european industrial pharmacy issue 17 (june 2013)

europeanINDUSTRIALPHARMACY

ISSUE 17 • JUNE 2013www.industrialpharmacy.eu

www.eipg.eu

features4 STABLE CYTOCHROME P450 ENZYMES FOR

TOXICITY AND METABOLISM TESTINGResearchers at De Montfort University, Leicester, UKhave made a breakthrough in stabilising CYPs thatcould save millions on the pre-clinical and clinicalstages of drug development.by Bob Chauduri and Bill Primrose

8 CONTROLLED ENVIRONMENTS: THE NEW IEQDemand controlled ventilation can optimise energyconsumption in laboratories and cleanroomswithout compromising performance or quality, thusachieving significant cost savings and greenhousegas reduction.by Chuck McKinney

10 COMPARISON OF BIOSAFETY TESTINGREQUIREMENTS OF BIOLOGICALS ANDVACCINESFailing to detect viral contamination in biologicalsand vaccines can cost drug developers dear interms of time and money. New technologies mayimprove our detection methods.by Daniel Galbraith

13 BRIDGING API MANUFACTURINGParticle design can have an important effect on theperformance of the final dosage form of an API.Examples of the use of micro particles and nanoparticles are shown.by Márcio Temtem, Filipe Neves, Conrad Winters

18 PHARMACOPOEIAL COMPLIANCEThis article serves as a general introduction to ashort series on the major pharmacopoeias. Thesecond article will describe and discuss the BritishPharmacopoiea.by Kevin F Goode

regulars3 EDITORIAL COMMENT21 REGULATORY REVIEW22 NEWS FROM THE EIPG24 EVENTS

2 european INDUSTRIAL PHARMACY June 2013 • Issue 17

europeanINDUSTRIALPHARMACY

Issue 17 June 2013ISSN 1759-202X

EDITORJoe Ridge, MRPharmS

PRODUCTIONDave Johnson

SUBSCRIPTIONSJill Monk

EDITORIAL BOARDMichael Anisfeld

Alexander FlorenceClaude Farrugia

Linda HakesJohn Jolley

European Industrial Pharmacyis published four times a year by: Euromed Communications Ltd

Passfield Business Centre,Lynchborough Road, Passfield,Liphook, Hampshire GU30 7SB

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

Email:[email protected]

www.industrialpharmacy.eu

Annual subscription rate £85

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

Publisher, Editor, Editorial Board, or byour corporate sponsors who accept noliability for the consequences of anyinaccurate or misleading information

©2013 Euromed Communications Ltd

europeanINDUSTRIALPHARMACYdiscussion group:

www.pharmweb.net/gmp.html

european INDUSTRIAL PHARMACYis the official publication of the EuropeanIndustrial Pharmacists Group (Groupement desPharmaciens de l’Industrie en Europe)www.eipg.eu

Cover picture: Blow-fill-seal vial (see articlein next issue). Image: Fotolia

associate editors

Belgium: Philippe Bollen

Bulgaria: Valentina Belcheva

Czech Republic: Ales Franc

Denmark: Marie Fog

Finland: Anni Svala

France: Jean-Pierre Paccioni

Germany: Armin Hoffmann

Great Britain: Shilpa Gohil, Janet Halliday

Greece: Margarita Efthymiopoulou

Hungary: Sylvia Marton

Ireland: Anna O’Mahony

Italy: Piero Iamartino

Latvia: Inta Saprovska, Anita Senberga

Malta: Claude Farrugia

Netherlands: Amon Wafelman

Norway: Wenche Gordon

Portugal: Luis Baiao, Sofia Guimas

Spain: Emma Fernández

Sweden: Marianne Andersson

Switzerland: Stephan Buchmann, Valter Gianesello

european INDUSTRIAL PHARMACY June 2013 • Issue 17 3

On the 21st April, at the General Assemblyorganized by hosts VAPI-UPIP in Brussels, theEuropean Industrial Pharmacists Group (EIPG)elected its new President, Jean-Pierre Paccioni,president of the Central Council of Section B ofthe French Ordre National des Pharmaciens andoutgoing Treasurer of EIPG, after outgoingPresident Gino Martini decided to call it a day.

Gino Martini was elected President of EIPG atthe General Assembly in Prague in 2007. JaneNicholson, Executive Director of EIPG, recalls:“Gino's Presidency was timely for EIPG, coming, asit did, when membership of the European Unionwas expanding, and the European pharmaceuticalindustry was coping with new challenges in thepractice of industrial pharmacy. He recognized theneed for EIPG to grow as the need for greatercollaboration amongst industrial pharmacistsacross Europe became more important.”

Indeed, Gino believed in seeing EIPG reach outas far as its resources would permit and beyond.Malta, Latvia, Portugal, Spain – Gino took EIPG tothe edges of Europe. His charisma and energyattracted new organisations to EIPG. In his eyes,none were too small or unimportant, and he wasdetermined that all members could, and should,each in their own way, contribute to theassociation.

Jean-Pierre is no stranger to the Presidency ofEIPG, having previously held the post between1998 and 2002. However, it is a different EIPG thathe now inherits from Gino, and the challenges thatthe organization faced a decade ago pale incomparison with those it faces today. Emergingmarkets, mergers and acquisitions, referencepricing, medicines shortages, the increasing role ofbiotechnology: these are but a few of thechallenges facing the European industrialpharmacist. Yet it is not an unprepared EIPG thatGino is bequeathing to Jean-Pierre. Throughouthis Presidency, Gino had long prophesied the

shape of things to come and prepared for them.Piero Iamartino, Vice-President Technical andProfessional Development of EIPG, reflects:“Gino's vision of the future of the industry, and thechallenges that such a future would present toindustrial pharmacists, were always of greatconcern to him. He strived tirelessly and selflesslyto see EIPG mature into an association that couldbe, and be seen to be, a key player in industrialpharmacy and a point of reference to theprofessionals to which this industry owes itscontinued ability to serve society.”

The baton of EIPG’s leadership has been passedinto the capable hands of an individual with anequally remarkable pedigree. Crucially, it has beenpassed with Olympic-winning smoothness, atransition so necessary in these troubled timeswhere the pharmaceutical industry appearsdelicately poised between Pharmageddon andRenaissance. Jean-Pierre has already declared thepriorities of his Presidential mandate as anincreased EIPG visibility: a strengthened influenceon the European institutions and consolidatedlinks with partner associations, and working groupson technical issues. Thus, in the words of the newPresident, Gino “will continue to be part of thefuture of EIPG in the same unique way that he ispart of its past and its present.”; but then, as thosewho have worked closely with them have longknown, both men share a kindred, determinedcommitment to European industrial pharmacists.“Industrial pharmacists in Europe should get toknow each other better and raise their profile tobe recognized by the European institutions. I ampleased to take over the presidency of EIPG togive a new impetus to that association and benefitfrom the pharmaceutical expertise of the differentmember countries.”, declared Jean-Pierre uponhis election. A statement to fill us with hope forthe future.

Bienvenue à la barre, mon ami.Claude Farrugia, Vice President CommunicationsEIPG

editorialEIPG elects a new President: Martinipasses the baton to Paccioni

european INDUSTRIAL PHARMACY June 2013 • Issue 174

The failure rate for drug candidatesin clinical trials clearly indicates theneed for massive improvement in thepredictive power of the pre-clinicaltools used to assess drug safety. It isestimated that an improvement of10% in predicting failures prior toclinical trials could save a company$100 million in development costsper approved drug.

During the drug discoveryprocess, it is imperative todetermine the rate of metabolism,and the nature and toxicity ofpotential drug candidates, before acompound is introduced intoexpensive human clinical trials.Drugs are often taken incombination, and the interaction oftwo drugs may cause unexpectedtoxicity in one or either; this is

mediated by cytochrome P450enzymes (CYPs) and is referred to asa drug-drug interaction (DDI).

CYPs are intracellular membrane-bound enzymes, belonging to afamily of proteins which reducemolecular oxygen to reactive oxygenatoms. There are 57 different CYPisozymes in the human genome, withsome expressed in significantquantities in the liver. They play acrucial role in detoxification,modification, and removal of naturalor synthetic chemical entities, byrendering hydrophobic moleculesmore water soluble, making themeasier for the body to excrete.Around 75% of the total metabolismin humans is mediated by CYPs.Figure 1 shows the reactionmechanism of CYPs and a few of the

drug-metabolising reactions thatparticular isoenzymes can catalyse.

There are a variety of methodscurrently used to obtain informationon the interactions of candidatedrugs with CYPs. These include useof liver slices, primary hepatocytecell cultures, stable cell lines, livermicrosomes and isolatedrecombinant CYPs, as well assimulation of hepatic toxicity usingin silico methods. Stem cell-derivedhepatocytes offer potentialadvantages over cells obtained fromresected human liver tissue in termsof product consistency andavailability. However, it has notproved possible to reliably producehepatocytes with defined CYPcompositions, and a particularproblem will be to accurately mimicmature hepatocytes present in anadult liver. Therefore, it remainsnecessary to use isolatedrecombinant CYP enzymes. In anycase, if a particular CYP is identifiedas being inhibited by thecompounds of a lead series, withpotential for an adverse DDI, thendirect optimisation against this CYPwill be a critical part of the leadoptimisation process.

Currently marketed recombinanthuman CYPs are available asmembrane suspensions frombacterial and insect cells and are onlystable at –80°C, thus requiring a coldchain. CYPs expressed in human cellsare of low activity, with considerablebatch to batch variation.

Alternative sources of high-qualityrecombinant human CYPs, suitablefor high-throughput studies, wouldimprove the drug developmentprocess. More predictive in vitrostudies would be expected toinform decision-making at an earlierstage and drive the synthesis andselection of better drug candidates.

The technologyCYP Design Ltd. (CDL, www.cyp-design.com) is building on thetechnological breakthroughs of itsfounder, Professor Bob Chaudhuri,and his team at De MontfortUniversity, Leicester, UK. CDL ismarketing Sacchrosomes™, yeastmicrosomal membranes containinghuman CYPs as reagents for earlystage drug discovery studies. These

STABLE CYTOCHROME P450ENZYMES FOR TOXICITYAND METABOLISM TESTINGAttrition in drug discovery anddevelopment: The importance of CYPs indrug metabolism and toxicity

by Bob Chaudhuri and Bill Primrose

Despite an estimated $50 billion in collective annualR&D spending by the large pharmaceutical companies,

it is estimated that only 1 in 24 of drug discovery projectsachieves a marketable product, and only 1 in 10,000 ofnew chemical compounds that are screened for abeneficial therapeutic effect is eventually approved as anew medicine. Most of the attrition occurs in thescreening and pre-clinical development phases. However,notwithstanding this, still only approximately 1 in 11compounds that do enter clinical trials eventually getsmarket approval. A major cause of attrition at the clinicalstage is safety and toxicology, amounting to 30% of allfailures. In addition, liver disease associated with drugtoxicity is the most common reason for market withdrawalof drugs after approval.

Professor Bob Chaudhuri is Professor in Cancer Studies at the School of Pharmacy,De Montfort University, Leicester, UK. [email protected] Dr Bill Primrose is CEO at CYP Design Ltd, Leicester, UK. [email protected] www.cyp-design.com


STABLE CYTOCHROME P450 ENZYMES FOR TOXICITY AND METABOLISM TESTING continued

PANEL A – The overall reactioncatalysed by cytochrome P450 (CYP)and NADPH-dependent cytochromeP450 reductase (CPR). CPR feedselectrons from the oxidation ofNADPH to the catalytic centre ofthe CYP, which is an iron atom in aheme cofactor

PANEL B – The catalytic cycle ofcytochrome P450 (CYP).(1) In the resting state, a watermolecule is bound to the distal axialco-ordination position of the hemeiron (III). The proximal side of theheme is bound to a cysteine sidechain of the CYP protein (-S-)(2) Substrate (RH) binds to the CYPactive site, close to the heme iron,displacing the water, and causing aconformational change(3) An electron is transferred fromCPR, reducing the ferric heme iron(III) to the ferrous (II) state(4) Molecular oxygen binds to thedistal axial co-ordination position ofthe heme iron, followed by asecond electron from CPR, reducingthe dioxygen to a short-livednegatively-charged peroxointermediate(5) The peroxo intermediate isprotonated twice, releasing water,and generating a highly reactiveiron(V)-oxo species. The exactnature of this intermediate and theoxidation state of the iron are stillunclear. In this example, the oxygenatom can then be inserted into anunactivated C-H bond of thesubstrate, to generate ahydroxylated product, whichdiffuses away from the active site,to be replaced by a water molecule.Other reactions can also take place,depending on the nature of thesubstrate.

PANEL C – Some drug metabolismreactions involving 4 of the majorCYP isozymesMetabolism of (clockwise from topleft) warfarin, tamoxifen,propanolol, codeine and ibuprofenby CYPs 1A2, 2C9, 2D6 and 3A4.This is a very small selection ofreactions catalysed. CYPs canperform hydroxylation, epoxidationof olefins, aromatic oxidation,heteroatom oxidation, N- and O-dealkylations, and dehydrogenation,amongst others, with a very widerange of substrates.

Figure 1: The mechanism of CYPs and some examples of the metabolism reactions they catalyse.

PANEL A

PANEL B

PANEL C


are straightforward to produce, moreactive and more stable than thosefrom other systems, and moreconvenient to use than othercommercially-available CYPs.Critically, they do not require a coldchain. These new products havebeen developed through acombination of three technologies:(i) Expression of recombinanthuman CYPs in eukaryotic yeastcells Active mammalian CYPs are naturallyembedded within the cell in themembranes of the endoplasmicreticulum (ER). Baker’s yeast(Saccharomyces cerevisiae) providesan ideal cell production model forrecombinant CYPs as it mirrors themammalian intracellular environmentand also shares large similarities inthe proteome. Yeast is also thesimplest unicellular eukaryote, whosegenetics are well understood,allowing rational manipulation andthe expression of proteins of humanorigin. Yeast is also a favouredsource for high yield “cell factories”with a world-wide knowledge base,

and sophisticated productiontechnologies.

Yeast microsomes offer particularsimilarities to microsomes obtainedfrom human cells and are thereforewell suited for human metabolic ortoxicity studies. In contrast, insectcells have an intracellularenvironment quite different from thatof mammalian and yeast cells.Bacterial (e.g. E. coli) cells have noER, meaning that ‘active’ CYPs haveto be packaged into artificialmembrane structures afterexpression of the recombinant CYP.

CYPs can be produced byengineering yeast cells to express adesired human CYP isozyme,creating a unique yeast strain, whichcan be grown in liquid culture toproduce biomass from which theCYP can be extracted. The systemcan be easily scaled using standardtechnology from shake flasks for afew litres of material up to industrialfermenters to produce thousands oflitres. Per volume of cell culture,yeast produces 20-30 times moreCYP than insect cells.

(ii) Novel NADPH-dependent P450reductaseCYPs require a redoxpartner enzyme,cytochrome P450reductase (CPR, seeFigure 1), to deliver theelectrons required forsplitting molecularoxygen into oxygenatoms. In a eukaryoticcell, both CYP and CPRare naturally integratedinto ER membranes,and must physicallyinteract for activity.However, excessivequantities of CPR cancause cell collapsethrough the productionof reactive oxygenspecies (ROS). Thus,CPR is toxic to cellswhen present in highconcentrations.

Co-expression orpost-expressioncombination of thesetwo proteins is

necessary for an active system invitro. However, production methodsdirected towards high productionyields tend to yield final productwith low activity.

We have discovered a novel,human variant CPR that allows CYPactivity to be raised in combinationwith high-yielding productiontechniques, without over-productionof ROS. The inclusion of this novelproprietary reductase thereforeprovides a leading competitive edge.(iii) Stabilisation of YeastMicrosomesThe CYP-containing yeastmicrosomes are amenable to aproprietary process that allows themto be safely lyophilised and storedat room temperature. Full activity ismaintained for at least 3 months(see Figure 2). This stabilisationprocess can also be adopted formicrosomal CYP preparations fromany production source.

Advantages of stable, activeCYPs in drug discoveryStabilised CYPs can be dried downinto a number of formats, including96- and 384-well microplates to fit inwith drug discovery workflows.Active enzyme is regenerated byadding buffer to the microsomalfilms, which are then ready to use. Incontrast, CYPs from other sourceshave to be thawed from -80°C, andthen transferred to the testingsystem, a process which involvespipetting viscous andheterogeneous suspensions.

We have produced nine of the mostimportant human CYPs (1A1, 1A2,1B1, 2A6, 2C8, 2C9, 2D6, 2E1, and3A4), responsible for the majority of alldrug metabolism, and packagedthem into Sacchrosomes™.Sacchrosomes have specific benefits:

• Stable for storage at roomtemperature

• Full activity restored by simplereconstitution in aqueoussuspension

• Enzyme performance unaffectedby the stabilisation procedure

• Flexible presentation; samplescan be formatted in vials, oraliquotted onto 96- or 384-wellplates, prior to stabilisation


Figure 2: Comparative activity of CYPs expressedin yeast cells (Sacchrosomes™) compared to thosefrom insect cells after storage at roomtemperature for 3 months.The activity of CYP1A2 expressed in yeast andstabilised (blue bars) is shown at time 0 (solid) andafter 3 months storage at room temperature(hatched). This is contrasted with CYP1A2expressed in insect cells (pink bars) stored underthe same conditions. Activity was measured usinga fluorescence assay with 3-cyano-7-ethoxycoumarin (CEC) as substrate and 3-cyano-7-hydroxycoumarin (CHC) as product. Other CYPsgive similar results on storage.



• Ready to use off the shelf andconvenient to handle,simplifying routine analyses bymedicinal chemists or withinthe DMPK laboratory

Sacchrosomes show specificactivities comparable to, or betterthan, CYPs produced in insect cellsor in E. coli, supporting our beliefthat yeast microsomes are moresimilar to the mammalian systemthan those expressed from othersources. Comparative data for nineof the most important human CYPsare presented in Figure 3.

Convenient-to-use CYPs will allowmore compounds to be tested at anearlier stage for potential toxicityproblems. Stabilised CYPs will alsofind further applicability in fully

automated drug discovery chemistryplatforms, where toxicity andmetabolism data are generatedsimultaneously with activity data.

Future developmentsThe technology can be furtherdeveloped in other areas. Forexample:

• Making CYPs available within aliving cell format for in vitrodrug metabolism (cfhepatocytes) andbiotransformations

• Multiple CYPs within artificialmicrosomes to mimic humanliver microsomes

• Stabilised human CYPs inhuman cells for use at a laterstage in the drug discovery

process, when a clinicalcandidate is being selected

• Biocatalysts for the manufactureof pharmaceuticals,agrochemicals and industrialchemicals (since CYPs facilitatemono-oxygenation reactionswith exquisite regio- and stereo-selectivity under extremely mildconditions, which arechallenging tasks for mostchemical catalysts)

• Cellular systems containingCYPs that have the potential foruse as bioremediation agents

Further InformationFor further information on CDL’sSacchrosomes™, please visit ourwebsite: www.cyp-design.com .

Figure 3: Comparative activities of CYP Design’s Sacchrosomes™ for 9 major CYP isozymes with those produced ininsect cells. Activities for yeast microsomes are shown with blue lines, activities for insect microsomes are shownwith pink lines


The energy savings opportunity incritical environments seems obvious.On average, labs consume 5 to 10times more energy per square footthan typical office space, with highlyspecialized facilities such asvivariums and cleanrooms greatlysurpassing those averages. Thesingle largest energy componentwithin these facilities is ventilation,which can account for 45 to 65% ofenergy use. Typical research facilities

operate at eight to 15 air changes/hr(ACH); vivariums often operate at 12to 25 ACH. Cleanroom rates beginat 15 ACH for Class 8 environmentsand top out at an amazing 750 ACH!

Variable air volume (VAV) controlsystems equipped with demandcontrol ventilation (DCV) solutionsare now widely recognised as asuccessful way to balance energyefficiency with comfort and qualityobjectives.

The promise of DCVDCV involves highly sophisticatedenvironmental sampling andmonitoring infrastructure. With DCV,air samples are routed to specialsensors that analyse conditions andthen interface with the BuildingManagement system thatautomatically adjusts airflow inresponse. The people responsiblefor indoor environmental quality(IEQ) in the facility are the ones whodetermine the appropriateparameters. Airflow is tailored to theneeds of each specific room orzone, rather than general "rules ofthumb."

By monitoring individual roomconditions and varying make-up airvolume based on those conditions,building owners are realisingsignificant energy savings whilemaintaining a high standard of IEQ.

Despite the success to date ofDCV deployment in multiple typesof facilities, questions remain:

• To what extent can DCV beused to optimise energyconsumption withoutcompromising performanceand quality?

• How can managers, users,researchers,and qualityassurance personnel beconfident about the conditionsof their facilities whenimplementing energy-efficiencyinitiatives that seek to lowertheir air change rates frompreviously established constantvolume rates?

During the past few years, ideasabout critical-environmentmanagement have undergone a seachange. Rather than prescribingstrict operational processes,regulatory and accreditationorganisations have begun to adoptperformance-based metrics thatinvolve actual environmentalconditions, leaving the "how to"process of achieving thoseperformance metrics to facilitiespersonnel.

Research labs (such asconventional "wet" chemistry andbiology labs) have been highlyinvolved in this trend, and theirexperiences will eventually begin toinfluence developments in other

CONTROLLEDENVIRONMENTS:THE NEW IEQby Chuck McKinney

Controlled environments, including laboratories andcleanrooms, consume tremendous amounts of

energy, making them highly visible targets for efficiencyinitiatives. Comfort, safety, and quality control objectivesoften restrict building owners' and facility managers'ideas about potential energy savings. Standardoperating practices and rules of thumb have morphedinto pseudo-code requirements. As research begins toquestion these practices (and even standards), designersand operators grapple with the ultimate challenge:becoming more energy efficient without compromisingthe performance of critical facilities.

Chuck McKinney is VP/marketing for Aircuity Inc. The company's patented OptiNettechnology offers demand-based control solutions for both critical environments andcommercial offices, significantly reducing energy consumption and greenhouse gasemissions while maintaining quality parameters.

Figure 1: A graphic "dashboard" interface is an easy tool for helping facilitiesgauge the financial effect of adjustments in air change rates.


types of critical environments,including cleanrooms. Opportunityand confusion have both arisen, asresearchers and facilities personnelstrive (and sometimes struggle) toagree on management protocolsthat will consistently meet orexceed stipulated environmentalconditions. The door has beenopened to new approaches thatmay include energy-efficiencyprojects, but how best to proceed?

Data, data, dataInformation services that can alertfacilities personnel regarding thecondition and performance of thespaces they manage will help buildthe confidence required to continuethe expansion of DCV. In fact, theavailability of information servicesthat can document compliance withIEQ performance metrics may wellbe the driving incentive forimplementing a monitoring andcontrol strategy.

Information solutions must bemulti-faceted, providing multipleperspectives relevant to differentaudiences. EH&S professionals willwant to examine IEQ and buildingperformance data, while energymanagers will likely be moreinterested in monthly savings andidentifying issues that may beimpacting those savings.

Other key attributes of effectivemonitoring systems include:

• Visual displays of analysedinformation, not just raw data

• Short- and long-term trendinformation

• Alerts for high-priority issuesbased on persistence orpervasiveness, not just simpleparameter thresholds

• Automated summary reportsthat can provide high-levelviews of how a facility isoperating.

Information services have evolvedto help organisations manage theircritical environments proactively andreport performance information inmeaningful ways to building owners,facility managers, EH&S personnel,and accreditation and regulatorybodies.

Graphics improveunderstandingThe diagrams illustrate some easy-to-understand, yet sophisticated,IEQ graphics. Figure 1 is a dualdisplay showing both the flowreduction over the previous monthand the average ACH rates duringthat period. ACH monitoring isimportant to help building ownersmeet regulatory guidelines anddetermine if energy savingsobjectives are being reached, and togive managers, users and/orresearchers peace of mind thatventilation rates are appropriate forthe conditions.

Continuous monitoring andreporting can also providetremendous insight, showing howactivities within a space directlyaffect the amount of airbornecontaminants.

Combining parameters on a graphcan quickly and easily illuminateadherence to (or departure from)prescribed IEQ boundaries. Figure 2comprises a "comfort analysis"graph in a vivarium, plottinghumidity and temperaturemeasurements. The shaded boxreflects the acceptable ranges for aparticular species; in one of thediagrams parameters are being met,but in the other, something hasgone awry.

How far can DCV extend intocritical environments? Given the factthat even a modest air changeimprovement of 10% can reduceenergy consumption by almost 27%,the boundaries will continue to betested. The new ANSI Z.9 regulationfor fume hood airflow requirementsresulted from years of analysis thatchallenged the status quo. Researchrelevant to controlled environmentsis underway now; the AmericanSociety of Heating, Refrigeratingand Air-Conditioning Engineers(ASHRAE) has recentlycommissioned a study to determinehow DCV may be applied tocleanrooms.

As DCVapplications expand,monitoring andreporting capabilitieswill play anincreasinglyimportant role inhelping companies,institutions, andother organizationsachieve significantgreenhouse gasreductions whilemaintaining high-quality, high-performance criticalenvironments.

All graphics courtesyof Aircuity

CONTROLLED ENVIRONMENTS: THE NEW IEQ continued

Figure 2: A "comfort analysis" for a vivarium includes a shaded box indicating theacceptable range of temperature and relative humidity parameters for a particular species(in this case, mice). The dots represent real-time sampling of temperature and humidity.Dots clustered in the box indicate acceptable conditions; the other diagram indicatesproblems.


This issue was well recognised by theregulators and almost in parallel withthe first products the early regulationswere put in place1,2,3. The firstproducts used a number of animal-derived products in their manufactureand the first regulations sought tocontain the risk by testing startingreagents and process intermediatesamples. As products and processeshave changed over time, newguidelines have been introduced toalmost keep pace with them. Alongnew guidelines4 there has been aharmonisation of the globalguidelines to help manufacturersmaintain product security.

Viral vaccine safetyThe first medicines to use living cellsas the basis of their manufacturewere viral vaccines. These treatmentswere very successful in preventingpreviously untreatable disease, mostfamously poliomyelitis which is nowalmost eradicated worldwide.Vaccines are administered to healthyindividuals who in many instances willnever encounter the pathogen, as inthe case of Poliovirus, the causativeagent of poliomyelitis. The balanceof safety risk of treatment versus theoutcome (protection from seriousdisease) with these healthy

individuals must be carefullyconsidered, especially in the case ofchildren. Clearly these drugs must bevery safe given the many millions ofpeople who need to be given them.

The vaccine regulations arecontrolled differently from those ofthe biologicals. In Europe, thevaccines guidelines with regard tovirus safety are contained within theEuropean Pharmacopeia (EP 2.6.16)and have changed little over thepast 20 years with respect to theformat and methodology. In theUnited States the vaccine guidelineswere specified within a number ofdifferent areas, both thePharmacopeia and the Code ofFederal Regulations being involved,but more recently the FDA havepublished guidelines on vaccinevirus safety5.

The nature of vaccine productionmethods makes them susceptible tocontamination, which has occurredon several occasions. Polio vaccinebatches, for example, have beencontaminated with a number ofdifferent monkey pathogens,particularly during early batcheswhere primary monkey kidney cellswere used. The contaminatingviruses hitchhiked with the cellstaken from the monkey kidney used

in the production, therebycontaminating the batch. Stringentcontrols were put in place to ensurethe safety of vaccines by pre-screening cells prior to use and thishas been successful in preventingcontamination. However, we can onlyever prevent our known risks and it isclear that new viruses are beingdiscovered and described each year.Therefore we need not only specificassays for known pathogen risks, butgeneral assays capable of detectinga broad spectrum of agents whichcould appear.

GuidelinesMore recently, a new category ofdrugs has been developed whichalso used living cells duringproduction. This has been governedby a raft of guidelines most usefullycovered by the ICH Q5A: ICHharmonised tripartite guideline on“Viral safety evaluation ofbiotechnology products derivedfrom cell lines of human or animalorigin”. This guideline was agreedby representatives from the USA,Europe and Japan to cover therelevant testing required forbiotechnology products and hasbeen enacted into guidelines ineach of these areas. RecombinantDNA technology has allowed anumber of different cell types tobecome the mode of manufactureof biologic or large protein drugs.These drugs have againrevolutionised disease treatmentallowing many more conditions tobecome treatable. Cell lines fromrodents, insects, yeast, bacteria,birds or even human origin are nowused in the manufacturing ofbiologic drugs. All of these productstogether present a myriad ofdifferent safety risks, particularlyviral, which need to be understoodand controlled to maintain safety inthe final product.

Safety profilesRegardless of the species or sourceof cells, the safety profile isconstructed from three principles: i)testing of the starting materials suchas cell banks or media ingredients, ii)testing of “in process” material andiii) validation of the process forclearance of contamination.

COMPARISON OF BIOSAFETYTESTING REQUIREMENTS OFBIOLOGICALS AND VACCINESby Daniel Galbraith

Advanced therapies and biologicals have introduced tous the possibility of treating and curing disease

previously without remedy. With these treatments,because they use living cells during production and theinability to terminally sterilise the product, there is anincreased risk of microbial contamination not seen withsmall molecule or chemically- produced drugs. This opensthe possibility of introducing new animal or humanpathogens to patients or possibly the wider communityby administration along with the drug.

Daniel Galbraith is Chief Scientist with BioOutsource Ltd a Contract TestingOrganisation based in Glasgow, Scotland, which supports the Biologics and VaccineIndustry.


Contamination with infectious agentscan come as two main types –microbial (bacteria or fungi) or asviruses. Virus contamination is seenas the more critical contaminationtype because viruses can destroycells in culture resulting inproduction loss and in someinstances are very resistant tobiocides. Viruses are also able tocause serious disease and in someinstances the contamination isdiscrete and not easy to detect. Thetesting for viruses takes a number ofdifferent methods, and includes invitro (tissue culture) and in vivo(animal culture) cultivation to supportthe growth of virus, moleculartechniques to detect viral nucleicacid and also microscopy (electron)which is the only means we have tovisualise viruses. The reason for thevariety of techniques is that noindividual method is capable ofidentifying all the potential range ofviral contaminants described, inaddition to being able to spot apreviously unrecognised virus.

Safety testingThere are two main repositories forguidance on the viral safety aspectsof vaccines and biologicals: theEuropean and United StatesPharmacopoeias and theInternational Conference onHarmonisation (ICH). ThePharmacopoeias focus mainly on

vaccine production whereas ICH hasset down global testing guidelinesfor biologicals. ICH Q5A is the coreguideline for virus safety assessmentof cell banks used in the productionof cell banks for biologicals. For thefirst time this brought together anumber of older documents indifferent countries and created a co-ordinated approach to safetytesting. There are a number of ICHguidelines in a series to provideassistance with the testing andsafety profile of biologicals. Many ofthe methods used are borrowedfrom the vaccine regulations.

All sets of regulations follow thesame patterns. Testing of startingmaterials includes cell banks andmedia ingredients that may or maynot have an animal component. Thecell banks themselves have aninherent risk of virus contaminationdependent on their source andhistory. Some cell lines are fromexotic species such as ChineseHamster or African Green Monkey.The risks associated with each speciescan be difficult to quantify as thestudy of the viruses that infect moreexotic animals is poorly understoodand therefore presents somedifficulties when determining themost appropriate virus testingregimen. Despite these difficulties,there is a formulaic approach tosafety testing. Virus risks are split intothree types for most regulatory

requirements; adventitious virus,species-specific viruses and retrovirus.

Adventitious viruses (see Figure 1)are those which can contaminate theproduction process from theenvironment or one of thesupplements used to grow the cells.These are very unpredictable andcan be from a variety of sources.Species-specific viruses are thoseviruses which are endogenouscontaminants of cells; an example ofthese is variousSimianpolyomaviruses which arecontaminants of monkey cells andcan remain latent in these cells. Alsoincluded in this subset would be thebovine virus contaminantsassociated with the use of serum toaid in cell growth or the porcineviruses associated with the use ofporcine trypsin in cell passage.These viruses are more predictableand a list of the critical viruses canbe created and used to screen allthose cells of this species.

One particular virus risk which isseen with all cell lines is that fromretroviruses (see Figure 2). Theseattained notoriety during the 1980swith the jump of the HIV virus tohumans causing the devastatingAIDS outbreak. This virus family issingled out for special considerationfrom regulators as these viruses cancause serious disease and becomesilent infections in cells. Retrovirusesfall into two types for the purposes ofsafety considerations – endogenousviruses such as Murine leukemia virus(which can be exogenous in someinstances) and exogenous virusessuch as Human immunodeficiencyvirus type 1 (HIV-1). Exogenousviruses can be screened typically bynucleic acid detection and can bereadily excluded; endogenousretroviruses, being integrated intothe genome of the cells, havespecific testing requirements asspecified in the earliest biologicsguidelines.

All animal cell lines have someretrovirus sequences integrated intotheir genome, some can expressvirus and others have only damagedsequences incapable of generatingan infectious particle. Some of theearly mouse cell lines used for the

BIOSAFETY TESTING REQUIREMENTS continued

Figure 1: Source of adventitious agents.


production of biologicals werepositive for the expression of C-typeretrovirus which was a known risk.The presence of these viruses in cellscaused concern but did not preventthese products being used inhumans as long as the appropriatecontrols were in place. This resultedin there being an assessment of eachfermenter harvest of product toascertain the titre of virus presentand this number was used in a riskassessment comparing the clearancevalues of the virus determinedexperimentally during thedownstream purification to drugproduct. In this way themanufacturers could convince theregulators that these viruses did notrepresent a risk to patients giventhese drugs.

Other virusesDuring the manufacture of eachbatch of biologic or vaccine there isthe risk of new viruses beingintroduced into the productionprocess and this has been recordedby a number of differentmanufacturers and products. One ofthe highest risk contaminants wasfrom bovine serum used in themedia to supplement the growth ofmost virus vaccine products andused to a lesser extent in biologicsproduction due to the advent of“serum free” media. Bovine serumhas been systematically reduced inbiologics due to an increase of riskfactors, particularly the bovine-transmissible spongiformencephalitis (BSE) outbreak seen in

Europe in the1990s.

As well as theBSE risk, there isalso a virus risk withthe serum as it isharvested fromanimals open to theenvironment andcapable of beinginfected fromnumerous virusesespecially thosetransmitted byinsects (Arbovirus).Arboviruses areperhaps the most

common contaminant of bovineserum and have resulted in thecontamination of fermenter batches.Testing of the fermenter harvests,along with the viricidal steps in thedownstream purification (DSP) of thedrug, has ensured that these viruseshave never reached patients. Othercontaminants of fermenters includeMouse minute virus that is thoughtto infect cells in a fermenter due torodent contamination of reagents.Viruses are fundamentally impossibleto exclude from the process andtherefore best practice is to test asmuch as possible the higher riskstarting materials and perform in-process testing to pick up anythingthat has been missed. Virusclearance during the DSP cannotprevent virus being introduced withthe starting material but this ensurescomfort that infection, should itoccur, will be prevented fromreaching the patient.

Virus detection methodsThe current methods we use forvirus detection have in many casesremained unchanged in 60 years. Invivo and in vitro methods for virusidentification can be traced back tothe work by Steinhardt from 1913and Enders and colleagues’ work togrow Poliovirus in tissue culture in1949. Other techniques such asnucleic acid detection have beensuccessfully introduced in the past20 years but the programme oftesting for biosafety still includesmany older techniques.

A new technique which has

attracted much interest recentlycould revolutionise the detection ofvirus in biologic samples. Massivelyparallel sequencing is a process bywhich the entire nucleic acidsequences in a sample aredetermined and a software algorithmused to identify which sequences areviral in nature. This method can notonly identify those viruses we alreadyare aware of but also thosesequences which are as yetunreported but have a “virus-like”characteristic – maybe pointing to anew virus species. Although in itsinfancy as a technique, this methodmay be a faster and more efficientmethod that these oldertechnologies and could speed up thecurrent somewhat lengthy protocols.

ConclusionBiosafety of vaccines and biologicalsis still something that requires to beclosely considered with respect torisk and regulatory requirements.Failure to adequately take accountof both of these will cost drugdevelopers both time and money.These products do, however, offerthe promise of curing or preventingsome devastating diseases and thecurrent risk based approach which isused has stood us in good stead.The future does offer some newtechnologies that may improve ourabilities to detect contaminationand these must be stringently testedbefore they can be put in place.

References1 Report of a WHO Study Group (I987)Acceptability of cell substrates forproduction of biologicals. World HealthOrganisation Technical Report Series 747.

2 Continuous cell Lines as Substrates forBiologicals. Vol. 70. Developments inBiological Standardisation, 1989.

3 Points to Consider in the Characterisationof Cell Lines used to Produce Biologicals(1993). Centre for Biologics Evaluationand Research, Food and DrugsAdministration, USA.

4 Viral Safety Evaluation of BiotechnologyProducts Derived from Cell Lines ofHuman or Animal Origin. ICH Topic Q5A.

5 Characterisation and Qualification of CellSubstrates and Other Biological MaterialsUsed in the Production of Viral Vaccinesfor Infectious Disease Indications. Centerfor Biologics Evaluation and Research,Food and Drugs Administration, USA.

BIOSAFETY TESTING REQUIREMENTS continued

Figure 2: Photomicrograph of retroviruses.


Particle size is a good example of aCritical Quality Attribute, oftendifficult to control during the finalAPI synthesis step but with thepotential to have a tremendousimpact on the performance of thefinal dosage form. Herein twoexamples are addressed: particlesize reduction aiming atbioavailability improvement throughnanoparticles with a focus on oraland IV administration, and particlesize control in the form ofmicroparticles, targeting effectiveinhalation delivery. Figure 2 providesan example of typical particle sizedistributions after a particleengineering step.

With the advent, in the 90s, ofcombinatorial chemistry,computational molecular modelingand high throughput screening indrug discovery there was asignificant increase in the number ofpoorly soluble drugs (Class II and IVcompounds – poor solubility –according to the BiopharmaceuticalClassification System, BCS1. Today

more than 90% of drugs, underdevelopment, present low aqueoussolubility2. Therefore, there is anincreasing need to use and furtherdevelop new formulation platforms,which increase oral bioavailability ofClass II and IV compounds.

Nanoparticles have proven thevalue (the size reduction leads to anincreased surface area andaccording to the Nernst equation to

an increased dissolution velocity3),utility and commercial viability toimprove bioavailability over the lastdecades with multiples productsapproved in the market (Table 1).The majority of those usingNanoCrystals® technology by ElanNanosystems (now Alkermes). OnNanoCrystals® a bead/pearl mill istypically used to achieve particlesize reduction of a suspension(generally in water) containing thedrug along with stabilisers. Althoughvery efficient, the platform alsopresents disadvantages as thepotential for product contaminationdue to the erosion of the beads,limited batch size or the fact ofbeing a batch process. Otherexamples of top down approaches,not encountering some of thesedisadvantages are thehomogenisation methods being themost important: Microfluidisertechnology (IDD-P® technology fromSkyePharma), Piston gaphomogenisation in water(Dissocubes® technology fromSkyePharma) or in mixture ofsolvents (Nanopure® technologyowned by PharmaSol3). Althoughmicrofluidisation and piston-gaphomogenisation have been usedwith success it is important tohighlight that piston-gaphomogenisation generally impartsgreater turbulent energy bycavitation, resulting in the exposureof the drug to higher temperaturesand pressures with potential impacton the stability (physical andchemical).

Drug nanoparticles can also beproduced using bottom up

BRIDGING APIMANUFACTURING ANDFORMULATION THROUGHPARTICLE DESIGNby Márcio Temtem, Filipe Neves, Conrad Winters

The interface between the Active PharmaceuticalIngredients (API) manufacturing and formulation

development is of paramount importance in thepharmaceutical world. Chemists, engineers andformulators are not exposed, by training, to the samechallenges. As presented in Figure 1, on the one handthere are API suppliers, characterised by a serviceorientation mindset, used to addressing synthesis routeissues (e.g. impurities, yields), solid statecharacterisation (e.g. polymorphs, polymorph control),raw material sourcing, etc); on the other hand,formulators are used to a different type of language anddaily concerns (e.g. bioavailability, patience compliance,administration route, efficacy and processibility).

The authors are with Hovione, R&D – Drug Product Development Group, Loures,Portugal.

Figure 1: Bridging API manufacturing and formulation through particledesign.


techniques where the drug isdissolved in a solvent andsubsequently precipitated by

controlled mixing with a non-solvent. PureNano® fromMicrofluidics is a good example of a

continuous crystallisation processwhere the contact between the twosolvents is made with the use ofinteraction chambers/reactors.Nanomorph® (Soliqs – Abbot) isanother example, where a drug insolution is precipitated inside apolymeric system that maintains thedrug substance with the desiredpolymorphic form and maintains thenanoparticulate state, preventingparticle aggregation and/or growth.

Regarding inhalation applications,and as shown in Table 2, drugdelivery systems can be divided intotwo main categories: pressurisedmetered-dose inhalers (pMDIs) anddry powder inhalers (DPIs) – none ofthe devices is clinically superior anddevice selection should be guidedby other factors, such asconvenience, cost, and patientpreference5. In a DPI (seven of thetop nine products in the marketconsider this delivery system – seeTable 2) the solid drug is fluidisedwhen the patient inhales and thisoffers unique benefits and uniquechallenges. The benefits comparedto pMDI’s are that little or nocoordination is required betweenactivation and inhalation, and theyprovide for superior stability sincethey are typically formulated as onephase, solid-particle blends. Thechallenges relate to the uniqueformulation strategies required andthe susceptibility of dry powders toforces of interaction caused by theirsurface and bulk energies, which caninhibit their dispersion and limitaerosol delivery and, therefore,efficacy6.

The inhalation dosage technologyhas primarily been focused on twoparallel development pathways: i) fabrication of novel inhaler deviceswith enhanced efficiency and ii) improvement of the powderformulations7. Although pulmonarydelivery can be enhanced by moresophisticated inhalers (e.g. utilisingelectronic synchronisation andactuation control), such devices tendto be complex and costly, and theirreliability and practicality have beenquestioned. Conversely, superiordelivery efficiency may be achievedmore cost-effectively by developing

BRIDGING API MANUFACTURING AND FORMULATION THROUGH PARTICLE DESIGN continued

Figure 2: Typical particle distributions of a micronised powder(Nanoparticles/Oral vs microparticles/inhalation).

Trademark (API) Therapeutic World Sales Platformapplication (2011) M$ (Developer)

TriCor NanoCrystal Lipid Lowering 632 Nanocrystal(a)®(Fenofibrate) (Elan/Alkermes)

Invega Sustenna Schizophrenia 499 Nanocrystal®(Paliperidone palmitate) (Elan/Alkermes)

Emend (Aprepitant) Nausea-Emesis 419 Nanocrystal®(Elan/Alkermes)

Abraxane Nanoparticle

(Paclitaxel) Cancer 386 Albumin Bound – NAB(b)®

(Abraxis BioScience)

Rapamune Organ 372 Nanocrystal®(Sirolimus) Transplantation (Elan/Alkermes)

Megace ES Cachexia, AIDS- 58 (US only) Nanocrystal®(Megestrol acetate) related� Anorexia (Elan/Alkermes)

Triglide Lipid lowering NA IDD-P Microparticle(c)®

(Fenofibrate) Hypertriglyceridemia (SkyePharma)

Feraheme Anemia, Iron Advanced Magnetics

(ferumoxytol) Deficiency 52 (US only) Nanoparticles(d)(AMAG Pharmaceuticals)

Table 1: Examples of market products using Nanoparticles4

(a) NanoCrystal® – Small particles of drug (less than 2,000nm) are produced using various wet millingapproaches but typically with Pearl or Ball milling. The nanosize particles are then stabilisedagainst agglomeration by surface adsorption of stabilisers. On September, 2011, Alkermes andElan Corporation, announced the completion of the merger between Alkermes, Inc. and Elan DrugTechnologies (EDT), the drug formulation and manufacturing business unit of Elan.

(b)Nanoparticle Albumin Bound – Nab® – Technology exploiting the transportation properties ofhuman serum albumin (a natural carrier of lipophilic molecules) to improve the bioavailability ofhydrophobic drugs – the drug is surrounded by an albumin shell to form a nanoparticle.

(c) IDD-P Microparticle – Insoluble Drug Delivery-P (IDD-P) technology involves drug particle sizereduction by high pressure microfluidisation in the presence of membrane-forming amphiphaticlipids to from stable dry powders from 0.1 to 10 micron with narrow particle size distributions.

(d) Advanced Magnetics Nanoparticles – Iron oxide polysaccharide colloids comprised of nanosizediron oxide particles coated with carboxymethyl reduced dextran to improve circulation time.Particles are prepared by precipitation and filtering.


optimised particulate formulationsfor use with simple and user-friendlyinhalers8. This alternative strategy,which is synonymous with thecontrolled production of drugparticles in pure physical forms (orwith carriers as composite materials)of optimised size, morphology andstructure, has been boosted due torecent advances in particleengineering.

Here the main goal of particleengineering is to incorporate intothe particles desirable attributessuch as optimal particle sizedistribution and improveddispersibility, thus favouringenhanced drug stability andoptimised bioavailability9. Amongthese attributes, particle size is oneof the most important designvariables, and this is valid both forDPI and MDI delivery systems;particle size relates with theaerodynamic diameter and this is acritical measure of the particledynamic behavior, describing themain mechanisms of aerosoldeposition (both gravitationalsettling and inertial impaction) –generally, an aerodynamic particlesize distribution of 1-6μm is required

for successful inhalation therapy10.Additionally, specific optimisation ofthe particle size distribution isimportant for several reasons:

• To reduce dose variability intothe lung

• To maximise the proportion ofdrug in the finished productformulation that reaches thetarget airway site; this in turnminimises the active content inthe formulation required for anefficacious response andreduces the likelihood ofpotential side effects

• In the area of generic productdevelopment, to be able todemonstrate in vitro andsubsequently in vivoequivalence to a referenceproduct

Different size-reductiontechniques may be capable oftargeting similar particle sizedistributions; however, even whenthe same size is obtained, thedispersibility of the powder (a criticalattribute, as mentioned before)tends to vary depending on theemployed technology. This is aconsequence of a delicate balance

between adhesive/cohesive forcesthat, besides size, also depend onother factors (e.g. particlemorphology and surface energy).Historically, the production of suchparticles has been performed usingthe processes of batch crystallisationfollowed by size reduction using airjet milling (micronisation), atechnology available for more than100 years. Micronisation (see Table3) has been used for thedevelopment of inhalation productssince the 1960s, with significantchallenges commonly referred in theliterature:

• It is a high energy sizereduction process that breaksdown active substance crystals,impacting surface energy andcrystal form. The outputmaterial often containssignificant amorphous content,which can influence the stabilityof the finished productformulation11.

• In order to produce the desiredparticle size, jet millingfrequently requires a number ofrepeat runs. It is therefore aninefficient process that createsthe potential for metalcontamination from theextended high energy contactwith the microniser metalcomponents and lower yielddue to repeated number ofpasses.

Other techniques for makingmicron-size particles involve directparticle formation from solution; inthis field, spray drying (SD) hasemerged as a noteworthy approachfor controlling particle size12. Thistechnique is distinctly different frommilling in the sense that particlesare built up by dissolving andspraying the drug into fine dropletsthat, once dried in a heat expansionchamber, leave behind tinyparticles; compared to milling, SDcan produce more sphericalparticles; however, these tend to bemostly amorphous, thus having ahigher potential for stabilityproblems (see Table 3) if notproperly stabilised withpolymer/excipients.


Trade name Therapeutic World Sales Platform(API) application (2011) M$ (carrier/media)

Advair (Fluticasone DPI (lactose carrier)propionate/Salmeterol Asthma & COPD 8132 MDI-suspension

xinafoate) (HFA-134A)

Spiriva(Tiotropium bromide) COPD 4391 DPI (lactose carrier)

Symbicort MDI-suspension(Budesonide/Formoterol Asthma & COPD 3148 (Apaflurante, PEG,

fumarate) Povidone K-25)

Flovent DPI (lactose)(Fluticasone Asthma 1306 MDI-suspensionproprionate) (HFA-134A)

Pulmicort (Budesonide) Asthma 892 DPI (lactose) Nebulizer**

Foradil(Formoterol fumarate) Asthma & COPD 312 DPI (lactose)

Serevent(Salmeterol xinafoate) COPD & Asthma 293 DPI (lactose)

Asmanex(Mometasone furoate) Asthma 206 DPI (lactose)

Alvesco MDI-solution (HFA-134A,(Ciclesonide) Asthma 93 (2010) ethanol)

Table 2: Inhalation market4

** Edetate disodium, polysorbate 80, sodium chloride, citric acid , purified water, sodium citrate


As presented in Figure 3, Spraydrying is a versatile technology,frequently used to dry/isolate thesuspensions of microparticles aftercrystallisation or wet millingprocesses or microencapsulate andstabilise nanoparticles13. WetPolishing® – a proprietary term usedby Hovione to describe a platformthat uses a range of particle sizeprocessing technologies (bothbottom up and top downtechniques) combined with asuitable isolating method, oftenusing spray drying technology is agood example of the latest. Ingeneral terms, the advantages ofWet Polishing for inhalationapplications are the production ofsize reduced APIs with tunablePSDs and a high level ofreproducibility as demonstrated inFigure 4a (2% standard variability in

the target PS against a typical rangeof 10 to 20% in jet milling).Additionally, in specific cases 14,Wet Polishing may be an enablingtechnology, to avoid the formationof amorphous domains or keep therequired polymorphic form.

When drug particles greater thana few microns are transformed intonanoparticles an important aspectof particle size reduction is thesurface energy generated. Theincreased surface area creates apositive gain in free energyinducing the potential toagglomerate/aggregate to a lessenergetic state. The micro-encapsulation of such instablematerials in polymeric systems (inthis example using spray drying) cansupport improvements in twodistinct critical quality attributes:stability (i.e. agglomeration, crystalgrowth, changes in the polymorphicform) and manipulation of powderproperties (e.g. flowability, density,PS). The properties of the micro-capsules will greatly depend on thematerials used, but can also bemodified to a great extent bymanipulation of the spray dryingprocess operating parameters (e.g. temperatures, droplet size,atomisation, concentration) (Figure 4b).


Technology Advantages Disadvantages

Pearl and Ball – Multiple products in the – Time consumingmilling market – Limited batch size

– Simple – Susceptible to product – High drug loading contamination

– Requires an isolation step

Controlled nano- – Very efficient in obtaining – Complex systems requiring a crystallisation nanoparticles with reduced PS good understanding of the “Bottom up” process

Homogenisers/ – Good control on the PS – Unsuitable for thermolabileMicrofluidisers distribution and highly compounds

reproducible – Requires an isolation step– Insignificant levels ofcontamination

– Easy scale up

Controlled – Eliminates addition PS – Typically PS Control (PS crystallisation reduction steps distribution, targets) is not as

straightforward as in other top down approaches

– Requires strict control of the process

Spray drying – Ideal to produce amorphous – Solvent based process (post materials drying may be required)

– Good control over powder – Amorphous content may be properties undesirable

– Easiness of scale up – Expensive– Processing of thermolabile materials

– Continuous process

Jet milling – Solvent free – High amorphous content– Ease of operation – Lack of control over, size, – Cost effective shape and surface properties

– Susceptible to product contamination

MICROPA

RTICLE

SNANOPA

RTICLE

STable 3: Particle engineering technologies:Advantages/Disadvantages

Figure 3: Key points during spray drying application on a) Wet Polishing®

process and b) Microencapsulation of nanoparticles.


ConclusionThrough the use of particle design itis possible to bridge two distinctrealities: Drug Substance and DrugProduct. Independent of theadministration route (e.g. oral, IV,inhalation) the selection of the mostappropriate technology is key toobtaining high performancematerials.

References1 Duarte I, Temtem M, Gil M and Gaspar F,Overcoming poor bioavailability throughamorphous solid dispersions, IndustrialPharmacy, 2011;30:4-6.

2 Water-Insoluble Drug Formulation (andreferences therein) 2nd Edition. Editor LiuR. CRC Press, Taylor & Francis Group.

3 Junghanns J-U A H and Müller RH.Nanocrystal technology, drug deliveryand clinical applications, InternationalJournal of Nanomedicine,2008;3:295–309.

4 Source – PharmaCircle.5 Dolovich M, et al. Device selection andoutcomes of aerosol therapy: evidencebased guidelines, American College ofChest Physicians, 2005;127:335–371.

6 Telko M and Hickey A. Dry Powder InhalerFormulation, Respiratory Care.2005;50:1209-1227.

7 Newman S and Busse W. Evolution of drypowder inhaler design, formulation, andperformance, Respiratory Medicine,2002;96:293-304.

8 Chow AH, Tong HH, Chattopadhyay P,Shekunov BY. Particle Engineering forPulmonary Drug Delivery A.,Pharmaceutical Research, 2007;24:411-436.

9 Koushik K and Kompella UB. Particle anddevice engineering for inhalation drugdelivery, Drug Delivery Technology,2004;4:40-50.

10 Bates DV, Fish BR, Hatch TF, Mercer TT,Morrow PE. Deposition and retentionmodels for internal dosimetry of thehuman respiratory tract, Health Physics,1966;12:173–207.

11 Shoyele S and Cawthorne S. Particleengineering techniques for inhaledbiopharmaceuticals, Advanced DrugDelivery Reviews, 2006;58:1009–1029.

12 Vehring R. Pharmaceutical ParticleEngineering via Spray Drying.Pharmaceutical Research, 2007;25:999-1022.

13Gil M and Gaspar F, Flexible Control,PMPS Manufacturing, 2009;3:92-97.

14Gil M, Cacela C, Mendonça R and GasparF, PT105058: a process for particle sizereduction of active pharmaceuticalingredients, 2010.


Figure 4: a) High reproducibility of the wet polishing process and b) Powder properties improvement during amicroencapsulation process.

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


What is PharmacopoeialCompliance? To understand this, you first need toknow what the Pharmacopoeias are,what they contain and how to usethem. So what are they? Essentiallythey are a repository for qualitystandards and test information formedicinal products and materialsused in their manufacture. Theycover everything from the activesand excipients used to makeproducts, to packaging andlabelling instructions and guidelines.So how many are there, and why arethey important?

The WHO IndexThe World Health Organisation(WHO) maintains an index ofPharmacopoeias. Currently there areabout 45 Pharmacopoeias on thelist. For the majority of cases, it isonly necessary to consider the majorPharmacopoeias (British, European,Japanese and United StatesPharmacopoeias) since many of theothers are either subsidiary to orrecognise the specifications ofthese. This article will concentrateon these, however the importanceof emerging markets is growing andthe respective governments are nowinsisting on compliance with theirown Pharmacopoeias unless they do

not have a specification within themfor a specific item. For example,India requires that products arelabelled compliant with the IndianPharmacopoeia by law and Chinawill test all products in accordancewith the stricter of registered andChinese Pharmacopoeiarequirements.

The British PharmacopoeiaThe British Pharmacopoeia wasfounded at the height of the BritishEmpire in 1857 and first published in1864. It was an amalgamation of thePharmacopoeias of London,Edinburgh and Dublin. It nowoperates under the MHRA and ismandated under UK legislation. It isrecognised as the OfficialPharmacopoeia by severalCommonwealth countries.

The EuropeanPharmacopoeiaThe European Pharmacopoeia,founded in 1964 and first publishedin 1969, is the umbrellaPharmacopoeia for the majority ofcountries within Europe.Pharmacopoeias from thosecountries that are signatory to theEuropean PharmacopoeiaConvention (including the BritishPharmacopoeia) are subsidiary to

the European Pharmacopoeia. TheEuropean Pharmacopeia isadministered by the EDQM, whichis part of the Council of Europe. Itcan be considered as the firstattempt at harmonisation of thePharmacopeias for all signatorycountries and is mandated underEU law. It has influence outside theEU with many Eastern Europe andWestern Asiatic countries asobservers.

The United StatesPharmacopoeiaThe United States Pharmacopoeiawas first published in 1820 and is theoldest continuously published andrevised Pharmacopoeia. It is also theonly private, voluntaryPharmacopoeia, independent ofGovernment, although it has beenlegally recognised by the USGovernment since 1906. Itsstandards are recognised in theFederal Food Drugs and CosmeticsAct (1938) and they are enforced bythe FDA. It is recognised by severalother countries, particularly withinLatin America.

The Japanese PharmacopeiaThe Japanese Pharmacopeia wasfirst published in 1887. It isadministered and its standards areenforced by the MHLW and thePharmaceutical Affairs Bureau.

Purpose of PharmacopoeiasTheir purpose is primarily to protectthe patient, which they achieve byestablishing and disseminatingofficially recognised qualitystandards for the preparation andtesting of medicines. The importantwords here are officially and qualitystandards. These standards are nottied to a particular company butestablish minimum standards forquality with the market territoryobserving that Pharmacopoeia.

A Legal RequirementAll medicinal products must complywith the general requirements andstandards of the Pharmacopoeiaswhich are legally applicable in thecountries where they are to be sold.Conformance with Pharmacopoeialstandards is a legal requirement.These legal requirements include:

PHARMACOPOEIALCOMPLIANCEby Kevin F Goode MRSC

Pharmacopoeial Compliance is a potential minefield.This article covers an introduction into the world of

Pharmacopoeias, what they are, what they contain, theirimpact on industry, their legal status and how theyshould be interpreted and used. The use of alternativemethods is discussed and a short summary ofPharmacopoeial Harmonisation is also given.

Kevin worked for the Wellcome Foundation/GlaxoWellcome/Glaxo Smith Kline forover 38 years in a variety of roles including Analytical Development and QualityAssurance, but most recently for 15 years liaising with the Pharmacopoeias andinterpreting Pharmacopoeial requirements. He was a member of the BritishPharmacopoeia Expert Committee B, a member of the PhRMA Compendial LiaisonTeam and the Mid-West Compendial Discussion Group. He was a member of theorganising committee for the 2008 PDA Compendial Conference. He took earlyretirement in 2009.


PHARMACOPOEIAL COMPLIANCE continued

UK: the Human MedicinesRegulations 2012, Part 15; EEC:Directive 2001/83/EC; USA: Section501 (b) of the Food, Drug andCosmetic Act; Japan:Pharmaceutical Affairs Law.

So what might happen if youfail to comply? Any of the following: Legal action;Loss of marketing rights; Loss ofproduct/import licence; Productrejected by customer and/orcountry; Adverse comments and/orcitation at audit; Warning letter fromRegulatory Authority. Examples ofthese are the tendency for China tosuspend or revoke import licencesfor repeat offences, or the penchantfor FDA to send Warning Letters forproduct adulteration. Any of theseactions could have an adverse effecton a manufacturer’s ability to markettheir products.

But what is Pharmacopoeialcompliance? Pharmacopoeial commissions/agencies and regulatory authoritiestend to be separate from each other.Pharmacopoeias establishcompendial standards for themanufacture and testing of medicinalproducts, primarily for establishedproducts. Regulators establishstandards and requirements for newdrugs and products,and enforcecompendial standards.

A DifferenceThere is however a differencebetween Pharmacopoeialcompliance and Regulatorycompliance. Compendial standardsestablished by the Pharmacopoeiashave a degree of flexibility which isnot present in Regulatory standards,which are strictly applied. In order tounderstand this, it is essential tounderstand what is in thePharmacopoeias and how to usethem.

Deliberately VaguePharmacopoeias are frequentlywritten in terms of “should” and“may” rather than in a prescriptivemanner. Many parts of thePharmacopoeia are non specific or

deliberately vague. This can lead todifficulties in interpretation, whichthen lead to differences inunderstanding between themanufacturers and regulators andthus issues during inspections. It istherefore essential to correctlyinterpret the requirements and to beclear as to what is mandated andwhat is guidance.

General Notices – the mostimportant sectionAll the Pharmacopoeias have similarcontent, consisting of sections asfollows: General Notices andRequirements; General TestMethods; General Monographs;Specific Monographs; Reagents;General Information. The reality formanufacturers is that it is mainly theMonographs that are used, alongwith the linked or associatedgeneral tests, methods andchapters. It is easy for an analyst togo to a specific monograph and tryto make sense of the requirements,but this is dangerous since withoutadequate knowledge of the GeneralNotices, which tell you how to useand interpret the specificmonographs, they could completelymisunderstand what the actualrequirements are. And who readsthe General Notices? They are infact the most important sectionsince they define the rules andstandards to be applied when usinga particular Pharmacopoeia.

General Notices is the mostimportant section since it tells youhow to use the Pharmacopoeia. Thisis probably the least understood orappreciated section of thePharmacopoeia by users. ThePharmacopoeias do not all operatein the same way or have the samerequirements. This is where theflexibility for monograph use can befound, and this is the most criticalsection in the Pharmacopoeia.

General Test MethodsPharmacopoeias contain a widerange of general test methods whichprovide input into specifications andsystem suitability requirements, andnot just for commercial product.They are also applicable to drugs/

actives in R&D and can be used as abasis for developing test methodsand procedures. They also giveguidance on validation requirementsfor new test methods. They arefrequently cross referenced fromother parts of the Pharmacopoeia,particularly the monographsthemselves.

General MonographsGeneral monographs define thetests, methods and specificationrequirements to be applied to typesof products and materials. Generalmonographs are requirements justas much as specific monographsthat define the tests, methods andspecification requirements to beapplied to individual products andmaterials.

General InformationChaptersGeneral Information Chaptersprovide additional usefulinformation on a wide range ofrelated topics. These sections areusually considered to be non-mandatory, however someregulators seek to make themobligatory which can causeproblems for manufacturers duringinspections. It is often the case thatthe Inspector’s understanding is notcorrect, and the manufacturershould be prepared to justify theirinterpretation of the requirements.

Can you use alternatives?It is permissible to use differentstandards, controls and methods tothose cited in the Pharmacopoeiasto ensure product quality. However,the use of alternatives must complywith the general requirements ofboth the Pharmacopoeias and theRegulatory Authorities of themarkets in which the products ormaterials are to be sold. Wherecompliance with a Pharmacopoeialmonograph or test method is notadequate to assure the quality of aproduct, action must be taken toregister or certify appropriatealternative standards and/ormethods. It is obligatory for theEuropean Pharmacopoeia andadvisable for others to offer the


alternative to the Pharmacopoeia asan additional or replacementmethod.

The use of any alternative control,standard, method or technique mustbe shown to be equivalent to orbetter than that defined in thePharmacopoeia in terms of accuracy,precision, reliability and/or quality.Any alternative test methodsemployed must be validated to asuitable standard, usually ICH.However, the Pharmacopoeiasusually incorporate into theirGeneral Notices that “In the eventof doubt or dispute, the methods ofanalysis of the Pharmacopoeia arealone authoritative”.

What is PharmacopoeialHarmonisation? That different test requirementscaused extra work and otherproblems was recognised by theUnited States, European andJapanese Pharmacopoeias in the1980’s and they were aware of theimpact on Industry. They set up thePharmacopoeial Discussion Group(PDG) prior to the formation of ICHto try and resolve some of theissues. The aim was to harmonisemethods for key general tests andprocedures and to createharmonised or interchangeablemonographs for the excipients incommon use within the Industry.ICH includes PharmacopoeialHarmonisation as Topic Q4,however the PDG operatesindependently of ICH.

Consensus is reached wherepossible, but this does notguarantee that the monograph isidentical. Differences may stillremain due to specific localcircumstances. It does not prejudgethe level of harmonisation obtained,and does not mean that the process

is complete. The concept of“Interchangeability” has recentlybeen introduced, and thePharmacopoeias are now workingtowards this end.

The biggest drawback of thisprocess is that it very bureaucratic –a 7-Stage process that is slow andcumbersome and taking far toolong. Having said this, the PDGprocess has lead to someinterchangeable methods with moreto follow. The long term hope is thatmore of these will come through ata faster rate.

Regulatory AcceptanceThe latest initiative under Q4 hasbeen the introduction of theconcept of Regulatory Acceptance(Topic Q4B). A working group wascreated to give advice onregulatory acceptance of PDGharmonised texts. A guideline wasproduced – Regulatory Acceptanceof Analytical Procedures and/orAcceptance Criteria (RAAPAC).Statements on individual texts arebeing included as annexes, ofwhich 14 have now been published.This has major benefits to Industrysince it simplifies procedures asonly a single test regime need beapplied.

How does this work? Followingsign-off of the harmonised texts byPDG at Stage 6 of theharmonisation process, the co-ordinating Pharmacopoeia preparesa package for Q4B including thesign-off text, details of publicationin the Pharmacopoeias and abriefing note. Q4B examines thispackage and either publishes anannex to the guideline or refersquestions back to PDG. De factoharmonisation is achieved when allthree Pharmacopoeias publish thesign-off text. Each Pharmacopoeia

will indicate harmonisation in itspublication.

Other New InitiativesOther initiatives which are of interestinclude the following, but there isinsufficient space to give details here:

• WHO Global GoodPharmacopoeial Practice guide,with the European and IndianPharmacopoeias being thebiggest supporters of it

• MERCUSOR activities – Brazil,Argentina etc collaborations.

• ASEAN collaboration – Korea,Indonesia etc.

• European and United Statescollaborations on APImonographs outside of the PDG

• British and United Statescollaborations on productmonographs

PharmacopoeialCompliance – the HowThe provisions in the generalstatements must be adhered to butthere is a degree of flexibility.Specification limits must be applied.Tighter limits could be consideredbut it would be difficult to justifywider limits. Suitability standardsare a given. It is possible to use in-house Chemical ReferenceStandards but you have to showthat these are equivalent to thePharmacopoeia CRS’s. Ambiguitiesmust be assessed and a judgementmade and documented. Validatedalternative methods could be used.You must also take into account themusts and maybes which are opento interpretation and can both helpand hinder manufacturers. Aboveall, you must be prepared to justifythe approach you take, and do notassume that the Regulators orInspectors interpretations arecorrect – frequently they are not.

PHARMACOPOEIAL COMPLIANCE continued

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


The current review period hasseen a number of changes inthe regulation of medicinesand regulatory guidance in theEU and the USA.

United States ofAmericaGuidance for Industry -Non-Penicillin Beta-Lactam DrugsThis Final cGMP Framework forPreventing Cross-Contaminationclarifies that manufacturers generallyshould utilise separate facilities for themanufacture of non-penicillin beta-lactams. Beta-lactam antibioticsinclude the following five classes: • penicillins (e.g., ampicillin, oxacillin) • cephalosporins (e.g., cephalexin,

cefaclor) • penems (e.g., imipenem,

meropenem) • carbacephems (e.g., loracarbef) • monobactams (e.g., aztreonam)

The guidance recommends that aswith penicillin, the section of a facilitydedicated to manufacturing any one ofthe above five classes should beisolated from each other and areas inwhich other products are manufactured.

Recommendations are also made inregard to beta lactamase inhibitors.

Guidance for Industry SUPAC:Manufacturing EquipmentAddendum SUPAC equipment addendareferencing specific equipment weremisinterpreted as equipment requiredby FDA. This could discourageadvancements in manufacturingtechnologies. Therefore, the reviseddraft SUPAC addendum containsgeneral information on SUPACequipment and no longer includestables referencing specific equipment.

EuropeEudraGMP database nowcontains information on gooddistribution practice (GDP)The new database, – EudraGMDP, is akey deliverable of the EuropeanFalsified Medicines Directive. It willmake the supervision of manufacturingand distribution of medicines morerobust by allowing all the actors in thesupply chain to check information

available on their suppliers.It will be gradually updated with

distribution-related information andinclude:• wholesale distribution authorisations;• GDP certificates;• statements of non-compliance with

GDP;• registrations of manufacturers,

importers (including information ontheir suppliers) and distributors ofactive substances.

A non publicly accessible moduleexists on planning GMP inspectionsoutside of the EU.

Implementation of the new ruleson importation of activesubstances This update gives an overview onsome 20 major API supplyingcountries and their status ofpreparation for compliance with therequirements of the FalsifiedMedicines Act with regard to importof APIs into the EU.

The July 2 deadline is fastapproaching with very few countrieslisted as equivalent to EU. India andChina need to do more to comply withthe EU requirements, but the situationis reported as being “Under control”for 14 of the countries listed.

MHRA is developing contingencyplans that would allow the Agency, incases where there is an overridingneed to ensure continued supply ofspecific ASs after 2 July 2013, toprovide an opinion on the importationof the AS to permit manufacture, QPcertification and supply of finishedmedicinal products.

Revised Q&A on rules forimportation of API V4.1V4.1 no longer contains Q&A onatypical active substances. It has 2new Q&As re:• Written Confirmation for blood

plasma and APIs manufactured withthem

• Written Confirmation for StartingMaterials for the manufacture of APIs

EDQM provides an update on itseTACT traceability project, formedicinesEDQM’s aim is to achieve a secure,patient-friendly and cost-effective

traceability service for medicines. Ithas been consulting businessstakeholders in order to fine-tune thedetails of all business processes to behandled in the deployment of such ananti-counterfeiting traceability servicefor medicines. This paves the way forthe establishment of a real-scale pan-European eTACT service that is fit-for-purpose.

New Q&As on GMPEMA has published 5 new GMPQ&As. Two of these relate to Annex 1:Manufacture of sterile medicinalproducts, and relate to bioburdenmonitoring of aseptically filledproducts.

The remainder concern MA holder’saudit reports concerning activesubstances used as starting materials.They cover why inspectors ask to seereports of such audits, whatexpectations they have for the contentof the reports and how activesubstance auditors should bequalified.

New tracking system for high-riskmedical devices in development MHRA announced that four NHS trustshave committed to piloting a newtracking system for high risk medicaldevices that will improve themonitoring of medical devices such asbreast implants, heart valves andpacemakers.

The new tracking system willultimately incorporate unique deviceidentifiers into hospital patientelectronic records and nationalHospital Episode Statistics databases.Subsequent analysis will enable theMHRA to better assess theperformance of high-risk medicaldevices and to trace patients in theevent of a device recall or safety alert.This project is one of 11 that theMHRA has established to strengthenthe regulation of medical devices.

For further information on these andother topics we suggest you refer to thewebsites of relevant regulatory bodiesand to current and past editions of“GMP Review News” published byEuromed Communications. To subscribeto this monthly news service [email protected]

regulatory review


General Assembly 20-21stApril, 2013During the April General Assembly,Jean-Pierre Paccioni was elected asPresident of EIPG and ValerieLacamoire as Treasurer for the next3 years. Gino Martini agreed tochair a new Finance Commission inhis position of Past-President.

The Associazione FarmaceuticiTicinese (AFTI, the SouthSwitzerland Association of IndustrialPharmacists) became a member ofEIPG.

Working Group on theFalsified Medicines Directive(FMD)A Working Group on the FalsifiedMedicines Directive (FMD)reconfirmed the EIPG positions onthe concept papers of December2011 and January 2012 on GMP andInspection of API manufacturers. Inaddition they agreed the formerEIPG positions on the conceptpaper of November 2011 regardingthe unique identifier and the safetyfeatures. Various concerns wereexpressed about the FMD includingthe July implementation date, non-compliance issues which will resultin shortages, control at receipt ofAPIs and excessively long chains ofwholesalers and brokers.

On the issue of the supply ofAPIs, India who currently supplyfrom 496 manufacturing sites, hasdecided the local health authoritywill issue a GMP certificate for eachAPI. In China there has been someprogress with the issue ofcertificates although they will not beissued for manufacturing sites whichare not under their FDAcertification. This will involve 30 ofthe 428 raw material manufacturingsites in China.

Regarding the unique identifier,there is still no final decision on

what is to be implemented resultingin some large companies appearingto influence the legislation byimplementing what they feel isappropriate, whilst leaving smallercompanies behind. The riskassessment is unclear and it is notknown whether there will be a whiteor black list. The position of over-the- counter products has not beenclarified.

A second Working Group onMedicines Shortages noted thatmany countries have shortages dueto parallel export from theircountries such as Finland, Norway,Romania and France.

Pharmaceuticals are in a highlycompetitive domain and HealthAuthorities are causing parallelexportation by driving down pricesin reimbursement systems. It wassuggested that short linewholesalers should not be allowedto parallel export. As has beenstated previously by EIPG,companies should be undertakingrisk assessments of all criticalproducts as predicting criticalproduct shortages and planning forsafety stocks is of major importance.

It was noted that hospitals insome countries enter intoagreements with companies withoutconfirming that they are capable ofproducing the volume requested.

There have been problems withreimbursement in Romania since2008 as this was the last time the listof new molecules approved forreimbursement by the Ministry ofHealth was open for additions.Since then more than 100 newproducts have been awaitingreimbursement and people who canafford to do so, travel overseas fortreatment.

There is an acute problem inBulgaria because the Governmenthas reduced the price of 700

products by between 10 to 80 % sothat generic companies can nolonger afford to manufacture at theprices set. There are 150 newwholesalers and the chain ofproduct supply is often throughcommunity pharmacies wheretraceability is a problem.

In Hungary, wholesalers are notallowed to export whereas inPortugal, where there are too manywholesalers, they need to exportmedicinal products if they are tosurvive as many pharmacies buydirect from manufacturers.

The meeting felt that there shouldbe better collaboration betweenhealth authorities and all the playersin the chain. Manufacturers,wholesalers and community andhospital pharmacists should reviewtheir missions of supplyingmedicines to the patient. Thereshould be improved monitoringsystems, coordinated by theEuropean Medicines Agency as isdone by the FDA.

The meeting suggested that weneed solid numbers of how much itis costing per man hour to manageout of stock situations.

EPHA Conference on Accessto MedicinesSome of the above points weremade at the European Public HealthAlliance (EPHA) May Conference onAccess to Medicines held in theEuropean Parliament at which GinoMartini acted as a respondent. Atthe meeting, a joint press releasewas issued by the threeorganisations representingpharmacists, PGEU, AEHP and EIPGas shown opposite.

Jane Nicholson, Executive DirectorEIPG, [email protected]

news from the EIPG


The representative organisations for European community,hospital and industrial pharmacists have issued a joint call foraction by Governments, regulators and the EuropeanCommission to tackle the growing problem of medicinesshortages.

Presenting evidence at the European Parliament on the scale ofthe difficulties being experienced across sectors, spokespersonsfrom the Pharmaceutical Group of the European Union (PGEU),European Association of Hospital Pharmacists (EAHP) andEuropean Industrial Pharmacists Group (EIPG) called for:

• heightened awareness by Governments and nationalregulators of the critical impacts medicines shortages have inrelation to patient welfare and safety, and the accompanyingneed for urgent action;

• greater investigation of the impact that national strategies onmedicines pricing and reimbursement are having on theoperation of the supply chain; and

• better sharing and implementation of best practices betweencountries in responding to medicines shortage, including theoperation of information portals and early warning systems.

John Chave, Secretary General of PGEU said: “Evidence fromPGEU members suggests that this is a problem affecting countriesfrom all corners of Europe, and a huge range of medicines. Whileall stakeholders need to work together to address the causes, as aminimum community pharmacists need to be in a position toproperly inform patients when a medicine is, or is likely tobecome, unavailable, and the causes and duration of theshortage. The pharmaceutical sector as a whole has a duty toavoid leaving patients in the dark”.

Roberto Frontini, President of EAHP said: “EAHP’s recent pan-European survey on medicines shortages clearly demonstratesthat the shortages problem does not respect national borders andis affecting virtually every hospital in Europe. Immense amounts ofhospital pharmacists’ time are being diverted from other elementsof patient care to simply source medicines. With the evidencestrongly suggesting the problem is becoming worse, doingnothing is no longer an option. Action is required and ourorganisations believe the proposals in our joint call todayrepresent a firm basis for European Governments and regulatorsto begin improving the situation.”

Luigi Martini, Immediate Past President of EIPG said: “Each fieldof the pharmacy profession brings an important perspective to theissue of medicines shortages. From the industrial pharmacistperspective we have strong concerns that some of therequirements of the otherwise welcome 2011 Directive on falsifiedmedicines may unintentionally increase the experience ofmedicines shortages. This relates in particular to new conditionsplaced on the import of active pharmaceutical ingredients fromoutside the EU, scheduled to be enacted this year. Overall, itreemphasises the multi-factoral nature of shortages, and the needto understand the inter-relatedness of pharmaceutical policydecisions. All supply chain partners need to work together insharing their experiences, identifying the problems, and advancingsolutions.”

For further information contact:PGEU: Giovanna Giacomuzzi, Communications and Policy Officer,[email protected] +322 238 0818

EAHP: Richard Price, Policy & Advocacy Officer,[email protected], +322 741 6835 +44 7895 292 076

EIPG: Luigi Martini, Immediate Past- President of EIPG,[email protected] + 44(0) 20 7848 3975

NOTES TO EDITORS:1. The context of the organisation’s joint call was an event in the EuropeanParliament entitled “The Economic Crisis & Access to Medicines inEurope”. The event included presentations from PGEU, EAHP and EIPGon pharmacist experiences of medicines shortage problems. Moreinformation here: http://www.epha.org/spip.php?article56742. The Pharmaceutical Group of the European Union (PGEU) is theEuropean association representing more than 400,000 communitypharmacists. PGEU’s members are the national associations andprofessional bodies of pharmacists in 32 European countries.www.pgeu.eu3. At the beginning of 2012, PGEU conducted a survey among itsmembers, national community pharmacy associations, in order to betterunderstand the extent of medicine shortages in the EU. According to thesurvey results, although some countries are more affected than others,medicine shortages have been reported by all respondents to the surveyand the problem is increasing. According to the survey, a broad range ofmedicines is affected, including even basic medication such as aspirin4.The survey suggests that the prevalence of medicine shortages hasincreased in the past year – just in the UK over 1 million branded medicinesupply failures occur each year. More information on the PGEU Statementon Medicines Shortages here: http://www.pgeu.eu/en/library.html4. The European Association of Hospital Pharmacists is an association of32 national organisations representing hospital pharmacists at Europeanand international levels. It represents and develops the hospital pharmacyprofession within Europe in order to ensure the continuous improvementof care and outcomes for patients in the hospital setting. This is achievedthrough science, research, education, practice, as well as sharing best-practice and responsibility with other healthcare professionals.http://www.eahp.eu5. The results of a recent pan-European survey by EAHP revealed that 99%of hospital pharmacists report experiencing problems with medicinesshortages in the past year, with 63% of hospital pharmacists reportingmedicines shortages to be a weekly, sometimes daily, occurrence. 77%consider that problem has become worse in the last year. Moreinformation here: http://www.eahp.eu/press-room/99-hpsexperience-medicines-shortages-past-year6. The European Industrial Pharmacists Group (EIPG) is a Europeanassociation representing the national, professional organisations ofpharmacists employed in the pharmaceutical or allied indust ries of theMember States of the European Union, the European Economic Area, orEuropean countries having a mutual recognition agreement with theEuropean Union on compliance control of regulated medicines.http://www.eipg.eu/7. At their recent General Assembly, EIPG members discussed the variouscauses of product shortages which include single source strategies bypurchasers, fewer manufacturers, low levels of contingency stocks, paralleltrade, downward pressure on generic prices and the complexities ofoutsourcing. It was agreed that it is crucial for all players in thepharmaceutical supply chain to exercise their best efforts to honour theirmain public service obligation of supplying medicines to the patient, andfor cost containment policies in pharmaceutical spending not to seek toachieve savings through measures that risk compromising thepharmaceutical supply chain.

JOINT PRESS RELEASE

16 May 2013

European pharmacist organisations make joint call for action on medicines shortages

European pharmacist organisations make joint call for actionon medicines shortages

JOINT PRESS RELEASE 16 May 2013


JULY4 July 2013 – London, UKMeeting stability challengeswww.jpag.org

AUGUST31 August-5 September 2013 – Dublin,Ireland73rd FIP World Congress ofPharmacy and PharmaceuticalScienceswww.fip.org/dublin2013

SEPTEMBER2 September 2013 – Edinburgh,ScotlandProgress in stability testingwww.jpag.org

8-9 September 2013 – Birmingham, UKRPS Annual Conference andAwards 2013www.rpharms.com

10-12 September 2013 – BarnardCastle, UKSterilisation: Principles inPracticewww.honeyman.co.uk

11-12 September 2013 – Basel,SwitzerlandPDA Europe 6th Workshop onMonoclonal Antibodieshttps://europe.pda.org/Monoclonal2013

11-13 September 2013 – Barcelona,Spain3rd Annual Pharma EmarketingCongresshttp://pharma.flemingeurope.com

17-18 September 2013 – Copenhagen,DenmarkGMP for Beginners in SterileManufacturingwww.gmp-compliance.org

19-20 September 2013 – Copenhagen,DenmarkRisk Management in SterileManufacturingwww.gmp-compliance.org

17-18 September 2013 – Berlin,Germany2nd Annual Pre-filled Syringes &Novel Injector Deviceswww.informa-ls.com/prefilled

24-26 September 2013, London, UKPharma Compliancewww.terrapinn.com

24-27 September 2013 – Düsseldorf,GermanyPharmaceutical Freeze DryingTechnologyhttps://europe.pda.org/FreezeDrying2013

30 September-1 October 2013 –Brussels, BelgiumThe Future of European Pharmawww.ispe.org

30 September-4 October 2013 –Chicago, USAGDP & TemperatureManagement Logisticswww.coldchainpharma.com

OCTOBER1-2 October 2013 – Berlin, Germany9th Annual Quality & Opex inPharma & Biotechhttp://pharma.flemingeurope.com

8-11 October 2013 – Berlin, GermanyPharmaceutical Cold ChainIntegrityhttps://europe.pda.org

10 October 2013 – London, UKIs there a scientific basis fortherapeutic equivalence?www.jpag.org

15-17 October 2013 – Barnard Castle,UKPharmaceutical Water Systems:Principles in Practicewww.honeyman.co.uk

17-18 October 2013 – Berlin, GermanyOperational Excellencewww.ispe.org

22-23 October 2013 – Dublin, IrelandBioProduction 2013www.bio-production.com

events

Industrial Insights at FIP Congress – 5th Sept 2013. Merck, DublinA one day event for early career individuals exploring opportunities in thepharmaceutical industry

Industrial Insights is brought to you by FIP and the Academy of Pharmaceutical Sciences (APS). It is being hosted at oneof Europe’s most advanced pharmaceutical sciences manufacturing facilities; Merck in Dublin.

Choosing the right career path... a done deal or still deciding?Either way, as a scientist, you have a wealth of choice out there, and we’d like to invite you to an informal, one-day event

that could open up new and unthought-of avenues.

Industrial Insights 2013 at FIP Annual Congress offers opportunities to find out about multiple roles within thePharmaceutical Industry, both technical and non-technical, help you networking with people already working for

pharmaceutical industry and give you valuable tips how to maybe proceed in your career.

A GOLDEN OPPORTUNITYWhen it comes to career-making decisions, don’t put all your eggs into one basket!

european industrial pharmacy issue 17 (june 2013)

Documents

clinicalstages of drug

european industrialpharmacy

new technologies

thesecond article

lindustrie en europewww

stephan buchmann

metabolism testingresearchers

ales francdenmark