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© 2009 Genentech, Inc.

Joseph C. FamulareSenior Director

Global Quality and Compliance Genentech, Inc.

Pharmaceutical Quality System (PQS) –Advantages for a Global Operation in the Implementation of Q8, 9, and 10

WCBP 2011Sunset Plenary Session

January 10, 2011


Outline

• ICH Vision for Pharmaceutical Quality

• Regulatory Expectations

• Implementation of Q10 at Genentech/Roche

• Conclusions


Existing GMP ss

Management

The RegulatorySystem

Pharmaceutical Quality System / PQS (Q10)

Quality Risk Management (Q9)

PharmaceuticalDevelopment(Q8 & Q8R)

An ICH Vision for Pharmaceutical Quality

Quality System

Existing GMP

Quality Risk Management

Pharmaceutical

Development

Source: Jacques Morénas, ISPE, Nov 2007

Drug Substance Guidance (Q11)Step 2 – Spring 2011?


ICH Guidance History

1. ICH Q8 - Pharmaceutical Development (2006; revised 2009)• describes the suggested contents for the pharmaceutical development section of a

regulatory submission in the ICH M4 common technical document (CTD) format; • indicates areas where the provision of greater understanding of pharmaceutical and

manufacturing sciences can create a basis for flexible regulatory approaches.• Q8(R) includes concepts of Quality by Design (QbD) and examples of design space.

2. ICH Q9 – Quality Risk Management (2006)• provides principles and examples of tools for quality risk management that can be

applied to all aspects of pharmaceutical quality throughout the lifecycle of drugsubstances, drug products, and biological and biotechnological products;

• intended to enable regulators and industry to make more effective and consistent risk based decisions.

3. ICH Q10 – Pharmaceutical Quality System (2009)• intended to provide a comprehensive approach to an effective pharmaceutical quality

system that is based on ISO concepts, includes applicable GMP regulations andcomplements ICH guidance on Q8 and Q9.


Q9 Goal is to reduce patient risk

Q10Q8

Process

Materials

Design

Manufacturing

Distribution

Patient

Facilities

Opportunities to impact risk using quality risk

management Q9


GMP

Pharmaceutical Development

CommercialManufacturing

ProductDiscontinuation

Technology Transfer

Investigational products

Management Responsibilities

Process Performance & Product Quality Monitoring SystemCorrective Action / Preventive Action (CA/PA) System

Change Management SystemManagement Review

PQSelements

Knowledge ManagementQuality Risk Management

Enablers

Q10 Pharmaceutical Quality System PQS


Guidance for Industry: Q10 Pharmaceutical Quality System (April 2009),Process Performance and Product Quality Monitoring System 3.2.1 -

Pharmaceutical companies should plan and execute a system for the monitoring of process performance and product quality to ensure a state of control is maintained.

• Use quality risk management to establish the control strategy.

• Provide the tools (e.g., data management and statistical tools) for measurement and analysis of parameters and attributes identified in the control strategy

• Verify continued operation within a state of control

• Identify sources of variation affecting process performance and product quality for potential continual improvement activities.

• Include feedback on product quality from both internal and external sources, e.g. complaints, product rejections, non-conformances, recalls, deviations, audits and inspection inspections and findings;

Regulatory Landscape and Need for Integrated Product Quality Management


Q10 - Where the PQS Applies

Operations

Make Assess Release

PQS

PharmaceuticalDevelopment

Technology Transfer

Commercial Manufacturing

Product Discontinuation

Product Life Cycle

Pharmaceutical Quality System (PQS)


Q10 PQS

Q10 encompasses the entire product lifecycle and can be applied whether or not QbD is employed.

• Documentation• Training and education• Outsourced activities / purchased materials• Control Strategy

–Use quality risk management to establish using parameters and attributes and related facility and equipment operating conditions

• Monitoring / Handling Quality Defects (CAPA)–The level of effort of the investigation should be commensurate

with the level of risk.–Result should be product and process improvements


Q10 PQS

• Auditing / Inspection–For regulators–For companies

• Periodic review

• Change management / change control–Driven by innovation, continual improvement, the outputs

of process performance and product quality monitoring, and CAPA

–Level and formality commensurate with risk

• Continual improvement – an opportunity to optimize science-and risk-based post-approval change process

11

PQS Management Responsibilities & Expectations


Outline




• Conclusions

13

Performance Expectations of the PQS

Health Authorities expecting ICH Q8-10 implementation

EU moving in direction of making ICH Q10 elements enforceable asdirectivesMore emphasis on role of managementQRM and KM are expected to be integrate in PQSPQS is expected to be applied consistently across a company


FDA Performance Expectations of the PQS

Establish and Maintain State of Control(Systemic, Comprehensive and Global)

• “It is our [FDA] expectation that firms take a systematic approach to correcting and complying with CGMP to ensure the identity, strength, quality, and purity of their drug products.”

• “In your response to this [warning] letter, please include an explanation of how you intend to implement, support, and sustain acomprehensive quality system at your firm that is consistent with CGMP.”

• “It appears that you have not taken a global quality systems approach to corrective actions at your firm…It is your responsibility to review your operations at all facilities and apply appropriate corrective actions to address deficiencies present at multiple sites.”

Source: 2010 FDA Warning Letters, at http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/default.htm


FDA Performance Expectations of the PQS

Management Commitment

• “It is our expectation that firm’s senior management ensure a systematic approach to designing their products, processes, and quality systems, and require that deviations and flaws are promptly identified and corrected to assure the identity, strength, quality, and purity of their drug products.”

• “Be advised that FDA expects that your corporate management will undertake a comprehensive evaluation of manufacturing operations to ensure compliance with CGMP.”

Source: 2010 FDA Warning Letters, at http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/default.htm


Outline




• Conclusions


Quality PhilosophyQuality is every patient’s right and every employee’sresponsibility. Quality provides a competitive advantage andis engrained in everything we do, from concept throughcontinuous improvement. Because our products touch humanlives, quality is the true measure of our success.

Our Prioritization Principles1. Right to Operate2. Quality Supply to Patients3. Contribution to Target

Our People

Our Patients

Quality Philosophy & Prioritization Principles


South San Francisco

Toluca

RioIsando

Leganés

Mannheim

Basel/KaiseraugstSegrate

Latin America

North America

Europe & Africa

Asia Pacific

Boulder

ClarecastlePenzberg

a

420

Vacaville

Oceanside

Hillsboro

Singapore

ShanghaiFlorence

Small MoleculesDrug Substance

PLUS: Over 200 contract manufacturing organizations (CMOs)

Global Technical Operations

BiologicsDrug Substance

Solid Dosage Drug Product

Sterile Drug Product

Over 20 Plant Operations at 17 sites, about 12,000 employees


Implementation of Modern Quality Systems

Why One Pharmaceutical Quality System (PQS)?

• Health Authority Requirements & Standardization

• LEAN Quality Process Expectations

• One Company…One PQS

• Network Wide Integrated with the Business

• Knowledge Management

• Reduce Product & Patient Risk

• Drive Down Costs



Product Quality Management

- Deliver an End to End (E2E) view of product quality for all Commercial products

- Critical to:– maintaining quality supply to patients– product consistency across sites– our right to operate

- End to End means that the product quality:– is managed throughout the product value stream– includes both API and drug product– is managed throughout Product Life Cycle (Q10 enabler-

Process Performance and Product Quality Monitoring)- Success requires knowledge transfer from Clinical to Commercial


Product Complaints• Early warning signals of product quality issues in

the field

Product Complaints• Early warning signals of product quality issues in

the fieldProduct Assessment & Trending• Proactive assessment of product quality

attributes across the manufacturing process

Product Assessment & Trending• Proactive assessment of product quality

attributes across the manufacturing process

Product Quality Stewards• Single point of Contact for Quality to key stakeholders• Routine health assessment of product to address trends• Planning provides foresight and proactive approach

Product Quality Stewards• Single point of Contact for Quality to key stakeholders• Routine health assessment of product to address trends• Planning provides foresight and proactive approach

QC testing network support• Harmonized approach to test method execution & support• Scalability & flexibility to balance test workload across network

QC testing network support• Harmonized approach to test method execution & support• Scalability & flexibility to balance test workload across network

Analytical methods managementScientific rigor engrained in analytical method performanceProduct control systems based on scienceSeamless product transfers & assessment of consistency

Analytical methods managementScientific rigor engrained in analytical method performanceProduct control systems based on scienceSeamless product transfers & assessment of consistency

Product Quality Management: Fundamental Elements



Product Quality Steward Model

- Dedicated resources overlooking each product to assurequality integrating activities - across all sites (Mfg, QC, QA, etc)

- Single point of contact: – from raw materials to distribution– across all technical disciplines Quality and the rest of the

organization- Early warning for product quality issues- Quality improvement activities are implemented across the network


Opportunities for Global Implementation

• Better understanding of a company’s capability and profile across a global network i.e., more assurance by regulators of consistentprocesses and global implementation;

• Companies can provide more assurance site to site for producingconsistent products and analytical procedures in a global network environment; and

• Enhanced ability for regulators to leverage shared assessments,inspections based on common standards globally for new products,changes, and site transfers.

24

Design of the PQS

PQS involves IT Tools, business processes and common requirements

described in QRs / GSPs

Proc

ess

Map

s, F

low

Char

ts

and

Visu

al A

ids

Standard Operating Procedures

Global Standards & Processes

Quality Requirements

Quality Policy

Other Document Types

In Alignment with ICH Q10:Four Categories to

Organize PQS Documents

One Document Hierarchy


Cost of Quality


Cost of Quality

• Encompasses the costs of creating a quality product and service

• More importantly it incorporates and focuses on the cost of NOT creating a quality product or service

• Encompasses Right First Time Principles to drive better quality decisions and improve the quality throughout processes


Cost of Quality

• Need to establish metrics including costs:InvestigationsRejects product removal actionsLabor and Time involved

• Too often the focus is on getting the product released, but not enough focus on getting to the root cause and preventing the issues from reoccurring. If conducting multiple investigations to deal with the same issues over and over again, is money really being spent wisely?

• “The Cost of Quality quantification provides a business case for well thought out preventive action."

© 2009 Genentech, Inc. 28

Quality Compliance Risk

Risk Assessment

Mitigation Planning

Reporting

Use of Quality Risk Management to utilize findings from inspections, audits, and trending data and to

eliminate or mitigate risks

29

Conclusion

• PQS is the foundation for quality products

• PQS covers

All of Supply Chain from raw materials to distributionOwn production and outsourcedFrom pre-clinical through commercial to decommissioningGMPs and should be integrated with business processes and supported by tools

• For multi site companies PQS consistency is achieved through standardization, common IT tools and management oversight

• ICH Q10 has increased expectations to Senior Management within PQS and to using the enablers QRM & Knowledge Management

• Quality is an attribute not just a function


Acknowledgements

Stephen Mahoney – Genentech

Jennifer Magnani – Genentech

Ann Gillian – Roche

Deb Bailey – Genentech

Ron Taticek - Genentech

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