Schutzkonzept und Einsatz von A Flexible and Scalable ... · Pharm. Ind. 79, Nr. 5, 725–730...

Pharm. Ind. 79, Nr. 5, 725–730 (2017)© ECV • Editio Cantor Verlag, Aulendorf (Germany) Bässler et al. • Isolator Platform 1

Generikum, Biosimilar,NBCD-Similar– eine neueKategorievon NachahmerpräparatenZu den Konsequenzen für die Haftung von Arzt, Apotheker und pharmazeutischem Unternehmer

Dr. Tanja Eisenblätter

Hogan Lovells International LLP, Hamburg

Generika und Biosimilars sind bekannte Kategorien von Nach-ahmerarzneimitteln, die sowohl im Hinblick auf ihre Zulassung alsauch auf ihre Austauschbarkeit aus gutem Grunde unterschiedlichenRegelungen unterliegen. Indes bilden sie die Realität nicht hinrei-chend ab, denn beide Kategorien lassen die Besonderheiten vonNon-Biological Complex Drugs (im Folgenden: NBCD) außerBetracht. Bei diesen Arzneimitteln mit komplexen chemischenStrukturen ist die Herstellung eines identischen Nachahmerprä-parates nur bedingt möglich. Dieses Problem wurde von der EMA ineinem „Reflection paper on non-clinical studies for generic nanop-article iron medicinal product applications“ für generische Eisenprä-parate mit Nanopartikel-Charakteristik jüngst erkannt.1) Im Fol-genden soll erläutert werden, worum es sich bei den NBCD handelt,wie diese rechtlich einzuordnen sind und welche haftungsrecht-lichen Folgen sich für Arzt und Apotheker bei der Abgabe vonNBCD-Similars ergeben.

1. Zum Begri f f derNon-Biological Complex

Drugs Similars(NBCD-Similars)

NBCD-Similars bezeichnen eine Ka-tegorie von Nachahmerpräparaten,die sich in das herkömmlicheSchema von Biosimilars und Gene-rika nicht einfügen lässt. Sie stelleneine neue Form von ähnlichen Arz-neimitteln dar, die keine Generika,aber auch keine Biosimilars sind:

1.1 GenerikaHerkömmliche Generika sind Nach-ahmerpräparate kleinmolekularer

Struktur von chemisch hergestelltenpatentfreien Arzneimitteln.2) Die Ori-ginalarzneimittel basieren auf einereinfachen Molekülstruktur mit gutdefinierten physiko-chemischen Ei-genschaften, sind also „small mole-cules“3), die mit bekannten und defi-nierten Methoden relativ einfach undidentisch hergestellt werden können.

Generika dieser Originalarzneimittelsind identische Kopien des Original-produktes, und für den Generikaher-steller stellt der Herstellungsprozessin der Regel keine Herausforderungdar. Gleichermaßen einfach ist es,nachzuweisen, dass sich Originalarz-neimittel und Generikum qualitativund quantitativ entsprechen, alsobioäquivalent sind. Die Tatsache,dass die Reproduzierbarkeit des Her-stellungsprozesses ebenso unproble-matisch wie die Identifizierungsmög-lichkeit ist, bildet die Basis für denZulassungsprozess von Generikamit „small molecules“.4)

Ein Beispiel für ein klassischesMolekül mit einer einfachen Mole-külstruktur ist das Aspirin (Acetylsa-licylsäure)-Molekül, C9H8O4, mit ei-ner Größe von 180 Dalton und ins-gesamt 21 Atomen. Sowohl Komple-xität als auch räumliche Struktur die-ses Moleküls sind einfach und defi-niert.

1.2 BiosimilarsAnders ist dies bei biologisch pro-duzierten Stoffen, den Biologicalsund ihren Kopien, den Biosimilars.Als Biosimilars bezeichnet man bio-technologisch hergestellte Nach-ahmerpräparate von Biologicals5),

Zur Verwendung m

it freundlicher Genehm

igung des Verlages / For use with perm

ission of the publisher

1) EMA/CHMP/SWP/100094/2011.

2) Rehmann, AMG, 3. Aufl., Vorbem. 4. Ab-schnitt, Rn. 37. Laut Richtlinie 2001/83/ EG„Arzneimittel, die die gleiche qualitative undquantitative Zusammensetzung von Wirk-stoffen und die gleiche Darreichungsform wiedas Referenzarzneimittel aufweisen und derenBioäquivalenz mit dem Referenzarzneimitteldurch geeignete Bioverfügbarkeitsstudiennachgewiesen wurden“.3) Moleküle gelten als „klein“, wenn sie nichtmehr als 500 Atome haben.

4) EMA/CHMP/SWP/100094/2011, Introduc-tion.5) Nach dem Verständnis der EMA. Manspricht auch von Biologika oder Biopharma-zeutika. Im Folgenden wird durchgängig derBegriff Biologicals verwendet.

Pharm. Ind. 74, Nr. 2, 266–276 (2012)© ECV · Editio Cantor Verlag, Aulendorf (Germany) Eisenblätter · Non-Biological Complex Drugs Similars 1

Arzneimittelwesen · Gesundheitspolitik · Industrie und GesellschaftGesetz und Recht

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Schutzkonzept und Einsatz vonIsolatoren beim Umgang mithochwirksamen SubstanzenDr. Torsten Wagner1 und Dr. Michael Pfeil2

Merz Pharma GmbH & Co. KGaA1, Dessau Roßlau, und Merz Pharma GmbH & Co. KGaA2, Reinheim

Eine konsequente Trennung von Personal und Umgebung vomProdukt wird durch Verwendung der Isolatortechnologie erreicht.Durch zusätzliche Kombination eines im Unterdruck betriebenenIsolators in Verbindung mit einem kombinierten Druckstufen- undReinraumkonzept der Isolatorumgebung lassen sich sowohl dieAnforderungen an die Arbeitssicherheit als auch an die cGMP-Richt-linien erfüllen. Dies stellt die Voraussetzung dar, um hochwirk-samste Substanzen bei ständig wachsenden regulatorischen Anfor-derungen sicher herstellen zu können.

Alle Dinge sind Gift, undnichts ist ohne Gift. Allein dieDosis macht’s, dass ein Dingkein Gift ist.

Paracelsus

1. Einleitung

Unter GMP-Aspekten steht derSchutz des Produktes im Sinne derEinhaltung von Sterilbedingungenund der Vermeidung von Kreuzkon-tamination im Mittelpunkt. Bei derVerarbeitung von hochwirksamenSubstanzen dagegen rückt der Ar-beits- und Umweltschutz in den Vor-dergrund. Aus Sicht des pharmazeu-tischen Unternehmers besteht dieHerausforderung darin, beideAspekte in ausreichendem Maßesinnvoll zu berücksichtigen.

Eine Reihe von Maßnahmen stehtzur Verfügung, um ein sicheres Ar-

beiten und eine Überexposition mithochwirksamen Substanzen wäh-rend der Verarbeitung zu vermeiden.Sehr effektive Maßnahmen sind ent-weder die Isolierung des Prozessesdurch Einhausung in geschlosseneEinrichtungen (Isolator, geschlos-sene Arbeitssicherheitswerkbank(„Glove-Box“), RABS-Technologie)oder die Verwendung einer persönli-chen Schutzausrüstung (Vollschutz-anzug, belüfteter Raumanzug). DieAuswahl der notwendigen Sicher-heitsmaßnahmen findet im Rahmeneiner Risikoanalyse statt. Das prakti-zierte Sicherheitskonzept beruht da-bei auf 5 Säulen [1]:. Klassifizierung von Stoffen zurBestimmung der Schutzkategorie,

. Klassifizierung prozessbezogenerRisiken im Pilot- und Produkti-onsmaßstab,

. Ermittlung von Schutzmaßnah-men im Pilot- und Produktions-maßstab,

. Informationsaustausch und Mit-arbeiterschulung und

. Arbeitsplatzmessungen.

2. Schutzkonzept zumUmgang mit hochwirksamen

Substanzen

2.1 Klassifizierung vonStoffen zur Bestimmung derSchutzkategorieFür Wirkstoffe kann basierend aufden vorhandenen toxikologischenund pharmakologischen Daten einsubstanzspezifischer Akzeptanz-bereich festgelegt werden.

Wenn von einem Wirkstoff keinArbeitsplatzrichtwert existiert, sindvom pharmazeutischen Unterneh-men eine Risikobewertung und dieEinstufung in eine Gefährdungs-klasse vorzunehmen. Zur Risiko-bewertung wird der OEL-Wert (Occu-pational Exposure Level) ermittelt[1]. Dieses Konzept ist anwendbarfür bekannte Wirkstoffe, die staub-förmig über die Atemluft in den Kör-per gelangen können und zu derenEigenschaften schon eine umfangrei-che Sammlung toxikologischer, phar-makokinetischer und pharmakologi-scher Daten existiert.

Bei der Festlegung eines Arbeits-platzrichtwertes sind mehrere Fak-toren zu berücksichtigen. Anhandder physiologischen Daten an Men-schen wird je Wirkstoff eine kleinstetherapeutisch wirksame, systemischverfügbare Tagesdosis festgelegt.Über einen Sicherheitsfaktor ergibtsich daraus eine größte duldbare,systemisch verfügbare Tagesdosisfür einen Mitarbeiter.

Die maximale Arbeitsplatzkon-zentration ergibt sich aus der Tages-

Pharm. Ind. 74, Nr. 1, 115–124 (2012)© ECV · Editio Cantor Verlag, Aulendorf (Germany) Wagner und Pfeil · Umgang mit hochwirksamen Substanzen 115

Wissenschaft und Technik

Technik

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Paracelsus

1. Einleitung









Substanzen







Technik


A Flexible and Scalable IsolatorPlatform for State of the Art AsepticProcessingDr. Hans-Jürgen Bässler1, Dr. Friedrich Haefele2, Frank Lehmann1

1SKAN AG, Allschwil, Switzerland, 2Boehringer Ingelheim, Biberach/Riß

This article describes a new way of investing and working withbarrier isolators in a much more flexible way than was previouslypossible. The key point is the interchangeable filling machineequipment for different packaging formats like vials or nestedsyringes that can be complemented with lyophilisation processes.Other process equipment can be mounted on L-flanges, e.g. sterilitytest pumps, bag fillers, stopper bag filling equipment and equip-ment for many other pharmaceutical processes. The compact de-sign of the isolator inside the cleanroom, including the air handlingsystem [11] and switchboards, enables the pharmaceutical industryto have a fast start-up of all needed equipment. The standardisationis another factor to shorten the project time schedule until the startof production for fully qualified equipment.

Introduction

The competitive environment of thepharmaceutical industry is chal-lenged by increased costs and timesfor development, lower chances forsuccess, challenges regarding pricing,reimbursement and lower sales ex-pectations. In this volatile environ-ment, the market for biopharmaceuti-cals is still growing and highly dy-namic. The nature of complex andsensitive large biomolecules requiressafe, flexible and efficient asepticmanufacturing and filling facilitiesfor a variety of systems for parenteraldrug delivery [1].

Innovative therapeutic approachesbeyond monoclonal antibodies(MAbs), patient screening and per-sonalised medicine result in a highvariability of products with relativelysmall batch sizes. The production ofhigh-potency biologics, the conjuga-tion of toxins with antibodies and

their aseptic processing set techno-logical challenges to avoid the risk ofcross-contamination in order to en-sure aseptic processing and to guar-antee the operator’s safety.

Some of these challenges can beaddressed by the use of dedicatedor single-use systems.

For facility construction, thistranslates into the requirement forlate decision points for project kick-off, less upfront capital expenditure,short timelines for project executionand equipment qualification, quickprocess transfer and validation at rel-atively low running costs in compli-ance with increasing quality stand-ards of the industry and the regula-tory authorities.

Improvements in aseptic manu-facturing have led from conventionalcleanrooms to restricted access bar-rier system (RABS) facilities. Themanual wipe-down for disinfection– difficult to reproduce and to docu-

ment – remains a disadvantage formany RABS facilities. RABS requiresignificant cleanroom space and rel-atively high running costs for non-value adding activities like personnelgowning and monitoring [2].

Isolator technology is getting moreand more mature – especially theautomated, reproducible, well-docu-mented system for bio-decontamina-tion is the key for the separation ofthe aseptic process and the operators.Installation of isolators of ISO 5 in anISO 7 environment leads to a smallercleanroom footprint and reduced run-ning costs for gowning and monitor-ing. However, many isolator facilitiesrequire relatively higher upfront cap-ital expenditures and longer change-over times. Changeover time can bereduced by manufacturing largercampaigns of a product over extendedproduction periods.

For small products, today's indus-try requirements like safe asepticprocessing of various parenteraldrug delivery systems, quickchange-over, short project timelinesand relatively low capital expendi-ture are achieved by the modular de-sign of several standard isolators [3]with easy to change filling machines[4] (Fig. 1) on so called L-flangeequipment carriers.

Standard isolator systems are de-signed to dock processing units (e.g.unpacking, filling and stoppering orfreeze-drying and capping) with a de-contamination airlock, or a conven-tional depyrogenation tunnel-/vial-washer combination, to allow trans-fer of sterile materials into the proc-


Technik


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Zur Verwendung m




1) EMA/CHMP/SWP/100094/2011.










Paracelsus

1. Einleitung









Substanzen







Technik







Paracelsus

1. Einleitung









Substanzen







Technik


A Flexible and Scalable IsolatorPlatform for State of the Art AsepticProcessingDr. Hans-Jürgen Bässler1, Dr. Friedrich Haefele2, Frank Lehmann1

1SKAN AG, Allschwil, Switzerland, 2Boehringer Ingelheim, Biberach/Riß

This article describes a new way of investing and working withbarrier isolators in a much more flexible way than was previouslypossible. The key point is the interchangeable filling machineequipment for different packaging formats like vials or nestedsyringes that can be complemented with lyophilisation processes.Other process equipment can be mounted on L-flanges, e.g. sterilitytest pumps, bag fillers, stopper bag filling equipment and equip-ment for many other pharmaceutical processes. The compact de-sign of the isolator inside the cleanroom, including the air handlingsystem [11] and switchboards, enables the pharmaceutical industryto have a fast start-up of all needed equipment. The standardisationis another factor to shorten the project time schedule until the startof production for fully qualified equipment.

Introduction

The competitive environment of thepharmaceutical industry is chal-lenged by increased costs and timesfor development, lower chances forsuccess, challenges regarding pricing,reimbursement and lower sales ex-pectations. In this volatile environ-ment, the market for biopharmaceuti-cals is still growing and highly dy-namic. The nature of complex andsensitive large biomolecules requiressafe, flexible and efficient asepticmanufacturing and filling facilitiesfor a variety of systems for parenteraldrug delivery [1].

Innovative therapeutic approachesbeyond monoclonal antibodies(MAbs), patient screening and per-sonalised medicine result in a highvariability of products with relativelysmall batch sizes. The production ofhigh-potency biologics, the conjuga-tion of toxins with antibodies and

their aseptic processing set techno-logical challenges to avoid the risk ofcross-contamination in order to en-sure aseptic processing and to guar-antee the operator’s safety.

Some of these challenges can beaddressed by the use of dedicatedor single-use systems.

For facility construction, thistranslates into the requirement forlate decision points for project kick-off, less upfront capital expenditure,short timelines for project executionand equipment qualification, quickprocess transfer and validation at rel-atively low running costs in compli-ance with increasing quality stand-ards of the industry and the regula-tory authorities.

Improvements in aseptic manu-facturing have led from conventionalcleanrooms to restricted access bar-rier system (RABS) facilities. Themanual wipe-down for disinfection– difficult to reproduce and to docu-

ment – remains a disadvantage formany RABS facilities. RABS requiresignificant cleanroom space and rel-atively high running costs for non-value adding activities like personnelgowning and monitoring [2].

Isolator technology is getting moreand more mature – especially theautomated, reproducible, well-docu-mented system for bio-decontamina-tion is the key for the separation ofthe aseptic process and the operators.Installation of isolators of ISO 5 in anISO 7 environment leads to a smallercleanroom footprint and reduced run-ning costs for gowning and monitor-ing. However, many isolator facilitiesrequire relatively higher upfront cap-ital expenditures and longer change-over times. Changeover time can bereduced by manufacturing largercampaigns of a product over extendedproduction periods.

For small products, today's indus-try requirements like safe asepticprocessing of various parenteraldrug delivery systems, quickchange-over, short project timelinesand relatively low capital expendi-ture are achieved by the modular de-sign of several standard isolators [3]with easy to change filling machines[4] (Fig. 1) on so called L-flangeequipment carriers.

Standard isolator systems are de-signed to dock processing units (e.g.unpacking, filling and stoppering orfreeze-drying and capping) with a de-contamination airlock, or a conven-tional depyrogenation tunnel-/vial-washer combination, to allow trans-fer of sterile materials into the proc-


Technik



PI7905_Inhalt.indd 725 19.05.2017 09:55:45

4 Bässler et al. • Isolator PlatformPharm. Ind. 79, Nr. 5, 725–730 (2017)

© ECV • Editio Cantor Verlag, Aulendorf (Germany)

Generikum,Biosimilar,NBCD-Similar–eineneueKategorievonNachahmerpräparatenZudenKonsequenzenfürdieHaftungvonArzt,ApothekerundpharmazeutischemUnternehmer

Dr.TanjaEisenblätter

HoganLovellsInternationalLLP,Hamburg

GenerikaundBiosimilarssindbekannteKategorienvonNach-ahmerarzneimitteln,diesowohlimHinblickaufihreZulassungalsauchaufihreAustauschbarkeitausgutemGrundeunterschiedlichenRegelungenunterliegen.IndesbildensiedieRealitätnichthinrei-chendab,dennbeideKategorienlassendieBesonderheitenvonNon-BiologicalComplexDrugs(imFolgenden:NBCD)außerBetracht.BeidiesenArzneimittelnmitkomplexenchemischenStrukturenistdieHerstellungeinesidentischenNachahmerprä-paratesnurbedingtmöglich.DiesesProblemwurdevonderEMAineinem„Reflectionpaperonnon-clinicalstudiesforgenericnanop-articleironmedicinalproductapplications“fürgenerischeEisenprä-paratemitNanopartikel-Charakteristikjüngsterkannt.

1)ImFol-

gendensollerläutertwerden,worumessichbeidenNBCDhandelt,wiedieserechtlicheinzuordnensindundwelchehaftungsrecht-lichenFolgensichfürArztundApothekerbeiderAbgabevonNBCD-Similarsergeben.

1.ZumBegriffderNon-BiologicalComplex

DrugsSimilars(NBCD-Similars)

NBCD-SimilarsbezeichneneineKa-tegorievonNachahmerpräparaten,diesichindasherkömmlicheSchemavonBiosimilarsundGene-rikanichteinfügenlässt.SiestelleneineneueFormvonähnlichenArz-neimittelndar,diekeineGenerika,aberauchkeineBiosimilarssind:

1.1GenerikaHerkömmlicheGenerikasindNach-ahmerpräparatekleinmolekularer

StrukturvonchemischhergestelltenpatentfreienArzneimitteln.

2)DieOri-

ginalarzneimittelbasierenaufeinereinfachenMolekülstrukturmitgutdefiniertenphysiko-chemischenEi-genschaften,sindalso„smallmole-cules“

3),diemitbekanntenunddefi-

niertenMethodenrelativeinfachundidentischhergestelltwerdenkönnen.

GenerikadieserOriginalarzneimittelsindidentischeKopiendesOriginal-produktes,undfürdenGenerikaher-stellerstelltderHerstellungsprozessinderRegelkeineHerausforderungdar.Gleichermaßeneinfachistes,nachzuweisen,dasssichOriginalarz-neimittelundGenerikumqualitativundquantitativentsprechen,alsobioäquivalentsind.DieTatsache,dassdieReproduzierbarkeitdesHer-stellungsprozessesebensounproble-matischwiedieIdentifizierungsmög-lichkeitist,bildetdieBasisfürdenZulassungsprozessvonGenerikamit„smallmolecules“.

4)

EinBeispielfüreinklassischesMolekülmiteinereinfachenMole-külstrukturistdasAspirin(Acetylsa-licylsäure)-Molekül,C9H8O4,mitei-nerGrößevon180Daltonundins-gesamt21Atomen.SowohlKomple-xitätalsauchräumlicheStrukturdie-sesMolekülssindeinfachunddefi-niert.

1.2BiosimilarsAndersistdiesbeibiologischpro-duziertenStoffen,denBiologicalsundihrenKopien,denBiosimilars.AlsBiosimilarsbezeichnetmanbio-technologischhergestellteNach-ahmerpräparatevonBiologicals

5),

Zur V

erwendung

mit fre

undlicher G

enehmigung des Verlages / F

or use

with

permission of

the publish

er

1)EMA/CHMP/SWP/100094/2011.

2)Rehmann,AMG,3.Aufl.,Vorbem.4.Ab-schnitt,Rn.37.LautRichtlinie2001/83/EG„Arzneimittel,diediegleichequalitativeundquantitativeZusammensetzungvonWirk-stoffenunddiegleicheDarreichungsformwiedasReferenzarzneimittelaufweisenundderenBioäquivalenzmitdemReferenzarzneimitteldurchgeeigneteBioverfügbarkeitsstudiennachgewiesenwurden“.3)Molekülegeltenals„klein“,wennsienichtmehrals500Atomehaben.

4)EMA/CHMP/SWP/100094/2011,Introduc-tion.5)NachdemVerständnisderEMA.MansprichtauchvonBiologikaoderBiopharma-zeutika.ImFolgendenwirddurchgängigderBegriffBiologicalsverwendet.

Pharm.Ind.74,Nr.2,266–276(2012)©ECV·EditioCantorVerlag,Aulendorf(Germany)Eisenblätter·Non-BiologicalComplexDrugsSimilars1

Arzneimittelwesen·Gesundheitspolitik·IndustrieundGesellschaftGesetzundRecht

messer (ID), Länge und Wand-stärke (normale, dünne oder ex-tradünne Wandstärke, je nachEinsatzzweck)

. Steifigkeit, Beständigkeit gegen-über Bruch und Korrosion

Bei Pharma- und Medizinproduktenwird der Außendurchmesser der Ka-nüle mit der Einheit „Gauge“ be-nannt, zum Beispiel 22 G, 27 G oder30 G. Gauge ist keine internationaleStandardeinheit, wird aber historischso verwendet. Aus diesem Grund istin der ISO-Norm 9626 neben den me-trischen Größen (mm) auch die Gau-ge-Zahl angegeben.

Je höher die Gauge-Zahl ist, destokleiner ist der Außendurchmesserder Kanüle. 29 G (0,324 mm) ent-spricht also einem kleineren Außen-durchmesser als 27 G (0,400 mm). Jenach Wanddicke der Kanüle ergibt

sich daraus ein entspre-chender Innendurchmes-ser.

Folgende Tab. 1 erläu-tert die Beziehungen zwi-schen den Außendurch-messern und den zur Ver-fügung stehenden Innen-durchmessern. Die Über-sicht beschränkt sich aufdie am häufigsten benutz-ten Kanülenstärken beivorfüllbaren Spritzen.

n 2.3. Design (K 3)Das Kanülendesign für vor-füllbare Spritzen folgt denallgemeinen Begriffen undDefinitionen der ISO-Norm 7864 „Sterile Ein-mal-Injektionskanülen –Anforderungen und Prüf-verfahren“.

Die Abb. 4a und 4b be-schreiben zwei typischeBegriffe von Kanülen:. Außendurchmesser/In-nendurchmesser

. Kanülenlänge (freie Län-ge)


Technik

Pharm. Ind. 77, Nr. 12, 1797–1809 (2015)© ECV • Editio Cantor Verlag, Aulendorf (Germany)1798 Koller und Busimi • Kanülendesign bei vorfüllbaren Spritzen

Abbildung 3: Schnittstellen der Kanüle eines vorfüllbaren Spritzensystems (PFS).

n AUTOR

Horst Kollerarbeitete mehr als 20 Jahre für Abbott Diagnosticund SCHOTT Pharmaceutical Packaging, bevor ersich als Berater selbstständig gemacht hat. SeinBeratungsunternehmen konzentriert sich auf dietechnische, regulatorische und QM-Unterstützungim Bereich von primären und sekundären Ver-packungssystemen einschließlich Medizinproduk-ten. Koller ist ein aktives Mitglied in den tech-nischen ISO-Komitees TC76 und TC84 und eingefragter Sprecher bei internationalen Konferen-zen.

n AUTOR

Anil Kumar Busimibegann seine berufliche Laufbahn 2003 bei derSCHOTT AG in Deutschland, wo er 2005 in denGeschäftsbereich Pharmaceutical Packagingwechselte. Hier war er eine treibende Kraft bei derstrategischen Unternehmensentwicklung undbeim Aufbau der Business Intelligence für das Ge-schäftsfeld Pharmaverpackungen. Von Aug. 2009bis Nov. 2011 war Busimi Global Product Managerfür SCHOTT TopPac® (COC-Spritzen) und ist seitDez. 2011 Leiter Global Product Management Sy-ringe Business.

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n AUTOR



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flange is movable on casters, whichcan be fixed. Guiding pins on the iso-lator assure that the flange is in thecorrect position before docking.

Being in position, the L-flange issealed with an inflatable gasket(Fig. 3) to the isolator. Other transfersystems for isolators are described in[9].

Ready to Use (RTU) PackagingMaterial

The isolator concept works effi-ciently in combination with ready-to-use vials and syringes. Glass andplastic packaging material which iswashed, depyrogenated, sterilisedand packed under aseptic conditionsis available on the market. Stoppersand caps in sterilised bags are also

available ready to use in bags with orwithout RTP connector.

In the future, all packaging mate-rial of ready-to-use products needs tobe H2O2 resistant for the usage in fastdecontamination airlocks. This is amandatory requirement for all sub-stances sensitive to oxidising prod-ucts which are to be handled in theisolator.

The major advantage of the RTUmaterial is to avoid material han-dling systems like washer and depyr-ogenation tunnels. This saves capitalinvestment and recurrent cost aswell as maintenance and qualifica-tion efforts.

Semi-automatic Vial Fi l l ing

The necessary filling equipment(Fig. 4), including tools and monitor-ing material and packaging materialfor the first filling steps, is installedon the L-flange (Fig. 2 – right) andafterwards brought into the isolator(Fig. 5, step 1). The isolator is thendecontaminated with the integratedH2O2 system. In parallel, the airlockcan be loaded with additional pack-aging material (Fig. 5, step 2). Afterthe successful decontamination, thefilling can start in the main chamberand the additional material is await-ing its use in the airlock. In a firststep, the packaging material is un-packed, (Fig. 5, step 3) and filled(Fig. 5, step 4). Stoppers and crimpscan be aseptically entered via an RTPin the back wall of the L-flange orthrough the rapid airlock. Stoppersand crimps can be put on the vialsmanually or semi-automatically(Fig. 5, steps 6 and 7). After closing,the finished products can be storedin a tray and later on forwarded tofurther steps through a mouse hole,a second air lock or a bag-out sys-tem. [9]

For the aseptic toxic isolator de-sign, one operator can fill, stopperand seal approx. 180 vials per hour.The non-toxic isolator can be oper-ated by 2 workers and can reach ap-prox. 360 vials per hour.


Technik

Pharm. Ind. 79, Nr. 5, 725–730 (2017)© ECV • Editio Cantor Verlag, Aulendorf (Germany)728 Bässler et al. • Isolator Platform

Figure 3: Isolator chamber view during thechange of the L-flange. The inflatablegasket is highlighted in red.

Figure 4: Semi-automatic filling equipment in the isolator withrapid airlock (Sources of Figures 4 and 7: Bausch+Ströbel Ma-schinenfabrik Ilshofen GmbH+Co. KG).

Figure 5: Manual or semi-automatic filling equipment in theisolator with rapid airlock (Source of Figures 5, 6, 8: FrankLehmann).

Zuletzt gesichert auf O:\ECV\Pharmind\PI_05_2017\PI7905_Inhalt.indd · 18. Mai. 2017 (08:44:12) Zuletzt gesichert auf O:\ECV\Pharmind\PI_05_2017\PI7905_Inhalt.indd · 18. Mai. 2017 (08:44:12)

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ess. The combination of these flexibleisolators with ready-to-use (RTU)components, which is a well-estab-lished technology for pre-fillable sy-ringes that is now also available forvials and cartridges, allows furtherreduction of the cleanroom footprintand up-front capital expenditure aswell as rapid product changeover.The isolators can be operated inoverpressure or low pressure modewith easy to change filters [5] for air-borne particles in the air return ductsto make them ready for high potencydrug processing.

Modular Isolator and RapidAirlock

The pharmaceutical safety isolatorwith removable L-flange is a modularisolator system with a unique L-shaped flange, which allows workingequipment and machinery to be ex-changed very quickly. Due to a shortdecontamination cycle and optionalreturn air filters, the isolator is a uni-versal, sterile workspace for asepticprocesses with highly active pharma-ceutical ingredients (API). Automaticfilling and closing machines speciallydesigned for the isolator give a widerange of applications.

Materials of Constructionand Dimensions

Themodular isolator is basically con-structed from a stainless steel 316L

chamber, SS 304 (support structure)and safety glass. These materialshave proven to have the best proper-ties for the H2O2 decontamination[6]. The material is free from cracksand crevices. The corners of thechamber are rounded and the insideis polished to Ra 0.8mm and 1.2mmoutside.

The working chamber of the basicisolator module is 2 m wide, up to1 m deep and 1 m high. This sizeprovides room for 4 to 5 glove/sleeveassemblies made from CSM andtranslucent PVC for the manual in-teraction of the operator with the fill-ing equipment. The overall dimen-sions of the module are 2 x 1.2 x2.9 m. A room height of 2.9 m(9.5 ft) is desired for installing theequipment. The rapid H2O2 airlockis an amendment to the basic isola-tor and is made from the same ma-terial.

Air Handling

The basic isolator module holds allnecessary infrastructure to createand maintain the desired pressureand airflow as well as the fully inte-grated H2O2 decontamination sys-tem. The airflow in the workingchamber is unidirectional down-wards with a speed of 0.45 m/s toreach an excellent air distributionwithin the chamber. The make-upair is taken from the environmentalroom via a pre-filter to the inletHEPA H14, which covers the whole

ceiling of the isolator chamber. IfAPIs are handled, safe changeable fil-ters in the return air are available.These filter cartridges (FiPa) aremounted in such a way that neitherthe safety of the operator nor theenvironment are compromised dur-ing replacement [5]. After passing theexhaust filter, the air is recirculated;15–20 % is released to the air ex-haust. For aseptic operation, thechamber is kept in overpressurereaching 50–100 Pa. This pressurerange guarantees that the pressuredoes not drop to a critical value dur-ing manual operation There is also apossibility to run the isolator in neg-ative pressure, if required.

The air in the rapid airlock ishandled differently. Coming fromthe environmental room via a pre-filter, the air passes a HEPA H14 inthe ceiling of the chamber and cre-ates a unidirectional flow in thechamber. After flowing through theH14 exhaust HEPA, the air leavesthe airlock via the exhaust duct.There is no air return in the rapidairlock.

Decontamination System

To assure the decontaminated statusin the isolator, it is necessary to treatthe isolator with an adequate spori-cidal decontamination system. Thedecontamination of isolators withhydrogen peroxide is widely used inthe pharmaceutical industry [7]. Theintegrated H2O2 decontamination iscontrolled by the isolator PLC andconsumes H2O2 in a concentrationof 35 % with an amount of approx.120 g per cycle in one isolator cham-ber. The cycle in the main chamberincludes leak testing and aeration toa level of 1.0 ppm H2O2 in the isolatorair. The H2O2 is pumped from a dos-ing station to the evaporator plate inthe air handling system above themain chamber. Here it is flash-evapo-rated, taken by the blower and passesthe inlet HEPA filter to the mainchamber where it is evenly distrib-uted by means of a directed air


Technik


Figure 1: Rapid H2O2 airlock with two modular isolators, built-invial filling, stoppering module and freezer loading, unloadingsystem (Source of Figures 1–3: SKAN AG).


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ess. The combination of these flexibleisolators with ready-to-use (RTU)components, which is a well-estab-lished technology for pre-fillable sy-ringes that is now also available forvials and cartridges, allows furtherreduction of the cleanroom footprintand up-front capital expenditure aswell as rapid product changeover.The isolators can be operated inoverpressure or low pressure modewith easy to change filters [5] for air-borne particles in the air return ductsto make them ready for high potencydrug processing.

Modular Isolator and RapidAirlock

The pharmaceutical safety isolatorwith removable L-flange is a modularisolator system with a unique L-shaped flange, which allows workingequipment and machinery to be ex-changed very quickly. Due to a shortdecontamination cycle and optionalreturn air filters, the isolator is a uni-versal, sterile workspace for asepticprocesses with highly active pharma-ceutical ingredients (API). Automaticfilling and closing machines speciallydesigned for the isolator give a widerange of applications.

Materials of Constructionand Dimensions

Themodular isolator is basically con-structed from a stainless steel 316L

chamber, SS 304 (support structure)and safety glass. These materialshave proven to have the best proper-ties for the H2O2 decontamination[6]. The material is free from cracksand crevices. The corners of thechamber are rounded and the insideis polished to Ra 0.8mm and 1.2mmoutside.

The working chamber of the basicisolator module is 2 m wide, up to1 m deep and 1 m high. This sizeprovides room for 4 to 5 glove/sleeveassemblies made from CSM andtranslucent PVC for the manual in-teraction of the operator with the fill-ing equipment. The overall dimen-sions of the module are 2 x 1.2 x2.9 m. A room height of 2.9 m(9.5 ft) is desired for installing theequipment. The rapid H2O2 airlockis an amendment to the basic isola-tor and is made from the same ma-terial.

Air Handling

The basic isolator module holds allnecessary infrastructure to createand maintain the desired pressureand airflow as well as the fully inte-grated H2O2 decontamination sys-tem. The airflow in the workingchamber is unidirectional down-wards with a speed of 0.45 m/s toreach an excellent air distributionwithin the chamber. The make-upair is taken from the environmentalroom via a pre-filter to the inletHEPA H14, which covers the whole

ceiling of the isolator chamber. IfAPIs are handled, safe changeable fil-ters in the return air are available.These filter cartridges (FiPa) aremounted in such a way that neitherthe safety of the operator nor theenvironment are compromised dur-ing replacement [5]. After passing theexhaust filter, the air is recirculated;15–20 % is released to the air ex-haust. For aseptic operation, thechamber is kept in overpressurereaching 50–100 Pa. This pressurerange guarantees that the pressuredoes not drop to a critical value dur-ing manual operation There is also apossibility to run the isolator in neg-ative pressure, if required.

The air in the rapid airlock ishandled differently. Coming fromthe environmental room via a pre-filter, the air passes a HEPA H14 inthe ceiling of the chamber and cre-ates a unidirectional flow in thechamber. After flowing through theH14 exhaust HEPA, the air leavesthe airlock via the exhaust duct.There is no air return in the rapidairlock.

Decontamination System

To assure the decontaminated statusin the isolator, it is necessary to treatthe isolator with an adequate spori-cidal decontamination system. Thedecontamination of isolators withhydrogen peroxide is widely used inthe pharmaceutical industry [7]. Theintegrated H2O2 decontamination iscontrolled by the isolator PLC andconsumes H2O2 in a concentrationof 35 % with an amount of approx.120 g per cycle in one isolator cham-ber. The cycle in the main chamberincludes leak testing and aeration toa level of 1.0 ppm H2O2 in the isolatorair. The H2O2 is pumped from a dos-ing station to the evaporator plate inthe air handling system above themain chamber. Here it is flash-evapo-rated, taken by the blower and passesthe inlet HEPA filter to the mainchamber where it is evenly distrib-uted by means of a directed air


Technik


Figure 1: Rapid H2O2 airlock with two modular isolators, built-invial filling, stoppering module and freezer loading, unloadingsystem (Source of Figures 1–3: SKAN AG).


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1) EMA/CHMP/SWP/100094/2011.





ständig dekontaminiert betreten wer-den. Die CIs zeigen nach dem Prozesssofort an, ob die Begasung den ent-sprechenden Erfolg erbracht hat, dabei diesen ein Farbumschlag stattfin-det, wenn sie einer bestimmtenMenge Wasserstoffperoxid über einebestimmte Zeit ausgesetzt waren. DieBIs müssen jedoch bebrütet werden,um ein Wachstum dieser Sporen aus-zuschließen und somit denDekontaminationserfolgbei diesen Sporen zu bele-gen. Mithilfe der Sporenwird ein Worst-Case-Sze-nario im Raum simuliert,da die Sporen nur sehrschwer abzutöten sind. Dadiese Sporen erst bei einerTemperatur von ca. 54 °Cwachsen können, ansons-ten aber gegenüber her-kömmlichen Desinfekti-onsmitteln sehr resistentsind, stellen diese Indikato-ren eine sichere Qualitäts-kontrolle dar. Zudem wirddas Handling im Labor ver-einfacht, da Hautkeime beidieser Temperatur nichtwachsen und somit auchbei nicht aseptischer Ar-beitsweise keine falsch po-sitiven Resultate vorkom-men. Man kann also davonausgehen, dass bei einemfehlenden Wachstum derSporen auch die evtl. vor-handene Kontaminationim Raum eliminiert wurde.

Der bisher dargestellteProzess sorgt für eine er-folgreiche Dekontaminati-on. Der Einsatz zusätzlicherQualitätskontrollmaßnah-men wie Abklatsche undLuftkeimsammlungen sol-len sicherstellen, dass sichdas Personal, welches dieDekontamination durch-geführt hat, richtig mit derentsprechenden Schutzklei-dung eingeschleust und sichkorrekt im Reinraum ver-halten hat. Dies verlangt,dass das Dekontaminati-

onspersonal auch die entsprechendenSchulungen durchlaufen hat. Geradedieser Punkt wird oft vernachlässigt.

Die Begasung mithilfe von H2O2

reduziert somit nachweisbar die Ri-siken der manuellen Desinfektion.Gerade in komplexen Räumen odernach Neu- und Umbauten führt dieseTechnologie zu einem signifikantbesseren Desinfektionserfolg, da alle

vorhandenen und sichtbaren Ober-flächen dekontaminiert werden [5].

Nicht zu vernachlässigen ist eben-falls die Gesundheit der Mitarbeiter.Der Einsatz von H2O2-Biodekontami-nationstechnologien kann die Benut-zung von Sporizid-Lösungen in derRoutine vermeiden. Bei einer manu-ellen Desinfektionsreinigung für eineRequalifizierung wird der Mitarbei-

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STERIS Deutschland GmbH

www.STERISLifeSciences.com

Eupener Str. 70 • D-50933 Köln

Tel.:+49 (0)221-46 61 20 • Fax:+49 (0)221-46 61 20 40

E-Mail: [email protected]

Life Sciences Group

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Die effektive Alternative:

Raumbegasung mit VHP statt Formalin

PI7711.indd 1679 19.11.2015 14:38:31

flow. Two isolator chambers can bedecontaminated independently, if adoor is installed between both.

The cycle in the rapid airlock ismuch shorter due to the fact thatH2O2 is directly evaporated into thechamber. Since there is no recircula-tion air, the aeration is much fasterthan in the main chamber. Depend-ing on the load, a cycle time of 15–30 min including leak test and com-plete aeration to 1.0 ppm H2O2 canbe reached.

Physical and microbiologicalmonitoring is a relevant part of theaseptic working or filling process. Inthe isolator, temperature, pressuredifferential to the surroundingroom, air velocity, relative humidity,particulates close to the filling proc-ess are the physical parameterswhich are continuously measuredand recorded. To assure the decon-taminated status, a sophisticated mi-crobiological monitoring programmeshould be established. This pro-gramme comprises the measure-ment of airborne viable count, thesurface sampling with RODAC-Casoplates or the swabbing of areas in theprocess equipment which are diffi-cult to access.

Isolator Design for ActiveSubstances

In the pharmaceutical industry,highly active pharmaceutical ingre-dients will become increasingly im-portant, making safe product han-dling and operator protection essen-tial. Therefore, barrier isolators withstate-of-the-art safe filter systems areneeded to meet these requirements.For working with APIs, there is anisolator version available with safechange filter cartridges in the returnair duct [5]. The filter is a safe andconvenient changeable cartridge foraseptic toxic barrier isolators, basedon continuous design improvements.Filter cartridges are suitable for theretention of airborne particles andairborne viables, for example fromliving vaccines based on viruses or

bacteria. The substances, removedfrom the process air, are capturedin the cartridge. Due to its small di-mensions, the cartridge is mountedclose to the working chamber of thecontainment, thus restricting thecontaminated zone to the smallestpossible area. Cleaning of return airand exhaust air ducts is not neces-sary.

Four parallel filters are installedright and left upstream of the isola-tor. The arrangement allows the re-moval of so much air from the work-ing zone that the unidirectional flowin the chamber is maintained. Thefilter cartridges ensure a distinct par-tition between the return air systemand the contaminated area of thecontainment chamber. After passingthe filter cartridges, the air is col-lected in the base frame of the iso-lator and passed in a vertical duct onthe backside to the recirculation sec-tion of the isolator. The version of theisolator with additional filters in therecirculation air is suitable for usewith manual spray guns and wetwash-down cleaning.

The integrity of the isolator, thesleeves and the gloves should be fre-quently monitored during asepticoperation [7]. Therefore, the isolatorhas an inbuilt integrity test anteced-ent to each decontamination proc-

ess. The integrity of the gloves ischecked with a wireless glove testingdevice, which allows the independenttesting of several gloves on site with apressure decay test at a test pressureof at least 2000 Pa. The test should beperformed before each filling cycle.

Removable Standard L-f lange

The removable flange in L-shape(Fig. 2 – left) will be delivered as anempty flange, which can be used fordifferent purposes or changed to thespecific needs of the customer proc-esses. Back wall, base frame andworkbench can be fitted with indi-vidual laboratory equipment suchas scales, incubators, mixers, sensorsetc. Electrical connections and pipesfor compressed air, nitrogen, liquidsas well as pipes for particulate andairborne viables testing can be at-tached upon request. Large processequipment like freezers, vacuum dry-ers, autoclaves and hot air ovens canbe interfaced with sealed flanges.

In the floor, compounding vesselsup to 100 l can be attached to a splitbutterfly valve, connected freely withRTP or fixed to the floor.

Depending on its use, the backwall of the flange can be straight orbuilt with a recess. Moreover, the


Figure 2: Left: changeable L-Flange on casters (fit into isolator back wall and floor).Right: Vial filling and stoppering machine, type Variosys [10].


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Tel.:+49 (0)221-46 61 20 • Fax:+49 (0)221-46 61 20 40


Life Sciences Group

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PI7711.indd 1679 19.11.2015 14:38:31

Automated Vial Fi l l ing withLyophil isat ion Process

The filling of vials in different sizeswith a subsequent lyophilisationprocess can be performed with 2 iso-lator modules in line and a rapid air-lock. In the first module, the fillingmachine is installed on the L-flange.On the second module, a lyophiliseris attached. All necessary materialsfor the filling process, like vial stop-pers, tools and monitoring material,are loaded into the rapid airlock(Fig. 6, step 1). After a valid decon-tamination cycle, the material can beunloaded into the first isolator mod-ule where it is unpacked (Fig. 6,step 2). The empty vials are manuallytransferred to a rotary table, filledand the stopper is set for lyophilisa-tion (Fig. 6, steps 3 and 4). The stop-pered vials are moved to the secondisolator module where they are set ina lyo frame and pushed manuallythrough the so called “pizza door”in the lyo shelves (Fig. 6, steps 5and 6). Standard sizes are availablein 1.5 m2, 4.5 m2 and 11 m2 and twocan stand next to each other. Afterthe lyo process the vials are closed inthe lyophiliser and manually re-moved. In the third module, a capperis installed where the vials arecrimped (Fig. 6, step 7). Finally,they leave the isolator through amouse hole on the right side(Fig. 6, step 8).

The filling line and the capper areremovable from the isolator mod-ules. Hence, this module combina-

tion can also be used for the follow-ing application.

Automated Processing ofTUBs with Syringes ,Cartr idges or Vials

The automatic, aseptic filling of sy-ringes in tubs (Fig. 7) can be per-formed with a special arrangementon the isolator. For this application,a rapid airlock and 2 isolators aremounted in line. The filling line isinstalled in the second module.

The rapid airlock is loaded withthe necessary syringes in tubs andpre-sterilised stoppers in a bag(Fig. 8, step 2) and is then decontami-nated. After completion of the shortdecontamination cycle, the tubs andstopper bags are transferred to thefirst chamber where the outer foil is

being removed (Fig. 8, step 3). After-wards, the Tyvek® layer is pulled off(Fig. 8, step 4) and the loose coversheet is removed manually (Fig. 8,step 5). The open tub is now trans-ferred to the second chamber and thewaste is fed back to the airlock fromwhere it is discarded.

In the second chamber, the sy-ringe nest is lifted out of the tub bya robotic device (Fig. 8, step 6), thesyringes are filled with the definedamount (Fig. 8, step 7) and the stop-pers are placed (Fig. 8, step 8). Beforeleaving the isolator via a mouse hole,the syringe nest is relocated in its tub(Fig. 8, step 9). The tub is transferredwith a conveyor to the mouse hole onthe right side in order to leave theisolator.

As an alternative to the tub trans-fer through the rapid airlock, a tubunpacking station can be installed at


Figure 6: Standard isolators with installed vial filler, lyophiliser including automatic loading/unloading unitand capping machine.

Figure 7: Fully automated nested syringe filling machine typeVariosys [10] moved into the modular isolator.


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1) EMA/CHMP/SWP/100094/2011.
















Tel.:+49 (0)221-46 61 20 • Fax:+49 (0)221-46 61 20 40


Life Sciences Group

®

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PI7711.indd 1679 19.11.2015 14:38:31


Integration of Atec bagging machine within an interchangeable PSI-L Isolator Flange Atec and Skan have teamed together to offer a compact, innovative solution for safe packaging of product contact parts under an aseptic, isolated environment. It combines Atec’s bagging machine with Skan’s versatile PSI-L flange to deliver a customized packaging process requiring minimal operator intervention.

How It Works: An Automated Process Components are transferred into the isolator through an RTP-Port and fall onto a vibratory chute. The operator is required only to attach a bag to the equipment. Bag opening, component dosing, bag closing and bag welding is completed automatically. After the bag is filled and sealed it falls into a container that transfers the bag out of the isolator.

The filling process is weight-controlled and achieved using vibrational frequencies to dose a range of comodities: e.g. Aluminum Seals, Plungers or Stoppers. For applications where high-accuracy is needed, filling accuracy can be achieved down to ± 5g.

The equipment can be designed to accommodate a range of different bag sizes. Larger bags feature a tipping function for discharging the bag out of the isolator.

SKAN Pharmaceutical Safety Isolator (PSI), integrated with bagging flange for packaging sterile parts

Atec Bag Filling Equipment (BFE), integrated into a PSI-L flanged isolator

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This trolley system enables pharmacists to fill and close IV bags under aseptic conditions. Different closing technologies for filled bags can be used. The VarioSys bag filling machine is equipped with a mass flow filling system and fulfills highest accuracies and can be integrated into a fully automated and monitored CIP-SIP system. It fits into the standard PSI-L isolator from SKAN. An integrated suction unit evacuates the bag prior to the filling process or removes the product afterwards. A waste collection container with automatic reject is included. The bags can be purged by using nitrogen or argon. There is an optional connection station for semi-automatic application of the ports for bag closing. All pipe connections are in accordance with DIN 11864-1/3 and other connection types are possible upon request.

Customized filling equipment for IV bags, tubes or aseptic handlingCustomized filling equipment for IV bags, tubes or aseptic handling

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PI7905_Inhalt.indd 731 19.05.2017 09:55:49














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Life Sciences Group

®

VHP Technologie



PI7711.indd 1679 19.11.2015 14:38:31








Anzeige



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PI7905_Inhalt.indd 731 19.05.2017 09:55:49














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1) EMA/CHMP/SWP/100094/2011.
















Tel.:+49 (0)221-46 61 20 • Fax:+49 (0)221-46 61 20 40


Life Sciences Group

®

VHP Technologie



PI7711.indd 1679 19.11.2015 14:38:31








Anzeige



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PI7905_Inhalt.indd 731 19.05.2017 09:55:49














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1) EMA/CHMP/SWP/100094/2011.
















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PI7711.indd 1679 19.11.2015 14:38:31








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PI7905_Inhalt.indd 731 19.05.2017 09:55:49

State-of-the-art freeze-dryers and automatic loading and unloading systems have been specifically developed to fit into the modular concept. Freeze-dryers are available in the standard sizes of 1.5 m², 4.5 m² and 11 m². All these systems comply with the GMP requirements. This small series has the same quality and functionalities as the company's custom-made isolators. They can be complemented with mass spectrometers, that can be used as a PAT (Process Analytical Technology) device or for the detection of impurities such as micro leaks of silicon oil within the freeze-dryer.

Pharmaceutical freeze-dryers

Figure: Fully automated loading and unloading system for a modular standard freeze-dryer (source of figure: GEA Lyophil GmbH)

Figure: Freeze-dryer shelves (source of figure: GEA Lyophil GmbH)

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the rear of the isolator, in which tubsare unpacked semi-automaticallyunder a unidirectional airflow(Fig. 8, step 1). An automatic bag cut-ting machine opens the outer bag ofthe tub and an operator pushes thetub out of the bag into the prepara-tion section of the isolator. The bag isleft outside the isolator and is dis-carded. Then the process continuesas depicted in Fig. 8, step 4. The ad-vantages are less waste material in-side the work chamber and no needfor additional waste process stepswith beta-bags connected on RTPports. This configuration can reacha line speed of 4200 syringes perhour (twin headed).

Summary and Outlook

For filling of vials and syringes, 3 dif-ferent filling line approaches that canbe realised in a modular adaptable,multifunctional isolator platform aredescribed. All of them can be realisedwith one aseptically operated isola-

tor in a class D environment. The L-shaped flange allows the fast change-over from vial filling to syringe fillingusing the same high-end aseptic con-tainment. The short decontamina-tion cycle and the optional returnair filter (FIPA) make it a universalsterile workspace for filling and proc-essing of aseptic and/or highly APIs.Operator and environment are pro-tected from hazardous materialprocessed inside the isolator.

The available semi- and fully auto-mated filling equipment allows anoutput of RTU or bulk vials reachingfrom 180 up to 35000 objects per8.5 hour shift, depending on objectsize and the automation grade of allmachines used.

Other applications like ampoulefilling, carpule filling, compoundingand formulation, stopper refilling[11] and machines for other packag-ing containers are in preparation orat concept stage. For the filling andclosing of vials and syringes, for smallbatches, clinical trials or very expen-sive drugs like cytotoxins and pro-

duction start-up periods, the modu-lar isolator is an easy to operate andeconomical alternative to conven-tional cleanroom operation and cus-tom-made filling lines with isolator.

n REFERENCES

[1] Haefele, F. Isolators: best practice foraseptic processing – a solution only forlarge product manufacturing? ECA acad-emy conference, 26.03.2014, Germany.

[2] Bässler, H.-J. and Lehmann, F. Contain-ment Technology 50–51, Springer: Berlin,Heidelberg (2013).

[3] Brochure, modular and flexible produc-tion Isolator, SKAN AG, 2014.

[4] Wieland, B. Presentation Variosys: flexi-ble filling machines for modular Isolators,Bausch+Ströbel, 2013.

[5] Lehmann, F. and Lümkemann, J. SafeChange Filter Systems for Containmentsin the Pharmaceutical Industry. PharmInd. 2011 Sept;73(9):1683–94.

[6] Sigwarth, V. and Stärk, A. Effect of CarrierMaterials on the Resistance of Spores ofBacillus stearothermophilus to GaseousHydrogen Peroxide. PDA J Pharm SciTechnol. 2003 Jan–Feb;57(1):3–11.

[7] Sigwarth, V. et al. Dekontaminationspro-zesse und -systeme bei der Abfüllunggenesteter Fertigspritzen. Pharm Ind.2008 Oct;70(10):1277–88.

[8] Gessler, A., Stärk, A., Sigwarth, V., Moir-andat, C. How Risky Are Pinholes inGloves? A Rational Appeal for the Integ-rity of Gloves for Isolators. PDA J PharmSci Technol. 2011 May–Jun;65(3):227–41.

[9] Bässler, H.J. and Lehmann, F. AsepticTransfer Systems into and out of BarrierIsolators and RABS. TechnoPharm 2013Jan;3(1):20–7.

[10] Bullinger, T. Beliebig kombinierbar,www.neue-verpackung.de, (2014).

[11] Ruffieux, P. PSI-L Isolator Platform, ISPENordic conference, Denmark (2016).

Correspondence:Frank LehmannSKAN AGBinningerstr. 1164123 Allschwil (Switzerland)e-mail: [email protected]


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Figure 8: Standard isolator with an unpacking area and the filling machine for nestedsyringes.


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Chefredaktion: Claudius Arndt. Sekretariat: Gudrun Below. Verlag: ECV · Editio Cantor Verlag für Medizin und Naturwissenschaften GmbH, Baendelstockweg 20,88326 Aulendorf (Germany). Tel.: +49 (0) 75 25 94 00, Fax: +49 (0) 75 25 94 01 80. e-mail: [email protected]. http://www.ecv.de. Herstellung: Reemers Publishing ServicesGmbH / Holzmann Druck GmbH & Co. KG. Alle Rechte vorbehalten.

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