© safeguarding public health global supply a regulatory perspective gerald w heddell director,...

©

Safeguarding public health

Global Supply

A Regulatory Perspective

Gerald W Heddell

Director, Inspection, Enforcement and Standards Division

Medicines & Healthcare products Regulatory Agency

PQG-Supply Chain Risk- Feb 2010 - G W Heddell ©

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


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

©

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?


FINGS AINT WHAT THEY USED TO BE!


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)


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)


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)


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)


More for less!


Global Supply

Adulterated Products

Poor GMP

Fraud

Counterfeits


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)


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


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


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


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


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


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


Global Supply

Poor GMP

Fraud

Counterfeits

Adulterated Products


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!



Outcome for Company A:

- No longer approved by MHRA

- Site removed from UKMAs



Company B

- Non sterile solid dose

- Re-inspection

- 8 critical deficienciesincluding:

- fraudulent GMP- Serious Quality System failures



Outcome for Company B

- Products recalled in UK

- GMP statement of non-compliance



Company C, D & E

- Sea freight shipment to UK

- Temperatures just below 60oc and 96% R.H

- Responsibility of QP



Outcome for Company C, D & E

RECALL OF ALL AFFECTED PRODUCTS

(111 batches of 12 product lines)


Global Supply

Counterfeits

Advantages

Poor GMP

Fraud


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


Singapore

BelgiumUK

Mauritius Money Counterfeit Medicine

UK Case Study

ChinaLuxembourg


MHRA Anti-Counterfeiting Strategy

• Launched by Health Minister in November 2007

• broad strands of work: 1. Communication

2. Collaboration

3. Regulation

4. Review


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


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


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


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


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


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.


THANK YOU FOR YOUR ATTENTION

Gerald W HeddellDirector

Inspection, Enforcement and Standards DivisionMedicines and Healthcare products Regulatory Agency

+44 (0) 207 084 [email protected]

© safeguarding public health global supply a regulatory perspective gerald w heddell director,...

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