eur opean in dustr ia l pha rmacy

ISSUE 23 • DECEMBER 2014www.industrialpharmacy.eu

www.eipg.eu

features4 ACHIEVING BIOSIMILAR PRODUCT APPROVAL

– KEY SUCCESS FACTORS FOR DEVELOPMENTBiosimilars have attracted increasing attentionover the past 10 years. This article describes keysuccess factors for biosimilar development, such asunderstanding of regulatory requirements and thescience of biological products.by Hideaki Nomura and Gary Trewartha

10 GAZING INTO THE CRYSTAL BALL: WHATWILL THE EU-FMD SAFETY FEATURESDELEGATED ACT BRING?In 2018, far reaching changes will come into forceacross Europe that were introduced by the EUFalsified Medicines Directive (2011/62/EU). Thisarticle examines the details and impact of theprovisions of the ‘Safety Features’ Delegated Actand how these will affect the pharma supplychain across Europe and beyond.by Christoph Krähenbühl

14 RECENT R&D BREAKTHROUGHS CONTINUETO REVOLUTIONISE THE ALREADY DYNAMICHEPATITIS C TREATMENT LANDSCAPEThis article outlines the past and present hepatitisC virus treatment landscape, placing a particularemphasis on the most recent developments andindustry trends.by Christopher Pace

18 QUALITY METRICS, QUALITY CULTURE,QUALITY MATTERS!This article examines measures to ensure qualitythroughout a medicine’s lifecycle from productdesign to manufacturing and distribution,emphasising the pivotal roles of patient centricityand quality culture. by Tom Sam and Henny Koch

regulars3 EDITORIAL COMMENT

22 REGULATORY REVIEW24 LETTER TO EDITOR25 BOTTLED BROWN26 NEWS FROM THE EIPG27 EVENTS

europeanINDUSTRIALPHARMACY

2 european INDUSTRIAL PHARMACY December 2014 • Issue 23

europeanINDUSTRIALPHARMACYIssue 23 December 2014

ISSN 1759-202X

MANAGING EDITORSue Briggs

PRODUCTIONDave Johnson

SUBSCRIPTIONSJill Monk

EDITORIAL BOARDMichael AnisfeldClaude FarrugiaMichael Gamlen

Linda HakesJohn Jolley

European Industrial Pharmacyis published four times a year by:

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Cover photo: The Uniique Identifier carriedin the form of a 2D DataMatrix (see Gazinginto the Crystal Ball: What Will the EU-FMDSafety Features Delegated Act Bring? onpage 10)

associate editors

Belgium: Philippe Bollen

Bulgaria: Valentina Belcheva

Czech Republic: Ales Franc

Denmark: Marie Fog

Finland: Anni Svala

France: Jean-Pierre Paccioni

Germany: Armin Hoffmann

Great Britain: Shilpa Gohil, Janet Halliday

Greece: Ioannis Nikolakakis

Hungary: Sylvia Marton

Ireland: Stan O'Neill

Italy: Piero Iamartino

Latvia: Inta Saprovska, Anita Senberga

Malta: Claude Farrugia

Netherlands: Amon Wafelman

Norway: Wenche Gordon

Portugal: Nuno Moreira

Spain: Beatriz Artalejo

Sweden: Marianne Andersson

Switzerland: Valter Gianesello

Will they? Won't they?Sir William Osler, Canadianphysician and a foundingprofessor of Johns HopkinsHospital, stated "Medicine is ascience of uncertainty and an artof probability". The same caneasily be said of thepharmaceutical industry, as thoseof our colleagues involved in theresearch and development of newpharmacological molecules andnew medicinal products will attest.Lately, however, this element of uncertainty has beencompounded beyond all expectations. Only asrecently as my last message to you, talk was rife of anexceptional year of merger and acquisition activity inthe sector. Fast forward a few months, and newfinancial rules across the Atlantic have disrupted thelargest merger to emerge from the first half of theyear, one that bore all the signs of a favourable unionbetween two complimentary companies, whilstanother merger that many were expecting todescend into an acerbic process of litigation hascome to naught, upstaged by an amalgamation thatwill create one of the ten largest pharmaceuticalcompanies worldwide. Thus, the attention now shiftsto two other companies free to return to thebargaining table, as all ask the question:

Will they? Won't they?

Against this backdrop of merger activity, industrialpharmacists unfortunately continue to experience adifferent kind of uncertainty. The ink was hardly dryon media reports of the largest pharmaceuticalmerger of the year thus far, when – as always –statements of the need for cuts were reported, and inthe eyes of friends, peers, colleagues who have givenyears of service to these players can be seen theconcern, the doubt, the unuttered question:


This issue of european Industrial Pharmacy includestwo topics that will define a new and emerging

pharmaceutical industry. The first ofthese is the issue of biosimilars. Theyears when these products will formthe backbone of global healthcareloom just over the horizon, andwhilst regulatory authorities havebegun to issue guidelines for theindustry, experience in biosimilardevelopment and especially in theunderstanding of the mindset ofdifferent authorities when evaluatingthese products is still lacking. Thesecond topic is that of the

Delegated Act on the detailed rules for a UniqueIdentifier for medicinal products, the publication ofwhich, by all accounts, is expected soon. While thebroader strokes of this legislation that will have far-reaching effects throughout the continent are by nowfairly clear to many, the minutiae of the processremain largely unknown, leaving actors in thepharmaceutical supply chain in a state of uncertainty,asking largely unanswered questions and left towonder:


Against this backdrop of uncertainty, however, onething can be safely taken for granted – pharma ischanging with time and the industrial pharmacist ofthe future will need new skill sets to continue to formthe backbone of this industry – tempora mutantur,nos et mutamur in illis. Therefore, it is imperative thatwe look to the future, to be prepared for thechallenges with which our profession will be faced.Meanwhile, however, I look to a more immediatefuture and extend to you all from EIPG the very bestwishes for a serene festive season and a prosperousnew year.

Professor Claude FarrugiaVice-President Communications, EIPG

3european INDUSTRIAL PHARMACY December 2014 • Issue 23

editorial

In many countries, specificguidelines for biosimilars have beenissued by authorities to regulate thedevelopment and approval of theseproducts. The companies involvedin biosimilar development need tofully understand regulatoryrequirements, master the science ofbiological medicinal products, havethe capability to manufacture theseproducts in accordance with currentgood manufacturing practice(cGMP), and crucially to havesufficient budget to complete thedevelopment program.

Biosimilars guidelineThe first biosimilar specific guideline

was issued by the Committee forMedicinal Products for Human Use(CHMP) of the European MedicinesAgency (EMA) in 20051.Subsequently, the CHMP releasedtwo further guidelines for biosimilarscovering specific aspects2,3. Theconstitution of the guidelines isdescribed in Table 1. Adistinguishing feature of the EMAguideline structure from thatestablished by other countries is tohave individual product-specificguidelines, such as those associatedwith erythropoietins, somatropin andmonoclonal antibodies4–12.Following a number of years ofimplementation, the CHMP is in the

process of revising some of theguidelines based on the experiencegained over these years and currentthinking on biosimilardevelopment13–17. Japanesebiosimilar guidelines were issued in200918, whereas in the US the much-anticipated package of draftbiosimilar guidance was initiallyreleased from the Food and DrugAdministration (FDA) in 201219–23.Additionally, there are issuedguidelines for biosimilars in severalother countries, which, to varyingdegrees, follow the standards set bythe EMA or the World HealthOrganization (WHO) guidelines24

(WHO guidelines issued in 2009). Though there are minor

differences in the guidelinesestablished within the ICH regions,the broad outline is the same, asshown in Figure 1. Broadly speaking,available guidelines recommend arisk-based stepwise approach tobiosimilar development followingthe path of (1) a detailedphysicochemical and analyticalcomparability between thebiosimilar and reference product; (2)in vitro functional testing; (3) in vivotoxicity; and (4) clinical studies(pharmacokinetic (PK),pharmacodynamic (PD), efficacy,safety including immunogenicity).

The data which was collected forthe original reference productshould, wherever possible, bereferred to during the developmentof its biosimilar, but this data areusually confidential and cannot beaccessed. For example, thecompany aiming to develop thebiosimilar cannot obtain the hostcell and the information tomanufacture the original referencebiologic product. Thus, thebiosimilar developer has to establishits own manufacturing process. Inthe next step of development, thecharacterisation of quality attributesshould be studied and, moreover,the similarity in quality must beinvestigated. In these steps, farmore data is needed whendeveloping a biosimilar comparedwith the development procedure ofthe original reference product. Onthe other hand, some studies can beomitted in the non-clinical andclinical phases of biosimilar

european INDUSTRIAL PHARMACY December 2014 • Issue 23

ACHIEVING BIOSIMILARPRODUCT APPROVAL – KEYSUCCESS FACTORS FORDEVELOPMENTby Hideaki Nomura and Gary Trewartha

Biosimilars have attracted increasing attention over thepast 10 years. As a growing number of biological

medicinal products which have reached blockbuster levelsin terms of sales will soon run out of patent protection,many pharmaceutical companies have initiated biosimilardevelopment programs. Although many biologicalmedicinal products provide remarkable efficacy in somediseases, these products concurrently cause a severefinancial burden for payers because of their extremelyhigh prices. This financial burden is coming under ever-increasing scrutiny and pressure. Therefore, biosimilarshave been much awaited as a means of introducingaffordable care to patients. On the other hand, biosimilardevelopment cannot follow the established genericregulatory pathway, because biological medicinalproducts have extremely complicated structure andcharacter, and to produce the exact same molecule as anoriginal reference product is impossible.

Hideaki Nomura is the President and CEO of Fujifilm Kyowa Kirin Biologics (FKB),Tokyo, Japan. FKB was established in 2012 and simultaneously he took his currentposition. FKB is a joint venture company under FUJIFILM and Kyowa Hakko Kirinconcentrating on the biosimilar business, and is developing a number of products forglobal markets.

Gary Trewartha is Regulatory Affairs Manager for Fujifilm Kyowa Kirin Biologics (FKB),EU Branch, based in the UK.

4

ACHIEVING BIOSIMILAR PRODUCT APPROVAL – KEY SUCCESS FACTORS FOR DEVELOPMENT continued


development. Typically, in the non-clinical phase, safety pharmacology,reproduction toxicology,mutagenicity and carcinogenicitydata are not required. Therequirements for in vivo toxicologystudies vary across the differentregions, especially with regard tothe requirement to conduct a repeatdose toxicology study in non-humanprimates. With a suitable risk-based

assessment of other non-clinicaldata, this study is generally omittedfor biosimilar development in theEU, whereas a repeat dosetoxicology study in non-humanprimates is still largely regarded as aprerequisite prior to a first-in-humanstudy in the US.

In the clinical phase of biosimilardevelopment, PK and PD study(ies)to show the similarity between

original reference product and itsbiosimilar is conducted as Phase 1.Generally, this is to show the bio-equivalency between the twoproducts. In many cases, it isdifficult to perform a PD studybecause there is no suitably robustand sensitive PD (surrogate marker)of efficacy. By definition, biosimilarswill be administered using the samedose and dosing regimen to treatthe same indications as thereference product, thus Phase 2clinical studies are not required.Within Phase 3, safety and efficacydata should be collected tocompare the biosimilar with theoriginal reference product. Head-to-head immunogenicity studiesbetween the reference andbiosimilar product should beconducted throughout clinicaldevelopment to ensure thebiosimilar does not display anysignals of increasedimmunogenicity.

A key current issue withinbiosimilar development is thequestion of extrapolation. Insituations where the original

Table 1: Construction of EU biosimilars guidelines

Figure 1: Required Data for Biosimilar Development

reference product has multipleapproved indications with the samemode of action, a clinical study toshow the similarity of safety andefficacy in each indication may notbe required. The extrapolation ofdata obtained from one indicationto allow approval in otherindications is potentially acceptedby authorities if the justification tosupport the extrapolation is fullydemonstrated. However, wheredifferent modes of action exist inapproved indications of the originalreference product, additionalclinical studies will usually have tobe performed to pursue otherindication approvals for thebiosimilar. The level of acceptanceby regulatory authorities ofextrapolation justifications made inthe licensing submissions forbiosimilars has been shown to varydepending on the country/regioninvolved, with assessmentconducted on a case-by-case basis.

Developed biosimilars Biosimilars are most firmlyestablished in EU countries, with theEMA leading the way in establishinga formal regulatory pathway for theapproval of biosimilars. Table 2provides a list of biosimilarsapproved in the EU, with centralapproval by the EMA rather thannational approvals being amandated requirement forbiosimilars. Six types of biosimilarshave been approved: somatropin,erythropoietin (epoetin alfa andzeta), granulocyte-colony stimulatingfactor (G-CSF; filgrastim), infliximab,insulin glargine, and folliclestimulating hormone (FSH; follitropinalfa). The first biosimilar, Omnitrope®

(somatropin), was approved by theEU authorities in 2006 and morerecently Remsima®/Inflectra®

(infliximab) was approved in 2013 asthe first biosimilar of a monoclonalantibody product (Remicade®).However, not all products could

obtain regulatory approval; withapplications for human insulin,interferon alfa and interferon beta-1abeing withdrawn because theavailable data did not sufficientlydemonstrate similarity to the originalreference product for the authority.

In Japan, somatropin,erythropoietin, G-CSF (filgrastim),and infliximab have already beenlaunched as biosimilars, having metthe requirements of the Japanesebiosimilar regulatory pathway. Inalmost all cases, foreign clinicalstudy data, which had beencollected primarily for EUsubmission, was submitted to andreviewed by the Japaneseregulatory authority, thePharmaceutical and Medical DevicesAgency. In every one of these cases,additional data was requested and aclinical study with Japanese subjectswas required and the data from thisstudy submitted to support theapplication.



Table 2: Biosimilars in the EU

In the US, there is currently nobiosimilar product approved usingthe defined regulatory pathway(Section 351(k) of the Public HealthService Act). Although non-innovator biologic product versionsof somatropin and G-CSF (filgrastim)have already been approved,somatropin was reviewed under anabbreviated new drug applicationpathway and G-CSF (filgrastim) wasreviewed as a novel product underthe 351(a) or biologics licenseapplication pathway. In 2014,infliximab and another G-CSF(filgrastim) were submitted underthe specific biosimilar regulatorypathway (351(k)), and are thought tobe the first products to do so.

Key success factors ofbiosimilars developmentFirstly, knowledge and experience ofbiological sciences is necessary todevelop biosimilars. A typicalmanufacturing procedure forbiological medicinal products isdescribed in Figure 2 and discussedin more detail below. Biosimilardevelopment starts from host cellclone selection. Screening for anadequate clone is very importantbecause it significantly impacts thefinal character of the product. Thereis still an opportunity to adjust thecharacter of the product in the

subsequent processes, but the rangeof possible adjustment is verynarrow. Therefore, it is necessary toselect a clone that produces aproduct as similar as possible to theoriginal reference. Equally,consideration of the titer of theclone to produce the biosimilarproduct is also important, because itwill influence the eventualmanufacturing cost and market priceof the biosimilar, which hasimplications for one of the mostimportant aims of developingbiosimilars that is to provideaffordable product to benefitpatients. In this early phase ofbiosimilar development, it is alsoimportant to establish an effectivescreening system to select a cloneeffectively. This requires thedevelopment of suitable andaccurate analytical methods toinvestigate the clone characteristics.In the upstream processes, theselection of culture media and itsadditives will also influence thecharacter and titer of the biosimilarproduct, and adequate cultureconditions should be adopted tointroduce similar characteristics tothe original reference. In thedownstream processes, the choice ofresin and the combination andordering of column purification alsoaffect the character of the product.

In this step, consideration of thepurification strategy to obtain thebiosimilar product is important,where levels of variant contentsshould be reduced. However, thisneed is balanced by the fact thatadoption of complicated purificationprocesses would lead to lowerpurification yield and cause highercost of the product. Prior toestablishing the manufacturingprocesses of a finished biosimilarproduct, formulation studies need tobe performed. Initially, a decision onwhether to adopt the sameformulation as the original referenceproduct should be made. If theformulation of the original referenceproduct is not to be used, anothersuitable formulation with therequired stability and safetyattributes must be developed.Additionally, the selection ofcontainer and closure system is alsoof high importance. In some cases,the original reference product ispresented as a self-injection dosageform, therefore, the development ofa pre-filled syringe and/or otherdevices, such as a pen or auto-injector, may be necessary.

Secondly, full understanding ofthe regulatory requirements forbiosimilars is vital. A companywishing to develop biosimilarsglobally should understand not onlythe specific guidelines in everycountry or territory, but also theauthorities’ way of thinking. Thecommunication with authorities,especially in the form of face-to-faceadvisory meetings, is very useful tounderstand this. To have a fruitfulmeeting, the data should becollected to the fullest extentpossible and a plan of the totaldevelopment package should beprepared and presented. Inevitably,in an area of evolving regulatorydemands, a company planning todevelop biosimilars globally willsometimes receive differentopinions from one authority toanother, but it should maintaincommunication with perseveranceand attempt to introduce anacceptable plan for all authorities.

Finally, it is necessary forbiosimilar developers to establish a



Figure 2: Manufacturing process of biologics

suitable manufacturing facility,especially for bulk drug. The costsassociated with commercial scalebiomanufacturing are significant. Itmay require from $150 million to$250 million to develop a biosimilarglobally (compared to an estimated$2–3 million for small moleculegenerics), with the final costdepending on the specific targetproduct. Also, the variation in therequirements to demonstrate clinicalefficacy (and similarity) betweendifferent products/indications affectsthe number of patients required inthe Phase 3 study and the price ofreference product impacts thesecosts directly. Moreover, sinceantibody products generally requirerelatively high doses to produceclinical efficacy, large quantities ofthe biosimilar product needs to bemanufactured for the developmentstudies. To compound this issue,regulatory authorities require thebiosimilar developer to showconsistency in the batch to batchmanufacturing, so many batchesmust be manufactured. As a result,the facility to manufacture theproduct is very important forbiosimilar development. Within thetypical biosimilar scenario, there isless opportunity to scale up themanufacturing capacity, due tolimited time before starting a pivotalPhase 3 clinical trial, therefore, asubstantial batch size is usually usedfor manufacture from the startingpoint of biosimilar development. Ifthe company has no suitable facility,it needs to build a new one orrequest support from a contractmanufacturing organisation tosupply the product. Both ways arecostly.

ConclusionsWhen considering biosimilarsdevelopment, you should confirmwhether enough budget is available,you have sufficient technology andknow-how to develop biologicalmedicinal products, and you canestablish or identify a suitable facilityfor manufacturing. Furthermore, youshould be ready to meet theguidelines and regulatory authorityrequirements. Biosimilars

development is different frominnovative biologics developmentand during the course of productapproval regulatory authorities willmake additional requests whichhave never been required in thecase of innovative biologicalproduct development.

References1 CHMP. Guideline on Similar BiologicalMedicinal Products. EMEA/CHMP/437/04.London: CHMP, EMEA; 30 October 2005.

2 CHMP. Guideline on Similar BiologicalMedicinal Products ContainingBiotechnology-Derived Proteins as ActiveSubstance: Quality Issues. EMEA/CHMP/BWP/49348/2005. London: CHMP, EMEA;22 February 2006.

3 CHMP. Guideline on Similar BiologicalMedicinal Products ContainingBiotechnology-Derived Proteins as ActiveSubstance: Non-Clinical and Clinical Issues.EMEA/CHMP/BMWP/42832/2005 Rev. 1.London: CHMP, EMA; 22 February 2006.

4 CHMP. Guidance on Similar MedicinalProducts Containing Recombinant HumanSoluble Insulin. EMEA/CHMP/BMWP/32775/2005_Rev. 1. London: CHMP, EMA;22 February 2006.

5 CHMP. Guidance on Similar MedicinalProducts Containing Somatropin.EMEA/CHMP/BMWP/94528/2005.London: CHMP, EMEA; 22 February 2006.

6 CHMP. Guideline on Non-Clinical andClinical Development of Similar BiologicalMedicinal Products ContainingRecombinant Erythropoietins (Revision).EMEA/CHMP/BMWP/301636/2008.London: CHMP, EMA; 18 March 2010.

7 CHMP. Guidance on Similar MedicinalProducts Containing RecombinantGranulocyte-Colony Stimulating Factor.EMEA/CHMP/BMWP/31329/2005.London: CHMP, EMEA; 22 February 2006.

8 CHMP. Reflection Paper: Non-Clinical andClinical Development of Similar MedicinalProducts Containing RecombinantInterferon Alpha. EMEA/CHMP/BMWP/102046/2006. London: CHMP, EMEA; 23April 2009.

9 CHMP. Guideline on Non-Clinical andClinical Development of Similar BiologicalMedicinal Products Containing Low-Molecular-Weight-Heparins. EMEA/CHMP/BMWP/118264/2007. London: CHMP,EMA; 19 March 2009.

10 CHMP. Guideline on Similar BiologicalMedicinal Products ContainingMonoclonal Antibodies － Non-Clinicaland Clinical Issues. EMA/CHMP/BMWP/403543/2010. London: CHMP, EMA; 30May 2012.

11 CHMP. Guideline on Similar BiologicalMedicinal Products Containing InterferonBeta. EMA/CHMP/BMWP/652000/2010.London: CHMP, EMA; 21 February 2013.

12 CHMP. Guideline on Non-Clinical andClinical Development of Similar BiologicalMedicinal Products ContainingRecombinant Human Follicle StimulatingHormone (r-hFSH). EMA/CHMP/BMWP/671292/2010. London: CHMP, EMA; 21February 2013.

13 CHMP. Guideline on Similar BiologicalMedicinal Products. EMEA/CHMP/437/04Rev 1. London: CHMP, EMA; 23 October2014.

14 CHMP. Guideline on Similar BiologicalMedicinal Products ContainingBiotechnology-Derived Proteins as ActiveSubstance: Quality Issues (Revision 1).EMA/CHMP/BWP/247713/2012. London:CHMP, EMA; 22 May 2014.

15 CHMP. Draft Guideline on SimilarBiological Medicinal Products ContainingBiotechnology-Derived Proteins as ActiveSubstance: Non-Clinical and ClinicalIssues. Draft. EMEA/CHMP/BMWP/42832/2005 Rev. 1. London: CHMP, EMA; 3 June2013.

16 CHMP. Guideline on Non-Clinical andClinical Development of Similar BiologicalMedicinal Products ContainingRecombinant Human Insulin and InsulinAnalogues. Draft. EMEA/CHMP/BMWP/32775/2005_Rev. 2. London: CHMP, EMA;25 April 2014.

17 CHMP. Guideline on Non-Clinical andClinical Development of Similar BiologicalMedicinal Products Containing Low-Molecular-Weight-Heparins. Draft.EMEA/CHMP/BMWP/118264/2007 Rev. 1.London: CHMP, EMEA; 17 January 2013.

18 Ministry of Health, Labour and Welfare.Guideline for the Quality, Safety, andEfficacy Assurance of Follow-on Biologics.PFSB/ELD Notification No. 0304007.Japan: Evaluation and Licensing Division,Pharmaceutical and Food Safety Bureau,MHLW; 4 March 2009.

19 FDA. Guidance for Industry QualityConsiderations in DemonstratingBiosimilarity to a Reference ProteinProduct. Draft Guidance. Rockville, MD:FDA; February 2012.

20 FDA. Guidance for Industry: ScientificConsiderations in DemonstratingBiosimilarity to a Reference Product.Rockville, MD: FDA; February 2012.

21 FDA. Guidance for Industry FormalMeetings Between the FDA and BiosimilarBiological Product Sponsors or Applicants.Rockville, MD: FDA; March 2013.

22 FDA. Guidance for Industry Biosimilars:Questions and Answers RegardingImplementation of the Biologics PriceCompetition and Innovation Act of 2009.Draft Guidance. Rockville, MD: FDA;February 2012.

23 FDA. Guidance for Industry ClinicalPharmacology Data to Support aDemonstration of Biosimilarity to aReference Product. Draft Guidance.Rockville, MD: FDA; May 2014.

24 Expert Committee on BiologicalStandardization, WHO. Guidelines onEvaluation of Similar BiotherapeuticProducts (SBPs). Geneva, Switzerland:WHO; October 2009.



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“Prediction is very difficult,especially about the future”As the Danish physicist Niels Bohrsaid, “prediction is very difficult,especially about the future”. Itmight, therefore, seem unwise todiscuss the technical details of theEuropean Falsified MedicinesDirective (FMD) ‘Safety Features’Delegated Act before this act hasbeen published and when, in fact,even the date of publication is notcertain.

The reasonable approach wouldseem to be ‘wait-and-see’ ratherthan second-guessing whatprescriptions the Delegated Act maycontain and how to prepare forthese. Indeed, it may seem foolishto start a readiness implementationprogramme before the legislationhas been published. It would ratherseem sensible to delay anyinvestment decisions until thedetails of the legislativerequirements are fully known andunderstood. Particularly so, sincereports from early adopters allsuggest that serialisation andtraceability implementation projectsare complex, costly and present a

major challenge to any pharmacompany. Even worse, companiesthat have completed their projectsand moved into business-as-usualmode testify just how significantlyimplementing serialisation andaggregation has impacted theirlines, reporting initial reduction inmanufacturing output andefficiencies in excess of 10%,sometimes up to 20%, and lengthyrecovery times to return to a levelthat is, at best, a few percentagepoints below current capabilities.

So why would any senior decisionmaker volunteer to expose theirorganisation to the risks and coststhat a serialisation readinessprogramme brings unless therequirements are clearly definedand tied to a firm legal compliancedeadline?

“Worried about the cost ofcompliance? – Try non-compliance…”The answer is that to wait and see isan even riskier and most likely evencostlier option: the learning fromearly adopters is that reaching thepoint where serialisation is a

business-as-usual capability can takeanything in the order of 2 to 3 years.Some companies have proudlytalked about implementationprogrammes completed in less than2 years, but, in my practicalexperience, I have yet to see apharma company that hassuccessfully implemented all parts oftheir serialisation readiness programin less than 18 months, and thenonly in auspicious circumstances,with vigorous senior stakeholdersupport and a level of investmentthat few companies can afford.

The stark fact is that the ‘wait-and-see’ approach does not avoid risks.On the contrary, any costs and risksassociated with implementing aserialisation readiness programmepale into insignificance whencompared to the alternative: beingunable to supply the Europeanmarket once the EU-FMDcompliance deadline comes intoforce and losing a – for a typicalpharma manufacturer – huge chunkof sales.

“Uncertainty? – Whatuncertainty?”But what about the argument thatthere is still too much uncertaintyregarding timing, scope of affectedmarkets and products as well as thetechnical details of the EU-FMDrequirements to commit at thisstage? A closer look shows quicklythat this argument, though oftenquoted, can be dispelled withoutthe reach for a Crystal Ball. First ofall, on the timing of the DelegatedAct publication: DG SANCO, theresponsible Commissiondepartment, updated their plan on20 November stating the intentionto adopt the Delegated Act by Q22015; publication in the OfficialJournal of the European Unionwould then follow in the second halfof 2015, due to Parliament, Counciland World Trade Organizationscrutiny rights. Given that theDirective sets out a clear timetableof 3 years from the Delegated Actpublication date, it is a safeplanning assumption that the ‘SafetyFeatures’ provisions of theDelegated Act will come into forcein the second half of 2018.

What about the scope, in

GAZING INTO THECRYSTAL BALL: WHAT WILLTHE EU-FMD SAFETYFEATURES DELEGATED ACTBRING?by Christoph Krähenbühl

This paper investigates the technical aspects of theanticipated ‘Safety Features’ Delegated Act and

gives a personal view on how key stakeholders, inparticular pharmaceutical manufacturers supplyingproducts to the European market, will be affected.

Christoph Krähenbühl is a respected serialisation expert and thought leader incoding and serialisation for the pharmaceutical industry. Along with partner IanHaynes, he runs 3C Integrity (www.3cintegrity.com), a specialist consulting firm whichalso offers comprehensive 2-day training programmes to fully prepare pharmacompanies of all sizes for the implementation of their serialisation/traceabilityreadiness programme.


GAZING INTO THE CRYSTAL BALL: continued


particular, which markets are in thescope of the FMD? After all, the lawdifferentiates two sets of markets,those where compliance is required3 years after the publication of theDelegated Act and the MemberStates where ‘equivalent features’are in use and that are, therefore,given an additional 3 years forcompliance? It is true that theDirective makes special provisionsfor markets where a comparableauthentication system has been inplace since 1 July 2011, but a quicklook at the main ‘Safety Features’provisions of the Directive showsthat only a very small number ofMember States would qualify forthe extended deadline: in practicalterms, 2018 will be the Europe-widecompliance deadline with thepossible exception of MemberStates, such as Italy and Belgium,that might argue that the Bollini orVignettes currently used for otherpurposes could qualify as ‘UniqueIdentifiers’ as defined by the FMD.

Another area of uncertainty raisedregards the question, whichmedicines are in the scope of theDirective. The law specifies that itsprovisions would apply, by default,to all prescription-only medicines

while over-the-counter drugs wouldbe excluded, but allows forexceptions subject to risk-basedassessment that would allow forsome prescription-only medicinesto be white-listed and, conversely,some over-the-counter products tobe black-listed. Before exploringthe provisions of the Delegated Actin more detail, it is worth setting outwhat the implementation of the EU-FMD will mean in practice.

Europe-wide medicinesverification processFor the European patient, the mostfar-reaching change to come intoforce in 2018 will be that theirprescription medicines will bechecked out at the point ofdispense against a complexEurope-wide medicines verificationinfrastructure of systems. Not thatthey, as patients, will be aware ofthis; there are really only two smallchanges to their packs they maynotice. One is that the pack ofmedicines they are given will betamper-evidenced – a change thatis unlikely to catch their attention as

it will bring the level ofphysical pack securityup to the standardexpected ofeverything else theypurchase, from packs

of sweets to pots of yoghurt. Thesecond change, equallyunremarkable, is that the pack ofmedicine will carry a 2D DataMatrixcode – different to, but not unlike,the QR codes that we are gettingincreasingly familiar with.

However, these two features arethe hardly visible tip of an enormousiceberg, the results of a multi-yearand multi-billion Euro effort byindustry and all supply chainstakeholders of putting in placetechnical measures, systems andprocesses aimed at ensuring thesupply of genuine medicinalproducts to patients in all 28Member States.

The unique pack identificationcode carried in the 2D DataMatrixlies at the centre of these efforts; asthe name says, this Unique Identifierwill be globally unique and containthe product code (and wherenecessary national healthcarereimbursement number), thebatch/lot number, the expiry dateand a highly randomised serialnumber. It will be used to scanevery single pack at the point ofdispense to carry out a series ofautomatic checks – within a fractionof a second – against a complex setof database repositories deployedacross Europe to feed back todispensing pharmacists information

about the status of theproduct. Pharmacists willsee instantaneouslywhether the packnumber has beendispensed before andcould, therefore, be acounterfeit product; theycan ensure it’s still withinits expiration date, andcheck whether there is arecall or other noticeagainst the batch.

Implementing thisunique pack codingsystem presents a hugestep forward in terms ofpatient safety. However,it will also require atremendous amount ofwork – not simply interms of thedevelopment and



deploymentof the complexEurope-widesystems infra-structure, but also theimplementation projectsneeded to achieve readinessfor compliance by everypharmaceutical manufacturersupplying the 28 EU MemberCountries, be they original brandowners, generics manufacturers,contract packers or repackagers/parallel importers.

Anticipating the details ofthe Delegated Act So what will manufacturers need toput in place to achieve compliancereadiness?

The Directive, adopted in July2011, has clearly set out the keyprovisions: that medicinal productssold in the EU should carry safetyfeatures that allow verification of theauthenticity and uniqueidentification of individual packs(which will also need to be tamper-evidenced) and that this verificationwould entail the use of repositorysystems (which manufacturers willhave to pay for).

The technical details of how this isto be achieved will be spelled out inthe Delegated Act, but that doesnot mean that manufacturers – andother stakeholders – are left in thedark as to what measures they willhave to implement to achievecompliance with the EU-FMD. Afterall, the provisions of the DelegatedAct will have been arrived atthrough extensive consultation andcontinuous engagement with allstakeholders since the publicationof the Directive. In fact, as will beshown, all the core technicalrequirements that manufacturershave to comply with are known andunderstood well enough for anymanufacturer – brand owner,

contract manufacturingorganisation, generics

manufacturer orrepackager – to be

able to specify,plan andimplementtheir EU-FMDreadinessproject today.

Let usexamine, then,

the key components ofsuch a manufacturer

readiness programme and theprovisions that have been set out sofar through the Delegated Actconsultations and stakeholderupdates.

The proposed technicalspecifications of the UniqueIdentifier confirming the use of amachine-readable 4- (or 5-) elementcode expressed as an ISO-standard2D DataMatrix barcode that willinclude the key data elements thatare, by now, familiar from codingrequirements that are already inplace in other parts of the world, forexample Turkey and Argentina. TheDataMatrix will contain: 1) theproduct identification code (usuallythe global trade item number(GTIN)/national trade item number(NTIN), 2) expiry date, 3) batch/lotnumber, and 4) the unique andrandomised serial number.

There is also the recognition thatthere may be a need to include anational product code, for examplefor reimbursement purposes (wherethat code is not part of the productcode, such as the NTIN); this wouldthen be included as a fifth elementin the barcode, an approach thathas been discussed extensively andis also supported by the GS1General Specifications.

It goes without saying that theseunique identifiers that have beenapplied to every pharmaceuticalpack will need to be collected inorder to upload them to theEurope-wide verification system. Inpractical terms, this meansmanufacturers have to establishtheir own serialised data repository.At the same time, there is a dataretention requirement on all

stakeholders, including therequirement to make theinformation available to theauthorities when requested. Thetimeframe is set, as widelyexpected, for the duration of expirydate plus 1 year. Note that, in thecase of manufacturers, the dataretention requirement also includesretaining a record of the anti-tampering device used.

Not directly relevant tomanufacturers are the provisionsregarding the modalities ofverification of the safety features,but indirectly these are, in fact, ofgreat interest as the Directiveobliges manufacturers to pay for therepository systems and infra-structure. The good news here isthat the Delegated Act describesthe establishment and managementof the repositories system in termsthat fully support a stakeholdermodel approach, such as that beingimplemented by the EuropeanFederation of PharmaceuticalIndustries and Associations (EFPIA)-led European Stakeholder Modelcoalition. This means that a modelis finding support that has beendeveloped with the aim of fulfillingthe EU-FMD requirements in a cost-effective way and that theinvolvement of the industrystakeholders who are most directlyimpacted by the system is endorsedby the European Commission.

What this also means is that anymanufacturer who is still uncertainabout how to prepare for EU-FMDcompliance would be well-advisedto engage, through their industryassociations, with the EuropeanStakeholder Model and access thetechnical guidance documents thatare available to any interestedparty. EFPIA and partnerorganisations, PharmaceuticalGroup of the European Union, theEuropean Association ofPharmaceutical Full-lineWholesalers and EuropeanAssociation of Euro-PharmaceuticalCompanies, have invested a greatdeal of effort into preparing anindustry-wide response that anyaffected stakeholder will benefitfrom.

ConclusionThe perception that there is stillmuch uncertainty around therequirements of the EU-FMD is afallacy, but, in combination with alack of understanding of just howlarge a challenge theimplementation of a compliance-ready solution will be for mostcompanies and how long this workwill take, can – and in someinstances will – prove fatal for somepharma manufacturers. Companiesthat have not yet started theirimplementation programme andmay not even have budgeted forany implementation activity in 2015,are running the very real risk that

they will be losing their Europeansales from 2018 onward.

Looking at a best-caseimplementation timeline for the firstpilot line to repository installationtaking at least 18 months, itbecomes obvious that the task ofimplementing the serialisationcapability and operating it reliablyand without a significant hit onproductivity across the majority of acompany’s packing lines is a multi-year endeavour that now clearlypushes hard against the 2018compliance deadline.

The conclusion is clear: the soonercompanies start their implementationprogramme, the better.

Bibliography1 European Commission. FalsifiedMedicines. Brussels, Belgium: EC.http://ec.europa.eu/health/human-use/falsified_medicines/index_en.htm

2 Testori Coggi P, Director General forHealth and Consumers. The FalsifiedMedicines Directive: improving the safetyof EU medicines. Focus article in Health-EU Newsletter 123. Brussels, Belgium: EC.http://ec.europa.eu/health/newsletter/123/focus_newsletter_en.htm

3 European Medicines Agency. FalsifiedMedicines. London, UK: EMA.http://www.ema.europa.eu/ema/index.jsp?curl=pages/special_topics/general/general_content_000186.jsp

4 GS1. Healthcare. Brussels, Belgium: GS1.http://www.gs1.org/healthcare

5 European Stakeholder Model. Ensuringpatients have access to safe medicines.Brussels, Belgium: ESM. http://www.esm-system.eu/home.html.



PharmacoVigilanceRevıew

Journal on drugsafety issues

Editor – Rob Begnett

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

also carries reviews of current methods of pharmacovigilance.

Order online at www.euromedcommunications.com

Or email: [email protected]

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

PharmacoVigilanceRevıewSupporting the safe use of

medicines and medical devices

Managing Reference SafetyInformation

The EU centralised applicationfrom a pharmacovigilance andrisk management prospective

Post-authorisation aggregatesafety reporting: the new PSUR

New European pharmacovigilancelegislation – an adequateresponse to current challenges?

Volume 7 Number 3/4 Nov 2013


In October, the US Food and DrugAdministration (FDA) approvedGilead Science’s Harvoni(ledipasvir/sofosbuvir), the world’sfirst single-tablet, once-daily therapyfor the treatment of chronic HCVgenotype 1 (GT1) infection in adults.The decision, which came less than12 months after the approval ofGilead’s blockbuster NS5Bnucleotide polymerase inhibitor,Sovaldi (sofosbuvir), represents thelatest in a long line of momentousdevelopments in the managementof HCV, a disease that was effectivelyunknown just 25 years ago.

This article outlines the past andpresent HCV treatment landscape,with a particular emphasis on themost recent developments and

industry trends. It begins with ahistorical overview of the evolutionof HCV management, from the useof interferon + ribavirin (1990s) topeginterferon + ribavirin (2000s),and concludes with a discussion ofthe arrival of the first-generationDAAs (2011–2013) and the present-day interferon-sparing andinterferon-free DAA regimens. It alsoprovides an overview of the currentlate-stage pipeline, the latest trendsin research and development (R&D)and commercialisation strategiesacross the traditional seven majorpharmaceutical markets (7MM; US,France, Germany, Italy, Spain, UKand Japan), and futureconsiderations for industrystakeholders.

From interferon to the adventof DAAs: a brief history of theHCV treatment landscapeThe history of HCV is a remarkablestory that highlights the power ofscientific and medical innovation.For decades prior to theidentification of HCV in 1989,clinicians had been aware of anunknown pathogen that causedsimilar clinical outcomes to hepatitisA virus (HAV) and hepatitis B virus(HBV) infections. These casesconfounded physicians becausethey consistently tested negative forHAV and HBV during the differentialdiagnosis, yet they had signs andsymptoms that were suggestive ofhepatitis. As a result, what laterbecame known as HCV was referredto as “non-A, non-B hepatitis” in theyears leading up to the identificationof the virus.

Since the discovery of HCVroughly 25 years ago, the treatmentalgorithm has evolved rapidly, whichis primarily a direct consequence ofthe pharmaceutical industry’scommitment to developing saferand more efficacious treatmentoptions for patients. The earliesttherapies, interferon and ribavirin(see Figure 1), were initially usedempirically, and rely chiefly on thepatient’s immune response toeliminate the virus. However, theireffectiveness is hampered bydebilitating side effects (severe flu-like symptoms for interferon andanaemia for ribavirin), theinconvenience of the requirementfor frequent administration ofinterferon by a healthcareprofessional, long treatmentdurations of up to 48 weeks, and ahigh propensity for viral resistance.Moreover, the interferon-basedtherapies are less effective incombatting GT1 infections, whichtoday represent a substantialproportion of the prevalent HCVcases — over 70% of all cases in theUS alone. Despite these limitations,interferon + ribavirin served as thestandard of care for HCVthroughout the 1990s.

The first breakthrough in thetreatment of HCV occurred at theturn of the century, whenresearchers at EnzonPharmaceuticals discovered that the

RECENT R&DBREAKTHROUGHSCONTINUE TOREVOLUTIONISE THEALREADY DYNAMICHEPATITIS C TREATMENTLANDSCAPEby Christopher J. Pace

The recent influx of late-stage pipeline candidates andnewly-approved regimens has stimulated an

unprecedented level of interest in the management andtreatment of hepatitis C virus (HCV). Notablebreakthroughs in the last few years, especially theemergence of all-oral, direct-acting antiviral (DAA)combinations, have revolutionised the treatmentalgorithm and forced pharmaceutical companies toreassess their portfolios in order to adapt to a rapidlychanging competitive landscape.

Christopher J Pace, PhD, is a Senior Analyst covering Infectious Diseases at researchand consulting firm GlobalData. He extensively researches and provides in-depthanalysis on a wide range of topics in the infectious diseases space, in particular,hepatitis C therapeutics; vaccine research, development, and immunisation policy;and market access strategies for antibiotics. Email: [email protected];www.healthcare.globaldata.com


RECENT R&D BREAKTHROUGHS CONTINUE TO REVOLUTIONISE HEPATITIS C TREATMENT continued

conjugation of polyethylene glycol(PEG) to interferon, a process knownas pegylation, increases its half-life,thus reducing the dosing frequencycompared with standard, non-pegylated interferon. Enzon licensedits proprietary PEG technology toRoche and Schering-Plough (nowMerck) in 2001, and the use ofpeginterferon — consisting ofRoche’s Pegasys (peginterferon alfa-2a) and Schering-Plough’s PegIntron(peginterferon alfa-2b) — incombination with ribavirin, soonbecame the new standard of carefor HCV. Despite the improvedconvenience of peginterferon overstandard interferon therapy, keydrawbacks remained — namely, aserious lack of efficacy in GT1patients, and the continuedpresence of highly undesirable sideeffects that hurt compliance.

Recognising the clear need fornew drug classes to combat HCV,particularly GT1 infections and forpatients who could not toleratepeginterferon-based regimens,pharmaceutical companies beganinvesting more aggressively in the

development of drugs that directlyinhibit the viral life cycle, known asDAAs. An improved understandingof the underlying molecular biologyand pathophysiology of HCVinfection were essential to theidentification of these novel drugtargets. In 2011, the first NS3/4Aprotease inhibitors, VertexPharmaceutical’s Incivek (telaprevir)and Merck’s Victrelis (boceprevir),were licensed for use in conjunctionwith peginterferon and ribavirin inGT1 patients. At the time, thesefirst-generation DAAs revolutionisedthe HCV treatment algorithm due totheir improved efficacy. However, inaddition to their own troubling sideeffects, they still required the co-administration of peginterferon andribavirin in order to prevent viralresistance. As a result, patientsbegan foregoing treatment, aphenomenon known as the“warehousing effect”, inanticipation of the approval of novelDAA regimens with reduced sideeffects, higher cure rates, andshorter treatment durations loomingon the horizon.

The Sovaldi era and thecurrent HCV pipelineThe launch of the first next-generation DAAs in late 2013,Gilead’s Sovaldi and Johnson &Johnson’s (J&J’s) Olysio (simeprevir),fundamentally altered the HCVtreatment landscape yet again, withcure rates of over 90% achieved formost patients. These drugs offeredthe first peginterferon-basedregimens with treatment durationsas short as 12 weeks, termed“interferon-sparing”, for GT1patients, and Sovaldi in combinationwith ribavirin became the first all-oral regimen for GT2/3 patients. Forcertain interferon-ineligible GT1patients, Sovaldi and Olysio wereadministered in combination withweight-based ribavirin. Warehousedpatients rapidly sought treatmentwith Sovaldi-based regimens,resulting in over $5 billion in sales byJune 2014 in the US alone, despitepayers having decried Sovaldi’s$84,000 price tag. Given theunprecedented success of Sovaldiand Olysio, key industry players areattempting to capitalise on the clear

Figure 1: Timeline of significant events in the history of HCV treatment.



demand for interferon-free, all-oralregimens, with this trend beingreflected in the current late-stageDAA pipeline for HCV (see Table 1).

The late-stage HCV pipeline ishighly diverse and is dominated by avariety of DAAs with distinctmechanisms of action, includingNS3/4A protease inhibitors, NS5Ainhibitors, NS5B nucleotidepolymerase inhibitors, and NS5Bnon-nucleotide polymeraseinhibitors. The efficacies ofnumerous DAA combinations, bothinterferon-sparing and interferon-free, are being assessed againstdifferent HCV genotypes (chiefly,GT1, 2, 3 and 4) and patientpopulations, which further enhancesthe overall diversity of the pipeline.The majority of these pipelinecandidates have demonstrated curerates of over 80% in clinical trials,with many topping 90% in theirtargeted cohorts.

For the past few years, theprevailing R&D strategy has been toadvance interferon-sparing andinterferon-free DAA regimens forthe treatment of HCV GT1, which, asnoted earlier, represents the largestHCV patient population across the7MM. However, most drugdevelopers, in recognition of thelimitations of interferon and therapid success of Sovaldi and Olysio,have shifted their efforts almostentirely towards the advancement ofall-oral, single-tablet DAA regimens

in order to compete with marketleader, Gilead. Firms, such as Merck,have also begun evaluating thepotential of ribavirin-free, single-tablet DAA regimens to competewith Harvoni.

With cure rates no longer akey differentiator, treatmentsimplicity and clevercommercialisation strategieswill drive competition in theHCV marketThe recent approval of Gilead’sHarvoni signalled the beginning of anew era in the treatment of HCV. Aspharmaceutical companies continueto revolutionise the treatmentalgorithm through the developmentof novel drugs, they must recognisethat efficacy and tolerability may nolonger represent an effective meansof product differentiation. Becausethe next-generation, all-oral DAAcombinations boast cure rates ofover 90%, along with minimal sideeffects, in most patients, companieshave already begun exploringalternative tactics for seizing marketshare, with one noteworthyapproach being the use ofaggressively competitive pricingstrategies.

For example, to counter themoves of Bristol Myers Squibb(BMS), J&J, and other competitors,Gilead has employed a shrewdpricing strategy for Harvoni — awholesale acquisition cost (WAC) of

$94,500 for a 12-week course oftherapy — with the hope offacilitating its rapid uptake,particularly in the US. This approachhas easily positioned Harvoni as themore cost-effective optioncompared with the interferon-sparing Sovaldi regimens (WAC of$94,726 for a 12-week course ofSovaldi in combination with Pegasysand ribavirin) for most GT1 patients,especially those who can be curedin 8 weeks (WAC of $63,000), whichcould be up to 40% of all patients.In fact, 12-week courses of Harvonior Sovaldi in combination withpeginterferon and ribavirin cost lessthan a 48-week regimen of the now-defunct Incivek in combination withpeginterferon and ribavirin (WAC of$109,060, not including the costsassociated with managing sideeffects). Gilead, after enduringmonths of scrutiny from US payersand policymakers surroundingSovaldi’s $84,000 price tag, willsilence some of its critics byessentially pricing its novel NS5Ainhibitor contained in Harvoni,ledipasvir, at $10,500 for a 12-weekcourse of therapy.

As a consequence of attributingthe bulk of Harvoni’s WAC toSovaldi, Gilead will also discouragethe off-label use of more expensiveSovaldi-containing DAA regimens,an opportunity that competingfirms, such as BMS and J&J, havehoped to exploit in their efforts to

Table 1. The current late-stage DAA pipeline for HCV*

Drug name Company Therapy class Most advanced development stage (region)

Sofosbuvir/ledipasvir Gilead NS5B nucleotide polymerase Marketed (US)(fixed-dose combination) inhibitor; NS5A inhibitor

Daclatasvir, asunaprevir, Bristol-Myers Squibb NS5A inhibitor, NS3 inhibitor; Marketed (EU and Japan;beclabuvir NS5B non-nucleoside daclatasvir and asunaprevir regimens

polymerase inhibitor only) Phase III (US; daclatasvir, asunaprevir, and beclabuvir regimens)

Paritaprevir (ritonavir- AbbVie NS3/4A protease inhibitor; Pre-registration (US and EU)boosted), ombitasvir, NS5A inhibitor; NS5B dasabuvir polymerase inhibitor

Vaniprevir Merck NS3/4A protease inhibitor Pre-registration (Japan only)

Grazoprevir/elbasvir Merck NS3/4A protease inhibitor; Phase III (US)(fixed-dose combination) NS5A inhibitor

Sofosbuvir/GS-5816 Gilead NS5B nucleotide polymerase Phase III (US)(fixed-dose combination) inhibitor; NS5A inhibitor

* The late-stage pipeline is defined as active programs having reached Phase III of clinical development as of October 2014 (source: GlobalData, Pipeline Products Pharma eTrack, October 2014).

seize market share. As previouslymentioned, an all-oral regimen ofSovaldi in combination with J&J’sOlysio has been prescribedfrequently to GT1 patients thus far in2014, despite carrying a hefty WACof $150,360 ($84,000 for Sovaldi and$66,360 for Olysio) for 12 weeks oftherapy. While Olysio’s unexpectedsuccess in 2014 (global salessurpassing $1 billion in only 6months) has been primarilyattributed to its off-label use incombination with Sovaldi, J&J hasalready acknowledged that itexpects sales of Olysio to decline in2015 due to the arrival of Harvoni asa cheaper and more convenientinterferon-free option for GT1patients. In recognition of the needto develop its own all-oral DAAregimen, the company recentlypurchased Alios BioPharma and itsnucleotide-based antivirals portfoliofor $1.75 billion. Gilead’s astutepricing strategy and lifecyclemanagement of its sofosbuvir-basedregimens (Sovaldi and Harvoni)should serve as a case study for howto achieve commercial success in arapidly maturing, competitivemarketplace.

What’s next? – future outlookThe HCV treatment landscape hasundergone a paradigm shift over thepast few years, and the impendingarrival of multiple interferon-free,fixed-dose combination regimenspromises even more dramaticchanges in the near future. In fact,the large number of effective next-generation therapies entering themarket may even make it possible tovirtually eradicate HCV in the nextdecade, although the jury is still out

on how payers will seek to regulatewho receives these cutting-edge, yetexpensive, therapies, particularlyonce the initial wave of warehousedpatients have been successfullytreated. From a public healthperspective, an increasingly crowdedand competitive HCV marketplace islikely to benefit patients, payers, andhealthcare providers.

Looking more closely at the futureHCV competitive landscape,Gilead’s strong pipeline,commercialisation strategies, andportfolio management have given ita key edge in the US over itscompetitors, but its position in therest of the 7MM is less tenable. Thesame bold pricing strategy that hasthus far succeeded in the US hasonly resulted in the delayed uptakeof Sovaldi-based regimens in theEU due to cost-effectivenessconcerns, particularly in the UK andFrance. Having received Europeanapproval for Daklinza (daclatasvir) inthe treatment of GT1–4 infections inAugust, BMS is also looking tomore aggressively commercialiseDaklinza-based regimens there, asthe proportion of non-GT1 patientsis greater in the EU than in the US.Meanwhile, in Japan, BMS alreadyhas a leg up on its competitors,having become the first company toreceive approval for an all-oralregimen (Daklinza and Sunvepra[asunaprevir]) for the treatment ofGT1b infections, which account forroughly 70% of Japanese HCVpatients, earlier this year.Nevertheless, Harvoni’s once-daily,single-tablet dosing will be hard forclinicians and eligible patients toignore once it launches in theEuropean and Japanese markets,

especially if Gilead leverages apricing strategy similar to the one itused in the US. For these reasons,Gilead, with its HCV portfolio ofSovaldi, Harvoni, and a promisingnext-generation pan-genotypicDAA regimen (sofosbuvir/GS-5816),has likely secured its leadingposition in the HCV marketplace forthe foreseeable future.

Stay tuned in 2015 for an updateon the next wave of innovation inthe treatment of HCV.

References/Suggested furtherreading1 American Association for the Study of

Liver Diseases (AASLD) and InfectiousDiseases Society of America (IDSA).Recommendations for testing, managing,and treating hepatitis C. Available from:www.hcvguidelines.org. Accessed 10October 2014.

2 Au JS, Pockros PJ. Novel therapeuticapproaches for hepatitis C. ClinPharmacol Ther 2014;95(1):78–88.

3 European Association for the Study of theLiver (EASL). Recommendations ontreatment of hepatitis C. Available from:http://files.easl.eu/easl-recommendations-on-treatment-of-hepatitis-C/index.html.Accessed 10 October 2014.

4 GlobalData. PharmaPoint: Hepatitis CVirus – Global Drug Forecast and MarketAnalysis to 2022: Event-Driven Update.May 2014, GDHC001EPIDR. Availablefrom: http://store.globaldata.com/market-reports/pharmaceuticals-and-healthcare/pharmapoint-hepatitis-c-virus-global-drug-forecast-and-market-analysis-to-2022-eventdriven-update#.VEEs6fnF-RY.

5 GlobalData. Pipeline Products PharmaeTrack. October 2014.www.pharmaetrack.com

6 Heim MH. 25 years of interferon-basedtreatment of chronic hepatitis C: an epochcoming to an end. Nat Rev Immunol2013;13(7): 535–542.

7 Lange CM, et al. Emerging therapies forthe treatment of hepatitis C. EMBO MolMed 2014;6(1):4–15.



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

• Learn about different aspects of these technologies from clearly written articles by experts• Keep up to date on standards with regular updates by standards committee members• Read about innovations• Understand the jargon• Become an expert yourself

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Quality matters, but to most of us itis a rather intangible property.Quality is hard to grasp and maymean different things to differentpeople in different circumstances. Inmost cases, we sense the importanceof quality only when we see defectsor clearly suffer from the fact that wecannot use the product properly. In a

similar way, the impact of poor-quality medicines is experiencedwhen we encounter drug shortagesand product recalls. The quality of amedicine is the degree to which theproduct is capable of consistentlydelivering its safety and clinicalattributes to the patient. To obtainsuch a quality product, quality

ingredients and qualitymanufacturing processes should bein place. However, it starts withselecting the appropriate dosageform to optimally use the therapeuticpotential of the medicine.

Patient-centric drug productdesignHow can one reduce the risk ofdeveloping a product that does notexhibit the required quality? It isimportant to start the developmentprocess by defining a target productprofile summarising the qualitycharacteristics of a drug product thatshould be achieved to ensure thedesired quality, taking into accountits safety and efficacy. Even for asingle drug, there are manycombinations of drug substanceform (e.g. specific salt, ester, prodrugor probiological compound),excipients and packaging materials.The goal should be to create theoptimal drug product with thehighest therapeutic value for thespecific patient target populationthat is appropriate for thesepatients1. It is also important toensure the drug can and will be usedas intended, which could lead tomodifications to prevent misuse orabuse.

The same active pharmaceuticalingredient (API) can be used as drugsubstance in various routes of drugdelivery, requiring differentformulations with different excipientsand packaging. Optimal developmentof the drug product should bepatient-centred2. Choosing the mostsuitable dosage form is notstraightforward since industrial factorslike manufacturability, cost and speedof development need to be taken into


QUALITY METRICS,QUALITY CULTURE,QUALITY MATTERS!by Tom Sam and Henny Koch

For quality medicines to deliver optimal therapy to thepatient, it is critical to select and develop a patient-

centric drug product design, and to subsequently controlproduct and process development, the manufacturingprocesses, and the external supply chain. Quality metricsare seen as a tool to evaluate and optimise themanufacturing process, and an enhanced quality culturemindset is needed to sustainably deliver qualitymedicines throughout their lifecycles.

Tom Sam, PhD, MBM ([email protected]) was, until his retirement in July 2014,Director Regulatory Affairs CMC of Merck Sharp & Dohme, managing four regulatoryteams at its site in Oss, the Netherlands, covering the entire spectrum from activepharmaceutical ingredients to new and existing pharmaceutical products, medicaldevices and combinations thereof. He is the current chair of the AAPS ManufacturingScience & Engineering section and past president of the Industrial Pharmacy Sectionof the International Pharmaceutical Federation (FIP). His new area of interest is theimpact of the new economy on pharmaceutical industry business management.

Henny Koch ([email protected]) is owner of Qimp Management Systems, a qualityconsultancy company for effective support to strongly regulated quality andmanagement systems. His specialties are medicinal product and medical devicesregulatory and compliance control and quality systems. Henny is a certified ISO9001:2008 and GxP lead auditor and member of the Medical Devices Committee ofthe Research Quality Association in the UK.

Figure 1: Use of an analytical hierarchy process to decide on the most appropriate formulation for a specificsetting. In this example, the most appropriate formulation is selected from three alternative formulations based onthe efficacy, safety and patient access.

account apart from safety and efficacy.In the current development paradigm,a risk-based approach should be usedto select the optimal patient-centricformulation. A procedure employedby several major companies usesthree sets of composite criteria toarrive at the formulation of choice:efficacy/ease of use, safety andpatient access (Figure 1).

Designing quality into theproduct during development For innovative medicines, we shouldconsider the clinical target productprofile (CTPP) and the interplaybetween clinical and pharmaceuticaldevelopment. The CTPP not onlyprovides guidance to the clinicalphase 1–3 studies, but also serves asan input for the quality targetproduct profile (QTPP; see Figure 2,step 1), which is the starting point forthe pharmaceutical developmentcycle. For generic drugs orbiosimilars, the pharmaceuticaldevelopment cycle holds, but theclinical development cycle isreduced to bioequivalence studiesor demonstration of biosimilarity.Pharmaceutical developmentguidance on quality by design andcontrol strategy is obtained throughthe International Conference onHarmonization (ICH) series of QualityGuidelines Q8–Q113,4. The emphasisis on managing quality throughoutthe product life-cycle, coveringdevelopment, manufacturing anddistribution through the end-to-endsupply chain, including thediscontinuation of the marketingauthorisation.

At the beginning of thepharmaceutical development cycle(step 2a), the desired quality of thedrug product is derived from theQTPP and laid down as a set ofpotential critical quality attributes(CQAs), quantitatively describing itsintended physical, chemical,biological or microbiologicalcharacteristics. The commercialformulation and the commercialmanufacturing process need to bedefined in parallel (step 2b) using thesame considerations as discussed forpatient-centric drug product design.Emphasis in the development cycle is

on product life-cycle managementand continual improvement (step 6).At the end of the process, the qualityattributes are established as trulycritical to ensure product quality andhence its safety and efficacy. TheseCQAs can be considered final aslong as no new insights are obtainedor changes occur in the formulationor manufacturing process.

Quality in the manufacturingprocess There is a strong recognition that aquality product requires not only adefined quality of ingredients, butalso quality of the manufacturingprocess. Quality products can onlybe developed by understanding andappropriately controlling the linkage(step 3 in Figure 2) of the ingredientattributes and the processparameters of the various processsteps in relation to their criticality forobtaining a quality product.

Traditionally, health authoritiescontrol the quality of the productson their markets by requiring anapproved marketing authorisation(e.g. new drug application) and aseries of good practices (GXPs) to beadhered to during the life-cycle ofthe product.

• Good laboratory practice fortoxicology studies.

• Good clinical practice for clinicalstudies.

• Good manufacturing practice. • Good distribution practice. • Good pharmacovigilance

practice.

Adherence to the GXPs is subjectto companies’ auditing processes andregulatory inspections. This dualsystem of approvals andaudits/inspections is intense, timeconsuming and costly and hasappeared to be vulnerable, especiallydue to the globalisation of the supplychain. APIs, excipients andpackaging, and their correspondingstarting materials are now sourcedfrom all over the globe, and theprocesses used and quality systemsapplied may not always be knownand may not be up to Food and DrugAdministration (FDA) regulatorystandards. Approximately 90% of theAPIs of products on the US marketand 50% of the drug products arenow imported from outside the USA5.Medicines originate in factories allover the world, moving into theAmerican marketplace throughsupply chains that can involvenumerous processing plants,manufacturers, suppliers, brokers,packagers and distributors. Thisintroduces additional vulnerability tothe quality of the drug product(Figure 3)6. The new Drug SupplyChain and Security Act (Title II, DrugQuality and Security Act, 2013)addresses risks in the pharmaceuticaldistribution supply chain byestablishing a national system thatallows stakeholders and regulators totrace each package of product. Theserialisation and traceabilityrequirements will be phased in overthe next 10 years. The act requires allsectors in the supply chain toparticipate, including the repackagers

QUALITY METRICS, QUALITY CULTURE, QUALITY MATTERS! continued


Figure 2: Science- and risk-based development of a drug productintegrating the clinical and quality-by-design cycle. MA: material attribute;PP: process parameter).

and wholesale distributors. With the increasing complexity of

the supply chain, it is increasinglydifficult to ensure quality viatraditional organised audits andinspections. Many incidentsinfluencing quality have beenreported, leading to regulatoryactions, recalls, drug shortages andcounterfeit medicines on the market.It has become an even biggerchallenge than ever to ensure publichealth. Therefore, health authoritieshave been evaluating ways torationalise their inspection practices.FDA has announced that it willcollect metrics on the quality ofpharmaceutical products and theirmanufacturing sites. Quality metricscould ideally provide objectivemeasures of the quality of theproduct or process, the quality of asite, and the effectiveness of qualitysystems associated with themanufacture of marketedpharmaceutical products.

Quality metrics Quality metrics are an essential tool forquality improvement and have beensuccessfully implemented in industry,with Six Sigma quality efforts beingone example. The emphasis is on thequality improvement bottom line andcost reduction, building on the Cost ofPoor Quality (COPQ) concept, whereCOPQ is defined as the cost incurredby the various non-value-addedactivities and inputs contributing tothe non-conforming output. COPQincludes appraisal (inspection, audit),internal failure (defectives, rework,scrap, ineffective use of resources,derailed stocks), external failure

(repairs, service calls, warranty claims,write-offs, lost business, lostopportunities) and prevention (costsincurred trying to minimise the cost ofappraisal and failures). Poor quality inthe supply chain also contributes tothese costs. COPQ typically accountsfor up to 30% of sales and 40% ofoperating costs.

In addition to “lean”/Six Sigmatype of improvement efforts, qualitymetrics should provide a standardlanguage tool for health authorities toevaluate site quality as a measure of asite’s ability to manufacture qualityproducts. The FDA Safety andInnovation Act gives the FDAauthority to request such data toallow for regulatory inspectionflexibility. The idea is that appropriateutilisation of metrics would allow FDAinspectors to do more efficient andeffective inspections or even usemetrics to waive inspections at goodperforming sites. It would also allowcompanies to improve the quality intheir manufacturing activities.However, the use of metrics is notstraight forward. While FDA is lookingfor absolute measures of site qualityto compare quality risk in the field,the industry is emphasising thatmetrics of manufacturing site qualitywould at best be semi-quantitativeand not comparable across sites ofthe same company let alone acrosssites from different companies. Trendanalysis for a specific site could bethe most realistic outcome.

Some examples of metrics currentlyproposed by not-for-profitassociations, such as the InternationalSociety for PharmaceuticalEngineering and the Parenteral Drug

Association, are batch rejection andout-of-specification rate. These arelagging metrics, but more effectivemetrics predict future qualityperformance, the so-called leadingmetrics. Examples of more advancedleading metrics are quality systemeffectiveness, process capability, and ameasure of the degree of qualityculture awareness in the company oron site7,8. Agreement on suitablemetrics across the pharmaceuticalindustry and with the healthauthorities will be a challenging goal,especially since companies varygreatly in processing activities. Expertswarn that metric definitions shouldnot be multi-interpretable and metricsshould not become a goal inthemselves, but a tool to achieve thecompanies’ quality objectives.

Quality culture as anessential element Why has quality culture received somuch attention recently? In dailypractice, existing GXPs led to aculture of complying with regulators’standards, but not necessarily with aquality environment resulting inreliable and consistent production ofhigh-quality products. A change ofawareness in our quality culture isnecessary to create full awarenessand understanding of theimplementation and application of aproperly functioning pharmaceuticalquality system suitable for metrics-based surveillance.

The main challenge for creatingand maintaining a quality culture isthat organisations may not besufficiently transparent whereunidentified failures or threats may be



Figure 3: The pharmaceutical supply chain with examples of vulnerability/potential failure modes (figure adaptedfrom PEW Health Group6).

at stake. Management goals mightnot be aligned with the qualityculture. Under the force of legalpressure, unexpected failures may bestashed and not used to learn andimprove. A more open attitude canbe achieved by taking failures awayfrom the individual and identifyingthe true cause as part of theestablished processes and systems.To achieve a more proactive attitude,a higher level of quality culture isneeded. Realising that culture (sharedvalues) is at the very heart of anyorganisation, its impact on day-to-daybusiness cannot be underestimated.In a brief historic overview of the 7-SMcKinsey management model,coinventor Tom Peters states thatchanging the attitude and behavioursof people is very, very hard and thatculture is not just one aspect of thegame—it is the game.

The Juran Institute defines qualityculture as the capabilities of theorganisation, its habits and beliefs,which enable it to design and deliverproducts and services that can meetcustomer needs and be successful inthe marketplace over the long term.Quality will prevail only in anenvironment where every person inthe company understands andembraces his or her responsibility forprotecting product quality andpatient safety. NASA, for instance,differentiates four levels of qualityculture: absence of quality emphasis,error detection, error prevention andcreative quality.

The proactive levels of a qualityculture are associated with higherlevels of organisational effectiveness.An advanced quality culture shouldbe able to enhance continualimprovement throughout thelifecycle by the following9.

1.Using risk- and science-basedapproaches.

2.Making decisions based onunderstanding of themanufacturing processes and theproduct’s intended use (having thepatient’s needs in mind).

3.Properly identifying and controllingareas of potential processweakness (including raw materials).

4.Having responsive deviation

investigation systems in place thatlead to timely remediation andpreventive actions.

5.Applying sound methods and avariety of tools for assessing risk.

6.Having well-defined and designedmanufacturing processes andproducts from developmentthrough the entire product life-cycle.

7.Having systems in place forbuilding in and careful analyses ofproduct quality.

8.Ensuring that senior managementis supportive, both philosophicallyand financially.

A real commitment to quality anddemonstration of the same by livingthe example is essential and shouldbe practiced from both the topdown and the bottom up. Qualityoversight and governances must beimplemented at every level both atthe site and globally. Goals andquality metrics should be developedand progress communicatedthroughout the organisation.Evidence of upper managementleadership and empowermentshould be provided to employees.To create this culture of quality, thedevelopment, implementation andharmonisation of the quality systemsshould be supported by meaningfulauditing. ICH Q10 describes the fourmajor systems to support the life-cycle approach as follows.

1.Process performance and productquality monitoring system.

2.Corrective action and preventiveaction system.

3.Change management system. 4.Management review of process

performance and product quality.

It would make sense to developleading metrics consistent with at leastthese four systems. The process ownerwould have the information about thehealth of the respective system. Thiswould allow optimisation and continualimprovement of these systems. Theassessment of quality culture could bedone by preparing anonymousquestionnaires for employees and/orby conducting focused discussionswith groups of employees. Feedback

from these activities and implementingchanges are crucial. By putting forth anextensive array of questions,companies can explore areas such asoverall product quality, conformance torequirements, equipment use, supplierquality, management commitment,work group performance, employeeparticipation and training.

Optimising the quality culture of anorganisation requires long-termdedication and investment both frommanagement and all other companyemployees on all levels throughoutthe organisation. However, the rewardsfor pharmaceutical companies, i.e.being able to deliver quality productsto our patients by abolishing drugshortages and product recalls, willmake the effort more than worthwhile.Quality matters!

References 1 Sam AP. Optimising the therapeutic trinity

of active ingredient, delivery system andfunctional packaging. J Control Release2003;87(1–3):153–157.

2 Sam T, Ernest T, Williams J, Walsh J. Abenefit/risk approach towards selectingappropriate pharmaceutical dosage forms—an application for paediatric dose formselection. Int J Pharm 2011;435(2):115–123.

3 Sam T, Potter C, Berridge J. Designspace—promoting quality by design. RegAffairs J 2007;18(1).

4 US Food and Drug Administration.Guidance for Industry Q8(R2)Pharmaceutical Development. Rockville,MD: FDA; 2009.

5 Hamburg MA. New realities ofglobalization—implications for health,medicine and the role of the regulator.Speech given at the Royal College ofPhysicians, London, UK; 6 March 2014.

6 PEW Health Group. After Heparin:Protecting Consumers from the Risks ofSubstandard and Counterfeit Drugs.Philadelphia, PA: PEW Health Group; 2011.

7 Parenteral Drug Association. PDA Pointsto Consider: Pharmaceutical QualityMetrics. Bethesda, MD: PDA; 2013.

8 International Society for PharmaceuticalEngineering. ISPE Proposals for FDA QualityMetrics Program. Tampa, FL: ISPE; 2013.

9 Friedman R. Pharmaceutical qualitysystems: US perspective. Paper presentedat: Pharmaceutical Quality System (ICHQ10) Conference, Brussels, Belgium;14–16 November 2011.

Reprinted with permission from AAPSNewsmagazine, Volume 17, No. 8(August 2014). ©AAPS 2014 by theAmerican Association of PharmaceuticalScientists.




regulatory reviewThe current review period hasseen a number of changes inthe regulation of medicines andregulatory guidance in the EU,International markets and theUSA

USA

Food and Drug Administration(FDA) Data DashboardThis new tool shares inspectional,compliance and enforcement-related data in various, easilyunderstood graphical formats. Itallows users to drill down onelements within the graphicalformats for a more detailed viewand to export the graphs andunderlying data.

Revocation of duplicativegeneral safety test regulations This proposal to amend thebiologics regulations by removingthe general safety test (GST)requirements for biological productsarises because GST regulations areduplicative of requirements that arealso specified in biologics licenses,or are no longernecessary/appropriate to helpensure the safety, purity, andpotency of licensed biologicalproducts.

Electronic submission of lotdistribution reports (LDRs)This draft guidance providesrecommendations to licensedmanufacturers of productsdistributed under an approvedBiologics License Application (BLA)on how to submit LDRs in anelectronic format that the FDA canprocess, review, and archive.

Abbreviated new drugapplication (ANDA)submissions – refuse to receivefor lack of proper justificationof impurity limits This draft guidance highlightsdeficiencies in relation toinformation about impurities thatmay cause FDA to refuse to receivean ANDA as it is not sufficientlycomplete to permit a substantive

review. Typical deficiencies arequoted.

EuropeEuropean Medicines Agency(EMA)Qualified person declarationtemplate Q&AThe final template and guidancewas published in June 2014. EMAhas now published answers to thecomments provided from industrygroups on the original 2011documents. These commentsprovide insight into EMA’sexpectations on activepharmaceutical ingredient supplierauditing and qualification.

Reflection paper – selectionand justification of startingmaterials for the manufactureof chemical active substancesDisagreements between applicantsand quality assessors on thesuitability of proposed startingmaterials have become morefrequent, suggesting that thecurrent (intentionally high level)guidelines are open tointerpretation. This documentexpands on some of the points inICH (International Conference onHarmonization) Q11 in order toharmonise opinions betweenassessors and clarify therequirements for applicants.

EU GMP GuideChapter 3: Premise andEquipmentThe only change from the previousdraft is to section 6 as part of theimproved risk-based guidance onprevention of cross-contamination.The Guidance indicates thatdedicated facilities are required formanufacturing when a medicinalproduct presents a risk because ofthe following.

• The risk cannot be adequatelycontrolled by operational and/ortechnical measures.

• Scientific data from thetoxicological evaluation does notsupport a controllable risk.

• Relevant residue limits, derivedfrom the toxicological evaluation,cannot be satisfactorilydetermined by a validatedanalytical method.

This guidance is effective from 1March 2015

Chapter 5: ProductionChanges have been made tosections 17 to 21, including adding anew section, to improve theguidance on prevention of cross-contamination and refers totoxicological assessment. (However,there is no longer mention as tohow the toxicological assessment aspart of the risk management processfor deciding whether dedicatedfacilities are required has to bedone, MH)

Changes were also introduced insections 27 to 30, including adding anew section on the qualification ofsuppliers in order to reflect the legalobligation of marketingauthorisation holders to ensure thatactive substances are produced inaccordance with GMP. The changesinclude supply chain traceability.Sections 35 and 36 are inserted toclarify and harmonise expectationsof manufacturers regarding thetesting of starting materials. Section71 introduces guidance onnotification of restrictions in supply.This guidance is effective from 1March 2015

Chapter 6: Quality ControlThis revised chapter was effectivefrom 1 October 2014. It involves anew section on technical transfer oftesting methods and covers otheritems such as Out Of Specificationresults.

Chapter 8: Complaints, QualityDefects and Product RecallsExtensive changes reflect thatquality risk management principlesshould be applied wheninvestigating quality defects orcomplaints and when makingdecisions in relation to productrecalls or other risk-mitigatingactions. It emphasises the need for


the cause(s) of quality defects orcomplaints to be investigated anddetermined, and that appropriatepreventative actions are put in placeto guard against a recurrence of theissue and clarifies expectations andresponsibilities in relation to thereporting of quality defects to thecompetent authorities. Thisguidance is effective from 1 March2015.

Medicines and Healthcareproducts Regulatory Agency(MHRA)Review of GMP inspectiondeficiencies 2013The most frequently encountereddefect categories raised over theprevious 5 years have remainedrelatively consistent with theexception of ‘contamination,chemical/physical (or potential for)’which has significantly increased.Deficiencies relating to ‘qualitysystems’ are by far the mostprevalent observed duringinspections.

New collaboration in thedevelopment of advancedtherapiesThe National Institute for BiologicalStandards and Control, a centre ofMHRA, has signed an agreementwith University College London tomaximise and further promotescientific collaboration in the field ofadvanced therapies.

InternationalICHFinal Concept Paper ICH Q12Guideline: Technical andRegulatory Considerations forPharmaceutical ProductLifecycleThis topic was endorsed inSeptember 2014 by the ICHSteering Committee. The proposedpurpose is to provide guidance on aframework to facilitate themanagement of post-approvalchemistry, manufacturing andcontrols (CMC) changes in a more

predictable and efficient manneracross the product lifecycle.

Pharmaceutical InspectionCooperation Scheme (PIC/S)Croatia applies for PIC/Smembership The Rapporteurs will be appointedsoon.

2014 PIC/S Annual Seminar on“Dedicated Facilities or Not”Unfortunately this Seminar held inParis in October 2014 was limited toNational Health Authorities only,despite the fact that it is likely tohave a significant impact onindustry.

For further information on these andother topics we suggest you refer to thewebsites of relevant regulatory bodiesand to current and past editions of “GMPReview News” published by EuromedCommunications. To subscribe to thismonthly news service [email protected]

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REGULATORY REVIEW continued

Dear Editor

In the last edition of european Industrial Pharmacy(issue 22), Tony Cartwright wrote a verycomprehensive article on the history ofpharmacopoeial harmonisation as a rebuttal to myprevious article in european Industrial Pharmacy titled“Unstandard Standards”. While he has done aneminent job, and I do not dispute a single fact thathe has raised, he has sadly not answered the severalcogent questions I raised in my articles.

Namely, why are reference standards betweenpharmacopoeias not harmonised andinterchangeable, why has the world’s most commonexcipient – purified water – not been harmonised, andwhy has it taken over 140 years to only harmoniseabout 14% of the general methods and 17% of theexcipient specifications listed in the US Pharmacopeia.At a recent conference, I asked, off-the-record, a

senior member of US Pharmacopeia staff as to whyreference standards were not harmonised – to whichthe first response I received was “we make moremoney selling the standards than selling the book”, apoint I alluded to in my article.

My article was in no way meant as a denigration ofthe technical and scientifically fine work done bymany hundreds of scientists worldwide, includingTony as a long-standing member of the BritishPharmacopoeia Commission. However, I raised thequestion for industry discussion as to whether vestedinterests might be in the way of true pharmacopoeialharmonisation into a “Global UniversalPharmacopoeia” – a topic which Tony has yet toaddress.

Michael Anisfeld


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over 25 years of advancing pharmaceutical and healthcare sciences

2012 Volume 17 Number 2

European Journal

of Parenteral

& Pharmaceutical

Sciences

over 25 o ov e r 25 years of advancing 5 pharmaceutical andp h a r rm a c healthcare sciencesh e a l t h c a

years of advancing y e a r rs of advancing f advancing a d v a n c i n gceutical andc e u t i c a l a n dare sciencesa r e s c i e n c e s

letter to the editor


ThornIn 1940, a garden rose thornscratched Albert Alexander, 48, apoliceman. A streptococcal/staphylococcal infection resulted. Itwas held at bay until the lastsupply of penicillin was given. Thenhe died. During the antibiotic erasuch fatalities have seldomoccurred in the developed world.

But antibiotics have beenoverused; microbial resistance isincreasing. Few novel antimicrobialagents have been marketed.Antibiotics, by definition, haveshort courses that are one-off; fewpeople use. So antibioticdevelopment has made littlecommercial sense for industry. Itappears the “bad guy”, onlyseeking profit, again. But read on.

Health professionals have warnedfor decades about the risk ofantibiotic resistance. In the 1960s, I urged “complete the course”…“only give if essential.” That plea isso old that it has grown whiskers.But professionals were only onevoice, often ignored. Therespected sociologist ElliotFreidson (1988) pointed out threegroups: practitioners (e.g. medicalpractitioners, pharmacists),academics and administrators (e.g.managers, politicians). Each groupthinks that they are “the best” andrespect other groups less.Practitioners have expert powerand some autonomy, such aschoosing not to give antibioticsand pleading to use them wisely.But the administrators retain powerwhere to invest and support withpublic relations expertise, behind

an opinion. It has taken thepoliticians about a generation tohear the practitioners’ message:antibiotics have problems ahead.

ZeitgeistBut, at last, politicians have got it.David Cameron recently publicisedthat a return to pre-antibiotic days(“dark ages”) is an “unthinkablescenario”. At last the publiczeitgeist is shifting. Somethingmust be done. But what?

One action is the (UK) LongitudePrize 2014 developed and run bythe innovation charity Nesta. It isfor a cost-effective, accurate rapidand easy-to-use test for bacterialinfections that will allow healthprofessionals worldwide toadminister the right antibiotic atthe right time. This is goodbecause any new antibiotic willeventually suffer microbialresistance. The prize is worth £10million: peanuts. It also ignores“the elephant in the room”:veterinarians and farmers use“industrial” amounts of antibiotics,globally, on other animals,especially poultry.

But industry here has a chance tobe the “good guy”. Think of thetetracycline from allotment soil, thecephalosporin from Sardiniansewage. Many species have wagedchemical warfare against another;those that adapt, survive. Thatcornucopia remains there forhumans to harvest. One example isants keeping fungus gardens overDarwinian time: gardens thathumans may harvest for powerfulantimicrobial agents. Dripping

within the rain forests, manygoodies may awaitpharmacognostical explorers. Theymay not, of course. But there is afighting chance and it is a simple-to-understand, powerful yetromantic story, a quest with(hopefully) a happy ending: apublic relations dream.

FluxAnother perspective exists. Babies,during non-Caesarean births, areborn face-first to their mother’sanuses, and so smeared withfaeces. The microbial gutcolonisation resulting is importantfor the babies’ survival. We needthose “good” archaea, bacteria,fungi, etc. Indeed, of our totalbodily cells, only 10% aremammalian and fully 90% aremicro-organisms.

Within Earth’s primordial soup,about 3.4 billion years ago,RNA/DNA developed. WelcomeLua (the Last universal ancestor),the mother of all mothers, themother of us all. Early descendentswere the archaea. Suchextremophiles seldom causedisease. But some of their bacterialcousins do. Normally we all survivein “happy” equilibrium. Bacterialdisease generally occurs whenequilibrium is disturbed or theyventure where they should not.Chemical (antibiotic) warfarebetween progeny, refined by trial-and-error “experiments” overbillions of years, is part of that flux.That awes me.

Malcolm E Brown

bottled brown


Anti-counterfeiting measuresThe Bureau has been keeping awatching brief on the progress ofthe Delegated Act which willimplement the requirement for aUnique Identifier on packs ofmedicinal products. It appears thatthe Commission is behind schedulewith publication which was due thisquarter. Nevertheless, oncepublished, there will be little time toinput any concerns via Members ofEuropean Parliament and theBureau would welcome youropinions on the practicalities ofimplementation as soon as the textis available.

European Medicines AgencyPiero Iamartino, EIPG Vice-PresidentTechnical and ProfessionalDevelopment, will represent EIPG ata meeting with the InspectorateWorking Group on 2 December. Themain topic of discussion will be theinitiatives in response to the EMA’sreflection paper on shortagescaused by manufacturing andquality/good manufacturing practice(GMP) problems.

On-line training Several GMP e-learning coursesaimed at process operators, courseson the Guide to Good DistributionPractice (including measuresinvolving the falsification ofmedicines) and a guide todeveloping nanomedicines arebeing added to the Pharma Consult

website by the end of December.The Pharma Consult short coursesare now under “Education” on thehome page of the EIPG website(http://eipg.eu/education/)

EPSA Seminar and AutumnAssemblyFollowing an idea of Anni Svala,EIPG Vice-President Education andTraining and the Executive of theEuropean Pharmaceutical StudentsAssociation (EPSA), the first of whatis expected to be a series of jointwebinars has been arranged for 9December. Speakers will be ClaudeFarrugia, EIPG Vice-PresidentCommunications on “TheSubject(ion) of Pharma” andGeorgina Gal, delegate to EIPG forthe Hungarian Society forPharmaceutical Sciences, who willspeak on “Regulatory Affairs – theCoordination Centre of the PharmaIndustry”. For registration, seewww.EPSA-online.org. Althoughaimed at students, members ofEIPG are welcome to attend.

At the end of October, AmonWafelman (EIPG Special InterestGroup, Production Co-Chair) spokeat the EPSA Autumn Assembly inHradec Kralove, Czech Republic. Hispresentation was entitled“Development ofBiopharmaceuticals: Structure andFormulation Considerations”. Theslides can be found on the EIPGwebsite under media library,presentations.

Proposed project for PhDstudentsEIPG has been invited to participatein a European Joint Doctorateproject proposal which will bearranged by a consortium of fouruniversities: Milan (Italy), Aberdeen(UK), Antwerp (Belgium) and Leiden(Netherland). The scope of theproject is to create, through ashared training programme, acommon knowledge and languagefor PhD students working in thepharmaceutical sciences.

To improve student knowledge ofthe pharmaceutical industry, EIPGwas identified as a non-academicconsultant to assist with the trainingprogramme definition, theevaluation of students’ experience intheir internships and in networking.A representative of EIPG will attendthe Project Management boardmeetings.

Special Interest GroupsAnyone interested in joining the“Regulatory Affairs” or “Production”groups should contact:Regulatory Affairs: Georgina Gal([email protected]) orMarianne Anderson([email protected])Production: Piero Iamartino([email protected] orAmon Wafelman([email protected])

Jane Nicholson, Executive DirectorEIPG, [email protected]

news from the EIPG

CALL FOR ARTICLESDear Colleague

We hope you enjoy the European Industrial Pharmacy and find it both useful andinformative.

We are currently seeking new articles for future issues of the journal and would like toinvite you to contribute an article or review paper on any aspect of industrialpharmacy to the journal. All issues of European Industrial Pharmacy are indexed byboth Scopus and Embase and thus are available through the listings for any otherindustrial pharmacist internationally.


eventsJANUARY 201511–14 January 2015 – Dubai,United Arab Emirates5th Annual Cold Chain MENASummitwww.pharma-iq.com

26–29 January 2015 – Frankfurt,GermanyCool Chain Europe 2015 www.pharma-iq.com

27–28 January 2015 –Washington, DC, USA12th Annual PharmaceuticalCompliance Congresswww.cbinet.com

29–30 January 2015 – Alexandria,VA, USA10th Annual Summit onBiosimilars www.cbinet.com

FEBRUARY 20155 February 2015 – Ware, UKQuality Risk Management: apragmatic approach www.jpag.org

11–12 February 2015 – Chicago,IL, USA11th Annual ComplianceCongress for Medical Deviceand Diagnostics www.cbinet.com

17–18 February 2015 – Berlin,GermanyPharmaceutical Microbiologywww.pda.org

18–19 February 2015 – Munich,GermanyDisposable Solutions forBiomanufacturing Summitwww.disposablebiomanufacturing.com

23–24 February 2015 – Baltimore,MD, USA2015 Aseptic AnnualConferencewww.ispe.org

23–26 February 2015 – Montreal,Quebec, Canada13th Annual Cold Chain GDP &Temperature ManagementLogistics Summitwww.coldchainpharm.com

24–25 February 2015 – London, UKWorld BioPharma Big DataCongress 2015www.healthnetworkcommunications.com

MARCH 20153 March 2015 – London, UKGood Clinical PracticeSymposium 2015www.mhra.gov.uk

3–4 March 2015 – Frankfurt,GermanyParenteral Packagingwww.pda.org

4–5 March 2015 – Madrid, SpainWorld Generic MedicinesCongress Europewww.healthnetworkcommunications.com

4–5 March 2015 – Madrid, SpainBiosimilar Drug DevelopmentWorld Europewww.terrapinn.com

10–11 March 2015 – London, UKClinical Outsourcing &Partnership World Europe 2015www.healthnetworkcommunications.com

19 March 2015 – London, UKCombating CounterfeitMedicines: The Solutionswww.jpag.org

22–25 March 2015 – NationalHarbor, MD, USAPharma Forum 2015 www.cbinet.com

24–25 March 2015 – Dusseldorf,GermanyPharma Congress 2015www.pharma-kongress.com

APRIL 20154–7 April 2015 – Glasgow, Scotland10th Pharmaceutics,Biopharmaceutics andPharmaceutical TechnologyWorld Meetingwww.worldmeeting.org

13–14 April 2015 – Reims, France1st European Conference onPharmaceutics – Drug Deliverywww.apv-mainz.de

14–15 April 2015 – Berlin, GermanyAseptic Manufacturingwww.pda.org

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