Industry experiences on multilingual packaging material for human &

veterinary medical products licensed through CP/DCP/MRP and National

Procedure (incl. CTAs)

Dr. Elke Hofer-LitzlbauerDr. Vladislav Kurtev

TOPRA in Austria, Vienna, 1st December 20111

Introductions

Dr. Elke Hofer-Litzlbauer• graduated in Natural and Medical Sciences• active in Regulatory Affairs since 2006• TOPRA MSc in Regulatory Affairs

Dr. Vladislav Kurtev• graduated in Natural Sciences• active in pharmaceutical industry since 2004, Regulatory

Affairs since 2008

The information presented and opinions expressed herein are those of the presenters and do not represent the view of any employer or

TOPRA. 2

Agenda

• Introduction - Importance & Role of Labelling• Overview - MAA procedures & labelling requirements• National requirements & mandatory elements in AT,

DE, CH• Labelling in non-EEA countries• QRD• Clinical Trials & labelling• Variations• Multilingual labelling – why?, pro‘s & con‘s• Innovative labelling solutions• Experiences, Do‘s and Don‘ts & Recommendations

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Packaging – then and now

© Dt. Apotheken Museum Stiftung

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Pharmaceutical Packaging“A big market”

• $ 46- 47.2 billion globally• Growing at 5.5% - 6.3% annually • Western Europe, US & Japan → 70% • Fastest growing markets: China, India and

Brazil• Products responsible for growth in Pharma:

– Inhalers & syringes (prefillable), Unit dose, Wallets and „sophisticated“ packs

[source: World Pharmaceutical Packaging, The Freedonia Group]5

Importance of labelling

• „Labelling is everywhere“[Ref.: EC, Unit E4 – Food law, nutrition &labelling, Dec 2006]

• Labelling does not end with its approval

• Changes to labelling are part of product lifecycle

• Post approval labelling changes might pose serious challenges

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The role of packaging“Why is proper packaging so important?”Products need to be packaged – clear regulations

• Preserve & Protect

• Promote safety

• Consumer/ patient friendly

but most importantly:

• Provide information – communication tool(manufacturer, product, strength, dosageform, storage conditions,) – the company‘s„voice“ 7

Changing environment“What challenges are we facing?”

• Sensitive drugs with critical packaging needs– Prefilled inhalers– Prefilled syringes – Infusion bags

• Changing regulatory environment– e.g. readability, stringent timelines, quality of

translations, braille, anti-counterfeiting,…

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Consequences of poor packaging/ (multi-) labelling

• Injuries/ death resulting from confusion• Poorly identifying products• Incorrect IFU - inappropriate use • Misdosing• Inconsistencies in translations (misleading

info/ confusion)• Inappropriate storage conditions

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Consequences of poor packaging/ (multi-) labelling

• Injuries/ death resulting from confusion• Poorly identifying products• Incorrect IFU - inappropriate use • Misdosing• Inconsistencies in translations (misleading

info/ confusion)• Inappropriate storage conditions

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Product recalls“From a labelling perspective…”

• Incorrect labelling

– Spelling errors, typos

• Noncompliance with (local) regulatory

requirements

[Ref.: presenation Chris Waterhouse, Idipac, Cork, June 2010]

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MAA procedures“Different requirements for labelling?”

• Centralized Procedure

• DCP/MRP

• National Procedure

• Clinical Trial Applications

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Centralized Procedure“Current regulatory framework”

• Directive 2001/83/EC as amended, Article 11 and Title V – Article 54vet.: Directive 2001/82/EC as amendedRegulation (EC) Nr. 726/2004 as amended

• Guideline on the readability of labelling and package leaflet…http://ec.europa.eu/health/files/eudralex/vol-2/c/2009_01_12_readability_guideline_final_en.pdf

• Guideline on SmPChttp://ec.europa.eu/health/files/eudralex/vol-2/c/smpc_guideline_rev2_en.pdf

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Centralized Procedure“Daily practice”

• No flexibility for labelling material – no deviations from the English final version allowed

• Mandatory use of QRD templates (& QRD convention)

• Strict & pre-defined timelines

• Centralized submission of PI to EMA in one go (no national submissions)

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Decentralised & Mutual Recognition Procedure• Directive 2001/83/EC as amended, Article 11

and Title V – Article 54vet.: Dir. 2001/82/EC as amended

• Guideline on the readability of labelling and package leaflet…http://ec.europa.eu/health/files/eudralex/vol-2/c/2009_01_12_readability_guideline_final_en.pdf

• Submission in English language• Revisions / corrections

– Part of LoQ– National requirements also possible

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DCP/MRP – National Phase„What happens after EoP?“

• One starting point, but independent submission in individual countries

• Guidelines/Best Practice Guides:– Translations within 5 days after EoP

• QRD convention strongly recommended• CA requests:

– Confirm Intent to Market & submission of national translations

– If not: MA issued without PI, subsequent variation necessary prior to marketing

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National Procedures„Are national procedures different?“

• Subject to national legislation• 210-day timeline for completion• PI as part of submission• During procedure

– e.g. AT: PI split into individual SmPC, PIL & Label

• Multiple rounds of revision (contradictory requests from separate assessors)

Ref.: http://www.basg.at/arzneimittel/faq/fach-und-gebrauchsinformation/17

Specifics for Austria• Based on national regulations:

– AMG, FI-VO, GI-VO and KE-VO• Minimum font sizes:

– 1.8 mm in PIL– 1.8 mm at least for Trade name on Label

• QRD wording is endorsed• Submission specifics:

– Nomenclature: nnnnnn-F-##-YY-MM-DD-free text– Submit to spc@ages.at resp. spc-vete@ages.at

http://www.basg.at/uploads/media/110907_Empfohlene_Vorgehensweise_f%C3%BCr_stilistische_Belange.pdfhttp://www.basg.at/uploads/media/110907_Blue_Box_Requirements.pdf

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Specifics for Germany

• Based on national regulations– Templates available for download from BfArM

• Template database available with downloadable standard wording for individual APIs*

• Vet.: specific PhV-wording in SmPC, specific disposal wording in PIL

• Other submission specifics:– Submit to translations@bfarm.de resp.

vet.: mrp@bvl.bund.de + 3x in hard-copy* https://sunset-clause.dimdi.de/Mustertexte/BStationServlet19

Specifics for Switzerland

• Regulated in Arzneimittel-Zulassungsverordnung

• 3 official languages (DE, FR, IT) mandatory for PIL, minimum font size 8 pt

• CH specific templates, similar to QRD

• Mock-Up submission mandatory (5 copies)

– Laserprinter print-outs acceptable with corresponding confirmation

http://www.admin.ch/ch/d/sr/812_212_22/index.htmlhttp://www.swissmedic.ch/org/00064/00067/00331/00632/index.html?lang=de 20

Other „Blue box“ requirements„Individual country specifics?“• Blue-Box requirements:

– CP: Notice to Applicantshttp://ec.europa.eu/health/files/eudralex/vol-2/c/bluebox_02_2008_en.pdf

– DCP/MRP: Notice to Applicantshttp://ec.europa.eu/health/files/eudralex/vol-2/a/vol2a_chap7_rev_2008_07_en.pdfhttp://ec.europa.eu/health/files/eudralex/vol-6/a/chapter7_rev9-7_vet_en.pdf

• General recommendations on packaging andlabelling available from EMA / HMA / CMD:

http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2009/10/WC500004442.pdfhttp://www.hma.eu/uploads/media/POS003_Ed-01_Pack_Conclusions_Recommendations_ED-01_Final_-_EMEA-CMDv-123457-2008.pdf

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Labelling in non-EEA countries„What‘s beyond the border?“• Highly diverse EEA and RoW• Examples:

– Anti-counterfeiting: Use of holograms

– Statement of ATC code on label

– …

• QRD templates beneficial as starting point• Local knowledge important

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QRD templates„Which documents should be used?“

• CP vs. MRP/DCP/national:– Version 8, Rev. 1, 07/2011 vs. Version 2, Rev. 1,

10/2011– Linguistic revisions relevant for national

translationshttp://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/document_listing/document_listing_000134.jsp&mid=WC0b01ac0580022c59

– Implementation asap, latest by 1st July 2014• Veterinary Medicinal Products:

– Version 7.3.2., 10/2011– Rev. in 10/2011 to further harmonise

CP/DCP/MRPhttp://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/document_listing/document_listing_000185.jsp&mid=WC0b01ac058002d9b0

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Labelling & Clinical Trials“Current legal framework”

• Eudralex Volume 4, GMP - Annex 13 Manufacture of Investigational Medicinal Products (→ Directive 2003/94/EC) http://ec.europa.eu/health/files/eudralex/vol-4/2009_06_annex13.pdf

• Eudralex Volume 10, Chapter 1: Detailed Guidance for the request for authorisation of a clinical trial on a medicinal product for human use to the competent authories, notification of substantial amendments and declaration of the end of the trial.http://ec.europa.eu/health/files/eudralex/vol-10/2010_c82_01/2010_c82_01_en.pdf

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Labelling & Clinical Trials“Daily practice”

• Master labelling in EN

• CTA(s) - national submission(s), local languages

• More flexibility compared to MAAs

• Close collaboration with local affiliates

• Single- or multilingual?

• Wait for national approvals or print at risk?

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Agenda

• Introduction - Importance & Role of Labelling• Overview - MAA procedures & labelling requirements• National requirements & mandatory elements in AT,

DE, CH• Labelling in non-EEA countries• QRD• Clinical Trials & labelling• Variations• Multilingual labelling – why?, pro‘s & con‘s• Innovative labelling solutions• Experiences, Do‘s and Don‘ts & Recommendations

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Variations…„Dealing with product lifecycle“

• Quality Dossier– e.g. In-Use stability studies– changes to specification – changes in appearance

• Safety reasons– In-house safety data/ PhVWP/ CA recommendations

• Administrative informationchanges in – distributor‘s address/ site of batch release– registration number following renewal

• Referrals27

Variation Regulation„What if variations can‘t be avoided?“

• Use of variation regulation also in EU countries where not yet implemented for nat. MA

• „Spotlight“ overview of packaging switch:Country (selection)

Safety Variations Non-safety variations

AT Immediate switch Switch within 12 monthsCZ Immediate switch Switch within 6 months*ES Immediate switch No official limit*/**FI Immediate switch Switch within 12 months*IT Immediate switch Switch within 6 months*SK Immediate switch Immediate switch* Subject to CA decision / specified in approval **sell-off possible Timelinesapply for VMPs 28

Multilingual labelling“Who are the stakeholders?”

• Legal framework – Joint labelling is not always “just for fun”mandatory for: e.g: Belgium (Dutch/ French/ German), Finland (Finnish/ Swedish); Switzerland (German/ French/ Italian)

[EMEA/CMDv/123457/2008 ed. 01-final]

• From a regulatory perspectiveCommon legal framework

• From a supply chain/ labelling perspectiveNo relabelling, more flexibility, cost reduction

• From a marketing perspectiveMore flexibility 29

Multilingual labelling“Challenges for RA professionals”

• Rationalisation of supply networks (one single site – different sites – different internal procedures – different labelling)

• Country specific requirements (product names, license no, manufacturer/ MAH, serialisation, changes introduced during national phases, etc.)

• Coordination of variations & national implementation, approval timelines, …

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Multilingual labelling“More challenges…”

• Increasing requirements – more details on the leaflets (legal info, readability guideline –execution of new requirements)

• Limited space• Nationally authorised products (info in product

literature shouldn‘t contradict itself (e.g. safetydata))

Multilingual labelling: current prevalence ofmultilingual labelling – serious economic concern(constantly highlighted by larger companies)

[E Ad i S i (EAS) N b 2004]

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Joint labelling – Pro‘s„Where can we benefit?“

• Reduction of pack complexity• One labelling material valid for all countries• Easy intercountry transfer – significant

advantage for manufacturing planning• Language combinations – facilitation of

review and approval timelines• Cost perspective

– Scale effect via larger volumes– Positive for small markets (small market – but

same administrative, regulatory requirements & fees) 32

Joint labelling – Con‘s„Yes, but…“

• One national change affects „all“ countries• Approval timelines may vary significantly

– e.g. 10 months from 1st to last approval• German ≠ German, French ≠ French• Different national understanding may apply

– Example: 101,2 mg/ml (Base) vs. 125 mg/ml (Salt)• Braille• Cost intensive material

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Joint labelling – Con‘s„1 + 1 + 1 >> 3“

• 3x english Mock-Up: reality may be different!– e.g. <Verschreibungspflichtig.> vs.

<Reseptilääke.> vs. <Médicament soumis à prescription médicale.>

• National requirements: added complexity

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Joint labelling procedures„Do CA‘s cooperate?“

• Joint labelling review procedures are well established:UK – IE : agreed procedure between IMB & VMDhttp://www.imb.ie/EN/Veterinary-Medicines/Licensing-Activities/Joint-labelling-

procedure.aspx

AT – DE : informal established procedureCH – DE : informal procedure…

• Other combinations: subject to discussion with CA‘s

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Innovative labelling“Potential solutions, many providers, just an example…”

[ Ref.: JHBERTRAND INC]http://www.jhbertrand.com/public/files/Multilingual-Labeling-for-limited-space-containers.pdf

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Innovative labelling

[Ref.: Burgopak‘s – innovative packaging – child resistent, senior friendly, 2009 ]http://www.packagingeurope.com/Packaging-Europe-News/28644/Un-innovador-envasado-de-Burgopak-consigue-el-

estndar-F1.htmlhttp://burgopakhealthcare.com/design/structural-design/

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Problem areas„What else can go wrong?“

• Changes not tracked by CA/ LA• Changes to numbering/ sequence of sections• „Creative“ revisions – unnecessary („stylistic“)

re-phrasing• Changes in wording with consequences for

e.g. administration information• Revisions not in line with QRD templates• CA revisions w/o MAH consultation• MAH has to actively request electronic docs

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Do‘s & Don‘ts„What lessons can be learned?“

• High-quality translations at start of procedure• Communicate timelines to project team and

keep them updated!• Project management• Keep contact with RMS regarding changes• Retain full version control• 200% check of CA-„approved“ texts

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Solutions „What can we do to avoid problems?“

• Use of standard terms and abbreviations• Insist on e.g. minimum particulars• Importance of local knowledge

– e.g. IV vs. i.v.

– e.g. ad us vet vs. for veterinary use only

• Keep an open mind!• Allocate sufficient ressources – team

structures40

Best practice „Work smarter, not harder“

• As little as possible, as much as needed• Use of generic names/ INN• Multiple pack sizes – „Not all pack sizes may

be marketed“• Dosing tables• Professional translations• LA/ distributor address – limit to minimum

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Thank you for your attention!

Questions?

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Abbreviations/ SynonymsAPI Active Pharmaceutical Ingredient KE Kennzeichnung

ATC Anatomical Therapeutic Chemical LA Local Affiliate(s)

BfArM Bundesinstitut für Arzneimittel und Medizinprodukte

LoQ List of Questions

CA Competent Authority MA Marketing Authorisation

CMD Co-cordination Group for MRP andDCP

MAA Marketing Authorisation Application

CP Centralized Procedure MAH Marketing Authorisation Holder

CTA Clinical Trial Application MRP Mutual Recognition Procedure

DCP Decentralized Procedure PhV Pharmacovigilance

EC European Commission PI Product Information

EEA European Economic Area PIL Product Information Leaflet

EMA European Medicines Agency QC Quality Check

EN English QRD Quality Review of Documents

EoP End of Procedure Ref. Reference

FI Fachinformation RMS Reference Member State

GMP Good Manufacturing Practice ROW Rest of World

GI Gebrauchsinformation SmPC Summary of Product Characteristics

HMA Heads of Medicines Agencies VMD Veterinary Medicines Directorate - UK

IFU Instructions for Use VO Verordnung

IMB Irish Medicines Board VMPs Veterinary Medicinal Products

INN International Nonproprietary Names

Future Prospect

• Topra In events on a regular basis (once per quarter/ every six months?)

• Open minded for any topics of interest • Joint events?

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Potential list of topics for future events• Russia - new „Federal Law on Circulation of Medicines“:

Implemented Sept 2010, current status? Impact to new & ongoing registrations; backlog of submissions; future trends; CTs; development of Russian Pharmacopoeia

• Medical Device Recast: aims, current status, feedback from industry re public consultation procedures; timelines; pros and cons

• Basics of QbD - impact on RA?

• New developments in ASEAN harmonization: ASEAN dossier-current status?, implementation status in MS; challenges?; future developments; impact on pharmaceutical companies

• Regulatory Compliance - Code of conduct – changes of law 2008/2009 – impact on Pharma industry

• Generics - European Reference Products – industry & authority experiences

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Working Party

• Cornelia Kothmayercornelia_kothmayer@baxter.com

• Elke Hofer-Litzlbauerelke_hofer_litzlbauer@baxter.com

• Martina Hoethmartina_hoeth@baxter.com

• Sandra Lechners.lechner@mundipharma.at

• Vladislav Kurtevvladislav.kurtev@richter-pharma.at

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