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Building a Quality Mindset with Your Partner to Manufacture Safe Clinical Materials

The 3rd DIA China Annual Meeting Quality & Standards – Elevating China Pharmaceutical Development

Hung-Chih Chang, Ph.D.Director, Product R&D

May 15-18, 2011

Agenda

• Background

• Collaboration Started with Process Chemistry to GMP API Manufacture in China

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The 3rd Drug Information Association China Annual Meeting 2

• Partnership is Expanding to Finished Product Manufacture for FHD

• Building a Quality Mindset through the Qualification of CT Manufacturing Facility

• Summary

Background

To reach clinical proof-of-concept more quickly and cost effectively than traditional R&D approaches :• Transforming from FIPCO to FIPNET

• Fully Integrated Pharmaceutical Co

US

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“source all, own all, do all at our cost structure”

• Fully Integrated Pharmaceutical Network

“many sources across the globe, share financial risk & rewards, and share work”

• Build external R&D network to manage capacity overflow for early-phase development

• Allow internal resource to focus on late-stage development

• Access global technical expertise

AsiaEU

Background (cont’d)

Why offshoring the clinical supply chain (preformulation, formulation development, CT manufacturing and packaging ) to the emerging markets? • Shift clinical research from traditional developed markets

to emerging markets• Recruitment rates are higher

• Competition for patients is lower

• Align CT material supply close to the sites of clinical trials • Eliminate import hurdles

• Increase speed

• Support local trials and expedite local drug registration

• 14-17% growth in Pharmerging markets thro’ 2014 vs. 3-6% in developed markets

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External Collaboration to Enable Information Generation & Material Supply

Clinical MilestonesPreclinical Phase 1 Phase 2 Phase 3 Submission Launch

Supply API for Supply Phase 1 Supply Phase 2 Supply Phase 3 Resupply Phase 3

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Information Generation

Developability Design Define Optimize Transfer

Material Supply

Supply API forToxicology

Supply Phase 1CT Materials



Resupply Phase 3CT Materials

Collaboration Started with Process Chemistry to GMP API Manufacture

• Initiated in 2004 • Process Chemistry • Building chemistry

blocks

• Set up a FTE program• 5 FTEs in 2006 – extension

to our in-house capabilities • API SMs, Intermediate• Laboratory Materials

• Helped to train the CORE group in the FTE program

• Building the technical expertise • Developed open communications

& business process

2004 2005/2006 2006

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• Conducted quality due diligence at CRO’s cGMP APIfacility

• 12 FTEs in ProcessChemistry

• 6 FTEs in Analytical • Completed formal quality

audit for API in mid 2007

• Enhanced process chemistry knowledge & experience

• Building trust & quality mindset over years of collaboration

• Started to mfg cGMP intermediate & API in late 2007

2006 2007 2007/2008

Steps to Manufacture Quality GMP API

Lilly RFP CRO Quotation Lilly PO Order Materials

Process R&D in Lab• Evaluating the existing route• Optimization/Scaleability

To discuss:• Responsibility

GMP Campaign Kick Off• Process chemists from both sides

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Analytical MethodDevelopment

Optimization/Scaleability• Safety assessment (e.g. RC-1)• Process details

• Agreement on analytical testing plan (ATP) for IPC & final release

ocess c e sts o bot s des• Analytical scientists from both sides• QA representative from both sides• Project Mgmt from both sides

cGMP Production

Lilly Scientists & QAare 24-hr on call during campaign

Testing per ATP

Send CoA，deviations, completed batch records to Lilly

Lilly Review &Approval

Building Quality Mindset with Your Partner

Continue to have mutual & open communications to improve partner’s overall QUALITY SYSTEM!

Gather Data

Analyze Data for

Major Investigation Step

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For example, Lilly Dev. QA shared experience on “Performing Effective Investigation, Root Cause Analysis & Documenting Deviations” to our partner’s QA & technical staff.

Analyze Data for Causal Factors

Determine Root Causes

Develop Countermeasures

Partnership is Expanding to Drug Product Manufacture for FHD

• Initiated in 2004 • Process Chemistry • Building chemistry

blocks

• Set up a FTE program• 5 FTEs in 2006 – extension

to our in-house capabilities • API SMs, Intermediate• Laboratory Materials

• Helped to train the CORE group in the FTE program

• Building the technical expertise • Developed open communications

& business process

2004 2005/2006 2006

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CRO built their cGMP CT mfg facility for drug product

Conducted quality due diligence at CRO’s cGMP APIfacility

• 12 FTEs in ProcessChemistry

• 6 FTEs in Analytical • Completed formal quality

audit for API in mid 2007

• Enhanced process chemistry knowledge & experience

• Building trust & quality mindset over years of collaboration

• Started to mfg cGMP intermediate & API in late 2007

2006 2007 2007/2008

Build Integrated CMC Capability with the Right Partner in China

After 3-Year’s collaboration:• CRO is building technical competence

• CRO is committed to strengthen quality system to provide quality GMP APIs

• Mutual trust, openness & spirit of collaboration

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• A strategic partner to build CMC capabilities & integrate our FHD API & drug product manufacture

One global quality standard for Lilly materials whether manufactured internally or externally.

Lilly and the CMO/CRO are both fully

Quality Standard -Clinical Trial Material Manufacture

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Lilly and the CMO/CRO are both fully responsible and accountable for Quality.

Quality is everyone’s responsibility.

Even though contract manufacturing of commercial products is now a well-established practice worldwide,

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established practice worldwide, manufacturing clinical materials is NOT something that everybody is capable of handling.

Things to Consider When Selecting a Partner for Clinical Material Manufacture

• Containment Strategy• Material, personnel, and waste flows – prevent cross-

contamination• Operability of physical barriers (pressure cascades &

airlocks) and appropriate operation procedures designed to

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) pp p p p greduce the risks of contamination

• Single-pass HVAC

• Cleaning Procedures• Cleaning validation will usually not be in place at this stage

but cleaning verification will be essential• Equipment Cleaning/Sanitization• Facility Cleaning/Sanitization

• Engineering Department • Is a skilled engineering department available to ensure the

flexibility of equipment, service, and utilities?• Willingness and ability to adapt custom design equipment • Have good contacts with local suppliers of small-scale GMP

equipment services and utilities

Things to Consider When Selecting a Partner for Clinical Material Manufacture

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equipment, services and utilities

• Personnel Qualifications (QC & Technical)• Personnel have a thorough understanding of the application

of GMP to clinical trial (or IMPs) • QC unit – clear responsibility, adequate authority & staffing • Personnel qualifications

– Education, training, experience for manufacturing, packing, or holding of a drug product

– Operation Staff vs. Supervision

• Pharmaceutical Dosage Forms

• Drug-in-Bottle

• Drug-in-Capsule

• Direct-blend Capsule

Desired Capability to Manufacture Clinical Material for Early Trials

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• Direct-blend Capsule

• Formulated Capsule

• Tablets

• Packaging (bottle & blister) and Labeling

• Analytical Testing and Release

• Bundling with GMP API manufacture is preferred

Outsourcing clinical material (finished products) manufacture in the Asia region is still developing. Our corporation is vigilant on this and very cautious in selecting the right

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partner(s) to manufacture the SAFE clinical materials. Our development organization also realized that our internal technical functions and the development quality organization have to work together closely to ensure that the clinical materials get to the patients in a SAFE and timely manner.

In the very beginning of this journey, we clearly emphasized to our partner that the END GOAL is to produce QUALITY CLINICAL MATERIALS in a

h i f ll li i h i l

Building a Quality Mindset with Your Partner

QUALITY

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manner that is fully compliant with our internal quality standard and all regulatory requirements.

It may take time but we are willingly to work with you on that if you choose to do so.

The Journey Has Begun……

Technical Capability

Assessment1st Quality

Due Diligence Formal

Quality Audit 3rd Quality

Due Diligence 2nd Quality

Due Diligence

2007 2008 2008 2008 2009

Technical EU QP Sr Mgmt of QA &Tech Org & EU QP & 3 US Auditors

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Personnel (Quality Dir.) Tech Org & CT Personnel Dev QA 1 EU QP

Lilly Personnel Involvement

Purpose of the Visit

Discuss preferred mfg platform& equipment to produce clinical materials for FHDs

1. Understand the quality system

2. Assess if EU-equiv standards of GMP are applied.

1. Assess readiness for a formal QA audit from Lilly

2. Technical readiness

Assess readiness for a formal Lilly QA audit from both EU & US regulatory perspective.

Conduct formal Lilly QA audit

1st Quality Due Diligence

• Purpose:• To have a high level understanding of the CT manufacturing facility• To provide an overview of the European legislation (e.g. Annex 13)

for the manufacture of CT materials • To discuss the role of the QP in Europe and the certification of a site

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against European GMPs

• Conducted by:• Director of European Dev QA (QP)

• Observations: • Facility - e.g. building management system • People - e.g. QA staff vs. technical staff • Quality system - e.g. clarity of contents in the SOPs

2nd Quality Due Diligence

• Purpose:• To assess our partner’s readiness to receive a formal QA Audit from

Eli Lilly and Company

• Conducted by:• VP of Quality Assurance API operations/Product R&D

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• VP of Chemical Product R&D • Team leader & member from CT manufacturing

• Strengths observed:• Facility cleanliness• Education of staff• Openness & spirit of collaboration• Good Set of equipment for multiple studies• Significant progress since last assessment• Previous successful collaboration on API manufacturing

2nd Quality Due Diligence (cont’d)

• Overall RecommendationShould consider to develop overarching Strategy Documentswhich explain the firm’s approach to key elements of Quality Assurance. This will provide several important advantages:• Improved Assurance of Quality for Patients

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– By having a well thought out, documented strategy for key elements of Quality Assurance, the firm can ensure that all elements of the strategy are consistent, and work together to assure quality for patients.

– Also a single strategy document allows the firm to explain the strategy more effectively.

Cross Contamination Prevention

Cleaning Programs

Bioburden Control

Materials Management

Validation Master Plan

2nd Quality Due Diligence (cont’d)

• Example: Prevention of Cross Contamination

One strategy which includes:• HVAC Rationale

– What is rationale for air balance?

G i

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• Gowning– Is gowning strategy appropriate?

• People Flow– What controls people moving from room to room?

• Material Flow• Facility Cleaning

Cross Contamination Prevention

Cleaning Programs

Bioburden Control

Materials Management

Validation Master Plan

Continue to Build Quality Mindset with Our Partner

• Two-day Quality System Discussion Forum in Indianapolis

Invited by Exec. Dir. of Global Quality API operations/Product R&D

• To exchange philosophy & experience on quality system and build strong collaboration

• Participants

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• Participants – Five of our partner’s quality & technical leaders– Twenty of Lilly quality & technical leaders

• Topics discussed:– Overview of Lilly global and development quality systems – Cleaning approach– Cross contamination– People qualification

Quality System - Partnership Expectations

• Strategically based Quality System which meet regulatory requirements (SFDA, FDA, ICH, EMEA) & the needs of firm’s business

Emphasized again the importance of the quality strategic documents.

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• Overarching Quality System strategy and philosophy to provide a foundation for addressing multiple customer requests, reflecting differing priorities and expectations

• Demonstrate through the Quality System how sponsor’s quality expectations are met

• Changes to firm’s Quality System should be consistent with its overall design and construct – effective change management is critical

3rd Quality Due Diligence

• Purpose:• To assess our partner’s readiness to receive a formal QA Audit

from Eli Lilly and Company

• Conducted by:• Director of European Dev QA (QP)

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Director of European Dev QA (QP) • Development Quality Representative (US based)

• Observation:• Significant progress since last assessment• SOPs and Quality Strategic documents are in place• Room to improve on material receiving area

• Recommendation:• To proceed with a formal Lilly quality audit

Facilities & Equipment

LaboratoriesQuality

System Based Approach Audit

• The audit focused on: • 21CFR211 & EU GMP’s • Quality System• Production System

F iliti d E i t S t

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Production Materials

Packaging & Labeling

• Facilities and Equipment System• Laboratory Control System • Material System• Packaging & Labeling

• The audit team included: • 3 QA representatives from US

• 1 QP from EU

Summary

• We appreciate our partner’s spirit of collaboration and strong commitments to improve their quality system.

• The overall progress our partner have made on

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p g ptheir quality system is very encouraging.

• We will continue to work with our partner to ensure the clinical materials manufactured at their CT facility will be meeting global regulatory requirement and safe for patients.

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Thank you!Please send you questions to [email protected]