry Date” and that the shelf or expiry of the product is marked accordingly to the shelf life assigned to the product as confirmed by stability studies. In such cases the expiry date of product would be beyond the expiry date of API. It is justifiable?

Response 1 – The Expiry Date for the formulated

products does not necessarily have anything to do with the Retest Date for the API. It is quite common for the former to be later than the latter. If you read the ICH Q1 series of guidelines you will see that the correct term to use for APIs is ‘retest date’. Expiry dates/shelf lives relate to formulated products.

This means that the API can be used to its retest date to make a formulated product. Indeed it is also possible to retest a lot of API that is past its retest date and if it meets the full specification it can be used to make a batch of formulated products. The shelf life of the formulated product will be calculated from the release date (with some restrictions on the length of time between the date of manufacture and the date of testing). Response 2 – I think the procedure followed by you

should be correct. The experience of the regulatory authority drafting these guidelines would also have it this way only. The API has a definite expiry period and no formulation containing it should be available on the shelf after the date of expiry of the API (or the expiry date of such ingredient of the formulation). I go by the simple logic – “would I give such medication to my kids?”. I cannot think of any justification to allow practices other than this. There may be cases where no medicines are available and people may be given such products – but that depends upon the circumstances and the prescriber has to weigh the pros and cons. No guidelines would address such issues.

Response 3 – I disagree with the previous

comments. Some drugs are not very stable in pure form but behave differently when compounded into a product. In such cases your formulation can have a shelf life more than that of the remaining shelf life of the drug

23


PHARMACEUTICAL FORUM (Con t.) substances (subject to proven stability, of course). The best example is vitamin D3. The shelf life of an API can be extended, based on proven stability including impurity profile up to the proposed extended shelf life. But we should not directly correlate the shelf life of a drug substance and drug product except through proven stability studies. Response 4 – The API has a retest period, not an

expiry date. As the name suggests it is possible to extend the useful life of an API by retesting, provided always that there is adequate supporting real time and accelerated stability data. This is why the term is ‘retest period’ and not ‘shelf life’ for APIs. It is also possible for a lot of API that is past its retest date and, provided that it is fully compliant with the agreed specification, used immediately to manufacture a batch of finished (drug) product/dosage form. The shelf life of the dosage form is established from ICHcompliant stability data.

Change in batch numbering

Q

Should a change in an API batch numbering system be registered as a minor or major variation?

Response 1 – I perceive such a change as major.

There will be a major change in initial SOP to how the

24

number must be done and when such changes become effective. Other points to be observed are: Why is there a change in the number system? How is this numbering system better than the previous one, how errors are minimised, and whether batches are tracked and identified more easily and reliably. Response 2 – From a regulatory perspective, it is minor one. But from a company perspective, pre and post implement changes may be of major concern. Tablets from other sites

Q

When you receive bulk tablets from another manufacturing site within the group, are you still required to do incoming identification of these tablets? Response 1 – Yes, if the plant where these tablets

have been manufactured is a multiproduct facility.

Response 2 – In my opinion, if the remote site is

from the same company (same legal entity) it is not mandatory to test their identity provided the labelling is clear. But if it is a different company within the same group, it is mandatory to test the ID.

Response 3 – Bulk tablets should be treated as an

incoming material into the site. So, it needs to be treated in the same as you treat other raw materials and API’s which come from suppliers.

e u rop ea n IN DU ST RI AL PHARMACY • Issue 9 June 2011


DATES FOR YOUR DIARY

J UNE

28-30 June 2011 – London, UK Annual improving solubility summit www.improvingsolubility.co.uk 29-30 June 2011 – London, UK Pharmaceutical Nanotechnology: Applications & Commercialisation www.pharma-nanotech.co.uk 29-30 June 2011 – London, UK Pharmaceutical portfolio & product life cycle management www.smi-online.co.uk

J U LY

21 July 2011 – London, UK Patent Issues in the Development of Biosimilar Medicines www.smi-online.co.uk

27-28 September 2011 – Amsterdam, The Netherlands Pharmaceutical Co-Crystals www.pharmacocrystals.com

21 July 2011 – London, UK Intellectual Property and Licensing in Biotech www.smi-online.co.uk

28 September 2011- Amsterdam, The Netherlands Pharmaceutical Amorphous Materials www.pharmaamorphous.com

AUG UST

O CTOB ER

31 August – 2 September – Nottingham, UK Academy of Pharmaceutical Sciences UK PharmSci 2011 Conference www.jpag.org

11-12 October 2011 – London, UK MHRA Good Manufacturing Practice (GMP) and Good Distribution Practice (GDP) email: mhraconferences@mhra.gsi.gov.uk

4-5 July 2011 – Oxford, UK PIPA Summer Conference www.piponline.org

S E PT E MB E R

5 July 2011 – London, UK POM to P – Critical Success Factors www.smi-online.co.uk

13-15 September 2011 – Manchester, UK Human Error: Causes and Prevention www.nsf-dba.com

6-7 July 2011 – London, UK Social Media in the Pharmaceutical Industry www.pharm-social-media.com

20 September 2011 – London, UK First steps in pharmacovigilance: a workshop for administrators (Training course provided by PIPA and the Institute of Clinical Research) email: operationssupport@pipaonline.org

7 July 2011 – London, UK Best practice for outsourcing of analytical support and use of contract laboratories www.jpag.org

11-13 October 2011 – Nuremberg, Germany TechnoPharm 2011 www.technopharm.de 13 October 2011- London, UK Modern methods of drug analysis in biological materials: analysis of drugs for the Olympic Games 2012 www.rphars.com 19-20 October 2011 – Berlin, Germany Bioproduction 2011 www.bio-production.com

26-27 September 2011 – London, UK Biosimilars and Biobetters www.biosimilars-biobetters.com

World Leader in GMP gap analyses, seminars and individual GMP training Hard hitting web-based GMP training in the comfort and convenience of your office or home (save on expensive and inconvenient travel: These seminars are offered as web-based learning:

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have wide expertise in evaluating GMP and • We Quality Systems at your facilities and in

For full details and registration check our website at: www.globepharm.org/seminars.html/course

Let us assist you. Speedily and cost effectively. Contact us at: consulting@globepharm.org

performing third-party supplier and contract manufacturer audits

e u ro pe an IN D US TR IA L PHARMACY • Issue 9 June 2011

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european Industrial Pharmacy Issue 9 (June 2011)  

European Industrial Pharmacy is the electronic journal of the European Industrial Pharmacists Group (EIPG). The journal contains articles, n...

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