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© Safeguarding public health Global Supply A Regulatory Perspective Gerald W Heddell Director, Inspection, Enforcement and Standards Division Medicines & Healthcare products Regulatory Agency
Slide 2 PQG-Supply Chain Risk- Feb 2010 - G W Heddell © THE MEANING OF LIFE work acceptably safe The MHRA’s mission is to enhance and safeguard the health of the public by ensuring that medicines and medical devices work, and are acceptably safe
Slide 3 PQG-Supply Chain Risk- Feb 2010 - G W Heddell © providing innovative, effective medicines that make a real difference in important areas of healthcare. at the cutting-edge of the research and development of medicines for humans and animals. to put the needs and well-being of the people we serve first. solutions that improve the quality of life
Slide 4 PQG-Supply Chain Risk- Feb 2010 - G W Heddell ©
© Safeguarding public health Counterfeit Heparin Blamed for 200 Worldwide Deaths FDA: Heparin Deaths Triple Melamine Death Toll Passes 8,000 Pets Diethyl glycol contaminates… How Many More Melamine Deaths?
Slide 6 PQG-Supply Chain Risk- Feb 2010 - G W Heddell © FINGS AINT WHAT THEY USED TO BE!
Slide 7 PQG-Supply Chain Risk- Feb 2010 - G W Heddell © SALES FROM NEWER PRODUCTS % Sales in last 3 Year % Sales in last 5 Years % Sales Sources: IMS Health and Price WaterhouseCoopers Analysis Pressures on Manufacturers (1)
Slide 8 PQG-Supply Chain Risk- Feb 2010 - G W Heddell © R&D EXPENDITURE 50 40 30 20 10 0 Sources: FDA, PhRMA, PWC R&D Spending (US$ millions) No. of NME and New Biologics Approved Pressures on Manufacturers (2)
Slide 9 PQG-Supply Chain Risk- Feb 2010 - G W Heddell © Source: OECD 2008 Pressures on Healthcare providers (1) Relative expenditure increases - % of GDP (1996-2006)
Slide 10 PQG-Supply Chain Risk- Feb 2010 - G W Heddell © The Impact of Global Recessions % of European countries with negative healthcare spending 77 59 1980 - 1983 1988 - 1993 Source OECD Pressures on Healthcare providers (2)
Slide 11 PQG-Supply Chain Risk- Feb 2010 - G W Heddell © More for less!
Slide 12 PQG-Supply Chain Risk- Feb 2010 - G W Heddell © Global Supply Adulterated Products Poor GMP Fraud Counterfeits
Slide 13 PQG-Supply Chain Risk- Feb 2010 - G W Heddell © Pure Heparin Sodium (Ph Eur) Stating Material Pig Mucosa Crude Heparin Sodium Broker Enoxaparin sodium API China +8 sites +1 site SITE C SITE D SITE E SITE F China +21 sites China SITE C SITE D SITE E SITE F SITE B SITE A CHINA GERMANY PIGS POLAND/ GERMANY PIGS SPAIN/ FRANCE PIGS FRANCE GERMANYSPAIN USASPAINNETHERLANDSFRANCE SINGAPORE EXTRACTION PURIFICATION 7 STEPS ENOXAPARIN SUPPLY CHAIN (Pedigree)
Slide 14 PQG-Supply Chain Risk- Feb 2010 - G W Heddell ©
Slide 15 PQG-Supply Chain Risk- Feb 2010 - G W Heddell © Pedigree: BASIS 1. FP Manufacturers are responsible for API quality 2. Consistent with 2001/83: FP Manuf obligations: (i) Article 46(f) Dir “… to comply with principles and guidelines of GMP … “ (ii) New Article 46(g) EC proposal to combat counterfeit medicines “… to inform CA of products …. which are suspected to be falsified in relation to the identity, history or source ….” : i.e. requires knowledge of supply chain to establish ‘truth’ 3. Take account of current EU guidelines: NtA guideline for Type IA/B variations EMEA Q&As on GMP Compilation of Community Procedures on Inspections
Slide 16 PQG-Supply Chain Risk- Feb 2010 - G W Heddell © API Pedigree (supply chain): PRINCIPLES 1. API manufacturer defines ‘critical materials’ with respect to GMP Registered route of synthesis to cover all such critical materials Put and end to “one-step synthesis” seen in MA dossiers, EDMFs, CEPs?!! 2. Semi-synthetic/synthetic APIs critical materials Contribute to the structure of the API molecule 3. API of animal/plant/human origin Original tissue is considered critical material …ctd
Slide 17 PQG-Supply Chain Risk- Feb 2010 - G W Heddell © API Pedigree (supply chain): PRINCIPLES/ …ctd 4. Fully detailed API pedigree comprising (i)Manufacturers/Suppliers of critical raw materials/intermediates concerned with manufacture of API up to the point of release of final API Includes contractors, traders, consolidators (ii)Suppliers/sites acting from the point of release of final API from the manufacturer to receipt by the finished product manufacturing site Includes re-packagers, re-labellers, brokers, importers
Slide 18 PQG-Supply Chain Risk- Feb 2010 - G W Heddell © API Pedigree: Where is it best placed? Annex to QP declaration: as part of an application for MA, renewal or variation Advantages Demonstrates supply chain verified at point of regulatory submission (rather than inspection) Demonstrates measures to prevent falsification the truth is known Is needed for critical medicinal products (heparin) Is not subject to variation applications if amended changes assessed during inspection Disadvantages Information becomes quickly outdated Regulatory burden for industry
Slide 19 PQG-Supply Chain Risk- Feb 2010 - G W Heddell © API Pedigree: Where is it best placed? /…ctd Under GMP requirements: Eudralex: Volume 4 : EU guidelines to GMP Part I: Basic Requirements for Medicinal Products Chapter 1: Quality management Annual Product Quality Review (includes review of starting materials; changes to be documented and available at inspection) Chapter 5: Production s5.2 Starting Materials (requires thorough knowledge of suppliers” Part II: Basic requirements for active substances
Slide 20 PQG-Supply Chain Risk- Feb 2010 - G W Heddell © API Pedigree: subject to GMP requirements? /…ctd Advantages Less of a regulatory burden for industry Subject to annual review (rather than ongoing) Could be acceptable for low-risk APIs Disadvantages Lack of inspection resource to monitor ·Can expect similar deficiencies as currently seen for QP declarations Requires amendment to EU guidelines May be unacceptable for high-risk APIs
Slide 21 PQG-Supply Chain Risk- Feb 2010 - G W Heddell © Global Supply Poor GMP Fraud Counterfeits Adulterated Products
Slide 22 PQG-Supply Chain Risk- Feb 2010 - G W Heddell © HOW THINGS CAN GO WRONG! Company A - Non sterile solid dose products - Re-inspection following regulatory action - Evidence of improvement in quality system since the previous inspection - Lack of document control - Destruction of original documentation, including documents requested by inspector!
Slide 23 PQG-Supply Chain Risk- Feb 2010 - G W Heddell © HOW THINGS CAN GO WRONG!
Slide 24 PQG-Supply Chain Risk- Feb 2010 - G W Heddell © HOW THINGS CAN GO WRONG! Outcome for Company A: - No longer approved by MHRA - Site removed from UKMAs
Slide 25 PQG-Supply Chain Risk- Feb 2010 - G W Heddell © HOW THINGS CAN GO WRONG! Company B - Non sterile solid dose - Re-inspection - 8 critical deficiencies including: - fraudulent GMP - Serious Quality System failures
Slide 26 PQG-Supply Chain Risk- Feb 2010 - G W Heddell © HOW THINGS CAN GO WRONG! Outcome for Company B - Products recalled in UK - GMP statement of non-compliance
Slide 27 PQG-Supply Chain Risk- Feb 2010 - G W Heddell © HOW THINGS CAN GO WRONG! Company C, D & E - Sea freight shipment to UK - Temperatures just below 60 o c and 96% R.H - Responsibility of QP
Slide 28 PQG-Supply Chain Risk- Feb 2010 - G W Heddell © HOW THINGS CAN GO WRONG! Outcome for Company C, D & E RECALL OF ALL AFFECTED PRODUCTS (111 batches of 12 product lines)
Slide 29 PQG-Supply Chain Risk- Feb 2010 - G W Heddell © Global Supply Counterfeits Advantages Poor GMP Fraud
Slide 30 PQG-Supply Chain Risk- Feb 2010 - G W Heddell © Counterfeit Incidents - UK Regulated supply chain Pharmacy (recalls) - Anti-cholesterol, Anti-platelet, Anti-psychotic, Erectile dysfunction, Prostate cancer, Appetite suppressants, Chronic asthma. Wholesale - Anti-cholesterol, Anti-inflammatory, Alopecia, Erectile Dysfunction. Clinical Trial - Anti-platelet
Slide 31 PQG-Supply Chain Risk- Feb 2010 - G W Heddell © Singapore Belgium UKUK Mauritius Money Counterfeit Medicine UK Case Study China Luxembourg
Slide 32 PQG-Supply Chain Risk- Feb 2010 - G W Heddell © MHRA Anti-Counterfeiting Strategy Launched by Health Minister in November 2007 broad strands of work: 1. Communication 2. Collaboration 3. Regulation 4. Review
Slide 33 PQG-Supply Chain Risk- Feb 2010 - G W Heddell © Analysis of UK Incidents The counterfeit product is usually manufactured in the Far East. Most involve complex global supply and money laundering routes Shipped to an EU port where Customs clearance is obtained. UK Freight carriers collect product and deliver to customer in the UK, or store in freight warehouse. The transactions are often negotiated by unlicensed brokers or traders operating outside of the UK. A holder of a wholesale dealer licence will be required to facilitate the product into the legitimate supply chain. Insufficient ‘due diligence’ conducted by purchaser
Slide 34 PQG-Supply Chain Risk- Feb 2010 - G W Heddell © European Proposals Extending regulation to traders and brokers ensuring all those persons engaged in trading pharmaceuticals are subject to licensing Increased auditing obligations placed on wholesale distributors Due diligence requirements placed on wholesalers Obligatory safety/authenticity traceability features for certain medicines e.g. bar coding to pack level, medicines selected on risk criteria Increased controls on imports of API’s from 3 rd countries Requirements placed upon manufacturers to audit API
Slide 35 PQG-Supply Chain Risk- Feb 2010 - G W Heddell © UK Review of Supply Chain Proposals Wholesale Dealers ‘fit and proper person’ requirements, due diligence obligations Responsible Persons minimum qualifications, due diligence obligations Medicines imported for export authority to inspect, due diligence, record keeping Storage and Transit of Medicines comply with GDP, powers to inspect, named on licenses Pharmacies pharmacies engaging in wholesaling to obtain wholesale dealers licence Criminal Sanctions consider new criminal offences for manufacturing or distributing counterfeits, with commensurate sentencing powers
Slide 36 PQG-Supply Chain Risk- Feb 2010 - G W Heddell © Assessing Risk Establish a watch list Regularly assess intelligence, incidents, seizures, recalls and markets Engage Police, Customs, Regulators and Industry Increase vigilance on watch list products from point of importation to point of dispensing Market survey watch list products Monitor internet for watch list products Establish counterfeit hotlines
Slide 37 PQG-Supply Chain Risk- Feb 2010 - G W Heddell © Supply Chain Risk Management “It is the responsibility of each organisation to ensure that their suppliers provide products that are fit for purpose throughout the product lifecycle” PHARMACEUTICAL QUALITY GROUP
Slide 38 PQG-Supply Chain Risk- Feb 2010 - G W Heddell © Crown copyright 2010 The materials featured within these MHRA presentation notes and delegate pack are subject to Crown copyright protection for this event. Any other copy or use of Crown copyright materials featured in this presentation, in any form or medium, is subject to prior approval of the MHRA which has Delegated Authority from Her Majesty's Stationery Office (HMSO) to administer Crown copyright for MHRA originated material. Applications should be in writing, clearly stating the proposed use/reuse of the information, and should be sent to the MHRA at the following address: Conference and Education Function, 16 th Floor, MHRA, 1 Nine Elms Lane, London SW8 5NQ. Fax 020 7084 3522 or e-mail email@example.com. You may not sell or resell any information reproduced to any third party without prior agreement. The permission to reproduce Crown copyright protected material does not extend to any material in this pack which is subject to a separate licence or is the copyright of a third party. Authorisation to reproduce such material must be obtained from the copyright holders concerned.
Slide 39 PQG-Supply Chain Risk- Feb 2010 - G W Heddell © THANK YOU FOR YOUR ATTENTION Gerald W Heddell Director Inspection, Enforcement and Standards Division Medicines and Healthcare products Regulatory Agency +44 (0) 207 084 2500 firstname.lastname@example.org
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