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Familial Hypercholesterolemia Patient

Pharmaceutical Quality SystemsDeclan Kelly,

VP of Quality, Europe, Genzyme, a Sanofi Company

October 4, 2012

8th Annual QUALITY & OPEX in Pharma & Biotech

The information within this presentation is based on the presenters expertise and experience, and represents the personal views of the presenter for the purposes of this conference and not necessarily those of Genzyme or Sanofi.

Disclaimer

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Pharmaceutical Quality Systems

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Relationship of ICH Q10 to Regulatory Approaches

Genzyme Approach: Creating Global Quality Standards Management Responsibility & Review Knowledge Management & Quality

Risk Management (including escalation process)

Lifecycle approach

Lessons learned & future developments

How did ICH Q10 originate? ICH Q10 was created from aspects of regional GMPs, ICH

Q7 GMP Guide for APIs, and ISO 9000 (and related guidelines). ICH Q10 augments GMP by describing specific quality system elements and management responsibilities.

ICH Q10 provides a harmonised model for a pharmaceutical quality system throughout the product lifecycle and is intended to be used together with regional GMP requirements. Regional GMPs dont explicitly address all stages of product lifecycle

(e.g. Development). The quality system elements and management responsibilities described in Q10 promote the use of science and risk based approaches at each lifecycle stage, thereby encouraging continual improvement across the entire product lifecycle.

Relationship of ICH Q 10 to Regulatory Approaches

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ICH Q10 states that regulatory approaches for a specific product or manufacturing facility should be commensurate with the level of product and process understanding, the results of quality risk management, and the effectiveness of the pharmaceutical quality system.

When implemented, the effectiveness of the pharmaceutical quality system can normally be evaluated during a regulatory inspection at the manufacturing site.

Potential opportunities to enhance science and risk based regulatory approaches are identified in ICH Q10 Annex 1*

Regulatory processes will be determined by region. *See back up slides

Relationship of ICH Q 10 to Regulatory Approaches

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GMP ISO 9000 ICH Q10

GMPs ++ _ ++

Management Responsibility

+ ++ ++

Continuous Improvement

_ ++ ++

Risk Management

_ + ++

Knowledge Management

_ + ++

Lifecycle Approach

_ + ++

Risk/ Science Based Approach

_ _ ++

ICH Q10 compared to GMPs & ISO 9000

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GMPs provide guidance on the manufacturing and control of pharmaceutical product

GMPs do not address the system needed to bring quality product to the market

GMPs do not drive lifecycle approach to quality GMPs do not specifically address CAPA or proactive

continual improvement

GMPs only briefly mention management responsibility

GMPs without a Modern Framework will Limit Improvements

7Source: Martin Van Trieste, Amgen

ICH Q10 PQS Framework Enables ImprovementWhile Assuring GMP Compliance

8 PQS = Pharmaceutical Quality System

ICH Q10 Defines the Space Where Modern Pharma Drug Development Lifecycle Can Operate

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Implement phase appropriate GMPs, while remaining within a robust GMP structure

Creating Global Quality Standards Management Responsibility & Review Knowledge Management & Quality Risk

Management (Including escalation)

Lifecycle approach

How did we interpret ICH Q10 at Genzyme?

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Genzyme Quality System Global Standards

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ICH Q10, Pharmaceutical Quality System, Section 2.6a recommends Senior management should be responsible for pharmaceutical quality system governance through management review to ensure its continuing suitability and effectiveness

Expectation versus requirement EMA: The content of ICH Q10 that is additional to the scope of GMP

is optional.

US GMP has no requirement for periodic management review of the quality system; although 211.180(e) requires annual product review

Expectation originated in ISO 9001, clause 5: the executive management team must routinely review the status of the quality management system

Management Responsibility & Review

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Does your company have systematic management review of the quality system? If so: How often?

Who participates?

How are results communicated?

What benefits have you experienced?

What problems have you encountered with the review process?

What has worked and what has not?

Management Review Quick Discussion

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Quality Councils: Governance structure within the PQS at Genzyme has 3 tiers of

Councils, each with specific area of focus and oversight:

Tier 1 Corporate level

Tier 2 Division (or science platform-based)

Tier 3 Site level.

Tier 1: Corporate Quality Council Corporate Quality Council provides vision, leadership, guidance,

and direction in establishing and maintaining the Companys commitment to Quality. The scope of Genzymes Corporate Quality Council includes product development, manufacturing, quality, distribution, and warehousing processes for regulated products. The Corporate Quality Council also provides oversight of the development and implementation of the Quality Standards.

Governance Structure: Quality Councils

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Quality Council Structure

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Tier 2: Division or Science platform-based Tier 2 Quality Council ensures alignment of Sites to the quality

goals and objectives set by the Tier 1 Quality Council and reviews performance of technology/product platform to goals and objectives. It also provides direction, feedback, and support to the Tier 3 (Site) Quality Councils within the platform and communicates directives and decisions from the Tier 1 or Tier 2 Quality Councils to the Tier 3 Quality Councils within the platform.

Tier 2 Quality Council also monitors compliance/quality risks of all Sites within the technology/ product platform and identifies and evaluates impact of business and regulatory environment changes, and identifies appropriate negative trends, results of periodic reviews, and compliance/quality risks for escalation to the Tier 1 Quality Council.

Quality Councils (continued)

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Tier 3: Site level Tier 3 Quality Council reviews Site performance to quality goals

and objectives set by the Tier 1 Quality Council and evaluates, monitors, and mitigates quality and compliance risks for the Site. Each site generates a monthly Site Risk Profile Report (SRPR) and identifies and evaluates impact of business and regulatory environment changes.

Tier 3 Council also provides direction, feedback and support to the site on directives and decisions from the Tier 1 and Tier 2 Quality Councils and identifies appropriate negative trends, results of periodic reviews and compliance/quality risks for escalation to the Tier 2 Quality Council.

Quality Councils (continued)

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Knowledge Management (KM): comprises a range of strategies and practices used in an organization to identify, create, represent, distribute, and enable adoption of insights and experiences.

One key KM improvement at Genzyme was the introduction of a Global Inspection Response Team (GRT) Process . When any site in our group receives a regulatory audit finding (e.g.

FDA 483 etc) or raises a critical complaint/deviation, every other site in the network raises a Corrective and Preventive Action (CAPA) to ensure they dont have the same issue in the future

These GRT actions are monitored at the Quality Council

Knowledge Management

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Risk Management is the identification, assessment, and prioritization of risks (defined in ISO 31000 as the effect of uncertainty on objectives, whether positive or negative) followed by coordinated application of resources to minimize, monitor, and control the probability and/or impact of adverse events or to maximize the realization of opportunities.

Risk Management & Escalation Process

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We follow a typical Risk Management model per ICH Q9

Risk Management

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The Quality Risk Program enables the Councils to meet their responsibilities. The initial phase of the Risk Program began in March 2009 when key sites were risk assessed by independent 3rd Party consultants

The second phase of the Risk Program was creation of Genzymes Global Standards, which provide the global network with a consistent set of requirements.

The third phase of the Risk Program was the formalization of a risk management tool and the management reporting mechanism known as the Site Risk Profile Report (SRPR). This tool is used at all manufacturing sites for the purpose of communicating their risks up through the Quality Council Governance structure.

Quality Risk Program

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Heat Map: Typical Site Risk Profile Report

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Risk Management : Waterford Site Journey

Establishing Presence Embedding Operational Performance Sustaining Growth

Q3 2010Informal ad hoc assessmentsSite Risk Profile

Q4 2010Formal FMEA

Q1 20113 FMEA FacilitatorsRisk Management Plan Process Control Strategy Pilot

Q4 2011Site Risk Management PlanAdditional Tools Standard Templates

Q3 20129 Facilitators11 Tools16 Departments

Q1 2012Change Control Batch Impact Assessment Risk Review

Genzyme Escalation Process

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Plus EscalationTo Sanofi Quality

Escalation Process: Detail part 1 (site level)

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Escalation Process: Detail part 2 (technical platform/corporate level)

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A robust CAPA process is essential for a properly functioning PQS. It prevents recurring mistakes, and drives continuous improvement

ICH Q10 states: CAPA methodology should result in product and

process improvements and enhanced product and process understanding

It is essential that the CAPA system does not work in isolation and that there are strong linkages with other aspects of the PQS, including Management Review

Corrective & Preventive Actions

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Continuous Improvement:

Certain inputs drive continuous improvement of the Genzyme PQS: Changes identified through regulatory intelligence monitoring

Changes to regulatory requirements

Changes to industry best practices

Changes to the interpretation or application of regulatory requirements as seen in our internal and external audit observation process, and

Changes required based on Sanofi requirements.

Also improvement areas are identified through the Council governance structure where external influences are compared to performance of the PQS and additional refinements where needed.

Global Standards are updated to reflect these improvements

Lifecycle Approach to the PQS at Genzyme

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A bad system will beat a good person every time W. Edwards Deming

Standardisation is good! Fully involve the Sites Ensure there is very strong Senior Management Support Have robust escalation and CAPA processes, and good

visibility of how the PQS is performing

Management's job is to optimize the whole system. Improve quality, you automatically improve productivity. Quality is everyone's responsibility. and it is a

competitive advantage

Major Lessons Learned

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Evolution of our Quality System

From To

Compliance

Controlling and reactive

Discrete activities

Site local

Mechanical

Training proficiency

General SOP focused

Fully integrated into the overall business processes

Proactive and confirmatory

Continuous monitoring and improvement

Company global

Risk and Knowledge based

Competence

Std. Work Instructions & Graphic SOPs

Ron Branning, (former) SVP Quality, Genzyme Martin Van Trieste, SVP Quality, Amgen Dave Chesney, VP of Strategic Compliance, Parexel

Consulting

Bernadette OBrien, QA Manager Fill Finish, Genzyme Ireland

Acknowledgements

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Back Up Slides

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Scenario Potential opportunity1. Comply with GMPs Compliance status quo

2. Demonstrate effective pharmaceutical quality system, including effective use of quality risk management principles (e.g., ICH Q9 and ICH Q10).

Opportunity to:increase use of risk based approaches for regulatory inspections.

3. Demonstrate product and processunderstanding, including effective use of quality risk management principles (e.g., ICH Q8 and ICH Q9).

Opportunity to: facilitate science based pharmaceutical quality assessment;enable innovative approaches to process validation;establish real-time release mechanisms.

4. Demonstrate effective pharmaceutical quality system and product and process understanding, including the use of quality risk management principles (e.g., ICH Q8, ICH Q9 and ICH Q10).

Opportunity to:increase use of risk based approaches for regulatory inspections;facilitate science based pharmaceutical quality assessment;optimise science and risk based post-approval change processes to maximise benefits from innovation and continual improvement;enable innovative approaches to process validation;establish real-time release mechanisms.

ICH Q10 Annex 1*

33*Note: This annex reflects potential opportunities to enhance regulatory approaches. The actualregulatory process will be determined by region.

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