Welcome and opening Message Dr. Charlotte Enghave Fruergaard, Honorable speakers, Distinguished guests, ladies and gentlemen It gives me a great pleasure to welcome all of you to 10 th anniversary ISPE Thailand conference. Thank you for coming. The conference is jointly with ASEAN Life Sciences Conference and exhibition , is co-organizing with Thailand Center Excellence for Life Sciences, Thai Food and drug Administration , Thai Industrial Pharmacist Association, Thai Pharmaceutical Manufacturers Association , and Faculty of Pharmaceutical Science Chulalongkorn University. This event is looking to the future, the next 10 years will bring many changes as countries and companies adapt to the greater competition of the ASEAN market situation. During the last 10 years since the formation of ISPE Thailand Affiliate in 2003 many companies in Thailand have invested in new facilities and we have provided guidance to help with facility design, layout, and designs for HVAC and water. We hope that ISPE can continue to provide much needed advice and we have put together a program which can help you think about your future requirements to make the industry more competitive. We have included Project Management, Modern Facility Design, IT requirements, Operations and Quality by Design (QbD). We hope that this will provide some inspiration for the future. Do take the opportunity to ask questions from our experienced speakers. We are greatly honoured by having with us the Chair of ISPE International Board of Director, Dr. Charlotte Enghave Fruergaard who has so kindly agree to grace this opening ceremony and address us, role of ISPE in the region. On behalf of ISPE Thailand I would like to take this opportunity to express my sincere thanks to Thailand Center Excellence for life Sciences for supporting this event and in particular our honorable speakers, co-organizers , participants and ISPE Thailand Affiliate Board members . Finally, this is the time for me to declare the official opening of 10 th 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
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Transcript
Welcome and opening Message
Dr. Charlotte Enghave Fruergaard, Honorable speakers, Distinguished guests, ladies and gentlemen
It gives me a great pleasure to welcome all of you to 10th anniversary ISPE Thailand conference.
Thank you for coming. The conference is jointly with ASEAN Life Sciences Conference and exhibition , is co-organizing with Thailand Center Excellence for Life Sciences, Thai Food and drug Administration , Thai Industrial Pharmacist Association, Thai Pharmaceutical Manufacturers Association , and Faculty of Pharmaceutical Science Chulalongkorn University.
This event is looking to the future, the next 10 years will bring many changes as countries and companies adapt to the greater competition of the ASEAN market situation.
During the last 10 years since the formation of ISPE Thailand Affiliate in 2003 many companies in Thailand have invested in new facilities and we have provided guidance to help with facility design, layout, and designs for HVAC and water.
We hope that ISPE can continue to provide much needed advice and we have put together a program which can help you think about your future requirements to make the industry more competitive. We have included Project Management, Modern Facility Design, IT requirements, Operations and Quality by Design (QbD). We hope that this will provide some inspiration for the future.
Do take the opportunity to ask questions from our experienced speakers.
We are greatly honoured by having with us the Chair of ISPE International Board of Director, Dr. Charlotte Enghave Fruergaard who has so kindly agree to grace this opening ceremony and address us, role of ISPE in the region.
On behalf of ISPE Thailand I would like to take this opportunity to express my sincere thanks to Thailand Center Excellence for life Sciences for supporting this event and in particular our honorable speakers, co-organizers , participants and ISPE Thailand Affiliate Board members .
Finally, this is the time for me to declare the official opening of 10th ISPE Thailand conference, I wish
all two fruitful days of interesting program will give you some insight into the kind of work that you have been doing.
To all of you, thank you for being here, welcome and enjoy the conference
Mrs. Sorada Wangmethekul President of ISPE Thailand Affiliate
ISPE Thailand Conference: Preparing for the Next Decade! Jointly together with
“Asean Life Sciences Conference & Exhibition 2013”
Wednesday 17th - Friday 19
th July 2013, Queen Sirikit National Convention Center, Bangkok, Thailand
DATE PROGRAMME
WED
17/07/2013
9.00 – 12.30 Morning Session (Open for All Participants)
OPENING CEREMONY Venue: Ballroom
Opening address by Minister of Ministry of Science and Technology
Keynote Address
“A Global Look at the Life Sciences Industry: Opportunities and Challenges”
Speaker: Mr. G. Steven Burrill, CEO of Burrill & Company
Keynote Panel Discussion
“Life Science Business in ASEAN: Opportunities and Challenges”
Speaker: Mr. G. Steven Burrill, CEO of Burrill & Company and Professor Dr. Pornchai Matangkasombut, Advisor to the
Board of TCELS
13.30 – 18.00 Afternoon Session (Open for All Participants)
TRACK 1
Venue: Ballroom
Regulator Track “Global Regulator Movement”
Global Regulatory Harmonization & Convergence for Health Products: Global Movement and Trend &
Best Practices & Approaches
Speaker: Dr. Justina A. Molzon, Associate Director of U.S. Food and Drug Administration
Dr. Petra Dörr, Head of Management Services and Networking of Swissmedic & Chair of International Pharmaceutical Regulator Forum
Panel: ASEAN Harmonization on Pharmaceuticals:- AEC and Beyond
DATE PROGRAMME
THU
18/07/2013
9.00 – 12.00 Morning Session (Open for All Participants)
Speaker: Dr. Charlotte Enghave Fruergaard, Chairman of the ISPE International Board of Directors
Panel Discussion: Regional Pharmaceutical Manufacture: Preparing for the next decade
Speaker: Dr. Charlotte Enghave Fruergaard, Mr. Chernporn Tengamnuay Greater Pharma Ltd Partnership, Dr. Anthony
Margetts, Factorytalk Co., Ltd, and Dr. Songpon Deechongkit, Siam Bioscience Co., Ltd.
ISPE Thailand AGM (Starting of ISPE Thailand until now …. Short history and review our
achievement). What will be in next decade?
Speaker: Ms. Sorada Wangmethekul, ISPE Thailand President and Mr. Chernporn Tengamnuay, First ISPE Thailand
President
13.00 – 16.30 Afternoon Session
TRACK 2A
Venue: Meeting room 1
Future Manufacturing Plant for Production
and Engineer
Design of potent facility Speaker: Ms. Deborah R Cohen and Mr.Nihir Parikh
,GE Healthcare Life Sciences
Sterile technology (Restricted Access Barrier
System (RABS) and Isolator) Speaker: Dr. Charlotte Enghave Fruergaard, NNE
Pharmaplan
TRACK 2B
Venue: Meeting room 2
Critical Utility Design and Maintenance
Critical Utility Design and Maintenance Speaker: Mr. Gaston Loo, MSD Singapore
Key Aspects of Comprehensive Calibration and
Maintenance Management System (CMMS)
Implementation Speaker: Mr.Tantra Tantraporn, Grand Thornton
FRI
19/07/2013
9.00 – 16.30 A Day Session
TRACK 3A
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 we will expect from you
What you can expect from ISPE
Why?
• A Professional • An employee • Charlotte
Volunteers
ISPE Mission
By 2015, ISPE will be recognized globally as the leading technical organization for professionals engaged in producing quality medicines and pharmaceutical devices throughout the product lifecycle
• Across all sectors • With all stakeholders • Globally
ISPE Directions
• Vibrant global association
• Technical & Scientific aspects
• Organizational aspects
ISPE Directions
• Leaders and regulators • Strategic Forum • Regional Forums (ASIA-PACIFIC, EUROPE, NORTH
AMERICA-SOUTH AMERICA)
• Regulatory and Compliance Committee
• Build a strategy for Europe
What we will expect from you
Expectations • Global and diverse culture • Leading and vibrant ISPE • Learning • Exchanging knowledge
What you can expect from me
What you can expect from ISPE
What you can expect from me
What you can expect from ISPE
What we will expect from you
ISPE Bringing together the
Right People to forge the
Right Relationships to address the
Right Issues and formulate the
Right Solutions to ensure the integrity of life-changing and life-saving pharmaceutical products
What you can expect from ISPE
What you can expect from me
What you can expect from me
to
Ra
Rtoa
What you can expect from ISPE
What you can expect from ISPE
What you can expect from me
YOU
Shaping the industry • Participate • Engage • Involve
The more you give – The more you get
What we will expect from you
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 Enforcement
Higher Transparency
Higher Requirements
Challenges
but you can learn to surf” Jon Kabat-Zinn Professor of Medicine emeritus at University of Massachusetts Medical School
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
1 ASEAN Life Sciences Conference & Exhibition
GE Proprietary & Confidential
Establishing biomanufacturing capacity in Asia
Nihir Parikh Enterprise Solutions GE Healthcare Life Sciences Bangkok, July, 2013
2 ASEAN Life Sciences Conference & Exhibition
GE Proprietary & Confidential
Agenda
• GE Life Sciences
• Demand for biopharmaceuticals
• KUBio™: An innovative and standardized manufacturing solution
2 ASEAN Life Sciences Conference & Exhibition
GE Proprietary & Confidential
General Electric Today
AVIATION TRANSPORTATION HOME &
BUSINESS SOLUTIONS,
MEDIA
GE CAPITAL GE ENERGY
Energy Services Oil & Gas Power & Water
HEALTHCARE
GE THEN/NOW SOLUTIONS ENVIRONMENT INNOVATION
Today
GE Healthcare Life Sciences Six decades supporting Biopharma
1960s
Sephadex™, Sepharose™, Large
scale columns
1980s
FPLC™, Sepharose Fast Flow, BioPilot™, Sepharose High
All goods and services are sold subject to the terms and conditions of sale of the company within GE Healthcare which supplies them. A copy of these terms and conditions is available on request. Contact your local GE Healthcare representative for the most current information.
For local office contact information, visit: www.gelifesciences.com/contact GE Healthcare Bio-Sciences AB, Björkgatan 30, SE-751 84 Uppsala, Sweden.
www.gelifesciences.com/enterprisesolutions
Thank you
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Trends in
Sterile Manufacturing Technologies
ISPE Thailand Annual Meeting
Charlotte Enghave Fruergaard
2013.07.18
Where we come from
1930s – Danish Novo and Nordisk
Gentofte (later Novo Nordisk)
employed the first engineers.
1974 – Pharmaplan was founded
as part of the medical care group
by Fresenius, Germany.
1991 – After functioning as in-
house consultants at Novo Nordisk
for years, NNE (Novo Nordisk
Engineering A/S) demerged as an
independent company.
2007 – Acquisition of Pharmaplan,
a company similar to NNE in DNA.
NNE Pharmaplan was founded.
With 80 years of
experience we are
passionate about
our services to the
pharma and biotech
industries.
Recent awards
2004 IChemE: “Haden Freeman Award for Engineering Excellence”
2005 ISPE Facility of the Year Award winner – Novo Nordisk’s NovoSeven (FVII) facility
2008 ISPE Company of the Year winner
2009 ISPE Facility of the Year Award winner – Facility Integration – hameln pharmaceuticals, Germany
2009 ISPE Facility of the Year Award winner – Operational Excellence – R&D division of US biotech company, Switzerland
2009 Emerson: “PlantWeb Excellence” for DeltaV application for Pronova BioPharma project (KalOmega)
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Who we are
We are the leading consulting and
engineering company in the complex
field of pharma and biotech.
We count close to 1,700
professionals with project
experience and knowledge
related to pharma and biotech.
More than 200 have hands-on
development or production
experience.
We executed 2,929 projects
in 2012.
Our project execution
and our staff
embody 10,000
years of
experience within
pharma and biotech
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Optimal production processes
Company
revenue
2012
USD 294M
EUR 224M
DEVELOP ESTABLISH IMPROVE
Project
development
Process & Product
development
Investment project
CD / BD / DD / CON / C&Q
Optimisation, training, revamps,
GAP analysis, operational support
Agenda
• Market changes forcing technology changes…
• Aseptic/Sterile processes
• Technology Trends
What is OSD and Biotech?
Small Molecules vs. Large Molecules
Chemical Synthesis
Drying or Granulating
Tableting Packaging
Chemical Active Pharmaceutical Ingredient
(API)
“Tablets” Oral Solid Dosage Form
(OSD)
Formulation
Fermentation or Cell Culture Inteferon molecule
vs Aspirin
Formulation Aseptic Filling
Packaging
Biologics Active Pharmaceutical Ingredient
(API)
“Injectables” Parenteral Dosage Form (aka Sterile Products)
• 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
Gaston Loo IPT Pharm West Maintenance Lead MSD International GmbH (Singapore Branch) 50 Tuas West Drive 638408 Singapore
Gaston Loo joined MSD (legacy Schering-Plough Ltd) in 1999 and currently is the Maintenance Lead for Pharm West facility. He is responsible for all Engineering and Maintenance activities for the facility and actively involved in all Projects development such as participation in the engineering design, construction, commissioning, validation and start-up of Biotech sterile facility in 2001-2003. His other responsibilities include operation and maintenance of the critical utilities system such as WFI & PFW and process engineering in the facility. Gaston has extensive knowledge on electrical, instrument calibration & maintenance, computer system validation, DCS / PLC / SCADA system installation and clean room / HVAC maintenance. Prior to MSD, he had more than 5 years engineering experiences in building automation industry, which include HVAC design / commissioning in SEA. With extensive and diversified experiences in the plant maintenance, operation, design and project management, Gaston has acquired the synergistic knowledge and skills for establishing good engineering design feature in equipment and process system, selection of equipment and maintainability of equipment at design stage. He is also involved in the design, operation and maintenance of various validated monitoring system in the plant such as Environmental Monitoring System (EMS) and Utility Monitoring System (UMS).
1
CRITICAL UTILITY DESIGN AND MAINTENANCE
Gaston Loo Maintenance Lead MSD SINGAPORE
ASEAN Life Sciences Conference and Exhibition - 2013
2
• Type of utilities system • Regulatory requirement • Design approach
– Design principle and strategic – GEP – System boundaries
• Maintenance plan – Rouging – Filter integrity testing – Contamination / microbial control
• Industry trend - PAT
Agenda
3
Critical utilities system – Gas system – Pure steam – Water system
Non-critical utilities system – Chilled water – Plant steam – Instrument air – Potable water
Type of utilities system
4
Critical utilities system
• Direct impact system (process system) – Contact the product – Direct impact product quality – Contact materials that ultimately become part of product
• Depend on process, can be raw material, component or
process aid (excipient)
• Application example: – N2 for vessel blanketing – Pure steam SIP – WFI for compounding
Definition
5
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
6
Gas system
Critical utilities system
Nitrogen – Storage tank – Distribution loop
Sterile air (filtered air) – Generation (compressed air)
• Oil free type – Distribution loop
• Buffer tank • Air dryer • 0.2μ filter
7
Pure steam
Critical utilities system
Pure steam – Generation – Distribution loop
Key feature
– Feed water from PFW – Use plant steam for distillation process
- Removal of endotoxins and other impurities via
multiple separation stages - For process sterilization purpose
8
Critical Utilities System
Water For Injection (WFI) – Generation
• Feed water from PFW – Storage and distribution
Water system Purified water system (PFW) – Generation – Storage and distribution
• Type of utilities system • Regulatory requirement • Design approach
– Design principle and strategic – GEP – System boundaries
• Maintenance plan – Rouging – Filter integrity testing – Contamination / microbial control
• Industry trend - PAT
Agenda
20
What might a regulator want?
For people to understand the intent of regulations, and then
implement programs to meet that intent.
21
FDA
Regulatory requirement
FDA has recently focused attention on critical utilities. End users and their qualification and quality assurance personnel must demonstrate that the facility complies with 21 CFR 211.65(a) which states: “Equipment shall be constructed so that surfaces that contact components, in-process materials or drug products, shall not be reactive, additive, or absorptive so as to alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements.”
22
PIC/S
Regulatory requirement
PIC/S is the abbreviation and logo used to describe both the - Pharmaceutical Inspection Convention (PIC) - Pharmaceutical Inspection Co-operation Scheme (PIC Scheme)
PIC Scheme PIC Scheme Convention An informal arrangement
A formal treaty
Has no legal status Has legal status
Between Health authorities Between countries
Exchange of information
Mutual recognition of inspections
The main differences between the PIC Scheme and PIC are :
operating together in parallel.
23
PIC/S
Regulatory requirement
• PIC/S develop guidance “The Aide-Memoire – Inspection
of Utilities” for GMP inspectors
• For training and preparation of inspection
• Checklist for critical utility on water, steam and gases
24
Standard
Regulatory requirement
Improved standard and guidelines such as - ASME Bioprocessing Equipment standard (BPE-2012) - ISPE Baseline@ Pharmaceutical Engineering Guides - International Standard ISO 8573 Compressed Air
have driven the quest of quality in pharmaceutical
industry.
• Vary of interpretation by different regulators
25
EMEA
Regulatory requirement
Reflection Paper on 5 March 2008 EP requirement for WFI be produced only by distillation Refer RO membranes as "bacterial fermenters" and production of WFI RO would not be “as safe as water prepared by distillation”
Mandatory for manufacture of all products shipped into the European Economic Area
EMEA reaffirms rejection of RO for WFI production in EEA
26
USP
Regulatory requirement
• Recognized and used in > 140 countries • Guide to produce medical products
• Specify standard for PFW and WFI
U.S. Pharmacopeia
Example: • Conductivity @ temperature (USP <645>) • TOC (USP <643>) • Bacteriological Purity Total Aerobic Count
(CFU/Ml)
27
• Type of utilities system • Regulatory requirement • Design approach
– Design principle and strategic – GEP – System boundaries
• Maintenance plan – Rouging – Filter integrity testing – Contamination / microbial control
• Industry trend - PAT
Agenda
28
GEP
Design approach
Design approach affect by following factors:
Factors
Critical Utility Design
Process
Budget
Timeline
Quality Validation
Safety & Environment
Automation
Feed Water Quality
Specification
29
Design and project workflow
Direct-impact systems only
Quality-critical requirements only
Design principle and strategic
30
GEP • Set the standard and specifies your requirements
• Document the functions you want
• Used as a live document up until the DQ is completed and
approved
• Traceability of PQ and OQ functionality testing (RTM)
• Part of procurement process e.g. tender document
• Minimize project expenditures, streamline validation, and forgo unnecessary processes or mechanical design options
• Serve to qualify the use of certain system and component
attributes that affect cost and performance • Determine what operations of critical utilities classified as
critical and non-critical
• Determine the scope and extend of validation
Objective
33
GEP
Risk assessment tool
Failure Mode Effects Analysis • Assessment tool to determine their potential value for process
design techniques
• Cause & effect analysis
• Assign each risk 1-10 for occurrence / severity / detection
• RPN = Occurrence x Severity x Detection
FMEA
34
GEP
Risk assessment tool
Example: Microbial development in the WFI storage tank - Surface finish on tank < 20 (Ra) - Temp > 80 oC With rating 0-10: RPN = O X S X D = 1 X 10 X 2 = 20 (low risk)
FMEA
Design specs
35
FMEA form
Risk Assessment & FMEA Risk Assessment FMEA
Structured by System Quality Attributes (SQA)
Structured by process steps
Begins with identifying hazards to SQA’s
Begins with identification of potential failure modes
Controls are assessed based on design features and procedures
Controls are grouped as prevention and detection controls
Used to identify controls that must be incorporated into the user requirements
Used to identify and prioritize risks of a given process
Used to establish acceptance criteria for validation
36
37
Good Engineering Practice (GEP)
“I don’t know how to explain them, but I know them when I
see them.”
38
GEP
Apply to all critical utility from design to operation stage: • Projects
• Operations – maintenance – calibration – safety and environmental
Scope
Good Engineering Practice (GEP)
39
General rule
Good Engineering Practice (GEP)
• Allow provision for future expansion • Utilities should be routed from plant room to process
area • Process utility systems are designed to satisfy the
requirement of facility • Meet regulatory requirements and expectations
pertaining to equipment • Drawing for utility systems must be approved and
updated.
40
Good Equipment Layout
Good Engineering Practice (GEP)
Keep design as simple as possible Ease of access for operation and maintenance
Follow process flow
Provide good spacing for equipment
Operators review equipment layout during design stage
Equipment and piping labeling
Good Engineering Practice (GEP)
System “Qualification Drawing” requirements: show the plant layout, with service connections and, as appropriate:
All isolating-, drain-, vent-, control-valves, and items served, complete with tag numbers where used. Any critical items, such as filters, outlets, sample points etc. The quantity, quality and direction of flow of the working fluid.
Component tagging Main components should be tagged or labelled, to ensure that there are unique references for items to use in:
Commissioning records Maintenance records SOP’s Asset registers
Good Equipment Layout
41
42
GEPs and EQ
System boundaries
URS
Engineering Specs
Design Details
EQ
SAT / Commissioning
FAT
GEP
GMP
Quality Critical Attributes
43
Design criteria
System boundaries
Utility quality
Use point criteria
System criteria
Re-evaluate system design boundaries and constraints
Basic requirement includes: – Eliminate dead legs where possible – Sanitary design for component – N2 seal storage tank or vent filter(0.2μm) – Piping material - SS316L – Orbital welding and inspection – Sampling point for distribution loop – Instruments for trending (TT / FT / PT) – Standby pump for water distribution loop – ISO/DIN type of gasket / seal e.g. PTFE, EPDM,
Viton® and Silicone
46
Why Stainless Steel 316L
L indicates low carbon – but note that the specification limits for 316 and 316 L overlap
316 C Mn Si P S Cr Mo Ni N
Min - - - 0 - 16.0 2.0 10.0 -
Max 0.08 2.0 0.75 0.045 0.03 18.0 3.0 14.0 0.10
316L
Min - - - - - 16.0 2.0 10.0 -
Max 0.03 2.0 0.75 0.045 0.03 18.0 3.0 14.0 0.10
SS 316L used when there is a danger of corrosion in the heat-affected zones of weldments
47
Why Stainless Steel 316L
Many reasons:
• Availability of tube and sheet material • Availability of valves and fittings • Corrosion resistance • Weldability
• ASTM A269 (unpolished ID and OD) and A270 (polished
ID and OD) • Tolerances are generally tighter for ASTM 270
48
Orbital Welding
• The standard approach is to use closed head orbital welding – Automated repeatable quality welds – Protection from oxidation on both sides by purge gas – Weld parameters (primary / background values of pulsed
welding current, primary / background pulse times and rpm), controlled by the power supply, which determines the surface travel speed of the tungsten electrode.
• Orbital welding provides precise control of the heat input into the weld results in better corrosion resistance than manual welding
• Ensure sample welds (coupon) are produced for all heat combinations.
49
Orbital Welding – test coupon
Test coupons that conform to the specification on the actual materials to be used before the start of the job
Others: - lines were labeled with the heat number of the tubing - date of welding - weld number on the ISO drawing - piping system number - weld log for future reference
50
Water system
Standard requirement
Air gap for drain point (min. 50mm)
Eliminate microbial contamination from common drain line
ASME 112.1.2: The minimum required air gap shall be twice the diameter of the effective opening
Dead Leg definitions
D
L
A dead leg is any area in a piping system where water can become stagnant and where water is not exchanged during flushing.
Bacteria in dead-end pipe lengths / crevices are protected from flushing and sanitization procedures and can recontaminate the piping system.
Zero deadleg valves were used to minimize deadlegs in critical areas of the piping system
Modern piping design limits the length of any dead-end pipe to 6 times the pipe’s diameter (even shorter dead legs are preferred).
This is the six diameter rule (6D).
51
Dead Leg guideline
As per ASME BPE 1997 : " For Bioprocessing systems, L/D of 2:1 is achievable with today's design technology for most valving and piping applications"
As per FDA - GUIDE TO INSPECTIONS OF HIGH PURITY WATER SYSTEMS: it defined dead-legs as not having an unused portion greater in length than six diameters of the unused pipe measured from the axis of the pipe in use.
D
L
If deadlegs exist in a system, some provision should be made for flushing them through routinely. 52
53
Case Study - Dead leg
IN
OUTLET
Dead leg section during normal
operation
Promotes microbial growth and formation
of bio-film
DRAIN
Affects performance of
carbon filter
Carbon filter manifold in operation
Carbon filter tank
54
Case Study - Dead leg
Dead leg section, collects ‘dirty’ backwash water
Drain
Carbon filter manifold during back-washing
IN
OUTLET
Carbon filter tank
55
After improvement
Outlet
Inlet
Drain
Carbon filter tank
Carbon filter manifold in operation
Case Study - Dead leg
Keep deadlegs between valves to minimum
56
After improvement
Outlet
Inlet
Drain
Keep dead legs between valves to minimum
Carbon filter tank
Case Study - Dead leg
Carbon filter manifold during back-washing
57
• Type of utilities system • Regulatory requirement • Design approach
– Design principle and strategic – GEP – System boundaries
• Maintenance plan – Rouging – Filter integrity testing – Contamination / microbial control
• Industry trend - PAT
Agenda
58
Maintenance challenge
• Maintenance always link to reliability / availability – 24hrs X 365 days
• Maintain the validated state
• Contamination / microbial control
• M
59
Rouging
• A form of surface corrosion – reddish / brownish
• Common problem in WFI / pure steam systems
• High temperatures and dissolved gases accelerate corrosion and formation of iron oxides
• Iron oxide can break away from SS surfaces and flow through the entire water system downstream
(migratory rouge)
60
Effect
Rouging
• Cr-oxide dominated passive-layer is changing to Fe-oxide enriched corrosion layer
• Influencing parameters: – Alloy quality – Surface treatment – WFI quality – Temperature – Exposition time – Gas content (type and quantity)
61
Example
Rouging
• Typically found in:
– Pump impellors and internal housing – Vessel spray balls – In-line filters and housings – Storage vessel surfaces (usually above water line) – PTFE surfaces e.g. tri-clamp gaskets and valve
diaphragms
62
Example
Rouging
Spray ball WFI storage tank
Pump impeller from WFI system
Pump volute from WFI system
63
Example
Rouging
Rouging on a PTFE tri-clamp gasket
Rouge discoloration found on a point of use
0.45 μm filter membrane
64
Example
Rouging
Rouge can be wiped off and can move throughout a system. The rouge layer consists of heavy-metal-oxides, preferably Fe-Oxides. The rouge-layer consists of particles of heavy-metal-oxides which can leave the surface based on stream conditions.
Wipe test of a production vessel Wipe test of a WFI pipe
65
Passivation
Rouging control
• Removal of rouging • Generate an oxide film that covers and protects the
surface of the SS surface by nitric acid or citric acid
• Recirculation through distribution loop (2 hrs) • Post passivation – PFW water flushing till pH 6 to 8
66
Before / After Derouging
before Derouging after Derouging
67
Monitoring
Rouging control
• Schedule inspection to check components in the loops for sign of rouge
• Establish baseline and identify possible problem area
• Establish SOP for derouging / repassivation process
• Routine sampling of water quality – Conductivity – TOC – Heavy metals – Nitrate
68
Filter integrity testing (FIT)
• Filter type: - Air / Gas filtration - Water filtration - Vent filtration for storage tank
• Purpose: - Sterile boundaries - Protect from contamination (bacteria retention) • Maintenance: - Routine schedule replacement - FIT (before and after)
69
Filter integrity testing
• What is FIT? A measure of the ability of a filter element to work as
designed through multiple cycles, is a sensitive process parameters that requires qualified testing
• Factors influencing FIT - Temperature - Upstream Volume - Wetting Agent
70
Filter integrity testing
Breaches may occur as a result of… • Factory defects • Shipping damage • Improper maintenance • Structural creep • Chemical degradation • Age
Breaches can occur in many locations… • Seals and O-rings • Membrane potting • Fibers (broken or
punctured)
Potential integrity breaches underscore the need for FIT
71
Type of FIT
- Water intrusion test (gas)
- Forward flow (water)
- Bubble point filter test
72
Water intrusion test (gas / vent)
For hydrophobic gas filters
WIT
The resistance to water flow is overcome by a specific pressure
73
• An integrity test measuring air diffusion • Measurement of diffusive (diffusional) flow of a gas
through a wetted filter. • Measured under pressure and evaluated by comparing
the results to a limit value.
Forward flow (water)
74
Contaminants in water
Dissolved inorganic Dissolved organics
Micro-organisms Particulate matter
75
Source of Contamination
Sources of Microbial Contamination
• Source supply water or feedwater • Unprotected Vents / unsealed tanks • Faulty air filters • Contaminated use points/sample points • Unsatisfactory drain air breaks • Replacement carbon/resin/sand • Contaminated chemical additions • Improper sampling
76
Contamination control
RO membrane cleaning
• Cleaning is activated by - fall in permeate - dramatic rise in permeate conductivity - rise in 1st pass differential pressure
• Acid clean - remove hardness scale and is effective in removing
iron precipitates.
• Alkaline clean - remove biological material, colloid, silica etc.
77
Contamination control
CDI cleaning
Cleaning removes debris, scale, and resin foulants from the module that can severely reduce performance It is very important to follow cleaning guidelines in the CDI O&M manual
- for cleaning to be effective - to avoid damaging the module
78
Microbial Control and Biofilms
There are a number of measures that control microbes:
1. Avoid or minimise dead legs 2. Continuous re-circulation of water 3. Avoid stagnant ambient temperature water 4. Allow for drainage of pipework 5. Use sanitary valves & suitable gaskets selection 6. Use suitable construction materials 7. Maintain system water temperature at > 70*C 8. Regular sanitation or sterilization 9. UV radiation 10. Air break for drains
79
Microbial Control
1. Continuous re-circulation of water 2. Avoid stagnant ambient temperature water 3. Allow for drainage of pipework and storage tanks 4. Use sanitary valves 5. Avoid or minimise dead legs
The above measures discourage bacteria from:
• Lingering longer and reproducing to larger numbers • Settling to establish biofilms • Good drainage of unused pipes and tanks allows
drying which prevents bacteria from multiplying, although they may remain dormant for periods of time
80
Microbial Control
1. Use suitable construction materials 2. Maintain system water temperature at > 70*C 3. Regular sanitation or sterilization 4. UV radiation
The above measures are designed to facilitate the killing of bacteria :
• Most, if not all water system bacteria are vegetative forms (do not have spores) and therefore killed at temperatures above 60*C. 70 – 80*C is recommended to allow for cooler spots in systems.
• Stainless steel is better for withstanding temperatures and providing better surface finish to prevent biofilm establishment.
81
Microbial Control
1. Regular chemical treatments can become expensive to get a system back under control
2. Chemical treatments have to be applied at correct concentrations and allow sufficient contact time for effectiveness. Handling of chemicals would require safety assessment
3. Heat at sufficient temperature is a more effective sterilizing agent
4. UV radiation is effective but • Need to be certain there is no shading of bacteria
(requires direct exposure to bacteria) • Need ensure UV intensity is maintained over time.
Can still have a blue light when UV energy is insufficient
82
Microbial control
Sanitization
Sanitization are performed periodically to control the microbial growth Weekly sanitization of the PFW - Generation - Distribution loop FDA – over 65 degrees C is considered self sanitizing EU – stored and distributed in a manner which prevents microbial growth, for example by constant circulation at a temperature above 70 degrees C
83
Microbial control
Sanitization On request when intrusive maintenance: After the distribution loop or storage tank is opened, altered or exposed for maintenance / calibration
83
After replacement of the filter element for the final filter or heated vent filter After the distribution loop or storage tank has remained out of service for > 4 hours
84
Case study – microbial contamination
Scenario: Total Viable Count (TVC) results for water which was sampled and tested on 1st Oct 12 hit action limit for PFW generation system (after 5-7 days incubation). Purified water (sampling point: SP-123 Final filter outlet): 25 cfu/100ml Alert limit – 1 cfu/100ml Action limit – 10 cfu/100ml Distribution loop is maintained at 80deg C
85
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
86
Case study – microbial contamination
CF, RO, UV & CDI system functionality
If any parts damage or choke on CF, RO, UV and CDI. Visual check functioning well. RO membranes,
Contamination of high bio film from CF and RO.
RO, UV & CDI parameters out of limit
Technician has been trained and experienced to operate PWF.
TVC hit action limit at CDI outlet SP-123: 25 cfu/100ml
Method Environment
Machine Man Material
Why? Any control failures or not monitored/tested/logged
Facility changes if any
Contamination of feed water supply
Chlorine supply
Why? Chlorine supply low?
Why? No malfunction and defects found and data logging ok.
No Maint carried out.
Why? Any cross contamination. NO-ruled out. No failures monitored & data
logging for last 4 weeks are within spec. Micro passes. Ruled out
Chlorine supply Ok and weekly sanitize CF. No Maint and breakdown works. Ruled out
Good and spec ok
Why? Any piping between CF, RO and CDI has bio growth. NO-ruled out
High microbial counts; ≥ 500cfu/1ml specification (frequently from end Sep 12)
Training provided?
Review log sheets and no abnormality found.
RO Pre-filter, RO membranes and final filter.
RO pre-filters, RO membranes and final filter visual check. No abnormality found
Free chlorine testing procedure.
Biofilm at the pipe
Performed as per SOP
Cause & effect diagram
87
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
88
• Type of utilities system • Regulatory requirement • Design approach
– Design principle and strategic – GEP – System boundaries
• Maintenance plan – Rouging – Filter integrity testing – Contamination / microbial control
• Industry trend - PAT
Agenda
89
Process Analytical Technology
FDA – Center for Drug Evaluation and Research
“a system for designing, analyzing, and controlling
manufacturing through timely measurements, (i.e., during process) of critical quality and performance attributes of raw and in-process materials and processes with the goal of ensuring final product quality.”
How: On-line release using qualified Analyzers with a
validated process
Definition
90
Guideline
FDA for PAT
PAT — A Framework for Innovative Pharmaceutical Manufacturing and Quality Assurance
FDA PAT Initiative “The goal of PAT is to enhance understanding and control the
manufacturing process, which is consistent with our current drug quality system: quality cannot be tested into products; it should be built-in or should be by design.”
These tools and principles should be used for process
understanding and to meet regulatory requirements for validating and controlling the process
91
Guideline
USP
USP Chapter <643> on TOC states … “On-line TOC measurements for bulk-produced water…have the
advantage of providing real-time measurements and opportunities for real-time process control and decisions, in addition to recording the TOC quality attribute for release of water to production…off-line measurements of bulk waters have the disadvantage of being impacted adversely by the sampling method, sample container and uncontrollable factors, such as organic vapors.”
92
Goal: 100% understanding and control • Improve Assurance • Improve Process Controls • Improve Understanding • Improve Quality
PAT drivers
WFI or PFW loop
In line sampling port
TOC analyzer SCADA system
93
Utilities / Maintenance • Equipment Owner • Execution of SOPs and protocols QA/QC • Input to SOPs and Protocols • Surveillance & inspections of equipment & components • Technical support • Release documentation
Moving to PAT – A company effort
94
Engineering • Equipment choice • Sampling conformity to design of water system (installation) • Review of as-builds • Functional testing (Commissioning, IQ,OQ) Validation • Master plan creation and owner • Documentation review • Validation testing (PQ) execution
Moving to PAT – A company effort
95
• Eliminate sampling errors • Reduced water system downtime and sanitization • Release water and product faster • Increase profits • Better control of the process • Reduce sampling cost
PAT benefit
Lab sampling On-line TOC analyzer
TOC and conductivity
96
On-line TOC vs. Laboratory TOC On-line Laboratory
Accurate measuring low ppb LOD above most water systems
No sample contamination Grab sample contamination
No sample handling Sample tracking protocols
Low cost-of-ownership
High cost-of-ownership (labor intensive)
Trending information No trending information Real-time data Delayed data
Continuous monitoring Infrequent results
Measure in own environment Data for valuable information
97
• Sample cost – Materials – Time – Labor • Laboratory analysis cost – Time – Equipment maintenance
Grab sample testing
Lab sampling
10 Points x 1 TOC x 365 days = 3,650 samples 10 Points x 1 conductivity x 365 days = 3,650 samples
TOC / Conductivity comparison
• Off-Line Testing (TOC & Conductivity): USP <643> and <645>
» Sample testing Turnaround Time = 1 to 2 Business Days
» Operator time to sample = ~30 minutes per day » Analyst time to test = ~1 hour per sample » Review Time = ~15 minutes/day » Instrument set-up (Daily & Weekly) = ~6 hours
• On-Line Testing » Sample testing Turnaround Time = Real Time » Operator time to sample = None » Analyst time to test = ~1 hour per sample » Review Time = ~15 minutes/day » Instrument set-up (Daily & Weekly) = ~2 hours
98
99
Estimate of samples taken in 24 hours • Increased process control & improved product quality • Eliminate sampling errors • Faster product / water release • Increased profits
Manual and Continuous sampling
0
50
100
150
200
250
Manual Continuous
ManualContinuous
240
10
100
Specific Goals • Most up-to-date concepts of risk management and quality systems approaches are incorporated into manufacturing • Encourage manufacturers to use latest scientific advances • FDA – submission review and inspection to improve – Risk based approach encourages innovations • Regulations and manufacturing standards rapidly applied
Industry direction – PAT for critical utility
FDA launches Pharmaceutical cGMP’s for the 21st Century: A Risk Based Approach
101
•Critical utility -Type of utility
•Regulatory - FDA / Standard / USP
•Design - Applying of GEP will ensure reliable equipment without compromise the cGMP expectation •Maintenance - Rouging / FIT / Contamination & Microbial control
•Industry trend - PAT - FDA risk based approach and PAT increase auditor confidence
Summary
102
Questions?
TRACK 2B
CRITICAL UTILITY DESIGN
AND MAINTENANCE
KEY ASPECTS OF COMPREHENSIVE
CALIBRATION AND MAINTENANCE
MANAGEMENT SYSTEM (CMMS)
IMPLEMENTATION
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
Certified Nuclear Power Plant Operator – U.S. Naval Nuclear Power Program Submarine Systems Qualified – U.S. Navy Bachelor of Science – Nuclear Engineering Technology from the University of the State of New York Master of Science – Management / Information Systems from Rensselaer Polytechnic Institute Master of Science – Advanced Business Practice from the University of South Australia
2013 Grant Thornton Management Services. All rights reserved. - 1 -
Grant Thornton Management Consulting
Key Aspects of Comprehensive Computerized Maintenance Management Systems
July 18, 2013
2013 Grant Thornton Management Services. All rights reserved.
1) Maintenance aspects of CMMS
2) Functional aspects of CMMS
3) Process data aspects of CMMS
4) Implementation aspects of the CMMS Roadmap
5) Change aspects of CMMS implementation
6) CMMS guidance and recommendations
Key Aspects of Comprehensive Computerized Maintenance Management Systems Agenda
tation
ons
Maintenance Aspects of CMMS
2013 Grant Thornton Management Services. All rights reserved.
Maintenance Operations
Operational Information Short-term
Operations Management
Feedback Response
“Failure” “Fix”
Typical Reactive Maintenance Cycle
Time
Constant Revenue
T2
T1 Initial Operations
T0 (+) $
(-) $
$0
Systems and equipment have fixed costs that need to be covered; even when idle and not contributing to services or revenues. These fixed costs often include equipment leases, building rent, maintenance staff and insurance.
Reactive Maintenance
Fixed Cost
Profit
Fixed Cost
Reactive maintenance programs allow systems and equipment to run until they fail.
T2 Equipment Failure
Prof
it / L
oss
Time
Constant Revenue
T2 Equipment Failure
T3 T1 Initial Operations
T0 (+) $
(-) $
$0
Reactive Maintenance
Fixed Cost
Profit
Fixed Cost
Profit
Fixed Cost
Prof
it / L
oss Profit
Cost of Repair or Replacement
Profit
Fixed CostFixed Cost
However, profits will be reduced by the amount needed to repair or replace the failed component.
Fixed costs will generally remain unaffected by system failures.
Time
Constant Revenue
T2 Equipment Failure
T3 Severe Equipment Failure
T4 Equipment Restored
T1 Initial Operations
Cost of Repair or Replacement
Cost of Repair or Replacement
Loss
T0 (+) $
(-) $
$0
Reactive Maintenance
Severe equipment failure often increase repair / replacement costs significantly. This may erode profitability to the point where operational losses are incurred for the entire period needed to replace or repair the system.
Profit
Fixed Cost Fixed Cost Fixed Cost
Fixed Cost
Fixed Cost
Profit
Profit
Note that fixed costs continue to be incurred, even during periods of reduced profitability or loss.
Prof
it / L
oss
Profit
Fixed Cost Fixed Cost
Profit
Profit
T3 Severe Equipment Failure
Time
T2 Equipment Failure
T4 Equipment Restored
T1 Initial Operations
Cost of Repair or Replacement
Cost of Repair or Replacement
Loss
T0 (+) $
(-) $
$0
Decreasing Revenue
Constant Revenue
Reactive Maintenance
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
Impact of Economic Downturn on Profit / Loss over Time
Fixed Cost Fixed Cost Fixed Cost
Time
Fixed Cost
Profit
T2 Equipment Failure
T3 Severe Equipment Failure
T4 Equipment Restored
T1 Initial Operations
Profit
Cost of Repair or Replacement
Cost of Repair or Replacement
Loss
T0 (+) $
(-) $
$0
Reactive Maintenance
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.
Fixed Cost Fixed Cost
Profit
Profit
Cost of Repair or Replacement
T5 Equipment Failure
T6 Severe Equipment Failure
Fixed Cost
Constant Revenue
Loss
Cost of Repair or Replacement
Average Profitability
Maintenance Costs
Prof
it / L
oss
Impact of System Aging on Profit / Loss over Time
Fixed Cost Fixed Cost Fixed Cost
Time
Fixed Cost
Profit
T2 Equipment Failure
T3 Severe Equipment Failure
T4 Equipment Restored
T1 Initial Operations
Profit
Cost of Repair or Replacement
Cost of Repair or Replacement
Loss
T0 (+) $
(-) $
$0
Reactive Maintenance
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.
Fixed Cost Fixed Cost
Profit
Profit
Cost of Repair or Replacement
T5 Equipment Failure
T6 Severe Equipment Failure
Fixed Cost
Constant Revenue
Loss
Cost of Repair or Replacement
Average Profitability
Maintenance Costs
Prof
it / L
oss
Impact of System Aging on Profit / Loss over Time
Reactive Maintenance Total Life-cycle Costs
Capital Costs Design Development / Build Purchase Installation Commissioning Staff Training Manuals & Documentation Maintenance Tools & Facilities Initial Spares Holding
Capital Costs
Maintenance Costs Labor Materials Spare part holding costs (stores) Engineering support costs (workshops) Contractors Overhead resources (admin, accounting)
Maintenance Costs
Lost Production & Quality-related Costs Facility non-availability costs Facility malfunction costs Legal liability costs Insurance costs
Lost Production &
Quality-related Costs
Operating Costs Labor Plant operations Engineering Energy Oil Gas Electricity Steam Water
Operating Costs
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Maintenance Operations
Operational Information
Maintenance History
Short-term Operations Management
“What, Who, When, Where”
Maintenance Plan (What, When)
“What, Why, How”
Feedback Planned Maintenance
Maintenance Planning and Management (Maintenance policies, objectives, procedures, processes)
Maintenance Audits & Performance Measurement
Near-term Tactical Management
“How Well”
Typical Preventive Maintenance Cycle
2013 Grant Thornton Management Services. All rights reserved.
Maintenance Planning and Management (Maintenance policies, objectives, procedures, processes)
Maintenance Audits & Performance Measurement
Maintenance Plan (What, When)
Maintenance Operations
Operational Information
Maintenance History
Corporate Planning and Management (Corporate policies, objectives, procedures, processes)
Corporate Audits & Performance Measurement
Strategic Plan
Short-term Operations Management
Near-term Tactical Management
Long-term Strategic Management
“What, Why, How”
“What, Who, When, Where”
“What, Who, When, Where”
“How Well”
“What, Why, How”
“How Well”
Feedback Response
2013 Grant Thornton Management Services. All rights reserved.
Maintenance Planning and Management (Maintenance policies, objectives, procedures, processes)
Measure
Test Results vs. Requirements &
Expectations
Monitor & Test
Test Plans, Schedules,
Work Orders & Parameters
Corrective Maintenance
Restore Equipment Condition Restore Operational Status
Reduce Downtime
Adjust “braces”
Repair “fillings”
Replace “dentures”
Parts / Stock
Parts / Stock
Preventive Maintenance
Extend Useful Life Reduce Unplanned Failures
Parts / Stock PASS
FAIL
Maintenance Management Preventive vs. Corrective Maintenance
Time
Constant Revenue
T2 Perform Scheduled Maintenance
T1 Initial Operations
T0 (+) $
(-) $
$0
Preventive Maintenance Pr
ofit
/ Los
s
Fixed Cost
Fixed Cost
Profit
Preventive maintenance programs address timing, cost or severity issues by proactively planning downtime
and maintenance in accordance with regular timeframes recommended by manufacturers of the
systems and components in use.
Variable Cost
Systems and equipment have variable costs associated with their operation, repair, environment and external market conditions. These variable costs include electricity, lubricants, and spare parts.
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.
2013 Grant Thornton Management Services. All rights reserved.
Cleaning $0 $1,800 Repair $4,000 $240 Planning $0 $100 Inspection $0 $1,800 Motor rewind $20,000 $2,500 (including new precision seals) Lost production $60,000 $0 Total Costs $84,120 $6,440
Sample 10-year maintenance cost profile of a typical motor
In this example, having a preventive management program would have saved around 92.3% in total maintenance costs (almost $80,000) associated with just this one motor over its typical 10-year lifespan.
Case 1)
Case 2)
Setting up a lamp maintenance plan that schedules the replacement all lamps in each designated area at the same time can save up to 90% in associated labor, inventory and lost productivity costs. When combined with maintenance strategies that use economic lamp types and ballast wiring designs, those planned, lower cost replacements could even be done 25-60% less often.
2013 Grant Thornton Management Services. All rights reserved.
Functional aspects of CMMS
Functional Aspects of CMMS Maintenance Management
Manage and control Maintenance Department functions - Planning and scheduling equipment maintenance - Planned (preventive) maintenance - Metered maintenance - Equipment runtime - Cycle time - Unplanned (reactive) maintenance - Work requests - Routine checks - Statutory checks - Mandatory checks - Overhauls
Manage Preventive
Maintenance
Manage Reactive
Maintenance
Manage Work
Requests
Monitor maintenance spending - Ensure that targets are met - Savings opportunities are pursued Integrate CMMS with accounting systems - Document and record all maintenance stock control and purchasing in enterprise software systems - SAP, J.D. Edwards
Provide maintenance reports and statistics - Downtime - Statistics-related KPIs - Maintenance costs - Location - Department - Personnel
Manage CbM
Initiate condition-based maintenance (CbM) on the basis of an asset’s condition - Vibration level - Oil particulates - Wear patterns - Time since last replacement - Meter readings
Manage Assets, Plant & Equipment
Manage and control asset, plant and equipment maintenance using IT systems and applications - Computerized Maintenance Management System (CMMS) - Predictive maintenance (PdM)
Functional Aspects of CMMS Computerized Maintenance Management Systems
2013 Grant Thornton Management Services. All rights reserved.
Process Data Aspects of CMMS
2013 Grant Thornton Management Services. All rights reserved.
A process is a series of tasks that lead to a final work state called the functional requirement.
Minimally, all processes provide information on: 1) What to do (tasks), and 2) How to do it (sequence)
Breaker Opened
Open Breaker
Replace Motor
Motor Replaced
Panel Tagged
However, it would often be useful to know more
Process Data Aspects of CMMS
2013 Grant Thornton Management Services. All rights reserved.
1) The breaker is in a panel located in a secure Data Center 2) DC Air Conditioning can only be off for 60 minutes 3) The Duty Officer has to give permission to access the DC 4) The Duty Officer will be here after 1:30PM 5) The panel is secured with screws 6) The motor weighs 75 kilograms
Breaker Opened
Motor Replaced
Panel Tagged
Process Data Aspects of CMMS
A process is a series of tasks that lead to a final work state called the functional requirement.
Open Breaker
Replace Motor
2013 Grant Thornton Management Services. All rights reserved.
Work flows document the series of work states that result from the performance of tasks within the process.
In business, work flows are sometimes referred to as "work-in-progress"
Breaker Opened
Open Breaker
Replace Motor
Motor Replaced
Panel Tagged
Work states are conditions that result from the successful completion of tasks.
Process Data Aspects of CMMS
2013 Grant Thornton Management Services. All rights reserved.
Task Input Output
Controls
Supports
In order to accommodate any additional data that might be available, the basic flow model needs to be expanded to include Controls and Supports,
This facilitates a more well-rounded understanding of the process.
Locations? Timeframes? Restrictions? Issue? Requirements? Costs? Work States?
Process Data Aspects of CMMS
2013 Grant Thornton Management Services. All rights reserved.
Task
How, Why, When
Who, Where, What
What What How Long, How Often
How Long, How Much
How Long, How Often
Input Output
Controls
Supports (mechanisms)
This establishes a model that minimally supports the additional capture of data related to how, why, when, where, and who.
Task
Process Data Aspects of CMMS
2013 Grant Thornton Management Services. All rights reserved.
Completed by 5PM Daily Approved Supplier List Engineering Specification Procedure P.1.1
Input Output
Supports (mechanisms)
How, Why, When
Who, Where, What
What What How Long, How Often
How Long, How Much
How Long, How Often
CONTROLS identify the laws, policies, procedures, timing requirements and criteria used to define how and why tasks are performed.
Task Prepare P.O.
Process Data Aspects of CMMS
2013 Grant Thornton Management Services. All rights reserved.
SUPPORTS (mechanisms) identify the infrastructure, resources, data stores, locations and personnel needed to conduct the task.
Purchasing Admin Saraburi Warehouse P.O. form F1 Purchasing Module AS400
How, Why, When
Who, Where, What
What What How Long, How Often
How Long, How Much
How Long, How Often
Completed by 5PM Daily Approved Supplier List Engineering Specification Procedure P.1.1
Input Output Task Prepare P.O.
Process Data Aspects of CMMS
2013 Grant Thornton Management Services. All rights reserved.
Task Prepare P.O.
How, Why, When
Who, Where, What
What What How Long, How Often
How Long, How Much
How Long, How Often
Completed by 5PM Daily Approved Supplier List Engineering Specification Procedure P.1.1
P.O. Requested
P.O. Prepared
Purchasing Admin Saraburi Warehouse P.O. form F1 Purchasing Module AS400
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.
Process Data Aspects of CMMS
2013 Grant Thornton Management Services. All rights reserved.
P.O. Requested
P.O. Prepared
How, Why, When
Who, Where, What
What What How Long
How Long
How Long
Purchasing Admin Saraburi Warehouse P.O. form F1 Purchasing Module AS400
Completed by 5PM Daily Approved Supplier List Engineering Specification Procedure P.1.1
Wait = 15 hrs Wait = 24 hrs
Process = 9 hrs Actual = 1 hr
Key TIME ELEMENTS are also captured to provide the means to assess, analyze and eventually improve throughput.
Task Prepare P.O.
Process Data Aspects of CMMS
2013 Grant Thornton Management Services. All rights reserved.
The FREQUENCY of each work state gives the team the ability to factor in the relative weighting of various processes
to assess impact and prioritization
P.O. Requested
P.O. Prepared
How, Why, When
Who, Where, What
What What How Long
How Long
How Long
Purchasing Admin Saraburi Warehouse P.O. form F1 Purchasing Module AS400
Completed by 5PM Daily Approved Supplier List Engineering Specification Procedure P.1.1
Wait = 15 hrs Wait = 24 hrs
Process = 9 hrs Actual = 1 hr
How Often How Often Freq = 100% Freq = 100%
Task Prepare P.O.
Process Data Aspects of CMMS
2013 Grant Thornton Management Services. All rights reserved.
P.O. Requested
P.O. Prepared
How, Why, When
Who, Where, What
What What How Long
How Long
How Long
Purchasing Admin Saraburi Warehouse P.O. form F1 Purchasing Module AS400
Completed by 5PM Daily Approved Supplier List Engineering Specification Procedure P.1.1
Wait = 15 hrs Wait = 24 hrs
Process = 9 hrs Actual = 1 hr
How Often
How Much
How Often Freq = 100%
B 40
Freq = 100%
Mid-scale payroll data from HR for each role provides a means to gauge and quantify RESOURCE COSTS / TASK. (e.g. If the average
Admin salary is B6,400/month, his hourly rate would be B40/hour.)
Task Prepare P.O.
Process Data Aspects of CMMS
2013 Grant Thornton Management Services. All rights reserved.
P.O. Requested
Purchasing Admin Saraburi Warehouse P.O. form F1 Purchasing Module AS400
Completed by 5PM Daily Approved Supplier List Engineering Specification Procedure P.1.1
The ability to analyze process information provides insight into utilization, capacity, workflow, redundancy, and productivity issues that impact the overall effectiveness of maintenance operations.
Process Data Aspects of CMMS
2013 Grant Thornton Management Services. All rights reserved.
1) What are the 10 most expensive work orders to perform?
2) Are Maintenance Electricians over or under-utilized?
3) Are Purchasing resources qualified for the tasks they participate in?
4) Which departments are impacted by or accountable for compliance with the requirements of 21CFR Part 11?
5) What areas can be addressed to improve overall throughput the most?
The ability to analyze process-related information provides the means to answer more difficult operational questions such as :
Process models show us ‘how’ to address various goals Process data allow us to address ‘how well’.
Process Data Aspects of CMMS
Here is a basic flow model for the process related to some scheduled preventive maintenance.
It consists of a series of tasks being done in sequence.
Process Data Aspects of CMMS The Value of Process Data
Maintenance Manager x x x xMaintenance Technician P x x xScheduler P x x x x
Adding roles, we can identify who the participants are on each task.
M iM i t MM
Process Data Aspects of CMMS The Value of Process Data
Add Controls, and we can see why they need to do each task, and how each should be done.
Chart of Accounts xCurrent Workload by Resource xInventory Reorder Level xMaintenance Policy x x x x xMaintenance Procedure x x x x x x x x xMaintenance Schedule x xPre-determined Maintenance Date x xStandard Cost List x
Maintenance Manager x x x xMaintenance Technician P x x xScheduler P x x x x
M iM i t MM
Process Data Aspects of CMMS The Value of Process Data
Resource Supports tell us what they are using, and where the work is being done.
CMMS Module - Inventory Module I x xCMMS Module - Preventive Maintenance I xCMMS Module - Purchase Order I xCMMS Module - Report I xCMMS Module - Work Management I x x x x xFinancial Software I xLocation: Plant Office I x x x x x x xLocation: Plant Spaces I xSpare Parts I x xTools I x x
Chart of Accounts xCurrent Workload by Resource xInventory Reorder Level xMaintenance Policy x x x x xMaintenance Procedure x x x x x x x x xMaintenance Schedule x xPre-determined Maintenance Date x xStandard Cost List x
Maintenance Manager x x x xMaintenance Technician P x x xScheduler P x x x x
M iM i t MM
Process Data Aspects of CMMS The Value of Process Data
Interactive supports are the data, document and interface whats needed to support specific tasks. The model is now set up to support data analysis.
CMMS Module - Inventory Module I x xCMMS Module - Preventive Maintenance I xCMMS Module - Purchase Order I xCMMS Module - Report I xCMMS Module - Work Management I x x x x xFinancial Software I xLocation: Plant Office I x x x x x x xLocation: Plant Spaces I xSpare Parts I x xTools I x x
Chart of Accounts xCurrent Workload by Resource xInventory Reorder Level xMaintenance Policy x x x x xMaintenance Procedure x x x x x x x x xMaintenance Schedule x xPre-determined Maintenance Date x xStandard Cost List x
Maintenance Manager x x x xMaintenance Technician P x x xScheduler P x x x x
M iM i t MM
Cost Allocation Screen xData - Cost x xData - Customer xWork Order x x x x x x
Process Data Aspects of CMMS The Value of Process Data
What does the Maintenance Technician do?
CMMS Module - Inventory Module I x xCMMS Module - Preventive Maintenance I xCMMS Module - Purchase Order I xCMMS Module - Report I xCMMS Module - Work Management I x x x x xFinancial Software I xLocation: Plant Office I x x x x x x xLocation: Plant Spaces I xSpare Parts I x xTools I x x
Chart of Accounts xCurrent Workload by Resource xInventory Reorder Level xMaintenance Policy x x x x xMaintenance Procedure x x x x x x x x xMaintenance Schedule x xPre-determined Maintenance Date x xStandard Cost List x
Maintenance Manager x x x xMaintenance Technician P x x xScheduler P x x x x
M iM i t MM
Cost Allocation Screen xData - Cost x xData - Customer xWork Order x x x x x x
Process Data Aspects of CMMS The Value of Process Data
What does the Scheduler use to allocate costs to specific work orders?
CMMS Module - Inventory Module I x xCMMS Module - Preventive Maintenance I xCMMS Module - Purchase Order I xCMMS Module - Report I xCMMS Module - Work Management I x x x x xFinancial Software I xLocation: Plant Office I x x x x x x xLocation: Plant Spaces I xSpare Parts I x xTools I x x
Chart of Accounts xCurrent Workload by Resource xInventory Reorder Level xMaintenance Policy x x x x xMaintenance Procedure x x x x x x x x xMaintenance Schedule x xPre-determined Maintenance Date x xStandard Cost List x
Maintenance Manager x x x xMaintenance Technician P x x xScheduler P x x x x
M iM i t MM
Cost Allocation Screen xData - Cost x xData - Customer xWork Order x x x x x x
Process Data Aspects of CMMS The Value of Process Data
Who are the people effected by tasks that are not covered by policy?
CMMS Module - Inventory Module I x xCMMS Module - Preventive Maintenance I xCMMS Module - Purchase Order I xCMMS Module - Report I xCMMS Module - Work Management I x x x x xFinancial Software I xLocation: Plant Office I x x x x x x xLocation: Plant Spaces I xSpare Parts I x xTools I x x
Chart of Accounts xCurrent Workload by Resource xInventory Reorder Level xMaintenance Policy x x x x xMaintenance Procedure x x x x x x x x xMaintenance Schedule x xPre-determined Maintenance Date x xStandard Cost List x
Maintenance Manager x x x xMaintenance Technician P x x xScheduler P x x x x
M iM i t MM
Cost Allocation Screen xData - Cost x xData - Customer xWork Order x x x x x x
Process Data Aspects of CMMS The Value of Process Data
2013 Grant Thornton Management Services. All rights reserved.
Implementation Aspects of the CMMS Roadmap
2013 Grant Thornton Management Services. All rights reserved.
CMMS Implementation Roadmap
To establish, improve and sustain the reliability of the facility.
2) Understand Facility Level
Maintenance Objectives
Support the facility’s operating pattern Achieve and sustain targeted availability levels Achieve and sustain targeted production and quality levels Achieve facility longevity expectations Achieve minimum safety standards Minimize resource and facility life-cycle costs Maximize productivity over the long-term Generate timely, relevant maintenance status reports
3) Understand Performance Expectations
and Priorities
Facility operating pattern is 3 shifts / day, 5 days / week Facilities must achieve greater than 99% availability during operating hours Production: 95% of tenant complaints resolved within 1 hour Systems must achieve 95% of their designed life-spans Safety first: 0 serious injuries / year Maintenance costs should not increase by more than 3% per year Spare part waste and defect costs shall not exceed 5% of overall budget A maintenance status report needs to be generated each week
1) Understand the Maintenance Mission
2013 Grant Thornton Management Services. All rights reserved.
5) Identify the Systems involved in satisfying each
Unit Objective
e.g.) HVAC units utilize heating, ventilation, chill water, and I&C control systems Need to inventory of all systems and relevant components through both document and visual verification.
6) Understand and document how those Systems satisfy Unit
Objectives
Need to document the temperature regulation process Need to document standard operating procedure (SOP) for water quality tests Need to document inventory stock reorder criteria
The HVAC system has to maintain temperatures between 70-75 degrees F The HVAC system only needs to be available on weekends per special request Lighting replacement costs need to be reduced by 15% Potable water quality needs to be improved within the next 12 months
4) Translate Facility Objectives into
Unit Level Objectives
Equipment hierarchy: Facility e.g. Office building Unit e.g. Potable water unit System e.g. Chill water system, chemical treatment system Component e.g. Condenser, Return water pump Part e.g. Pressure seal, valve bonnet, motor bearing
CMMS Implementation Roadmap
2013 Grant Thornton Management Services. All rights reserved.
Identify maintenance tasks that need to be performed (e.g. lubrication, inspection) Identify how often those maintenance tasks will need to be performed (frequency) Categorize each maintenance task by job type (e.g. minor, major, overhaul)
7) Develop Life Plans for each Unit
1st line maintenance: Emergency jobs - work needing to be carried out in the shift of occurrence. Small jobs (corrective, preventive) that can be 'fitted' into the schedule without a lot of detailed planning.
8) Develop Maintenance Schedules for all Units
Integrate maintenance requirements and frequencies from all unit life plans Factor in key operating requirements (e.g. summer break, promotion campaigns) Classify all maintenance tasks by their scheduling profiles (1st line, 2nd line, etc.)
2nd line maintenance: Larger preventive jobs (services, small overhauls) Corrective jobs that require planning Mid-size jobs that can be scheduled based on priority into a weekend or some other available time window.
3rd line maintenance: Major plant overhauls (or parts of plant) Jobs requiring the plant to be offline for considerable lengths of time (downtime) Jobs that are generally carried out at long to medium-term intervals (Low periodicity) Jobs requirement long lead-time for planning
CMMS Implementation Roadmap
2013 Grant Thornton Management Services. All rights reserved.
Workload dictates required size & composition of the maintenance. organization. Two other key considerations are the distribution of resources and authority.
9) Assess the Maintenance Organization
Resource structure is the logistic distribution of personnel, spares, tools and information that is best suited to meeting defined maintenance requirements (e.g. response time, output quality) Think about the resources in a hospital emergency room vs. those in a typical patient room. The additional emergency room equipment was geographically distributed to meet the need for timely response. The resource structure should be designed to achieve the best resource utilization
9a) Determine the appropriate
Resource Structure
Administrative structure is the distribution of decision making authority that is best suited to meeting defined maintenance requirements Think about each person’s authority to pull a fire alarm without having to first gain permission from the Maintenance Engineer It is the hierarchy of work roles ranked by authority and responsibilities, that determines what, when and how maintenance should be conducted
9b) Determine the appropriate
Administrative Structure
CMMS Implementation Roadmap
2013 Grant Thornton Management Services. All rights reserved.
Enter facility objectives and expectations (SLA, control parameters, priorities) Enter unit objectives and expectations (SLA, control parameters, priorities) Enter in-scope equipment data (unit, system, component, part) Enter in-scope processes, critical work states and workflow criteria Enter life plan data (required maintenance jobs, frequencies, type) Enter the maintenance schedule and scheduling characteristics Enter the resource structure (logistic distribution, quantity, requirements) Enter the administrative structure (roles, responsibilities, authority)
10) Configure and Implement the
Maintenance System (CMMS)
CMMS Implementation Roadmap
2013 Grant Thornton Management Services. All rights reserved.
Change Aspects of CMMS Implementation
2013 Grant Thornton Management Services. All rights reserved.
Most companies naturally focus on system-related factors when preparing to install a CMMS product. However, factors that delay or even prevent successful implementation are usually "soft side" issues related to maintenance processes, procedures and people. These factors need to be addressed holistically to ensure the impact of CMMS changes are fully accounted for in an integrated manner.. In turn, each of these issues needs to be assessed and verified against maintenance operation and corporate policies, to ensure management alignment and compliance with requirements.
Maintenance Mission Are maintenance operations aligned with business goals and requirements?
Program & Controls Are maintenance issues effectively managed and controlled?
Process Is maintenance conducted in the most productive manner possible?
People & Organization Are maintenance resources adequately qualified and motivated?
System & Facilities Are systems suited and fully utilized to support maintenance operations?
Improved Maintenance Environment
Corporate Mission
“As-is” Maintenance Environment
The Real Impact of Change The Nature of Change Holistic CMMS Impact
2013 Grant Thornton Management Services. All rights reserved.
Strategic Level Corporate Planning & Management
Tactical Level Maintenance Planning & Management
Operational Level Maintenance Operations
Top management unaware of issues Maintenance is not valued
Uncoordinated effort Poor knowledge management
Reactive Maintenance High inventory-related costs
The Nature of Change Problems by Level
TacticMaint
Maint
UncoPoor
2013 Grant Thornton Management Services. All rights reserved.
Existing Maintenance Organization, Processes,
Systems, and Data
“Ideal” Usage New CMMS
Features, Functions and Capabilities
Maintenance “Best Practice”
All CMMS software products are designed and built around some “ideal” set of assumptions, processes and data sets to handle maintenance management
However, companies soon realize that these ideals rarely fit their operations or meet their requirements, without some, often significant, degree of customization.
2013 Grant Thornton Management Services. All rights reserved.
Effective CMMS change then became dependent upon the ability to clearly define the balance between the adoption of design features and best practice scenarios
Adopt Adapt
eeee etweebebbbbsss
en thhee doption of desiadaen t gn featuressgn s nndn nanand the adaptation of existing operations.
2013 Grant Thornton Management Services. All rights reserved.
CMMS Guidance and Recommendations
2013 Grant Thornton Management Services. All rights reserved.
Avoid associating maintenance with just repairs. The value of maintenance management is increased reliability and
a lower overall cost of ownership.
Maintenance Management Primary Functions and Benefits
Maintenance Management
Preventive Management
Inventory Management
Report Management
Work Management
Purchase Order Management
Reactive Management
CMMS
Cost Accounting
Key Maintenance Management Functions
2013 Grant Thornton Management Services. All rights reserved.
General CMMS
Software Selection Criteria
Cost Effectiveness
Customization Capabilities
Multi-Level, Training
Graphic Capabilities
Simultaneous
review of data & drawings
Attached pictures
Multi-Tasking Capabilities
Integrated Functions
"Nice-to-have"
CMMS Features,
Functions & Capabilities
Work Order System
Schedule
maintenance
Generate Work Orders
Ability to customize on-line
Existing
screen layouts,
Extra tables, Reports
Ability to attach user-defined
value lists to any entry field
Data Quality, User-friendly
Ability to access the CMMS database
SQL queries
Standard Queries,
Ad hoc Queries
Ability to add new or
non-maintenance related screens
Recertification or Inspection-related
"Have-to-have"
CMMS Modules
Equipment Module
Contains all information about
the equipment being maintained
Preventive Maint. Module
Maintenance Schedules
Reliability, Availability
Work Order Tracking Module
Work Requests,
Work Orders
Meets monitoring requirements
Job Plan Module
Work Plans
(Procedures)
Reference Library Links
CMMS Selection Software Selection Criteria
2013 Grant Thornton Management Services. All rights reserved.
"Think carefully about the equipment number scheme. You will be stuck with it forever." "Don't rush your implementation. Have a well thought plan and SOPs" "Don't try to make the software fit your business practices. Some practices may need to be changed." "Get the naming convention in place. Treat equipment and location as separate entities." "Use drop down menus with pick lists whenever possible." "Be very generous with the amount of training provided to all users." "Be aware that the size of spares inventory and other procurement costs are often higher in pharmaceutical plants. New or frequently upgraded products require frequent changes in inventory and plant equipment."
Random Notes from the Field Recommendations and Caveats
2013 Grant Thornton Management Services. All rights reserved. - 60 -
Tantra Tantraporn
Partner Grant Thornton Management Consulting Co., Ltd. 18th Floor Capital Tower, All Season Place 87/1 Wireless Road Bangkok 10330 Thailand.com (w) 02-206-8222 x8230, (m) 089-075-6400 [email protected]
TRACK 2C
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 Managing Director of PhC PharmaConsult
Since 1992 Managing Director/ Partner with i+o Industrieplanung + Organisation
GmbH & Co. KG, Heidelberg, Germany
1991 – 1992 Head of Department of Information Systems with i+o
■ 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
MKT_io-consultants_Project_Management_20130709
14
Elements of io-consultants project management
15
Elements of io-consultants project management
▐ The project management of io-consultants is basically separated into five elements.
MKT_io-consultants_Project_Management_20130709
Defining project target
Determining framework
requirements Coordinating and steering
Quality assurance
and risk monitoring
Documenta-tion and
filing
16
Elements of io-consultants project management MKT_io-consultants_Project_Management_20130709
Defining project target
Determining framework
requirements Coordinating and steering
Quality assurance
and risk monitoring
Documenta-tion and
filing
▐ Determination of project targets and frame of action
■ Individuality of the customer
■ Project definition and planned actions
■ Basis and background information
■ Resource planning and organizational formation (customer side, external planner)
▐ Budgeting of overall project and subprojects
▐ Creation of an overall project schedule (MS Project)
17
Elements of io-consultants project management MKT_io-consultants_Project_Management_20130709
Defining project target
Determining framework
requirements Coordinating and steering
Quality assurance
and risk monitoring
Documenta-tion and
filing
▐ Clear task definition using project organization charts
▐ Determination of project standards and glossary with document filing
▐ Definition of meeting types and cycles
▐ Preparing and updating of a project member list
▐ Documentation of project guidelines in project manual
18
Elements of io-consultants project management MKT_io-consultants_Project_Management_20130709
Defining project target
Determining framework
requirements Coordinating and steering
Quality assurance
and risk monitoring
Documenta-tion and
filing
▐ Deadline tracing and appointment coordination
▐ Securing of handling quality and keeping of standards
▐ Moderation of meetings
▐ Sticking to communication and information paths
▐ Tool based project steering
▐ Follow-up of tasks
19
Elements of io-consultants project management MKT_io-consultants_Project_Management_20130709
Defining project target
Determining framework
requirements Coordinating and steering
Quality assurance
and risk monitoring
Documenta-tion and
filing
▐ Regular reports to steering committees
▐ Securing of budget keeping
▐ Management summaries after important project steps (content: project progress, results, documentation, deadlines, budget)
▐ Keeping of mile stones by means of project status reports
▐ In time activation of crisis managements
20
Elements of io-consultants project management MKT_io-consultants_Project_Management_20130709
Defining project target
Determining framework
requirements Coordinating and steering
Quality assurance
and risk monitoring
Documenta-tion and
filing
▐ Structured and transparent data filing
▐ Clarity and simple handling
▐ Auditing acceptability
▐ Final documentation
21
io-consultants Project portal
22
io-consultants Project portal
▐ 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
MKT_io-consultants_Project_Management_20130709
23
io-consultants Project portal
▐ 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
MKT_io-consultants_Project_Management_20130709
io-consultants Project Portal
Specialist 1
Specialist 2
Project steering
Customer
io-consultants
24
io-consultants Project portal
▐ 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
MKT_io-consultants_Project_Management_20130709
25
io-consultants Project portal
Modules of the Portal
Document Administrat.
Minutes Keeping
Task Administrat.
Deadline Keeping
MKT_io-consultants_Project_Management_20130709
26
io-consultants Project portal
Modules of the Portal
Document Administrat.
Minutes Keeping
Task Administrat.
Deadline Keeping
MKT_io-consultants_Project_Management_20130709
27
io-consultants Project portal
▐ 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
MKT_io-consultants_Project_Management_20130709
28
io-consultants Project portal
Modules of the Portal
Document Administrat.
Minutes Keeping
Task Administrat.
Deadline Keeping
MKT_io-consultants_Project_Management_20130709
29
io-consultants Project portal
▐ 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
MKT_io-consultants_Project_Management_20130709
30
io-consultants Project portal
Modules of the Portal
Document Administrat.
Minutes Keeping
Task Administrat.
Deadline Keeping
MKT_io-consultants_Project_Management_20130709
31
io-consultants Project portal
▐ 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
MKT_io-consultants_Project_Management_20130709
32
io-consultants Project portal
Modules of the Portal
Document Administrat.
Minutes Keeping
Task Administrat.
Deadline Keeping
MKT_io-consultants_Project_Management_20130709
33
io-consultants Project portal
▐ 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
MKT_io-consultants_Project_Management_20130709
34
Standardization
35
Standard Layout – Solid Dosages MKT_Pharma_Focus_Material_Flow_20130709
Personnel Flow
Material Flow
36
Standard Layout – Material Flow MKT_Pharma_Focus_Material_Flow_20130709
Inbound via truck docks Transport to warehouse via sampling booth (raw materials)
Transport to central weighing area via material lock
Transport to granulation and / or bin blender
Transport to tablet press and / or capsule filling
Transport to coating (optional)
Transport to primary packing (blister, bottles, wallets etc.)
Transport through the wall to secondary packing (cartons, cases, pallets)
Transport to outbound area via material lock
Storage of finished goods
Outbound via truck docks optional with previous commissioning
Return
37
Standard Layout – Personnel Flow MKT_Pharma_Focus_Material_Flow_20130709
Main staff entrance Direct access to admin offices and / or laboratories
Access to central lockers for production and logistics personnel
Direct access to logistics area (black)
Access to production and prim. packaging area (white) via additional air locks with changing procedure
Access to secondary packaging (grey) via air lock with addtional gowning measures (e.g. caps)
Return
38
Examples
39
Success factors for a good project management
40
Success factors for a good project management
▐ Clear communication
▐ Target orientated project work
▐ Structure and project transparency
▐ Fast recognition of project risks
▐ Usage of modern communication means to increase project efficiency
▐ Permanent supervision of all parties involved
MKT_io-consultants_Project_Management_20130709
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
Building technology
Approvals (pharmaceutical)
Approvals (non-pharmaceutical)
Planning
Execution
Internal Planner Authorities
PLANNING TEAM(S)
SCHEDULE EXAMPLE
Company standards, planning conditions (quantities, technologies, products, deadlines, budget ...)
Specific guidelines, (Biosafety, Fed Std, OSHA) for conception, planning, operation ...
• Static • Dominated by Economical Criteria • No Project Alternatives: • Yes / No only • No Influence on Schedule of
Subsequent Phases
Feasibility
• Includes the Feasibility Study • Dynamic / prospective • Dominated by Technical Criteria • Project Alternatives are generated • User oriented • Choices possible
- Costs - Technology - Organisation
• Reduces Time spent on subsequent Phases, while increasing their Precision
Conceptual Study
Strong Conceptual
design
Basic Design
Detail Design
Execution
PLANNING MODELS
It pays to invest into a strong conceptual design • Low initial costs • Early clarification of main issues • Powerful decision tool • Possibility to develop alternatives • “Freewheeling”
PLANNING SEQUENCE AND ITERATION PROBLEMS Planning Task Start
Task Definition Targets Requirements
Analysis
Conceptional Design with Alternatives
Basic Design
Execution
easy
difficult
Detail Design
100%
90%
80%
60%
50%
40%
30%
20%
10%
70%
100%
RELATIVE COSTS OF THE DIFFERENT PHASES
The cheapest and most promising Phase is the Conceptual Phase !
Detail Engineering
Factory size Factory organisation
Technology GMP concept
Basic Design Conceptual Design
Execution
Cost saving potentials
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
POSSIBILITIES OF COST MINIMISATION
Basic Design
The best and cheapest chance to minimise cost of investment and operation is in Phase 1 !
Detail Engineering
Execution
Costs saving potential
Conceptual Design
Factory size Factory organization
Technology GMP
Small teams Brainstorming
Alternatives New ideas
Feasibility Conceptual design
Basic design
Detail design
Execution Supervision
Documentation
Cost estimation
Cost calculation
Tender documents Offers
Final quotations
The better the concept, the higher the precision
DETERMINATION OF COSTS in relation to the planning stage
PRICE PAID
PRECISION OF COSTS in relation to the planning stage stage
± 30% Cost estimation Feasibility
Conceptual design
± 5% Final Quotations Execution
Supervision Documentation
± 20% Cost calculation Basic Design
± 10% Tender documents Offers
Detail Design
The better the concept, the higher the precision
Feasibility Conceptual design
Basic design
Detail design
Execution Supervision
Documentation
DETERMINATION OF COSTS in relation to the planning system
Turnkey price: poor control
General planner: good control
- +
The Purpose of the Conceptual Design is to arrive to • Layout • General Factory Organisation Procedures • Hygiene Concept • Technology Concept • Air Handling and Utilities Concepts which can be successfully presented to Authorities for a Pre-Approval Design Review
GMP Considerations and Factory Planning go Hand in Hand
PURPOSE OF CONCEPTUAL DESIGN
and to get a high degree of safety about • Investments • Schedule
- Planning of a production plant
• future oriented • flexible • economical in investments and operating costs • GMP conform • conform to local / international regulations
- High motivation of staff by high quality of working place - Efficient planning - Adequate quality standard (value for money) - Architecture compatible with local surroundings
TARGETS OF PHARMACEUTICAL FACTORY PLANNING
HOW TO REACH A GOOD CONCEPTUAL DESIGN RESULT ?
Right team Good method Discipline Good data Some fantasy
Right team Good method Discipline Good data Some fantasy
Right team Good method Discipline Good data Some fantasy
Right team Good method Discipline Good data Some fantasy
Right team Good method Discipline Good data Some fantasy
PEOPLE AND PLANNING
A Quote: You do not really understand something
unless you can explain it to your grandmother." Albert Einstein
The idea is to work intensively with a small group of people, possibly detached from their daily chores. These people must have the necessary know-how (or back-ups) and the power of decision
• Economy of scale • Efficiency / Best practice • Flexibility • Performance • Organisation
Analysis of • Product range • Process • Technologies • Organisation
Conceptional design • Make or buy • Specialisation • Capacity increase • Technology • Standardisation • Regulatory aspects • Results versus costs
• Requirements • Vision of client
PLANNING METHOD DEVELOPMENT OF IDEAL ORGANISATION
Information Strategy
Identification key problems
Analysis Material /
Information flow
Idenfication necessary
infrastructure
Analysis process
START
Definition Modules
Functional units
Vertical Horizontal
Resulting Organisation
END
Verification process flow, material flow
Other requirements,
constraints, etc.
Calculation necessary
space
Definition of constraints,
etc. Adaptation Process,
machinery + equipment
Evaluation +
Selection
Plant strategy
+
Process architecture
Rough layout development
Layout alternatives
Combination material flows
functional inter-
dependencies
B/W-Orientation of factory
Analysis organisation
Analysis space situation
Analysis machinery / equipment
Analysis of products
and production
volumes
Verification GMP
concept
Morphological Analysis + Search for Solutions Capacity and Rationalisation Analysis
Existing Technology
GMP-Concept
Technological Alternatives
Investment / Budget
Forecasts, Quantities, Product Mix
Batch Sizes
Galenical Properties
Degree of Automation
Project- Technology
Degree of Automation
Batch Sizes
Shifts ?
Product Seasonality
Campaign Sizes
Cleaning + Change-over
Times
Foreseen Equipment
Dimension. Machines
(Type/ Quantity)
PLANNING METHOD RATIONALISATION, INNOVATION AND OPTIMISATION
GMP-Concept
Plant strategy
+
Process architecture
PLANNING PROCEDURE: CONCEPTUAL DESIGN
Development of the masterplan for the design onthe green field
Development of the integration of the layout into an existing building structure
Production forecasts / next 6-10 years
Description of process flows from starting materials until
finished product
Design of the overall flow diagram indicating all
GMP-classes
Calculation of material flow quantities
Definition of personnel, shifts, etc.
Design of the ideal layouts + modules for each step
Ideal layouts personnel areas
Ideal layouts peripheral areas
Combination of individual layouts to functional units --> Granulation, tabletting, preparation of liquids, filling ...
Design of the ideal overall total layout
Definition of - Process technology - Machinery + equipment - Transport systems + containers
PLANNING PROCEDURE: CONCEPTUAL DESIGN FORECASTS
Product lists, quantities
Sorting by galenical forms
Sorting by types (“conventional”, toxic, hormones, beta-lactames, etc.)
Strategy for marginal products (quantities, types, galenical
forms): Make or buy
ABC ANALYSIS
SELECTION OF TECHNOLOGY AND EQUIPMENT EXAMPLES OF SELECTION FACTORS
• Vision of client • Properties of products to be processed • Output requirements • Degree of automation, sophistication • Supplier: price, service and serviceability • Cleanability and maintenance needs • Space constraints • Previous experience, available equipment
(standardization) • GMP issues • Safety of operator
SELECTION OF TECHNOLOGY AND EQUIPMENT
• Vision of client: size, degree of sophistication, automated guided vehicles, architecture, budget, future-oriented or not
• Properties of products to be processed • Output requirements • Degree of automation, sophistication • Supplier: price, service and serviceability • Cleanability and maintenance needs • Space constraints • Previous experience, available equipment (standardization) • GMP issues • Safety of operator
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 needs • Space constraints • Previous experience, available equipment (standardization) • GMP issues • Safety of operator
NUMBER OF PRODUCTS
Q U A N T T I T E S
AUTOMATION POSSIBILITIES
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
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 • Previous experience, available equipment (standardization) • GMP issues
Aseptic processing problems: automated loading of freeze-dryer, increased automation
• 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 • Safety of operator: containment or PPE ?
In most cases, several factors will play a role simultaneously
ABA ADAACA
BAA BAEBADBACBAB
CAA CAB
DAA DADDACDAB
EAA EACEAB
FAA FAEFADFACFAB
GAA GAB
HAA HACHAB
AAA
BBB
CCC
DDD
EEE
FFF
GGG
HHH
SELECTION OF TECHNOLOGY AND EQUIPMENT MORPHOLOGICAL ANALYSIS
P R O C E S S S T E P S
PROCESS ALTERNATIVES
PLANNING METHOD PROCESS AND ORGANIZATION FLOW CHARTS
Whereas a process flow chart reflects the process only, an organization flow chart includes the process, its organization as well as additional elements such as quantities, personnel needs, hygiene zoning, equipment and inter-relationships within the production or between production and related functions. The process flowchart must be transformed into an organisational flow chart Organization flow charts exist at different levels, micro- and macro:
Micro: within a department Macro: within a production unit/plant
PLANNING METHOD PROCESS FLOWCHART
Granulation Binder preparation
Drying
Sieving
Addition lubricants
Blending
Compression
dit
Granulation Binder
preparation Drying
Sieving
Addition lubricants
Blending
Compression
Weighing
Staging m2 ?
Staging m2 ?
Staging m2 ?
Container washing
Staging m2 ?
Granulation
Drying
Sieving
Addition lubricants
ding
Compression
m2 ?
Binder preparatiopreparat
n
GGnddddddder
Blend
r
Stagi
dit
PLANNING METHOD ORGANIZATION FLOWCHART
PLANNING METHOD FLOWS PERSONNEL AND MATERIALS
Exterior
Lockers G
G
Lockers D
D
Lockers C
C
A/B
Lockers A/B
Exterior
Lockers G
G
Lockers D
D
Lockers C
C
A/B
Lockers A/B
Selection of alternative important, later changes practically impossible
LOGISTICS Raw material Primary packaging material Secundary packaging material Finished products
Receiving
area
Prep
arat
ion
area
for r
aw -
and
prim
ary
pack
agin
g m
ater
ial
Sampling Booth
Shipping
wei
ghin
g Production
area
Marshalling
Bul
k st
ore
Packaging
lines
pal / h
pal / h
pal / h
pal / h pal / h
pal / h pal / h pal / h
pal / h pal / h pal / h
pal / h
pal / h
pal / h
pal / h
Warehouse
Pharma
Storage
capacity:
pallet
places
Sampling Quarantine separation
Change of pallets to/from production Procedures in material air locks
« GOOD GMP »
• Minimized risk of contamination / cross-contamination • Clear material flows (uni-directional whenever possible) • Clear personnel flows (uni-directional whenever possible) • Unambiguous definition of GMP zones • Separation clean – dirty (washing areas)
Overkill Cost issues Nice to have GMP is not an attribute, no black and white attitudes
SUMMARY
A good pharmaceutical factory is a factory that is: • Pharmaceutically approved (qualification / validation )
• Economical to operate and maintain
• Flexible and adaptable quantity-wise and for new technologies
To design such an excellent pharmaceutical plant, an integrated, multi-disciplinary and experienced team is required. The objectives, the vision, the method and the involvement of each member of the team will achieve this goal, and not the principle “function follows adding up individual inputs”
TRACK 2C
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. 11
th, 12
th Floor, Home Place Office Building
283/52 Sukhumvit 55 (Thonglor) Klong Ton Nua, Wattana Bangkok 10110 Thailand Education - Thummasat University, Master Degree of Business Administration - Chulalongkorn University, Bachelor Degree of Electrical Engineer
Career Summary Over 18 years of ERP implementation, Project management and business process improvement experiences in various industries such as Auto parts, Chemical, Packaging, Electric equipment, Foods & Beverage, Pharmaceutical etc. Service Capabilities
ERP Project Management
Implementation Consulting in Trade and Logistics,Production & MRP, Project
Training in Trade and Logistics, Production & MRP, Project
Project Implementation Record
Exedy Co.,Ltd
Siam Calsonic Co.,Ltd
Microchip Co.,Ltd
Useful Food Co.,Ltd.
Siam Ruammit Co.,Ltd
Thai Summit Autoparts Co.,Ltd
Ampas Industries Co.Ltd.
SVI Co.,Ltd.
Professional Certification Microsoft Dynamics Implementation Certified Microsoft
® Business Solutions Certified Professional in Axapta – Trade & Logistic
Microsoft® Business Solutions Certified Professional in Axapta – Production
Microsoft Dynamics AX (2.5,3.4,2009,2012) Axapta Baan IV Baan ERP Hyperion CADAM
ERP for Pharmaceutical Industry (Microsoft Dynamics AX) Prateep Juavijitjan Vantage Business Solutions
Our Agenda Today
How Microsoft Dynamics AX can help
Powerful Agile Simple
Key solution advantages for Pharmaceutical Industry
Questions?
Global business imperatives
Global trends and business challenges A new generation of enterprise resource planning (ERP)
Global Business and IT Trends
Global competition and global expansion Organizational change Outsourcing and complex value chains Changing supply and demand Fluctuating workforce demographics Increasing need for compliance and transparency
Keeping pace with trends and competition with legacy systems Need for IT governance and to modernize, simplify, and standardize Enabling users of consumer devices and social networking technologies Changing role of IT
Challenges for Organizations
Achieve operational insight across the organization Need for business agility Reduce operational costs Align IT and business objectives
Increase ERP adoption
Reduce IT operational costs
Enable business strategy and respond quickly to line-of-business (LOB) requests
Challenges for Enterprise Applications
“Enterprise Apps Customers Have Issues,” Forrester Research, Inc., February 26, 2010
A new generation of ERP That works for you, not against you
Powerful Powerfulembedded embeddedembedded
analytics and BIIB analytics and Bnalytics and BBIB
Applications that Applications tare an asset
hat hatt t
Simplicity and mplicityagility
y any any y
Works the way you need it to Simple to use Get the right data
to decision makers
Complete industry- specific solutions
Manufacturing
Distribution
Retail
Services
Public Sector
ring
n
toor
Tailored to meet your needs
Simple
Powerfully Simple
Powerful Agile Pervasive interoperability
Powerful
Deliver more value faster with a single, powerful solution:
“The ability to view and apply various manufacturing processes through a single ERP solution is revolutionary to our business. With Microsoft we are confident we will remain on the cutting edge of technology.” —Hubert Meisterjahn CIO, Dornbracht
Gain immediate insight and unlock greater productivity with a RoleTailored user experience.
Scale your organization quickly with a single global solution.
Gain value quickly with purpose-built industry and operational capabilities in a single solution.
f t i
eatteerr perience.
on.
tt
Prebuilt Industry and Operational Capabilities
• Single solution for five industries
• Rich core ERP capabilities • Large partner ecosystem
Gain value quickly with purpose-built industry and operational capabilities in a single solution.
ne
Core ERP Suite (Finance, HCM, Compliance Management, SRM,
Environmental Sustainability, Expense Management)
Public Sector
Services Sector
Retail Manufacturing Distribution
Global Solution
• Prebuilt, country-specific localizations for 36 countries
• Highly scalable • Shared data and unified
processes across the organization
Scale your organization quickly with a single global solution.
RoleTailored User Experience
Gain immediate insight and unlock greater productivity with a RoleTailored user experience.
• RoleTailored user experience • Self-service business
intelligence and reporting • Notifications and alerts from
workflows
Differentiate your business easily with model-driven layered architecture.
Agile
Support your business today and tomorrow with flexible deployment alternatives.
Plan, visualize, and change your business by using unified natural models.
Increase opportunities and reduce risk with an agile solution.
“For us, it’s all about agility—if we can’t deliver in weeks what used to take months, we’re holding back the business.” —Greg Smith CIO, Royal Canadian Mint
Unified Natural Models
• Easy-to-use financial dimensions
• Organization model • Configurable graphical
workflows • Single business process
repository
Plan, visualize, and change your business by using unified natural models.
Flexible Deployment
• Selection of governance models
• Cloud-based services • On-premises and partner
hosted • Flexible solution architecture
Support your business today and tomorrow with flexible deployment alternatives.
Partner hosted On-premises
Model-Driven, Layered Architecture
• Models combined with layered architecture
• Development within Visual Studio®
• Table-inheritance and more granular metadata
• Enhancements in modeling the user experience
Differentiate your business easily with model-driven layered architecture.
Simple
Connect employees, customers, suppliers, and partners easily through integrated collaboration capabilities
Drive user involvement and innovation with an easy-to-use solution.
“The familiar look of the product will immediately remove barriers that some people might experience when it comes to financial information.” —Mike Bailey Director of Finance and Information Services City of Redmond, Washington
Streamline IT processes by simplifying management of your ERP solution at every stage of the life cycle
Provide access to data and business processes with an ERP solution that is simple to use
Familiar and Intuitive
• Looks and works like Microsoft Office
• Common UI across web browser and Windows® UI
• Bidirectional integration with Microsoft Office 2010
• Enterprise Search
Provide access to data and business processes with an ERP solution that is simple to use.
Lean Kanban Boards
Integrated Collaboration
• SharePoint-based employee, vendor and customer portals
• Adaptable web services, such as Sites Services
• Microsoft Lync integration • Creation of SharePoint
collaboration sites directly from within ERP
Connect employees, customers, suppliers, and partners easily through integrated collaboration capabilities.
Application Life-Cycle Management
• Microsoft Dynamics ERP RapidStart Services
• Highly streamlined, user-friendly installation
• Simplified Role-based security setup
• Accelerated upgrade through upgrade advisors and tools
Streamline IT processes by simplifying management of your ERP solution at every stage of the life cycle.
Simplify
Powerfully Simple
Pervasive interoperability
Solution investments + Related ecosystems = = Solution investments + Related ecosystemsImproved productivity and lower IT costs
s tsts prov
Enhanced Industry functionality
Services Sector Public Sector Retail Distribution Manufacturing
1,000+ new features and enhancements
Simple Powerful Agile Pervasive interoperability
f l
Microsoft Solutions for Life Sciences and Pharmaceutical Manufacturing
- Can introduce new products in a timely, least-cost manner
- Manage electronic quarantines, quarantine release by user and material type, printed material control/obsolete components, lot control/segregation, lot tracking, and enable drug and hazardous material reconciliation. - Model the processing of costly ingredients to help minimize overruns and short-runs - Shelf life tracking to consider expiration dates during production and distribution
- Centrally manage co-products and by-products in your formulas or recipes, and always know the correct inventory status for any given item. - Tight integration with other Microsoft® products extends Microsoft Dynamics AX capabilities to help ensure a fast return on investment - Compliance Management
Key Function of MS Dynamics AX (For Pharmaceutical Industry)
-Input-driven process specification -Attribute tracking and dynamic formula adjustment - Centralized quality control and compliance support (Help support U.S. Food and Drug Administration (FDA) reporting, plus GMP and FDA regulation 21 CFR Part 11) - Batch optimization and balancing - Yield planning and tracking - Co-product/by-product management - Integrated quality control (QC) capabilities - Customized product and packaging capabilities - Detailed production cost analysis - Optimized picking - Manufacturing process validation - Extensive audit & compliance
Key Investments to the Application Foundation
Master Data Reference Data Global Engines
Master Data • Organization Model • Global Address Book • Product Information Management Reference Data • Time zone enhancements • Unit of measure Global Engines • Policy Management • Questionnaire • Support for unlimited financial dimensions
Key Investments in Horizontal Capabilities
Financials GRC HCM & Payroll*
Financials • Financial data across legal entities • Improved Chart of Accounts • Budget Control • Separation of Operations and Accounting • Accounting distributions • Collections • 3-way match
GRC • Audit Workbench (audit rules and policies) • Enhanced Compliance Center • Environmental Sustainability Dashboard
HCM/HRM • Employee Self Service • Streamlined HR process • Site Services enable external applicants
to apply for job postings
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 Public Sector
Manufacturing: • Mixed-mode capabilities
(process and discrete manufacturing) • Operations Resource Model (resource scheduling) • Touch-enabled time recording on the Shop Floor • Master Planning with Machine Sequence or Machine Capabilities • Potency Management & Lot Attribute
Distribution: • Intercompany supply and demand visibility • Intercompany demand visible upstream supply chain • Sales order process enhancements (fast order entry) • Mass price changes and prices in multiple currencies.
Role Centers and R l C t dRole Centeers aers aDashboardDashboarddsds
MS Exceel
MS SharePoint
Presentation Cubes AX2012 Database
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.
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).
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
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
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
Each equipment can be managed as an 'object' Point-of-use identification & status verification Electronic equipment logbook (automatic) Equipment related cleaning recipes
1 234567 890128
Facilitating the plant-wide & paperless electronic
Deviation and event handling; Analysis and acknowledgement anytime Controlling CQAs and CPPs Focus on deviations / non conformities Traffic light functions to control the process Review-by-exception Follow pre-defined release workflow
Quality “Do it right the first time!” Minimize lost batches or rework Prevent Errors by means of pro-active online checks
Full Compliant Process Identify and eliminate compliance problems No efforts on paperwork Review-by-Exception (incl. CQA, CPP)
Reduce Work-In-Progress Save material costs
Complete Documentation & Deviation Report Automated up-to-date logbooks Streamlined Event and Deviation Management Reduced Release time through ‘Review by Exception’
Optimized Process Reduce lead time Tight integration and interaction with DCS / SCADA / PLC
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
Further use of mobile devices, phones, etc., Cloud Computing and fully internet based systems RFID Continuous batch process PAT / QbD – initiative of risk-based approach MES is already relevant for those topics. Customers have implemented this already. This will be further developed and established in near future.
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)
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.
TOPIC: THE ROLE OF MANUFACTURING IT - AN INTEGRATED APPROACH (LIMS)
Michael Wang Director, Solution Consulting, APAC Accelrys KK Singapore Branch 80 Robinson Rd. #02-00 068898 Singapore Education - National University of Singapore, MSc Singapore
2012 – Present Director, Solution Consulting, APAC, Accelrys Lead pre-sales team in APAC for sales of informatics solutions from Accelrys. Provide business impact analysis to prospects and customers. Provide consulting service to customers in lab management, computer validation and system deployment for LIMS, LES, ELN, etc. 2004 - 2012 Manager, Technical Sales, APAC, ThermoFisher Scientific Lead the pre-sales team in APAC for sales of LIMS and CDS solutions from ThermoFisher. He has worked on projects in ONO, CSL, AMO, Glenmark, Weeda, Wuxipharma, etc as project manager, validation consultant, services consultant, etc. 2001 - 2004 LIMS Project Manager, Pfizer Manufacturing, Singapore Lead the LIMS project team to implement and validate the LIMS system in the QC lab for the API plant. The system has passed US FDA audit without any findings. 1998 - 2001 Lab Supervisor, Schering Plough, Singapore Set up the new DCL lab and lead a team of 15 chemists for instrument qualification, method validation and product testing. The lab has passed many audits from US FDA, corporate QA and local HSA.
Accelrys Informatics Platform for QA/QC and Compliance
Michael Wang Director, Solution Consulting, APAC July, 2013
A Bit About Accelrys
Accelrys is
• Public: ACCL (NASDAQ)
• LTM Non-GAAP Revenue: $174M
• Clear Leader in Scientific Innovation Lifecycle Mgmt
• Employees: 650 (200+ PhD’s)
• Customers: Over 1,300
• Headquarters: San Diego, CA
• Industries Served: Life Science – Pharma, Biotech, Academic, Government
Consumer Packaged Goods, Chemicals, Energy , High Tech
• Recent Developments: Introduced the Process Management & Compliance Suite and groundbreaking LIMS
Announced the acquisition of Vialis Corp based in Switzerland
Announced the acquisition of Aegis Analytical Corp for $30 million in cash
3
United States San Diego, CA (WWHQ)
San Ramon, CA Milford, MA Boulder, CO
Bedminster, NJ Bend, OR
Europe Cambridge, UK (EHQ) Stockholm, Sweden
Paris, France Basel, Switzerland Cologne, Germany
Asia Tokyo, Japan (AHQ)
Seoul, Korea Singapore
India
49% 29%
22%
Accelrys LIMS
Modern technology architecture = Lower total cost of ownership + Less time to deploy Key Benefits: • Dynamic data structure workflow vs traditional static template LIMS • Innovative workflow editors with a simple drag-and-drop process • Quickly add additional LIMS capabilities without custom coding • Built-in compliance enables automatically created validation/qualification
documents • Easy creation of instrument connections with drag-and- drop capabilities • Flexible deployment options - selectively implement applications • Standalone deployment or in combination with the Process Management and
Compliance(PMC) Suite
The Accelrys LIMS
Workflow Editors Create LIMS Applications
Accelrys LIMS Workflow
Editors (drag & drop)
Entity or Inventory
Scheduling
Workflows
Reporting
Sample and Spec Management
Metrology/Calibration Management
Microbiological Environmental
Monitoring
Work Requests
Stability Management
Inventory Management
Qualification
Dashboard Views at Login
Sample or Process Workflows Easily Created & Managed
No complicated programming or IT support needed to convert existing plant or analytical work process - include checks, logic, links to other systems and automatically assign the electronic SOP or Work Instruction
• Enterprise level workflow • Harmonize business
processes across work groups
• Track work request progress against key projects, campaigns and studies
• Streamline communications and increase productivity
• Gain visibility into laboratory resource utilization and bottlenecks
Work Requests
Inventory Management
• Samples, Reagents, Standards, HPLC Columns, etc.
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
(Instrument integration and test SOP viewing/data capture)
Review and Approval of Test Results
Reporting and Trending
Scheduling, Sampling, Testing, Result Entry and Reporting with Location Hierarchy Support
Scheduling, Sampling, Testing, Result Entry and Reporting with Location Hierarchy Support
Reporting with Export ing to Other Formats : PDF, RTF, Excel , XML, etc.
• “This is the first time that a lab informatics vendor has developed a process-centric LIMS with automated compliance features.”
• “Traditional LIMS vendors’ sample-centric tools have proved to be inflexible and difficult to validate.”
• Accelrys LIMS enable customers in GxP and associated regulated manufacturing environments to obtain more tools through a single vendor and to develop insights between lab, quality and manufacturing groups.”
LES creates an electronic copy of SOP and enforce analysts to perform the analysis through step by step paperless execution so as to minimize human errors and inconsistency.
Accelrys Lab Execution System(LES)
Method “under glass”
Accelrys LES
• Access to correct & current SOP
• Testing process monitoring and standardization
• Automated raw data and meta capture and management
• Automated calculations
• Dashboard data review
• Automated data exchange
• Automated report generation
• Complete integration with instruments
“Purpose-built” for cGMP Quality Operations
SOP/Digital Method Execution
The method IS the GUI !!!!
“Method under glass” with integrated direct data capture to database
Best Practice Test Methods - “Right First Time”
AT - Audit Trail
OL - Out of Limit
OD - Out of Date
SD - Source Data
An - Annotation
A/A -Attest/Approve
Data Review - Approve at-a-Glance
Data Review - See Source Data at the touch of a button
Accelrys IDS
Accelrys Instrument Data System (IDS) Data Capture Hundreds of Instruments
Deliver to ELN: SOP from document
system Work assignment
from LIMS
Final Lab Report and
COA
Process limit checking and automated compliance
Electronic Lab Notebook ELN is the hub for data capture, calculations, data review, and approval.
Provides a single work environment for lab analysts.
Chromatography Data Systems ELN pushes sample prep data to CDS pre-run.
CDS output files go to ELN for post-run analysis
Data from Complex Instruments via networked PC
(UV-Vis, PDA, etc.)
Statistics and Analytics Programs
Data from Simple Instruments via RS232 (pH, KF, balances, etc.)
Data from Human
Observations
Supported Integrations- 3 Modes of Operation
4.210 mg
4.21mg
00
Empower I Empower II Chromeleon Chem Station Open Lab Easy Chrome Microsoft Excel
oooo
oommnn
ooooooower Iooooooower IImmmmmmmeleon
mmmmmm Stationnnnn LabCCCCCChrome
rooooooosoft Excel
….hundreds of validated and out-of-the-box integrations
Complete the Lab Picture – An Integrated Approach
Accelrys Confidential
QA/QC Laboratories Lab Execution System
ELN LES
LaLabobooraracution
Environmental Monitoring Inventory
Management Work Request
Sample Management Accelrys
LIMS Stability
Metrology
Instrument Data Service (IDS)
Accelrys Process Management & Compliance(PMC) Suite
Accelrys Confidential
QA/QC Laboratories Lab Execution System
Manufacturing Electronic Batch Records Transfer Transfer
ELN LES EBR
C C LaLabobobbbbxecutio
Environmental Monitoring Inventory
Management Work Request
Sample Management Accelrys
LIMS Stability
Metrology
Accelrys Discoverant Process Management Informatics (PMI)
Accelrys Enterprise Platform (AEP) for Data Exchange
Instrument Data Service (IDS)
Development Labs Electronic Laboratory Notebook
Use Cases: What others have achieved
Laboratory Workflow Efficiency Gains: Saving Time and Resources using ELN/LES
Test Time
Paper Based LES % Resource Savings
Hardness 20 minutes 10 minutes 50
Appearance 20 minutes 10 minutes 50
Dissolution (6 vessels) 3.0 hours 2 hours 33
Potency & Impurities 2 hours 1.5 hour 25
Productivity Metrics
AstraZeneca : Right First Time Initiatives
Year # Batches/Week (one product)
# Errors/Month
2002 10 20
2003 10 10
2004 thru 3Q 12-15 11
4Q04-Present (LES) 12-15 0*
Figure: Significant lab deviation reductions from multi-plant deployments of LES.
“An ERP, LIMS, and Lab Execution System Architecture – Global Deployment Update and Operational Excellence Metrics”
Lukas Gogis, Team Leader, Global LIMS, Manufacturing Information & Control Systems Eli Lilly & Company, Indianapolis, IN USA
Compliance Benefits Observed • Compliance to method criteria enforced
• Entry errors & manual transcription reduced
• Precise time/date, analyst, and equipment information captured real-time
• Reagent and other expiry dating enforced
• Equipment availability controlled by system
• Elimination of paper documents ensures retrieval of critical records at need
• System enforces good documentation practices
• Audit trail information for system is immediately retrievable and reviewable
• The most current method is automatically associated with the testing of any sample
• Method text is available to analyst during testing without recourse to other systems
Compliance Metrics
Deviation Rate vs Accelrys LES Usage
A Transformative Change …
“When everything else you’re doing is already electronic, an electronic notebook makes a lot of sense.”
Reduce Paper, Environment Friendly
Innovation
Productivity, Efficiency
Documentation Quality, Compliance
IP Protection, Security
Collaboration
Thank You
Questions
www.accelrys.com/pmc
TRACK 2C
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)
Mr David Margetts is a co-founder of Factorytalk with more than 13 years working experiences in Consulting to the
Pharmaceutical and Biotech industries including overseeing a widely experienced team of technical experts executing
manufacturing IT projects across the region and US/Europe ranging from shop floor SCADA control to enterprise-wide
ERP systems. Also being Project Manager and Technical expert for the world’s leading Manufacturing Execution Systems
provider to the Pharmaceutical and Biotech industries, expertise and experience over 50 successful global projects such
as Amgen, Bayer, Novartis, MerckSerono, and AstraZeneca.
Mr. Margetts also participates in a team of GAMP guideline reviewer and contributor and involve in writing a Pharmaceutical Eng. article and numerous event management for ISPE Asia-Pacific.
MasterControl eQMS: Supporting the next 10 years
19/07/2013 Thailand ISPE Conference
About MasterControl
Compliance Accelerated A global company founded in 1993 with offices in the United States, United Kingdom, Germany and Japan.
Provides industry specific software solutions to improve regulatory compliance and accelerate product time to market.
In-house industry and process expertise delivering successful project from conception to completion.
Committed to developing new innovative products that help customers succeed in their respective regulatory environments.
Over 500 corporate customers worldwide. Over 150 Medical Device Over 150 Pharma and Biotech Over 50 Blood and Biologics Over 200 in other regulated Industries
MasterControl Integrated Compliance
Suppliers
Regulatory Submission Publishing
gueguRegRe atototoolatola ooatatttatatatataaa rymbmubSuS ssiis iiiionooooooooooooooooolbPP hii hlblPubPuP hiish ng
• Document Control • Training Management • Quality Event Management
PICS Key Management Tools
Document Control • Document preparation • Document approval • Document layout • Document review • Document issue • Document change control • Record retention • Electronic records
Specifications • Specifications for starting materials • Specifications for packaging • Specifications for finished products • Manufacturing formula or bill of materials • Processing instructions • Packing instructions • Batch records • Packing batch records
SOPs & Records • SOP and records for materials receipt • SOP for labelling • SOP for sampling • SOP for testing • SOP for release • SOP & records for distribution
SOPs & Records • SOPs & records for validation • SOPs & records for calibration • SOPs & records for cleaning • SOPs & records for personnel • SOPs & records for environmental
monitoring • SOPs & records for pest control
SOPs & Records • SOPs & records for complaints • SOPs & records for recalls • SOPs & records for returns • SOPs for processing equipment • SOPs for lab equipment • Log books for equipment • Log books for lab equipment
• Deviations are fully recorded and investigated • Review of relevant production documentation
and an assessment of deviations from specified procedures
• Any deviations from the Manufacturing Formula and Processing Instructions.
• If a deviation occur, it should be approved in writing by a competent person, with QC involvement
PICS Quality Event Management
• Training Management must ensure: • Appropriately qualified and trained personnel • Appropriate records are kept
PICS Training Management
Look familiar?
Paperless Quality Management
• Implement best practices with standard functions to integrate the key areas
• Central and secure access from anywhere, anytime
• System automatic monitoring and control
CAPA Required
Fully integrated Quality system
Quality Events CAPA Document
Approvals Tracking & Trending
Close Incident
Quality Event
Risk-Based Issue Review
Close Incident
CA
PA
N
ot R
equi
red
Investigation
Tracking & Trending
Effectiveness Checks
CAPA Initiation
Corrective Preventive Action
Exams
Course Management
Training Delivery
QEM QMS Customer Complaint
Rules
Release
Docs
Quality Events
alityents
Training
cs
Risk
Change Control
5 3 9 2 6 1 3 5
Document control of revisions and approvals ocum
Change Control
Revision & Collaboration
Document Approvals
Training Controls
Close Incident
Change Control
Revision & Collaboration
Document Approvals
Training Control
Release
Archive Course Management
Docs
Training
Example: Handling Complaints
Customer Complaint
Issue Review
CAPA
Risk Assessment
Change Control
Update Document
Training
unacceptable
Launch Quality Event for Issue Review!
Electronic data entry and built in best practices for Issue handling
Risk Assessment used to define the next steps and actions
Immediate containment of problem and follow-on CAPA initiation
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
Secure and compliant access controls
Document Management
Open any Document, anywhere, and secure
Approvals and Task Management
Approvals and Task Management
Approvals and Task Management
Approvals and Task Management
Quality Event Management
Quality Event Management
Audit Management
Audit Management
Audit Management
Audit Management
GMP Group
GCP Group
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
Quality Events
Event Analyzer
Tracking & Trending
Rules Audit
Finding (Requires a SOP Change)
Change Control
Implementation Project Plan
Training Control Collaboration
Deviations Complaints NCMR RMA Others…
Quality Events Monitoring Audit Change
Control Training
Exams
Course Management
Training Delivery TT
Projects
Docs
Quality Events
alityents
Training
Audit
System monitoring and control
TRACK 2D
FUTURE QUALITY SYSTEM
AND PROCESS ANALYTIC
QUALITY BY DESIGN (QBD) AND
PROCESS ANALYTICAL
TECHNOLOGY (PAT)
Friday 19 July 2013
SPEAKER PROFILE
TOPIC: QUALITY BY DESIGN (QBD) AND PROCESS ANALYTICAL TECHNOLOGY (PAT)
Bikash K Chatterjee
President & Chief Technology Officer Pharmatech Associates Inc. 22320 Foothill Blvd. Suite 330 Hayward CA 94541 U.S.A. Education - University of California, B.A. in Biochemistry - University of California, B.S. in Chemical Engineering
Mr. Chatterjee has more than 30 years’ experience in the pharmaceutical, biosciences, medical device/diagnostic and nutraceutical/dietary supplement industries. He has held senior management positions in operating companies for more than a decade and has successfully brought multiple drug and product platforms through the FDA regulated development process to market. Throughout his career he has been responsible for product development including Quality by Design, technology and process transfer and technology, process validation and established global supply chain processes in over 40 different countries around the world and been responsible for the commercialization of over a dozen products. Mr. Chatterjee sits on several scientific advisory boards for pharmaceutical and medical device companies. He is a standing member of the editorial advisory board for Pharmaceutical Manufacturing and Pharmaceutical Technology Magazines and writes a recurring column for several magazines on industry trends and challenges. He has published over 70 articles and editorials throughout his career in peer reviewed journals. Mr. Chatterjee is a Certified Lead Assessor and a Lean Six Sigma Master Black Belt. He holds a BA in Biochemistry and a BS in Chemical Engineering from the University of California at San Diego.
Applying Quality by Design to Generic Drug Manufacturing
Bikash Chatterjee President & CTO Pharmatech Associates
1
2
Agenda• What is QbD?• Why it has become important • What companies need to know, overview• How to set up a team to develop QbD• Process understanding• Knowledge space• Design space• Required statistical processes• Practical application of the ideas-Case Study• Review of past records to determine CPP-Case Study• Development of acceptable operation range• Benefits• Cost savings
3
QbD’s Proposition• QbD concerns the making of drug substances and drug products• QbD is the new pharmaceutical quality system that:
• Replaces current GMP concepts• Does not depend on the trial and error approach of drug
substance and drug product development & production• Is a systemic, knowledge and risk-based quality methodology • Complies with the general purpose of product quality: the
product is suitable for use • Patient driven philosophy• A quality system customized for pharmaceuticals
•QbD is GMP for the 21st century
4
What is Quality by Design (QbD)?
• First introduced in 1985 by Dr. Juran
• Juran said most quality problems are designed into the process. A clear plan is needed to identify and eliminate these issues
• No single definition…
5
a systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk
ICH Q8 Definition of QbD
6
Another Way of Thinking about QbD
Once a system has been tested to the extent that the test results are predictable, further testing can be replaced by establishing that the system was operating within a defined design space.
7
Understanding what factors have an impact on variation in your process and also on your product’s performance; then establishing a control plan tomonitor and maintain product quality
Agenda• What is QbD?• Why QbD has become important • What companies need to know, overview• How to set up a team to develop QbD• Process understanding• Knowledge space• Design space• Required statistical processes• Practical application of the ideas-Case Study• Review of past records to determine CPP- Case Study• Development of acceptable operation range• Benefits• Cost savings
13
Business Dynamics
14
Why Has QbD Become Important?• Business Drivers
o New market opportunities
o Improved market competitiveness
o Improved profitability
o Reduced product risk exposure
15
QbD
Three Areas of Improvement...
• Better
• Faster
• Cheaper
• Quality
• Time/Flow
• Waste/Costs
16
Drive Financial Performance
Increase Revenue: Grow the Business• Improve customer satisfaction, sales, throughput, and
competitive position
Decrease the Cost of Goods Sold• Reduce process variation and defects, improve yield
• Identify and eliminate root causes of problems
• Develop systems robust to problems
• Reduce unnecessary costs and excessive cycle time
17
QbD is a Better Business Model• R&D drives new innovative products• Do we really need QbD? The conservative criticism
• “All the billions of dollars poured into research and development in the U.S. won’t mean a thing. We must streamline and strengthen the regulatory science”
• Areas cited where this is being accomplished include FDA’s partnership with ICH around Quality by Design (QbD)
New FDA commissioner Margaret Hamburg’s keynote address at Regulatory Affairs Professionals Society annual conference in Philadelphia, September 2009
Conclusion: QbD is a way to innovate within the pharmaceutical industry
18
Regulatory Drivers for QbD
Escalating and non-uniform compliance expectations:
• A-CTD Implemented• A-CTR & technical guidelines established (maintenance and
enhancement of common interpretation ongoing)• Post-Market Alert System established• GMP Inspection MRA finalized• Training identified• Pan-ASEAN registration
1999 2002 2005 2006 2009
PPWG IWG GMPMRATF
BA/BETF
A-CTDImplementation
20
21
Regulatory Drivers-ICH Q8, 9, 10, 11
ICH Q8, Q9, Q10 & Q11are designed as separate but linked in a series of documents exploring pharmaceutical products lifecycle (www.ich.org)
• ICH Q8 - Pharmaceutical Development • ICH Q9 - Quality Risk Management • ICH Q10 - Pharmaceutical Quality System • ICH Q11 - Development and Manufacture of Drug
Substances
22
Agenda• What is QbD?• Why it has become important• What companies need to know, overview• How to set up a team to develop QbD• Process understanding• Knowledge space• Design space• Practical application of the ideas-Case Study• Review of past records to determine CPP-Case Study • Required statistical processes• Development of acceptable operation range• Benefits• Cost savings
23
Is QbD a Shift in Quality Philosophy?You can’t test quality into drug products” has
been heard for decades – so what s new?• Quality is based on process and product
understanding, not just test results• It’s a shift in culture: incorporates quality principles
and strong compliance function• Incorporates risk assessment and management• Refocuses attention and resources on what’s
important to the customer, i.e. the patients, health professionals, payors and distribution chain
24
QbD is a Commitment to Improve• Continuous improvement is a key element of QbD
- G. Taguchi on Robust Design: Design changes during manufacture can result in the last product produced being different from the first product
• However, in pharmaceutical manufacturing, we want improvement that improves consistency–patients and physicians must count on each batch of drug working just like the batches that came before
25
QbD for Generic Drugs
In generic pharmaceutical manufacturing, there are additional constraints:
• Fixed bioequivalence targets
• Regulatory requirements to duplicate formulation of innovator drug
• Lack of access to innovator development data
26
The Changing Regulatory Compliance Environment
Quality by Design
• Adequate resources for quality: number, qualifications, etc.
• Self-assessments play key role
• Continuous analysis & improvement
• Change management based on good science
• Focus on what’s important (risk management)
Current Regulatory Situation: US/EU
• Little guidance on adequate resources or qualifications
• Self-assessments not trusted• Annual product reviews instead
of continuous analysis• Formidable barriers to change,
including intimidating enforcement emphasis
• Seldom admit that anything is not important; test everything
27
Quality by Design (QbD) CharacteristicsBasics: • Uses systemic (multivariate statistics) development and
manufacturing by use of prior knowledge• Risk assessment guided design and process control• Applies to the total life cycle of a product (continuous
improvement)
Implications:• Quality back to the roots: product suited for its purpose• Quality is dynamic: continuous improvement• Quality must be built in• Quality means first time right
28
The QbD Development Model is Different
•
Patient Idea Design Space Control Strategy Risk Assessment Product Life Cycle
Idea Development Preclinical & Licensing Manufacturing Marketing/
Clinical Testing Sales
Traditional
QdB In the QbD Development Concept The Chain is Reversed
29
QbD Will Require Enhanced Supplier Management
• Why?You will need to measure and control the important characteristics of your raw materials and API
• Clearly defined supplier quality and supply agreements are necessary
30
Agenda• What is QbD?• Why it has become important • What companies need to know, overview• How to set up a team to develop QbD• Process understanding• Knowledge space• Design space• Required statistical processes• Practical application of the ideas• Review of past records to determine CPP • Development of acceptable operation range• Benefits• Cost savings
31
Building a QbD Organization
• Starts in product development
• Multidisciplinary team representing the product development lifecycle
• Presents opportunities to build in existing commercial experience into the product and process design phase
• Presents the opportunity to not repeat mistakes in formulation and product design
32
Team Structure
QbDCore Team
R&D & Marketing
Corporateand Mfg.
Engineering
Technical Services
Regulatory and QA
Compliance
Facilities/GC
Validation
Oversight Committee
33
QbD Core Team• Program Manager• Decision makers from all
six areas• Clear mandate to deliver
product. In the US FDA market measured by being the First to File
QbDCore Team
34
Team Chartering Process
Define and Identify:• Success metrics for the project• Timeline• Budgetary and cost tracking assumptions• Key stakeholders• Project champion and project milestones• Extended Chartering to discussion of communication, review
and issue resolution mechanism• Also established initial team rules: what behaviors would be
encouraged and what would not be encouraged
35
Managing Team Dynamics
TeamCharter
Structure
Systems
Staff
Strategy
Skills Style
Knowledge Management
ProductSelection
Development And
Characterization
Site Selection/Process Design/Tech Transfer
Reg.Filing
Process Understanding Process Predictability Measurement
ContinuousMonitoring
Phase 1 Phase 2 Phase 3 Phase 4 Phase 5
Key Activity
• QTPP• Strategic
Analysis• Site
Capability Analysis
• ProjectTimeline
• Risk Analysis
KeyActivity
• Platform Knowledge
• Identify CPP• MSA• CMA Risk
Analysis• Process Risk
Analysis• Commercial
Factors
Go/N
oGo
Go/N
oGo
Go/N
oGo
KeyActivity
• Site Suitability• Mapping CPP• MSA• Process Risk
Analysis• Confirmation
Process • DOE • Process
Validation
Key Activity• Filing
Prep.
Key Activity
• Metrics Review
A Generic Drug QbD Framework
Go/N
oGo
36
37
Agenda• What is QbD?• Why it has become important • What companies need to know, overview• How to set up a team to develop QbD• Process understanding• Knowledge space• Design space• Required statistical processes• Practical application of the ideas-Case Study• Review of past records to determine CPP-Case Study• Development of acceptable operation range• Benefits• Cost savings
Reducing Variation by Robust Design (QbD)
By Robust Process Design ...
By tighter controls of the inputs ...
Input
Proc
ess
"Y"
Traditional Method of Reducing Variation Alternate Method of Reducing Variation
•TransferRelationship
•$ $ $
38
39
Effect of Design on the Product Development Life Cycle
Design Produce/Build Deliver Service Support
Cost &Time vs. Impact
Potential is PositiveImpact >Cost and Time
Impact< Cost &Time
40
Scope of Recent Guidances
ProductDesign ManufacturingProcess
Design
ProcessMonitoring
/ContinuousVerification
ICH Q8/Q8(R) - Pharmaceutical DevelopmentICH Q11 Development and Mfg. of Drug Substances
PAT Guidance
ICH Q9 – Quality Risk Management
FDA Guidance on Quality Systems (9/06)FDA Process Validation GuidanceICH Q10 – Pharmaceutical Quality Systems
41
ICH Q8- Pharmaceutical Development
• Introduces the concept of pharmaceutical Quality by Design
• Defines QbD as:
A systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science andquality risk management.
42
ICH Q8 Concept of QbD
Process Understanding
• Process Parameters• Process Controls
43
Designing a Robust Process
Problems detected after they
occur, throughproduct testing and
inspection
Reproducible process within
narrow operatingranges
Robust & reproducible
process
Low High
Low
High
PROCESS UNDERSTANDINGPR
OCE
SSCO
NTR
OL
High potential for failures
44
Role of Quality Risk Management inDevelopment & Manufacturing
ManufacturingImplementation
Process Scale-up & Tech Transfer
Risk Management
ProcessDevelopment
ProductDevelopment
Product qualitycontrol strategy
RiskControl
RiskAssessment
Processdesign space
ProcessUnderstanding
Excipient & drug substance
design space
Product/priorKnowledge
RiskAssessment
Continualimprovement
ProcessHistory
RiskReview
44
45
Define desired product performance
upfront;identify product CQAs
Design formulation and process to meet product CQAs
Understand impact of material attributes and process parameters on
product CQAs
Identify and control sources of variability
in material and process
Continually monitor and update
process to assure consistent quality
Risk assessment and risk control
Product & process design and development
Qualityby
Design
The FDA QbD Model
46
Process Step Analysis
For product and process:
- Risk assessment- Design of experiments- Design space definition- Control strategy- Batch release
CRM DOEs Design Space
Control Strategy
Batch Release
47
Adding the QbD Framework
CMA DOEs Design Space
Control Strategy
Batch Release
QTPP/ CQAs CPPs
Quality Risk Management
48
Quality Target Product Profile (QTPP)
“A prospective summary of the quality characteristics of a drug product that ideally will be achieved to ensure the desired quality, taking into account safety and efficacy of the drug product”
• Defines the product development requirements. Used to be called the product Requirement Specification (PRS)
• ICH Q8 Definition is:
49
QTTP- PRS Example
Dosage form and strengthImmediate release tablet taken orally containing 30 mg of active ingredient
Specifications to assure safety and efficacy during shelf-life
Assay, Uniformity of Dosage Unit (content uniformity) and dissolution
Description and hardness Robust tablet able to withstand transport and handling.
Appearance
Film-coated tablet with a suitable size to aid patient acceptability and compliance
Total tablet weight containing 30 mg of active ingredient is 100 mg with a diameter of 6 mm
50
QTTP- Safety and Efficacy ExampleTablet Product Requirements Critical to Quality
Attributes (CQA)Dose 30 mg Identity, assay and
CUMarketing Taste masking, coated
tablet, suitable for global market
Size, Appearance, Potency
Safety- Purity Impurities and degradation products meet ICH guideline
API impurities and degradation products <1%, residual Solvents
Efficacy-API PSD* Drug bioavailable with PSD that meet mfg needs
Dissolution >60% 1 hour per USP 711
Shelf Life 2 years and meets ICH guidelines
Primary packaging oxygen barrier required for shelf life
*PSD: Particle Size Distribution
51
Risk Analysis
• It doesn’t need to be complex• High, medium and low risk ratings are
acceptable• Anything with a high rating should be
justified• Apply the risk analysis to the product
design (formulation) and the process design activity at the outset
52
Example Product Risk AnalysisCQA Microcrystalline
cellulosePovidone Mg. Stearate API
Appearance Low Low Low LowAssay Low Low Low HighContentUniformity Low Low Medium High
Dissolution Low Medium Medium HighHardness Medium Low Low LowJustification PSD critical to
solubility of drug. Low loaded dose can affect CU
53
Process Unit Operation Risk Assessment
CQA Process StepsGranulation Drying Milling Blending Compression Coating
Drug Release Low Low Low Medium Medium HighParticle Size Distribution
Medium Low High Low Low Low
Justificationsfor High Rating
N/A N/A
Milling screen size and speed can affect the PSD and therefore the powder flow and tablet fill weight control
Blending can affect blend uniformity, assay, and drug release profile
Compression can affect drug uniformity in the tablet based upon particle size variability and flow
The final appearance and drug release rate are affected by the coating quality and reproducibility
54
Risk Analysis
• Important to go back to the risk assessments at the end of the process development activity and finalize the risk assessment based upon real data
55
Agenda• What is QbD?• Why it has become important? • What companies need to know, overview• How to set up a team to develop QbD• Process understanding• Knowledge space• Design space• Required Statistical processes• Development of acceptable operation range• Practical application of the ideas-Case Study• Review of past records to determine CPP-Case Study• Benefits• Cost savings
56
The QbD Framework for Process Space
57
Knowledge Space
The potential range of limits for all parameters controlled or measured during the process characterization process
58
Knowledge Space Determination
• Determine which parameters have an impact on the products performance
• Requires establishing a range for each parameter to evaluate for each unit operation
• Pharma has historically used One-Factor-At-A-Time (OFAT) to do this but this is not adequate today
59
Design of Experiments (DOEs)• An approach which allows us to
understand the contribution to variation of a parameter(s) upon a known response variable
• Establish a mathematical model which describes the impact of each variable controlled on the dependent variable of interest
• OFAT studies cannot do this
60
DOE vs. OFAT• DOEs allow you to understand the
process behavior in a very few studies
• DOEs allows the experimenter to apply statistics to back-up their conclusion
• The only way to have confidence your conclusion is correct
61
Experimental VariabilityAny experiment is likely to involve three kinds of variability:• Planned, systematic variability This type of variability we want
since it includes the differences due to the treatments
• Chance-like variability This type of variability our probability models allow us to live with. We can estimate the size of this variability if we plan our experiment correctly
• Unplanned, systematic variability This type of variability threatens disaster! We deal with this variability in two ways, by randomization and by blocking. Randomization turns unplanned, systematic variation into planned, chance-like variation, while blocking turns unplanned, systematic variation into planned, systematic variation
The management of these three sources of variation is the essence of experimental design.
Taken from In Introduction to the Design and Analysis of Experiments, George Cobb (1998)
Does Turret Speed matter?Does Compression Forces matter?
67
Example DOE- Compression ANOVADo these variables have an impact on tablet hardness? = 0.05
Estimated Effects and Coefficients for Tablet Hardness (coded units)
Term Effect Coef SE Coef T PConstant 11.3750 0.3750 30.33 0.000Turret Speed -1.2500 -0.6250 0.3750 -1.67 0.171Compression Force 2.7500 1.3750 0.3750 3.67 0.021Turret Speed*Compression Force
Example DOE- Compression ANOVADo these variables have an impact on tablet dissolution? = 0.05
Estimated Effects and Coefficients for 4 Hr Dissolution (coded units)
Term Effect Coef SE Coef T PConstant 75.3750 1.068 70.58 0.000Turret Speed -0.7500 -0.3750 1.068 -0.35 0.743Compression Force 1.2500 0.6250 1.068 0.59 0.590Turret Speed*Compression Force
Agenda• What is QbD?• Why it has become important? • What companies need to know, overview• How to set up a team to develop QbD• Process understanding• Knowledge space• Design space• Required Statistical processes• Development of acceptable operation range• Practical application of the ideas- Case Study• Review of past records to determine CPP-Case Study• Benefits• Cost savings
71
Design Space
72
Look Only at the Parameters that Affect the Drugs Performance
• In our example Compression force affected tablet hardness which was a drug release criteria
• Narrow the range to be evaluated and this becomes your new Design Space limits for this variable, e.g. conform the contribution from 12-18 kN
73
Agenda• What is QbD?• Why it has become important? • What companies need to know, overview• How to set up a team to develop QbD• Process understanding• Knowledge space• Design space• Required Statistical Processes• Development of acceptable operation range• Practical application of the ideas- Case Study• Review of past records to determine CPP-Case Study• Benefits• Cost savings
74
Statistical Testing
• The purpose of applying statistical tests is to compensate for the fact that we cannot test every unit we make
• So we make a guess ,i.e. a hypothesis of whether, within a predefined level of error, our decisions are correct
75
What is a Test of Hypothesis?
• A statistical test designed to answer a question, or allow one to choose between two or more alternatives:
• Is material A better than material B?
• Does the new process have a larger yield over the our older process?
• Does this lot meet our specifications?
• Tests of hypothesis provide a structure for learning
• Properly handle uncertainty
• Minimize subjectivity
• Question assumptions
• Prevent the omission of important information
• Manage the risk of decision errors
Hypothesis testing concepts allow us to.....?
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Ho: Parameter or Measure = a value, or is trueHA: Parameter or Measure {< or > } a value, false
= a low probability typically of 1%, 5%, or 10%
• The hypothesis of equality,or that condition that is considered true is typically called the Null Hypothesis
• The hypothesis of non-equality is called the Alternate Hypothesis
• All hypothesis' include a level of significance, , which is the risk of incorrectly rejecting a true Null Hypothesis
Hypothesis Test Configuration
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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
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Hypothesis and Decision Risk• When testing a hypothesis, we do so with a known
degree of risk and confidence• We must specify in advance:
• Magnitude of acceptable decision risk • Test sensitivity
• These provide the necessary information to determine an appropriate sample size
• Consider practical limitations of cost, time, and available resources to arrive at a rational sampling plan
• We can never acheive absolute certainty
TheTruth
The Decision Errors
Your Decision
Ho is True
Ho is False
Type IError
Risk)
Type II Error
Risk)
Correctdecision
Correctdecision
Reject HoDo not reject Ho
Keller and Warrack, Statistics for Management and Economics
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Alarm’s Decision
Nothing In Bag
TheTruth
Nothing In Bag
Weapon In Bag
Type IError
Risk)
Type II Error
Risk)
Correct
Correct
Weapon In Bag
Consequences: _____________
Consequences:__________________________
Example: Airport Security
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• Sampling from a distribution must be representative or independent• Random sampling is the key assumption• Often Normality is the key assumption• The random sampling assumption is also
known as the statistical independence assumption
• A plot of the data in time order should not show any trends
• Check by finding out how the samples were chosen and tested
Hypothesis Testing – Assumptions
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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)
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Hypothesis Testing –Procedure
The Test is on Populations, NOT Samples…
1. Write the null hypothesis
2. Write the alternate hypothesis
3. Decide on the p value
4. Choose hypothesis test
5. Gather evidence and test/conduct analysis
6. Reject H0 /not reject H0 and draw conclusion
H0 : x Sample A = x Sample B (e.g. new way is the same as the old way)
HA : There is a difference between Samples A and B
p = .05 (typical for characterization projects)
Choose the correct test, given the type of X and Ydata (in this example, a t-test)
Collect data, run analysis, get p value
If p >.05 conclude that your data does not show a significant difference between samplesIf p<.05 conclude the samples are different
Steps •Example (2 Samples)
• Key Question: Do you have sufficient evidence to reject the Ho ?
• The p-value is the most common way to evaluate the results of your test
• Common ways to remember what the p-value means:
If p is low, Ho must go!
or
If the p is high keep the guy!
Making Decisions with Hypothesis Tests
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For most cases we will use .05
How Low Must the p-value Be?
• We would like there to be less than a 10% chance of falsely rejecting Ho ( = .10)
• 5% is much more comfortable ( = .05)
• 1% feels very good ( = .01)
• This alpha level is based on our assumption of “no difference” and a reference distribution of some sort
• But, it depends on interests and consequences
P-value is required to reject Ho
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Data Types
• Discrete• Counts of discrete events (1, 2, 3, …
defects)• Qualitative descriptions
• Good / Bad • Supplier 1, Supplier 2, …• Method A, Method B, …
• Continuous• Decimal sub-divisions are meaningful
• Time, money, etc.
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Hypothesis Testing Roadmap
• Different statistical tools apply to different types of input and output data combinations
• Minitab supports all these combinations• Structured approach to choosing the right
analysis method
“If the only tool you have is a hammer...every problem looks like a nail” - Abraham Maslow
Testing Rubric
X DataSingle X Multiple Xs
Sing
le Y
X DataDiscrete Continuous
Y D
ata D
iscr
ete
Con
tinuo
us
•Chi-Square•Logistic
•Regression
•ANOVA
•T-test •Regression
X DataDiscrete Continuous
Y D
ata D
iscr
ete
Con
tinuo
us
•Multiple
•Regression
•Logistic•Regression
•Multiple
•Medians Tests
•2, 3, 4+ way•ANOVA
•Logistic•Regression
•Multiple
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Sampling Strategy
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Sampling Strategy
• Commonly Overlooked in terms of its importance in establishing process understanding
• If you do not have confidence your sample is representative of your true process population you cannot be sure your conclusions are correct
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Terms: Additional Definitions
• Sample: A subset of a population. For us this is the data we collect
• Population: Not the same as “sample”, rather this is the data we would have collected if you had repeated the experiment an infinite number of times
Form of inspection applied to lots or batches of items before or after a process, to judge conformance with predetermined standards
• Sampling Plans: Plans that specify lot size, sample size, number of samples, and acceptance/rejection criteria• Single-sampling• Double-sampling• Multiple-sampling
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Sampling Myths• Sampling plans can make a bad process better
• A stringent sampling plan ensures only good product goes out the door
• My sampling plan justifies my quality decision for my production lots
Sampling plans have no impact on process capability and are not a surrogate for process improvement
No. The only way to ensure 100% good product goes out the door isto make 100% good product
No. Your sampling plan can only extrapolate the behavior of the population from which it was sampled. You must use scientific inference to apply this to other lots
• Process Development: Understanding process behavior• Process Optimization: Improving process behavior• Quality Control: Verifying incoming raw materials,
API, components and product release testing
• Stability: Product Expiration testing• In-Process Testing: Establishing an effective control
strategy
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Operating Characteristic Curves
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Acceptance Sampling
• Modern acceptance sampling involves a system of principles and methods. Their purpose is to develop decision rules to accept or reject product based on sample data. Factors are: • The quality requirements of the product in the
marketplace • The capability of the process • The cost and logistics of sample taking
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Probability of Acceptance (Pa)• The primary characteristics when evaluating a
sampling plan is to understand what the probability of accepting a lot is as the percentage defects in the population changes
• The behavior the sampling plan is defined by its Operating Characteristic (OC) Curve
• All OC Curves have certain properties in common:• At 0% defective the probability of acceptance is 1• At 100% defective, the probability of acceptance is 0• As the percent defective is increased the OC curve
decreases
Operating Characteristic Curve
00.10.20.30.40.50.60.70.80.9
1
0 .05 .10 .15 .20 .25
Pro
babi
lity
of a
ccep
ting
lot
Lot quality (fraction defective)
3%
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Decision Criteria
0
1.00
Pro
babi
lity
of a
ccep
ting
lot
Lot quality (fraction defective)
“Good”
“Bad”
Ideal
Not verydiscriminating
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Sampling Terms• Acceptance Quality Level (AQL)
the percentage of defects at which consumers are willing to accept lots as “good”
• Lot Tolerance Percent Defective (LTPD)the upper limit on the percentage of defects that a consumer is willing to accept
• Consumer’s Riskthe probability that a lot contained defectives exceeding the LTPD will be accepted
• Producer’s Riskthe probability that a lot containing the acceptable quality level will be rejected
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OC Definitions on the Curve
•Pro
babi
lity
of A
ccep
ting
Lot
Lot Quality (Fraction Defective)
100%
75%
50%
25%
.03 .06 .09
= 0.0590%
= 0.10
AQL
LTPD
Indifferent
Good Bad
Producer Risk
Consumer Risk
OC Curves can be summarized by two points:
AQL: Percent defectivewith a 95% chanceof acceptance
LTPD: Percent defectivewith a 10% chance of acceptance
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OC CurvesP
roba
bilit
y of
Acc
epti
ng L
ot
Lot Quality (Fraction Defective)
100%
75%
50%
25%
.03 .06 .09
OC Curves come in various shapes depending on the sample size and risk of and errors
This curve is more discriminating
This curve is less discriminating
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Pro
babi
lity
of A
ccep
ting
Lot
Lot Quality (Fraction Defective)
100%
75%
50%
25%
.03 .06 .09
This curve distinguishes perfectly between good and bad lots.
The Perfect OC Curve
What would allow you to achieve a curve like this?
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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
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Acceptance Criteria
• At a minimum all process testing must meet specifications
• The specifications should be derived from the product requirements and the process’ capability
• Ideally you can steer and predict the process’ performance
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Establishing Acceptance Criteria
• Confidence Intervals: Determines the probability that the confidence interval produced will contain the true parameter value. Common choices for the confidence level Care 0.90, 0.95, and 0.99. These levels correspond to percentages of the area of the normal density curve
• Because the normal curve is symmetric, half of the area is in the left tail of the curve, and the other half of the area is in the right tail of the curve. For a 95% confidence interval, the area in each tail is equal to 0.05/2 = 0.025.
Measures our degree of uncertainty in the population mean
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Establishing Acceptance Criteria
• Prediction Intervals: Determines the probability interval that a single value will fall. Tends to be larger than confidence intervals.
Measures our degree of uncertainty and the variability in the distribution of the population mean is affected by sampling error.
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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
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CASE STUDY
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Case Study Framework
• This case study is a real process that has been qualified to US, EU and PIC/S standards
• Applies the principles of QbD to demonstrate process understanding and process control
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Pharmatech’s Technology Transfer Roadmap
Point...Point...Point...Point...
PointPointPointPoint
ProductDesign
CPPs/RiskAssessment
HistoricalPerformance
EquipmentDesign
CharacterizationStudies
EstablishPAR/NOR
PPQPrerequisites
PPQ
RiskAssessmentVerification
Change Controland Stage 3
Recommendation
Pro
cess
Und
erst
andi
ng
Pro
cess
Rep
rodu
cibi
lity
ContinuousImprovement
RiskAssessmentVerification
Pro
cess
Mon
itorin
g
Pro
cess
Und
erst
andi
ng
Pro
cess
Rep
rodu
cibi
lity
Pro
cess
Mon
itorin
g
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Case Study Application
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Lexicon• Critical Process Parameter (CPP): A process parameter
whose variability, within defined limits, has an impact on a critical quality attribute and therefore should be monitored or controlled to ensure the process produces the final drug product quality
• Critical Quality Attribute (CQA): A physical, chemical or microbiological property or characteristic that should be within a predetermined range, range or distribution to ensure the desired final product drug quality
• Critical To Quality Attribute (CTQ): An in-process output parameter that is measured and/or controlled that should be within a predetermined range, range or distribution to ensure the desired final product drug quality
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Stage 1 Process Understanding
• Product Design• Process Risk Assessment• Equipment/Process Characterization Studies
Drug Release Low Low Low Medium Medium HighParticle Size Distribution
Medium Low High Low Low Low
Justificationsfor High Rating
N/A N/A
Milling screen size and speed can affect the PSD and therefore the powder flow and tablet fill weight control
Blending can affect blend uniformity, assay, and drug release profile
Compression can affect drug uniformity in the tablet based upon particle size variability and flow
The final appearance and drug release rate are affected by the coating quality and reproducibility
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•Target Set Point
•Max Set Point Run(s)
•Min Set Point•Run(s)
•PAR•NOR
•Limit of individual•excursions
•Duration of process
•Variability of actual data•around set point
Relationship Between Proven Acceptable Range and Normal Operating Range
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Historical Analysis
• The absence of development data establishing the PAR and NOR for the CPP can be ascertained to some extent by evaluating the historical behavior of each parameter along with the corresponding behavior of the CQAs for the unit operation
• Data should be extracted from multiple batch records to determine whether the process is stable within lot and between lots
• The team went back into the batch records of approximately 30 lots across a period of one year to extract the necessary data. This exercise also gave some indication as to whether the parameter was truly a CPP, based upon whether it had an impact on the corresponding CQA for the unit operation
• Evaluate scale independent and scale dependent parameters
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Control Charts
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Process Capability Analysis
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I Chart of PSD
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Correlation Plot
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Equipment Design Considerations• Compare underlying equipment design and
configuration differences• Focus on impact of equipment design on scale
dependent parameters• Objective during transfer and scale-up is to
understand where equipment can affect the PAR And NOR for the transferred process
• Also consider final PV considerations such as sampling plans, sampling technique, and method robustness
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Historical data Review Conclusion
• Dissolution testing of uncoated tablets across the process range were 100% dissolved in 3 hours
• Storage studies determined bulk granulation and uncoated tablets were sensitive to humidity
• Operating characteristic (OC) curves developed for each unit operation to understand the relationship between sampling size and sampling risk (AQL vs. LTPD)
• Highlight sampling challenges prior to design space activity
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Tech Transfer Equipment Comparison
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Summary of CPP/CTQ and CQAAssumptionfor Tech Transfer
Unit Operation CPP CTQ CQACompounding Mixing speed Fully Dissolved-
Visual
Water temperature Addition rate Fluid Bed Granulation/Drying
Spray Rate Granulation PSD-d10, d50, d90
Content Uniformity
Inlet Air Humidity Moisture content Potency Atomization
• Sampling Methodology QualificationGage R&R conducted with sampling equipment for each unit operation. GRR< 20%, Distinct Categories > 5
• Sampling Plan DevelopmentCould use ANSI Z1.4-2008 or Zero-Acceptance Plan. Used Power calculation, e.g. Powered at 80% with 5% as significant difference for a known SD
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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.
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Drug Dissolution Dependence on Coating Weight
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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
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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
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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
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Establishing Acceptance Criteria• Based upon reproducibility criteria• For example if the Stage 1 performance for the 4 hr.
dissolution was 32% 2% against a specification of 20-40%:• Acceptance criteria could be: 95% confidence
interval applied to a spec of 32 6%• Used a 2 sided t-Test with an = 0.05 (0.025 on
the HA for < comparison)• We used the 6% because it is 3 x std. dev. In a
normal distribution this covers 99.7 of the data variability for a controlled process
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Why Can’t I Just Compare My Result Against the Acceptance Limits?
• We did not know the true mean and standard deviation of the population That is the premise behind the t-test. If we knew it we would use the z-test
• We only knew the behavior of our sample population and we must infer that the process population behaves the same. That is why we apply the confidence interval to the assessment and apply the alternative hypothesis to test if the variability and mean is within what has historically seen
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Agenda• What is QbD?• Why it has become important? • What companies need to know, overview• How to set up a team to develop QbD• Process understanding• Knowledge space• Design space• Required Statistical processes• Development of acceptable operation range• Practical application of the ideas- Case Study• Review of past records to determine CPP-Case Study• Benefits• Cost savings
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Benefits• Improved new product development
capability and flexibility• Reduced quality overhead and reduced
quality issues• Greater productivity and predictability of
the process and overall business operations
• Ability to correct for process drift without impacting quality or yield
• Access to larger profitable pharmaceutical markets
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Cost of Poor Quality (COPQ)
COPQ is derived from the non-value adding activities of waste in a process and is made up of costs associated with one of the following five categories:
1. Internal failure2. External failure3. Appraisal4. Prevention5. Lost Opportunity
•Reference; Basu and Wright, Quality Beyond Six Sigma 2003
144
COPQ Components
•Reference: Wild 2002
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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
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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
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Questions?
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Thank You for Your Attention!Bikash Chatterjee, President & CTO