Global Outsourcing - Current Challenges and Future Direction - IPQ

Safeguarding public health 

Global Outsourcing 

Current Challenges 

and Future Direction 

A UK Inspector‟s View 

Rachel Carmichael, GMP Inspector. 

GOC, June 2010 

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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 effective 

and 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 – 20 th Century 

Manufacturer 

Pharmacy 

Wholesale dealer 



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Supply Chains – 21 st Century 

API 

Source 

Excipient 

Source 

Repacker 

Broker 

Manufacturing 

site 

Packing site 

Marketing 

Authorisation 

Holder 

Contract 

QC testing 

Distribution hub 

QP Release 

Site 

In-transit hubs 

Importation 

storage site 

Wholesale 

Dealer 

Pharmacy 

Importation 

QC testing 



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API 

Source 

Excipient 

Source 

Repacker 

Broker 

Manufacturing 

site 

Packing site 

Marketing 

Authorisation 

Holder 

Contract 

QC testing 


QP Release 

Site 


Importation 

storage site 

Wholesale 

Dealer 

Pharmacy 

Importation 

QC testing 



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Supply Chains 

Wholesale 

Dealer 

(non UK) 

Parallel 

Importer 

(UK) 

Relabelled 

Wholesale 

Dealer 

(UK) 

UK 

Pharmacy 

Wholesale 

Dealer 

Parallel 

Exporter 

(UK) 

Parallel 

Importer 

(non UK) 

Wholesale 

Dealer 

(non UK) 

Relabelled 

Collation 

Non UK 

Pharmacy 



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API 

Source 

Excipient 

Source 

Repacker 

Broker 

Manufacturing 

site 

Packing site 

Marketing 

Authorisation 

Holder 

Contract 

QC testing 


QP Release 

Site 


Importation 

storage site 

Wholesale 

Dealer 

Pharmacy 

Importation 

QC testing 



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EMA revision process outline 

Problem 

Statement 

Concept Paper 

Drafting Group 

Appointed 

Drafting group 

considers public 

comments 

Second public 

consultation 

Release for 

consultation 

by EC 

Draft adopted by 

GMP/GDP IWG 

Final text 

adopted by IWG 

Final text 

adopted by EC 

Publish 



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· Managing a contract 

· QP duties – API GMP 

· Transportation 

· Counterfeit materials 



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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 

Extract from a Technical Agreement 

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 

x 

(x) 

= Primary responsibility 

= 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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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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QP duties – API GMP – Current challenge 

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” 



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QP duties – API GMP – Future Direction – 1 

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 



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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 

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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Transportation – Current challenge 

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 



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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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· QP duties – including API GMP 





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Counterfeit Incidents - UK Regulated supply chain 

6 

5 

4 

3 

2 

Wholesale level 

Clinical Trials 

Pharmacy level 

1 

0 

1994-2003 

2004 

Wholesale 

2005 

Clinical Trial 

Pharmacy 

2006 

2007 

2008 

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

Alopecia, Erectile dysfunction 

Anti - platelet 

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

dysfunction, Prostate cancer, Appetite suppressants, 

Chronic asthma 



2009 

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MHRA Anti-counterfeiting Strategy 

Communication 

Public and Healthcare Professionals 

Collaboration 

International, Industry, Law Enforcement and Regulators 

Regulation 

Threat Assessment, Targeted Market Surveillance, 

Investigation and Prosecution 

Review 

UK 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 3 rd countries 

• Increased transparency of inspection results 

– publish through EudraGMP database 



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API 

Source 

Excipient 

Source 

Repacker 

Broker 

Manufacturing 

site 

Packing site 

Marketing 

Authorisation 

Holder 

Contract 

QC testing 


QP Release 

Site 


Importation 

storage site 

Wholesale 

Dealer 

Pharmacy 

Importation 

QC testing 



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Summary 

• 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 



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Global Outsourcing - Current Challenges and Future Direction - IPQ

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