Meeting the Quality Challenge for Orally Inhaled Drug Products. Review Impact of Emerging EMA/MHRA Guidelines and Standards

Transcription

1 IPAC-RS/RDD 2016 SYMPOSIUM Meeting the Quality Challenge for Orally Inhaled Drug Products Review Impact of Emerging EMA/MHRA Guidelines and Standards Joseph Lim (PhD) Senior Pharmaceutical Assessor (MHRA) -1-

2 Disclaimer The views represented here are my personal views and not necessarily those of MHRA/EMA as an organisation. -2-

3 Reflections on the regulatory landscape and scanning the horizon of EU/UK guidelines and standards 3-3-

4 European legislations for medicinal products and medical devices Regulatory Requirements CHMP guidelines British Pharmacopoeia inhalation products policy and monographs Drug Device combination changes -4-

5 European legislations for medicinal products and medical devices Medicinal Products Directive 2001/83/EEC as amended quality, safety and efficacy authorisation required for each member state Medical Devices Directive 93/42/EEC as amended: safety and performance manufacturer responsible for affixing CE mark involvement of notified bodies depending on risk classification European wide market access -5-

6 Regulatory Requirements Pharmaceutical Quality Guideline CHMP/QWP/49313/2005 Orally Inhaled Guideline CPMP/EWP/4151/00 Rev. 1 Inhalation Products Regulatory Requirements Pharmacopoeias Inhalanda monograph

7 Relevant EU Inhalation Products Guidelines Guideline on the Pharmaceutical Quality of Inhalation and Nasal Products (EMEA/CHMP/QWP/49313/2005) Effective 1 October 2006 Requirements for clinical documentation for orally inhaled products (OIP) including the requirements for demonstration of therapeutic equivalence between two inhaled products for use in the treatment of Asthma and Chronic Obstructive Pulmonary Disease (COPD) in adults and for use in the treatment of asthma in children and adolescents (CPMP/EWP/4151/00 Rev. 1) Effective -1 August

8 OIP Guideline Revision 1 Principal features Stepwise approach to demonstrate equivalence Step 1 In vitro data Criteria not fulfilled Not equivalent Criteria fulfilled Equivalent Approved Step 2 Lung deposition Not equivalent Step 3 PD models Therapeutic effect Equivalent Equivalent safety? No Refused Yes -8-

9 Questions arising from the OIP guideline Fine Particle Dose Product specifications Acceptable range limits for FPD Impact of aging Equivalency of test vs reference product based on FPD Demonstration of dose linearity for strength waiver on PK studies. Demonstration of flow rate dependency for waiver of patients vs volunteers 9-9-

10 Q&A following on from the OIP Guideline Incorporated into the Questions & Answers: positions on specific questions addressed to the Pharmacokinetics Working Party (PKWP) (EMA/618604/2008 Rev. 13) 17. Evaluation of orally inhaled medicinal products Date of publication: 22 January 2015 (Rev. 11) 1. The extent to which plasma levels reflect bio-availability in the lung 2. Scaling of acceptance limits (for Cmax and perhaps AUC) to allow for variability in reference product for fine particle dose -10-

11 Recently Agreed Clinical Respiratory Guideline Revision of the guideline on the clinical investigation of medicinal products for the treatment of asthma (EMEA/CHMP/EWP/2922/01 Rev.1) Draft Agreed by Respiratory Drafting Group 22 April 2013 Draft Agreed by PDCO 15 March 2013 Adoption by CHMP for release for consultation 27 June 2013 Start of public consultation 1 July 2013 End of consultation (deadline for comments) 31December 2013 Agreed by Respiratory Drafting Group May 2015 Adoption by CHMP 22 October 2015 Date for coming into effect 1 May

12 Upcoming Clinical guideline- Revision 2016/2017 1) Revision of the guidelines on clinical development of medicinal products for the treatment of cystic fibrosis (EMEA/CHMP/EWP/9147/2008-corr*) 2) 2 nd Revision of the Orally inhaled medicinal products Guideline - (Guideline on the Requirements for Clinical Documentation for Orally Inhaled Products (OIP) Including the Requirements for Demonstration of Therapeutic Equivalence Between Two Inhaled Products for Use in the Treatment of Asthma and Chronic Obstructive Pulmonary Disease (COPD) in Adults and for Use in the Treatment of Asthma in Children and Adolescents) - CPMP/EWP/4151/00 Rev. 1. Public consultation: 1) Concept stage 2) Revision stage Please provide feedback and comments. -12-

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14 Background- BP Inhaled Products Policy Timeline 2011/ 2012 BP Inhaled Products Working Party 2013/ onwards Stakeholder consultation BP Inhaled Products Policy Document EAG PCY Informal stakeholder consultation Revised policy BP Monographs for inhaled Products BP Commission approval Implementation Stakeholder feedback Planned review Implementation & review -14-

15 British Pharmacopoeia Monographs for Inhaled Products- Recommendations (For comments) Terminology aligned with the Ph. Eur. for the naming of specific finished inhaled product monographs and test methods. Specific finished inhaled product monographs Fine Particle Dose - upper and lower limits should be included Uniformity of delivered dose test should be aligned with the Ph. Eur. General monograph Assay - The type of Assay included in the monograph should follow the approach taken by the innovator product. Preparations for Inhalation B.P. (general monograph) - revised in future BP publication if suitable method for the Content of Active Ingredient on Actuation of the Valve test is established. Water content - include in product monographs, harmonise with the methodology and specifications used for established products. -15-

16 European regulation of drug-device combination products No legal definition as per FDA Medical Device Directives: safety and performance manufacturer responsible for affixing CE mark involvement of notified bodies depending on risk classification European wide market access Medicinal Products Directives quality, safety and efficacy authorisation required for each member state 28 member states; 60 + notified bodies -16-

17 Human Factors and Usability Engineering Devices are increasingly common and correct use by the patient or healthcare professional is vital. EU Annex I MDD Essential Requirement 1 : reducing, as far as possible, the risk of use error due to the ergonomic features of the device and the environment in which the device is intended to be used (design for patient safety), and consideration of the technical knowledge, experience, education and training and where applicable the medical and physical conditions of intended users (design for lay, professional, disabled or other users). (BS EN :2015 Applicability of Usability Engineering to medical devices) -17-

18 European legislations for medicinal products and medical devices Medicinal Products Directive 2001/83/EEC as amended quality, safety and efficacy authorisation required for each member state Proposed changes: Amendment to Annex I of Directive 2001/83/EC, point 12 of Section 3.2. (12) Where applicable and if needed, a CE marking which is required by Community legislation on medical devices shall be provided. -18-

19 Devices Legal Framework- Revision 26 September 2012 EC adopted: A proposal for a Regulation on medical devices (to replace: Directive 90/385/EEC regarding active implantable medical devices and Directive 93/42/EEC regarding medical devices); A proposal for a Regulation on in vitro diagnostic medical devices (to replace Directive 98/79/EC regarding in vitro diagnostic medical devices). Once adopted by the European Parliament and by the Council, will replace the existing three medical devices directives. Texts of the proposals and related documents are available on EC website. European Parliament Amendments are on their website Possible adoption in mid Following transition period not likely to be fully in force until Additional measure on Notified Body Audit already in force (Regulation 920/2013) and Commission Recommendation -19-

20 Proposals for the future: Amendment of Annex 1 to 2001/83/EC New Regulation on medical devices currently under negotiation proposes amending Annex 1 of 2001/83/EC to require: If CE marked - Results of the assessment of the conformity of the device part (manufacturer s EU declaration of conformity or the relevant certificate issued by a notified body) If not CE marked - An opinion on the conformity of the device part with the relevant general safety and performance requirements of Annex I of that Regulation issued by a notified body. (Unless the authority is advised by its experts for medical devices that involvement of a notified body is not required) -20-

21 Proposed amendment to the Medicinal Products Directive 2001/83/EEC Article 91 Amendments to Directive 2001/83/EC In Annex I of Directive 2001/83/EC, point 12 of Section 3.2. is replaced by the following: (12) Where a product is governed by this Directive in accordance with the second subparagraph of Article 1(4) or the second subparagraph of Article 1(5) of Regulation (EU) [ / ] on medical devices [1], the marketing authorisation dossier shall include, where available, the results of the assessment of the conformity of the device part with the relevant general safety and performance requirements of Annex I of that Regulation contained in the manufacturer s EU declaration of conformity or the relevant certificate issued by a notified body allowing the manufacturer to affix a CE marking to the medical device. If the dossier does not include the results of the conformity assessment referred to in the first subparagraph and where for the conformity assessment of the device, if used separately, the involvement of a notified body is required in accordance with Regulation (EU) [ / ], the authority shall require the applicant to provide an opinion on the conformity of the device part with the relevant general safety and performance requirements of Annex I of that Regulation issued by a notified body designated in accordance with that Regulation for the type of device in question, unless the authority is advised by its experts for medical devices that involvement of a notified body is not required. - Conformity assessment by manufacturer or, where applicable a notified body - Results to be provided in dossier - What exactly should be provided? -21-

22 Interaction of formulation, device and patient on the performance and usability of inhalation product Particle size Drug concentration Physico-chemical properties of DS & excipients Formulation Patient Age or severity of disease - Flow rate range Lung function and capacity Manual Dexterity and Visual acuity Fine Particle dose Delivered dose Metered Dose Plume shape Spray pattern Co ordination Pressure drop Dose Preparation Hand pressure Volume Resistance Flow rate trigger Colour Grip features Delivery Device -22-

23 Pharmaceutical Development Studies (CTD 3.2.P.2) -23-

24 Pharmaceutical Development Studies (CTD 3.2.P.2) -24-

25 Delivered dose uniformity and fine particle mass through container life A study should be conducted to demonstrate the consistency of the minimum delivered dose (e.g., one or more actuations) and the fine particle mass through the life of the container from the first dose (post-priming dose for products with priming instructions) until the last labelled dose. The containers should be used and tested according to the information for the patient with respect to storage orientation and cleaning requirements, as well as minimum dosing interval Delivered dose uniformity and fine particle mass over patient flow rate range A study should be conducted to demonstrate the consistency of the minimum delivered dose and the fine particle mass over the range of flow rates (through the delivery device) achievable by the intended patient population, at constant volume. The range of flow rates should be justified in relation to clinical studies or published data for the same delivery device. The minimum (e.g., 10th percentile), median, and maximum (e.g., 90th percentile) achievable rate should be investigated. -25-

26 Fine particle mass with spacer/holding chamber use A study should be conducted to determine whether the use of the spacer or holding chamber changes the fine particle mass. Instructions accompanying the spacer include an in-use cleaning schedule (e.g., weekly cleaning), performance - tested before and after cleaning the spacer according to the device instructions. Test used for routine testing of the product may be altered to mimic patient performance with the spacer or holding chamber (e.g., a 2 second delay, tidal breathing) Re-priming of the container Study to support - length of time that the product may be stored without use (after initial priming) before re-priming as recommended in the labelling, as well as the number of re-priming actuations required. Containers stored in various orientations prior to and during study - determine effect of orientation. Different stages through container life. The number of re-priming actuations required. -26-

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28 Breath simulator Inhaler Piston Sampling chamber Constant flow Pressure drop Flow profile Time Pump Impactor -28-

29 Examples of HFE impact on Inhalation Product Development MDIs priming/re-priming- Considerations of usage such as multiple cans for COPD patients, clarity of instructions, difficulties with BOI Storage orientation between use - rescue therapy e.g. salbutamol 1 st actuation after storage. Need for storage in specific orientation. DPIs complicated actuation procedure e.g. multiple steps to actuate desired dose with need to interpret colour changes on dosing window etc. Cleaning/maintenance disassembly and reassembly -29-

30 Examples of HFE impact on Inhalation Product Development (con t) Introduction of a dose counter as variation or as a new hybrid application referring to a reference product that does not include a dose counter. Counting down vs counting up. Training of inhalation technique improves flow rate achieved by patients (improves flow rate dependency) of some device and not others Colour differentiation (e.g. blue associated with reliever) Capsule shell breakage -30-

31 State of the negotiations Council agreed a full General Approach on 5 October 2015 mandate for informal trilogue negotiations with European Parliament and Commission 5 trilogues under the Luxembourgish Presidency progress not as fast as expected Dutch Presidency (January-June 2016) NL have significant resources / expertise and are committed to reaching agreement 3 political trilogues (17 Feb, 16 March, 7 April) Expectation: Agreement by end of Dutch Presidency (June 2016) followed by accelerated 2 nd reading by EP and adoption of final Regulations (summer/autumn 2016) -31-

32 The transition period 3-year transition period for the MDR is in all likelihood fixed new Regulation is expected to apply from year transition period for IVDR Key dates Entry into force : publication of the new Regulation 6 months after entry into force: Notified Bodies can apply for re-designation and start issuing certificates under the MDR once re-designated Devices in compliance with MDR can be placed on the market Certain requirements start to apply Date of application (DoA): 3 years after entry into force Publication of notice of full functionality of Eudamed / UDI system (timing unclear) Related requirements start applying 6 / 24 months later -32-

33 Challenges and priorities For the MHRA: Defining UK policy (where there are Member State derogations) Re-processing In-house manufacturing Public consultation / impact assessment UK Parliament statutory instrument Re-designating UK Notified Bodies Influencing the Commission: implementing / delegated acts, CS, guidance Communication and wider stakeholder engagement -33-

34 Certificate validity during the transition There is no requirement that all devices must be re-certified under the MDR by the date of application of the new Regulation. Transitional provisions for certificates issued under the old Directives: Certificates issued prior to the entry into force of MDR remain valid for the period indicated on the certificate. Except certificates under Annex 4, Directive 90/385/EEC or Annex IV, Directive 93/42/EEC, which expire at the latest 2 years after the DoA. Certificates issued during the transition period remain valid for the period indicated (maximum 5 years), but expire at the latest 4 years after the DoA. Devices legally placed on the market under the Directives prior to the DoA may be made available up to 4 years after that date. Devices containing non-viable human or animal tissues / cells legally placed on the market prior to the DoA in accordance with national rules can continue to be sold / put into service in the Member State concerned. -34-

35 Update on Current activity MHRA Human Factors stakeholders meeting Feb now Task and Finish workgroup with representatives from NICE, notified bodies, industry trade organisations, academia and clinicians Devices and drug-device combination products (but focused on all devices and led by MHRA Devices) Aim to ensure device manufacturers take usability and human factors into account in design for safety and performance all classes of devices including Class I low risk, also to ensure regulators focus more on this area Planned for release for comment in UK Spring 2016 with 2nd invited stakeholder day. -35-

36 Update on Current activity MHRA Human Factors stakeholders meeting Feb 2015 (cont ) Will be general guidance, referring to more specific, detailed resources, including FDA guidance for Human Factors requirements for DDCs Aim to be consistent with, but not totally in line with FDA guidance documents adapted to EU MDD Annex I Essential Requirements A notable difference will be that US will insist on studies on US citizens, EU unlikely to do this, so will likely accept US studies unless a good reason (e.g. significant differences in practice between US and EU) Initially UK document, will be taken to Europe when agreed in UK -36-

37 Update on Current activity Discussions with other EU regulators Challenges of innovative DDCs being raised in different forums with notified bodies, medicines CAs: TOPRA Drug-device combination product joint Pharma / MedTech session October 2015, Symposium 2016 will have three joint sessions, including mhealth and electronic devices, convergence and innovative drug delivery devices and FDA Office of Combination Products will be there to discuss the challenges and improvements to communication on working across drug-device interface Working closely in Europe to agree on a common strategy for dossier requirements for DDCs FDA interactions Guidance and work to aid with consistency in a global environment. -37-

38 Update on Current activity EMA Pharmacovigilance Risk Assessment Committee (PRAC) Now published, contains multiple references to usability, human factors and risk management of device component of medicinal products Good practice guide on risk minimisation and prevention of medication errors Medical Devices revision to be agreed by European Parliament, agreed and published June 2016? notified bodies will need to review integral device components of medicinal products. (3 years transition) we will continue as we do currently. -38-

39 Acknowledgements Thank you to colleagues at the MHRA: Liz Baker Janine Jamieson Vikas Jaitley Emma Rooke (Devices) Louise Mulroy (Devices) Adrian Bartlett (Devices) Catherine Pitt (BP) -39-