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Welcome and opening Message Dr. Charlotte Enghave Fruergaard, Honorable speakers, Distinguished guests, ladies and gentlemen th

It gives me a great pleasure to welcome all of you to 10 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 . th

Finally, this is the time for me to declare the official opening of 10 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” th

th

Wednesday 17 - Friday 19 July 2013, Queen Sirikit National Convention Center, Bangkok , Thailand

DATE

WED 17/07/2013

PROGRAMME

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

THU 18/07/2013

PROGRAMME

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



TRACK 2B Venue: Meeting room 2 Critical Utility Design and Maintenance



Speaker: Mr. Gaston Loo, MSD Singapore



Sterile technology (Restricted Access Barrier System (RABS) and Isolator)

Key Aspects of Comprehensive Calibration and Maintenance Management System (CMMS) Implementation Speaker: Mr.Tantra Tantraporn, Grand Thornton

Speaker: Dr. Charlotte Enghave Fruergaard, NNE Pharmaplan

FRI 19/07/2013

Critical Utility Design and Maintenance

9.00 – 16.30 A Day Session TRACK 3A Venue: Meeting room 1 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 Venue: Meeting room 2 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 you can expect from ISPE

What we will expect from you

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 What you can expect from me

What you can expect from ISPE

• • • •

Global and diverse culture Leading and vibrant ISPE Learning Exchanging knowledge What we will expect from you

ISPE What you can expect from me

Bringing together the

Right People to forge the

Right Relationships Whatthewe to address expect Right R willIssues What you can expect from ISPE

from you

and a formulate the

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

YOU What you Shaping thecanindustry expect • Participatefrom me

• Engage • Involve

The more you give – What you The more youcanget expect from ISPE

What we will expect from you

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 Requirements

Higher Enforcement

Higher Transparency

Challenges “You can't stop the waves… but you can learn to surf” Jon Kabat-Zinn Professor of Medicine emeritus at University of Massachusetts Medical School

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."

Thor Heyerdahl Norwegian adventurer and explorer

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

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

Goals – Taglines Working together for a healthier world™

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 Thursday 18 July 2013

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

Establishing biomanufacturing capacity in Asia

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

1 ASEAN Life Sciences Conference & Exhibition GE Proprietary & Confidential

Agenda • GE Life Sciences

• Demand for biopharmaceuticals • KUBio™: An innovative and standardized manufacturing solution


GE THEN/NOW

SOLUTIONS

ENVIRONMENT

INNOVATION

Today

General Electric Today GE ENERGY Energy Services Oil & Gas Power & Water

HEALTHCARE

AVIATION

TRANSPORTATION

GE CAPITAL

HOME & BUSINESS SOLUTIONS, MEDIA

GE Healthcare Life Sciences Six decades supporting Biopharma 1960s Sephadex™, Sepharose™, Large scale columns

1980s

2000s

FPLC™, Sepharose Fast Flow, BioPilot™, Sepharose High Performance, Custom Designed Media (CDM)

MabSelect SuRe™, Capto™ family, BioProcess membranes, AxiChrom™ columns, ReadyToProcess™ singleuse systems

pure plasma proteins pure insulin

monoclonal antibodies recombinant insulin

biosimilars cell-based vaccines

1970s

1990s

2010s

Protein A Sepharose, Sephacryl™, Immobilized Metal Affinity, Hydrophobic Interaction

Fast Trak Services, ÄKTA™ systems family, UNICORN™ control system, SOURCE™ resins, OligoPilot™/ OligoProcess™

MabSelect SuRe LX, Capto ImpRes, Capto L, Capto Core 700, PAA cell culture media, Xcellerex™, Primer Support 5G


Across the bioprocessing spectrum…

DEMAND FOR BIOPHARMACEUTICALS 6

Biopharma market dynamics • Healthcare cost reduction • Growing disease prevalence in developing nations • Dynamic pricing & reimbursement schemes • Biosimilars regulation not Political finalized

• Aging population • Chronic disease increase

• Pandemic risks • Patient consumerism

Social

• New biopharma company strategies • Manufacturing optimization Economic

• Emerging markets • New business models

Technological • New medicines: FABs,

ADCs,…

• Manufacturing trends: higher yields, smaller batch sizes • Biobetters

Increasing demand for healthcare …. growing pressure on healthcare 7 funding…..need for cost-effective, flexible manufacturing solutions ASEAN Life Sciences Conference & Exhibition GE Proprietary & Confidential

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

900 million people in Asia to move from “poverty” to “middle class” by 2020 BREAST CANCER EPIDEMIOLOGY: Breast cancer mortality / incidence ratios (Globocan 2008)

• 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

Cell culture capacity and need

Capacity: > 100,000 L > 50,000 L > 10,000 L

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


Cell culture capacity and need

> 100,000 L > 50,000 L > 10,000 L 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 11 ASEAN Life Sciences Conference & Exhibition GE Proprietary & Confidential

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 12 ASEAN Life Sciences Conference & Exhibition GE Proprietary & Confidential

The supply of a start to finish biomanufacturing solution

Technology access

Process development

Engineering design

Manufacturing technologies & tools

Facility construction

Plant operation

Project Management

Partners 13 ASEAN Life Sciences Conference & Exhibition GE Proprietary & Confidential

The challenge: addressing the global healthcare needs

 Prevention  Cost reduction  Pandemic preparedness

 Aging population  Cost reduction  Increase access to modern therapies

 Aging population  Fast growing needs  Cost reduction

Localised production capability

• Essential biopharmaceutical • Improve access to blood protein products • Safer & optimized blood management


Life Sciences Enterprise Solutions Customized solutions

KUBioTM

FlexFactory TM

Tailored to

Standard,

Integrated,

needs

Off-the-shelf

Platform

Facility

Equipment

Services

Therapy area 15 ASEAN Life Sciences Conference & Exhibition GE Proprietary & Confidential

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™

Facility layout 1. Upstream prep 2. Upstream 3. Harvest and capture 4. Downstream purification 5. Central utilities 6. Buffer prep


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

Vial

Shake flask

WAVE BioreactorTM 20 L 100 L

Depth filtration train

Cell culture seed train

XDR™ Bioreactor 1000 L

Production bioreactor

ÄKTA ready 20 L IEC

UF /DF conditioning

ÄKTA ready 20 L IEC

Purification operations

Viral ÄKTATM ready inactivation 20 L Protein A chromatography

Harvest operations

Nano-filtration

UF/DF conditioning

Sterile filtration

Bulk formulation 22 ASEAN Life Sciences Conference & Exhibition GE Proprietary & Confidential

The KUBio™ project phases KUBio investment decision

Detailed design

Basic design

Conceptual design

Realisation

Start-up and handover

Project close-out

The conceptual design and most of the basic design is already completed at the 23 ASEAN Life Sciences Conference & Exhibition time of the investment decision GE Proprietary & Confidential

General execution timeline

Stick built, stainless steel facility Activity

36-40 months

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


Speed to Market: KUBio Execution time schedule Activity / Months

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

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

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


Maximal production capacity Over 100kg of bulk MAb/year

Product titer (g/L)

4

101-120 kg

3.5

High titre expression systems allow for high facility capacity output even for multi-product production

81-100

3 2.5

61-80

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

2

41-60

1.5 1

0-40

0.5 1

2

3

4

5

6

Number of products to be manufactured 26 ASEAN Life Sciences Conference & Exhibition GE Proprietary & Confidential

FINANCIAL MODELS 27

KUBio™/FlexFactory™ NPV Analysis* Revenue

Variable

Fixed

Profit

+20%

±10%

↓

↑

*Comparative analysis with a SS Stickbuilt facility as a basis 28 ASEAN Life Sciences Conference & Exhibition GE Proprietary & Confidential


Variable

Fixed

Profit

+20%

±10%

↓

↑

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



Variable

Fixed

Profit

+20%

±10%

↓

↑

↑ High Flexibility ↑ Multiproduct ↓ Turnaround time




Variable

Fixed

Profit

+20%

±10%

↓

↑

↑ High Flexibility ↑ Multiproduct ↓ Turnaround time


*Comparative analysis with a SS Stickbuilt facility as a basis

↓↑ 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 31 ASEAN Life Sciences Conference & Exhibition GE Proprietary & Confidential

CONCLUSION 32

Summary: global needs….global reach  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



Thank you 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


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 inhouse 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)

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

Optimal production processes DEVELOP Process & Product development

Project development

ESTABLISH Investment project CD / BD / DD / CON / C&Q

IMPROVE Optimisation, training, revamps, GAP analysis, operational support

Company revenue 2012 USD 294M EUR 224M

Agenda • • •

Market changes forcing technology changes… Aseptic/Sterile processes Technology Trends

What is OSD and Biotech? Small Molecules vs. Large Molecules Small Molecules OSD

Chemical Active Pharmaceutical Ingredient (API)

Chemical Synthesis

Large Molecules Biotech

Drying or Granulating

Biologics

Active Pharmaceutical Ingredient (API)

Inteferon molecule vs Aspirin

Fermentation or Cell Culture

“Tablets” Oral Solid Dosage Form (OSD)

Tableting

Formulation

“Injectables” Parenteral Dosage Form (aka Sterile Products)

Formulation

Aseptic Filling

Since “1899”

Packaging

Since “1982”

Packaging

Large Molecules grows faster Small Molecule drugs is the big market Shifting roles: • The shift from small to large molecules became visible in 2003

The Economist 2005

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

Manufacturing of Sterile Products API Components etc.

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

Assembly & Packaging Assembly Labelling Packaging

Logistics & Controls in Manufacturing Logistics Material Handling Inspection Controls

Filled units

Finished Products

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 (Autoclave/SIP)

121°C, minimum 15 minutes, pressure + 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

Filled and inspected Glass Glass Combi seals

Pistons

Washing

Sterilization

Filling

Product from Compounding

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) HEPA Filters

• ISO 5 (class A) surrounded by ISO 7 (class B) room 3-6" From HEPAS

• Pressure difference (15 Pa) between the clean room classes Filling • Critical operations with products are carried out Class 10,000 Class 100 open sensitive Mechanism (ISO 7) (ISO 5) under Unidirectional Airflow (class A protection)

• Manipulations (i.e. trouble shooting, change of format parts) are Vial done directly by opening of the machine cladding Nozzle

• Operator gets directly in contact with critical surfaces (class A area) Conveyor • Gowning of the operator according to class B requirements Plastic • Material curtains 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

Definitions – RABS •

PassiveBarrier System (RABS) Restricted Access HEPA Filters

Active

HVAC • Surrounding clean room class B for the filling operation 3-6" From HEPAS HEPA Filters • Pressure difference (15 Pa) between the clean room classes • All manipulations during production are done via gloves of the Filling Class 10,000 Class 100 Mechanism (ISO 7) RABS (ISO 5) Filling Class Class 100 Mechanism 10,000 (ISO 5) Nozzle designed system for the process • Ergonomic inside (Mock-up (ISO 7) Nozzle studies)Vial • Transfer of format parts via Rapid Transfer PortVial(RTP) Conveyor • Material transfer via Rapid Transfer Port (RTP) or material locks Conveyor • Gowning of the operator according class B requirements Plastic Doors with • Conventional cleaning and disinfection curtains gloves • 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)

Definitions – Isolators •

Isolators • ISO 5 (class A) inside isolator HEPA Filters • Surrounding clean room ISO 8 (class D or C) for the filling operation

• Positive pressure difference towards the filling room Class Filling 100,000 (ISO 8)

Class 100 (ISO 5)

• Ergonomic designed system for the process inside (Mock-up studies) Nozzle Mechanism

• Complete closed system Vial with Vaporized Hydrogen Peroxide (VHP) decontamination of all surfaces Conveyor Air • Complete independent Return HVAC-unit

• All manipulations during production are done via gloves Doors with 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

The Technologies RABS

Clean Room

Conventional Clean Room

• Environment: B/A • Complexity: Low

garment Aseptic quality: Low SAL~3 (*) Campaigning unusual

• •

Isolator

Closed RABS

• Environment: B • No overpressure to surroundings • Complexity: High, due to transfer •

(*) Sterility Assurance Level

Restricted Access Barrier Systems

Open RABS (active or passive)

• Comfort: Low, due to clean room • •

Barrier Systems

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

Isolator

• 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

The Technologies Clean Room


Currently most installed aseptic production lines are based on this Technology. For new projects not anymore “state-of-the-art“. (*) Sterility Assurance Level

RABS

Barrier Systems Restricted Access Barrier Systems

Open RABS (active or passive)

Closed RABS

Rather new technology, with large increase in terms of installations within the past years.

Isolator

Isolator

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

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

Realization time

Low

Medium

High

Higher productivity with campaigning

Better for isolator due to garment

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 Industry Economical

– – –

• •

Manning Risk

– –

•

Environmental –

• •

Cost Operator

– –

Less scrutiny “State of Art” Cheaper per unit produced (with comparable SAL) Less microbiological sampling/testing No scrap of product due to sterility issues or failure in Media fills Eliminating high class cleanroom environment, less space Reduction of running costs 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

Guiding rail

Fixing elements Plungers

Fixing elements

Stopper chute Stopper hopper Vacuum star wheel

Picture courtesy Belimed Sauter AG

Vacuum star wheel

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

Technology Trends Stopper treatment Lifecycle process: * Cleanroom A/B or Isolator

Receiving: Unclassified area

* Picture courtesy ATEC Steritec GmbH ** Picture courtesy GETINGE-LA CALHENE

Treatment & Transfer: Cleanroom D or C

Connection: Rapid Transfer Port

**

Technology Trends Stopper treatment Aseptic stopper transfer:

Technology Trends Sterilisation technology VHP Passbox:

Picture courtesy Metall + Plastic GmbH

Technology Trends Sterilisation technology 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

Technology Trends Sterilisation technology E-Beam:

Picture courtesy Metall + Plastic GmbH

Technology Trends Disposable Systems 6

5

3 1 1. 2. 3. 4. 5.

4

10

8

7

9

2

Coupling for bag or vessel connection Peristaltic pump when delivery container is not pressurized Bioburden sample bag Sterilizing grade product filter Vent bag

6. 7. 8. 9. 10. 11.

11

Intermediate reservoir bag Disposable manifold Peristaltic dosing pumps Beta-Bag Isolator/RABS wall towards filling Filling needles

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 Design Trends: Less important

• • • •

• Very important

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

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):

Industry Trends – Isolators Barrier Isolator Filling Line – Deliveries by Year 40

Year

Asia

Europe

N.America

Total

35

2004

42

116

90

248

30

2006

50

146

105

301

25

2008

59

196

133

388

20

2010

64

218

139

421

15 10 5

ISPE Barrier Isolation Technology Conference Brussels, September 2010 Lysfjord/Porter – Final Survey Results 2010

2011

2010

2009

2008

2007

2006

2005

2004

2003

2002

2001

2000

1999

1998

1997

1996

1995

1994

1993

1992

1991

1990

1989

1988

1985

0

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

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

Abbreviations •

CCR

•

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 Thursday 18 July 2013

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).

ASEAN Life Sciences Conference and Exhibition - 2013

CRITICAL UTILITY DESIGN AND MAINTENANCE Gaston Loo Maintenance Lead MSD SINGAPORE 1

Agenda • 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

2

Type of utilities system Critical utilities system – Gas system – Pure steam – Water system Non-critical utilities system – Chilled water – Plant steam – Instrument air – Potable water

3

Critical utilities system Definition

• 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 4

Critical utilities system

Equipment that use critical utility: – – – – – – –

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

5

Critical utilities system 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 6

Critical utilities system 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

7

Critical Utilities System Water system

Purified water system (PFW) – Generation – Storage and distribution Water For Injection (WFI) – Generation • Feed water from PFW – Storage and distribution

8

Storage and Distribution System Key components

• • • • • •

Tanks Pumps Heat exchangers Valves Sample Valves Instrumentation • What’s critical? • Location

9

PFW Generation Schematic RETURN FROM PURIFIED WATER TANK

SOFT WATER INLET

MULTIMEDIA FILTER

STORAGE TANK PUMP

CARBON FILTER

CARTRIDGE FILTERS

HEAT COOL

HEAT EXCHANGERS

HYPOCHLORITE DOSING

TO PURIFIED WATER TANK FINAL FILTER TWIN PASS REVERSE OSMOSIS UNIT

CONTINUOUS DEIONISATION UNIT

10

PFW Generation Multi-media filter

• 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.

11

PFW Generation Break tank

• 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 12

PFW Generation Activated carbon filter

The activated carbon filter removes – light weight organics – any residual chlorine Daily backwash cycle (Auto or manual)

13

PFW Generation Reverse Osmosis (RO) unit

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.

14

PFW Generation Continuous Deionisation (CDI) Unit

- 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).

15

PFW Generation Water quality

Micro-siemens/cm μS/cm@25oC 0.055

0.1

0.2

1

5

10

100

18.2

10

5

1

0.2

0.1

0.01

PFW

Mega-ohms/cm M:/cm@25oC USP 29 •Conductivity < 1.3 PS/cm at 25°C •TOC < 500ppb (0.5 mg/l)

16

PFW Generation Conductivity of different water

Pure water

Purified Drinking Brackish Sea water water water water

LOW

0.01

MEDIUM

0. 1

1.0

10

100

1000

HIGH

10000

100000

Conductivity μS/cm 100

10

1.0

0.1

0.02

0.001

0.0001 0.00001

Resistivity MΩ/cm 17

PFW Generation Final Filter

• The water is passed through 0.2 μm before entering into storage tank. • Bioburden reduction • Removal of particulate contamination down to 0.2 μm. Microbio limits: - drinking water < 500 cfu/ml - PFW < 100 cfu/ml - WFI < 10 cfu/ml

18


19

What might a regulator want? For people to understand the intent of regulations, and then implement programs to meet that intent.

20

Regulatory requirement FDA

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.”

21

Regulatory requirement 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)

operating together in parallel.

The main differences between the PIC Scheme and PIC are : PIC Scheme

PIC

Scheme

Convention

An informal arrangement Has no legal status Between Health authorities Exchange of information

A formal treaty Has legal status Between countries Mutual recognition of inspections

22

Regulatory requirement 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 23

Regulatory requirement 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

24

Regulatory requirement EMEA

EMEA reaffirms rejection of RO for WFI production in EEA 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 25

Regulatory requirement USP

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

• Specify standard for PFW and WFI Example: • Conductivity @ temperature (USP ) • TOC (USP ) • Bacteriological Purity Total Aerobic Count (CFU/Ml)

U.S. Pharmacopeia 26


27

Design approach GEP Factors

Design approach affect by following factors: Validation

Quality

Process

Feed Water Quality Critical Utility Design

Timeline

Specification

Budget Automation

Safety & Environment

28

Design principle and strategic Design and project workflow

Direct-impact systems only Quality-critical requirements only

29

User requirement specification GEP URS

• 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

30

Engineering specification Design phase

FDS - Functional Design Specification HDS - Hardware Design Specification

Vendor

SDS - Software Design Specification DQ - Design Qualification

Owner

31

Risk assessment GEP Objective

• 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

32

Risk assessment tool GEP FMEA

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

33

Risk assessment tool GEP FMEA

Example: Microbial development in the WFI storage tank

- Surface finish on tank < 20 (Ra) - Temp > 80 oC

Design specs

With rating 0-10: RPN = O X S X D = 1 X 10 X 2 = 20 (low risk) 34

FMEA form

35

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

Good Engineering Practice (GEP)

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

37

Good Engineering Practice (GEP) GEP Scope

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

38

Good Engineering Practice (GEP) 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.

39

Good Engineering Practice (GEP) Good Equipment Layout

Equipment and piping labeling

Operators review equipment layout during design stage Keep design as simple as possible

Provide good spacing for equipment

Follow process flow Ease of access for operation 40 and maintenance

Good Engineering Practice (GEP) Good Equipment Layout

System “Qualification Drawing” requirements: y show the plant layout, with service connections and, as appropriate: y All isolating-, drain-, vent-, control-valves, and items served, complete with tag numbers where used. y Any critical items, such as filters, outlets, sample points etc. y The quantity, quality and direction of flow of the working fluid. Component tagging y Main components should be tagged or labelled, to ensure that there are unique references for items to use in: y Commissioning records y Maintenance records y SOP’s 41 y Asset registers

System boundaries GEPs and EQ

Quality Critical Attributes

URS

EQ GMP GEP

Engineering Specs

Design Details

SAT / Commissioning

FAT 42

System boundaries Design criteria

- Product - Regulatory - Dosage form

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

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

Utility quality

Use point criteria

Re-evaluate system design boundaries and constraints

Detailed system design 43

System criteria

43

System boundaries Compressed air to sterile air

Galvanized piping Non critical Critical SS piping Sanitary valve Sanitary sampling point

0.2 μm sterile filter

44

Standard requirement Critical utility design

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 45

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

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

316L

SS 316L used when there is a danger of corrosion in the heat-affected zones of weldments 46

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

47

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. 48

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

49

Standard requirement Water system

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 50

Dead Leg definitions 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

L

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

D

This is the six diameter rule (6D).

51

Dead Leg guideline

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.

L D

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"

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

Case Study - Dead leg Carbon filter manifold in operation

Carbon filter tank

IN

DRAIN

OUTLET Dead leg section during normal operation

Promotes microbial growth and formation of bio-film

Affects performance of carbon filter 53

Case Study - Dead leg Carbon filter manifold during back-washing Dead leg section, collects ‘dirty’ backwash water

IN

Carbon filter tank

OUTLET

Drain 54

Case Study - Dead leg Carbon filter manifold in operation After improvement Drain

Carbon filter tank

Inlet

Outlet

Keep deadlegs between valves to minimum 55

Case Study - Dead leg Carbon filter manifold during back-washing After improvement Drain Inlet

Carbon filter tank

Outlet

Keep dead legs between valves to minimum 56


57

Maintenance challenge

• Maintenance M always link to reliability / availability – 24hrs X 365 days • Maintain the validated state • Contamination / microbial control

58

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)

59

Rouging Effect

• 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)

60

Rouging Example

• 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

61

Rouging Example

Pump volute from WFI system

Spray ball WFI storage tank

Pump impeller from WFI system 62

Rouging Example

Rouging on a PTFE tri-clamp gasket

Rouge discoloration found on a point of use 0.45 μm filter membrane 63

Rouging Example

Rouge can be wiped off and can move throughout a system. The rouge layer consists of heavy-metal-oxides, preferably FeOxides. 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

64

Rouging control Passivation

• 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

65

Before / After Derouging before Derouging

after Derouging

66

Rouging control Monitoring

• 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 67

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) 68

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

69

Filter integrity testing

Potential integrity breaches underscore the need for FIT 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)

70

Type of FIT - Water intrusion test (gas) - Forward flow (water) - Bubble point filter test

71

Water intrusion test (gas / vent) WIT

The resistance to water flow is overcome by a specific pressure

For hydrophobic gas filters

72

Forward flow (water) • 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.

73

Contaminants in water Dissolved inorganic

Dissolved organics

Micro-organisms Particulate matter 74

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

75

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.

76

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

77

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

78

Microbial Control 1. 2. 3. 4. 5.

Continuous re-circulation of water Avoid stagnant ambient temperature water Allow for drainage of pipework and storage tanks Use sanitary valves 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 79

Microbial Control 1. 2. 3. 4.

Use suitable construction materials Maintain system water temperature at > 70*C Regular sanitation or sterilization 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. 80

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

81

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 82

Microbial control Sanitization

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

83

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 84

Case study – microbial contamination 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

85

Case study – microbial contamination Cause & effect diagram High microbial counts; ≥ 500cfu/1ml specification (frequently from end Sep 12)

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

Material

Technician has been trained and experienced to operate PWF.

Man

Review log sheets and no abnormality found.

RO Pre-filter, RO membranes and final filter.

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

Good and spec ok Why? Chlorine supply low? Chlorine supply Ok and weekly sanitize CF. No Maint and breakdown works. Ruled out

Contamination of high bio film from CF and RO. Free chlorine testing procedure.

Biofilm at the pipe

TVC hit action limit at CDI outlet cfu/100ml

Facility changes if any

Environment No failures monitored & data logging for last 4 weeks are within spec. Micro passes. Ruled out

Performed as per SOP

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

SP-123: 25 RO, UV & CDI parameters out of limit

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

Method

Why? No malfunction and defects found and data logging ok. No Maint carried out.

CF, RO, UV & CDI system functionality

Training provided? Contamination of feed water supply

Machine

Why? Any cross contamination. NO-ruled out.

86

Case study – microbial contamination 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

87


88

Process Analytical Technology Definition

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 89

FDA for PAT Guideline

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 90

USP Guideline

USP Chapter 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.”

91

PAT drivers Goal: 100% understanding and control

• Improve Assurance • Improve Process Controls • Improve Understanding • Improve Quality In line sampling port WFI or PFW loop

SCADA system

TOC analyzer

92

Moving to PAT – A company effort 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

93

Moving to PAT – A company effort 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

94

PAT benefit TOC and conductivity

Lab sampling

On-line TOC analyzer

• Eliminate sampling errors • Reduced water system downtime and sanitization • Release water and product faster • Increase profits • Better control of the process • Reduce sampling cost 95

On-line TOC vs. Laboratory TOC On-line Accurate measuring low ppb No sample contamination

Laboratory LOD above most water systems Grab sample contamination

No sample handling

Sample tracking protocols

Low cost-of-ownership

High cost-of-ownership (labor intensive)

Trending information Real-time data

No trending information Delayed data

Continuous monitoring

Infrequent results

Measure in own environment Data for valuable information

96

Grab sample testing Lab sampling

• Sample cost – Materials – Time – Labor

• Laboratory analysis cost – Time – Equipment maintenance

10 Points x 1 TOC x 365 days

= 3,650 samples

10 Points x 1 conductivity x 365 days

= 3,650 samples 97

TOC / Conductivity comparison

• Off-Line Testing (TOC & Conductivity): USP and » 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

Manual and Continuous sampling Estimate of samples taken in 24 hours 250

240 200 150 Manual Continuous

100 50

10

0 Manual

Continuous

• Increased process control & improved product quality • Eliminate sampling errors • Faster product / water release • Increased profits

99

Industry direction – PAT for critical utility FDA launches Pharmaceutical cGMP’s for the 21st Century: A Risk Based Approach

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

100

Summary •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 101

Questions?

102

TRACK 2B

CRITICAL UTILITY DESIGN AND MAINTENANCE KEY ASPECTS OF COMPREHENSIVE CALIBRATION AND MAINTENANCE MANAGEMENT SYSTEM (CMMS) IMPLEMENTATION Thursday 18 July 2013

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

Grant Thornton Management Consulting Key Aspects of Comprehensive Computerized Maintenance Management Systems

July 18, 2013

2013 Grant Thornton Management Services. All rights reserved.

-1-

Key Aspects of Comprehensive Computerized Maintenance Management Systems Agenda

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 tation 6) CMMS guidance and recommendations ons


Maintenance Aspects of CMMS

Typical Reactive Maintenance Cycle

“Failure”

Maintenance Operations

Feedback

Short-term Operations Management


“Fix”

Response

Operational Information

Reactive Maintenance T0 (+) $

T1 Initial Operations

T2 T2 Equipment Failure

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

Fixed Cost

Profit / Loss

Profit

Time

$0 Fixed Cost

(-) $

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.



T2 Equipment Failure

Fixed Cost

Profit / Loss

Profit

Fixed Cost

Fixed Cost

(-) $

Fixed costs will generally remain unaffected by system failures.

Constant Revenue

Cost of Repair or Replacement Profit

Profit $0

T3

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

Time




T4 Equipment Restored

T3 Severe Equipment Failure

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

Fixed Cost

Profit / Loss

Profit

Fixed Cost

Fixed Cost

Cost of Repair or Replacement

Fixed Cost


Profit

Profit Time

$0 Fixed Cost

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.

Loss

(-) $

Reactive Maintenance Impact of Economic Downturn on Profit / Loss over Time T0 (+) $




T4 Equipment Restored Constant Revenue

Fixed Cost

Profit / Loss

Profit

Fixed Cost Cost


Fixed Fi Fix ed d Cos C Costt


Fixed Fi Fix ed d Cos C Costt

Decreasing Revenue

Profit

Profit Time

$0 Fixed Cost

Loss

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

Reactive Maintenance Impact of System Aging on Profit / Loss over Time T0 (+) $






T6 Severe Equipment Failure Constant Revenue

Fixed Cost

Profit / Loss

Profit

Fixed Cost

Fixed Cost


Fixed Cost


Profit

Fixed Cost

Fixed Cost



Maintenance Costs

Average Profitability

Profit Profit

Time

$0 Loss

Fixed Cost

Loss

(-) $

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.

Reactive Maintenance Impact of System Aging on Profit / Loss over Time T0 (+) $






T6 Severe Equipment Failure Constant Revenue

Fixed Cost

Profit / Loss

Profit

Fixed Cost


Fixed Cost


Fixed Cost

Profit

Fixed Cost

Fixed Cost



Maintenance Costs

Average Profitability

Profit Profit

Time

$0 Fixed Cost

Loss Loss

(-) $

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.

Reactive Maintenance Total Life-cycle Costs

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

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

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

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

Maintenance Costs Capital Costs

Operating Costs

Lost Production & Quality-related Costs

Typical Preventive Maintenance Cycle

Near-term Tactical Management Maintenance Planning and Management (Maintenance policies, objectives, procedures, processes) “What, Why,

How”

“What, Who, When, Where”


Maintenance Plan (What, When)

Feedback


Planned Maintenance


Maintenance History

Maintenance Audits & Performance Measurement


“How Well”

Long-term Strategic Management Corporate Planning and Management (Corporate policies, objectives, procedures, processes) “What, Why,

How”

Strategic Plan “What, Who,

When, Where”

Near-term Tactical Management Maintenance Planning and Management (Maintenance policies, objectives, procedures, processes)

“What, Why,

How”

“What, Who, When, Where”


Maintenance Plan (What, When)

Feedback


Response


Maintenance History

Maintenance Audits & Performance Measurement

“How Well”

Corporate Audits & Performance Measurement

“How Well”


Maintenance Management Preventive vs. Corrective Maintenance

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

Parts / Stock PASS

Monitor & Test Test Plans, Schedules, Work Orders & Parameters

Preventive Maintenance

Adjust “braces”

Extend Useful Life Reduce Unplanned Failures

Measure

Parts / Stock Test Results vs. Requirements & Expectations

Corrective Maintenance

Repair “fillings”

Restore Equipment Condition Restore Operational Status Reduce Downtime

Parts / Stock

FAIL

Replace “dentures” 2013 Grant Thornton Management Services. All rights reserved.

Preventive Maintenance T1 Initial Operations

T0 (+) $

T2 Perform Scheduled Maintenance Constant Revenue

Fixed Cost Variable Cost

Profit / Loss

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.

Profit

Time

$0 Fixed Cost

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. (-) $

Preventive Maintenance T1 Initial Operations

T0 (+) $

T2 Perform Scheduled Maintenance




Fixed Cost

Fixed Cost

Variable Cost

Variable Cost




Profit / Loss

Variable Cost Range

Profit

Time

$0 Fixed Cost

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

(-) $

Preventive Maintenance T0 (+) $






Fixed Cost

Fixed Cost

Fixed Cost

Fixed Cost

Fixed Cost

Variable Cost

Variable Cost

Variable Cost

Variable Cost

Profit

Profit

Profit

Profit

Profit

Profit / Loss

Variable Cost

Time

$0 Fixed 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?”

Case 1)

Sample 10-year maintenance cost profile of a typical motor Task

Reactive Maintenance (unplanned / unscheduled / corrective work)

Preventive Maintenance (planned / scheduled work)

Lubricate bearings Cleaning Repair Planning Inspection Motor rewind Lost production

$120 $0 $4,000 $0 $0 $20,000 $60,000

$0 (precision seal installed when purchased) $1,800 $240 $100 $1,800 $2,500 (including new precision seals) $0

Total Costs

$84,120

$6,440

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 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 Manage Reactive Maintenance

- Planned (preventive) maintenance - Metered maintenance - Equipment runtime - Cycle time - Unplanned (reactive) maintenance - Work requests - Routine checks - Statutory checks - Mandatory checks - Overhauls Monitor maintenance spending

Manage Preventive Maintenance

CMMS

Monitor Maintenance Spending

Manage Work Requests

Integrate Stock Control & Purchasing

- 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

Functional Aspects of CMMS Computerized Maintenance Management Systems Manage CMMS databases - Maintenance operations - Maintenance personnel - Maintenance contractors / subcontractors 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

Manage CbM

Manage Maintenance Operations

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

CMMS

Provide Reports & Statistics

Manage Assets, Plant & Equipment

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

Process Data Aspects of CMMS



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

Panel Tagged

Open Breaker

Breaker Opened

Replace Motor

Motor Replaced

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

2) How to do it (sequence)

However, it would often be useful to know more



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

Panel Tagged

Open Breaker

Breaker Opened

Replace Motor

Motor Replaced

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



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

Panel Tagged

Open Breaker

Breaker Opened

Replace Motor

Motor Replaced

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"



Controls

Input

Task

Output

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

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. 2013 Grant Thornton Management Services. All rights reserved.


Controls

Input

Task

How, Why, When

Output

What

Task

What How Long, How Often

How Long, How Often How Long, How Much

Supports (mechanisms)

Who, Where, What

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



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

Input

Prepare P.O.

Output

How, Why, When

What

Task



Supports (mechanisms)

Who, Where, What

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




Input

Prepare P.O.

Output

How, Why, When

What

What

Task

How Long, How Often


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

Who, Where, What

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




P.O. Requested

Prepare P.O.

P.O. Prepared

How, Why, When

What

Task




Who, Where, What

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. 2013 Grant Thornton Management Services. All rights reserved.



P.O. Requested

Prepare P.O.

Wait = 15 hrs

P.O. Prepared

How, Why, When

What

What

Task

How Long

How Long

Wait = 24 hrs How Long Process = 9 hrs Actual = 1 hr


Who, Where, What

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




P.O. Requested

Prepare P.O.

Wait = 15 hrs Freq = 100%

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

How, Why, When

What

Task

What How Long How Often

How Long How Often How Long

Process = 9 hrs Actual = 1 hr


Who, Where, What

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 2013 Grant Thornton Management Services. All rights reserved.



P.O. Requested

Prepare P.O.


How, Why, When

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

What

What How Long How Often

How Long How Often How Long How Much

Process = 9 hrs Actual = 1 hr B 40


Task

Who, Where, What

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.) 2013 Grant Thornton Management Services. All rights reserved.



P.O. Requested

Prepare P.O.


Engineering Spec Approval Criteria Procedure P.2.0 P.O. Approved P.O. Prepared Wait = 24 hrs Freq = 100%

Process = 9 hrs Actual = 1 hr B 40



Approve P.O. P.O.

Disapproved Process = 4 hrs Actual = 0.5 hr B 200

Wait = 17.5 hrs Freq = 15%

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

Capturing data on each task in this structured format quickly produces an integrated source of valuable process-related information. 2013 Grant Thornton Management Services. All rights reserved.


Engineering Spec Completed by 5PM Daily Approval Criteria Approved Supplier List Procedure Engineering S pecification P rocedure P.2.0 P.2.0 Engineering Specification The ability to analyze process information provides insight into P.O. P.O O. Procedure Proced dure e P.1.1 P.1.1 1 Approved A Ap ppr prove ve d utilization, capacity, workflow, redundancy, and productivity issues Wait W Wa it = 5 hrs hrs hr rs that impact the overall effectiveness of maintenance operations. Freq 85% Freq Fr q=8 5% % Prepare P repare Approve A pprove P.O. P.O. O O P.O. P.O. Requested Prepared ested P repared P.O. P.O. Wait = 15 15 hrs hrsTherefore, supplementing Wait a the t = 24 process hrs s model, information Disapproved Dissappr Split 100% S plit = 10 0% % 0 % 00 Freq = 1 100% Wait 17.5 W it = 1 Wa 7 hrs Process P Pr ocess s = 4 hrs about Process the process should also be captured within a database. hrs Proc ro ess s = 9 hr h s Actual A Ac cttu ctu ual al = 0. 0 0.5 5 hr hr B 200

Actu Ac tual al = 1 h hrr Actual B 40

Freq Frreq F eq = 15%

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


CMMS 2013 Grant Thornton Management Services. All rights reserved.


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

Process models show us ‘how’ to address various goals

Process data allow us to address ‘how well’. 2013 Grant Thornton Management Services. All rights reserved.

Process Data Aspects of CMMS The Value of Process Data

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.


Maintenance M i t Manager M Maintenance Technician Scheduler

x P

P

x

x x

x

x x

x

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

x

x

x


Maintenance M i t Manager M Maintenance Technician Scheduler Chart of Accounts Current Workload by Resource Inventory Reorder Level Maintenance Policy Maintenance Procedure Maintenance Schedule Pre-determined Maintenance Date Standard Cost List

P

P

x

x x

x x

x x

x

x

x

x

x x

x x

x x x

x x

x

x x x x x

x

x

x x x

x

x

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


Maintenance M i t Manager M Maintenance Technician Scheduler Chart of Accounts Current Workload by Resource Inventory Reorder Level Maintenance Policy Maintenance Procedure Maintenance Schedule Pre-determined Maintenance Date Standard Cost List CMMS Module - Inventory Module

P

P

x

x x

x x

x x

x

x

x

x

x x

x x

x x x

x x

x

x x

x

x x x x x

x

x

x x x

x

I

CMMS Module - Preventive Maintenance

I

CMMS Module - Purchase Order

I

CMMS Module - Report

I

CMMS Module - Work Management

I

Financial Software

I

Location: Plant Office

I

Location: Plant Spaces

I

Spare Parts

I

Tools

I

x x x x

x

x

x x x

x x x

x

x

x

x

x

x x x

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

x



P

P

x x

x x

x

x

x

x

x x

x x

x x x

x x

x

x x

x

x x x x x

x

x

x x x

x

I


I


I


I


I

Financial Software

I


I


I

Spare Parts

I

Tools Cost Allocation Screen

x

x x

x x x x

x

x

x

x x x

x x

x

x

x

x

x

x x x

x x

I

x

x

Data - Cost

x

Data - Customer

x

Work Order

x

x

x

x

x

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



P

P

x x

x x

x

x

x

x

x x

x x

x x x

x x

x

x x

x

x x x x x

x

x

x x x

x

I


I


I


I


I

Financial Software

I


I


I

Spare Parts

I


x

x x

x x x x

x

x

x

x x x

x x

x

x

x

x

x

Data - Cost

x

Data - Customer Work Order

x

x x x

x x

I

x

x

x

x

x

What does the Maintenance Technician do?

x

x



P

P

x

x x

x x

x x

x

x

x

x

x x

x x

x x x

x x

x

x x

x

x x x x x

x

x

x x x

x

I


I


I


I


I

Financial Software

I


I


I

Spare Parts

I


x x x x

x

x

x

x x x

x x

x

x

x

x

x

x x x

x x

I

x

x

Data - Cost

x

Data - Customer

x

Work Order

x

x

x

x

x

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



P

P

x x

x x

x

x

x

x

x x

x x

x x x

x x

x

x x

x

x x x x x

x

x

x x x

x

I


I


I


I


I

Financial Software

I


I


I

Spare Parts

I


x

x x

x x x x

x

x

x

x x x

x x

x

x

x

x

x

Data - Cost

x

Data - Customer Work Order

x

x x x

x x

I

x

x

x

x

x

x

x

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

Implementation Aspects of the CMMS Roadmap


CMMS Implementation Roadmap

1) Understand the Maintenance Mission

2) Understand Facility Level Maintenance Objectives

3) Understand Performance Expectations and Priorities

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

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

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



4) Translate Facility Objectives into Unit Level Objectives

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

Equipment hierarchy: Facility Unit System Component Part

5) Identify the Systems involved in satisfying each Unit Objective

6) Understand and document how those Systems satisfy Unit Objectives

e.g. Office building e.g. Potable water unit e.g. Chill water system, chemical treatment system e.g. Condenser, Return water pump e.g. Pressure seal, valve bonnet, motor bearing

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.

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



7) Develop Life Plans for each Unit

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)

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.)

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.

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 2013 Grant Thornton Management Services. All rights reserved.


9) Assess the Maintenance Organization

9a) Determine the appropriate Resource Structure

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

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

9b) Determine the appropriate Administrative 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



10) Configure and Implement the Maintenance System (CMMS)

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)


Change Aspects of CMMS Implementation


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

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.

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

“As-is” Maintenance Environment

Process Is maintenance conducted in the most productive manner possible?

Program & Controls Are maintenance issues effectively managed and controlled?

People & Organization Are maintenance resources adequately qualified and motivated?

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


Improved Maintenance Environment

The Nature of Change Problems by Level

Strategic Level Corporate Planning & Management Top management unaware of issues Maint Maintenance is not valued

Tactical Tactic Level Maintenance Planning & Management Maint Unco Uncoordinated effort Poor knowledge management

Operational Level Maintenance Operations Reactive Maintenance High inventory-related costs


The Nature of Change Suitability of Fit

New CMMS Features, Functions and Capabilities

“Ideal” Usage Existing Maintenance Organization, Processes, Systems, and Data

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. © 2012Grant Grant Thornton Management Consulting. All rights 2013 Thornton Management Services. All reserved. rights reserved.

- 54 -

The Nature of Change Suitability of Fit

New CMMS Features, Functions and Capabilities

Adopt

Adapt

Maintenance “Best Practice”

Existing Maintenance Organization, Processes, Systems, and Data

Effective CMMS change then became dependent upon the ability to e be b etwee en th tthe he ad a doption of design design features s and an nd clearly define the balance between adoption best practice scenarios s and the adaptation of existing operations. © 2012Grant Grant Thornton Management Consulting. All rights 2013 Thornton Management Services. All reserved. rights reserved.

- 55 -

CMMS Guidance and Recommendations


Maintenance Management Primary Functions and Benefits

Key Maintenance Management Functions Work Management Preventive Management Reactive Management

Purchase Order Management

Maintenance Management

Cost Accounting Report Management

Inventory Management CMMS

Avoid associating maintenance with just repairs. The value of maintenance management is increased reliability and a lower overall cost of ownership.


CMMS Selection Software Selection Criteria

General CMMS Software Selection Criteria

Multi-Tasking Capabilities

Cost Effectiveness

Integrated Functions

Graphic Capabilities

Customization Capabilities

Multi-Level, Training

Simultaneous review of data & drawings Attached pictures

"Have-to-have" CMMS Modules

"Nice-to-have" CMMS Features, Functions & Capabilities

Work Order Tracking Module

Preventive Maint. Module

Job Plan Module

Work Requests, Work Orders

Maintenance Schedules

Work Plans (Procedures)

Meets monitoring requirements

Reliability, Availability

Reference Library Links

Work Order System

Ability to access the CMMS database

Ability to attach user-defined value lists to any entry field

Ability to customize on-line

Data Quality, User-friendly

Extra tables, Reports

Schedule maintenance

SQL queries

Generate Work Orders

Standard Queries, Ad hoc Queries


Equipment Module

Contains all information about the equipment being maintained

Existing screen layouts,

Ability to add new or non-maintenance related screens

Recertification or Inspection-related

Random Notes from the Field Recommendations and Caveats

"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."


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]


- 60 -

TRACK 2C

FUTURE MANUFACTURING 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 Since 1992 1991 – 1992 1990 – 1991 1986 – 1989

1983 – 1986

Managing Director of PhC PharmaConsult Managing Director/ Partner with i+o Industrieplanung + Organisation GmbH & Co. KG, Heidelberg, Germany Head of Department of Information Systems with i+o Industrieplanung + Organisation GmbH, Heidelberg, Germany Head of Department of Industrial Planning with i+o Industrieplanung + Organisation GmbH, Heidelberg, Germany Project Manager in the Department of Material Flow and Storing Technique with i+o Industrieplanung + Organisation GmbH, Heidelberg, Germany 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

Content MKT_io-consultants_Project_Management_20130709

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

2

3

Project Structure

Project Phases MKT_Pharma_Focus_Presentation_20130709

▐ 

Project structure

▐ 

Conceptual design

▐ 

Basic/detailed design

▐ 

Supervision/handover

▐ 

Qualification/validation

▐ 

Experience

4

Project Phases

Production Support

MKT_Pharma_Focus_Presentation_20130709

5

Production support Ramp-up support

~ 12 months

Organisation

3 months

SOPs

Planning

Q +V

Organisational HR: hiring structure & training VMP Conceptu al Design

DQ

IQ

Basic Detailed Design Design

OQ

CV

PQ

Validation

Construction commissioning

Project Management

Stage I

Stage II

Stage III Production

Project Phases - Conceptual Design MKT_Pharma_Focus_Presentation_20130709

▐ 

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 %

6

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


7


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

Project Phases - Qualification / Validation 9


▐ 

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)

Project Organisation MKT_io-consultants_Project_Management_20130709

10

Steering Committee Customer

Authorities Third Parties

Project Management io-consultants

Qualification & Validation

Production Process

Logistics Process

Qualification & Validation

Production Processes

Logistics Processes

Supplier Supplier 2 1

Supplier n

Specialists Customer

Architecture & Structure

MEP and IT Services MEP and IT Services

Main Contractor

11

Targets of io-consultants project management

Steering, Clarifying, Coordinating MKT_io-consultants_Project_Management_20130709

Resources Budget Deadlines HR

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

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

Disciplines Functionality of the future facility = Quality

Logistics Production IT and Processes Construction Technique

12

Targets of io-consultants project management MKT_io-consultants_Project_Management_20130709

▐ 

▐ 

13

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

Elements of io-consultants project management MKT_io-consultants_Project_Management_20130709

▐ 

15

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

Documentation 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)


16






▐ 

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

17







▐ 

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


18






19


▐ 

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





▐ 

Structured and transparent data filing

▐ 

Clarity and simple handling

▐ 

Auditing acceptability

▐ 

Final documentation



20

21

io-consultants Project portal

io-consultants Project portal MKT_io-consultants_Project_Management_20130709

▐ 

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

22


▐ 

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

Customer Specialist 1

Project steering io-consultants Project Portal

Specialist 2

io-consultants


▐ 

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

24


25

Document Administrat.

Deadline Keeping

Modules of the Portal

Minutes Keeping

Task Administrat.



Deadline Keeping


Task Administrat.

Minutes Keeping

26


▐ 

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



Deadline Keeping


Task Administrat.

Minutes Keeping

28


▐ 

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



Deadline Keeping


Task Administrat.

Minutes Keeping

30


▐ 

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



Deadline Keeping


Task Administrat.

Minutes Keeping

32


▐ 

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

Standard Layout – Solid Dosages MKT_Pharma_Focus_Material_Flow_20130709

35

Material Flow Personnel Flow

Standard Layout – Material Flow MKT_Pharma_Focus_Material_Flow_20130709

36

Outbound Inbound Transport via to via Storage of through the wall finished truck warehouse docks tablet press primary packing central weighing granulation coating outbound area to area goods optional sampling withlock andmaterial / or bottles, (blister, bin (optional) via secondary booth wallets etc.) lock via material blender previous capsule packing filling commissioning (raw materials) (cartons, cases, pallets)

Return

Standard Layout – Personnel Flow MKT_Pharma_Focus_Material_Flow_20130709

37

Main staff Direct Access access to central to entrance secondary production admin lockers to logistics offices for packaging and prim. and production area/ or (grey) and packaging via air lock with laboratories logistics (black) area (white) personnel addtional via additional air gowning measures locks with (e.g. caps) changing procedure

Return

38

Examples

39

Success factors for a good project management

Success factors for a good project management MKT_io-consultants_Project_Management_20130709

▐ 

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

40

TRACK 2C

FUTURE MANUFACTURING 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

Planning

Approvals (pharmaceutical)

Execution Approvals (non-pharmaceutical)

Building technology

Internal

Planner

Authorities

PLANNING TEAM(S)

SCHEDULE EXAMPLE

NORMS, REGULATIONS AND REQUIREMENTS General laws + regulations

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

Labour and environmental requirements... Norms ISO, ATEX, etc...

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

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

PLANNING STEPS

Process / Equipment GMP and Hygiene Zoning Quantitative data Layout

Feasibility Concept

Basic Design

Refining of elements Calculations Functional tendering Layouts 1:100

Detail Design

Execution

Complete detailing for all disciplines Layouts 1:20, 1:50 Tendering

HOAI

PLANNING MODELS

CONVENTIONAL MODEL Feasibility Concept

Basic Design

Detail Design

Execution

IMPROVED MODEL Conceptual design

Basic Design

Detail Design

Execution

FEASIBILITY VERSUS CONCEPTUAL STUDY Feasibility

• • • • •

Conceptual Study

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

• • • • • •

•

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

PLANNING MODELS

Strong Conceptual design

Basic Design

Detail Design

Execution

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

easy Analysis

Conceptional Design with Alternatives

difficult Basic Design

Detail Design

Execution

RELATIVE COSTS OF THE DIFFERENT PHASES

100% 90% 80% 70% 60%

Factory size Factory organisation Technology GMP concept

Conceptual Design Basic Design Detail Engineering

Execution

50% 40% 30% 20% 10%

Cost saving potentials The cheapest and most promising Phase is the Conceptual Phase !

POSSIBILITIES OF COST MINIMISATION Costs saving potential

Small teams Brainstorming Alternatives New ideas

100%

80%

Factory size Factory organization Technology GMP

70%

Conceptual Design

90%

60%

Basic Design

50%

Detail Engineering

40% 30%

Execution

20% 10%

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

DETERMINATION OF COSTS in relation to the planning stage

Feasibility Conceptual design

The better the concept, the higher the precision

Cost estimation

Basic design

Cost calculation

Detail design

Tender documents Offers

Execution Supervision Documentation

Final quotations

PRICE PAID

PRECISION OF COSTS in relation to the planning stage stage Feasibility Conceptual design

Cost estimation ± 30% The better the concept, the higher the precision

Basic Design

± 20%

Detail Design

± 10%

Tender documents Offers

± 5%

Final Quotations

Execution Supervision Documentation

Cost calculation

DETERMINATION OF COSTS in relation to the planning system -

+

Feasibility Conceptual design

Turnkey price: poor control

Basic design

Detail design Execution Supervision Documentation

General planner: good control

PURPOSE OF CONCEPTUAL DESIGN GMP Considerations and Factory Planning go Hand in Hand 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

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

TARGETS OF PHARMACEUTICAL FACTORY PLANNING

- 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

HOW TO REACH A GOOD CONCEPTUAL DESIGN RESULT ? Right team Good method Right team Discipline

Good method Right team

Good data

Discipline

Some fantasy Good data

Good method Right team Discipline


Good method Right team Discipline


Good method Discipline

Some fantasy 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

PEOPLE AND PLANNING

CORE TEAM Quality Assurance Production Manager Process GMP Expert Integrated Factory Planning Experts AD HOC MEMBERS Utilities Specialist Controller Other Specialists Logistics Engineering

PEOPLE AND PLANNING Generalists

Specialists

Number of people

PLANNING

Conceptual Design

Basic Design

Detail Design

Execution

Number of people

Generalists

Specialists VALIDATION

JUDGEMENT ERRORS 100% 90%

Judgement Errors

80% 70% 60%

Large Organisations

50% 40% 30% 20% 10%

Individuals Concept Team Number of Participants

Role of participants : To plan AND to decide

PLANNING METHODS By Experimenting and Innovating By Adding Individual Functions

There are many design methods

By Cloning Existing Units

By Systematic Planning

By Turnkey Contracting

OPTIMAL PLANNING METHOD Site, Site selection Masterplan General organisation factory Departments Functional groups Equipment, single units

PLANNING FROM INSIDE TO OUTSIDE PLANNING FROM MACRO TO MICRO PLANNING FROM IDEAL TO REAL

NEED FOR FOCUSING

•  •  •  •  • 

Economy of scale Efficiency / Best practice Flexibility Performance Organisation Analysis of •  Product range •  Process •  Technologies •  Organisation

•  Requirements •  Vision of client

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

PLANNING METHOD DEVELOPMENT OF IDEAL ORGANISATION Information Analysis process

Strategy

Identification key problems

Verification process flow, material flow

Analysis Material / Information flow

Other requirements, constraints, etc. Plant strategy

Idenfication necessary infrastructure

Analysis of products and production volumes

Resulting Organisation

Definition Modules Functional units Vertical Horizontal

+ Process architecture

Combination material flows functional interdependencies

B/WOrientation of factory

Verification GMP concept

Calculation necessary space

Analysis space situation

Rough layout development

Definition of constraints, etc.

Analysis machinery / equipment Evaluation + Selection

Analysis organisation

Layout alternatives

Adaptation Process, machinery + equipment

START

END

PLANNING METHOD RATIONALISATION, INNOVATION AND OPTIMISATION Morphological Analysis + Search for Solutions Existing Technology

GMP-Concept

Technological Alternatives Degree of Automation Investment / Budget

Plant strategy

Forecasts, Quantities, Product Mix

ProjectTechnology

Capacity and Rationalisation Analysis

GMP-Concept Degree of Automation Batch Sizes Foreseen Equipment Shifts ? Product Seasonality Campaign Sizes

Batch Sizes + Process architecture

Galenical Properties

Cleaning + Change-over Times

Dimension. Machines (Type/ Quantity)

PLANNING PROCEDURE: CONCEPTUAL DESIGN 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 - Process technology - Machinery + equipment - Transport systems + containers

Definition of personnel, shifts, etc. Ideal layouts peripheral areas

Design of the ideal layouts + modules for each step

Ideal layouts personnel areas

Combination of individual layouts to functional units --> Granulation, tabletting, preparation of liquids, filling ... Design of the ideal overall total layout

Development of the masterplan for the design onthe green field

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

PLANNING PROCEDURE: CONCEPTUAL DESIGN FORECASTS

Product lists, quantities Sorting by galenical forms Sorting by types (“conventional”, toxic, hormones, betalactames, 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

SELECTION OF TECHNOLOGY AND EQUIPMENT •  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

SELECTION OF TECHNOLOGY AND EQUIPMENT •  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

SELECTION OF TECHNOLOGY AND EQUIPMENT •  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

SELECTION OF TECHNOLOGY AND EQUIPMENT •  •  •  • 

•  •  •  •  •  • 

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 needsQ U Space constraints AUTOMATION A POSSIBILITIES Previous experience, available equipment (standardization) N T GMP issues T Safety of operator I T E S

NUMBER OF PRODUCTS

SELECTION OF TECHNOLOGY AND EQUIPMENT •  •  •  •  •  •  •  •  •  • 

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 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

SELECTION OF TECHNOLOGY AND EQUIPMENT •  •  •  •  •  •  •  •  • 

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

SELECTION OF TECHNOLOGY AND EQUIPMENT MORPHOLOGICAL ANALYSIS P R O C E S S S T E P S

AAA

ABA

ACA

ADA

BBB

BAA

BAB

BAC

BAD

CCC

CAA

CAB

DDD

DAA

DAB

DAC

DAD

EEE

EAA

EAB

EAC

FFF

FAA

FAB

FAC

GGG

GAA

GAB

HHH

HAA

HAB

FAD

BAE

FAE

HAC

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, microand macro: Micro: within a department Macro: within a production unit/plant

PLANNING METHOD PROCESS FLOWCHART Granulation

Binder preparation

Drying

Sieving Addition dit lubricants Blending

Compression

PLANNING METHOD ORGANIZATION FLOWCHART Granulation G Binder nd der preparatio preparat n

Staging m2 ?

Weighing

Staging m2 ? Containerr washing

Drying

Sieving

Addition dit lubricants Blending Blend ding

Stagi Staging m2 ?

Compression

Staging m2 ?

PLANNING METHOD FLOWS PERSONNEL AND MATERIALS Exterior

Exterior

Lockers G

Lockers G

Lockers D

G

Lockers D

G

D

D Lockers C Lockers A/B

Lockers C

C Lockers A/B A/B

C A/B

Selection of alternative important, later changes practically impossible

LOGISTICS

Goods IN handling

Goods OUT handling

•  •  •  •  • 

•  •  •  • 

Cleaning Administration Sampling Palletisation Etc

Picking Commissioning Administration Etc

Production Storage activities •  Main storage •  Special storages

Exterior Clients Logistic centre

LOGISTICS Raw material Primary packaging material Secundary packaging material Finished products

pal / h

pal / h

Pharma pal / h

Booth

pal / h

packaging material

Sampling

Preparation area

pal / h

area

for raw - and primary

pal / h

Warehouse

pal / h

weighing

Receiving

Production area

pal / h pal / h

Shipping

Storage capacity: pal / h

pal / h

pal / h

Marshalling

pal / h

pal / h

Packaging

pal / h

lines

Sampling Quarantine separation

Bulk store

pallet places

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

FUTURE MANUFACTURING 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. th th 11 , 12 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 Global business imperatives Global trends and business challenges A new generation of enterprise resource planning (ERP) How Microsoft Dynamics AX can help Powerful Agile Simple Key solution advantages for Pharmaceutical Industry Questions?

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-ofbusiness (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 Applications tthat hat are an assett

Simplicity mplicity y an and agility y

Complete industryspecific solutions

Powerful embedded analytics nalytics and B BII

Manufacturing ring Distribution n Retail Services Public Sector to or

Works the way you need it to

Simple to use

Tailored to meet your needs

Get the right data to decision makers

Powerfully Simple

Powerful

Agile

Simple

Pervasive interoperability

Powerful Deliver more value faster with a single, powerful solution: Gain value quickly with purpose-built industry and operational capabilities in a single solution. on. Scale your organization quickly with a single global solution. Gain immediate insight and unlock greater eatter perience. productivity with a RoleTailored user experience. “The ability to view and apply various manufacturing f t i 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

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

• Single solution for five industries • Rich core ERP capabilities • Large partner ecosystem

ne Manufacturing

Distribution

Retail

Public Sector

Services Sector

Core ERP Suite

(Finance, HCM, Compliance Management, SRM, Environmental Sustainability, Expense Management)

Global Solution Scale your organization quickly with a single global solution.

• Prebuilt, country-specific localizations for 36 countries • Highly scalable • Shared data and unified processes across the organization

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

Agile Increase opportunities and reduce risk with an agile solution. Plan, visualize, and change your business by using unified natural models. Support your business today and tomorrow with flexible deployment alternatives.

Differentiate your business easily with model-driven layered architecture. “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 Plan, visualize, and change your business by using unified natural models.

• Easy-to-use financial dimensions • Organization model • Configurable graphical workflows • Single business process repository

Flexible Deployment Support your business today and tomorrow with flexible deployment alternatives.

• Selection of governance models • Cloud-based services • On-premises and partner hosted • Flexible solution architecture

Partner hosted

On-premises

Model-Driven, Layered Architecture Differentiate your business easily with 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

Simple Drive user involvement and innovation with an easy-to-use solution. Provide access to data and business processes with an ERP solution that is simple to use Connect employees, customers, suppliers, and partners easily through integrated collaboration capabilities Streamline IT processes by simplifying management of your ERP solution at every stage of the life cycle “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

Familiar and Intuitive Provide access to data and business processes with an ERP solution that is simple to use. Lean Kanban Boards

• Looks and works like Microsoft Office • Common UI across web browser and Windows® UI • Bidirectional integration with Microsoft Office 2010 • Enterprise Search

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

• 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

Application Life-Cycle Management Streamline IT processes by simplifying management of your ERP solution at every stage of the life cycle.

• Microsoft Dynamics ERP RapidStart Services • Highly streamlined, userfriendly installation • Simplified Role-based security setup • Accelerated upgrade through upgrade advisors and tools

Simplify

Powerfully Simple Enhanced Industry functionality Manufacturing

Distribution

Retail

Public Sector

Services Sector

Pervasive interoperability Solution investments + Related ecosystemss = Improved prov productivity and lower IT costs ts

1,000+ new features and enhancements

Powerful f l

Agile Pervasive interoperability

Simple

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

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

HCM & Payroll*

Key Investments in Horizontal Capabilities 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

Key Investments in Horizontal Capabilities 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

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 AX2012 Database

Cubes

Presentation

Role Centers R l Cente C ters ers and a d Dashboard ds ds Dashboards

AX 201 2012 12 Analytic l ti Report Reports R ts

Pre-built Prre-bu built ui + custom cube ube be es cubes MS Exce Excel el MS SharePoint

Public Sector

CEO Role Center

Q&A

TRACK 2C

FUTURE MANUFACTURING PLANT FOR MANAGEMENT LEVEL THE ROLE OF MANUFACTURING IT - 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


2

From Past to Present to Future Nokia 5100

iPhone 5

15 years rs

1998

2013


3

From Past to Present to Future Nokia 5100

iPhone 5

14 years rs

1987

2012


4

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).


5

MES – From Past to Present to Future Introduction I Werum M MES concept

MES M overview – A modular approach

M MES benefits P Past – Present – Future scenarios


6

Werum at a Glance ႛ ႛ ႛ ႛ

480+ employees Founded 1969 Constant growth Strong financials

Werum AG, Headquarters, Lueneburg, Germany

ႛ Best-in-class MES product for Pharma & Biotech Werum America Inc., Headquarters, Parsippany, NJ, USA ႛ Professional services ႛ Customer satisfaction & long term partnerships


7

Your Leading MIT Partner for Life Sciences Werum US HQ Parsippany, NJ

Werum Germany HQ, Lueneburg St. Augustin Hausach Basel

S. Francisco, CA

Cary, NC

Werum SAS Toulouse, France

Werum K.K. Tokyo, Japan

Werum Ltd. Asia Support Centre Singapore, Subsidiary Bangkok


8

Werum & PAS-X Success Stories

380

490

470

450

400

Stable Growth h per Year

Employees

2009

2010

Pharma 50%

2011

+ 15 %

2012 2013(e.)

Biotech and API 40% Others 10%

Revenue by Region

Revenue by Industry


Europe 45% USA 45%

Asia Pacific 10%

9

International Key Customers in Asia/Pacific


10





11

Producing Paper & Pharmaceuticals...

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


12

Where do we come from?

ERP

MES

Equipment


13

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


14





15

MES Overview – a modular approach by PAS-X


16

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


17

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


18

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 Audit Trail

Clear workflow guidance for shop floor operators


19

Flexible User Guidance – Mobile Workstations Portable unit from a single workstation provides full access to all processes

Source: Novartis, NJ, USA


20

EQUIPMENT MANAGEMENT

1 2 3 4 5 6 7 8 9 0 1 2 8

ႛ ႛ ႛ ႛ

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


21

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


22

Warehouse and inventory management in combination with ERP functions

MATERIAL TRACK & TRACE – WIP Material Flow Control Dispensing

Reactor

Material flow ▪ ▪

Definition of transports Controlling of transports

Source: Blend01 Dest.: Press99

Blend01

Press99

Print label

Identify label

Eliminating risk of material loss or mix-ups


23

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 Significantly improving Review-by-exception Right-First-Time Follow pre-defined release workflow


24

Electronic Compliant Batch Record


25

Integrated MES Solution – Standardizations Enterprise Level

Production Level

Equipment Level


26





27

MES Right First Time

Identifying room and reading its status from the system Source: Novartis, NJ, USA


28

Operator Guidance and Manufacturing Control


29

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


30

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

Q

Product quality

ႛ 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


31



M MES benefits Present – Future scenarios


32

PRESENT – vertical integration Æ Electronic Batch Recording (EBR) ERP Handling the batch record

Electronic Batch Recording

Field Level

Packaging

Manufacturing


33

PRESENT – product lifecycle integration Æ Manufacturing IT Business Platform Pre Clinical Phase 0

Discovery Manually or Electronic

Phase I & II & III

Process Development Library 1 EBR

1 MBR

Phase IV V Launch h Commercial

Clinical Production

Commercial Production

PAS PAS-X P AS-X X 1 MBR

n EBR

1 MBR 1 EBR

1 MBR

1 EBR

Commercial GMP Batches


34

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


35

Today – Electronic recording of shop floor operator Prepare IPC

Decision: manually executed by operator “More IPC checks?” Perform IPC Decision: automatically executed by system “End of manufacturing?”


36

Today – Process controlled by decisions


37

Today – Process controlled by signals (simple)


38

Today – Process controlled by signals (complex)


39

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 Æ MES is already relevant for those topics. Æ Customers have implemented this already. Æ This will be further developed and established in near future.


40

New Devices: Mobility on Tablets Web and Native Applications


41

Day after tomorrow – unpredictable

We will see what the future brings… A few possible scenarios


42

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) Glass,อร่say อย delicious in Thai delicious, Thai

Source: http://www.closetcooking.com


43

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.


44

The Future of MES – Vision The only place in your plant that will still need paper.


45

Thank you Florian Seitz Senior Consultant Werum Asia Support Centre


46

TRACK 2C

FUTURE MANUFACTURING PLANT FOR MANAGEMENT LEVEL THE ROLE OF MANUFACTURING IT - 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)

29%

22%

49%

• 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

United States

Europe

Asia

San Diego, CA (WWHQ) San Ramon, CA Milford, MA Boulder, CO Bedminster, NJ Bend, OR

Cambridge, UK (EHQ) Stockholm, Sweden Paris, France Basel, Switzerland Cologne, Germany

Tokyo, Japan (AHQ) Seoul, Korea Singapore India

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

3

Accelrys LIMS

The 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

Workflow Editors Create LIMS Applications Metrology/Calibration Management

Sample and Spec Management

Microbiological Environmental Monitoring

Entity or Inventory Reporting

Workflows

Accelrys LIMS Workflow Editors (drag & drop)

Scheduling

Qualification Stability Management

Work Requests

Inventory Management

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

Work Requests • 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

Inventory Management • 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 Inventory Management

Sampling Plan Creation and Scheduling

Plan Execution (“under glass”; labeling; bar code control; plan viewing)

Incubation and Micro Lab Procedure Execution

Reporting and Trending

(Instrument integration and test SOP viewing/data capture)

Review and Approval of Test Results

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.

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

• “Traditional LIMS vendors’ samplecentric 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.”

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

Accelrys LES

Accelrys Lab Execution System(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. 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 “Method under glass” with integrated direct data capture to database The method IS the GUI !!!!

Best Practice Test Methods - “Right First Time”

Data Review - Approve at-a-Glance

AT - Audit Trail

OL - Out of Limit

OD - Out of Date

An - Annotation

SD - Source Data

A/A -Attest/Approve

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

Electronic Lab Notebook ELN is the hub for data capture, calculations, data review, and approval. Provides a single work environment for lab analysts. Data from Complex

Data from Human Observations

via Data from SimpleInstruments networked PC Instruments via RS232 (UV-Vis, PDA, etc.) (pH, KF, balances, etc.)

Statistics and Analytics Programs

Process limit checking and automated compliance

Final Lab Report and COA

Chromatography Data Systems ELN pushes sample prep data to CDS pre-run. CDS output files go to ELN for post-run analysis

Supported Integrations- 3 Modes of Operation ….hundreds of validated and out-of-the-box integrations

4.210 4.210 ower I mg Empower

Empower ower II Chromeleon omeleon Chem m Station Open n Lab Easy C Chrome hrome ro osoft Excel Microsoft

Complete the Lab Picture – An Integrated Approach

Accelrys LIMS

Environmental Monitoring Work Request


Sample Management

Stability Metrology

QA/QC La Labo Laboratories bo ora cution System Lab Execution

ELN

LES Instrument Data Service (IDS)

Accelrys Confidential

Accelrys Process Management & Compliance(PMC) Suite Accelrys Discoverant Process Management Informatics (PMI) Accelrys LIMS

Environmental Monitoring Work Request

Development Labs Electronic Laboratory Notebook

ELN

Transfer


Sample Management

QA/QC C La Labo Laboratories b bo xecutio System Lab Execution

Stability Metrology

Transfer

Manufacturing Electronic Batch Records

LES

EBR

Instrument Data Service (IDS)

Accelrys Enterprise Platform (AEP) for Data Exchange Accelrys Confidential

Use Cases: What others have achieved

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

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*

Compliance Metrics Compliance Benefits Observed Deviation Rate vs Accelrys LES Usage

• 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 Figure: Significant lab deviation reductions from multiplant deployments of LES.

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

• 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

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

A Transformative Change … Innovation

Productivity, Efficiency Documentation Quality, Compliance IP Protection, Security

Collaboration

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

Thank You

Questions www.accelrys.com/pmc

TRACK 2C

FUTURE MANUFACTURING PLANT FOR MANAGEMENT LEVEL THE ROLE OF MANUFACTURING IT - 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. 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

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.

MasterControl Integrated Compliance Regulatory Re Reg egu gulato la ato a at tto ory Sub Su bm misssiion o Submission Regulatory Publishing P bl Pu Pub blish i h hing

Submission Publishing

Customers

Suppliers Su S u up ppliie pp iers

Suppliers

BOM

Guest Connect

Risk

PLM PDM Links

Audit

Documents Partners

Training

Supplier Quality Events

External Links & APIs

Projects

ERP

LIMS

MES

Global Services

Americas

EMEA

Asia

• • • •

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

DISCOVER

• Schedule System Administrator Training • Setup and Install MasterControl Test/Validation/Prod Environments • Execute Installation Qualification (IQ) • Define Customer Requirements

CONFIGURE

• Configuration of Portal, Documents, Training Modules • Test Import • Process Solution Configuration/Design • Define Key Process Workflows

Go Live

Validate Gate Review

VALIDATE

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

DEPLOY

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

eQMS across the product lifecycle Research & Development GLP

Clinical Trials GCP

Registration GxP

Technology Transfer

ManufacTuring GMP

Quality Assurance GMP

Distribution GDP

Manufacture & Distribution

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

Product Lifecycle Management

PICS Key Management Tools • Document Control • Training Management • Quality Event Management

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

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

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

Fully integrated Quality system Quality Events

Document Approvals

CAPA

Tracking & Trending

Close Incident

Exams

Quality Event

Close Incident

Customer Complaint

Risk-Based Issue Review

CAPA Not Required

Rules

Tracking & Trending

Effectiveness Checks

QEM

Course Management

Training Delivery

QMS Change Control

5 3 9 2 6 1 3 5

CAPA Required

CAPA Initiation

Investigation

Corrective Preventive Action

Release

Risk Docs cs Training Quality ality Events ents

Document ocum control of revisions and approvals Change Control

Change Control

Revision & Collaboration

Document Approvals

Revision & Collaboration

Document Approvals

Training Controls

Training Control

Close Incident

Release

Archive Course Management

Docs

Training

Example: Handling Complaints Customer Complaint

Issue Review

CAPA

Change Control

unacceptable

Risk Assessment Update Document

Training

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

GCP Group GMP Group


System monitoring and control Quality Events

Monitoring

Audit

Change Control

Training

Collaboration

Training Control Exams

Quality Events

Deviations Complaints NCMR RMA Others…

Event Analyzer

Tracking & Trending

Rules

Audit

Finding (Requires a SOP Change)

T Training Delivery

Course Management

Change Control

Implementation Project Plan

Audit

Docs

Training Quality ality Events ents

Projects

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

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

2

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 3

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…

4

ICH Q8 Definition of QbD 䇾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䇿

5

Another Way of Thinking about QbD 䇾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.䇿

6

My definition of QbD 䇾Understanding what factors have an impact on variation in your process and also on your product’s performance; then establishing a control plan to monitor and maintain product quality䇿

7

Elements of Quality by Design (QbD)

Risk

• • • • • •

GMPs EU USFDA PIC/S

ICH Q8,Q9 Q10 Q11 GMPs EU USFDA PIC/S

Critical Quality Attributes CQAs

Control Strategy

QbD

GMPs

Quality Target Product Profile CTPP

Critical Process Parameters CPPs

Design Space 8

Quality by Design Stages Quality Planning Quality Target Product Profile (QTPP) Quality Critical Attributes (QCAs)

Quality Planning

QbD Quality Improvement

Quality Control

Quality Control Critical Process Parameters (CPPs) Control Strategy Quality Improvement Process Control Process Monitoring

9

What is Quality by Design (QbD)? Pharma䇻s version of Juran䇻s Model QTPP CQAs

Process

Product Development

Outputs

Process Control Features

QbD Implementation

Inputs

10

Sources of Variation

Management

Man

Method

Cause

Cause

Cause

Cause

Cause

Cause

Cause

Cause

Cause

Effect (Y)

Cause

Cause

Cause

Cause

Cause

Cause

Cause

Measurement

Cause

Cause

Machine

Material

11

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

12

Business Dynamics

13

Why Has QbD Become Important? • Business Drivers o New market opportunities o Improved market competitiveness o Improved profitability o Reduced product risk exposure

14

Three Areas of Improvement... QbD

• Better

• Quality

• Faster

• Time/Flow

• Cheaper

• Waste/Costs 15

Drive Financial Performance Increase Revenue:䇾䇾Grow the Business䇿 • 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 16

QbD is a Better Business Model •

R&D drives new innovative products

•

Do we really need QbD? The conservative criticism

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

•

“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)

Conclusion: QbD is a way to innovate within the pharmaceutical industry 17

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)

18

US/EU/PIC/S QbD Regulatory Timeline

19

ASEAN Harmonization Milestones 1999

2002

2005

2006

PPWG

IWG

GMP MRA TF

BA/BE TF

• • • • • •

2009

A-CTD Implementation

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

20

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 21

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

22

Is QbD a Shift in Quality Philosophy? 䇾You can’t test quality into drug products” has been heard for decades – so what䇻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 23

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

24

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 25

The Changing Regulatory Compliance Environment 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

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) 26

Quality by Design (QbD) Characteristics Basics: • 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 27

The QbD Development Model is Different Traditional Idea

Development

Preclinical & Clinical Testing

QdB

Licensing

Manufacturing

Marketing/

Sales

In the QbD Development Concept The Chain is Reversed •

Patient Idea Design Space Control Strategy Risk Assessment Product Life Cycle

28

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 29

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

30

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 31

Team Structure R&D & Marketing

Corporate and Mfg. Engineering

Validation

Oversight Committee

QbD Core Team

Technical Services

Facilities/GC

Regulatory and QA Compliance

32

QbD Core Team

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 䇾First to File䇿

33

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 34

Managing Team Dynamics Structure

Strategy

Systems

Team Charter

Skills

Style

Staff 35

A Generic Drug QbD Framework Development And Characterization

Key Activity

Key Activity

• QTPP • Strategic Analysis • Site Capability Analysis • Project Timeline • Risk Analysis

• Platform Knowledge • Identify CPP • MSA • CMA Risk Analysis • Process Risk Analysis • Commercial Factors

Process Predictability Go/No Go

Product Selection

Go/NoGo

Process Understanding

Phase4

Site Selection/Process Design/Tech Transfer Key Activity • • • •

Site Suitability Mapping CPP MSA Process Risk Analysis • Confirmation Process • DOE • Process Validation

Phase5

Measurement Reg. Filing Key Activity • Filing Prep.

Go/NoGo

Phase3

Phase2

Go/NoGo

Phase1

Continuous Monitoring Key Activity

•

Metrics Review

Knowledge Management 36

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

37

Reducing Variation by Robust Design (QbD) By tighter controls of the inputs ...

Process "Y"

•Transfer Relationship

By Robust Process Design ...

•$ $ $ Input 38 Traditional Method of Reducing Variation

Alternate Method of Reducing Variation

Effect of Design on the Product Development Life Cycle Cost &Time vs. Impact

Potential is Positive Impact >Cost and Time Impact< Cost & Time

Design

Produce/Build

Deliver

Service Support 39

Scope of Recent Guidances Product Design

Process Design

Manufacturing

Process Monitoring / Continuous Verification

ICH Q8/Q8(R) - Pharmaceutical Development ICH Q11 Development and Mfg. of Drug Substances PAT Guidance ICH Q9 – Quality Risk Management FDA Guidance on Quality Systems (9/06) FDA Process Validation Guidance ICH Q10 – Pharmaceutical Quality Systems 40

ICH Q8- Pharmaceutical Development • Introduces the concept of pharmaceutical Quality by Design • Defines QbD as:

䇾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 management. 䇾 41

ICH Q8 Concept of QbD

Process Understanding • Process Parameters • Process Controls

42

Designing a Robust Process PROCESS UNDERSTANDING High

PROCESS CONTROL

Low High potential for failures Low

High

Problems detected after they occur, through product testing and inspection

Reproducible process within narrow operating ranges

Robust & reproducible process

43

Role of Quality Risk Management in Development & Manufacturing Product Development

Process Development

Process Scale-up & Tech Transfer

Product/prior Knowledge

Process Understanding

Risk Assessment

Risk Assessment

Risk Control

Process design space

Product quality control strategy

Excipient & drug substance design space

Manufacturing Implementation

Process History

Risk Management

Risk Review Continual improvement

44 44

The FDA QbD Model Product & process design and development Quality by Design

Define desired product performance upfront; identify product CQAs

Design formulation and process to meet product CQAs

Identify and control sources of variability in material and process

Understand impact of material attributes and process parameters on product CQAs

Continually monitor and update process to assure consistent quality

Risk assessment and risk control 45

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 46

Adding the QbD Framework

QTPP/ CQAs CMA

Quality Risk Management

CPPs

DOEs

Design Space

Control Strategy

Batch Release

47

Quality Target Product Profile (QTPP) • Defines the product development requirements. Used to be called the product Requirement Specification (PRS) • ICH Q8 Definition is: “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” 48

QTTP- PRS Example Immediate release tablet taken orally

Dosage form and strength containing 30 mg of active ingredient Assay, Uniformity of Dosage Unit (content Specifications to assure safety and efficacy during uniformity) and dissolution shelf-life Robust tablet able to withstand transport and

Description and hardness handling.

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

Appearance Total tablet weight containing 30 mg of active ingredient is 100 mg with a diameter of 6 mm 49

QTTP- Safety and Efficacy Example Tablet

Product Requirements

Critical to Quality Attributes (CQA)

Dose

30 mg

Identity, assay and CU

Marketing

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 60% 1 hour per USP 711

Shelf Life

Primary packaging oxygen barrier required for shelf life

2 years and meets ICH guidelines

*PSD: Particle Size Distribution

50

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 51

Example Product Risk Analysis CQA

Microcrystalline cellulose

Povidone

Mg. Stearate

API

Appearance

Low

Low

Low

Low

Assay

Low

Low

Low

High

Content Uniformity

Low

Low

Medium

High

Dissolution

Low

Medium

Medium

High

Medium

Low

Low

Low

Hardness Justification

PSD critical to solubility of drug. Low loaded dose can affect CU 52

Process Unit Operation Risk Assessment CQA Appearance Assay Impurity Blend Uniformity Drug Release Particle Size Distribution Justifications for High Rating

Process Steps Blending Low Medium Low High

Granulation Low Low Low Low

Drying Low Low Low Low

Milling Low Low Low Medium

Low Medium

Low Low

Low High

N/A

N/A

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

Compression Medium Low Low High

Coating High Low Low Low

Medium Low

Medium Low

High Low

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

53

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

54

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

55

The QbD Framework for Process Space

56

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

57

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 OneFactor-At-A-Time (OFAT) to do this but this is not adequate today 58

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 59

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 60

Experimental Variability Any 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. 61 Taken from In Introduction to the Design and Analysis of Experiments, George Cobb (1998)

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 62

High Level Map of Experiments Screening Designs

One Factor at a time Fractional Factorials

Characterization Studies

Full Factorials

Optimization Studies

Response Surface Methods

63

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

64

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 65

Example DOE - Compression Turret Speed (rpm) 30 15 30 30 15 30 15 15

Compression Force (kN) 20 20 20 10 10 10 10 20

Tablet Hardness (kP) 11 13 12 11 10 9 10 15

4 Hr Dissolution (%) 76 79 78 72 76 74 77 71

Does Turret Speed matter? Does Compression Forces matter? 66

Example DOE- Compression ANOVA Do these variables have an impact on tablet hardness?

D = 0.05

Estimated Effects and Coefficients for Tablet Hardness (coded units) Term Effect Coef Constant 11.3750 Turret Speed -1.2500 -0.6250 Compression Force 2.7500 1.3750 Turret Speed*Compression Force -1.2500 -0.6250 0.3750 -1.67

SE Coef T P 0.3750 30.33 0.000 0.3750 -1.67 0.171 0.3750 3.67 0.021

Yes!

0.171

S = 1.06066 PRESS = 18 R-Sq = 82.61% R-Sq(pred) = 30.43% R-Sq(adj) = 69.57% 67

Example DOE- Compression ANOVA Do these variables have an impact on tablet dissolution?

D = 0.05

Estimated Effects and Coefficients for 4 Hr Dissolution (coded units) Term Effect Coef SE Coef Constant 75.3750 1.068 Turret Speed -0.7500 -0.3750 1.068 Compression Force 1.2500 0.6250 1.068 Turret Speed*Compression Force 2.7500 1.3750 1.068

T P 70.58 0.000 -0.35 0.743 0.59 0.590 1.29 0.267

S = 3.02076 PRESS = 146 R-Sq = 34.68% R-Sq(pred) = 0.00% R-Sq(adj) = 0.00% 68

What if I am Not Strong In Statistics?

The Pareto Chart provides the same answer

69

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

70

Design Space

71

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 72

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

73

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 74

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

75

Hypothesis testing concepts allow us to.....? • Properly handle uncertainty • Minimize subjectivity • Question assumptions • Prevent the omission of important information • Manage the risk of decision errors

76

Hypothesis Test Configuration Ho: Parameter or Measure = a value, or is true HA: Parameter or Measure z {< or > } a value, false D = 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, D, which is the risk of incorrectly rejecting a true Null 77 Hypothesis

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 78

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 79

The Decision Errors Keller and Warrack, Statistics for Management and Economics

Your Decision

Do not reject Ho

Ho is True The Truth Ho is False

Correct decision Type II Error ERisk)

Reject Ho

Type I Error D Risk) Correct decision

80

Example: Airport Security Alarm’s Decision

Nothing In Bag

Nothing In Bag

Weapon In Bag

Correct

Type I Error

The Truth

Consequences: _____________ _____________

D Risk)

Weapon In Bag

Type II Error

Correct

ERisk)

Consequences: _____________

81

Hypothesis Testing – Assumptions • 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

82

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) 83

Hypothesis Testing – Procedure Steps

•Example (2 Samples)

1. Write the null hypothesis

H0 : x Sample A = x Sample B (e.g. new way is the same as the old way)

2. Write the alternate hypothesis

HA : There is a difference between Samples A and B

3. Decide on the p value

p = .05 (typical for characterization projects)

4. Choose hypothesis test

Choose the correct test, given the type of X and Y data (in this example, a t-test)

5. Gather evidence and test/conduct analysis

Collect data, run analysis, get p value

6. Reject H0 /not reject H0 and draw conclusion

If p >.05 conclude that your data does not show a significant difference between samples If p 5 • Sampling Plan Development Could 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

133

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. 134

Drug Dissolution Dependence on Coating Weight

135

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

136

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 137

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 3 138

Establishing Acceptance Criteria • Based upon reproducibility criteria • For example if the Stage 1 performance for the 4 hr. dissolution was 32% 㼼 2% against a specification of 20-40%: • Acceptance criteria could be: 95% confidence interval applied to a spec of 32 㼼 6% • Used a 2 sided t-Test with an Į = 0.05 (0.025 on the HA for < comparison) • We used the 㼼 6% because it is 3 x std. dev. In a normal distribution this covers 99.7 of the data variability for a controlled process 139

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 ztest • 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 140

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

141

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 142 markets

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. 2. 3. 4. 5.

Internal failure External failure Appraisal Prevention Lost Opportunity 143

•Reference; Basu and Wright, Quality Beyond Six Sigma 2003

COPQ Components

144 •Reference: Wild 2002

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

145

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 146

Questions?

147

Thank You for Your Attention! Bikash Chatterjee, President & CTO

Pharmatech Associates, Inc. 22320 Foothill Blvd. #330 Hayward CA 94541 510-732-0177 [email protected] Or visit our website at: www.pharmatechassociates.com 148