Qualification, Monitoring and

Challenges in Working with International

Suppliers

Elaine DymondVice President, Quality

August 10th, 2011

1

Topics to be discussed:

• The challenges faced by the Pharma industry in dealing with suppliers from within the EU vs. USA / Rest of World.

• Understanding the diversity of rules and regulations associated with supply, especially from within the EU and in meeting QP (Qualified Person) requirements.

• The EU GMP guidelines in relation to Supplier Quality – how these must be applied and considered when working with International Suppliers.

• The wide range of risk from different products around the world supplied by the same supplier and how to overcome and mitigate these risks.

• Ways to approach qualifying and then monitoring your supplier, ensuring compliance with EU guidelines.

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The challenges faced by the Pharma industry in dealing with suppliers from within the EU vs. USA / Rest of World.

General Challenges:

• Diversity of supplied product

— OTC/VMS P/POM Rx

• Diversity of Dosage forms

- Solid Dose: Tablets, Softgel, Modified Release, Rapid Melt /Buccal release, Suppositories

- Liquids: Parenterals, Biologicals, Creams, Ointments, Patches

• Wide range of risk from different products:

- Animal sources: Gelatin, Fish Oils

- Biological Seed Banks

- Rx: API, Excipients

- Plant Extracts: Herbals

- VMS: Mineral Extraction

3

The challenges faced by the Pharma industry in dealing with suppliers from within the EU vs. USA / Rest of World.

General Challenges:

• Varying complexity of obtaining materials and components from International suppliers

- Material manufactured in one continent, transported for use in another region, e.g. China into EU

- Different products provided by the same supplier to the same customer

- Same product provided by different supplier

- Same product but with different chemical standards

Consistency of Quality ?

• Diverse regulatory standards –

- WHO, ISO, PDA, ICH

• Wide ranging multinational standards –

- FDA, Eudralex EU, TGA, ANVISA, Asia (Japan & Korea), Middle East (Saudi Arabia)

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The challenges faced by the Pharma industry in dealing with suppliers from within the EU vs. USA / Rest of World.

EU Challenges

• Generally challenging GMP standards

- Diversity of standards within the EU Regulatory Agencies:

MHRA to developing EU member states

- Increased focus on raw material standards / suppliers: FalsifiedMedicines Directive (2001/83/EC)

USA / Rest of World challenges

• Geographical locations

• Complexity of standards

— Difference in stringency

— Difference in inspection styles

• Significance of emerging markets: China, S.E Asia, India

• Increase in contamination and counterfeiting e.g. Glycerine in Panama, Odour from transportation pallets

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Understanding the diversity of rules and regulations associated with supply, especially from within the EU and in

meeting QP requirements

Diversity of Global Regulations facing Suppliers

• FDA – 21CFR Parts 210/211

• WHO guidelines/Annexes

• PIC/S guidelines (Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme)

- Virtually identical to EU GMP Guide

- 39 countries participate

• ICH guidelines

- ICH Q7A - Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients

- ICH 9 – Quality Risk Management

- ICH 10 – Guidelines for Quality Risk Management

• GMP guidelines from Industry Organisations: IPEC/ISPE/PDA

• Pharmacopoeias: USP / EP / JP

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Understanding the diversity of rules and regulations associated with supply, especially from within the EU and in

meeting QP requirements

Diversity of EU Regulations facing Suppliers

EU:

1. European Medicines Agency (EMA)

- 11 Quality Guidelines (Similar to EU GMP Guidelines)

2. EU EudraLex - Volume 4 Good Manufacturing Practice (GMP) Guidelines

UK: Rules and Guidance for Pharmaceutical Manufacturers and Distributors (the “Orange Guide”) 2007

- Part 1

- Part 11

- Increased focus on raw material standards andsuppliers: Falsified Medicines Directive (2001/83/EC)

7

The EU GMP guidelines in relation to Supplier Quality – how these must be applied and considered when working with

International Suppliers.

EU GMP Guidelines: Eudralex Vol. 4: "The rules governing medicinal products in the European Union" - Contains guidance for GMP for medicinal products for human and veterinary medicines (Directive 2003/94/EC, and 91/412/EEC)

- Divided into 3 parts:

Part 1- Basic Requirements for Medicinal Products

Chapter 1 Quality Management

Chapter 2 Personnel

Chapter 3 Premises and Equipment

Chapter 4 Documentation

Chapter 5 Production

Chapter 6 Quality Control

Chapter 7 Contract Manufacture and Analysis

Chapter 8 Complaints and Product Recall

Chapter 9 Self Inspection

Part II - Basic Requirements for Active Substances used as Starting Materials

Basic requirements for substances used as Starting Materials

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The EU GMP guidelines in relation to Supplier Quality

EU GMP Guidelines: Eudralex Vol. 4: "The rules governing medicinal products in the European Union"

Part 111- GMP Related DocumentsSite Master FilesQ9 Quality Risk ManagementQ10 Pharmaceutical Quality Systems

Annexes1 – 19 covering different Dosage Form Manufacture, Key Quality Systems, Validation etc.

Key Annexes1 Sterile manufacturing2 Biologicals8 Starting and Packing Materials9 LCO’s15 Validation16 QP and Batch Release

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The EU GMP guidelines in relation to Supplier Quality -Supplier Requirements in order to comply to EU Regulations.

Part 1,

General Requirements for Pharma Suppliers – Vol. 4, Part 1:

• Only purchase from an approved supplier named in the spec (? How to approve)

• Relevant specifications must be in place

• Purchase preferably directly from manufacturer

• Supplier must have QMS System in place, including

• Complaints

• Rejection procedures

• Materials Handling procedures

• Labeling procedures

• Material Packing procedure

• All aspects of GMP must be in place at manufacturing facility (? How to confirm)

• Prevention of cross contamination measures must be in place

• Integrity of containers / drums must be confirmed together with appropriate labeling

• Material must be fit for purpose and tested accordingly for dosage form

10

The EU GMP guidelines in relation to Supplier Quality -Supplier Requirements in order to comply to EU Regulations.

Part II.

General Requirements for Pharma Suppliers – Vol. 4, Part II:

Basic Requirements for Active Substances used as Starting Materials

• Adopted in January 2010 (Linked to Annex 18 & ICH Q7)• Relevant specifications must be in place• Purchase preferably directly from manufacturer• Supplier must have QMS System in place, including

• Complaints• Rejection procedures• Materials Handling procedures• Labeling procedures• Material Packing Procedure

• All aspects of GMP must be in place at manufacturing facility (? How to confirm)• Prevention of cross contamination measures must be in place• Integrity of containers/ drums must be confirmed together with appropriate

labeling• Material must be fit for purpose and tested accordingly for dosage form

-

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Vol. 4, Part II: Basic Requirements for Active Substances used as

Starting Materials

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Eudralex Vol. 4, Part II: Basic Requirements for Active Substances used as Starting

Materials

Chapter 1 Objectives

Chapter 2 Quality Management

- Risk Management,

- Self Inspection

- Product Quality Reviews

- QA, QC, Production Management

Chapter 3 Personnel

- Qualifications

- Consultants

Chapter 4 Buildings and Facilities

- Design

- Utilities

*Areas of concentration

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Eudralex Vol. 4, Part II: Basic Requirements for Active Substances used as Starting

Materials

Chapter 5 Process Equipment

- Design

- Cleaning

- Maintenance

- CSV

Chapter 6 Documentation / Records

- Manufacturing and Quality

Chapter 7 Materials management

- Receipt

- Quarantine

- Sampling and Testing

Chapter 8 Production and In Process Control

- Blending

- Contamination Control

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Eudralex Vol. 4, Part II: Basic Requirements for Active Substances used as Starting

Materials

Chapter 9 Packaging of API’s

- Identification

- Labeling (including intermediates)

Chapter 10 Storage and Distribution

- Warehousing

- Distribution Control

Chapter 11 Laboratory Controls

- Testing of Intermediates and API’s

- Reference Samples

- Analytical Validation

- C of A’s

- Stability testing

- Expiry Dating and Retesting

- Retention Policy/testing

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Eudralex Vol. 4, Part II: Basic Requirements for Active Substances used as Starting

Materials

Chapter 12 Validation- Qualification- Process, Analytical, Cleaning validation

Chapter 13 Change Control

Chapter 14 Rejects and reuse of Material- Rejection- Reprocessing- Reworking- Recovery- Returns

Chapter 15 Complaints and Recall

Chapter 16 Contract Manufacturers and Laboratories- Need for GMP- Contact / Quality Agreements- QMS

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Falsified Medicines Directive (2001/83) – EU law May, 2011

• Adopted in May 2011 by EU Parliament • To become transposed into EU national law within 18 months.• Significant change to EU law and responsibilities of the

manufacturer, supplier and the QP!• QP Declaration for API/Excipient manufacture

Falsified Medicine False representation of:False representation of:

1. Excipient / API Identity, including packaging, labelling, composition and strength

2. API source, including manufacturer, country of manufacture, country of origin, MA holder

3. Its history, including records relating to its distribution4. Directive extends to all Excipients and API’S5. All API’s to be made to GMP and distributed to GDP

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Falsified Medicines Directive (2001/83) – implications for Suppliers and Manufacturers

• The manufacturer of the API MUST follow GMP regardless if made in the EU or imported.

• The manufacture in third countries of active substances which are intended for export to the EU, MUST provide for a level of protection of public health equivalent to that provided by EU law.

• Importers must be registered with the competent authority.

• Manufacturers MUST ensure that Excipients are suitable for use in medicinal products.

• Manufacturers will be obliged to inform competent authorities ofmedicines they suspect of being falsified.

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Falsified Medicines Directive –Implications for Suppliers and Manufacturers QP’s

-

Suppliers and

Manufacturers

MUST be ready

for the challenges this

change will bring !

NEW!!

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Implications for Suppliers and Company QP’s on the QP Declaration

IT WILL BE THE QP AT THE SUPPLIER (IF APPLICABLE) AND THE RECEIVING MANUFACTUER QP TO ENSURE COMPLIANCE.

• Be ready for challenges to Ch 5 of EU GMP guidelines relating to Qualification of Suppliers of Starting Materials and Supply Chain Reliability

• Primary responsibility of the manufacturer to qualify and audit their API suppliers

• The Supply chain of each starting material MUST be known i.e. ‘The Supply Chain Pedigree’

- Will include all API’s - verification must be done via auditing and through documentation - All Excipients will be included – risk assessment to qualify use allowed

• Significant change to EU law and responsibilities of the manufacturer, supplier and the QP!

QP Declaration for API/Excipient manufacture

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How to Mitigate risk when choosing and qualifying your Supplier, ensuring compliance with EU guidelines

TO REDUCE RISK AUDIT !

• Establish a sound sourcing strategy

• Select Key, Well known, Reliable suppliers

• Establish who will evaluate the Supplier (In the EU, from May 2011, needs to be a QP)

• Select an appropriate method of evaluation - Pre – audit Questionnaire / Past Audit reports

• Perform the audit (? To what standards/Guidelines)- In the EU, Supplier must be audited against EU GMP Guidelines: Eudralex Vol. 4 Part II

• Include all aspects of ICH 9 & 10 and in relation to ‘Risk Assessment’(The Regulators will!)

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How to Monitor your Supplier, ensuring compliance with EU guidelines

CONTINUE TO REDUCE RISK!

1. Develop and utilise Supplier Performance Information

2. Set up Supplier Scorecards with them

3. Use meaningful Scorecards to BOTH parties

4. Establish robust KPI’s to evaluate, track and continue to rate your suppliers

5. Use the 80/20 rule, those with most risk/impact to your business to select the most appropriate KPI’s

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How to Monitor your Supplier, ensuring compliance with EU guidelines

CONTINUE TO REDUCE RISK

6. Think of other ways to assess and track your supplier – Quality metrics

1. - BRnRFT rate

2. - Deviations rate – real time metrics

3. - On time CAPA closure

4. - Non-Conformance rate

7. Establish excellent channels of communication between you and your Supplier (Especially between QP’s)

8. Ensure they are aware of what's expected of them from you e.g. Continuous Improvement, Six/Lean Sigma, Black Belts, ISO Certification etc

9. Make their Metrics portal visible to them – Supplier Self tracking / Assessment!

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How to Monitor your Supplier, ensuring compliance with EU guidelines

CONTINUE TO REDUCE RISK

10. Make sure they understand the requirements of the new EU Guidelines Part II, Chapter 5!

1. - Supply Chain Pedigree

2. - Will result in increased Regulatory & Customer Scrutiny of API Suppliers

3. - Suppliers understand the requirements of the QP Declaration andprovide it!

11. Finally – agree on a re-audit schedule with the Supplier and stick to it!

CONTINUE TO COMMUNICATE BETWEEN YOU AND YOUR SUPPLIER

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Qualification, Monitoring and Challenges in Working with International Suppliers

THANK YOU!

ANY QUESTIONS?

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References / Web links

• www.gmp-compliance.org/eca_link_navigator.html

• www.ec.europa.eu/health/files/eudralex/vol-4

• www.ema.europa.eu/ema/indexWHO guidelines

• www.ich.org/products

• www.picscheme.org

• http://www.edqm.eu/en/Homepage-628.html

• http://www.usp.org/

• http://www.tga.gov.au/index.htm

• http://www.mhra.gov.uk/Publications/Regulatoryguidance/Medicines/Othermedicinesregulatoryguidance/CON2030291

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