EIP43 EPSA.qxp Journal 10/03/2020 22:55 Page 1 eur opean ... · pharmaceutical isolators: an...

europeanINDUSTRIAL

ISSUE 43 • FEBRUARY/MARCH 2020www.industrialpharmacy.eu

Transitioning to continuousprocessing from batch

operations

Standards forpharmaceutical isolators:

an overview

Opportunities andapplications of 3D drugprinting in pharmacies

The future is now! The evolution of

pharmaceutical education

Transitioning to continuousprocessing from batch

operations

Standards forpharmaceutical isolators:

an overview

Opportunities andapplications of 3D drugprinting in pharmacies

The future is now!The evolution of

pharmaceutical education

PHARMACYESSENTIAL READING FOR ALL PHARMACISTS

EIP43 EPSA.qxp_Journal 10/03/2020 22:55

2 european INDUSTRIAL PHARMACY February/March 2020 • Issue 43

europeanINDUSTRIALPHARMACY

Issue 43 February/March 2020

ISSN 1741 4911

MANAGING EDITORPhoebe Speis

PRODUCTIONSue Feather

SUBSCRIPTIONSJill Monk

ADVERTISEMENTSStephanie Painter

EDITORIAL BOARDMichael AnisfeldMichael Gamlen

Ching-Yi HsuUlf JanzonJohn Jolley

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features4 TRANSITIONING TO CONTINUOUS PROCESSING FROM

BATCH OPERATIONSby Barry Perlmutter

8 STANDARDS FOR PHARMACEUTICAL ISOLATORS: ANOVERVIEWby Tim Coles

14 OPPORTUNITIES AND APPLICATIONS OF 3D DRUGPRINTING IN PHARMACIESby Josep M Guiu, Netta Beer, and Robert Moss

16 THE FUTURE IS NOW! THE EVOLUTION OFPHARMACEUTICAL EDUCATIONby Stefan Grgić

regulars3 EDITORIAL COMMENT

20 PHARMA IN PLENARY

23 REGULATORY REVIEW

31 BOTTLED BROWN

32 EVENTS

Cover photo: A complete aseptic vial filling line using a unidirectional air flow isolator for thefilling process, and a RABS for the capping stage. See article on page 8.


3european INDUSTRIAL PHARMACY February/March 2020 • Issue 43

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.

Creativity and change

I have always been interestedin the creative process andhow it comes about. The splitbetween arts and sciences,which happens at a relativelyearly stage in education,implies that there is ameaningful difference betweenthem. However, many artistsand sculptors require detailedscientific and technicalknowledge to achieve theiraims. The works of Al Wei Weiand Anish Kapur, for example,required exquisite engineeringand optical skills. As a scientist,I am interested in how we canbring the creative process into science.

During the mid 1980s I was working as theHead of Solid Dosage Form Development atthe Wellcome Foundation Ltd in Dartford,Kent. Wellcome was one of the most creativeR&D companies of all time with the discoveryof the first antivirals (acyclovir and zidovidine)and the first new anticonvulsant andantimalarials for a generation, amongst manyother drugs I worked on.

In Development we were using small scalebatch extruders to make pellets by extrusionspheronisation, for coating as extendedrelease dosage forms. I had the idea of using

a continuous twin screwextruder in tandem with thespheroniser to produce acontinuous process for largerscale use. I set up a trial withCyril Eardley at Baker Perkinsin Stoke on Trent and setabout transporting thespheroniser and the materials.The spheroniser weighedabout 500 kg and the smallestvehicle with a tail lift of thatcapacity was a 5-ton truck, so Ihired one for a day, drove upto Baker Perkins, and did thetrial. The results were mixed;the product quality was largelygranular under the testconditions we used but we

were able to easily adjust the process tochange product quality quickly and easily.The potential for the process was clear.

I published the results of the trial in 1986and was the first person to publish a paperon twin screw continuous granulation in thepharma industry. When you start a creativeprocess, the output is not always what youexpect – but if you don’t take the first step,you will never go on the journey!

Michael Gamlen



IntroductionMost chemical operations are batchoperated plants. Batch reactors areused where one can control thepressure, temperature, agitation,residence time, crystal seeding andcrystal growth. In these batchoperations, for filtration, theprocesses use filter presses, vacuumnutsche filters, filter-dryers, plateand leaf filters and batchcentrifuges. Finally, batch dryers areused, such as conical designs, whereheating/temperature can becontrolled as well as agitation tominimize the effects of the pasty orthixotropic phase on the drying.Batch processing is easy as batch-to-batch integrity and quality can bemaintained but significantly lacksflexibility in scaling capacity, andtypically requires largermanufacturing footprints and lessefficient use of space.

However, batch processing is alsomaking a comeback. For example,

most pharmaceutical plants arebatch operations so that each batchcan be identified for humanconsumption. Further, as chemicalplants become more flexible andtoll manufacturers take a larger rolein production campaigns, productsare changed quickly, sometimes ona daily basis, then a batch processrecipe can be implemented muchmore simply than a continuousprocess. The same holds true forcontract manufacturingorganizations (CMOs) or contractdevelopment and manufacturingorganization (CDMOs), which areorganizations which providecomprehensive services from drugdevelopment through drugmanufacturing.

With the push to become moreefficient, many process industriesstarted thinking about continuousprocessing. For example, acontinuous filter is typically 1⁄3rd ofthe size of a batch filter. Every

engineer is reaching for the “goldenring” to convert to a continuousprocess to increase yield andoptimize quality by

1. using lessreslurry/holding/buffer tanks,

2. eliminating transfer pumps, 3. minimizing the complications

of solids handling, 4. using less agitation which can

impact crystal size and finesgeneration,

5. maintaining constant flows,pressures and temperatures,etc.

Sometimes it’s easy and sometimesit’s impossible.

In my career, I have helpedengineers move from batch tocontinuous operations for suchapplications in pharma andbiochemical, specialty polymers,starch and cellulose, aromatic acidsand fly ash wetting. Of course, Ihave also tried and failed withbioprocessing for reaction-filtrationand specialty metals processing. Butfailures are equally as important assuccesses. Let me give you someexamples of successes, which are alot more fun.

Specialty chemical polymerapplicationThe existing process was a batchcrystallizer operating at 0-5 degreesC with 13-20% solids. The filtrationwas a batch vacuum operation witha 6-inch cake and a heptane wash.Following the wash, there is a drying/ blowing step to remove theheptane down to 1.0-0.5% and thenthe product is fully dissolved inmethanol for pumping to anotherdownstream reactor. For anexpansion, the decision was totransition to continuous processingto eliminate solids handling andreslurry tanks as well as to reducethe energy costs by eliminating theliquid ring vacuum pump requiredfor vacuum filtration.

After lab and pilot testing, theRotary Pressure Filter (RPF), shown inFigure 1, was selected. It is acontinuous pressure filter designedfor thin cake (5 mm) filtration,

TRANSITIONING TOCONTINUOUSPROCESSING FROM BATCHOPERATIONSby Barry Perlmutter

Batch processing has been the mainstay ofproduction for both pharma and nutraceuticals for

the past decades. However, in some productionprocesses like specialty, fine chemical or bulkchemicals continuous production has its advantages.This article discusses the pros and cons of bothmethods and looks at the preparations required forchanging from batch to continuous processing.

Barry A. Perlmutter is an internationally recognized solid-liquid separation expert andis currently President and Managing Director of BHS-Sonthofen Inc. Barry has over 37years of technical engineering and business marketing experience in the field of solid-liquid separation including filtration & separation, centrifugation and process drying.He has been responsible for introducing many European companies and technologiesinto the marketplace. His new book, Handbook of Solid Liquid Filtration, publishedby Elsevier, UK in February 2016 is part of a Chemical Engineering series and isreferenced by practitioners in the field. He received a BS degree in Chemistry fromAlbany State (NY) University, MS degree from the School of Engineering atWashington University, St. Louis and an MBA from the University of Illinois.



TRANSITIONING TO CONTINUOUS PROCESSING FROM BATCH OPERATIONS continued

washing and drying with a slowlyrotating drum (6-60 rph). The drumis divided into segments (calledcells) each with their own filtermedia (2-5 um multilayer metal) andoutlet for filtrates and gas. The cakefrom each cell is dissolved withspray bars and directly pumped intothe next reactor. Along with the RPF,the client installed a continuousreactor. The RPF startup went verywell while the continuous reactorwas quite a challenge. This we candiscuss at another time.

Protein-lipid biochemicalapplicationThis was a new process using animalrenderings to produce proteins andlipids. The process was ratherinvolved using formic acid anddimethyl ether (DME) underpressure so that the DME behavedas a liquid rather than a gas. Theinitial thinking was a batch operationwith reslurry tanks; investigationsincluded centrifuges, horizontalplate filters and enclosed filterpresses. This phase of the projectinvolved testing for over one year.Unfortunately, while there was agreat deal of learnings about theprocess, the batch operationrequired many agitated tanks and

pumps with a great deal of solidsand solvent handling. In addition,these technologies could notmaintain the pressure for the DMEduring cake discharge. The decisionwas made for continuous processingand again, after special lab and pilottesting, the Rotary Pressure Filter,was selected as shown in Figure 1.

The RPF provided the continuouspressure filtration, cake washing anddrying/flashing with completecontainment. A secondary benefitwas a consistent back pressure andcake discharge pressure to keep theDME as a liquid rather than a gas.

Phospholipids pet foodadditiveIn this process the pharmaceuticalcompany extracts phospholipidsfrom egg yolk and prepares the finalproduct as an additive for pet food.In the existing process, the ethanolslurry was mixed in various reslurrytanks for dilution washing and thenmanual vacuum filtration. For theexpansion, it was decided totransition to continuous processingto eliminate the reslurry tanks,improve the cake washing andeliminate the manual handling ofsolids. As vacuum filtration was avalidated process though still a

manual operation, the engineersevaluated vacuum belt filters.

The choice was a Continuous-Indexing Vacuum Belt Filter forvacuum filtration, cake washing anddewatering of the cake. Thetechnology is based upon fixedvacuum trays, continuously feedingslurry system and indexing orstepwise movement of the filtermedia. In practical terms, theoperational features of the BeltFilter can be viewed as a series ofBuchner funnels.

For the process operation, due tothe stepwise operation of the belt,washing and dewatering efficienciesare maximized with the stopped beltand the mechanism of “plug-flow”for gases and liquids. The “plug-flow” or displacement washingefficiency require a lower wash ratioas compared with multiple reslurrywashes. Finally, the fixed trays allowfor the mother liquor and the washfiltrates to be recovered individuallyand recirculated/recovered/reusedfor a more efficient operation. Theclient installed the fully enclosedand pressure-tight unit of 2.25 m2 offilter area for the egg yolk powderand ethanol slurry, as shown inFigure 2. The filter is validated, as aGMP installation, for pharmaceuticalproduction and has increased theyield of the phospholipids by 3-5 %.

Initial batch process forlab/pilot plant to continuousprocess for demonstration/production process

This was another interesting casestudy which illustrates how theprocess can be changed basedupon the scale of operation. Theresearchers, during theirdevelopment, used batch reactorsfollowed by batch filtration, cakewashing and drying. The liquid,succinic acid, is the product from anatural feedstock while the cake iswaste. In the lab/pilot scale, batchcandle filters were used, as shown inFigure 3. However, as the processdevelopment continued, there wereadditional washing steps withdifferent liquids. During thetransition stage from lab researchers

Figure 1 – BHS Rotary Pressure Filter




to process and project engineers, itbecame apparent that batch candlefilters would not be able to handlethe multiple operations. Furthertesting on a larger scale resulted ina more reliable continuous processwith vacuum belt filters, as shown inFigure 4. The lessons learned forprocess engineers, from thisexample, is that the process scalehas to be taken into account andthat what works in the lab may notwork in the plant.

Continuous and batchoperations in the sameprocess lineIn this bulk pharma/specialtychemical application, each step ofthe process required a differentcontinuous or batch operation. Theengineers approached the projectfrom a “continuum” or “holistic”view and looked at each stepindividually and then in total. Thetwo reactors were batch operated.They feed one continuous-indexingvacuum belt filter (see Figure 2).From the continuous belt filter, thesolids are discharged in aFigure 2 – Contained Continuous-Indexing Vacuum Belt Filter

1. In a candle filter, the slurryenters through the bottom of apressure vessel and flows acrossthe filter media. The filter candlesare attached to registeres thatcollect hte filtrate. Gas is fed intothe top of the pressure vesel forcake drying discharge.

2. During operation, filtrate exitsfrom the top of the candle, whilethe solids collect on the syntheticfilter sock.

3. During discharge, gas is fed into the top of the candle, whichexpands the flexible filter sock. This causes the dry cake to crackand break away from the filter. The solids are collect at the bottom of the pressure vessel.

PressureVessel

Registers

Candles

Filter Cake

Filtrate and Gas Pipe

Low-PressureGas

Dry FilterCake

Tie-rods

Perforated Core

Filter SockSlurry Feed Inlet

FiltrateOutlets

GasInlet

Figure 3 – Batch Candle Filter Operation




concentrated wet cake and fed to afully-contained batch filter press.The dried cake from the batch filterpress is packaged for finalprocessing at another API (activepharmaceutical ingredient) plant. Asin the previous example, processengineers need both a “silo”approach to the optimization as wellas a “continuum” approach tounderstand how one upstreamdecision may impact the down -stream process.

Final thoughtsThe current state of batch versuscontinuous processing dependsupon the process, product and typeof application. For specialty or finechemical operations, continuousprocessing is becoming moreprevalent. For pharma andnutraceuticals, batch remains thechoice. For bulk chemicals,

continuous processing is generallypreferred. However, with this inmind, there are no rules and if aprocess can be transitioned frombatch to continuous, the benefitswill be clear.

Preparing to make a transitionfrom batch to continuous processingoperations requires more than justnew equipment: it demands atransformation of the entiremanufacturing operation and themindset of the staff. Operatorsaccustomed to batch processes willneed to be retrained, not only onindividual pieces of equipment butalso on the new, broadermanufacturing strategy. The choiceof the “continuous” vendor is alsocritical to support the transition.

Process engineers have manychoices to transition to a continuousoperation. Testing, both lab scaleand pilot, is necessary to support

the decision. A continuousoperation is more challenging, asbeing a “steady-state operation”there are less chances to make achange so automation/instrumentation and controls mustalso be updated; or as the newthought is “digitalization” ofprocesses and plants. In the end,whatever you decide, you need tobe ready to face new issues duringcommissioning and start-up. I cantell you, first-hand, there will bemany unexpected consequences.

You can follow my blog at myhttps://perlmutter-ideadevelopment.com/and my “Handbook of Solid-LiquidFiltration” athttps://www.elsevier.com/books/solid-liquid-filtration/perlmutter/978-0-12-803053-0 for further insights.

Figure 4 – Commercial Scale Production Operation


https://perlmutter-ideadevelopment.com/

https://perlmutter-ideadevelopment.com/

https://www.elsevier.com/books/solid-liquid-filtration/perlmutter/978-0-12-803053-0 for further insights




Existing isolator standardsand guidelines When gloveboxes first came intogeneral use in the pharmaceuticalindustry, around 40 years ago, therewere no specific standards availableto give guidance on their design,construction and operation. Today,decades on, there is still no standarddirectly relating to what we nowterm ‘isolators’. Instead, we rely on amixture of cleanroom standardssuch as the ISO 14644 series ofstandards1- 6 and containmentstandards such ISO 10648.7-8

Perhaps the most focussed currentdocument is ISO 13408-6; 2005.9 Atthe time of writing this standard isunder periodic review at the DIS(Draft International Standard) stage– ISO DIS 13408-6.10 It is also justone part of a standard devoted toaseptic processing, thus leavingaside the all-important containmentaspect of isolator technology. Thereare also guidelines such as the bookPharmaceutical Isolators11 and, ofcourse, EU GMP Annex 1.12

Where aseptic applications areconcerned, ISO 14644 is useful andinformative, but it has a fundamentalflaw in relation to isolators:cleanrooms are manned by humanoperators. As a result, the greaterpart of these standards are devotedto the means to first minimise, andthen to manage, the particulatesgenerated by personnel. Isolators,by definition, do not have toaccommodate human operatorsand, as a consequence, areliberated to be designed,constructed and operated incompletely different ways.

One very significant advantage ofisolators over cleanrooms, in asepticoperation, is the capacity for gas-phase or aerosol bio-decontamination. Hydrogenperoxide has become the biocidalagent of choice for sound reasonsbut, here again, there are nodefinitive standards. However, ISODIS 13408-6 does provideconsiderable discussion, and thePHSS Guidance Note No. 113 gives

a lot of practical guidance followingMHRA comment on the applicationof vapour phase hydrogen peroxidein isolator bio-decontamination.

Where toxic or pathogenicapplications are considered, ISO10648 is again useful andinformative, but essentially comesout of radiological protection, and isvery dated. Significant advanceshave been made in containmentisolators over the last 25 years andtherefore design, construction,testing and operation standards aresurely due for review.

Where the application is bothaseptic and toxic, as for example inthe preparation of cytotoxicparenteral solutions, the ISOstandards 14644 and 10648 are oflimited use since neither cover thissituation, and ISO DIS 13408-6 istechnically not applicable.

It is clear that both aseptic andcontainment isolators offer majoradvances over previous technology,but neither is covered by specificstandards. The UK PharmaceuticalIsolator Group (UKPIG) did startdown this route, but the organisationeffectively closed down in 2005 whenthe driving force, Brian Midcalf,iretired. Standards in general, andISO standards in particular, take along time to develop and bepublished, often years andsometimes decades, as in the case ofEU GMP Annex 1. It seems unlikelythat any individual or group is likelyto take up the official challenge inthe near future, but perhaps someunofficial draft standards could bedrafted in the meantime.

What aspects of isolatortechnology might such drafts tackle,where the current standards fallshort? One is the apparent anomalyin airborne particulate figures, whereEU GMP Grades A and B do notseem appropriate for isolators.Although the industry should beadopting ISO standards for airborneparticulates, many operators stillprefer to use the EU GMPdesignations. Both Grade A andGrade B permit up to 3,520 particlesof ≥0.5µm per m3. In terms of isolator

STANDARDS FORPHARMACEUTICALISOLATORS: AN OVERVIEWby Tim Coles

Pharmaceutical isolators have wide application in criticalprocesses such as aseptic filling and genetic engineering,

and yet they are not covered by any specific UK, orinternational standard. At present, users have to rely onstandards essentially written around cleanrooms, which area very different contamination control system. There is alsoone standard which is a sub-section of an aseptic processingstandard. This paper highlights areas where these existingstandards are perhaps deficient.

Tim Coles, BSc (Hons), M.Phil., Technical Director, Pharminox Isolation Ltd., hasworked in the field of isolator technology for over twenty years. He was a foundingmember of the UK Pharmaceutical Isolator Working Party that producedPharmaceutical Isolators, Pharmaceutical Press, 2004, and more recently of the PDAcommittee that produced Technical Report No 51. “Biological Indicators for Gas andVapour Phase Decontamination Processes” [for the validation of isolator sanitisation].His book Isolation Technology – a Practical Guide, CRC Press Inc. 2004, is now in itssecond edition.

i Brian Midcalf very sadly died in 2019.



HEPA filtered air through isolatorswhich provides the clean conditions.In unidirectional airflow (UDAF)isolators, which are normally downflow, the requirement is easilydefined as the conventional 0.45m/s, plus or minus 20%. However, anisolator standard might present arequirement to demonstrateunidirectional airflow down to aspecific height above the worksurface. A suggested minimummake-up air flow rate might also beproposed, for example 10% of theunidirectional airflow. In the case ofturbulent flow isolators, an isolatorstandard should set a minimum airchange rate of perhaps 60 total airchanges per hour. It could go on torequire demonstration that theturbulent flow purges all parts of theisolator volume, and that there areno standing vortices which wouldretain airborne particles for longperiods of time. Furtherdemonstration might include amaximum purge-down time from,for example, GMP Grade D particleburden, down to the values given in

technology, such a particle burden isappalling! Even a turbulent flowisolator will give virtually zero particlecount at rest. If an isolator gives ≥0.5µm particle counts above a few tens,there is likely to be an investigation.Why then do we apply cleanroomstandards to isolators? The regulatorsin general, and the MHRA inparticular, are keen to advance thetechnology of pharmaceuticalproduction where possible. Thisbeing the case, the particulatestandards for isolators need to beaddressed to match the achievableresults.

The threshold limits for airborneparticles in isolators might perhapslook something like the valuesshown in Table 1. These are all verymuch lower than the 3,520 particlesallowed under both A and B gradesof EU GMP Annex 1.

Some guidance would be neededas to how and where particlecounting is to take place in theisolator.

Total particle counts of courseinclude the all-important sub-setwhich are the viable particles. Hereagain, the much betterenvironmental conditions insideisolators offer the possibility ofsetting more stringent standards,however it may not be possible toset better values than thosetabulated in the EU GMP for purelypractical reasons. PharmaceuticalIsolators offers a set of viableparticle limits for isolators and states“This represents a reducedacceptance level for settle platescompared to the EC [sic] GMPguidance.” This probably representsthe current best standard for viableparticles in isolators.

Moving on, it would seemreasonable to set some standardsfor the basic functional aspects ofisolators. It is primarily the flow of

the conjectural table above. HEPA filtration of the air passing

through an isolator is, of course,fundamental to operation, both forpositive and negative pressureapplications. Cleanroom standardsdo offer some guidance, but anisolator standard could be morespecific. The need to fully test thesupply filters on aseptic isolators,and the exhaust filters oncontainment isolators, is paramount.Our conjectural standard mightspecify correctly-sited and well-labelled DOP test ports, and itshould place defined limits on themeasured filter penetration, undertest. Again, some discussion wouldbe needed to set these values,involving filter manufacturers andisolator users. This issue really has tobe addressed with absolute clarity inany isolator standard.

Isolator operating pressure isgenerally viewed as a primary aspectof isolator function, although studiesin the past have indicated thatisolator pressure is actually not acritical parameter in achieving therequired conditions. Handlingcytotoxic drugs in isolators in NHSpharmacies14 states: “As statedpreviously, there is much more toconsider than merely the pressuredifferential of the system. If theabove sources of exposure and

STANDARDS FOR PHARMACEUTICAL ISOLATORS: AN OVERVIEW continued

Table 1: Suggested maximum number of particles ≥0.5 µm per m3 for isolators Unidirectional flow isolator Turbulent flow isolatorAt rest 5 50In normal operation 50 500

Figure 1 – A complete aseptic vial filling line using a unidirectional air flowisolator for the filling process, and a RABS for the capping stage


product contaminationii can beminimised, then the type of systemselected should be less important.This assumes that there is nocatastrophic leakage. In this case,alarm systems and training systemsbecome paramount.” That said, anisolator standard might reasonablyrequire that the isolator holds asufficient pressure so that a positivepressure isolator cannot go negativeduring rapid glove withdrawal, and anegative pressure isolator cannot gopositive during a rapid gloveinsertion. The standard might alsopromulgate a maximum time forreturn to set pressure after a givenfluctuation. Beyond this, thestandard might offer an acceptablerange of pressures for positivepressure aseptic work, and fornegative pressure toxic containment.

Leak rate is an issue whichexercises isolator users considerably,and here the standards ISO 14644Part 7 and ISO 10648 Part 2 doactually provide us with a choice offour classes of leak rate with whichan isolator might conform. However,there is no guidance as to what classof leak rate is appropriate to whatapplication and manufacturers stilluse leak rates other than thosespecified in these standards.Furthermore, there is very littleguidance as to how the leak rateshould actually be measured inpractice: what test pressure shouldbe applied, what should the lengthof time be for the test, what decayvalue is appropriate, and shouldchanges in atmospheric pressureand isolator temperature beconsidered. A standard might offer arange of suitable tests, and thelimits which would be applied. Table 2 shows a suggested

structure for isolator leak rate andapplication.

In passing, EN 12298:199815

mentions the concept of BATNEEC(best available technology notentailing excessive cost) with regardto leak rates, but offers no further



Table 2: Suggested isolator leak rates by application

ISO Class of Leak Rate % Volume Loss per Hour Application

1 0.05 Class 3 MSCs2 0.25 Negative pressure aseptic

isolators. High containment isolators.

3 1.00 Positive pressure aseptic isolators. Medium containment isolators.

4 10.0 Not applicable

Figure 2 – A flexible film half-suit isolator designed for sterility testing,using roof-mounted HEPA filters for turbulent air flow, and fitted with anon-board hydrogen peroxide vapour generator for bio-decontamination.This isolator also incorporates instrumentation of the hydrogen peroxideconcentration at both high and low levels.

ii The factors specific to productcontamination are listed in the precedingsection of the document.


guidance. ISO DIS 13408-6 ducksthe issue of leak rate and refers thereader to ISO 14644-7, which meansyet again, the user has to sortthrough another document to findthe appropriate information.

Some consideration might begiven in an isolator standard to theissue of instrumentation and alarms.This is a topic which is singularlylacking in the otherwise quitecomprehensive ISO DIS 13408-6. Arelatively small isolator oncereviewed by the author boastedover 400 separate alarms, of whichthe manufacturer declared over 80as critical. Only five factors arecritical to the general operation ofan isolator:

1. HEPA filtered air-flow rate,either UDAF or turbulent.This is easily measured andalarmed.

2. Isolator pressure. Whilstisolator pressure does notseem to be critical as such, itis a strong indicator that theisolator is working as normal.For this reason, it should bestandard practice to fit analarm system on the isolatorpressure gauge. Such analarm might be arranged tooperate on both high and lowexcursions from the values setby either the isolatormanufacturer or the user.

3. Pressure drop across the mainfilter is often measured andalarmed.

4. HEPA filter integrity. This canonly be measured during DOPtesting and is not ‘alarmable’.

5. Leak rate. This can only bemeasured by out-of-servicemethods and is also not‘alarmable’.

Thus, the only critical alarms on anisolator are, in practice, the air-flowrate, the pressure inside the isolatorand the pressure drop across themain filter. Any standard should notethis. Failures, other than HEPA filterintegrity and leak rate, will show upas changes in these threeparameters and therefore do notneed to be alarmed as such. Thatsaid, it is comforting to have anindication of what item has failed,when an alarm does occur. Forexample, if the pressure in apneumatic door seal were to dropbelow a set value, a message to thiseffect would allow rapid remedialaction.

Various existing standards give anindication of the requirements forthe bio-decontamination of asepticisolators (e.g. BS EN 14937: 200116),but again none are specific. ISO DIS13408-6 alone provides quite gooddiscussion of bio-decontamination,and is recommended as a usefulguide. The application of hydrogenperoxide to the bio-decontamination of isolatorsperhaps merits a whole standard inits own right, however an isolator-specific standard might give somebasic requirements for bio-decontamination. This could, forinstance, list the demonstration oflog 6 reduction of G.stearothermophilus spores, andaeration down to 1 ppm beforeopening the isolator, as primary bio-decontamination requirements.

Isolator room conditions wouldreally have to be addressed by theproposed standard. In theory ofcourse, room standards need not behigh since the isolator, by definition,provides the required standard forthe process. In reality, definedisolator room conditions are neededfor setting up the open isolator, forcleaning, and for minimising thebio-burden on the isolator and itstransfer systems. Leading on fromthis, a standard might indicate theminimum requirement for garmentsand gowning for given isolatorapplications and the roomconditions.



Figure 3 – A flexible film half-suit isolator for sterility testing, specially-designed for use in a room with a low ceiling, the HEPA filters thereforebeing mounted on the walls of the canopy. The control system maintains aset canopy pressure via two-fan ventilation, and provides digital display andalarms on the air flow rate and the canopy pressure.


On a personal and more generalpoint, standards such as ISOs canbe difficult to read and to interpretin a practical sense, even whennumbers and values are provided.To some extent, this may stem fromthe fact that they are drafted bycommittees, often with variedcultural backgrounds and languages.This is apparent in ISO DIS 13408-6which whilst containing much usefulinformation, is illogically organised,and needlessly repetitive in places.Final editing by a native Englishspeaker might be helpful in thisrespect.

Conclusions Clearly, a standard for pharmaceuticalisolators could be extended into alengthy document including themany aspects of isolator design,construction and operation. Asmentioned, the application ofhydrogen peroxide vapour to bio-decontamination, could in itself bethe subject of a standard. However, apractical and workable standardneeds to be pared down to thebasics for safe operation. It needs tolay down absolute requirements, butit also needs to offer a range ofvalues or choices where appropriate.Both isolator manufacturers andisolator users are naturally keen toconform to standards, but standardstend to flag up various parameters,without providing applicable valuesor numbers. Clearly standards cannot

be highly prescriptive, but theaudience for isolator standards isquite desperate to see figures theycan use in practice. Perhaps a set ofguidelines in the format of a standardmight be established in the firstinstance.

References 1 International Organization for

Standardization. ISO 14644-1:2015 –Cleanrooms and associated controlledenvironments – Part 1: Classification of aircleanliness by particle concentration.Geneva 2015.

2 International Organization forStandardization. ISO 14644-2:2015 –Cleanrooms and associated controlledenvironments – Part 2: Monitoring toprovide evidence of cleanroomperformance related to air cleanliness byparticle concentration. Geneva 2015.

3 International Organization forStandardization. ISO 14644-3:2015 –Cleanrooms and associated controlledenvironments – Part 3: Test methods.Geneva 2019.

4 International Organization forStandardization. ISO 14644-4:2001 –Cleanrooms and associated controlledenvironments – Part 4: Design,construction and start-up. Geneva 2001.

5 International Organization forStandardization. ISO 14644-5:2004 –Cleanrooms and associated controlledenvironments – Part 5: Operations.Geneva 2004.

6 International Organization forStandardization. ISO 14644-7:2004 –Cleanrooms and associated controlledenvironments – Part 7: Separative devices(clean air hoods, gloveboxes, isolators andmini-environments). Geneva 2004.

7 International Organization forStandardization. ISO 10648-1: 1997 –Containment enclosures – Part1: Designprinciples. Geneva 1997.

8 International Organization forStandardization. ISO 10648-2: 1994 –Containment enclosures – Part2:Classification according to leak tightnessand associated checking methods.Geneva 1994.

9 International Organization forStandardization. ISO 13408-6: 2005 –Aseptic processing of healthcareproducts, Part 6: Isolator systems. Geneva2005.

10 International Organization forStandardization. ISO/DIS 13408-6 –Aseptic processing of healthcareproducts, Part 6: Isolator systems. Underdevelopment.

11 Pharmaceutical Isolators, B.Midcalf et al.Pharmaceutical Press, 2004

12 EudraLex – Volume 4 Good manufacturingpractice (GMP) Guidelines EU GMP Annex1:2008: Manufacture of Sterile MedicinalProducts

13 PHSS Clarity on GMP – Guidance NoteNo. 1: Assurance of Sterility for containerclosure in-direct product contact surfacesin Aseptic process filing. Role ofvaporised hydrogen peroxide bio-decontamination in a contaminationcontrol strategy combining Sterilisation +Bio-burden control + VHP/vH202

14 HSE MS37: Handling cytotoxic drugs inisolators in NHS pharmacies. HSE 2015

15 CEN. EN 12298:1998 – Biotechnology.Equipment: Guidance on testingprocedures for leaktightness. CEN 1998

16 International Organization forStandardization. ISO 14937:2009 –Sterilization of health care products –General requirements for characterizationof a sterilizing agent and thedevelopment, validation and routinecontrol of a sterilization process formedical devices.

This article first appeared in CleanAir and Containment Review, Issue40, 2019.





groups of patients and/or medicines.Either way, production of highlypersonalized medicine for individualpatients is already a reality inpharmacies today.

Traditional drugcompoundingCompounding or production ofmagisterial preparations has alwaysbeen one of the integral roles ofpharmacies. Compoundingpractices and regulations differbetween countries and are intendedfor cases in which registeredproducts are not suitable for thepatients. These individualizedmedicines are often required forpaediatric patients but are alsorelevant for elderly patients orpatients with metabolicimpairments. Traditional drugcompounding comprises sequentialmanipulations to build ahomogeneous mixture of powders,suspensions, or solutions fromvarious amounts of startingmaterials. This process is both timeconsuming and labour intensive. Itrequires training and knowhow ofpharmacy staff, as well as adherenceto GMP-like standards for the staff,production processes and locationof the compounding. Solidpreparations include capsules moreoften than tablets. The productionprocess is often carried out withtraditional equipment that relies onthe pharmacist’s skilled hands and isdifficult to complete with accuracy.

3D printing drugcompoundingWith 3D printing arise opportunitiesto design and produce medicationsin an automated manner, which cansave on resources and achieve saferand more precise compoundedformulations. The different 3Dprinting techniques would becapable of coping withcompounding challenges arisingfrom highly precise dosing, coatingof surfaces, production of slow-release galenic forms, formulation ofgastric acid-resistant coating,complex release kineticsformulations, and easily dissolvinghydrogels for dysphagia patients or

OPPORTUNITIES ANDAPPLICATIONS OF 3DDRUG PRINTING INPHARMACIESby Josep M Guiu1,2, Netta Beer3, and Robert Moss1,4

3D printing of medicines is a novel technique thatpromises a more personalized and patient-centered

approach to the manufacture of medicines. In this article,based on a talk given at last year’s FIP World Congress inAbu Dhabi, the authors look at the pros and cons of sucha radical shift in technology as applied to future humanhealth care.

Introduction3D printing is a disruptivetechnology that has the potential tocause a paradigm shift in the waythat drugs are designed, produced,and used. 3D printing is an additivemanufacturing technique thatenables the fabrication of computerdesigned objects in a layeredmanner. 3D printing has been usedin many different fields for differentapplications. In medicine it has beenused especially in dentistry andorthopaedics, for the production ofprosthetics and implants, and alsofor producing stents, includingdrug–eluting stents and implants.

Pharmaceutical applicationsMore recently, 3D printing researchhas exponentially grown in thepharmaceutical field, driven by theFood and Drug Administration(FDA) authorization of Spritam®(levetiracetam, a drug used to treatepilepsy) in 20151. One of theadvantages of Spritam® overprevious levetiracetam versions ishighly porous layers that increase itsdissolvability due to the fact that thepowder-bed 3D printing techniqueboasts porous layers. Although this

1 Hospital Pharmacy section executive committee. International PharmaceuticalFederation

2 Catalan Health and Social Care Consortium, Barcelona, Spain3 Department of Pharmacy, University of Copenhagen, Denmark4 GS1 Global Office, Brussels, Belgium

was a landmark case with theintroduction of 3D printed drugs intherapy, it is a case of thepharmaceutical industry using 3Dprinters for the mass production ofregistered drugs. Thus, this case hadno real influence on the possibilityof printing 3D medicine inpharmacies, but it did spark theinterest and imagination ofresearchers and pharmacists to seehow 3D printing might be applied inthe pharmacy setting.

There are different definitions andinterpretations of what personalisedmedicine means. While some limitthis term to medicine adapted togroups of people with a certaingenetic property, others take a moreindividualized approach and believethat medicine should be personalizedon an individual basis according tothe specific patient's characteristics,including age, weight, metabolism,co-morbidities, medication historyand lab results. While some believepersonalized medicine will eventuallychange the current drugdevelopment and manufacturingpractices, others are sceptical aboutthis prediction and believe that it willalways be limited to very specific



for elderly patients who havedifficulties with swallowing. Inaddition to the ability of creatingpolypills by combining different APIsin the same tablet, 3D printing alsoenables the production of medicinestaking into account the patient'sindividual preferences such asshapes, size, colours and flavours(see Figure 1). These new attributescould improve patient’s adherence totheir medical treatments2,3. Anadditional advantage is, arguably,that the new technology mightminimize waste production4. Theautomation of the technology couldalso provide further protection forpharmacists and technicians fromexposure to hazardous ingredients,which is becoming increasinglyimportant in healthcare institutions.Another important advantage of 3Dprinting on-site is when time is acritical factor, for example, whencompounding and delivering low-stability drugs.

Although there are many possibleadvantages to 3D printing as acompounding technology, there areseveral factors which need to betaken into account with itsintroduction in the daily routine ofdrug compounding in the clinicalsetting5. The main barriers relate tothe technical aspects as well as thesocietal aspects of implementation6.Technical challenges include the factthat printers, software and materialsare still being developed and, for themoment, compared with currentcompounding techniques, theprinting techniques are still slowerand not as safe as traditionalcompounding methods. The societalaspects include legal/regulatory andorganizational challenges. These will

ConclusionsAt the moment, just pilot studies inthe clinical trial setting7 have beenconducted in the hospital pharmacysetting, where 3D printing offers afeasible, rapid and automatedapproach to prepare oral tailored-dose therapies in a hospital setting.These first experiences are thebeginning of a learning curve toovercome difficulties concerning theadoption of this technology.

Nonetheless, once the technical,organizational and regulatoryhurdles are overcome,implementation into practice of 3Dprinting could be attained, changingthe face of pharmaceuticalmanufacture and initiating a new eraof digital production in pharmacypractice. In this scenario, we canenvision that point of care pharmacy-based drug production may be thefuture of pharmaceuticals.

References1 Di Prima M, Coburn J, Hwang D, Kelly J,

Khairuzzaman A, Ricles L. Additivelymanufactured medical products – the FDAperspective. 3D Print Med. 2016; 2.

2 Goyanes A, Scarpa M, Kamlow M,Gaisford S, Basit AW, Orlu M. Patientacceptability of 3D printed medicines. IntJ Pharm. 2017; 530(1–2).

3 Fastø MM, Genina N, Kaae S, KälvemarkSporrong S. Perceptions, preferences andacceptability of patient designed 3Dprinted medicine by polypharmacypatients: a pilot study. Int J Clin Pharm.2019 Oct 23; 41(5): 1290–8.

4 Awad A, Trenfield SJ, Goyanes A,Gaisford S, Basit AW. Reshaping drugdevelopment using 3D printing. DrugDiscov Today. 2018 Aug; 23(8): 1547–55.

5 Trenfield SJ, Awad A, Goyanes A,Gaisford S, Basit AW. 3D PrintingPharmaceuticals: Drug Development toFrontline Care. Trends Pharmacol Sci.2018 May; 39(5): 440–51.

6 Lind J, Kälvemark Sporrong S, Kaae S,Rantanen J, Genina N. Social aspects inadditive manufacturing of pharmaceuticalproducts. Expert Opin Drug Deliv. 2017;14(8): 927–36.

7 Goyanes A, Madla CM, Umerji A, DuranPiñeiro G, Giraldez Montero JM, LamasDiaz MJ, et al. Automated therapypreparation of isoleucine formulationsusing 3D printing for the treatment ofMSUD: First single-centre, prospective,crossover study in patients. Int J Pharm.2019 Aug 15; 567: 118497.

OPPORTUNITIES AND APPLICATIONS OF 3D DRUG PRINTING IN PHARMACIES continued

Figure 1 – Examples of mock 3D printed tablets. Photo courtesy of MarkFastø

need to be overcome beforeadoption of this technology ispossible. An important organizationalissue is the need to replace existingequipment with the new 3D printers.This represents not only an importantinvestment for the organization, but amajor effort in upgradingprofessionals with a new technologythat is continuously evolving withcurrently few potential products tobe compounded. The adoption ofthe 3D printing technology mightalso necessitate acquiring newcompounding competences forclinical pharmacists, and possiblyintroducing the challenge ofintegrating biomedical engineersinto a multidisciplinary pharmacyteam in more complex pharmacyenvironments.

Regulatory aspectsAs for the legal and regulatory side,the main challenge is that there iscurrently no regulatory framework orguidance for 3D printers and 3Dprinted drug products. Whenproducing large batches, qualitycontrol relies on the testing of thefinal products, while in thecompounding situation where only asmall amount of the same medicineis produced, it is often not possibleto check the final product. In thesecases, the quality of the productrelies on in-process controls, and itis still unclear which in-processcontrols can be applied to 3Dprinting. Moreover, in the hospital orcommunity pharmacy setting, 3Dprinting would most likely dependon the pharmaceutical companies toprovide the intermediate productsfor the on-site printing, which alsoneed further regulation.


Figure 1 – Methodology Booklet.

Figure 2 – Survey participants


One of the main pillars of theEuropean Pharmaceutical Students’Association (EPSA) has been and willalways be – Education. For thisreason, EPSA has always been apioneer in showcasing the mostcontemporary and significantmatters in the world of pharmacy tothe European pharmaceutical youth.

Historically speaking, pharmacy, asa discipline which combines scienceand art, has been evolving,changing and adapting with theneeds of the global population.

Today, the word pharmacy meansso much more! Communitypharmacy, clinical pharmacy,ambulatory pharmacy, compoundingpharmacy, industrial pharmacy,regulatory pharmacy, etc. There arecountless adjectives which pairperfectly with the word pharmacy,and we gain countless possibilitiesto perceive pharmacy in thatparticular aspect. This is whypharmacy, as a sophisticatedsynergy of life sciences, healthsciences as well as social sciences, issimply and in one word - unique.

To help pharmaceutical studentsof today become highly competentpharmacists of tomorrow, EPSAreleased its first MethodologyBooklet in October 2018. This is adocument based on the opinions of

1478 European pharmaceuticalstudents and recent graduates onthe teaching methodologiescurrently utilised by the Europeanfaculties of pharmacy. This advocacytool assists educators andpolicymakers to continue to evolveand improve Europeanpharmaceutical education. Sinceeducation is developedcontinuously, this will help us toshowcase what students and recentgraduates think of the currentsituation of the methodologiesapplied to teaching and what theywant for the future regardingeducation. Higher education shouldfacilitate the gaining of theknowledge we all aspire to. Webelieve that continuous dialogue isimportant and we endeavour tomotivate students and recentgraduates to seek further

THE FUTURE IS NOW! THEEVOLUTION OFPHARMACEUTICALEDUCATIONby Stefan Grgić

Stefan Grgić , Mpharm, is EPSA Educational Affairs Coordinator 2019/2020. Afterobtaining his MPharm Degree, Stefan has been working as Research Assistant at theResearch Institute for Health and Medical Sciences in Dubai. In April 2019, he joinedEPSA as the Educational Affairs Coordinator, and in November 2019 joined the DIA(Drug Information Association) as Junior Scientist. Believing that academic studiesfamiliarize students with only a few aspects of Pharmacy, Stefan emphasizes thatsoon-to-be pharmacists are not prepared or taught to face obstacles and challengesin the current job market. Therefore, Stefan’s activities in EPSA are oriented towardsovercoming those challenges while giving the opportunities to students to acquire alifelong learning mindset through projects like Educational Chronicles, MethodologyBooklet and LifeLong Learning Platform.


THE FUTURE IS NOW! THE EVOLUTION OF PHARMACEUTICAL EDUCATION continued


knowledge and opportunities. Ourcause is supported by the EuropeanAssociation of Faculties ofPharmacy, and together we evaluatethe process of teaching andlearning, and tailor it towards theexpected knowledge andcompetency development amongthe European pharmaceutical youth.

In order to ensure a continuouspromotion and preserve a strongvoice within Europe, for the next fiveyears EPSA will focus on fourAnnexes which will go hand in handwith the Methodology Booklet andrepresent a more detailed follow upon the main outcomes of theMethodology Booklet itself:

● 1st Methodology BookletAnnexe 1: Soft Skills

● 1st Methodology BookletAnnexe 2: TeachingMethodologies Techniques

● 1st Methodology BookletAnnexe 3: Unification ofCurricula in Europe

● 1st Methodology BookletAnnexe 4: MandatoryInternships

As much as it is important toadvocate for a better acquisition ofknowledge, and familiarisingpharmaceutical students with theversatile aspects of the world ofpharmacy, it is of equal importanceto focus on the transition fromstudent to an emergingprofessional.

This is something EPSArecognised and in November 2019launched a new project -Educational Chronicles, which takepharmaceutical students on thelifelong journey of learning andcontinuous professionaldevelopment. It also helps them tolearn more about the necessaryeducation for a soon-to-bepharmacist to pursue a meaningfulcareer. Educational Chronicles isconceptualised as a set of online

Figure 3 – Educational Chronicles


THE FUTURE IS NOW! THE EVOLUTION OF PHARMACEUTICAL EDUCATION continued


activities consisting of sevenWebinars, called Chapters. ThreeChapters have been organised onthe following topics:

● Educational ChroniclesChapter 1 - Academia,Research and Clinical Trials incollaboration with EUFEPS(European Federation for thePharmaceutical Sciences) andACRP (Association of ClinicalResearch Professionals)

● Educational ChroniclesChapter 2 - Drug Informationin collaboration with EAHP(European Association ofHospital Pharmacists)

● Educational ChroniclesChapter 3 - The Pharmacy ofTomorrow in collaborationwith PGEU (PharmaceuticalGroup of European Union)

and ESCP (European Societyof Clinical Pharmacists)

The remaining four chapters will beorganised this year (2020), with aspecial focus on the educationalbackground necessary in Regulatoryand Policy Affairs in Pharmacy,along with Quality Control andQuality Assurance, whileemphasizing the importance theaforementioned fields have in thepharmaceutical industry.Furthermore, pharmaceuticalstudents will have the opportunityto learn more about RegulatoryCMC, Market Access and MarketingAuthorization – which are essentialaspects within the pharmaceuticalindustry, yet very obscure tostudents. Pharmaceutical students,and students with a life sciencebackground in general, who arehighly motivated towards starting

their career in the pharmaceuticalindustry remain unaware of both theopportunities and the variety ofpossibilities pharmaceutical industryhas to offer. EPSA would like toprovide students with a glimpse ofthis whole other world, yet veryimportant aspect of pharmacy ingeneral.

With the immense expansion ofknowledge, scientific andtechnological achievements, alongwith the pharmaceutical industry,pharmacy continues to be describedas a discipline of lifelong learning.

As pharmacists of tomorrow, bothstudents and graduates need to beupdated with the current andongoing trends within pharmacy andthe pharmaceutical sciences.Therefore: “Tomorrow's illiterate willnot be the man who can't read; hewill be the man who has not learnedhow to learn."

trialpharmactps:/

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80th FIP World Congress of Pharmacy and Pharmaceutical SciencesSeville, Spain13-17 September 2020

Digitalisation is already allowing us to keep structured patient

records, facilitate electronic prescribing, and provide tools for

monitoring the effi cacy and safety of medicines in use. Further

advances will enable pharmacists to interact with patients in

a new, more effi cient way. Come to the 2020 FIP congress in

Seville, Spain, to prepare for these new technologies that will

empower our profession.

The technological revolution Impact on pharmacy and health careMobile supercomputing. Intelligent robots. Neurotechnological brain enhancements. News of dramatic change is all around us and it’s happening at exponential speed. We are at the beginning of a revolution that is fundamentally changing the way we live, work and relate to one another.

B > Passion for pharmacy

innovation

We will look at scientifi c and

technological innovations

occurring around the world and

how to adapt to and exploit

these advances in pharmacy.

C > From children’s health to

healthy ageing — Impact of

technologies on quality of life

The foundations for lifelong

good health are best laid in

childhood. We will explore how

to do that together with the

many possibilities for healthy

ageing.

D > Targeting special interests

We will offer sessions catering

for special interests in pharmacy

and pharmaceutical sciences.

SEVILLE AWAITS YOU!

Discover a city where centuries of history have left an impressive

legacy that will amaze you. The old city of Seville is one of the

oldest in the world. Add to this a wonderful climate, a vibrant

atmosphere and the iconic fl amenco, and you are likely to fall

in love with this place. Kindness and hospitality ensure that

visitors feel welcome. Bring a camera! Seville promises you some

unforgettable pictures.

CONGRESS STREAMS

Find out more here:

congress.fi p.org/seville2020/

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

A > Enabling change —

Is your country ready?

We will focus on change in both

developed and developing

countries, education, workforce,

advocacy, regulation and the

cost of change.



Brexit became a reality on 31stJanuary 2020, when the UK left theEU. For the next 11 months, the UKwill remain in a transitionary periodwhere it will still follow EU rules.1However, what does Brexit mean forthe EU pharmaceutical industry?

The imminent problem now is thepossibility of a ‘no-deal’ Brexit oncethe transition period is over, whichwould mean a complete dissolutionof all of the UK’s ties to the EU. Ano-deal Brexit would effectivelydisintegrate the complex medicinemarkets of Europe.2 It is noteworthy,however, that analysts havesuggested that a ‘soft’ Brexit -withdrawal from the EU whilemaintaining some ties - could stillhappen as an alternative to a no-deal.3

Many Challenges AheadThe UK being part of the EU meantthe ability to participate in a singlemarket that allowed goods andmoney to be freely transacted overborders. After Brexit, disentanglingthe political and economic ties thatcame from decades of participationin this market is likely to be a long,difficult, and messy task.

While Brexit has created somelevel of uncertainty for most sectors,this uncertainty could be detrimentalfor the pharmaceutical industry inparticular. Take productdevelopment, for instance; drugdevelopment takes years and needsto be planned in advance. Drugsupplies also need to be planned outand monitored. Market approval andshipping of drugs are other areasthat Brexit is expected to impact.4

Post-Brexit MedicineShortages The Brexit Health Alliance reportsthat approximately 45 million packs

of medicine go from the UK to theEU annually.5 Post-Brexit hurdles inmoving goods across borders couldresult in temporary, but crucial,medicine shortages for both the UKand EU countries.

The same report suggests thatsince half of the assessment workneeded for the authorization of newmedical devices takes place in theUK, it is likely that patients in the EUmay face delays in being able to usenew medical devices. It is also likelythat certain standard medicaldevices may not be available topatients. For instance, large volumesof the needles and tubes neededfor blood collection were suppliedfrom South West England to the restof Europe before Brexit.6

The European Federation ofPharmaceutical Industries andAssociations (EFPIA) has called formeasures such as allowing the useof fast track lanes or priority routesfor medicines at airports when itcomes to shipping, as well as thenecessary paperwork beingcompleted away from the border tosave time. Additionally, the EFPIAsuggests that active pharmaceuticalingredients or medical raw materialbe declared exempt from borderchecks.7

The European Medicines Agency(EMA) has a dedicated task forceattempting to deal with potentialdrug shortages by minimizingsupply disruptions and developingstrategies to manage disruptionsthat are already present in thesupply chain.8

It is important to note, however,that such medicine shortages can bereasonably expected but are notconfirmed yet.9 Confirmedshortages are promptly reported bythe EMA and similar medicalauthorities.10

Changes in RegulationsThe UK played a significant role indrug regulation in the EU pre-Brexitthrough the Medicines andHealthcare Products RegulatoryAgency (MHRA). Before Brexit, itcontributed up to a third of the EU’spharmacovigilance work.11 TheMHRA will need to be replacedpost-Brexit, and finding similarexpertise in that capacity is achallenge that could affect drugregulations.12

The EMA’s relocation, discussednext, also impacts drug regulations.Indeed, uncertainty surroundingBrexit is especially relevant when itcomes to medical regulations, withmany questions regardingpharmacovigilance activitiesremaining unanswered. This is whereregulatory professionals in pharmaneed to take the lead and mitigaterisk. The Regulatory AffairsProfessionals Society (RAPS) isamong those keeping an eye onsuch issues during this shakytransition period.13

The EMA’s RelocationThe key EU medicines regulator, theEMA, has been required to close itspre-Brexit London office of 24 yearsand to relocate to Amsterdam. Theclosing of the EMA office hasresulted in around 900 people losingtheir jobs because they did not wishto leave London.14

Although a certain amount of stafflosses can be absorbed under itspost-Brexit business continuity plan,the EMA could still lose more staff.The worst-case scenario in thissituation is that the EMA might notbe able to protect the health of EUcitizens, as is its mandate. Therecould even be permanent damageto the country’s medicine regulatorysystem.15 If forced to invoke its

PHARMA IN PLENARYEU Pharma in the Aftermathof Brexitby Nicola Davies



PHARMA IN PLENARY continued

2 The Scientist Magazine® (2020) The UKPharmaceutical Industry Braces for Brexit.https://www.the-scientist.com/news-opinion/the-uk-pharmaceutical-industry-braces-for-brexit--64926. AccessedFebruary 12, 2020.

3 BBC News (2020) No deal now more likelybut can be avoided - Barnier.https://www.bbc.com/news/uk-politics-47783127. Accessed February 14, 2020.

4 PwC (2020) Brexit Monitor: The impact onPharma & Life Sciences.https://www.pwc.nl/en/brexit/documents/pwc-brexit-monitor-pharma-life-sciences.pdf. Accessed February 12, 2020.

5 Brexit Health Alliance (2020) Brexit andthe impact on patient access to medicinesand medical technologies.https://www.nhsconfed.org/-/media/Confederation/Files/Brexit-Health-Alliance/Brexit-impact-patient-access-medicines-medical-technology.pdf.Accessed February 12, 2020.

6 Brexit Health Alliance (2020) Brexit andthe impact on patient access to medicinesand medical technologies.https://www.nhsconfed.org/-/media/Confederation/Files/Brexit-Health-Alliance/Brexit-impact-patient-access-medicines-medical-technology.pdf.Accessed February 12, 2020.

7 Staines R (2020) Pharma calls for 'no deal'preparation after Brexit deal rejected -.Pharmaphorum.com.https://pharmaphorum.com/news/pharma-calls-for-no-deal-preparation-after-brexit-deal-rejected/. Accessed February 12,2020.

8 European Medicines Agency (2020)Availability of medicines - EuropeanMedicines Agency.https://www.ema.europa.eu/en/human-regulatory/post-authorisation/availability-medicines. Accessed February 12, 2020.

9 European Medicines Agency (2020)European authorities working to avoidshortages of medicines due to Brexit –questions and answers.https://www.ema.europa.eu/en/documents/other/european-authorities-working-avoid-shortages-medicines-due-brexit-questions-answers_en.pdf. AccessedFebruary 12, 2020.

10 European Medicines Agency (2020)Shortages catalogue - EuropeanMedicines Agency.https://www.ema.europa.eu/en/human-regulatory/post-authorisation/availability-medicines/shortages-catalogue. AccessedFebruary 12, 2020.

11 Brexit Health Alliance (2020) Brexit andthe impact on patient access to medicinesand medical technologies.https://www.nhsconfed.org/-/media/Confederation/Files/Brexit-Health-Alliance/Brexit-impact-patient-access-medicines-medical-technology.pdf.Accessed February 12, 2020.6

12 WIRE B (2020) How Brexit will impactEurope’s pharmaceutical industry | Expertsat Infiniti predict how Brexit will affect lifescience and pharma industry.Businesswire.com.

https://www.businesswire.com/news/home/20190924005614/en/Brexit-impact-Europe%E2%80%99s-pharmaceutical-industry-Experts-Infiniti. AccessedFebruary 12, 2020.

13 Pharmafield (2020) The impact of Brexiton the regulatory and marketinglandscape - Pharmafield.https://pharmafield.co.uk/in_depth/impact-brexit-regulatory-marketing-landscape/.Accessed February 12, 2020.

14 O’Carroll L (2020) Key EU medicinesregulator closes London office with loss of900 jobs. the Guardian.https://www.theguardian.com/politics/2019/jan/26/european-medicines-agency-closes-london-office-with-loss-of-900-jobs-brexit. Accessed February 12, 2020.

15 Pharmaceutical Journal (2020) Relocationof the EMA: implications for medicinesregulation. https://www.pharmaceutical-journal.com/news-and-analysis/relocation-of-the-ema-implications-for-medicines-regulation/20203731.article?firstPass=false.Accessed February 12, 2020.

16 Pharmaceutical Journal (2020) Relocationof the EMA: implications for medicinesregulation. https://www.pharmaceutical-journal.com/news-and-analysis/relocation-of-the-ema-implications-for-medicines-regulation/20203731.article?firstPass=false.Accessed February 12, 2020.

17 Luxner L (2020) With Post-Brexit Move toAmsterdam Complete, EMA Renews Rare.Pompe Disease News.https://pompediseasenews.com/2020/02/06/post-brexit-move-amsterdam-completed-ema-now-renews-rare-disease-focus/. Accessed February 12, 2020.

18 European medicines Agency (2020)European authorities working to avoidshortages of medicines due to Brexit –questions and answers.https://www.ema.europa.eu/en/documents/other/european-authorities-working-avoid-shortages-medicines-due-brexit-questions-answers_en.pdf. AccessedFebruary 12, 2020.


20 Wellcome (2020) Regulation of clinicaltrials: Brexit and beyond | Wellcome.Wellcome.https://wellcome.ac.uk/reports/regulation-clinical-trials-brexit-and-beyond. AccessedFebruary 12, 2020.


business continuity plan, the EMAwill have to decrease its activities tolimit the impact of Brexit uncertaintyon public health.16

The good news is, now that therelocation is complete, the EMA isreturning to its business of studyingand promoting effective medicalpractices, one of which includes thetreatment of rare diseases. The EUhas about 25 million rare diseasepatients, and the EMA will now beworking on the further developmentof orphan-designated medicines.17

Clinical Trials and DrugTestingCompanies that used to conductclinical trials in the UK may need totransfer operations into an EUmember state before the transitionperiod ends,18 which will take timeand could have similarconsequences to the staff lossexperienced by the EMA movinglocation.

The EFPIA has suggested that theEU be allowed to recognize UK-based drug testing for the timebeing, until this testing can takeplace in the EU.19 Since more than4,800 UK-EU clinical trials took placebetween 2004 and 201620 and giventhat 1,500 current registered clinicaltrials in the EU have a UK basedsponsor,21 future collaboration onclinical trials might be the bestoption.

Hoping for a Soft BrexitUnless a ‘soft Brexit’ deal is passedinstead of a no-deal, which wouldallow the UK to maintain someregulatory consistency with the EU,pharmaceutical companies shouldboth expect and be prepared todeal with a certain amount ofupheaval, especially whereregulatory approvals are concerned.

References1 BBC News (2020) Brexit: What happens

next? https://www.bbc.com/news/uk-politics-50838994. Accessed February 12,2020.


https://www.the-scientist.com/news-opinion/the-uk-pharmaceutical-industry-braces-for-brexit--64926



https://www.bbc.com/news/uk-politics-47783127


https://www.pwc.nl/en/brexit/documents/pwc-brexit-monitor-pharma-life-sciences.pdf



https://www.nhsconfed.org/-/media/Confederation/Files/Brexit-Health-Alliance/Brexit-impact-patient-access-medicines-medical-technology.pdf








https://pharmaphorum.com/news/pharma-calls-for-no-deal-preparation-after-brexit-deal-rejected/



https://www.ema.europa.eu/en/human-regulatory/post-authorisation/availability-medicines



https://www.ema.europa.eu/en/documents/other/european-authorities-working-avoid-shortages-medicines-due-brexit-questions-answers_en.pdf




https://www.ema.europa.eu/en/human-regulatory/post-authorisation/availability-medicines/shortages-catalogue







https://www.businesswire.com/news/home/20190924005614/en/Brexit-impact-Europe%E2%80%99s-pharmaceutical-industry-Experts-Infiniti




https://pharmafield.co.uk/in_depth/impact-brexit-regulatory-marketing-landscape/

https://pharmafield.co.uk/in_depth/impact-brexit-regulatory-marketing-landscape/

https://www.theguardian.com/politics/2019/jan/26/european-medicines-agency-closes-london-office-with-loss-of-900-jobs-brexit




https://www.pharmaceutical-journal.com/news-and-analysis/relocation-of-the-ema-implications-for-medicines-regulation/20203731.article?firstPass=false








https://pompediseasenews.com/2020/02/06/post-brexit-move-amsterdam-completed-ema-now-renews-rare-disease-focus/











https://wellcome.ac.uk/reports/regulation-clinical-trials-brexit-and-beyond

https://wellcome.ac.uk/reports/regulation-clinical-trials-brexit-and-beyond







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

United States ofAmericaCMC information for humangene therapy INDsThis guidance finalizes the draftguidance of the same title datedJuly 2018 and supersedes thedocument entitled “Guidance forFDA Reviewers and Sponsors:Content and Review of Chemistry,Manufacturing, and Control (CMC)Information for Human GeneTherapy Investigational New DrugApplications (INDs),” dated April2008 (April 2008 guidance). The fieldof gene therapy has progressedrapidly since the previous April 2008guidance. Therefore, FDA isupdating that guidance to providecurrent FDA recommendationsregarding the CMC content of agene therapy IND. This guidance isorganized to follow the structure ofthe FDA guidance on the CommonTechnical Document (CTD).

The CMC information submittedin an IND describes the sponsor’scommitment to performmanufacturing and testing of theinvestigational product as stated.FDA acknowledges thatmanufacturing changes may benecessary as product developmentproceeds, and informationamendments should be submittedto supplement the initial informationsubmitted for the CMC processes.The CMC information submitted inthe original IND for an early phasestudy may be limited, and therefore,the effect of manufacturing changes,even minor changes, on productsafety and quality may not besufficiently understood. Thus, if amanufacturing change could affectproduct safety, identity, quality,purity, potency, or stability,

applicants should submit themanufacturing change for FDAreview prior to implementation.

FDA Continues Strong Supportof Innovation in Developmentof Gene Therapy ProductsThis is a pivotal time in the field ofgene therapy as the FDA continuesits efforts to support innovatorsdeveloping new medical productsfor Americans and others aroundthe world. To date, the FDA hasapproved four gene therapyproducts, which insert new geneticmaterial into a patient’s cells. Theagency anticipates many moreapprovals in the coming years, asevidenced by the more than 900investigational new drug (IND)applications for ongoing clinicalstudies in this area. The FDAbelieves this will provide patientsand providers with increasedtherapeutic choices.

In that spirit, today, the FDA isannouncing the release of a numberof important policies: six finalguidances on gene therapymanufacturing and clinicaldevelopment of products and adraft guidance, ‘InterpretingSameness of Gene TherapyProducts Under the Orphan DrugRegulations’.

Applications Affected by theReorganization of the Office ofNew DrugsThe approved restructuring of theOffice of New Drugs (OND) createsoffices that align interrelateddisease areas, and divisions withclearer and more focused areas ofexpertise. As a result, the names ofOND’s offices and divisions havechanged. If there is a change insignatory, or point of contact forapplications currently under review,then sponsors will be notified.However, at the start of each phase,FDA encourages sponsors to searchwithin the provided Excel file forapplications currently under reviewthat may be affected by thereorganization.

Clinical immunogenicityconsiderations for biosimilarand interchangeable insulinproductsThe purpose of this draft guidanceis to provide recommendations toapplicants regarding whether andwhen comparative clinicalimmunogenicity studies may beneeded to support licensure ofproposed biosimilar andinterchangeable recombinanthuman insulins, recombinant humaninsulin mix products, andrecombinant insulin analog productsthat are intended for the treatmentof patients with Type 1 or Type 2diabetes mellitus (collectivelydescribed as “insulin products”).

In this guidance, FDA describes itsupdated thinking that, generally, if acomparative analytical assessmentbased on state-of-the-arttechnology supports ademonstration of “highly similar” fora proposed biosimilar orinterchangeable insulin product,there would be little or no residualuncertainty regardingimmunogenicity; in such instances,the proposed biosimilar orinterchangeable insulin product, likethe reference product, would beexpected to have minimal or no riskof clinical impact fromimmunogenicity. In such instances, acomparative clinical immunogenicitystudy generally would beunnecessary to support ademonstration of biosimilarity orinterchangeability. For someproposed biosimilar orinterchangeable insulin products, acomparative clinical immunogenicitystudy may still be needed toaddress residual uncertaintyregarding immunogenicity. Forexample, such a study would beneeded to address uncertaintyraised by, among other things,differences in certain impurities ornovel excipients, but that would bea case-by-case scientificdetermination in the context ofindividual applications.



REGULATORY REVIEW continued

Transdermal and topicaldelivery systems - productdevelopment and qualityconsiderationsThis draft guidance providesrecommendations to applicants andmanufacturers of transdermal andtopical delivery systems (TDS)regarding the pharmaceuticaldevelopment and qualityinformation to include in new drugapplications (NDAs) andabbreviated new drug applications(ANDAs). Specifically, the guidancediscusses FDA’s current thinking onproduct design and pharmaceuticaldevelopment, manufacturingprocess and control, and finishedproduct control. It also addressesspecial considerations for areaswhere quality is closely tied toproduct performance and potentialsafety issues, such as adhesionfailure and the impact of appliedheat on drug delivery.

Transdermal delivery systems aredesigned to deliver an activeingredient (drug substance) acrossthe skin and into systemiccirculation, while topical deliverysystems are designed to deliver theactive ingredient to local tissue.Both delivery systems presentsimilar manufacturing and qualitycontrol concerns and similar risks topatients. TDS can be broadlydivided into matrix type and liquidor gel reservoir type deliverysystems.

• Matrix type TDS contain oneor more active ingredientsdissolved or partiallysuspended in a mixture ofvarious components, includingadhesives, penetrationenhancers, softeners, andpreservatives, and are typicallymanufactured using solvent,hydrogel, or hot melt-basedpractices.

• Reservoir type TDS similarlycontain a variety ofcomponents in liquid or semi-solid form; however, reservoirtype TDS utilize a heat-sealed

area to entrap the active gelbetween the backingmembrane and a microporousmembrane. Because of theinherent failure modes andsafety risks associated with thereservoir TDS, FDArecommends TDSmanufacturers and applicantsfocus development efforts onmatrix type TDS.

EuropeEDQMTEDQM launches newPharmeuropa websiteEDQM has developed a newPharmeuropa website, which wentlive on 23 January 2020.The new website has beenredesigned and now has morefeatures that are expected toimprove the user experience. Forexample:

• single sign-on with otherEDQM websites using thesame authenticationdatabase, including Ph. Eur.online and PaedForm;

• improved navigation usingstandard web browserfunctionality;

• tablet and smartphonefriendly;

• improved search querymanagement;

• a notification tool enablingusers to set alerts forimportant information for theirbusiness, based onmonograph numbers or Ph.Eur. groups of experts.

All users will have to register foraccess, even those who had accessto the previous site.

New approach to extraneousagents testing ofimmunological veterinarymedicinal products (IVMPs)During its 164th session on 18 June2019, the European PharmacopoeiaCommission adopted 43 texts

related to its new approach toextraneous agents testing ofimmunological veterinary medicinalproducts (IVMPs). The new approachconstitutes a move away from thedescription of detailed methodstowards greater flexibility andallowing tailoring to individualproduct needs. From startingmaterial to final product, users willnow have to follow an overall risk-management approach to ensurethey apply the best testingstrategies in the context of aconsistent manufacturing process.

Pharmeuropa 31.4 released53 drafts have been published inPharmeuropa 31.4. Comments wereto be provided by 30 Dec 2019.

Comments made after adoptionof the text and/or publication in thePh. Eur. will be too late to beconsidered. Users may then be in aposition where their product is notcompliant with the Ph. Eur.monograph, which is a legalstandard in Europe. This couldultimately lead to a situation wherea product can no longer bemarketed in Europe.

Pharmeuropa 32,1All new texts and texts that haveundergone technical revisions arepublished in Pharmeuropa for publicconsultation. The deadline forcomments is 31 March 2020.

European Paediatric FormularyonlineLaunched by the EuropeanCommittee on Pharmaceuticals andPharmaceutical Care (CD-P-PH) andthe European PharmacopoeiaCommission, the EuropeanPaediatric Formulary project iscarried out by experts of adedicated working party. The aim isto bring together, for the first time,formulations of appropriate qualityfrom all around Europe to allowpharmacists and clinicians toprepare paediatric treatments whenno licensed alternative is available.

The formulary can be accessedfree of charge.



of e.g. sodium Nitrite, recoveredsolvents etc., that under section 12point 8 “Use of certain packagingmaterials” that nitrosaminecontamination has been observed byone MAH in a finished productstored in blister. The MAH hashypothesised that the lidding foilcontaining nitrocellulose printingprimer may react with amines inprinting ink to generate nitrosamines,which would be transferred to theproduct under certain packagingprocess conditions.” MBH.]

UK withdrawal from the EU on31 January 2020The United Kingdom formally left theEuropean Union on 31 January 2020and became a third country to theEU. On 1 February 2020 a transitionperiod started which is due to end on31 December 2020. During thetransition period, EU pharmaceuticallaw as laid out in the ‘AcquisCommunautaire’ will continue to beapplicable to the UK, meaning thatpharmaceutical companies cancontinue to carry out activities in theUK until the end of the year.Companies have until 31 December2020 to make the necessary changesto ensure that their authorisedmedicines comply with EU law andcan remain on the EU market.Marketing authorisation holders/applicants can still be established inthe UK and Qualified Persons forPharmacovigilance (QPPVs) andpharmacovigilance system masterfiles (PSMFs), as well as quality controltesting sites, can still be based in theUK until the end of 2020.

As of 1 February 2020, no onewho represents the UK, or isappointed or nominated by the UKcan participate in meetings of EMA’sscientific committees, workingparties or the Agency’sManagement Board.

Updated Brexit-related guidancefor companies has also beenpublished.

European authorities workingto avoid shortages ofmedicines due to Brexit –


EMARevised Q&A on impact of EU-USA MRA on marketingauthorisation applications andrelevant variationsQ&A 1, relating to ‘How does theEU-USA Mutual RecognitionAgreement (MRA) affect marketingauthorisation applications orvariations’, has been revised.

Updated Q&A on “Informationon nitrosamines for marketingauthorisation holders”This very important Q&A documentwas updated on Dec 20 2019.

Q&As subject to update were:-

#1 Are all products to bereviewed?

#6 What limits will apply fornitrosamines detected in anyproducts??

#11What limits will apply fornitro samines detected in anyproducts?

#12What are the currentlyidentified root causes forpresence of nitrosamines?

New Q&As are :-#13What is the approach for

new and ongoing marketingauthorisation applications(MAA)?

#14Are biological productscontaining excipientspotentially at risk ofcontamination withNitrosamines in the scope ofthe review?

#15What to do if aftercompleting step 1 and /orstep 2 new information onnew potential root causes isidentified?

#16What limits will apply fornitrosamines in medicinalproducts based on lifetimeand less than lifetime use?

Readers attention is drawn to thisdocument which should be urgentlyand carefully reviewed for scope,methodology and timelines.

[Note that as well as the involvement

updated Q&AThe relationship between the UKand the EU after the transitionperiod started which is due to endon 31 December 2020 is currentlyunknown and will be determined byfuture negotiations. During thetransition period, European Unionlaw in its entirety will continue toapply to the UK, meaning thatpharmaceutical companies cancontinue to carry out activities in theUK as before until the end of thetransition period. However, allinterested parties should be mindfulof legal repercussions when thetransition period ends. To ensurethat medicines can continue to besupplied in the EU after this period,companies carrying out certainactivities in the UK will need to makechanges to comply with EU law.

Availability / shortages ofmedicines Since April 2019, the task force hasbeen running a pilot programme onestablishing a Single Point ofContact (SPOC) network to improveinformation sharing betweenMember States, EMA and theEuropean Commission on importantmedicine shortages of human andveterinary medicines and tocoordinate actions to help preventand manage shortages. Thisincludes information sharing onalternative medicines that areavailable in other Member States.

The first phase of the pilot ranfrom April to August 2019 to test thefunctioning and usefulness of theinformation exchange via theSPOCs. During this phase, 24Member States used the SPOCsystem and circulated 52notifications of shortages.

The task force plans to run a secondphase of the pilot in 2020, to test thecriteria for identifying cases deservingEU-wide coordinated action and fornetwork alerts of upcoming publiccommunications that could have ahigh impact on patients.

The task force will publish moreinformation after completion of thesecond phase of the pilot.



International collaboration onGMP inspections –manufacturers of sterilemedicines.In December 2019, EMA and itsEuropean and international partnerslaunched a pilot programme to shareinformation on GMP inspections ofmanufacturers of sterile medicineslocated outside the participatingcountries and to organise jointinspections of manufacturing sites ofcommon interest.

The products in scope includesterile medicines for human use ofchemical origin and certaintherapeutic biotechnology - derivedproducts, such as monoclonalantibodies and recombinant proteins.

Vaccines, cell and gene therapiesand plasma-derived pharmaceuticalsare currently out of the scope of thispilot.

For the terms of reference,objectives and full scope, see:

Participating authorities andorganisations include:

• EU Member States (Franceand the United Kingdom);

• the United States FDA;

• the Australian TGA;

• Health Canada

• the Japanese PMDA;

• the World HealthOrganization (WHO).

The pilot will last for a minimum oftwo years. After this period,participating authorities will assessthe programme and determine thenext steps.

This initiative builds on thesuccess and experience with the APIinspection programme.

Substances considered as notfalling within the scope ofRegulation (EC) No.470/20091, with regard toresidues of veterinarymedicinal products infoodstuffs of animal originSince the implementation of CouncilRegulation (EEC) No. 2377/90, theCVMP has deliberated on manysubstances (including excipients,

adjuvants and preservatives) to beused in veterinary medicinalproducts intended for foodproducing species, and regularlyreceives requests (either scientificadvice or ad hoc requests) toconsider whether such substancesfall within the scope of the MRLregulation. The substances for whichthe CVMP has concluded that noMRL evaluation is required are listedin the CVMP publication“Substances considered as notfalling within the scope ofRegulation (EEC) No. 2377/90”(EMEA/CVMP/046-00), also oftenreferred to as the ‘out of scope list’.The list also includes a small numberof compounds that do not fall withinthe categories of excipients,adjuvants or preservatives but arenatural substances essential for lifeor are biologically activeconstituents. Due to the nature ofthese specific compounds theCVMP considered that an evaluationfor the establishment of maximumresidue limits would not beappropriate. Following theimplementation of Regulation (EC)No. 470/2009 there was a need toupdate the background informationand legal references included in thedocument containing the ‘out ofscope list’. This document performsthat function and supersedes theCVMP publication Substancesconsidered as not falling within thescope of Council Regulation (EEC)No. 2377/90. The list includes all thesubstances included in thesuperseded document. It should benoted that this list of substances isin no way exhaustive and includesonly substances for which requestsin this respect were made to CVMPby a company or a national authority

Tripartite meeting held todiscuss regulatory approachesfor the evaluation ofantibacterial agentsThis fourth tripartite meetingbetween the EMA, the US FDA andthe Japanese PMDA discussedfurther alignment on clinical trialdesigns for key indications for

antibacterial drugs for whichconvergence has not yet beenreached. They agreed that data fromcontemporary clinical trials would bepivotal in defining the most suitableway forward. They also expandedthe discussions to include antifungalagents, an area which is also affectedby growing antimicrobial resistanceand where clinical developmentprograms can be challenging.

The agencies discussed:

• methods to facilitate obtainingpaediatric clinical data andutilisation of modelling andsimulation. Paediatricdevelopment is an importantaspect in the development ofanti-infective products;

• differences in test methodsand derived interpretivecriteria for susceptibilitytesting in the European Union,Japan and the Unites States.To facilitate multi-regionalanti-infective medicinedevelopment, communicationand collaboration amongscientific and public healthbodies involved in suchactivities are key and optionsfor harmonisation are stronglyencouraged;

• clinical trial considerations fornew treatment modalities suchas monoclonal antibodies andother non-traditional therapiesfor the treatment and/orprevention of infectiousdiseases. The need to worktogether to facilitate newapproaches and to aim forconvergence was recognised.

The agencies plan to meet again in2020. They also plan to publish theoutcome of their discussions, in ascientific journal.

Regulators' Advice Can Makea Difference: EuropeanMedicines Agency Approval ofZynteglo for Beta ThalassemiaZynteglo is a gene therapy for thetreatment of patients with beta-thalassemia, a rare inherited blood




condition that causes severeanaemia. Some patients can be curedthrough a stem cell transplant from ahealthy donor. However, patients whohave no matched family donor missout. For them, Zynteglo could be agame changer. Using a lentiviral viralvector, it adds functional copies of amodified �-globin gene into apatient’s own stem cells, therebyaddressing the underlying geneticcause of the disease.

Ground-breaking therapies such asZynteglo present specific challengesfor those who assess their benefitsand risks for the initial authorisationand those who assess their value as abasis for pricing and reimbursementdecisions. Continuous dialoguethroughout the development of themedicine, without compromising theimpartiality of the assessment at themarketing-authorisation applicationstage, can help overcome thesechallenges.

In the case of Zynteglo, themedicine benefited from PRIME,EMA’s platform for early andenhanced dialogue with developersof promising new medicines thataddress an unmet medical need andseveral interactions with EMA’sscientific advice office with inputfrom patients’ representatives.

An article, accessible via openaccess in Clinical Pharmacology &Therapeutics, describes how suchinteractions led to a more robustapplication package to demonstratethe medicine’s benefits and risks,which in turn allowed acceleratedassessment. In the article, theauthors describe some of thespecific clinical and manufacturingprocess issues which were identifiedand how these were overcome. Theyalso show that early acceleratedapprovals are only possible if arobust post-approval plan is definedat the marketing authorisation stage.

[Perhaps not a typical example but itis yet another example of how earlydialogue with a regulator can speedup an approval process, whether it isfor a new product, a process ormanufacturing facility.

In these times of significantdevelopments in the field ofmedicines and their sources plusnovel manufacturing techniquessuch early dialogue is surely GoodPractice [GxP]. MBH]

Dutch Authorities hand overfinal building to EMA inAmsterdamOn 15 November the Dutchauthorities handed over to EMA itsnewly built tailor-made premises,located in the Zuidas area ofAmsterdam. Staff moved into theirnew offices and workspaces inJanuary 2020.

EMA Management Board:highlights of December 2019meetingExecutive Director Guido Rasistressed the challenges that theAgency now faces in reinitiating itsactivities following three years ofrelocation and Brexit andpostponed investment intobusiness-critical infrastructure. In themeantime, important new demandshave been placed on the Agencythat will need to be prioritised, suchas the implementation of the newlegislation for veterinary medicinesand on medical devices.

The Agency now has an availableworkforce of 775 which issignificantly less compared to end2017 when EMA’s relocation planstook shape.

In defining its work programmefor 2020 and beyond, EMA will focuson the core activities identified inthe last phase of business continuityas a baseline and will prioritiseadditional tasks depending onavailable resources. The Agency willcontinue to monitor staff levels andreview whether additional activitiescan be relaunched in June 2020.

To help the Agency make best useof available resources and be bestprepared for future challenges, EMAis currently conducting an in-depthreview of its organisation.

This future-proofing exercise willhelp EMA to strengthen its ability toperform important new activities

together with the Europeanregulatory network and to tackleimportant challenges ahead such asbig data, digitalisation and newscientific methods and technologies.

Highlight topics from the meetinginclude:-

EMA budget for 2020The 2020 budget is set at EUR 358million, a 3.3% increase on 2019.

EU cooperation on medicines’availabilityThe Board heard an update on theoutcome of the first phase of a piloton the EU SPOC (single point ofcontact) network for cooperation onavailability of human and veterinarymedicines.

A second phase is foreseen for2020 during which additionalresponsibilities of the SPOCs will betested which are expected toimprove the handling of shortages.Before moving to the second phase,however, it is important to ensurethat necessary resources cancontinue to be made available byEMA and the national authorities inthe Member States.

More information will bepublished once the second phase ofthe pilot is completed.

Update on the EU IT systemsrequired by the Clinical TrialRegulationThe Board endorsed the outcome ofthe ‘audit readiness assessment’ andendorsed the proposal to commencethe audit in December 2020.

In the first few months of 2020,product owners will work with EMAand the IT supplier to perform theanalysis and design of the items thathave been prioritised as stillneeding to be fixed/developedbefore the audit can begin. Theapproach will be carried out in a waythat ensures efficient delivery.

Handling new information onnitrosamine presence inmedicinesThe European medicines regulatorynetwork has agreed to reinforce the




use of interim limits for theevaluation of cases wherenitrosamines are identified, in linewith the report issued by the Agencyon the sartan review. Should theinterim limits be exceeded this willbe handled through the EU network’sexisting rapid alert systems. TheBoard welcomes the cooperation onthe issue that is already ongoing atEuropean level and encouragescontinued discussion with regulatorsfrom outside the EU.

Other meeting highlights were:-

• Mandatory use ofinternational standard forreporting side effects toimprove safety of medicines

• HMA-EMA Joint Big DataTaskforce Report

• Key principles and roadmapon electronic productinformation (ePI)

• Key principles and roadmapon electronic productinformation (ePI)

Post-authorisation proceduraladvice for users of thecentralised procedureGrouping of variations: Q&A – Thisupdated document lists questionsthat marketing-authorisation holders(MAHs) may have on grouping ofvariations. It provides an overview ofthe EMA's position on issues thatare typically addressed indiscussions or meetings with MAHsin the post authorisation phase.Revised topics are marked 'New' or'Rev.'.

Q&A on comparabilityconsiderations for advancedtherapy medicinal products(ATMP)This document addresses questionson how to demonstratecomparability for gene and cell-based medicinal products followingchange to the manufacturingprocess or due to introduction ofadditional manufacturing sites.

FAQ about parallel distributionThis page lists questions about

parallel distribution of human &veterinary medicines. Theinformation is available as Q&As,which the EMA revises as necessary.

InternationalAustralia – Therapeutic GoodsAdministration (TGA)Safety review of coumarin intopical listed medicinesCoumarin is a naturally occurringchemical found in a number of foodproducts such as cinnamon and tonkabean. Coumarin is currently permittedfor use as a listed medicine; however,it is only permitted for use as anactive homoeopathic ingredient (witha maximum concentration of 0.001%).During a review of listed sunscreenproducts, the TGA became awarethat coumarin was being used as afragrance in sunscreen and othertopical listed medicines however wasnot on the Therapeutic Goods(Permissible Ingredients)Determination ('the Determination').Therefore, the TGA conducted apreliminary safety review todetermine whether coumarin wasappropriate for use in listedmedicines and sunscreens as afragrance ingredient.

The review was unable toestablish a safe concentration limitfor the topical use of coumarin, andidentified some safety concernssuch as liver injury, skin sensitisation,and populations at greater risk suchas children and pregnant/breastfeeding women.

Additional data was providedwhich addressed some of the safetyconcerns in the preliminary safetyreview. This information has beenconsidered and used to finalise thesafety review.

The additional data provided hasbeen considered and incorporatedinto the final safety review. Inparticular, data for reproductive anddevelopmental toxicity was able toaddress the safety concernsregarding coumarin in pregnancy andbreastfeeding. However, concernsregarding the use of coumarin inchildren remains outstanding. Assunscreens may be used by the entire

family, sunscreens containingcoumarin will need to specify theyshould only be used by adults. Thisrequirement will also apply to anyother topical listed medicines.

The safety review establishes thatthe appropriate tolerable daily limitfor coumarin exposure from allsources (including diet, cosmeticproducts and sunscreens) is 0.1mg/kg bodyweight. The IFRAstandard proposes a limit of 0.3%coumarin in products for use on thebody. A sunscreen containingcoumarin at this level would provide6 mg/kg bodyweight of coumarin(60-times the tolerable daily limit)when used as recommended for afull-day. A sunscreen containing0.001% coumarin used in the sameway would provide 0.02 mg/kgbodyweight (this is 20% of thetolerable daily limit). In the absenceof a reliable estimation of Australianintake of coumarin from dietary andcosmetic sources, this lower limit isconsidered to be more appropriatefor low risk listed medicines. Assuch, the requirements for listedmedicines will specify that topicalproducts may not exceed aconcentration of 0.001% coumarin.

Sponsors of existing listedmedicines and sunscreens will haveuntil 2 March 2021 to bring theirproducts into compliance.

Consultation: Draft standardsfor faecal microbiotatransplant (FMT) productsTGA is seeking comments frominterested parties on proposedstandards for faecal microbiotatransplant (FMT) products inAustralia. This is a new area ofregulation for TGA from 2020.

Reforms to the genericmedicine market authorisationprocess: implementationupdateIn early 2019, TGA consulted onproposed reforms to the genericmedicine market authorisationprocess. In response to thefeedback received, TGAimplemented the following changes:




• Reduced requirements for useof overseas reference productsin bioequivalence studies.

• Options to use newinternationally alignedtemplates for summarisingbioequivalence or biowaiverstudy data.

Uniform recall procedure fortherapeutic goods (URPTG)A new version of the Uniform RecallProcedure for Therapeutic Goods(URPTG) (V2.2, December 2019) hasbeen implemented, with effect from12 December 2019.

This version updates V2.1 toinclude:

• additional clarity on theprovision of surgeon contactdetails for implantedtherapeutic goods

• amendments related to theonline notification of recalland non-recall actions

• removal of the placeholderreferring to the NationalPatient Contact Principles forPatients with ImplantedMedical Devices subject toHazard Alerts

• a second example templatefor the sponsor's customerletter.

This version also includes a numberof other minor editorialamendments.Medicinal cannabismanufactureThis guidance is for manufacturers ofmedicinal cannabis products. Itoutlines and provides information on:

• manufacturing license andcertification requirements

• differences betweenTherapeutic GoodsAdministration (TGA) andOffice of Drug Control (ODC)requirements

• TGA interpretation andexpectations for compliancewith specific sections of thecurrent PIC/S Guide to GMP.

Export of therapeutic goodsfrom AustraliaThe TGA is seeking comments frominterested parties on an update toguidance for

• Export of medicines fromAustralia

• Export certification formedical devices

Comments were to be submitted by3 Feb 2020

PIC/SDraft PIC/S Recommendationon How to Evaluate /Demonstrate the Effectivenessof a Pharmaceutical QualitySystem in relation to Risk-based Change ManagementPIC/S has published on a draft basisa Recommendation on How toEvaluate / Demonstrate theEffectiveness of a PharmaceuticalQuality System in relation to Risk-based Change Management (PI 054-1 (Draft 1)) developed by the PIC/SExpert Circle on Quality RiskManagement (QRM).

This draft Recommendation willbe applied on a 6-month trial basisby PIC/S Participating Authorities.

The purpose of this draftdocument is to provide guidance onevaluating and demonstrating theeffectiveness of a PQS in relation torisk-based change management.This is in recognition of the fact thatthe PIC/S GMP Guide requirescompanies to demonstrate theeffectiveness of their PQS and toapply quality risk management(QRM) principles to change controlactivities. Further information on thebackground to thisRecommendation and theanticipated benefits of this guidanceare provided in PIC/S Concept Note(PS/INF 88/2019).

This draft document is not openfor comments by industry.

PIC/S events in Toyama,Japan, 11-15 November 2019PIC/S Committee met on 11-12November 2019 in Toyama (Japan).The meeting was followed by the

PIC/S annual training Seminar on 13-15 November 2019. The topic of theseminar was "Quality Assurance ofSterile Medicinal Products - Annex 1".

The press release regardingthese events is available innewsletter format on the PIC/swebsite.

ProductsFirst oral GLP-1 treatment fortype 2 diabetesEMA’s human medicines committee(CHMP) has recommended grantinga marketing authorization in theEuropean Union (EU) for Rybelsus(semaglutide) for the treatment ofadults with insufficiently controlledtype 2 diabetes to improveglycaemic control as an adjunct todiet and exercise. It is the firstglucagon-like peptide (GLP-1)receptor agonist treatment - a classof non-insulin medicines for peoplewith type 2 diabetes - developed fororal use, providing patients withanother option to treat the diseasewithout injections. The activesubstance in Rybelsus, semaglutide,acts in the same way as the incretinhormone GLP1: it reduces bloodglucose by stimulating pancreaticsecretion of insulin and lowering thesecretion of glucagon (a hormonethat works to raise blood sugarconcentration) when blood sugar ishigh. The opinion adopted by theCHMP is an intermediary step onRybelsus’s path to patient access.The CHMP opinion will now be sentto the European Commission for theadoption of a decision on an EU-wide marketing authorisation.

This review is produced byMalcolm Holmes an independentpharmaceutical consultant. Forfurther information on these andother topics we suggest you referto the websites of relevantregulatory bodies and to currentand past editions of “GMP ReviewNews” published by EuromedCommunications.




Cleanroom Management in Pharmaceuticals and HealthcareEdited by Tim Sandle and Madhu Raju SagheeISBN 978-0-9573491-6-2

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

In 26 Chapters and over 600 pages this book provides a unique tool to help youachieve regulatory compliance. It first creates a foundation in history and establishedpractice and then helps you understand how state of the art technology andengineering solutions can deliver the best practice and so provide reliable systemsperformance.

An essential read for practitioners in cleanroom technology.

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.

Includes 25 chapters, 23 authors and over 600 pages of text. With many illustrations, tables and diagrams

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.

*Vice President, Strategic Compliance, PAREXEL Consulting, USA

Advances in Cleanroom TechnologyWilliam WhyteISBN 978-0-9956666-5-8

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.

At over 500pp, this book is a comprehensive and valuable source book for anyoneinvolved in the design, testing and operation of cleanrooms.

For more information on these and other books and journals published byEuromed Communications visit http://www.euromedcommunications.com/

Euromed booksBooks on pharmaceutical management and clinical research



Trying to do goodAre you a comparatively humbleperson who believes that the worldcan be made a better place, tries todo good and is made happy byevidence that it has been done? Ifyou are, you are a “meliorist”according to the Nobel Laureatescientist Peter Medawar (1915 –1987).

Ends and meansYou wish to improve drug therapysuch as for ovarian cancer. It remainsso common that the lifetimelikelihood for a woman is one inabout 50; I will revisit that disease.The financial model for the Britishpharmaceutical industry is that acompany profits from a newmedicine during the patent periodand that pays for discovery anddevelopment costs of products that,otherwise, might not be invented.Government, during negotiations,achieves some market control bydeciding how much the NHS iswilling to pay, or similar means. Forexample, for wet age-relatedmacular degeneration (AMD), theregulatory authority in the UK onlylicensed Lucentis and Eylea.However, the National Institute forClinical Excellence (NICE) and thehigh court (supreme court appealpending) ruled that the NHS couldsubstitute Avastin — 24 timescheaper. That enables NHStreatment of more patients for thesame money but perhaps patientsand clinicians may become

uncertain whose advice they cantrust.

Of course, any (non-charitable)commercial undertaking requiressome profit to survive. Both partiesnegotiating (the industry andgovernment) sincerely share thesame honourable desired “end(result)”: improvement of people’shealth but use different means toachieve that end. Arguably, anotherperspective is that the “good” oftreating more patients short-termbecomes the “bad” of improvedtherapies being unavailable long-term.

UncertaintyAnother complication churns.Companies may be accused ofdoing harm and suffer expensivelitigation. For example, talc hasbeen claimed to be contaminatedwith asbestos. This contaminationhas always been potentially present;geologically, the two minerals areoften close together. Courts haveawarded damages following claimsthat asbestos-contaminated talc,used genitally, increases the risk ofovarian cancer by 33%. Court casesstimulate such eye-catchingheadlines. They presumably boostmedia circulation. In fairness,academic researchers, who mustfind funding, “the beggars of theuniversities”, also make as much asthey can of their results. However,simple arithmetic, assumptions andapproximations allow a restatementof that relative risk as an absoluterisk of an extra one in about 2,421.

Then, over the oft-quoted five-year,not lifetime, period, a rectangularpictogram of 1,000 icons of womenshows, by shading, that only about0.41 of one woman is affected and,crucially, that all the rest are not.That understanding can be taken inat a glance of the visual field. Theinformed patient could then decidewhether the likelihood was bigenough for concern; individualstolerate risk differently. The 2015edition of the British National RiskRegister of Civil Emergencies wasthe last to quantify likelihoods. Itsuggested that at least a hundredtimes more likely was a flu pandemicor severe space weather such as the“Carrington event” (1859). Thatcaused chaos in telegraphcommunication. It could in today’selectronically-interconnected globalworld including intercontinental just-in-time fragile industrial supplychains.

Some implications are worthhighlighting. Although the Britishgovernment has power to choose toinvest or not, other countries maybe willing to pay more. Taxation andintellectual property rights varyacross countries. Private individualsalso leap to pay especially if novelmedicaments become available.Imagine block-buster “Dorian Gray”or intelligence-boosting drugs. Youcan play your part in safeguardingthat your company is careful and fairin its data presentation, so makingthe world a better place.

Malcolm E Brown

bottled brown



APRIL1– 2 April 2020 – London, UK 13th European BiosimilarsCongress 2020https://biosimilars-biologics.pharmaceuticalconferences.com/europe/

12–14 April 2020 – Lisbon,Portugal5th International Conference onNanomedicine, Drug Delivery,and Tissue Engineeringhttps://nddte.com/

20–22 April 2020 – Munich,Germany14th InternationalPharmaceutical and MedicalDevice Compliance Congresshttps://www.internationalpharmacongress.com/

21–22 April 2020 – Berlin,GermanyVisual Inspection Forumhttps://www.pda.org/global-event-calendar/event-detail/visual-inspection-forum

21–23 April 2020 – Berlin,GermanyGlobal PharmaceuticalRegulatory Affairs Summithttps://informaconnect.com/global-pharmaceutical-regulatory-affairs/

29 April–1 May 2020 –Washington, DC, USA17th Annual PharmaceuticalCompliance Congresshttp://www.cbinet.com/conference/pc20001

29 April–1 May 2020 – Oxon Hill,MD, USAWorld Orphan Drug CongressUSA 2020https://www.terrapinn.com/conference/world-orphan-drug-congress-usa/index.stm

JUNE1–3 June 2020 – Boston, MA, USA2020 ISPE BiopharmaceuticalManufacturing Conference https://ispe.org/conferences/2020-ispe-biopharmaceutical-manufacturing-conference

2–3 June 2020 – Montreal,CanadaPharmaceutical ComplianceCongress Canadahttps://informaconnect.com/pcc-canada-pharmaceutical-compliance-congress/

3–4 June 2020 – Boston, MA, USA2020 ISPE ContinuousManufacturing Workshophttps://ispe.org/conferences/2020-ispe-continuous-manufacturing-workshop

9–10 June 2020 – Dublin, IrelandQuality and RegulationsConferencehttps://www.pda.org/global-event-calendar/event-detail/quality-and-regulations-conference

18–19 June 2019 – Arlington, VA,USA3rd Annual CompoundingPharmacy Compliancehttps://informaconnect.com/compounding-pharmacy-compliance/

24–25 June 2020 – Washington,DC, USA2020 PDA Advanced TherapyMedicinal Products Conference https://www.pda.org/global-event-calendar/event-detail/2020-pda-advanced-therapy-medicinal-products-conference

24–25 June 2020 – Brussels,Belgium2020 PDA Europe AdvancedTherapy Medicinal ProductsConference https://www.pda.org/global-event-calendar/event-detail/advanced-therapy-medicinal-products

eventsMAY13 May 2020 – London, UK4th Annual Global Clinical TrialsConnect 2020https://london.eventful.com/events/4th-annual-global-clinical-trials-connect-2020-/E0-001-129088129-5

18–19 May 2020 – Berlin,Germany 30th Annual European PharmaCongresshttps://europe.pharmaceuticalconferences.com/

18–19 May 2020 – Berlin,Germany22nd Annual European PharmaCongresshttps://www.clocate.com/conference/annual-european-pharma-congress/64205/

18–20 May 2020 – Brussels,BelgiumClinical Trial Supply Europehttps://10times.com/clinical-trial-supply-europe

25–26 May 2020 – Osaka, Japan26th World Congress onNanomaterials andNanotechnologyhttps://nanomaterials.materialsconferences.com/

29–30 May 2019 – Istanbul,Turkey27th International Conferenceon Nanomedicine andNanomaterialshttps://www.vydya.com/events/nano-med-2020/

29–30 May 2020 – London, UK14th World Drug DeliverySummithttps://www.clocate.com/conference/world-drug-delivery-summit/55121/


https://biosimilars-biologics.pharmaceuticalconferences.com/europe/



https://nddte.com/

https://www.internationalpharmacongress.com/

https://www.internationalpharmacongress.com/

https://www.pda.org/global-event-calendar/event-detail/visual-inspection-forum



https://informaconnect.com/global-pharmaceutical-regulatory-affairs/



http://www.cbinet.com/conference/pc20001

http://www.cbinet.com/conference/pc20001

https://www.terrapinn.com/conference/world-orphan-drug-congress-usa/index.stm



https://ispe.org/conferences/2020-ispe-biopharmaceutical-manufacturing-conference



https://informaconnect.com/pcc-canada-pharmaceutical-compliance-congress/






https://www.pda.org/global-event-calendar/event-detail/quality-and-regulations-conference




https://informaconnect.com/compounding-pharmacy-compliance/

https://informaconnect.com/compounding-pharmacy-compliance/

https://www.pda.org/global-event-calendar/event-detail/2020-pda-advanced-therapy-medicinal-products-conference




https://www.pda.org/global-event-calendar/event-detail/advanced-therapy-medicinal-products




https://london.eventful.com/events/4th-annual-global-clinical-trials-connect-2020-/E0-001-129088129-5




https://europe.pharmaceuticalconferences.com/

https://europe.pharmaceuticalconferences.com/

https://www.clocate.com/conference/annual-european-pharma-congress/64205/



https://10times.com/clinical-trial-supply-europe

https://10times.com/clinical-trial-supply-europe

https://nanomaterials.materialsconferences.com/

https://nanomaterials.materialsconferences.com/

https://www.vydya.com/events/nano-med-2020/

https://www.vydya.com/events/nano-med-2020/

https://www.clocate.com/conference/world-drug-delivery-summit/55121/



EIP43 EPSA.qxp Journal 10/03/2020 22:55 Page 1 eur opean ... · pharmaceutical isolators: an...

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Transcript of EIP43 EPSA.qxp Journal 10/03/2020 22:55 Page 1 eur opean ... · pharmaceutical isolators: an...