european industrial pharmacy issue 3 (june 2009)

europeanINDUSTRIALPHARMACY

ISSUE 3 • JUNE 2009www.industrialpharmacy.eu

www.eipg.eu

FEATURES4 SWEDISH ENVIRONMENTAL CLASSIFICATION OF

PHARMACEUTICALSThe impact of the residues of medicines on the environment hasbeen investigated in Sweden, resulting in an environmental riskclassificationby Pär Tellner

6 CONTINUING PROFESSIONAL DEVELOPMENT –THE RPSGB AND TOPRA SCHEMESThe author compares the compulsory RPSGB scheme with thevoluntary TOPRA one.by Tony Cartwright

9 BIOSIMILARS: EXTENDING BIOLOGICALS’ BENEFITSProducing a generic biopharmaceutical is not as straightforward asproducing a small molecule drug. It not only has to bebioequivalent but has to go through a much more rigorous clinicaltrial programme and very strict quality control.by Mark Greener

12 FREEZE-DRYING OF SHAPED PHARMACEUTICALDOSAGE FORMSA non-traditional capability of freeeze-drying shaped dosage formsneeds an improved understanding of the scientific principles involved.by Kerr H Matthews

16 MAKING SUPERIOR PARTICLES FOR DRUG DELIVERYUSING POWER ULTRASOUNDMicronisation of large particles has many drawbacks, especially in theformulation of dry powder inhalers. Sonication technology usingpower ultrasound of 20-100kHz results in superior engineered drugparticles, whose advantages are outlined in this article.by Graham Ruecroft

18 WEB 2.0 – WHAT DOES IT MEAN TO THEPHARMACEUTICAL INDUSTRY?The rapidly changing ways in which interactive technology isenhancing communications for the consumer need to beexamined and exploited by the pharma industry.by Marta Garrido

20 MANAGEMENT AND REVISION OF DOCUMENTATIONAn organisational structure is described followed by the stages of adocument’s life cycle.by Michael Hiob

REGULARS3 EDITORIAL COMMENT22 NEWS FROM THE EIPG23 REGULATORY REVIEW24 DATES FOR YOUR DIARY

europeanIINNDDUUSSTTRRIIAALLPHARMACY

Issue 3 June 2009ISSN 1759-202X

EDITORJoe Ridge, MRPharmS

PRODUCTIONSue Feather

SUBSCRIPTIONSJill Monk

EDITORIAL BOARDMichael AnisfeldMichael GamlenLinda HakesLarry HurstJohn JolleyPär Tellner

European Industrial Pharmacy is published three times a year by: Euromed Communications LtdThe Old Surgery, Liphook RoadHaslemere, Surrey GU27 1NL, UK

Tel: +44 (0)1428 656665 Fax: +44 (0)1428 656643

Email: [email protected] subscription rate £58

Views expressed in European IndustrialPharmacy are those of the contributors andnot necessarily endorsed by the Publisher,Editor, Editorial Board, or by our corporatesponsors who accept no liability for theconsequences of any inaccurate or

misleading information

©2009 Euromed Communications Ltd

Belgium: Philippe Van der Hofstadt

Bulgaria: Valentina Belcheva

Czech Republic: Miloslava Rabiskova

Denmark: Michiel Ringkjøbing Elema

Finland: Tuula Lehtela

France: Jean-Pierre Paccioni

Germany: Armin Hoffmann

Great Britain: Jane Nicholson

Greece: Kiriasis Savvas

Hungary: Sylvia Marton

Ireland: Anna O’Mahony

Italy: Piero Iamartino

Latvia: Inta Saprovska

Malta: Claude Farrugia

Netherlands: Ineke Kleefsman, Michiel Storimans

Portugal: [email protected]

Spain: Mercé Pujol

Sweden: Pär Tellner

Switzerland: Renato Kaiser

europeanIINNDDUUSSTTRRIIAALLPHARMACYdiscussion group:

www.pharmweb.net/gmp.html

Associate Editors

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

Cover picture: Highly porous structure of a freeze-concentrated phase of a formulation showing theair-filled voids previously occupied by ice crystals prior to primary drying – see page 14.

A special thanks to the companies who havekindly supported the publication of thisnewsletter

2 eeuurrooppeeaann IINNDDUUSSTTRRIIAALL PHARMACY • Issue 3 June 2009

GMP Forum The online discussion group for industrial pharmacy


EEDDIITTOORRIIAALL CCOOMMMMEENNTTPharmaceutical Society of GreatBritain, then by rights you will haveaccess to this publication.

So please feel free and point out toyour colleagues where they canaccess this journal within yourcountry. You can find out more byaccessing our website: www.eipg.eu

As usual we have provided a widevariety of topics for your interestand a report from our GeneralAssembly in Riga, Latvia. I wouldlike to thank Inta Saprovska fororganizing an excellent meeting andJohn Jolley for standing in for me atthe last moment. The GeneralAssembly covered many topics fromeducation to counterfeit medicinesand the report is well worth a read.

If there are any questions you would

Dear Colleagues

This is the third issue of the journalthat has been published under theauspices of EIPG. The feedback fromour readers has been very positiveand we hope to improve access tothis fine publication. However, I dohave concerns that with all thingselectronic and web-based perhapsthe messages contain in thispublication are not getting throughto everyone.

I do urge you to encourage yourfellow Pharmacists to read thisjournal that has been createdspecifically for you, ie. allPharmacists working in Industry inEurope. If you are a member of yourPharmacy Association, eg. amember of the Royal

like ask about the meeting or ontopics discussed you can contacteither me at: [email protected] or our Executive DirectorMrs Jane Nicholson at:[email protected]

Finally, I would like to thank oursponsors GSK and Pfizer and, inparticular, Dr David Tainsh and DrSteve Wicks whose support was vitalin making this publication availableto all European Pharmacists workingin Industry.

Best wishes

Dr Gino Martini FRPharmSPresident, EIPG

3eeuurrooppeeaann IINNDDUUSSTTRRIIAALL PHARMACY • Issue 3 June 2009

36

www.controlledreleasesociety.org/meeting

Innovation in Discovery, Diagnostics, and Delivery

Featured Plenary Speakers

Gary ClearyCorium International, Inc., U.S.A.�e Emergence of Innovative Transdermal-based Delivery Systems

Heico FrimaEuropean Commission, Belgium Nanomedicine Research in the EU 7th Framework Program for RTD

Silvio GarattiniMario Negri Institute forPharmacological Research, ItalyWhat is Needed to Further Improve the Health in the World?

Allan HoffmanUniversity of Washington, U.S.A.�e Early History and Evolution of the Controlled Drug Delivery Field

Robert KissBelgian National Fund of ScientificResearch, BelgiumTargeting the Na+-ATPhase to CombatMetastatic and/or Multidrug-ResistantCancers

Bella Center by Claus Starup courtesy of the Bella Center; Tivoli, and Canal Tours by Cees van Roeden, courtesy of Wonderful Copenhagen.

SWEDISHENVIRONMENTALCLASSIFICATION OFPHARMACEUTICALSby Pär Tellner

Since the end of 2005, pharmaceutical product texts inFass.se may also include an environmental classification

of the pharmaceutical substance. Fass.se is the biggest andmost important information database for pharmaceuticalinformation in Sweden, containing all information neededwhen prescribing or dispensing a medicine. Fass.se is openfor everyone and widely used by prescribers andpharmacists as well as the Swedish public. Theenvironmental classification is a unique system oftransparency of environmental data on pharmaceuticalsubstances.

The most common way forpharmaceutical substances to reach theenvironment is after consumption. Activesubstances or metabolites follow thewater in the drain to a sewage watertreatment plant after excretion in urineor faeces. If the substances cannot befully eliminated in the treatment plant,by degradation or deposit in the sewagesludge, they may reach the surroundingwater compartments. We know howeverthat the levels of pharmaceuticalsubstance residues found in the Swedishwaters are very low and have noimmediate effects on animals or plants.The risk for adverse effects in the longerterm is probably also low for most

substances. Nevertheless, research in thearea of long-term effects is important.

In the beginning of the 21st century,findings of residues of pharmaceuticalsubstances in the water supply were agrowing issue in the Swedish mediadebate. The question did also become apolitical topic and the Swedishgovernment appointed a commission in2002 in order to assess the knowledge ofthe environmental impact ofpharmaceutical substances. Thecommission report from 2004 concludedthat there were big data gaps and that amandatory environmental classificationin Sweden was not compatible withEuropean laws. At the same time, theSwedish county councils started todemand environmental data from thepharmaceutical companies with theintention of taking this into accountwhen making recommendations for thedoctors on what medicines to prescribe.Due to the political pressure from thegovernment and the different demandsfrom the county councils, LIF, the Swedishassociation of the PharmaceuticalIndustry, decided to initiate a voluntaryenvironmental classification system in theFass.se database. Fass.se, which is fullyowned by LIF, is the most visitedinformation database for pharmaceuticalproducts in Sweden, used by prescribers,pharmacists and the public, andtherefore an appropriate source for thistype of information.

Together with several other Swedishstakeholders (the Medical ProductsAgency (MPA), the Swedish Association ofLocal Authorities and Regions (SKL), theSwedish monopoly pharmacy chain(Apoteket AB) and the Stockholm CountyCouncil (SLL)) as well as with internationalenvironmental experts from bigpharmaceutical companies, a model wasdeveloped on how to presentenvironmental data for prescribers, thepublic and others with special interest inthis issue. A reference group withrepresentatives from the academies,patients, physicians and governmentalagencies was also part of the developingprocess.

Review and classification

Since the mid 1990s all newpharmaceutical substances in Europe are

PÄR TELLNER is ComplianceOfficer of Leg Apotekare andDirector of VeterinaryMedicine of LIF, the SwedishAssociation of thePharmaceutical Industry.email: [email protected]

Depuis la fin 2005, les textes relatifs aux produitspharmaceutiques sur le portail Fass.se peuvent

également comprendre une classificationenvironnementale de la substance pharmaceutique.Fass.se est la plus importante base de données del’industrie pharmaceutique en Suède. Elle contient toutesles informations nécessaires pour prescrire et distribuerun médicament. Fasse.se est ouvert à tous et est souventutilisé par les prescripteurs et les pharmaciens ainsi quele public suédois. La classification environnementale estun système inédit de transparence des donnéesenvironnementales sur les substances pharmaceutiques.


assessed for environmental riskbefore approval by the authorities.It was decided to use the dataalready existing from thestandardized studies in the approvalprocess, but to classify theenvironmental risk in a scale of foursteps from insignificant to high risk,to make it easier to understand.

The pharmaceutical companies areresponsible for presenting data andmaking the classifications from thestudy results. To ensure that theclassifications follow the developedguidelines, an independent party,the Swedish Environmental ResearchInstitute (IVL) reviews the databefore publishing on www.fass.se.

The first environmentalclassifications were published inOctober 2005 for SSRIs (selectiveserotonin reuptake inhibitors) andPPIs (proton pump inhibitors). Byspring 2009, around 60 % of thesubstances in Fass.se have beenreviewed. By the end of 2010, allsubstances should have beenreviewed according to the plan.

Risks vs. hazards

The environmental classification wasdecided to focus primarily on theenvironmental risk instead of thehazard. The risk also takes intoaccount the potential exposure inSwedish waters and not only theinherent hazard of the substanceitself. Thus, a poisonous cytotoxicsubstance may constitute aninsignificant risk for the Swedishenvironment if given to very fewpatients. Less poisonous substancesused in greater quantities mayresult in a higher risk for theenvironment, something that couldbe missed if only studyingenvironmental hazard. Even if thefocus is environmental risk, thehazard is also presented in Fass.sein terms of how degradable thesubstance is or if there is anypotential for bioaccumulation inaquatic organisms. Anyone can alsoread the background data to see the

tests and results leading to theclassification.

The environmental risk classificationin Fass.se is based on the ratiobetween the predictedconcentration of the substance inSwedish water systems (PEC,Predicted EnvironmentalConcentration) and theconcentration predicted to be safefor organisms and plants (PNEC,Predicted No Effect Concentration).The PEC value is calculated mainlyby comparing the sold amount inkilograms during one year with thewater consumption of Swedishcitizens during the same period oftime. The PNEC value is usually aconcentration from acute ecotoxicitytests in organisms from threetrophic levels (fish, daphnia andalgae). The value from the mostsensitive organism is used for thecalculation. If the predictedconcentration in the environment(PEC) is lower than the PNEC (i.e.PEC/PNEC is lower than 1), the riskof environmental impact is low orinsignificant. If, on the other hand,PEC is higher than PNEC (the ratioPEC/PNEC is higher than 1), there isa moderate or high risk of impacton the environment.

Some pharmaceutical substancesare exempted in the guidelines fromEMEA (the European MedicinesAgency) and no environmental riskassessment is demanded during theapproval process. These includevitamins, proteins, peptides, aminoacids, electrolytes, lipids,carbohydrates, vaccines and herbalmedicinal products and they arealso exempted in the Swedishenvironmental classification system.They are marked with the phrase“Use of X has been considered toresult in insignificant environmental

SSWWEEDDIISSHH EENNVVIIRROONNMMEENNTTAALL CCLLAASSSSIIFFIICCAAIITTOONN OOFF PPHHAARRMMAACCEEUUTTIICCAALLSS ((CCoonntt..))IINN


impact” (where X means “vitamins”,“electrolytes” etc.).

The results of the classification, sofar, tell us that the averagepharmaceutical substance has aninsignificant environmental risk andno potential to bioaccumulate inaquatic organisms. Instead it has aslow degradation in theenvironment. Those results are notsurprising as pharmaceuticalsubstances usually are designed tobe relatively stable in the humanbody. Very few substances havereached a high risk; among themwe can find some sex hormones,known to have effects in lowconcentrations.

Is environmental informationnecessary for pharmaceuticals andhow can it be used? There is agrowing interest in the area ofenvironmental impact ofpharmaceuticals but the use of theclassification is a complex question.The therapeutic effect for thepatient must of course always havepriority over potentialenvironmental effects of themedicine and prescribers alreadyhave many other factors to take intoaccount when choosing the righttherapy for their patients. However,mapping the potential risks raisesthe level of knowledge of thepotential problem and hopefullyleads to more rational discussionsand decisions.

References

1. www.fass.se/environment2. Swedish Environmental Classification of

Pharmaceuticals, LIF (2008)http://www.lif.se/cs/default.asp?id=29916

3. MPA, August 2004,www.lakemedelsverket.se/upload/Om%20LV/publikationer/040824_miljouppdraget-rapport.pdf

4. Guidance document for Companies, January2007 www.fass.se/LIF/produktfakta/fakta_lakare_artikel.jsp?articleID=76074.



CONTINUINGPROFESSIONALDEVELOPMENT – THE RPSGB AND TOPRA SCHEMESby Tony Cartwright

The RPSGB CPD scheme

The RPSGB is the professional body for pharmacists in theUK. It introduced Continuing Professional Development

(CPD) for pharmacists in 1999 via an initial pilot projectwith 500 pharmacists. Nine years later the Pharmacists andPharmacy Technician Order 2007 introduced the need formandatory recording of CPD. However statutory CPD willnot be introduced before 2010 at the earliest under rulemaking for the General Pharmaceutical Council which willbe the new regulatory body for pharmacists in the UK.

Principle 5 of the August 2007 RPSGBCode of Ethics under “Develop yourknowledge and competence” states that apharmacist must undertake and maintainup-to-date evidence of CPD relevant tohis/her area of practice1. The RPSGBconsulted at the end of 2008 on asupplementary professional standardsand guidance document on goodpractice2. This proposed that:

� A legible record must be kept in aformat published or approved by theSociety

� The record should be kept eitherelectronically at the Society’s websiteor on another computer or ashardcopy

� The record should comprise between 6and 12 CPD entries per year

� The record should comply with goodpractice criteria for recording CPD,including how the CPD has contributedto the quality or development ofpractice

� The record must be submitted to theSociety on request for review andfeedback on maintaining a suitablerecord.

The RPSGB CPD competences

The RPSGB CPD website3 includes aframework of general competences which

might apply to pharmacists working inany sector of practice4. These are not corecompetences. They include interactingand working with people, being amanager, upholding quality andcontinuous improvement, helping othersto learn and develop, working withinformation, and participating in researchand development.

There are some more specificcompetences in a list entitled“Competences for Pharmacists in thePharmaceutical Industry”5. The list ofnine competency areas includes forexample “knowledge and application ofthe principles of Good ManufacturingPractice and quality assurance”,“knowledge and application of the lawsapplying to the pharmaceutical industry,including current EU directives” and“knowledge and application of theprinciples of Good Clinical Practice (inrespect of clinical trials), including currentEU directives”.

TOPRA

The Organisation for Professionals inRegulatory Affairs (TOPRA) is a globalorganisation for Regulatory Affairs (RA)professionals with members in 40countries. Members are drawn from theindustry, the regulatory agencies, theconsultancy and contract community.Members work in pharmaceuticals,biotechnology, veterinary products,medical devices, cosmetics andcomplementary therapies.

TOPRA is a voluntary membership bodyfor RA professionals. There is no legalrequirement for RA professionals tobelong to TOPRA or indeed any otherprofessional body. TOPRA membersinclude pharmacists, lawyers, chemistsand physicians, all of which have theirown professional bodies with specific CPDrequirements. Most members have a lifesciences degree, and may not belong toany other professional body.

Categories of TOPRA members are:

� Members

� Registered Members – who arecurrently working in RA, and who signa declaration that they are qualified todegree level, have a minimum of 2years RA experience, and are taking

TONY CARTWRIGHT is theChairman of the TOPRALifelong Learning Committee.He is a (part-time)pharmaceutical regulatoryconsultant based in the UK.e-mail:[email protected]

eeuurrooppeeaann IINNDDUUSSTTRRIIAALL PHARMACY • Issue 3 June 20096

steps to keep their knowledgeand skills up to date

� Fellows – Members with at least10 years RA experience and whohave made a significantcontribution to the profession.

� Honorary Life Members –appointed by the TOPRA Board

Registered Members make anannual declaration that they aretaking steps to keep their knowledgeand skills up-to-date. RegisteredMembers can use the designationMTOPRA and Fellows FTOPRA.

TOPRA’s mission is to seek toadvance the status of the regulatoryprofession through education andprovision of information to itsmembers. It provides a very wideprogramme of training andcontinuing education to itsmembers, including an introductorycourse for new entrant, an annualsymposium and two modularMSc/Diploma qualifications.

TOPRA lifelong learningscheme (LLL)

TOPRA set up its Lifelong LearningCommittee in 2004 to propose ascheme for CPD for its members. Itreviewed CPD requirements in a rangeof professional bodies (including theRPSGB), and benchmarked a range ofthe CPD schemes using theProfessional Associations ResearchNetwork (PARN). It also surveyedexisting CPD arrangements used byTOPRA members by a series of annualquestionnaires sent out at subscriptionrenewal. All of the RegisteredMembers stated that they alreadyundertook CPD. The areas of CPDundertaken by Members wasinvestigated in these questionnairesand published in reviews in the TOPRAjournal (the Regulatory Rapporteur).

The “user requirement” for LifelongLearning agreed by the TOPRABoard included the following:

� The emphasis of LifelongLearning is for it to be a service

to its members which helps focustheir personal and professionaldevelopment

� Compliance with CPD to beinitially voluntary

� Compliance with CPD to be self-certified annually

� Type of CPD record to be left tothe discretion of the member,but to be as simple aspracticable, recording only itemsof CPD undertaken and not theprocess of review, planning andoutput achievement

The TOPRA Lifelong LearningScheme was approved by the TOPRABoard as a tool for professionalplanning and development ofmembers, and which would alsoprovide managers with a moresystematic way to analyse andreview the development needs ofstaff. The scheme was rolled out tomembers in 2008. It sets a target of50–100 hours per year of LLL. Alibrary of information is providedon the TOPRA website6 and thisincludes a Practical Guide, aPersonal Learning Plan, a form forrecording Lifelong Learning, a list ofthe key Regulatory Competences,and an overview of the keycompetences with the numbers ofhours of LLL associated with each ofthe TOPRA conferences and trainingevents.

The definition of LLL includesattendance at formal in-house orexternal training events, but alsoincludes mentoring, using theInternet to access professionalwebsites, reading technical andprofessional publications,preparation of presentations, E-learning, work-based projects,attending TOPRA working partymeetings, and attending industry oragency working party meetings.

TOPRA regulatory affairscompetences

TOPRA has produced lists ofcompetences for each of the major

areas of regulatory work of itsmembers – human medicines, OTCproducts, medical devices, cosmeticsand borderline products, chemicals,food additives, pesticides andbiocides, veterinary medicines, thenational regulatory agencies, ITskills and “soft skills”. Examples ofsoft skills include negotiation andinfluencing, presentation, teamworking in a global environment,project management and strategicthinking, leadership, performancemanagement, marketing and crisismanagement.

The Human Medicines RegulatoryCompetences include 20 specificcompetences ranging from“knowledge about the discovery anddevelopment of pharmaceuticalproducts” to “knowledge andapplication of advertising andpromotional material clearance”. Itincludes such topics as clinical trialapplications, Good Clinical Practice,GMP, European registrationprocedures, and technical, chemical,pharmaceutical and biologicalrequirements for registration ofchemical entities.

Customisation of the TOPRAlist of competences toprovide a personal listing

The lists of competences are “pickand mix” lists which individualTOPRA members are expected to useto develop their own customised listwhich reflects their own particularjob, experience and seniority withintheir company. This list would needto be discussed and agreed with theline manager in a company, andcould then be used to secureappropriate training anddevelopment to ensure that therelevant competences are acquired.

An example of the way thiscustomisation can be applied fordifferent levels of responsibility isshown below for the competencerelating to “knowledge and applicationof European registration procedures”.

eeuurrooppeeaann IINNDDUUSSTTRRIIAALL PHARMACY • Issue 3 June 2009 7

CCOONNTTIINNUUIINNGG PPRROOFFEESSSSIIOONNAALL DDEEVVEELLOOPPMMEENNTT –– TTHHEE RRPPSSGGBB AANNDD TTOOPPRRAA SSCCHHEEMMEESS ((CCoonntt..))

TOPRA personal learningplan

A key element of LLL is to writedown a Personal Learning Plan todefine the key skills the RAprofessional wants to acquire in thenext one or two years. This can thenbe used to develop a plan todevelop these competences via LLL.

Recording of LLL

Recording of LLL can be done in anysuitable way. Since RA professionalswho belong to other professionalbodies may already record theirCPD, these records will be suitable.There is no formal TOPRArequirement to use any particularform of record, but the website does

give an example of a format whichwould suit most TOPRA members.

Members will be asked to submit asummary record every year, butthese will not be audited or reviewed,only analysed by an independentcompany to provide information toTOPRA on the changing futuretraining needs of its members.

Future developments

The lists of competences are beingreviewed to provide furtherdefinitions for each competence forstaff at Entry Level, Intermediate,Senior Level and Director. E-learningis being extended – which will beparticularly useful for one manconsultants and staff on maternity

or paternity leave to enable them tokeep up to date.

Consideration is also being given tothe development of an on-line toolto help members to record their LLL,analyse their development needsagainst the lists of competences, andthen to find suitable training tomeet these needs.

In due time the TOPRA LLL schemewill become mandatory, when thetime is right, it will then be avaluable formal reassurance that RAprofessionals will maintain andimprove their commitment topatient safety.

Implications for industrialpharmacists

Membership of the RPSGB and infuture of the GeneralPharmaceutical Council is notlegally essential for many industrialpharmacists in the UK; they maytherefore be interested in the moreflexible TOPRA voluntary scheme asa model for their own CPD. TheTOPRA list of competences forRegulatory Affairs professionals area much more detailed listing thanthe RPSGB currently provides. TheTOPRA listings are an importantreference for industrial pharmacistsin the UK and elsewhere to devise apersonal list of competences whichthey can use to produce their ownpersonal and professionaldevelopment programme.

References

1. http://www.rpsgb.org/pdfs/coeppt.pdfRPSGB Code of Ethics for Pharmacists andPharmacy Technicians

2. http://www.rpsgb.org/pdfs/cpdconsultationdoc.pdf RPSGB Consultation on CPDProfessional Standards

3. http://www.uptodate.org.uk/home/welcome.shtml RPSGB CPD Online website

4. http://www.uptodate.org.uk/PlanandRecord/Pharm_PandR/Pharm_PandR_Competences.pdf RPSGB CPD Plan and Record, Appendix7 Competences

5. http://www.uptodate.org.uk/PlanandRecord/newComps/Industry.pdf RPSGB Plan andRecord, Competences for Pharmacists in thePharmaceutical Industry

6. http://www.topra.org/careers/lifelong-learning TOPRA website, Lifelong Learning


CCOONNTTIINNUUIINNGG PPRROOFFEESSSSIIOONNAALL DDEEVVEELLOOPPMMEENNTT –– TTHHEE RRPPSSGGBB AANNDD TTOOPPRRAA SSCCHHEEMMEESS ((CCoonntt..))

Level of responsibility within organisation Competence

Entry level Understanding of procedures, systems and guidelines,needs of particular authorities, timelines

Intermediate Ability to assess drug development activities againstregulatory requirements of procedures

Senior Ability to evaluate and analyse basis of approval ofcompetitor products to inform strategic decisionsabout company’s new products

Director Analysis and interpretation of new legal requirementsfor impact on company development pipeline

Comparison of RPSGB and TOPRA Schemes

Aspect of Scheme RPSGB CPD TOPRA Lifelong Learning

Mandatory or voluntary Mandatory Voluntary, but will become mandatory at some future time

Sanctions likely if no Yes Norecords kept

Format of records Defined, approval needed Not defined, format for other formats given only as an example

Recommended extent 6–12 entries per year 50–100 hours per yearof CPD

List of competences General list of competences Detailed list of + 9 specific ones for competences for all RAindustrial pharmacists specialisms

Review of members Every 3 – 5 years by No individual review, butrecord contract reviewers analysis of records to provide

TOPRA with information on training needs of its members


BIOSIMILARS:EXTENDINGBIOLOGICALS’ BENEFITSby Mark Greener

Generic substitution helps contain healthcare costs.Biologicals account for more than a fifth of new

chemical entities and cheaper versions (“biosimilars”)should increase accessibility to these important medicines.However, a plethora of issues inherent inbiopharmaceutical manufacturing resulted in the EMEArequiring a more extensive clinical trial programme andmore rigorous quality control for biosimilars than wouldtypically apply to a small molecule generic.

The inherent complexity ofmanufacturing biopharma ceuticals alsomeans that the difference in pricebetween a typical brand and its smallchemical generic is much greater thanthat between the reference product andbiosimilar. Nevertheless, even a 20% pricereduction on five off-patent biopharma -ceuticals could save the EU more than€1.6 billion per year.

Current techniques may not detect allpotentially clinically relevant differencesbetween the biosimilar and the originalbrand, mandating effective pharmaco-vigilance and prescribing by brand. Whilesuch issues pose challenges formanufacturers and regulators, biosimilarsshould release some of the pressure fromincreasingly compressed healthcarebudgets.

Governments worldwide employ genericsubstitution to help contain the spirallingcosts of medical care. In the USA, each 1%increase in generic prescribing reducesdrug costs by $1.32 billion annually1. Inthe UK, the average costs of a generic andthe original brand are £4.83 and £19.33respectively [www.britishgenerics.co.uk/marketkeyfacts.htm]. Healthservices invest the money releasedthrough generic substitution to help meetother health needs.

Producing a generic version of a smallmolecule drug is relativelystraightforward. Essentially, the genericcompany needs to show identicalchemical composition and similar

pharmacokinetics to the originatorbrand2. For example, regulatoryauthorities may consider the drugs to bebioequivalent when the 90% confidenceintervals for the ratios of AUC and Cmax ofthe generic to brand fall between 80%and 125%1. Synthesising small moleculesis usually relatively inexpensive, resultingin marked savings compared to theoriginal brand.

Applying the same principles tobiologicals – therapeutic substancesproduced by, or extracted from, abiological source3 – is more difficult. Forexample, a typical biological is between100 and 1000 times larger, and is morecomplicated to manufacture, than a smallmolecule drug. Moreover, a biological’sactivity often depends on maintaining aspecific, but fragile, 3-dimensionalstructure. Finally, the cells used toproduce the biological usually releaseseveral isoforms4 rather a single, distinctchemical.

Nevertheless, biologicals accounted for22% of new chemical entities approvedby the European Medicines Agency (EMEA)between 2003 and 20063. Somebiologicals, such as bevacizumab andtrastuzumab, markedly improveoutcomes in difficult-to-treat cancers.Other biologicals, including recombinanthuman epoetin (rHuEPO) andgranulocyte-colony stimulating factor (G-CSF), reduce the incidence of problematiccomplications, such as anaemia andneutropenia respectively. For example,rHuEPO reduces the need for bloodtransfusions in patients with end stagerenal disease5.

Biosimilars

Several first-generationbiopharmaceuticals are approaching orhave passed the end of patent protection.This allows rival companies to developcheaper alternatives to the original brand– so called biosimilars. As a recentreview2 comments, “Biosimilars shouldprovide cost savings and greateraccessibility to biopharmaceuticals”. TheEMEA approved the first biosimilar – thehuman growth hormone Omnitrope(somatropin; somatrophin) from Sandoz –in April 2006 and the numbers areincreasing steadily. For example, inSeptember 2008 ratiopharm direct

MARK GREENER is amedical writer andformer researchpharmacologist based inCambridge, UK

launched Ratiograstim, the firstEMEA-approved biosimilarfilgrastim.

However, the EMEA rejected abiosimilar interferon-α. Side effectsand disease recurrence were morefrequent with the biosimilarcompared with the original brand.The biosimilar company also failedto satisfy the EMEA that themanufacturing process andimmunogenicity testing wereadequate. In another case, the EMEAapproved different precautions andwarnings for a biosimilar growthhormone to the reference brand.The differences probably arise fromthe different cell lines (yeasts andEscherichia coli) used during themanufacturing processes4. The EMEAalso requires a much more rigorousclinical trial programme beforeapproving a biosimilar than wouldtypically apply to a small moleculegeneric. This feature examines G-CSFbiosimilars to illustrate these points.

An importantbiopharmaceutical

G-CSF is the major cytokine thatcontrols neutrophil production. G-CSF allows oncologists to useintensive chemotherapy regimens –such as the combination ofdoxorubicin, paclitaxel, andcyclophosphamide – that wouldotherwise cause profound andprolonged neutropenia6.Furthermore, between 25% and 40%of patients receiving commonchemotherapy regimens for the firsttime develop febrile neutropenia7.As a result, oncologists increasinglyuse G-CSF to support less intensiveregimens6.

Clinicians also use G-CSF to treatcongenital and acquiredneutropenias, as well as to mobilisehaematopoietic stem cells beforestem cell donation from healthypeople. G-CSF may also enhanceregeneration of the heart followingmyocardial infarction and reduceinfarct size following acute

ischaemic stroke, although the latterapplications remain experimental6.

Natural G-CSF is a 18.8 kDa proteinthat contains 174 amino acids, twodisulphide bonds and singleglycosylation site. Glycosylationreduces the risk of aggregation butdoes not influence activity.Recombinant G-CSF is identical tothe endogenous protein apart froman extra methionine on thepeptide’s N-terminal and the lack ofglycosylation8.

The clinical trial programme thatsupported Ratiograstim enrolledapproximately 900 patients. Forexample, randomised, single blind,crossover studies in 190 healthyvolunteers compared thepharmacodynamic andpharmacokinetic profile ofRatiograstim and the referenceproduct Neupogen, from Amgen,after subcutaneous and intravenousadministration. Ratiograstim’s keypharmacokinetic parameters(including AUC, Cmax, tmax andelimination half life) were generallywithin 80% to 125% of therespective parameter for Neupogen.Relative bioavailabilities wereestimated to be 12% and 4% higherfor Ratiograstim compared withNeupogen at 5 and 10µg/kgrespectively.

Another study enrolled 348 patientswith high-risk stage II, stage III or IVbreast cancer who receiveddocetaxel and doxorubicin. Patientsreceived Ratiograstim, Neupogen orplacebo. Patients on placeboswitched to Ratiograstim after onecycle. In the per protocol analysis of320 women, mean duration ofsevere neutropenia (DSN) in cycle 1,the primary end point, was 1.1, 1.1,and 3.9 days with Ratiograstim,Neupogen and placebo respectively.DSN ranged from zero to 5 dayswith Ratiograstim and Neupogen,compared with zero to 9 days in thepatients who received placebo. Theoverall incidence of febrileneutropenia across all cycles was

lower with Ratiograstim (20.7%) andNeupogen (22.1%) than placebo(41.7%). The difference in theincidence of febrile neutropeniabetween Ratiograstim andNeupogen was not statisticallysignificant.

According to EMEA guidelines, asRatiograstim demonstrated clinicalcomparability in chemotherapy-induced neutropenia, clinicians canassume that this biosimilarfilgrastim is equivalent to Neupogenin other indications. Trials thatenrolled 240 patients with lungcancer and 92 people with non-Hodgkin lymphoma confirmed thatNeupogen and Ratiograstim showequivalent safety and efficacy.

Manufacturing issues

Living cells – often geneticallyengineered micro-organisms –produce biologicals. The expressedprotein is purified and formulatedto yield the final biopharmaceutical.Much of the process is the originalmanufacturer’s proprietaryknowledge. Therefore, thebiosimilar manufacturer needs toestablish a proprietary cell line, DNAexpression vector, andmanufacturing and purificationprocess4. As a result, companiesneed to invest more in themanufacturing process for abiosimilar than in developing astandard generic, with the averagecost €50 million to €80 million tobring a new biosimilar to market.

Partly because of the complexity ofmanufacturing, EMEA imposes strictquality standards on biosimilars.Small differences or changes in anyone of these manufacturing stepspotentially influence the activeproduct’s characteristics, such asthree-dimensional structure, acid-base variants and glycosylationprofile2 and, therefore, potentiallyinfluence immunogenicity,tolerability3 and efficacy. Forexample, deamidation of asparagineand glutamine side chains,


BBIIOOSSIIMMIILLAARRSS:: EEXXTTEENNDDIINNGG BBIIOOLLOOGGIICCAALLSS’’ BBEENNEEFFIITT ((CCoonntt..))

replaced human serum albumin3.However, cancer patients do notseem to develop PRCA, despite thewidespread use of rHuEPO.Differences in immune competence,concurrent therapies and reducedexposure between cancer andchronic renal disease patients mightaccount for the discordance10.

PRCA associated with rHuEPOunderscores the difficulty inextrapolating betweenbiopharmaceuticals and patientgroups, as well as the need tocognisant of the potential impact ofdifferences in the manufacturingprocess for the reference brand andthe biosimilar. EPO-associated PRCAalso highlights the potential forbiologicals to induce immunogenicreactions. Many cases ofimmunogenicity are asymptomatic.However, immunogenicity canundermine therapeutic efficacy (forexample, by stimulating productionof neutralising antibodies) or induceautoimmunity to endogenousmolecules3.

Effective pharmacovigilancedepends on being able to trace theproduct responsible for the adverseevent4. Therefore, clinicians shoulduse brand names when prescribingbiosimilars and when spontaneouslyreporting suspected adversereactions. This principal is acceptedin other therapeutic areas. Cliniciansproceed cautiously whensubstituting drugs used to manageepilepsy1. In some cases, evenrelatively small changes in bloodconcentration – such as thosearising from switching betweengenerics or from generic to brand orvice versa – can lead tobreakthrough seizures. Therefore,clinicians often prescribeantiepileptic drugs by brand.

The savings arising from a switch tobiosimilars are potentiallyimportant. However, the variousissues mentioned above means thatregulators, manufactures andclinicians must scrutinise eachbiosimilar in detail and remain alertfor any reactions that emerge oncethe biosimilar enters regular clinicaluse. Nevertheless, biosimilarsshould release some pressure onincreasingly compressed budgetsand allow more patients to benefitfrom the fruits of the molecularbiological revolution.

References1. Privitera MD. Generic antiepileptic drugs:

current controversies and future directionsEpilepsy Curr 2008; 8: 113–7.

2. Mellstedt H, Niederwieser D, Ludwig H. Thechallenge of biosimilars Ann Oncol 2008; 19:411–9.

3. Giezen TJ, Mantel-Teeuwisse AK, Straus SM etal. Safety-related regulatory actions forbiologicals approved in the United Statesand the European Union JAMA 2008; 300:1887–96.

4. Nowicki M. Basic facts about biosimilarsKidney Blood Press Res 2007; 30: 267–72.

5. Covic A and Kuhlmann MK Biosimilars:recent developments Int Urol Nephrol 2007;39: 261–6.

6. Touw IP and Bontenbal M. Granulocytecolony-stimulating factor: key (f)actor orinnocent bystander in the development ofsecondary myeloid malignancy? J NatlCancer Inst 2007; 99: 183–6.

7. Dale DC Colony-stimulating factors for themanagement of neutropenia in cancerpatients Drugs 2002; 62(1): 1–15.

8. Vanz AL, Renard G, Palma MS et al. Humangranulocyte colony stimulating factor (hG-CSF): cloning, overexpression, purificationand characterization Microb Cell Fact 2008;7: 13.

9. European Generic Medicines Association EGAHandbook on Biosimilar Medicines 2007 p2.

10. Stasi R, Amadori S, Littlewood TJ et al.Management of cancer-related anemia witherythropoietic agents: doubts, certainties,and concerns Oncologist 2005; 10: 539–54.

Ratiograstim and Neupogen are Registered TradeMarks


oxidation of methionine,dimerisation and a range of otherchanges can reduce activity to only15% of that of naturally produced G-CSF8. Attaining the strict qualitycontrol standards imposed by theEMEA also requires considerableinvestment. One in ten employees atthe manufacturing facilityresponsible for the distribution ofRatiograstim, works solely in qualitycontrol.

As a result, the difference in pricebetween the original brand andsmall chemical generic is muchgreater than that between thereference product and biosimilar2.Nevertheless, according to theEuropean Generic MedicinesAssociation, a 20% price reductionon five off-patentbiopharmaceutical medicines couldsave the EU more than €1.6 billionper year9.

Post-marketingpharmacovigilance

Despite the investment in qualitycontrol, current analyticaltechniques and preclinicalexperimental studies cannot detector predict all the biological andclinical differences, includingimmunogenicity, between thebiosimilar and the original brand.Therefore, biosimilars requireintensive post-marketing scrutiny toensure that the small difference inthe product that potentially arisefrom manufacturing variations dono cause clinically significantreactions2,4.

Pure red cell aplasia (PRCA)associated with rHuEPO offers astriking, albeit rare, example of thepotential impact of seemingly smallmanufacturing changes. The risk ofthis immune-mediated adverseevent increased among patientswith chronic renal disease takingrHuEPO that had been reformulatedso that polysorbate 80 and glycine

BBIIOOSSIIMMIILLAARRSS:: EEXXTTEENNDDIINNGG BBIIOOLLOOGGIICCAALLSS’’ BBEENNEEFFIITT ((CCoonntt..))



FREEZE-DRYING OFSHAPEDPHARMACEUTICALDOSAGE FORMSby Kerr H Matthews

The technique of freeze-drying is interchangeably referred to aslyophilisation and is traditionally used in the pharmaceutical

industry to give parenteral solutions containing hydrolysabletherapeutic agents a greatly extended shelf life.

The ubiquitous glass vial with foil-sealedseptum being a common manifestationof such products. Closer scrutiny of thecontents of such a vial reveals a (white)friable plug or ‘dry’ powder as opposed toa liquid. Traditional lyophilised productsobtainable in this form include vaccines,blood products and certain classes ofantibiotics. In fact, proteinaceouscompounds, that increasingly includerecombinant DNA technologies, areinevitably processed or stored as such. Inmicrobiology, freeze- dried bacterialcolonies are regularly sold as whitepowders in sealed glass ampoules thatare brought to life by the addition of asuitable growth medium.

Freeze-drying or lyophilisation is, by andlarge, a well understood physical processthat doesn’t require much thought orplanning… or so the popular mythprevails! This article sets out to try andexpound some of these ingrained beliefsand uses the example of shaped,pharmaceutical dosage forms to do so.

Practice and theory

Unfortunately, it is not uncommon to seeundergraduate and even postgraduatestudents ‘freeze-drying’ samples in acylinder drier, common to mostbiomedical laboratories, not appreciatingthat they are in fact merely vacuumdrying at low temperatures! Similarly,there is the common misconception thatsuccessful freeze-drying requires a ‘trialand error’ approach to determine a usefulprocess cycle. On the contrary, anyonewho attempts to freeze-dry anythingshould first of all consider the following:

Freezing

A liquid is subjected to low temperaturesso that it may solidify. In the case of anaqueous solution, the solutionconcentration does not change untilfreezing occurs, ie. water crystallises asice. The onset of ice formation causes thesolute to concentrate and form asaturated solution. Continued coolingcauses more ice to form and the solutionbecomes supersaturated. If the solute is acrystallisable salt such as sodium chloride(NaCl), eventual solidification of thesupersaturated solution will occur at theeutectic composition (4 mol/L and –21ºCfor NaCl/H2O)

1.

More formally, the eutectic temperaturecan also be defined as the lowesttemperature, on the equilibriumsolubility curve, at which the liquid phasecan exist in a system that is inthermodynamic equilibrium. Thisdefinition suffices for simplesolute/solvent, binary systems where aclear eutectic transition exists.

In the case of dosage forms containingwater soluble polymers, however, adifferent scenario is presented as thefreezing cycle proceeds. High molecularweight polymer chains are incapable ofcrystallising to any great extent andfurther cooling only serves to increase theviscosity to a point where translationalmolecular motion is effectively stoppedand the viscosity increases by severalorders of magnitude. This vitrificationprocess is characterised by a criticaltemperature Tg' (Tg prime) at the point ofmaximum freeze concentration. This isthe single most critical parameter fordefining the maximum temperature atwhich freeze-drying, to preserve the castshape of the liquid formulation, can beundertaken. Exceeding this temperatureduring the primary drying process willresult in the freeze concentrate losing therequired shape due to the ‘melt-back’ ofice into the glassy phase causing collapseof the shaped glass.

Primary drying

At some point below Tg, the pressure isreduced, controlled amounts of heat areapplied and the ice is removed bysublimation. A notable temperaturedifference between the product and a

KERR H MATTHEWS is aLecturer inPharmaceutics at theSchool of Pharmacy &Life Sciences, The RobertGordon University,Aberdeenemail:[email protected]


cooler, proximal condensing surfacedrives the sublimation process.

Other factors that affect theefficiency of sublimation includeheat transfer coefficients, chamberpressure, product composition, thetotal volume of water to beremoved and the overall efficiencyof the freeze-drier.

As the ice front travels from the topof the sample to the bottom duringsublimation so the dried productoffers a barrier to the furtherdiffusion of water vapour. Thesample fill depth should thereforebe minimised and sample areamaximised where possible tooptimise the primary drying cycle. Itis critically important for theproduction of a shaped article thatthe product temperature should notexceed Tg until all of the ice hasbeen removed so that melt-backmay be avoided.

Secondary Drying

At some indistinct point in the freeze-drying process, water molecules‘trapped’ in the freeze concentratethat were unable to form ice duringthe freezing cycle, are desorbed tothe gaseous phase. The removal ofthis ‘non-freezing’ water is referred toas ‘secondary drying’. Low pressure ismaintained for the remainder of thecycle and the process temperatureincreased at a controlled rate as anincrease in temperature allowsdesorption of more water.

As for primary drying, however, caremust be exercised to avoid exceedingthe Tg of the lyophilised matrixformed from the freeze concentratedphase. Residual water acts like aplasticiser to the lyophilised matrixand although the value of Tgincreases as residual water, ie.plasticiser concentration, decreases,the process temperature (and hencethe sample temperature) must notrise above the instant value of Tg.Collapse of the matrix structure willresult in the irrecoverable loss of theintended shape.

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Assuming that collapse has beenavoided, the final water content ofthe shaped product may be as lowas 1-2% towards the end of thesecondary drying cycle.

For hygroscopic materials such aspolysaccharides, the equilibriummoisture content (EMC) undernormal laboratory conditions (say,18-25ºC/50-70%RH) will increasequickly when the vacuum is releasedto atmosphere. Interestingly,collapse does not generally occureven at EMCs of 15-20%w/w as theTg of lyophilised polysaccharidestructures is above roomtemperature thus ensuring thestability of such shaped products.

Shaped dosage forms

Despite all this sound physical science,the final shape or form of thelyophilised product is generally of noconsequence to the end-user. This isnot the case however, with bioadhesiveproducts designed as oral, topical,nasal or buccal dosage forms. In thesecases, the final shape will be suitablefor the particular application and willbe determined by the mould intowhich the solutions or gels are cast.

Fast-dissolving tablets

A good example of a shapedproduct is the ‘fast-dissolving’ oraldosage form known as Zydis™(Catalent Pharma Solutions,Swindon, UK). This is a small,blister-packed ‘tablet’ designed todisintegrate within a couple ofseconds of placing on the uppersurface of the tongue. It willimprove patient compliance inchildren, geriatrics or thoseindividuals where swallowing ofconventional tablets and capsules isproblematic. For these products,often wrongly referred to as ‘fastmelt’, the size and shape of thelyophilised form is also important asthe lyophilised form must becoherent and non-friable to besuccessfully removed from theblister-pack and applied.

Wound healing wafers

Of particular interest to this authoris the use of lyophilised wafers astopical delivery systems. Recentlydeveloped for the direct delivery oftherapeutic agents to chronic ulcers,these highly porous, lyophilisedpolymer matrices are able toincorporate many times their weightof both soluble and insolublecompounds2,3. They are producedby the casting and subsequentfreeze-drying of polymer solutionsand gels (including gel suspensions)in an appropriately shaped mould(Figure 1). Scanning ElectronMicroscopy (SEM) of the finalproduct indicates a highly porousnetwork structure that reflects thefreeze-concentrated phase of thefrozen formulation (Figure 2). Thebulk of the product is composed ofair-filled voids previously occupiedby ice crystals prior to primarydrying.

As an example of this type oflyophilised product, wound healingwafers containing proprietaryinhibitors of proteinases that areover-expressed in chronic woundfluid have been described4,5. Thesenovel materials are designed to beplaced directly onto the surface of amoderate to heavily suppuratingwound where they immediatelyadhere and revert, at a controlledrate, to the pre-lyophilised state,releasing the contained therapeuticagent directly to the wound bed.

The rheological properties of thereconstituted solution or gel willreflect those of the material ormaterial combinations used. Naturaland semi-synthetic water-solublepolymers that form weak gelnetworks at given concentrationsare particularly useful as they willremain in situ on the wound fordays at a time.

This advantageous state of affairs ispossible if a balance between fluiduptake and loss of water to theatmosphere is achieved.Additionally, from consideration of



desirable conditions for efficientfreeze-drying already discussed,wound healing wafers tend to beless than 5 mm deep and 1-100 cm2

so they are ideal for relatively shortprocess cycles.

Buccal dosage forms

Nicotine has been delivered to sheepand insulin to humans via alyophilised nasal insert composedpredominantly of shaped, freeze-driedhydroxypropyl methyl cellulose(HPMC)6,7 and there are manyexamples of buccal dosage formsfabricated from lyophilised polymers.The hydrophobic cerebrovasculartreatment, denbufylline has beenadministered to rabbits usingmodified chitosan8 but like most suchdosage forms, the freeze-driedpolymers are inevitably compressedinto buccal tablets. More recently,selegiline, a treatment for Parkinson’sdisease, has been formulated as amultiparticulate, lyophilisedCarbomer™ formulation9. For thisrecent example, for Zydis™ and forwound healing wafers in particular,the shape, mechanical properties andstorage stability are all critical to thesuccess of the application.

Critical considerations forshaped dosage forms

As discussed, carefully designedprocess cycles originating from arational knowledge of the freeze-drying process and the thermalproperties of the formulation to beprocessed are required to ensure theshape and form of the lyophilisedproduct during freeze-drying. Asound knowledge of critical thermalevents such as the point ofmaximum freeze concentration (Tg')or eutectic melting points1 arenecessary to ensure that no collapseof the product during processingoccurs.

The freeze-thaw properties ofpolymer solutions and gelscontaining either soluble orinsoluble compounds can be

studied using thermoanalyticalmethods such as DifferentialScanning Calorimetry (DSC) orHot/Cold-Stage Optical Microscopy(HCSOM) – more popularly known asa ‘freeze-drying microscope’. Thelatter technique has been developedby Biopharma Technology Limited toinclude a vacuum chamber in whichthe general conditions inside a freezedrier can be modelled.

The formulation, prior tolyophilisation, is placed on the hot-stage, enclosed within a vacuumchamber, and frozen by thecontrolled circulation of liquid


Figure 1. Casting and freeze-drying to produce lyophilised wafers

nitrogen. Specific conditions oftemperature and pressure can beapplied to the sample and changesof morphology and state can beviewed and digitally recorded in realtime. The progress of icesublimation, the collapsetemperature (exceeding the glasstransition of the freeze-concentrate),‘melt-back’ (exceeding the melting-point of ice and/or a eutectic melt)can all be discerned. This knowledgecan be applied to the design of aprocess cycle that should consistentlyproduce the required shapedproducts.

Figure 2. Porous network structure of the frozen formulation.

5. Matthews KH, Stevens HNE, Auffret AD, et al.Formulation, stability and thermal analysisof lyophilised wound healing waferscontaining an insoluble MMP-3 inhibitor anda non-ionic surfactant. Int J Pharm, 2008;356: 110-120.doi:10.1016/j.ijpharm.2007.12.043.

6. McInnes FJ, Thapa P, Baillie AJ, et al. In vivoevaluation of nicotine lyophilised nasalinsert in sheep. Int J Pharm, 2005; 304:72–82.

7. McInnes FJ, O’Mahony B, Lindsay B, et al.Nasal residence of insulin containinglyophilised nasal insert formulation, usinggamma scintigraphy. Eur J Pharm Sci, 2007;31: 25–31.

8. Martin L, Wilson CG, Koosha F, Uchegbu IF.Sustained buccal delivery of thehydrophobic drug denbufylline usingphysically cross-linked palmitoyl glycolchitosan hydrogels. Eur J Pharm Biopharm,2003; 55: 35–45.

9. Placzek M, Sznitowska M. Preparation andevaluation of physicochemical properties ofmucoadhesive, freeze-dried buccal systemswith selegiline. Proceedings of the 5thMultidisciplinary Conference on DrugResearch, May 14-18, Darłówko, Poland. ActaPol Pharm, 2006; 63(5): 329–466.http://www.science24.com/paper/6481


The future

Although freeze-drying is generallyrecognised as an expensive batchprocess for producing stable dosageforms of hydrolysable and thermo-labile therapeutic agents, the relativeexpense of the purified proteins,peptides and cytokines that arenecessarily freeze-dried, negates suchconsiderations. Furthermore, if ageneric drug can be delivered withimproved patient compliance,bioavailability and bioequivalencethan existing methods, and/or theinherent properties of a shaped,mucoadhesive dosage form are moresuited to a specific application than aparenteral injection, then lyophilisedproducts are considered ‘value-added’and priced accordingly.

Whatever one’s standpoint, freeze-drying is an important process inthe pharmaceutical industry with an

assured future. An improvedunderstanding of the scientificprinciples underpinning it and anability to exploit its non-traditionalcapabilities, ie. the production ofshaped dosage forms, cancontribute to the development ofmodern medicine.

References1. Franks F, Auffret AD. Freeze-drying of

Pharmaceuticals and Biopharmaceuticals –Principles and Practice. 2007. RSCPublishing.

2. Matthews KH, Stevens HNE, Auffret AD, et al.Wafer for Wounds. 2003. Int Patent, PfizerLtd., WO 03,037,395 (05 August).

3. Matthews KH, Stevens HNE, Auffret AD, et al.Lyophilised wafers as a drug delivery systemfor wound healing containingmethylcellulose as a viscosity modifier. Int JPharm, 2005; 289: 51–62.

4. Matthews KH, Stevens HNE, Auffret AD, et al..Gamma-irradiation of lyophilised woundhealing wafers. Int J Pharm, 2006; 313:78–86.




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technologies are now being developed toassist in both drug development andmanufacture. Production of drug particlesusing supercritical fluids has generatedsignificant interest, albeit with limitedsuccess to date. Questions are being askedabout scalability, cost-effectiveness due tohigh pressure, limited productivity andinherent amorphicity. Conversely, theSolution, Atomisation and Crystallisation bySonication (SAX) technology, developed inconjunction with the inventor, Dr Rob Priceof the University of Bath, avoids all theseissues to give superior engineered drugparticles3,4 see Figure 1.

Power ultrasound andcrystallation

Almost all chemical processes utilisecrystallisation – cooling, evaporative, anti-solvent or reactive – but this can be one ofthe most difficult unit operations to control.Ultrasound is used routinely in areas such asmedical imaging, diagnostics and biologicalcell disruption and now the application ofpower ultrasound (20-100kHz) has risen toprominence in sonochemistry (to modifychemical reactions) and sonocrystallisation5.High energy transient cavitation isparticularly effective for primary nucleationand reproducibly generating micro-crystalline seed crystals (to avoidconventional seeding). As a result we cancontrol crystal size distribution, morphology,impurities and solid-liquid separation. Thein-line continuous flow or batch modeprocess can be applied to intermediates,excipients, APIs, binders and sugars and,importantly, can be validated across scale incGMP environments.

Polymorph control with ultrasound

An understanding of the metastable zone(MZ) and the zone width (MZW) is


MAKING SUPERIORPARTICLES FOR DRUGDELIVERY USINGPOWER ULTRASOUNDby Graham Ruecroft

Drug delivery by inhalation offers significant potential foradministering otherwise injectable drugs. Therapeutic areas to

be addressed by this approach now and in the future includediabetes, cancer, pain, migraine and osteoporosis.

Pharmaceutical manufacturing iscommitted to making particles and thenmodifying their properties in order to turnthem into structured products but,surprisingly, 5-10% of manufacturedformulations fail to meet specifications.Typically, particles for drug inhalation aremanufactured by very primitivepharmaceutical technologies such asmicronisation, a destructive and energy-inefficient technique to turn large, regularcrystals into irregular 1-5µm particles thatcan undergo morphological change andsurface polymorph transformations leadingto amorphicity and decreased stability1. Theparticles can also be highly charged, whichaffects the flow-rates essential foraerosolised and dry powder inhalers.

Many molecules with excellent biologicalactivity – but poorly water-soluble – can beused by formulating them into crystallinenanosuspensions2, sub-micron colloidaldispersions of pure particles of drugsubstance stabilised (usually) by surfactants.Oral nanosuspensions have been specificallyused to increase the rate of absorption andbioavailability of drug compounds. Also,marketed drugs can be reformulated usingmore suitably engineered particles,potentially leading to new drug products.

Such mesoscopic crystals need to beengineered by ‘ground-up’ molecule-to-crystal approaches, in order to control theirmicro and macro structure and fullycharacterise their performance enhancingattributes. This will allow control of surfacecharacteristics and geometry whilemaintaining high throughput, low cost andindustrial scalability. Thankfully, emergingcrystallisation and particle engineering

GRAHAM RUECROFT, PhDhas over 20 years’experience in finechemical and lifesciences industries. He isa co-founder and directorof Oxford-based Prosonixwhere he is the ChiefTechnical Officer.Email:[email protected] Figure 1. The SAX process.


fundamental to controllingcrystallisation. The application of high-intensity 20kHz ultrasound can lead tonarrowing of the MZW and, by sodoing, it is possible to ‘tailor’ a crystalsize distribution using a short burst ofultrasound to nucleate at lowsupersaturation and then allow growthto large crystals, and the production ofsmall crystals via continuousinsonation and mechanical disruptionof crystals or loosely boundagglomerates. The optimum needs tobe determined by experimentalinvestigation. Ultrasound can alsoinduce secondary nucleation bymechanically disrupting crystals orloosely bound agglomerates.

The overall technique lends itselfextremely well to polymorphic systems;polymorphism is common amongstorganic materials resulting in theexistence of two or more crystallinephases with different packing in thecrystal lattice. Isolation of the ‘wrong’polymorph brings substantial problemsin pharmaceutical applications but, bycareful application of ultrasound, theground state polymorph (the mostthermodynamically favoured and leastsoluble) can be isolated.

From laboratory tomanufacture

One of the principal barriers to theadoption of power ultrasound technologyin pharmaceutical manufacturing hasbeen the lack of industrial scaleequipment. To address this need Prosonixhas designed industrial equipment toallow effective and focused distribution ofacoustic energy into a liquid by using anumber of low-power transducersbonded to the outside of a cylindricalduct6. This avoids the problems of usinghigh-powered probe-based equipmentwhere metal particles can be shed into thecrystallising liquor.

The technology can be applied fromkilogramme to tonne scale for finechemical and pharmaceuticalmanufacture. Value-added benefits caninclude identification of new processpatents for individual products, thussecuring and extending marketing

timescales. An attractive feature ofsonocrystallisation is that it can be appliedat any stage in a product pipeline, thenensuring that success in the laboratory canbe replicated across scale.

Mesoscopic particles

We have seen specific benefits in theproduction of particles for inhaledtherapeutics, and also see potential inthe production of nanosuspensions,pharmaceutical co-crystals andcombination-based products (Figure 2).SAX allows production of sphericalparticles, with a well-defined size rangeand with control of the macroscopicmorphology, including polymorphismand surface topology. These propertiesare invaluable in defining aerodynamicproperties of particles, shelf life,stability, bioavailability and efficacy.

Combination particles

Combination particles are singleparticles containing two or more APIsor API and excipient such as lactose.These particles should have a highdegree of crystallinity with respect toboth ingredients. Often the two drugshave synergistic action (at molecularand cellular level) and need to bedelivered in an exact ratio such as ininhaled corticosteroid (ICS) and Long-Acting Beta-Agonist (LABA)formulations (Figure 2). For optimalinteraction the two drugs must bedelivered to the same site of action inadequate doses, since the synergisticaction may be reduced with variableICS and LABA doses.

SAX introduces the potential for a novelparticle engineering solution wherebya single droplet containing the twoAPIs in an exact ratio can be convertedto a particle containing the very samedrug substances as separate crystallineentities. Indeed triple therapy shouldbe possible with SAX.

Future for sonocrystallisation

Power ultrasound can be applied tocrystallisation at manufacturing scaleand now in technologies to producemicron-sized particles for druginhalation. Sonocrystallisation can

become a core technology in thepharmaceutical industry and we canexpect to see many more industrialapplications in the near future.Processing techniques such as SAXshould become superior technology forthe manufacture of microcrystallinedrug substances, complex APIs,combination particles, andnanosuspensions leading to significantbenefits to drug innovator, technologyprovider and, importantly, the patient.

References1. Clarke J. Conference proceedings. Resp Drug

Delivery X, 2006; Florida 2006.2. Rabinow BE. Nature Reviews, Drug Discovery

2004; September: 785–794.3. Price R, Kaerger JS. World Patent

2004/0738274. Kaerger JS, Price R, J Pharmaceut Res 2004;

21(2): 372–381.5. Ruecroft G, Hipkiss D, Ly T, et al. J Org Proc

Res Dev. 2005; 9: 923–932.6. Perkins JP. World Patent 2000/35579.

This article is based on aPharmaVentures Drug Delivery Report,with kind permission of the publishers.

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Figure 2. SAX particles of budesonidex7,000 (top) and ICS/LABA combinationparticles x5,000 (bottom).

WEB 2.0 – WHAT DOESIT MEAN TO THEPHARMACEUTICALINDUSTRY?by Marta Garrido

We are bombarded with information about Web 2.0 and how tobenefit from this influx of digital marketing in the coming years.

What does it really mean? We have moved from a straight based Web1.0 linear marketing paradigm, where information is presented to theclient without any thought to the individual’s need, to a world of socialcommunication. This shift has paved the way for increased interactivitybetween businesses and consumers1. The information age has movedfrom a static model to one in which data are dynamically presented.Interactive technology has moved beyond the browser.

patient. A video clip about a product isnot going to generate return visits ordevelop loyalty to a brand. It may answera momentary question but ideally,patients would like information tailoredto newly prescribed drugs, their ownsymptoms and side effects. The newtechnology of Web 2.0 provides theopportunity of interactive communicationwith the patient, provided that patient’sinformation is kept secure and private,and the patient is aware of how his/herpersonal information is being used.

Pharmaceutical e-marketing can enhancehealth by alerting specific populations toproblems and solutions. This particularmode answers the question of “who issick?” and matches the information to theparticular segment being targeted, suchas individuals with diabetes, Parkinson’sdisease, or other disease-specific group. Itcan augment patients’ compliance, bysending out personal messages, such asRSS (Rich Site Summary) to remind themto take their medications, or to keepappointments. These instant feeds can berouted to computers, ipods, mobiles,and/or telephones. Put simply, an RSS is aweb feed, like Email or similar to amailing list. You can get informationstraight to your desktop. You choose theinformation that you want and you canread it in your own time. The consumersigns up with individual sites to receiveinformation of relevance to their lives.

Pharmaceutical marketing is still behindwhen it comes to taking advantage ofnew interactive technology because itcontinues to function in the areas it hasalways used, such as print and television.Using the web as a means ofdisseminating information creates a lifeof its own. For example, clinical trialinformation which, if positionedappropriately, can enhance credibility,information sharing and positiveoutcomes. The industry can use web-based applications for efficiently andeffectively communicating with criticalaudiences such as thought leaders,speakers, advisers, and investigators. Theweb can become a living market research.

Maintaining credibility

The challenges facing the industry lie inusing the new interactive technologywhile maintaining credibility, and

DR MARTA GARRIDO isCo-director of MeritPublishing International

E: [email protected]


Web 2.0 facilitates communicationbetween two universes. It fills the humanneed to connect, share information andsupport over the internet2. An individualdoes not need to leave his/her home inorder to have meaningfulcommunications with Email buddies,colleagues, and like-minded individuals.Nowadays, consumers are well-informed.They seek information through theinternet, family doctors and friends.Patients seek not only support but oftensecond opinions through web sites.

By the year 2011, pharmaceuticalcompanies’ online spending will reach$2.2 billion but is this budgetaryexpenditure benefiting the bottom line?How can a regulated industry participatein a deconstructed environment? First, itmust look at Web 2.0 as more than asocial medium with open-endedparameters. The wisdom of the crowd inthis new social networking must beclosely monitored. Pharma must complywith regulations and codes of practice,which spell out what it can and cannotdo. According to Amber Link, theprinciples inherent in the codes ofpractice remain the same regardless ofthe medium used3.

Consumers now want fast, efficient accessto information that can answer theirquestions. What often happens is thatwhen a patient logs into a company’sweb page, the information presented isstagnant and does not relate to the

adhering to the differentparameters of the various codes ofpractice. It must do this whileenhancing its image as patients’advocates, and reducing the public’sview of controlling attitudes anddata management to enhancerevenues at the expense ofconsumers’ health. While the socialmedia of the web can effectivelyenhance the industry’s image, it stillis an uncontrolled medium. The‘wisdom of the crowds’ can end asnot wisdom at all. Inaccurateinformation can be generated andswiftly spread like wildfire throughthe web. It must be closelymonitored and regulated perhapsby a neutral third-party, thereforelimiting liability to thepharmaceutical company.

Social media

Conversely, social media can be anunknown quagmire for thepharmaceutical industry and carefulscrutiny and vigilance are requiredto stay abreast of regulatory codesand avoid potential problems.

One example is Blogs, which caneither be beneficial or detrimentalto the industry. If a companyundertakes blogging, it has to beopen to the opinions of others,which can be both good and bad.Also, there is the possibility ofpatients reporting adverse reactions,and pharma has to be ready inadvance to deal with theseeventualities.

Podcasts, which can be customisedto specific conditions, can addtremendous impact to e-marketingcampaigns. Podcasts are maintainedon a regular basis to keep them on

the cutting age of new developmentin a particular field. YouTube alsoprovides an opportunity to reachthe public with information relayedwithin a real setting. Using real-lifepatients speaking about positiveexperiences can do for a brand whata leaflet will never accomplished.

companies’ marketing strategies andhow they affect their bottom line.Web 2.0 has levelled the playingfield and it can be seen as beingagainst pharma’s controllingattitudes and data management.The Pharma industry has torecognise the influence of theconnected consumer. Millions arelinked in a worldwide network andthese consumers have becomesimilar to KOLs (key opinion leaders)within the lay community. Socialcomputing is growing exponentiallyand it cannot be ignored.

Social media has empoweredpatients by giving them anopportunity to voice opinions andexperiences and consequently learnfrom one another. The era of non-transparency and keepinginformation from the consumers ispast. Patients’ forces will impacthealthcare policies worldwide andthey will have to be heeded andharnessed.

Now it is time for thepharmaceutical industry to askwhether it can meet the challengeof social media and take thisopportunity to answer patients’needs and offer sophisticatededucational and behaviouralsupport, tailored to the individual.By doing so, the industry couldregain public trust, improve healthoutcomes and in the process, seetheir ROI soar.

References

1. Akami Technologies, White Paper on TheEvolution of Web 2.0.

2. Heather Simmonds, PharmaceuticalMarketing Magazine, 2008; 20(3): 24–26

3. Link A. Online Technology. September 26,2007. Cadient Group, PA, USA.


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The Pharma Industry hasto recognise the influenceof the connectedconsumer.

FAQs can be a useful tool wherepatients can actually send inpersonal questions and have themanswered by a clinician on the web.An off-shoot of FAQ sites, patient-generated health journals are onthe horizon, such as the recentlylaunched ‘Knol’ by Google. Knols arelay-person orientated, authors areidentified and their identitieschecked. The initial Knol on the webis on health issues and consumerscan find information written aboutanything from migraine headachesto shingles. Also available is‘Trusera’, an online health networkwith real health stories by realpeople. Additionally, Caring.comprovides help and checklists forthose caring for elderly parents.

The new consumer

As a result of this amazing influx ofinformation and interactivetechnology, there is a new breed ofconsumers on the receiving end ofthe marketing landscape. Today’sconsumer is hungry for informationand fully understands the various



MANAGEMENT ANDREVISION OFDOCUMENTATIONby Michael Hiob

All pharmaceutical and biopharmaceutical companiesdepend on documentation systems as a major part of

GMP compliance. In this article, we take a look at a typicalsystem for organisation of documentation. We also review atypical documentation life cycle and considerations to betaken at each stage.

Organisation

In order to administer the vast number ofdocuments in a pharmaceutical company,a hierarchical structuring of thedocument system in three levels (seeFigure 1) is useful.

Strategic level

Documents at this level describe cross-company objectives. Typical examples arethe quality management policy and thequality management handbook.

The highest level of companymanagement determines this procedureitself and also authorises it.

Operational, cross-companylevel

The quality policy defined at the highestlevel should be applied across thecompany in the form of (standard)process instructions. Therefore,documents at this level apply to all

departments, or across the company, andare generally not product-related.However, they already include thedetailed provisions required in order toimplement the objectives defined indocuments at the strategic level.

Detailed level

This level contains detailed provisionssuch as manufacturing instructions, testprocedures or sanitation programmes forspecific products, procedures or areas.These are compiled on-site on the basisof higher-level instructions (eg. procedurefor the compilation of instructions).

Life cycle

As is the case with facilities, equipment orprocedures, documents must also beadapted to accommodate changingoperational, scientific and regulatoryrequirements. A document will passthrough a number of typical stages in itslife cycle (see Figure 2) that reflect itscurrent status. The document should behandled at each stage in accordance withestablished requirements to ensure that itis suitable for its intended purpose.

Compilation and changes

New documents should only be compiledand existing documents should only bechanged by the person who deals inpractice with the provisions in thedocument and is familiar with theprocedure concerned.

Analysis

Once the above has been carried out, theform and content of the documentshould be analysed. The formal analysisto verify compliance with theorganisational and format requirementscan be carried out by the qualityassurance department. The technicalcheck should be carried outindependently of the compiler by aperson who has the appropriate technicalknowledge and experience to evaluatethe provisions set out by the compiler.

Implementation

GMP-relevant documents must beformally approved before use. Thisapproval should be carried out by theperson who is responsible for the area

MICHAEL HIOB, PhD isDirector, Ministry ofHealth, Social Affairs,Kiel, Germany


Strategiclevel

QA instruction manual

Operational,cross-company level

(Standard) operating procedures

Detailed leveleg. manufacturing instructions and test procedures,

sanitation programmes, operating instructions

Figure 1. Organisation of a documentation system

regulated by the document –examples being the head ofproduction or the head of qualitycontrol. The start and end of thedocument's period of validity mustbe defined independently of theapproval. Where no specificationsare made in this regard, thedocument's period of validity isunlimited and begins automaticallyon the day it isimplemented/approved.

Training

In order to be able to implementthe contents of the documents, therelevant staff must know,understand and also be able toapply them. These requirementsmust be acknowledged by signature.Managers must check whethertraining in the handling of thedocument is required and, if so,arrange for this to be carried out.

Use

The document should be availableon-site for the duration of itsvalidity. This may be achieved byusing a hardcopy or providingauthorised access to a

corresponding file in a computersystem. Provisions should exist thatspecify whether personal workingcopies may be made and passed onto third parties, if required. Theprocedure used for the distributionof new versions must be defined.

Inspection

Checks should be carried out withinthe scope of self-inspections todetermine whether the documents


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Figure 2. Life cycle of a document

Compilationand changes

Analysis

Implemen-tation

TrainingUse

Inspection

Archive

Invalidation

are being complied with andwhether their contents are still up-to-date and suitable.

Invalidation

Documents that become invalid mustbe withdrawn from current operationsby means of a regulated procedure inorder to prevent unintentional use ofnon-valid documents.

Archiving

The national regulations apply forthe storage of documents once theyhave been used.

Implementation

In addition to requirements inrelation to documents, specificprerequisites must also be fulfilled bystaff to ensure that the documentsare actually “lived out” – ie. compliedwith and implemented. Staff mustnot only know and understand theprovisions laid down in thedocuments, it is also extremelyimportant that they are prepared toimplement these and that therequired general operating conditions(organisation, resources) exist.

This article is based on excerpts fromthe GMP Manual, a comprehensivereference book published by Maas &Peither AG Publishing, www.gmp-publishing. com.

NEWS FROM EFPIAInnovative MedicinesInitiative

Funds of 246 million euros will bemade available through a jointinitiative of the EC and EFPIA tosupport public-private research co-operation for the fast developmentof better medicines.

The projects will involve healthissues such as diabetes, pain, severeasthma and psychiatric disorders,while increasing drug safety.www.efpia.org/content/default.asp?

EFPIA launches anti-counterfeiting pilotproject in Sweden

Pharmacists in Sweden will check aunique identification code onindividual packs as an anti-counterfeiting measure. The codeswill be generated and applied bymanufacturers as a barcode thatpharmacists will be able to scan andcheck when the product isdispensed.www.efpia.org/content/default.asp?


NEWS FROM THE EIPGLacamoire (France). Two new sectionswill be added and the finaldocument published on the EIPGwebsite in October.

European Industrial Pharmacy, theEIPG Journal was successfullylaunched and feedback on the firsttwo published issues was presentedby the editor, Joe Ridge.

The President of EAFP, JeffreyAtkinson (France) led a discussion onWorking Party 5 (pharmacists inindustry) of PHARMINE, the EULifelong Learning Programme. At thenext General Assembly, Greece willlead on a brain-storming session ofthe employment opportunitiesavailable for pharmacists in thefuture pharmaceutical industry.

Several country initiatives werereviewed at the meeting, including aBelgian document submitted to theirAgency on the Guidance on GMPrequirements in Phase 1 andexploratory clinical trials. Previously,it had been agreed that this shouldbe “Europeanised” and a group ofdelegations will provide further inputto Philippe Van der Hofstadt.

Harold Smeenge (Netherlands)agreed to take the lead in developingcontacts with the EuropeanPharmacy Students Association (EPSA)that had been initiated by Denmarkover the past 12 months. A Belgiumrepresentative of EIPG attended theEPSA Annual Congress in April, inReims (his report is below).

Piero Iamartino issued an invitationfrom Associazione Farmaceuticidell’Industria (AFI) to hold the 2010General Assembly in Italy and thiswas agreed with acclamation. A voteof thanks was made to IntaSaprovka, Berlin-Chemie and allmembers of the IPS of thePharmacists Society of Latvia, whohelped organise the meeting andprovided generous hospitality.

Jane NicholsonExecutive Director EIPG

Report on the EPSASymposium

I was invited by Philippe Van derHofstadt to represent EIPG at theEPSA Symposium on 21 April. TheSymposium’s topic was “Informationto the Patient” and, at first Iwondered how industry could beinvolved in information to patients –typically a matter for communitypharmacists, regulators andconsumer associations. But, from myown experience in industry, I quicklyrealised that pharmacists working inthe industry may have to deal withinformation to patients at severalstages of the development andproduction of medicinal products.My abstract paper emphasised thosevarious functions and the influencethey have on such information.Starting with Regulatory Affairs, Imoved to Medical Information,linking this to Marketing andRegulations on promotion andended with Manufacturing and theneed to have compliant packaginginformation.

During the Symposium and thepanel discussion, it was clear thatmost of the students were not awareof the role an industrial pharmacistmay have concerning patientinformation. The other panelmembers (Mr Rothert (DG Enterprise),Mrs Dr Moulon (EMEA), Mr Parrot(Association des PharmaciensFrançais) and Mr Tromp (EuroPharmForum) explained the links betweenthe various stakeholders the patients,the Regulators, the communitypharmacists and the pharmaceuticalindustry. I drew the studentsattention to the fact that pharmacistshave an optimal education tointerface and integrate that process.Pharmacists’ role in medicalinformation clearly goes further thanjust information to patients.

Roland Schots

2009 General Assembly ofEIPG in Riga, Latvia

The 2009 General Assembly of theEIPG was held in Riga on the 18thand 19th April. During the meeting,the Association for IndustrialPharmacists of the Hungarian Societyfor Pharmaceutical Sciences waswelcomed as a new member of theEIPG. Dr Sylvia Marton and EmokeKiss-Csikos were congratulated ontheir persistent and successfulnegotiations to achieve the resultingmembership.

The Italian delegation, representedby Piero Iamartino, was elected asVice-President of EIPG for the next 3years.

Representatives from sister EuropeanAssociations, PGEU (communitypharmacists), AEHP (hospitalpharmacists) and EAFP (colleges ofpharmacy) attended our meeting asobservers.

A report by John Jolley (Great Britain)of the EMEA meeting with “interestedparties” demonstrated a largenumber of pending GMP relatedissues. Although legislation, includingAnnex 16, is still to be updated andthe QP discretionary powers remainunder discussion in Brussels, it wasagreed that the updated EIPG Codeof Practice for Qualified Personsshould be issued subject to furtheramendments in line with newregulations.

A discussion of the threat fromcounterfeit medicines was led byClaude Farrugia (Malta). Furtherrepresentation to the EuropeanCommission concerning theresponsible pharmacist and draftEIPG Guidelines on Good DistributionPractice of Medicinal Products wereagreed.

A working group considered a draftdocument on ContinuingProfessional Development forRegulatory Affairs prepared byregulatory staff in Germany andGreat Britain, and chaired by Valérie


The past quarter has been relativelyquiet regarding regulatorydevelopments that affect thepharmaceutical industry.

Thus the items covered in this issueare limited to the following:

� New Quality related Q&A fromthe EMEA.

� New guidance on justifying theuse endotoxin testing of plasmaderived products.

� Draft Guidance from the FDA ondata requirements for injectorpens and similar devices.

� New Q&A on the implementationof ICH Q8, Q9, and Q10.

Europe

The European Medicines Agency(EMEA)

New questions and answers on stabilitytesting

The EMEA’s Quality Working Partyhas added two new items to its listof Q&As.

These are pretty straightforwardquestions concerning endotoxintesting and sterility testing at theend of the shelf-life period (duringstability studies).

You can find this new informationunder the heading “Stability” in theQuality Working Party’s Q&A pageson the EMEA’s website.

Guideline on the replacement of rabbitpyrogen testing of plasma derivedproducts

This document sets out the points toconsider in justifying (in marketingauthorisation submissions) the useof a test for bacterial endotoxins asan alternative to the rabbit pyrogentest for plasma derived products.

It covers:

� The scope and legal basis of theguidance.

REGULATORY REVIEW:Review of major developments in GMP and the regulationof medicines in the EU and on the International Scene,September to December 2008

by Steve Fairchild

� The limitations of the LAL test.

� Process related and clinicalconsiderations.

� Regulatory issues.

� Alternative test methods

To see this new guideline go to theEMEA website under CHMP.

It is due to come into effect onNovember 1st 2009.

United States of America

The US Food and DrugAdministration (FDA)

Draft guidance on pen, jet and relatedinjectors

The FDA has recently issued the draftversion of a document intended toprovide points to consider indeveloping technical and scientificinformation to support a marketingapplication for pen, jet or relatedinjector devices intended for use withdrugs or biological products.

This draft document covers injectorssupplied alone and products combiningthe injector and the drug dosage form.

It can be seen on the FDA websiteunder “Draft Guidance for Industryand FDA Staff”.

Comments can be submitted [email protected]. until July27th 2009.

International

International Conference onHarmonisation (ICH)

New questions and answers on theimplementation of ICH qualityguidelines Q8, Q9 and Q10.

Towards the end of 2007 the ICH setup a working group to facilitate theimplementation of its qualityguidelines on:

� Pharmaceutical development (Q8),

� Quality risk management (Q9) and

� Pharmaceutical quality systems(Q10).

This group recently published a setof answers to frequently askedquestions on the implementation ofthese guidelines by pharmaceuticalcompanies and drug regulatoryauthorities (DRA).

These Q&As cover the following topics:

� The need to have a defined “DesignSpace” or implement “Real TimeRelease” testing in order to implement“Quality by Design “(“QbD”).

� The development and use of“Design Space” in relation to themanufacture of a medicine.

� The operation of “Real-TimeRelease Testing”.

� Control Strategies and GMPrequirements for “QbD” products.

� The relationship between “DesignSpace” and “QbD”.

� The benefits of a“Pharmaceutical Quality System”in accordance with ICH Q10, itsoperation and relevance toregulatory activities.

� The impact of ICH Q10 on(regulatory) GMP inspection practices.

� The impact of ICH Q8, 9 and 10on “Knowledge Management”.

� The relevance of specific softwaresolutions to the implementationof ICH Q8, Q9 and Q10.

These Q&As provide usefulinformation on the implementationof these guidelines. They can beseen by going to the ICH websiteunder “Quality ImplementationWorking Group on Q8, Q9 and Q10”.

Steve Fairchild is a PharmaceuticalConsultant and an ExecutiveDirector of IAGT Ltd. Email: [email protected]

For a list of useful website addressesassociated with “Regulatory Review”go to www.industrialpharmacy.eu


JJUUNNEE

22-25 June 2009 – Cork, IrelandActive pharmaceutical ingredientswww.DBA-global.com

30 June-1 July 2009 – London, UKSupply chain assurancewww.DBA-global.com

JJUULLYY

1 July 2009 – London, UK6th Eudra vigilance information daywww.diahome.org

2-3 July 2009 – London, UKEU pharmaceutical regulations –for the pharmaceutical andbiotechnology industrieswww.management-forum.co.uk

6 July 2009 – London, UKThe contract QPwww.management-forum.co.uk

8-10 July 2009 – Edinburgh, UKBritish Pharmacological Society (BPS)Summer Meetingwww.bps.ac.uk

18-22 July 2009 – Copenhagen,Denmark36th Annual Meeting and Expositionof the Controlled Release Societywww.controlledreleasesociety.org

29-31 July 2009 – Bonn, GermanyPhytopharm 2009www.adaptogen.ru

AAUUGGUUSSTT

2-7 August 2009 – Glasgow, UK42nd IUPAC Congress – Qualityassurance of medicines and detectionof counterfeits www.jpag.org

3-7 August 2009 – Vienna, Austria11th International Congress on aminoacids, peptides and proteinswww.meduniwein.ac.at

SSEEPPTTEEMMBBEERR

2-9 September 2009 – Manchester, UKscience@BPC 2009: Technologies forhealthcarewww.bpc2009.org

3-8 September 2009 – Istanbul, TurkeyFIP 2009 – Responsibility for patientoutcomes – are you ready?email: [email protected]/istanbul2009

7-9 September 2009 – Manchester, UKThe British PharmaceuticalConference – Technologies forhealthcarewww.bpc2009.org

7-11 September 2009 – Manchester, UKAuditor/lead auditor forpharmaceutical QA, IT andengineering personnel (3 differentcourses)www.iagtgroup.com

8-9 September 2009 – Munich, GermanyIntroduction to QuantitativePharmacology and PK/PD for DrugDiscovery & Development Scientistswww.lakemedelsakademin.se

15-18 September 2009 – London, UKWorld Drug Safety Congress Europe2009www.healthnetworkcommunications.com

16-18 September 2009 – WashingtonDC, USAPDA/FDA Joint regulatory conference:Securing the future of medicalproduct qualitywww.pda.org

17-19 September 2009 – Stockholm,SwedenRosenšn Meeting 2009: DMPK aspectsof drug combinationswww.swepharm.se

21-24 September 2009 – Manchester, UKPharmaceutical GMPwww.DBA-global.com

21-25 September 2009 – Sheffield, UKHands-on Workshops on concepts andapplications of population based invitro-in vivo extrapolation of ADMEpropertieswww.simcyp.com

21-25 September 2009 – Bath, UKFundamentals of GMP – a practicalapproachwww.phss.co.uk

24 September 2009 – London, UKRecent developments in woundmanagement: intelligent biomaterialsto novel antimicrobialswww.rpsgb.org

27 September-1 October 2009 – Rovinj,Croatia1st World Conference on physico-chemical methods in drug discoveryand developmentwww.iapchem.org

28-30 September 2009 – London, UKPractical aspects of controlledtemperature storage and distributionwww.DBA-global.com

28-30 September 2009 – Manchester, UKHuman error: causes and preventionwww.DBA-global.com

30 September-1 October 2009 – Berlin,GermanyModern concepts in pharmaceuticalprofiling and pre-formulation – fromcompound screening to candidateselectionwww.apv-mainz.de

OOCCTTOOBBEERR

1 October 2009 – London, UKAnti-counterfeiting measures:implications for quality professionalsand QPswww.DBA-global.com

5 October 2009 – London, USAInternational conference onpharmacokinetics: spearheadingadvances and delivering the sciencewww.eufeps.org

5-8 October 2009 – Bethesda, MD, USAPDA’s 4th Annual Global Conferenceon pharmaceutical microbiologywww.pda.org

12-13 October 2009 – London, UKFIP Quality International 2009 –managing quality across the drugsupply chain: from product inceptionto patient utilizationwww.rpsgb.org

15 October 2009 – London, UKAnalysis of inhaled productswww.rpsgb.org

25-29 October 2009 – Barcelona, SpainThe 16th intermediate workshop onPK/PD data analysiswww.lakemedelsakademin.se

26-28 October 2009 – Antalya, Turkey3rd BBBB Conference onPharmaceutical Scienceswww.bbbb-eufeps.org

DATES FOR YOUR DIARY

european industrial pharmacy issue 3 (june 2009)

Documents

superior particles

michiel storimansportugal

thevoluntary topra

pr tellnerswitzerland

compulsory rpsgb scheme

topra schemesthe author

shaped dosage formsneeds

merc pujol sweden