Vivian Leung GMDP Inspector MHRA 29 October 2014

RX-360 Symposium Global Supply Chain Impacts Overview

Presentation Outline • Changes in Pharmaceutical Marketing and

Distribution • Global Supply Chain Challenges • Implementation of Falsified Medicine

Directives • Internet Sales – Operation PANGEA • Project ICMRA • MHRA Inspection Deficiencies • Industries’ Responsibilities • Closing Remarks

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Changes in Pharmaceutical Marketing

and Distribution

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Why?

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Changing pharmaceutical portfolios

• Future patent expiry • R&D under-productivity

Payers Influence

• Use of generics • Increasing prescription

volumes • Ageing population

A shift in geographic drug adoption towards emerging economies

Supply Chains - 20th Century

Supply Chains - 21st Century

Supply Chain Risks to Organisations

• Loss of Critical Skills • Loss of Intellectual Property and Counterfeiting • Dependence on Suppliers • Different Visions and Culture Differences • Loss of Operational Control • Lower Visibility into Quality and Performance

Global Supply Chain Challenges

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Is it just Pharma?

Aston Martin recalls 17,590 cars due to

counterfeit material Aston Martin expanded a recall …. to cover most of its sports cars built since

late 2007 after discovering a Chinese sub-supplier was

using counterfeit plastic material in a part supplied to the British luxury sports

carmaker.

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What are you eating?

The complex food supply chain that led to the horsemeat scandal

The web of companies is so complex that pinning

down the point at which the crime of mislabelling took place in the horsemeat

scandal has proved elusive.

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Not just manufacturing issues

The UK's Medicines and Healthcare Products Regulatory Agency

(MHRA) has ordered the recall of 100 batches of drugs sold by generics firm Karib Kemi Pharm.

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Supply Chain Challenges

It only takes one bad link

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Implementation of Falsified Medicine Directives

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Regulatory Responses EU Falsified Medicines Directive

Safety features

Internet sales

Actors in the supply chain (Distribution)

Active substances

Directive 2011/62/EU on falsified medicinal products

Adopted in July 2011

Entry into force in January

2013

Regulatory Responses Changes to EU GMDP

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FMD Drivers

GDP Guide

WDA Format

GDP Certs

EUDRA GMDP

Import Export

GDP API

Brokers

Active Substances

Objective: strengthen obligations and supervision • Manufacturing authorisation holder legally obliged to audit

(or have audited on its behalf) manufacturers and distributors of Active Substances used.

• Applicants for marketing authorisation required to submit a written statement confirming that the Active substance used is manufactured in accordance with Good Manufacturing Practice (GMP) and must refer to an audit date

42 third country sources supply the EU:

0

100

200

300

400

500

600

Source country

No. s

ites

INDCHNUSAJPNCHEKORISRMEXBRACANTWAARGTURMYSSGPPRITHAAUS

3rd Country AS sites

Baseline Situation regardless of available EU-GMP or local GMP

certificate

Waiver 1

Waiver 2 “exceptional circumstances”

• API exporting country has no proven equivalence to EU GMP system

• Written confirmation of compliance by exporting 3rd country

• API exporting country is on EC list of GMP equivalent countries

• Medicines availability issue in the EU, AND

• Existing EU GMP certificate (<3 years), AND

• EC informed

FMD - new rules on API import after 2nd July 2013

Further update 1 • Principles and Guidelines of GMP for active

substances to be included in EU legislation – EU GMP Guide Part II: Basic Requirements for

Active Substances used as Starting Materials • Effective on 01 September 2014

– EU GMP Guide Annex 16: The Annex has been revised to reflect the globalisation of the pharmaceutical supply chains and the introduction of new quality control strategies. • Proposed draft. Effective 6 months after

publication

Further update 2 • Chapter 5 of the EU GMP Guide

– Reinforces guidance on qualification of suppliers – Introduces “pedigree concept”

• Known, authorised, qualified and controlled supply chain

– Starting materials, intermediates suppliers, active substance manufacturers, (re)labellers, (re)packagers, analytical laboratories…

• Confirmation of sourcing of each batch of active substance from the authorised supply chain

• Come into operation on 01 March 2015

Further update 3

• Guideline on principles of GDP for active substances – Draft based on ICH Q7 for public consultation

ended 30 April 2013 • Guideline on formalised risk assessment for

ascertaining appropriate GMP for excipients – Draft for public consultation ended 30 April 2013

Distribution

Objective: Strengthened Good Distribution Practice (GDP) provisions

– Revised GDP Guideline published • e.g. Obligation for wholesalers to notify authorities when in

receipt of or offered products identified or suspected of being falsified

– Introduction of brokers into scope of pharmaceutical legislation • Registration with relevant National Competent Authority • Some GDP obligations • Possibility for inspection Union database for Wholesale Distribution Authorisation Holders (and GDP Certificates, GDP non-compliance)

Safety Features

Objective: To secure integrity and authenticity of products 1. Tamper-evidence: At discretion of manufacturer 2. Unique identifier: Subject to further legislation

The Drug Quality and Security Act (DQSA)

• Signed by President Obama on 27 November 2013.

• Two-part bill – Title I: Compounding Quality Act – Title II: Drug Supply Chain Security Act

Internet Sales

Objective: Protection of public health with regard to retail purchase of medicines through the internet 1. Registration of suppliers of medicines at a

distance 2. Common European Logo

Transposition of the FMD in the UK SI 2013 / 1855 The Human Medicines (Amendment) Regulations 2013

• Came into force on 20th August 2013

It’s now the law!!

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Requirements and Expectations Applied To

• Manufacturers, Importers and Distributors of Active Substances

• Manufacturing Authorisation Holders • Import for Export • Wholesale Distributors • Brokers • EU Competent Authorities

Internet Sales

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Internet purchase

Spiceway, Rutherglen products

GSR Distributions Ltd, trading as Spiceway, Rutherglen, Glasgow have

been found to be operating as an unapproved cutting plant.

These products are sold loose in polythene bags. No information available on specific product names, brand name, batch codes,

durability dates or country of origin. Full distribution is not available and the

product could have been distributed nationally. Some/all of the food items listed have been supplied and distributed internet

sales.

OPERATION PANGEA

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Operation PENGEA

• Coordinated by INTERPOL • An annual operation with customs, health

regulators, national police and private sector • Combat online sale of counterfeit and illicit

medicines by targeting: – Internet Service Provider – Electronic payment systems – Mail delivery service

• Highlight the dangers of buying medicines online

Operation PENGEA Date Participating

countries Results

I Nov 2008 10 • Commercial websites taken down • Postal depots monitored and parcels

examined • Counterfeit medicines confiscated • Counterfeit medicines withdrawn from

circulation • Money seizure • Individuals arrested/under investigation • Consumer awareness raised via global

press coverage

II Nov 2009 25

III Oct 2010 44

IV Sep 2011 81

V Oct 2012 100

VI Jun 2013 99

VII May 2014 113

Operation PENGEA

So far in estimate……….. 57450 websites taken down 28million fake and illicit medicines seized Seizures worth more than USD $92m 880 arrests

Work Continuation at the MHRA

• The MHRA Enforcement Team continually monitors internet sites, especially those known to be selling Prescription Only Medicines.

• Spot checks are made to see if the Internet sites selling prescription only medicines are based in the UK. If so, appropriate actions e.g. prosecutions will take place.

• Overseas sites are referred to the appropriate regulatory body in that country.

Work Continuation at the MHRA

• Ensure that there is proper guidance to support the safe purchase of medicines over the Internet.

• A key role in a Department of Health working party on the sale and supply of medicines in the UK over the Internet.

• These moves are intended to reconcile the increasing trend towards electronic commerce, including the growth of e-pharmacies supplying prescription only medicines, with the protection of patient safety and public health.

Project ICMRA International Coalition of

Medicines Regulatory Authorities

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ICMRA - Introduction

Provide a global architecture to support enhanced communication, information sharing, crisis response and address research gaps

MRA Challenges • Growing complexity in medicinal products and their

ingredients (e.g. new chemical entities and innovative drugs)

• Growing complexity of globalised supply chains • Ensuring the safety, quality and efficacy of medicinal

products domestically requires knowledge of and confidence in these supply chains

• Growing number of international regulatory initiatives, lacking integration and strategic oversight

• Gaps/vulnerabilities in global regulatory oversight providing opportunities for the tampering and counterfeiting

• Pressures to harmonise and align regulatory practices and activities

Management Committee

There are 20 management committee including 12 interim management committee. 7 Working Groups set up by ICMRA 1. Governance 2. Mapping existing initiatives 3. Communication 4. GMP inspections 5. Generic medicines 6. Information sharing 7. Capacity Building

MHRA Inspection Deficiencies

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Overview of GMP Inspections Carried Out Of 630 GMP inspections carried out in 2013, 216 resulted in Major or Critical Deficiencies.

– Of the inspections with Major/Critical deficiencies • 174 were in the UK • 42 were overseas

– The sites with Major/Critical deficiencies comprised of • 170 Facilities with MIA, MS & IMP licences, or

overseas manufacturers • 32 Blood Sites • 14 API Manufacturing Facilities

Overview of GMP Inspections Carried Out

432 critical/major deficiencies raised (29/403) 23 of these were related to Supplier and contractor audits This made it the 5th most frequent critical/major category in 2013

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Most Common Findings for Sites (Excluding Blood Sites)

All Critical/Major Defect Areas

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1. Quality Management 262 3. Materials Management 102 7. Validation 65

Batch release procedures Supplier and contractor audit Validation master plan and documentationComplaints and Product recall Compliance with TSE guidelines Analytical Validation

Quality management Warehousing and distribution activities – General Issues

Cleaning validation

Quality management – change control Warehousing and distribution activities - Transportation Temp Control and Monitoring

Equipment validation

Quality management – product quality review Warehousing and distribution activities - General Storage Temp Control and Monitoring

Computerised systems – validation

Quality management – risk management Warehousing and distribution activities - Lack of inventory control and segregation

Computerised systems – documentation and control

Self inspection Warehousing and distribution activities - Records – receipt and distribution

Process validation

Investigation of anomalies Warehousing and distribution activities - Returns Management

Process validation - rework/reprocessing

Investigation of anomalies – CAPA Starting material – API compliance with GMP 8. Regulatory Compliance 41

Investigation of anomalies – OOS Supplier and contractor technical agreements Regulatory issues – non compliance with MIA

Documentation - procedures/PSF/TAs 4. Premises and Equipment 86 Regulatory issues – non-compliance with MA/CTA

2. Production 127 Design and maintenance of equipment Regulatory issues – unauthorized activity

Sterility Assurance - Aseptic Practices Design and maintenance of premises Regulatory issues – non compliance with DMFSterility Assurance - Sterilisation Environmental control Failure to respond to previous inspection findings

Sterility Assurance - Process Design Calibration of measuring and test equipment 10. Personnel 38

Sterility Assurance - Media Fill 5. Quality Control 68 Personnel issues – training

Sterility Assurance - Sterility Investigations Sampling procedures and facilities Personnel issues – duties of key personnel

Contamination, chemical/physical – potential for Sampling procedures &facilities – retention & retain samples

Personnel issues – hygiene and clothing

Documentation – manufacturing Documentation – specifications and testing

Line clearance, segregation and potential for mix-up Starting material and packaging component testing

Housekeeping – cleanliness and tidiness Computerised systems – data manipulationContamination, microbial – potential for Finished product testing - chemicalStatus labelling – work in progress, facilities, equipment

Finished product testing - microbiological

Environmental monitoring Finished product testing – on-going stability monitoring

In-process control and monitoring of production operations

Intermediate and bulk product testing

Handling and control of packaging components Calibration of reference materials and reagentsProduction planning and scheduling

• The total number of Critical/Major Deficiencies observed in each category is shown in the table above.

• It can be seen that ‘Quality Management’ related deficiencies are by far the most frequent.

Additional Deficiencies

• Audits had not been performed • There was no CV of the auditor who performed the audit. • Audit of a sterile site – the auditor CV showed no evidence

of steriles knowledge / experience • Where the audit reported "critical" cleanliness/mix up

issues, no action had been taken and the site was still used a year later.

Critical GDP Deficiency

1.1 System for receiving medicinal products in to the warehouse: 1.1.1 A significant quantity of medicines was identified on site that had been reviewed, placed in to storage and offered for sale. There was no paper available to demonstrate these medicines were reviewed from an approved supplier. There were no records to indicate when the redelivery had been made and by what company. The identified products had been stolen from other wholesaler.

Critical GDP Deficiency 1.2 The qualification of suppliers was deficient: 1.2.1 The medicines noted in 1.1 had been sourced from XXX Limited. The qualification of this supplier consisted of a check on the MHRA website only. There had been no due diligence check on this company to establish suitability, competence and reliability of the other party. XXX Limited are stated on Companies House as a dissolved company. 1.2.2 The company SOP for supplier verification had not been followed and no copy of XXX Limited wholesale dealers licence had been obtained prior to dealing with them.

Critical GDP Deficiency

1.3 The responsible Person had failed carry out their role effectively: 1.3.1 The RP had failed to properly assess and implement changes to wholesale dealing activities introduced by the “Guidance of 5 November 2013 on Good Distribution Practice of Medicinal Products for Human Use” (2013/C 343/01). The RP had not read the new GDP guidelines. 1.3.2 The RP had failed to implement and maintain an appropriate and effective quality system as evidence from the deficiencies at 1.1 and 1.2

Areas for Attention Data Integrity (DI) DI issues, both as a result of bad practice and to a significantly lesser extent intentional fraud, have been observed across all geographical locations and sectors of the industry with some very high profile cases being observed recently. There will therefore be a focus on this area during inspections in the near future. In addition; the MHRA has communicated an expectation that companies will carry out a routine effectiveness review of their governance systems to ensure data integrity and traceability are maintained (see MHRA communication issued on the 16th Dec 2013) http://www.mhra.gov.uk/Howweregulate/Medicines/Inspectionandstandards/GoodManufacturingPractice/News/CON355490

Areas for Attention Falsified Medicines Directive (FMD) When the FMD legislation (European Directive 2011/62/EU) came into force in the UK on 20 August 2013, a number of requirements were introduced, including; – manufacturers, importers and distributors of APIs are required to register with the MHRA. MIA holders are required to confirm the registered status of their API suppliers. – API imported from a third country is required to be accompanied by a third country authority written confirmation of EU GMP equivalence, or a waiver described in Art 46(b) of the Directive. – Brokers of finished medicinal products in the UK have to register with the MHRA Compliance with the requirements of the FMD legislation along with the knowledge and maintenance of the supply chain will be a focus during inspections.

Industries’ Responsbilities

• Strengthen existing Quality Management System • Extend Quality to the Supply Chain • Maintain Supplier Compliance Management • Implement Risk Management Processes to the

Supply-Chain

Closing Remarks

• Compliance with the requirements introduced by the FMD is now a legal obligation

• New Guidance documents are available or are in the process of being issued

• Further changes and requirements will be introduced once the delegated act on safety features comes into force

• MHRA Falsified Medicines Directive Webpage – http://www.mhra.gov.uk/Howweregulate/Medicines/Over

viewofmedicineslegislationandguidance/TheFalsifiedMedicinesDirective/index.htm

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A supply chain is

Thank You

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