The Role of EPAG in Standards and Regulatory Guidance Development

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1 The Role of EPAG in Standards and Regulatory Guidance Development Jolyon P. Mitchell on behalf of EPAG Session 4: The Remit, Activities and Achievements of The European Pharmaceutical Aerosols Group 1

2 SUMMARY The standards and regulatory guidance landscape The processes adopted by EPAG to provide effective input into the public review process Examples of EPAG involvement Future directions 2

3 EPAG OBJECTIVES FOCUS ON PHARMACEUTICAL ISSUES RELEVANT TO PULMONARY AND NASAL DELIVERY PRODUCTS ESTABLISH SCIENTIFICALLY BASED BEST PRACTICES PROVIDE CONSENSUS COMMENT TO INDUSTRY AND GOVERNMENT AGENCIES TO PROMOTE SAFETY AND QUALITY STANDARDS RECOMMEND HARMONISED STANDARDS AND METHODOLOGY 3

4 STANDARDS AND REGULATORY GUIDANCE LANDSCAPE Canada USA EU Japan Others Differing national and regional standards exist: The ISO process may result in a common set of standards Differing regulatory guidance between regions: Some exceptions, such as the Health Canada-EU guidance on Pharmaceutical Quality of Inhaled and Nasal Products ICH (drug product) and GHTF (devices) processes seek harmonization 4

5 STANDARDS/GUIDANCE BY INHALER CLASS Inhaler class Purpose pmdi DPI MLI Nasal Nebulizers inc. mesh/membrane International Standards National/Regional Standards CAN/CSA Z264.1 Spacers/ Holding Chambers ISO ISO EN13544:2001 Nebulising Systems Pharmacopeia Monographs Ph. Eur oral, nasal preparations (in progress) Ph. Eur (preparations for nebulisation) Regulatory Guidances Joint HC-EMEA Guidance: Pharmaceutical Quality of Inhaled & Nasal Products 5

6 CHALLENGES FACING EPAG How to participate in the process of shaping these documents at as early a stage as possible Identifying core areas of expertise Development of efficient processes: Scientifically robust Evidence driven Consensus based Recognition as an expert group with a useful contribution to make 6

7 GENERIC STANDARDS DEVELOPMENT PROCESS Influence by participating in the responsible committee where possible Review process Review process Published Standard Draft for Public Comment Committee Draft Responsible Committee Public Participation Private or Restricted Outside Involvement 7

8 EPAG CORE COMPETENCIES Pulmonary and Nasal Drug Delivery Products: In Vitro Performance Evaluation: CMC aspects Measurement equipment Good Laboratory Practices Underlying Aerosol Science: Particle transport behavior Inhaler use/mis-use Clinical Performance (with assistance from external clinician experts) 8

9 FIRST STEPS Examine and review documentation as it was published for public comment CSA Standard Z Spacers and Holding Chambers for Use with Metered-Dose Inhalers Provide consensus feedback An early success was participation in the development of the Canadian Standards Association Spacer/ Holding Chamber Standard in Registered trade-mark of Canadian Standards Association Published in October 2002 by Canadian Standards Association A not-for-profit private sector organization 5060 Spectrum Way, Suite 100, Mississauga, Ontario, Canada L4W 5N

10 CSA STANDARD No other standards that deal specifically with these addon devices TC responsible had good national representation from stakeholders, but only limited participation from experts involved with inhaler testing EPAG provided suggestions that made the standard more workable: methods harmonized where possible with those already in the pharmacopeias advice on appropriate test methods specific to spacers/holding chambers consistent set of terms and definitions 10

11 INHALER PERFORMANCE A further milestone was the development of guidance on development of test methods to check inhaler performance under normal use and unintentional mis-use NORMAL USE TESTS CONSUMER TESTS UNINTENTIONAL MIS-USE TESTS PRODUCT DESIGN IN-USE STABILITY STABILITY TESTS ICH/FDA STABILITY Purewal, T.S. 2002: PharmEuropa 14(3): LABELLING 11

12 NORMAL USE/UNINTENTIONAL MIS-USE Aspects included: Varying flow rate, simulating inhalation Simulated patient use of inhaler through life Inhaler emitted mass profile at exhaustion Effect of cleaning pmdis and DPIs Priming and re-priming pmdis Orientation of DPIs during actuation and inhalation 12

13 INPUT INTO REGULATORY GUIDANCE From time-to-time EPAG has provided commentary as draft regulatory guidance documents come up for review: An example was the contribution that was made to the joint Health Canada-EMEA guidance: Pharmaceutical Quality of Inhaled and Nasal Products during the period from

14 PHARMACEUTICAL QUALITY OF INHALED AND NASAL PRODUCTS This comprehensive guidance applies to the CMC package for all types of portable inhaler: Drug substance specification Drug product manufacture Drug product container closure system Drug product stability Tables to identify studies appropriate for each inhaler category Considerations for appropriate study designs 14

15 PHARMACEUTICAL QUALITY OF INHALED AND NASAL PRODUCTS EPAG made recommendations to make the guidance more usable and consistent with current practices Supported the unified approach being taken by both agencies: improve consistency of regulation across regional boundaries and across inhaler forms reduced regulatory guidance creep Participated in a unique public meeting organized by both agencies in late 2005 to review stakeholder feedback 15

16 PHARMACEUTICAL QUALITY OF INHALED AND NASAL PRODUCTS A successful outcome was recognition by the regulator representatives of the contribution by EPAG and other expert bodies as a useful step in the development of these documents 16

17 INPUT TO USFDA DRAFT GUIDANCE Has generally been in collaboration with other expert groups, such as IPAC-RS and PQRI Issues addressed include: parametric interval tolerance testing (PTIT) for dose content uniformity appropriate use of the mass balance determination in association with cascade impactor measurements International Pharmaceutical Aerosol Consortium on Regulation and Science US Product Quality Research Institute 17

18 MAKING THE PROCESS MORE EFFICIENT In 2004, EPAG began to formalize the process of developing sub-teams to improve effectiveness at addressing topics: Specific Terms of Reference (TOR) Narrow focus Work plan with clear objectives Finite life Sub-teams can co-opt outside experts to enhance team capabilities when needed Operate through plenary group 18

19 Consensus Building MAKING THE PROCESS MORE EFFICIENT Commentary on Documents For Public Review DIRECT Plenary Group COMBINED IPAC-RS/Other Expert Groups Outside Experts Position Statements Sub-Team Technical Papers Representatives To Plenary Group Evidence base Literature Surveys Laboratory Studies The sub-team is the focus of efforts to identify the evidence base in support of commentary from EPAG 19

20 PHARMACOPEIAL MONOGRAPHS Nebuliser sub-team: Ph.Eur. Monograph : Preparations for Nebulisation Assist Inhalanda Committee Resolve uncertainties in proposed measurement techniques Nasal sub-team: Helping develop proposed monograph covering droplet size analysis of nasal sprays 20

21 ISO STANDARD DEVELOPMENT A substantially different approach was needed to participate in the process of developing new ISO inhaler standards that started around 2002: The ISO process is not easily influenced by outside expert bodies TC84/JWG5 has accepted expert group commentary in connection with ISO (Portable Inhalers) TC121/SC2 responsible for ISO (Nebulising Systems) only accepts input through committee members accredited via participating national standards organizations 21

22 ISO STANDARD DEVELOPMENT APPROVED STANDARD 5-year period before review Current Status Both Standards VOTE ONLY VOTE + COMMENT FINAL DRAFT INTERNATIONAL STANDARD DRAFT INTERNATIONAL STANDARD vote only by participating national standards bodies 2 nd public review opportunity VOTE + COMMENT COMMITTEE DRAFT 1 st public review opportunity WORKING DRAFT private development by TC members 22

23 EPAG INVOLVEMENT IN ISO PROCESS 1. Consensus building through discussion by plenary group 2. Support for individual member participation at TC by obtaining accreditation through national standards body populate TCs with individuals having knowledge of issues concerning inhaler assessment successful with TC84/JWG5 because of strong company interest in focus of ISO

24 PROCESS WITHIN EPAG ISO PROCESS Consensus Building Commentary on Documents For Public Review IPAC-RS COMBINED RESPONSE EPAG Plenary Group Individual Members Individual Members Individual Members ISO TCs Evidence base Representatives To Plenary Group Participation Through National Standards Bodies 24

25 EPAG AND ISO EPAG has had a direct and substantial input into the development of ISO (Portable Inhalers): Risk assessment led development of device performance profile General Requirements that are pertinent Assessment of inhaler performance based on manufacturer-chosen methods drawn from existing sources Consistent nomenclature Significant problems still remain to be resolved: Interpretation of measured metrics Severity of some recommended test environments 25

26 EPAG AND ISO The situation is less clear with the development of ISO (Nebulising Systems): EPAG has fewer members with interest in this class of inhalers Representation on the TC has been less effective Strong desire by non-epag participants to base the standard on EN13544 performance rather than a design verification standard EPAG and IPAC-RS are working together to develop common comments for both standards that can be fed back to TCs via the ISO process 26

27 CONCLUDING REMARKS EPAG is effective as a regional expert group in the development of standards, pharmacopeia monographs and regulatory guidance documents Ability to draw on the collective experience of many companies across industry is an asset at developing strong consensus positions The evidence-based approach that has been adopted is appreciated by organizations receiving feedback 27

28 CONCLUDING REMARKS EPAG will continue to seek alliances with other expert groups where this aids in broadening the consensus, particularly beyond Europe EPAG is well positioned to provide input as standards and guidance develop with increasing emphasis on risk assessment and quality by design 28

29 ACKNOWLEDGEMENTS I acknowledge the support and assistance of colleagues within the European Pharmaceutical Aerosol Group in the preparation of this presentation 3M, Almirall Sofotec, Astra Zeneca, Bespak Europe, Boehringer Ingelheim, Chiesi, Clinical Designs, GlaxoSmithKline, Hovione, Lab Pharma, Pari, Novartis, Novo Nordisk, Pfizer, sanofi-aventis, Siegfried Pharma Development, SkyePharma, Teva, Trudell Medical International, Valois, Vectura 29