european Industrial Pharmacy Issue 14 (September 2012)

european INDUSTRIAL

PHARMACY features 4

ORAL INSULIN DELIVERY SYSTEMS Oral insulin treatment may soon be a reality concludes this review of various delivery systems.

by E Castellanos Ruiz, M Garcia Hierro and P Medel Torres

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FLUSHING AWAY OUR FUTURE The medicines consumed by millions daily contain ingredients that could destroy the environment and ultimately our future.

by Fred Massoomi

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CONCORDANCE IN CULTURAL CONTEXT Concordance, unlike compliance, is the mutual agreement between a well-informed patient and his physician to take the prescribed treatment.

by Malcolm E Brown

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MEDICAL DEVICES DESIGNED WITH PATIENTS IN MIND Device manufacturers need to design medical devices to make them more appealing to the patient, and lead to success in the marketplace.

by Steve May-Russell

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THE EPSRC CENTRE FOR INNOVATIVE MANUFACTURING IN REGENERATIVE MEDICINE Research in regenerative medicine requires collaboration between industrial and academic partners.

by Catherine Rogers, et al.

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INTEGRATING IT TOOLS WITH THE PHARMACEUTICAL INDUSTRY AND EDUCATION IN INDIA In order to generate a competent workforce, pharmacy education needs to incorporate IT skills and industry practices.

by Shyamal Kalani

regulars 3 22 23 24 26 27

EDITORIAL COMMENT BOOK REVIEW REGULATORY REVIEW PHARMACEUTICAL FORUM NEWS FROM THE EIPG EVENTS

ISSUE 14 • SEPTEMBER 2012 www.industrialpharmacy.eu www.eipg.eu

associate editors

european

INDUSTRIAL

PHARMACY

Belgium: Philippe Bollen

Issue 14 September 2012 Bulgaria: Valentina Belcheva

ISSN 1759-202X

Czech Republic: Ales Franc

EDITOR Joe Ridge, MRPharmS

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PRODUCTION Dave Johnson

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european INDUSTRIAL PHARMACY is the official publication of the European Industrial Pharmacists Group (Groupement des Pharmaciens de l’Industrie en Europe) www.eipg.eu

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EDITORIAL BOARD Michael Anisfeld Alexander Florence Michael Gamlen Linda Hakes John Jolley

Views expressed in European Industrial Pharmacy are those of the contributors and not necessarily endorsed by the Publisher, Editor, Editorial Board, or by our corporate sponsors who accept no liability for the consequences of any inaccurate or misleading information © 2012 Euromed Communications Ltd

Cover picture: Water treatment plant (see pages 6-8) Image: Fotolia

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editorial Dear Colleagues I cannot believe that we are in September already – as they say, time flies when you are having fun!

This term will be my final year in office as President of the EIPG and where an elected member state will take over the reins of leadership in April 2013.

However, I am far from wanting a quiet few months in office, anything but, I can assure you.

The EIPG has much work to do and one of my key objectives is to continue to expand the membership of the EIPG. Over the last 45 years, we have had difficulty, for example, in inviting pharmacy associations in Switzerland (of which there are two) to join as active members of the EIPG as our statutes dictated that a member state had to be part of the European Union. I felt that as President of the EIPG that it was wrong to be constrained by statutes which were constituted in 1966 and not fit for purpose for a 2012 Europe.

Now, due to the sterling work of Bureau Members, Claude Farrugia, Helene Le Blanc and Jane Nicholson, we have been able to revise the statutes with the support of the General Assembly, to widen the scope of membership to those member states which are in Europe but not in the European Union.

It is vitally important that the EIPG grows and

actively expands its membership and influence across all of Europe during these difficult times.

I have stated many times before and I will state it again, the EIPG represents the individual pharmacist or pharmaceutical scientist working within the industry – it does not represent a Corporate Body or Trade Organisation. It is these 'grass roots' pharmaceutical professionals who can often provide a reasoned and dare I say it, an impartial view when a European Directive has been circulated for consultation.

In those countries where there is currently no National Association of industrial pharmacists, I would be very interested to hear from any Industrial Pharmacists who is willing to form an Association and who wants to join the EIPG. Please contact me directly on luigi.martini@kcl.ac.uk or Mrs Jane Nicholson, Executive Director on jane@nicholj.plus.com

Best wishes

Gino Martini President of EIPG

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3

ORAL INSULIN DELIVERY SYSTEMS

by Emilia Castellanos Ruiz, M García Hierro and P Medel Torres

D

iabetes mellitus is an illness caused by an absolute or relative deficiency of insulin. It is a universal disease, with a relatively uniform distribution across all continents. Until 1922, when Frederick Banting and Charles Best isolated insulin from bovine pancreas, diabetes was often fatal.

The authors are from the Department of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of Complutense, Madrid. Spain.

Insulin is a protein released by the beta cells of the pancreatic |Islets of Langerhans. Being a polypeptide, it is degraded by proteolytic enzymes, tends to aggregate in polymer form, adheres to surfaces, can induce an immune response, and does not readily cross physiological membranes because it is not lipophilic. The only effective way of administering insulin to date has been parenterally, via subcutaneous injections. The challenge is to find alternative routes, to avoid daily insulin injections, by looking for less invasive methods and more convenient treatment regimens that are nonetheless safe and effective.

The oral route would allow better simulation of pulsed insulin release in response to glucose levels, thus reducing the incidence of peripheral hyperinsulinaemia, which tends to be associated with glomerulopathy and retinopathy.

However, there are various challenges, such as overcoming enzymatic degradation, solving the problem of poor absorption in the gastrointestinal tract, and preserving the drug’s biological activity during the formulation process. Various pharmaceutical strategies have thus been proposed to maximise the bioavailability of orally delivered insulin, by removing barriers and developing safe, effective therapeutic systems.

Studies have followed five lines of research: • Absorption enhancers • Enzyme inhibitors

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• Mucoadhesive polymer systems • Particulate carrier delivery systems • Targeted delivery systems Absorption enhancers

These improve the absorption of drugs by increasing their transport across cells by various mechanisms of action: • Changes in membrane fluidity • Reduction in mucosal viscosity • Opening cell channels to allow proteins to cross membranes Examples of non-specific permeability enhancers are: bile salts, fatty acids surfactants, salicylates, chelating agents and zonula occludens toxin.

However, the use of absorption enhancers may be limited by the fact that, because some cell membranes open their channels when permeabilised, there may be enhanced transport of not just the peptides or proteins of interest, but also undesirable molecules present in the gastrointestinal tract.

Enzyme inhibitors

Insulin is a peptide hormone, so is subject to degradation by enzymes.

It is degraded strongly by trypsin, α-chymotrypsin and elastase, and to a lesser extent by other enzymes located in brush-border membranes.

Some way must therefore be found to evade this enzyme barrier, in order to prevent it from being broken down and enable it to be absorbed in unaltered form, to reach its site of action and exert its therapeutic effect.

A number of studies1-4 have therefore been done to test the coadministration of enzyme inhibitors. However, the main disadvantage of these inhibitors is their high toxicity, especially in chronic treatments, and the lack of a specific intestinal application site for these compounds. This could alter the pattern of metabolism in the gastrointestinal tract, because the absorption and digestion of food proteins might be affected.

Mucoadhesive polymer systems

The term “mucoadhesion” refers to adhesion between polymeric carriers and the mucosa, a property of certain polymers that become adhesive after hydration.

The aim of mucoadhesive delivery systems is to increase the time drugs spend at their absorption site, intensify contact with the mucosa, and increase the concentration gradient of the drug at its absorption site, thus ensuring its immediate absorption with no dilution or degradation in the luminal fluid. To do this, the specific drug absorption site needs to be located, in order to link it to its delivery system.

The mucoadhesive polymer systems that have been developed provide intimate contact with the mucosa, thus reducing degradation of the drug between the delivery system and the absorbing membrane. They are controlledrelease systems that simultaneously release both drug and inhibitor and allow enzyme inhibitors to be immobilised in the delivery systems.

New polymers that have appeared have shown excellent inhibitory activity against proteolytic enzymes and reasonable mucoadhesivity, so might prove very useful for overcoming the enzyme barrier to oral peptide therapy.

The binding of hydrophilic polymers, such as polyacrylates, cellulose derivatives and chitosan derivatives, to biological surfaces is based on hydrogen bonds and ionic interactions.

In the last few years, many mucoadhesive systems have been developed:

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ORAL INSULIN DELIVERY SYSTEMS

• Systems based on superporous hydrogel compounds • Lipid-based nanocarriers • Thiolated polymers and • Chitosan-based carriers These systems are considered effective because they enhance the intestinal absorption of biological molecules vulnerable to proteolytic enzymes5-6. However, their toxicity in long-term treatments is not yet well defined, and more data from human studies would be needed in order to regulate their potential use in clinical applications.

Particulate carrier delivery systems

Most oral insulin delivery strategies based on carrier particles have been developed to avoid the inherent problems involved in administering peptides by the oral route. These carriers effectively protect peptide drugs against enzymatic degradation and the adverse environment of the gastrointestinal tract (GIT), provide high-level transfer of the drug across the epithelial mucosa, allow the rate of release to be controlled, and enable drug delivery to be directed to certain sites within the intestine.

In order to overcome all the above barriers and improve peptide formulations, colloidal transport systems have been investigated, such as: microemulsions, liposomes, polymeric nano- and micro-particles and polymeric micelles. These have all been formulated with adhesive polymers, protease inhibitors, insulin aggregation inhibitors and functional excipients for inducing transcellular or paracellular transport across Peyer’s patches, as well as receptor-mediated insulin transport in the GIT. Some studies7 suggest using oilbased vehicles to protect peptides from the GIT environment, and water/oil (W/O) microemulsions have proved the most promising.

Microemulsions show signs of becoming intelligent proprietary systems for the potential delivery of these peptides and proteins.

Liposomes are colloidal systems of

continued

a vesicular nature, made up of one or several phospholipid bilayers surrounding an aqueous compartment. They can incorporate hydrophilic or lipophilic drugs, so peptide molecules, including insulin, could be inserted into liposomes.

They may thus represent a potential carrier option for oral protein delivery.

Nanoparticles have also been widely studied as carrier vehicles for insulin. These nanoparticles are solid colloidal particles of 0.01µm to 1µm in size, made of macromolecular materials into which the active ingredient is incorporated.

Depending on the nature of the matrix, they are classed as: a) nanoparticles made from natural macromolecules (albumin and gelatin); and b) acrylic nanoparticles (acrylamide, methylmethacrylate and alkylcyanoacrylate). Polyacrylamide and polymethacrylate nanoparticles have the disadvantage of being non-biodegradable, whereas those made of polyalkylcyanoacrylate are degradable. From the biopharmaceutical point of view, alkylcyanoacrylate nanoparticles have the advantage of a high loading capacity compared with other drug carrier systems.

The oral administration of nanocapsules containing insulin has been observed to reduce glucose levels in diabetic rats for prolonged periods. Nanoencapsulation protects the hormone from proteolytic degradation in the GIT and preserves its biological activity after passing through the intestinal mucosa8.

Targeted delivery systems

The targeted delivery of peptides and proteins to specific sites has been used to reduce the total dose of drug administered and concentrate the therapeutic dose at the sites of pharmacological action.

Absorption from the GIT is not uniform, but occurs at specific sites depending on differences in formulation composition, thickness of the mucous layer, pH, surface area and enzyme activity.

The administration of targeted

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drugs for absorption in the colon has various features: long residence time, low enzyme activity and increased tissue response for enhanced absorption.

The administration of insulin via colon-targeted delivery systems has been extensively developed and studied in the last few years.

Targeted insulin delivery has thus been tested using sodium glycocholate and polyethylene oxide, which achieved a reduction in glycaemia following oral dosing.

In 2008, Ainslie et al.9 managed to make a microdevice by overlaying various polymer layers loaded with different drugs intended for the oral administration of multiple therapies, which was shown to be capable of delivering drugs orally in a unidirectional manner. A multilayer polymeric microdevice loaded with insulin and the chemotherapy agent camptothecin was thus obtained, and controlled release of both insulin and camptothecin was observed in vitro for 180 minutes, from the microdevice towards the cell interface, achieving a drug concentration in the intestinal epithelium 10-fold higher than that attained using unprotected, drugloaded hydrogels.

While it is true that creating a microdevice of this type may be a viable method for oral drug delivery, helping to improve the patient’s treatment compliance and reduce associated toxicity, the problem is that it has not been tested on its own specifically with insulin (only in combined release with camptothecin) and no glycaemia tests have been done to support its in-vivo effectiveness.

Conclusions

Since Banting and Best first isolated insulin from bovine pancreas in 1922, and recombinant DNA technology subsequently provided a form of insulin that is active in humans when administered by injection and available at reasonable cost, we have come a long way towards finding new routes of Continued on page 9

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FLUSHING AWAY OUR FUTURE Environmental impact and pharmaceutical waste management

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An estimated 90 percent of pharmaceuticals in the environment come from consumers. Many drugs end up in toilets un-metabolised by the body or thrown away.

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Sewage treatment plants were designed to remove disease causing microbes and pathogens from water – not pharmaceuticals.

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Testing has confirmed more than 100 different pharmaceuticals in surface waters. Fish, molluscs and algae are adversely affected by contamination.

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Standard treatments used to clean drinking water not good at removing pharmaceuticals.

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Humans may be affected by the consumption of water that contains pharmaceuticals.

by Fred Massoomi

T

he very life-saving medicines that millions of us consume on a daily basis could be the same molecules that are destroying the environment, and ultimately, our own existence. Both chemicals and pharmaceuticals enter our environment every day from human activity.

However, pharmaceuticals, whilst chemical in nature, do not generally represent what is found naturally; in other words, they have been engineered to have a pharmacoIogical effect and to resist breaking down in the harshest of environments, the human body.

Firouzan "Fred" Massoomi, PharmD, is Pharmacy Operations Coordinator at Nebraska Methodist Hospital, Omaha, Nebraska, USA. Email: fred.massoomi@nmhs.org

The ability to persist in extreme conditions also prevents the medicines breaking down in the natural environment. Even with water treatment facilities, the ability to remove all pharmaceutical entities from our water supply is next to impossible (see Table 1) as these drug molecules come in various forms ranging in Iipo-/ hydro-philicity, ionicity, and may exist as the parent molecule, a metabolite or a conjugate. Thus, pharmaceuticals exhibit characteristics that are not typical of most chemicals found in nature.

So how can they be removed if it is not fully understood how they exist in our environment? There are multiple technologies used by water treatment facilities to 'purify' our water supplies ranging from sediment filtration to chlorine oxidation, and each varying in effectiveness and selectivity. Of note, these technologies are NOT consistently available globally (especially in the US) at current water treatment plants. Although all of these technologies exist, it would be very cost prohibitive to retro-fit existing facilities. In the US, it is

6

estimated to cost $2 trillion to modernise the facilities to address this problem, and there could be no guarantee that it would be 100% effective.1 The concept of pharmaceuticals as pollutants in our water supply is not new, with Health authorities such as the World Health Organization (WHO) concluding that “While pharmaceuticals are emerging as contaminants, the parts-per-billion or even parts-pertrillion traces of pharmaceuticals in the water supply do not pose significant risk to human life”.2 However, evidence is mounting on the impact to aquatic and terrestrial life, particularly as many are disruptors of the endocrine system (see Table 2). Thus wild geese are becoming resistant to ampicillin, tetracycline, penicillin and erythromycin; diclofenac has been proven to be toxic to vultures in decimating populations in the Indian subcontinent due to its ubiquitous use in cattle; fluoxetine and fluvoxamine Induced spawning In bivalves at significantly lower concentrations; fluoxetlne enhances the release of ovary-stimulating

hormones in crayfish; and selective serotonin re-uptake inhibitors elicit aggressive behavior in lobsters, causing subordinates to engage in fighting against the dominant member and reducing the propensity to retreat.3,4 But are these regulatory bodies missing key concepts when considering how these pharmaceuticals behave in our environment? I believe they should look at the following three terms: 1. Persistence, the continuous presence in the environment; 2. Bioaccumulation, an increase in the concentration of a chemical in a biological organism over time, compared to the chemical's concentration in the environment; 3. Ecotoxicity, a lethal concentration of chemical 96 hours after exposure. There is no defined minimum exposure to a pharmaceutical in our environment to assess whether or not they have a negative impact.

The primary culprits for the residues in our water are human excretion of drugs and their metabolites, over-prescribing by

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FLUSHING AWAY OUR FUTURE

healthcare professionals, and discharge from pharmaceutical companies and agricultural use).5 US studies on patient adherence and compliance estimate that 20% of prescriptions are never filled, half of all prescriptions fail to have the proper effect because of failure to take the drug or follow instructions, up to 50% of people with chronic ailments are non-compliant, and only one-third of all patients actually take their medications as directed.6 Where do these medications go then if they are not consumed?

When it comes to pharmaceutical pollution: 54% of people throw medicines into the trash, 35% of people flush medicines down the toilet, and 95% of antibiotics are excreted unaltered into the environment.6 In addition, many donations of medicines to Third World countries are made for dubious reasons and are of dubious Table 3 overleaf). quality (T The community pharmacist should advise patients not to throw out their unwanted/unused prescriptions into the garbage, down the sink or flush them into the toilet. Some countries have systems in place to bring back medicines to pharmacies for proper disposal. For example, in Canada, whilst there is no overall requirement for proper disposal of medicines, many provinces have taken the initiative to set up their own policies. In the province of Manitoba, prescription medications have always been allowed back in the pharmacy for proper disposal at the owner’s cost.

Whilst this cost has hindered the advertising of this program to the public and subsequently patient education on how to properly dispose of medications, it did not stop nearly 9,400kg of expired medications from being returned for destruction. In early 2010, the Manitoba government Issued regulations for stewards to take responsibility for household hazardous waste (of which, pharmaceuticals are included) where the costs to collect, transport, and destroy the medications would be covered by

continued

drug manufacturers; a similar venture was set up in the province of British Columbia. Statistics on how well the program is working in Manitoba have yet to be released (see Figure 1 overleaf).

Global policies needed

To protect the environment the

following needs to take place on a global scale: • Ban landfill and sewering of unwanted pharmaceuticals; • Provide universal rules/regulations for the handling of unwanted pharmaceuticals; • Regulations to be easy to implement, monitor and control;

Table 1: Are water treatment plans effective?

Sediment filtration ●

Particle-bound drugs

Activated charcoal ●

50% effective, selective

UV/UV H2O ●

50% effective, selective

Chlorine oxidation ●

50% effective, selective

Ozone ●

95% effective, selective

Reverse osmosis ●

80% effective

Iron-TAML ●

Fluoroaromatics – 17-beta-estradiol – by-product toxicities?

Source: NRDC White Paper December 2009

Table 2: Pharmaceuticals as endocrine disrupters Drug name

Endocrine system

Chloroform

Reproductive

Dioctyl phthalate (DEHP)

Estrogen/Androgen

Ketoconazole

Reproductive

Lindane

Estrogen/Androgen

Malathion

Thyroid

Permethrin

Androgen mimic

Nonylphenol

Estrogen

Arsenic (Trisenox, Atrivex)

Glucocorticoid

Mercury (Thiomersal, Mersol, Aeroaid)

Reproductive/Thyroid

Note: No minimal exposure limits fully defined for all species.

Source: www.ourstolenfuture.org/Basics/chemlist.htm

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FLUSHING AWAY OUR FUTURE

• Design drugs using the European Union Green Pharmacy concept with the end product and the impact to environment in mind;

continued

Table 3: Third world ‘donations’ (dumping) Genuine gifts versus dubious ‘gifts’

• Establish a pharmaceutical industry and government sponsored global take-back program that engages pharmacies across the globe to easily and safely take unwanted medications from the public. Pharmacists are the best healthcare professionals to help with addressIng this issue based on the security of the pharmacies, possible engagement with pharmacovigilance studies, and cost/waste estimation for governments providing universal health care;

• Educate the public on their role, minimising the expectation of receiving a 'pill for every ill' and emphasising the need to properly dispose of unwanted medications sitting in their medicine cabinets;

• Engage the pharmaceutical industry in designing 'green

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Clear out of nearly-expired stocks

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Tax write-offs (up to 2x production costs)

Examples ●

Expired antibiotics to Central Africa

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Garlic pills and Tums ® to Rwanda

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50% of donations to Bosnia expired/medically worthless

Recommendations ●

WHO list of essential drugs

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Expired date at least 1 year away Source: WHO Guidelines on Drug Donations

pharmacy' drugs, ensure that studies are done not only on humans but on the environment, and more importantly, ensuring that refuse and waste from all of their facilities adhere to strict environmental regulations and standards;

• Globalise the Stockholm County Council's Environmentally Classified Pharmaceuticals drug reference 7 and consider a global formulary based on the PBT index for safety. If a drug has a negative PBT (Persistence; Bioaccumulation; Toxicity) score, hold

Figure 1: Current Practice Drug Waste Process

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the pharmaceutical industry responsible for redesigning the drugs if possible and require it to set up a process to properly collect and dispose of unwanted negative PBT drugs; • Educate health professionals to minimise unnecessary prescribing of medications, look to quantity limits for starting new therapies, and globally ban the use of drug samples (33% of samples patients receive are never used; • Ensure that unwanted and waste pharmaceuticals are properly collected in communities and sent to a highly regulated wasteto-energy incineration facility.

There are facilities throughout the world that can effectively do this now.

Whereas community pharmacists have the opportunity to start changing the way people dispose

continued

their medicines and their packaging in an environmentally sound manner, a team approach is needed by all stakeholders: researchers, drug manufacturers, distributors, prescribers and users as pollution affects everyone from the rich to the poor, and because fresh, clean, potable water is becoming a finite resource.

Developed countries with sound programs in place should offer to help developing countries set up the necessary facilities needed to mitigate pharmaceutical environmental pollution. Drug manufacturers should lead the way with green pharmacy initiatives instead of waiting for government legislation to enforce better environmental practices. Patient safety not only pertains to the patient and the drug but to the patient, drug and the environment as a whole.

Some helpful links: www.enviroadvisory.com/pdf/Takeback.pdf. www.medicationsreturn.co/manitoba_en.php

References 1.Personal communication, Benjamin L Hammond, Professional Staff Member, Committee on Appropriations, US Senate, 2009 2.WHO (2011). Guidelines for drinking water quality. 4th ed. Geneva, WHO. 3.Shah. H. Pharmaceuticals in our environment. International Pharmacy Journal 2011; 27(2): 12-15.

4.Sumpter JP, Johnson AC. Lessons from endocrine disruption and their application to other issues concerning trace organics in the aquatic environment. Environmental Science and Technology 2055; 39(12):4321-4332.

5.http:/ hosted.ap.org/specials/interactives(national/pharmawater_update/index.html 6.http:/earth911.com/recycling/hazardous/ medications/what-happens-topharmaceuticals/ 7.www.janusinfo.se/Global/Miljo_och_ lakemedel_uppslag_eng.pdf

ORAL INSULIN DELIVERY SYSTEMS continued from page 5

administration for insulin, from rectal to oral, and much work has been done in search of a wide range of delivery systems.

In the last few decades, many research studies have concentrated on obtaining oral insulin delivery systems, with the aim of achieving bioavailable insulin therapy by the oral route, able to circumvent the obstacles presented by the gastrointestinal tract and enable the right blood insulin concentrations to be attained to achieve regulation of glucose metabolism.

Although some problems have not yet been overcome and extensive clinical trials are still needed, many innovative research studies have recently shed promising light on the new future of oral insulin therapy.

Progress achieved in the last few years with pulmonary (Exubera ® ) and oromucosal (Oral-lyn™ ) insulin delivery widens the horizon for investigating new administration routes, although there have been

major problems with both these products; Exubera was discontinued by the manufacturer after poor sales and Oral-lyn is awaiting further clinical trial results. In the not too distant future, it is possible that pharmaceutical companies may be able to provide patients currently dependent on subcutaneous insulin with new options, and that oral insulin delivery may soon be a reality rather than just wishful thinking.

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3

4

5

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Translated and adapted from an article first published in Spanish in Industrial Farmaceutica July-August 2011.

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A complete translation of the original article is available on request from the publishers: publisher@euromedcommunications.com

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References 1

Yamamoto A, Tanigushi T, Rykyuu K et al.

Effect of various protease inhibitors on the intestinal absorption and degradation of insulin in rats. Pharm Res 1994;11:1496-1500.

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Agarwal V, Reddy IK, Khan MA. Polymethylacrylate dissolution stability in the presence of enzyme inhibitors. Int J Pharm 2001;225:31-39.

Marschütz MK, Bernkop-Schnürch A. Oral peptide drug delivery:poymer-inhibitor conjugates protecting insulin from enzymic degradation in vitro. Biomaterials 2000;21:1499-1507.

Marschütz MK, Caliceti P, BernkopSchnürch A. Design and in vitro evaluation of an oral delivery system for insulin.

Pharm Res 2000;17:1468-1474.

Junginger HE. Bioadhesive polymer systems for peptide delivery. Acta Pharm Technol 1990;36:119-126.

Bernkop-Schnürch A, Clausen AE. Biomembrane permeability of peptides: strategies to improve their mucosal uptake. Min Rev Med Chem 2002;2:295305.

Talegaonkar S, Azeem A, Ahmad FJ, et al.

Microemulsions: a novel approach to enhanced drug delivery. Recent Pat Drug Deliv Formul 2008;2:238-257.

Damgé C, Socha M, Ubrich N, Maincent P. Poly (epsilon-caprolactone)/eudragit nanoparticles for oral delivery of aspartinsulin in the treatment of diabetes. J Pharm Sci 2010;99:879-889.

Ainslie KM, Kraning CM, Desai TA, et al.

Microfabrication of an asymmetric, multilayered microdevice for controlled release of orally delivered therapeutics. Lab Chip 2008;8:1042-1047.

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CONCORDANCE IN CULTURAL CONTEXT

and contested. For example the NHS hires chaplains, clinical psychologists and homeopaths in the third domain: professional.

The professional domain

by Malcolm E Brown

C

oncordance is a partnership approach to medicine prescribing and taking. It is different from 'compliance' where the patient takes medicine exactly as the prescriber instructed. Patients may not do so. That is analogous to a significant portion of the medicine from a non-homeopathic pharmaceutical facility containing no active pharmaceutical ingredient. That situation would have serious consequences.

Malcolm E Brown, MPhil PhD, MRPharmS is an author, a retired pharmaceutical consultant and QP, with a special interest in sociology.

Concordance recognises that patients choose whether to take a prescribed treatment. Concordance acknowledges that after learning about the relative benefits and risks a well-informed patient may decide to decline treatment. Patients who were involved in deciding about their treatment are more likely to be committed to taking their medicine.

Professor Sir Mansel Aylward recently said that "the power of belief and the misconceptions that patients have about their illness is the real challenge for all health practitioners." (my emphasis) and that "patient adherence(i) is more strongly influenced by their own common sense interpretation of their illness and treatment than by medical advice or instructions."

This article examines beliefs of patients and healers and highlights their importance for industrial pharmacy. I addressed issues about compliance in 2004 1. Since then, concordance has become more widely accepted. The World Wide Web encouraged that paradigm shift; I will explain later.

Two and a half thousand years before, the Talmud, a religious work, stated that we do not see the world as it is but as we are. Today’s sociologists would support that statement; it remains true and includes our health beliefs.

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Modern health domains

The anthropologist Kleinman described three health worlds.2 The popular domain

Almost all healthcare is within the popular domain. There resides the domestic medicine cupboard including its OTC medicines.

Patients suffering a cough concoct their own remedies from lemon juice, honey, hot water – and a generous tot of their favourite tipple. Personally, I prefer that prescription to similar industrial medicaments despite their meticulous quality assurance.

The folk domain

The second domain is the stubbornly independent “folk”.

British illustrations include Aloe vera purveyors, art and music therapists, acupuncturists, aromatherapists, homeopaths and traditional Chinese medicine practitioners. A pastoral priest may lay on hands that heal.

Talking cures flourish. Some may diminish demand for medicines acting on, for example, the central nervous system.

It is crucial to appreciate that both popular and folk domains offer beliefs that possess their own coherent logic and offer sophisticated interpretation of patients’ life experience. Boundaries between domains are permeable

Within that professional domain, pharmacists or medical practitioners, for example, believe in their respective worlds where they possess expertise and established theoretical models. For example, some drugs work by restoring the equilibrium of the diseased body that is an unbalanced biochemical machine. Professionals’ belief helps them earn their bread. So they suffer a trained incapacity that tends to make them “blind”, in a Freudian sense, to popular or folk worlds. A professional is like a child with a hammer; (s)he will think that everything is a nail and not for example a screw (that needs a screwdriver).

Moreover, all professionals have over history fought to maximise the status gulf between themselves and their patients. Accumulating prestigious credentials is one strategy; wealth tended to follow.

Professionals believe that they should be on top. That is why perceiving the patient’s world, and allowing it to prevail is so challenging. It is indeed, as Prof.

Aylward urged, the real challenge.

Historical health words

To better understand the context of that challenge, I now outline health worlds over history and place today’s healers and patients within a continuum focussed upon whether the opinion of healer or patient prevails.

Infested by demons

The health world (cultural landscape) of early men contained men and gods. Demons infested patients so causing disease. During early times one member of the tribe was a priest, scientist, magician, medicine man and pharmacist who practised magic against the demons.3 That investigator ejected the demons and developed the foul-tasting remedies presumably intended to so disgust the demon inside the body that the demon left. This may be the

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CONCORDANCE IN CULTURAL CONTEXT

origin of the popular belief that nasty medicine does you good. The healer was privy to sacred knowledge. The laity (patient) could not, in principle, possess it so the healer’s opinion prevailed.

A whole poorly person

I now fast forward millennia, past monks, pepperers and spicers, grocers and herbalists, to around 1770 – 1800 when physicians, apothecaries and chemists dominated. The health world has become the bedside. The investigator has become a practitioner with a bedside manner.

The patient, who chose which practitioner to pay, liked that manner, that treatment as a whole poorly person. Sufficient sediments of the medicine man remained for the practitioner to prevail.

A case

By 1800 – 1840, the health world had moved into the hospital. The investigator had become a clinician who focussed not on the whole person but a case e.g. a typhoid.

The professionalisation endeavour racketed upwards. One caricature is the patrician physician looking down on the poor patient. Sediments of previous eras remained. The clinician still prevailed.

A cell complex

By 1840 – 1870, the cultural landscape included professionalisation endeavours such as the foundation of the Pharmaceutical Society of Great Britain. The location migrated to the laboratory. The investigator has become a scientist healing a cell complex. Sediments from previous eras remained. In particular, mystery remained but not that of the priest who was a conduit to the gods; a kind of mystery resulted from the esoteric knowledge of the healer.

That became so vast that lay people could not understand it and so had to continue to trust the healer. The scientist’s opinion prevailed.

Risk assemblies

By 1900, the landscape became

continued

surveillance of whole populations.

The investigator had become an epidemiologist who investigated patterns using statistical techniques to address risk assemblies.

Illustrations are diet, clean water, infectious and occupational disease.

Government afforded public health doctors such as the local Medical Officer of Health had high status.

Residues of all previous worlds remained and the healers’ views continued to prevail.

Expert patients and health seekers

Again I fast forward, through the therapeutic revolution such as antibiotics, hormones, monoclonal antibodies and vaccines and the graduate status of many healers, to 1989. Then, engineer and computer scientist Sir Tim Berners-Lee wrote a proposal for the European Organisation for Nuclear Research (CERN) for what would eventually become the World Wide Web. Mass production, which had originated with the “Spinning Jenny” in cotton mills in England (1764), was applied to personal computers. The dominant landscape became hyperspace. Today that includes “e-scaped medicine”: knowledge about medicine escaped into the cultural landscape of hyperspace.4 A gargantuan literature, a tidal wave of information, is today accessible to anyone, anywhere, who is wealthy enough to possess an internet connection. The investigator had become the information scientist. Professional healers initially attempted to disparage such literature and argued that only their approved literature (such as “Martindale on line”) was reliable; sites without officially legitimated “kite marks” and so on were dangerous. Indeed some sites do mislead. However, the savvy surfer can find authoritative sources such the National Institute for Health and Clinical Excellence or Summaries of Product Characteristics. Today, expert patients and health seekers surf this health world and present printouts to their GPs. An example

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is urging a change to a less lipophilic statin so that dreams become less disturbing. Residues of every previous world still remain.

But the crucial change is that, in contrast to the shaman’s client who, in principle, could not understand sacred treatment, today’s patient, in principle, has access to knowledge.

Of course, professionals also use the web and their knowledge also includes professional experience so always will be greater. Knowledge of healers and patients has advanced in parallel. But so vast is web knowledge that the lead of the professionals represents a much smaller portion. Moreover, two other factors have also reduced the status gap: a perfect storm has brewed.

Since the 1960s, professional status in the West has eroded as part of the reduction of respect given to all authority figures. Finally, the British government has decreed that where professional and patient differ in opinion about treatment, the patient view should prevail. All that suggests that for the first time the opinion of patients – instead of healers – prevails. Table 1 summarises this process.

Meaning for industrial pharmacy

How can industrial pharmacy facilitate concordance today?

1. Industry contributes to confirming that patients are sick by its printed packaging. For example, patients realise that only certain prescribers may authorise access to prescription only medicines.

Industry labels: POM

Similarly for medicines that only a pharmacy may sell, industry labels: P

The continuing physical presence of those medicines within patients’ homes reinforces official

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CONCORDANCE IN CULTURAL CONTEXT

continued

Table 1: Health worlds pertinent to the development of concordance Approximate date of start

Group that prevails

Cultural landscape

Investigator/ healer

Perception of situation

Early history

World shared by humans and spirits

Priest/Magician/ Medicine man

Infestation by evil spirit

Healer

1770 – 1800

Bedside

Practitioner

Whole person

Healer

1800 – 1840

Hospital

Clinician

Case

Healer

1840 – 1870

Laboratory

Scientist

Cell complex

Healer

1900

Surveillance

Epidemiologist

Risk assembly

Healer

1989

E-scaped medicine in hyperspace

Information scientist

Expert patient/health seeker

Healed (facilitated patient)

sick status. One advantage is release from day-to-day duties.

2. Industry has responsibility during all phases of clinical trials to contribute to healthy volunteers (phase 1) or trial patients (phases 2 and 3) giving full informed consent and wanting to conform.

Industry continues its surveillance function in phase 4 (post marketing) trials.

3. Industry is responsible to ensure that patients understand patient information leaflets. Continued input from patients is valuable.

Address any concerns raised. If a product is relicensed or a similar product is “evergreened” give full weight to that patient opinion.

4. Monitor patient opinion on the web so see if extra information should be placed in the public domain that would increase concordance. Consider, within legal constraints, whether a company’s charitable arm could assist self-help patient groups.

Patients may trust the subjective opinion of fellow patients suffering from “their” disease more than the objective opinion of professional healers. Witness patients receiving chemotherapy

within an oncology day centre.

A spirit of camaraderie and understanding leaps out. Patients hang onto and believe the (encouraging) personal reports of their comrades in adversity.

5. Horizon scan to attempt to predict the next health belief. The sheer variety of beliefs to date suggests future belief may be disparate to anything that has previously emerged. The American politician Donald Rumsfeld (paraphrased) said, “There are things that we know. There are things that we know we don’t know. But there are things that we don’t know that we don’t know.” For example, Guttenberg (around 1440) knew nothing about the web. As ancient healers and clients believed in magic, it is probable that they would have perceived modern high-technology medicines as magic. Remember the “third law of prediction” of the engineer and science fiction writer Sir Arthur C Clarke.5 He stated that any sufficiently advanced technology is indistinguishable from magic.

6. Returning to today with a bump, an able and empathetic GP discussing the drive to

concordance observed with a headshake, “Fine. We have seven minutes per consultation”.

Industrial pharmacy should strive to assist making such consultations as time-effective as possible. Input such as in negotiating skills to postgraduate training and/or patient self-help groups might be one illustration.

The challenge of concordance is with us now. By reflecting and acting upon concordance, industrial pharmacy can contribute to creating a better joint future.

Notes: (i)

Adherence refers to individuals, concordance to parties.

References 1

2

3

4

5

Brown ME. Compliance: some psychosocial issues. Industrial Pharmacy 2004; 4:14-6.

Kleinman A. Patients and healers in the context of culture… Berkeley: University of California Press. 1980.

Madge M. A brief History of Pharmacy: With Some Observations on Alchemy.

Plymouth: Marchelle Publications. 1986.

Nettleton S. The Emergence of E-scaped Medicine. Sociology 2004; 38: 661-79.

Clarke AC. Hazards of Prophesy: The Failure of Imagination in Profiles of the Future: An Enquiry into the Limits of the Possible. London: Pan (1962; rev. 1973).

Visit the website: www.industrialpharmacy.eu for PharmaTV and Quality by Design videos, Regulatory Review, Financial Pharma News and other current items concerning Industrial Pharmacy

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MEDICAL DEVICES DESIGNED WITH PATIENTS IN MIND

by Steve May-Russell

T

he medical industry has a tendency to forget that medical devices are developed for human beings.

There is often an enormous amount of science, technology and research behind new devices, making them extremely clever in terms of functionality and efficacy, but too often there is a disregard for the people that they have actually been made for. For users it is often not just a case of what the device does, but how it makes them feel that really matters. Med tech companies and device manufacturers often forget the importance of designing devices that are focused on the user and all of their needs.

Steve May-Russell is Managing Director of Smallfry, Coventry, UK www.smallfry.com

Empowering patients

Traditionally there have been many stakeholders involved in getting a medical device to the patient; it had to be approved by the physician, explained by an educator, accepted by the caregiver, well received by the pharmacist, compliant with the NHS procurement procedures and – in the case of private healthcare – reimbursable by the insurance company. However, as the point of care moves from the doctor's room to the home, power is now shifting to the patients themselves.

Consequently, patients are starting to have more of a say in where their money is spent. No longer will they rely on the doctor to tell them which device to use, they will do their own research and select the product that best suits their lifestyle and meets their personal needs. This means that device manufacturers are going to have to work really hard to winover the end users.

The way to do this is to design devices with the patient, and their lifestyle, in mind. If a device is easy to use it will have a huge impact on patient acceptance, dosage compliance and ultimately the

health outcomes. As with consumer products, users choose to buy not just for what the product can do, but also for what it offers on an emotional level. Products therefore need to go beyond being merely functional and useable and start to offer pleasurable and meaningful experiences. Of course, medical devices are different from consumer products in that there are many levels of compliance and legislation that have to be adhered to, but if a patient has the choice between two devices they will opt for the one that is easier to use and offers the better experience.

Outside-in thinking

In order to have a more user focused approach, device manufacturers need to move away from the traditional way of developing devices that takes an engineering-focused mindset, developing new products based around technology and resources.

This is what we would call 'insideout thinking' – taking a technology, engineering a good solution and delivering it to market. The ultimate outcome is to gain profits through

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sales volume. But being technology driven will not always lead to success in the marketplace. True innovation comes from 'outside-in thinking' – focusing on user needs throughout the product development process and considering how the end user will interact and emotionally relate to the end product. This is where the silver bullets lie and will result in increased profits through continued customer satisfaction.

Another incentive to change the way medical devices are designed, making them more appealing to the end user, is the fact that many key drugs will reach the end of their patent protection in the next five years. According to a report from market analysts Datamonitor, drug makers are facing 'unrelenting generic competition' with medicines worth nearly $140 billion in sales due to lose patent protection by 20161.

In many areas up until now a single patented medication has monopolised the market. The medication has been the same for everyone and is delivered in the same universally generic medical device. But soon generic drug manufacturers will be fiercely competing with the large pharmaceutical companies for their market share, armed with identical formulations. The only way to compete will be through differentiation.

Also, with the latest revisions of the Medical Device Directive (MDD 2), manufacturers will have to start giving more consideration to human factors. Amongst the new revisions is an addition to the Essential Requirement highlighting clearer usability requirements and the need to consider ergonomic design.

Need for a well-designed solution

A means of gaining a competitive edge in this tough marketplace and ensuring that devices are user friendly is through effective design.

Many medical devices are inherently complex because the technology within them is complex, but everybody benefits from a welldesigned solution that makes this complexity simple to understand

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MEDICAL DEVICES DESIGNED WITH PATIENTS IN MIND

continued

Figure 1: Pyramid diagram A product needs to go beyond being merely functional and useable, it has to cross over the chasm to offer pleasurable and meaningful experiences to the user.

and easy to use. Smallfry is a Coventry-based industrial design and innovation consultancy that increasingly works in the healthcare industry, helping clients to create innovative and practical products that can become real market leaders. The key to their success is to go beyond thinking about the equipment and technology and focus on the user experience Figure 1).

(F A product Smallfry designed for Nurofen (ibuprofen) illustrates this thinking. The ear thermometer, aimed at parents with young children, has a sophisticated electronic function yet is simple, Figure 2). friendly and easy to use (F The device, with its colourful graphics and soft design, appeals to youngsters and does not look out of place in their bedroom. When inserted in the ear, the device not only gives a reading but also indicates the reading via a ‘happy’, ‘ok’ or ‘sad’ smiley icon. This is easily

14

understood by both parent and child and, although it is a very simple design feature, it provides a more meaningful experience for the user.

The same thinking was applied to a concept product that Smallfry worked on dubbed the Figure 3) which ‘Granogotchi’ (F allowed family and carers to keep up-to-date with their elderly relatives. The name came from the mid-90’s craze for the virtual digital ‘pet’ the Tamagotchi, where users checked on the status of their electronic pet and interacted, fed or played with them. The Granogotchi is intended to help keep an eye on elderly parents to ensure that they are getting out and about, eating well and taking their medication. It also includes instant voice messaging technology to help maintain an interactive connection between the user and their friends and carers.

Focus groups with elderly people and their children were carried out

Figure 2: Nurofen thermometer A premium branded ear thermometer designed by Smallfry for Nurofen. A simple yet very effective device that both parents and children can easily understand.

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MEDICAL DEVICES DESIGNED WITH PATIENTS IN MIND

Figure 3: Granogotchi The Granogotchi is a concept designed by Smallfry that allows family and carers to keep an eye on and stay in touch with their elderly parents.

together with CELS (The Centre of Excellence for Life Sciences), an initiative to help drive the growth of the healthcare and life sciences economy of North East England.

Many of the participants in the focus groups preferred the Granogotchi’s simple interface to their frustrations with mobile phones and enjoyed the experience it gave them. Although the Granogotchi is only a concept at this stage, it demonstrates the need to help humanise technology and make it more accessible.

One of the most recent products we designed for the medical industry is the Powerbreathe Kinetic Figure 4), the world's first portable (F precision electronic inspiratorymuscle training system, designed for HaB International. In simple terms, Powerbreathe is a ‘gym for your lungs’. It helps to strengthen the breathing muscles, reduce breathlessness and improve stamina by providing a carefully tailored resistive-breathing programme. The device can be used in athletic

continued

Figure 4: Powerbreathe Kinetic Smallfry designed the world’s first portable precision electronic inspiratory-muscle training system for HaB International.

training but is also of great benefit to those with medical conditions such as asthma, COPD or emphysema. Patented autooptimising IMT technology automatically selects the most effective training load based on respiratory muscle strength. Training results, progress and physiological respiratory measurements are continuously monitored and displayed on the high contrast LCD display.

Smallfry worked with the client from the early prototype stage all the way through to manufacture.

The challenge was how to integrate complex technology and mechanical requirements into a design that was appealing and userfriendly. When launched, not only did the product receive rave reviews from users it also resulted in commercial success for the client.

Amongst other medical devices currently under development is an innovative device for those living with Parkinson's disease. Designed with the user in mind, this new drug

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delivery system aims to help destigmatise the disease partly by having a more ‘consumer product’ appearance. Although having to take constant medication can be difficult for the patient, the device aims to improve their daily experience.

In conclusion, it should be obvious that, as medical devices are made to be used by human beings, their needs cannot be ignored during product development. If the design of a medical device has been more carefully considered and the product is more socially acceptable and more pleasurable to use, then it is more likely to be chosen over its competitors. The end result will be happy customers and a manufacturer who has gained a competitive edge in the marketplace.

References 1

2

Generics: Global Industry Guide 2011.

Datamonitor, August 2011.

Council Directive 93/42/EEC. OJ L 169,12.7 1993, p.1.

15

THE EPSRC CENTRE FOR INNOVATIVE MANUFACTURING IN REGENERATIVE MEDICINE

by Catherine Rogers, Melissa Mather, Felicity Rose, Kevin Shakesheff and David Williams.

T

his article outlines the scope and activity of the EPSRC Centre for Innovative Manufacturing in regenerative medicine and summaries the progress we have made during our first year. The EPSRC Centre is a collaboration between Loughborough University, University of Nottingham and Keele University. The Centre will focus on addressing major long-term manufacturing challenges and emergent manufacturing opportunities for regenerative medicine and will be a ‘go-to’ resource for companies developing novel therapeutic products.

Dr Catherine Rogers (1), Dr Melissa Mather (1), Dr Felicity Rose (1), Professor Kevin Shakesheff (1) and Professor David Williams (2).

(1) The University of Nottingham, (2) Loughborough University Correspondence: Catherine.Rogers@nottingham.ac.uk

Regenerative medicine (RM)

A rapidly evolving and exciting interdisciplinary field of research encompassing tissue engineering, biomaterials, bioengineering, developmental and stem cell biology. RM aims to produce novel cell and biomaterial based therapies to restore the function of diseased or damaged tissues, such as skin and bone, and to improve drug testing and disease modelling. This emerging industry is widely seen as the next major innovation in health care, as RM products will reduce the socioeconomic impact of our aging populations.

Types of RM products:

• Stem cells/Differentiated cells e.g. ReNeuron Plc, a novel therapy currently in early clinical development for stroke patients • Growth factors/Genes e.g. Medtronic INFUSE ®, a bone graft containing recombinant human bone morphogenetic protein (BMP) which initiates bone growth in the spine

16

• Biomaterials e.g. Apatech Actifuse, a biostimulative scaffold that accelerates bone formation.

Key obstacles in developing a successful RM therapy:

– Defining, formulating and delivering the product – Testing safety and efficacy – How to scale-up and manufacture the goods.

Launch of Centre

In September 2010, the EPSRC Centre for Innovative Manufacturing in Regenerative Medicine was launched to address these issues.

The Centre has been awarded £5.3 million funding for 5 years. There are three academic partners: • Loughborough University • Keele University • The University of Nottingham The Centre brings together a broad range of expertise: – Manufacturing and engineering (Loughborough University)

– Pharmacy and Tissue Engineering (University of Nottingham) – Biology and links to the clinic (Keele University).

The team comprises key people from multiple groups at all levels from senior academics (internationally recognised players in RM) and ‘new blood’ lecturers, through to the contributions of experienced researchers and doctoral students.

Aims of Centre

The Centre will be an integrated platform of world-class fundamental and translational research in tissue engineering and stem cell science, specialising in the design of biomaterials, the application of growth factors as drugs and in the scale-up and manufacturing of RM products. The centre will focus on addressing major long-term manufacturing challenges and emergent manufacturing opportunities for RM and will be a ‘go-to’ resource for companies developing novel therapies.

The primary objectives of the Centre:

• To create a critical mass of capacity and capability • To strategically anticipate needs and opportunities • To understand the RM value and innovation systems • To inform and engage in practical debate to influence • To generate capable processes, process platforms, quantitative and qualitative characterisation methods • To create a portfolio of supporting projects and studies.

Progress to date

We are now a year into the operation of the Centre and have started to build a research community willing to exchange ideas in an informal, interdisciplinary environment and have appointed an experienced Steering Group to guide us.

We have begun some very exciting projects that are beginning to deliver important results. These

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THE EPSRC CENTRE FOR INNOVATIVE MANUFACTURING IN REGENERATIVE MEDICINE

initial studies have been designed to influence public policy and regulation, to explore highly speculative ideas and manufacturing-led feasibility studies using state of the art production platforms and control.

Current industrial collaborators include Lonza, TAP Biosystems, Critical Pharmaceuticals, Haemostatix Ltd, Pfizer, ReNeuron Plc, and Intercytex.

There are three core research themes in the Centre: 1. Manufacturing and Automation

Project example – Efficient Manufacturing Platform for Adherent Allogenic Cell therapies.

In order to commercialise RM products, there is need for capable, scalable and manufacturing technologies. Therapies must meet regulatory requirements and be economically viable. Automated cell culture systems provide a platform for complex experiments (factorial design), cost effective process development and independent control and remove operationdependent variation.

Current methods to automate the production of cells in quantities necessary for therapy result in inconsistent products and high costs due to use of disposable plasticware and cell culture media. A new design concept for the production of RM cell products therefore has the potential for major impact in delivery of cellular therapies.

In collaboration with TAP Biosystems, we are using both current and near to market technologies, to design a highdensity stem cell manufacture system for RM applications that delivers process control and economic efficiency improvements over existing methods. We have successfully designed a novel fully automated cell culture platform system that minimises the requirement for manual intervention in cell production and provides opportunities for economies of scale. Culture of human embryonic stem (ES) cells, mesenchymal stem

cells (MSCs) and osteoblasts in this automated system results in lower variation than manual culture, with comparable growth profiles and differentiation.

Project team: Robert Thomas, Elizabeth Ratcliffe, Victoria Workman, Mark McCall, Craig Milner (Loughborough University).

Collaborators: TAP Biosystems.

2. Characterisation

Project example – Non-invasive, Label-free Quantitative Characterisation of Live Cells in Monolayer Culture.

We are currently developing a novel cell imaging technique that has already attracted researchers from Moorfields Eye Hospital in London and ReNeuron Plc. The tools being developed allow information to be gathered from living cells, relating cell quality to treatment outcomes for stem cell therapy. This breakthrough research will be of great benefit to patients at Moorfields in terms of corneal regeneration and to ReNeuron Plc in development of new cell lines for neural repair.

During processing, the phasecontrast and resolution of the cell

continued

image is improved to provide detailed Figure 1). structural information (F This research programme aims to engineer a new monitoring tool and develop a suitable computational framework to characterise the quality of live cells in culture. The information acquired will be used to optimise the overarching manufacturing process of RM products.

The key aim of the programme is to provide the necessary insight into the nature of the cell culture process to: – Enable design of optimised and automated imaging processes necessary for effective scale-up – Reduce operator-to-operator variability in culture processes – Develop methodologies to objectively characterise and compare different cell lines – Identify baseline parameters for long-term monitoring of cell lines The live cell imaging technique will be very useful to further understand cell well-being and allow optimised design of cell culture strategies.

Project team: Melissa Mather, Mike Somekh, John Crow, Virginie Sottile (University of Nottingham).

Collaborators: ReNeuron Plc, National Physical Laboratory.

Figure 1: Image processing of Total Internal Reflection Microscopy images: (a) Unprocessed image of neural cell, (b) filtered image to identify boundaries of the cell, (c) segmented image displaying three levels of information content, (d) segmented image showing areas of highest information content corresponding to cell boundaries.

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THE EPSRC CENTRE FOR INNOVATIVE MANUFACTURING IN REGENERATIVE MEDICINE

Formulate with growth factors

continued

Growth factor release stimulates repair

Scaffold In vivo regeneration

Form cells/scaffold composites

Cells build tissue within scaffold

Figure 2: The role of scaffolds in regenerative medicine.

3. Delivery and 3D Constructs

Project example – A New 3D Delivery Platform for Regenerative Medicine.

Stem cell and differentiated cell based therapies to restore tissue function have received much interest. The development of novel scaffold materials to aid in the scaleup of cell manufacture is therefore of great commercial value and strategic importance to the RM industry. Scaffolds orchestrate biological signals, determine local mechanical properties and transport cells with high viability and minimal phenotypic changes. Hence, the selection of the appropriate material for scale-up production of cells is of Figure 2). critical importance (F Biomaterials play many pivotal roles in RM. These include providing an appropriate 3D environment that supports cell attachment, proliferation and differentiation and mechanical support for developing tissues.

Current methods for scaling-up cell numbers, involve 2-dimensional (2D) culture systems, trypsination for subculturing and multiple freeze and thawing steps for cell storage. We are currently working on a new 3D

18

delivery platform for RM, in which cells are entrapped during the assembly of the material. The novel design allows cells to grow within the supporting material and subsequently be safely released through scaffold disassembly. This project has already received great interest for commercialisation and marketing from established companies such as RegenTec. To date, both 2D and 3D systems have been investigated for cell culture use, leading to an exciting proposition of large scale-up of cellbased RM products. The project is currently passing through an initial proof-of-concept stage, in which the production of individual scaffold components have been scaled-up and the cytocompatibility of the novel 3D delivery system has been tested with a variety of cell types useful for RM. Project team: Kevin Shakesheff, Cameron Alexander, Aram Saeed (University of Nottingham), Alicia El Haj (Keele University), Robert Thomas (Loughborough University), Brian Saunders (University of Manchester).

Collaborators: RegenTec.

Future Opportunities

There will be many opportunities in the Centre to form new collaborations with both industrial and academic partners, who are developing a RM product. There are postdoctoral researchers employed in the Centre who are dedicated to working on short demonstrator projects (up to 12 months) on behalf of our collaborators. The Centre can provide 50% of the funding for these proof-of-concept projects. As the Centre supports the development of long-standing collaborator relationships, we hope that any successful demonstrator projectors will develop into full proposals.

Current collaborators include Pfizer, Haemostatix Ltd, RegenTec Ltd, The University of Cambridge and Newcastle University.

For further information about the Centre, please visit: www.esprc.ac.uk/research/centres/innov ativemanufacturing/pages/default.aspx

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INTEGRATING IT TOOLS WITH PHARMACEUTICAL INDUSTRY AND EDUCATION IN INDIA

by Shyamal Kalani

I

n recent times, the pharmaceutical industry has undergone extensive globalisation and harmonisation of regulatory affairs. With the introduction of new Good Manufacturing Practices and Good Laboratory Practices, the Indian pharmaceutical sector is undergoing widespread up-grading, both technologically as well as perceptually. In the current scenario, it is important for the education system to strengthen and update as per the current industry requirements, incorporating elements of IT skills and industry practice, to generate a more competent workforce.

Shyamal Kalani, B Pharm, MSc is Vice President Technical with Oasis Infotech (a division of Oasis Test House Ltd.), Jaipur, India, a leading software provider for pharma, healthcare and other industries, offering customized LIMS, ERP and related solutions to automate operations.

Email: kalanishyamal@gmail.com Web: www.oasislims.com

Introduction

The Indian pharmaceutical industry has emerged today as the most dynamic manufacturing segment of the Indian economy; coming a long way from the 1950s when it had little technical competence to manufacture modern drugs locally1.

It has achieved technological capabilities to manufacture quality drugs indigenously and costeffectively, and emerged as a major competitor in the world market1.

The past few years have seen a dramatic rise in the level of regulation in the pharma and life sciences sectors. The introduction of new Good Manufacturing Practices and Good Laboratory Practices under Drugs and Cosmetics Rules, has led to vast scale up-grading of the industry.

And, the Indian pharmaceutical industry is looking at this era both as an opportunity and as a challenge.

The new regulations have

implications for the entire industry, and as a result, pharmaceutical organisations are reviewing their compliance strategies, methodologies and associated costs 2. High competition, less time to reach the market and a highly regulated environment have forced Indian pharma companies to adopt advanced and latest IT and automation solutions. Various software systems such as Enterprise Resource Planning (ERP), Laboratory Information Management Systems (LIMS), etc. are being increasingly accepted and implemented across the industry.

The growth in the pharma sector has opened up a host of career opportunities. And, in order to exploit the numerous job opportunities offered, it has become necessary for pharmacy graduates to keep themselves updated with the current practices, information technology in use and industry requirements.

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Emerging role of IT in pharma sector

In the area of pharmacy, there are volumes of data with respect to drug formulations, chemical compounds for drugs, details of clinical trials, etc. which can be stored using IT 3. Pharmaceutical companies are using IT across various functional areas like R&D, QC, QA, Manufacturing and Supply Chain, Marketing, Sales and Corporate Management. Not just the industries, but also clinical, hospital and community pharmacies are acknowledging the importance of IT solutions. Information Technology is used to assist the delivery of pharmaceutical care, medication regimen adherence, patient safety, measurement of therapeutic outcomes and patients’ self-care management 4.

As a result of the regulatory changes, documentation has become an essential and integral part of the functioning of pharma industry. Software systems make the documentation work easy, accurate and time efficient, thereby helping to achieve regulatory compliance.

Moreover, IT systems provides increased security to the company data and prevent unauthorised access to the company procedures, documents, STPs, SOPs, etc. This data security is perceived as a necessity, due to the data-sensitive nature of the pharma industry.

In addition to compliance and security issues, the need for a rise in productivity is also a significant driver of IT adoption and implementation2. Software solutions aid the smooth functioning of pharma units by simplifying the work of managers and increasing company returns. As a result, IT now plays a strategic role in organisations rather than just as a support system.

Software tools commonly used in the pharma industry

In recent years, there has been a significant rise in the use of the computer-related systems in the pharma industry. Many industries have got most of their operations computerised. Not just the big pharma companies, but even about

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INTEGRATING IT TOOLS WITH PHARMACEUTICAL INDUSTRY AND EDUCATION IN INDIA

continued

Table 1: Some commonly used software solutions and their key features S.No 1

Software tool

Key features

Laboratory Information Management Systems (LIMS) Automates laboratory processes to increase productivity, efficiency and quality in analysis

Enables laboratories to handle complex work flow and sample data management requirements Provides complete sample tracking automatic calculations of test methods, instrument management, specification maintenance, standards/reagent management, user certification, report/ worksheets/CoA generation, etc.

Other features such as trend analysis, vendor rating, stability scheduling and data compilation, market complaints management, trade returns analysis, training management, etc.

2

Enterprise Resource Planning (ERP) Integrates all data and processes of an organisation; reducing information silos in various departments

Production and inventory management, weighing and dispensing, electronic batch records, electronic packaging records, financial accounting, personnel management, training and development, etc.

Helps users maintain entire documents/records correctly, completely and timely as per new GMP requirements

3

Sales Force Automation (SFA) Manages data, controls on-line the movement of goods and manpower, including distribution network for pharmaceutical marketing

Web-enabled field sales, force automation solution, on-line records, doctor visit reports, tour plans and approvals, sales summaries, booking sales orders, Expense details, stock inventory, etc.

4

Customer Relationship Management (CRM) Automates and manages the entire customer life cycle within an organisation including, sales, marketing, customer support, and contact centres 2

On-line customer portals for troubleshooting and support, sales schemes and resolving queries Also used for market surveys, identification and development Systems are available for providing medical representatives with sales and marketing strategy and in-field computer-aided instructions Aids the conversation of a prospect into a customer and helps an organisation retain its existing customers by building and maintaining successful relationships 2

5

eBR (Electronic Batch Records) Software for on-line management of batch manufacturing and packaging

Secured document management, checks data integrity, performs automatic calculations Automatic audit trail and other control measures to help ensure compliance with 21 CFR Part 11 regulations

70% of the small and medium enterprises in India utilise automation in one form or other.

Software systems are being increasingly accepted as an essential part of a modern and progressive pharma industry. Table 1 shows some of the commonly used software solutions and their key features.

As a result of the computerisation of pharma enterprises, industries require qualified and skilled manpower exposed to IT systems, with up-to-date knowledge of the current industry practices. However, the education system has been struggling to keep pace with the

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rapidly changing industrial scenario.

Gap between industry practices and education systems

Over the past decade, there has been a significant rise in the number of institutions offering pharmacy programmes in India. There are thousands of pharmacy graduates in the country today. However, their exposure to the latest systems, industry practices and IT operations is inadequate.

Though the pharmacy curriculum in India is primarily industry and product focussed 5, lack of practical orientation and interdisciplinary

knowledge, make it difficult for the students to keep pace with the changing trends of the industry.

There is an immediate need to acquaint the pharmacy students in GLP, analytical techniques, validations, innovations in pharmaceutical technology, clinical research, communication and interpersonal skills and shop floor relations 6. There is a vast difference between the knowledge and skills received by pharmacy graduates at educations institutes and the actual work requirements at the industry.

There is a dire need to bridge this gap between the academia and the industry practices. Industry-

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INTEGRATING IT TOOLS WITH PHARMACEUTICAL INDUSTRY AND EDUCATION IN INDIA

Academia interaction is a matter of great relevance in the present context of globalisation of pharmaceutical education. Such an industry-institute relationship would be mutually beneficial. The institutes would become self-reliant, the course curriculum practical oriented and the students shall be better trained and skilled for a career in the industry.

Conclusion

Information Technology has become an indispensable part of the pharmacy profession and it should be integrated into pharmacy education and curriculum. Now that the “Decade of Health Information Technology” has arrived, pharmacy education needs a new philosophical and conceptual basis consistent with the emerging technology. The primary focus of pharmacy education system should be on providing scientific and technological training in various

aspects such as, drug identification, formulation, distribution, quality control, quality assurance and drug use8, and imparting knowledge of IT tools and Management Information Systems (MIS).

Pharmacy informatics can be defined as the specialised application of information technologies used to advance the pharmacy profession 4. Pharmacy graduates should understand and have the capabilities to update and maintain pharmacy information systems; query, report, use and analyse the data.

Pharmacy education should be designed and updated to create pharmacists who are more competent to apply their skills for strengthening the pharma industry.

It is a relatively new concept to impart training to pharmacy students based on software tool; however, it has become the need to the hour with the changing scenario of the profession.

continued

References 1

Pradhan J P. Global Competitiveness of Indian Pharmaceutical Industry: Trends and Strategies, Institutes for Studies in Industrial Development, Working Paper, 2006.

2

Julian E. What pharma wants from IT today. Pharmaceutical Executive, July 2005.

3

Mukherjee R. Application & Scope of IT in the Indian pharma sector. Journal of Medical Marketing, 2006; 6 (2): 146-150.

4

Felkey B and Villaume W. The Integration of technology into pharmacy education and practice. International Journal of Pharmacy Education, 2004.

5

Basak S and Sathyanarayana D. Pharmacy Education in India. American Journal of Pharmacy Education. 2010; 74 (4).

6

Report of the working group on drugs and pharmaceuticals for the eleventh fiveyear plan (2007-2012). Planning Commission of India, 1st December 2006.

7

Flynn A. The current state of pharmacy informatics education in professional programs at US Colleges of Pharmacy.

American Journal of Pharmaceutical Education, 2005; 69 (4), 490-494.

8

Ligade V, Sreedhar D, Manthan J, Ajay P and Udupa N. Pharmacy education in India-marching with the times. The Pharma Review, December 2008.

Handbook of

Pharmaceutical Excipients New seventh edition

Additional content.

More up-to-date.

Complete confidence.

Pharmaceutical Press is the publishing division of the Royal Pharmaceutical Society

“A good knowledge of the excipients to be used in future formulations or for drugs on the market, is vital, and the Handbook greatly aids this process…”

British Toxicology Society Newsletter

european INDUSTRIAL PHARMACY September 2012

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SS tio fre al he n. e

EDITORS: Raymond C Rowe, Paul J Sheskey, Walter G Cook and Marian E Fenton ISBN 978 0 85711 027 5 • £299 Also available online as part of MedicinesComplete.com

New and updated content that makes the 7th edition a vital resource to have at your side: • 40 new monographs including Cellaburate, Dextran, Ethylene Glycol and Vinyl Alcohol Grafted Copolymer, d-Mannose, Polyvinyl Acetate Dispersion, Pullulan, Pyroxylin and Sucrose Palmitate.

• New infra-red (IR) spectra figures for over 100 excipients • New Appendix created in response to user requests • New regular updates online to keep information current • 340 existing monographs fully revised in the light of current knowledge • Supplier index updated

Y IN EAR ce CL Ha ss t UDON o Ex ndb th L cip oo e o wi ie k n ED IN th nt of lin E th s is Ph e v e p in ar er FR A C rin clu ma sio E t e de ceu n o E CE di d tic f t

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book review Handbook of Pharmaceutical Excipients 7th Edition Edited by Raymond C Rowe, Paul J Sheskey, Walter G Cook and Marion E Fenton Reviewed by Iain Moore

Excipients are an essential part of the safe and effective delivery of the active ingredient to the patient. It is critical therefore, that not only the properties of the excipients are understood but also the safety, interactions and typical functionality of excipients are known. The selection of excipients is crucial and this will be readily aided by over 350 excipient monographs contained in the 7th edition of the Handbook of Pharmaceutical Excipients.

The consistent layout and structure is reader-friendly and provides an excellent reference point. The tables listing the properties of families of excipients are particularly useful and informative as are the comparisons of the various compendial requirements.

However, the quality of the individual monographs is variable no doubt due to the expertise and knowledge of the individual writers and the goodwill of the manufacturers and suppliers of the excipients to provide accurate and up-to-date information to these authors.

Some monographs cover details from one region but omit information from others. For example, the poloxyethylene stearates monograph states that typical residual levels of free ethylene oxide should be less than 100ppm (noting the explosion hazard this presents in the bulk containers!). No comparison of the compendial specifications for this class of product from the European Pharmacopoeia specifications is included in the monograph, in which case the stricter limits of 1ppm max would have been apparent. Nor is mention made of residual 1,4 dioxane levels, a toxic impurity, which is again limited in the European Pharmacopoeia monographs.

For the oleochemical based monographs, I would prefer to see greater emphasis and consistency on the fact that the molecular weight, as well as the empirical and structural formulas, is an indicative value only because many of these excipients are made with fatty acids or fatty alcohols that are mixtures of different carbon chain length components.

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The details on the method of manufacture can be rather vague and do not therefore provide the reader with enough information or leads to begin to assess the impurities or processing aids that may remain in the product. For example, catalytic hydrogenation of triglycerides is referenced in the manufacture of cetyl alcohol, but no hints are given as to the likely catalysts used.

The section on regulatory status is particularly useful as it indicates if the excipient is listed in the FDA inactive ingredients database and in what kind of applications as well, thereby setting precedence of use.

The section on handling precautions appears to have been taken from material safety data sheets and should be interpreted accordingly in terms of the precautions needed when handing these materials in large quantities in an industrial environment. In some cases however, they refer to the inhomogeneity of the product and therefore reflect prudent GMP precautions to be applied when dispensing the excipient.

This is a very valuable additional detail.

Some details on published safety studies are included, although, a lot of these references are now quite old and so may not be representative of the quality of material available from today’s suppliers.

Some tradenames are obsolete but it is useful, as the authors acknowledge, to include these for historic and reference purposes.

It must be challenging to keep the appendices accurate and in this regard it would be helpful if the suppliers themselves were able to validate the details on their entries. The Index can be incomplete with some tradenames being listed and referenced to the monographs and others not.

The knowledgeable reader will not have any issues with these minor observations and in this regard the Handbook is an essential companion in the excipient formulators’ reference collection.

There is no better or succinct source of information on excipients available and the editors and author are to be credited with producing such a valuable reference work.

Iain Moore is Global Head of QA, Croda Europe Ltd. Published by Pharmaceutical Press 2012 (7th Edition) ISBN: 978-0857110275 Hardcover: 1,064 pages. Price £260.00

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regulatory review Introduction The current review period has seen a number of changes in the regulation of medicines and regulatory guidance in the EU, International markets and the USA.

United States of America Thiomersal in vaccines

Thiomersal is a mercury-containing organic compound. An increasing awareness over many years of the theoretical potential for neurotoxicity of even low levels of such compounds raised concerns about the use of Thiomersal in vaccines and other products. FDA continues to work with vaccine manufacturers and Thiomersal has been removed from, or reduced to trace amounts in all vaccines routinely recommended for children age 6 and younger, with the exception of inactivated influenza vaccine.

FDA has published a discussion of preservatives, including: • the use of Thiomersal as a preservative • guidelines on exposure to organomercurials • Thiomersal toxicity • recent and future FDA actions • conclusions – Institute of Medicine's most recent review of Thiomersal in vaccines • Frequently asked questions & answers Guidance for Industry Pyrogen and Endotoxins Testing: Q&A

USP and AAMI documents describing methods and calculation of pyrogen and endotoxins testing limits provide industry with appropriate information on endotoxin testing. Continued development of USP Chapters <85> and <161> and FDA guidance documents led FDA to withdraw its 1987 Guidance which no longer reflects current thinking. The compendial chapters and standards do not address certain regulatory perspectives. FDA is providing supplemental information to explain its current thinking regarding the submission and maintenance of

pyrogen and endotoxins testing for FDA-regulated products.

USP New Chapter<1660> Inner Surface Durability of Glass Containers

In response to the recent product recalls USP proposes a new general information chapter to recommend approaches to predict potential formation of glass particles and delamination.

Europe Compilation of Community Procedures on Inspections and Exchange of Information

This latest version contains new templates under the ‘Forms used by regulators’ section covering: • Wholesale Distribution Authorisation • Good Distribution Practice Certificate • Good Distribution Practice Certificate for Active Substances • Statement of non-compliance with GDP • Statement of non-compliance with GDP of a distributor of active substances • Registration of Manufacturer, Importer or Distributor of Active Substance • Co-ordinating GMP Inspections for Centrally Authorised Products In addition a procedure for dealing with serious GMP non compliance information originating from third country authorities or international organisations has been added.

EU GMP Guide The European Commission has updated part 3 of the Guide

A template for the written confirmation for active substances exported to the EU for medicinal products for human use, has been added as the fifth document to be published under Part 3 of the Guide.

A Q&A document has also been published which sets out FAQs. The template appears quite simple but the Q&A contains 32 Q&A This is indicative of the complexity of the possible scenarios for import of active substances.

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e-TACT Round-table Discussion

The Council of Europe hosted a Round-Table for high level discussion on “Identifying falsified medicines/How best to protect European citizens?” Central to the eTACT proposals is the ability of patients to be able to verify the authenticity of their medicine.

Industry proposed mechanisms tend to fall short of this goal.

CEPs Help on Submission of Notifications, Revisions and Renewals

A guide has been established to help applicants when compiling their submissions of notifications, revisions and renewals of dossiers for CEPs. UK Human Medicines Regulations 2012

These Regulations greatly simplify the legislative framework for medicines. They replace most of the Medicines Act 1968 and 200+ statutory instruments. Subject to Parliamentary clearance, the Regulations come into force on 14 August 2012.

International Excipients

Both China and Brazil have put forward proposals for GMPs for excipients. China has achieved this via a guideline and Brazil via a Normative Act. In the case of China instances of the use of gelatine made from the waste products of tanneries, rather than from approved animal sources was a factor. Under both proposals, drug manufacturers have the primary responsibility to assure the quality of the excipients and additives that they obtain from their excipient suppliers.

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 Euromed Communications. To subscribe to this monthly news service contact info@euromed.com

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pharmaceutical forum The following is a selection of the questions and answers taken from recent exchanges in the PharmWeb GMP Discussion Group. This Forum is held on the Internet at www.pharmweb.net/gmp.html and sponsored by the publishers of European Industrial Pharmacy and GMP Review.

The Forum is free of charge and open access. It serves as means of exchanging views within the context of international regulations affecting the manufacturing side of the pharmaceutical industry. Your own questions and answers are very welcome. Send them to www.pharmweb.net/gmp.html but please remember to write your name and email address at the bottom of your message.

Dissolution Q Initial dissolution results, were as follows: 93.5, 91.7, 63.9, 90.6, 98.8, 81.8 and so an S2 was required. But the S2 results averaged 91.5 with a maximum of 63.9 and a maximum of 100.9.

Should I now have to go to an S3?

Response: 1 Go to S3 as one result under 65% Response: 2 What’s your Q value?

If 75% then will pass S2, otherwise you must go for S3. You should issue OOS and investigate.

Response: 3 Please note – there is no OOS for dissolution as such...see the FDA guidance…anything that reflects potential non-homogeneity cannot be subject to OOS (obviously it is beyond the lab investigation if you find that someone made a silly mistake).

So indeed you can have a situation where at 6 tablets you have one tablet that falls outside the S2 results then there is actually no point in going on because you have failed at all three levels. In such a case – unless there is a lab error, you have a failed batch which is not retrievable.

Response: 4 OOS and investigation should be done even if the batch has failed the release criterion for following reasons: – If this is an RnD batch, one can learn more.

– If this is a commercial batch and will be destroyed, the data should form part of the annual product review.

– A CAPA can be drawn up to avoid future such problems. It should be determined if there is a need for

24

change in formula/process or analysis as the failing criterion is drug release.

– If no root cause is arrived at, batches should be evaluated statistically.

Response: 5 To my mind USP dissolution testing is analogous to USP Conductivity testing of Purified Water. If you fail level 1 (<1.3 mS/cm), go to level 2, if you fail that go to level 3.

If you failed level 3, then this is an OOS. If you normally pass level 1 and need to go to levels 2 or 3, then you have an Out-of-Trend.

Why would such a situation with dissolution – needing to go from S1 to S2 – be any different, or have I missed something?

Response: 6 FDA guidance on OOS makes it quite clear that the normal rules of OOS do not apply to any measure that may reflect the homogeneity of the product-simply because you can never be sure that the result is not a real reflection of non-homogeneity. Obviously, silly analytical errors are still correctable if confirmed.

However, going to level 2 or 3 as part of the dissolution test is not considered an OOS because actually the USP dissolution test is not considered an OOS because actually the USP dissolution test is on 24 tablets and if you pass with the first six at level 1 you do not need to continue…so that is not an OOS situation (stated categorically

by FDA in a Q&A).

Now I agree that if in year one you pass at level 1 and in year two you pass at level 2 you obviously

have an OOT which requires RCA – but the occasional drop of level is not OOS. Interestingly, because of the situation with dissolution, you now find the term OODS used in some 483s.

New SKU stability requirements Q We have a mature product with two SKUs (Stock Keeping Unit), and want to launch a new SKU of this product with similar packaging but with little difference of flavours. Do you think, we need a stability study as per new products guideline or do we need a risk assessment and market the new SKU with concurrent stability?

Response: 1 Definitely you need it!

Response: 2 In my experience, a product with a different flavour is a different product, and so needs a dedicated stability study. Of course, this may depend on how small the stated “little difference of flavours” is. And also how similar the “similar packaging” is. If the flavour includes a natural product, then it can be very sensitive to storage conditions and packaging.

Hold time study Q What is the actual process of the hold time study.

Response: 1 “Holding time” study is simply the validation of the maximum duration time during which you can hold something in a “steady” state.

For example “clean holding time” is the maximum time during which a cleaned equipment/room is expected to be kept in a state of cleanliness. “Sterile holding time” to the maximum time an item can be stored after sterilisation and expected to be sterile (it of course depends on the type of packaging it has).

Expiry date of formulation vs API Q There do not appear to be any guideline as to the expiration date of formulation compared with the

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expiry date of the API used, apart from Schedule M. Are there any other references or articles on this subject?

Response: 1 APIs are almost always characterised by a retest date, not an expiry date. The retest date describes the date by which the API must be used in a formulation; or if not used in a formulation by that date, the API must be retested before use.

The expiry date of the formulation is determined separately and is independent of the age of the API. Response: 2 I already have seen a number of APIs packed in fibre drums and labelled with an expiry date “expiry” and not a retest date “retest” during the audits I have conducted in the past and recently.

However, I have no memory of which materials there were so I have no idea of the reason why they were labelled “expiry” and not “retest”.

While it is not a rule, I often see “expiry” dates 5 years ahead and “retest” dates 2 years ahead. My guess is that where companies have 5 years data they consider that 5 years are enough (not taking Schedule-M into account) and were they do not have this information they label their products with a 2year retest period.

It might be better to ask some APIs companies about their SOPs. Response: 3 The idea should be to have a retest for an API as it can be tested at the facility undertaking the formulation. If the API results are good, it can be used unless the manufacture has cause or data to believe it would deteriorate and defines an expiry date. One must take into account the possibility that the storage conditions specified can be compromised and even if the API is within the retest date, it can deteriorate.

However, for a formulation that would be consumed by a consumer who is unlikely to check for quality, an expiry date would serve as a go/no-go test.

Response: 4 The expiry date for any product whether it’s an API or formulated is always based on stability studies conducted at normal and accelerated conditions based on statistical analysis, normally with three batches, taking into consideration factors such as storage condition, packing container material, etc.

Response: 5 A full risk analysis may be needed. Remember that there are several possibilities. For example, very often the drug substance is more stable than the finished dosage form in which case the possibility of taking a close to expiry API could be critical, particularly if there is an autocatalytic reaction involved. On the other hand, there are examples where the finished formulation is more stable than the API, where I would guess there is less of a risk.

It is also very important to remember that the predictability (extrapolation) of data for shelf life is dependent not only on the kinetics involved but also on the reproducibility of the analytical method.

Mapping of small warehouse Q Does anyone have any suggestions for mapping a small warehouse at room temperature?

Warehouse is about 50 m 2, all walled-in and centrally heated.

Response: 1 You should put loggers around the warehouse to be sure that the temperature and/or humidity in the work-space is within the specifications. Do not forget to put loggers near some critical points (doors, arrival of clean air, etc). You

could apply the international standard CEI 60068-3-11.

Response: 2 The aim of temperature mapping is twofold.

Firstly, you need to establish that the warehouse will maintain temperature to specification.

Secondly, you are trying to identify hot spots and cold spots within the warehouse that you will monitor on a regular basis that will provide confidence that the remainder of the warehouse will be within your defined temperature range.

As part of your temperature mapping plan you need to identify areas of risk where product may be exposed to extremes of temperature, for example: central heating duct blowing hot air over product, doors that open to the unconditioned areas and racking or shelving that may obstruct air circulation. You should also map at high medium and low levels to find out if you get temperature stratification in the facility.

The number of measuring points you need will depend on the size of the warehouse. The recommendation I have seen is that you should have a grid where the temperature loggers are spaced between 100 and 300 feet apart. For frequency of measurement, I would choose a reading every 15 minutes. This should allow you to pick up temperature trends throughout the day.

In terms of how long to map the temperature, I would look for a minimum of 3 days. If you have redundant HVAC in the system I would want to see each of the units working for a minimum of 3 days and at least 3 switches between the HVAC systems. The maximum length of time I would map for would be 7 days. Finally, you will need to map the warehouse in both summer and winter conditions.

Visit the website: www.industrialpharmacy.eu for PharmaTV and Quality by Design videos, Regulatory Review, Financial Pharma News and other current items concerning Industrial Pharmacy

www.industrialpharmacy.eu european INDUSTRIAL PHARMACY September 2012

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news from the EIPG Draft Technical Documents

Unique Identifier – EIPG has submitted comments on the European Commission’s concept paper for a Unique Identifier for medicinal products and its verification (see EIPG website, position papers).

Active Substances – Following our comments on the concept paper on the Regulatory Framework for their manufacture, EIPG submitted comments on the Commission’s paper on the Principles and Guidelines of Good Manufacturing Practice for Active Substances (see EIPG website, position papers).

Good Pharmacovigilance Practices – Guidelines on Good Pharmacovigilance Practices are under development by the European Medicines Agency (EMA) and EIPG comments on Modules IV and XI are about to be submitted.

Drafts of further modules will be released for consultation before the end of the year.

Medication Errors – The EMA’s draft position paper on potential medication errors in the context of benefit/risk balance and risk minimisation measures has been circulated to Member Associations for comment by 1st October to allow for a consolidated response.

The document can be found on the EIPG website under consultation deadlines. Comments should be sent to: jane@nicholj.plus.com.

education and training of a sectoral profession in which studies are governed by an EU directive and characterised by their long (5 year) duration, the important role of the apprenticeship/training and the continuing professional development.

Formation of new association in Ireland

PIER (Pharmacists in Industry Education and Regulatory) is a group that has recently formed to represent the interests of pharmacists in Ireland engaged outside of the traditional patient facing dispensing roles. Over 200 pharmacists work in the various sectors that support the Irish pharmaceutical industry and education sectors. The main

objectives of PIER are to promote the professional status for these pharmacists in Ireland and to support their further education as a formal CPD system is implemented.

PIER will also support the three Schools of Pharmacy in the rollout of the fully integrated MPharm degree.

The first PIER committee meeting took place on 4th July 2012 and a launch event is planned for November 2012. For further details contact: Maura.Kinahan@pfizer.com Potential new members of EIPG

Anyone in contact with pharmacists working in the pharmaceutical industry of Poland or Slovakia, please write to: jane@nicholj.plus.com Jane Nicholson

EIPG Symposium

During a Bureau teleconference, plans for the Friday 19th April 2013 Symposium prior to the EIPG General Assembly in Brussels were discussed.

EIPG Representation

Next month, Dr Nuno Moreira, VicePresident Education and Training, will attend a working party meeting on Pharmine 2 to develop a quality assurance system for pharmaceutical education. This will be in the context of Bologna and the principles of

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european INDUSTRIAL PHARMACY September 2012

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events OCTOBER 1-3 October 2012 – Dublin, Ireland TOPRA Annual Symposium Medical device regulation in Europe: Now and the future www.toprasymposium.org 3-8 October – Amsterdam, Netherlands Improving Health Through Responsible Medicines Use www.fip.org/amsterdam2012 7-10 October 2012 – Cortona, Italy Advances in Pharmaceutical Innovation and Manufacturing Control www.ifpaccortona.org 9-11 October 2012 – Madrid, Spain CPhI Worldwide/ICSE/P-MEC Europe/InnoPack www.icsexpo.com 15-16 October 2012 – Windsor, UK Sterile Manufacturing Dialogue 2 www.sterilemanufacturingdialogue.com 23 October 2012 – Manchester, UK How to Perform Effective Product Quality Reviews www.nsf-dba.com 23-24 October 2012 – London, UK Pharmaceutical Labelling www.informa-ls.com/pharmalabelling 24 October 2012 – Manchester, UK Pharmaceutical Legislation Update www.nsf-dba.com 24 October 2012 – London, UK Thermal and Spectroscopic Characterisation of Higher Order Structure of Bio-molecules www.jpag.org

24-25 October 2012 – Berlin, Germany 10th Annual BioProduction www.bio-production.com 31 October-1 November – Washington DC, USA Process2Product www.IBCLifesciences.com/Procces s2Product/program.xml

DECEMBER 3-4 December 2012 – London, UK Cold Chain Distribution www.coldchain-distribution.com 3-5 December 2012 – London, UK 3-day MBA: Pharmaceuticals

NOVEMBER

www.thembatrainingcompany.com 3-5 December 2012 – London, UK 3-day MBA:Vaccines www.thembatrainingcompany.com

7-8 November 2012 – Birmingham, UK Lab Innovations www.easyfairs.com/labinnovations

4-5 December 2012 – Sheffield, UK Post Market Surveillance and Vigilance for Medical Devices www.nsf-dba.com

15-16 November 2012 – London, UK Filing Variations www.ptiglobal.co.uk/filingVariations

4-6 December 2012 – London, UK Evidence Based Healthcare for Pharmaceutical Products www.healthnetworkcommunicatio ns.com/htabrochure

19-21 November 2012 – Cambridge, UK Tabletting Technology for the Pharmaceutical Industry www.rpsgb.org

5-6 December 2012 – Berlin, Germany Pre-Filled Syringes & Injector Devices for Biologicals www.informa-ls.com/prefilled

26-27 November 2012 – Mumbai, India BioPharma India Convention 2012 www.terrapinn.com/biopharmaindia 26-28 November 2012 – Dusseldorf, Germany World Drug Manufacturing Summit www.wdmsummit.com 27-29 November 2012 – Washington DC, USA Innovations in Development for the Biosimilar Industry www.healthnetworkcommunicatio ns.com

5-6 December 2012 – London, UK Driving value and Efficiency in Phase lllb and IV trials www.healthnetworkcommunicatio ns.com/latephaseeurbro 12-13 December 2012 – London, UK Good Manufacturing Practice (GMP) and Good Distribution Practice (GDP) 2012 Symposium www.mhra.gov.uk/conferences 13 December 2012 – London, UK Solving Complex Pharmaceutical Analytical Challenges www.jpag.org

www.fip.org/amsterdam2012

3-8 OCT 2012 AMSTERDAM, THE NETHERLANDS FIP’S WORLD CONGRESS OF PHARMACY AND PHARMACEUTICAL SCIENCES banner_H_EN_print_35x125.indd 1

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