european industrial pharmacy issue 27 (december 2015)

ISSUE 27 • DECEMBER 2015www.industrialpharmacy.eu

www.eipg.eu

features4 DEMAND FOR OTC MEDICINES CONTINUES TO

RISEThe UK over-the-counter pharmaceutical marketbenefits from an ageing population and changesin the healthcare system.by Kitty Zhang

6 PHARMACEUTICAL POLYMORPHS ANDCOCRYSTALS: IS THE SAME ALWAYS THESAME?The recent addition of polymorphs and cocrystalsto the EMA guidelines regarding classification ofmaterials as new active substances or otherwise hasinspired the formulation of a brief clarificationdetailing the fine line between what is equivalentand what is not, in the context of pharmaceuticalpolymorphs and cocrystals.by Liana Vella-Zarb

9 MANIPULATING DOSAGE FORMS FORCHILDREN: UNDERSTANDING ANDIMPROVING PRACTICEManipulation of adult medicines is frequently usedto provide paediatric doses. The guidelineManipulation of Drugs Required in Children(MODRIC): A Guide for Health Professionals wasproduced and emphasises the lack of evidencearound manipulation whilst suggesting goodpractices that might reduce potential risks.by Roberta Richey, Utpal Shah, Matthew Peak, Jean Craig,Jim Ford, Catrin Barker, Tony Nunn and Mark Turner

14 PROTECTING MEDICAL RECORD DATAThe healthcare industry, valued at $3 trillion, hasbecome an increasingly valuable target for cyberthieves, and in some cases, a much easier targetto attack, due to their often less than adequateinvestment in cyber security. What is it about thehealthcare industry that has captured the cybercriminal’s interest in the last few years?by Lauren Sporck

regulars3 EDITORIAL COMMENT17 NEWS FROM THE EIPG18 REGULATORY REVIEW20 EVENTS

europeanINDUSTRIALPHARMACY

2 european INDUSTRIAL PHARMACY December 2015 • Issue 27

europeanINDUSTRIALPHARMACY

December 2015ISSN 1759-202X

MANAGING EDITORSue Briggs

PRODUCTIONDave Johnson

SUBSCRIPTIONSJill Monk

EDITORIAL BOARDMichael AnisfeldClaude FarrugiaMichael Gamlen

Linda HakesJohn Jolley

European Industrial Pharmacyis published four times a year by:

Euromed CommunicationsPassfield Business Centre,

Lynchborough Road, Passfield,Liphook, Hampshire GU30 7SB

Tel: +44 (0)1428 752222Fax: +44 (0)1428 752223

Email:[email protected]

www.eipg.eu/eipg-journal

Indexed by:Scopus & Embase

Views expressed in European IndustrialPharmacy are those of the contributorsand not necessarily endorsed by the

Publisher, Editor, Editorial Board, or by ourcorporate sponsors who accept no liabilityfor the consequences of any inaccurate or

misleading information

©2015 Euromed Communications

europeanINDUSTRIALPHARMACYdiscussion group:

www.pharmweb.net/gmp.html

european INDUSTRIAL PHARMACYis the official publication of the European IndustrialPharmacists Group (Groupement des Pharmaciens del’Industrie en Europe) www.eipg.eu

Cover photo: OTC medicines (seeDemand for OTC medicines continues torise on page 4)

associate editors

Belgium: Philippe Bollen

Bulgaria: Valentina Belcheva

Czech Republic: Ales Franc

Finland: Anni Svala

France: Jean-Pierre Paccioni

Germany: Armin Hoffmann

Great Britain: Janet Halliday

Greece: Ioannis Nikolakakis

Hungary: Sylvia Marton

Ireland: Stan O'Neill

Italy: Piero Iamartino

Latvia: Inta Saprovska, Anita Senberga

Malta: Claude Farrugia

Netherlands: Amon Wafelman

Norway: Wenche Gordon

Spain: Beatriz Artalejo

Sweden: Marianne Andersson

Switzerland: Valter Gianesello, Maurizio Battistini

An interestedpartyInfluencing the evolution of EUregulations and guidelinesconcerning standards of quality,safety and efficacy of medicinalproducts is one of the mainobjectives of the EIPG. Thisactivity has always beenperformed regularly since thefoundation of our group, relyingon the contribution of ourmembers. A considerable numberof documents have beengenerated over the years and,nowadays, one can easily find the latest EIPG positionpapers on our website. There is no doubt that one of our points of strength

is the presence of a very large number of memberswith varying experience in all fields where anindustrial pharmacist can be employed, allowing us tocall on a multiple competency support. It was in orderto build on this solid foundation that 2 years ago – atthe 2014 General Assembly in Sofia – Special InterestGroups (SIGs) were set up with the aim of facilitatingthe communication and collection of opinions onspecific topics among our members. In spite of thegeneral consensus of all delegations to this initiative,we still have to make some additional organisationalefforts in order for these groups to be adequatelyproductive, as it is not always so easy to stimulateand maintain a constant participation of delegates inthis activity, which is based exclusively on theexchange of written communications.Nevertheless, we always try to express the EIPGopinion on the most important issues, mainlyfocusing on the technical papers under consultation,which are published by the European MedicinesAgency (EMA) or the Commission, requiring

comments from the so-called“interested parties”. In fact, theEIPG is fully recognised as aprofessional European associationentitled to communicate theposition of industrial pharmacists,like other pharmaceutical groupsrepresenting professionals andentrepreneurs operating in thepharmaceutical area. In the last few years, the EIPG has

been regularly invited to attend theannual meeting of the InterestedParties organised by the GMP/GDP(good manufacturing/distributionpractice) Inspectors Working Group

of the EMA, where we have the opportunity to beinformed about the work in progress on theGMP/GDP guidance and to make our voice directlyheard on the most critical issues. At the meeting thisNovember, the EIPG made a presentation onRegulation No. 536/2014, noting the elementsmissing from Annex 13 on GMPs and emphasisingthe importance of quality risk management in settingup the appropriate technical agreements betweenthe sponsor and the manufacturer of samples forclinical trials (see News from the EIPG for a report oflast month's meeting).With the contribution of all our members through

the coordination of each country delegate, we lookforward to keeping the EIPG actively present in thepharmaceutical arena as a standing interested party.

Piero IamartinoVice-President Technical and ProfessionalDevelopment

3european INDUSTRIAL PHARMACY December 2015 • Issue 27

editorial

Visit the website: www.industrialpharmacy.eu for PharmaTV andQuality by Design videos, Regulatory Review, Financial Pharma News

and other current items concerning Industrial Pharmacy

www.industrialpharmacy.eu

According to government figures,over the last three decades, themedian age of the UK population(the age at which half thepopulation is younger and half thepopulation is older) increased from35.4 years in 1985 to 40 years in2014. The UK’s ageing population isexpected to continue to grow and,by 2035, the number of peopleaged 65 and over is predicted toaccount for 23% of the total UKpopulation. An ageing population iscreating unprecedented demand forhealth products and services.Based on data from IRI, the UK’s

OTC pharmaceuticals market grewby an estimated 9.2% in valuebetween 2010/2011 and 2014/2015.The largest sector is analgesics,which made up 21.5% of the totalOTC pharmaceutical sales in2014/2015, followed by skincaretreatment (19.4%), cough, cold andsore-throat remedies (17.8%), andgastro-intestinal remedies (9.6%),with the remaining 31.7% accountedfor by other OTC products, such asvitamins and minerals and smokingcessation products (see Figure 1).

AnalgesicsRetail sales of analgesics witnesseda dramatic increase of 8.3% in the

year ending February 2015,compared with moderate growthrates of 1.1% and 1.7%, in the yearsending February 2013 and 2014,respectively. Demand for analgesicsis mainly driven by seasonal sales, aswell as price discounts andpromotional offers by retailers. Adultoral analgesics comprise the largestsubsector within the analgesicsmarket, accounting for 61.9% oftotal sales in 2015. An estimatedtwo-thirds of the adult populationpurchase an analgesic every yearand oral analgesics are the mostpopular choice.

Skincare treatmentThe market for skincare treatment isdiverse and covers a wide range of

products for different treatmentpurposes, including those for footcare and anti-fungal treatment, dryskin treatment, medicated skincare,antiseptic creams/liquids/spray, coldsore treatment, scalp and cystitistreatment, and adult infestationtreatment. Foot care is the largestsubsector within the skincaretreatment market and demand forthese products has been rising,driven by the UK’s ageingpopulation and rising obesity rates,as well as increased awareness ofproducts regarding foot-relatedproblems, such as dry cracked feet.

Cough, cold and sore throatremedies Demand for cough, cold and sorethroat remedies is influenced byseasons and weather conditions.Cold viruses survive better in wintermonths due to low humidity, whilethe lining of the nose also gets drierin winter, thus becoming morevulnerable to cold and flu viruses.Sales of cough, cold and sore-throatremedies witnessed double digitgrowth during winters of 2012/2013and 2014/2015 when flu viruscirculated at the highest level. Bysector, cold and flu decongestantsare the largest subsector, accountingfor more than half (52.5%) of thetotal sales of this sector in 2015,followed by medicatedconfectionery (25.7%) and coughliquids (21.8%).

Gastro-intestinal remediesSales of gastro-intestinal remediesincreased by a moderate 5.7%between 2010/2011 and 2014/2015,fuelled by increasingly health-conscious consumers and improvedeating habits. Indigestion remedies

european INDUSTRIAL PHARMACY December 2015 • Issue 27

DEMAND FOR OTCMEDICINES CONTINUES TO RISEby Kitty Zhang

The market for over-the-counter (OTC) pharmaceuticalsin the UK has been growing in recent years, driven

by the country’s increasingly ageing population, cuts topublic healthcare spending, and a rise in National HealthService (NHS) prescription charges. The OTC medicinesmarket has also benefitted from the emergence of theInternet and social media platforms in the past twodecades, which have enabled patients and healthconsumers to more easily acquire medical informationand purchase OTC pharmaceutical products.

Kitty Zhang joined Key Note in 2010, and works as Key Note’s Senior Business Analyst.She specialises in the following areas: healthcare, energy, utility, agriculture and chemistry.

4

Analgesics

Skincare treatment

Coughs, cold and sore throat remedies

Gastro-intestinal remedies

Other

Figure 1: The UK OTCpharmaceuticals market by sectorshare of sales, year endingFebruary 2015 (Source: IRI).

DEMAND FOR OTC MEDICINES CONTINUES TO RISE continued


are the most used type of gastro-intestinal remedies, making upnearly half (49.5%) of total sales ofgastro-intestinal remedies in 2015,followed by anti-diarrhoea remedies(19.7%) and laxatives (19.1%). Theremaining 11.7% was accounted forby remedies for stomach upsets,irritable bowel syndrome (IBS) andtravel sickness.

Other OTC products Sales of other OTC products –including vitamins and minerals,smoking cessation products,nutritional foods, hay feverremedies, eye care treatment,sleeping aids and stress aids –experienced consistent growth overthe past 3 years, with vitamins andminerals representing the largestsubsector within the other OTCpharmaceutical products sector,followed by nutritional foods,smoking cessation products and hayfever remedies.In recent years, the Government

has introduced national initiatives toincrease uptake of OTC medicinesand help to make better use of NHSresources. In 2010, the Self CareCampaign was launched, bringingtogether key stakeholders in the UK,including professionals from theNHS Alliance, the Royal College ofNursing, the Proprietary Associationof Great Britain and the NationalAssociation of Primary Care. TheSelf Care Forum was created thefollowing year to help organise andraise awareness of Self Care Week.The Forum produces a series of factsheets for minor illnesses, such aseczema, back pain and heartburn, tohelp doctors and patients discussissues surrounding self care duringconsultation.Changes in the healthcare system

in the UK in the past few years havehad strong implications forpharmaceutical companies and thedemand for OTC pharmaceuticals.As in many other developednations, the recent economicdownturn has led to a fall inhealthcare expenditure in the UK.Government figures reveal that UKhealthcare expenditure grew by anannual average of 8.1% between

1997 and 2009; however, the rate ofgrowth slowed significantly from2010 onwards as the Government’sausterity measures started to bite.The NHS in England has beeninstructed to make efficiency savingsof up to £20 billion between 2010and 2015, while at the same timedealing with the demographicpressure of a growing and ageingpopulation. Indeed, between 2010and 2013, growth in healthcareexpenditure slowed to an averageannual increase of just 2%. Changesin the healthcare system have led togreater rationing of services andincreased waiting times for patients,as well as a diminished ability acrossthe NHS to provide care.General practitioners (GPs), which

are often the first point of contactfor patients, are under increasingpressure from rising patient demandcombined with NHS funding cuts.According to data published byDeloitte, 8.4% of NHS budgets werespent on GP services in 2012/2013,down from 10.3% in 2004/2005. Overthe same period, the number ofpatient consultations in Englandincreased. GP services arestruggling to meet the needs ofincreasing numbers of patientsdemanding appointments and thereare mounting concerns that over-stretched GP services have resultedin accident and emergency unitscoming under strain as patients failto get appointments at surgeries.Meanwhile, prescription charges inEngland have risen dramatically inrecent years: the cost of an NHSprescription charge in England has

increased from £7.20 per item in2010 to £8.20 per item in 2015. TheOTC pharmaceuticals market hasbenefitted from the rise inprescription charges in England inrecent years, as OTCpharmaceuticals are often cheaper.The OTC market is highly

competitive and the market in the UKis dominated by a small number ofmultinational companies. Thesecompanies often have establishedbrands that are well known andtrusted by consumers. Examplesinclude: Rennie, for heartburn andindigestion, produced by Germanhealthcare company Bayer;Beechams Cough & Cold andPanadol by GlaxoSmithKline; andVoltarol pain relief and Nicotinell, bySwiss company Novartis. All of thesecompanies have large operations inother countries. There have beenmajor changes in the competitivestructure of the OTC market in recentyears. The year 2014 saw two of theworld’s top pharmaceuticalcompanies, GlaxoSmithKline andNovartis, enter a consumerhealthcare joint venture and combinetheir OTC businesses. In the sameyear, Bayer announced it agreed toacquire the consumer care division ofMerck & Co for $14.2 billion. The UK’s growing population over

the next few decades will help todrive demand for all consumergoods, including OTCpharmaceutical products. Economicgrowth will help to restore consumerconfidence and increaseexpenditure on all consumer goods,including OTC pharmaceuticals.

The physical properties of acrystalline material are, in great part,dictated by the three dimensionalarrangement of its constituentatoms. In the case ofpharmaceuticals, most of which areadministered in crystalline form, thecrystal geometry of the activeingredient and its excipients directlyaffect the drug’s bioavailability, andconsequently its activity andtoxicity1.As new molecular materials are

being developed, thecharacterisation of their solid stateproperties is shifting the conceptson which we base ourunderstanding of theircrystallisation. Instead of a moleculehaving a unique crystal structure, itoften appears as if the number ofknown solid forms, or polymorphs, isproportional to the time and moneyspent investigating the compound2.The term ‘polymorphism’ is used todescribe the existence of asubstance in more than onecrystalline form. Organic molecularcrystals often display multiplepolymorphs and pseudo-polymorphs (solvates and hydrates).There is a close relationshipbetween the unique crystal structure

of a compound and its properties,such that different polymorphicstructures of a material often havedifferent physical, chemical,biological and pharmaceuticalproperties. The unexpected appearance of

novel crystalline forms in apharmaceutical context can be ascientific, industrial, or commercialdisaster. The case of the proteaseinhibitor ritonavir (Norvir®), AbbottLaboratories’ anti-HIV drug, is ahigh-profile example of polymorphsexhibiting different properties. Thedrug was formulated and marketedas an encapsulated solution inethanol and water. However, a newcrystal form appeared in 1998, firstat a production plant in NorthChicago, then at a plant in Italy.Ritonavir was the victim of a late-appearing polymorph with differentsolubility properties3, a case whichwas not the only one of its kind tohit the pharma industry. Anotherpractical example is paracetamol;form I can only be formulated as asuspension and was thecommercially available form until thediscovery of form II, whichundergoes plastic deformation andis suitable for direct compression,

thus making it potentiallyadvantageous to the pharmaceuticalindustry as it lends itself to themanufacture of tablets, if itsproduction in bulk is feasible4. The appearance of different

polymorphic forms can be attributedto both kinetic and thermodynamicparameters. Polymorphs tend toconvert from less stable to morestable forms, the rate of conversiondepending mainly on the requiredactivation energy and thedifferences in free energies betweenthe two forms. The relative stabilityof these crystals as a function ofconditions and the ability toproduce a desired polymorph ondemand are areas of great currentinterest. In some systems, onepolymorph is the stable form at alltemperatures (monotropic) while inother systems the stable form varieswith temperature (enantiotropic). Inaddition, many organic systemsdisplay multiple metastablepolymorphs. In the ideal thermodynamic case,

each polymorph is stable over itsown individual range oftemperatures and pressures and,when that range is exceeded, itchanges into a new polymorph.These interconversions arereversible and occur at a fixedtransition temperature analogous tothe melting and freezing points,which separate the solid and liquidstates. In actual practice, however,several polymorphs may coexist atthe same temperature and pressure,in which case only one of them isthermodynamically stable. In thiscase, the other polymorphs are saidto be “kinetically metastable”. TheGibbs free-energy values of thevarious polymorphs define thedepth of each energy minimum anddetermine which of the variouscoexisting polymorphs is thethermodynamically stable form5.Thus, knowledge of thethermodynamic stability is importantfor the selection of the appropriatepolymorph for pharmaceutical andchemical development, and one ofthe goals of pharmaceuticalmanufacturers is to develop themost thermodynamically stablepolymorph to ensure bioavailabilityof the product over its shelf-life.


PHARMACEUTICALPOLYMORPHS ANDCOCRYSTALS: IS THE SAMEALWAYS THE SAME?by Liana Vella-Zarb

The recent addition of polymorphs and cocrystals tothe European Medicines Agency (EMA) guidelines

regarding classification of materials as new activesubstances or otherwise has inspired the formulation ofa brief clarification detailing the fine line between whatis equivalent and what is not, in the context ofpharmaceutical polymorphs and cocrystals.

Dr Liana Vella-Zarb is currently a lecturer in solid state chemistry at the University of Malta.Her research interests lie in crystal structure determination using X-ray powder diffractiontechniques, as well as in crystal structure prediction and crystal engineering of materials,specifically those that are of relevance in a pharmaceutical or cultural heritage context.

Over the past few decades, eversince the ritonavir disaster hit theheadlines3, the influence ofpolymorphism on dissolutionkinetics and bioavailability has beena hot topic also from a regulatorypoint of view. It has been shownhow different crystal forms of drugsubstances exhibit different physicalproperties, includingphotostability6–8, compressibility,flow rate, and solubility, as well asdifferences in their solid statechemistry relating to stability andbioavailability. For these reasons, itis essential for regulatory bodies topay close attention to suchdifferences so as to ensure thatpolymorphic differences, if present,are borne in mind during the designstages via the tailoring offormulation and process conditionsto ascertain physical and chemicalstability of the product over theintended shelf-life, as well asproduct bioavailability/bioequivalence.Cocrystals are crystalline materials

made up of two or more differentmolecular entities that aresynthesised with the aim of alteringthe physical properties of theirconstituents without the need to

make or break any chemical bonds.Their synthesis is based on theformation of supramolecularsynthons that leads to a variation inthe three-dimensional arrangementof their components, leading to achange in one or more physicalproperties. There has been a steadyincrease in the number ofpharmaceutical cocrystals reportedin the literature over the past fewyears, and a quick search in theCambridge CrystallographicDatabase9 yielded more than 1505excluding ethylacetate solvates.While some do have improvedphysical properties when comparedto the active pharmaceuticalingredient (API) alone10–13, othersare interesting from a purelycrystallographic perspective.While the inclusion of polymorphs

and cocrystals in the recent EMAnotice is undoubtedly a step in theright direction, there are someaspects that need clarification.Although many polymorphs do

differ morphologically, some mayhave the same crystal morphologybut still be different crystallographicforms. Differences in crystal packingand lattice energies may result in adifferent solubility profile which will

inevitably cause differences in thedrug’s bioavailability. Therefore,control of the crystal form informulation is essential if the qualityof the drug product is to beascertained. In some instances,different polymorphic forms doresult in comparable bioavailability,but this is not always the case.The impact of polymorphism on

formulation bioequivalence, as wellas on other factors such asphotostability5, which mightnecessitate different packaging,must not be overlooked.Classification of polymorphs ashaving identical pharmacologicalaction based solely upon theirchemical structure does not givedue consideration to thepharmacokinetic aspects affected bythe material’s variation in physicalproperties. Prior to the marketing ofa drug, applicants must quantify anycrystal form impurity14,15, as highlevels of polymorphic contaminantswith differing physical propertieswould have an impact on the finalefficacy of the drug.In the case of cocrystals, it is

assumed that the API and acoformer are present in their neutralstates (thereby classifying them aspharmaceutical cocrystals ratherthan salts). Their status as cocrystalsimplies stoichiometric amounts oftheir consituents, whereby alterationof such stoichiometries would implydiffering physical properties.Specification of thesestoichiometries, along withassurance of complete dissociationof the API from its coformer, shouldbe required.If one is to classify cocrystals or

polymorphs of a drug as the sameactive substance, one must firstunderstand the implications this hasupon developers and patients alike,and set limits to this genericdefinition. Two substances may beclassified as “the same” in terms ofpharmaceutical activity, but havevery different physical propertiesthat would make one form muchmore bioavailable than the other, ormake one compressible into tabletsas opposed to the other, which canonly be marketed in liquid form. It is

PHARMACEUTICAL POLYMORPHS AND COCRYSTALS: IS THE SAME ALWAYS THE SAME? continued


Figure 1: Molecular structure of the cocrystallisation of piracetam andgentisic acid as published by Vishweshwar et al16,17. C, H, N, O atoms arein black, grey, blue and red, respectively. (Program used to create thepicture: H. Putz, K. Brandenburg, DIAMOND, Program for X-ray structureanalysis, Crystal Impact GbR, Bonn, Germany, 2012).

PHARMACEUTICAL POLYMORPHS AND COCRYSTALS: IS THE SAME ALWAYS THE SAME? continued

important to distinguish betweensubstances that exert the samepharmaceutical activity but areotherwise very different. Much effortgoes into the improvement ofphysical properties of materials, notjust in a pharmaceutical setting, butalso in food, construction, materials,and agriculture scenarios.Classifying compounds as the sameregardless of the physical propertiesthey exhibit is a dangerous practicethat could result in patenting andpatentability issues in the bestinstance, not to mention thepotential to market sub-par drugproducts without any legalimplications.

References1 Almarsson O, Peterson ML, Zaworotko M.The A to Z of pharmaceutical cocrystals: adecade of fast-moving new science andpatents. Pharm Pat Analyst2012;1(3):313–327.

2 McCrone WC. In: Physics and Chemistryof the Organic Solid State; Fox D, LabesMM and Weissberger A, Eds. London, UK:Interscience Publishers; 1965, Volume 2,pp. 725-767.

3 Bauer J, Spanton S, Henry R, et al.Ritonavir: an extraordinary example ofconformational polymorphism. Pharm Res2001;18:859–866.

4 Nichols G, Frampton CS. Physicochemicalcharacterization of the orthorhombicpolymorph of paracetamol crystallizedfrom solution. J Pharm Sci1998;87:684–693.

5 Bernstein J. Polymorphism in MolecularCrystals. New York, NY, USA: OxfordUniversity Press; 2002.

6 Matsuda Y, Akazawa R, Teraoka R, OtsukaMJ. Pharmaceutical evaluation ofcarbamazepine modifications:comparative study for photostability ofcarbamazepine polymorphs by usingFourier-transformed reflection-absorptioninfrared spectroscopy and colorimetricmeasurement. J Pharm Pharmacol1994;46:162–167.

7 Byrn SR, Pfeiffer RR, Stowell JG. Solid-State Chemistry of Drugs, 2nd Edition.West Lafayette, IN, USA: SSCI, Inc.; 1999,p. 205.

8 Kiss A, Repasi J, Salamon Z, et al. Solidstate investigation of mefloquinehydrochloride. J Pharm Biomed Anal1994;12:889–893.

9 Cambridge Crystallographic Data Centre.www.ccdc.cam.ac.uk

10 Reddy LS, Bethune SJ, Kampf JW,Rodríguez-Hornedo N. Cocrystals andsalts of gabapentin: pH dependentcocrystal stability and solubility. CrystGrowth Des 2009;9(1):378–385.

11Harriss BI, Vella-Zarb L, Evans IR.Furosemide cocrystals: structures,hydrogen bonding, and implications forproperties. Cryst Growth Des2014;14(2):783–791.

12 Tao Q, Chen J-M, Ma L, Lu T-B.Phenazopyridine cocrystal and salts thatexhibit enhanced solubility and stability.Cryst Growth Des 2012;12(6):3144–3152.

13Grossjohann C, Serrano DR, Paluch KJ, etal. Polymorphism in sulfadimidine/4-aminosalicylic acid cocrystals: solid-statecharacterization and physicochemicalproperties. J Pharm Sci2015;104(4):1385–1398.

14 Vitez IM. Utilization of DSC forPharmaceutical crystal form quantitation.J Therm Anal Calorimetry 2004;78:33–45.

15 Yamada H, Masuda K, Ishige T, et al.Potential of synchrotron X-ray powderdiffractometry for detection andquantification of small amounts ofcrystalline drug substances inpharmaceutical tablets. J Pharm BiomedAnal 2011;56(2):448–453.

16 Vishweshwar JA, McMahon ML, PetersonMB, et al. Crystal engineering ofpharmaceutical co-crystals frompolymorphic active pharmaceuticalingredients. Chem Commun (Camb)2005;September 28(36):4601–4603.

17 Bruno IJ, Cole JC, Edgington PR, et al.New software for searching theCambridge Structural Database andvisualizing crystal structures. Acta Cryst2002;B58:389-397.


Industrial

Pharmaceutical

Microbiology

Standards & Controls

Editors

Geoff Hanlon

Tim Sandle

2015 edition

Expert Guidance on IndustrialPharmaMicrobiologyEdited by Geoff Hanlon and Tim Sandle

This new second edition is an excellentreference work for those working in industrial

pharmaceutical microbiology. It covers allaspects of this complex subject with

contributions from many leading figures in thefield and is highly recommended

European Journal of Parenteral and

Pharmaceutical Sciences

This book is essential for every pharmaceutical laboratory: scientific, topical and practical.

Pharmig

order online at www.euromedcommunications.comOr contact the publishers: email: [email protected];

Tel: +44 (0)1428 752222; Fax: +44 (0)1428 752223.

Industrial Pharmaceutical Microbiology:Standards and Controlsprovides clear, practical and up‐to‐date guidance for handling virtually everycompliance and operational challenge associated with pharmaceuticalmicrobiology.

Expert Advice

In over 600 pages and 25 chapters a team of twenty four internationalauthorities answer all your questions concerning regulatory expectationsin areas such as microbiological audits, rapid microbiological methods,conducting risk assessments, both proactive in terms of minimisingcontamination, and reactive in terms of addressing microbial data deviation;and also ensuring that processes meet “quality by design” principles.

International Applications

Connect instantly with regulations and current best practices on everythingfrom disinfectants to sterility testing; environmental monitoring to hazardanalysis; and from pharmaceutical processes to biological indicators. All ofthis is developed from an international perspective, where differentregulations are compared and contrasted together with insightfulcommentary as to best practices.

BackgroundManipulation of any medicinalproduct is not without risk. Forinstance, modifying the dosageform just before administration mayresult in an inaccurate or poorlyreproducible dose, altered productefficacy, or medication error1. Manymedicines given to children aredosage forms designed andauthorised for adults (e.g. tabletsand capsules), and manipulated justbefore administration in an attemptto deliver the desired dose2. Themagnitude of the dose required,throughout childhood can vary upto 100-fold3 and often is aproportion of the dose in themarketed product4. Manipulationsinclude cutting, breaking or splitting

of tablets, suppositories ortransdermal patches into smallersegments, dispersing whole tabletsinto liquids to take a proportionaldose, crushing tablets or openingcapsules and mixing the resultantpowder with liquid and takingproportions of enemas or nebulisercontents. Any manipulation shouldraise concerns about the resultantdose accuracy5, stability, andbioavailability of the activepharmaceutical ingredient (API)6.The quality and performance of amedicine is assured only if used inaccordance with the marketingauthorisation. Manipulation is,therefore, an uncontrolled practicewhich remains essential if children,especially in hospital, are to receive

the required dose.Older medicines are often used

for children who were not includedin the original product licence ormarketing authorisation (e.g. theintended patient age group andintended route of administration).These medicines are often moresuited to adults than children.Manipulation of adult medicineswith the aim of achieving therequired paediatric doses iscommonly acknowledged amongprofessionals as a widespreadpractice, but poorly evidenced inthe literature. Even when age-appropriate formulations aremarketed, the need formanipulation will remain, asformulation development is notable to take account of all thepossible circumstances ofadministration. We were commissioned by the

National Institute for HealthResearch (NIHR) to developguidelines on manipulation ofmedicines for children. Observationof clinical practice, a questionnaire-based survey and a systematicreview were used to collect data toconstruct draft guidelines that werefinalised following reviews by aguideline committee and areavailable7. This article summarisesthe development and content ofthese guidelines.

Study protocolsA structured, undisguised,observational study of dosage formmanipulations in paediatric in-patient areas was conducted atthree sites; a large regionalchildren’s hospital, a regionalspecialist neonatal unit and adistrict general hospital8. Threehundred and ten manipulationswere identified (Table 1), 54 ofwhich were observed. To provide a national context,

paediatric nurses across the UKwere surveyed via a questionnaire8.Five hundred and sixtyquestionnaires were distributed with153 returned (Table 1). Respondentsreported 189 manipulations thatmet the inclusion criteria to beconsidered.Four databases were searched for

the systematic review; International

european INDUSTRIAL PHARMACY December 2015 • Issue 27 9

MANIPULATING DOSAGEFORMS FOR CHILDREN:UNDERSTANDING ANDIMPROVING PRACTICEby Roberta Richey, Utpal Shah, Matthew Peak, Jean Craig, JimFord, Catrin Barker, Tony Nunn and Mark Turner

Lack of authorised age-appropriate formulations canmake it difficult to administer medicines to children.

Manipulation of dosage forms, although outside licensingrequirements is undertaken by carers to achieve therequired dose. A free to access guideline Manipulation ofDrugs Required in Children (MODRIC): A Guide forHealth Professionals was produced following asystematic review, observations of clinical practice, andquestionnaires surveying manipulations andprofessionals’ experiences and views. Concerns aboutthe accuracy of the dose achieved followingmanipulations and a lack of practice guidance werehighlighted. This paper summarises some of thisguideline and draws attention to the lack of evidencearound manipulation processes. The guideline aims toprovide guidance on avoiding manipulations (wherepossible), dosage form specific guidance whereunavoidable and highlights medicines that should not bemanipulated. The guideline also draws attention to theregulatory bodies and the pharmaceutical industry of theneed to provide their known data for the benefit ofchildren.

Pharmaceutical Abstracts (IPA),PubMed, CINAHL and EMBASE,using the protocol of Richey et al9.The findings have recently beenupdated (unpublished data) withoutfinding significant developments tothose reported in the guideline.

Observation and surveyresultsOf the 310 recorded manipulations,62% involved tablets8, 21% wereintravenous drugs and 10% weresachets. Of 40 manipulations oftablet observed, 25 were splitting,12 aqueous dispersion, and oneeach involved crushing, breaking byhand and splitting followed bydispersion in liquid andmeasurement of a proportion of theliquid to provide the dose. Three ofthe 25 tablet manipulations wererepeated due to crumbling oruneven splitting. Visible powderwas generated during nine of thesemanipulations. One tabletmanipulation was due to childpreference over the taste of anavailable liquid. Questionnaire responses8

confirmed that the common tabletmanipulations were splitting,crushing or dispersing in water andgiving a proportion (used by >50%respondents). The predominantmethod reported to split tabletswas with a tablet splitter. The

predominant proportions of dosetaken for non-intravenous (IV)administration were ¼, ½, or ¾ ofthe dosage form prior tomanipulation; however, dosesequivalent to, e.g. 1%, 7%, 19% and80% content were also reported.Observations of manipulation ofother dosage forms are alsosummarised in Table 1. Over 50% of respondents

reported that the sole reason formanipulation was that there was ‘nosuitable preparation or strengthavailable’. Other reasons given werepatient preference and usualpractice. Concerns with the doseaccuracy achieved by manipulationwas reported by 35% ofrespondents. Major risks of

manipulation are summarised inTable 2.

Systematic reviewNo studies identified the resultantbioavailability followingmanipulation of tablets to obtain aproportion of the original dose, buttwo studies indicated no significantchanges in bioavailability followingthe administration of crushedsustained-release tablets. Wheresustained-release tablets were splitand administered, no significantchanges to bioavailability and peakplasma concentrations wererecorded.Seven studies halved tablets and

used adapted pharmacopoeiacriteria for assessment; no

MANIPULATING DOSAGE FORMS FOR CHILDREN: UNDERSTANDING AND IMPROVING PRACTICE continued


Table 1: Summary of data used to construct guidelines

Observational Use noted in Systematic review Dosage form study: procedures questionnaire papersb Most frequent medicines identifieda (%/153)a

Tablet 191 59 (38.6%) 42 40+

Capsule 4 13 (8.5%) Nil Loperamide, melatonin, oseltamivir

Sachets 30 2 (1.3%) Nil Vigabatrin, morphine sulphate (MST), Gaviscon (compound alginate), Movicol (macrogol 3350)

Liquids for oral 0 0 (0%) Nil n/aadministration

Nebuliser solutions 4 22 (14.4%) Nil Ipratropium bromide

Intravenous injection 65 19 (12.4%) Nil Omeprazole, phenobarbitone, ranitidine, midazolam

Transdermal patches 10 20 (13.1%) Nil Hyoscine hydrobromide

Suppository 6 15 (9.8%) 1 Paracetamol, diclofenac, glycerine

Enemas 0 6 (3.9%) Nil Phosphate enemaa Data taken from Richey et al.8b Data taken from Manipulation of Drugs Required in Children (MODRIC): A Guide for Health Professionals7

Table 2: Risks of manipulationa

Patient – Delivery of inaccurate and/or non-reproducible doses– Altered efficacy of the product (e.g. sub-therapeutic doses)– Increased adverse events

Product – Alteration to the integrity of the dosage is untested, possibly resulting in altered pharmaceutical, pharmacokineticand pharmacological properties and stability

– Contamination

Person performing – Exposure to the API or excipients into the atmosphere the manipulation potentially causing sensitisation or inhalation of powder

Environment – Release of APIs– Release of antimicrobials, and their use in sub-therapeutic

doses may predispose drug resistancea Data taken from Manipulation of Drugs Required in Children (MODRIC): A Guide for Health Professionals7



pharmacopoeial specifications forsubdivided tablets existed at thetime these studies were published.Such specifications are nowincluded in the BritishPharmacopoeia 201610 for scoredtablets. Results varied with onestudy finding that up to 75% ofhalved and quartered tablets wereoutside ±15% of the desired weight.Several methods of splitting tabletswere evidenced including manualsplitting and the use of tabletsplitters, razor blades, kitchenknives and scissors. No one methodwas ranked as consistently the bestor worse technique. Halvedirregularly shaped tablets did notmeet the weight specification.Importantly, halving scored tabletsdid not always produce halves thatmet specified criteria. Dispersibletablets can also yield inconsistentdoses when doses are withdrawnfrom different depths of thecontainer11. Table 1 also indicatesthat only one other publication,investigating suppositories, wasidentified as being helpful ininforming the guidelinedevelopment.

Guideline development andpurposeThe three data sets summarisedabove were used to draft theguidelines which covered themanipulation of medicines todeliver appropriate, reproducibledoses to paediatric patients whereno suitable product is available at

the point of care. A guidelinedevelopment group consisting ofhealthcare professionals, research,academic, formulation andpharmaceutical quality controlexperts and parent representativesreviewed the presented evidenceand developed the guideline. Itdescribes options available to avoidmanipulation, but whenmanipulation is unavoidableprovides readily accessible, easy toread guidance for deliveringappropriate and reproduciblemedicine doses to neonatal andpaediatric patients.The guideline is intended for use

by healthcare professionals workingin UK hospitals in neonatal andpaediatric in-patient settings and itsuse should increase the numbers ofbabies and children who get theprescribed dose. Additionally, itprovides a risk assessment tool foruse at ward level to minimise risk tothe product, patient, operator andenvironment. Finally, the guidelineinforms professions, regulators andthe public of best practice andpotential risks associated withmanipulation of medicines.

Summary of guidelinerecommendationsThe guideline has not beenreproduced in its entirety in thispaper. Primarily, dosage forms whichare appropriate to the age andability of the patient, of appropriatestrength and licensed should beprocured where possible; however, it

may be necessary to procureunlicensed special formulations orimported medicines to meet thisneed. Consideration should also begiven to rounding the dose to anavailable product strength orconvenient measurable volume, towhether an alternative dosage formcan be used or whether analternative medicine within the sametherapeutic class can be substituted.If this is impossible, the questionsraised in Table 3 must be answeredprior to healthcare professionalsundertaking any manipulation. Theaim is to avoid manipulatingmedicines wherever possible.Simple guidelines include thefollowing.

• Do not manipulate medicineswith a narrow therapeutic index.

• Never manipulate hazardousmedicines outside a controlledenvironment.

• Do not manipulate medicineswhich are modified releasedosage forms unless specificinformation from themanufacturer or pharmacistpermits manipulation.

• Any manipulation should beundertaken immediately priorto administration.

• As the effects of a manipulatedproduct may differ from thosedescribed for the non-manipulated product, carefulmonitoring of the patient isrecommended particularly afteradministration of the first dose.

If a manipulation is considerednecessary, further information maybe required to ensure this is carriedout safely and as accurately aspossible. Suggested practices aregiven in Table 4. Any newmanipulation in an acute situationshould be reported to pharmacy atthe earliest opportunity and a riskmanagement process implemented.

The futureIn 2007, legislation13 was introducedin Europe to provide impetus intothe development of appropriate

Table 3: Questions to be considered before manipulation is undertakena

Is a more appropriate formulation available?

What is the acceptable dose range for a particular patient/medical condition?

Is the commercial product suitable for such a manipulation?

Is there evidence that the manipulation can be performed adequately and reproducibly?

Is drug stability maintained?

Are there indications that manipulation may not provide dose accuracy (e.g. tablet crumbling)?

Is there a risk of an adverse event if a 20% over-dose or under-dose is given?

Has the manipulation been performed previously?

Is the manipulation usual practice and been approved by a pharmacist? b Data taken from Manipulation of Drugs Required in Children (MODRIC): A Guide for Health Professionals7

medicines for children. Eight yearslater, it will be some time before theinfluence of this legislation andcampaign strategy is realised.Children will always requirealternative administration strategiesfor medicines when they cannotmanage the authorised dosageform even though it has been

deemed ‘age appropriate’14. Anunderstanding of the current,imperfect situation must berecognised by regulators and thepharmaceutical industry. All mustrecognise the following:

• the lack of evidence relating tothe manipulation of medicines

for the purposes of achieving asuitable dose;

• the research findings within theguidelines and be prepared tosupport practitioners in theirrequests for information aroundmanipulations of medicines;

• that children may require a rangeof doses that require



Table 4: Some suggested practicesa

Tablets – Where patient preference requires manipulation, the implications should be discussed with the patient, parents or carers

– Tablets should be split using a tablet splitter in preference to dispersing or crushing– Dispersion in liquid should be used only if there is knowledge of the dispersibility or solubility of the API,

and formulation characteristics– Scored tablets should be split along the score-line, with the score-line uppermost– Do not split tablets into less than ¼ segments– Visually assess the segments to establish if they appear equal in size

Capsule – Unless designed as a sprinkle formulation, do not open capsules to take a proportion of their contents without consulting a pharmacist

– Do not disperse the contents and take a proportion without knowledge of the solubility characteristics of the drug

– Dispersion in liquid should be used only if there is knowledge of the dispersibility or solubility of the API, and formulation characteristics

– Avoid removing the contents from liquid-filled capsules, but where necessary withdraw the required volume into a syringe when the fill volume is known

Sachets – Do not disperse the contents and take a proportion without knowledge of the solubility characteristics of the drug

Liquids for oral – Volumes of <5mL should be administered using an oral syringe administration – If volumes <0.1mL are required, they should be diluted to ensure that a volume can be measured

accurately– Prepare single doses: diluted liquids should not be stored for future use– The chosen diluent should be compatible with the medicinal product

Nebuliser solutions – Withdraw the required dose volume from the vial into the syringe and add to the nebuliser chamber– To avoid inadvertent IV administration, nebuliser solutions should be drawn up and added to the nebuliser

chamber in one uninterrupted operation– Any diluent should be added to the chamber and the solution mixed using a suitable, preferably sterile,

device

IV and sub- – The National Patient Safety Agency 2012 advises that certain injectable therapy manipulations are cutaneous undertaken in a pharmacyinjections – Consult local/hospital IV guidelines prior to any manipulation

– The chosen diluent must be compatible with the injectable product– The measurement of volumes of <0.1mL should be avoided (with the exception of insulin) but, if required,

the dose should be measured after appropriate dilution. The diluent should not be added to the syringe containing the drug. Mix the active drug and diluent and withdraw the required volume into a separate syringe

Transdermal – Check the product’s release characteristics with the pharmacy department as different brands of the same patches API may have different release characteristics and may not be equivalent

– Do not manipulate reservoir transdermal patches– Where a proportion of a matrix patch is required, cut along the full thickness of the patch to produce

symmetrical segments– Do not cut patches into more than four segments

Suppository – Consult with pharmacy whether drug distribution is homogenous– Cut suppositories from tip to base using a scalpel blade – Assess the suppository segments to establish equality in size

Enema – Withdraw the proportion of the enema which is not required from the container using a syringe and needle and discard

– Administer the remainder of the enema from the original container – If the enema nozzle is unsuitable for administration, the required dose should be withdrawn and

administered via a suitable rectal tubea Data taken from Manipulation of Drugs Required in Children (MODRIC): A Guide for Health Professionals7


manipulation of ‘adult’ medicines;

• that manipulation is beingundertaken, despite itsinadequacies for the paediatricpopulation;

• that carers would not have tomanipulate if age-appropriatedosage forms were moregenerally available.

The full guideline is now publishedand freely available for healthprofessionals7 and presents resultsfrom independent researchcommissioned by the NIHR under itsResearch for Patient Benefit (RfPB)Programme (Grant ReferenceNumber PB-PG-0807-13260). Theviews expressed are those of theauthors and not necessarily those ofthe NHS, the NIHR or theDepartment of Health.

References1 Ernest TB, Elder DP, Martini LG, et al.

Developing paediatric medicines:identifying the needs and recognizingthe challenges. J Pharm Pharmacol2007;59:1043–1055.

2 Conroy S, Choonara I, Impicciatore P, etal. Survey of unlicensed and off labeldrug use in paediatric wards in Europeancountries. European Network for DrugInvestigation in Children. BMJ2000;320(7227):79–82.

3 Rocchi F, Tomasi P. The development ofmedicines for children. Pharmacol Res2011;64:169–175.

4 Standing JF, Tuleu C. Paediatricformulations – getting to the heart ofthe problem. Int J Pharmaceut2005;300:56–66.

5 Kayitare E, Vervaet C, Ntawukulilyayo JD,et al. Development of fixed dosecombination tablets containingzidovudine and lamivudine for paediatricapplications. Int J Pharmaceut2009;370:41–46.

6 Quinzler R, Gasse C, Scheider A, et al.The frequency of inappropriate tabletsplitting in primary care. Eur J ClinPharmacol 2006;62:1065–1073.

7 Barker C (Chair), Nunn T, Turner M, et al.Manipulation of Drugs Required inChildren (MODRIC): A Guide for HealthProfessionals. Commissioned by NIHRRfPB Programme.www.alderhey.nhs.uk/wp-content/uploads/MODRIC_Guideline_FULL-DOCUMENT.pdf.

8 Richey RH, Shah UU, Peak M, et al.Manipulation of drugs to achieve therequired dose is intrinsic to paediatricpractice but is not supported byguidelines or evidence. BMC Pediatrics2013;13:81. doi: 10.1186/1471-2431/13/81.

9 Richey RH, Craig JV, Shah UU, et al. Themanipulation of drugs to obtain the

required dose: systematic review. J AdvNursing 2012;68:2103–2112.

10 Medicines and Healthcare ProductsRegulation Agency. Subdivision oftablets. In: British Pharmacopoeia VolumeIII, Formulated Preparations > GeneralProducts > Tablets > Production.London, UK: MHRA; 2016

11 Broadhurst EC, Ford JL, Nunn AJ, et al.Dose uniformity of samples preparedfrom dispersible aspirin tablets forpaediatric use. Eur J Hosp Pharm Sci2008;14:27–31.

12 National Patient Safety Alert 20,Promoting safer use of injectablemedicines, Reference number 0434,Central Alert System (CAS) referenceNPSA/2007/20, Issue Date: March 2007

13 Regulation (EC) no 1901/2006 of theEuropean Parliament and of the Councilof 12 December 2006 on medicinalproducts for paediatric use andamending Regulation (EEC) No 1768/92,Directive 2001/20/EC, Directive2001/83/EC and Regulation (EC) No726/2004. Official Journal of theEuropean Union 2006;L 378:1–19.

14 European Medicines Agency.EMA/CHMP/QWP/805880/2012 Rev.2.Guideline on pharmaceuticaldevelopment of medicines for paediatricuse. Brussels, Belgium: EMA; 1 August2013. Available atwww.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2013/07/WC500147002.pdf [accessed 27November 2015].


Roberta Richey works in national clinical guideline development for the NationalInstitute for Health and Care Excellence. She was a Research Associate at Alder HeyChildren’s NHS Foundation Trust.

Utpal Shah was formerly post-doctoral formulation research fellow for the NIHRMedicines for Children Research Network supporting clinical study groups in issuessurrounding age-appropriate formulations and clinical trial supplies for investigatorand industry led paediatric trials. He was also Research Associate at Alder HeyChildren’s NHS Foundation Trust and Liverpool John Moores University where he wasinvolved in pharmaceutics projects and the development and conduct of numerousnational and multinational paediatric formulation research studies.

Matthew Peak is Director of Research at Alder Hey Children’s NHS Foundation Trustand Clinical Lead for NIHR Clinical Research Network: Children in the NW Coast. Hehas extensive experience in the design and delivery of both basic science and appliedresearch studies in child health, including medicines use and optimisation. Along withMark Turner, he leads the Liverpool Paediatric Medicines Research Unit which is ajoint initiative between Alder Hey and Liverpool Women’s NHS Foundation Trust andLiverpool John Moores University.

Jean Craig previously worked as a Paediatric Nurse at Alder Hey Children’s NHSFoundation Trust and as a Research Associate in the Evidence Based Child HealthUnit, University of Liverpool, undertaking systematic reviews and contributing todevelopment of national evidence-based guidelines. Her PhD included systematicreview methodological research. She now works as a Research Adviser with the NIHRResearch Design Service and as a Senior Research Associate in the School ofMedicine, University of East Anglia.

Jim Ford is Emeritus Professor in Pharmaceutics at the School of Pharmacy andBiomolecular Sciences at Liverpool John Moores University. He gained his PhD inSolid Dispersions in 1980 and spent 34 years working in academia becoming Directorof the School. He has published over 250 papers on topics including soliddispersions, controlled release matrices, thermal analysis and paediatric medicines.

Catrin Barker was appointed Chief Pharmacist at Alder Hey Children’s NHSFoundation Trust in 2012. She has spent 30 years working in paediatric pharmacypractice and has specific interests in clinical pharmacy practice, medicines informationand implementation and delivery of paediatric research. She has several publicationsin the area of paediatric clinical pharmacy practice.

Tony Nunn was Clinical Director of Pharmacy at Alder Hey Children’s NHS Trust until2011. He has honorary positions at Liverpool John Moores University and Universityof Liverpool and continues to work with various organisations to get ‘bettermedicines for children’.

Mark Turner is a Neonatal Consultant at Liverpool Women’s NHS Foundation Trustand Senior Lecturer in Neonatology at the University of Liverpool. Mark currentlychairs the European Network of Paediatric Research at the EMA (Enpr-EMA).


Overview of data breachesin 2014At the end of each year, the IdentityTheft Resource Center (ITRC)produces a data breach reportshowing the total number of databreaches and records stolen foreach industry3. The data is takenfrom credible sources, including theAttorney General’s website, andincludes data breaches thatoccurred in the year of the report orbreaches that were made public inthe year of the report. 2014 was abig year for data breaches ingeneral, with a total of 761breaches, amounting in 83,176,279exposed records. The followingindustries were included in thereport.

• Credit/Financial (5.5%)• Business (32.7%)• Education (7.6%)• Government/Military (11.8%)• Healthcare (42.3%)

Of the industries represented, thehealthcare industry had the highestnumber of total breaches in 2014:322 out of a total of 761 breaches. In terms of the total amount of

records stolen or compromised bybreaches in 2014, the business

sector had the highest at65,896,115, followed by thehealthcare industry at 8,255,247records4. It might be surprising thatthe banking industry only had1,185,492 records stolen, especiallywhen considering how frequentlycredit card fraud makes the news.It’s not often that you hear aboutsomeone who had their medicalrecord stolen. Unfortunately, stolen medical

record data is not usually reportedin a timely manner; often takingyears before someone discoversthat the data has beencompromised. Unlike stolenmedical records, stolen credit cardinformation is usually reportedrather quickly, due to banks’monitoring for suspicious accountactivity.

Comparing medical recordsto credit card dataIn order to understand why thehealthcare industry is such a bigtarget for cyber-criminals, you haveto understand the value of a stolenmedical record. Personal bankinginformation is still valuable to theaverage cyber thief, but it doesn’thave nearly as high a payout as thatof a medical record. Reuters placeda value on stolen medical

information that is 10 times morethan that of credit card data5.According to data collected frommonitoring exchanges on the blackmarket, the director of threatintelligence at PhishLabs estimatesthe value of stolen medicalinformation to be around $10 perrecord, and that is on the low endof black market prices. Somesources claim that they can be soldfor as much as $60 to $70 perrecord. In the ITRC report mentioned

above, of 322 reported breaches forthe healthcare industry, 289breaches resulted in confirmedquantities for the number of recordsstolen. The average amount ofrecords stolen per known breachwas about 28,564. If each medicalrecord is assumed to be worth aminimum of $10, then the averagepayout for cyber-criminals fromeach breach would be at least$285,640, and that is considered tobe a conservative estimate. If arecord were assumed to be wortharound $60–$70, then the averagepayout would be over $1.7 millionper breach6. Credit card data on theother hand is worth around $1 perrecord, so cyber-criminals wouldhave to steal at least 10 times asmany banking records to realisesimilar profits. Medical records sell at a high

price because they contain personaldata such as names, addresses,social security numbers, birth dates,billing information, among otherinformation. This information is usedby cyber-criminals to create fake IDsthat can be used to buy drugs thatcan be resold later, or to file falseinsurance claims using patient data7.

Industry spending on cybersecurityHospitals are often easier targetsfor cyber-crime because they lackthe proper cyber security defenses8.Healthcare spending for cybersecurity is known to be low,compared to other regulatedindustries. In a 2012 report releasedby the Ponemon Institute, thehealthcare industry listed a lack offunds as one of the main obstaclespreventing them from taking theproper steps towards better data

PROTECTING MEDICALRECORD DATAby Lauren Sporck

After a slew of data breaches in 2014, the FBI warnedthe healthcare industry that cyber-criminals would

be directing more attention their way in 20151. Thehealthcare industry, valued at $3 trillion, has become anincreasingly valuable target for cyber thieves and, insome cases, a much easier target to attack due to theiroften less than adequate investment in cyber security.What is it about the healthcare industry that hascaptured the cyber criminals’ interest in the last fewyears2?

Lauren assists in OPSWAT’s research and content development; her editorial backgroundincludes writing for Urbanspoon and Optify. She received her Bachelor's degree inBusiness from the University of Washington.


PROTECTING MEDICAL RECORD DATA continued

security practices9. ABI Researchrecently reported estimates thatworldwide healthcare spending oncyber security will be around $10billion by 202010. This only amountsto about 10% of the amount spenton cyber security by the criticalinfrastructure industry. Bycomparison, the financial industry isexpected to spend $9.5 billion in2015 alone12. We know how much cyber-

criminals stand to gain from ahealthcare industry data breach, buthow much do these data breachescost the companies who areaffected? With the average cost of adata breach for a company in thehealthcare industry of about $2million over a 2-year period12, thecase for investing in additionalcyber security defenses becomesclearer.

The problem with BYODOne of the biggest concerns facingthe healthcare industry is theincreased adoption of “bring yourown device” (BYOD) by medicalprofessionals. According to a recentreport, 88% of healthcareorganisations said they permittedemployees and other medical staffto use personal devices for workpurposes13. More than half of thosesame organisations claimed theydid not have visibility to the securitystatus of those BYOD devices. Iforganisations are not certain of thesecurity of a device, how can theyeffectively protect any patient datacontained therein? Although many healthcare

organisations allow medical staff touse personal devices for workpurposes, their IT departments donot adequately support that use14.There seems to be some sort ofdisconnect between the ElectronicMedical Record (EMR) tools that arechosen by the IT department andthe willingness of medicalprofessionals to use those tools. Ina study recently released bySpyglass Consulting, 70% ofphysicians interviewed claimed thattheir IT department wasn’t makingadequate progress towardssupporting mobile computing and

communication requirements. This statistic is alarming as 96% of

those same physicians claim to beusing their personal smartphone forclinical communication purposes.Inefficient support of physician’smobile devices results incommunication issues, which in turnleads to higher costs created bycommunication delays. The healthcare industry clearly

needs to find a way to integrateBYOD trends without compromisingthe security of devices.

Solutions for preventingfuture breachesWith healthcare industry databreaches predicted to haveincreased in 2015, organisationsmust take the proper precautions toavoid hefty fines resulting fromfederal Health Insurance Portabilityand Accountability Act (HIPAA)violations.

Multi-scanning technologyAs a requirement for the HIPAA,installing an antivirus product is animportant layer of protection. Bychoosing multi-scanning,organisations reduce the risk of thatmalware entering their network;what one antivirus engine doesn’tdetect another often will. Documentsanitisation capabilities are alsouseful, allowing users to preventinfections by advanced threatsand/or zero-day attacks byconverting potentially dangerousfile types to remove embeddedmalware.

Protection of endpointsIf devices connecting to a hospital’sinternal network cannot beconfirmed as secure, how canorganisations expect to avoid apossible data breach? Proper hostchecking and monitoring ofendpoint security status isimperative as more physiciansadopt BYOD practices. This endpoint visibility challenge

is unique and difficult to addresswhile still maintaining the spirit ofBYOD policies. Some MDM (MobileDevice Management) products haveaddressed this using techniques like

containerisation, but the issue islargely unaddressed for desktopsand laptops.

Improved email security A phishing attack is believed to bethe cause of the recent Anthembreach, where stolen employeecredentials were used to gainaccess to a secure network. In orderto avoid this type of attack, thehealthcare industry must invest inthe proper email security software. Industry-wide spending on cyber

security remains low, despite thefact that healthcare is the largesttarget for cyber-criminals. Iforganisations in the healthcaresector want to reduce their risk ofcyber-attack, they have to re-evaluate their views on security. Toooften, investment in cyber securityoccurs after a breach has alreadytaken place and patient data hasalready been compromised. Iforganisations find the right securitytools they can protect patient datawhile addressing organisation-widecommunication issues, saving thevaluable time of medical staff andavoiding the potential loss ofmillions in data-breach recoverycosts.

References1 Finkle J. Exclusive: FBI warns healthcaresector vulnerable to cyber attacks. NewYork, NY, USA: Thomson Reuters; 23 April2014. Available at:www.reuters.com/article/2014/04/23/us-cybersecurity-healthcare-fbi-exclusiv-idUSBREA3M1Q920140423 [Accessed 5March 2015].

2 Orcutt M. “2015 Could be the year of thehospital hack. MIT Technology Review; 23December 2014. Available at:www.technologyreview.com/news/533631/2015-could-be-the-year-of-the-hospital-hack/ [Accessed 5 March, 2015].

3 Identity Theft Resource Center. 2014Data Breach Stats. San Diego, CA, USA:ITRC; 27 August 2015. Available at:www.idtheftcenter.org/images/breach/ITRC_Breach_Stats_Report_2014.pdf[Accessed 5 March, 2015].

4 Identity Theft Resource Center. 2014Data Breach Category Summary. SanDiego, CA, USA: ITRC; 23 December2014. Available at:www.idtheftcenter.org/images/breach/ITRCBreachStatsReportSummary2014.pd[Accessed 5 March, 2015].

5 Waugh R. Healthcare data worth tentimes price of credit card data. Bratislava,

Slovakia: ESET; 25 September 2014.Available at:www.welivesecurity.com/2014/09/25/healthcare-security/ [Accessed 5 March, 2015].

6 Van Cleave K. Anthem highlightsdesireability of stolen health records.New York, NY, USA: CBS; 5 February2015. Available at:www.cbsnews.com/news/do-hackers-have-your-health-records/ [Accessed 5March, 2015].

7 Humer C. Your medical record is worthmore to hackers than your credit card.New York, NY, USA: Thomson Reuters; 24September 2014. Available at:www.reuters.com/article/2014/09/24/us-cybersecurity-hospitals-idUSKCN0HJ21I20140924 [Accessed 5March, 2015].

8 Murphy T. Health records are easy targetsfor hackers. Columbus, OH, USA: TheColumbus Dispatch; 15 February 2015;Available at:www.dispatch.com/content/stories/busine

ss/2015/02/15/health-care-records-are-easy-targets-for-hackers.html?utm_content=12155422&utm_medium=social&utm_source=linkedin[Accessed 5 March, 2015].

9 Ponemon Institute. 2012 Cost of CyberCrime Study. Traverse City, MI USA:Ponemon Institute; October 2012.Available at:www.ponemon.org/local/upload/file/2012_US_Cost_of_Cyber_Crime_Study_FINAL6%20.pdf [Accessed 5 March, 2015].

10ABI Research. Healthcare cybersecurity amassive concern as spending set to reachonly US $10 billion by 2020. London, UK:ABI Research. Available at:www.abiresearch.com/press/healthcare-cybersecurity-a-massive-concern-as-spen/[Accessed 5 March, 2015].

11Cybersecurity Ventures. CybersecurityMarket Report. Menlo Park CA, USA:Cyber Security Ventures. Available at:http://cybersecurityventures.com/cybersecurity-market-report-q2-2015/

[Accessed 5 March, 2015].12 Ponemon Institute. Fourth AnnualBenchmark Study on Patient Privacy & DataSecurity. Traverse City, MI USA: PonemonInstitute; March 2014. Available at:www.privacyrights.org/sites/privacyrights.org/files/ID%20Experts%204th%20Annual%20Patient%20Privacy%20&%20Data%20Security%20Report%20FINAL.pdf. [Accessed 5March, 2015].

13Weisbaum H. Heath care system’s $5.6billion security problem. EngelwoodCliffs, NJ, USA: CNBC; 12 March 2014.Available at:www.cnbc.com/id/101488137 [Accessed5 March, 2015].

14Comstock J. Report: Most physicians useBYOD smartphones, but lack supportfrom hospital IT. MobiHealthnews 14January 2015. Available at:http://mobihealthnews.com/39718/report-most-physicians-use-byod-smartphones-but-lack-support-from-hospital-it/[Accessed 5 March, 2015].


PROTECTING MEDICAL RECORD DATA continued

PharmacoVigilanceRevıew

Journal on drugsafety issues

Editor – Rob Begnett

This quarterly journal providesinformed comment and analysis ofinternational pharmaceuticalregulations relating to the safe use ofmedicines and medicinal devices. It

also carries reviews of current methods of pharmacovigilance.

Order online at www.euromedcommunications.com

Or email: [email protected]

Tel: +44 (0)1428 752222 Fax: +44 (0)1428 752223

PharmacoVigilanceRevıewSupporting the safe use of

medicines and medical devices

Managing Reference SafetyInformation

The EU centralised applicationfrom a pharmacovigilance andrisk management prospective

Post-authorisation aggregatesafety reporting: the new PSUR

New European pharmacovigilancelegislation – an adequateresponse to current challenges?

Volume 7 Number 3/4 Nov 2013


Bureau meeting A Bureau meeting is to be held on15/16 January 2016. Anyone wishingto raise a subject concerning the EIPGshould write to Jane Nicholson([email protected]).

Reminder – nominations for theEIPG Emerging IndustrialPharmacist AwardNominations for the 2016 awardshould be submitted by any EIPG FullMember no later than 1 January to amember of the Bureau or to JaneNicholson ([email protected]).The purpose of this award is to

recognise significant intellectualcontributions by emerging industrialpharmacists within EIPG that promotestate of the art in industrial pharmacyand the pharmaceutical sciences. Atthe time of nomination, the nomineeshould be a person who is within 10years of having started a career inindustrial pharmacy.

European PharmaceuticalStudents Association (EPSA)Claude Farrugia (Vice-PresidentCommunications) was invited by EPSAto attend their Autumn Assembly inMalta, where he delivered apresentation on the formulation ofprotein based drugs.The next joint EPSA/EIPG Webinar

will be held at the beginning ofFebruary and will be on the subject ofPharmaceutical Marketing. The EPSAexecutive would like to encourageindustrial pharmacists working inmarketing to participate in thediscussion.

Medicines shortagesClaude Farrugia and Jane Nicholsonhave both been appointed to theManagement Committee of the COST(International Cooperation andSpecific Organisations Participation)Project on Medicines Shortages. Theproject will commence during thesecond quarter of 2016 and aims toimprove the sharing of research andevidence about the problem ofmedicines shortages in Europe.

European Medicines Agencyand Interested Parties MeetingEIPG comments on the proposed GMP(good manufacturing practice) andGCP (good clinical practice) inspection

procedures for investigationalmedicinal products (IMPs) weresubmitted to the EuropeanCommission (see EIPG website) andpresented at the Interested PartiesMeeting held at the EuropeanMedicines Agency in November.Piero Iamartino (Vice-President

Technical and ProfessionalDevelopment), Jane Nicholson andMounir Rizovsky (VAPI/ UPIP Belgium)represented EIPG at this meeting. Thefuture work plan of the Inspectors'Working Group (IWG) was presentedby the IWG and discussed with theindustry representatives:

GMP Annex 1 – Sterile Products There has been substantial feedbackon the need to revise the ConceptPaper and a draft revision of theAnnex is to be distributed for publicconsultation during 2016. This will takeaccount of the revised EuropeanPharmacopoeia Monograph for Waterfor Injection. A preliminary guidancewill be published in the form of Q&Asduring 2016.

GMP Annex 13 and IMPsAs a result of Regulation 536/2014, aminor update is required. However,the European Commission hasadvised that for legal reasons thiscannot take the form of an Annex,hence the draft which has beenpublished for consultation.There was concern expressed by all

industry representatives that GMPfragmentation will lead to confusionand misunderstanding by staff incompanies. Industry would like to seea single, common approach to GMPsthat continues to focus on the ‘whatto do’. Annexes on specific operationsshould identify additional hazards tocontrol without repeating theprinciples. This could be supported by‘how to do/best practice’ documentsand standards outside the regulatoryframework.An analysis of the practical impact

of the Clinical Trial Regulation onGMP inspection-related activities willbe undertaken by the IWG in 2016.

GMP Annex 17 – Real Time ReleaseAn updated draft has been publishedand the aim is to finalise during 2016.

GMP Annex 21 – ImportationThis document is intended to clarifythe expectations for importers and toensure that third country manufactureis carried out in accordance with GMPstandards equivalent to those in forcein the EU. Following commentsreceived on the concept paper,drafting has been initiated and theaim is to publish for publicconsultation during 2016.

Other GMP-related activities The European Commission plans tocreate specific GMP guidelines for“Advanced Therapy MedicinalProducts” and held a targetedconsultation this year. The IWG willcontinue to engage on this topic.

Lack of harmonisationVarious industry examples ofinconsistencies with interpretationamongst national GMP inspectorswere discussed. Industry would like tosee a greater focus on science andrisk. In particular, industryrepresentatives felt that there appearsto be a lack of appreciation of therelationship between hazard and riskand an enhanced understandingwould benefit both industry andregulators. There have been problems with

revised Chapter 5 of Eudralex Volume4 since active pharmaceuticalingredient (API) producers have beenasked to disclose details of suppliersof API starting materials and thisappears to be a contradiction to otherguidance documents.It was noted that the IWG will

continue to devote a significantproportion of its resources toharmonisation and EuropeanMedicines Agency members willcontinue to run workshops, andattend meetings and case studies aswell as producing advice inpublications. A brief update on the Shortages

Workshop was made and it was notedthat a training document is freelyavailable on the InternationalSociety for PharmaceuticalEngineering website.

Jane Nicholson, Executive DirectorEIPG [email protected]

news from the EIPG


regulatory reviewThe current review periodhas seen a number ofchanges in the regulation ofmedicines and regulatoryguidance in the EU,International markets andthe USA

USAEntities considering whether toregister as outsourcingfacilitiesThe Food and Drug Administration(FDA) has received questions aboutwhether entities engaged in varioustypes of activities, such ascompounding only non-steriledrugs or only repackagingbiological products, should registeras an outsourcing facility. The FDAhas issued guidance to answer suchquestions and to provide additionalinformation about the regulatoryimpact of registering as anoutsourcing facility.

Endotoxin TestingRecommendations for Single-

Use Intraocular OphthalmicDevicesToxic Anterior Segment Syndrome(TASS) has been associated withsingle-use intraocular ophthalmicdevices (IODs) and single-useintraocular ophthalmic surgicalinstruments/accessories that arecontaminated with endotoxins. Thisguidance document providesrecommendations for endotoxinlimits as well as endotoxin testingto manufacturers and other entitiesinvolved in submitting premarketapplications or premarketnotification submissions for IODs tomitigate future outbreaks of TASS.

United States Pharmacpeia(USP) Visual Inspection ofInjections (USPPharmacopoeial Forum 41(6)In-Process Revision: <1790>)The General Chapters–DosageForms Expert Committee proposesthis new chapter to provideguidance on the inspection ofinjectable drug products for visibleparticles. The methods discussed

are also applicable to detection ofother visible defects that may affectcontainer integrity or cosmeticappearance of the product.

EuropeAnnex 16 – Certification by aQualified Person and BatchReleaseThis Annex has been revised toreflect the globalisation of thepharmaceutical supply chains andthe introduction of new qualitycontrol strategies. The revisionincludes the prevention of the entryinto the legal supply chain offalsified medicinal products. It alsoimplements InternationalConference on Harmonisation (ICH)Q8, Q9 and Q10 plus interpretationdocuments, e.g. the manufacturingand importation authorisationinterpretation document. Areaswhere the interpretation byMember States has not beenconsistent have been clarified. TheAnnex becomes operational on 15April 2016.

Clean Air and Containment ReviewThe journal to enhance your knowledge of cleanroom, clean air and containment technology

• Learn about different aspects of these technologies

from clearly written articles by experts

• Keep up to date on standards with regular updates

by standards committee members

• Read about innovations

• Understand the jargon

• Become an expert yourself

To subscribe, or for more information including contents lists for all previous issues, visit www.cleanairandcontainment.com

Clean Air and Containment Review ISSN 2042-3268

Issue 6 | April 2011

Measurement of air velocitiesSettle plates in unidirectional airflowThe ISO calibration standard for particle counters: a user’s comments

Biological safety cabinets: operator protection tests on narrow cabinets Zoned ultra clean air operating theatres


New EU guidance to speed updevelopment of antibioticsThe European Medicines Agencyhas released a draft guideline whichprovides guidance for the conductof robust analyses to facilitate andspeed up the development of newantibiotics, in particular thosetargeting multi-drug resistantbacteria.

Medical devices – proposal fora regulation of the EuropeanParliament and of the CouncilFollowing on from the Poly ImplantProthèse breast implant scandal,this revised proposal would, ifadopted, amend Directive2001/83/EC, Regulation (EC) No178/2002 and Regulation (EC) No1223/2009.

Implementing Act onPrinciples and Guidelines onGMP for Medicinal Products forHuman UseThe purpose of this consultation isto collect views, evidence andinformation from stakeholders tohelp the European Commissiondevelop its thinking in this area.

CEP – Content of the Dossierfor Chemical Purity andMicrobiological QualityThis new guidance is applicableimmediately. It takes account of theincreased requirements of newly

published and revised ICH and EUguidelines. CEP (Certificate ofSuitability) applicants should ensurecompliance with these newrequirements. Failure to do so couldresult in the application beingconsidered deficient.

Medicines and HealthcareProducts Regulatory Agency(MHRA) advises the CellTherapy Catapult on emergingclinical grade inducedpluripotent stem cells bankregulationUsing induced pluripotent stemcells (iPS) is an exciting newdevelopment, which sees medicinego beyond its traditionalboundaries. iPS cells are developedby taking specialised adult dividingcells (e.g. skin cells) and‘reprogramming’ them back to stemcells. These stem cells areconsidered to be ‘pluripotent’,meaning that they can be used tomake any type of cell in the body.The MHRA provided advice on a

wide variety of novel issues faced bythe organisation.

TxCell manufacturing facilityin Besançon shut downfollowing inspection by theFrench ANSMA non-compliance report has beenpublished in the Eudra GMPdatabase for this facility. The action

taken is suspension ofmanufacturing/release anddistribution, including suspension ofdistribution of released batches.There were 22 deficienciesobserved, including seven majordeficiencies.

(This serves as a reminder that EUregulatory authorities will nothesitate to take action againstmanufacturers when serious GMPdeficiencies are noted at inspection– MH.)

InternationalWHOGuidance on Good Data andRecord Management PracticeThis guidance consolidates existingprinciples and gives further detailedillustrative implementationguidance. Additionally, it givesguidance as to what theserequirements mean in practice andwhat should be demonstrablyimplemented to achievecompliance.

For further information on theseand other topics, we suggest yourefer to the websites of relevantregulatory bodies and to currentand past editions of “GMP ReviewNews” published by EuromedCommunications. To subscribe tothis monthly news service [email protected]

REGULATORY REVIEW continued

CALL FOR ARTICLESDear Colleague

We hope you enjoy the European Industrial Pharmacy and find it both usefuland informative.

We are currently seeking new articles for future issues of the journal and wouldlike to invite you to contribute an article or review paper on any aspect ofindustrial pharmacy to the journal. All issues of European Industrial Pharmacyare indexed by both Scopus and Embase and thus are available through thelistings for any other industrial pharmacist internationally.

Please contact the Managing Editor, Sue Briggs ([email protected]) forfurther information or submissions.

eventsJANUARY 201619–21 January 2016 – Brussels,Belgium6th Annual Clinical Trial SupplyEurope www.clinicalsupplyeurope.com

19–21 January 2016 – London, UKFestival of Genomicswww.festivalofgenomicslondon.com

20–21 January 2016 – London, UKPharmaceutical Microbiology2016www.pharma-microbiology.com

24–27 January 2016 – Arlington,VA, USAIFPAC-2016: InternationalForum & Exhibition ProcessAnalytical Technology…Qualityby Designwww.ifpacglobal.org

25–28 January 2016 – Frankfurt,Germany15th Annual Cool ChainTemperature ControlledLogistics Europewww.coolchaineurope.com

26–27 January 2016 –Washington, DC, USACBI’s 13th AnnualPharmaceutical ComplianceCongresswww.cbinet.com

28–29 January 2016 –Alexandria, VA, USA11th Summit on Biosimilars www.cbinet.com

FEBRUARY10–11 February 2016 –Barcelona, SpainWorld Generic MedicinesCongress Europe 2016www.healthnetworkcommunications.com

10–11 February 2016 –Barcelona, SpainBiosimilar Drug DevelopmentWorld Europe 2016www.healthnetworkcommunications.com

11–12 February 2016 – Basel,SwitzerlandTargeted Drug Deliveryhttp://pharma.flemingeurope.com/targeted-drug-delivery

22–24 February 2016 – Munich,GermanySoftware Design for MedicalDevices Europewww.sdmdeurope.com

23–24 February 2016 – Berlin,GermanyPharmaceutical Microbiologywww.pda.org

23–24 February 2016 – London, UKEarly Clinical Developmentwww.informa-ls.com

25–26 February 2016 –Manchester, UK11th Annual BiomarkersCongresswww.biomarkers-congress.com

29 February–1 March 2016 –Arlington, TX, USA2016 ISPE 25th AsepticConferencewww.ispe.org

29 February–3 March 2016 –Toronto, Ontario, Canada4th Annual Cold ChainManagement & TemperatureControl Summitwww.coldchainpharm.com

29 February–3 March 2016 –Munich, GermanyDisposable Solutions forBiomanufacturingwww.disposablebiomanufacturing.com

MARCH7–9 March 2016 – Frankfurt, Germany2016 European Annual Conference www.ispe.org

7–9 March 2016 – Madrid, Spain8th International Conference andExhibition on Pharmaceutics andNovel Drug Delivery Systemshttp://novel-drugdelivery-systems.pharmaceuticalconferences.com

7–10 March 2016 – Athens, GA, USA40th International GoodManufacturing PracticesConferencewww.georgiacenter.uga.edu/uga-hotel/conferences-events/register/international-manufacturing-practices-2016

9–10 March 2016 – London, UKClinical Outsourcing &Partnering World Europe 2016www.healthnetworkcommunications.com

13–16 March 2016 – San Antonio,TX, USA2016 PDA Annual Meetingwww.pda.org

16–18 March 2016 – Vienna, Austria21st Congress of the EAHPwww.eahp.eu

17 March 2016 – London, UKJPAG Annual General Meetingwww.jpag.org

APRIL4–7 April 2016 – Glasgow, UK10th World Meeting onPharmaceutics,Biopharmaceutics andPharmaceutical Technologywww.worldmeeting.org

11–12 April 2016 – Ware, UKAPS Industrial Insights 2016www.apsgb.co.uk

12–13 April 2016 – Venice, ItalyParenteral Packagingwww.pda.org

12–13 April 2016 – Dusseldorf,Germany2016 Pharma Congress:Production and Technologywww.pharma-kongress.com

17–21 April 2016 – Phoenix, AZ, USARDD 2016www.rddonline.com

19–20 April 2016 – Chicago, IL,USA12th Annual Medical DeviceCompliance Congress www.cbinet.com


www.healthnetworkcommunications.com


www.georgiacenter.uga.edu/uga-hotel/conferences-events/register/international-manufacturing-practices-2016




http://novel-drugdelivery-systems.pharmaceuticalconferences.com



www.disposablebiomanufacturing.com

www.disposablebiomanufacturing.com

http://pharma.flemingeurope.com/targeted-drug-delivery

http://pharma.flemingeurope.com/targeted-drug-delivery



