©
Safeguarding public health
Global Supply
A Regulatory Perspective
Gerald W Heddell
Director, Inspection, Enforcement and Standards Division
Medicines & Healthcare products Regulatory Agency
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THE MEANING OF LIFE
The MHRA’s mission is to enhance
and safeguard the health of the
public by ensuring that medicines
and medical devices workwork, and are
acceptably safeacceptably safe
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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
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©
Safeguarding public healthCounterfeit Heparin Blamed
for 200 Worldwide Deaths
FDA: Heparin Deaths Triple
Melamine Death Toll Passes 8,000 Pets Diethyl glycolcontaminates…
How Many More
Melamine Deaths?
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FINGS AINT WHAT THEY USED TO BE!
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SALES FROM NEWER PRODUCTS
0
5
10
15
20
25
30
35
ABT AZN BMY GSK JNJ LLY MRK NVS PFE ROG SGP
% Sales in last 3 Year % Sales in last 5 Years
%
Sa
les
Sources: IMS Health and Price WaterhouseCoopers Analysis
Pressures on Manufacturers (1)
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R&D EXPENDITURE
0
5,000
10,000
15,000
20,000
25,000
30,000
35,000
40,000
45,000
50,000
1995 1996 1997 1998 1999 2000 2001 2002 2003 2004* 2005* 2006*
R&D Spending NMEs and New Biologics Approved
50
40
30
20
10
0Sources: FDA, PhRMA, PWC
R&
D S
pend
ing
(US
$ m
illio
ns)
No.
of N
ME
and
New
Bio
logi
cs A
ppro
ved
Pressures on Manufacturers (2)
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0
5
10
15
20
25
Italy UK USA Canada France Scandinavia Germany
Source: OECD 2008
Pressures on Healthcare providers(1)
Relative expenditure increases - % of GDP (1996-2006)
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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)
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More for less!
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Global Supply
Adulterated Products
Poor GMP
Fraud
Counterfeits
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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
PIGSPOLAND/
GERMANY
PIGSSPAIN/
FRANCE
PIGSFRANCE
GERMANY SPAIN
USA SPAIN NETHERLANDS FRANCE
SINGAPORE
EXTRACTION
PURIFICATION
7 STEPS
ENOXAPARIN SUPPLY CHAIN (Pedigree)
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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
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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
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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
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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
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API Pedigree: Where is it best placed? /…ctd
Under GMP requirements: Eudralex: Volume 4 : EU guidelines to GMP
Part I: Basic Requirements for Medicinal ProductsChapter 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
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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
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Global Supply
Poor GMP
Fraud
Counterfeits
Adulterated Products
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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!
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HOW THINGS CAN GO WRONG!
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HOW THINGS CAN GO WRONG!
Outcome for Company A:
- No longer approved by MHRA
- Site removed from UKMAs
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HOW THINGS CAN GO WRONG!
Company B
- Non sterile solid dose
- Re-inspection
- 8 critical deficienciesincluding:
- fraudulent GMP- Serious Quality System failures
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HOW THINGS CAN GO WRONG!
Outcome for Company B
- Products recalled in UK
- GMP statement of non-compliance
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HOW THINGS CAN GO WRONG!
Company C, D & E
- Sea freight shipment to UK
- Temperatures just below 60oc and 96% R.H
- Responsibility of QP
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HOW THINGS CAN GO WRONG!
Outcome for Company C, D & E
RECALL OF ALL AFFECTED PRODUCTS
(111 batches of 12 product lines)
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Global Supply
Counterfeits
Advantages
Poor GMP
Fraud
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0
1
2
3
4
5
6
1994
-200
320
0420
0520
0620
0720
0820
09
Pharmacy level
Wholesale level
Clinical Trial
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
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Singapore
BelgiumUK
Mauritius Money Counterfeit Medicine
UK Case Study
ChinaLuxembourg
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MHRA Anti-Counterfeiting Strategy
• Launched by Health Minister in November 2007
• broad strands of work: 1. Communication
2. Collaboration
3. Regulation
4. Review
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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
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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 3rdcountries Requirements placed upon manufacturers to audit API
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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
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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
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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
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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, 16th Floor, MHRA, 1 Nine Elms Lane, London SW8 5NQ. Fax 020 7084 3522 or e-mail [email protected]. 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.
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THANK YOU FOR YOUR ATTENTION
Gerald W HeddellDirector
Inspection, Enforcement and Standards DivisionMedicines and Healthcare products Regulatory Agency
+44 (0) 207 084 [email protected]