in dustr ia l pha rmacyhow best to use these medicines, collecting experience (rwd) from pa tiens,...

ISSUE 59 • NOVEMBER 2018www.industrialpharmacy.eu

Industrial PharmacySector Report from the

2018 FIP Congress

Biosimilars – Challengesand Opportunities

Growth and Globalisationof Pharma Products

The Rise of TraditionalMedicine (TM) in Malaysia

Regulatory Convergenceand Global Trends inExpedited Regulatory

Pathways

Industrial PharmacySector Report from the

2018 FIP Congress

Biosimilars – Challengesand Opportunities

Growth and Globalisationof Pharma Products

The Rise of TraditionalMedicine (TM) in Malaysia

Regulatory Convergenceand Global Trends inExpedited Regulatory

Pathways

INDUSTRIALPHARMACYESSENTIAL READING FOR ALL PHARMACISTS

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INDUSTRIALPHARMACYIssue 59 November 2018

ISSN 1741 4911

MANAGING EDITORPhoebe Speis

PRODUCTIONSue Feather

SUBSCRIPTIONSJill Monk

ADVERTISEMENTSStephanie Painter

EDITORIAL BOARDMichael AnisfeldMichael Gamlen

Ching-Yi HsuJohn Jolley

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features4 INDUSTRIAL PHARMACY SECTOR REPORT FROM THE

2018 FIP CONGRESSby Gabrielle Wiederkehr and Anna Laven

8 BIOSIMILARS – CHALLENGES AND OPPORTUNITIES by Paul Fleming

10 GROWTH AND GLOBALISATION OF PHARMA PRODUCTSby John Jolley

15 THE RISE OF TRADITIONAL MEDICINE (TM) IN MALAYSIA:POTENTIALS, CHALLENGES AND OPPORTUNITIES FORENHANCEMENTby Ai Ch’i Liew

18 REGULATORY CONVERGENCE AND GLOBAL TRENDS INEXPEDITED REGULATORY PATHWAYSby Marisa Carcione

regulars3 EDITORIAL COMMENT

20 PHARMA IN PLENARY

22 LEGAL LETTER FROM AMERICA

26 REGULATORY REVIEW

30 CORPORATE PROFILES

31 BOTTLED BROWN

32 EVENTS

Cover photo: View of the Armadillo Auditorium at the Scottish Events Campus (SEC),Glasgow, venue of the FIP 2018 Congress. Courtesy of SEC and Peter Sandground.

INDUSTRIAL PHARMACY November 2018 • Issue 59

INDUSTRIAL PHARMACY is an official publicationof the Industrial Pharmacy Section of the FIPThe FIP represents 4 million pharmacists worldwide

3

editorial


CALL FOR ARTICLESDear ColleagueWe hope you enjoy Industrial Pharmacy and find it both useful and informative. We arecurrently seeking new articles for future issues of the journal and would like to invite you tocontribute an article or review paper on any aspect of industrial pharmacy to the journal. Weare also pleased to receive letters on any aspect of pharmacy or with respect to any articlepublished in the journal. All issues of Industrial Pharmacy are indexed by both Scopus andEmbase and thus are available through the listings for all other pharmacist internationally.

Expanding the horizons ofthe Industrial Pharmacyjournal

The world is changing at anincreasingly rapid speed. Newmedicines are more and morespecialised (personalised), andthis often comes at a higherprice. Real world data (RWD) isthen required to show that thenew medicines produce thehealth gains promised. And withthe high access to informationprovided by the media and theinternet, patients are aware of and demand thenew medicines without delay, often before theyare approved!Despite these advances, a lack of essential

medicines is still a reality in many parts of theworld. Not only is the financial situation in manycountries such that it is difficult or impossible toafford all the medicines needed, but also withinan individual country it is not uncommon to findthat inequalities exist between different sectionsof the population.To make it even more complicated the

expectations to be healthy are increasing andmedical care is seen as a cure to almosteverything. The reality is that in many countrieslarge groups live a life that is far from healthy.Smoking, abuse of alcohol/narcotics, lack ofphysical exercise and obesity are important riskfactors to health, resulting in illnesses likediabetes, depression and cancer, and these arerisk factors that can be avoided or reduced bythe individual. In whatever way you look at the current

situation pharmacists are in a unique position toguide the developments in a positive direction.

From research and developmentof new medicines, to advising onhow best to use these medicines,collecting experience (RWD) frompatients, and helping patientslive a healthier life, includingvaccination and other preventivemedicines, but also by advisingand supporting a healthier life forthe individual. To achieve this ambitious vision

of the pharmacist’s role we mustwork across all relateddisciplines, be it in practice,science or education, community

pharmacy, in industry or in regulatory sciences. Afirst step is to increase the understanding of whatother pharmacists do, not only in other countriesbut also in other parts of the profession. The FIPand the FIP Congress plays an extremelyimportant role. As incoming President of the Industrial

Pharmacy Section I am very happy that theIndustrial Pharmacy journal will be distributed toall FIP members worldwide, providing anopportunity to improve the understanding ofwhat industrial pharmacists do. The journal alsocovers other areas of pharmacy and hopefully,this increased shared knowledge will work bothways throughout the pharmacy profession.

Ulf Janzon


as private and government payersgrow more powerful, market accessto innovative new drugs is far morechallenging due to the need tocontain rising costs, theproliferation of competing drugs inthe same therapeutic area, relianceon evidence-based medicine andhealth technology assessmentwhich drive payer decisions. Inaddition, growth of the genericssegment and the emergence ofbiosimilar drugs have given payersadditional choices when decidingwhich products they will cover. This complex topic was

competently addressed by fourspeakers representing differentstakeholders.

Presentations

The first speaker, Sola Solarin,Savanté Consulting, Nigeria, talkedabout barriers to market access inemerging markets. According to aninformed estimate access tomedicines globally is 67%. Whendisaggregated, emerging markethave an average of 50%. The WHOdefinition of “Access to Medicines”

reads: “Access to medicines isdefined as having essentialmedicines continuously availableand affordable at public or privatehealth facilities or medicine outletsthat are within one hour’s walk fromthe homes of the population”.Clearly this is not met in most of theemerging markets. A number offactors have been identified asresponsible for poor access tomedicines in emerging markets.They include poor infrastructure andaccessibility, sub-optimal supplychain management, infiltration ofdistribution system by falsifiedmedicines, cost/economics aspectsas payment for healthcare is oftenout of pocket and pricing systemsare not transparent. Also, policychoices may limit medicines accessand long patent protection andexclusivity periods granted to theoriginator companies, which blockavailability of generics.Hermann Schulze, Mallinckrodt

Pharmaceuticals Ltd, Switzerland,pointed out that fast access ofinnovative medicines is not only ofbig interest to patients – it is also ofbig interest to the pharmaceuticalindustry. Drug development andobtaining marketing authorisationsare the time-limiting hurdles to passbefore medicines become availableto patients, which can take up to 10years or more. Additionally, the timerequired to provide evidence that anew medicine is safe and effectivefor treatment up to market approvalcan take about two years; a timewhen patients cannot benefit fromthe new medicine and a time whenthe pharmaceutical companycannot receive any return on itsinvestment. Various tools weredescribed, which regulators havedeveloped and which help toexpedite rapid access of newinnovative medicines. For example,the US FDA offers fast-trackdesignation, accelerated approval,priority review and break-throughdesignations and the EMAaccelerated assessment, PRIME andparallel EMA/EUnetHTA scientificadvice. Richard Huckle, Pope Woodhead

& Associates Ltd, UK, highlightedthe benefits and risks of early

Breaking down barriers topatient access – how tobring stakeholders together

by Gabrielle Wiederkehr

Introduction

There are several barriers toeffective access to medicines acrossthe pathway from drugdevelopment through regulatoryapproval to initial treatment andproper patient management. Thenature of those barriers differssubstantially in various parts of theworld. In emerging markets, theyinclude low awareness of patientsand healthcare professionals of theright treatments or the benefits ofnew medicines, inadequateaccessibility to care as often thereare not enough hospitals,diagnostic equipment or trainedmedical staff, lack of availability ofmedicines in local pharmacies orhospitals and affordability. In the industrialised world, market

access used to be assured if apharmaceutical product was safe,effective and of good quality. Today,

Gabrielle Wiederkehr is Managing Director, ACCESS Regulatory Consulting,Switzerland, and Executive Committee Member of the Industrial Pharmacist Sectionof the FIP. Anna Laven is a Researcher and Trainer at Pharmabrain GmbH, Germany, andExecutive Committee Member of the Industrial Pharmacists Section of the FIP.

INDUSTRIAL PHARMACYSECTOR REPORT FROM THE 2018 FIP 78th WORLDCONGRESSby Gabrielle Wiederkehr and Anna Laven

The 2018 annual FIP Congress of Pharmacy andPharmaceutical Sciences was held at the Scottish

Events Campus (SEC) in Glasgow between 2-6September. This year the Congress hosted two fullsessions dedicated to the Industrial Sector of the FIP.We provide reports on each of these sessions by thesession chairpersons.

5INDUSTRIAL PHARMACY November 2018 • Issue 59

market access. The evolving earlyaccess pathways require multiplestakeholder interactions (includingregulators, HTA bodies/payers andpatients) with the aim to facilitateand accelerate development,marketing authorisation and accessof medicines to patients in areas ofhigh unmet needs. Early accessdecisions are particularlychallenging due to the limitedclinical evidence available on thebenefit–risk and relative (cost-)effectiveness of innovative drugs fortreating unmet needs. For severediseases with unmet medical need,regulators increasingly acceptclinical trial packages that lack largePhase 3 comparative randomisedcontrolled trial data and useintermediate surrogate endpoints todemonstrate a positive benefit-riskprofile. HTA bodies/payers want tosee that a new product deliversclinically meaningful benefits (i.e.,improvement in quality-of-life andmorbidity/mortality endpoints thatare directly relevant to patients), aswell as in more diverse, real-worldsettings. Patients and caregiversdemand sufficient information tomake informed benefit/risktreatment decisions and managerisks effectively. So clearlyaccelerated access of promisingdrugs that fulfil an unmet medical

need often results in tradeoffs ofthe current system and ongoinginitiatives from patient and otherstake-holders perspectives.The last speaker, Katja

Hakkarainen, EPID Research,Sweden, discussed the contributionof real-world evidence (RWE) tofaster access to medicines forpatients. RWE research and real-world data are used to furtherinvestigate a medicine and itseffects and use once the medicineis on the market. The used datasources include electronic healthrecords, prescription databases,patient registries, and claimsdatabases. RWE studies areincreasing in the pharmaceuticalindustry, which is reflected in thenumber of studies registered at theEuropean Network of Centres forPharmacoepidemiology andPharmacovigilance (ENCePP). RWEstudies by the pharmaceuticalindustry are typically conducted toinvestigate a safety concern raisedfrom pre-clinical and clinical studiesor to study the effectiveness of themedicine in real-world clinicalpractice. RWE studies also enableinvestigating medication use inpatient groups excluded from trials,such as pregnant women andchildren. Furthermore, RWEsupports health economic

evaluations and the development oftreatment guidelines. The earlyaccess initiatives of the EuropeanMedicines Agency (EMA) and theUS FDA provide an opportunity tobring new, innovative medicineavailable to patients faster thanthrough the normal approvalprocess. As part of the early accessinitiatives, the authorities requireRWE to complement evidence fromclinical trials. The overall conclusion of the

session was that over the last yearsall stakeholders have been pursuingmany approaches and have made alot of progress in facilitating globalaccess to medicines in a timelymanner. Nevertheless, there wasagreement that further efforts arerequired to improve existing toolsand introducing similar programsparticularly in developing countries.

Strategies to improveadherence – technologyneeds communication.

by Anna Laven

Introduction

Life-saving drugs are fully effectiveonly when they are prescribed forthe right patient and if patients use

INDUSTRIAL PHARMACY SECTOR REPORT FROM THE 2018 FIP 78th WORLD CONGRESS continued

Figure: Aerial view of the SEC complex with spire of Glasgow University in the background

Photo: Peter Sandground

6 INDUSTRIAL PHARMACY November 2018 • Issue 59

them correctly. This includes theresponsible use of the drug andoften life-long therapy adherence.The reasons why patients areunable to use drugs correctly varyenormously. Additional andindividual support, e.g. via patient-centred counselling or appropriate(digital) devices are thereforerequired to foster adherence.Community pharmacists are not theonly pharmacists that can enhanceadherence - hospital pharmacistsand the pharmaceutical industryalso have their contribution. In thissession, different and innovativeways and concepts were presentedand discussed.

Presentations

The first speaker was BernardVrijens from Belgium. He is thefounder of the European Society forPatient Adherence, Compliance andPersistence. Bernard stated thatideal adherence might be the goalbut is rarely the reality. Even whenpatients are taking the samepercentage of prescribed doses, thereason for missed doses might bevery different, such as drugholidays, weekend stoppers, orpatients who have problems with

evening doses. Depending onwhether patients do not initiate thetreatment, or have problemsimplementing it into daily practice,or stop the treatment prematurely,different digital devices might behelpful to support adherence. Thisis important, as non-adherenceleads to treatment failure, diseaseprogression or acute events andsubsequently to more complextreatments that would foster evenmore non-adherence. Adherence is the key to

therapeutic success, as drugs donot work in patients who do nottake them. One reason for missingadherence might be drug-relatedproblems that are linked tophysiological factors such as age,sex, weight and disease status, orenvironmental factors such as co-administered drugs, diet, tobaccouse and chemicals. They also occurmore often if the patients have acorresponding genomicbackground, as variation in genesare related to drug metabolicenzymes and drug transporters thatcontrol the number of active drugmetabolites in the system. In thatsituation, a standard dose couldlead to an excess, to inefficacy orordinary efficacy, depending on the

patient’s genes. When drugs are notprocessed at the expected oraverage rate, it leads to adverseside effects or lack of efficacy.Examples are poor codeinemetabolisers, or increasedpantoprazole or escitaloprammetaboliser. John Papastergiou from Canada

is a community pharmacistspecialising in pharmacogenomics.He outlined the basic principles ofpharmacogenomics, explainedstrategies for implementation ofpharmacogenomic services intocommunity pharmacy practice andexplored real-world case examplesthat highlighted the improvement inadherence from one of the world’sfirst community pharmacy-directedpharmacogenomic clinics.Kerstin Neumann from Johnson

and Johnson Germany showed howusing QR Codes for patienteducation works. She explained thatthe pharmaceutical industry plays asignificant role in supportingadherence and that this work needsto be reinforced by the communitypharmacist to reach the patient. The next speaker was Sheila

Ryder from Trinity College inDublin. Sheila presented smartdevices for adherence, and the do’sand the don’ts that pharmacistsneed to take into account whenchanging to digital. Many hundredsof apps already exist, but only a fewhave been evaluated in detailregarding adherence functionality,medication managementfunctionality, connectivity, healthliteracy considerations and generalfeatures. Factors affectingengagement, tailoring content tosubgroups and considering healthliteracy attributes were consideredas a clear “Do” as they reducebarriers, connect with the patient’sidentity and sustain motivation.However, we should not assumethat smart devices can replacedirect counselling.Stephen Chapman from Keele

University was the next speaker. Heintroduced the audience to virtualreality. Avatars have been built at


Delegates at one of the sessions answering the question "Do you think thatyou can influence the patient’s adherence to medication?"

Keele University that can be used inthe training of counselling skills. Forexample, an avatar can mimic apatient with atrial fibrillation whosees his pharmacist in order to gethis anticoagulant drug. Thepharmacist then needs to decidewhich questions to ask and whatadvice to give. The consultationfollows a specific algorithm and isbuilt to foster responsible use andadherence. At the end of theconsultation, the avatar(representing the patient) givesfeedback to the pharmacist on theconsultation and suggestsimprovements for the future.The last speaker was Anna Laven

who presented the structuredpharmaceutical counselling process.

Due to time restraints, pharmacistsall over the world need to developa strategy to counsel their patientseffectively and efficiently at thesame time. Anna Laven hasdeveloped the “PharmaceuticalAction Plan”. The method consistsof a) a trust-building phase coveringthe introduction of the healthcareprofessional, the identification ofthe patient and the review of thepatient’s record, b) the medicationhistory that covers what thephysician has already told thepatient about the drug and thecondition, other drugs that thepatient uses, and that may interactwith the prescribed one, furthermedical conditions that could leadto contraindications and c) the drug

counselling including the mode ofaction of the drug,dosage/duration/drug information(“Laven’s DDD”) and drug-relatedproblems that might occur. It endswith a joint decision making and areachable goal until the next visit.Depending on whether theconsultation is aimed to enforceresponsible use in new drug usersor to foster adherence in chronicpatients, Anna suggests appropriatewordings that lead to a very fruitfulshort intervention in the everydaypractice of a community pharmacist. The session was very well

received by the participants whosuggested that a master-class onadherence could be included at oneof the future congresses.



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The patent expiry of adalimumab,the world’s top selling prescriptionmedicine, in mid-October isexpected to make the singlebiggest contribution to reducing theNHS budget. Between £200 millionto £300 million per year by 2021 willbe saved through the uptake ofbiosimilar medicines. Building onthe experience gained with otherrecent biosimilar introductions, theNHS is in a strong position to makethe most of the opportunity throughdeep and rapid uptake of biosimilarcompetition. As real-world experience has

grown with UK patients; very highlevels of biosimilar usage are nowbeing achieved (May 2018 NHSdata):

• Infliximab (from March 2015) = 89%

• Etanercept (from April 2016) = 89%

• Rituximab (from April 2017) = 73%

It is particularly important that therapid introduction and take up ofthe opportunities from newbiosimilar medicines is consistentacross the NHS. To help achievethat, a monthly briefing update onadalimumab is being rolled outthrough the coordination of theRegional Medicines OptimisationCommittees (RMOCs). The mainpurpose of the four RMOCs of NHSEngland is working together as asingle system to avoid unnecessaryvariations in the best use ofmedicines. Alongside the budget savings to

the NHS from the increased use ofbiosimilars is the equally important

benefit of freeing up resources sothat more patients can have accessto biological medicines and thesignificant health improvementbenefits they can provide. There isemerging data that when biosimilarintroduction leads to a reduction of50% in price it delivers a 50%increase in the number of patientsthat can be treated. The higherrelative cost of biological medicinesboth in R&D and manufacturing hastended to place constraints onaccess and routine use. Therefore,the availability of interchangeablebiosimilar medicines gives anopportunity for prescribers to revisitpatient treatment pathways and thegroup of people considered suitablefor biological treatments to bewidened.It is vital that the biosimilars

following adalimumab are notdelayed by uncertainty ordisruptions to the licensing systemfor new medicines. Today, the oneand only licensing route forbiosimilar medicines in Europe is theCentralised Procedure, operated bythe European Medicines Agency(EMA) from their offices in CanaryWharf, London. The uncertaintiesover Brexit could have majorimpacts. The relocation of EMAfrom London to Amsterdam will bedisruptive. According to a recentstaff survey by EMA of their staff, atleast 30% will not relocate to theNetherlands. Therefore, the EMA isalready having to strictly prioritiseand reduce its range of work. Thelicensing of new medicines is a coreactivity for all medicines regulatorsso it is hoped that impacts in thisarea will be minimised. However,relocation will inevitably bechallenging for systems, processesand timelines. For these reasons,delays in the approval of newbiosimilar medicines is a significantrisk factor.Due to the lack of political

certainty, the life sciences industryhas had to include in its plans theworst case “no deal” Brexitscenario. If that happens and the UKis separated from the EMA and theEU regulatory network then it hasnot been made clear how the UK

BIOSIMILARS –CHALLENGES ANDOPPORTUNITIESby Paul Fleming

The UK is entering a critical period for biosimilarmedicines. The biggest savings opportunity for the

NHS from the use of biosimilars is about to happen.However, during the current Brexit negotiations, wehave continuing uncertainty on the regulatorymechanism for licensing future biosimilars. This articlelooks at the upcoming challenges and opportunities.

Paul Fleming is Technical Director of the British Biosimilars Association and the BritishGeneric Manufacturers Association and prior to that Chair of its Regulatory WorkingGroup for several years. The role includes close and regular discussions with MHRA,Department of Health, the NHS and other stakeholders. At a European level, Paul is akey member of the regulatory and quality committees of Medicines for Europe. Inboth these roles, he is involved in the development, influence and implementation ofnew regulatory and quality guidance.

Paul has more than 15 years’ experience from working in the generic sector of theEuropean pharmaceutical industry, in a variety of senior board level roles coveringR&D, drug regulation, pharmacovigilance and clinical development. Earlier in hiscareer he spent six years with the MHRA as a pharmaceutical assessor and is anappointed expert to the British Pharmacopoeia. He is a registered pharmacist andholds a higher degree in pharmaceutical technology. Throughout his professional lifePaul has maintained an involvement with the science of pharmaceutical developmentconnecting to how medicines can be used for the maximum benefit of patients andthe NHS.


August. These indicate that MHRAwill continue to reference opinionsand decisions coming out of theEMA procedure when a companyapplies to EU27 and UK in parallel.However no mention is made ofnational control laboratory testing(National Institute for BiologicalStandards & Control - NIBSC - inUK) which is an important pillar ofthe regulatory control of biologicalmedicines. It is important that evenif the UK and EU regulatory systemsstart off in parallel they do notgradually diverge over time.Overall, we are at an important

licensing authority, the Medicinesand Healthcare products RegulatoryAgency (MHRA) would operate. It ishoped that MHRA would review inparallel to EMA for the assessmentof biosimilar medicines, takingaccount of EMA opinions and notduplicate or diverge on scientificissues. It is vital that the samescientific dossier can be submittedat the same time to EMA andMHRA, followed by the sameassessment and approval timetable.Some reassurance has come fromthe technical notices published bythe UK Government at the end of

BIOSIMILARS – CHALLENGES AND OPPORTUNITIES continued

milestone moment in the history ofbiosimilar medicines. In the comingmonths the largest opportunity forsaving scarce health resources andtreating more patients will takeplace. However, it is important thatthis is not the high-water mark forthe sector and that it is not thenfollowed by uncertainty on thetimely availability of the next waveof biosimilar medicines. The BritishBiosimilars Association is fullycommitted to work with its membercompanies to help navigate thisperiod of challenge.

http://www.excipact.org


of raw materials and medicines dueto companies seeking low cost rawmaterials from emerging marketssuch as China and India that havebeen responsible for 75% of theadulterated and counterfeitmedicines in to the global supplychain. This has resulted in theintroduction of expensive controls toimplement “pack realization” indeveloped global markets to

attempt to control the quality ofpharma products.As pharmaceutical companies

grapple with expiring patents andpricing pressures in developedmarkets, they are starting to expectmore from emerging markets.Although the global economicenvironment is depressing near-termGDP growth, countries such asChina, India, Russia, and Brazil havea bright medium and long-termfuture as some of the world’s largesteconomies. Rapid growth can alsobe expected in some smallereconomies in Eastern Europe,Southeast Asia, Latin America, andthe Middle East. As GDP growthconverts into greater personalwealth and higher disposableincomes, spending on health risesdisproportionately, and drugsconsumption even more so. Even inthe near term, large emergingpharmaceutical markets are likely togrow more strongly than developedmarkets.

Pharma EconomicsThe share of revenues and profitscontributed by emerging countriesis lower in pharma than in otherglobal industries, and majormultinationals have yet to engagewith the emerging middle classes inthese countries. At a typical globalconsumer goods company,emerging markets account for ashare 1.5 to 3 times higher than at atypical multinational pharmacompany. Such figures indicate thatemerging markets are still emergingand offer significant opportunitiesfor further growth. Such optimismmust, however, be tempered by anawareness of the challenges andvolatility that multinational pharmacompanies face in emergingmarkets:

a) Government intervention isincreasing through both directactions (such as price settingand compulsory licensing) andindirect measures (such aschanges in manufacturingrequirements and the terms ofgovernment tenders).

b) Promotions are reachingsaturation point, especially in

GROWTH ANDGLOBALISATION OFPHARMA PRODUCTSby John Jolley

Pressures on the cost of public services in regions suchas Europe and the US are beginning to restrict growth

in pharmaceuticals, forcing companies to compete forlimited funds as the current level of pharma business nolonger reflects demand when compared with theproportion of their population. Sales in the US marketwill reach USD 1,430 billion by 2020 and market shareincrease from 40.3% in 2015 to 41% in 2020, butEurope’s share will fall from 13.5% in 2015 to 13.1% in2020, and sales in Pharma emerging countries willaccount for 25% of global sales by 2020. Emergingeconomies will account for 90% of the incrementalgrowth in global pharmaceutical sales over the next fiveyears. Manufacturing sources in emerging markets (Indiain particular) already account for 15 percent of themedicines sold in US, which will only be improved ifcompanies are prepared to be flexible in their approachto the differing regulatory strategies that might limitmarket entry.

This paper identifies some of thesocio-economic factors that areinfluencing growth in thepharmaceutical markets byintroducing issues of affordability inboth developed and emergingmarkets and comparing these withthe effects of demand to identify themarkets that are likely to see highgrowth. In recent years we haveseen increased regulatory controls

John Jolley is a Director of PharmaConsult providing technical consultancy andbespoke training solutions to Global Healthcare organisations. John has a degree inPharmacy and has been awarded fellowships with the Royal Pharmaceutical Societyand Chartered Quality Institute. He has held positions in Clinical Research, ProductRegistration, Manufacturing, Quality Assurance, and General Management and wasmember of the Council at the RPS 2003-2008. He was Technical Director forBoehringer Ingelheim UK for 15 years before his work in International consultancyand is a practicing Qualified Person (QP) with experience of sterile productmanufacture and clinical trials.

PharmaConsult is supporting companies trading in the EU and UK to systematicallyevaluate their Company’s regulatory strategy and pharmacovigilance operationalstatus with respect to the changes resulting from Brexit. It has offices in both London(UK) and Sofia (Bulgaria) and is well placed to advise on mitigating the effects ofBREXIT for EU and UK companies. Further details are available at:www.pharmaconsult.co.uk and www.pharmaconsulteurope.com

http://www.pharmaconsult.co.uk

http://www.pharmaconsulteurope.com


the big cities wheremultinational and localcompanies have expandedtheir sales forces rapidly overthe past few years.

c) As some multinationals shifttheir focus toward specialtyproducts, managing portfoliosof drugs with very differentcommercial needs isbecoming considerably morecomplex.

d) The competition isintensifying in some countries.Looking ahead, we believethat emerging marketscontinue to offer attractiveopportunities for growth, butpharma companies will needto navigate the intricacies ofindividual markets and tailorcommercial models andapproaches to their specificneeds

Product InnovationThe biggest challenge to thepharma Industry is to recoverdevelopment costs within the patentperiod remaining after obtainingMarketing Authorisation, and stillmeet the fiscal challenges of themarket place. The cost ofdeveloping a successful medicinenow can exceed USD 2.6 billioncompared to USD 179 million in1970s. This huge increase reflectsthe various technical, regulatory andeconomic challenges facing R&Dpipelines. Companies oftenexperience lost R&D investments(that is, R&D expenditures that donot materialize in a market-approved medicine) becausepharmaceutical R&D is marked byhigh failure rates. An early-phasecompound may have a promisingoutlook, but only preclinical andclinical trials will demonstrate itsefficacy, quality, and safety. Inaddition, lost investments mayincrease when a failure occurs inlater R&D phases. A phase III failureis significantly more costly than apreclinical failure because eachphase is associated with a certainamount of required investment.

Market GlobalizationThe exciting growth forecast inemerging markets come with somekey challenges, particularly marketsegmentation in balancing thedifferentiated capacity of the super-rich versus low-income consumers,along with pricing and access topublic versus private market. Globalmultinationals have typicallyfocused on the smaller high-endprivate payer population. Thegreatest opportunity, however, willcome from the expanding middle-class segment, which, with itsgreater purchasing power, willexpect access to the full range ofpharmaceuticals and the very bestin healthcare. Growth in emergingmarkets over the last decade hasdeveloped with compound annualgrowth rates (CAGR) of 10-14 %versus 0.6-2 % in many newlydeveloped markets (see Figure 1).The pharmaceutical market is

changing. China is now the thirdlargest pharmaceutical market in theworld – almost 50 percent larger thanGermany — and other emergingmarkets are working up the ranking.In fact, growth in this sector isforecast to continue for theforeseeable future. Over the next fiveyears, emerging markets areexpected to nearly double theirspending on drugs, reaching nearly30 percent of the globalpharmaceutical spend (see Figure 2).

Improving HealthcareSystemsEmerging markets have seen a risein the number of individuals whohave moved from a subsistencelifestyle to one with an increase inpersonal net worth and disposableincome. These markets have alsoseen rising numbers of employmentopportunities with company healthinsurance schemes. Experts believethat more people, with greaterdisposable income, will seek anincreasing number of healthcaretreatments, thus expanding themarkets for medicines. Politicalpressure and demand from themiddle-class to increase availabilityand access to healthcare has alreadyresulted in significant health reformsdesigned to provide basic universalhealthcare coverage. Examples ofrecent reforms include:

China – Reforms will provideaffordable medical care for all by2020.Russia – The Health andPharmaceutical 2020 reform willextend basic healthcare coverageand reimburse outpatient drugs.Also, 50 % of all generic drugs willbe replaced by domesticalternatives by 2017, and 50 % of allinnovative drugs will bemanufactured domestically by 2020,fuelling domestic and internationalpharmaceutical investment.

GROWTH AND GLOBALISATION OF PHARMA PRODUCTS continued

Figure 1. Global pharmaceutical market growth for the period 2011 – 2016,by region (CAGR). Source: IMS Health.

Southeast & East AsiaIndian Subcontinent

Latin AmericaAfricaCIS

Middle EastJapan

OceaniaEurope without EU countries

North AmericaEuropean Union

13.9% 13.3% 13.2%

10.5%10.5%

7.5% 2.6% 2.5%

2% 1.6%

0.6%

Growth

0.0% 2.0% 4.0% 6.0% 8.0% 10.0% 12.0% 14.0% 16.0%



India – The hospital sector hasgrown considerably in recent years,and improving access to healthcareremains a priority for India’s Ministryof Health.Brazil – The Brazilian governmentpledges universal health coveragefor all, although many drugs will stillrequire out-of-pocket payments.Generics account for about one-quarter of all medicines sold inBrazil, making it the largest genericsmarket in Latin America. Analystsbelieve there is still room for growthin this sector.Africa – Pharmaceutical expenditureis expected to reach $45 billion by

2020. The sub-Saharan Africaneconomy, excluding South Africa, isgrowing faster than anywhere else inthe world – a trend that is expectedto continue.

Disease PrevalenceEmerging markets face thechallenge of dual epidemiologicalburden, with high rates of infectiousdisease, as well as the risingnumbers of non-communicablediseases. Increase in “Westerndiseases” due to changing diet andlifestyle are contributing to this rise,with diabetes reaching epidemicproportions in countries like

Indonesia. Seventy percent of allcancer deaths now occur in low- andmiddle-income countries, whichmean the demand for chronictreatments continues to increase.(see Figure 3).

Policy Supporting Genericsand BiosimilarThe final feature contributing to thegrowth in many emerging markets isthe increasing demand for genericsand biosimilar, which is encouragedby government policy. Brazil’sGeneric Medicines Policy of 1999resulted in generics now having over60 % of market share by volume.The expansion of the brandedgenerics/biosimilar market may bethe greatest opportunity for pharmadue to the mass population thatrequires access to medicines.Countries, such as Saudi Arabia,South Africa, China, India andRussia, are keen to promote andsustain a robust generics industry byimplementing policies to encourageuse and manufacture.

Factors affectingdevelopment in EmergingMarketsAdapting and applying businessdecisions should be customized forthe emerging markets as eachcountry differs in terms ofepidemiology, awareness, treatmentprotocols, compliance and, aboveall, pricing. Innovator companies willhave to customize their strategieswhen launching into these marketsin order to make the productaccessible and affordable to themasses. Over the next ten years forexample, Russian pharma will morethan double in size. Companiesseeking to capture a share of thisgrowth must prepare to face thechallenges of increasing pharmaregulation and intensifyingcompetition. However, theenvironment will also become muchmore challenging as the stateregulates market access, pricing,and competitive pressure intensifiesfrom both multinationals and localpharma companies.

Figure 2. Projected spending on medicine in selected emerging markets in2018 (in billion U.S. dollars). Source; IMS Health.

Figure 3. Top therapy areas in pharma-emerging markets in 2018, byspending (in billion U.S. dollars). Source IMS Health.

China Brazil Russia India Tier3 Pharmerging

Expenditure in billion U.S. dollars 170

4125 26

110Pain

Antibiotics

Hypertension

Oncolog

ics

Diabetes

Other CNS drugs

Anti-ulcerants

Dermatolog

yCholesterol

Mental health

Immunostimulants

Respiratory

Other CNS

Viral hepatitis

Antiplatelets

Wom

ens health

Nasal preps

Anticoagulants

Erectile dysfunction

Immunosuppresants

Minimum estimate Maximum Estimate

Spending in billion U.S. dollars

180

160

140

120

100

80

60

40

20

0


The Indian pharmaceutical marketpresents a unique set of opportunitiesand challenges that arise from itsdistinctive nature. Branded genericsaccount for a huge share – more than80 % of the retail market. Local playersdominate thanks to their earlyinvestments and capabilities informulation development. Intensecompetition has kept prices low,which explains why India ranks in thetop three markets in the world interms of volume yet only in the topfifteen in value.Mexico’s health care has improved

thanks to recent public initiatives, butrising costs, capacity constraints, andgrowing disparities pose newchallenges. To keep pace with theseshifts, pharma companies need toraise their capabilities to globalstandard and preserve the flexibility toupdate their plans as often as everyquarter. Health care in Mexico is at aninflection point. Recent advances inpublic policy have helped bringnoticeable improvements in health

indicators, but the system is underpressure. Over the past five years, generic

and branded generic have continuedto grow strongly in emerging markets,often at a pace two to five times fasterthan branded originals. In thoseemerging markets where brands areseen a proxy for quality, and wherephysicians retain considerable controlover prescriptions and patients overpurchasing decisions, brandedgenerics have been more successfulthan their unbranded counterparts,and have maintained their prices forlonger. Recognizing this opportunity,many global pharma companies haveannounced plans to boost theiremerging market business byinvesting in branded generics,whether by launching their ownportfolios or by acquiring those ofother companies. However, thelandscape for branded generics is farfrom uniform, with individual marketsevolving in markedly different ways. Insome markets, such as Turkey and


Saudi Arabia, governments areimplementing cost reductionmeasures. In other markets, such asSouth Africa, payers are puttingpressure on prices. By contrast, somemarkets, such as Brazil, are continuingto see rapid growth in brandedgenerics as the emerging middle classacquires increasing purchasing power.Sales growth in the emerging

markets will only occur if companiesregister newly developed productsin emerging markets. Price will be alimitation but this will be less thanthe restrictions imposed by publicexpenditure in developed markets.Pharma companies will need to takeaccount of appropriate regulatoryaffairs and marketing strategies thatwill establish realistic costs for newlyintroduced drugs tailored toemerging market needs. They willalso need advice on the right localpartners, and organizationalresources necessary to managepartnerships in the emergingmarkets.


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The increased worldwide popularityin the use of Traditional andComplementary Medicine (T&CM)has escalated public health policyissues. The WHO has developed theTraditional Medicine (TM) 2014-2023framework to promote the safe andeffective use of T&CM. It aims toregulate products and practices forpractitioners to ensure a safeintegration of T&CM into nationalhealth systems1. A 2004 Malaysian national survey on

T&CM found that 69.4% of Malaysiansused T&CM during their lifetime, anincrease of 55.6% from the previousyear2. Annual sales of T&CM/alternative medicines were estimatedto be MYR 1000 million as comparedto MYR 900 million for allopathicpharmaceuticals3. This figure isprojected to increase in the future. Malaysia established the National

Policy on T&CM to emphasizecapacity resources on practice,education, training, raw materials,

products and research4. On 11thJanuary 2006, the Malaysiangovernment established TCM unitswithin the Ministry of Health Malaysia(MOH) facilities. These units providechoices of Chinese Herbal Medicine(CHM), acupuncture and Malaymassage services across threehospitals, namely the Kepala BatasHospital in Penang, PutrajayaHospital in Federal Territory ofPutrajaya and Sultan Ismail Hospital inJohor. This pioneer project wasaimed at integrating T&CM into thepre-existing public healthcare deliverysystems. An integrated medicalsystem would promote rationalizationin the use of T&CM through thedevelopment of technical guidelines,regulatory procedures and standardsof T&CM practices5. With various ethnicities, Malaysia’s

rise of T&CM systems is diversifiedwith allopathic medicine, traditionalMalay medicine, traditional Chinesemedicine (TCM) and Ayurveda, each

reflecting the accustomed Malay,Chinese, Indian and indigenousheritage. Other forms of T&CMinclude homeopathy, aromatherapyand chiropractic. Malaysians have integrated TM into

their daily lives, although the practicecorrelates with ethnic culture andbeliefs. TM treatment mostlydepends on the individualpractitioner’s experience. Albeit, TMin Malaysia is sharing some principlesand taboos6, there are somedifferences as well across differentethnic groups. TM practice is notsolely restricted to one’s own ethos orculture, as it has now diversifiedacross to other ethnicities. Forexample, Malay postnatal massage ispopular among the Chinese, whileacupuncture and CHM were wellaccepted by other ethnicities in thecountry. As a T&CM pharmacist for the past

10 years, I have found that TMprovides numerous benefits to cancerpatients when the practices are addedto the conventional medical system.However, there is a lack of evidenceon the efficacy of TM when it isintegrated to allopathic medicine.Many TM modalities are based onbeliefs and traditions of the culture.The effectiveness when assessed todate has mainly been based onpatients’ testimonials with littlescientific rigour. Therefore, thepractice of TM is still limited due topatient safety concerns.Safety and efficacy of TM are major

concerns. To offset these concerns,more research either in vivo or invitro, should be performed. Thecomplex mixture of chemicalcompounds present in various herbsshould also be assessed. Modernmedicine and TM postulate differentphilosophies towards the treatmentof illness. Modern medicine hasmethodologically reviewed thestructure and function of organsystems with therapeutic drugs beingtargeted against pathologicaldiseased cells, tissue and/orpathogens. On the other hand TMadvocates the philosophy of holismand the interrelationship with theenvironment. Variation of researchmethodologies are needed in orderto assess the possible integration


THE RISE OF TRADITIONALMEDICINE (TM) INMALAYSIA: POTENTIALS,CHALLENGES ANDOPPORTUNITIES FORENHANCEMENTby Ai Ch’i Liew

Traditional Medicine (TM) is gaining popularity inMalaysia and many other countries globally. The

adoption of TM may be due to the limitation ofconventional treatments. An increasing role for TMcould herald great opportunities for pharmacists,researchers and pharmaceutical industries to take upthe challenges to overcome the obstacles to ensurebetter future treatments for patients.

Ai Ch’i Liew graduated at Universiti Sains Malaysia in 2006 and finished herpostgraduate study of Master in Science (Clinical Pharmacy) at Universiti SainsMalaysia in 2014. She worked as a Traditional & Complementary Medicine (T&CM)pharmacist and served in the first T&CM unit in Malaysia between 2006 and 2017.She is currently working as a clinical pharmacist in the Clinical Research Centre inSeberang Jaya Hospital, Penang, Malaysia.

between modern medicine and TMpractices. Although randomizedcontrolled trials (RCTs) are consideredto be the “gold standard” approachto provide the most reliable and validresults in evidence-based practice,they may not be so suitable for TMtherapeutic evaluation.Observational studies and case

reports are often found to be moresuitable for the assessment of TMrather than RCTs. RCTs often neglectTM practices as the approach oftenemphasize a highly personalizedtherapeutic regimen. Anobservational approach may be moresuitable to generate valuableinformation through scrutinizingindividual patient’s outcomes and thefactors influencing it. Individualizedtreatment success was shown by a 14week follow-up trial that highlightedthe continued improvement ofpatients who received Chinese herbalmedicine (CHM) formulations post-treatment as compared to those whoreceived standard CHMformulations7. As a result, Evidence-informed practice and Value-basedmedicine might be more suitable inTM research which integratesresearch evidence with clinicalexpertise and patients’ value.However, it would be an immensechallenge for the pharmaceuticalindustry to commercialize TM to alarge scale. Integrated objective measurements

such as Quality of Life (QOL)instruments for patient reportedoutcome (PRO) and systems biologytechnology that provide biomarkermeasurements during treatmentintervention will substantiate thesubjective assessment of TM practice,where Reverse Pharmacologypractice could be employed. ReversePharmacology is defined as thescience of integrating documentedclinical/ experiential hits into leads bytransdisciplinary exploratory studiesand further development of drugs byexperimental and clinical research8.Bioinformatics, pharmacogenomicsand systems biology are expected toopen new channels for theconvergence of TM and modern

medicine. Advancement of theseapproaches will create a buildingblock to measure the mechanism ofaction of TM formula by modernpharmacology methods withoutneglecting the common TMpractice9. This traditional knowledge-inspired reverse pharmacology is ableto prove better leads to explorepotential herbal drug development.This approach is an important way toelucidate the mechanism of action ofTM formulas in clinical management.The efficacy of TM may be reducedwhen essential factors do not meetcertain criteria such as differentcombinations or pairing in a variety offormulations. Drug discovery in the

pharmaceutical industry shouldexplore the classic herbalformulations which have been usedfor centuries for therapeutic andprophylactic purposes. Integrateddigital databases of TM use in Taiwanfor example, would be able togenerate safety and efficacy profilesin an integrated medicine practice.This is an easy economical way todiscover new drugs throughexploring such databases. Theincorporation of TM syndromeclassification into biomedical diseasediagnosis will lead to a new era in thedevelopment of medical sciences toprovide improved treatment efficacywith specific indications of integrativetherapy. The safety of TM should be taken

into consideration. Misconception ofadverse effects of TM may limit thetherapeutic model potential.Qualitative and quantitative studymethods should be applied intoresearch, exploring the safety of TM.Quantitative study is sufficient todetermine the seriousness of adverseeffects within the routine practice ofTM while qualitative study coulddetermine patients’ perceptions ofTM, and at the same time weighingthe perceived costs of adverse effectsand/or its perceived benefits. Authorities should also undertake

pharmacovigilance of herbalmedicine treatment, to monitor herb-drug safety and identify adverse

reactions in humans, assessing risksand benefits and responding to andcommunicating herb-drug safetyconcerns with practitioners and thepublic. This will be an importantfactor in forming a national herbalmedicine safety database to extendknowledge of safety in TM ratherthan focusing on the harmful side ofTM. In conclusion, the deficiency or

insufficient outcomes of conventionalmedical treatment may lead to theadoption of TM. TM utilization shouldat the same time undergo qualitycontrol procedures to overcome anypotential issues in the use of TM.

Acknowledgement:I would like to thank the DirectorGeneral of Health Malaysia for thispermission to publish this article.

References1 WHO. WHO Traditional Medicine Strategy

2014-2023. 2014.2 Siti ZM, Tahir A, Farah AI, Fazlin SMA, Sondi

S, Azman AH, et al. Use of traditional andcomplementary medicine in Malaysia: abaseline study. Complementary Therapies inMedicine. 2009; 17(5–6): 292-9.

3 Cumming N, Gagne J, Lasseur S, Li Y,Maddalena S, Ramillien M, et al. LegalStatus of Traditional Medicine andComplementary/ Alternative Medicine: AWorldwide Review. 2001.

4 National Policy of Traditional andComplementary Medicine M. NationalPolicy of Traditional and ComplementaryMedicine. In: Division TaCM, editor. 2007.

5 Laws of Malaysia Act 756. Laws of Malaysia:Traditional and Complementary MedicineAct 2013. 2013.

6 Ganasegeran K, Rajendra Ak, Al-Dubai SAR.Psycho-Socioeconomic Factors AffectingComplementary and Alternative MedicineUse among Selected Rural Communities inMalaysia: A Cross-Sectional Study. PLOSONE. 2014; 9(11):6.

7 Bensoussan A, Talley NJ, Hing M, MenziesR, Guo A, Ngu M. Treatment of irritablebowel syndrome with chinese herbalmedicine: A randomized controlled trial.JAMA. 1998; 280(18): 1585-9.

8 Vaidya ADB, Devasagayam PA. CurrentStatus of Herbal Drugs in India. Journal ofClinical Biochemistry Nutrition. 2006; 41: 12.

9 Wang J, van der Heijden R, Spruit S,Hankermeier T, Chan K, van der Greef J, etal. Quality and safety of Chinese herbalmedicines guided by a systems biologyperspective. Journal of Ethnopharmacology.2009; 126(1): 31-41.

THE RISE OF TRADITIONAL MEDICINE (TM) IN MALAYSIA continued



79th FIP World Congress of Pharmacy and Pharmaceutical SciencesAbu Dhabi, United Arab Emirates22-26 September 2019

As we develop new skills to manage new technologies such as

robotics and the digitalisation of health care, it is important that

we do not compromise quality and safety.

Come to the Abu Dhabi congress, which will help you develop

the knowledge and attitudes to adapt to emerging new roles

through networking with pharmacists and scientists from all

areas of practice and from all around the world.

New horizons: Navigating winds of changeNew technologies, new roles, new opportunities for pharmacy

Do you want to be inspired to take on new roles and be prepared for success in a worldof change? Wherever you practise, FIP can help you stay ahead of the game so that you can provide the best care for patients.

A > New trends in science, practice

and education

Focuses on new technologies,

digitalisation of health care,

robotics, individualisation of

therapy, the provision of edu-

cation via virtual classrooms,

integrating science and practice

in teaching, communication,

people-centred care, and ethical

challenges.

B > New roles, opportunities and

responsibilities

Examines pharmacists’ roles and

the roles of individuals, looks

at new services and the skills

required to advance them, and

highlights the importance of

education and of collaboration

not only with pharmacy collea-

gues but also with other health-

care professionals.

C > Health now! Responding to the

challenges of today

Recognises that challenges can be

faced by looking at new research,

ethical considerations, new values,

access to health, health systems,

sustainability, environmental

sustainability, non-communicable

diseases, empowerment of patients,

empowerment of women, quality

and assessment.

D > Targeting special interests

Looks at special interests in the

different fi elds of pharmacy and

pharmaceutical sciences.

WELCOME TO ABU DHABI

Abu Dhabi is a modern, cosmopolitan city with an ancient heritage

where respect for the past informs the present and shapes the

future. There are historic buildings, engaging tours and a packed

calendar of events covering the arts, culture, sports and trade.

Visitors will encounter a diverse emirate, with deserts, beaches,

oases and mountains, and there are ultra-modern malls and small

souk-like stores to cater for their every (tax-free) shopping need.

CONGRESS STREAMS:

Please fi nd more information:

abudhabi2019.congress.pharmacy

NoteSome congress sessions are accredited for continuing education. Check our website.


Why do we need alternativeexpedited registrationpathways?

Among the most relevant causes arethe following:

• Medical needs which are notmet by medicines available inthe market.

• More information for patients,even in early stages of thedevelopment of products,demanding faster access tothem.

• Developing alternative ways

to conduct reviews in a rapidmanner, withoutcompromising the safety,efficacy, and quality of themedicine.

• Alternative registrationpathways are needed toexpedite access, but must beestablished within aframework that is sustainablefor all stakeholders.

• Improved allocation of localresources, improved patientaccess, and increased equityof access are urgent globalneeds.

Key points to consider toaccelerate access tomedicines

Regulatory agencies focus on:

• applying the principles ofWHO draft guidelines on GoodRegulatory Practice andCollaborative RegistrationProcedures when establishingexpedited regulatory pathways;

• focussing on submissiondocuments on what is absolutelyrequired for purposes of localassessment;

• consider allowing face-to facemeetings with applicants todiscuss the overall filing strategy,especially for productsaddressing unmet medical needs.

Main global regulatoryadvances

In the US, companies have regularlybeen using available expeditedpathways such as Priority Review,Breakthrough Designation, and FastTrack for many years.FDA Regulatory advances have

impact outside the US, showing awide readjustment of priorities in theEuropean Medicines Agency (EMA)and in Japan (PMDA). This effect hasalso been emulated in otheragencies such as Health Canada,China FDA, and Korea MFDS withtheir recent establishment ofpathways to accelerate the review ofcertain types of products or toestablish conditional approval basedon a more limited clinical datapackage. Many agencies are assessing the

outcomes of the medicines reviewspreviously conducted by otheragencies and then ensuring that anyadditional work conducted by thelocal agency adds value to priorwork. This approach centres on theuse of two related but differentconcepts:

¨RELIANCE¨ (Dependence basedon trust), whereby a regulatoryauthority in one jurisdiction maygive significant weight to workperformed by another regulator or

REGULATORYCONVERGENCE ANDGLOBAL TRENDS INEXPEDITED REGULATORYPATHWAYSby Marisa Carcione

Regulators in both established and maturingagencies are facing challenges in their effort to

provide faster access to medicines to patients whoneed them.

Marisa Carcione is Partner & Director of IPRAT, a business development, intellectualproperty & regulatory affairs consultancy firm for Latin America. She has a Pharmacydegree from the University of Buenos Aires and has more than 20-years’ service in theHealth Industry in Latin America (Pharmaceutical Products, Medical Devices,Cosmetics and Food Supplement).

Prior to joining IPRAT in 2015 to lead the consultancy team, she worked forBoehringer Ingelheim in a broad range of regulatory leadership roles, with global,regional and local scope. Marisa's experience covers strategic, tactic and operationalroles, in positions of Head of Regional Regulatory Affairs for LATAM and Head ofLocal Regulatory Affairs for Argentina, Uruguay, Paraguay and Bolivia, both based inBuenos Aires, Argentina. During a three-year assignment in Germany, she coveredinternational responsibilities as Manager for the Regional Coordinating Centre inGlobal Regulatory Affairs, supporting other regions like Europe, Middle East andAsia.

Her current responsibilities are business development, management and leading oftechnical teams for international, regional and local companies in consultancy,including regulatory strategy development for innovative products and newtechnologies, regulatory management system and compliance. She activelyparticipates in public health and regulatory intelligence forums and working groups,supporting FIFARMA and other industry associations in convergence initiatives andregulation development.


other trusted institution in reachingits own decision.

Recognition, the routine acceptanceof the regulatory decision of anotherregulator or other trusted institution.

Reliance pathways tofacilitate regulatorydecisions

Recognition procedures: authoritiesreview medicinal products intendedto be marketed in countries orregions other than their own.

Verification review procedure: isused to reduce duplication of effortby agreeing that the importingcountry will allow certain products tobe marketed locally once they havebeen authorized by one or moreSRAs (Stringent RegulatoryAuthorities). Review on the basis ofCPPs, GMP certificates, and/or theassessment reports of referenceauthorities.

Abridged review procedure:assessments of data that have beenalready reviewed and approved bySRAs but includes an abridgedindependent review of a certain partof the dossier relevant to use underlocal conditions.

Expedited regulatorypathways for medicinestargeting unmet medicalneed

Expedited review: regulatoryauthorities speed up the review ofcertain products to enable fasterapproval.

Expedited submission (rollingsubmissions): information and data-packages can be submitted andreviewed as they become available.

Expedited development: earliersubmission and approval with a dataset which may be less completethan from a standard developmentprogram (e.g., surrogate endpoints,phase 2 data only).

¨RELIANCE¨ models in CentralAmerica and the Caribbean, andequivalence agreements in Mexico,provide the benefit of movingapproval times from nine months tothree to four months. Other emerging market countries,

such as Saudi Arabia, Egypt, Jordan,and the UAE, have recentlyapproved accelerated pathways withreview timelines ranging from 60 to90 days. Recently, “Priority Review”criteria for products that meet atleast one of the eligibility criteriahave been established in Brazil, forexample medicines for neglecteddiseases, and vaccines to beincorporated in the nationalimmunization program.Likewise, expedited procedures

for clinical trial applications,certificate of good manufacturingpractices, and registration of newdrugs intended for diagnosis,prevention, or treatment of rarediseases have been established.

Recently, ANVISA publishedtwo new guidelines with thepurpose of accelerating theapproval of medicines inBrazil:

Resolution 204/2017 establishes“Priority Review” criteria forproducts that meet at least one ofthe eligibility criteria; for example,medicines for neglected diseases,and vaccines to be incorporated inthe national immunization program.This guidance also addressespriority review processes for post-approval applications when there isa public health risk of drugshortages. Publication of a specialprocedure for registration of drugsintended to treat rare diseases wasanother effort to expedite drugapprovals.

Resolution 205/2017 establishesexpedited procedures for clinicaltrial applications, certificate of goodmanufacturing practices, andregistration of new drugs intendedfor diagnosis, prevention, ortreatment of rare diseases.

Service Orientation 45 is anotherrecent (February 2018) regulatoryadvance from ANVISA, whichestablishes optimized review forregistration and post-registrationchanges for biological products.According to the agency, this is alsobeing considered a “Reliance PilotProject” open for one year. Productsalready approved by the FDA andEMA with same indications, dosage,adverse reactions, and precautionsare eligible. Applicants must submitreports containing the criteria usedby both agencies to review andapprove these applications.

Conclusion

Progress has been remarkable andhas not been limited to the SRAs ofdeveloped countries, but also tothose of emerging countries.Looking to the future, wheretailored therapies will gain specialprominence, we still have a way togo. The evolution of regulation,accompanying the development ofscience, will be the key toguarantee the access of patients tonew health technologies. Although FDA was a pioneer in

providing expedited approvalpathways, other established andemerging markets agencies havejoined by incorporating therecognition and reliance concept inprevious evaluations performed byother health authorities. Regulatoryagencies attempt to facilitate reviewand approvals, simplifyingprocedures, and reducing timelinesand backlogs in reviews anddecisions. Collaboration amongregulatory agencies, and thesupport of the industry and theacademy, make it possible to buildupon existing frameworks, deepenlocal needs aligned with globalstandards, building trust andsharing resources and experiences.The ultimate goal is to providefaster access to medicines for thepopulation, ensuring their safetyand efficacy.

REGULATORY CONVERGENCE AND GLOBAL TRENDS IN EXPEDITED REGULATORY PATHWAYS continued


An initiative to amend thelegislation (Regulation (EC) No469/2009) on SupplementaryProtection Certificates (SPCs) is inmotion.1 SPCs afford companies anextended patent protection of up tofive years on top of the typical 20-year market exclusivity period forinnovative medicines.2 In particular,SPCs disallow the manufacturingand selling of generic versions of apatented medicine in the EuropeanUnion (EU) during the SPC term. While SPCs are granted to

compensate drug makers for thelengthy development stage andreward them for their efforts atresearch and innovation, SPCsreportedly have given rise tounintended consequences thatdisadvantage small to medium-sizeddrug makers of generic andbiosimilar products.3 To facilitateinvestment, job creation, and growthin pharmaceutical companies basedin the EU, the EuropeanCommission has proposed to adjustthe intellectual property rulescontained in SPCs.4

At risk: The EU’s globalcompetitiveness in genericsand biosimilars

One of the unintendedconsequences of SPCs is the loss ofopportunities in the export marketfor medicinal products that areexperiencing global growth. In 2017, the global demand for

medical products reportedlyreached €1.1 Trillion.4 TheCommission also acknowledges thatthere is an increased demand foraffordable alternative treatmentssuch as generics and biosimilars.Indeed, the European Parliamentestimates that these products would

represent 80% of the global volumeof medicines by 2020.1 A significantnumber of pioneering biologics arealso set to lose their marketexclusivity starting 2020, whichwould open up massiveopportunities for investments andjob creation in relation to biosimilarmanufacturing.1

However, since SPCs preclude theearly manufacturing of generics andbiosimilars, EU-based manufacturerscan only begin production after theSPC for the related product expires.This delay places EU-basedmanufacturers at a competitivedisadvantage to non-EU-basedmanufacturers that can market theirproducts in Member Statesimmediately after a certificateexpires.1

The original SPC legislation is alsono longer relevant to the currentstate of the pharmaceuticalmarketplace. It was implementedalmost three decades ago; it doesnot reflect the rapid pace oftechnological advancementsapplied in pharma research and theemergence of novel products suchas biosimilars.1

The risk of a having an SPClegislation that is lacking in industrialrelevance is that manufacturersmight move their facilities outside ofEurope where they can manufactureand market sooner. This exodus ofmanufacturers might lead to lossesin investment and employmentopportunities in Europe.

The manufacturing waiver forexported medicines

To boost the competitiveness ofmanufacturers in the EU, theCommission has proposed to adoptan SPC manufacturing waiver for

generics and biosimilars. Under thewaiver, manufacturers can begin theproduction of generics andbiosimilars within the EU evenduring the SPC protection period.1

However, the waiver only applies toproducts that are intended forexport to countries outside the EU,countries without an SPC in place,or countries where an SPC hasalready expired.5

In addition, the waiver will enable“Day-1 entry” of EU-made genericsand biosimilars. The waiver enablesstockpiling, where manufacturerscan make and store their product sothat they can readily market theirmedicine to EU Member Nations onthe first day following a certificate’sexpiry.According to the Commission, the

Day-1 entry provides addedincentive to small- and medium-sized manufacturers to retain theirproduction within the Union bordersrather than relocate to non-EUcountries.4,5 With the expectedgrowth in the global demand forgenerics and biosimilars, theCommission expects that themanufacturing of these products(within the EU) will generatebetween 20,000 and 25,000 directjobs.1 Moreover, EU-basedmanufacturers can deliver theirproducts to patients in MemberStates in a timely manner, enablingthem to more effectively competewith global competitors.5

The implications of Brexit onSPCs

The UK Parliament might need toconsider the potential impacts ofthe proposed adjustments on SPClegislation. The granting of thesecertificates is under EU regulation.

PHARMA IN PLENARYA Manufacturing Waiver forSupplementary ProtectionCertificates in the EUby Nicola Davies


PHARMA IN PLENARY continued

during the consultation period.5

Consultations were important forthe Commission to ensure limited,targeted, and balanced content inthe proposal.1 The amendments aredesigned to be limited in that theexception to the SPC rights onlyrelates to manufacturing productsfor export. The legislationadjustments are also targetedbecause they are designed toremedy the specific unintendedconsequences of Regulation (EC)No 469/2009 on the EU’smanufacturing competitiveness.Lastly, the legislative changes arebalanced; the initiative shallpromote the competitiveness of EU-made generics and biosimilarswithout undermining the marketexclusivity afforded to druginnovators and certificate holders inthe EU.1

According to the Commission, acareful consideration of the need forsafeguards and stakeholderinvolvement can help to diffuse thethreat on the EU’s drugmanufacturing sector.1 The timelyadjustment of SPC-relatedintellectual property rules mayprovide an intervention that doesnot simply lead to growth but alsomaintains Europe’s status as a keycompetitor and innovative leader inthe global pharma industry.

References1 European Commission (May, 2018).

‘Proposal for a REGULATION OF THEEUROPEAN PARLIAMENT AND OF THE

COUNCIL amending Regulation (EC) No469/2009 concerning the supplementaryprotection certificate for medicinalproducts‘. European Commission.Retrieved from: https://eur-lex.europa.eu/legal-content/EN/TXT/?uri=COM%3A2018%3A317%3AFIN

2 Marks and Clerk (2018). ‘Brexit &Supplementary Protection Certificates’.Marks and Clerk. Retrieved from:https://www.marks-clerk.com/Direct-Access-Pages/BREXIT-Supplementary-Protection-Certificates.aspx#.W7GmwdXsjHp

3 QuintilesIMS (2018). ‘Assessing the impactof proposals for a SupplementaryProtection Certificate (SPC) ManufacturingExemption in the EU’. QuintilesIMS.Retrieved from:https://www.efpia.eu/publications/downloads/efpia/assessing-the-impact-of-proposals-for-a-supplementary-protection-certificate-spc-manufacturing-exemption-in-the-eu/

4 European Commission (May 2018).‘Pharmaceuticals: Commission refinesintellectual property rules’. EuropeanCommission. Retrieved from:http://europa.eu/rapid/press-release_IP-18-3907_en.htm

5 Wölken, T. (September, 2018). ‘DraftOpinion of the Committee on theEnvironment, Public Health and FoodSafety for the Committee on Legal Affairson the proposal for a regulation of theEuropean Parliament and of the Councilamending Regulation (EC) No 469/2009concerning the supplementary protectioncertificate for medicinal products(COM(2018)0317 – C8-0217/2018 –2018/0161(COD)) ‘. European Parliament.Retrieved from:http://www.europarl.europa.eu/sides/getDoc.do?pubRef=-%2f%2fEP%2f%2fNONSGML%2bCOMPARL%2bPE-627.040%2b01%2bDOC%2bPDF%2bV0%2f%2fEN

So, while the certificates grantedprior to the date of Brexit shallremain in force, the UK may berequired to develop an equivalentlegal framework that would replaceEU-granted SPCs. The EU(Withdrawal) Bill, which is still beingassessed by the UK Parliament, isset to introduce domestic legalequivalents of EU-directed laws andregulations.2

Safeguards in the proposal

To avoid abuses of themanufacturing waiver, the proposalincludes a notification requirement.Manufacturers are required toinform the national public agency intheir Member State that isdesignated to monitor SPCmanufacturing waivers. In addition,manufacturers must meet certainproduct labelling requirements forexport and supply chainrequirements to demonstrate duediligence.1

The Commission has developedthe proposal as part of numerousstakeholder consultations. InFebruary 2017, an inception impactassessment (an in-depth roadmap ofthe initiative) was published.Between October 2017 and January2018, the Commission also heldmany public consultations.1 In aresponse to a question posed to theCommission, a Commissionrepresentative revealed that theyanalysed a total of 231 contributionsfrom public and private stakeholders

Astute quality professionals knowthat the U.S. Food & DrugAdministration (FDA) has markedlyincreased its focus in the past fewyears on issues relating to dataintegrity (DI). Indeed, when FDAsuspects/identifies data integrityissues at a regulated company, it nowuses a warning letter formatspecifically dedicated to DIremediation. Paradoxically, however,the most recent detailed discussionof DI issues comes to us not fromFDA or the Department of Justice, ora federal judge, but from a 247-pageOctober 1, 2018 decision by a judgefrom a chancery court in Delaware.1

What’s a Delaware JudgeGot to Do With It?

A little background – in April 2017,Germany-based Fresenius Kabi AG(“Fresenius”) entered into anagreement to buy Akorn, Inc., anIllinois-based generic drug makerspecializing in sterile parenterals,topicals, and other less commonformulations. At the time, Freseniusmanagement hailed the deal asrepresenting a great opportunity forFresenius to expand its presence inNorth America, especially theUnited States.The deal valued Akorn at $34 per

share for a total price of $4.3 billionand was subject to many typicalconditions prior to closing, whichwas scheduled to occur no laterthan one year later, or by April 24,2018. On April 22, 2018, Freseniusinformed Akorn in writing that it wasterminating the agreement andpulled out of the deal. The next day,Akorn sued in Delaware ChanceryCourt (the locus of many corporatelegal battles due to Delaware’s pro-business corporations laws) seeking

to have the court force Fresenius toconsummate the deal – and at theoriginal $4.3 billion price. Whatensued was an accelerated schedulethat led to a week-long trial in Julybefore a single judge, leading to theOctober 1 decision.

About the Deal and the DueDiligence Conducted byFresenius Prior to Contracting

Prior to entering the agreement,Fresenius conducted detailed duediligence regarding Akorn, itsoperations, and its future businessprospects. However, even the mostextensive due diligence effort cannotexamine every potential issueimpacting an FDA-regulated company.To address potential unknowns, dealssuch as the Fresenius/Akornagreement contain a number ofcontract clauses that, among others,require that, in the period betweenentering the deal and closing:

a) the seller (Akorn) continue tooperate its business in “theordinary course;”

b) that the seller continue tomake information available tothe buyer (Fresenius); and

c) that there be no changes inthe business of the seller thatwould equal a “materialadverse event” (i.e..,substantially undermine thevalue of the deal).

In addition, in the mergeragreement, Akorn made certainrepresentations and warranties as toits operations, including itscompliance with applicable law,especially those relating to itsadherence to FDA’s varied

requirements governing themanufacture and marketing ofdrugs. If any of thoserepresentations or warranties turnedout to be untrue, then the buyerpotentially could void the deal.

Why Did Fresenius Cancelthe Deal?

Unexpectedly, beginning in theautumn of 2017, Fresenius receivedthe first of three anonymous lettersalleging, in increasing levels ofdetail, that serious DI issues existedat Akorn. As the level of detailincreased, Fresenius reached out toAkorn for explanations and,ultimately, both Akorn and Freseniusinitiated investigations – using bothoutside counsel and independentquality experts with deepexperience in DI issues. Because theOctober 1 Decision goes into greatdetail as to the conduct of thoseinvestigations, I will not repeat themhere, although I will review some keyfindings from those investigationsand what we can learn from thoseefforts. Suffice it to say that, by earlyApril, Fresenius was convinced thatsignificant DI issues existed at Akornthat arguably raised questions aboutvirtually Akorn’s entire product line.In addition, in the 9 months after theApril 2017 signing of the deal, Akornsales had plummeted. Thus, a dealthat potentially had a valueestimated as high as $5 billion haddegraded to being worth less than$3.5 billion, meaning Freseniuswould be paying, absent arenegotiation of the purchase price,$4.3 billion for a deal that potentiallywas worth almost one third less thanoriginally contemplated.


How Data Integrity Issues Sunka $4.3 Billion Drug CompanyAcquisition – Lessons Not Justfor Quality Professionals, ButAlso Their Top Management

by Michael Swit

Legal Letter From America


What Were the Data IntegrityIssues?

The DI issues ran the gamut and, aswill be discussed, how Akornapproached them also impacted thejudge’s decision in the case. Hereare key Data Integrity issueshighlighted by the decision:

• A senior executive submittedstability data to FDA inresponse to a completeresponse letter that he knew(or should have known) hadbeen falsified;

• Falsified data was later foundin a number of othersubmissions;

• FDA inspectors witnessedAkorn employeesretrospectively modifyinglaboratory notebooks;

• Some Logbooks were missingand other contained data onPost-it notes or data that wereentered late or not at all;

• Many computerized systemslacked passwords and, withother systems, any user couldchange the time/date settingon the computer;

• Akorn “invalidated” negativetest results in more than 70%of cases between January2017 and July 2017 withoutadequate support;

• Akorn quality control personneloften “tested” products intocompliance, a practice that isunacceptable at an FDA-regulated company and firstpublicly highlighted over 25years ago in the seminal U.S.drug GMP legal case, U.S. v.Barr Laboratories;2 and

• In August 2018, during an FDAinspection of Akorn’s Somersetfacility –after Fresenius hadterminated the deal and thesubsequent July trial was held toreview the evidence relating todata integrity and whetherFresenius had grounds to kill thedeal, but before the judge issued

his decision – an unidentifiedAkorn employee intentionallydeleted a database of a stand-alone high accuracy liquidparticle counter, along with thebackup file and electronicsecurity logs. This deletion mayhave been done with an“electronic shredding utility.” Inresponse to this, the court’sopinion commented:

“Given the timing of the deletion,it is reasonable to infer that theperpetrator may have been tryingto hide information from theFDA, or from personnel whowould follow up on thedeficiencies that the FDAidentified in its Form 483.”3

In commenting on Akorn’s dataissues as a whole, the opinion wasvery blunt:

After hearing the evidence at trial,I did not have any confidence thatAkorn would be able to supportits data if the FDA called uponAkorn to do so. Based ondevelopments since trial, Akorn’ssituation has grown even worse.4

How Did Akorn End Up WithSo Many DI Issues?

The Opinion contains a lengthydiscussion of Akorn’s approach to DIissues that is a roadmap for whatnot to do. Although DI concernshad been raised at various timesprior to the Fresenius deal beingsigned, Akorn failed to addressthem both before and after themerger agreement was signed inApril 2017. Among the questionableDI management approaches were:

• Akorn’s InformationTechnology function, which iscrucial to sound DI practices,failed to support efforts toimprove DI. Indeed, once thedeal was signed, IT deferredall DI-related projects andeffectively regarded DI issues

as something that Freseniuscould address – after theagreement closed.

• After the deal was signed,rather than perform formalaudits as would beappropriate in the qualityarena to follow up on findingsfrom prior audits, Akorndecided to instead perform“verifications,” which involve amuch more abbreviatedapproach to probing qualityissues such as those thatconstitute DI concerns.

• Management at the highestlevels of Akorn displayed littleconcern for ensuring thatquality issues, including DI,were properly handled, aconclusion reached by thejudge in his opinion, where hestated:

Rai5 made claims about quality,but having considered hisanswers and evaluated hisdemeanor while he was beingcross-examined about hiscommitment to quality, I amforced, to conclude that he doesnot regard it as a priority.

In fact, testimony at trialrevealed that, although AkornCEO Raj Rai received copiesof audit reports, he never hadread any of them.6

What Are the Lessons of theFresenius-Akorn MergerDemise?

The Opinion’s discussion of thepervasive deficiencies in Akorn’squality culture are extensive andworth a careful review by qualityprofessionals as an exemplar ofwhat not to do. The Opinion alsoraises questions as to how a sellercan adequately protect themselvesfrom similar DI issues arising in thefuture. A few suggestions follow:

• Ensuring DI issues don’t arise(or properly addressing them

LEGAL LETTER FROM AMERICA continued

when they do) is theresponsibility of seniormanagement. It is essentialthat a compliance culture notonly emanate proactively fromthe CEO, but that thoseefforts are supported activelyby the Board of Directors.Indeed, a commitment tocomplete compliance shouldbe a specific obligation of allcompany personnel (includingcontractors) and memorializedin writing and ratified by theBoard (e.g., in a Code ofConduct).

• You can’t put a bandage on DIissues. When they arediscovered, they must beaddressed promptly,proactively, thoroughly, andpervasively throughout theorganization.

• And, ideally, the discovery ofDI issues should arise in thecontext of an active andeffective internal auditprogram, supported, whennecessary, by outside experts.

• Training on proper datamanagement and recordkeeping must be vigorous,comprehensive, validated, andreinforced periodically.

What does a potentialacquirer do to not end up inFresenius’ position?

It is fairly clear from the Opinion thatFresenius conducted a vigorous due

diligence campaign, although it isnot stated how Freseniusapproached quality issues in generaland whether they had any specificdue diligence tactics relating to DImatters. Thus, with the benefit ofhindsight, an acquirer shouldconsider these additional efforts7 inconducting quality8-related duediligence in acquiring an FDA-regulated company:

• Read everything relating tothe target company’s qualityhistory – inspection reports(FDA and other regulatoryagencies), warning anduntitled letters, audit reports(both internal and those bythird parties such ascustomers of the target), etc.;

• Conduct your own audits ofthe target’s operation,including all facilities;

• Talk to not only seniormanagement and middlemanagement, but also asampling of line workers(whether on themanufacturing floor or in aQC lab, etc.) to get as candida picture of the target’scompliance culture.

Mergers are unique scenarios. Thebusiness drivers often can overrideother concerns in the “heat of thedeal.” However, as Akorn/Freseniusillustrates, quality issues, especiallythose that are key elements of thevery value underlying a transaction

such as data integrity concerns,cannot be ignored. While not allissues are easily found, especiallyones such as data integrityviolations, the acquirer must beaggressive and vigilant, preferablybefore signing a deal, butparticularly prior to closing, asFresenius was able to do here (with a little help from one or more anonymous whistleblowers).

References1 https://courts.delaware.gov/Opinions/

Download.aspx?id=279250 (hereafterreferred to as “Opinion”)

2 https://law.justia.com/cases/federal/district-courts/FSupp/812/458/1762275/

3 Opinion at 110.4 Opinion at 113.5 Akorn CEO Raj Rai.6 Opinion at 32, Footnote 112.7 To facilitate these efforts, the merger

agreement should grant the acquirerbroad powers to probe the inner workingsof the target company. Of course, thetarget will insist upon confidentiality in theprocess, all of which can be addressed ina properly drawn merger agreement (bythe way, while I use the term “merger,”not all corporate acquisitions aretechnically mergers. I am using that termfor convenience here).

8 This article focuses primarily on qualityissues that can unwind a deal involving anFDA-regulated transaction. Care alsoneeds to be given to regulatory concernssuch as whether a drug or device makerhas made changes to the approvedmanufacturing processes and has failed tosecure FDA approval (when needed) forthe change. Several examples of thisoccurring in the early days of the genericdrug industry resulted in companies facingsituations where they were marketingmultiple products that did not comply withapproved manufacturing processes, manyof which had to be recalled as they wereunapproved new drugs.

LEGAL LETTER FROM AMERICA continued


Michael A. Swit, Esq., has been tackling critical FDA legal and regulatory issues since 1984. His private FDA regulatory lawpractice included service as Special Counsel in the FDA Law Practice Groups of several major law firms. Michael has lecturedand written on a variety of subjects relating to FDA law, regulation and related commercial activities, and is a formermember of the Food and Drug Law Journal Editorial Board. He can be reached at [email protected]


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Everything you need to know about the operation and management of cleanrooms.

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Industrial Pharmaceutical Microbiology:Standards &Controls – 5th EditionEdited by Tim SandleISBN 978-0-9573491-1-7

The contamination control of pharmaceutical and healthcare environments andprocesses, together with pre-clinical drug development labs, requires a far moreholistic approach than simply choosing technologies and disinfectants. Today themicrobiologist is expected to understand industrial processes and cleanrooms, andhow to effectively evaluate microbial risks to products from personnel and processes.

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Pharmaceutical Regulatory InspectionsEdited by Tim Sandle and Madhu Raju SagheeForeword by Peter D. Smith*ISBN 978-1-899015-89-4

A unique and comprehensive guide to ensure regulatory compliance and success inpharmaceutical regulatory inspections. In over 600 pages and fourteen chapters thisunique book provides a focussed account of regulatory issues from pre-approvalinspections and the inspection itself to post inspection and maintaining compliance.This is a book that every pharmaceutical company will wish to study before and duringany inspection process to ensure a successful outcome.

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This book is based on the author’s work, published over the last sixteen years toadvance knowledge of cleanroom technology. Thirty-four articles are collected anddivided into seven sections that cover common themes, with helpful introductions.The themes include the history of cleanrooms and operating theatres; risk assessment;ventilation design and air supply rates; required cleanroom standard for specifiedproduct contamination; and the dispersion, transfer and deposition of contamination.

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Euromed booksBooks on pharmaceutical management and clinical research


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

United States ofAmericaField Alert Report (FAR)submission - Q&AThis draft guidance provides theagency’s current thinking regardingthe requirements for submission ofFARs by applicants of new drugapplications (NDAs) andabbreviated new drug applications(ANDAs) and outlines FDA’srecommendations for FARsubmissions to help increase theirconsistency and relevancy. Theguidance also addresses certainfrequently asked questions.

Dissolution testing andacceptance criteria forimmediate-release solid oraldosage form drug productscontaining high solubility drugsubstances This guidance is developed toprovide manufacturers withrecommendations for submissionNDAs, INDs, or ANDAs, asappropriate, for orally administeredimmediate-release (IR) drugproducts that contain highly solubledrug substances. The guidance isintended to describe when astandard release test and criteriamay be used in lieu of extensivemethod development andacceptance criteria-setting exercises.

Elemental impurities in drugproductsThis guidance providesrecommendations regarding thecontrol of elemental impurities ofhuman drug products marketed inthe USA consistent withimplementation of ICH guidance forindustry Q3D Elemental ImpuritiesThis guidance will also assistmanufacturers of compendial drug

products in responding to theissuance of the USP requirement forthe control of elemental impurities.

Quality Attributeconsiderations for chewabletabletsThis guidance providesmanufacturers of chewable tabletsfor human use with the CDERcurrent thinking on the criticalquality attributes that should beassessed during the development ofthese drug products. It also providesrecommendations for sponsors /applicants regarding the submissionof developmental, manufacturing,and labeling information forchewable tablets in applications.Chewable tablets are an oral

dosage form intended to bechewed and then swallowed by thepatient rather than swallowedwhole. They should be designed tobe palatable and be easily chewedand swallowed. Chewable tabletsshould be safe and easy to use in adiverse patient population ofpediatric, adult, or elderly patientswho are unable or reluctant toswallow intact tablets due to the sizeof the tablet or difficulty withswallowing. The availability of safe,easy-to-use dosage forms isimportant in clinical practice.Chewable tablets are available formany over-the-counter (OTC) andprescription drug products. The USP recognizes anddifferentiates between two types ofchewable tablets:

• those that may be chewed forease of administration, and

• those that must be chewed orcrushed before swallowing toavoid choking and/or toensure the release of theactive ingredient.

The concepts in this guidance areapplicable to both types ofchewable tablets. This guidance describes the

critical quality attributes that shouldbe considered when developingchewable tablets and recommends

selection of acceptance criteria thatare appropriate and meaningfulindicators of product performancethroughout the shelf life of theproduct.

Q12 Technical and regulatoryconsiderations forpharmaceutical productlifecycle management FDA has issued this ICH documentas a draft Guidance.A harmonised approach regarding

technical and regulatoryconsiderations for lifecyclemanagement will benefit patients,industry, and regulatory authoritiesby promoting innovation andcontinual improvement in thebiopharmaceutical sector,strengthening quality assurance andimproving supply of medicinalproducts. This guideline provides a

framework to facilitate themanagement of post-approval CMCchanges in a more predictable andefficient manner. It is also intendedto demonstrate how increasedproduct and process knowledge cancontribute to a reduction in thenumber of regulatory submissions.Effective implementation of thetools and enablers described in thisguideline should enhance industry’sability to manage many CMCchanges effectively under the firm’sPharmaceutical Quality System(PQS) with less need for extensiveregulatory oversight prior toimplementation. The extent ofoperational and regulatory flexibilityis subject to product and processunderstanding, application of riskmanagement principles, and aneffective pharmaceutical qualitysystem.

EuropeShortages of MedicinesThe Commission met with expertsfrom EU countries to discussshortages of medicines. Shortagesoccur when supply cannot meet thedemand for a specific medicinalproduct at national level. This


centrally authorised products (CAP)with an important step in theirregulatory processes in the UnitedKingdom (UK), are on track withtheir regulatory planning to ensurethat their marketing authorisationremains valid once the UK leavesthe European Union (EU).However, for 108 (88 human

products and 20 veterinary products),or 16%, of these medicines withmanufacturing sites located in the UKonly, there are serious concerns thatthe necessary actions will not becarried out in time.For 10% of the products included

in the survey, EMA received nofeedback from companies.EMA is liaising directly with the

marketing authorisation holders whoeither did not reply to the survey orhave indicated in the survey thatthey do not plan to submit thechanges required by 30 March 2019and have manufacturing sites in theUK only, as this could potentiallylead to supply disruptions.EMA has analysed feedback from

the survey and is now looking indetail at those medicines wherethere are risks of supply shortagesand will assess how critical these are.

InternationalICHNew ICH Guidelines Q13 &Q14The ICH Assembly agreed to beginwork on two new Q topics for ICHharmonisation:-

• Continuous manufacturing(Q13)

• Analytical ProcedureDevelopment and Revision ofQ2(R1) Analytical Validation(Q2(R2)/Q14)

ICH prepares for future newtopics The Assembly agreed to begin workon three new topics for ICHharmonisation:-

• Analytical ProcedureDevelopment and Revision of

REGULATORY REVIEW continued

serious problem affects manypatients across the EU andrepresents a threat to the wellbeingof all citizens.The meeting was a response to

the calls from the Council andEuropean Parliament for theCommission to monitor theobligation of marketingauthorisation holders to ensurecontinuous supply of medicines laiddown in EU legislation. A summaryof Member States measures toensure continuous supply and apaper on the obligation ofcontinuous supply to tackleshortages were agreed at themeeting.

EDQM publishes a new sectiondedicated to biotherapeuticson its websiteThe new biotherapeutics sectionsummarises Ph. Eur. Commissionactivities and achievements in thisfield. In addition to clarification ofthe role of Ph. Eur. monographs inthe biosimilars regulatory pathway, itdescribes the recently concludedP4-BIO pilot phase and the ongoingpilot phase on monoclonalantibodies (“MAB pilot phase”),explaining the strategy followed bythe Ph. Eur. when settingrequirements for the quality of thisimportant class of biotherapeutics. Italso describes various levels offlexibility integrated into Ph. Eur.texts, including those introducedrecently to address the structuralcomplexity, heterogeneity andcompound diversity derived fromdifferent manufacturing processes ofcomplex biotherapeutics.

New EDQM guideline "How toread a CEP"This document is intended to giveIndustry and Competent Authoritiesclarification on the meaning of thestatements laid down on the CEPs.

EMA identifies gaps in industrypreparedness for BrexitA recent EMA survey shows thatmarketing authorisation holders formore than half (58%) of the 694

Q2(R1) Analytical Validation(Q2(R2)/Q14);

• Continuous manufacturing(Q13);

• Clinical electronic StructuredHarmonised Protocol(‘CeSHarP’) (M11).

The Assembly also discussed futurestrategic areas for harmonisation byendorsing a strategic reflectionpaper entitled AdvancingBiopharmaceutical Quality Standardsto Support Continual Improvementand Innovation in ManufacturingTechnologies and Approaches.(clearly ICH supports continuousmanufacturing however there aresome worries particularly in industrythat such manufacturing is beingheld back because of lack ofunderstanding / expertise in certainmarkets making global registrationsand supply uncertain – mh)

ProductsFirst two marketingauthorisations for chimericantigen receptors (CAR) T-celltherapies in the EU:The EMA Committee for MedicinalProducts for Human Use (CHMP) atits June 2018 meetingrecommended granting marketingauthorisations for the first twochimeric antigen receptors (CAR) T-cell therapies in the EuropeanUnion: Kymriah (tisagenlecleucel)and Yescarta (axicabtageneciloleucel) are both advancedtherapy medicinal products (ATMPs)intended for the treatment of certainblood cancers. Both weredesignated as orphan medicinesduring their development. They arealso the first medicines supportedthrough EMA’s PRIME scheme toreceive a positive opinion from theCommittee.

USFDA approves first genericversion of EpiPenUSFDA has approved the firstgeneric version of EpiPen andEpiPen Jr (epinephrine) auto-injectorfor the emergency treatment of


allergic reactions, including thosethat are life-threatening(anaphylaxis), in adults and pediatricpatients who weigh more than 33pounds. Teva Pharmaceuticals USAgained approval to market itsgeneric epinephrine auto-injector in0.3 mg and 0.15 mg strengths.

Recall of porcine thyroid APIfrom Sichuan FriendlyPharmaceutical Co., Limited,ChinaFDA is alerting activepharmaceutical ingredient (API)repackagers and distributors,finished drug manufacturers, andcompounders that Sichuan friendlyPharmaceutical Co. LTD China, isrecalling certain lots of porcinethyroid API due to inconsistentquality of the API. FDA recommendsthat manufacturers andcompounders not use Sichuan

Friendly’s porcine thyroid APIreceived since August 2015. Thisthyroid API comes from porcine (pig)thyroid glands and is used to makea non-FDA approved drug product,composed of levothyroxine andliothyronine, to treat hypothyroidism(underactive thyroid). FDA placed Sichuan Friendly on

import alert (66-40) on March 22,2018, based on current goodmanufacturing practice (CGMP)deviations observed during an FDAinspection.

Ranier’s Rx Laboratory issuesvoluntary recall of all sterilecompounded products Ranier’s Rx Laboratory is nowvoluntarily recalling all sterilecompounded drug products withinexpiry to the hospital or consumerlevel.These drug products are being

voluntarily recalled due to concernsthat practices at the pharmacy havethe potential to pose a risk ofcontamination to products that areintended to be sterile. Theseconcerns arose following a routineinspection of the pharmacy by FDA.(yet another worrying example oflack of sterility assurance in productfrom a compounding pharmacy.-how much longer will this go on?-mh)

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

REGULATORY REVIEW continued


gmp revıewEditor: Peter Savin

Editorial Board:Elizabeth Allanson (UK) • Michael Anisfeld (USA) • Gary Bird (USA)

David Cockburn (UK) • Malcolm Holmes (UK) • Sabine Paris (Germany)Hedley Rees (UK) • Madhu Saghee (India)

Four issues per year: £190ISSN: 1476-4547Indexed in Scopus and Embase

Summary

GMP Review provides information and informedcomment on Good Manufacturing Practice andprovides in-depth analyses of internationalpharmaceutical manufacturing regulations.

The journal also keeps readers up to date on thelatest Directives, Regulations and Guidelinesapplicable to the pharmaceutical industry includingthe latest details on such important documents asDirectives and Regulations from the FDA, EU, CPMPand ICH positions. Each item comes with analysisand comment on its effect on pharmaceuticalmanufacturers and their company.

In addition GMP Review provides the followinginformation:

• News and commentaries on theimplementation of new annexes to theGuide to Good Manufacturing Practice.

• Advanced warning on any proposals forfurther annexes.

• Informed discussion on revisions or additionsto the FDA and other key regulatory andreference documents.

A selection of readers’ comments:

“This journal has filled a gap in the market and is consequently very useful. I find it readable andaccessible and hope that it continues in the same vein for the foreseeable future”.

“We all find GMP Review the most useful publication about Quality Systems”.

“Generally the issues are interesting, easy to read, understandable and informative – links are good”.

“GMP Review is a very useful source of information, particularly for FDA issues. It covers a broad rangeof countries and gives just the right amount of information”.

For further information and to subscribe please visithttp://www.euromedcommunications.com/publications/journals

http://www.euromedcommunications.com/journals


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Beware the BlackBox

Understanding“What I cannot create, I do notunderstand.,” said Richard Fenyman(1918 – 1988), Nobel Laureatephysicist.Do you understand how you

create your medicines? I am sureyou understand your part:development, pharmacovigilance,production, quality control, research,or whatever. However, I wager thatyou do not understand every part ofthe endeavour. You rely on a teamof specialists. They do understandtheir specific areas. An example isqualified persons, with differentareas of responsibility, trusting eachother’s certifications. You arecomfortable with that becauseothers are trained, competent andbound by financial, legal and moralresponsibilities. I will return to thattheme. What if your team memberwas an intelligent machine?

ProgressAutomatons mimicking humanbehaviour have been designed.Clockwork was commonplaceduring the Renaissance. Edison’stalking doll (1877) mechanicallyamplified sound from bumps in agrove of an internal gramophonerecord. We have, according to thephilosopher and cognitive scientistDaniel Dennett (1942 - ), developedall sorts of “clever tricks” (artefactsand thought-tools). These act as

“cranes” to give our culture abilitiesthat it lacked. General examples arecomputers, double entrybookkeeping and language; thepharmaceutical industry favours theCRISPR–Cas 9 technique, double-blind clinical trials and cGxP.Broadly, these lift humans’peripheral intellectual power. Theyhelp us do whatever we havechosen to do such as recognisepatterns for new therapeutic usesfor established marketed medicinesin gargantuan data sets. Thedevelopment of computers hasbeen explosively rapid. Witness thatthe computer memory on Voyager(1977 technology) now travellingbetween the stars, is probably lessthan that in your car’s key fob. Until recently computers worked

by brute number crunching. Now,cleverer algorithms and deeplearning enable computers to solveproblems that were previouslyinsoluble, at least within one shorthuman lifetime.

Buy meNew, equipment off-the-shelfentices us. We can buy somethingthat tells us what we want to knowbut no longer fully understand howit does so. Moreover, as time passes,equipment proves reliable andtumbles in price. We undertake thetask less ourselves, even while thewarning “use it or lose it,” nigglesus. We know what goes into thebox, what comes out and we check.Output is so useful, increasingly, thatwe cease to care that we are not

sure about everything going oninside. Are you not part of a humanteam while not understanding whatothers are doing?I now lay bare the danger. The

black box vendor may over-hype theblack box because that increasessales. It may be trusted to giveopinion that facilitates choice ofaction. That is not a peripheral but acentral human intellectual power.Humans may cede to the black boxcompetence that it does notpossess – yet. Adverse effects couldbe imaginable such as asubstandard batch being releasedor not yet imaginable. Remember,too, that machines, like people, gowrong. If the default remedy ofpressing the reset button fails, is ahuman repairer to hand? Is buying anew black box cheaper?It is probably too late to avoid

black boxes. Maybe, shortly, mycaution will seem as quaint as a manwith a red flag walking ahead of anyself-propelled vehicle. But, arguably,humans should design in robustsafety precautions to black boxesjust as, in a sword, a guardseparates grip from blade. Weshould use black boxes with eyeswide open, full training onlimitations and risks, financialbonding and after signing acompulsory legal agreementaccepting full moral and financialstrict liability for the black boxoutputs.

Malcolm E Brown

bottled brown


7 February 2019 – London, UKAccelerated Development andApprovalwww.jpag.org

12-13 February 2019 – Munich,GermanySoftware Design for MedicalDevices Europewww.sdmdglobal.iqpc.co.uk

19-21 February 2019 –Amsterdam, HollandDisposable Solutions forBiomanufacturingwww.disposablebiomanufacturing.com

21-22 February 2019 –Manchester, UK14th Annual BiomarkersCongresswww.biomarkers-congress.com

25–26 February 2019 – Berlin,Germany19th World Congress onPharmaceutical Sciences andInnovations in Pharma Industryhttps://industry.pharmaceuticalconferences.com/

25-28 February 2019 – Toronto,Ontario, CanadaCold Chain Global Forum 2019www.coldchainpharm.com

27-28 February 2019 – Rome,ItalyParenteral Packagingwww.pda.org

MARCH 20195 March 2019 – Preston, UKDissolution testing: current andfuture considerationswww.jpag.org

11-13 March 2019 – San Diego,California2019 PDA Annual Meetingwww.pda.org

13-14 March 2019 – Milan, Italy20th Annual Clinical Trial SupplyEuropewww.arena-international.com/ctseurope

DECEMBER4–6 December 2018 –Amsterdam, The NetherlandsCell Therapy Manufacturing &Gene Therapy Congresshttps://lifesciences.knect365.com/celltherapy/

10–11 December 2018 – Rome,Italy23rd International Conferenceon PharmaceuticalBiotechnologyhttps://biotech.pharmaceuticalconferences.com/

10-12 December 2018 –Huntington Beach, California2018 ISPE BiopharmaceuticalManufacturing Conferencehttp://isp.org/conferences/

JANUARY 201921-22 January 2019 – London, UKPharmaceutical Microbiology2019www.smi-online.co.uk

23-24 January 2019 –Washington, DC14th Biosimilars Summitwww.biosimilardevelopment.com

23-24 January 2019 – London, UKFestival of Genomicswww.festivalofgenomicslondon.com

28-30 January 2019 –Washington, DC, USA9th Annual Pharmacovigilanceand Risk ManagementStrategies Conferencewww.diaglobal.org/pharmacovigilance

28-31 January 2019 –Twickenham, UK7th Annual Cool ChainTemperature ControlledLogistics Conferencewww.coolchaineurope.com

FEBRUARY 20196-7 February 2019 – Prague,Czech RepublicCleaning Validationwww.jpag.org

events18-19 March 2019 – Paris, France15th International Conferenceon Nanomedicine andPharmaceutical Nanotechnologywww.osa.org

18-20 March 2019 – Edinburgh,UK17th International Conferenceand Exhibition onPharmaceutics & Novel DrugDelivery Systemswww.novel-drugdelivery-systems.pharmaceuticalconferences.com

20-21 March 2019 – Houston,USA9th Int Conference on PharmaAudit, GMP, GCP and QualityControlhttps://gmp-gcp-quality-control.pharmaceuticalconferences.com/

25-26 March 2019 – Bologna,Italy3rd European Conference onPharmaceuticswww.europeanmeeting.org

APRIL 20193-4 April 2019 – Knutsford,Manchester, UKAseptic Processing Workshophttp://phss.co.uk

JUNE 201917-18 June 2019 – Stockholm,Sweden7th European BiopharmaCongresswww.biopharmaceutics.pharmaceutical conferences.com

SEPTEMBER 201922-26 September 2019 – AbuDhabi, United Arab Emirates79th FIP World Congress ofPharmacy and PharmaceuticalScienceshttps://abudhabi2019.congress.pharmacy

www.jpag.org

www.sdmdglobal.iqpc.co.uk

www.disposablebiomanufacturing.com

www.disposablebiomanufacturing.com

www.biomarkers-congress.com

https://industry.pharmaceuticalconferences.com/

https://industry.pharmaceuticalconferences.com/

www.coldchainpharm.com

www.pda.org

www.jpag.org

www.pda.org

http://www.arena-international.com/ctseurope

http://www.arena-international.com/ctseurope

https://lifesciences.knect365.com/celltherapy/

https://lifesciences.knect365.com/celltherapy/

https://biotech.pharmaceuticalconferences.com/

https://biotech.pharmaceuticalconferences.com/

http://isp.org/conferences/

www.smi-online.co.uk

www.biosimilardevelopment.com

www.festivalofgenomicslondon.com

www.diaglobal.org/pharmacovigilance

www.diaglobal.org/pharmacovigilance

www.coolchaineurope.com

www.jpag.org

http://www.osa.org

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



https://gmp-gcp-quality-control.pharmaceuticalconferences.com/



www.europeanmeeting.org

http://phss.co.uk

www.biopharmaceutics.pharmaceutical conferences.com

www.biopharmaceutics.pharmaceutical conferences.com

https://abudhabi2019.congress.pharmacy

https://abudhabi2019.congress.pharmacy

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