©2012, Genentech

Implement A Holistic Approach To Justification

Building The Business Case

Hairong (Angela) Zhou

Sr. Sourcing Manager

SMPS Sourcing

Genentech

July 15th, 2015

©2012, Genentech

Outline

• Effectively breakdown organizational silos

• Implement a cross functional approach to HPAPI

development and production

2

©2012, Genentech

The History of HPAPI and It’s Categorization 3

• By early 1980’s:

• API OELs were assigned based on known tox and pharmacology studies

• How about those APIs which did not have tox data yet? • No standard quantitative occupational health tools were available

• Later in 1980’s~1990s:

• The above issue was discussed for the first time • A safety meeting held by safety directors from 15 largest pharmaceutical companies

• Safety officers from 5 companies volunteered to find a solution • Merck, Syntex, Abbott, Upjohn and Lilly

• The concept of “categorization” emerged

• The “Hand in glove” system

• The “default” concept : for APIs with little tox data available deemed unsafe

• Established a general concept for individual customization: • the “number” system that can be transferable

--J. Farris, A.W. Ader, R. H. Ku. Chimica Oggi Chemistry Today, Vol 24, No. 2 March/April 2006

©2012, Genentech

The History of HPAPIs: Risks Still Exist 4

• By early 2000’s ~ today: still no standard definition for HPAPI

• The “categorization” approach demonstrated to be effective & widely

accepted/adopted through out the pharma industry

• The SafeBridge System with customization • “Occupational Health Toxicity / Potency Categorization and Handling Practices”

• Risks in handling HPAPI:

• Occupational exposure to personnel

• Product cross contamination: product quality thus patient safety

The risk level has increased due to much more potent APIs we discovered

with advanced technology

©2012, Genentech

HPAPI Challenges: Regulatory Aspects

• For cross contamination:

• Europe Commission has issued proposed changes to Vol. 4, EU

Guidelines for Good Manufacturing Practice for Medicinal Products for

Human and Veterinary Use in Part 1, Chapter 3 and 5

• Risk assessment programs:

• ICH Q9 Quality Risk Management

• ISPE Baseline Guide for Risk Based Manufacture of Pharmaceutical Product

• For occupational safety:

• Towards HPAPI, most pharma companies adhere to widely accepted

ADE/OEL settings

--------Trends in High Tox Manufacture, 2014, 08

5

©2012, Genentech

Business Trends

• “Compared with the overall growth in the pharmaceutical market of about 7% per year, HPAPIs are estimated to have an annual growth of 12%. They account for about 12% of the total pharmaceutical market, and this share is set to rise strongly”

--------High-Potency APIs: Containment and handling issues, PharmaTech.com

• “The global HPAPI market was worth USD 9.1 billion in 2011 and is expected to reach USD 17.5 Billion in 2018”

--------Transparency Market Research

• “With over 25% of drugs manufactured worldwide being classified as HPAPI, its market is being cited as one of the most important segments of pharma industry”

--------Trends in High Tox Manufacture, 2014, 08

• “Pharmas outsource more and more HPAPI productions to CMOs …”

--------SAFC

6

©2012, Genentech

HPAPI Outsourcing: The Uneven Landscape

• North America and Europe: advanced for HPAPI handling

• The market leaders for high potent API remain in North America and

Europe: e.g. US, Canada, Germany and Switzerland

• Germany and Switzerland have increased their output over the number

years at API processing level

• The number of CMOs are limited and the cost is high

• Asia Pacific: lagging behind

• Asian and Pacific area are the fastest growing markets for oncology drugs,

but the HPAPI handling is not ready

• Pharma/biotech companies outsource significant amount of work there

due to low cost and have established key partners in this region

How can we achieve safe, robust and cost effective HPAPI

development and production?

7

©2012, Genentech

Ethical Behavior per Roche Group SHE

• Anybody‘s employees must be safe when handling Roche‘s

compounds on behalf of Roche

• Standards and working conditions must be comparable to those

we would require in-house

• We will not go to companies with bad SHE standards to save a

few dollars

8

Dr. Andreas Fluekinger

©2012, Genentech

Roche and Genentech In a Few Words

• Genentech is a leading biotechnology company (founded in 1976)

• Discovers /develops medicines to treat patients with life-threatening medical conditions.

• Biologics and small molecule division (established ~10 years ago) • All small molecule drug candidates are development in SMPS department • Outsource a significant amount of HPAPI production at CMOs

• Became a wholly owned member of the Roche Group in March 2009

• Roche is a global pharmaceutical company (founded in 1896)

• ~80 years older than Genentech • Specializes in in vitro diagnostics, small molecule R&D, etc. • Gradually outsources more and more to third parties

9

©2012, Genentech

Roche’s Group SHE 10

Roche’s mission of Safety, Security, Health and Environmental Protection

• It abstracts our everlasting efforts in SHE:

• Build awareness

• Motivate

• Inform and educate

• Audit

• Report

• Feedback for improvement to a higher level

©2012, Genentech

Roche Group SHE Directives

K1 – Occupational Hygiene and Health

K2 – Polychlorinated Biphenyls (PCBs)

K3 – Process Safety Management

K4 – Prevention of Hearing damage

K5 – Precursors of Chemical Weapons, Drugs and Narcotics

K6 – Substances Affecting the Ozone Layer and the Climate

K7 – Explosion Protection Measures

K8 – Asbestos

K9 – SHE Risk Management

K10 – Health Surveillance

11

©2012, Genentech

Roche Group SHE Directives

K11 – Accident/Incident Reporting

K12 – Safety Data Sheets

K13 – Dealing with Contractors

K14 – Transport of Dangerous Goods

K15 – Dealing with Third Parties

K16 – Asphyxiating Gases

K17 – Biosafety

K18 – Energy Conservation

K19 – Security

K20 – Key figure reporting

K21 – Fire safety

12

©2012, Genentech

K1 and K15 Directives on Exposure Control

Roche internal standard:

Engineering Controls must be the primary means to control chemical exposure

• Hierarchy of measures to control exposure:

• Elimination of or substitute the hazardous material or process step

• Use of engineering controls (i.e. filter dryers, continuous liners, isolators for weighing chemicals) as the primary protection

• Use of administrative controls

• Use of personal protective equipment (PPE) as the secondary protection

• Required measures are:

• Ensure all operators are trained on use and maintenance of equipment

• Obtain air monitoring data

• Must have an efficient cleaning method in place

The same principles apply to third parties as well

13

©2012, Genentech

Continuous Improvement Expected 14

©2012, Genentech

Roche Occupational Exposure Bands (OEL) 15

Category 1 Category 2 Category 3A Category 3B Category 4

100 µg/m3 10µg/m3 1µg/m3 50ng/m3

no/slight hazard moderate hazard high hazard high hazard very high hazard

• Occupational exposure levels defined as upper limit on the acceptable concentration of a chemical in air for a particular material or class of materials

• Apply not only to APIs but also to RSMs and API intermediates

©2012, Genentech

Roche and Genentech: Building the Business Case 16

Back in 2011:

• Not all internal equipment and facilities were qualified

• GNE has a rich development pipeline of oncology drug candidates

• Some CMOs did not have mature HPAPI evaluation process, nor

proper containment/cleaning at their facilities

Could not continue our business as usual

• What would be a holistic approach? • Work as one team to achieve the following goals:

• Protect the workers internally as well as at third parties

• Eliminate cross contaminations

• Deliver one and the same SHE message across the board

• Balance the cost, quality, timeline, efficiency and SHE compliance for

business continuity

©2012, Genentech

• Within the organization: • Overcome philosophical differences on handling HPAPIs

• Overcome culture differences on resolving issues

• Work across multiple functional groups and lines

• Increase the awareness via education

• Audit, document and provide feedback for improvement

• Be in compliance

• With external collaborators • Educate CMOs with Roche’s SHE expectations

• Provide training, guidance and suggestions

• Act as SHE consultants

• Conduct audit, provide feedback for improvement

• Conduct follow up audit to bring CMOs into compliance

Updated 09July12

July 2012

17

Work Together: Break the Silo – Inside and Out

©2012, Genentech

• Who are involved: (along with respective teams) • Dr. Andreas Flueckiger

• Chief Occupational Health Officer, Roche Group SHE, Roche Basel

• Dr. Patricia Weideman

• Director, Product Quality/Occupational Toxicology, Genentech

• Dr. Michael Cerreta

• EHS Administration, Genentech

• Dr. Greg Sowell, SMPS Pilot Plant Head, Genentech

18 Break the Silo: Within the Organization

©2012, Genentech

Roche’s Expectations: at Each Roche Site

Operational SHE at the Site • Build awareness, motivate for and promote SHE

• Support the organization for compliance with all regulations

• Support local line management in educating and training employees

• Ensure risk management process for the site

• Conduct periodic internal SHE audits

• Report critical SHE situations and events

• SHE is a part of business, not a side project

19

©2012, Genentech

• Who are involved: (along with respective teams)

• Dr. Andreas Flueckiger

• Chief Occupational Health Officer, Roche Group SHE, Roche Basel

• Dr. Patricia Weideman

• Director, Product Quality/Occupational Toxicology, Genentech

• Dr. Michael Cerreta

• EHS Administration, Genentech

• Dr. Shreen Babu

• SMPS sourcing team, Genentech

• Dr. Larry Fisher

• PTDMX sourcing team, Roche Pharma Tech Dev

• CMO EHS department

20 Break the Silo: With Third Parties

©2012, Genentech

Roche's Philosophy in General for CMOs

• Third parties are expected to meet internationally recognized standards of:

• Safety

• Health and environmental performance

• Ethical business practices and social responsibility

• Third parties are expected to operate in full compliance with all local applicable laws, rules and regulations.

• Third parties are expected to meet Roche’s SHE expectations

• Group SHE will audit sites of suppliers that pose a high SHE risk

• CMOs that manufacture API’s, intermediates, raw materials, which fall into the occupational health categories 4, 3b, 3a and – at high quantities – even category 2

21

©2012, Genentech

Strategies to Bring CMOs Into Compliance

Educate CMOs through site visits and providing practical solutions

• Site plant tour and meet the EHS staff

• Identify gaps in facilities, equipment and procedures

• Provide guidance and education

• Consult on trainings and equipment purchase based on Roche standards

• Follow up with visit to close the gap

• Follow up with audit to qualify the SHE operation

Potential exposure for HPAPI powder handling • Solids sampling and dispensing

• Solids charging

• Material transfering

• Drying and discharging of powders

• Packaging

22

©2012, Genentech

What We Have Achieved So Far

• Raised the awareness of Roche’s SHE expectations /requirements • Internally as well as at third parties

• Identified/built a network of capable CMOs who can safely conduct

HPAPI development and production • re-evaluated our original CMO network with additions and removals

• Helped /are helping key partners at APAC region to bridge the SHE gap • Kept high performers by providing trainings, consulting, etc.

• It’s a multi pronged approach • Western CMOs for API production

• Most Asia CMOs are used for RSMs and API intermediates • Some can do HPAPI manufacture as well

• All CMOs had Roche’s assistance one way or another

• Not one size fits all

©2012, Genentech

Continuous Improvement Towards SHE Excellence

It is an ongoing effort…

To balance the cost, quality, efficiency , timeline and safety in order to

achieve robust HPAPI development and production

©2012, Genentech

25

Acknowledgements

• SMPS Leadership Team

• SMPS Sourcing Group

• EHS Team at Genentech

• Product Quality/Occupational

Toxicology Team at Genentech

• PTDMX Team

• Roche Group SHE

• Roche Process Engineering

• CMO Teams

Special thanks to:

Dr. Shreen Babu, Mr. Herbert Yajima, Dr. Michael Cerreta,

Dr. Patricia Weideman , Dr. Andreas Fluekinger (Roche)