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

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

3. 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.

4. 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.
(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

5. 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

6. 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)
11/11/2018

7. 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)

8. 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

9. 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

10. 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

11. 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

12. 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
11/11/2018

13. 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
11/11/2018

14. 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

15. 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

16. 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 ??

17. 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

18. 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

19. 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

20. 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

21. 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

22. 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 ing 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

23. 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

24. 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

25. 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

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