Global Outsourcing Current Challenges and Future Direction · 2014-10-16 · Global Outsourcing -...

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Safeguarding public health

Global Outsourcing

Current Challenges

and Future Direction

A UK Inspector‟s View

Rachel Carmichael, GMP Inspector.

GOC, June 2010

Rachel Carmichael, GMP Inspector June 2010

Global Outsourcing - Current Challenges and Future Direction 2

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Introduction

Background

Current challenges and future direction

Summary



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Rachel Carmichael, GMP Inspector

BSc. Biochemistry

MSc. Marketing

MSc. Industrial Pharmaceutical Studies

Eligible, EU Qualified Person (QP)

Babcock King-Wilkinson

Placements at Glaxo, Wellcome and Eli Lilly

Eli Lilly, Non Sterile, Dry products production

MHRA since 2004



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Medicines and Healthcare products Regulatory Agency

(MHRA)

Mission

to enhance and safeguard the health of the public by

ensuring that medicines and medical devices work, and

are acceptably safe

Aims

Protecting public health

Promoting public health

Improving public health



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The UK Inspectorate

UK Inspectorate comprises 5 disciplines:

Good Laboratory Practice (GLP)

Good Clinical Practice (GCP)

Good Manufacturing Practice (GMP)

Good Distribution Practice (GDP

Good Pharmacovigilance Practice (GPvP)

Located at three sites in the UK



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The UK Inspectorate

Inspections mainly within UK but:-

Perform inspections on behalf of:

• Organisation for Economic Co-operation and Development (OECD)

• European Medicines Agency (EMA) • Mutual Recognition Partners (MRA)• European Directorate for the Quality of Medicines & HealthCare

(EDQM)• Veterinary Medicines Directorate (VMD)• World Health Organisation (WHO)

Inspect in over 30 countries, each GMP Inspector may work approx. 6 – 8 weeks / annum overseas



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The function of a GMP Inspector

Compilation of Community Procedures

6. General Considerations on Inspections

6.1 …primary role …protection of public health in accordance with Community provisions.

6.2 …function …to ensure adherence by manufacturers to GMP principles and guidelines including licensing provisions.

6.3 …primary goal ….. to determine whether the various elements within the quality assurance system are effectiveand suitable for achieving compliance with GMP principles…………



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Polling Question

Are you currently outsourcing:

1. Manufacturing

2. Laboratory testing

3. Artwork – leaflets, labels

4. More than one of a) to c)

5. None of the above



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Supply Chains – 20th Century

Manufacturer Pharmacy

Wholesale dealer



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Supply Chains – 21st Century

Marketing

Authorisation

Holder

Pharmacy

API

Source

Excipient

Source

Broker

Repacker

Manufacturing

site Packing site

Distribution hub

In-transit hubs Importation

storage site

Importation

QC testing

Wholesale

Dealer

Contract

QC testing QP Release

Site



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Marketing

Authorisation

Holder

Pharmacy

API

Source

Excipient

Source

Broker

Repacker

Manufacturing

site Packing site

Distribution hub


storage site

Importation

QC testing

Wholesale

Dealer

Contract


Site



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Supply Chains

Wholesale

Dealer

(non UK)

Parallel

Importer

(UK)

Relabelled

Wholesale

Dealer

(UK) UK

Pharmacy

Wholesale

Dealer

Parallel

Exporter

(UK)Collation

Wholesale

Dealer

(non UK)

Parallel

Importer

(non UK)

Relabelled

Non UK

Pharmacy



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Marketing

Authorisation

Holder

Pharmacy

API

Source

Excipient

Source

Broker

Repacker

Manufacturing

site Packing site

Distribution hub


storage site

Importation

QC testing

Wholesale

Dealer

Contract


Site



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Problem

StatementConcept Paper

Drafting Group

Appointed

Draft adopted by

GMP/GDP IWG

Release for

consultation

by EC

Drafting group

considers public

comments

Final text

adopted by IWG

Final text

adopted by ECPublish

Second public

consultation

EMA revision process outline



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· Managing a contract

· QP duties – API GMP

· Transportation

· Counterfeit materials




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· Transportation




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Managing a contract

Chapter 7 of EU Guide to GMP

There must be a written contract between the Contract Giver and

the Contract Acceptor which clearly establishes the duties of each

party

Often referred to as a Technical Agreement



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Managing a contract – common deficiencies

No (signed) Technical Agreement

No requirement for an Agreement to be in place

Agreement essentially commercial in nature

Agreements not routinely reviewed

Lack detail concerning GMP responsibilities

Lack detail concerning technical requirements

Document refers to Appendices that do not exist



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Managing a contract – interesting deficiencies

Failure to address three-way responsibilities

Failure to incorporate “new” requirements into the Technical

Agreement

Contract Acceptor and Contract Giver defined incorrectly

Uncontrolled subcontracting



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Managing a contract – Expectations

Section No.

Subject / Terms Customer Manufacturer

4.1 Quality Management

4.1.1 GMP, Health and Safety Compliance X X

4.1.2 Customer Audit Rights X

4.1.3 Subcontracting (X) X

4.1.4 Self-Inspection X

4.2 Regulatory Requirements

4.2.1 Permits X

4.2.2 Regulatory Filing / Registration Change Control X (X)

4.2.3 Regulatory Compliance X

4.2.4 Government Agency Inspections, Communications and Requisitions

(X) X

Extract from a Technical Agreement

x = Primary responsibility

(x) = Secondary responsibility



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Managing a contract – future direction – 1

What about other “outsourced” activities such as:

· Qualification and validation work for new premises

· Maintenance and calibration of equipment and premises

· Storage and distribution

· Artwork generation and print ready material

· Assessment and sourcing of starting and packaging materials



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Managing a contract – future direction – 2

Any outsourced activity which if it were performed would normally

be subject to inspection

Current proposal

Review the scope and detailed content of Chapter 7

Prepare gap analysis between the existing guidance

and modern pharmaceutical supply chain management

Aim Proposals for a revision of guidance

Initial draft June 2010

Start Consultation September 2010

Finalised guideline September 2011



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· Transportation




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QP duties

The duties of the Qualified Person(s) are fully described in

Article 51 of Directive 2001/83/EC

EU GMP, notably Annex 16, details the requirements

Eligibility as a QP depends on the Country within Europe



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Basic expectation

API manufacturer audited in line with Part II of EU GMP

QP “declares” that the API manufacturer is Compliant

The API used should be that listed in the Marketing

Authorisation (MA) and as per the “QP declaration”

QP duties – API GMP – Current challenge



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Proposal - Fully detailed API Supply Chain “pedigree”

Suppliers of critical raw materials / intermediates

Manufacturers concerned with manufacture of API up to the point

of release of final API

• Includes contractors, traders, consolidators

QP duties – API GMP – Future Direction – 1



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Proposal - Fully detailed API Supply Chain “pedigree”

Suppliers/sites acting from the point of release of final API

to receipt by the finished product manufacturing site

• Includes re-packagers, re-labellers, brokers, importers

Risk assessments for sites in the supply chain




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Update EU GMP

Chapter 1: Quality management

Product Quality Review (includes review of starting materials; change to require this to include the supply chain)

Chapter 5: Production

Include a requirement to verify, on receipt, that materials have come via the expected supply chain




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“The QP Declaration Template”

Concerning GMP compliance of the active pharmaceutical ingredients used as starting material and verification of existence of an associated supply chain




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· Transportation





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Transportation

Guidelines on Good Distribution Practice of Medicinal Products for

Human Use (94/C 63/03)

20. Medicinal products should be transported in such a way that :

d) they are secure and not subjected to unacceptable degrees

of heat, cold, light, moisture or other adverse influence, nor

to attack by microorganisms or pests



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Transportation – common deficiencies

No temperature data available during transit

No review of the temperature data conducted prior to QP Certification

Number of dataloggers vary between shipments: - Driven by what the manufacturer has available- Not prescribed and driven by customer specification

Lack of awareness of the distribution chain Use of unapproved transport hubs en route to final destination



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Transportation – Interesting deficiency – 1

2009 Recall – 111 product lines

Imported into the EU

– shipped under “ambient” conditions

Nearly 60ºC, Rh over 90%, 30 to 50 days

worse than accelerated stability

set at 40ºC and 75%Rh



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Use of Mean Kinetic Temperature (MKT)

• Require shipping conditions to be reasonable, consistent and

controlled

• MKT more appropriate for a transient excursion in a warehouse

due to local extremes

• MKT should not be used to justify the use of low-cost transport

around the world and is hard to justify unless entire history of

batch is known

Transportation – Current challenge



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Transportation – Expectations

Goods will be shipped under „acceptable‟ conditions of temperature

and humidity

Transport conditions will be monitored throughout the supply chain

including areas such as road transport and docks

Transport times will be monitored and „excessive‟ journey times

avoided

The QP will audit/seek further information about the stages where

general services (rather than Pharma-specialists) are used



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Transportation – Expectations

Dataloggers will be calibrated with traceability to national

standards, accurate to ±0.5ºC, and subject to a planned

maintenance schedule

Data will be downloaded, read and acted upon promptly

The QP will certify that acceptable conditions - temperature,

humidity and time - have existed during shipment prior to product

release



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Storage Conditions during Transport

– future direction – 1

The proposed guideline will consider the need to revise guideline:

CPMP/QWP/609/96/Rev2 – „Guideline on Declaration of Storage

Conditions: A: In the Product Information of Medicinal Products B:

For Active Substances‟ and the relevant veterinary guidance

Align with the text in the GDP guidance (under revision) and GMP

Chapters 5, 6 and 7, Annex 15 (all currently under revision), Annex

16 and create new „Frequently Asked Questions‟



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Storage Conditions during Transport

– future direction – 2

Aim Proposals for a revision of guidance

Concept Paper June 2010

Initial Draft November 2010

Start Consultation December 2010

Finalised guideline May 2011



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Wholesale Anti- cholesterol, Anti- inflammatory, Anti-platelet,

Alopecia, Erectile dysfunction

Clinical Trial Anti - platelet

Pharmacy Anti-cholesterol, Anti-platelet, Anti-psychotic, Erectile

dysfunction, Prostate cancer, Appetite suppressants,

Chronic asthma

0

1

2

3

4

5

6

1994

-200

320

0420

0520

0620

0720

0820

09

Wholesale level

Clinical Trials

Pharmacy level

Counterfeit Incidents - UK Regulated supply chain



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MHRA Anti-counterfeiting Strategy

CommunicationPublic and Healthcare Professionals

CollaborationInternational, Industry, Law Enforcement and Regulators

RegulationThreat Assessment, Targeted Market Surveillance, Investigation and Prosecution

ReviewUK Supply chain, point of importation to point of dispensing, Influence European directives



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UK Review of Supply Chain Proposals

Wholesale Dealers

„fit and proper person‟ requirements, due diligence obligations

Responsible Persons

minimum qualifications, continuous presence, due diligence

Medicines imported for export

authority to inspect, due diligence, record keeping

Storage and Transit of Medicines

compliance, powers to inspect, named on licenses



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European Proposals

EU Directive 2001/83/EC

Amendment - prevention of the entry into the legal supply chain of medicinal products which are falsified in relation to their identity, history or source

• Extending regulation to traders and brokers

• Increased auditing obligations placed on wholesale distributors

• Legal basis for obligatory specific safety-features on certain medicines

• Increased controls on imports of API‟s from 3rd countries

• Increased transparency of inspection results – publish through EudraGMP database



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Marketing

Authorisation

Holder

Pharmacy

API

Source

Excipient

Source

Broker

Repacker

Manufacturing

site Packing site

Distribution hub


storage site

Importation

QC testing

Wholesale

Dealer

Contract


Site



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• Understand your Supply Chain

• Manage the relationship – Technical Agreement

• In the EU – The QP is responsible

from API to finished product dispatch

• Transportation conditions should be clearly specified

and compliance to transportation conditions demonstrated

Summary

Global Outsourcing Current Challenges and Future Direction · 2014-10-16 · Global Outsourcing -...

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