ISPE Thailand

Welcome and opening Message

Dr. Charlotte Enghave Fruergaard, Honorable speakers, Distinguished guests, ladies and gentlemen

It gives me a great pleasure to welcome all of you to 10th anniversary ISPE Thailand conference.

Thank you for coming. The conference is jointly with ASEAN Life Sciences Conference and exhibition , is co-organizing with Thailand Center Excellence for Life Sciences, Thai Food and drug Administration , Thai Industrial Pharmacist Association, Thai Pharmaceutical Manufacturers Association , and Faculty of Pharmaceutical Science Chulalongkorn University.

This event is looking to the future, the next 10 years will bring many changes as countries and companies adapt to the greater competition of the ASEAN market situation.

During the last 10 years since the formation of ISPE Thailand Affiliate in 2003 many companies in Thailand have invested in new facilities and we have provided guidance to help with facility design, layout, and designs for HVAC and water.

We hope that ISPE can continue to provide much needed advice and we have put together a program which can help you think about your future requirements to make the industry more competitive. We have included Project Management, Modern Facility Design, IT requirements, Operations and Quality by Design (QbD). We hope that this will provide some inspiration for the future.

Do take the opportunity to ask questions from our experienced speakers.

We are greatly honoured by having with us the Chair of ISPE International Board of Director, Dr. Charlotte Enghave Fruergaard who has so kindly agree to grace this opening ceremony and address us, role of ISPE in the region.

On behalf of ISPE Thailand I would like to take this opportunity to express my sincere thanks to Thailand Center Excellence for life Sciences for supporting this event and in particular our honorable speakers, co-organizers , participants and ISPE Thailand Affiliate Board members .

Finally, this is the time for me to declare the official opening of 10th ISPE Thailand conference, I wish

all two fruitful days of interesting program will give you some insight into the kind of work that you have been doing.

To all of you, thank you for being here, welcome and enjoy the conference

Mrs. Sorada Wangmethekul President of ISPE Thailand Affiliate

ISPE Thailand Conference: Preparing for the Next Decade! Jointly together with

“Asean Life Sciences Conference & Exhibition 2013”

Wednesday 17th - Friday 19

th July 2013, Queen Sirikit National Convention Center, Bangkok, Thailand

DATE PROGRAMME

WED

17/07/2013

9.00 – 12.30 Morning Session (Open for All Participants)

OPENING CEREMONY Venue: Ballroom

Opening address by Minister of Ministry of Science and Technology

Keynote Address

“A Global Look at the Life Sciences Industry: Opportunities and Challenges”

Speaker: Mr. G. Steven Burrill, CEO of Burrill & Company

Keynote Panel Discussion

“Life Science Business in ASEAN: Opportunities and Challenges”

Speaker: Mr. G. Steven Burrill, CEO of Burrill & Company and Professor Dr. Pornchai Matangkasombut, Advisor to the

Board of TCELS

13.30 – 18.00 Afternoon Session (Open for All Participants)

TRACK 1

Venue: Ballroom

Regulator Track “Global Regulator Movement”

Global Regulatory Harmonization & Convergence for Health Products: Global Movement and Trend &

Best Practices & Approaches

Speaker: Dr. Justina A. Molzon, Associate Director of U.S. Food and Drug Administration

Dr. Petra Dörr, Head of Management Services and Networking of Swissmedic & Chair of International Pharmaceutical Regulator Forum

Panel: ASEAN Harmonization on Pharmaceuticals:- AEC and Beyond

DATE PROGRAMME

THU

18/07/2013

9.00 – 12.00 Morning Session (Open for All Participants)

TRACK 2

Venue: Meeting room 1 and 2

Opening ISPE Thailand 10th Anniversary, Ms. Sorada Wangmethekul, ISPE Thailand President

Key Note Speech 1: Role of ISPE in the region

Speaker: Dr. Charlotte Enghave Fruergaard, Chairman of the ISPE International Board of Directors

Panel Discussion: Regional Pharmaceutical Manufacture: Preparing for the next decade

Speaker: Dr. Charlotte Enghave Fruergaard, Mr. Chernporn Tengamnuay Greater Pharma Ltd Partnership, Dr. Anthony

Margetts, Factorytalk Co., Ltd, and Dr. Songpon Deechongkit, Siam Bioscience Co., Ltd.

ISPE Thailand AGM (Starting of ISPE Thailand until now …. Short history and review our

achievement). What will be in next decade?

Speaker: Ms. Sorada Wangmethekul, ISPE Thailand President and Mr. Chernporn Tengamnuay, First ISPE Thailand

President

13.00 – 16.30 Afternoon Session

TRACK 2A

Venue: Meeting room 1

Future Manufacturing Plant for Production

and Engineer

Design of potent facility Speaker: Ms. Deborah R Cohen and Mr.Nihir Parikh

,GE Healthcare Life Sciences

Sterile technology (Restricted Access Barrier

System (RABS) and Isolator) Speaker: Dr. Charlotte Enghave Fruergaard, NNE

Pharmaplan

TRACK 2B


Critical Utility Design and Maintenance

Critical Utility Design and Maintenance Speaker: Mr. Gaston Loo, MSD Singapore

Key Aspects of Comprehensive Calibration and

Maintenance Management System (CMMS)

Implementation Speaker: Mr.Tantra Tantraporn, Grand Thornton

FRI

19/07/2013

9.00 – 16.30 A Day Session

TRACK 3A


Future Manufacturing Plant for Management

level

Project Management for Pharmaceutical Production Facilities Speaker: Mr. Harald Geitz ,io-consultants

Factory Design

Speaker: Alain Kupferman

The role of Manufacturing IT - An Integrated Approach (ERP, MES, LIMS, eQMS) Speaker: ERP - Mr. Prateep Juavijitjan, Microsoft Partner (Vantage Business Solutions (Thailand) Co.,Ltd.) MES - Mr. Florian Seitz, Werum Software & Systems AG LIMS - Mr. Michael Wang, Accelrys, Inc. eQMS , Mr. David Margetts, Factorytalk Co., Ltd.

TRACK 3B


Future Quality System and Process Analytic

Quality by Design (QbD) and Process Analytical Technology (PAT) Speaker: Mr. Bikash Chatterjee, Pharmatech Associates, USA Wrap up in Thai by Ms. Mukdavan Prakobvaitayakit, The Government Pharmaceutical Organization (GPO)

TRACK 2

OPENING ISPE THAILAND

10th

ANNIVERSARY

Thursday 18 July 2013

SPEAKER PROFILE

TOPIC: ROLE OF ISPE IN THE REGION

Charlotte Enghave Fruergaard, Ph.D. - Director of Nordic Competences - The Chairman of ISPE Education - Copenhagen University College of Engineering, EBA in Enginnering Business Administration - Danmarks Tekniske Universitet, Ph.D. in Mechanical Engineering

Charlotte Enghave Fruergaard, PhD, is employed as Director, Nordic Competences at NNE Pharmaplan. Previously she was manager of Sales & Marketing and before that responsible for conceptual designs of new pharmaceutical facilities. Enghave Fruergaard has over 18 years of experience with pharmaceutical projects. She has a broad experience within pharmaceutical manufacturing of sterile products and is a leading expert within isolator and barrier technology and associated sterilisation techniques. Enghave Fruergaard holds an MSc in mechanical engineering and a PhD in measuring technique. She has international experience from an EU founded project where she was stationed at Physicalische Technische Bundesanstalt in Germany. During this project, she also gained the PhD degree within metrology. Enghave Fruergaard has been a Member of ISPE since 1995, and is the Chairman of the International Board of Directors. She is co-founder of ISPE Nordic Affiliate in 2000, and was Chairman of the Nordic Affiliate in 2006-2007. She is a member of ISPE Sterile Products Processing Community of Practice steering committee as well as on the Editorial Board for the magazine Pharmaceutical Engineering. Furthermore she has been the co-chairman of the yearly reoccurring ISPE “Barrier Isolation Technology Conference” in Europe since 1999. NNE Pharmaplan is the world’s leading engineering and consulting company in the complex field of pharma and biotech. We cover all segments from biopharmaceuticals and vaccines to medical devices and help our customers develop, establish and improve their product manufacturing. NNE Pharmaplan employs 1,700 people at more than 30 locations around the world. Engineering for a healthier world – our role in an industry that improves people’s lives worldwide. To learn more about our company, please visit nnepharmaplan.com

Key Note Charlotte Enghave Fruergaard

Director NNE Pharmaplan Chairman ISPE Board of Directors

ISPE India Affiliate Annual Conference

11-12 January 2013

A LOOK AHEAD

THE FUTURE

A Look Ahead Charlotte Enghave Fruergaard

Chairman ISPE 2013

Why?

What you can expect from me

What we will expect from you

What you can expect from ISPE

Why?

• A Professional • An employee • Charlotte

Volunteers

ISPE Mission

By 2015, ISPE will be recognized globally as the leading technical organization for professionals engaged in producing quality medicines and pharmaceutical devices throughout the product lifecycle

• Across all sectors • With all stakeholders • Globally

ISPE Directions

• Vibrant global association

• Technical & Scientific aspects

• Organizational aspects

ISPE Directions

• Leaders and regulators • Strategic Forum • Regional Forums (ASIA-PACIFIC, EUROPE, NORTH

AMERICA-SOUTH AMERICA)

• Regulatory and Compliance Committee

• Build a strategy for Europe


Expectations • Global and diverse culture • Leading and vibrant ISPE • Learning • Exchanging knowledge






ISPE Bringing together the

Right People to forge the

Right Relationships to address the

Right Issues and formulate the

Right Solutions to ensure the integrity of life-changing and life-saving pharmaceutical products




to

Ra

Rtoa




YOU

Shaping the industry • Participate • Engage • Involve

The more you give – The more you get



For every minute, the future is becoming the past.

Thor Heyerdahl

The Future Charlotte Enghave Fruergaard

Director NNE Pharmaplan Chairman ISPE Board of Directors

ISPE India Affiliate Annual Conference

11-12 January 2013

Look into the Future

• Industry • Companies • Members

Challenges

• Difficult times – Price pressure – Cost cutting

• Regulatory requirements

• Harmonization

Challenges

Higher Enforcement

Higher Transparency

Higher Requirements

Challenges

but you can learn to surf” Jon Kabat-Zinn Professor of Medicine emeritus at University of Massachusetts Medical School

“You can't stop the waves…

Opportunities

• Change & Innovation • Process & Performance

Improvement • Harmonization • Compliance → Quality Culture

Industry Trends

• Drug shortage • Patents expiring • Innovative drug delivery

methods • Counterfeit drugs • Automated, integrated,

smart machinery

Big Pharma Companies are investigating • OTC market through

mergers and acquisitions • Innovating new drugs - new

molecular entities • New drug packaging • New formulations that

enhance patient compliance and safety and are easier to use

ISPE India Annual Conference

Quality by Design

Supply Chain Security & Integrity

Quality by Design – QbD

• Quality in this respect is more than compliance

• It is about the true inherent attributes of a product

• It is created by a profound design and knowledge

• It can’t necessary be seen – but it can be felt

• It is an old engineering discipline that in many cases has been forgotten for the sake of compliance

Quality by Design – QbD When QbD is implemented, there will normally be a lot of benefits:

• Safer medicine/product • Lesser variation between

batches/products • Better manufacturing yield and

lesser scrap • A more robust process that

easier can be transferred to other sites

“Real” Quality

…is often an inherent attribute

Supply Chain Security & Integrity • Counterfeiting has become one of the biggest

problems facing the pharmaceutical industry • Counterfeiting all types of products and medical

devices • In the old days counterfeiters were only looking

for cold hard cash, but now they are after your brand

Borders "Borders? I have never seen one. But I have heard they exist in the minds of some people."

KonTiki was the raft used by Thor Heyerdahl in his 1947 expedition.

Thor Heyerdahl Norwegian adventurer

and explorer

Global Network

Building the Bridge

A Mutual Goal of Industry, Society and the Regulators

A maximally efficient, agile, flexible pharmaceutical manufacturing sector

that reliably produces high quality drug products without extensive

regulatory oversight

Dr. Janet Woodcock Director of CDER at FDA

Redefining the “C” in cGMP ISPE Conference – June 2012

Working together for a healthier world™

Goals – Taglines

Blue

Contact Info Charlotte Enghave Fruergaard, PhD Director, Nordic Competences Chairman ISPE Board of Directors

Nybrovej 80, 2820 Gentofte, Denmark Mobile: +45 3079 7208 [email protected] www.nnepharmaplan.com

Prediction is very difficult, especially about the Future.

Niels Bohr

2013 ISPE INDIA Annual Conference

TRACK 2A

FUTURE MANUFACTURING

PLANT PRODUCTION AND

ENGINEER

DESIGN OF POTENT FACILITY


SPEAKER PROFILE

TOPIC: DESIGN OF POTENT FACILITY

Deborah R Cohen Senior Scientist GE Healthcare Life Sciences Singapore Education - The State University of NJ, BA in Biochemistry, Rutgers

1996 to present: Senior Scientist, GE Healthcare Life Sciences 1996 Manufacturing Scientist, Roche Molecular Systems 1995-1996 Associate Scientist, Merck & Co 1994-1995 QC Analyst, Celgene 1991-1993 Senior Associate Scientist, Celgene

SPEAKER PROFILE

TOPIC: DESIGN OF POTENT FACILITY

Nihir Parikh Business Development, Enterprise Solutions, Asia GE Healthcare Life Sciences Singapore Education - INSEAD in MBA - Stanford University, MS in Chemical Engineering (focus: Biotech) - UDCT (Mumbai), BE in Chemical Engineering

Currently, Business Development Manager, Asia, GEHC Life Sciences, Singapore Previously, BioProcess Manager, Asia, GEHC Life Sciences, Singapore Previously, Process Development Engineer, Genentech Inc., South San Francisco Expertise and relevant Experience

Manager business development in Asia, including commercial projects, engineering, coordination of government affairs, finance, regulatory and other contacts in support of opportunities

Consultative interaction in over 20 bio manufacturing company projects with regard to facility flexibility, biologics downstream processes, scale up and chromatography equipment

Hand on process scale up & technology transfer experience from lab scale to pilot plant to manufacturing for multiple Monoclonal Antibodies

Developed multiple scenario based financial models and business plans

Led various strategic marketing projects focused on Asia

1 ASEAN Life Sciences Conference & Exhibition

GE Proprietary & Confidential

Establishing biomanufacturing capacity in Asia

Nihir Parikh Enterprise Solutions GE Healthcare Life Sciences Bangkok, July, 2013



Agenda

• GE Life Sciences

• Demand for biopharmaceuticals

• KUBio™: An innovative and standardized manufacturing solution



General Electric Today

AVIATION TRANSPORTATION HOME &

BUSINESS SOLUTIONS,

MEDIA

GE CAPITAL GE ENERGY

Energy Services Oil & Gas Power & Water

HEALTHCARE

GE THEN/NOW SOLUTIONS ENVIRONMENT INNOVATION

Today

GE Healthcare Life Sciences Six decades supporting Biopharma

1960s

Sephadex™, Sepharose™, Large

scale columns

1980s

FPLC™, Sepharose Fast Flow, BioPilot™, Sepharose High

Performance, Custom Designed Media (CDM)

2000s

MabSelect SuRe™, Capto™ family, BioProcess membranes, AxiChrom™

columns, ReadyToProcess™ single-use systems

1970s

Protein A Sepharose, Sephacryl™, Immobilized

Metal Affinity, Hydrophobic

Interaction

1990s

Fast Trak Services, ÄKTA™ systems family, UNICORN™

control system, SOURCE™ resins,

OligoPilot™/ OligoProcess™

2010s

MabSelect SuRe LX, Capto ImpRes, Capto L, Capto Core 700, PAA cell culture media,

Xcellerex™, Primer Support 5G

pure

insulin

pure

plasma proteins

recombinant

insulin

monoclonal

antibodies

cell-based

vaccines

biosimilars



Across the bioprocessing spectrum…

6

DEMAND FOR BIOPHARMACEUTICALS



Political Economic

Social Technological

Increasing demand for healthcare …. growing pressure on healthcare funding…..need for cost-effective, flexible manufacturing solutions

Biopharma market dynamics

• Aging population

• Chronic disease increase

• Pandemic risks

• Patient consumerism

• Manufacturing trends: higher

yields, smaller batch sizes

• Biobetters

• New medicines: FABs, ADCs,…

• New biopharma company strategies

• Emerging markets

• New business models

• Manufacturing optimization

• Healthcare cost reduction

• Growing disease prevalence in developing nations

• Dynamic pricing &

reimbursement schemes • Biosimilars regulation not

finalized

900 million people in Asia to move

from “poverty” to “middle class” by 2020

By 2030, the number of people > 65 will • Increase 140% in developing world

• Increase 51% in developed world Almost half of lifetime healthcare expenditure is made after age 65

Older, sicker, fatter, but richer in parts of Asia

• Health reform package to provide

universal basic care by 2020, adding $40bn annually

• $6bn investment in bio pharma industry in latest 5 year plan

• $2.2bn venture fund for supporting

drug discovery & research infrastructure development projects

• 1 state health insurance program

has quadrupled India’s health insurance penetration by covering 23.5 million households in its first three years

BREAST CANCER EPIDEMIOLOGY: Breast cancer mortality /

incidence ratios (Globocan 2008)

Cell culture capacity and need > 100,000 L

> 50,000 L

> 10,000 L

Capacity:

Source: “The State of Mammalian Cell Culture Biomanufacturing”, report prepared by Bioprocess Technology Consultants (BPTC), 2011



> 100,000 L

> 50,000 L

> 10,000 L

Cell culture capacity and need

Need



Source: GE internal assessment



Traditional capacity decisions Timing & unknowns

TIME PRESSURE Timing cycle of 3-4 years required early decisions

on building production capacity

+ UNKNOWNS

• Process development outcomes unknown • Clinical outcomes unknown • Inaccurate market volume for products

RESULTS • Capacity that doesn’t match the product

requirements & never fully utilized • Major gamble of capital and human resource,

without assurance that you have a viable

product



What is needed to establish biomanufacturing capacity in Asia?

An integrated solution which will bring product technology, process and facility together

A standard platform which will ensure GMP compliance

Package together project management, from start to finish

Assistance to qualify the process and facility, ready for operations

Assistance to establish an operational system with a trained and capable workforce

A solution that can be implemented on a shorter timeline and at lower CAPEX



The supply of a start to finish bio-manufacturing solution

Technology access

Manufacturing technologies &

tools

Plant operation

Process development

Engineering design

Facility construction

Project Management

Partners

Prevention

Cost reduction

Pandemic

preparedness

Aging population

Cost reduction

Increase access to

modern therapies

Aging population

Fast growing

needs

Cost reduction

• Essential biopharmaceutical

• Improve access to blood protein products

• Safer & optimized blood management

Localised production capability

The challenge: addressing the global healthcare needs





Life Sciences Enterprise Solutions Customized

solutions KUBioTM FlexFactoryTM

Tailored to

needs

Standard,

Off-the-shelf

Integrated,

Platform

Facility

Equipment

Services

Therapy area

KUBio™

An innovative and standardized manufacturing solution

16



The off-the-shelf MAb manufacturing solution, enhancing speed to market and driving innovation through single-use process systems



KUBio™



1. Upstream prep 2. Upstream 3. Harvest and

capture 4. Downstream

purification 5. Central utilities 6. Buffer prep

Facility layout



Delivery and assembly on site



FlexFactory™ processing platform in KUBio™



FlexFactory™: Basis of Design

FlexFactory is an end-to-end biomanufacturing platform,

predominantly based on single-use technology, integrated

by a process automation system and single use tubing sets

Production bioreactor

Cell culture seed train

Nano-filtration Sterile filtration

Vial Shake flask

20 L

100 L

XDR™ Bioreactor 1000 L

Depth filtration train

ÄKTATM ready 20 L Protein A

chromatography

ÄKTA ready 20 L IEC

ÄKTA ready 20 L IEC

UF /DF conditioning

UF/DF conditioning

Viral inactivation

Harvest operations

Purification operations Bulk formulation

WAVE BioreactorTM



The KUBio™ project phases

Detailed

design

Realisation

Start-up and

handover

KUBio

investment decision

Conceptual

design

Basic

design

Project

close-out

The conceptual design and most of the basic design is already completed at the time of the investment decision



General execution timeline Stick built, stainless steel facility

Activity

Conceptual

Design

Basic Design

Site permitting

Site preparation , Building + HVAC Construct

Cleanroom commissioning

Start-up and Process installation including, IQ/OQ

Hand-over and ready-to-start PV

36-40 months



*Due to site location, transportation time could be shorter than two months

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 Activity / Months

Planning, requirements definition

Site permitting and preparation (Client)

Workshop execution, module construction, installation

Transportation and customs clearance*

Assembly at site

Start-up, commissioning cleanrooms

Process installation incl. IQ/OQ

Ready to start engineering runs/process

validation (PV) runs (Client)

Speed to market: 14-18 months

Speed to Market: KUBio Execution time schedule



Number of products to be manufactured

Pro

du

ct

tite

r (g

/L)

1 2 3 4 5 6

4

3.5

3

2.5

2

1.5

1

0.5

101-120 kg

81-100

61-80

41-60

0-40

High titre expression systems allow

for high facility capacity output even for multi-product production

Assumptions: each product to be manufactured having identical expression levels i.e. best case

scenario

Maximal production capacity Over 100kg of bulk MAb/year

27

FINANCIAL MODELS



KUBio™/FlexFactory™ NPV Analysis*

Revenue

+20%

Variable

±10%

Fixed

↓

Profit

↑

*Comparative analysis with a SS Stickbuilt facility as a basis




Revenue

+20%

Variable

±10%

Fixed

↓

Profit

↑

↑ Consumables ↓ Water ~ 80% ↓ Waste treatment ↓ Labor ~ 30% ↓ Power ~ 40% ↓ AHU ~ 30% ↓ QA/QC ~ 30% ↓ Inc automation ↑ Reproducibility ↑ Pay as you go





Revenue

+20%

Variable

±10%

Fixed

↓

Profit

↑

↑ High Flexibility ↑ Multiproduct ↓ Turnaround time






Revenue

+20%

Variable

±10%

Fixed

↓

Profit

↑

↑ High Flexibility ↑ Multiproduct ↓ Turnaround time


↓↑ CAPEX ±20% ↓ Time to First Rev ~ 18 mths ↓ Time to Recurring revenue ~ 20 mnths ↓ Facility Size ~ 20% ↓ Cleaning Validation ↓ Financing cost ~ 50% ↓ Cost/gm Other key considerations

↓ Risk ↓ Training and manpower ↓ Carbon Footprint ↑ GMP compliance ↑ Robust technology ↑ Patient Safety ↑ Market Demand visibility


32

CONCLUSION



Speed to market: 14-18 months to qualified facility

Flexibility: Multi-product/higher throughput from single-use

Decreased risk: Standardized GMP facility design platform

Simplified project management: Single point of contact

Wherever its needed

Summary: global needs….global reach





GE, imagination at work, healthymagination, and GE Monogram are trademarks of General Electric Company.

ÄKTA, ÄKTAprocess, AxiChrom, Biacore, BioPilot , BioProcess, Capto, CyDye, Cytodex, Cytodex, Cytopore, ECL, FlexFactory, FPLC, FTA, HiScale, HiScreen, HiTrap, ImageQuant, IPGphor, KUBio,

Kvick, MabSelect SuRe, Mono P, Mono Q, Mono S, Multiphor, NanoVue, OligoPilot, OligoProcess, PhastSystem, PreDictor, ReadyToProcess, Sephacryl, Sephadex, Sepharose, SOURCE, Superdex, Typhoon, Ulta, UNICORN, UniFlux, WAVE Bioreactor, Xcellerex are trademarks of GE Healthcare companies.

Ultrospec is a trademark of Biochrom Ltd, Wonderware is a trademark of Invensys PLC, and ControlLogix is a trademark of Rockwell Automation.

© 2013 General Electric Company—All rights reserved. First published March 2013.

All goods and services are sold subject to the terms and conditions of sale of the company within GE Healthcare which supplies them. A copy of these terms and conditions is available on request. Contact your local GE Healthcare representative for the most current information.

For local office contact information, visit: www.gelifesciences.com/contact GE Healthcare Bio-Sciences AB, Björkgatan 30, SE-751 84 Uppsala, Sweden.

www.gelifesciences.com/enterprisesolutions

Thank you

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Trends in

Sterile Manufacturing Technologies

ISPE Thailand Annual Meeting

Charlotte Enghave Fruergaard

2013.07.18

Where we come from

1930s – Danish Novo and Nordisk

Gentofte (later Novo Nordisk)

employed the first engineers.

1974 – Pharmaplan was founded

as part of the medical care group

by Fresenius, Germany.

1991 – After functioning as in-

house consultants at Novo Nordisk

for years, NNE (Novo Nordisk

Engineering A/S) demerged as an

independent company.

2007 – Acquisition of Pharmaplan,

a company similar to NNE in DNA.

NNE Pharmaplan was founded.

With 80 years of

experience we are

passionate about

our services to the

pharma and biotech

industries.

Recent awards

2004 IChemE: “Haden Freeman Award for Engineering Excellence”

2005 ISPE Facility of the Year Award winner – Novo Nordisk’s NovoSeven (FVII) facility

2008 ISPE Company of the Year winner

2009 ISPE Facility of the Year Award winner – Facility Integration – hameln pharmaceuticals, Germany

2009 ISPE Facility of the Year Award winner – Operational Excellence – R&D division of US biotech company, Switzerland

2009 Emerson: “PlantWeb Excellence” for DeltaV application for Pronova BioPharma project (KalOmega)

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Who we are

We are the leading consulting and

engineering company in the complex

field of pharma and biotech.

We count close to 1,700

professionals with project

experience and knowledge

related to pharma and biotech.

More than 200 have hands-on

development or production

experience.

We executed 2,929 projects

in 2012.

Our project execution

and our staff

embody 10,000

years of

experience within

pharma and biotech

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Optimal production processes

Company

revenue

2012

USD 294M

EUR 224M

DEVELOP ESTABLISH IMPROVE

Project

development

Process & Product

development

Investment project

CD / BD / DD / CON / C&Q

Optimisation, training, revamps,

GAP analysis, operational support

Agenda

• Market changes forcing technology changes…

• Aseptic/Sterile processes

• Technology Trends

What is OSD and Biotech?

Small Molecules vs. Large Molecules

Chemical Synthesis

Drying or Granulating

Tableting Packaging

Chemical Active Pharmaceutical Ingredient

(API)

“Tablets” Oral Solid Dosage Form

(OSD)

Formulation

Fermentation or Cell Culture Inteferon molecule

vs Aspirin

Formulation Aseptic Filling

Packaging

Biologics Active Pharmaceutical Ingredient

(API)

“Injectables” Parenteral Dosage Form (aka Sterile Products)

Small Molecules OSD

Large Molecules Biotech

Since “1899”

Since “1982”

http://images.google.dk/imgres?imgurl=http://www.pharmaceutical-machinery-manufacturer.com/rimages/126/tablet-fluid-bed-dryer-B.jpg&imgrefurl=http://www.pharmaceutical-machinery-manufacturer.com/tablet/fluid-bed-dryer.htm&h=238&w=250&sz=19&hl=da&start=16&tbnid=sBvwA7uE80wL0M:&tbnh=106&tbnw=111&prev=/images?q=drying+pharmaceuticals&svnum=10&hl=da&lr=

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http://www.millipore.com/catalogue.nsf/docs/C8685

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Large Molecules grows faster

Small Molecule drugs is the big market

The Economist 2005

Shifting roles:

• The shift from small to large

molecules became visible in

2003

Market changes forcing technology changes…

• Products

New products are more and more classified as high potent and require

both a very high level of aseptic processing and operator /

environmental protection

• Batch sizes

Small batch sizes of very high value. Based on better diagnostic

methods, personalized treatment (1 vial = 1 batch) will increase

• Processes

New products (mainly Biopharmaceuticals) are usually produced by

aseptic processes

• Primary containers

Pre-filled syringes and new developed devices are growing fast

• Automation

Elimination of the “human factor” to avoid direct human impact for all

critical process steps (class A operations) in a reproducible,

validatable and documentable way

Agenda




From API to Finished Product excl. QA/QC

Finished Products API Components etc.

Manufacturing of Sterile Products

Wash & Sterilisation (incl. Comp. Prep.) Compounding (Preparation) Filling Barrier Isolator Lyophilizing

Assembly & Packaging

Assembly Labelling

Packaging

Filled units

Logistics & Controls in Manufacturing Logistics Material Handling Inspection Controls

Sterile Products – Definition

Sterile products are products free from living micro organisms

Ph. Eur. section 5.1.1. Methods of Preparation of Sterile Products

• It is expected that the principles of good manufacturing practice will

have been observed in the design of the process including, in

particular, the use of

• qualified personnel with appropriate training

• adequate premises

• suitable production equipment, designed for easy cleaning and sterilisation

• adequate precautions to minimise the bio burden prior to sterilisation

• validated procedures for all critical production steps

• environmental monitoring and in-process testing procedures

• Sterilisation shall be done in the final container if at all possible

• Sterility Assurance Level (SAL) of minimum 1:1,000,000

Sterile or Aseptic manufacturing?

Can the solution tolerate heat treatment?

• Yes Sterile manufacture

• Sterilization takes place in the end of the process

(= terminal sterilisation)

• No Aseptic manufacture

• The solution is sterile filtered and thereafter only comes in

contact with sterilised utensils and tanks in a classified

environment (grade A/ISO 5 with a grade B/ISO 7

background)

• Filter pore size is 0.22 µm = 0.00022 mm

Why do we have GMP?

• Manufacturing of pharmaceutical products is all about “Risk for

the patient”

• This is why we document, train and qualify…

• Traceability is being able to trace BACK – especially when

something goes wrong (batch numbers and documentation)

Washing Process

• Purpose of washing

• Secure no leftover from previous product, i.e. no cross

contamination

• Reduction of endotoxin and

particles

• Items to be washed in a

utensil washer

• Utensils

• Machine parts

• Hoses

• Typical process

• Rinse

• Wash with or without detergent

• Several rinse phases.

Conductivity measurement

• Drying

Sterilization Process

• Purpose of sterilization:

• Secure a product free of living microorganisms with a sterility assurance

level of 10-6 or better

• Terminal sterilization

• Product produced at least in grade D and sterilized in final container

• Aseptic preparation

• Each primary packaging component sterilized individually

• Solutions sterile filtered

• All handling and filling of aseptically prepared products must be done in

grade A/ISO 5 with grade B/ISO 7 background

• Items to be sterilized

• All items going to grade B/ISO 7 including sanitizers and gowning

Methods of Sterilization

• Saturated steam 121°C, minimum 15 minutes, pressure +

(Autoclave/SIP) 0,1 bar

• Hot water 121 °C, minimum F0 15 minutes

• Dry heat sterilization 160 °C, minimum FH 38 minutes

• Dry heat depyrogenation 250 °C, minimum FH 15 minutes, lead to a

3 log reduction of endotoxin

• VHP sterilization Demonstrate a SAL of 10-6

• Filtration Pore size < 0,22 µm

• Radiation /e-beam A minimum dose of 25 kGy

Liquid Compounding – Preparation

Liquid compounding of Sterile Products is mixing of

• Water for Injection (WFI)

• Active Pharmaceutical Ingredient (API)

• Other raw materials, e.g.

• Stabilisers

(physical/chemical)

• Preservatives

(if multiple use product)

• Isotonic substances

Filling Process

• To take the sterile product from Compounding and fill it into a

primary packing, which must protect the product and keep it

sterile until use

• Multiple Batch Filling: Filling more than one batch between full

cleaning/decontamination of the filling line

• During filling protection against contamination from the

following must be avoided:

• The primary packing itself

• Surroundings & People

Surroundings & People

• People are the most contaminating source for the product

Why is this necessary?

Surroundings & People

• People are the most contaminating source for the product

• This must be reduced by protecting the filling process:

• Conventional Clean Room (CCR)

• Restricted Access Barrier System (RABS)

• Isolator

Material Input/Output

Glass

Washing

Sterilization

Pistons

Filling

Product from

Compounding

Combi seals

Filled and

inspected

Glass

What are Barrier Systems?

• A physical barrier which separates the operator from the

process.

• As important as the barrier itself are the linked features and

processes such as:

• Properly designed equipment (ergonomics) and HVAC system

• Material transfer procedures

• Working procedures and training of the operators

• Procedures in terms of intervention and accidents

• That’s why it is called a “system”

Definitions – CCR

• Conventional Clean Rooms (CCR)

• ISO 5 (class A) surrounded by ISO 7 (class B) room

• Pressure difference (15 Pa) between the clean room classes

• Critical operations with open sensitive products are carried out

under Unidirectional Airflow (class A protection)

• Manipulations (i.e. trouble shooting, change of format parts) are

done directly by opening of the machine cladding

• Operator gets directly in contact with critical surfaces (class A area)

• Gowning of the operator according to class B requirements

• Material transition to class B (autoclave, pass box, dry heat oven)

• Regular wipe sanitization

• Heavy routine viable monitoring

• Periodical room sanitization

• Machine parts pre-sterilized or disinfected in situ

Conveyor

Vial

Nozzle

Filling

Mechanism

HEPA Filters

Class 100

(ISO 5)

3-6" From

HEPAS

Class 10,000

(ISO 7)

Plastic

curtains

Definitions – RABS

• Restricted Access Barrier System (RABS)

• Surrounding clean room class B for the filling operation

• Pressure difference (15 Pa) between the clean room classes

• All manipulations during production are done via gloves of the

RABS

• Ergonomic designed system for the process inside (Mock-up

studies)

• Transfer of format parts via Rapid Transfer Port (RTP)

• Material transfer via Rapid Transfer Port (RTP) or material locks

• Gowning of the operator according class B requirements

• Conventional cleaning and disinfection

• Same viable monitoring as CCR

• Locked doors (barrier) during operation

• The system isolates the operator from the critical areas to increase

Sterility Assurance Level (SAL)

Conveyor

Vial

Nozzle

Filling

Mechanism

HEPA Filters

Class 100

(ISO 5)

3-6" From

HEPAS

Class 10,000

(ISO 7)

Plastic

curtains

Passive

Conveyor

Vial

Nozzle

Filling

Mechanism

HEPA Filters

Class 100

(ISO 5)

HVAC

Class

10,000

(ISO 7)

Doors with

gloves

Active

Definitions – Isolators

• Isolators

• ISO 5 (class A) inside isolator

• Surrounding clean room ISO 8 (class D or C) for the filling operation

• Positive pressure difference towards the filling room

• Ergonomic designed system for the process inside (Mock-up

studies)

• Complete closed system with Vaporized Hydrogen Peroxide (VHP)

decontamination of all surfaces

• Complete independent HVAC-unit

• All manipulations during production are done via gloves

• Gowning of the operator according class C or D requirements

• Material transfer via Rapid Transfer Port (RTP) or material locks

• Area to be monitored is very limited

• Very high SAL

Conveyor

Vial

Nozzle

Filling

Mechanism

HEPA Filters

Class 100

(ISO 5)

AirReturn

Class

100,000

(ISO 8)

Doors with

gloves

The Technologies

• Environment: B/A

• Complexity: Low

• Comfort: Low, due to clean room

garment

• Aseptic quality: Low SAL~3 (*)

• Campaigning unusual

• Environment: B

• No overpressure to surroundings

• Complexity: High, due to transfer

techniques and restricted access by gloves

• Comfort: Even lower, due to clean room

garment and restricted access

• Aseptic quality: Slightly improved SAL~4

• Several days campaign unusual

• Environment: D

• Overpressure

• Complexity: Highest, due to transfer

techniques and biodecontamination

• Comfort: Medium, no clean room

garment, but some restrictions

• Aseptic quality: Highest SAL~6 log

• Week(s) campaign possible

Clean Room RABS Isolator Restricted Access

Barrier Systems

Barrier Systems

Open RABS

(active or passive)

Conventional Clean Room Isolator Closed RABS

(*) Sterility Assurance Level

The Technologies

Clean Room RABS Isolator Restricted Access

Barrier Systems

Barrier Systems

Open RABS

(active or passive)

Conventional Clean Room Isolator Closed RABS

(*) Sterility Assurance Level

Currently most installed

aseptic production lines

are based on this

Technology.

For new projects not

anymore

“state-of-the-art“.

Rather new technology, with

large increase in terms of

installations within the past

years.

Since more than ten years

developing quite fast, first in

Europe, then also USA and

Japan.

First choice technology for

handling of high potent APIs.

Conflict of GMP vs. operator protection

Pro and Cons

CCR RABS Isolator Comments

Validation, start-up risk Low Low High Complex isolator validation

Necessity of experts Low Low High External consultants?

Skill of personnel Medium Medium High Aseptic behavior needed in all 3

Investment, equipment Low Medium High

Investment, building High High Low

FMC high cost countries High High Low

FMC elsewhere No real difference

Suitability for campaigning Low Medium High Higher productivity with campaigning

Sterility Assurance Level (SAL) Low Medium High

Regulatory scrutiny High Low Low

Risk – SAL – Media Fill High Medium Low

Microbial Sampling Normal Normal Less

Suitability for processing potent

drugs

Not given Limited Very good

Maintenance complexity Low Medium High

Access for service Easy Restricted Restricted Better for isolator due to garment

Realization time Low Medium High

Considerations – Product

• Multi product production

• One product

• No of individual preparations per Year

• Containment

• Preservatives ?

• Explosion proof

• Batch sizes – Multiple batch filling

• Protein – H2O2 sensitivity

• Price of product

Considerations – Process

• Complexity of process

• Ampoules Vials Syringes Cartridge

• Powder ?

• Freeze Drying

• Material Transfer

• Transfer door/lock

• α/β-ports

• Gloves

• Sterile mounting

• Integrity testing

• Replacement period

• Leak testing

• H2O2-decontamination

Considerations – Working Environment

• Product and Operator Safety (positive or negative Δ pressure)

• Working procedures and training of users

• Procedures in terms of intervention and accidents

• Surrounding room environment (operator comfort)

• Energy saving

Main Challenges

• Vaporised Hydrogen Peroxide sensors (VHP-sensors)

• Inaccurate

• Biological Indicators

• BI’s are biological

• D-value determination

• Needed Log-value

• VHP as a sterilising agent

• Surface decontamination

• Parts with in-direct product contact

• Harmful to proteins

• Gloves

• Integrity testing

Technology Evaluation

• Technology ready!

• But still some inexpedient issues ~ VHP sensors, biological

indicators, gloves. Challenges for experts, not obstacles.

• Suppliers ready!

• All major suppliers are of high standard.

• Filling line, isolator/RABS and facility designed together.

• Knowledge ready!

• It seems as the use of properly chosen consultants/experts can

minimize both the change over time and the time for and risk of

validation.

• Isolators call for experts

• Goal/level setting, process development, decision of acceptance

criteria, validation and interpretation of results.

• RABS may be a solution

Regulatory requirements

The regulatory authorities are demanding more and more

barrier systems to eliminate direct operator impact to critical

processes:

• There is no doubt that the operator is biggest risk of a potential

particulate and microbiological contamination for the production

of pharmaceuticals

• US-FDA – Rick Friedman comments in March 2013:

• ”Conventional cleanrooms are on the borderline of

compliance”

ISPE Aseptic Conference Baltimore, March 2013

Rick Friedman, Associate Director, OMPQ, FDA

Regulatory – Guidelines

The regulatory authorities are demanding more and more

barrier systems to eliminate direct operator impact to critical

processes:

• EU GMP Guideline (New Annex 1):

‘Manufacture of Medicinal Products‘, Section ‘Isolator

Technology‘

• 21. The utilization of isolator technology to minimize human

interventions in processing areas may result in a significant

decrease in the risk of microbiological contamination of

aseptically manufactured products from the environment…

• 122. Restricted access barriers and isolators may be beneficial in

assuring the required conditions and minimising direct human

interventions into the capping operation.

Regulatory – Guidelines

• FDA Guidance „Sterile Drug Products Produced by

Aseptic Processing“, Published version September 2004:

• ASEPTIC PROCESSING ISOLATORS (Appendix 1)

Aseptic processing using isolation systems minimizes the extent of

personnel involvement and separates the external cleanroom

environment from the aseptic processing line. A well-designed

positive pressure isolator, supported by adequate procedures for

its maintenance, monitoring, and control, offers tangible

advantages* over classical aseptic processing, including fewer

opportunities for microbial contamination during processing.

However, users should not adopt a false sense of security with

these systems. Manufacturers should also be aware of the need to

establish new procedures addressing issues unique to isolators.

Regulatory – Why

Regulatory – EU Statement

• What is the general position on the use of isolators and

restricted access barriers vs. old conventional thinking?

• “The transfer of materials into the aseptic processing zone and the

role of people in the process are key concerns.”

• “Robust material transfer strategies together with automation and

enhanced product protection (from people) are therefore key to

minimising risk.”

• “Use of isolators for aseptic processing is therefore to be supported

but ultimately it is for industry to select and justify the technologies it

used.”

ISPE Barrier Isolation Technology Conference Berlin, September 2007

Presentation by Ian Thrussell, MHRA

Regulatory – FDA Statement

• “The FDA would not tell a manufacturer that they must use a

specific single technology to assure adherence to aseptic

processing requirements. The FDA does indicate its general

preference for isolators and provides corresponding regulatory

incentives for them. A sound RABS concept also can provide

added protection versus traditional processing approaches.”

Article in PHARMACEUTICAL ENGINEERING MARCH/APRIL 2007

Article made from panel discussion by Rick Friedman and Bob Sausville during ISPE Barrier

Isolation Technology Conference Washington, June 2006

Why consider Isolator Technology

• Authorities – Less scrutiny

• Industry – “State of Art”

• Economical – Cheaper per unit produced (with

comparable SAL)

• Manning – Less microbiological sampling/testing

• Risk – No scrap of product due to sterility issues

or failure in Media fills

• Environmental – Eliminating high class cleanroom

environment, less space

• Cost – Reduction of running costs

• Operator – Protection with potent products

Why consider Isolator Technology

• Increasing amount of high potent APIs

• The protection of the operator as well as the environment for

the production of pharmaceutical products becomes more and

more important because of the following reasons:

• The ratio of new APIs which are classified to be high potent is rising

continuously:

1990: approx. 5%

2002: approx. 30%

2015: ?

• Existing APIs which were originally classified as not high potent are

re-classified to be high potent

• The importance of operator and environment protection is

constantly growing in our society with the result of stricter laws and

regulations

Summary – Isolator

• Isolator benefits:

Higher product quality (e.g. SAL 6 log), reduced risk

Better protection of personnel (containment)

More comfort for personnel

Lower facility cost and running costs (Class C or D)

• Isolator appropriate for:

High output machines

Long filling campaigns

Expensive products

Aseptic and potent drug

Conclusion / Recommendation

• Barrier systems are important to improve the product quality, and

if required to provide an operator and environmental protection

• For new facilities the use of barrier technology is almost

mandatory

• Barrier systems which are using gloves for manipulations have to

be designed very well in order to give the operator good

ergonomics for all required manipulations

• In order to avoid gloves and manual handling operations the trend

go to a fully automized process

• An evaluation based on the products and processes about the

kind of barrier systems should be done in an early project phase,

because this has a huge impact in the overall facility design.

• The technology is a mature, ready to use, but experts are

necessary to secure the right solution and to educate.

Agenda




Industry Trends – Overall

• Avoiding of aseptic handling

Trend to avoid any manual aseptic handling of pre-sterilized

components. If it cannot be avoided the use of a barrier system

is almost mandatory

• Automation

Trend to automize GMP critical processes in order to eliminate

the “human factor” at all

• Energy efficiency

Trend to save energy because it becomes more and more a

significant cost factor

• PAT (Process Analytical Technology)

Biopharmaceutical products are becoming more and more

expensive, therefore PAT becomes more and more importance

to decrease / avoid product loses

Technology Trends Equipment cleaning

• Automation / Validation

Clear industry trend to avoid any manual handling steps.

Very difficult to achieve reproducible cleaning result by performing

cleaning processes of critical equipment parts manually

Stopper chute

Stopper hopper

Vacuum star wheel

Guiding rail Fixing elements

Vacuum

star wheel

Plungers Plungers

Fixing

elements

Picture courtesy Belimed Sauter AG

Technology Trends Stopper treatment

• Automation

Clear industry trend to avoid any manual handling steps, especially

after sterilization

• Aseptic transfer (Use of Barrier Technology)

Charging of stoppers into the stopper hopper of a filling machine

equipped with a RABS or an isolator is more time consuming

compared to a filling line in conventional design. As higher the filling

machine speed, and / or as larger the rubber stopper size is, as more

relevant this issue gets.

• Process control

A closed automated process combining all or partly the following

process steps in one unit provides better process control:

• Washing (with or without detergents)

• Siliconization

• Sterilisation

• Drying


Lifecycle process:

Treatment & Transfer:

Cleanroom D or C

*

Receiving:

Unclassified area

Cleanroom

A/B or Isolator

Connection:

Rapid Transfer Port

**

* Picture courtesy ATEC Steritec GmbH

** Picture courtesy GETINGE-LA CALHENE


Aseptic stopper transfer:

Technology Trends Sterilisation technology

VHP Passbox:

Picture courtesy Metall + Plastic GmbH


E-Beam:

• E-Beam is the only continuous sterilization method to supply

high speed pre-filled syringe filling machines

• Lifetime of the emitters are not satisfying for some suppliers,

nevertheless it will become the standard sterilization method

for tub sterilization

• A DIN/ISO standard for tubs of pre-filled syringes is currently

under examination


E-Beam:

Picture courtesy Metall + Plastic GmbH

Technology Trends Disposable Systems

1. Coupling for bag or vessel connection

2. Peristaltic pump when delivery container

is not pressurized

3. Bioburden sample bag

4. Sterilizing grade product filter

5. Vent bag

6. Intermediate reservoir bag

7. Disposable manifold

8. Peristaltic dosing pumps

9. Beta-Bag

10. Isolator/RABS wall towards filling

11. Filling needles

1 2

3 4

5

6

7 8

9

10

11

Technology Trends Single Use Technology

• Now available from all well known filling machine suppliers

Costs are between 600 – 6.000 Euro per set

Picture courtesy Robert Bosch GmbH

*

*

Technology Trends Disposable Systems

• Saving of utilities (CIP/SIP)

• Saving of investment costs

• Avoiding of cleaning validation

• Faster filling machine set up

between two batches/products

(less filling machine downtime,

especially in combination with an

isolator)

• Less product loss at batch end

Less

important

Very

important

Design Trends:

Technology Trends Filling equipment

• Filling system

Peristaltic pump systems are often the preferred system for

Biopharmaceuticals and / or Disposable systems

• Robot / Handling systems

Individual positive transport, avoidance of glass to glass contact,

minimizing rejects and glass breakage rate and very flexible (fast)

format change

• Performance

• High speed filling equipment for pre-filled syringes up to 1.000

units/min.

• Low speed filling for very small batches with fast format/product

change

• Process Analytical Technology (PAT)

• 100% check of filling volume

• Camera inspection for stopper and cap placement

Technology Trends Filling equipment

• Filling machine with handling systems and check weighing:

Technology Trends Barrier Technology

History (1947):

Year Asia Europe N.America Total

2004 42 116 90 248

2006 50 146 105 301

2008 59 196 133 388

2010 64 218 139 421

Industry Trends – Isolators

ISPE Barrier Isolation Technology Conference Brussels, September 2010

Lysfjord/Porter – Final Survey Results 2010

Barrier Isolator Filling Line – Deliveries by Year

0

5

10

15

20

25

30

35

40

19

85

19

88

19

89

19

90

19

91

19

92

19

93

19

94

19

95

19

96

19

97

19

98

19

99

20

00

20

01

20

02

20

03

20

04

20

05

20

06

20

07

20

08

20

09

20

10

20

11

Process technology RABS – Pictures

Technology Trends Freeze Dryer Loading & Unloading Technology

• Automation

Clear industry trend to avoid any manual handling steps,

especially during the freeze dryer loading

• Use of Barrier Technology

Loading: Mainly to fulfil GMP purposes

Unloading: Mainly to fulfil operator safety requirements

• Pass-through freeze dryer configuration

Increases the overall performance especially when freeze drying

cycle is short and number of freeze dryer connected to a filling

line is 2 or more

• Vertical execution

Technical area as well as condenser below chamber to create a

maintenance access through unclassified areas

Technology Trends Freeze Dryer Loading & Unloading Technology

Mobile automated cart for freeze dryer loading:

Summary Future developments (subjective)

• Filling Equipment

• The technical development will go in the direction of handling / robot systems which do not require a direct human intervention

“...the emergence of the robotics industry, which is developing in much the same way that the computer business did 30 years ago. Think of the manufacturing robots currently used on automobile assembly lines as the equivalent of yesterday's mainframes.”

– Bill Gates; A Robot in Every Home; Sci Am; 2006

• RABS

• RABS technology is on the long-term not a succeeding technology

“Conventional aseptic filling should become passé soon.”

– Rick Friedman, Director, Div. of Mfg and Quality, FDA-CDER

• The regulatory requirements for RABS systems will become more strict

• Isolator

• Technology of the future

• Gloves as a weak point of the isolator will more and more disappear

• The VHP cycle times will become significantly shorter

• Disposable technology

• Will increase significantly in the near future

ISPE Member Benefits

• Guidelines

• Baseline® Guide: Sterile Product Manufacturing Facilities

(Second Edition)

• COP’s

• Sterile Products Processing COP

• Containment COP

• Biotech COP

• Webpage www.ispe.org

http://www.ispe.org/index.php/ci_id/2780/la_id/1.htm

https://www.ispe.org/cop/sppcop

https://www.ispe.org/cop/sppcop

https://www.ispe.org/containmentcop

https://www.ispe.org/biotechcop

http://www.ispe.org/

Contact Info

Charlotte Enghave Fruergaard, PhD

Director

Chairman ISPE Board of Directors

Nybrovej 80, 2820 Gentofte, Denmark

Mobile: +45 3079 7208

[email protected]

www.nnepharmaplan.com

mailto:[email protected]

http://www.nnepharmaplan.com/

Abbreviations

• CCR Conventional Clean Room

• RABS Restricted Access Barrier System

• UDF Unidirectional Airflow

• SAL Sterility Assurance Level

• VHP Vaporized Hydrogen Peroxide

• RTP Rapid Transfer Port

• BI Biological Indicators

TRACK 2B

CRITICAL UTILITY DESIGN

AND MAINTENANCE


SPEAKER PROFILE

TOPIC: CRITICAL UTILITY DESIGN AND MAINTENANCE

Gaston Loo IPT Pharm West Maintenance Lead MSD International GmbH (Singapore Branch) 50 Tuas West Drive 638408 Singapore

Gaston Loo joined MSD (legacy Schering-Plough Ltd) in 1999 and currently is the Maintenance Lead for Pharm West facility. He is responsible for all Engineering and Maintenance activities for the facility and actively involved in all Projects development such as participation in the engineering design, construction, commissioning, validation and start-up of Biotech sterile facility in 2001-2003. His other responsibilities include operation and maintenance of the critical utilities system such as WFI & PFW and process engineering in the facility. Gaston has extensive knowledge on electrical, instrument calibration & maintenance, computer system validation, DCS / PLC / SCADA system installation and clean room / HVAC maintenance. Prior to MSD, he had more than 5 years engineering experiences in building automation industry, which include HVAC design / commissioning in SEA. With extensive and diversified experiences in the plant maintenance, operation, design and project management, Gaston has acquired the synergistic knowledge and skills for establishing good engineering design feature in equipment and process system, selection of equipment and maintainability of equipment at design stage. He is also involved in the design, operation and maintenance of various validated monitoring system in the plant such as Environmental Monitoring System (EMS) and Utility Monitoring System (UMS).

1

CRITICAL UTILITY DESIGN AND MAINTENANCE

Gaston Loo Maintenance Lead MSD SINGAPORE

ASEAN Life Sciences Conference and Exhibition - 2013

2

• Type of utilities system • Regulatory requirement • Design approach

– Design principle and strategic – GEP – System boundaries

• Maintenance plan – Rouging – Filter integrity testing – Contamination / microbial control

• Industry trend - PAT

Agenda

3

Critical utilities system – Gas system – Pure steam – Water system

Non-critical utilities system – Chilled water – Plant steam – Instrument air – Potable water

Type of utilities system

4

Critical utilities system

• Direct impact system (process system) – Contact the product – Direct impact product quality – Contact materials that ultimately become part of product

• Depend on process, can be raw material, component or

process aid (excipient)

• Application example: – N2 for vessel blanketing – Pure steam SIP – WFI for compounding

Definition

5


Equipment that use critical utility:

– Blow-fill-seal (BFS) packaging machines – Compounding system – Filling line – Freeze-drying (lyophilization) – Part washer – Autoclave – SIP skid

6

Gas system


Nitrogen – Storage tank – Distribution loop

Sterile air (filtered air) – Generation (compressed air)

• Oil free type – Distribution loop

• Buffer tank • Air dryer • 0.2μ filter

7

Pure steam


Pure steam – Generation – Distribution loop

Key feature

– Feed water from PFW – Use plant steam for distillation process

- Removal of endotoxins and other impurities via

multiple separation stages - For process sterilization purpose

8

Critical Utilities System

Water For Injection (WFI) – Generation

• Feed water from PFW – Storage and distribution

Water system Purified water system (PFW) – Generation – Storage and distribution

9

Storage and Distribution System Key components

• Tanks • Pumps • Heat exchangers • Valves • Sample Valves • Instrumentation

• What’s critical? • Location

10

Schematic

PFW Generation

UNIT

MULTIMEDIA FILTER

DOSING HYPOCHLORITE

FILTER CARBON

FILTERS CARTRIDGE

TO PURIFIED WATER TANK

HEAT

HEAT EXCHANGERS

COOL

REVERSE OSMOSIS TWIN PASS

CONTINUOUS DEIONISATION

STORAGE TANK PUMP

RETURN FROM PURIFIED

WATER TANK

UNIT

SOFT WATER INLET

FINAL FILTER

11

PFW Generation

• The softened and chlorinated water is fed to a multi-media filter unit (MMF).

• Remove particulate present within the feed water supply.

• After filtration, the water flows to a break tank for storage.

Multi-media filter

12

Break tank PFW Generation

• Feeds into break tank – The MMF water – Water re-circulated back from

final filter

• The It consist of – spray ball – heated vent filter – bursting disc – level sensors

13

PFW Generation

The activated carbon filter removes – light weight organics – any residual chlorine

Daily backwash cycle (Auto or manual)

Activated carbon filter

14

Reverse Osmosis (RO) unit PFW Generation

To remove up to 90 - 98% of inorganic ions together with all large contaminants and organic molecules contained in the feed water.

A twin pass RO unit protect

the system from bacteria and pyrogens.

15

PFW Generation

- RO permeate is fed to the CDI unit for polishing.

- Uses high purity resins materials to remove all ionic materials from the water effectively.

- Give a maximum resistivity of 18.2M -cm (25oC).

Continuous Deionisation (CDI) Unit

16

Water quality

PFW Generation

1

1 5 10 0.1 0.055 100 0.2

0.2 0.1 0.01 5 10 18.2

Micro-siemens/cm μS/cm@25oC

Mega-ohms/cm M /cm@25oC

USP 29 •Conductivity < 1.3 S/cm at 25°C •TOC < 500ppb (0.5 mg/l)

PFW

17

Conductivity of different water

PFW Generation

Pure water

Purified water

Drinking water

Brackish water

Sea water

Conductivity μS/cm 0.01 0. 1 1.0 10 100 1000 10000 100000

LOW MEDIUM HIGH

Resistivity MΩ/cm 100 10 1.0 0.1 0.02 0.001 0.0001 0.00001

18

PFW Generation

• The water is passed through 0.2 μm before entering into storage tank.

• Bioburden reduction • Removal of particulate

contamination down to 0.2 μm.

Final Filter

Microbio limits: - drinking water < 500 cfu/ml - PFW < 100 cfu/ml - WFI < 10 cfu/ml

19





Agenda

20

What might a regulator want?

For people to understand the intent of regulations, and then

implement programs to meet that intent.

21

FDA

Regulatory requirement

FDA has recently focused attention on critical utilities. End users and their qualification and quality assurance personnel must demonstrate that the facility complies with 21 CFR 211.65(a) which states: “Equipment shall be constructed so that surfaces that contact components, in-process materials or drug products, shall not be reactive, additive, or absorptive so as to alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements.”

22

PIC/S


PIC/S is the abbreviation and logo used to describe both the - Pharmaceutical Inspection Convention (PIC) - Pharmaceutical Inspection Co-operation Scheme (PIC Scheme)

PIC Scheme PIC Scheme Convention An informal arrangement

A formal treaty

Has no legal status Has legal status

Between Health authorities Between countries

Exchange of information

Mutual recognition of inspections

The main differences between the PIC Scheme and PIC are :

operating together in parallel.

23

PIC/S


• PIC/S develop guidance “The Aide-Memoire – Inspection

of Utilities” for GMP inspectors

• For training and preparation of inspection

• Checklist for critical utility on water, steam and gases

24

Standard


Improved standard and guidelines such as - ASME Bioprocessing Equipment standard (BPE-2012) - ISPE Baseline@ Pharmaceutical Engineering Guides - International Standard ISO 8573 Compressed Air

have driven the quest of quality in pharmaceutical

industry.

• Vary of interpretation by different regulators

25

EMEA


Reflection Paper on 5 March 2008 EP requirement for WFI be produced only by distillation Refer RO membranes as "bacterial fermenters" and production of WFI RO would not be “as safe as water prepared by distillation”

Mandatory for manufacture of all products shipped into the European Economic Area

EMEA reaffirms rejection of RO for WFI production in EEA

26

USP


• Recognized and used in > 140 countries • Guide to produce medical products

• Specify standard for PFW and WFI

U.S. Pharmacopeia

Example: • Conductivity @ temperature (USP <645>) • TOC (USP <643>) • Bacteriological Purity Total Aerobic Count

(CFU/Ml)

27





Agenda

28

GEP

Design approach

Design approach affect by following factors:

Factors

Critical Utility Design

Process

Budget

Timeline

Quality Validation

Safety & Environment

Automation

Feed Water Quality

Specification

29

Design and project workflow

Direct-impact systems only

Quality-critical requirements only

Design principle and strategic

30

GEP • Set the standard and specifies your requirements

• Document the functions you want

• Used as a live document up until the DQ is completed and

approved

• Traceability of PQ and OQ functionality testing (RTM)

• Part of procurement process e.g. tender document

URS

User requirement specification

31

Design phase

Engineering specification

FDS - Functional Design Specification HDS - Hardware Design Specification SDS - Software Design Specification

DQ - Design Qualification Owner

Vendor

32

GEP

Risk assessment

• Minimize project expenditures, streamline validation, and forgo unnecessary processes or mechanical design options

• Serve to qualify the use of certain system and component

attributes that affect cost and performance • Determine what operations of critical utilities classified as

critical and non-critical

• Determine the scope and extend of validation

Objective

33

GEP

Risk assessment tool

Failure Mode Effects Analysis • Assessment tool to determine their potential value for process

design techniques

• Cause & effect analysis

• Assign each risk 1-10 for occurrence / severity / detection

• RPN = Occurrence x Severity x Detection

FMEA

34

GEP

Risk assessment tool

Example: Microbial development in the WFI storage tank - Surface finish on tank < 20 (Ra) - Temp > 80 oC With rating 0-10: RPN = O X S X D = 1 X 10 X 2 = 20 (low risk)

FMEA

Design specs

35

FMEA form

Risk Assessment & FMEA Risk Assessment FMEA

Structured by System Quality Attributes (SQA)

Structured by process steps

Begins with identifying hazards to SQA’s

Begins with identification of potential failure modes

Controls are assessed based on design features and procedures

Controls are grouped as prevention and detection controls

Used to identify controls that must be incorporated into the user requirements

Used to identify and prioritize risks of a given process

Used to establish acceptance criteria for validation

36

37

Good Engineering Practice (GEP)

“I don’t know how to explain them, but I know them when I

see them.”

38

GEP

Apply to all critical utility from design to operation stage: • Projects

– design – construction – commissioning

• Standards & Practices – drawing control – equipment change management – documentation

• Operations – maintenance – calibration – safety and environmental

Scope


39

General rule


• Allow provision for future expansion • Utilities should be routed from plant room to process

area • Process utility systems are designed to satisfy the

requirement of facility • Meet regulatory requirements and expectations

pertaining to equipment • Drawing for utility systems must be approved and

updated.

40

Good Equipment Layout


Keep design as simple as possible Ease of access for operation and maintenance

Follow process flow

Provide good spacing for equipment

Operators review equipment layout during design stage

Equipment and piping labeling


System “Qualification Drawing” requirements: show the plant layout, with service connections and, as appropriate:

All isolating-, drain-, vent-, control-valves, and items served, complete with tag numbers where used. Any critical items, such as filters, outlets, sample points etc. The quantity, quality and direction of flow of the working fluid.

Component tagging Main components should be tagged or labelled, to ensure that there are unique references for items to use in:

Commissioning records Maintenance records SOP’s Asset registers

Good Equipment Layout

41

42

GEPs and EQ

System boundaries

URS

Engineering Specs

Design Details

EQ

SAT / Commissioning

FAT

GEP

GMP

Quality Critical Attributes

43

Design criteria

System boundaries

Utility quality

Use point criteria

System criteria

Re-evaluate system design boundaries and constraints

Detailed system design

- Product - Regulatory - Dosage form

- Pressure - Temp - Flow rate - Demand - Auto/manual

- Storage - Future capacity - Generation rate - Feed water Quality

43

44

Compressed air to sterile air

System boundaries

Sanitary sampling point

Galvanized piping

Sanitary valve

0.2 μm sterile filter

Critical

Non critical

SS piping

45

Critical utility design

Standard requirement

Basic requirement includes: – Eliminate dead legs where possible – Sanitary design for component – N2 seal storage tank or vent filter(0.2μm) – Piping material - SS316L – Orbital welding and inspection – Sampling point for distribution loop – Instruments for trending (TT / FT / PT) – Standby pump for water distribution loop – ISO/DIN type of gasket / seal e.g. PTFE, EPDM,

Viton® and Silicone

46

Why Stainless Steel 316L

L indicates low carbon – but note that the specification limits for 316 and 316 L overlap

316 C Mn Si P S Cr Mo Ni N

Min - - - 0 - 16.0 2.0 10.0 -

Max 0.08 2.0 0.75 0.045 0.03 18.0 3.0 14.0 0.10

316L

Min - - - - - 16.0 2.0 10.0 -

Max 0.03 2.0 0.75 0.045 0.03 18.0 3.0 14.0 0.10

SS 316L used when there is a danger of corrosion in the heat-affected zones of weldments

47

Why Stainless Steel 316L

Many reasons:

• Availability of tube and sheet material • Availability of valves and fittings • Corrosion resistance • Weldability

• ASTM A269 (unpolished ID and OD) and A270 (polished

ID and OD) • Tolerances are generally tighter for ASTM 270

48

Orbital Welding

• The standard approach is to use closed head orbital welding – Automated repeatable quality welds – Protection from oxidation on both sides by purge gas – Weld parameters (primary / background values of pulsed

welding current, primary / background pulse times and rpm), controlled by the power supply, which determines the surface travel speed of the tungsten electrode.

• Orbital welding provides precise control of the heat input into the weld results in better corrosion resistance than manual welding

• Ensure sample welds (coupon) are produced for all heat combinations.

49

Orbital Welding – test coupon

Test coupons that conform to the specification on the actual materials to be used before the start of the job

Others: - lines were labeled with the heat number of the tubing - date of welding - weld number on the ISO drawing - piping system number - weld log for future reference

50

Water system

Standard requirement

Air gap for drain point (min. 50mm)

Eliminate microbial contamination from common drain line

ASME 112.1.2: The minimum required air gap shall be twice the diameter of the effective opening

Dead Leg definitions

D

L

A dead leg is any area in a piping system where water can become stagnant and where water is not exchanged during flushing.

Bacteria in dead-end pipe lengths / crevices are protected from flushing and sanitization procedures and can recontaminate the piping system.

Zero deadleg valves were used to minimize deadlegs in critical areas of the piping system

Modern piping design limits the length of any dead-end pipe to 6 times the pipe’s diameter (even shorter dead legs are preferred).

This is the six diameter rule (6D).

51

Dead Leg guideline

As per ASME BPE 1997 : " For Bioprocessing systems, L/D of 2:1 is achievable with today's design technology for most valving and piping applications"

As per FDA - GUIDE TO INSPECTIONS OF HIGH PURITY WATER SYSTEMS: it defined dead-legs as not having an unused portion greater in length than six diameters of the unused pipe measured from the axis of the pipe in use.

D

L

If deadlegs exist in a system, some provision should be made for flushing them through routinely. 52

53

Case Study - Dead leg

IN

OUTLET

Dead leg section during normal

operation

Promotes microbial growth and formation

of bio-film

DRAIN

Affects performance of

carbon filter

Carbon filter manifold in operation

Carbon filter tank

54


Dead leg section, collects ‘dirty’ backwash water

Drain

Carbon filter manifold during back-washing

IN

OUTLET

Carbon filter tank

55

After improvement

Outlet

Inlet

Drain

Carbon filter tank

Carbon filter manifold in operation


Keep deadlegs between valves to minimum

56

After improvement

Outlet

Inlet

Drain

Keep dead legs between valves to minimum

Carbon filter tank


Carbon filter manifold during back-washing

57





Agenda

58

Maintenance challenge

• Maintenance always link to reliability / availability – 24hrs X 365 days

• Maintain the validated state

• Contamination / microbial control

• M

59

Rouging

• A form of surface corrosion – reddish / brownish

• Common problem in WFI / pure steam systems

• High temperatures and dissolved gases accelerate corrosion and formation of iron oxides

• Iron oxide can break away from SS surfaces and flow through the entire water system downstream

(migratory rouge)

60

Effect

Rouging

• Cr-oxide dominated passive-layer is changing to Fe-oxide enriched corrosion layer

• Influencing parameters: – Alloy quality – Surface treatment – WFI quality – Temperature – Exposition time – Gas content (type and quantity)

61

Example

Rouging

• Typically found in:

– Pump impellors and internal housing – Vessel spray balls – In-line filters and housings – Storage vessel surfaces (usually above water line) – PTFE surfaces e.g. tri-clamp gaskets and valve

diaphragms

62

Example

Rouging

Spray ball WFI storage tank

Pump impeller from WFI system

Pump volute from WFI system

63

Example

Rouging

Rouging on a PTFE tri-clamp gasket

Rouge discoloration found on a point of use

0.45 μm filter membrane

64

Example

Rouging

Rouge can be wiped off and can move throughout a system. The rouge layer consists of heavy-metal-oxides, preferably Fe-Oxides. The rouge-layer consists of particles of heavy-metal-oxides which can leave the surface based on stream conditions.

Wipe test of a production vessel Wipe test of a WFI pipe

65

Passivation

Rouging control

• Removal of rouging • Generate an oxide film that covers and protects the

surface of the SS surface by nitric acid or citric acid

• Recirculation through distribution loop (2 hrs) • Post passivation – PFW water flushing till pH 6 to 8

66

Before / After Derouging

before Derouging after Derouging

67

Monitoring

Rouging control

• Schedule inspection to check components in the loops for sign of rouge

• Establish baseline and identify possible problem area

• Establish SOP for derouging / repassivation process

• Routine sampling of water quality – Conductivity – TOC – Heavy metals – Nitrate

68

Filter integrity testing (FIT)

• Filter type: - Air / Gas filtration - Water filtration - Vent filtration for storage tank

• Purpose: - Sterile boundaries - Protect from contamination (bacteria retention) • Maintenance: - Routine schedule replacement - FIT (before and after)

69

Filter integrity testing

• What is FIT? A measure of the ability of a filter element to work as

designed through multiple cycles, is a sensitive process parameters that requires qualified testing

• Factors influencing FIT - Temperature - Upstream Volume - Wetting Agent

70

Filter integrity testing

Breaches may occur as a result of… • Factory defects • Shipping damage • Improper maintenance • Structural creep • Chemical degradation • Age

Breaches can occur in many locations… • Seals and O-rings • Membrane potting • Fibers (broken or

punctured)

Potential integrity breaches underscore the need for FIT

71

Type of FIT

- Water intrusion test (gas)

- Forward flow (water)

- Bubble point filter test

72

Water intrusion test (gas / vent)

For hydrophobic gas filters

WIT

The resistance to water flow is overcome by a specific pressure

73

• An integrity test measuring air diffusion • Measurement of diffusive (diffusional) flow of a gas

through a wetted filter. • Measured under pressure and evaluated by comparing

the results to a limit value.

Forward flow (water)

74

Contaminants in water

Dissolved inorganic Dissolved organics

Micro-organisms Particulate matter

75

Source of Contamination

Sources of Microbial Contamination

• Source supply water or feedwater • Unprotected Vents / unsealed tanks • Faulty air filters • Contaminated use points/sample points • Unsatisfactory drain air breaks • Replacement carbon/resin/sand • Contaminated chemical additions • Improper sampling

76

Contamination control

RO membrane cleaning

• Cleaning is activated by - fall in permeate - dramatic rise in permeate conductivity - rise in 1st pass differential pressure

• Acid clean - remove hardness scale and is effective in removing

iron precipitates.

• Alkaline clean - remove biological material, colloid, silica etc.

77

Contamination control

CDI cleaning

Cleaning removes debris, scale, and resin foulants from the module that can severely reduce performance It is very important to follow cleaning guidelines in the CDI O&M manual

- for cleaning to be effective - to avoid damaging the module

78

Microbial Control and Biofilms

There are a number of measures that control microbes:

1. Avoid or minimise dead legs 2. Continuous re-circulation of water 3. Avoid stagnant ambient temperature water 4. Allow for drainage of pipework 5. Use sanitary valves & suitable gaskets selection 6. Use suitable construction materials 7. Maintain system water temperature at > 70*C 8. Regular sanitation or sterilization 9. UV radiation 10. Air break for drains

79

Microbial Control

1. Continuous re-circulation of water 2. Avoid stagnant ambient temperature water 3. Allow for drainage of pipework and storage tanks 4. Use sanitary valves 5. Avoid or minimise dead legs

The above measures discourage bacteria from:

• Lingering longer and reproducing to larger numbers • Settling to establish biofilms • Good drainage of unused pipes and tanks allows

drying which prevents bacteria from multiplying, although they may remain dormant for periods of time

80

Microbial Control

1. Use suitable construction materials 2. Maintain system water temperature at > 70*C 3. Regular sanitation or sterilization 4. UV radiation

The above measures are designed to facilitate the killing of bacteria :

• Most, if not all water system bacteria are vegetative forms (do not have spores) and therefore killed at temperatures above 60*C. 70 – 80*C is recommended to allow for cooler spots in systems.

• Stainless steel is better for withstanding temperatures and providing better surface finish to prevent biofilm establishment.

81

Microbial Control

1. Regular chemical treatments can become expensive to get a system back under control

2. Chemical treatments have to be applied at correct concentrations and allow sufficient contact time for effectiveness. Handling of chemicals would require safety assessment

3. Heat at sufficient temperature is a more effective sterilizing agent

4. UV radiation is effective but • Need to be certain there is no shading of bacteria

(requires direct exposure to bacteria) • Need ensure UV intensity is maintained over time.

Can still have a blue light when UV energy is insufficient

82

Microbial control

Sanitization

Sanitization are performed periodically to control the microbial growth Weekly sanitization of the PFW - Generation - Distribution loop FDA – over 65 degrees C is considered self sanitizing EU – stored and distributed in a manner which prevents microbial growth, for example by constant circulation at a temperature above 70 degrees C

83

Microbial control

Sanitization On request when intrusive maintenance: After the distribution loop or storage tank is opened, altered or exposed for maintenance / calibration

83

After replacement of the filter element for the final filter or heated vent filter After the distribution loop or storage tank has remained out of service for > 4 hours

84

Case study – microbial contamination

Scenario: Total Viable Count (TVC) results for water which was sampled and tested on 1st Oct 12 hit action limit for PFW generation system (after 5-7 days incubation). Purified water (sampling point: SP-123 Final filter outlet): 25 cfu/100ml Alert limit – 1 cfu/100ml Action limit – 10 cfu/100ml Distribution loop is maintained at 80deg C

85


Immediate Action: - Notified production to stop using water and

perform impact assessment - Lab to conduct internal investigation e.g. SOP,

personnel, human error, contamination during sampling, ID test, trending, etc.

- Informed system owner to check water system condition • PM record, daily log sheet (fact finding) • Root cause analysis • Review trending and alarm log from PLC • Recovery actions as per SOP

86


CF, RO, UV & CDI system functionality

If any parts damage or choke on CF, RO, UV and CDI. Visual check functioning well. RO membranes,

Contamination of high bio film from CF and RO.

RO, UV & CDI parameters out of limit

Technician has been trained and experienced to operate PWF.

TVC hit action limit at CDI outlet SP-123: 25 cfu/100ml

Method Environment

Machine Man Material

Why? Any control failures or not monitored/tested/logged

Facility changes if any

Contamination of feed water supply

Chlorine supply

Why? Chlorine supply low?

Why? No malfunction and defects found and data logging ok.

No Maint carried out.

Why? Any cross contamination. NO-ruled out. No failures monitored & data

logging for last 4 weeks are within spec. Micro passes. Ruled out

Chlorine supply Ok and weekly sanitize CF. No Maint and breakdown works. Ruled out

Good and spec ok

Why? Any piping between CF, RO and CDI has bio growth. NO-ruled out

High microbial counts; ≥ 500cfu/1ml specification (frequently from end Sep 12)

Training provided?

Review log sheets and no abnormality found.

RO Pre-filter, RO membranes and final filter.

RO pre-filters, RO membranes and final filter visual check. No abnormality found

Free chlorine testing procedure.

Biofilm at the pipe

Performed as per SOP

Cause & effect diagram

87


Typical recovery actions: - Flushing and initiate sanitisation cycle on water

generation & distribution loop - Dismantle and inspect final filter, internal parts and

O-ring before replaced - Inspect U.V Steriliser - “Chlorine shock” on inlet of MMF filter - Chemical cleaning & sanitisation of RO membrane &

CDI unit - Chemical sanitization of incoming feed water pipe - Inspect internal water pipe for any sign of biofilm

build up and leakage - Inspect chorine dosing pump for abnormality

88





Agenda

89

Process Analytical Technology

FDA – Center for Drug Evaluation and Research

“a system for designing, analyzing, and controlling

manufacturing through timely measurements, (i.e., during process) of critical quality and performance attributes of raw and in-process materials and processes with the goal of ensuring final product quality.”

How: On-line release using qualified Analyzers with a

validated process

Definition

90

Guideline

FDA for PAT

PAT — A Framework for Innovative Pharmaceutical Manufacturing and Quality Assurance

FDA PAT Initiative “The goal of PAT is to enhance understanding and control the

manufacturing process, which is consistent with our current drug quality system: quality cannot be tested into products; it should be built-in or should be by design.”

These tools and principles should be used for process

understanding and to meet regulatory requirements for validating and controlling the process

91

Guideline

USP

USP Chapter <643> on TOC states … “On-line TOC measurements for bulk-produced water…have the

advantage of providing real-time measurements and opportunities for real-time process control and decisions, in addition to recording the TOC quality attribute for release of water to production…off-line measurements of bulk waters have the disadvantage of being impacted adversely by the sampling method, sample container and uncontrollable factors, such as organic vapors.”

92

Goal: 100% understanding and control • Improve Assurance • Improve Process Controls • Improve Understanding • Improve Quality

PAT drivers

WFI or PFW loop

In line sampling port

TOC analyzer SCADA system

93

Utilities / Maintenance • Equipment Owner • Execution of SOPs and protocols QA/QC • Input to SOPs and Protocols • Surveillance & inspections of equipment & components • Technical support • Release documentation

Moving to PAT – A company effort

94

Engineering • Equipment choice • Sampling conformity to design of water system (installation) • Review of as-builds • Functional testing (Commissioning, IQ,OQ) Validation • Master plan creation and owner • Documentation review • Validation testing (PQ) execution

Moving to PAT – A company effort

95

• Eliminate sampling errors • Reduced water system downtime and sanitization • Release water and product faster • Increase profits • Better control of the process • Reduce sampling cost

PAT benefit

Lab sampling On-line TOC analyzer

TOC and conductivity

96

On-line TOC vs. Laboratory TOC On-line Laboratory

Accurate measuring low ppb LOD above most water systems

No sample contamination Grab sample contamination

No sample handling Sample tracking protocols

Low cost-of-ownership

High cost-of-ownership (labor intensive)

Trending information No trending information Real-time data Delayed data

Continuous monitoring Infrequent results

Measure in own environment Data for valuable information

97

• Sample cost – Materials – Time – Labor • Laboratory analysis cost – Time – Equipment maintenance

Grab sample testing

Lab sampling

10 Points x 1 TOC x 365 days = 3,650 samples 10 Points x 1 conductivity x 365 days = 3,650 samples

TOC / Conductivity comparison

• Off-Line Testing (TOC & Conductivity): USP <643> and <645>

» Sample testing Turnaround Time = 1 to 2 Business Days

» Operator time to sample = ~30 minutes per day » Analyst time to test = ~1 hour per sample » Review Time = ~15 minutes/day » Instrument set-up (Daily & Weekly) = ~6 hours

• On-Line Testing » Sample testing Turnaround Time = Real Time » Operator time to sample = None » Analyst time to test = ~1 hour per sample » Review Time = ~15 minutes/day » Instrument set-up (Daily & Weekly) = ~2 hours

98

99

Estimate of samples taken in 24 hours • Increased process control & improved product quality • Eliminate sampling errors • Faster product / water release • Increased profits

Manual and Continuous sampling

0

50

100

150

200

250

Manual Continuous

ManualContinuous

240

10

100

Specific Goals • Most up-to-date concepts of risk management and quality systems approaches are incorporated into manufacturing • Encourage manufacturers to use latest scientific advances • FDA – submission review and inspection to improve – Risk based approach encourages innovations • Regulations and manufacturing standards rapidly applied

Industry direction – PAT for critical utility

FDA launches Pharmaceutical cGMP’s for the 21st Century: A Risk Based Approach

101

•Critical utility -Type of utility

•Regulatory - FDA / Standard / USP

•Design - Applying of GEP will ensure reliable equipment without compromise the cGMP expectation •Maintenance - Rouging / FIT / Contamination & Microbial control

•Industry trend - PAT - FDA risk based approach and PAT increase auditor confidence

Summary

102

Questions?

TRACK 2B

CRITICAL UTILITY DESIGN

AND MAINTENANCE

KEY ASPECTS OF COMPREHENSIVE

CALIBRATION AND MAINTENANCE

MANAGEMENT SYSTEM (CMMS)

IMPLEMENTATION


SPEAKER PROFILE

TOPIC: KEY ASPECTS OF COMPREHENSIVE CALIBRATION AND MAINTENANCE MANAGEMENT

SYSTEM (CMMS) IMPLEMENTATION

Tantra Tantraporn Partner in the Management Consulting Practice Grant Thornton Management Consulting Co., Ltd. 18th Floor Capital Tower All Seasons Place 87/1 Wireless Road Lumpini Pathumwan Bangkok 10330 Thailand Education - Rensselaer Polytechnic Institute, Master of Science in Management/ Information Systems - University of South Australia, Master of Science in Advanced Business Practice

Partner Tantra Tantraporn moved permanently to Thailand in early 1994 and is currently a Partner in the Management Consulting Practice. Prior to joining Grant Thornton, Tantra held senior roles in multinational firms that included: Associate Director at PricewaterhouseCoopers, regional Senior Solution Architect at Hewlett Packard, Vice President Process Improvement at Hutchison CAT and Asia Pacific Business Consulting Director for Oracle Systems. Experience Tantra is a subject matter expert in operations management, with an emphasis in process analysis and reengineering. He has 37 years of experience in power plant operations, engineering management, business requirement assessment, systems suitability and productivity improvement. His background in engineering, IT and corporate management brings a realistic perspective to consulting engagements in:

Telecommunications Information systems Facilities management Supply chain management Utilities Manufacturing Banking Operations management Process reengineering

Sector experience Financial services, telecommunications, IT, utilities, facilities management, non-profit organizations, manufacturing and government. Education

Certified Nuclear Power Plant Operator – U.S. Naval Nuclear Power Program Submarine Systems Qualified – U.S. Navy Bachelor of Science – Nuclear Engineering Technology from the University of the State of New York Master of Science – Management / Information Systems from Rensselaer Polytechnic Institute Master of Science – Advanced Business Practice from the University of South Australia

2013 Grant Thornton Management Services. All rights reserved. - 1 -

Grant Thornton Management Consulting

Key Aspects of Comprehensive Computerized Maintenance Management Systems

July 18, 2013

2013 Grant Thornton Management Services. All rights reserved.

1) Maintenance aspects of CMMS

2) Functional aspects of CMMS

3) Process data aspects of CMMS

4) Implementation aspects of the CMMS Roadmap

5) Change aspects of CMMS implementation

6) CMMS guidance and recommendations

Key Aspects of Comprehensive Computerized Maintenance Management Systems Agenda

tation

ons

Maintenance Aspects of CMMS


Maintenance Operations

Operational Information Short-term

Operations Management

Feedback Response

“Failure” “Fix”

Typical Reactive Maintenance Cycle

Time

Constant Revenue

T2

T1 Initial Operations

T0 (+) $

(-) $

$0

Systems and equipment have fixed costs that need to be covered; even when idle and not contributing to services or revenues. These fixed costs often include equipment leases, building rent, maintenance staff and insurance.

Reactive Maintenance

Fixed Cost

Profit

Fixed Cost

Reactive maintenance programs allow systems and equipment to run until they fail.

T2 Equipment Failure

Prof

it / L

oss

Time

Constant Revenue


T3 T1 Initial Operations

T0 (+) $

(-) $

$0


Fixed Cost

Profit

Fixed Cost

Profit

Fixed Cost

Prof

it / L

oss Profit

Cost of Repair or Replacement

Profit

Fixed CostFixed Cost

However, profits will be reduced by the amount needed to repair or replace the failed component.

Fixed costs will generally remain unaffected by system failures.

Time

Constant Revenue


T3 Severe Equipment Failure

T4 Equipment Restored




Loss

T0 (+) $

(-) $

$0


Severe equipment failure often increase repair / replacement costs significantly. This may erode profitability to the point where operational losses are incurred for the entire period needed to replace or repair the system.

Profit

Fixed Cost Fixed Cost Fixed Cost

Fixed Cost

Fixed Cost

Profit

Profit

Note that fixed costs continue to be incurred, even during periods of reduced profitability or loss.

Prof

it / L

oss

Profit

Fixed Cost Fixed Cost

Profit

Profit


Time






Loss

T0 (+) $

(-) $

$0

Decreasing Revenue

Constant Revenue


During economic downturns, business / tenant loss will decrease revenue and gradually reduce profit over time. If the cost of repair / replacement is severe, decreased revenue will impact the amount of overall loss

Prof

it / L

oss


Fixed Cost

FixFixFixFixFiFi ededededdd CosCosCosCosCC ttttt FixFixFixFixFiFi ededededdd CosCosCosCosCC tttttosCC tt

Impact of Economic Downturn on Profit / Loss over Time


Time

Fixed Cost

Profit





Profit



Loss

T0 (+) $

(-) $

$0


As systems age, the frequency and severity of failure will increase. As a result, a gradual increase in maintenance repair / replacement

costs will decrease average profitability over time.


Profit

Profit




Fixed Cost

Constant Revenue

Loss


Average Profitability

Maintenance Costs

Prof

it / L

oss

Impact of System Aging on Profit / Loss over Time


Time

Fixed Cost

Profit





Profit



Loss

T0 (+) $

(-) $

$0


Thought quite common, reactive maintenance programs provide the least amount of control on the timing, cost or severity of

maintenance-related activities and their impact on business operations.


Profit

Profit




Fixed Cost

Constant Revenue

Loss


Average Profitability

Maintenance Costs

Prof

it / L

oss

Impact of System Aging on Profit / Loss over Time

Reactive Maintenance Total Life-cycle Costs

Capital Costs Design Development / Build Purchase Installation Commissioning Staff Training Manuals & Documentation Maintenance Tools & Facilities Initial Spares Holding

Capital Costs

Maintenance Costs Labor Materials Spare part holding costs (stores) Engineering support costs (workshops) Contractors Overhead resources (admin, accounting)

Maintenance Costs

Lost Production & Quality-related Costs Facility non-availability costs Facility malfunction costs Legal liability costs Insurance costs

Lost Production &

Quality-related Costs

Operating Costs Labor Plant operations Engineering Energy Oil Gas Electricity Steam Water

Operating Costs



Operational Information

Maintenance History

Short-term Operations Management

“What, Who, When, Where”

Maintenance Plan (What, When)

“What, Why, How”

Feedback Planned Maintenance

Maintenance Planning and Management (Maintenance policies, objectives, procedures, processes)

Maintenance Audits & Performance Measurement

Near-term Tactical Management

“How Well”

Typical Preventive Maintenance Cycle



Maintenance Audits & Performance Measurement

Maintenance Plan (What, When)


Operational Information

Maintenance History

Corporate Planning and Management (Corporate policies, objectives, procedures, processes)

Corporate Audits & Performance Measurement

Strategic Plan

Short-term Operations Management

Near-term Tactical Management

Long-term Strategic Management




“How Well”


“How Well”

Feedback Response



Measure

Test Results vs. Requirements &

Expectations

Monitor & Test

Test Plans, Schedules,

Work Orders & Parameters

Corrective Maintenance

Restore Equipment Condition Restore Operational Status

Reduce Downtime

Adjust “braces”

Repair “fillings”

Replace “dentures”

Parts / Stock

Parts / Stock

Preventive Maintenance

Extend Useful Life Reduce Unplanned Failures

Parts / Stock PASS

FAIL

Maintenance Management Preventive vs. Corrective Maintenance

Time

Constant Revenue

T2 Perform Scheduled Maintenance


T0 (+) $

(-) $

$0

Preventive Maintenance Pr

ofit

/ Los

s

Fixed Cost

Fixed Cost

Profit

Preventive maintenance programs address timing, cost or severity issues by proactively planning downtime

and maintenance in accordance with regular timeframes recommended by manufacturers of the

systems and components in use.

Variable Cost

Systems and equipment have variable costs associated with their operation, repair, environment and external market conditions. These variable costs include electricity, lubricants, and spare parts.

Time

Constant Revenue



T0 (+) $

(-) $

$0

Preventive Maintenance

Prof

it / L

oss

Fixed Cost

Fixed Cost

Profit




Fixed Cost Fixed Cost Fixed Cost Fixed Cost

Variable Cost Variable Cost Variable Cost Variable Cost Variable Cost

Facilities with properly designed preventive maintenance programs can effectively plan and manage variable costs within defined ranges.

Variable Cost Range

Profit Profit Profit Profit

Time

Constant Revenue



T0 (+) $

(-) $

$0

Preventive Maintenance Pr

ofit

/ Los

s

Fixed Cost

Fixed Cost

Profit




Fixed Cost Fixed Cost Fixed Cost Fixed Cost

Variable Cost Variable Cost Variable Cost Variable Cost Variable Cost

Though unplanned failures may still occur, they tend to be fewer in number and less severe. Preventive maintenance programs generally result in less volatile, more manageable maintenance and profitability profiles over the lifetime of the facility.


Maintenance Management “Is it worth the effort?”

Task Reactive Maintenance Preventive Maintenance (unplanned / unscheduled / corrective work) (planned / scheduled work) Lubricate bearings $120 $0 (precision seal installed when purchased)

Cleaning $0 $1,800 Repair $4,000 $240 Planning $0 $100 Inspection $0 $1,800 Motor rewind $20,000 $2,500 (including new precision seals) Lost production $60,000 $0 Total Costs $84,120 $6,440

Sample 10-year maintenance cost profile of a typical motor

In this example, having a preventive management program would have saved around 92.3% in total maintenance costs (almost $80,000) associated with just this one motor over its typical 10-year lifespan.

Case 1)

Case 2)

Setting up a lamp maintenance plan that schedules the replacement all lamps in each designated area at the same time can save up to 90% in associated labor, inventory and lost productivity costs. When combined with maintenance strategies that use economic lamp types and ballast wiring designs, those planned, lower cost replacements could even be done 25-60% less often.


Functional aspects of CMMS

Functional Aspects of CMMS Maintenance Management

Manage and control Maintenance Department functions - Planning and scheduling equipment maintenance - Planned (preventive) maintenance - Metered maintenance - Equipment runtime - Cycle time - Unplanned (reactive) maintenance - Work requests - Routine checks - Statutory checks - Mandatory checks - Overhauls

Manage Preventive

Maintenance

Manage Reactive

Maintenance

Manage Work

Requests

Monitor maintenance spending - Ensure that targets are met - Savings opportunities are pursued Integrate CMMS with accounting systems - Document and record all maintenance stock control and purchasing in enterprise software systems - SAP, J.D. Edwards

Monitor Maintenance

Spending

Integrate Stock Control & Purchasing

CMMS

CMMS

Manage CMMS databases - Maintenance operations - Maintenance personnel - Maintenance contractors / subcontractors

Manage Maintenance Operations

Manage maintenance operation functions - Work orders (WO) - Preventive maintenance (PM) - Asset management (AM) - Inventory control (IC) - Safety management (SfM) - Gauge and calibration management (G&C) - Contractor maintenance management (CnM) - Maintenance audits

Provide Reports & Statistics

Provide maintenance reports and statistics - Downtime - Statistics-related KPIs - Maintenance costs - Location - Department - Personnel

Manage CbM

Initiate condition-based maintenance (CbM) on the basis of an asset’s condition - Vibration level - Oil particulates - Wear patterns - Time since last replacement - Meter readings

Manage Assets, Plant & Equipment

Manage and control asset, plant and equipment maintenance using IT systems and applications - Computerized Maintenance Management System (CMMS) - Predictive maintenance (PdM)

Functional Aspects of CMMS Computerized Maintenance Management Systems


Process Data Aspects of CMMS


A process is a series of tasks that lead to a final work state called the functional requirement.

Minimally, all processes provide information on: 1) What to do (tasks), and 2) How to do it (sequence)

Breaker Opened

Open Breaker

Replace Motor

Motor Replaced

Panel Tagged

However, it would often be useful to know more



1) The breaker is in a panel located in a secure Data Center 2) DC Air Conditioning can only be off for 60 minutes 3) The Duty Officer has to give permission to access the DC 4) The Duty Officer will be here after 1:30PM 5) The panel is secured with screws 6) The motor weighs 75 kilograms

Breaker Opened

Motor Replaced

Panel Tagged


A process is a series of tasks that lead to a final work state called the functional requirement.

Open Breaker

Replace Motor


Work flows document the series of work states that result from the performance of tasks within the process.

In business, work flows are sometimes referred to as "work-in-progress"

Breaker Opened

Open Breaker

Replace Motor

Motor Replaced

Panel Tagged

Work states are conditions that result from the successful completion of tasks.



Task Input Output

Controls

Supports

In order to accommodate any additional data that might be available, the basic flow model needs to be expanded to include Controls and Supports,

This facilitates a more well-rounded understanding of the process.

Locations? Timeframes? Restrictions? Issue? Requirements? Costs? Work States?



Task

How, Why, When

Who, Where, What

What What How Long, How Often

How Long, How Much

How Long, How Often

Input Output

Controls

Supports (mechanisms)

This establishes a model that minimally supports the additional capture of data related to how, why, when, where, and who.

Task



Completed by 5PM Daily Approved Supplier List Engineering Specification Procedure P.1.1

Input Output

Supports (mechanisms)

How, Why, When

Who, Where, What


How Long, How Much

How Long, How Often

CONTROLS identify the laws, policies, procedures, timing requirements and criteria used to define how and why tasks are performed.

Task Prepare P.O.



SUPPORTS (mechanisms) identify the infrastructure, resources, data stores, locations and personnel needed to conduct the task.

Purchasing Admin Saraburi Warehouse P.O. form F1 Purchasing Module AS400

How, Why, When

Who, Where, What


How Long, How Much

How Long, How Often


Input Output Task Prepare P.O.



Task Prepare P.O.

How, Why, When

Who, Where, What


How Long, How Much

How Long, How Often


P.O. Requested

P.O. Prepared


This model differs from most others by simultaneously capturing WORK STATES between tasks. This gives the plant

the ability to quickly define and support workflow implementation.



P.O. Requested

P.O. Prepared

How, Why, When

Who, Where, What

What What How Long

How Long

How Long



Wait = 15 hrs Wait = 24 hrs

Process = 9 hrs Actual = 1 hr

Key TIME ELEMENTS are also captured to provide the means to assess, analyze and eventually improve throughput.

Task Prepare P.O.



The FREQUENCY of each work state gives the team the ability to factor in the relative weighting of various processes

to assess impact and prioritization

P.O. Requested

P.O. Prepared

How, Why, When

Who, Where, What

What What How Long

How Long

How Long





How Often How Often Freq = 100% Freq = 100%

Task Prepare P.O.



P.O. Requested

P.O. Prepared

How, Why, When

Who, Where, What

What What How Long

How Long

How Long





How Often

How Much

How Often Freq = 100%

B 40

Freq = 100%

Mid-scale payroll data from HR for each role provides a means to gauge and quantify RESOURCE COSTS / TASK. (e.g. If the average

Admin salary is B6,400/month, his hourly rate would be B40/hour.)

Task Prepare P.O.



P.O. Requested



Wait = 15 hrs


Freq = 100%

B 40

P.O. Prepared Wait = 24 hrs Freq = 100%

Engineering Spec Approval Criteria Procedure P.2.0

Purchasing Manager Bangkok HQ P.O. record Purchasing Module AS400

P.O. Approved

P.O. Disapproved

Wait = 5 hrs Freq = 85%

Wait = 17.5 hrs Freq = 15%

Process = 4 hrs Actual = 0.5 hr

B 200

Capturing data on each task in this structured format quickly produces an integrated source of valuable process-related information.

Approve P.O.

Prepare P.O.



P.O. Requested P.O.

Disapproved

Prepare P.O.



Wait = 15 hrs


Freq = 100%

P.O. Prepared Wait = 24 hrs Split = 100%

Engineering Spec Approval Criteria Procedure P.2.0

Purchasing Manager Bangkok HQ P.O. record Purchasing Module AS400

P.O. Approved

Approve P.O.

Wait = 5 hrs Freq = 85%

Wait = 17.5 hrs Freq = 15%

Process = 4 hrs Actual = 0.5 hr

B 200 B 40

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O55111111 hhhrs

rrProco sess == 9 hrh sssAcAcAccAcAAcAcAcAcAcAccAccAAcAcAAAAAAAA tututuutuututututuutututtttt alalallaalaalalalllaalallll ============= 1111111111111111111111111 hrhrhrhrhhrhhrhrhrhrhhrhhhhhhhhhhh

11111000 %

PPPPPPPrrrrrrrrreeeeeeeeeeepppppppppppppppppppaaaaaaaaaarrrrrrrrreeeeeeeddddddddddaWaitt == 24 hrsspS lit === 10 %0%

O

WaWaW it == 71111111111FrFrFrrFFFrrFFrFFFrFFrrFFFFFF eqeqeqeqeeeqeqeeqeqeqeqeq =====================================

PrP ocess ss = 4 4 hrsAcAcAcAAcAcAAcAcAAcAcAAAAAcAAcAcAAcAcAActutuututuutuututututtuutututututututututuut alalalaalaalaalaalallaaalalalalaalalala ============= 0.0.0.0.000000000000000000000000 555555555555555 hrhrhhhrhhhrhhrhhhrhrhrhrhrhrhrhrhrhrhrhrhrh

Therefore, supplementing the process model, information about the process should also be captured within a database.

CMMS

PPPPPPPPPPPPPPPPPrrreeepppaaarrreee

EEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnggggggggggggggggggggggggggggggggggggggggiiiiiiiiiiiiiiiiiiiiinnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnneeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeerrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrriiiiiiiiiiiiiiiiiiiiiiiiiiiiinnnnnnnnnnnnnnnnnnnnnnnnnnnngggggggggggggggggggggggggggggg SSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSppppppppppppppppppppppppppppppppppppppppeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeccccccccccccccccccccccccccccccccciiiiiiiiiiiiiiiiiiiiiffffffffffffffffffffffffffffffiiiiiiiiiiiiiiiiiiiiicccccccccccccccccccccccccccccccccccaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaatttttttttttttttttttttttttttttttttiiiiiiiiiiiiiiiiiiiiiiiooooooooooooooooooooooooooooooooonnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnPPPPrrooocceddddduureee PP.1.111

PPPPPPPPPPPPPPPPPPPPPPPPPPPPPPPPPPrrrrrrrrrrrrrrrrrrrrrrrooooooooooooooooooooooooooooooooooccccccccccccccccccccccceeeeeeeeeeeeeeeeeeeeeeeeeeeeeeddddddddddddddddddddddddddduuuuuuuuuuuuuuuuuuuuuuuuuuuuurrrrrrrrrrrrrrrrrrrrrrrreeeeeeeeeeeeeeeeeeeeeeeeeeeeee PPPPPPPPPPPPPPPPPPPPPPPPPPPPPPPPPPPP......2222222222222222222222222.......0000000000000000000000000000000P.OO..AApppppprrroovveeeeeeeeeeeddddddddddAppprrooveeeeeeedddddddddd

AAAAAAAAAAAAAApppppppprrrooovvveeeeWaWaWaW itit = 5 rrrrrrrhrhhhrsssssssFrFrFrFFrFrFFrFrFrFrFFrFrFFrFrFrFrFr qqqqeqqqeqqeqeqqqeqeqeqeqeqeqeqeqeqeqeqqqeqeqeq ======= 88888888888888888 %%%%%%%%5%%%%%%%5%%%%%%%%%%%%%5%%%%%%5%%%%%%%%%5%%%%5%%%%5%%%5%%%%%%5%%%5%%%5%5%5%5%%%%%%%%%%%5%%%%%%%%

The ability to analyze process information provides insight into utilization, capacity, workflow, redundancy, and productivity issues that impact the overall effectiveness of maintenance operations.



1) What are the 10 most expensive work orders to perform?

2) Are Maintenance Electricians over or under-utilized?

3) Are Purchasing resources qualified for the tasks they participate in?

4) Which departments are impacted by or accountable for compliance with the requirements of 21CFR Part 11?

5) What areas can be addressed to improve overall throughput the most?

The ability to analyze process-related information provides the means to answer more difficult operational questions such as :

Process models show us ‘how’ to address various goals Process data allow us to address ‘how well’.


Here is a basic flow model for the process related to some scheduled preventive maintenance.

It consists of a series of tasks being done in sequence.

Process Data Aspects of CMMS The Value of Process Data

Maintenance Manager x x x xMaintenance Technician P x x xScheduler P x x x x

Adding roles, we can identify who the participants are on each task.

M iM i t MM


Add Controls, and we can see why they need to do each task, and how each should be done.

Chart of Accounts xCurrent Workload by Resource xInventory Reorder Level xMaintenance Policy x x x x xMaintenance Procedure x x x x x x x x xMaintenance Schedule x xPre-determined Maintenance Date x xStandard Cost List x


M iM i t MM


Resource Supports tell us what they are using, and where the work is being done.

CMMS Module - Inventory Module I x xCMMS Module - Preventive Maintenance I xCMMS Module - Purchase Order I xCMMS Module - Report I xCMMS Module - Work Management I x x x x xFinancial Software I xLocation: Plant Office I x x x x x x xLocation: Plant Spaces I xSpare Parts I x xTools I x x



M iM i t MM


Interactive supports are the data, document and interface whats needed to support specific tasks. The model is now set up to support data analysis.




M iM i t MM

Cost Allocation Screen xData - Cost x xData - Customer xWork Order x x x x x x


What does the Maintenance Technician do?




M iM i t MM



What does the Scheduler use to allocate costs to specific work orders?




M iM i t MM



Who are the people effected by tasks that are not covered by policy?




M iM i t MM




Implementation Aspects of the CMMS Roadmap


CMMS Implementation Roadmap

To establish, improve and sustain the reliability of the facility.

2) Understand Facility Level

Maintenance Objectives

Support the facility’s operating pattern Achieve and sustain targeted availability levels Achieve and sustain targeted production and quality levels Achieve facility longevity expectations Achieve minimum safety standards Minimize resource and facility life-cycle costs Maximize productivity over the long-term Generate timely, relevant maintenance status reports

3) Understand Performance Expectations

and Priorities

Facility operating pattern is 3 shifts / day, 5 days / week Facilities must achieve greater than 99% availability during operating hours Production: 95% of tenant complaints resolved within 1 hour Systems must achieve 95% of their designed life-spans Safety first: 0 serious injuries / year Maintenance costs should not increase by more than 3% per year Spare part waste and defect costs shall not exceed 5% of overall budget A maintenance status report needs to be generated each week

1) Understand the Maintenance Mission


5) Identify the Systems involved in satisfying each

Unit Objective

e.g.) HVAC units utilize heating, ventilation, chill water, and I&C control systems Need to inventory of all systems and relevant components through both document and visual verification.

6) Understand and document how those Systems satisfy Unit

Objectives

Need to document the temperature regulation process Need to document standard operating procedure (SOP) for water quality tests Need to document inventory stock reorder criteria

The HVAC system has to maintain temperatures between 70-75 degrees F The HVAC system only needs to be available on weekends per special request Lighting replacement costs need to be reduced by 15% Potable water quality needs to be improved within the next 12 months

4) Translate Facility Objectives into

Unit Level Objectives

Equipment hierarchy: Facility e.g. Office building Unit e.g. Potable water unit System e.g. Chill water system, chemical treatment system Component e.g. Condenser, Return water pump Part e.g. Pressure seal, valve bonnet, motor bearing



Identify maintenance tasks that need to be performed (e.g. lubrication, inspection) Identify how often those maintenance tasks will need to be performed (frequency) Categorize each maintenance task by job type (e.g. minor, major, overhaul)

7) Develop Life Plans for each Unit

1st line maintenance: Emergency jobs - work needing to be carried out in the shift of occurrence. Small jobs (corrective, preventive) that can be 'fitted' into the schedule without a lot of detailed planning.

8) Develop Maintenance Schedules for all Units

Integrate maintenance requirements and frequencies from all unit life plans Factor in key operating requirements (e.g. summer break, promotion campaigns) Classify all maintenance tasks by their scheduling profiles (1st line, 2nd line, etc.)

2nd line maintenance: Larger preventive jobs (services, small overhauls) Corrective jobs that require planning Mid-size jobs that can be scheduled based on priority into a weekend or some other available time window.

3rd line maintenance: Major plant overhauls (or parts of plant) Jobs requiring the plant to be offline for considerable lengths of time (downtime) Jobs that are generally carried out at long to medium-term intervals (Low periodicity) Jobs requirement long lead-time for planning



Workload dictates required size & composition of the maintenance. organization. Two other key considerations are the distribution of resources and authority.

9) Assess the Maintenance Organization

Resource structure is the logistic distribution of personnel, spares, tools and information that is best suited to meeting defined maintenance requirements (e.g. response time, output quality) Think about the resources in a hospital emergency room vs. those in a typical patient room. The additional emergency room equipment was geographically distributed to meet the need for timely response. The resource structure should be designed to achieve the best resource utilization

9a) Determine the appropriate

Resource Structure

Administrative structure is the distribution of decision making authority that is best suited to meeting defined maintenance requirements Think about each person’s authority to pull a fire alarm without having to first gain permission from the Maintenance Engineer It is the hierarchy of work roles ranked by authority and responsibilities, that determines what, when and how maintenance should be conducted

9b) Determine the appropriate

Administrative Structure



Enter facility objectives and expectations (SLA, control parameters, priorities) Enter unit objectives and expectations (SLA, control parameters, priorities) Enter in-scope equipment data (unit, system, component, part) Enter in-scope processes, critical work states and workflow criteria Enter life plan data (required maintenance jobs, frequencies, type) Enter the maintenance schedule and scheduling characteristics Enter the resource structure (logistic distribution, quantity, requirements) Enter the administrative structure (roles, responsibilities, authority)

10) Configure and Implement the

Maintenance System (CMMS)



Change Aspects of CMMS Implementation


Most companies naturally focus on system-related factors when preparing to install a CMMS product. However, factors that delay or even prevent successful implementation are usually "soft side" issues related to maintenance processes, procedures and people. These factors need to be addressed holistically to ensure the impact of CMMS changes are fully accounted for in an integrated manner.. In turn, each of these issues needs to be assessed and verified against maintenance operation and corporate policies, to ensure management alignment and compliance with requirements.

Maintenance Mission Are maintenance operations aligned with business goals and requirements?

Program & Controls Are maintenance issues effectively managed and controlled?

Process Is maintenance conducted in the most productive manner possible?

People & Organization Are maintenance resources adequately qualified and motivated?

System & Facilities Are systems suited and fully utilized to support maintenance operations?

Improved Maintenance Environment

Corporate Mission

“As-is” Maintenance Environment

The Real Impact of Change The Nature of Change Holistic CMMS Impact


Strategic Level Corporate Planning & Management

Tactical Level Maintenance Planning & Management

Operational Level Maintenance Operations

Top management unaware of issues Maintenance is not valued

Uncoordinated effort Poor knowledge management

Reactive Maintenance High inventory-related costs

The Nature of Change Problems by Level

TacticMaint

Maint

UncoPoor


Existing Maintenance Organization, Processes,

Systems, and Data

“Ideal” Usage New CMMS

Features, Functions and Capabilities

Maintenance “Best Practice”

All CMMS software products are designed and built around some “ideal” set of assumptions, processes and data sets to handle maintenance management

However, companies soon realize that these ideals rarely fit their operations or meet their requirements, without some, often significant, degree of customization.

- 54 - © 2012 Grant Thornton Management Consulting. All rights reserved.

The Nature of Change Suitability of Fit


Effective CMMS change then became dependent upon the ability to clearly define the balance between the adoption of design features and best practice scenarios

Adopt Adapt

eeee etweebebbbbsss

en thhee doption of desiadaen t gn featuressgn s nndn nanand the adaptation of existing operations.

Existing Maintenance Organization, Processes,

Systems, and Data

New CMMS Features, Functions

and Capabilities

Maintenance “Best Practice”

- 55 - © 2012 Grant Thornton Management Consulting. All rights reserved.

The Nature of Change Suitability of Fit


CMMS Guidance and Recommendations


Avoid associating maintenance with just repairs. The value of maintenance management is increased reliability and

a lower overall cost of ownership.

Maintenance Management Primary Functions and Benefits

Maintenance Management

Preventive Management

Inventory Management

Report Management

Work Management

Purchase Order Management

Reactive Management

CMMS

Cost Accounting

Key Maintenance Management Functions


General CMMS

Software Selection Criteria

Cost Effectiveness

Customization Capabilities

Multi-Level, Training

Graphic Capabilities

Simultaneous

review of data & drawings

Attached pictures

Multi-Tasking Capabilities

Integrated Functions

"Nice-to-have"

CMMS Features,

Functions & Capabilities

Work Order System

Schedule

maintenance

Generate Work Orders

Ability to customize on-line

Existing

screen layouts,

Extra tables, Reports

Ability to attach user-defined

value lists to any entry field

Data Quality, User-friendly

Ability to access the CMMS database

SQL queries

Standard Queries,

Ad hoc Queries

Ability to add new or

non-maintenance related screens

Recertification or Inspection-related

"Have-to-have"

CMMS Modules

Equipment Module

Contains all information about

the equipment being maintained

Preventive Maint. Module

Maintenance Schedules

Reliability, Availability

Work Order Tracking Module

Work Requests,

Work Orders

Meets monitoring requirements

Job Plan Module

Work Plans

(Procedures)

Reference Library Links

CMMS Selection Software Selection Criteria


"Think carefully about the equipment number scheme. You will be stuck with it forever." "Don't rush your implementation. Have a well thought plan and SOPs" "Don't try to make the software fit your business practices. Some practices may need to be changed." "Get the naming convention in place. Treat equipment and location as separate entities." "Use drop down menus with pick lists whenever possible." "Be very generous with the amount of training provided to all users." "Be aware that the size of spares inventory and other procurement costs are often higher in pharmaceutical plants. New or frequently upgraded products require frequent changes in inventory and plant equipment."

Random Notes from the Field Recommendations and Caveats

2013 Grant Thornton Management Services. All rights reserved. - 60 -

Tantra Tantraporn

Partner Grant Thornton Management Consulting Co., Ltd. 18th Floor Capital Tower, All Season Place 87/1 Wireless Road Bangkok 10330 Thailand.com (w) 02-206-8222 x8230, (m) 089-075-6400 [email protected]

TRACK 2C


PLANT FOR

MANAGEMENT LEVEL

PROJECT MANAGEMENT FOR

PHARMACEUTICAL PRODUCTION

FACILITIES

Friday 19 July 2013

SPEAKER PROFILE

TOPIC: PROJECT MANAGEMENT FOR PHARMACEUTCIAL PRODUCTION FACILITIES

HARALD J. GEITZ Managing Director

2006 – 2011 Managing Director of PhC PharmaConsult

Since 1992 Managing Director/ Partner with i+o Industrieplanung + Organisation

GmbH & Co. KG, Heidelberg, Germany

1991 – 1992 Head of Department of Information Systems with i+o

Industrieplanung + Organisation GmbH, Heidelberg, Germany

1990 – 1991 Head of Department of Industrial Planning with i+o Industrieplanung

+ Organisation GmbH, Heidelberg, Germany

1986 – 1989 Project Manager in the Department of Material Flow and Storing

Technique with i+o Industrieplanung + Organisation GmbH,

Heidelberg, Germany

1983 – 1986 Consultant in the Logistics Department of i+o Industrieplanung +

Organisation GmbH, Heidelberg, Germany

1

Form and Function in Concert

Managing Projects by Harald J. Geitz ISPE Thailand conference on July 17-19th 2013

2

Content

1.  Project structure

2.  Targets of io-consultants project management

3.  Elements of io-consultants project management

4.  io-consultants project portal

5.  Standardization

6.  Examples

7.  Success factors of a good project management

MKT_io-consultants_Project_Management_20130709

3

Project Structure

4

Project Phases

▐  Project structure

▐  Conceptual design

▐  Basic/detailed design

▐  Supervision/handover

▐  Qualification/validation

▐  Experience

MKT_Pharma_Focus_Presentation_20130709

5

Project Phases MKT_Pharma_Focus_Presentation_20130709

Plan

ning

O

rgan

i- sa

tion

Q +

V

Stage II

Stage I

Prod

uctio

n Su

ppor

t

Project Management

IQ DQ OQ CV Validation

HR: hiring & training

SOPs

Conceptual Design

Basic Design

Detailed Design

Stage III - Production

Ramp-up support

Production support

Organisational structure

Construction commissioning

PQ VMP

3 months

~ 12 months

6

Project Phases - Conceptual Design

▐  Process and Packaging Technology

▐  Warehousing and Material Flow

▐  Area / Staff Requirements

▐  Master Plan Development

▐  Layout Alternatives 1:200

▐  Architectural / Structural Concept

▐  Building Services Concept

▐  GMP Requirements

▐  Rough Time Schedule

▐  Cost Estimate ±25 %


7

Project Phases - Basic / Detailed Design

▐  Process Engineering

▐  Detailed Layout and Arrangement Drawings

▐  Work Centres 1:20

▐  HVAC / M&E / Utilities Engineering

▐  Architectural / Structural Design

▐  IT / Supply Chain

▐  Specification of Equipment

▐  Documentation of Regulatory Issues

▐  Refined Cost Estimate


8

Project Phases - Supervision / Handover

▐  Factory Acceptance Tests (FAT)

▐  Site Management and Site Organisation

▐  Scheduling

▐  Supervision of Works according to GMP Requirements

▐  Supervision of Commissioning

▐  Supervision of Remedial Action

▐  Documentation and Handover


9

Project Phases - Qualification / Validation

▐  Validation Master Plan (VMP)

▐  User Requirement Specification (URS)

▐  Supplier Audit

▐  Design Qualification (DQ)

▐  Acceptance Tests (FAT / SAT)

▐  Installation Qualification (IQ)

▐  Operation Qualification (OQ)

▐  Performance Qualification (PQ)

▐  Computer Software Validation (CSV)

▐  Standard Operation Procedure (SOP)


10

Project Organisation MKT_io-consultants_Project_Management_20130709

Steering Committee Customer

Authorities Third Parties

Project Management io-consultants Specialists Customer

Qualification & Validation

Production Process

Logistics Process

Architecture & Structure

MEP and IT Services

Qualification & Validation

Production Processes

Logistics Processes

MEP and IT Services

Main Contractor Supplier 2

Supplier 1 Supplier

n

11

Targets of io-consultants project management

12

Steering, Clarifying, Coordinating

Functionality of the future

facility = Quality

Tasks Concept QM Process Definition HR Management Technique Testing scenarios Training Acceptances

Resources Budget Deadlines HR

Tools io-consultants Project portal: - document admin. - deadline keeping - minutes keeping - task administration

Disciplines Logistics Production IT and Processes Construction Technique


13

Targets of io-consultants project management

▐  Targets

■  Highly profitable factory = minimizing running cost

■  Staying on agreed budgets, time lines and human resources

■  Minimizing risk factors

▐  Tasks

■  Organisation of information exchange

■  Creation of transparency by consistent, clear structures

■  Consistent communication and information paths

■  Consistent deadline coordination

■  Consistent project documentation

■  Comprehensive support of the customer and targeted steering of the projects


14

Elements of io-consultants project management

15

Elements of io-consultants project management

▐  The project management of io-consultants is basically separated into five elements.


Defining project target

Determining framework

requirements Coordinating and steering

Quality assurance

and risk monitoring

Documenta-tion and

filing

16

Elements of io-consultants project management MKT_io-consultants_Project_Management_20130709




Quality assurance

and risk monitoring

Documenta-tion and

filing

▐  Determination of project targets and frame of action

■  Individuality of the customer

■  Project definition and planned actions

■  Basis and background information

■  Resource planning and organizational formation (customer side, external planner)

▐  Budgeting of overall project and subprojects

▐  Creation of an overall project schedule (MS Project)

17





Quality assurance

and risk monitoring

Documenta-tion and

filing

▐  Clear task definition using project organization charts

▐  Determination of project standards and glossary with document filing

▐  Definition of meeting types and cycles

▐  Preparing and updating of a project member list

▐  Documentation of project guidelines in project manual

18





Quality assurance

and risk monitoring

Documenta-tion and

filing

▐  Deadline tracing and appointment coordination

▐  Securing of handling quality and keeping of standards

▐  Moderation of meetings

▐  Sticking to communication and information paths

▐  Tool based project steering

▐  Follow-up of tasks

19





Quality assurance

and risk monitoring

Documenta-tion and

filing

▐  Regular reports to steering committees

▐  Securing of budget keeping

▐  Management summaries after important project steps (content: project progress, results, documentation, deadlines, budget)

▐  Keeping of mile stones by means of project status reports

▐  In time activation of crisis managements

20





Quality assurance

and risk monitoring

Documenta-tion and

filing

▐  Structured and transparent data filing

▐  Clarity and simple handling

▐  Auditing acceptability

▐  Final documentation

21

io-consultants Project portal

22


▐  io-consultants developed this web-based and customised project management tool. It enables:

■  Simple information exchange

■  Standardised communication and information channels

■  Resource allocation and control

■  Permanent process tracking and documentation of all activities

■  Keeping open issue lists

■  Budget management and control

■  Risk management

■  Early warning system

■  Individual access for all involved project members


23


▐  Using the io-consultants Project Portal, the following can be secured:

■  Availability of latest data

■  Smooth cooperation of all project members

■  Creation of clarity and transparency

■  Structured project steering

■  User friendly thanks to office integration


io-consultants Project Portal

Specialist 1

Specialist 2

Project steering

Customer

io-consultants

24


▐  Every project member is able to do the following password protected from every part of the world:

■  Inspecting, controlling and spreading of important documents

■  Inspecting appointments and their status

■  Inspecting and executing tasks, supervising und communicating status

■  Resource planning

■  Tracing project costs

■  Creation of numerous reports


25


Modules of the Portal

Document Administrat.

Minutes Keeping

Task Administrat.

Deadline Keeping


26




Minutes Keeping

Task Administrat.

Deadline Keeping


27


▐  Document Administration

■  Explorer functions for data and indexes (creating / renaming / cancelling)

■  Downloading of complete indexes and index structures

■  Differentiated assignment of rights on the different index levels

■  Working with Word, Excel and PowerPoint documents directly in the portal

■  Sending of e-mail links to documents

■  Comprehensive search function for documents and contents


28




Minutes Keeping

Task Administrat.

Deadline Keeping


29


▐  Deadline keeping

■  Administration of all project related appointments

■  Creation and sending of invitations

■  Transferring of appointments into MS Outlook calendar

■  Confirmations of participants

■  Booking overview

■  Project calendar


30




Minutes Keeping

Task Administrat.

Deadline Keeping


31


▐  Minutes Keeping

■  Creation of minutes related to the appointments

■  Importing of minutes (Import)

■  Showing of minutes to the relevant appointments

■  Overview of all open, processed and adopted minutes

■  Central filing of minutes

■  Automated versioning of minutes


32




Minutes Keeping

Task Administrat.

Deadline Keeping


33


▐  Tasks Administration

■  Tasks, Decisions etc. transferring from minutes

■  Adding tasks manually

■  Journal function manually as well as via minute

■  Journal administration via claim

■  Filtering tasks according to any criteria (subproject, status, responsibilities, maturities, etc.)

■  PDF evaluation of tasks

■  Decision lists


34

Standardization

35

Standard Layout – Solid Dosages MKT_Pharma_Focus_Material_Flow_20130709

Personnel Flow

Material Flow

36

Standard Layout – Material Flow MKT_Pharma_Focus_Material_Flow_20130709

Inbound via truck docks Transport to warehouse via sampling booth (raw materials)

Transport to central weighing area via material lock

Transport to granulation and / or bin blender

Transport to tablet press and / or capsule filling

Transport to coating (optional)

Transport to primary packing (blister, bottles, wallets etc.)

Transport through the wall to secondary packing (cartons, cases, pallets)

Transport to outbound area via material lock

Storage of finished goods

Outbound via truck docks optional with previous commissioning

Return

37

Standard Layout – Personnel Flow MKT_Pharma_Focus_Material_Flow_20130709

Main staff entrance Direct access to admin offices and / or laboratories

Access to central lockers for production and logistics personnel

Direct access to logistics area (black)

Access to production and prim. packaging area (white) via additional air locks with changing procedure

Access to secondary packaging (grey) via air lock with addtional gowning measures (e.g. caps)

Return

38

Examples

39

Success factors for a good project management

40

Success factors for a good project management

▐  Clear communication

▐  Target orientated project work

▐  Structure and project transparency

▐  Fast recognition of project risks

▐  Usage of modern communication means to increase project efficiency

▐  Permanent supervision of all parties involved


TRACK 2C


PLANT FOR

MANAGEMENT LEVEL

FACTORY DESIGN

Friday 19 July 2013

SPEAKER PROFILE

TOPIC: FACTORY DESIGN

Alain Kupferman Industry Pharmacist

We are very honoured to have Mr. Alain Kupferman as one of our speakers; Mr. Alain Kupferman has a long experience in pharmaceutical process planning and Risk Management. Mr. Alain Kupferman is active in the pharmaceutical industry since 1967. With over 40 years of experience in production, feasibility and conceptual studies, Master planning, GMP aspects, Technological aspects and personnel training to many pharmaceutical organizations in Europe and Asia. He was also Lecturer at the University of Strasbourg in France from 2006 to 2011.

PLANNING OF PHARMACEUTICAL FACTORIES CONCEPT AND IMPLEMENTATION

WORLD CLASS PHARMA FACILITY

PRESENT SCENARIO : The globalization and open market policies have proved to be a boon for the industries, but also have generated the need for globally acceptable manufacturing facilities. There are many flourishing manufacturing facilities, but not all are in compliance with the various regulatory standards. NEED FOR A FACILITY : Rapid change in manufacturing technology & various regulatory compliances to upgrade for better solution in line with cGMP. With globalization, the need for a compliant facility has become a statutory necessity.

PARTICIPANTS TO THE PLANNING PROCESS

Forecasts for x years

Objectives Budget Company internal approvals

Technology

Logistics

Building services

Building technology

Approvals (pharmaceutical)

Approvals (non-pharmaceutical)

Planning

Execution

Internal Planner Authorities

PLANNING TEAM(S)

SCHEDULE EXAMPLE

Company standards, planning conditions (quantities, technologies, products, deadlines, budget ...)

Specific guidelines, (Biosafety, Fed Std, OSHA) for conception, planning, operation ...

Norms ISO, ATEX, etc...

Labour and environmental requirements...

Pharmaceutical regulations, EU, FDA, PIC/S, WHO, requirements of pharmacy inspectors, product registration ...

NORMS, REGULATIONS AND REQUIREMENTS

General laws + regulations

Process / Equipment GMP and Hygiene Zoning

Quantitative data Layout

Feasibility Concept

Basic Design

Detail Design

Execution

Complete detailing for all disciplines

Layouts 1:20, 1:50 Tendering Refining of elements

Calculations Functional tendering

Layouts 1:100

PLANNING STEPS

HOAI

Feasibility Concept

Basic Design

Detail Design

Execution

Conceptual

design

Basic Design

Detail Design

Execution

CONVENTIONAL MODEL

IMPROVED MODEL

PLANNING MODELS

FEASIBILITY VERSUS CONCEPTUAL STUDY

• Static • Dominated by Economical Criteria • No Project Alternatives: • Yes / No only • No Influence on Schedule of

Subsequent Phases

Feasibility

• Includes the Feasibility Study • Dynamic / prospective • Dominated by Technical Criteria • Project Alternatives are generated • User oriented • Choices possible

- Costs - Technology - Organisation

• Reduces Time spent on subsequent Phases, while increasing their Precision

Conceptual Study

Strong Conceptual

design

Basic Design

Detail Design

Execution

PLANNING MODELS

It pays to invest into a strong conceptual design •  Low initial costs •  Early clarification of main issues •  Powerful decision tool •  Possibility to develop alternatives •  “Freewheeling”

PLANNING SEQUENCE AND ITERATION PROBLEMS Planning Task Start

Task Definition Targets Requirements

Analysis

Conceptional Design with Alternatives

Basic Design

Execution

easy

difficult

Detail Design

100%

90%

80%

60%

50%

40%

30%

20%

10%

70%

100%

RELATIVE COSTS OF THE DIFFERENT PHASES

The cheapest and most promising Phase is the Conceptual Phase !

Detail Engineering

Factory size Factory organisation

Technology GMP concept

Basic Design Conceptual Design

Execution

Cost saving potentials

100%

90%

80%

70%

60%

50%

40%

30%

20%

10%

POSSIBILITIES OF COST MINIMISATION

Basic Design

The best and cheapest chance to minimise cost of investment and operation is in Phase 1 !

Detail Engineering

Execution

Costs saving potential

Conceptual Design

Factory size Factory organization

Technology GMP

Small teams Brainstorming

Alternatives New ideas

Feasibility Conceptual design

Basic design

Detail design

Execution Supervision

Documentation

Cost estimation

Cost calculation

Tender documents Offers

Final quotations

The better the concept, the higher the precision

DETERMINATION OF COSTS in relation to the planning stage

PRICE PAID

PRECISION OF COSTS in relation to the planning stage stage

± 30% Cost estimation Feasibility

Conceptual design

± 5% Final Quotations Execution

Supervision Documentation

± 20% Cost calculation Basic Design

± 10% Tender documents Offers

Detail Design

The better the concept, the higher the precision

Feasibility Conceptual design

Basic design

Detail design

Execution Supervision

Documentation

DETERMINATION OF COSTS in relation to the planning system

Turnkey price: poor control

General planner: good control

- +

The Purpose of the Conceptual Design is to arrive to •  Layout •  General Factory Organisation Procedures •  Hygiene Concept •  Technology Concept •  Air Handling and Utilities Concepts which can be successfully presented to Authorities for a Pre-Approval Design Review

GMP Considerations and Factory Planning go Hand in Hand

PURPOSE OF CONCEPTUAL DESIGN

and to get a high degree of safety about • Investments •  Schedule

- Planning of a production plant

• future oriented • flexible • economical in investments and operating costs • GMP conform • conform to local / international regulations

- High motivation of staff by high quality of working place - Efficient planning - Adequate quality standard (value for money) - Architecture compatible with local surroundings

TARGETS OF PHARMACEUTICAL FACTORY PLANNING

HOW TO REACH A GOOD CONCEPTUAL DESIGN RESULT ?

Right team Good method Discipline Good data Some fantasy





PEOPLE AND PLANNING

A Quote: You do not really understand something

unless you can explain it to your grandmother." Albert Einstein

The idea is to work intensively with a small group of people, possibly detached from their daily chores. These people must have the necessary know-how (or back-ups) and the power of decision

CORE TEAM

Production Manager

Quality Assurance

Integrated Factory Planning Experts

Process GMP Expert

Controller

AD HOC MEMBERS

Utilities Specialist

Other Specialists

Logistics

Engineering

PEOPLE AND PLANNING

Generalists Specialists

Execution Detail Design Conceptual Design Basic Design

PLANNING

VALIDATION

Generalists Specialists

Number of people

Number of people

PEOPLE AND PLANNING

90%

100%

80%

70%

60%

50%

40%

30%

20%

10%

Individuals Concept

Team

Large Organisations

Judg

emen

t Err

ors

Number of Participants

Role of participants : To plan AND to decide

JUDGEMENT ERRORS

By Experimenting and Innovating

By Cloning Existing Units

By Adding Individual Functions

By Turnkey Contracting

PLANNING METHODS

There are many design methods

By Systematic Planning

Masterplan

General organisation factory

Site, Site selection

Departments

Functional groups

Equipment, single units

PLANNING FROM INSIDE TO OUTSIDE

PLANNING FROM MACRO TO MICRO

PLANNING FROM IDEAL TO REAL

OPTIMAL PLANNING METHOD

NEED FOR FOCUSING

•  Economy of scale •  Efficiency / Best practice •  Flexibility •  Performance •  Organisation

Analysis of •  Product range •  Process •  Technologies •  Organisation

Conceptional design •  Make or buy •  Specialisation •  Capacity increase •  Technology •  Standardisation •  Regulatory aspects •  Results versus costs

•  Requirements •  Vision of client

PLANNING METHOD DEVELOPMENT OF IDEAL ORGANISATION

Information Strategy

Identification key problems

Analysis Material /

Information flow

Idenfication necessary

infrastructure

Analysis process

START

Definition Modules

Functional units

Vertical Horizontal

Resulting Organisation

END

Verification process flow, material flow

Other requirements,

constraints, etc.

Calculation necessary

space

Definition of constraints,

etc. Adaptation Process,

machinery + equipment

Evaluation +

Selection

Plant strategy

+

Process architecture

Rough layout development

Layout alternatives

Combination material flows

functional inter-

dependencies

B/W-Orientation of factory

Analysis organisation

Analysis space situation

Analysis machinery / equipment

Analysis of products

and production

volumes

Verification GMP

concept

Morphological Analysis + Search for Solutions Capacity and Rationalisation Analysis

Existing Technology

GMP-Concept

Technological Alternatives

Investment / Budget

Forecasts, Quantities, Product Mix

Batch Sizes

Galenical Properties

Degree of Automation

Project- Technology

Degree of Automation

Batch Sizes

Shifts ?

Product Seasonality

Campaign Sizes

Cleaning + Change-over

Times

Foreseen Equipment

Dimension. Machines

(Type/ Quantity)

PLANNING METHOD RATIONALISATION, INNOVATION AND OPTIMISATION

GMP-Concept

Plant strategy

+

Process architecture

PLANNING PROCEDURE: CONCEPTUAL DESIGN

Development of the masterplan for the design onthe green field

Development of the integration of the layout into an existing building structure

Production forecasts / next 6-10 years

Description of process flows from starting materials until

finished product

Design of the overall flow diagram indicating all

GMP-classes

Calculation of material flow quantities

Definition of personnel, shifts, etc.

Design of the ideal layouts + modules for each step

Ideal layouts personnel areas

Ideal layouts peripheral areas

Combination of individual layouts to functional units --> Granulation, tabletting, preparation of liquids, filling ...

Design of the ideal overall total layout

Definition of - Process technology - Machinery + equipment - Transport systems + containers

PLANNING PROCEDURE: CONCEPTUAL DESIGN FORECASTS

Product lists, quantities

Sorting by galenical forms

Sorting by types (“conventional”, toxic, hormones, beta-lactames, etc.)

Strategy for marginal products (quantities, types, galenical

forms): Make or buy

ABC ANALYSIS

SELECTION OF TECHNOLOGY AND EQUIPMENT EXAMPLES OF SELECTION FACTORS

•  Vision of client •  Properties of products to be processed •  Output requirements •  Degree of automation, sophistication •  Supplier: price, service and serviceability •  Cleanability and maintenance needs •  Space constraints •  Previous experience, available equipment

(standardization) •  GMP issues •  Safety of operator

SELECTION OF TECHNOLOGY AND EQUIPMENT

•  Vision of client: size, degree of sophistication, automated guided vehicles, architecture, budget, future-oriented or not

•  Properties of products to be processed •  Output requirements •  Degree of automation, sophistication •  Supplier: price, service and serviceability •  Cleanability and maintenance needs •  Space constraints •  Previous experience, available equipment (standardization) •  GMP issues •  Safety of operator


•  Vision of client •  Properties of products to be processed:

eg granulation properties: is direct compression possible or dry granulation ?

•  Output requirements •  Degree of automation, sophistication •  Supplier: price, service and serviceability •  Cleanability and maintenance needs •  Space constraints •  Previous experience, available equipment (standardization) •  GMP issues •  Safety of operator


•  Vision of client •  Properties of products to be processed:

type of granulation, aseptic processing or terminal sterilization, ampoules or syringes

•  Output requirements •  Degree of automation, sophistication •  Supplier: price, service and serviceability •  Cleanability and maintenance needs •  Space constraints •  Previous experience, available equipment (standardization) •  GMP issues


•  Vision of client •  Properties of products to be processed •  Output requirements

High capacity / one shift, low capacity / 2 or 3 shifts •  Degree of automation, sophistication •  Supplier: price, service and serviceability •  Cleanability and maintenance needs •  Space constraints •  Previous experience, available equipment (standardization) •  GMP issues •  Safety of operator


•  Vision of client •  Properties of products to be processed •  Output requirements •  Degree of automation, sophistication

fully automated preparation of solutions, with CIP/SIP, equipment for solids with CIP capability, cartoning, palettisation, etc.

•  Supplier: price, service and serviceability •  Cleanability and maintenance needs •  Space constraints •  Previous experience, available equipment (standardization) •  GMP issues •  Safety of operator

NUMBER OF PRODUCTS

Q U A N T T I T E S

AUTOMATION POSSIBILITIES


•  Vision of client •  Properties of products to be processed •  Output requirements •  Degree of automation, sophistication •  Supplier: price, service and serviceability •  Cleanability and maintenance needs •  Space constraints •  Previous experience, available equipment (standardization) •  GMP issues •  Safety of operator


•  Vision of client •  Properties of products to be processed •  Output requirements •  Degree of automation, sophistication •  Supplier: price, service and serviceability •  Cleanability and maintenance needs •  Space constraints

Can influence the type or the supplier: eg difference in size between FBG and “one-pot” system

•  Previous experience, available equipment (standardization) •  GMP issues •  Safety of operator


•  Vision of client •  Properties of products to be processed •  Output requirements •  Degree of automation, sophistication •  Supplier: price, service and serviceability •  Cleanability and maintenance needs •  Space constraints •  Previous experience, available equipment (standardization) •  GMP issues •  Safety of operator


•  Vision of client •  Properties of products to be processed •  Output requirements •  Degree of automation, sophistication •  Supplier: price, service and serviceability •  Cleanability and maintenance needs •  Space constraints •  Previous experience, available equipment (standardization) •  GMP issues

Aseptic processing problems: automated loading of freeze-dryer, increased automation

•  Safety of operator


•  Vision of client •  Properties of products to be processed •  Output requirements •  Degree of automation, sophistication •  Supplier: price, service and serviceability •  Cleanability and maintenance needs •  Space constraints •  Previous experience, available equipment (standardization) •  GMP issues •  Safety of operator: containment or PPE ?

In most cases, several factors will play a role simultaneously

ABA ADAACA

BAA BAEBADBACBAB

CAA CAB

DAA DADDACDAB

EAA EACEAB

FAA FAEFADFACFAB

GAA GAB

HAA HACHAB

AAA

BBB

CCC

DDD

EEE

FFF

GGG

HHH

SELECTION OF TECHNOLOGY AND EQUIPMENT MORPHOLOGICAL ANALYSIS

P R O C E S S S T E P S

PROCESS ALTERNATIVES

PLANNING METHOD PROCESS AND ORGANIZATION FLOW CHARTS

Whereas a process flow chart reflects the process only, an organization flow chart includes the process, its organization as well as additional elements such as quantities, personnel needs, hygiene zoning, equipment and inter-relationships within the production or between production and related functions. The process flowchart must be transformed into an organisational flow chart Organization flow charts exist at different levels, micro- and macro:

Micro: within a department Macro: within a production unit/plant

PLANNING METHOD PROCESS FLOWCHART

Granulation Binder preparation

Drying

Sieving

Addition lubricants

Blending

Compression

dit

Granulation Binder

preparation Drying

Sieving

Addition lubricants

Blending

Compression

Weighing

Staging m2 ?

Staging m2 ?

Staging m2 ?

Container washing

Staging m2 ?

Granulation

Drying

Sieving

Addition lubricants

ding

Compression

m2 ?

Binder preparatiopreparat

n

GGnddddddder

Blend

r

Stagi

dit

PLANNING METHOD ORGANIZATION FLOWCHART

PLANNING METHOD FLOWS PERSONNEL AND MATERIALS

Exterior

Lockers G

G

Lockers D

D

Lockers C

C

A/B

Lockers A/B

Exterior

Lockers G

G

Lockers D

D

Lockers C

C

A/B

Lockers A/B

Selection of alternative important, later changes practically impossible

LOGISTICS

Goods IN handling •  Cleaning •  Administration •  Sampling •  Palletisation •  Etc

Storage activities •  Main storage •  Special storages

Goods OUT handling •  Picking •  Commissioning •  Administration •  Etc

Production

Exterior Clients Logistic centre

LOGISTICS Raw material Primary packaging material Secundary packaging material Finished products

Receiving

area

Prep

arat

ion

area

for r

aw -

and

prim

ary

pack

agin

g m

ater

ial

Sampling Booth

Shipping

wei

ghin

g Production

area

Marshalling

Bul

k st

ore

Packaging

lines

pal / h

pal / h

pal / h

pal / h pal / h

pal / h pal / h pal / h

pal / h pal / h pal / h

pal / h

pal / h

pal / h

pal / h

Warehouse

Pharma

Storage

capacity:

pallet

places

Sampling Quarantine separation

Change of pallets to/from production Procedures in material air locks

« GOOD GMP »

•  Minimized risk of contamination / cross-contamination •  Clear material flows (uni-directional whenever possible) •  Clear personnel flows (uni-directional whenever possible) •  Unambiguous definition of GMP zones •  Separation clean – dirty (washing areas)

Overkill Cost issues Nice to have GMP is not an attribute, no black and white attitudes

SUMMARY

A good pharmaceutical factory is a factory that is: •  Pharmaceutically approved (qualification / validation )

•  Economical to operate and maintain

•  Flexible and adaptable quantity-wise and for new technologies

To design such an excellent pharmaceutical plant, an integrated, multi-disciplinary and experienced team is required. The objectives, the vision, the method and the involvement of each member of the team will achieve this goal, and not the principle “function follows adding up individual inputs”

TRACK 2C


PLANT FOR

MANAGEMENT LEVEL

THE ROLE OF MANUFACTURING IT

- AN INTEGRATED APPROACH (ERP)

Friday 19 July 2013

SPEAKER PROFILE

TOPIC: THE ROLE OF MANUFACTURING IT - AN INTEGRATED APPROACH (ERP)

Prateep Juavijitjan Project Director & Chief Customer Officer Vantage Business Solutions (Thailand) Co.,Ltd. 11

th, 12

th Floor, Home Place Office Building

283/52 Sukhumvit 55 (Thonglor) Klong Ton Nua, Wattana Bangkok 10110 Thailand Education - Thummasat University, Master Degree of Business Administration - Chulalongkorn University, Bachelor Degree of Electrical Engineer

Career Summary Over 18 years of ERP implementation, Project management and business process improvement experiences in various industries such as Auto parts, Chemical, Packaging, Electric equipment, Foods & Beverage, Pharmaceutical etc. Service Capabilities

ERP Project Management

Implementation Consulting in Trade and Logistics,Production & MRP, Project

Training in Trade and Logistics, Production & MRP, Project

Project Implementation Record

Exedy Co.,Ltd

Siam Calsonic Co.,Ltd

Microchip Co.,Ltd

Useful Food Co.,Ltd.

Siam Ruammit Co.,Ltd

Thai Summit Autoparts Co.,Ltd

Ampas Industries Co.Ltd.

SVI Co.,Ltd.

Professional Certification Microsoft Dynamics Implementation Certified Microsoft

® Business Solutions Certified Professional in Axapta – Trade & Logistic

Microsoft® Business Solutions Certified Professional in Axapta – Production

Microsoft Dynamics AX (2.5,3.4,2009,2012) Axapta Baan IV Baan ERP Hyperion CADAM

ERP for Pharmaceutical Industry (Microsoft Dynamics AX) Prateep Juavijitjan Vantage Business Solutions

Our Agenda Today

How Microsoft Dynamics AX can help

Powerful Agile Simple

Key solution advantages for Pharmaceutical Industry

Questions?

Global business imperatives

Global trends and business challenges A new generation of enterprise resource planning (ERP)

Global Business and IT Trends

Global competition and global expansion Organizational change Outsourcing and complex value chains Changing supply and demand Fluctuating workforce demographics Increasing need for compliance and transparency

Keeping pace with trends and competition with legacy systems Need for IT governance and to modernize, simplify, and standardize Enabling users of consumer devices and social networking technologies Changing role of IT

Challenges for Organizations

Achieve operational insight across the organization Need for business agility Reduce operational costs Align IT and business objectives

Increase ERP adoption

Reduce IT operational costs

Enable business strategy and respond quickly to line-of-business (LOB) requests

Challenges for Enterprise Applications

“Enterprise Apps Customers Have Issues,” Forrester Research, Inc., February 26, 2010

A new generation of ERP That works for you, not against you

Powerful Powerfulembedded embeddedembedded

analytics and BIIB analytics and Bnalytics and BBIB

Applications that Applications tare an asset

hat hatt t

Simplicity and mplicityagility

y any any y

Works the way you need it to Simple to use Get the right data

to decision makers

Complete industry- specific solutions

Manufacturing

Distribution

Retail

Services

Public Sector

ring

n

toor

Tailored to meet your needs

Simple

Powerfully Simple

Powerful Agile Pervasive interoperability

Powerful

Deliver more value faster with a single, powerful solution:

“The ability to view and apply various manufacturing processes through a single ERP solution is revolutionary to our business. With Microsoft we are confident we will remain on the cutting edge of technology.” —Hubert Meisterjahn CIO, Dornbracht

Gain immediate insight and unlock greater productivity with a RoleTailored user experience.

Scale your organization quickly with a single global solution.

Gain value quickly with purpose-built industry and operational capabilities in a single solution.

f t i

eatteerr perience.

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• Single solution for five industries

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Gain value quickly with purpose-built industry and operational capabilities in a single solution.

ne

Core ERP Suite (Finance, HCM, Compliance Management, SRM,

Environmental Sustainability, Expense Management)

Public Sector

Services Sector

Retail Manufacturing Distribution

Global Solution

• Prebuilt, country-specific localizations for 36 countries

• Highly scalable • Shared data and unified

processes across the organization

Scale your organization quickly with a single global solution.

RoleTailored User Experience

Gain immediate insight and unlock greater productivity with a RoleTailored user experience.

• RoleTailored user experience • Self-service business

intelligence and reporting • Notifications and alerts from

workflows

Differentiate your business easily with model-driven layered architecture.

Agile

Support your business today and tomorrow with flexible deployment alternatives.

Plan, visualize, and change your business by using unified natural models.

Increase opportunities and reduce risk with an agile solution.

“For us, it’s all about agility—if we can’t deliver in weeks what used to take months, we’re holding back the business.” —Greg Smith CIO, Royal Canadian Mint

Unified Natural Models

• Easy-to-use financial dimensions

• Organization model • Configurable graphical

workflows • Single business process

repository

Plan, visualize, and change your business by using unified natural models.

Flexible Deployment

• Selection of governance models

• Cloud-based services • On-premises and partner

hosted • Flexible solution architecture

Support your business today and tomorrow with flexible deployment alternatives.

Partner hosted On-premises

Model-Driven, Layered Architecture

• Models combined with layered architecture

• Development within Visual Studio®

• Table-inheritance and more granular metadata

• Enhancements in modeling the user experience

Differentiate your business easily with model-driven layered architecture.

Simple

Connect employees, customers, suppliers, and partners easily through integrated collaboration capabilities

Drive user involvement and innovation with an easy-to-use solution.

“The familiar look of the product will immediately remove barriers that some people might experience when it comes to financial information.” —Mike Bailey Director of Finance and Information Services City of Redmond, Washington

Streamline IT processes by simplifying management of your ERP solution at every stage of the life cycle

Provide access to data and business processes with an ERP solution that is simple to use

Familiar and Intuitive

• Looks and works like Microsoft Office

• Common UI across web browser and Windows® UI

• Bidirectional integration with Microsoft Office 2010

• Enterprise Search

Provide access to data and business processes with an ERP solution that is simple to use.

Lean Kanban Boards

Integrated Collaboration

• SharePoint-based employee, vendor and customer portals

• Adaptable web services, such as Sites Services

• Microsoft Lync integration • Creation of SharePoint

collaboration sites directly from within ERP

Connect employees, customers, suppliers, and partners easily through integrated collaboration capabilities.

Application Life-Cycle Management

• Microsoft Dynamics ERP RapidStart Services

• Highly streamlined, user-friendly installation

• Simplified Role-based security setup

• Accelerated upgrade through upgrade advisors and tools

Streamline IT processes by simplifying management of your ERP solution at every stage of the life cycle.

Simplify

Powerfully Simple

Pervasive interoperability

Solution investments + Related ecosystems = = Solution investments + Related ecosystemsImproved productivity and lower IT costs

s tsts prov

Enhanced Industry functionality

Services Sector Public Sector Retail Distribution Manufacturing

1,000+ new features and enhancements

Simple Powerful Agile Pervasive interoperability

f l

Microsoft Solutions for Life Sciences and Pharmaceutical Manufacturing

- Can introduce new products in a timely, least-cost manner

- Manage electronic quarantines, quarantine release by user and material type, printed material control/obsolete components, lot control/segregation, lot tracking, and enable drug and hazardous material reconciliation. - Model the processing of costly ingredients to help minimize overruns and short-runs - Shelf life tracking to consider expiration dates during production and distribution

- Centrally manage co-products and by-products in your formulas or recipes, and always know the correct inventory status for any given item. - Tight integration with other Microsoft® products extends Microsoft Dynamics AX capabilities to help ensure a fast return on investment - Compliance Management

Key Function of MS Dynamics AX (For Pharmaceutical Industry)

-Input-driven process specification -Attribute tracking and dynamic formula adjustment - Centralized quality control and compliance support (Help support U.S. Food and Drug Administration (FDA) reporting, plus GMP and FDA regulation 21 CFR Part 11) - Batch optimization and balancing - Yield planning and tracking - Co-product/by-product management - Integrated quality control (QC) capabilities - Customized product and packaging capabilities - Detailed production cost analysis - Optimized picking - Manufacturing process validation - Extensive audit & compliance

Key Investments to the Application Foundation

Master Data Reference Data Global Engines

Master Data • Organization Model • Global Address Book • Product Information Management Reference Data • Time zone enhancements • Unit of measure Global Engines • Policy Management • Questionnaire • Support for unlimited financial dimensions

Key Investments in Horizontal Capabilities

Financials GRC HCM & Payroll*

Financials • Financial data across legal entities • Improved Chart of Accounts • Budget Control • Separation of Operations and Accounting • Accounting distributions • Collections • 3-way match

GRC • Audit Workbench (audit rules and policies) • Enhanced Compliance Center • Environmental Sustainability Dashboard

HCM/HRM • Employee Self Service • Streamlined HR process • Site Services enable external applicants

to apply for job postings


Sales and Marketing Procurement SCM Inventory

Sales and Marketing: • Case Management • Customer Relationship Management (CRM) Procurement • Request for Quotation (RFQ) • Purchase requisitions • Purchase order & agreement • Decentralized product receipt • Vendor Catalogues • Centralized procurement desk SCM & Inventory: • Sales and purchase agreements • Trade agreement improvements • Report value of goods in transit • Intercompany planning • Delivery schedules • Decouple order management from Inventory Control


Projects

Travel and Expense 4

R&D Projects • Manage and maintain R&D project • Budget control for projects • Microsoft Project Server interoperability • Project cost control & tracking

Key Investments in Industry-specific Capabilities

Manufacturing Distribution Retail* Services Sector Public Sector

Manufacturing: • Mixed-mode capabilities

(process and discrete manufacturing) • Operations Resource Model (resource scheduling) • Touch-enabled time recording on the Shop Floor • Master Planning with Machine Sequence or Machine Capabilities • Potency Management & Lot Attribute

Distribution: • Intercompany supply and demand visibility • Intercompany demand visible upstream supply chain • Sales order process enhancements (fast order entry) • Mass price changes and prices in multiple currencies.

Dynamics AX 2012 BI solution

AX 2012

Pre-built + custom cubes

Analytic Reports

Role Centers and Dashboards

MS Excel

AX 20112

PrreePrree- uilt + custom bubbuiltuibubcubecubeubebeesse

Analytic Reportl ti R ttst

Role Centers and R l C t dRole Centeers aers aDashboardDashboarddsds

MS Exceel

MS SharePoint

Presentation Cubes AX2012 Database

CEO Role Center

TRACK 2C


PLANT FOR

MANAGEMENT LEVEL


- AN INTEGRATED APPROACH (MES)

Friday 19 July 2013

SPEAKER PROFILE

TOPIC: THE ROLE OF MANUFACTURING IT - AN INTEGRATED APPROACH (MES)

Florian Seitz

Senior Consultant and Project Manager

Werum Asia Support Centre 12th Floor, Liberty Square Building, 287 Silom Rd. Silom, Bangrak, Bangkok 10500, Thailand

Florian is Senior Consultant and certified Project Manager (PMP). He works for the software company Werum Software & Systems AG that specializes on manufacturing execution systems (MES) for the pharmaceutical and biotech industry. After obtaining his master degree in business informatics in 2007, Florian started his career with Werum at its global headquarters in Lueneburg, Germany. In 2010 he joined Werum Asia Support Centre in Bangkok, Thailand, and manages and consults projects mainly in Asia Pacific. Florian conducts consulting, project management and trainings in all pharmaceutical areas (Pharma, Biotech, API, Fill/Finish, Chemical and Blood Plasma) on five continents.

19-July-2013 © Werum Software & Systems, Florian Seitz MES – From Past to Present to Future 1


MES Middle Ages – Evolution – Space

Florian Seitz Werum Asia Support Centre


From Past to Present to Future

15 yearsrs

Nokia 5100

1998

iPhone 5

2013


From Past to Present to Future

14 yearsrs

Nokia 5100

1987

iPhone 5

2012


What is MES?

MES stands for Manufacturing Execution System. Specify, execute and document all pharmaceutical production operations. The main purpose is to minimize production and documentation errors, optimize the manufacturing processes and increase efficiency. An MES needs to ensure compliance with regulations (e.g. cGxP of the FDA, GMP of the EU, PIC/S).


Introduction Werum I

MES concept MM

Past – Present – Future scenarios P

MES – From Past to Present to Future

MES overview – A modular approach MM

MES benefits MM


Werum at a Glance

Werum AG, Headquarters, Lueneburg, Germany

Werum America Inc., Headquarters, Parsippany, NJ, USA

Best-in-class MES product for Pharma & Biotech Professional services Customer satisfaction & long term partnerships

480+ employees Founded 1969 Constant growth Strong financials


Your Leading MIT Partner for Life Sciences

Werum K.K. Tokyo, Japan

Werum Germany HQ, Lueneburg

Werum US HQ Parsippany, NJ

Werum Ltd. Asia Support Centre Singapore, Subsidiary Bangkok

S. Francisco, CA

Cary, NC

Hausach

Werum SAS Toulouse, France

St. Augustin

Basel


Revenue by Region

Revenue by Industry

Werum & PAS-X Success Stories

Pharma 50%

Biotech and API

40%

Others 10%

USA 45%

Europe 45%

Asia Pacific

10%

Stable Growth per Year Employees

380 400 450 470 490

2009 2010 2011 2012 2013(e.)

h + 15 %


International Key Customers in Asia/Pacific


Introduction Werum II

MES concept MM




MES benefits MM


Producing Paper & Pharmaceuticals...

Looks familiar? Manufacturing pharmaceutical products and flooding yourself in paper documents?


Where do we come from?

ERP

MES

Equipment


Key Pain Points in Pharma Manufacturing

Manufacturing execution, batch record and batch release Paper batch records

Manual, error prone (humans) and time consuming Hundreds of manual entries for every paper batch record Non-readable / wrong / uncompleted entries No sequence and completeness control of work instructions

Resulting in long review and release times Operator spends more time on batch record and equipment logs as on manufacturing procedures

Equipment and material Difficult tracking, locating and cycle counting of in-process material Availability of material for manufacturing Unknown status of equipment and batch record WIP might be scrapped due to low and manual visibility of material



MES concept M




MES benefits MM


MES Overview – a modular approach by PAS-X


MASTER BATCH RECORD ADMINISTRATION

Recipe / MBR development Version control, history, audit trail

MBR creation based on libraries Graphical workflow and material flow engine

Electronic release workflow (approvals, changes, releases, etc.)

Generation of manufacturing documents for paper based manufacturing documentation

Define & manage processes in API,

formulation & packaging


WEIGH & DISPENSE GMP Compliant Best Practice Business Processes Interface to different types of scales Easy-to-operate user interface Generation of weighing report Calibration checks and procedure Order and Campaign Weighing, incl. Reconciliation Material point-of-use checks Large selection of weighing methods Waste and Scrap management

Industry proven weigh & dispense system enforcing

compliance


Electronic Work Instructions: Easy to operate EBR

Paperless production – “Right First Time” Electronic Work Instructions – User Guidance Order and workplace control Parallel execution in different workplaces Generation of manufacturing reports and documentation Genealogy

Clear workflow guidance for shop floor operators

Audit Trail


Flexible User Guidance – Mobile Workstations

Source: Novartis, NJ, USA

Portable unit from a single workstation provides full access to all processes


EQUIPMENT MANAGEMENT

Each equipment can be managed as an 'object' Point-of-use identification & status verification Electronic equipment logbook (automatic) Equipment related cleaning recipes

1 234567 890128

Facilitating the plant-wide & paperless electronic

logbook


WAREHOUSE MANAGEMENT SYSTEM

Warehouse management (storage places/bin, silos, tanks) Stock keeping of Raw Materials, Finished Goods, Tools, Intermediate Materials Concepts for storage areas (hazardous goods, cold storage)

Functions for receiving and dispatching goods Systems for order picking, dispatch control Warehouse and

inventory management in combination with ERP

functions


MATERIAL TRACK & TRACE – WIP Material Flow Control

Reactor Dispensing Material flow ▪ Definition of transports ▪ Controlling of transports

Print label Identify label

Blend01 Press99

Source: Blend01 Dest.: Press99

Eliminating risk of material loss or mix-ups


PROCESS QUALITY CONTROL

Deviation and event handling; Analysis and acknowledgement anytime Controlling CQAs and CPPs Focus on deviations / non conformities Traffic light functions to control the process Review-by-exception Follow pre-defined release workflow

Significantly improving Right-First-Time


Electronic Compliant Batch Record


Integrated MES Solution – Standardizations

Enterprise Level

Production Level

Equipment Level



MES concept M



MES overview – A modular approach M

MES benefits MM


MES Right First Time

Identifying room and reading its status from the system

Source: Novartis, NJ, USA


Operator Guidance and Manufacturing Control


MES – Transform Pain to Benefits (Customer Example)

>150 manually managed Recipes 20 data driven MBR templates represent all products

Documentation Errors are a constant struggle

100% Right First Time, system captures work as it is performed

Operator has no strict guidance through the process Guided procedures enforce compliance

Process deviations are late discovered at end of process

Real time deviation reporting / investigation

Inventory not reconciled during production – no up to date inventory

Real time inventory, enabling waste and scrap reporting

Equipment status recorded in 100s of paper logbooks

Equipment management embedded

Over 6 million entries reviewed annually for correctness Review by exception only


Key Benefit Areas of MES – Summary

Quality “Do it right the first time!” Minimize lost batches or rework Prevent Errors by means of pro-active online checks

Full Compliant Process Identify and eliminate compliance problems No efforts on paperwork Review-by-Exception (incl. CQA, CPP)

Reduce Work-In-Progress Save material costs

Complete Documentation & Deviation Report Automated up-to-date logbooks Streamlined Event and Deviation Management Reduced Release time through ‘Review by Exception’

Optimized Process Reduce lead time Tight integration and interaction with DCS / SCADA / PLC

Q Product quality



MES concept M

Present – Future scenarios


MES overview – A modular approach M

MES benefits MM


PRESENT – vertical integration Electronic Batch Recording (EBR)

ERP

Field Level

Manufacturing Packaging

Electronic Batch

Recording

Handling the batch record


PRESENT – product lifecycle integration Manufacturing IT Business Platform

Manually or Electronic

Discovery

Pre Clinical Phase 0 Phase I & II & III Phase IV

Process Development

Clinical Production

PAS-X PASSS-XXX

1 MBR 1 EBR

Library 1 EBR 1 MBR

1 EBR 1 MBR

PPPAAASSSSSSSSSSSSSSSSSSSS XXX

V Launch h Commercial

Commercial Production

1 MBR n EBR

Commercial GMP Batches


Today – MBR simulation and validation tool box

Faster process testing Create an executable EBR “with one click” out of MBR Start where ever needed, no sequence enforced Option to disable e-signatures


Today – Electronic recording of shop floor operator

Decision: automatically executed by system “End of manufacturing?”

Decision: manually executed by operator “More IPC checks?”

Prepare IPC

Perform IPC


Today – Process controlled by decisions


Today – Process controlled by signals (simple)


Today – Process controlled by signals (complex)


Near Future...

Further use of mobile devices, phones, etc., Cloud Computing and fully internet based systems RFID Continuous batch process PAT / QbD – initiative of risk-based approach MES is already relevant for those topics. Customers have implemented this already. This will be further developed and established in near future.


New Devices: Mobility on Tablets Web and Native Applications


Day after tomorrow – unpredictable

We will see what the future brings…

A few possible scenarios


Future scenario 1 – Augmented reality

What is it? AR is the concept of merging the digital world with the physical world by having an overlay representing data (either via glasses, screens or by projecting the image onto the physical object)

Source: http://www.closetcooking.com

Glass, say delicious in Thai

อร่อย delicious, Thai


Future scenario 2 – Gesture control

What is it? Gesture or Motion Control allows the Operator to control the system using gestures instead of typing on keyboard or using the mouse

In the pharmaceutical environment this could be especially helpful since keyboards are hard to clean and a potential source of contamination and cross contamination of the product.


The Future of MES – Vision

The only place in your plant that will still need paper.


Thank you

Florian Seitz Senior Consultant

Werum Asia Support Centre

TRACK 2C


PLANT FOR

MANAGEMENT LEVEL


- AN INTEGRATED APPROACH (LIMS)

Friday 19 July 2013

SPEAKER PROFILE

TOPIC: THE ROLE OF MANUFACTURING IT - AN INTEGRATED APPROACH (LIMS)

Michael Wang Director, Solution Consulting, APAC Accelrys KK Singapore Branch 80 Robinson Rd. #02-00 068898 Singapore Education - National University of Singapore, MSc Singapore

2012 – Present Director, Solution Consulting, APAC, Accelrys Lead pre-sales team in APAC for sales of informatics solutions from Accelrys. Provide business impact analysis to prospects and customers. Provide consulting service to customers in lab management, computer validation and system deployment for LIMS, LES, ELN, etc. 2004 - 2012 Manager, Technical Sales, APAC, ThermoFisher Scientific Lead the pre-sales team in APAC for sales of LIMS and CDS solutions from ThermoFisher. He has worked on projects in ONO, CSL, AMO, Glenmark, Weeda, Wuxipharma, etc as project manager, validation consultant, services consultant, etc. 2001 - 2004 LIMS Project Manager, Pfizer Manufacturing, Singapore Lead the LIMS project team to implement and validate the LIMS system in the QC lab for the API plant. The system has passed US FDA audit without any findings. 1998 - 2001 Lab Supervisor, Schering Plough, Singapore Set up the new DCL lab and lead a team of 15 chemists for instrument qualification, method validation and product testing. The lab has passed many audits from US FDA, corporate QA and local HSA.

Accelrys Informatics Platform for QA/QC and Compliance

Michael Wang Director, Solution Consulting, APAC July, 2013

A Bit About Accelrys

Accelrys is

• Public: ACCL (NASDAQ)

• LTM Non-GAAP Revenue: $174M

• Clear Leader in Scientific Innovation Lifecycle Mgmt

• Employees: 650 (200+ PhD’s)

• Customers: Over 1,300

• Headquarters: San Diego, CA

• Industries Served: Life Science – Pharma, Biotech, Academic, Government

Consumer Packaged Goods, Chemicals, Energy , High Tech

• Recent Developments: Introduced the Process Management & Compliance Suite and groundbreaking LIMS

Announced the acquisition of Vialis Corp based in Switzerland

Announced the acquisition of Aegis Analytical Corp for $30 million in cash

3

United States San Diego, CA (WWHQ)

San Ramon, CA Milford, MA Boulder, CO

Bedminster, NJ Bend, OR

Europe Cambridge, UK (EHQ) Stockholm, Sweden

Paris, France Basel, Switzerland Cologne, Germany

Asia Tokyo, Japan (AHQ)

Seoul, Korea Singapore

India

49% 29%

22%

Accelrys LIMS

Modern technology architecture = Lower total cost of ownership + Less time to deploy Key Benefits: • Dynamic data structure workflow vs traditional static template LIMS • Innovative workflow editors with a simple drag-and-drop process • Quickly add additional LIMS capabilities without custom coding • Built-in compliance enables automatically created validation/qualification

documents • Easy creation of instrument connections with drag-and- drop capabilities • Flexible deployment options - selectively implement applications • Standalone deployment or in combination with the Process Management and

Compliance(PMC) Suite

The Accelrys LIMS

Workflow Editors Create LIMS Applications

Accelrys LIMS Workflow

Editors (drag & drop)

Entity or Inventory

Scheduling

Workflows

Reporting

Sample and Spec Management

Metrology/Calibration Management

Microbiological Environmental

Monitoring

Work Requests

Stability Management


Qualification

Dashboard Views at Login

Sample or Process Workflows Easily Created & Managed

No complicated programming or IT support needed to convert existing plant or analytical work process - include checks, logic, links to other systems and automatically assign the electronic SOP or Work Instruction

• Enterprise level workflow • Harmonize business

processes across work groups

• Track work request progress against key projects, campaigns and studies

• Streamline communications and increase productivity

• Gain visibility into laboratory resource utilization and bottlenecks

Work Requests


• Samples, Reagents, Standards, HPLC Columns, etc.

• Receipt to waste workflows

• MSDS and Certificate of Analysis linking

• Labeling (bar code) • Expiration date

monitoring and tracking • Inventory quantity

tracking • Alliquotting and sub

sampling

Metrology/Instrument Management

• Instrument Inventory • Calibration date

monitoring • Daily verification • Integrated execution

of calibration procedure

• Maintenance log • Dashboard reporting • Calibration reports • CDS Adapters

Sample Management

• Inspection Lot management

• Sample location management

• Sample Chain of Custody Management

• Test execution and result entry

• Result Review and Reporting

Multiple Tier Specifications Are Managed in the System

Stability Management

• Stability Sample management

• Stability Specifications

• Stability Chambers and inventory

• Stability Study and protocol execution

• Stability testing/result entry

• Data review and reporting

Environmental Monitoring

Comprehensive Workflow Automation for ALL Environmental Monitoring Tasks Preparation, Sampling, Execution, Review and Reporting

Materials Qualification and


Sampling Plan Creation and Scheduling Plan Execution

(“under glass”; labeling; bar code control; plan

viewing)

Incubation and Micro Lab Procedure Execution

(Instrument integration and test SOP viewing/data capture)

Review and Approval of Test Results

Reporting and Trending

Scheduling, Sampling, Testing, Result Entry and Reporting with Location Hierarchy Support

Scheduling, Sampling, Testing, Result Entry and Reporting with Location Hierarchy Support

Reporting with Export ing to Other Formats : PDF, RTF, Excel , XML, etc.

• “This is the first time that a lab informatics vendor has developed a process-centric LIMS with automated compliance features.”

• “Traditional LIMS vendors’ sample-centric tools have proved to be inflexible and difficult to validate.”

• Accelrys LIMS enable customers in GxP and associated regulated manufacturing environments to obtain more tools through a single vendor and to develop insights between lab, quality and manufacturing groups.”

Gartner on Accelrys LIMS

http://www.gartner.com/DisplayDocument?id=2382315&ref=g_sitelink

Accelrys LES

LES creates an electronic copy of SOP and enforce analysts to perform the analysis through step by step paperless execution so as to minimize human errors and inconsistency.

Accelrys Lab Execution System(LES)

Method “under glass”

Accelrys LES

• Access to correct & current SOP

• Testing process monitoring and standardization

• Automated raw data and meta capture and management

• Automated calculations

• Dashboard data review

• Automated data exchange

• Automated report generation

• Complete integration with instruments

“Purpose-built” for cGMP Quality Operations

SOP/Digital Method Execution

The method IS the GUI !!!!

“Method under glass” with integrated direct data capture to database

Best Practice Test Methods - “Right First Time”

AT - Audit Trail

OL - Out of Limit

OD - Out of Date

SD - Source Data

An - Annotation

A/A -Attest/Approve

Data Review - Approve at-a-Glance

Data Review - See Source Data at the touch of a button

Accelrys IDS

Accelrys Instrument Data System (IDS) Data Capture Hundreds of Instruments

Deliver to ELN: SOP from document

system Work assignment

from LIMS

Final Lab Report and

COA

Process limit checking and automated compliance

Electronic Lab Notebook ELN is the hub for data capture, calculations, data review, and approval.

Provides a single work environment for lab analysts.

Chromatography Data Systems ELN pushes sample prep data to CDS pre-run.

CDS output files go to ELN for post-run analysis

Data from Complex Instruments via networked PC

(UV-Vis, PDA, etc.)

Statistics and Analytics Programs

Data from Simple Instruments via RS232 (pH, KF, balances, etc.)

Data from Human

Observations

Supported Integrations- 3 Modes of Operation

4.210 mg

4.21mg

00

Empower I Empower II Chromeleon Chem Station Open Lab Easy Chrome Microsoft Excel

oooo

oommnn

ooooooower Iooooooower IImmmmmmmeleon

mmmmmm Stationnnnn LabCCCCCChrome

rooooooosoft Excel

….hundreds of validated and out-of-the-box integrations

Complete the Lab Picture – An Integrated Approach

Accelrys Confidential

QA/QC Laboratories Lab Execution System

ELN LES

LaLabobooraracution

Environmental Monitoring Inventory

Management Work Request

Sample Management Accelrys

LIMS Stability

Metrology

Instrument Data Service (IDS)

Accelrys Process Management & Compliance(PMC) Suite

Accelrys Confidential

QA/QC Laboratories Lab Execution System

Manufacturing Electronic Batch Records Transfer Transfer

ELN LES EBR

C C LaLabobobbbbxecutio

Environmental Monitoring Inventory

Management Work Request

Sample Management Accelrys

LIMS Stability

Metrology

Accelrys Discoverant Process Management Informatics (PMI)

Accelrys Enterprise Platform (AEP) for Data Exchange

Instrument Data Service (IDS)

Development Labs Electronic Laboratory Notebook

Use Cases: What others have achieved

Laboratory Workflow Efficiency Gains: Saving Time and Resources using ELN/LES

Test Time

Paper Based LES % Resource Savings

Hardness 20 minutes 10 minutes 50

Appearance 20 minutes 10 minutes 50

Dissolution (6 vessels) 3.0 hours 2 hours 33

Potency & Impurities 2 hours 1.5 hour 25

Productivity Metrics

AstraZeneca : Right First Time Initiatives

Year # Batches/Week (one product)

# Errors/Month

2002 10 20

2003 10 10

2004 thru 3Q 12-15 11

4Q04-Present (LES) 12-15 0*

Figure: Significant lab deviation reductions from multi-plant deployments of LES.

“An ERP, LIMS, and Lab Execution System Architecture – Global Deployment Update and Operational Excellence Metrics”

Lukas Gogis, Team Leader, Global LIMS, Manufacturing Information & Control Systems Eli Lilly & Company, Indianapolis, IN USA

Compliance Benefits Observed • Compliance to method criteria enforced

• Entry errors & manual transcription reduced

• Precise time/date, analyst, and equipment information captured real-time

• Reagent and other expiry dating enforced

• Equipment availability controlled by system

• Elimination of paper documents ensures retrieval of critical records at need

• System enforces good documentation practices

• Audit trail information for system is immediately retrievable and reviewable

• The most current method is automatically associated with the testing of any sample

• Method text is available to analyst during testing without recourse to other systems

Compliance Metrics

Deviation Rate vs Accelrys LES Usage

A Transformative Change …

“When everything else you’re doing is already electronic, an electronic notebook makes a lot of sense.”

Reduce Paper, Environment Friendly

Innovation

Productivity, Efficiency

Documentation Quality, Compliance

IP Protection, Security

Collaboration

Thank You

Questions

www.accelrys.com/pmc

TRACK 2C


PLANT FOR

MANAGEMENT LEVEL


- AN INTEGRATED APPROACH (eQMS)

Friday 19 July 2013

SPEAKER PROFILE

TOPIC: THE ROLE OF MANUFACTURING IT - AN INTEGRATED APPROACH (eQMS)

David Margetts

Managing Director

Factorytalk Co., Ltd. 12th Floor, Liberty Square Building, 287 Silom Rd. Silom, Bangrak, Bangkok 10500, Thailand

Mr David Margetts is a co-founder of Factorytalk with more than 13 years working experiences in Consulting to the

Pharmaceutical and Biotech industries including overseeing a widely experienced team of technical experts executing

manufacturing IT projects across the region and US/Europe ranging from shop floor SCADA control to enterprise-wide

ERP systems. Also being Project Manager and Technical expert for the world’s leading Manufacturing Execution Systems

provider to the Pharmaceutical and Biotech industries, expertise and experience over 50 successful global projects such

as Amgen, Bayer, Novartis, MerckSerono, and AstraZeneca.

Mr. Margetts also participates in a team of GAMP guideline reviewer and contributor and involve in writing a Pharmaceutical Eng. article and numerous event management for ISPE Asia-Pacific.

MasterControl eQMS: Supporting the next 10 years

19/07/2013 Thailand ISPE Conference

About MasterControl

Compliance Accelerated A global company founded in 1993 with offices in the United States, United Kingdom, Germany and Japan.

Provides industry specific software solutions to improve regulatory compliance and accelerate product time to market.

In-house industry and process expertise delivering successful project from conception to completion.

Committed to developing new innovative products that help customers succeed in their respective regulatory environments.

Over 500 corporate customers worldwide. Over 150 Medical Device Over 150 Pharma and Biotech Over 50 Blood and Biologics Over 200 in other regulated Industries

MasterControl Integrated Compliance

Suppliers

Regulatory Submission Publishing

gueguRegRe atototoolatola ooatatttatatatataaa rymbmubSuS ssiis iiiionooooooooooooooooolbPP hii hlblPubPuP hiish ng

pppppppupuSuSuSuS ppS ppS pSSu liiererieiei ssssssssssRisk

Documents

Supplier

Quality Events

Training

Audit

Regulatory Submission Publishing

PLM

BOM

PDM Links

External Links & APIs

LIMS

MES

ERP

Guest Connect

Customers

Suppliers

Partners

Projects

Americas

Asia

EMEA

Global Services

DISCOVER

CONFIGURE

VALIDATE

DEPLOY

• Project Kickoff • Define Project Success • Identify Project Team • Draft Project Charter (Objectives,

Scope, Deliverables, Budget, etc) • Plan Communication Strategy • Detail Project Change Control Process • Draft Project Plan

PLAN Installation Gate Review

• Schedule System Administrator Training • Setup and Install MasterControl

Test/Validation/Prod Environments • Execute Installation Qualification (IQ) • Define Customer Requirements

• Configuration of Portal, Documents, Training Modules

• Test Import • Process Solution Configuration/Design • Define Key Process Workflows

Validate Gate Review

• OQ – Operation Qualification Execution • PQ – Performance Qualification Execution • User Acceptance Testing

Go Live

• Document Maintenance & Support Procedures • Data Import to Production Environment • End User training • GO LIVE

eQMS across the product lifecycle

Clinical Trials GCP

Registration GxP

Manufac- Turing GMP

Distribution GDP

Research & Development

GLP

Quality Assurance

GMP

Technology Transfer Manufacture & Distribution

COMMON REG ASPECTS (Document control, Training, Quality Event Management) = eQMS

Product Lifecycle Management

• Document Control • Training Management • Quality Event Management

PICS Key Management Tools

Document Control • Document preparation • Document approval • Document layout • Document review • Document issue • Document change control • Record retention • Electronic records

Specifications • Specifications for starting materials • Specifications for packaging • Specifications for finished products • Manufacturing formula or bill of materials • Processing instructions • Packing instructions • Batch records • Packing batch records

SOPs & Records • SOP and records for materials receipt • SOP for labelling • SOP for sampling • SOP for testing • SOP for release • SOP & records for distribution

SOPs & Records • SOPs & records for validation • SOPs & records for calibration • SOPs & records for cleaning • SOPs & records for personnel • SOPs & records for environmental

monitoring • SOPs & records for pest control

SOPs & Records • SOPs & records for complaints • SOPs & records for recalls • SOPs & records for returns • SOPs for processing equipment • SOPs for lab equipment • Log books for equipment • Log books for lab equipment

• Deviations are fully recorded and investigated • Review of relevant production documentation

and an assessment of deviations from specified procedures

• Any deviations from the Manufacturing Formula and Processing Instructions.

• If a deviation occur, it should be approved in writing by a competent person, with QC involvement

PICS Quality Event Management

• Training Management must ensure: • Appropriately qualified and trained personnel • Appropriate records are kept

PICS Training Management

Look familiar?

Paperless Quality Management

• Implement best practices with standard functions to integrate the key areas

• Central and secure access from anywhere, anytime

• System automatic monitoring and control

CAPA Required

Fully integrated Quality system

Quality Events CAPA Document

Approvals Tracking & Trending

Close Incident

Quality Event

Risk-Based Issue Review

Close Incident

CA

PA

N

ot R

equi

red

Investigation

Tracking & Trending

Effectiveness Checks

CAPA Initiation

Corrective Preventive Action

Exams

Course Management

Training Delivery

QEM QMS Customer Complaint

Rules

Release

Docs

Quality Events

alityents

Training

cs

Risk

Change Control

5 3 9 2 6 1 3 5

Document control of revisions and approvals ocum

Change Control

Revision & Collaboration

Document Approvals

Training Controls

Close Incident

Change Control

Revision & Collaboration

Document Approvals

Training Control

Release

Archive Course Management

Docs

Training

Example: Handling Complaints

Customer Complaint

Issue Review

CAPA

Risk Assessment

Change Control

Update Document

Training

unacceptable

Launch Quality Event for Issue Review!

Electronic data entry and built in best practices for Issue handling

Risk Assessment used to define the next steps and actions

Immediate containment of problem and follow-on CAPA initiation





Secure and compliant access controls

Document Management

Open any Document, anywhere, and secure

Approvals and Task Management


Quality Event Management

Quality Event Management

Audit Management

Audit Management

Audit Management

Audit Management

GMP Group

GCP Group





Quality Events

Event Analyzer

Tracking & Trending

Rules Audit

Finding (Requires a SOP Change)

Change Control

Implementation Project Plan

Training Control Collaboration

Deviations Complaints NCMR RMA Others…

Quality Events Monitoring Audit Change

Control Training

Exams

Course Management

Training Delivery TT

Projects

Docs

Quality Events

alityents

Training

Audit

System monitoring and control

TRACK 2D

FUTURE QUALITY SYSTEM

AND PROCESS ANALYTIC

QUALITY BY DESIGN (QBD) AND

PROCESS ANALYTICAL

TECHNOLOGY (PAT)

Friday 19 July 2013

SPEAKER PROFILE

TOPIC: QUALITY BY DESIGN (QBD) AND PROCESS ANALYTICAL TECHNOLOGY (PAT)

Bikash K Chatterjee

President & Chief Technology Officer Pharmatech Associates Inc. 22320 Foothill Blvd. Suite 330 Hayward CA 94541 U.S.A. Education - University of California, B.A. in Biochemistry - University of California, B.S. in Chemical Engineering

Mr. Chatterjee has more than 30 years’ experience in the pharmaceutical, biosciences, medical device/diagnostic and nutraceutical/dietary supplement industries. He has held senior management positions in operating companies for more than a decade and has successfully brought multiple drug and product platforms through the FDA regulated development process to market. Throughout his career he has been responsible for product development including Quality by Design, technology and process transfer and technology, process validation and established global supply chain processes in over 40 different countries around the world and been responsible for the commercialization of over a dozen products. Mr. Chatterjee sits on several scientific advisory boards for pharmaceutical and medical device companies. He is a standing member of the editorial advisory board for Pharmaceutical Manufacturing and Pharmaceutical Technology Magazines and writes a recurring column for several magazines on industry trends and challenges. He has published over 70 articles and editorials throughout his career in peer reviewed journals. Mr. Chatterjee is a Certified Lead Assessor and a Lean Six Sigma Master Black Belt. He holds a BA in Biochemistry and a BS in Chemical Engineering from the University of California at San Diego.

Applying Quality by Design to Generic Drug Manufacturing

Bikash Chatterjee President & CTO Pharmatech Associates

1

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Agenda• What is QbD?• Why it has become important • What companies need to know, overview• How to set up a team to develop QbD• Process understanding• Knowledge space• Design space• Required statistical processes• Practical application of the ideas-Case Study• Review of past records to determine CPP-Case Study• Development of acceptable operation range• Benefits• Cost savings

3

QbD’s Proposition• QbD concerns the making of drug substances and drug products• QbD is the new pharmaceutical quality system that:

• Replaces current GMP concepts• Does not depend on the trial and error approach of drug

substance and drug product development & production• Is a systemic, knowledge and risk-based quality methodology • Complies with the general purpose of product quality: the

product is suitable for use • Patient driven philosophy• A quality system customized for pharmaceuticals

•QbD is GMP for the 21st century

4

What is Quality by Design (QbD)?

• First introduced in 1985 by Dr. Juran

• Juran said most quality problems are designed into the process. A clear plan is needed to identify and eliminate these issues

• No single definition…

5

a systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk

ICH Q8 Definition of QbD

6

Another Way of Thinking about QbD

Once a system has been tested to the extent that the test results are predictable, further testing can be replaced by establishing that the system was operating within a defined design space.

7

Understanding what factors have an impact on variation in your process and also on your product’s performance; then establishing a control plan tomonitor and maintain product quality

My definition of QbD

8

Elements of Quality by Design (QbD)

•• •

• ••

GMPsGMPs

EUUSFDAPIC/S

ICHQ8,Q9Q10Q11

GMPsEU

USFDAPIC/S

Risk

QualityTargetProductProfileCTPP

CriticalQualityAttributesCQAs

QbD

CriticalProcessParametersCPPs

ControlStrategy

DesignSpace

9

Quality by Design Stages

QbD

Quality PlanningQuality Target Product Profile (QTPP)Quality Critical Attributes (QCAs)

Quality ControlCritical Process Parameters (CPPs)Control Strategy

Quality ImprovementProcess ControlProcess Monitoring

Quality Planning

Quality Improvement

Quality Control

10

What is Quality by Design (QbD)?

Pharma s version of Juran s Model

ProcessControl Features

Product Development

QTPPCQAsInputs

Process

Outputs

QbD

Implem

entation

11

Sources of VariationManagement Man Method

Cause Cause Cause

Cause

Cause

Cause

Cause

Cause

Cause

Effect(Y)

Cause

Cause

Cause

Cause Cause

Cause

Cause Cause Cause

Measurement Machine Material

12

Agenda• What is QbD?• Why QbD has become important • What companies need to know, overview• How to set up a team to develop QbD• Process understanding• Knowledge space• Design space• Required statistical processes• Practical application of the ideas-Case Study• Review of past records to determine CPP- Case Study• Development of acceptable operation range• Benefits• Cost savings

13

Business Dynamics

14

Why Has QbD Become Important?• Business Drivers

o New market opportunities

o Improved market competitiveness

o Improved profitability

o Reduced product risk exposure

15

QbD

Three Areas of Improvement...

• Better

• Faster

• Cheaper

• Quality

• Time/Flow

• Waste/Costs

16

Drive Financial Performance

Increase Revenue: Grow the Business• Improve customer satisfaction, sales, throughput, and

competitive position

Decrease the Cost of Goods Sold• Reduce process variation and defects, improve yield

• Identify and eliminate root causes of problems

• Develop systems robust to problems

• Reduce unnecessary costs and excessive cycle time

17

QbD is a Better Business Model• R&D drives new innovative products• Do we really need QbD? The conservative criticism

• “All the billions of dollars poured into research and development in the U.S. won’t mean a thing. We must streamline and strengthen the regulatory science”

• Areas cited where this is being accomplished include FDA’s partnership with ICH around Quality by Design (QbD)

New FDA commissioner Margaret Hamburg’s keynote address at Regulatory Affairs Professionals Society annual conference in Philadelphia, September 2009

Conclusion: QbD is a way to innovate within the pharmaceutical industry

18

Regulatory Drivers for QbD

Escalating and non-uniform compliance expectations:

- ASEAN Harmonization Activities

- ICH, PIC/S, EU, CFDA (China), MHLW (Japan), CDSCO (India), MOH (Malaysia), FDA Thailand, NA-DFC (Indonesia)

19

US/EU/PIC/S QbD Regulatory Timeline

ASEAN Harmonization Milestones

• A-CTD Implemented• A-CTR & technical guidelines established (maintenance and

enhancement of common interpretation ongoing)• Post-Market Alert System established• GMP Inspection MRA finalized• Training identified• Pan-ASEAN registration

1999 2002 2005 2006 2009

PPWG IWG GMPMRATF

BA/BETF

A-CTDImplementation

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Regulatory Drivers-ICH Q8, 9, 10, 11

ICH Q8, Q9, Q10 & Q11are designed as separate but linked in a series of documents exploring pharmaceutical products lifecycle (www.ich.org)

• ICH Q8 - Pharmaceutical Development • ICH Q9 - Quality Risk Management • ICH Q10 - Pharmaceutical Quality System • ICH Q11 - Development and Manufacture of Drug

Substances

22

Agenda• What is QbD?• Why it has become important• What companies need to know, overview• How to set up a team to develop QbD• Process understanding• Knowledge space• Design space• Practical application of the ideas-Case Study• Review of past records to determine CPP-Case Study • Required statistical processes• Development of acceptable operation range• Benefits• Cost savings

23

Is QbD a Shift in Quality Philosophy?You can’t test quality into drug products” has

been heard for decades – so what s new?• Quality is based on process and product

understanding, not just test results• It’s a shift in culture: incorporates quality principles

and strong compliance function• Incorporates risk assessment and management• Refocuses attention and resources on what’s

important to the customer, i.e. the patients, health professionals, payors and distribution chain

24

QbD is a Commitment to Improve• Continuous improvement is a key element of QbD

- G. Taguchi on Robust Design: Design changes during manufacture can result in the last product produced being different from the first product

• However, in pharmaceutical manufacturing, we want improvement that improves consistency–patients and physicians must count on each batch of drug working just like the batches that came before

25

QbD for Generic Drugs

In generic pharmaceutical manufacturing, there are additional constraints:

• Fixed bioequivalence targets

• Regulatory requirements to duplicate formulation of innovator drug

• Lack of access to innovator development data

26

The Changing Regulatory Compliance Environment

Quality by Design

• Adequate resources for quality: number, qualifications, etc.

• Self-assessments play key role

• Continuous analysis & improvement

• Change management based on good science

• Focus on what’s important (risk management)

Current Regulatory Situation: US/EU

• Little guidance on adequate resources or qualifications

• Self-assessments not trusted• Annual product reviews instead

of continuous analysis• Formidable barriers to change,

including intimidating enforcement emphasis

• Seldom admit that anything is not important; test everything

27

Quality by Design (QbD) CharacteristicsBasics: • Uses systemic (multivariate statistics) development and

manufacturing by use of prior knowledge• Risk assessment guided design and process control• Applies to the total life cycle of a product (continuous

improvement)

Implications:• Quality back to the roots: product suited for its purpose• Quality is dynamic: continuous improvement• Quality must be built in• Quality means first time right

28

The QbD Development Model is Different

•

Patient Idea Design Space Control Strategy Risk Assessment Product Life Cycle

Idea Development Preclinical & Licensing Manufacturing Marketing/

Clinical Testing Sales

Traditional

QdB In the QbD Development Concept The Chain is Reversed

29

QbD Will Require Enhanced Supplier Management

• Why?You will need to measure and control the important characteristics of your raw materials and API

• Clearly defined supplier quality and supply agreements are necessary

30

Agenda• What is QbD?• Why it has become important • What companies need to know, overview• How to set up a team to develop QbD• Process understanding• Knowledge space• Design space• Required statistical processes• Practical application of the ideas• Review of past records to determine CPP • Development of acceptable operation range• Benefits• Cost savings

31

Building a QbD Organization

• Starts in product development

• Multidisciplinary team representing the product development lifecycle

• Presents opportunities to build in existing commercial experience into the product and process design phase

• Presents the opportunity to not repeat mistakes in formulation and product design

32

Team Structure

QbDCore Team

R&D & Marketing

Corporateand Mfg.

Engineering

Technical Services

Regulatory and QA

Compliance

Facilities/GC

Validation

Oversight Committee

33

QbD Core Team• Program Manager• Decision makers from all

six areas• Clear mandate to deliver

product. In the US FDA market measured by being the First to File

QbDCore Team

34

Team Chartering Process

Define and Identify:• Success metrics for the project• Timeline• Budgetary and cost tracking assumptions• Key stakeholders• Project champion and project milestones• Extended Chartering to discussion of communication, review

and issue resolution mechanism• Also established initial team rules: what behaviors would be

encouraged and what would not be encouraged

35

Managing Team Dynamics

TeamCharter

Structure

Systems

Staff

Strategy

Skills Style

Knowledge Management

ProductSelection

Development And

Characterization

Site Selection/Process Design/Tech Transfer

Reg.Filing

Process Understanding Process Predictability Measurement

ContinuousMonitoring

Phase 1 Phase 2 Phase 3 Phase 4 Phase 5

Key Activity

• QTPP• Strategic

Analysis• Site

Capability Analysis

• ProjectTimeline

• Risk Analysis

KeyActivity

• Platform Knowledge

• Identify CPP• MSA• CMA Risk

Analysis• Process Risk

Analysis• Commercial

Factors

Go/N

oGo

Go/N

oGo

Go/N

oGo

KeyActivity

• Site Suitability• Mapping CPP• MSA• Process Risk

Analysis• Confirmation

Process • DOE • Process

Validation

Key Activity• Filing

Prep.

Key Activity

• Metrics Review

A Generic Drug QbD Framework

Go/N

oGo

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Agenda• What is QbD?• Why it has become important • What companies need to know, overview• How to set up a team to develop QbD• Process understanding• Knowledge space• Design space• Required statistical processes• Practical application of the ideas-Case Study• Review of past records to determine CPP-Case Study• Development of acceptable operation range• Benefits• Cost savings

Reducing Variation by Robust Design (QbD)

By Robust Process Design ...

By tighter controls of the inputs ...

Input

Proc

ess

"Y"

Traditional Method of Reducing Variation Alternate Method of Reducing Variation

•TransferRelationship

•$ $ $

38

39

Effect of Design on the Product Development Life Cycle

Design Produce/Build Deliver Service Support

Cost &Time vs. Impact

Potential is PositiveImpact >Cost and Time

Impact< Cost &Time

40

Scope of Recent Guidances

ProductDesign ManufacturingProcess

Design

ProcessMonitoring

/ContinuousVerification

ICH Q8/Q8(R) - Pharmaceutical DevelopmentICH Q11 Development and Mfg. of Drug Substances

PAT Guidance

ICH Q9 – Quality Risk Management

FDA Guidance on Quality Systems (9/06)FDA Process Validation GuidanceICH Q10 – Pharmaceutical Quality Systems

41

ICH Q8- Pharmaceutical Development

• Introduces the concept of pharmaceutical Quality by Design

• Defines QbD as:

A systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science andquality risk management.

42

ICH Q8 Concept of QbD

Process Understanding

• Process Parameters• Process Controls

43

Designing a Robust Process

Problems detected after they

occur, throughproduct testing and

inspection

Reproducible process within

narrow operatingranges

Robust & reproducible

process

Low High

Low

High

PROCESS UNDERSTANDINGPR

OCE

SSCO

NTR

OL

High potential for failures

44

Role of Quality Risk Management inDevelopment & Manufacturing

ManufacturingImplementation

Process Scale-up & Tech Transfer

Risk Management

ProcessDevelopment

ProductDevelopment

Product qualitycontrol strategy

RiskControl

RiskAssessment

Processdesign space

ProcessUnderstanding

Excipient & drug substance

design space

Product/priorKnowledge

RiskAssessment

Continualimprovement

ProcessHistory

RiskReview

44

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Define desired product performance

upfront;identify product CQAs

Design formulation and process to meet product CQAs

Understand impact of material attributes and process parameters on

product CQAs

Identify and control sources of variability

in material and process

Continually monitor and update

process to assure consistent quality

Risk assessment and risk control

Product & process design and development

Qualityby

Design

The FDA QbD Model

46

Process Step Analysis

For product and process:

- Risk assessment- Design of experiments- Design space definition- Control strategy- Batch release

CRM DOEs Design Space

Control Strategy

Batch Release

47

Adding the QbD Framework

CMA DOEs Design Space

Control Strategy

Batch Release

QTPP/ CQAs CPPs

Quality Risk Management

48

Quality Target Product Profile (QTPP)

“A prospective summary of the quality characteristics of a drug product that ideally will be achieved to ensure the desired quality, taking into account safety and efficacy of the drug product”

• Defines the product development requirements. Used to be called the product Requirement Specification (PRS)

• ICH Q8 Definition is:

49

QTTP- PRS Example

Dosage form and strengthImmediate release tablet taken orally containing 30 mg of active ingredient

Specifications to assure safety and efficacy during shelf-life

Assay, Uniformity of Dosage Unit (content uniformity) and dissolution

Description and hardness Robust tablet able to withstand transport and handling.

Appearance

Film-coated tablet with a suitable size to aid patient acceptability and compliance

Total tablet weight containing 30 mg of active ingredient is 100 mg with a diameter of 6 mm

50

QTTP- Safety and Efficacy ExampleTablet Product Requirements Critical to Quality

Attributes (CQA)Dose 30 mg Identity, assay and

CUMarketing Taste masking, coated

tablet, suitable for global market

Size, Appearance, Potency

Safety- Purity Impurities and degradation products meet ICH guideline

API impurities and degradation products <1%, residual Solvents

Efficacy-API PSD* Drug bioavailable with PSD that meet mfg needs

Dissolution >60% 1 hour per USP 711

Shelf Life 2 years and meets ICH guidelines

Primary packaging oxygen barrier required for shelf life

*PSD: Particle Size Distribution

51

Risk Analysis

• It doesn’t need to be complex• High, medium and low risk ratings are

acceptable• Anything with a high rating should be

justified• Apply the risk analysis to the product

design (formulation) and the process design activity at the outset

52

Example Product Risk AnalysisCQA Microcrystalline

cellulosePovidone Mg. Stearate API

Appearance Low Low Low LowAssay Low Low Low HighContentUniformity Low Low Medium High

Dissolution Low Medium Medium HighHardness Medium Low Low LowJustification PSD critical to

solubility of drug. Low loaded dose can affect CU

53

Process Unit Operation Risk Assessment

CQA Process StepsGranulation Drying Milling Blending Compression Coating

Appearance Low Low Low Low Medium HighAssay Low Low Low Medium Low Low Impurity Low Low Low Low Low Low BlendUniformity

Low Low Medium High High Low

Drug Release Low Low Low Medium Medium HighParticle Size Distribution

Medium Low High Low Low Low

Justificationsfor High Rating

N/A N/A

Milling screen size and speed can affect the PSD and therefore the powder flow and tablet fill weight control

Blending can affect blend uniformity, assay, and drug release profile

Compression can affect drug uniformity in the tablet based upon particle size variability and flow

The final appearance and drug release rate are affected by the coating quality and reproducibility

54

Risk Analysis

• Important to go back to the risk assessments at the end of the process development activity and finalize the risk assessment based upon real data

55

Agenda• What is QbD?• Why it has become important? • What companies need to know, overview• How to set up a team to develop QbD• Process understanding• Knowledge space• Design space• Required Statistical processes• Development of acceptable operation range• Practical application of the ideas-Case Study• Review of past records to determine CPP-Case Study• Benefits• Cost savings

56

The QbD Framework for Process Space

57

Knowledge Space

The potential range of limits for all parameters controlled or measured during the process characterization process

58

Knowledge Space Determination

• Determine which parameters have an impact on the products performance

• Requires establishing a range for each parameter to evaluate for each unit operation

• Pharma has historically used One-Factor-At-A-Time (OFAT) to do this but this is not adequate today

59

Design of Experiments (DOEs)• An approach which allows us to

understand the contribution to variation of a parameter(s) upon a known response variable

• Establish a mathematical model which describes the impact of each variable controlled on the dependent variable of interest

• OFAT studies cannot do this

60

DOE vs. OFAT• DOEs allow you to understand the

process behavior in a very few studies

• DOEs allows the experimenter to apply statistics to back-up their conclusion

• The only way to have confidence your conclusion is correct

61

Experimental VariabilityAny experiment is likely to involve three kinds of variability:• Planned, systematic variability This type of variability we want

since it includes the differences due to the treatments

• Chance-like variability This type of variability our probability models allow us to live with. We can estimate the size of this variability if we plan our experiment correctly

• Unplanned, systematic variability This type of variability threatens disaster! We deal with this variability in two ways, by randomization and by blocking. Randomization turns unplanned, systematic variation into planned, chance-like variation, while blocking turns unplanned, systematic variation into planned, systematic variation

The management of these three sources of variation is the essence of experimental design.

Taken from In Introduction to the Design and Analysis of Experiments, George Cobb (1998)

62

Things to Consider

• Sample size• Sampling Plan• Additional characterization tests, e.g,

powder flowability, bulk/tapped density, PSD- d10, d50 an d90, intermediate dissolution time points

• Acceptance criteria. Specifications are not always fully descriptive

63

High Level Map of Experiments

Screening Designs

CharacterizationStudies

OptimizationStudies

One Factor at a timeFractional Factorials

Full Factorials

Response Surface Methods

64

Knowledge Space Output

• Will reduce the number of variables that matter in terms of product performance

• Will define the broad limits of the knowledge space which will be used to drive the Design Space

65

Example DOE - Compression

• Examine the impact of Turret Speed (rpm) and Compression Force (N) on Tablet Hardness and Tablet Dissolution

• Turret Speed: 15-30 rom• Compression Force : 10-20 kN• So we have 2 factors each with 2

levels

66

Example DOE - CompressionTurret Speed Compression Force Tablet Hardness 4 Hr Dissolution

(rpm) (kN) (kP) (%)30 20 11 7615 20 13 7930 20 12 7830 10 11 7215 10 10 7630 10 9 7415 10 10 7715 20 15 71

Does Turret Speed matter?Does Compression Forces matter?

67

Example DOE- Compression ANOVADo these variables have an impact on tablet hardness? = 0.05

Estimated Effects and Coefficients for Tablet Hardness (coded units)

Term Effect Coef SE Coef T PConstant 11.3750 0.3750 30.33 0.000Turret Speed -1.2500 -0.6250 0.3750 -1.67 0.171Compression Force 2.7500 1.3750 0.3750 3.67 0.021Turret Speed*Compression Force

-1.2500 -0.6250 0.3750 -1.67 0.171

S = 1.06066 PRESS = 18R-Sq = 82.61% R-Sq(pred) = 30.43% R-Sq(adj) = 69.57%

Yes!

68

Example DOE- Compression ANOVADo these variables have an impact on tablet dissolution? = 0.05

Estimated Effects and Coefficients for 4 Hr Dissolution (coded units)

Term Effect Coef SE Coef T PConstant 75.3750 1.068 70.58 0.000Turret Speed -0.7500 -0.3750 1.068 -0.35 0.743Compression Force 1.2500 0.6250 1.068 0.59 0.590Turret Speed*Compression Force

2.7500 1.3750 1.068 1.29 0.267

S = 3.02076 PRESS = 146R-Sq = 34.68% R-Sq(pred) = 0.00% R-Sq(adj) = 0.00%

69

What if I am Not Strong In Statistics?

The Pareto Chart provides the same answer

70

Agenda• What is QbD?• Why it has become important? • What companies need to know, overview• How to set up a team to develop QbD• Process understanding• Knowledge space• Design space• Required Statistical processes• Development of acceptable operation range• Practical application of the ideas- Case Study• Review of past records to determine CPP-Case Study• Benefits• Cost savings

71

Design Space

72

Look Only at the Parameters that Affect the Drugs Performance

• In our example Compression force affected tablet hardness which was a drug release criteria

• Narrow the range to be evaluated and this becomes your new Design Space limits for this variable, e.g. conform the contribution from 12-18 kN

73

Agenda• What is QbD?• Why it has become important? • What companies need to know, overview• How to set up a team to develop QbD• Process understanding• Knowledge space• Design space• Required Statistical Processes• Development of acceptable operation range• Practical application of the ideas- Case Study• Review of past records to determine CPP-Case Study• Benefits• Cost savings

74

Statistical Testing

• The purpose of applying statistical tests is to compensate for the fact that we cannot test every unit we make

• So we make a guess ,i.e. a hypothesis of whether, within a predefined level of error, our decisions are correct

75

What is a Test of Hypothesis?

• A statistical test designed to answer a question, or allow one to choose between two or more alternatives:

• Is material A better than material B?

• Does the new process have a larger yield over the our older process?

• Does this lot meet our specifications?

• Tests of hypothesis provide a structure for learning

• Properly handle uncertainty

• Minimize subjectivity

• Question assumptions

• Prevent the omission of important information

• Manage the risk of decision errors

Hypothesis testing concepts allow us to.....?

76

77

Ho: Parameter or Measure = a value, or is trueHA: Parameter or Measure {< or > } a value, false

= a low probability typically of 1%, 5%, or 10%

• The hypothesis of equality,or that condition that is considered true is typically called the Null Hypothesis

• The hypothesis of non-equality is called the Alternate Hypothesis

• All hypothesis' include a level of significance, , which is the risk of incorrectly rejecting a true Null Hypothesis

Hypothesis Test Configuration

78

Fundamentals of Hypothesis Testing

• Based on existing knowledge, we form a hypothesis to explain something about the unknown observation

• Frequently, the hypothesis is the opposite of what we hope to show

• Collect data to evaluate the null hypothesis • Assume the null hypothesis is true (favored hypothesis)

• Seek compelling evidence in the data to support or contradict that hypothesis

• If the null hypothesis is contradicted we reject the null hypothesis and accept the alternative hypothesis

79

Hypothesis and Decision Risk• When testing a hypothesis, we do so with a known

degree of risk and confidence• We must specify in advance:

• Magnitude of acceptable decision risk • Test sensitivity

• These provide the necessary information to determine an appropriate sample size

• Consider practical limitations of cost, time, and available resources to arrive at a rational sampling plan

• We can never acheive absolute certainty

TheTruth

The Decision Errors

Your Decision

Ho is True

Ho is False

Type IError

Risk)

Type II Error

Risk)

Correctdecision

Correctdecision

Reject HoDo not reject Ho

Keller and Warrack, Statistics for Management and Economics

80

Alarm’s Decision

Nothing In Bag

TheTruth

Nothing In Bag

Weapon In Bag

Type IError

Risk)

Type II Error

Risk)

Correct

Correct

Weapon In Bag

Consequences: _____________

Consequences:__________________________

Example: Airport Security

81

82

• Sampling from a distribution must be representative or independent• Random sampling is the key assumption• Often Normality is the key assumption• The random sampling assumption is also

known as the statistical independence assumption

• A plot of the data in time order should not show any trends

• Check by finding out how the samples were chosen and tested

Hypothesis Testing – Assumptions

83

Hypothesis Testing – Common Tests• 1 sample t-test (compares sample mean to a value)

• 2 sample t-test (compares one sample mean to another)

• 1 way analysis of variance (ANOVA) (compares more than two sample means)

• Correlation and Regression Analysis (compares paired data to a linear model)

• Design of Experiments(compares the effects of factors on the process output)

• Chi square test for independence (compares multiple proportions)

84

Hypothesis Testing –Procedure

The Test is on Populations, NOT Samples…

1. Write the null hypothesis

2. Write the alternate hypothesis

3. Decide on the p value

4. Choose hypothesis test

5. Gather evidence and test/conduct analysis

6. Reject H0 /not reject H0 and draw conclusion

H0 : x Sample A = x Sample B (e.g. new way is the same as the old way)

HA : There is a difference between Samples A and B

p = .05 (typical for characterization projects)

Choose the correct test, given the type of X and Ydata (in this example, a t-test)

Collect data, run analysis, get p value

If p >.05 conclude that your data does not show a significant difference between samplesIf p<.05 conclude the samples are different

Steps •Example (2 Samples)

• Key Question: Do you have sufficient evidence to reject the Ho ?

• The p-value is the most common way to evaluate the results of your test

• Common ways to remember what the p-value means:

If p is low, Ho must go!

or

If the p is high keep the guy!

Making Decisions with Hypothesis Tests

85

86

For most cases we will use .05

How Low Must the p-value Be?

• We would like there to be less than a 10% chance of falsely rejecting Ho ( = .10)

• 5% is much more comfortable ( = .05)

• 1% feels very good ( = .01)

• This alpha level is based on our assumption of “no difference” and a reference distribution of some sort

• But, it depends on interests and consequences

P-value is required to reject Ho

87

Data Types

• Discrete• Counts of discrete events (1, 2, 3, …

defects)• Qualitative descriptions

• Good / Bad • Supplier 1, Supplier 2, …• Method A, Method B, …

• Continuous• Decimal sub-divisions are meaningful

• Time, money, etc.

88

Hypothesis Testing Roadmap

• Different statistical tools apply to different types of input and output data combinations

• Minitab supports all these combinations• Structured approach to choosing the right

analysis method

“If the only tool you have is a hammer...every problem looks like a nail” - Abraham Maslow

Testing Rubric

X DataSingle X Multiple Xs

Sing

le Y

X DataDiscrete Continuous

Y D

ata D

iscr

ete

Con

tinuo

us

•Chi-Square•Logistic

•Regression

•ANOVA

•T-test •Regression

X DataDiscrete Continuous

Y D

ata D

iscr

ete

Con

tinuo

us

•Multiple

•Regression

•Logistic•Regression

•Multiple

•Medians Tests

•2, 3, 4+ way•ANOVA

•Logistic•Regression

•Multiple

89

90

Sampling Strategy

91

Sampling Strategy

• Commonly Overlooked in terms of its importance in establishing process understanding

• If you do not have confidence your sample is representative of your true process population you cannot be sure your conclusions are correct

92

Terms: Additional Definitions

• Sample: A subset of a population. For us this is the data we collect

• Population: Not the same as “sample”, rather this is the data we would have collected if you had repeated the experiment an infinite number of times

93

Terms: Additional Definitions• Acceptance Sampling:

Form of inspection applied to lots or batches of items before or after a process, to judge conformance with predetermined standards

• Sampling Plans: Plans that specify lot size, sample size, number of samples, and acceptance/rejection criteria• Single-sampling• Double-sampling• Multiple-sampling

94

Sampling Myths• Sampling plans can make a bad process better

• A stringent sampling plan ensures only good product goes out the door

• My sampling plan justifies my quality decision for my production lots

Sampling plans have no impact on process capability and are not a surrogate for process improvement

No. The only way to ensure 100% good product goes out the door isto make 100% good product

No. Your sampling plan can only extrapolate the behavior of the population from which it was sampled. You must use scientific inference to apply this to other lots

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When to Use Sampling

• Product Development: Demonstrating product performance

• Process Development: Understanding process behavior• Process Optimization: Improving process behavior• Quality Control: Verifying incoming raw materials,

API, components and product release testing

• Stability: Product Expiration testing• In-Process Testing: Establishing an effective control

strategy

96

Operating Characteristic Curves

97

Acceptance Sampling

• Modern acceptance sampling involves a system of principles and methods. Their purpose is to develop decision rules to accept or reject product based on sample data. Factors are: • The quality requirements of the product in the

marketplace • The capability of the process • The cost and logistics of sample taking

98

Probability of Acceptance (Pa)• The primary characteristics when evaluating a

sampling plan is to understand what the probability of accepting a lot is as the percentage defects in the population changes

• The behavior the sampling plan is defined by its Operating Characteristic (OC) Curve

• All OC Curves have certain properties in common:• At 0% defective the probability of acceptance is 1• At 100% defective, the probability of acceptance is 0• As the percent defective is increased the OC curve

decreases

Operating Characteristic Curve

00.10.20.30.40.50.60.70.80.9

1

0 .05 .10 .15 .20 .25

Pro

babi

lity

of a

ccep

ting

lot

Lot quality (fraction defective)

3%

99

Decision Criteria

0

1.00

Pro

babi

lity

of a

ccep

ting

lot

Lot quality (fraction defective)

“Good”

“Bad”

Ideal

Not verydiscriminating

100

101

Sampling Terms• Acceptance Quality Level (AQL)

the percentage of defects at which consumers are willing to accept lots as “good”

• Lot Tolerance Percent Defective (LTPD)the upper limit on the percentage of defects that a consumer is willing to accept

• Consumer’s Riskthe probability that a lot contained defectives exceeding the LTPD will be accepted

• Producer’s Riskthe probability that a lot containing the acceptable quality level will be rejected

102

OC Definitions on the Curve

•Pro

babi

lity

of A

ccep

ting

Lot

Lot Quality (Fraction Defective)

100%

75%

50%

25%

.03 .06 .09

= 0.0590%

= 0.10

AQL

LTPD

Indifferent

Good Bad

Producer Risk

Consumer Risk

OC Curves can be summarized by two points:

AQL: Percent defectivewith a 95% chanceof acceptance

LTPD: Percent defectivewith a 10% chance of acceptance

103

OC CurvesP

roba

bilit

y of

Acc

epti

ng L

ot


100%

75%

50%

25%

.03 .06 .09

OC Curves come in various shapes depending on the sample size and risk of and errors

This curve is more discriminating

This curve is less discriminating

104

Pro

babi

lity

of A

ccep

ting

Lot


100%

75%

50%

25%

.03 .06 .09

This curve distinguishes perfectly between good and bad lots.

The Perfect OC Curve

What would allow you to achieve a curve like this?

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106

Acceptance Criteria

• At a minimum all process testing must meet specifications

• The specifications should be derived from the product requirements and the process’ capability

• Ideally you can steer and predict the process’ performance

107

Establishing Acceptance Criteria

• Confidence Intervals: Determines the probability that the confidence interval produced will contain the true parameter value. Common choices for the confidence level Care 0.90, 0.95, and 0.99. These levels correspond to percentages of the area of the normal density curve

• Because the normal curve is symmetric, half of the area is in the left tail of the curve, and the other half of the area is in the right tail of the curve. For a 95% confidence interval, the area in each tail is equal to 0.05/2 = 0.025.

Measures our degree of uncertainty in the population mean

108

Establishing Acceptance Criteria

• Prediction Intervals: Determines the probability interval that a single value will fall. Tends to be larger than confidence intervals.

Measures our degree of uncertainty and the variability in the distribution of the population mean is affected by sampling error.

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110

CASE STUDY

111

Case Study Framework

• This case study is a real process that has been qualified to US, EU and PIC/S standards

• Applies the principles of QbD to demonstrate process understanding and process control

112

Pharmatech’s Technology Transfer Roadmap

Point...Point...Point...Point...

PointPointPointPoint

ProductDesign

CPPs/RiskAssessment

HistoricalPerformance

EquipmentDesign

CharacterizationStudies

EstablishPAR/NOR

PPQPrerequisites

PPQ

RiskAssessmentVerification

Change Controland Stage 3

Recommendation

Pro

cess

Und

erst

andi

ng

Pro

cess

Rep

rodu

cibi

lity

ContinuousImprovement

RiskAssessmentVerification

Pro

cess

Mon

itorin

g

Pro

cess

Und

erst

andi

ng

Pro

cess

Rep

rodu

cibi

lity

Pro

cess

Mon

itorin

g

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Case Study Application

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Lexicon• Critical Process Parameter (CPP): A process parameter

whose variability, within defined limits, has an impact on a critical quality attribute and therefore should be monitored or controlled to ensure the process produces the final drug product quality

• Critical Quality Attribute (CQA): A physical, chemical or microbiological property or characteristic that should be within a predetermined range, range or distribution to ensure the desired final product drug quality

• Critical To Quality Attribute (CTQ): An in-process output parameter that is measured and/or controlled that should be within a predetermined range, range or distribution to ensure the desired final product drug quality

115

Stage 1 Process Understanding

• Product Design• Process Risk Assessment• Equipment/Process Characterization Studies

• Sampling Plans• Sampling Techniques• Method Robustness

• Design Space Establishment• Validation Master Plan

116

Product Design• Why go back to product design?

• Understand what is important: ProductRequirement Specification (PRS)

• Have solid grasp of formulation and product design rationale

• Formulation may provide insight as to which processing steps are critical downstream

• Rationale for product design helps define how the formulation, raw materials and process steps are related to achieving desired product performance

117

Key QTPP PRS SpecificationsKey criteria from the PRS include:• Greater than 50 percent Active

Pharmaceutical Ingredient (API)• Round 200 mg tablet• Coated to mask taste• 12-hour drug release with the following

specifications:• 4 hour dissolution 20-40 percent• 8 hour dissolution 65-85 percent

118

Raw Material and API Considerations

• Consider existing qualified Suppliers when choosing excipients

• Includes a review of products with similar PRS requirements

• Foundation for Knowledge Management effort

• API characterization includes Supply Chain and Quality Engineering feedback from current products

119

Tablet FormulationRaw Material %w/w Function

API 60 Active ingredientMicrocrystalline cellulose 22 Excipient fillerPovidone K 29-32 5 Granulation binderLactose 12 Excipient fillerMg Stearate 1 LubricantPurified water QS SolventCoating Solution Raw Material %w/w FunctionEudragit Coating Solution 12 Controlled release

polymerTriethyl Citrate 1 PlasticiserTalc 1.5 GlidantWater QS Solvent

120

Process Risk Assessment• Helps identify which processing steps could

affect process stability in Stage 2• Process map to capture inputs, outputs,

and control variables• Process FMEA’s to prioritize key process

steps and KPIV’s• Critical to Quality Attributes(CTQs) identified

• Helps focus characterization studies

121

Risk Assessment Process Map

• Identify formulationdriven PRS requirements

• Establish boundaries forthe process step riskassessment

• Conduct risk map• Review development data• Analyze historical

performance to setacceptance criteria

Develop Process MapIdentifyCPP/CTQ/CQAs

Development/HistoricalData Gap Analysis

• Identify controlled/uncontrolled variables

• Establish basicmeasurement approach

• Separate between scaleindependent anddependent variables

122

Process Unit Operation Risk Assessment

CQA Process StepsGranulation Drying Milling Blending Compression Coating

Appearance Low Low Low Low Medium HighAssay Low Low Low Medium Low Low Impurity Low Low Low Low Low Low BlendUniformity

Low Low Medium High High Low

Drug Release Low Low Low Medium Medium HighParticle Size Distribution

Medium Low High Low Low Low

Justificationsfor High Rating

N/A N/A

Milling screen size and speed can affect the PSD and therefore the powder flow and tablet fill weight control

Blending can affect blend uniformity, assay, and drug release profile

Compression can affect drug uniformity in the tablet based upon particle size variability and flow

The final appearance and drug release rate are affected by the coating quality and reproducibility

123

•Target Set Point

•Max Set Point Run(s)

•Min Set Point•Run(s)

•PAR•NOR

•Limit of individual•excursions

•Duration of process

•Variability of actual data•around set point

Relationship Between Proven Acceptable Range and Normal Operating Range

124

Historical Analysis

• The absence of development data establishing the PAR and NOR for the CPP can be ascertained to some extent by evaluating the historical behavior of each parameter along with the corresponding behavior of the CQAs for the unit operation

• Data should be extracted from multiple batch records to determine whether the process is stable within lot and between lots

• The team went back into the batch records of approximately 30 lots across a period of one year to extract the necessary data. This exercise also gave some indication as to whether the parameter was truly a CPP, based upon whether it had an impact on the corresponding CQA for the unit operation

• Evaluate scale independent and scale dependent parameters

125

Control Charts

126

Process Capability Analysis

127

I Chart of PSD

128

Correlation Plot

129

Equipment Design Considerations• Compare underlying equipment design and

configuration differences• Focus on impact of equipment design on scale

dependent parameters• Objective during transfer and scale-up is to

understand where equipment can affect the PAR And NOR for the transferred process

• Also consider final PV considerations such as sampling plans, sampling technique, and method robustness

130

Historical data Review Conclusion

• Dissolution testing of uncoated tablets across the process range were 100% dissolved in 3 hours

• Storage studies determined bulk granulation and uncoated tablets were sensitive to humidity

• Operating characteristic (OC) curves developed for each unit operation to understand the relationship between sampling size and sampling risk (AQL vs. LTPD)

• Highlight sampling challenges prior to design space activity

131

Tech Transfer Equipment Comparison

132

Summary of CPP/CTQ and CQAAssumptionfor Tech Transfer

Unit Operation CPP CTQ CQACompounding Mixing speed Fully Dissolved-

Visual

Water temperature Addition rate Fluid Bed Granulation/Drying

Spray Rate Granulation PSD-d10, d50, d90

Content Uniformity

Inlet Air Humidity Moisture content Potency Atomization

pressure LOD

Bulk/Tapped Bulk Density

Milling Screen size PSD Blending Mixing Speed Content

Uniformity Mixing Time Potency-Assay Compression Pre-compression

force Tablet Thickness Dissolution

profile Compression force Tablet Weight Content

Uniformity Tablet Hardness Potency-Assay Friability Coating Spray Rate Percent Weight

Gain Dissolution Percentage at 4 and 8 hours

Atomization Air Pressure

Appearance Potency-Assay

Inlet Air Temperature

133

Tech Transfer-Sampling Qualification

• Sampling Methodology QualificationGage R&R conducted with sampling equipment for each unit operation. GRR< 20%, Distinct Categories > 5

• Sampling Plan DevelopmentCould use ANSI Z1.4-2008 or Zero-Acceptance Plan. Used Power calculation, e.g. Powered at 80% with 5% as significant difference for a known SD

134

Tech Transfer Characterization Study

• Historical review concluded final product CQA for dissolution is not affected by upstream process before coating

• Confirmation DOEs are required to establish PAR and NOR upstream with a focus on process predictability

• Coating process DOE’s designed to demonstrate comparability, confirm CPP’s, and provide supportive data for PAR and NOR

• Also included commercial studies, e.g. solution hold time, pan load studies, etc.

135

Drug Dissolution Dependence on Coating Weight

136

Validation Master Plan• Summarizes the rationale for Process performance

Qualification• CPPs, CTQs and CQAs• Summarizes the impact of controlled variables• Introduces approach for understanding impact of

uncontrollable parameters• Justifies sampling plan based upon process risk• Defines acceptance criteria based upon product

CQA’s

137

Stage 2- Process Qualification

• Demonstration phase of the PV cycle• Precursors to this stage

• Facility and utilities that support the process must be in state of control

• Process equipment must be qualified (i.e. IQ, OQ, PQs are complete)

• In-process and release methods used for testing must be validated and their accuracy and precision well understood

• Cleaning validation is complete• Essential to have precursors completed to ensure

unknown variability is due to process alone

138

Stage 2 Process Qualification (cont.)• New term: Process Performance Qualification (PPQ)

• Intended to include all known variables from the manufacturing process

• Focused on demonstrating reproducibility. This drives the acceptance criteria

• Cumulative understanding of Stage 1 and Stage 2• No more three lots and we’re done• Performed as many lots needed to demonstrate a clear

understanding of variables and process is in control• Data derived from studies will be used to measure

manufacturing process in Stage 3

139

Establishing Acceptance Criteria• Based upon reproducibility criteria• For example if the Stage 1 performance for the 4 hr.

dissolution was 32% 2% against a specification of 20-40%:• Acceptance criteria could be: 95% confidence

interval applied to a spec of 32 6%• Used a 2 sided t-Test with an = 0.05 (0.025 on

the HA for < comparison)• We used the 6% because it is 3 x std. dev. In a

normal distribution this covers 99.7 of the data variability for a controlled process

140

Why Can’t I Just Compare My Result Against the Acceptance Limits?

• We did not know the true mean and standard deviation of the population That is the premise behind the t-test. If we knew it we would use the z-test

• We only knew the behavior of our sample population and we must infer that the process population behaves the same. That is why we apply the confidence interval to the assessment and apply the alternative hypothesis to test if the variability and mean is within what has historically seen

141


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Benefits• Improved new product development

capability and flexibility• Reduced quality overhead and reduced

quality issues• Greater productivity and predictability of

the process and overall business operations

• Ability to correct for process drift without impacting quality or yield

• Access to larger profitable pharmaceutical markets

143

Cost of Poor Quality (COPQ)

COPQ is derived from the non-value adding activities of waste in a process and is made up of costs associated with one of the following five categories:

1. Internal failure2. External failure3. Appraisal4. Prevention5. Lost Opportunity

•Reference; Basu and Wright, Quality Beyond Six Sigma 2003

144

COPQ Components

•Reference: Wild 2002

145

Cost Savings Examples

• Generic drug could not be made consistently. Off market for 1 year, Applying QbD principles over 6 weeks restored $200 million revenue stream

• Applying QbD to a platform drug product reduced the number of non-conformance reports by 75%saving nearly $1million/annually

146

Conclusion• The principles of Quality by Design have been

proven in multiple industries including pharmaceutical

• Pursuing Quality by Design does not require additional capital or overhead. Just good science

• The business benefits of improved control and greater productivity provide for amore stable and predictable business operation

147

Questions?

148

Thank You for Your Attention!Bikash Chatterjee, President & CTO

Pharmatech Associates, Inc.22320 Foothill Blvd. #330

Hayward CA 94541510-732-0177

[email protected]

Or visit our website at:www.pharmatechassociates.com

ISPE Thailand

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