european Industrial Pharmacy Issue 10 (September 2011)

europeanINDUSTRIALPHARMACY

ISSUE 10 • SEPTEMBER 2011www.industrialpharmacy.eu

www.eipg.eu

FEATURES4 WICKED PROBLEMS

The technique of General Morphological Analysis provides a virtualmodel for complex, apparently insoluble “wicked problems” that arenormally difficult to define and structure.by Nassir Hussain and Tom Ritchey

8 TOWARDS A EUROPEAN PATENT LITIGATIONSOLUTIONIntellectual property protection is now harmonised throughout most ofEurope but there is still disagreement in setting up a central court todeal with infringements.by Gareth Williams and Graham Burnett-Hall

11 ACHIEVINGCLEANLINESS INMEDICALENGINEERINGModern cleaning processes for medical instruments, devices andimplants are described and discussed.by Doris Schulz

14 THE CHALLENGES OF BACTERIOPHAGE THERAPYBacteriophages should now be considered as possible alternatives toantibiotics providing that technical and non-technical problems can beovercome.by Alexander Sulakvelidze

19 INNOVATION – SCIENCE OR ART?Willingness to Innovate is a key factor in the development of asuccessful drug discovery unit.by Robert Bates and Anna Bruns

REGULARS3 EDITORIAL COMMENT

21 BOOK REVIEWS

23 REGULATORY REVIEW

24 PHARMACEUTICAL FORUM

26 NEWS FROM THE EIPG

27 EVENTS

europeanIINNDDUUSSTTRRIIAALLPHARMACYIssue 10 September 2011

ISSN 1759-202X

EDITORJoe Ridge, MRPharmS

PRODUCTIONDave Johnson

SUBSCRIPTIONSJill Monk

EDITORIAL BOARDMichael AnisfeldMichael Gamlen

Linda HakesJohn Jolley

European Industrial Pharmacy is published four times a year by:

Euromed Communications LtdPassfield Business Centre,

Lynchborough Road, Passfield,Liphook, Hampshire GU30 7SB

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

Email:[email protected]

www.industrialpharmacy.euAnnual subscription rate £65

Views expressed in European IndustrialPharmacy are those of the contributors andnot necessarily endorsed by the Publisher,Editor, Editorial Board, or by our corporate

sponsors who accept no liability for theconsequences of any inaccurate or

misleading information

©2011 Euromed Communications Ltd

Belgium: Kristina Bindus, Bart de Greef

Bulgaria: Valentina Belcheva

Czech Republic: Ales Franc

Denmark: Marie Fog

Finland: Anni Svala

France: Jean-Pierre Paccioni

Germany: Armin Hoffmann

Great Britain: Shilpa Gohil

Greece: Margarita Efthymiopoulou

Hungary: Georgina Gal

Ireland: Anna O’Mahony

Italy: Piero Iamartino

Latvia: Inta Saprovska

Malta: Claude Farrugia

Netherlands: Florentine Nieuwmeyer

Portugal: Luis Baiao, Sofia Guimas

Spain: Emma Fernández

Sweden: Pär Tellner

Switzerland: Stephan Buchmann, Valter Gianesello

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 photo: Canulas cleaned by theCO2 snow jet process (see page 13)

eeuurrooppeeaann IINNDDUUSSTTRRIIAALL PHARMACY • Issue 10 September 20112

EDITORIAL COMMENT

gmp-review newsfree news service for gmp revıew subscribersMonthly news service will keep you up-to-date on new developments

in GMP and associated regulations. gmp-review news will be sent by email only to current gmp revıew subscribers.

Subscribers should contact [email protected] to register

Dear Colleagues

This editorial is slightly different inthat I will be writing this editorialno longer as a pure IndustrialPharmacist but as an Academic, inmy case as Professor ofPharmaceutical Innovation at King'sCollege London. I will be the firstexample of an Industrial-Teachingpractitioner in the UK. It is perhapssynchronicity occurring but thisedition of the journal covers a bookreview I composed on 'The Futureof Pharma' written by ProfessorBrian D Smith who is a formerIndustrial Chemist but now aleading Academic at the OUBS andSDA Boccini and consultant adviserfor a number of corporations.

Perhaps it was findings in ProfessorSmith's research which spurred thischange in direction for me, whoknows? But what is known is thatinnovation or productivity withinthe Pharma sector is at an all timelow! In very simple terms thePharma Industry is only about two-thirds as productive as it once was,when measured in new drugapprovals.

It is clear when you read ProfessorSmith's book or at least my reviewand, from your personalexperiences in your own company,that Pharma is going through

change. We all know this but it isthe RATE OF CHANGE which isunprecedented and we are nowseeing companies undertake variousdefensive strategies or businessmodels in order to overcome theproductivity gap.

In the UK, the Government is keento forge closer links betweenAcademia and Industry and are inthe progress of establishingTechnology Innovation Centres(TICs) in order to jump-startinnovation and creativity. This TICmodel is based upon the Germanmodel of the Fraunhofer Instituteswhere there is great emphasis onapplied research in order totranslate ideas from paper toproduct.

What relevance is this to IndustrialPharmacy you may ask? Well, myview is that there will be a widevariety of business models inoperation which will require amulti-skilled workforce in order todeliver new medicines or noveltherapies/healthcare programmes.Clearly, Pharmacists with theirmulti-disciplinary background andtraining, can and should play activeroles in the Future of Pharma.

Thus, it is imperative thatAssociations such as the EIPG, FIPand the various national

associations continue to worktogether to encourage morePharmacists to enter Industry andalso to provide mentoring andcareer advice to experiencedPharmacists on opportunities fordevelopment and to 'think outsidethe box'.

Providing mentoring and careeradvice to Industrial Pharmacists andPharmacists in general will be mymain focus as I enter my last 24months as President of EIPG.

Without a succession plan we arenothing!

Please enjoy the current edition ofthe Journal and please do nothesitate to contact me or contactthe EIPG on www.eipg.eu. We lookforward to hearing from you.

Best wishes

Dr Gino Martini FRPharmsEIPG President

eeuurrooppeeaann IINNDDUUSSTTRRIIAALL PHARMACY • Issue 10 September 2011 3

Nasir Hussain, PhD andTom Ritchey, PhD are FoundingPartners of Strategy Foresight,London, UK.email:[email protected]


Analysing such complex socio-technicalsystems presents a number of problems.Firstly, many of the variables involvedare not readily quantifiable, containingstrong social, political and cognitivedimensions. Secondly, the uncertaintiesinherent in complex problems are inprinciple non-reducible, and oftencannot be fully described or delineated.

Compounding this is the extremeconnectivity of socio-technical systemsthat results in elements within theproblem complex being inextricablylinked to each other. What might seem tobe the most marginal of factors can,under the right circumstances, becomean overwhelming force of change (the so-called butterfly effect). In short,traditional quantitative methods,mathematical modelling and simulationsimply do not suffice to tackle suchcomplex issues which have been termed‘wicked problems’.

Wicked problems

Relatively unknown in thepharmaceutical sector, the term ‘wickedproblem’ is transdisciplinary, citedprincipally in public planning, policyformulation and socio-political arenas. Itdescribes a state of extreme complexitydefined by criteria listed in TTaabbllee 11.

Although sounding a touch comical,wicked problems are neither ‘evil’ in thetraditional sense, or indeed even‘problems’ as no stable problemstatements have actually been defined.For this reason, Russell Ackoff in hisbook ‘Redesigning the Future’ used theequivalent term unstructured reality todescribe such ‘social messes’. Morerecently, the uncertainties embeddedwithin such conundrums have been(in)famously termed ‘unknownunknowns’ and the unintendedconsequences of ill-thought outdecisions highlighted in theFreakonomics series of publications.

In short, wicked problems are ill-defined,ambiguous, and associated with strongmoral, political and professional issues.

As they are strongly stakeholderdependent, there is often little consensusabout what the problem is, let alone howto resolve it. Examples in the healthcaresector include end-of-life decisions,assessing the cost-benefit ratio for newdrug approvals, the difficulty ofintegrating vast amount of disparate datainto any meaningful outcome and thetypes of emerging business models forthe pharmaceutical-governmental-privatepayer complex.

As an alternative to mathematicalmodelling and other ‘hard’ operationalresearch methods, a number of non-quantified problem structuring methods(PSMs) have been developed during thepast 40 years. One such method,Morphological Analysis, enables multi-dimensional problems to be analysed,structured and displayed in twodimensions.

Modelling wicked problemswith morphological analysis

The kneejerk reaction that often befallsregulators, senior executives andpoliticians in tackling complex issues ismost aptly summed up by Michael Pidd:

WICKED PROBLEMSAchieving clarity in complex pharmaceuticalproblems: from innovation to policy formulation

by Nasir Hussain and Tom Ritchey

In pharmaceutical and healthcare planning sectors, amodelling environment must interrelate diverse issuessuch as technology development, national policy directives,organisational structure, public perception, ethical issuesand educational requirements. Furthermore, it should beable to take account of global forces shaping healthcareand novel emergent business models.

Table 1: The five principal criteria of a wicked problem as proposed by Rittel andWebber (1973).

Continually developing and mutating (no stable problem statement)Full of ambiguities, contradictions and circular causalityStrongly stakeholder orientatedAssociated with strong political, moral and professional issuesReactive: the problem complex fights back


“one of the greatest mistakes thatcan be made when dealing with amess is to carve of off part of themess, treat it as a problem and thensolve it as a puzzle – ignoring itslink with other aspects of the mess.”And while one is busy solving thepuzzle, the mess is still mutating –retrofitting the solution to thepuzzle merely puts it into anotherstate of flux. PSMs engagestakeholders of the wicked problemexpressly at the level of the mess –this requires experiencedindependent facilitation to map theboundary conditions of theproblem complex, as well asmanaging strongly held opinionsand beliefs of the participants.

When dealing with complexplanning problems, PSMs such asMorphological Analysis offer anumber of distinct advantages.PSMs must be able to:

� Accommodate multiplealternative perspectives to dealwith uncertainties

� Facilitate a process of collectivecreativity amongst thestakeholders to develop sharedconcepts, terminology and

ownership of the problemformulation

� Generate, in real time, a visualrepresentation of the problemspace for the systematic andtransparent group exploration ofa solution space

� Focus on relationships betweendiscrete alternatives

� Concentrate on possibility ratherthan probability.

Morphological analysis is fullyattuned to meeting these criteria asit is an objective method forstructuring and analysing wickedproblems that are naturally non-quantifiable, contain ineradicableuncertainties and cannot be causallysimulated or modelled in ameaningful way.

Computerised in the mid-90s,Morphological Analysis made itpossible to create non-quantifiedmulti-dimensional inference modelsthat endeavoured to represent thetotal problem space, and as many ofthe potential solutions as possible.This, in itself, went a long way insatisfying the first – seeminglyincredible – criterion concerningwicked problems: ‘in order to

describe a wicked problem insufficient detail, one has to developan exhaustive inventory for all theconceivable solutions” ahead of time.

In complex, dynamic, planningproblems, the concern is with formover function i.e. forming thehyperspace, the extreme boundaryconditions to encompass thepossibilities (and even absurdities)before developing any strategies.These possibilities arise from theinteraction of the various stateswithin multiple dimensions – athree dimensional typologicalconstruction and its equivalentmorphological field is shown inFFiigguurree 11. Typologies of greaterdimensions can be represented byplacing the dimensions as columnsbeside each other as shown inFFiigguurree 22. In 1995, the SwedishDefence Research Agencydeveloped a dedicated, highlyflexible, workshop orientatedcomputer support forMorphological Analysis that couldincorporate multiple dimensionsand millions of constructedconfigurations. What tookresearchers months to constructand model can now be done in

WWIICCKKEEDD PPRROOBBLLEEMMSS ((CCoonntt..))

FFiigguurree 11:: Visually, a typology uses the (Cartesian)dimensions of a physical space to represent itsdimensions – however this ends at three (a). Extradimensions can be embedded as hyperspaces butvisually this is not particularly appealing, prone toerrors and merely adds another layer of complexityto an already complex situation. The equivalent 3Dtypological format can easily be represented as 3-columnar morphological table (b).

a)

b)

P(1) P(2) P(3)

P11 P21 P31

P12 P22 P32

P13 P23 P33

P14 P24

P15 P25


matter of few days provided thatfacilitated, interactive groupworkshops are conducted.

Morphological analysis forthe pharmaceutical andhealthcare sectors

PSMs are uniquely equipped tomodel complexities anduncertainties that healthcareprofessionals, scientists andadministrators face in healthcaresystems planning, policyformulation and regulatory issues.FFiigguurree 22 displays an 8-dimensionalmorphological field developed forthe Swedish National RescueServices for dealing with chemicalaccidents. This relatively smallproblem space of 57,600 possibleconfigurations (fields of up to 105 to106 configurations are frequentlyencountered) is an example of aninput-output inference model that

can be adapted for a variety ofsituations e.g. dealing with drugrecalls, drug interactions, andQuality by Design issues.

To give decision support, the groupmust be facilitated to conduct aCross Consistency Assessment,which is a pairwise comparison ofevery pair in the multi-dimensionalfield as shown in FFiigguurree 33.Analytical, empirical andoccasionally normative“contradictions” between any twostates results in the removal of anyand all “strings” that contain thatcontradiction: the example shownin FFiigguurree 22 displays a configurationthat is entirely internally consistenti.e. every pair can co-exist asdetermined by the working group.This reduces the entire problemspace to a workable solution ordesign space – up to 99% of the

configurations in the problem spacecan be removed to yield aninteractive inference model inwhich any dimension or multipledimensions can be selected as inputand any others as output. Thisresulting “design space” allows forexploring scenarios, testingassumptions and interventions andidentifying unintendedconsequences – the principalconsiderations for engaging awicked problem in the first instance.

Concluding remarksThe earliest known publication citingthe use of Morphological Analysis forhealthcare systems planning dates tothe 70s in the design and evaluationof healthcare provision for a largemetropolis. Here the authors statedthat “modern day healthcare hasbecome a highly complex system,having numerous components


FFiigguurree 22:: An 8-dimensional morphological field developed for the Swedish National Rescue Services on evaluatingpreparedness for chemical accidents, accidental or deliberate, for different municipalities. One possible configuration (outof 57,600) is shown – cells shaded in red are inputs while blue cells represent possible responses. Each and every pair ofcells shown in the configuration below is mutually compatible. Any single contradictory pair knocks out the entire string(e.g. ‘standard routine for general case’ and the top three response cells are not highlighted as this was deemedcontradiction in terms by the subject-matter specialist working group).


whose relationships are generallynot well understood.” They furthercited problems that included i) thetypes of care rendered ii) access tohealthcare for different populationsiii) utilisation of scarce manpowerand iv) structuring and evaluatingthe consequences of incentives inthe health sector – does this soundfamiliar? In the current economicenvironment of austerity measures(a wicked problem in itself,particularly what to do with banker’sbonuses) where the healthcare andpharmaceutical sectors are expectedto “innovate with less”, the industryis already in the midst of a wickedproblem (the patent cliff) that hasbeen brewing for at least a decadebefore the recent financial crash.

Receding drug pipelines, increasedregulatory scrutiny, governmentalpricing pressures, the rise of patientadvocacy groups and how to(bio)ethically integrate emerging

technologies are all but a fewsymptoms of the ‘Kondratievwinter’, the trough of the super-economic cycle, in which we findourselves. A new line of questioningis needed in these post-normaltimes, defined as a line of enquiry“where facts are uncertain, valuesare in dispute, stakes are high anddecisions urgent.” Causal modelling,such as Bayesian Belief Networks,when applicable, can and should beused as an aid to judgement.However at a certain level ofcomplexity i.e. social, political,cognitive processes, judgmentsmust often be used – and workedwith – more or less directly. PSMssuch as Morphological Analysisallow judgmental processes to beplaced on a sound methodologicalbasis, with a digital audit trail, togive decision makers systematicsupport in identifying a consensualframework for engaging with theircomplex problems.

Further Reading

Ackoff RL. Redesigning the future: a systemsapproach to societal problems. New York: JohnWiley and Sons; 1974

Funtowicz SO, Ravetz JR. Uncertainty,complexity and post-normal science. Environ.Toxicol. Chem. 1994; 1133: 1881-1885.

Levitt SD, Dubner SJ. Freakonomics. New Work:Harper Collins; 2005

Mingers J, Rosenhead J. Problem structuringmethods in action. Eur. J. Oper. Res. 2004; 115522:530-554

Pidd M. Tools for thinking: modelling inmanagement science. 2nd ed. Chichester: JohnWiley and Sons; 2003

Ritchey T. Problem structuring using computer-aided morphological analysis. J. Oper. Res. Soc.2006; 5577; 792-801

Rittel H, Webber M. Dilemmas in a generaltheory of planning. Policy Sci 1973; 44: 155-159

Turley RE, Richardson WC, Hansen JV.Morphological analysis for healthcare systemplanning. Socio. Econ. Plan. Sci. 1975; 99: 83-88

Zwicky F. Discovery, invention, research –through the morphological approach. Toronto,Macmillan Company; 1969


FFiigguurree 33:: In the CrossConsistency Matrix (denoted bythe C toggle), all conditionsunder each dimension in themorphological field of Figure 2are pitted against each other,pairwise. As each pair ofconditions is examined, ajudgement is made, as towhether or not, or to whatextent, the pair can coexist. It isimportant to note that there isno reference here to direction orcausality, but only to mutualconsistency. This approachallows a typical problem spaceto be reduced up to 99%

Gareth Williams is a patentattorney and Graham Burnett-Hall is a solicitor at Marks &Clerk UK.


Pharmaceutical companies depend ontheir patent portfolios to protect theirproduct pipelines, with any gaps inprotection leaving them vulnerable tocompetitors, generic or otherwise. WithEurope being the second largestpharmaceutical market in the world,robust protection of drugs and medicinesis extremely important. However, thecurrent system’s fractured and complexnature leaves many companies withincomplete and partial protection.

Unlike other areas of intellectualproperty, such as trade marks, patents inEurope can currently only be obtainedand enforced on a national basis, countryby country, albeit through a centralapplication system administered by theEuropean Patent Office (EPO). The EPOexamines applications and, if approved,patents are granted in whicheverEuropean countries the applicantchooses, with multiple national patentsreferred to as a ‘bundle’.

While other patent-dependent industries,such as engineering, may file applicationsfor patents only in countries where theyhave a definite market for their product,pharmaceutical companies prefer to filemore widely. All European countriesprovide a potential market forpharmaceutical products and this strategyprevents companies’ competitors fromgaining a European foothold.

High costs

The fragmented application processincurs higher costs than in territories likethe US where one patent covers an entiremajor market. For example, according to

the EU, a bundle of patents covering all27 EU member states costs €32,000,compared to the €1,850 for a US patent.A major component of the expense is thecost of translating the patent applicationsinto the official languages of the differentcountries, although the LondonAgreement (2000) went some way tolessen the effect by eliminating the needfor translation in certain countries. In theprevious €32,000 figure, translation costscounted for €23,000.

Increased costs result in some companiesquestioning the value of seekingprotection in all European countries butincomplete protection can havecommercially and financially damagingconsequences. It is known that in the US,generic products already capture a largeshare of prescriptions dispensed (44%)and market sales (50%).1 Generic prices atlaunch are on average 25 per cent lowerthan the originator brand price, falling toone fifth of the initial generic price asmore generics enter the market.2 Whilesimilar figures are not available forEurope, the patchy protection systemleaves originator brands even morevulnerable than in the US.

Enforcement

The system for protecting and enforcingpatents is, on the whole, kept separatefrom that of granting them. As patentsonly exist at a national level, when theyare infringed or questioned, cases aredealt with in individual national courts.Consequently, enforcement of patentsacross Europe has been inconsistent andunpredictable. A decision by one courtmay have some persuasive influence onthe courts in other countries but it is notbinding on them. Patent law isharmonised to some extent withinEurope but this does not preventinconsistent decisions being given fromtime to time.

EPO decisions are also not able to bringabout judicial consistency throughoutEurope. Although decisions of the Boardsof Appeal of the EPO are authoritative,they are not binding and decisions of thenational courts can and do differ. Onerecent example is Human GenomeSciences v Eli Lilly & Co. In August 2005,HGS was awarded a patent for thenucleotide and amino-acid sequence of anovel member of the TNF ligand super-

TOWARDS A EUROPEANPATENT LITIGATIONSYSTEMby Gareth Williams and Graham Burnett-Hall

Efforts to establish a single European patent system haveseen both progress and setback in the first half of 2011.

Such a system has the potential to provide protection forpharmaceutical and other products across the entirety ofthe EU, with recourse to one central court system shouldpatents be infringed or attacked.


family, the polypeptide neutrokine-alpha. Eli Lilly sought to revokeHGS’s patent on grounds includingfailure to disclose an industrialapplication for the invention.Whereas the Technical Board ofAppeal of the EPO upheld thepatent with more limited claimsthan those originally granted, theEnglish and Welsh Court of Appealrevoked the patent altogether, fullyconscious that its decision wascontrary to that of the EPO. Thedecision of the UK Supreme Court isnow keenly awaited.

The uncertainty which arises fromnot knowing if patent infringementand validity decisions in oneterritory will be replicated inanother leads to higher costs forpharmaceutical companies.Organisations are forced to rely onlocal legal representation in eachcountry where their product ismarketed. While countries like theUK, Germany and the Netherlandshave judges experienced in patentdisputes, other countries lack suchjudges, leading to increaseduncertainty when it comes tolitigation in those markets.

Harmonisation

The current system, although farfrom ideal, is the fruit of manydecades’ work to harmoniseintellectual property protection inEurope. Much is owed to the EPO, aswell as the European PatentConvention (EPC), which served toestablish it.

Signed in 1973 by seven countries,the EPC standardised much of thepatent law and the EPO has sincebecome responsible for assessingand administering applications forEuropean patents potentially validin all EPO member states. A non-EUbody, since its inception it hasgrown to include 38 member states,including all major Europeanmarkets, with Serbia becoming themost recent full member in October2010 (see TTaabbllee 11).

Other landmarks for standardisationinclude the Strasbourg Convention,

and even the failed unitary patentproject, the Community PatentConvention, which sought toestablish a single patent for all theCommunity but which failed to beratified by sufficient states. TheLondon Agreement, signed in 2000,achieved significant cost reductionsfor patent applications byeliminating the need for translationsto national languages at variousstages of patent applications forsignatory states (currently 16 of the38 EPO members).

While previous efforts have beencommendable, the principalobjective has always been a singleEurope-wide patent enforced in aEuropean court system. Following adecade-long stalemate overlanguage issues, the last eightmonths have seen a great deal ofactivity in Brussels and Luxembourg.

Previous attempts at establishingsuch a system have failed, primarilydue to objections over the plannedlanguage regime. States such asSpain and Italy have challenged anyplan which excludes their nationallanguages from the workinglanguages of the proposed system.Such stances are reflected in theirrefusal to participate in the LondonAgreement.

At the end of 2010, 12 of theremaining 25 EU member statesexpressed their desire to theCommission to go ahead with plansfor the EU patent, through aprocedure known as ‘enhancedcooperation’. The procedure allows agroup of member states to pursuean area of integration without theconsent or participation of all 27.Subsequently, all 25 remaining statesjoined the proposal. The proposedpatent system would require futureapplications only to be submitted inthe EPO’s working languages(English, French and German). TheEuropean Parliament has approvedthe use of the enhanced cooperationprocedure, though its use is beingchallenged by Italy and Spain inlegal proceedings commenced inMay 2011.

Proposed unified system

Meanwhile, the Court of Justice of theEuropean Union (CJEU) had beenconsidering a proposal for a unifiedpatent litigation system – a courtsystem which would haveresponsibility for the enforcement ofthe new unitary patents. In March ofthis year, the Court handed down its

TTOOWWAARRDDSS AA EEUURROOPPEEAANN PPAATTEENNTT LLIITTIIGGAATTIIOONN SSYYSSTTEEMM ((CCoonntt..))

Table 1: EPO memberstates, by date of joining

Belgium 7 October 1977Germany 7 October 1977France 7 October 1977Luxembourg 7 October 1977Netherlands 7 October 1977Switzerland 7 October 1977United Kingdom 7 October 1977Sweden 1 May 1978Italy 1 December 1978Austria 1 May 1979Liechtenstein 1 April 1980Greece 1 October 1986Spain 1 October 1986Denmark 1 January 1990Monaco 1 December 1991Portugal 1 January 1992Ireland 1 August 1992Finland 1 March 1996Cyprus 1 April 1998Turkey 1 November 2000Bulgaria 1 July 2002Czech Republic 1 July 2002Estonia 1 July 2002Slovakia 1 July 2002Slovenia 1 December 2002 Hungary 1 January 2003Romania 1 March 2003Poland 1 March 2004Iceland 1 November 2004Lithuania 1 December 2004Latvia 1 July 2005Malta 1 March 2007Croatia 1 January 2008Norway 1 January 2008FYR of Macedonia 1 January 2009San Marino 1 July 2009Albania 1 May 2010Serbia 1 October 2010


opinion, stating that the currentproposals were inconsistent withEuropean law on several counts. Aparticular objection was that theproposed court would lie outside theEU jurisdictional framework andwould lack accountability in the eventthat the court failed correctly to applyany applicable principles of EU law.

New proposals have been drawn upwhich ensure that the patent courtis subject to the same controls asnational courts when dealing withEU law. A major consequence ofthis is that only EU member stateswill be able to participate in thepatent litigation system, not otherEPC-contracting states such asSwitzerland.

Separately the EU Commission haspublished draft regulationsregarding the grant of the proposedunitary patent.

One of the main points ofcontention in the proposals is theinvolvement of the CJEU insubstantive questions of patent law.The lesson from the alreadycentralised trade mark system is thatnational courts frequently consider itnecessary to refer questions of law

to the CJEU, whose judges, in themain, are not specialised in IP.Industry needs certainty, but suchreferrals inevitably add to the cost ofproceedings and result inconsiderable delays. Therefore, bothindustry and the legal communityconsider it very important that theCJEU not be granted jurisdiction infundamental IP matters.

Procedural matters, such as theavailability and use of disclosure,expert witnesses and cross-examination are also likely to affectindustry’s enthusiasm for anylitigation system.

Italy and Spain’s refusal toparticipate in plans for a centralpatent system on language groundshas caused headaches forproponents of the system, Both theSpanish and Italian pharmaceuticalmarkets are large, being valued at$22.1 billion and $24.9 billion in2009, respectively.3 This, combinedwith the presence of significantgenerics industries in both countries,means that pharmaceuticalcompanies will want to protect theirproducts in Spain and Italyregardless of whether the twocountries sign up to the centralised

patent or not. Their self-imposedexclusion from the single EU patentwill limit the reduction in cost anduncertainty for the industry, whichthe plans otherwise seek to achieve.

Conclusion

Although plans for the EU patentcurrently appear to be moredeveloped than those for the patentlitigation system, neither is likely tobe adopted without the other. Thebenefits of an EU-wide patent willonly become apparent whenaccompanied by those of an EU-wide litigation system that providesconsistency and increased certaintyof protection.

References1. Congressional Budget Office (United States

CBO), ‘How increased competition fromgeneric drugs has affected prices andreturns in the pharmaceutical industry’,(Washington: 1998); Grabowski H, Vernon J.Brand loyalty and price competition inpharmaceuticals after the 1984 Drug Act.Journal of Law and Economics, 1992; 3355(2):331-350

2. Kanavos P, Costa-Font J, Seeley E,‘Competition in Off-Patent Drug Markets:Issues, Regulation and Evidence’, Lisbon;2007

3. Datamonitor, ‘Spain Pharmaceutical MarketOverview’, (2010);Datamonitor, ‘ItalyPharmaceutical Market Overview’; 2010

TTOOWWAARRDDSS AA EEUURROOPPEEAANN PPAATTEENNTT LLIITTIIGGAATTIIOONN SSYYSSTTEEMM ((CCoonntt..))

For more information contact: www.euromedcommunications.com


On the one hand, sticky residues from themanufacturing process such as releaseagents, machining media, chips and dustmust be removed from medical devicesduring the cleaning process in a reliable,reproducible and documentable fashion.On the other hand, biocompatibility isrequired. The cleaning industry offersvarious processes in order to fulfil theserequirements both cost effectively andecologically, such as wet chemicalcleaning processes, cleaning with carbondioxide, and plasma processes. Differentprocesses are also frequently combined.

Wet chemical cleaning –interaction amongst cleaningagents and process technology

The effectiveness of wet chemicalcleaning processes, such as immersion,spray and ultrasonic cleaning, isdetermined by interaction between thedissolving performance of the utilisedcleaning agent and the cleaning system’sprocess technology. The most commonlyused cleaning media are aqueouscleaning agents and solvents. Essentialcriteria for the selection of the idealcleaning process include the material tobe cleaned, type of contamination, partshape, cleanliness requirements withregard to film-like contamination andparticulates, as well as production

throughput. The most suitable processcan be selected on the basis of thesefactors, and the final choice is frequentlycorroborated by cleaning tests conductedby equipment or cleaning agentmanufacturers.

Aqueous cleaning agents are based on anorganic or an inorganic builder andtensides. The latter are able to “push”themselves in between the contaminationand the material to be cleaned, anddislodge non-polar contamination such asoil and grease, as well as polarcontamination (e.g. emulsions, salts andparticles). In order to prevent residues leftby the cleaning agent or surface spotswhich would impair quality orbiocompatibility, a multi-stage rinsingprocess is usually required – often withdeionised water in the final rinsingstage(s). Continuous monitoring of thebath and bath replacement at regularintervals are necessary for consistentlygood results.

Solvent systems which are available aschlorinated hydrocarbons (CHC), non-halogenated hydrocarbons, modifiedalcohols and polar solvents aredistinguished by great diversity withregard to the type of material to becleaned. Grease, oil, particles, etc. can beremoved. Corresponding legal regulationsregarding emissions limits and worksafety apply to the use of solvents, andthese must be taken into consideration inmodern system concepts.

In order to be able to achieve the desiredcleaning results within the shortestpossible period of time, the effectivenessof the cleaning medium is usuallyenhanced by means of various physicalprocesses which demonstrate effects ofvarying magnitude, for example spraying,ultrasound and flushing under pressure.

When manufacturing implants, forexample, it’s advisable to use anintermediate cleaning step after eachchip removing machining process. This

ACHIEVING CLEANLINESSIN MEDICAL ENGINEERINGby Doris Schulz

Whether instruments, implants or accessories areinvolved, cleaning is an imperative step in the

manufacturing process for medical devices. Moderncleaning processes make it possible to comply with therequired degrees of cleanliness in a reliable andreproducible fashion with short processing times, thuscontributing to enhanced value creation.

Doris Schulz is a journalistbased in Korntal, Germany.

PARTS2CLEAN 2010parts2clean, an International Trade Fair for industrial parts and surface cleaning will take placeat the Exhibition Centre Stuttgart (Germany) from the 25th through the 27th of October, 2011. Itallows visitors to gather comprehensive information regarding cleaning systems, alternativecleaning techniques, cleaning agents, quality assurance and inspection procedures, cleaning andtransport containers, disposal and reprocessing of process media, handling and automation,services and consulting, as well as research and technical literature. www.parts2clean.com


reduces the risk of anyaccumulation of deposits in themicron range on the parts, whichmay lead to tolerance deviationsduring further processing. Beyondthis, intermediate cleaning preventsany mixing of lubricants andprocessing oils on the parts, whichoften causes cleaning problems. Lastbut not least, the quality ofdownstream mechanical processingis improved by intermediate partscleaning. Final cleaning is usuallyexecuted by means of a validatedprocess with an aqueous mediumwhich assures biocompatibility.

Economic batch processes– using the right cleaningrack

Batch processes are often used toclean medical devices in bulk goodsbaskets, or in workpiece carrierswhich have been laid outspecifically for the parts to becleaned (FFiigguurree 11). In addition tothe utilised process technology, theselected chemical and the durationof treatment, the cleaning rack alsohas a decisive effect on cleaningresults and operating costs. Itfrequently offers potential foroptimising the cleaning process

with regard to cleaning results,processing time and costs.

Cleaning baskets made of roundwire are ideal for assuring quick andreliable removal of contamination.They allow for easy, uniform accessto the workpieces by the cleaningagent, so that the mechanicalwashing process can develop its fulleffectiveness and wash out film-likecontamination and particulates asefficiently as possible. As opposed toclosed containers orbaskets made ofperforated sheetmetal, cleaningbaskets made ofround wire are alsodistinguished bysignificantly betterdrainingcharacteristics.Consequently,considerably lesscontamination andcleaning agent iscarried over, resultingin a longer servicelife for the cleaningbath, and thusimproved cleaningsystem availabilityand efficiency.

Cleaning with supercriticalcarbon dioxide – includingGMP validation

When parts are cleaned withsupercritical carbon dioxide, the CO2is used in an aggregation state inwhich its physical characteristics liebetween the liquid and the gaseousstate. While in this state, itdemonstrates only minimal viscosityand surface tension. Both of theseattributes are importantprerequisites for mass transport,which makes it possible to removecontamination such as oils andgreases from even the smallestcracks and pores (FFiigguurree 22). Cleaningwith supercritical carbon dioxide,which usually takes place within atemperature range of 20 to 40°C, isthus even capable of achieving goodresults with porous structures.

Additionally, “biological”parameters are favourablyinfluenced as a result of lowercytotoxicity values than thosefound in conventional cleaningprocesses. Uses for CO2 cleaning inmedical engineering include, forexample, intermediate and finalcleaning of implants, instrumentsand components made of variousmaterials (e.g. metals and plastics).Amongst other things, a GMPvalidation package is part of thescope of delivery for manufacturers

EEFFFFIICCIIEENNTT AACCHHIIEEVVEEMMEENNTT OOFF CCLLEEAANNLLIINNEESSSS IINN MMEEDDIICCAALL EENNGGIINNEEEERRIINNGG ((CCoonntt..))

FFiigguurree 22. Cleaning with supercritical carbon dioxide, a processwhich can be validated in accordance with GMP, makes itpossible to remove grease and oil from parts and poroussurfaces made of metal, ceramics, plastic and compositematerials. Image source: eCO2

FFiigguurree 11. This workpiece carrier for implants allows for easy accessibility by the cleaningagent from all sides. In order to prevent damage of the workpieces due to metal-to-metalcontact, the part holders have a plastic coating. Image source: Metallform

of systems for cleaning withsupercritical CO2.

CO2 snow – dry andresidue-free

Liquid carbon dioxide is used as ablasting medium for CO2 snow jetcleaning. It is expanded through anozzle and accelerated to ultrasonicspeeds with compressed air. Thanksto a combination of mechanical,thermal and chemical effects, theCO2 snow jet gently removesnumerous types of film-likecontamination and particulateswhen it strikes the surface in a dryand residue-free fashion. Itscharacteristics make CO2 snow jettechnology suitable for cleaning andactivating almost all materialsincluding metals, plastics, glass andceramic substrates, even with finelystructured surfaces (FFiigguurree 33).

The jet stream can be well focused,and the process is thus also capableof treating specific functional areas,for example sealing and bonding

surfaces, without subjecting theentire component to the complexprocessing which is necessary inorder to achieve the levels ofcleanliness which are only required

for the functionalsurfaces.

The process’s good inlinecapabilities and minimalspace requirementsallow for easyintegration of cleaninginto the manufacturingprocess, thus ruling outthe possibility orrenewed contaminationof the component, forexample duringtransport or storage.

Plasma – morethan just clean

Plasma is a gaseousmixture of atoms,molecules, ions andfree electrons. Medicaldevices made of variousmaterials, for examplesteel, non-ferrousmetals, plastics, glassand ceramics, can betreated either in batchprocesses or as

individual parts with this technology(FFiigguurree 44). Depending upon theapplication, various plasma gasescan be used, by means of which thesurface is simultaneously cleanedand activated. This dual function isbased on both physical andchemical reactions involved in theprocess: The atoms released in theplasma “bombard” the surface ofthe component to be cleaned. Thisfunctions like a miniature sand-jetin the nano-range, thus removingorganic contamination whichadheres to the surface such as oiland grease. At the same time, freeions and electrons are deposited on,and enter into a chemical bondwith the surface. As a result, surfacetension is adjusted to an ideal valuefor subsequent bonding, coating orprinting processes.

Applications for biocompatibleplasma in the field of medicalengineering include, for example,final cleaning of stents, surgical anddental implants, as well as guidewires prior to coating with hydrogelor PTFE, increasing the surfaceenergy of microtitre plates andother diagnostic instruments,silicone breast implants, cathetersand syringes.

FFiigguurree 44. The surfaces of a great variety of medical instruments and devices can be ideallyprepared for the respective application, as well as for subsequent bonding, coating orprinting processes, through the use of a plasma process. Image source: Reinhausen Plasma

FFiigguurree 33. The CO2 snow jet process is suitable for cleaningand at the same time deburring sensitive and finelystructured surfaces such as canulas. Image source: acp

BEFORE

AFTER


EEFFFFIICCIIEENNTT AACCHHIIEEVVEEMMEENNTT OOFF CCLLEEAANNLLIINNEESSSS IINN MMEEDDIICCAALL EENNGGIINNEEEERRIINNGG ((CCoonntt..))

Adapted with permission from article first published in June 2011 in Process Cleaning.

Alexander Sulakvelidze, PhD, isChief Scientist of Intralytix, Inc.,Baltimore, USA.


Initially, bacteriophages were used toprevent and treat human infections, atherapy which began shortly after theirdiscovery during the second decade ofthe 20th century. Recently, however,nonclinical applications (e.g., thosedesigned to improve food safety) forbacteriophages have been receivingincreased attention.

The term “phage intervention” may bemore appropriate than “phage therapy”when discussing such nonclinicalapplications. However, for the purpose ofthis review, the terms “bacteriophagetherapy” and “phage therapy” are looselyused for applications where phages areused to reduce the concentration of theirspecifically targeted pathogenic bacteria,irrespective of whether they are used inclinical or nonclinical settings.

Historical perspective

Bacteriophages were first identified byFrederick Twort (in 1915) and,independently, by Felix d’Herelle (in 1917)who called them bacteriophages orbacteria-eaters (from the Greek phagomeaning to eat or devour).1,2 At that time,with the age of antibiotics still in thefuture, bacteriophages were proposed tobe a powerful cure for infectious diseases,and they were utilized therapeuticallythroughout the world during the pre-antibiotic era. The use of phages inhumans was apparently very safe, withvirtually no serious adverse reactions everreported. However, phage therapy did notalways work and, with the advent of

antibiotics that seemed like “magicbullets” against a very broad spectrum ofbacteria, the use of phage therapygradually fell out of favour in the UnitedStates and Western Europe.

In an intriguing twist of fate, after all buteliminating “phage therapy” in the Westand starting the “antibiotic era”, thecommercial development of newantibiotics has been on the decline overthe past 20 years. Thus, only nine newantibiotics were approved by the FDAduring 1998-2003. The underlying reasonsare complex but may be grouped intotwo categories.

First, antibiotics were initially so effectivethat there appeared to be little need tocontinue developing new classes ofantibiotics and other antibacterials.

Second, from a business point of view,although the worldwide current marketfor antibiotics is still highly significant (ca. US$26 billion/year), it is still lessprofitable than medications for treatingchronic conditions. Thus there is lessincentive for pharmaceutical companiesto invest in developing new antibiotics(typically used for acute conditions) thanto develop drugs for treating chronicconditions. However, the emergence ofmulti-resistant bacterial pathogens andthe need for “green” antibacterialinterventions has rekindled interest indeveloping novel antimicrobial agents,including bacteriophages.

Prevalence and safety ofbacteriophages in theenvironment

Bacteriophages, the most ubiquitousmicro-organisms on Earth, are virusesthat infect bacteria. It has been estimatedthat there are >100 different phagespecies and at least 10 phages for eachbacterium. Also, one tablespoon (ca. 15ml)of non-polluted water has been estimatedto contain approximately 3 x 109 phageparticles/plaque-forming units (PFU), andthe total number of phages on Earth hasbeen estimated to be 1030-1032 PFU.Furthermore, phages are consumed dailyby humans as they are present in virtuallyall fresh and non-processed foods.Therefore, using naturally occurring, lyticbacteriophages for clinical and non-clinical applications may be the safest,“green”, antibacterial applicationscurrently available.

THE CHALLENGES OFBACTERIOPHAGETHERAPYby Alexander Sulakvelidze

Introduction

Bacteriophages (also called “phages”) are viruses that killbacteria. They are the oldest (3 billion-years-old, by

some estimates) and most ubiquitous (total numberestimated to be 1030-1032) known organisms on Earth.Phages have a specific prey-predator relationship withbacteria, and they have had and continue to have a key rolein maintaining microbial balance in every ecosystem wherebacteria exist.


Bacteriophages can killantibiotic-resistantbacteria

The beginning of the antibiotic eramay be considered to have begunwith the brief publication, entitled“Penicillin as a chemotherapeuticagent,” by Chain et al.3 which waspublished in Lancet in 1940. Sincethat time, antibiotics arguablyhave saved more human lives thanany other medications in thehistory of mankind, and they weredeservedly called “miracle drugs”by many.

However, the antibiotic “safety net”against bacterial infections has

become increasingly fragile becauseof the emergence of multi-antibiotic-resistant mutants.

Also, the development of newantibiotics has been on the wane ingeneral, and only two antibioticsapproved by the FDA during 1998to 2003 have novel modes of action– a critical consideration in thebattle against antibiotic-resistance.In this context, phages offer a veryattractive complementary tool formanaging bacterial infections,including those caused by multi-antibiotic-resistant bacterialpathogens, because (i) their modeof action differs from those of

antibiotics, and (ii) the mechanismsof resistance against phagesaredifferent from those forresistance to antibiotics. Thesefactors are briefly reviewed below.

MMooddeess ooff aaccttiioonn.. Antibiotics are low-molecular weight compounds thatkill bacteria (bactericidal antibiotics;e.g., streptomycin and vancomycin)or inhibit their growth(bacteriostatic antibiotics; e.g.,chloramphenicol and tetracyclines).

Lytic phages, on the other hand,are fairly large (approx. 100-200nm) micro-organisms that kill theirtargeted bacteria predominantlyvia a lytic cycle – a complex

TTHHEE CCHHAALLLLEENNGGEESS OOFF BBAACCTTEERRIIOOPPHHAAGGEE TTHHEERRAAPPYY ((CCoonntt..))

FFiigguurree 11. Replication cycle of lytic phages

Step 1: The first step in the replication process is attachment of the phage to the bacterial cell, a two-step process: (i) reversibleattachment is mediated by the phage's tail fibres which attach to a specific receptor on the bacterial cell surface, and typically occursalmost instantaneously after exposing the host cell to the phage, and (ii) irreversible adsorption occurs when the baseplate fibrilsirreversibly attach the phage to the bacterial cell. Step 2: Injection of phage DNA into the bacterial host’s cytoplasm. Tail sheathcontraction is triggered by expansion of the baseplate, and the injection step is typically accomplished in <1 min (?3 kb aretransferred/second) under optimal conditions. Steps 3-4: Shut-off of synthesis of host components, replication of phage DNA andproduction of new capsids. The phage DNA takes over the host's biosynthetic machinery, and phage-specified proteins are synthesized.Step 5: Assembly of phages. Nucleic acids and structural proteins are assembled, and phage particles accumulate in the cell. Step 6:Intracellular mature phages are released by host cell lysis. The number of phage particles released per infected bacterial cell may be ashigh as 1,000 (usually it is 200-250 for the T4 phage).

Reproduced with permission from the American Society for Microbiology (Microbe, January 2006, p. 20-24).



process consisting of a cascade ofevents involving several structuraland regulatory genes ((FFiigguurree 11)). Alllytic bacteriophages are, bydefinition, bactericidal rather thanbacteriostatic.

RReessiissttaannccee mmeecchhaanniissmmss.. Mechanismsof bacterial resistance againstantibiotics are fairly complex, and asingle bacterium often possessesseveral of them simultaneously.However, in general, they may begrouped into three majorcategories: (i) enzymaticinactivation of the antibiotics. Forexample, many Gram-negativebacteria and some Gram-positivebacteria produce beta-lactamase,an enzyme that hydrolyzes thebeta-lactam ring of beta-lactamring-containing antibiotics, therebyinactivating them; (ii) limiting theantibiotic’s access to its intracellulartarget; e.g., resistance totetracycline depends upon thebacterium’s ability to pump theantibiotic out of the cytoplasm (alsocalled “efflux resistance”); and (iii)altering the antibiotics’ targets. Forexample, resistance to thequinolones often arises from pointmutations that alter the affinity ofDNA gyrase for those antibiotics,and resistance to rifampin often isdue to mutations in the geneencoding bacterial RNA polymerase,so that the antibiotic can no longerbind to it.

In contrast, resistance to phagestypically results from changes in the(i) bacterium’s phage receptors, sothat the phage tail fibres cannot“recognise” the target bacteriumand attach to it, and (ii) bacterium’santi-phage DNA-restriction enzymes.After attachment, a phage’s abilityto lyse its bacterial host depends onits ability to survive the host’srestriction-modification defenses;therefore, if the phage’s DNAbecomes susceptible to its host’srestriction-modificationmechanisms, the phage may not beable to kill the bacterium.

Thus, because of major differencesbetween the mechanisms for

resistance to antibiotics and tophages, antibiotic resistance doesnot correlate with resistance tophages, and vice-versa. What thismeans in practice is that antibiotic-resistant bacteria remain sensitiveto, and can be killed by, lyticphages – which provides anexcellent safety net for preventingand treating diseases caused bymulti-antibiotic-resistant bacteria.

Challenges of phagetherapy

Properly selected phages kill theirspecifically targeted host bacteriavia mechanisms that are differentfrom those of antibiotics and areapparently very safe. Therefore, itseems puzzling that phagepreparations are not widelyavailable for clinical and agriculturalapplications in the United Statesand Western Europe. The reasonsare both technical (e.g. they involvethe specificity of phages) and non-technical (i.e., the “novelty” of thephage therapy approach) in nature.

Novelty. This problem is counter-intuitive because phages haveexisted on Earth for about 3 billionyears and have been usedtherapeutically in humans for atleast 90 years; hence, they arehardly novel antibacterialmodalities. Nevertheless, becausephage therapy applications weremostly forgotten in the West afterthe introduction of broad-spectrumantibiotics, they may seem to benovel and of unproven efficacy tomany Western scientists andphysicians. Also, since phagetherapy is a significant departurefrom the modern, currentlyaccepted small moleculeantimicrobials approach, its“novelty” may be a factor hinderingits acceptance.

Specificity of phages. Paradoxically,one of the most important of thepotential technical limitationsinvolves the specificity of phages,which is also considered to be oneof their strengths. In this context,bacteriophages are, indeed, very

specific; i.e., they will only lysestrains or subgroups of strains,typically within the same species.Therefore, incorrectly identifyingthe bacterial etiologic agent willrender phage therapy ineffective;whereas, broad-spectrumantibiotics will be more likely to killor prevent the growth of theetiologic agent.

The high specificity of phages wasone of the main reasons for thedecline of interest in phage therapywhen antibiotics became widelyavailable. However, because thecurrently available, robust diagnosticapproaches and tools have made itpossible to identify bacterialpathogens much more rapidly andaccurately than was possible duringthe early days of phage therapy, itshould now be possible to selectappropriate phages for many, if notmost, clinical treatment regimens.Furthermore, the high specificity ofphages can now be viewed as anadvantage in certain applications,because it makes targeted therapypossible.

Despite the above-noted advancesin bacterial diagnostics, the highspecificity of phages may still beproblematic if the mainstreamcommercial phage product is noteffective against one or morestrains of the targeted species thathappen to predominate in aparticular hospital or clinicalcentre. One approach to addressthis potential problem is to haveall targeted bacterial strainsexamined for their sensitivity tovarious phage preparations, and toselect and use only the phages thathave shown strong lytic potencyagainst the infecting bacterialstrain – much like antibiotics areused today.

The ideal scenario – tentativelycalled the “Pharmacy Approach,”which takes advantage of theflexibility that phage therapy offersas an antibacterial approach – is tocustom-design phage preparationsfor each patient. For example, thehospital’s clinical microbiology


laboratory will determine the lyticpotency of a library of well-characterized, cGMP-producedbacteriophages against thepathogen isolated from the patient.After identifying two or morephages possessing potent lyticactivity against the isolated bacterialpathogen (we expect that phagecocktails will be always used ratherthan single monophage-containingpreparations), the hospital’spharmacy will prepare the optimalphage cocktails for that patient.Using such custom-designed phagepreparations has been and still is acommon practice in Eastern Europe.

From a technical standpoint, itshould be possible to use thisapproach, although it will requirethe development of phagesensitivity testing kits, streamliningof methods, and training hospitallaboratory personnel to use themto perform phage sensitivity testswith the etiologic agents. Anotherchallenge will be to developstrategies for properly regulatingsuch products, as discussed in“Regulatory approvals.”

EEffffiiccaaccyy aanndd ootthheerr tteecchhnniiccaallcchhaalllleennggeess.. Bacteriophages are veryeffective in lysing their specificbacterial hosts in many in vitro andin vivo models. However, althoughphages significantly reduce thelevels of their targeted pathogensin those systems, they do notalways completely eradicate them,unless very high concentrations ofphages are applied.

For most practical applications, aphage preparation’s incompleteeradication of the etiologic agentmay not be a problem as asignificant reduction in thepathogen’s concentration is likelyto help a patient’s natural defencesdeal with the infection. Thus, it isimportant to design interventionstrategies based on a thoroughunderstanding of the biologicalstrengths and weaknesses ofbacteriophages.

Among other potential technicalproblems, the following three issues

are most frequently raised: (i) Rapidelimination of the bacteriophagesmay reduce available phages tolevels insufficient to combat theinfection; (ii) During i.v.administration of phages (e.g., totreat septicaemia), the developmentof bacteriophage-neutralisingantibodies may negate the efficacyof long-term phage therapy; and(iii) Phage-resistant bacterialmutants may rapidly emerge andnegatively impact the phagepreparation’s efficacy. However, inpractice, none of these potentialscenarios has proven to be asignificant problem, and could berelatively easy to circumvent, ifneed be.

RReegguullaattoorryy aapppprroovvaallss.. The firsttherapeutic use of phages inhumans occurred in 1919, whenFelix d’Herelle used phages to treatfour children suffering from severe,bloody dysentery in France.4

However, the first published reportof phage therapy appeared 2 yearslater, when Bruynoghe andMaising5 successfully used phagesto treat human skin infections inBelgium. Since those two earlyuses, probably hundreds ofthousands of people worldwidehave been treated with variousbacteriophage preparations.

However, none of thosepreparations or clinical trials weresubjected to the same regulatoryapproval processes that otherantimicrobial agents must undergotoday, before they are approved forhuman therapy or othercommercial applications.

One relatively little known fact isthat the FDA actually reviewedbacteriophage applications forhuman use during the 1970s,1980s and 1990s, when phage phiX174 was intravenouslyadministered to patients withvarious immuno-deficiencydisorders. In all of those instances,the goal of phage administrationwas to determine the immunestatus of the patients rather thanto treat disease.

The FDA also conducted a safetyreview of bacteriophages during1973, after phages were found to bepresent in some vaccines used inthe United States, and concludedthat the phages were safe andallowed the continued use of thosevaccines.6

Despite the above-mentioned FDA-approved uses, well-definedguidelines for obtaininggovernmental approval of phage-based human therapeutic productswere not formulated at that time.The issue was further complicatedby the fact that the existingregulatory guidelines developed forsmall molecule antimicrobials werenot immediately applicable tobacteriophages. Thus, navigatingthe nuances of regulatory strategiesfor various types of applicationswas and remains a significantchallenge for phage therapy,although this situation seems to beimproving lately and severalapprovals were issued for variousphage preparations during the lastfew years. For example, in 2008,the FDA approved a physician-initiated, phase I clinical trialdesigned to evaluate the safety of aphage cocktail (containing eightdistinct monophages targetingStaphylococcus aureus,Pseudomonas aeruginosa and E.coli) developed to treat patientswith infected venous leg ulcers.7

According to www.clinicaltrials.gov,the recruitment of patients for atleast two more phage therapy trialsis currently in progress. Thus, thenumber of regulatory approvals forvarious phage preparations for foodsafety and clinical applicationsseems likely to increase in thefuture.

Another, yet to be addressed,regulatory unknown is how theWestern regulatory agencies mightregulate phages for the “PharmacyApproach” described earlier. Thatapproach stipulates that custom-designed phage cocktails will beprepared (by licensed hospitalpharmacists) from distinct, cGMP-manufactured phage lots, instead of



all hospitals using the samecommercial phage preparation.That approach is a clear departurefrom the traditional FDA approvalprocess for other antimicrobials;i.e., it requires “thinking outside ofthe box”, and it may take sometime to eliminate its psychologicaland technical obstacles. However,for phage therapy to reach its fullpotential, such custom-designingmust be implemented.

A positive development in thatregard was the FDA’s flexibilityregarding its recent approval ofListShield™ for food safetyapplications; i.e., the FDA approvedthat phage cocktail’s future efficacyto be updated with new phages, ifand when necessary. All new phageswill need to meet the samestringent safety and efficacy criteriaas the original phages inListShield™, and the manufacturingprocess (as well as all quality controlprotocols) approved for ListShieldmust be strictly adhered to for allnew phages – but these are logicaland technically-feasiblerequirements.

PPaatteenntt pprrootteeccttiioonn.. Therapeutic phageapplications have been madepublically available since thepreviously mentioned publicationby Bruynoghe and Maisin in 1921.5

Thus, the ability to protect thetechnology and/or phage-basedproducts from competition isanother challenge for thecommercially successfulestablishment of phage therapy.Over the years, numerous otherscientific papers were publishedconcerning phage therapy. Also,several patents were obtained forvarious applications ofbacteriophages after the first phagepatent (US 1,668,814) was issued in1926. The first patent was notclinically-oriented; instead, itfocused on preventing the lyticactivity of phages against bacteriaused for industrial fermentationprocesses.

Surprisingly, despite the fairlycommon sale of therapeutic phage

preparations by some majorpharmaceutical companies, afterthe discovery of phages during1915-1917, patents for therapeuticapplications in humans were notissued until 1990, when two patentsUS 4,891,210 and US 4,957,686were issued for the use ofbacteriophages in oral hygiene.More recently (in 2000), the USPatent Office issued US 6,121,036 toGhanbari and Averback for verybroad-spectrum phage therapyclaims. Given the fact that thepatent’s issuance was preceded byalmost 80 years of usingbacteriophages therapeutically, andby hundreds of relevant scientificand general media publicationsfrom various countries (includingthe United States and Canada), it isnot clear why that patent wasissued – and its value may bequestionable.

However, the same reasons thatmake that patent potentiallyinvalid also has made it verydifficult for any other individual orcompany to obtain patentprotection for phage therapy per se,which has created a significantproblem for acquiring the fundsrequired to advance thedevelopment andcommercialization of productsdesigned for phage therapy.

MMaarrkkeett aacccceeppttaannccee.. Finally, no matterhow effective and safe phage-basedproducts may be for specificapplications in food safety or clinicalsettings, their popularity along withother modalities for preventing andtreating bacterial infections isultimately dependent on their“market acceptance.” The latter termencompasses a fairly broad range ofissues, from consumer acceptance tothe products’ cost.

Even if the price is acceptable,educating the general public aboutthe nature of phages, their ubiquityin the environment, and the safe(and natural/green) nature of theirapplications for managing bacterialinfections is of paramountimportance.

Conclusions

Several factors make bacteriophagesvery attractive antibacterial agentsfor a variety of applications.However, phages are not “magicbullets” and they have limitationsthat make them more effective forsome applications than for others.

Thus, it is important to understandtheir properties in order to designintervention strategies based on aclear understanding of theirbiological strengths and weaknesses.Moreover, several technical andnon-technical problems must beovercome before phage therapy iswidely accepted as a valuableadditional tool for managingbacterial infections andcontamination in clinical andnonclinical settings. However, thepotentially devastating impact ofmulti-antibiotic-resistant bacterialpathogens makes those efforts verymuch worth pursuing.

REFERENCES

1. Summers WC. Bacteriophage discovered.Felix d'Herelle and the origins of molecularbiology. New Haven, CT: Yale UniversityPress; 1999. p. 47-59

2. Duckworth DH. "Who discoveredbacteriophage?". Bacteriol Rev. 1976;4400(4):793-802

3. Chain E, Florey HW, Gardner AD, Heatley NG,Jennings MA, Orr-Ewing J et al. Penicillin asa chemotherapeutic agent. Lancet1940;22:226

4. Summers WC. The hope of phage therapy.Felix d'Herelle and the origins of molecularbiology. New Haven, CT: Yale UniversityPress; 1999. p. 108-24

5. Bruynoghe R, Maisin J. Essais dethérapeutique au moyen du bactériophagedu Staphylocoque. J Compt Rend Soc Biol.1921;8855:1120-1

6. Moody EE, Trousdale MD, Jorgensen JH,Shelokov A. Bacteriophages and endotoxinin licensed live-virus vaccines. J Infect Dis.1975;113311(5):588-91

7. Wolcott R, Rhoads D, Kuskowski M, Ward L,Sulakvelidze A. Bacteriophage therapy ofvenous leg ulcers in humans: results of aPhase I safety trial. Journal of Wound Care.2009;1188(6):237-43.



Robert Bates is ManagingDirector and Anna Bruns isPsychologist and ProjectManager at the life sciencesexecutive search and interimmanagement company, RSAConsulting GmbH.Email:[email protected]

“Innovation,” says Apple Inc. co-founderSteve Jobs, “distinguishes between aleader and a follower”. It has certainlybeen the cornerstone of his company’ssuccess. In fact, innovation is critical toany company’s long-term prosperity. Thisis especially true in the pharmaceuticaland life sciences industries where R&Daccounts for a large proportion ofinvested time, money and manpower.

The innovation process

Innovation is inherently human. Fromthe printing press to semiconductors,every invention first takes shape in themind of its inventor.

Ultimately, it is people – on their own orin groups – who evolve and implementtheir own ideas,bringing them to life.Companies whounderestimate, oreven ignore, thehuman factor ofinnovation andinvention do so attheir peril.

When it comes topeople, there are two key innovationingredients. People need to be able tocreate new ideas on the one hand, andbe willing to evolve and implement thesenew ideas on the other. The latter can bereferred to as Willingness to Innovate(WTI). An interesting difference betweenthese two ingredients is their stabilityover time.

Ability – defined by personal traits, likeintelligence – is somewhat fixed, especiallyin adult populations. Willingness, however,can change significantly and rapidly,

depending on the motivational aspectsand facilitatory qualities of an employee’sworking environment. Because willingnessis both important for innovation andhighly susceptible to influence, it is criticalto identify those environmental factorsthat can speed up or facilitate innovation,or indeed slow it down. High WTI byemployees therefore means highinvestment of energy in the innovationprocess.

Above and beyond their duty

Employees’ performance can be brokendown into two distinct categories. First,there is in-role performance, whichrefers to those activities clearly definedin an employee’s job description anddirectly related to that employee’sindividual contribution to thecompany’s overall output. Second, istheir extra-role performance which isless well defined, referring to anemployee’s behaviour above andbeyond their explicit duties – examplesbeing excessive helpfulness tocolleagues and clients, taking initiativeand being a catalyst for change.

Positive in-role performance helpsmaintain a company’s success. Extra-roleperformance, on the other hand builds onthat success, significantly enhancing it.

For most, innovation is an extra-roleperformance and probably the most

powerfully differentiatingone. Innovation variesmassively, even in R&Dteams whose primary role isgenerating andimplementing new ideas.

Capturing innovation

Despite WTI being an extra-role factor and not being

written into job descriptions, most linemanagers know who their top performinginnovators are. However, the truedifferentiator that makes a teamsuccessful does not always come from the10% of highly motivated, innovativeemployees who have the greatest impact.

Often it is the remaining 90%, onlyslightly more or less motivated andinnovative than they should be, whomake the biggest difference, either forbetter or worse – a slight deviation fromthe innovation “norm” when uniformly

INNOVATION – SCIENCEOR ART?by Robert Bates and Anna Bruns

Despite more than doubling its spending on R&D in thelast decade, the drug industry's success rate in finding

new drugs has been disappointing. Middle managers ofthe drug discovery units of the major players ought to bekey enablers in developing new ideas but this depends onbehaviour not often taught or developed in thecommercial world.

� Innovation,” saysApple Inc. co-founder

Steve Jobs, “distinguishesbetween a leader and a

follower �


present in the majority ofemployees can dramatically affectthe ROI.

In order to minimise the risk ofmissed opportunities and lostrevenue it is necessary to audit theWTI of not only a few individuals,but of all employees. This is ofutmost importance in the R&Ddepartment where commerciallysuccessful innovation is the numberone priority. Continuouslymonitoring innovation can identifycreative hot spots and weak spots,give insight into the presence offactors that either promote orhinder innovation, and provide thefoundation for carefully designed,carefully delivered interventions tomaintain or enhance innovation.

Peaks and troughs

Monitoring WTI is especiallyimportant during times of changeand on a regular basis thereafter.This is because a change toworking conditions can have adramatic impact on an employee’smotivation and hence WTI,whether it ’s a move betweencompanies, within a company orrestructuring. Our research datashow that typically, in a new unitor role employees tend to be

highly innovative for up to oneyear, the degree of theirmotivation increasing with time(see CChhaarrtt 11).

During their second year, WTI fallsdramatically to its minimum oftheir complete time of employment.After that time, to reach the headyone-year height of WTI, it usuallytakes more than 20 years in a stableworking environment and apersonnel development plan, basedon a programme of consistentmonitoring and intervention.

The good news is, that with thecompany showing a commitment tothe development of theiremployees, both employee retentionand innovation can be greatlyimproved.

Similar results can be found foremployees recently promoted toleadership positions, although herethe effects are more marked. Froman extremely high level WTI in theirfirst six months within a leadershipposition, an employee’s motivationfalls off sharply to its minimum inthe second half of their first year.After that, it takes more than 20years of hard work both from theemployer and employee, for theinnovation peak to be regained.

Measuring innovationscientifically

Of course, this rise and fall ininnovation is susceptible toinfluence and intervention.However, in a similar way tomedicine, before treatment comesdiagnosis. It is for this reason thatthe routine monitoring of WTI on aregular basis is so important.

What is needed are tools that canprovide validated, reliable, objectivescales for measuring therequirements for innovation. Onlythese will allow companies toconduct meaningful innovationaudits, the results of which willallow comparison of WTI withindifferent departments, detectchanges in innovation over time,

and help guide thedesign and delivery ofinterventions to helpmaintain or enhanceinnovation. These toolsnow exist and can helpto ensure the long-term success of thecompany, contributingto an environment inwhich each and everyemployee can researchtheir full potential.

In the world ofdiminishing pharmapipelines this is criticalto ensure that valuableR&D employees areworking together withmaximum creativityand motivation.

IINNNNOOVVAATTIIOONN –– SSCCIIEENNCCEE OORR AARRTT?? ((CCoonntt..))

Chart 1: Employees’ Willingness to Innovate (WTI) depending on the duration of employment.

� From an extremelyhigh level WTI in their first

six months within aleadership position, an

employee’s motivation fallsoff sharply to its minimumin the second half of their

first year. �

Adapted with permission from article first published in June 2011 in InPharm.

WHO Expert Committeeon Specifications forPharmaceuticalPreparationsReviewer: Andrei Meshkovsky

This latest report contains a wealth of practicalrecommendations relevant to manufacturers as well asthose involved in QC and supply system in the Pharmasector. While the advice is addressed predominantly toprofessionals working outside the three ICH regions,some pieces might be of practical interest to colleaguesfrom countries with highlyevolved National MedicinesRegulatory Authorities (NMRAs).This may be true for annexes onHVAC systems, technologytransfer, GMP for bloodestablishments, storage andtransportation of unstablepharmaceutical products etc.

Some might consider that theWHO GMP Guide is inferior toother well-known standardssuch as those of the EU or theUS FDA. It seems that thisnegative view was formedbecause on the national levelWHO is often supported by aweak inspection system makingits GMP certificates less reliablethan those issued by widelyrecognised NMRAs. However, itshould be borne in mind thatthe WHO GMP guide is used insome 100 member states and serves as a basis for theWHO Certification Scheme on the Quality of Medicinesin International Commerce.

The material presented in the annexes is highlydiversified. For the purpose of this review only two areasare commented upon: GMP and the Distribution system.

GMP

WHO good manufacturing practices: main principles forpharmaceutical products (Annex 3)

This is a revised text of the WHO GMP guide (mainpart) published in 2003. The part on main principlescorresponds to Part 1 of the EU GMP guide. The textincludes a new section on “Product quality review”, aswell as reference to the concept of quality riskmanagement. A new wording: “quality unit” isintroduced and “drugs” are replaced by “medicines”

throughout the text. These additions andamendments brought the text more in line with thetwo other internationally recognized guidelines: thoseof EU and PIC/S.

This main text on GMP is supported by fivesupplementary annexes: on GMP for bloodestablishments, on technology transfer, and on draftingsite master files (new guidelines) as well as on GMP forsterile products and on HVAC systems (revision ofpreviously published material).

Distribution system

Good pharmacy practice: standards for quality ofpharmacy services (Annex 8)

This annex is of special interest to FIP since it wasdeveloped in close cooperationwith the Federation. The firstversion of GPP developed jointlyby FIP and WHO was appended tothe 35th EC report in 1999. Sincethen, significant developments inpharmacy practice, science andtechnology as well as in policyhave occurred.

On the WHO side, important WHAresolutions were adopted recently,e.g. on accessibility of essentialmedicines, quality of care, andrational use of medicines. On theside of FIP, an initiative wasestablished in 2007 with the viewof updating the guidelines onGPP. The issue was discussed in2008 in Basel during the 68th FIPCongress.

The revised GPP guidelines arebased on the premise that it is up

to countries to determine what can be done accordingto existing regulatory framework. The document isaddressed to civil society as a baseline to be adjusted tothe needs of each specific country.

A considerable part of the report is related to thePrequalification of pharmaceutical products (Annexes 10to 15). This area of work requires detailed explanationsand may be the subject of a separate review.

Andrei Meshkovsky is Assistant Professor at Moscow Medical Academy,Department of Postgrade Training for Pharmacists and WHO expert onthe International Pharmacopoeia and Pharmaceutical Preparations.Email: [email protected]

Published by WHO Press, Geneva, 2011Price: CHF/US$ 70.00; in developing countries CHF/US$ 49428pp paperback

ISBN: 978-92-4-120961-8


BOOK REVIEW


The Future of PharmaEvolutionary Threats and Opportunities

Reviewer: Gino Martini

This volume is not the usual fare describing the woesbecoming the Pharmaceutical Industry (or Pharma).True it does discuss the ‘perfect storm’ swamping theIndustry in the form of lack of innovation, lowerproductivity, increased regulation, changes in attitudestowards risk and reimbursement challenges affecting‘me-too’ medicines.

However, where the text differs and differs markedly isthat Professor Smith proposes that the Theory ofNatural Selection first proposed by Charles Darwin in1859 can be applied to thePharma Industry. To remindthe reader, natural selection isthe process by which heritabletraits that increase anorganism’s chances of survivaland reproduction are favouredmore than less beneficial traits.Natural selection is the processthat results in the evolution oforganisms.

The author believes (andprovides supportive material)that Evolutionary Theoryprovides a clearer explanationof how the Industry hasdeveloped and moreimportantly how it will developin the future – it is refreshingto see an author come off thefence for a change!

The drivers for naturalselection are as follows:

� A maturing concept of value� A bigger fragmented market� A more risk averse market� A more informed, sceptical public� Contemplative investors� A more preventative approach to healthcareThese drivers have precipitated the following reactionsor strategies by the various Pharma companies whichrevolve around:

� A quest for innovation leadership� Expansion out of the developed markets� The drive to demonstrate value� Dealing with risk� Extension of the pharmaceutical value proposition

What makes this text a transition from an ‘interestingread’ to a ‘must do’ read is that Professor Smith has hadremarkable access to senior leaders within the industryand as such, he is very well informed. Of the Future?Professor Smith believes that the industry will evolve intoseven distinct entities with differentiating capabilities thatallow them to compete or gain competitive advantage.These entities are described as follows:

� The monster imitator – ultra efficient operations andpatent busters

� The Genii-spotting viable markets and developingnew products

� The Trust manager-brand management and brandedproposition development

� The Disease manager-developand manage therapies andprogrammes around chronicdisease more effectively than thestate� The Lifestyle manager-focuson preventative healthcare� Value pickers-focus onspecific clinical niche areas� The Health concierge-focus onsupplying superior healthcare forminor conditions compared to thestate.Radical stuff indeed and that’swhy this book is well worth aread if only to stimulate thinkingand debate. Even if you do notshare in Professor Smith’s visionof the future, one thing is sure –change is on the horizon forPharma and the timeframe isscaringly short with 2012 to 2015being viewed by most observersas the critical period for survival.

I leave this review with a quote from Darwin himself,which I feel supports Professor Smith’s hypothesis andmy own views of how Pharma will evolve in the next 5years as follows: “It is not the strongest of the speciesthat survives, nor the most intelligent that survives. It isthe one that is the most adaptable to change.” CharlesDarwin, The theory of evolution by natural selection.

Luigi G Martini is Professor of Pharmaceutical Innovation at King'sCollege, London.Email: [email protected]

Author: Brian D Smith

Published by: Gower Publishing, 2011. Price: £65; 214 pages

ISBN: 978-1-4094-3031-5 (hardback)

978-1-4094-3032-2 (e-book)

BOOK REVIEW


REGULATORY REVIEWReview of developments in GMP and the regulation ofMedicines July – September 2011

by Malcolm Holmes

Introduction

The current review period has seena number of actual/proposedchanges in the regulation ofmedicines and regulatory guidancein both the EU and USA. Worryinglyit has also seen incidents related tothe deliberate contamination ofpharmaceutical products which inone case led to the deaths of anumber patients in the UK.

United States of America

The United States Food and DrugAdministration (FDA) has. Issued New/Updated/Draft Regulatory Guidancecovering the following topics:

Validation of the Limulus AmebocyteLysate Test (withdrawal)FDA has withdrawn the 1987Guideline on Validation of theLimulus Amebocyte Lysate (LAL) Testas an End-product Test.

Drug manufacturers are now advisedto use the United StatesPharmacopeia (USP) General Chapter<85>Bacterial Endotoxins Test,which provides information on theperformance and acceptance criteriafor endotoxin testing. (The LAL test isharmonised in the USP,JP and EP.).

Tablet Scoring (draft).Insurance companies and doctors inthe USA are increasinglyrecommending that patients splittablets, either to adjust the patients’dose or as a cost-saving measure.

FDA believes that in some cases,there are possible safety issues,especially when tablets are notscored or evaluated for splitting.Prime concerns with splitting atablet included variations in thetablet content, weight,disintegration, or dissolution, andpotential stability issues.

Europe

EMA and US FDA receive first parallelquality-by-design application.The EMA and the United States FDA

have agreed to accept the firstapplication under their pilotprogramme for the parallelevaluation of Marketing-Authorisation (MA) applicationsinvolving 'quality by design' (QbD).

Potential use of membrane systems forthe production of Water For Injections Following review of the outputfrom an Expert workshop EDQMconsiders that sufficient reasonshad been provided for theEuropean PharmacopoeiaCommission to recommendinitiating discussions regardingpotential use of membrane systemsfor the production of Water forInjections. It is probable that futurediscussions will be held in amultidisciplinary forum involvingthe various stakeholders.

Position statement CJD and Advancedtherapy medicinal Products (ATMPs)For human cells contained inATMPs, there is no manufacturingprocess to add a further barrier totransmission of a TSE agent. Thefinal risk-benefit for the therapeuticuse of these medicinal productsderived from human cells andtissues will have to be decided on acase-by-case basis.

The collection and storage of cellsfrom umbilical cords is becomingincreasingly common Such cells areof foetal origin but the possibility oflow levels of contamination withmaternal blood cannot bedefinitively excluded.

Guideline on stability testing forapplications for variations to an MA(Draft)Guidance is provided on the stabilitydata which have to be generated inorder to support a variation to anMA. Guidance on stability testing fortype I (A and B) variations plus datarequirements for widelyencountered cases of type IIvariations are covered.

ICH guideline Q11 on developmentand manufacture of drug substances(chemical & biotechnological/biological entities)

EMA and FDA have published thisICH document for comments by 30September 2011. It describesapproaches to developing processand drug substance understanding.It also provides guidance on whatinformation should be provided inCTD sections 3.2.S.2.2 – 3.2.S.2.6.

Products

Deliberate adulteration ofpharmaceuticals.There is already considerable focus onthe security of the supply chain formedicines, but once again ourindustry and the patients it serveshave come under threat from criminalactivity within the supply chain.

Two serious incidents are underinvestigation. The first, involvingcontamination of saline drips withinsulin has resulted in the death ofpatients at Stepping Hill hospital.The second, involving Nurofen Plustablets has involved strips of theNurofen Plus tablets beingsubstituted within the strips withpotent prescription only medicinesfrom two different manufacturers.

International

Q&A – Distribution Activities for APIsA PIC/S Expert circle has providedthis Q&A as guidance to inspectorswhen inspecting Supply Chain &Distribution and Repackaging &Relabelling operations. It shouldalso be of use to Industry.

For further information on these andother topics we suggest you refer tothe websites of relevant regulatorybodies and to current and pasteditions of “GGMMPP RReevviieeww NNeewwss”published by EuromedCommunications. To subscribe to thismonthly news service contact:[email protected]


QQ CCaann ssoommeeoonnee aaddvviissee oonn tthhee pprroocceessss ffoorr oobbttaaiinniinnggaann EEUU CCeerrttiiffiiccaattee ooff GGMMPP ccoommpplliiaannccee ffoorr aaPPhhaarrmmaacceeuuttiiccaall MMaannuuffaaccttuurriinngg ffaacciilliittyy?? DDooeess tthhiissiinnvvoollvvee tthhee ccoonnttrraaccttiinngg ooff aann aauutthhoorriisseedd tthhiirrdd ppaarrttyy ttooccoonndduucctt aann iinnssppeeccttiioonn bbaasseedd oonn EEUU ssttaannddaarrddss oorr ddooeesstthhee EEMMEEAA ddiirreeccttllyy iinnssppeecctt tthhee ssiittee??

Response: 1 Up to now, there is not any third partyinvolved in the EU scheme of GMP inspections. Moreover,what we call “EU” inspections are generally inspectionsperformed by inspectors of one of the 27 Europeancountries. The conclusions of such an inspection areautomatically endorsed by the 26 other authorities. Forexample a German inspection in Asia will be used by theother countries. The status of every non-European siteinspected in that scheme can be found in the EUDRAGMPfile maintained by the EMA (ex-EMEA).

Speaking about EMA there are also some “European”inspections scheduled on behalf of the EMA butperformed by a team of inspectors from one or twoEuropean countries. These inspections have the status asthe other European inspections. The main difference isthat they generally focus on one or two named products.

So, how to obtain a EU-GMP Certificate of Compliance?Simply by being successfully inspected by one or moreEuropean inspectors on behalf of EMA or anotherNational European Authority. Such inspections are onlytriggered when the concerned manufacturing site isnamed in a Marketing Application or a variation of anexisting Marketing Authorisation.

You will therefore not find any private company whoseconclusions could be endorsed by Europeanauthorities. But, of course, you can select who istrained in receiving a European-style GMP inspectionwhile awaiting the real official inspection.

Response: 2 The answer is correct if you refer tomanufacturing facilities of marketed products. Formanufacturing facilities of clinical materials, you canget a GMP certificate from a European certifiedQualified Person.

Response: 3 For clinical supplies, it is the QP of theimporter in the European Union that will establish anddocument the verification of the compliance of theclinical manufacturing site. Usually, the QP can alsoreply on third party audits provided he has himselfchecked the qualification and the professionalism ofthat third party. But in no way can this declaration beconsidered as a “GMP Certificate of Compliance” whichis solely issued by authorities.

QQ AAss wwee kknnooww,, nnoonn--ddeeddiiccaatteedd eeqquuiippmmeenntt sshhoouulldd bbeevvaalliiddaatteedd ffoorr cclleeaanniinngg pprroocceedduurreess.. BBuutt wwhhaatt aabboouutt tthheeddeeddiiccaatteedd eeqquuiippmmeenntt?? IIff tthheessee pprroocceedduurreess sshhoouulldd bbeevvaalliiddaatteedd ttoooo,, wwhhaatt iiss tthhee aacccceeppttaabbllee ccrriitteerriiaa ooff tthheerreessiidduuee??

Response: 1 There is no regulatory obligation tosystematically validate the cleaning of dedicatedequipment for residues. You can also refer to WHO-GMP guide paragraph 13.12

Having said that, there might be a NEED to validatesuch cleaning, taking into consideration thecleanability of the product and the risk of leavingdegradation products on the inner parts of theconcerned equipment.

Response: 2 What really matters is how we convinceFDA in this matter of cleaning validation.

Acceptance criteria for dedicated equipment are nodifferent from that of non-dedicated equipment. Limitsfor detergents must be based on toxicity; standardindustry practices are followed for bioburdendetermination evaluation; visually clean criteria arebased on the active ingredient used.

Response: 3 A company’s decision should be basedon FDA 483 citations too. There are no rules of thumbbased on WHO guidance or whatever guidance we referto or follow. One must evaluate based on good scienceand risk management which has its priority focus onpatient compliance.

Response: 4 At least for the FDA, the “Guide toInspections: Validation of Cleaning Processes” sectionIV says “When the cleaning process is used onlybetween batches of some of the same product (ordifferent lots of the same intermediate in a bulkprocess) the firm need only meet a criteria of, “visiblyclean” for the equipment. Such between batch cleaningprocesses do not require validation.” However, if youuse a detergent, you should confirm removal of thedetergent between batches as well.

The following is a selection of the questions andanswers taken from recent exchanges in thePharmWeb GMP Discussion Group. This Forum isheld on the Internet atwww.pharmweb.net/gmp.html and sponsored bythe publishers of Industrial Pharmacy and GMPReview.

The Forum is free of charge and open access. Itserves as means of exchanging views within thecontext of international regulations affecting themanufacturing side of the pharmaceuticalindustry. Your own questions and answers are verywelcome. Send them towww.pharmweb.net/gmp.html but pleaseremember to write your name and email addressat the bottom of your message.

PHARMACEUTICAL FORUM


QQ CCaann aannyyoonnee ccoommmmeenntt oonn ccaappssuulleeddiissssoolluuttiioonn//ddiissiinntteeggrraattiioonn rreeqquuiirreemmeennttss?? AA ggiivveennpprroodduucctt wwhhiicchh hhaass oonnllyy oonnee ccoommppoonneenntt ((AAPPII)) sshhoowwssbbiiooaavvaaiillaabbiilliittyy wwhheenn rreeccoonnssttiittuutteedd wwiitthh wwaatteerr iinn aa vviiaallaanndd ddoosseedd.. TThhee pprroodduucctt iiss tthheenn ffoorrmmuullaatteedd iinn aa hhaarrddggeellaattiinn vviiaall,, aaggaaiinn wwiitthh AAPPII oonnllyy,, aanndd bbiiooeeqquuiivvaalleenncceessttuuddiieess aarree ssuucccceessssffuull..

IIss tthheerree aa nneeeedd ffoorr rroouuttiinnee ddiissssoolluuttiioonn oorr ddiissiinntteeggrraattiioonntteessttiinngg?? EExxppeerriimmeennttaall ddiissssoolluuttiioonn rreessuullttss sshhooww tthhaattccoommpplleettee ddiissssoolluuttiioonn iiss rreeaacchheedd vveerryy qquuiicckkllyy..

Response: 1 The answer is definitely that you need aspecification and testing. There are a number ofpossibly changes, albeit somewhat theoretical, in thecase you mention. As examples, you might havepolymorphic transitions, or hydration, or you couldhave pellicle formation caused by gelatin cross-linking.All of these could alter the dissolution, so you wouldbe required to have dissolution as part of a stabilityprogram. If it is part of a stability program then youmust also have it at time zero, ie. at product release.

Response: 2 Is there any other test in yourspecifications that gives assurance of drug release forevery lot/batch?

Dissolution specifications are necessary to show thatthe drug will be available for absorption from each lot.

Response: 3 As per ICH guideline Q6A, if dissolutionis more than 85% in 15 minutes in all physiologicalmedia then an upper time limit for disintegration timeis acceptable.

QQ II aamm ffaacciinngg aa pprroobblleemm wwiitthh cclleeaanniinngg vvaalliiddaattiioonn ooffaann AAPPII mmuullttiippuurrppoossee ppllaanntt:: uussuuaallllyy II wwoouulldd sseelleecctt tthheewwoorrsstt ccaassee aanndd pprroocceessss tthhrreeee ccoonnsseeccuuttiivvee lloottssppeerrffoorrmmiinngg aa ccoommpplleettee cclleeaanniinngg aannaallyyssiiss.. HHoowweevveerr,,ssoommeeoonnee ttoolldd mmee tthhaatt iiddeeaallllyy tthheerree sshhoouulldd bbee 1100 lloottss,,aanndd aatt tthhee ssaammee mmeeeettiinngg aannootthheerr mmaannaaggeerr aasskkeedd mmeettoo ppeerrffoorrmm oonnllyy oonnee……II hhaavvee nneevveerr hheeaarrdd ooffppeerrffoorrmmiinngg 1100 lloottss ooff cclleeaanniinngg vvaalliiddaattiioonn,, aanndd iinn mmyyooppiinniioonn oonnee lloott iiss nnoott eennoouugghh.. II wwoonnddeerr iiff ssoommee ooff yyoouuccoouulldd sshhaarree yyoouurr ooppiinniioonn//eexxppeerriieennccee oonn tthhiiss iissssuuee..

Response: 1 You are right. It is most unlikely that aunique (cleaning) validation cycle would be acceptedby an inspector.

The right number of cycles depends on how much yourcleaning process is automated or, if manual, how manydifferent operators are concerned.

Response: 2 As long as the analytical work is wellvalidated and you have a good sampling program thenthe only issue in a multipurpose API plant is to makesure you really have a worst case…often you may needtwo worst cases because of the range of chemicals andsolvents used.

However, 10 batches? No idea where that comes from.With all validations there is always the question of howmany and although there is no statistical basis thenumber that seems to keep every happy is three. I thinkthat one is not a good number but I have seen, mainly infinished dosage plants, that one seems to be accepted.

Response: 3 Ideally three consecutive batches shouldbe selected because when FDA was asked why we docleaning validation three times, the answer was that ifa result comes out right once – it might be an accident;twice – a coincidence; three times – validation.

Response: 4 Validation should be a demonstration ofwhat you already know, not an experiment to find outwhat’s going on.

If a process (equipment, materials, methods, people,etc) has been properly designed, developed andimplemented, then the performance characteristics ofthe critical parameters will be understood and incontrol – and this will be known before the process isrun. Validation is simply a practical demonstration thatthe process is reliable and repeatable. Threeconsecutive, successful runs is usually sufficient.

(I understand that the concept of three batches camefrom the FDA many years ago where a comment wasmade along the lines of there being a need to balancestatistical relevance against the cost of validation andthat a “minimum of three consecutive batches withinspecification” was considered to demonstrate control.Note the inclusion of: MINIMUM.)

If “validation” is being carried out to find out how aprocess performs, then a full statistical analysis will berequired. This will involve the collection and analysis of50 or more sets of data – and the results maydemonstrate that the process is not in control!

The latest Guidance for Industry: General Principlesand Practices – hhttttpp::////wwwwww..ffddaa..ggoovv//ddoowwnnllooaaddss//DDrruuggss//GGuuiiddaanncceeCCoommpplliiaanncceeRReegguullaattoorryyIInnffoorrmmaattiioonn//GGuuiiddaanncceess//UUCCMM007700333366..ppddff is the most up-to-date referencedocument on the topic. The EU Commissioners are due(overdue) to issue an updated version of the EUGuidance on the topic which, it is understood, will besimilar to the published FDA guidance.

Response: 5 An old boss of mine always asked thequestion “If that process were an aircraft, would youget on it?”.

Readers are invited to send their Q&A to:www.pharmweb.net/gmp.html

PPHHAARRMMAACCEEUUTTIICCAALL FFOORRUUMM ((CCoonntt..))


NEWS FROM THE EIPG

Representation

The green paper on Modernising theProfessional Qualifications Directivehas been published and the EIPGresponse will be added to ourwebsite during the next few days.

Since publication of the FalsifiedMedicines Directive on 1st July, EIPGis keeping a watching brief on theCommission’s moves towards itsimplementation. The EIPG responsesto the consultation are published onthe Commission’s website alongwith those of various otherorganizations.

José Manuel Massó, a member ofAEFI in Spain will represent EIPG atan EMA Ophthalmology Workshopin London on 27-28th October.

Education

Following Par Tellner’s contacts inEFPIA, EIPG has been invited to senda representative to an InnovativeMedicines Initiative (IMI) workshopin Manchester to discuss a commonframework of continuingprofessional developmentprogrammes for staff in medicinesresearch and development.

Student contact

Inkatuuli Heikkinen, EPSA Educationand Professional Affairs Coordinatorhas indicated that career planning,some industrial career profiles andan indication of the main areas ofemployment in industry will beadded to the EPSA website.

Membership

We welcome Ms MargaritaEfthymiopoulou, BusinessDevelopment Manager for Viofar Ltd asthe new Greek representative to EIPG

We are still looking for pharmacistsin Member Associations with aninterest in production/GMP issues,quality assurance, regulatory andcommercial/marketing aspects ofindustry to help with commentingon scientific guidelines, codes anddirectives. Anyone interested inassisting with lobbying, pleasecontact your national representativeor me at [email protected]

Jane NicholsonExecutive Director EIPG,


OCTOBER

3-6 October 2011 – Rome, ItalyPK/PD data analysis: a hands-oncourse using phoenix WinNonlin www.efmc.info

5-7 October 2011 – Prague, CzechRepublicThe GMP lead auditorwww.improvingsolubility.co.uk"

5-8 October 2011 – Amboise, France12th International Conference onBioencapsulationwww.irnpascience.eu

11 October 2011 – Stockholm, SwedenPharma package –Pharmacovigilance in the NordicCountries beyond 2012www.lakemedelsakademin.se

11 October 2011 – London, UKGood Manufacturing Practice (GMP) [email protected]

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

12 October 2011 – London, UKGood Distribution Practice (GDP) [email protected]

13 October 2011 – Cirencester, UKEnvironmental Monitoring andCAPPA investigations – PHSS AutumnConferencewww.phss.co.uk

13 October 2011 – London, UKAnalytical challenges in thequalification and validation ofpharmacodynamic biomarkerswww.rpharms.com

18-19 October 2011 – Manchester, UKRisk-Based Decision Making forQuality Professionals and QPswww.nsf-dba.com

18-20 October 2011 – London, UKWorld Pharma Innovation [email protected]

18-20 October 2011 – Biarritz, France24th Congress of A3Pwww.a3p.org

19 October 2011 – London, UKFunding the future of drugdevelopment in the UKwww.inside-pharma.co.uk

19-20 October 2011 – London, UKPharmaceutical labellingwww.informa-Is.com/pharmalabelling

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

23-27 October 2011 – Washington DC, USA2011 AAPS Annual Meeting andExpositionwww.aaps.org

24-25 October 2011 – London, UKPoint of care diagnostics – marketadoption and technology trendswww.pointofcarediagnostics.com

24-27 October 2011 – Manchester, UKGMP for Clinical Trials Manufactureand Supplywww.nsf-dba.com

25-27 October 2011 – Stuttgart, GermanyParts2cleanwww.biztradeshows.com

25-28 October 2011 – Barcelona, SpainPharmaceutical freeze-dryingtechnologywww.pda.org

31 October – 1st November 2011 – Basel,SwitzerlandEuropean pharmaceutical pricing &reimbursementwww.smi-online.co.uk/2011europricing.asp

NOVEMBER

8 November 2011 – Florence, Italy3rd International Congress onBiohydrogelswww.biohydrogels2011.it

8-10 November 2011 – Budapest,HungaryGMP meets GCPwww.good-development-practice.org

10 November 2011 – London, UKBlue pill, pink pill? does gendermatter?www.rpharms.com

14-15 November 2011 – Mumbai, IndiaNanomedicine: prospects andchallengeswww.ictmumbai.edu.in

14-16 November 2011 – Cambridge, UKTabletting technology for thepharmaceutical industrywww.rpharms.com

16-17 November 2011 – Coventry, UKEuropean Isolator & RABSConferencewww.phss.co.uk

21-22 November 2011 – London, UKCell-based assayswww.smi-online.co.uk/cell-based.asp

29 November 2011 – Berlin, Germany10th Annual World DrugManufacturing Summitwww.allconferences.com

29-30 November 2011 – Manchester, UKClean validationwww.nsf-dba.com

29 November – 1 December 2011 –Manchester, UKPharmaceutical water systems:troubleshooting and risk assessmentwww.nsf-dba.com

DECEMBER

5-6 December 2011 – London, UKCold chain distribution: Temperaturecontrol managementwww.smi-online.co.uk/2011coldchain.asp

6-7 December 2011 – Bordeaux, FranceModern biopharmaceuticalmanufacturingwww.pda.org

8 December 2011 – London, UKPredictive tools in the developmentof solid oral dosage formswww.ipag.org

12 December 2011 – Cambridge, UKDissolution testing for thepharmaceutical industrywww.rpharms.com

EVENTS

european Industrial Pharmacy Issue 10 (September 2011)

Documents

Transcript of european Industrial Pharmacy Issue 10 (September 2011)