QP Forum Regulatory Update Paul Sexton, GMP Manager, HPRA Trinity College Dublin – 12th April 2018

Content Revised Statement of Non Compliance Control of Cross Contamination - Q&A Safety Features Annex 21 – Importation MRA - EU / US Brexit Update

Statement of Non Compliance (SNC) Revised SNC issued for consultation (3rd April – 15th May) QRM to facilitate continued supply of critical medicines Risk / Benefit report on use of product with involvement of: Marketing Authorisation Holder Manufacturing / Importer Authorisation Holder (Site of batch certification) QP, Manufacturer which is subject of SNC (if different) Report sent to relevant National Competent Authorities (NCA) in affected markets. Written confirmation of product criticality and no objection to distribution from National Competent Authority in market concerned. Supervisory Authority informed.

Control of Cross Contamination - Q&A Q&A on implementation of risk based prevention of cross contamination and use of the Safety Working Party guidance on use of Health Based Exposure Limits. http://www.ema.europa.eu/docs/en_GB/document_library/Other/2017/01/WC500219500.pdf (original Q&A) Consultation on Q&As : January – April 2017 Meeting with industry representatives : June 20 & 21st, 2017 Discussion Points - classification of ‘highly hazardous’ products - use of 1/1000th minimum therapeutic dose

Control of Cross Contamination - Q&A Q&As revised based on feedback Undergoing final approval process at EMA Anticipate publication on EMA website in Quarter 2, 2018

Safety Features Two elements 1. Unique identifier for individual pack (2D barcode) 2. Anti Tampering Device Rules applicable from 9th Feb 2019 Commission Publication Safety Features for Medicinal Products for Human Use Questions & Answers (Version 9) https://ec.europa.eu/health/sites/health/files/files/falsified_medicines/qa_safetyfeature_v9.pdf 11/11/2018

GMP Guidance Updates Annex 21 – Importation of Medicinal Products Outsourced activity Oversight of manufacturers Technical / Quality agreements Site of batch certification (MIA required) Site of physical importation (MIA required) Sampling of imported products (Annex 16)

Financial Transactions as Importation Activity Product Manufactured by MIA holder in EU Physical Movement within EU Sold to Non-EEA Company Purchase by EU Wholesaler Wholesaler in EU Wholesaler outside EEA 11/11/2018

Financial Transactions as Importation Activity Purchase of product from entity in 3rd Country Discussed previously at GMDP IWG Some Member States have implemented MIA requirement HPRA has not issued MIAs yet for this activity New area for consideration 11/11/2018

Financial Transactions as Importation Activity Commission Q&A on Safety Features (Version 9 ) 5.5. Question: Article 22(a) requires a wholesaler to verify the authenticity of and decommission the unique identifier of all medicinal products he intends to distribute outside of the Union. Is it necessary to decommission the unique identifier if the medicinal product is sold to a party established outside the EU but that product does not physically leave the wholesaler's premises in the EU? Answer: No. The purpose of Article 22(a) is to ensure the decommissioning of unique identifiers on packs which leave the EU territory, in order to avoid that those active codes may be harvested by traffickers. In case the medicinal product is sold to a party established outside the EU but physically remains in the wholesaler's premises in the EU, the unique identifier on the product should not be decommissioned. If that medicinal product is subsequently imported (while physically remaining in the EU) by a holder of a manufacturing and import authorisation (a wholesaler cannot import medicinal products), no action is required with regard to the safety features. 11/11/2018

MRA with USA Transition Phase : November 2017 up to July 2019 FDA Assessment of EU Member States ongoing Date Member States Recognised Nov ‘17 8 - Austria, Croatia, France, Italy, Malta, Spain, Sweden, UK March ‘18 4 - Czech Rep, Greece, Hungary, Romania 1st June ‘18 2 further Member States to be recognised 1st Dec ’18 6 further Member States to be recognised 15th July ’19 8 remaining Member States to be recognised

EU – US MRA Inspection Activity No routine inspections by EU Authorities in US for products within scope of the MRA HPRA will continue to conduct inspections for products outside scope of the MRA. MRA excludes – vaccines, blood products, veterinary products (to be considered for inclusion within specified timeframes) Voluntary recognition of inspections in Third Countries possible under the MRA. Sources of information EMA website Q&A on the MRA http://www.ema.europa.eu/docs/en_GB/document_library/Other/2017/10/WC500237908.pdf 11/11/2018

EU – US MRA Marketing Authorisation Applications / Variations No GMP certificates issued by the FDA for US sites. Certificate of Pharmaceutical Product (CPP) Also referred to as Export Certificates WHO format document & valid for 2 years from issue date. Should be clear that the scope of the CPP includes the US based manufacturing site. EMA Q&A on impact of EU-US MRA on MA applications & variations http://www.ema.europa.eu/docs/en_GB/document_library/Other/2017/07/WC500232411.pdf 11/11/2018

EU – US MRA MIA Variations CPPs may be provided to support addition of a US based contract manufacturer to an MIA. Inspection Classification Database Search NAI - No Action Indicated VAI - Voluntary Action Indicated OAI - Official Action Indicated FDA inspection reports may be requested to support variations 11/11/2018

Brexit Regulatory Update Supply Aspects Actions at EU Level Impact for EMA HPRA Priorities Transfer of EU batch release sites to IE FAQs regarding QPs MAH transfers Points for consideration

Supply Aspects Products Transiting Through the UK Ireland has a unique geographic location with UK land border and reliance of the UK landbridge Transportation of medicines by road through the UK Ireland ↔ Mainland Europe Estimates of 80% of trade to and from Ireland in 2016 via UK Additionally, 60% (by value) of airfreight with a 3rd country destination was exported via the UK. 44% of all imports (air and sea) from 3rd countries arrived via the UK. Import status of product transiting through the UK ??

Supply Aspects Ireland – small market Common language with UK Significant number of products have dual pack labelling (Irish & UK markets) Some MAs may not be maintained for the Irish market for commercial reasons 11/11/2018

Supply Aspects Currently wholesale trade exists between Ireland and UK Common Labelling – e.g. Dual Pack Labelling or CAPs Free movement of batches without additional QP certification Wholesalers are not authorised to import from 3rd Countries Potential for delays in supply and product shortages

Actions at EU Level IWG subgroup established 09/01/2012 Actions at EU Level IWG subgroup established Looking at impact for EU 27 and UK Focus is to avert potential product shortages Competent Authorities (CA) need adequate resourcing to deal with additional workload created by Brexit. Not an easy task. Significant number of products – ha

Impact of Brexit for EMA Relocation of the EMA to Amsterdam Relocation of EMA staff Reduction in GMDP IWG meetings (3 for 2018) Similar reduction in meetings across other areas

09/01/2012 HPRA Priorities Patients & animals - committed to ensuring continuity of supply of medicines Engagement with industry, associations and Government departments to facilitate trade Participation in EU Brexit working groups to collaborate on guidance, Q&As etc. Work with individual companies, as requested, to discuss their plans for changes Currently following transfer of an MA from one MAH to another, the HPRA requires immediate cessation of QP certification of medicinal products bearing the current MA number once the transferred authorisation has been granted Difficulties highlighted by MAH’s include:   The supply chain is complex and global. With forecasts in a typical 18 month planning cycle, and the complexity of multiple stock keeping units with variable forecasts, supply chain experts advise that it is impossible to plan with a fixed zero day implementation date without incurring periods of stock-out. The issue impacts a significant proportion of the industry and stock-outs across multiple products around the uncertain period of ‘Brexit’ in 2019/2020 are likely. Even with careful forecasting, demand by customers has the potential to skew forecast product availability in the marketplace, as uncertainty around Brexit may lead to customers ordering extra stock. 11/11/2018

Transfer of EU ‘batch release’ site to IE 09/01/2012 Transfer of EU ‘batch release’ site to IE A number of companies are relocating the responsibility for EU batch certification of products from the UK to Ireland  New applications should be submitted 6 months before the Brexit date or the end of transition period, as appropriate. The HPRA also encourages intending applicants to make early contact with the Compliance Department by emailing inspect@hpra.ie prior to submission of the application If the company intends to transfer this responsibility to an existing manufacturing site, i.e. one holding a Manufacturer’s / Importer’s Authorisation (MIA) it will be necessary to determine if any variations to this MIA are required (e.g. to cover batch certification of the particular product type or to add contract manufacturers / contract laboratories).  Please refer to the HPRA website for guidance on applications for variations to an MIA and this will assist in determining what variations may be required to the MIA concerned. These variations may be progressed in advance of any variations to the Marketing Authorisations for the products concerned. 11/11/2018

FAQs regarding QP Does the QP need to be an Irish resident? No, the EU directives don’t include this requirement and the HPRA does not have a national policy setting a requirement for residency Can the QP work from another jurisdiction? The batch certification should take place at the premises detailed on the MIA as this is a prescribed activity and under Irish law must take place at that address. Batch certification cannot be delegated to anyone who is not a named QP on the MIA Will a QP, who is named on a UK licence, be accepted here? The educational qualifications would be accepted if they had been named on a UK MIA. Separate assessment would be undertaken of their experience in relation to the dosage forms to be certified. Does a company need to obtain an MIA in IE to perform batch certification? No , they may contract another MIA holder to perform the certification on their behalf. The site at which certification takes place would be named on the PIL. 11/11/2018

Zero day’ policy will not apply to MAH transfers resulting from Brexit MAHs be allowed up to 6 months to implement packaging changes following issue of the transferred application Reference to rundown and recall of product bearing the ‘old’ MA number will be removed from the transfer forms and guidance documents 11/11/2018

Points for consideration HPRA recommend that QPs consider how to manage this transition at site level If Irish site takes on additional products the QP may also request data to support their role e.g. previously reported quality defects, PQRs, etc. Contractual arrangements may be required to address on-ward reporting of complaints and ADRs, if required 11/11/2018

Thanks for your attention 09/01/2012 Thanks for your attention Questions ??? Not an easy task. Significant number of products – ha