european industrial pharmacy issue 9 (june 2011)

europeanINDUSTRIALPHARMACY

ISSUE 9 • JUNE 2011www.industrialpharmacy.eu

www.eipg.eu

FEATURES4 FORMULATION AND DELIVERY OF CANNABINOIDS

The poor solubility of cannabinoids led GW Pharmaceuticals to developan oral spray delivery system.by Mark Rogerson

7 PHARMACEUTICAL INDUSTRY’S PERSPECTIVE ONSWITCHES AND ITS RELATIONSHIP WITH THEPHARMACY/PHARMACISTReclassifying a medicine is becoming more widely accepted but thereare challenges of trust to consider.by Mafalda Martins

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

12 BACTERIAL BILE ACID MODIFICATION ANDPOTENTIAL PHARMACEUTICAL APPLICATIONSManipulation of bacterial bile acid metabolism could lead to a numberof opportunities in disease prevention and treatment.by Brian V Jones

15 NOVEL ZERO-SACCHARIDE ORALLYDISINTEGRATING TABLETSThe saccharide mannitol is commonly used as an excipient in theformulation of orally disintegrating tablets. This study investigates someamino acids as possible non-saccharide alternatives.by Farhan AlHusban and Afzal R Mohammed

18 REACHING THE TIPPING POINT:PHARMACEUTICALS OUT OF BALANCEThis report by the international consultants, AT Kearney, argues that thetraditional model of a global pharmaceutical industry will struggle tosurvive and will need to shift from being R&D-driven to market-driven.by Jonathan Anscombe and Michael Thomas

REGULARS3 EDITORIAL COMMENT

20 REGULATORY REVIEW

21 NEWS FROM THE EIPG

23 PHARMACEUTICAL FORUM

25 DATES FOR YOUR DIARY

europeanIINNDDUUSSTTRRIIAALLPHARMACY

Issue 9 June 2011ISSN 1759-202X

EDITORJoe Ridge, MRPharmS

PRODUCTIONDave Johnson

SUBSCRIPTIONSJill Monk

EDITORIAL BOARDMichael AnisfeldMichael Gamlen

Linda HakesJohn Jolley

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Finland: Anni Svala

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Germany: Armin Hoffmann

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Greece: Kiriasis Savvas

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Cover photo: Cannabis sativa

eeuurrooppeeaann IINNDDUUSSTTRRIIAALL PHARMACY • Issue 9 June 20112

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Dear Colleagues

I would like to welcome you all tothe latest edition of the EuropeanIndustrial Pharmacy Journal. TheEIPG has had an extremely busyyear which culminated in ourGeneral Assembly meeting held inMadrid. I would like to personallythank the Spanish Association, AEFI,and in particular Carmen Castanonand Emma Fernandez forcoordinating such a great meeting.

I would also like to acknowledge thesterling support from the Bureauand from the rest of theAssociations for making the EIPG thesuccessful and influential body thatit is. Of particular note is that ourgreat friend and supporter KiriasisSavvas has decided to stand down asthe EIPG representative for Greece, arole which he has conducted soeffectively for over 10 years. I andmany of our members will miss youmy friend and we wish you the verybest for the future!

I also need to acknowledge thegreat work of the publishersEuromed and in particular Joe Ridgefor producing such a high qualityjournal. I know of no other journalwhich covers such a diverse range ofpharmacy subject matters rangingfrom drug delivery challenges to thelatest changes in the regulation ofdrug products. Consider the articles

under review in this latest offeringas follows:

1. Formulation and delivery ofcannabinoids

2. Switching from prescription tonon- prescription medicines

3. Social media in life sciences

4. Pharmaceutical potential of bileacids

5. Reaching the tipping point:pharmaceuticals off-balance

6. Novel orally disintegrating tablets

No wonder the feedback that Ireceive is so positive for this Journalwith many Industrial pharmacistsfinding the subject matter of greatutility including the regular items ofRegulatory Review andPharmaceutical Forum.

I know that the readership is broadand includes some pharmacistsworking in community and hospitalwho find the Journal a usefulreference tool.

I would recommend reading thethought provoking commentary byJonathan Anscombe and MichaelThomas which was based on the ATKearney White paper on‘Pharmaceuticals out of balance’and which summarises the ThreeTipping Points affecting the currentPharmaceutical and Healthcarebusiness models.

Due to the positive feedback, theEIPG and Euromed have decided toincrease the Journal frequency fromthree to four times a year and at thesame time to expand the circulationto all pharmaceutical practitionersworking in industry. The Journal isalso available as a download on ourwebsite www.eipg.eu and I wouldencourage you to direct yourcolleagues to the website if they donot receive the Journal direct.

As always, we welcome ideas andsuggestions for the Journal andplease feel free to send yoursuggestions and feedback either tomyself as President of the EIPG [email protected] or to theExecutive Director Mrs JaneNicholson at [email protected].

Please enjoy this edition of theEuropean Industrial PharmacyJournal in the knowledge that morefascinating editions are to come!

Best wishes

Dr Gino Martini FRPharmsEIPG President

eeuurrooppeeaann IINNDDUUSSTTRRIIAALL PHARMACY • Issue 9 June 2011 3

medicine in the USA for more than twodecades. Dronabinol (Marinol®) is availableas soft gelatin capsules, which are takenorally. Once in the stomach the gelatindissolves, releasing the drug. Thedronabinol is formulated in sesame oil,forming an emulsion, which is thenabsorbed during passage through the gut.One of the disadvantages of dronabinol isthat much of the active drug ismetabolised during passage from the gutvia the liver, with the consequence thatonly 10–20% of the administered dosereaches the general circulation1. Effects ofthe drug begin 30–60 minutes or longerafter administration, and there is a highdegree of between-subject variability.Another disadvantage of dronabinol is thatconsiderable quantities of thepsychoactive metabolite, 11-hydroxy-THC,are produced in the liver from metabolismof THC. Dronabinol has been approved fortwo medical indications; nausea andvomiting associated with cancerchemotherapy and as an appetitestimulant to treat HIV-AIDS wastingsyndrome. Prior to the recent approval ofSativex® in Canada, Spain and the UK,dronabinol and the synthetic THCanalogue, nabilone, are the only approvedcannabinoids medicines available.

There are several other areas that can betargeted for administration of a cannabis-based medicine. It is desirable to avoid thefirst pass effect due to hepatic metabolismof cannabinoids. The logical sites for drugdelivery that may do this are the oro-pharyngeal,or sublingual/buccal mucosae,the respiratory tract and the distal rectum.Mucosae at these sites all have venousdrainage directly into the vena cava andthe right side of the heart. Cannabinoidsabsorbed at these sites are therefore notexposed to the liver during their first passinto the systemic circulation. FFiigguurree 11shows that the concentration of THCabsorbed by the oral route is an order ofmagnitude lower than that absorbed byeither the smoked or intravenous route 2.

The first problem encountered in theformulation of a cannabis-based medicinelies in the insolubility of cannabinoids inaqueous systems. For this reason theproduct developed by GWPharmaceuticals concentrated on drugdelivery to the oromucosal membranes.The oromucosal application of medicationinvolved the development of an

While the pulmonary surface looks like anattractive target for the delivery of amedicine, in fact it is not well-suited tothe delivery of cannabinoids. Firstly, therespiratory mucosa is very sensitive, to theextent that very few medicines have everbeen approved for use via the pulmonaryroute, except for the treatment ofpulmonary disease. The burden ofdemonstrating the safety of pulmonarymedicines is very substantial and presentsa significant challenge to the drugdeveloper.

With particular regard to psychoactivemedicines, there is the additional problemof abuse liability. Uptake of drug from thelungs is fast, with the result that the drugreaches the target quickly, thus maximisingpsychoactivity and abuse liability. Whendeveloping a medicine with centralnervous system effects for chronic use, thelungs are not an appropriate site fordelivery.

Delivery sites for cannabinoids

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

MARK ROGERSON is Press andPR Executive forGW Pharmaceuticals plcPorton Down Science Park,Salisbury, Wiltshire SP4 0JQ, UK

email: [email protected]

FORMULATION ANDDELIVERY OFCANNABINOIDSby Mark Rogerson

Mankind has used cannabis for many years, but thepotential for the use of cannabinoids as prescription

medicines is often obscured by the use of cannabis as arecreational drug. In recent years the historical uses ofcannabis have been re-examined. Preparations of cannabishave been administered by most of the routes commonlyemployed in the pharmaceutical industry. Pulmonaryadministration is the fastest way of producingpharmacological effects for THC, the principal psychoactivecomponent of cannabis, and is virtually equivalent tointravenous administration. Smoking as a route ofadministration of a prescription medicine cannot be justifiedon ethical, medico-legal or safety grounds. The problemfaced by a pharmaceutical company developing a cannabis-based medicine, is how to get enough of the therapeuticcomponents of cannabis to the site of action without usingsmoking as a delivery device.


FFOORRMMUULLAATTIIOONN AANNDD DDEELLIIVVEERRYY OOFF CCAANNNNAABBIINNOOIIDDSS ((CCoonntt..))

oromucosal spray, whereby thematerial is dissolved in a solventvehicle and applied directly to themucosae as measured, discrete andcumulative fractions of the totaldaily dose.

In the development of Sativex, GWPharmaceuticals opted for the sub-lingual/buccal mucosa as the mostappropriate way to deliver themedicine.

Formulation of anoromucosal spray device

GW Pharmaceuticals have developedSativex using a botanical source ofcannabis rather than synthetic THC.Specific Cannabis plant varieties thatexpress a high and uniformproportion of their cannabinoids aseither THC or cannabidiol (CBD) areused to prepare a standardisedcannabis extract. Milled, harvestedcannabis is extracted using CO2 as thesolvent; the resulting extract is thenchilled in an alcoholic solution toremove waxy ballast from the extract(a process referred to as winterisation)to produce a partially purified liquidextract that can then be used toformulate the finished product whichcontains more or less equalquantities of THC and the non-psychoactive cannabinoid,cannabidiol (CBD).

Although cannabis extract is solublein a norfluorane/ethanol/propyleneglycol vehicle, its solubility is

insufficient to give the required dosein a convenient volume, and there aregood environmental and regulatoryreasons to avoid propellants ifpossible. Consequently, a manuallyoperated pump-action spray waschosen to deliver the product inmetered doses. This allows patients totitrate gradually, up to a total dailydose that provides the optimumbalance between effectiveness andtolerability. The total daily doserequired varies between patients butremains very consistent for individualpatients over time.

The pump-action spray deviceproduces a lower velocity spray thanpowered devices and there is

therefore less possibility of ‘bounce-back’ of material. The pump-actionspray is also preferred to otherpressurised spray systems for thedelivery of cannabinoids as it deliversa larger droplet size thus eliminatingthe possibility of inhalation into thelungs. For example, the meanaerodynamic particle size deliveredby a pressurised system is generallybetween 5 and 10 microns while theparticles delivered from a pump-action spray are between 20 and 40microns3.

The oromucosal application ofcannabinoids requires the transfer ofthe material from a hydrophilicvehicle to the cell membrane of the


Cannabis sativa

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

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

FFOORRMMUULLAATTIIOONN AANNDD DDEELLIIVVEERRYY OOFF CCAANNNNAABBIINNOOIIDDSS ((CCoonntt..))

6 eeuurrooppeeaann IINNDDUUSSTTRRIIAALL PHARMACY • Issue 9 June 2011

sublingual or buccal mucosae. Inconsequence this results in slowerabsorption of the drug than via therespiratory route, although it hasbeen shown that delivery by thisroute is fast enough for the patient toreceive benefit, and slow enough toavoid undesirable CNS effects.

During the development of Sativex,various delivery methods were testedfor their appropriateness in thetransfer of cannabinoids to theoromucosal membranes. FFiigguurree 22shows the plasma concentrations ofTHC after application to thesublingual/buccal mucosae by threeroutes, a pump-action spray device,sublingual tablets and buccal tablets.The optimum dosage form chosenwas the pump-action spray, whereby100 microlitres of product is deliveredat a time, containing 2.7mg THC and2.5mg CBD, together with a numberof other plant components.

Cannabinoids could also be deliveredto the systemic system and avoid thefirst pass effect via the distal rectum.Thus, enemas and suppositories maybe useful in therapeutic areas thatcertain cannabinoids are able totreat4. However, for chronicadministration of a medicine, the

rectal route is not generallyconsidered suitable. Similarly, thenasal mucosa could theoretically beused. The sensitivity of the nasalmucosa means that very fewmedicines for chronic use areadministered by this route, and thenature of the solvent system used inthe formulation of Sativex, with 50%ethanol and 50% propylene glycol,means that nasal delivery would beirritating to the patient.

Future considerations

Although professional attitudes tothe medical use of cannabis can bepolarised, it was once a prescriptionmedication of some repute.Historically, cannabis has been usedto treat ailments as diverse asepilepsy, migraine, rheumatoidarthritis and dysmenorrhoea5. Theuse of cannabis as a prescriptionmedicine continued until the middleof the twentieth century when socialabuse caused the drug to beprohibited by legislation.

But the role of cannabis as aprescription medicine is now beingrevisited. Cannabis-based medicinesare being investigated for thetreatment of various symptoms of

multiple sclerosis includingspasticity, pain, lower urinary tractsymptoms and sleep disturbance,rheumatoid arthritis, migraine,cancer pain and other neurologicalpains. Initial indications are thatthey are effective in patients notwell served by available types ofmedications. These studies,predominantly involving themedicine Sativex, have resulted inthe marketing authorisation ofSativex as a prescription medicine inthe UK, Spain and Canada. Thedevelopment of Sativex serves as awelcome reminder of the potentialvalue of exploring the therapeuticproperties of plants, using anapproach that meets the aspirationsof patients, of doctors and ofregulatory authorities.

REFERENCES

1. Iverson L L. The Science of Marijuana. 2000;Oxford: Oxford University Press.

2. Ohlsson A, Lindgren J-E, Wahlen A et al.Plasma delta-9-tetrahydrocannabinolconcentrations and clinical effects after oraland intravenous administration andsmoking. 1980; Clin Pharmacol Ther 2288:409–416.

3. UK Patent Application No. 0218930.6.4. UK Patent Application No. 0126150.2.5. Merck’s Manual. 1899; New York: Merck

Publishers. Part 1, 26–27.

Cannabis plants being grown for pharmaceutical use.


MAFALDA MARTINS isTechnical Manager atGlaxoSmithKline ConsumerHealthcare, Alges, Portugal.Email:[email protected]

Factors influencing demand

On the other hand, patients andconsumers, with an improved generalknowledge and level of education, alsodemand switches for prescriptionmedicines. Some factors influencing thisdemand are convenience (antacids,antihistaminies, antifungals), urgency(headache/migraine, cough & cold andemergency contraception),embarrassment (overactive bladder,alopecia, chlamydial infection, erectiledysfunction, emergency contraception,overweight) and efficacy (smokingcessation, weight management andbehaviour management).

In these cases, when patients are deniedaccess to non-prescription medicines,they become silent sufferers. Anexample is described in a researchproject report by the Association of theEuropean Self-Medication Industry(AESGP) about overactive bladder/urgeincontinence sufferers2. This reportconcludes that patients with suchconditions suffer in silence because theyfeel embarrassed even to inform theirdoctors. In fact, about 23% have neverdiscussed the condition with theirdoctor and 31% of women with urgeincontinence have not discussed theircondition with anybody.

Quality of life is negatively impacted bythis condition and it is worrying that onlya very small percentage of sufferers arediagnosed and treated with drugs (Figure 1).

Overactive bladder is a good switchcandidate from prescription to self-medication because it can be self-diagnosed and drugs commonly used forthe treatment, such as oxybutynin andtolterodine, have shown adequate efficacyand safety profile for non-prescription use.

Effect on healthcare systems

The World Health Organization (WHO), intheir guideline on non-prescriptionmedicines3 says that the reclassification ofmedicinal products from prescription tonon-prescription is of great currentinterest in many countries and it hasbecome widely accepted that self-medication has an important place in thehealthcare system.

Years of safe experience in manycountries and increased patient and

Candidates for switch status come fromthe prescription territory. New drugs havea patent lifetime protection that whenexpired, allows them to become potentialnon-prescription medicines, but only ifthey are used for a condition that haseasily recognized symptoms and have ahigh margin safety under conditions ofwide availability. Regulatory authoritiesmust evaluate the benefits of easieraccess against the potential harm fromunsupervised or inappropriate use. Incase of switch products the safety profilehas been established through years ofexperience and use as a prescriptionmedicine1.

So, switches are usually driven by patentlifetime and some examples are:

♦ Non steroidal anti-inflamatory drugs(NAIDs) such as ibuprofen

♦ H2 antagonists such as cimetidine andranitidine

♦ Antihistamines such as acrivastine,cetirizine and loratadine

♦ Proton pump inhibitors such asomeprazole

But switches can also be influenced bycost containment motives (de-reimbursement) such as magnesium andcalcium supplements, statins, somedecongestants and cough medicine, etc.

PHARMACEUTICALINDUSTRY’SPERSPECTIVE ONSWITCHES AND ITSRELATIONSHIP WITHTHE PHARMACY/PHARMACISTby Mafalda Martins

Aswitch is the regulatory process that converts aprescription medicine to a non-prescription status. The

objective is to increase patient and consumer access to safeand effective medicines for minor self-treatable conditions,with or without the intervention of a healthcareprofessional1.


consumer interest and knowledgeabout self-medication is a solidbasis for switching prescriptionmedicines to non prescriptionstatus, including self-treatment forlonger term use in chronicconditions such as heart disease,stroke and diabetes1.

Self-medication enablescomprehensive patient andconsumer interventions by usingsafe and effective medicines, whichcan help give people a sense ofcontrol over their individual healthsituation. It also drives patients tomake lifestyle changes. Responsibleself-medication gives people morechoice and responsibility, but it isalso necessary to ensure that theyhave the correct necessaryinformation, usually providedthrough the packs and leaflets onnon-prescription medicines.Information on the outer packagingallows consumers to easily make achoice about the appropriateness ofthe medicine for their needs at thepoint of sale. Additional informationfor consumers can be provided bybooklets and website links.Advertising has an important role in

communicating to the patient andconsumer the existence of acondition and the appropriatetreatment.

Impact on public health

In future, prescription to non-prescription switches can helpgovernments relieve pressures onhealthcare systems, as patients andconsumers can treat more of theireveryday health conditions withoutthe costs associated with the formalsystem. Switches can enable doctorsto spend their time and attention onmore important illnesses.

Also, pharmacists can use theirknowledge to recommendappropriate self-care actions andresponsible use of non-prescriptionmedicines, increasing pharmacycontribution to a better healthcaresystem. People can visit a pharmacyrather than wait for a doctorappointment. They can treatthemselves for common conditionsthat have easily recognisablesymptoms, such as cold sores andhay fever, reducing the time fromthe onset of symptoms to thetreatment. They can more easily

obtain time-critical products such asemergency hormonal contraceptionwhich needs to be taken early to bemost effective1,4.

Self-medication reduces resources onconsultations and prescriptions forminor ailments that can beredirected to more pressing areas.

Chronic diseases (cardiovasculardiseases, cancer, chronic respiratorydiseases and diabetes) are emergingas primary sources of diseaseburden in both developed anddeveloping countries. Theimportance of these diseases is thatthey are preventable throughappropriate self-care behavioursalthough current health systems arenot generally prepared for diseaseprevention and self-careimprovement.

Globally, of the 58 million deaths in2005, approximately 35 million (60%)were the result of chronic diseases.In fact, common, modifiable riskfactors underlie the major chronicdiseases. These factors includetobacco use, obesity and highcholesterol levels. Switching somemedicines to non-prescription statuscontributes to the control of theserisk factors by empowering peopleto look after themselves throughbetter self-care behaviours1.

Switching prescription medicines tonon-prescription status is also anopportunity to improve publichealth. Some conditions areimportant for switching, includingappropriate regulatory and politicalsupport to harmonise theclassification system for medicinalproducts and make switchingprocedures transparent. Althoughthe industry is using EU procedures,such as Mutual Recognition andDecentralisation in Europe, mostswitches still use nationalprocedures5.

Switching under the EuropeanMedicines Agency’s (EMA) Centralizedregulatory procedure was recentlyintroduced in Europe. This was anew step to help switches and

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Figure 1. Silent suffers with overactive bladder.


thereby facilitate market access tonon-prescription medicines througha pan-European license which allowsa company to market in 27countries. However, this procedure islimited to products originallyapproved through the centralisedprocedure.

The experience of EMA’s Committeefor Medicinal Products for HumanUse (CHMP) with non-prescriptionmedicines has so far been limited toonly three products and moreexperience at the central level isneeded for non-automatic switches,i.e. switches of products notoriginally approved through thecentralised procedure5.

First experiences

The first switch licensed under EMA’scentralized procedure was alli,indicated for weight loss in adultswho are overweight with a BMI≥286. Considering that obesity is aproblem of epidemic proportions7

and that important health risks arerelated to obesity such as type 2diabetes, hypertension, coronaryheart disease and cholelithiasis(Figure 2), alli had the potential tocontribute to the promotion of self-care and the improvement of publichealth.

The alli switch was approved by theEuropean Commission in 2009. alliwas the first weight loss medicineapproved without prescription,filling the gap in products availablefor weight loss treatment. As a non-prescription medicine, alli offeredconsumers the opportunity to havea weight loss product with the sameaccess as medical devices or dietarysupplements, and also the sameclinical efficacy as prescriptionmedicines, such as Xenical andReductil.

The role of the pharmacist wasimportant in alli’s centralised switchand the concept of “Pharmacistintervention” was introduced.

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

interested consumers into well-prepared pharmacies”. Strategyimperatives included press releases(press launches; KOL engaged; 1,750articles), internet (24 websites;>500k visits to EU sites; >1m pageviews on UK website), advertising(TV and print advertising; aconsistent media strategy), visibility(85% distribution; available inpharmacies; consistent campaign)and endorsement (pharmacytraining; “ambassador” pharmacies).

Considering many of switch’schallenges, the challenge of trust isone of the most important:

♦ Trust patients and consumers tochoose and use non-prescriptionmedicines appropriately,provided they have all theinformation they need and ifsuch information is simple,understandable and correct.

♦ Trust companies to promoteresponsibly, accepting that directcommunication with consumersis a key for responsiblepromotion.

♦ Trust pharmacists to be first-linehealthcare professionals for less

serious conditions, but ensurethat relevant training is provided.

♦ Trust regulators to be open tohealthcare provision withoutprescription, but accept thatsafety concerns need to beaddressed.

All stakeholders must work inpartnership to ensure optimumbenefits from switching prescriptionmedicines to non-prescriptionstatus.

References

1. WSMT 2009. Switch – Prescription tononprescription medicines switch

2. AESGP. Final report research project“Development of an information policy formedicinal products”, January 2002. Annex 2– Overactive bladder – Urge incontinencecase.

3. WHO. Guidelines for the RegulatoryAssessment of Medicinal Products for use inSelf-Medication.

4. AESGP. Study on the Economic and PublicHealth value of Self-Medication, January2004.

5. AESGP Conference – Making the EuropeanSelf-Care Industry More Competitive,London 19-20 January 2010

6. alli Summary of Product Characteristics.GlaxoSmithKline Consumer Healthcare.

7. European Conference on CounteractingObesity: WHO; Istambul, 15-17 November2006.

PPHHAARRMMAACCEEUUTTIICCAALL IINNDDUUSSTTRRYY’’SS PPEERRSSPPEECCTTIIVVEE OONN SSWWIITTCCHHEESS ((CCoonntt..))

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


What are social media?

Since the Internet’s inception, websiteshave continually evolved, becomingdynamic, interactive applications thatallow users to exchange information withanyone in the world – be it friends,colleagues, or even companies. Unlessyou have been living in a cave over thelast few years, you have likely heardabout Facebook, LinkedIn, Twitter, andother applications. When used correctly,companies can leverage social media tobuild relationships for marketing,business development andcorporate/investor relations.

How is this relevant for biotechand life science?

At the core of our industry lies a wealthof information that must be shared andutilized to better understand the sciencebehind our business and to use it tomake greater progress. I encourage you tothink beyond the specific applicationsand how to embrace a new way ofthinking about how we communicate andgather information. There are so manyways our industry can benefit from usingnew media now.

LLiiffee sscciieennccee ccoommppaanniieess that sell non-FDAregulated products have no governmentimposed restrictions for utilizing socialmedia. I have talked to many life sciencecompanies that are beginning to see thevalue of using tools such as blogs, twitterand Facebook to reach out to customers.While many of them are just gettingstarted, my conversations with those whoare implementing campaigns show that

they are impressed with the results theyhave seen so far. The benefits for lifescience companies in employing socialmedia are clear – they strengthen theirbrand by developing stronger relationswith their customers and gaining morefeedback from them, as more lines ofdialogue are opened.

The rules of the new media mean lessbroadcasting (eg. traditionaladvertisements) and more engagement.Perhaps I am biased, as I am a strongproponent of social media, but I feel asthough life science companies that don’tengage in social media run the risk ofspending more marketing dollars for lesseffect, and at the same time becomingmore out of touch with customer needs.

SSmmaallll ccoommppaanniieess.. The great news with thesocial media is that smaller companiescan do more. Previously, only companieswith large advertising budgets could getexposure through print ads in life sciencepublications. Today, a small companywith a great product can build anengaging content-rich website and befound by search engines, sparking a lot ofinterest in so-called “inbound marketing”where emphasis is placed on leadingvisitors to a company’s website. They canthus extend their reach with a smallbudget. Social media tools allow creativesmall companies to carve a niche and toleverage the web and applications suchas LinkedIn to grow their business.

Small companies can also leverage third-party social media applications outsidetheir websites. LinkedIn is a great tool forsmall companies, as individuals candevelop a large personal network or creategroups based on their company’s offering.

Mary Canady, PhD is founderand president at ComprendiaConsulting Group.Email: [email protected]: www.comprendia.com Twitter: twitter.com/comprendia

SOCIAL MEDIA IN LIFESCIENCESby Mary Canady

In November 2009, the FDA held hearings to discuss howcompanies involved with regulated products should use

social media. The meetings were effective in getting thedialogue started, but it became clear that social mediacommunication guidelines would not be made availablefrom some time. This outcome has led many to mistakenlybelieve that social media are stalled from the entireindustry when in fact, many opportunities exist forcompanies in both nonregulated and regulated industries.


When used correctly, LinkedIn can bea great source to generate leads. Theinformation stored in LinkedIn, fromuser and company information tothe way it connects professionals, hasenormous potential to enable smallcompanies and the industry to grow.

SSoocciiaall mmeeddiiaa mmoonniittoorriinngg.. Webcontent about life science,biotechnology and pharmaceuticalcompanies is becoming more user-generated because scientists andconsumers can now easily share anddiscuss news and opinions openly.

All companies, regardless ofwhether they are regulated, canbenefit from monitoring thesentiment about their companyand products. From free tools suchas Google Alerts, to myriadspecialized tools, companies cangain useful feedback from

customers that they can respond toor use for product development.

Of course, larger brands such aspharmaceutical companies will findmuch more information as theircustomer base is significantlybroader. I’m sure that manymarketing professionals in pharma

companies are closely trackingsocial media sentiment about theirproducts and brands, even thoughthey might not yet have theregulatory guidance to takeexternal actions.

In summary, there are many ways inwhich social media are relevant toour industry now, and all evidencepoints to it gaining traction. I see itas a natural progression from theways scientific companies havecommunicated with customers fordecades. How different is a blogfrom a useful newsletter, oranswering questions on Twitter fromcustomer service calls? The biggestbarriers I see are in companies thatview social media as being strange,new and risky, rather thanembracing them as a powerful andessential tool.

SSOOCCIIAALL MMEEDDIIAA IINN LLIIFFEE SSCCIIEENNCCEESS ((CCoonntt..))

❝ Many websites arenow dynamic, interactiveapplications that allow

users to exchangeinformation with anyonein the world, be it friends,

colleagues, or evencompanies ❞

www.euromedcommunications.com

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BACTERIAL BILE ACIDMODIFICATION ANDPOTENTIALPHARMACEUTICALAPPLICATIONSby Brian V Jones

Introduction

Modification of bile acids by gut bacteria has thepotential to influence host physiology and risk of

metabolic disease through effects on bile acid signalling,and may be involved in the pathogenesis of colorectalcancer via a range of mechanisms. We have recentlyexamined the distribution, abundance, and function of bilesalt hydrolase (BSH) activity (a key microbial enzymeinvolved in bacterial bile acid modification) in the humangut microbial ecosystem, and found this to be a specificfunction, which may be of pharmaceutical interest1. Thisarticle summarises current knowledge regarding thepotential for microbial bile acid metabolism to influencehuman health and highlights possibilities forpharmaceutical intervention.

Bile acids and their functions

Bile acids (BA) are cholesterol derivativessynthesised in the liver and linked byamide bonds with either glycine ortaurine to form conjugated bile acids(CBA). The formation of bile acids is theprimary pathway for cholesterolelimination in humans and it is estimatedthe liver converts ~500 mg of cholesterolper day into BA2. The major bile acids inhumans are cholic acid andchenodeoxycholic acid, which areconjugated to glycine or taurine. CBAconstitute a major component of bile andfacilitate the emulsification andabsorption of dietary lipids from thesmall intestine through the formation ofmixed micelles (for comprehensivereviews see references 2,3,4).

BA are also efficiently reclaimed from theileum through a combination of activetransport and passive diffusion, andreturned to the liver via the portal veinwhere they are reconstituted into the bile

acid pool and reused. This process isreferred to as the enterohepaticcirculation, and serves to reclaim andrecycle BA in a highly efficient process2,3.However, around 400–800 mg of CBA perday still reach the colon and are largelylost in faeces, while a portion ofreclaimed bile acids entering the portalvein are not sequestered by the liver onthe first pass and instead enter thesystemic circulation2,3. Bile acids lostthrough excretion in faeces aresubsequently replaced though de novosynthesis of new BA in the liver,maintaining the overall size of theavailable BA pool.

The physiological functions of BA arediverse and not limited to lipidabsorption. As well as having animportant digestive function, BA havealso recently been highlighted as keysignalling molecules involved in theregulation of various aspects of hostphysiology including triglyceride,cholesterol, and glucose homeostasis inaddition to regulation of their ownsynthesis2,5. Bile acid signalling is thoughtto be controlled by the activation of twodedicated bile acid receptors, designatedFXRα and TGR5, by various forms of bileacids (Figure 12,5). Because different typesof bile acids have been found to activatethese receptors to varying degrees, theseinsights have also illuminated thepotential for perturbations in BAsignalling to play a role in a range ofmetabolic diseases including obesity,diabetes (Type 2), and atherosclerosis.

In addition to their digestive andsignalling roles, CBA are also thought tobe integral to the repression of bacterialgrowth in the small intestine through twodistinct but overlapping mechanisms(Figure 15,6). In contrast to the distalcolon, the microbial population in thesmall intestine is relatively low, anduncontrolled growth of micro-organismsin this section of the gastro-intestinaltract (GIT) can be damaging to health.CBA are thought to prevent overgrowth ofbacteria in the small intestine, eitherthrough the direct antibacterial effects ofCBA, the enhancement of mucosaldefences, or the joint action of bothmechanisms3,5,6.

Due to the involvement of BA in a rangeof important physiological and

DR BRIAN V JONES is SeniorLecturer in Microbiology atthe Centre for Biomedical andHealth Science Research,School of Pharmacy andBiomolecular Sciences at theUniversity of Brighton, UK.

Email:[email protected]


homeostatic processes, BA signallingpathways or other functions of BAhave become attractive targets forpharmaceutical intervention in arange of human diseases. Forexcellent reviews of bile acidsignalling and other functions seereferences 2 and 5.

Bacterial bile acidmodification and humanmetabolic disease

The human gut harbours a complexand diverse microbial ecosystemcollectively referred to as the gutmicrobiota, and members of thiscommunity are responsible for thetransformation of endogenous bileacids to alternate forms. The initial“gateway” reaction in the bacterialmetabolism of CBA is mediated bybile salt hydrolase, which catalyses

the de-conjugation of CBA toliberate free primary BA (de-conjugated cholic acid orchenodeoxycholic acid) and aminoacids3,4. Free primary BA aresubsequently open to a widerpathway of BA modificationencoded by the gut microbiota,which generates secondary andtertiary forms of BA throughdehydroxylation, dehydrogenationand sulphation3,4.

Free primary and secondary BAhave been directly implicated in thepathogenesis of a range of humandiseases8-13, and recent studiesindicate that the mammalian gutmicrobiota can modulate host bileacid synthesis, which may influencehost lipid metabolism14. ModifiedBA have also been shown to displayaltered binding characteristics for

bile acid receptors, with microbialBA derivatives constituting some ofthe most potent agonists forreceptors such as TGR52. Therefore,BSH activity and subsequent BAmodification in this communitycould impact significantly on hostphysiology through disturbances ofBA controlled endocrine functionsand influence the risk of metabolicdiseases1,2.

Bacterial bile acidmodification and colorectalcancer

There is also much evidenceimplicating the products ofmicrobial bile acid metabolism withthe initiation and progression ofcolorectal cancer (CRC) throughseveral mechanisms9-13. Theseinclude the carcinogenicity of freeprimary or secondary BA, theinduction of pro-inflammatory, anti-apoptotic pathways which facilitatethe survival of malignant cells, andeffects on cell proliferation andcancer cell invasion which mayenhance disease progression. Incontrast, some studies indicate apotential protective function againstCRC for certain products ofmicrobial bile acid modification,and BSH activity in particular hasthe potential to be either protectiveagainst this disease or involved in itspathogenesis. For comprehensivereviews of the role of bile acids incolorectal cancer see references 8and 12.

Overall, there is increasing evidencethat the indigenous gut microbialpopulation is a significant factor inthe pathogenesis of CRC, and thatthis community mediates the effectsof diet on colonic health11, 12.Increased fat intake has beenconsistently linked with CRC andleads to elevated levels of BAsecretion. The influence of bile acidsand microbial derivatives onexpression of pro-inflammatory andanti-apoptotic pathways, coupledwith the reported carcinogenicity ofmodified bile acids, highlights

BBAACCTTEERRIIAALL BBIILLEE AACCIIDD MMOODDIIFFIICCAATTIIOONN ((CCOONNTT..))

FFiigguurree 11.. Overview of physiological function associated with bile acids. Black arrowsindicate functions directly associated with physical properties of bile acids, once secretedinto the lumen of the intestine. Blue arrows indicate aspects of host physiologyinfluenced or controlled by bile acid signalling pathways via the dedicated bile acidreceptors FXRa and TGR5. For comprehensive reviews of functions of bile acids and bileacid signalling see references 2 and 5.

FXR ααTGR5


BBAACCTTEERRIIAALL BBIILLEE AACCIIDD MMOODDIIFFIICCAATTIIOONN ((CCOONNTT..))

microbial BA modification as a keyfunction by which the human gutmicrobiota may integrate knownrisk factors, such as diet andinflammation, to direct CRCpathogenesis.

Pharmaceutical potential

A greater understanding ofmicrobial bile acid modification bythe human gut microbiota, and theimpact of this activity on the humanhost promises to uncover a range ofpharmaceutical opportunities, andfacilitate the development ofstrategies to manipulate or exploitthe gut microbiota to enhancehuman health. For example, thepotential for inter-individualvariation in capacity for bile acidmodification may have diagnosticvalue and facilitate theidentification of individuals atgreatest risk of acquiring diseasessuch as CRC1.

Alternatively, the manipulation orinhibition of various stages ofbacterial bile acid metabolism maylead to novel approaches to diseaseprophylaxis, or strategies tomodulate aspects of BA signalling toimprove features of hostmetabolism such as energy balanceand regulation of fat storage.Paradoxically, there is also potentialfor aspects of microbial BAmetabolism to be protective againstCRC as well as important in itspathogenesis. BSH in particular has

the potential to be protective in thisregard and, if so, enhancing thisactivity of the gut microbiota maybe a viable strategy forpharmaceutical intervention.

Understanding the mechanisms bywhich bacteria colonising thehuman gut overcome the toxiceffects of bile and bile acids willalso facilitate the rational design ofbetter, more effective probiotics.Probiotics may also constitute ameans to manipulate BAmodification in this community.Since synthesis of new bile acidsutilises cholesterol, there issignificant scope for thedevelopment of novel cholesterollowering probiotics which functionthough modulation of microbialbile acid metabolism in the gutmicrobiota, leading to increasedsynthesis of new bile acids. Incontrast, the potential role ofmicrobial BA modification indiseases such as CRC may make thisan undesirable trait in probiotics,and in this context it is notable thatmany commercially availableprobiotic species exhibit BSHactivity.

Clearly, much fundamentalinformation regarding the role ofmicrobial BA metabolism in humanhealth and disease is currentlylacking, and significant study is stillrequired before the pharmaceuticalpotential of this microbial activitymay be realised. In particular, the

contribution of microbial BAtransformations to the pathogenesisof diseases such as CRC should beclarified. A greater understanding ofthis promises to provide muchinsight into mechanisms of disease,and identify new targets andstrategies for prophylaxis anddiagnosis.

References

1. Jones BV, Begley M, Hill C, et al. Proceedingsof the National Academy of Sciences USA,2008; 105: 13580–13585.

2. Thomas C, Pellicciari R, Pruzanski M, et al.Nature Reviews Drug Discovery, 2008; 77::678–693.

3. Ridlon JM, Kang D-J, Hylemon PB. Journal ofLipid Research, 2006; 47: 241–259.

4. Begley M, Gahan CGM, Hill C. FEMSMicrobiology Reviews, 2004; 29: 625–691.

5. Hylemon PB, Zhou H, Pandak WM, et al.Journal of Lipid Research 2009; 50:1509–1520.

6. Inagaki T, Moschetta A, Lee Y-K, et al.Proceedings of the National Academy ofSciences USA, 2006; 103: 3920–3925.

7. Hoffman AF and Eckmann L. Proceedings ofthe National Academy of Sciences USA, 2006;103: 4333–4334.

8. Berr F, Kullak-Ublick GA, Paumgartner G,Münzing W, Hylemon PB. Gastroenterology1996; 111: 1611–1620.

9. Bernstein H, Bernstein C, Payne CM,Dvorakova K, Garewal H. Mutation Research2005; 589: 47–65.

10. Hill MJ. Mutation Research, 1990; 238:313–320.

11. O’Keefe SJD. Current Opinion inGastroenterology, 2008; 24: 51–58.

12. Huycke MM and Gaskins RH. ExperimentalBiology and Medicine, 2004; 229: 586–597.

13. Debruyne PR, Bruyneel EA, Li X, et al.Mutation Research, 2001; 480–81: 359–369.

14. Martin F-P, Dumas M-E, Wang Y, et al.Molecular Systems. Biology 2007; 3: 112.

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Currently, three main approaches areused to prepare ODTs, namely, directcompression, moulding andlyophilisation. ODTs prepared bylyophilisation have been considered themost successful in terms of sales value,sales volume and number of productsavailable on the market3.

Regardless of the preparation method, allODT formulations in the market contain ahigh concentration of saccharides, withmannitol being one of the mostcommonly used. Extensive use ofsaccharides and polyols limits theirapplication in delivering drugs for thetreatment of long term chronic conditionsand also for multiple dose medications,primarily due to limitations on dailyintake of saccharides, especially forchildren, diabetic and obese patients.

Therefore, replacement of saccharide inthe lyophilised ODT formulation requiresan excipient that fulfills stringentcharacteristics such as reasonable dryingtime, good stability during and afterfreeze-drying process as well as theformation of elegant tablets with shortdisintegration time, adequate mechanical

Farhan AlHusban PhD, is aresearcher at the MedicinesResearch Unit, Aston PharmacySchool, Aston University,Birmingham, UK

Afzal-Ur-Rahman MohammedPhD, is a Lecturer inPharmaceutics at the AstonPharmacy School, AstonUniversity, Birmingham, UKTel: 0121 204 4183email:[email protected]

NOVEL ZERO-SACCHARIDE ORALLYDISINTEGRATINGTABLETSby Farhan AlHusban and Afzal R Mohammed

Formulations of orally disintegrating tablets (ODTs) wereoriginally developed to address swallowing difficulties of

conventional solid oral dosage forms (tablets and capsules)experienced by wide range of patients, especially childrenand the elderly. However, due to their convenience ofadministration (they do not require water), ease ofswallowing and fast onset of action, ODTs have becomeappreciated and even preferred by other patient groups1.Moreover, for pharmaceutical companies, the developmentand formulation of drugs into ODTs allows extension oftheir patent life and ensures market exclusivity. In 2004,ODTs were the main driver for a significant growth in themarket for oral drug delivery products which resulted in aturnover of $35 billion2.

properties and suitability for a widepatient population.

Naturally occurring amino acids areprospective candidates because of theirversatility in terms of physicochemicalproperties, high safety profile andavailability. In the current study, thefundamental physicochemical propertiesof mannitol that contribute to itssuperiority in the lyophilised ODTformulation were investigated andcompared with four naturally occurringamino acids, alanine, glycine, threonineand proline, to assess their potential asmatrix-forming agents within theformulation.

Thermal profiling

Thermal analysis of the frozenformulations is crucial in thedevelopment of lyophilised ODTs tooptimise the freeze-drying process and toensure the formation of intact tablets, asit determines the maximally tolerableproduct temperature during primarydrying, known as thecollapsetemperature. Differential scanningcalorimetry (DSC) scans of formulationsconsisting of 5% gelatin (binder) and 5%mannitol, alanine, proline, glycine orthreonine are presented in Figure 1. Theresults show that alanine and glycine-based formulations resemble mannitol byexhibiting a tendency to crystallise, whileproline and threonine formulations retaintheir amorphous state with a glasstransition temperature of -50.4°C and -35.4°C, respectively.

The crystallisation behaviour of theexcipient is critical in the formulation oflyophilised ODT as it limits the mobilityof the molecules within the system andaccordingly raises its collapsetemperature, which allows freeze-dryingat a higher temperature andconsequently a shorter production cycle.In the case of amorphous excipient,lyophilisation of the frozen solution at atemperature 1 to 3°C higher than its glasstransition results in physical damage toits structure (collapse).

Mechanical properties

Successful ODT formulations must haveenough mechanical strength to withstandthe mechanical stresses during packaging,shipping and handling by patients.

Measurement of hardness oflyophilised ODTs using theconventional tablet hardness testeris not a suitable method due to thespongy nature of the tablets thattend to deform rather than break inresponse to the applied force.Alternatively, texture analysers havebeen used extensively, where acombination of compression andshear forces are applied.

Previous research from ourlaboratory has shown that a highconcentration of mannitol (greaterthan 30% of the dried tablets) is

required to enhance the mechanicalproperties of lyophilised ODTs4.Inclusion of a high concentration ofamino acids in the formulationrequires solubilisation of the addedexcipient within the binder solution.The solubility of the investigatedamino acids (alanine, proline,glycine or threonine) was examinedin 5% gelatin solution (binder). Theresults (data not shown) revealedthat all the studied amino acidswere completely soluble up to aconcentration of 70% of the totalsolid materials, suggesting their

suitability in enhancing themechanical properties of theresultant tablets.

Disintegration time

Disintegration time is the key issuein the development of ODTformulations. According to the USFDA industrial guidance, thestipulated disintegration time ofODTs should be less than 30seconds, whereas the EuropeanPharmcopoeia has set a limit of 3minutes, both based upon theconventional disintegrationapparatus. Despite this regulatoryvariation, it is generally agreed thata lower disintegration timeimproves the practicality andpatient compliance of the ODTdosage form.

At present, ODTs prepared bylyophilisation have the shortestdisintegration time. This is due totheir highly porous structures thatallow fast diffusion of water(disintegrating medium) through ahighly wettable matrix, whichdisintegrates/dissolves rapidly uponcontact with saliva. Therefore, thewettability of the excipient plays amajor role in determining thedisintegration time of ODTs.

In this study, the wetting profiles ofmannitol and the amino acidpowders were analysed bymeasuring their contact angle usingthe Wilhelmy method, where apowder-coated glass slide was usedas a measurement plate. The results(Figure 2) revealed that mannitoland the all thetested amino acidsdisplayed zero contact angle(complete wetting).

However, analysis of wetting time,the time taken for the completewetting phase to finish and appearin the wettability profile as asudden increase in the contactangle, showed differences for thedifferent excipients (Figure 3).Compared to mannitol (wettingtime of 23.5 ± 1.8s, n=3), proline,alanine and glycine exhibitedshorter wetting times of 2.7 ± 0.4,


NNOOVVEELL ZZEERROO--SSAACCCCHHAARRIIDDEE OORRAALLLLYY DDIISSIINNTTEEGGRRAATTIINNGG TTAABBLLEETTSS ((CCOONNTT..))

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

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

34.87

30

25

20

15

10

6.81

Hea

t Flo

w E

ndo

Up

(mW

) –––

–––

––

-64.49 -60 -55 -50 -45 -40 -35 -30 -25 -20 -15 -10 -5 -2.30

Temperature (°C)

Mannitol Cr

Glycine Cr

Alanine Cr

Proline Tg

Threonine Tg


15.4 ± 1.1 and 19.8 ± 2.0s (n=3),respectively, whereas threonine hadlonger wetting time (34.2 ± 2.6s,n=3). Shorter wetting timetranslates into enhancedinteraction between the materialand water, resulting in a quickerdisintegration of ODT.

Moisture uptake

As explained above, the lyophilisedODTs consist of a highconcentration of hydrophilicmaterial with a porous anatomicalarchitecture which results in highsusceptibility to moisture uptake.This can in turn affect both thephysical and chemical stability ofthe dosage form. Therefore, thehygroscopicity of the materials isanother key criterion when

selecting an excipient for theformulation of lyophilised ODTs.

The moisture uptake test wasmeasured by keeping 1g of thefreeze-dried powder in a labdesiccator along with saturatedsodium chloride solution togenerate 75% relative humidity atroom temperature for 7 days.Figure 3 shows the percentage ofweight gain due to moisture uptakeof the freeze-dried mannitol andthe four amino acids. The resultsindicated that all the testedpowders absorbed a relatively smallamount of moisture despite thehigh relative humidity (75%).

The non-hygroscopic nature ofmannitol is another crucial featurefor its incorporation in ODTformulation. Interestingly, all the

amino acids displayed lowerhygroscopic profiles than mannitol.While alanine and threonineabsorbed minimal amount ofmoisture (less than 0.11%), prolineand glycine showed a slightly higheruptake of 0.19 ± 0.02 and 0.30 ±0.02%, respectively, furtherstrengthening their application asreplacements for the conventionalsaccharides within the ODT.

Summary

Mannitol is one of the mostcommonly used excipients in theformulation of lyophilised ODTsbecause of its crystallisingbehaviour in the frozen state, itsnon-hygroscopic nature, highaqueous solubility and fast wettingprofile. Analysis of the properties ofthe amino acids has shown theirsuitability as matrix-forming agentsas they exhibit all the essentialproperties required in theformulation of lyophilised ODTs(Table 1).

Conclusions

Alanine and glycine showed greatpotential with a similar thermal andmechanical profile to that ofmannitol, along with the addedbenefit of better wettability andlower moisture uptake. These aminoacids provide an alternative choicein the formulation of lyophilizedorally disintegrating tablets as theyhave added benefits whencompared to mannitol and requireno manipulation to the existingmanufacturing protocols.

References

1. Van Arnum P. Avancing ODT technology.Pharm. Technol. 2007; 31(10): 66–76.

2. Ghosh T, Pfister W. Drug delivery to the oralcavity: molecules to market. CRC Press 2005,Boca Raton, USA.

3. Muir I. Growing sales and new opportunitiesfor oral fast dissolve. Oral delivery: whenyou find the holy grail. ONdrugDeliveryLtd2007; 4-6.

4. Chandrasekhar R, Hassan Z, AlHusban F,Smith A, Mohammed A. The role offormulation excipients in the developmentof lyophilised fast-disintegrating tablets.European Journal of pharmaceutics andbiopharmaceutics 2009; 72: 119–129.

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Figure 3. The percentage of moisture uptake (w/w) of the freeze-dried powders.

Table 1. Summary of the various physico chemical properties of amino acids whencompared to mannitol.

Amino acid Thermal Mechanical Wettability Moisture property property uptake

Alanine ✔ ✔ ✔ ✔ ✔ ✔

Glycine ✔ ✔ ✔ ✔ ✔ ✔

Threonine ✘ ✔ ✘ ✔ ✔

Proline ✘ ✔ ✔ ✔ ✔ ✔

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

0.45

0.4

0.35

0.3

0.25

0.2

0.15

0.1

0.05

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Mannitol Alanine Glycine Threonine Proline

REACHING THE TIPPINGPOINT: PHARMACEUTICALSOUT OF BALANCE

by Jonathan Anscombe and Michael Thomas

There is a danger that the current pharmaceutical modelmay become irrelevant in the context of 21st century’s

global healthcare needs. Healthcare is out of balance and,therefore, so is the pharmaceutical industry. The fortunes ofthe pharmaceutical industry are driven by the healthcaresystems it serves – and virtually every healthcare system isrestructuring.

The same forces driving global healthcarereform are having a major impact on thepharmaceutical industry, which is at atipping point – indeed, threeinterconnected tipping points – and thatit will emerge in a much different form.These tipping points relate to what theindustry sells, to whom, and how it mustbe organised.

Tipping Point 1: From therapiesto service models

The pharmaceutical sales model hasalways assumed that the prescribingdoctor is the primary decision maker andthat prescribing decisions are based solelyon the doctor’s perception of patientneed. This assumption has led to thecurrent dual-track market-access model,in which sales and marketing focus oninfluencing doctors and pricing.

However, the doctor is increasinglyconstrained or influenced by formularies,guidelines, IT systems and financialmechanisms. These mechanisms aredriven by payers and regulators or byprovider organisations responding topayer costs and political pressures. Whilethe doctor-patient relationship is similareverywhere, the payer landscape isexceedingly complex, with prioritiesvarying by country, locality and evenethnic group.

In the pharmaceutical industry, thetraditional view is that volume is not elasticto price. However, the growing influence ofpayers is changing this assumption.

Organisations such as the UK’s NationalInstitute for Health and ClinicalExcellence (NICE) define where a drug isused in the care pathway on the basis ofclinical cost-effectiveness. Expensivedrugs are often relegated to second-,third- or even fourth-line treatmentseven if they have high efficacy as a first-line treatment. There is also a trendtowards changing the use of drugs fromtreatment to preventative use as theydecline in cost.

Over the past few years, there has beena dramatic change in what payers arelooking to achieve with the effectivenessof the treatment pathway becomingmore relevant than the cost-effectiveness of a particular drug.Therefore, payers are far moreinterested in pathways than in drugs.

Moreover, epidemiological shifts towardschronic diseases, the emergence oftechnologies that can turn diseases fromterminal to chronic, and a growingsophistication in understanding whatreally drives health costs have expandedthe concept of value to encompass itsimpact on the healthcare system.

For payers seeking to address complexdiseases, the availability of a marginallymore effective, but much more expensivetherapy, is far from compelling. Theproblem with many drugs is not theirefficacy, but getting patients to takethem as instructed. Compliance is pooreven for life-threatening diseases such ascancer. What would be compelling forpayers is a service model that enablestherapies to be administered with highcompliance and can be proven to resultin fewer admissions. It would be evenmore compelling if this could bedemonstrated in the payer’s specific caresystem and target population.Positioning a therapy in this contextdramatically increases its value.

Tipping Point 2: From richniches to global mass markets

The US dominates the pharmaceuticalindustry. Prices are based on what theUS market will bear and pricing policyseeks to defend this “list price”regardless of revenue impact in othercountries. However, the US market isfailing. Whether the new legislation for

Jonathan Anscombe is a partnerand co-head of AT Kearney’spharmaceutical and healthcarepractice in Europe. He is basedin Londonemail: [email protected]

Michael Thomas is a principal inAT Kearney’s globalpharmaceutical and healthcarepractice. He is also based inLondon.email: [email protected]



universal healthcare insuranceturns out to be successful or not,mechanisms to limit access tomedicines based on their costeffectiveness will inevitably spread.The likely outcome will be that theUS pharmaceutical industry maywell see revenues decline.

Meanwhile, healthcare demand isshifting rapidly towards thedeveloping world, with emergingmarkets experiencing a dramaticincrease in diseases long commonin developed countries. Thedeveloping world is todaycharacterised by high levels of self-pay and rudimentary public healthsystems. However, most countrieswill develop some form ofcomprehensively funded healthcaresystem as soon as they can affordto do so. This scenario offersenticing but challengingopportunities for the globalpharmaceutical industry. Emergingstate-funded systems will need todevelop cost-effective solutions toWestern-style health problems, butthey will not be prepared to payWestern-style prices.

As the size of developing marketsbecome too attractive to ignore, thepharmaceutical companies willneed to drop their obsession withhigh-priced solutions and insteadprice in a way that maximisesrevenue over the drug’s life cycleand throughout the global portfolio.

Low-cost mass-marketsolutions

There are signs that the pressures tocreate low-cost mass-marketsolutions are appearing in thepharmaceutical industry. Indian andChinese biotech companies whoonce focused on treatments for localpatients are becoming significantinnovators on a global scale.

Pharmaceutical companies need toview emerging markets in a newlight – not just as an opportunityfor lowering R&D costs ordemonstrating market

commitment, but as a source oflow-price, breakthrough innovation.If the global pharmaceuticalindustry does not respond to thesechallenges, then local companiessurely will.

Tipping Point 3: Fromintegration to connection

The traditional model of a globallyintegrated pharmaceutical industrywill struggle to survive. It will be toolarge, unwieldy and unfocused toconnect with the payers, providersand potential partners in markets itseeks to serve. Successfulpharmaceutical companies of thefuture will shift from being R&D-driven to market-driven, and thiswill require a complete re-wiring oftheir organisations.

Given the complexity of healthcaresystems and treatment pathways,the challenge for pharmaceuticalcompanies is to decide on whichtherapy areas to focus. The currentR&D-driven trend to specialise inspecific therapy areas willaccelerate further. This will requirea very different kind of sales-and-marketing organisation. Virtuallyall pharmaceutical companies havedramatically reduced theirtraditional sales forces in favour oflocalised “market access”organisations and that trend willcontinue.

The shift towards mass-marketsolutions introduces a dramaticallydifferent dynamic to the supplychain. When margins are 80% ormore, working capital,manufacturing costs anddistribution costs have little impact

on profitability. However, for massmarket products, supply-chain costsbecome a key profit driver.

We expect to see the furtheremergence and consolidation ofhighly efficient outsourcemanufacturers. Management of thecontractual relationships with theseproviders will become a corecompetence of the truly connectedpharmaceutical company – and amajor driver of profitability.

Shifts in distribution strategies willalso accelerate. There is anincreasing trend for healthcaresystems to focus away from hospitalsand towards home- and community-based care. Thus, the current shiftfrom wholesale distribution towardsdirect-to-pharmacy will shift again todirect-to-patient.

Different types ofcompanies

There are several different types ofpharmaceutical companies, all withdifferent competencies, that willoperate in the space currentlyoccupied by integratedpharmaceutical firms. Value-delivery companies will focus onspecific therapies in certaincountries, and will gear valuepropositions in response to localmarket needs. Health innovationcompanies will develop andleverage technologies in as manyapplications as possible to gain areturn on investment at areasonable cost. Supply-chaincompanies will focus on optimisingoperating efficiencies. The trulyconnected pharmaceutical companywill have to decide which of thesefunctions it wishes to deliver, andwhich companies it needs topartner with to deliver otherservices.

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

RREEAACCHHIINNGG TTHHEE TTIIPPPPIINNGG PPOOIINNTT ((CCoonntt..))

❝ Successful pharmasof the future will shiftfrom being R&D drivento market-driven ❞


Introduction

The current review period has seena number of actual/proposedchanges in the regulation ofmedicines and regulatory guidancein both the EU and USA. Worryingly,it has also seen incidents related tothe microbial contamination of IVfluids, potentially leading to the thedeaths of a number patients in boththe USA and India.

United States of America

Retrospective review of RegulationsFDA has announced this review viaits blog. It is asking for submissionson how to improve existingregulations. It hopes to improveinnovation by both itself andstakeholders.

Formation of glass lamellaeFollowing the recall of several drugproducts, FDA has issued anAdvisory Note to drugmanufacturers. The Advisory –identifies some contributory factorsto this problem.

Draft Guidance for Industry – Non-Penicillin Beta-Lactam RiskAssessment: A CGMP Framework

This guidance is intended to assistmanufacturers in assessing whetherseparate facilities should be usedbased on the relative health risk ofcross-reactivity.

Europe

EU Directive on counterfeit medicinesAmendments to Directive EC2001/83/EC aimed at combatingcounterfeit medicines have beenadopted and will have to betransferred into national law withintwo years. The amendments include:

• introduction of safety features(serial numbers and/or tamper-evident seals)

• more stringent rules forimportation of APIs

• better controls of the supplychain (traders and wholesalers)

• Rules for the internet sale ofmedicines.

Suspension or withdrawal of aCertificate of Suitability (CEP)The EDQM has issued a revisedpolicy document. Changes include:

• Greater transparency on thepossibility for appeal against adecision taken by the EDQM

• The procedures applied when theholder asks to withdraw a CEP.

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

Refusal of information from thirdparties in reply to EDQM's request forinformationEDQM has noted that third parties(e.g. manufacturers of startingmaterial or purchased intermediates)are requesting that information iskept confidential from the CEPholder/applicant. EDQM considers itnecessary however that manufacturersof a final substance detain fullinformation on the manufacture of astarting material or intermediate inorder to suitably control the quality ofthe final substance.

EMA Q&A on computerised systemsTopics covered include:

• Requirements for spreadsheets

• Data security of databases

• Risk management in the systemlifecycle

• Use requirements as part of theretrospective validation of legacysystems

• Revalidation of computerisedsystems

• Storage time of electronic dataand documents

• Validation efforts for smalldevices

• Alternative controls in case asystem is not capable to generateprintouts.

Contamination of drug productsarising from the preservative used onwooden palletsMHRA has published a noticerelating to a recall of productfollowing complaints of musty andmouldy odours. Source of the odourwas trace amounts of 2, 4, 6-tribromoanisole (TBA) in somebottles arising from a preservativeused on wooden pallets used fordistribution.

Other such incidents in the USA(different company/products) led torecalls and an FDA Warning Letter.In this case, from exposure ofpackaging materials to TBA fromwooden pallets.

Comment: companies may be welladvised to perform risk assessments/take risk management action,wherever they make use of woodenpallets within the supply chain.

International

Training Material on ICH Q8, Q9 & Q10Following international workshopsthe Quality Implementation WorkingGroup has published on the ICHwebsite a consolidated trainingpackage on the above guidelines.

Contaminated IV fluids implicated indeaths of patients in USA and India9 people died in Alabama USA afterreceiving contaminated IV fluids froma US manufacturer. 13 women diedin India after receiving contaminatedIV fluids from an Indianmanufacturer.

For further information on these andother topics we suggest you refer to thewebsites of relevant regulatory bodiesand to current and past editions of“GGMMPP RReevviieeww NNeewwss” published byEuromed Communications. Tosubscribe to this monthly news servicecontact [email protected]

REGULATORY REVIEWReview of developments in GMP and the regulation ofMedicines March 2011 – June 2011

by Malcolm Holmes

NEWS FROM THE EIPGGeneral Assembly inMadrid

The 2011 General Assembly of theEuropean Industrial PharmacistsGroup held in Madrid on 9/10thApril was preceded on the Friday bya seminar for staff and students ofthe Faculty of Pharmacy of AlcaláUniversity. The Dean, Dr JulioÁlvarez-Builla, noted that pharmacyin Alcalá gives every encouragementto students to enter thepharmaceutical industry which heconsiders strategic in all modernsocieties. Everyone at Alcalá,including a group of postgraduatestudents studying industrialpharmacy, made the pharmacistsfrom EIPG extremely welcome.

During the seminar, severalpresentations were made on thefuture of the pharmaceuticalindustry, the future education andtraining of pharmacists and thechallenges of the cold supply chain.Overheads from these presentationsare on our website: www.eipg.euunder “media library”.

Past year’s activities

The report on the year's activitiesshowed EIPG to have had a busyyear since the last GeneralAssembly, particularly in its role asan active partner in consultationswith the European Commission oneducational matters and with theEuropean Medicines Agency ontechnical guidelines. EIPG responseto consultations on variouschapters of the GMP Guide, the QPDeclaration Template and theProfessional QualificationsDirective can be found on ourwebsite: www.eipg.eu under“position papers”.

An update to the EIPG guidelines onGood Distribution Practices has beenpublished and a working group ledby the Ordem dos Farmaceuticos,Portugal, is drafting a Code ofPractice for Pharmacovigilance.

Presentation on QualityRegulation Update

Michael Murray, ABPI, presented aEuropean Quality RegulationUpdate. He discussed the industryviews on the recent consultationsof proposed amendments toChapters 5 and 7of GMP guidance,the concept paper on storageconditions during transport andthe QP declaration for APIs. Also,he described the status, key issuesand timelines for implementationof the Falsified MedicinesDirective.

Enlargement of EIPGconsidered

A draft of the updated Statutes ofEIPG was considered by theGeneral Assembly, initially broughtabout by the proposal to updatethe membership of the Bureau butnow having been extensivelymodernised. One of the proposalswhich elicited most discussion waswhether the Member Associationsshould be restricted to MemberStates of the European Union orhave a wider definition to includethe European Economic Area,Accession countries, Europeancountries which have a MutualRecognition Agreement with theEuropean Union in relation toconformity assessment ofregulated medicinal products or

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

Membership survey

The results of the recentMembership Survey were debated,including ways of improving oursystems of lobbying in Europe. Alist of pharmacists who are expertin specialist areas of industry is tobe compiled from MemberAssociations to assist withresponding to scientific issues.These areas would include:Production/Quality Assurance; Rand D; Commercial/Sales andMarketing; Regulatory Affairs;Biotechnology products/MedicalDevices; Counterfeits; Clinical Trialsmanagement; WholesaleDistribution; Pharmacy Education.Anyone interested in assisting withlobbying, please contact yournational representative or mail to:[email protected]

Education working group

An education working groupreviewed the report of Pharmine 1and considered a submission tothe Education, Audiovisual andCulture Executive Agency (EACEA)for a pilot to review specificadvanced level competencies andhow best these should bedelivered ( for example, part-timedistance learning in conjunction

Malta and Sweden re-elected Vice-PresidentsThe General Assembly re-elected Malta (Claude Farrugia, left) to the

Bureau as Vice-President forCommunications forthe next three yearsand Sweden (PärTellner, right) asVice-President forEducation & Careersfor a further year’sco-option to theBureau.



with an HEA) for pharmacistsworking in industry.

National reports

National reports from MemberAssociations described variousmethods used to lower the prices ofpharmaceuticals, in order to reducehealth care budgets. Some membersindicated the price reductions wereconsidered so low that they were

unsustainable. Site closures andheadcount cuts, particularly in thebiotechnology industry werereported. However, it was not alldoom and gloom. Italy marked the50th anniversary of the founding ofAFI with a national symposiumattended by over 1,000 participants.During the year, AEFI has run 36specialist courses in Spain attendedby 1,753 participants.

Anyone looking for employmentshould note that there is a lack ofpharmacists in all sectors inGermany and pharmaceuticalcompanies are looking forpharmacists to fill variouspositions.

Jane Nicholson,Executive Director EIPG,[email protected]

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Total Viable Count test

Q If a product’s Pharmacopoeial monographdoes not contain a “Total Viable Count” test,

do we need to conduct it at all? In brief, what isthe significance of the test for a nonsterileproduct? Can it be substitute for a BacterialEndotoxin Test (BET)?

Response 1 – To perform or not to perform a TotalViable Count test totally depends on the risk and extentof contamination/bioburden. It is alwaysrecommended to monitor bioburden to check/monitorthe process controls. Usually, preservatives are added tonon-sterile drugs to prevent an increase in microbialload, but every preservative has its owncapacity/limitations to control the load, after that it willnot work and the product is exposed to extreme risk. Inanswer to the second question – “No”, BET and TotalViable Count are different tests for different purposes,and cannot be substituted.

Response 2 – The microbial limit tests are designedto perform the qualitative and quantitative estimationsof specific viable micro-organisms present inpharmaceutical dosage forms, which include tests forTotal Viable Count (bacteria and fungi) and specifiedmicrobial species (Escherichia coli, Salmonella,Pseudomonas aeruginosa and Staphylococcus aureus).

Although adequate care is taken to exclude micro-organisms during manufacturing by incorporatingpreservatives, it again depends upon the efficacy of thepreservative in the long term. Therefore, a test should beperformed to establish that the formulation has not beencontaminated inadvertently by any undesirable microbialflora and hence safe to be consumed by humans.

BET is a different analytical tool to determinepyroburden in pharmaceuticals and hence cannot beused as an alternative to TVC.

Response 3 – Preservatives should be used to dealwith possible user contamination in non-sterile productsand also in sterile products intended to be used on morethan one occasion. It is not GMP to include them to covermanufacturing defects or lack of control on raw materials.

Expiry and re-test dates

Q I understand that the expiry date of thefinished product cannot be beyond the date

of expiry marked on the Active PharmaceuticalIngredient/s. However, some APIs do not have“Expiry Dates”, rather they have “Retest Dates”.How many retests would be acceptable in suchcases? Also, I am told in some countries the APIcan be used for preparing formulations until the“Expiry Date” and that the shelf or expiry of theproduct is marked accordingly to the shelf lifeassigned to the product as confirmed by stabilitystudies. In such cases the expiry date of productwould be beyond the expiry date of API. It isjustifiable?

Response 1 – The Expiry Date for the formulatedproducts does not necessarily have anything to do withthe Retest Date for the API. It is quite common for theformer to be later than the latter.

If you read the ICH Q1 series of guidelines you will seethat the correct term to use for APIs is ‘retest date’.Expiry dates/shelf lives relate to formulated products.

This means that the API can be used to its retest dateto make a formulated product. Indeed it is alsopossible to retest a lot of API that is past its retest dateand if it meets the full specification it can be used tomake a batch of formulated products. The shelf life ofthe formulated product will be calculated from therelease date (with some restrictions on the length oftime between the date of manufacture and the date oftesting).

Response 2 – I think the procedure followed by youshould be correct. The experience of the regulatoryauthority drafting these guidelines would also have it thisway only. The API has a definite expiry period and noformulation containing it should be available on theshelf after the date of expiry of the API (or the expirydate of such ingredient of the formulation). I go by thesimple logic – “would I give such medication to mykids?”.

I cannot think of any justification to allow practices otherthan this. There may be cases where no medicines areavailable and people may be given such products – butthat depends upon the circumstances and the prescriberhas to weigh the pros and cons. No guidelines wouldaddress such issues.

Response 3 – I disagree with the previouscomments. Some drugs are not very stable in pure formbut behave differently when compounded into aproduct. In such cases your formulation can have a shelflife more than that of the remaining shelf life of the drug

PHARMACEUTICAL FORUMThe following questions and responses are a recentselection of those published on an open onlinediscussion group wwwwww..pphhaarrmmwweebb..nneett//ggmmpp..hhttmmll. TheForum serves as a means of exchanging views oninternational regulations affecting thepharmaceutical industry. Readers are invited tocontribute to the Forum by sending their Q&As towww.pharmweb.net/gmp.html.


PPHHAARRMMAACCEEUUTTIICCAALL FFOORRUUMM ((CCoonntt..))

substances (subject to proven stability, of course). Thebest example is vitamin D3.

The shelf life of an API can be extended, based onproven stability including impurity profile up to theproposed extended shelf life. But we should not directlycorrelate the shelf life of a drug substance and drugproduct except through proven stability studies.

Response 4 – The API has a retest period, not anexpiry date. As the name suggests it is possible to extendthe useful life of an API by retesting, provided alwaysthat there is adequate supporting real time andaccelerated stability data. This is why the term is ‘retestperiod’ and not ‘shelf life’ for APIs. It is also possible for alot of API that is past its retest date and, provided that itis fully compliant with the agreed specification, usedimmediately to manufacture a batch of finished (drug)product/dosage form.

The shelf life of the dosage form is established from ICH-compliant stability data.

Change in batch numbering

Q Should a change in an API batch numberingsystem be registered as a minor or major

variation?

Response 1 – I perceive such a change as major.There will be a major change in initial SOP to how the

number must be done and when such changes becomeeffective. Other points to be observed are: Why is therea change in the number system? How is this numberingsystem better than the previous one, how errors areminimised, and whether batches are tracked andidentified more easily and reliably.

Response 2 – From a regulatory perspective, it isminor one. But from a company perspective, pre andpost implement changes may be of major concern.

Tablets from other sites

Q When you receive bulk tablets from anothermanufacturing site within the group, are you

still required to do incoming identification ofthese tablets?

Response 1 – Yes, if the plant where these tabletshave been manufactured is a multiproduct facility.

Response 2 – In my opinion, if the remote site isfrom the same company (same legal entity) it is notmandatory to test their identity provided the labelling isclear. But if it is a different company within the samegroup, it is mandatory to test the ID.

Response 3 – Bulk tablets should be treated as anincoming material into the site. So, it needs to betreated in the same as you treat other raw materialsand API’s which come from suppliers.


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28-30 June 2011 – London, UKAnnual improving solubility summitwww.improvingsolubility.co.uk

29-30 June 2011 – London, UKPharmaceutical Nanotechnology:Applications & Commercialisationwww.pharma-nanotech.co.uk

29-30 June 2011 – London, UKPharmaceutical portfolio & productlife cycle managementwww.smi-online.co.uk

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4-5 July 2011 – Oxford, UKPIPA Summer Conferencewww.piponline.org

5 July 2011 – London, UKPOM to P – Critical Success Factorswww.smi-online.co.uk

6-7 July 2011 – London, UKSocial Media in the PharmaceuticalIndustrywww.pharm-social-media.com

7 July 2011 – London, UKBest practice for outsourcing ofanalytical support and use of contractlaboratorieswww.jpag.org

21 July 2011 – London, UKPatent Issues in the Development ofBiosimilar Medicines www.smi-online.co.uk

21 July 2011 – London, UKIntellectual Property and Licensing inBiotechwww.smi-online.co.uk

AAUUGGUUSSTT

31 August – 2 September –Nottingham, UKAcademy of Pharmaceutical SciencesUK PharmSci 2011 Conferencewww.jpag.org

SSEEPPTTEEMMBBEERR

13-15 September 2011 – Manchester, UKHuman Error: Causes and Preventionwww.nsf-dba.com

20 September 2011 – London, UKFirst steps in pharmacovigilance: aworkshop for administrators(Training course provided by PIPA andthe Institute of Clinical Research)email: [email protected]

26-27 September 2011 – London, UKBiosimilars and Biobetterswww.biosimilars-biobetters.com

27-28 September 2011 – Amsterdam,The NetherlandsPharmaceutical Co-Crystalswww.pharmacocrystals.com

28 September 2011- Amsterdam, TheNetherlandsPharmaceutical Amorphous Materials www.pharmaamorphous.com

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11-12 October 2011 – London, UKMHRA Good Manufacturing Practice(GMP) and Good Distribution Practice(GDP) email: [email protected]

11-13 October 2011 – Nuremberg,GermanyTechnoPharm 2011www.technopharm.de

13 October 2011- London, UKModern methods of drug analysis inbiological materials: analysis of drugsfor the Olympic Games 2012www.rphars.com

19-20 October 2011 – Berlin, GermanyBioproduction 2011www.bio-production.com

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DATES FOR YOUR DIARY

european industrial pharmacy issue 9 (june 2011)

Documents

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