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Overcoming Tech Transfer Challenges and Optimizing CMO Management

6th Annual HPAPI Summit

June 21st ~22rd, 2017 Boston

Hairong (Angela) Zhou Sr. Sourcing Manager

SMPS, Genentech June 22nd, 2017

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Outline

• Assessing key factors involved for outsourcing in the highly potent space

• Managing CMO effectively and ensuring safety standards are maintained to the levels comparable to internal process

• Ensuring timeline and budget restrains are met by effectively working with CMOs throughout the process

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Key Factors for Outsourcing HP Materials

• Containment capabilities at CMOs • Proper equipment for each unit operation matching the material’s HHC • Trained and experienced staff • Proper SOPs for handling HP materials

• Timeline and cost • Longer and more expansive

• Technical capabilities

How will we start the process? Which CMO? What is the HHC for the to be outsourced material?

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Brief Introduction of Roche/Genentech • Genentech is a leading biotechnology company (founded in 1976)

• Discovers/develops medicines to treat patients with serious medical conditions • Biologics and small molecule divisions

• All small molecule drug candidates are development in SMPS department • Outsourced a significant amount of HPAPI production at CMOs • CMOs assumed all the responsibilities to ensure proper containment used

• Became a wholly owned member of the Roche Group in March 2009 • Roche would like to assume all the responsibilities

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

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

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Roche Team’s Expectations

In general: • All workers must be safe when handling our product • Standards and working conditions at CMOs must be comparable to those we would require in-house

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Roche’s Group SHE 6

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

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Expectations on Exposure Control

Engineering controls must be the primary means to control chemical exposure

• Control exposure: hardware • Elimination or substitution of 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 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

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Expectations 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

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Occupational Exposure Bands (OEL) 9

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 any API intermediates

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Roche and Genentech: Building the Business Case 10

• Back in early 2010s: • 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 at CMOs: • Deliver one and the same SHE message across the board • Help key partners to enhance their containment capabilities

Balance cost, quality, timeline, efficiency and SHE compliance for business continuity

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• It’s a multi-pronged approach • Exam our CMO portfolio and strategize who can do what and where

• Select key partners and provide help to close the SHE gaps ASAP

• Optimize CMO management with added-on SHE aspect

• Overcome new challenges in tech transfer related to material

handling

11 Working Together: Overall Strategies

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With selected key external collaborators

• Educate them with Roche’s SHE expectations

• Provide basic training, guidance and suggestions • Direct them to reputed SHE trainings, consulting firms and facility

designers • Conduct audit, provide feedback for improvement • Conduct follow up audit to bring them into compliance

12 Working Together

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Steps Taken to Bring CMOs Into Compliance

Educate CMOs through site visits and provide practical solutions • Visit plants and meet the EHS staff • Identify gaps in facilities, equipment and processes • Provide guidance and education • Help with SOP establishment and refinement • Consult on trainings and equipment purchase based on Roche standards • Follow up visit to close the gap • Follow up with audit to qualify the SHE operation

Potential exposure for HP chemical powder handling: key unit operations

• Solid sampling and dispensing • Solid charging • Material transferring • Drying and discharging of powder • Packaging

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Achieved So Far for Bringing CMOs to SHE Compliance

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

• Helped key partners to close the SHE gap • Kept high performers by providing trainings, consulting, etc. • Some partners already passed our audit • Key partners are totally aware of the containment concept, rational and

requirement

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

manufacture HPAPI and it’s intermediates • re-evaluated our original CMO network with additions and removals

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Key Factors for Outsourcing HP Materials

• Key factors:

• Potency assessment for each outsourced material • HHCs or ADEs, MSDS

• Make vs. buy • Type of chemistry, scale, capacity, timeline and cost

• CMO selection • Type of chemistry, scale, capacity, timeline and cost • Containment capability to handle the signed HHC category

Important aspect: plan ahead

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Optimizing CMO Management for HP Material Production

• Ensuring safety standards are maintained to the levels comparable to internal process

• Added HHC information to the RFP • Qualified CMOs and their equipment trains • Helped with setting up proper SOPs, procedures for handling Genentech

compound • Visited plants during the production

Key: know your partners and their plants/production trains

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Ensuring Timeline and Budget Restrains Are Met

• Communicate effectively • Plan ahead and get ready • Share project timeline and expectations • Bring awareness of how to handle potent materials

• Stay within the budget

• Plan ahead • HPAPI will cost more • Asian CMO’s price is still better than Western CMOs

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• Who are involved: (along with respective teams)

• Dr. Andreas Flueckiger • Chief Occupational Health Officer, Roche Group SHE, Roche Basel

• Dr. Michael Cerreta • EHS Administration, Genentech

• Dr. Shreen Babu

• SMPS sourcing team, Genentech

• Dr. Larry Fisher • PTDMX sourcing team, Roche Pharma Tech Dev

• CMO management team and EHS staff

18 Working Together

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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

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CMOs’ Containment Level: The Landscape in 2017

A sourcing manager’s observation

• Western CMOs very much stayed the same

• Asian CMOs are catching up • key partners have improved significantly

• The gap is getting smaller

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Progress Made by Asian CMOs Since 2012

Hardware: • They built new facilities designed by world known designers

• e.g. Amec Foster Wheeler • They upgraded some existing plants • They learned to use the flexible containment technology

• e.g. the Doverpac

Software: • They hired experienced Western SHE personnel to head up the SHE team • They identified and participated SHE trainings available worldwide

• e.g. SafeBridge Boot Camp in Boston • They hired reputed SHE firm as their consultant

• e.g. Golder in Shanghai • They established regular trainings for their employees • Plus: more and more IH graduates went back to their home country

They are catching up quickly…

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22 Acknowledgements

• SMPS Leadership Team

• SMPS Sourcing Group

• EHS Team at Genentech

• Product Quality/Occupational Toxicology Team at Genentech

• PTDMX Team • Roche Group SHE • CMO Teams

Special thanks to: Dr. Andreas Flueckiger , Dr. Mike Cerreta, Dr. Shreen Babu, Mr. Herbert Yajima, Mr. Dave Stirling