ASTM E2500 A New Approach to Validation
Peter K. Watler, Ph.D., Principal Consultant and CTO, Hyde Engineering + Consulting, Inc.
Where you can find it
Only 5 pages http://www.astm.org/Standards/E2500.htm $36.00 -Page 1-
Where you can find it
Only 5 pages http://www.astm.org/Standards/E2500.htm $36.00 -Page 1-
ASTM ASTM E 2500 – 07, What What is it?
“A risk-based and science-based approach to the specification, design, and verification of manufacturing of manufacturing systems and equipment that have the potential to affect product quality and patient safety.”
“The overall objective is to provide manufacturing capability to support defined and controlled processes that can consistently produce product meeting defined quality requirements.”
Approved June 1, 2007 A voluntary consensus standard It has legal relevance
Stresses expert analysis of critical critical element that affect product quality
“quality”, (not Quality Assurance or Quality Unit) appears 44 times “expert” appe appear ars s 21 time times s “critical” appear appears s 20 20 time times s
-Page 2-
The National Technology Transfer Act of 1995
Public Law 104-113 “The Congress finds the following:
(1) Bringing technology and industrial innovation to themarketplace is central to the economic, environmental, and social well-being of the people of the United States. (2) The Federal Government can help United States business to speed the development of new products and processes”
Provision (12(d)) - Utilization of Consensus Technical Standards by Federal Agencies;
all Federal agencies and departments shall use technical standards that are developed or adopted by voluntary consensus standards bodies , using such technical standards as a means to carry out policy objectives or activities deemed by the agencies and departments.
-Page 3-
What the Law Looks Like http://www.nist.gov/director/ocla/Public_Laws/PL104-113.pdf
-Page 4-
What ASTM E 2500 Applies To
Pharmaceutical and biopharmaceutical manufacturing systems:
Facility equipment
Process equipment
Supporting utilities
Process monitoring systems
Process control systems
Automation
Systems that have the potential to affect
product quality patient safety -Page 5-
ASTM E 2500-07 Highlights
The ASTM standard focuses on
Specification Design Verification Lifecycle
Alternative to ISPE Baseline Guide Vol 5 Commissioning & Qualification
complexity, cost, time
Replaces Design Qualification with a Design Review by Subject Matter Experts
Risk Assessments by Subject Matter Experts (SMEs)
Replaces sequential Commissioning and Qualification with “Verification”
Eliminate Impact Assessment
“Fit for intended use” - Not bound by the formal IQ, OQ PQ phases
Lifecycle Change
Continuous process improvements and real-time monitoring (PAT) -Page 6-
Why is it needed now?
“It is estimated that validation can add up to 25% of the total installation cost for new facilities.” −
I know Nothing!
M Guyader, LBP
E 2500 – puts focus on Critical areas that affect
Product Quality Patient Safety Let’s Validate Everything! -Page 7-
What’s Driving us to Consider new Validation Approaches
“Pharmaceutical manufacturing operations are inefficient and costly .”
s e t s a W y r t will need to i e n t “Pharmaceutical manufacturing s u c d i f n f I employ innovation cutting edge scientific , a & e l n I c o “If FDA cknowledge.” could the way it t i change t u e e engineering u a D r m r a a ” e regulated… h g Y n P i a “ r n u t o i c l l a i f B u n 0 a 5 $ M the industry could save
•Source:
6 r 2 0 0 e b o t t y, O c i s r e v n i Group Report”, 2004 “PAT Team & Manufacturing Science Working w n U o t e g r , G e o t c e j o c h P r r a e s e in g R r u t c a f M a n u l a c i t a c e u P h a r m
"if we change the way both manufacturers and 10regulators to 50%operate, of thethecost of could goods industry savesold.” an Pharmaceutical Manufacturing Research Project Benchmarking Study, Georgetown University, October 2006 average of 15 per cent of manufacturing costs ".
-Page 8-
They Have!
FDA 2004: Pharmaceutical cGMPs for the 21st Century – A Risk Based Approach “ Encourage implementation of risk-based approaches”
FDA 2004: PAT — A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance “ encourage the voluntary development and implementation” of “Process Analytical Technology”
FDA 2006: A Regulatory Paradigm to Encourage Innovation. Keith Webber, CDER/OPS, FDA
FDA 2006: Guidance for Industry – Q9 Quality Risk Management
FDA 2007: Pharmaceutical Quality for the 21st Century A RiskBased Approach Progress Report
FDA 2009: Guidance for Industry Q8(R1) Pharmaceutical Development
“science- and risk-based submissions” QbD
-Page 9-
Focus on Criticality, Ongoing Verification
3 -Page 10-
Why Now?
Industry and Regulatory Agencies are striving to be more efficient, reduce costs and improve quality and safety
Decades of pharma & bio manufacturing experience
More knowledge of systems
Solid understanding of operations
Less ‘anything can happen’ philosophy -Page 11-
Implementing ASTM E 2500
Some will wrongly interpret this as simply shifting validation responsibilities:
Some will wrongly interpret this as simply changing the terminology:
“This new approach will significantly shift the current qualification responsibilities and activities associated with facility qualification, equipment qualification, and utility qualification to the company’s corporate engineering group ”
“Out goes the Design Qualification (DQ) with a Design Review (DR). Also for those that do them, Impact Assessments are out. Commissioning and Qualification are replaced by “Verification ”, the qualification phases (IQ, OQ, PQ) are obsolete.”
ASTM E 2500 is a new Concept, requiring new Approaches
It’s more than simply re-naming documents It’s more than a ‘re-org’ of shifting responsibilities from one group
-Page 12-
Implementing ASTM E 2500
To implement the concepts of E 2500
Approach has to change Expertise (of the people involved) has to change Tools have to change
Otherwise there will be no real change
-Page 13-
Is ASTM E 2500 About This?
OLD
NEW? -Page 14-
GAMP Validation “V” Model
-Page 15-
ASTM E 2500 Is:
A standard approach for validating equipment, facilities, processes
Streamlined process
Risk based – based – redu reduce ce cos costs ts
QbD – QbD – develop develop then then employ employ best best practi practices ces
More consistent qualification
Supports current regulatory guidance (FDA, ICH) − Knowledge (expert) based − Risk based
-Page 16-
ASTM E 2500 Process Map
-Page 17-
E2500 System Lifecycle and Validation Approach Planning & Documentation
Identify Subject Matter Experts
User Requirements Specification
Risk Assessment
Functional Specifications and Design
Verification Plan Traceability Matrix Factory Acceptance Tests
Site Acceptance Tests
Installation/ Operational Qualification Tests
Performance Qualification Tests
Vendor Documentation
Verification Summary Report ETOP
GMP Operation and Change Management -Page 18-
The New Standard is About Fundamental Change! To more efficiently and better , design and implement manufacturing systems… ASTM E 2500 embraces, leverages and brings together the cutting edge concepts of:
RiskBased Approach
Knowledge & Understanding
Science Based Approach
Subject Matter Experts (SMEs)
Quality by Design (QbD)
Process Analytical
Good Engineering Practice, (GEP)
Technologies (PAT)
Lifecycle concepts
Design Space
Change implementation
Critical Parameters
Critical Quality Attributes (CQA)
Continuous process improvement
Vendor documentation -Page 19-
E 2500 Key Concepts for Design & Implementation of Manufacturing Systems
Methodologies 1. Requirements 2. Specification & Design 3. Verification
Toolbox 1. Design Review 2. Subject Matter Experts 3. Risk Management Process 4. Change Management Plan
-Page 20-
Benefits of Implementing E 2500
LEANer manufacturing systems
Elevate our industry to more knowledge, better understanding of our manufacturing systems
Remove waste
Data, PAT, Design Space
Focus on what’s important (Critical)
More is not better
Better technical understanding (Subject Matter Experts)
Less waste & repetition
Use vendor doc’s
-Page 21-
Implementing ASTM E 2500
1. Planning and Documentation :
VMP
Verification Team and Responsibilities
Document Matrix (planning, design & verification)
Eligible vendor documentation Document Matrix
prepared by:
Phase 1 Planning and Definition HYDE Task
002
Title
Doc. #
Doc. #
Status
FMECA RISK ASSESSMENT SOP C OMM IS SI ON IN G PL AN
TEC-005
VERIFICATION PLAN PROTOCOL TEMPLATE HVAC SYSTEM- AIR HANDLERS
APPROVED 04AUG09 URS-50058- APPROVED 66 29SEP09
RSK-50058- DRAFT 66
AUTOCLAVE (2 DOOR)
URS-50043
RSK-50043
BAS- BUILDING AUTOMATION SYSTEM
URS-50054
CHILLER SYSTEM
URS-50050
APPROVED 02JUL09
CLEAN DRY AIR SYSTEM URS-50049
APPROVED 25JUN09
COOLING TOWER SYSTEM
URS-50056
APPROVED 09JUL09
URS-50053
APPROVED 03AUG09
C OM -00 1
002 002
Status
Date: 20-Oct-09
Phase 2 Design & Development Doc. #
Status
Doc. #
Status
FAT
SAT
Validation IOQ
PQ
Enhanced Comm
IOQ
PQ
Summary Reports
APPROVED 19MAY09 A PP ROV ED 24JUL09
003 004 005
APPROVED 13MAY09 APPROVED 08AUG09
RSK-50054
APPROVED 25JUN09 DRAFT
006 007
RSK-50049
APPROVED 18SEP09
RSK-50053
APPROVED 03AUG09
008 009
ELECTRICAL/ LIGHTING SYSTEM EMERGENCY GENERATORS
010
-Page 22-
Implementing ASTM E 2500
2. Identify Subject Matter Experts :
(§6.7) SMEs have primary responsibility for specification, design and verification of the manufacturing systems “individuals with specific expertise and responsibility in a particular area or field (for example, quality unit, engineering, automation, development, operations.”
CFR21 §211.34 “Consultants advising on the manufacture, processing, packing, or holding of drug products shall have sufficient education, training, and experience , or any combination thereof, to advise on the subject for which they are retained.”
Who are they?
Where do you find them?
-Page 23-
SME Qualifications
Experience >10 y experience Designed & implemented systems or practices
Process/System Expertise Knowledge of GMP, compliance, design elements, risk factors Applies engineering equations, principles to the design, sizing & scaling of systems. In-depth knowledge of the subject
Methodology Expertise Proficient in standard methodologies for design and implementation, such as ICH Quality Guidelines (Q8, Q9, Q10), FDA Guidance, CFRs, ASME Standards (BPE, E 2500), ISPE Guides (GAMP, Baseline) Completed formal training courses
Recognized Competence Recognized by peers and professional associations, published, teaches topic Professional credentials, license -Page 24-
Implementing ASTM E 2500
3. Requirements Specification :
Identify specific requirements Basis for specification, design, and verification of the system (§7.2)
SMEs
SME
product and process knowledge and understanding based on scientific data (QbD, Design Space).
This knowledge is the basis of scientific understanding for the system
FDA 2009: Guidance for Industry Q8(R1) Pharmaceutical Development
What is critical
-Page 25-
Implementing ASTM E 2500
4. Risk Management Process FDA 2006: Guidance for Industry – [ICH] Q9 Quality Risk Management
Perform risk assessments at appropriate stages to evaluate the risks to product quality and patient safety
Performed by an appropriate SME
Identify controls and verification techniques to manage risk to an acceptable level
-Page 26-
Implementing ASTM E 2500
5. Specification and Design :
Leverage qualified equipment vendor expertise (SME) to identify & document elements which affect critical quality attributes
Communicate the factors that impact product quality to the system (e.g. equipment) designer.
Strive to mitigate product quality & patient safety risks through the design
Functional Specifications provide acceptance criteria for functional tests specified in the Verification Plan.
-Page 27-
Potential Design Requirements Requirements Definition : Temperature Shear Flow rate Membrane Area
-Page 28-
Implementing ASTM E 2500
6. Verification Plan (§5.1, §7.4)
Verify the critical aspects of the manufacturing system
Identifies all required testing & documentation
Extent of verification and documentation should be based on risk to product quality and patient safety Criticality, risk factors identified in the URS, FMECA Risk Analysis, and detailed design Testing occurs from “FAT” to “PQ”
Acceptance criteria:
Design Properly installed Operating correctly Meets performance requirements “Fit for intended use”
Developed and approved by subject matter experts Critical aspects approved by the quality unit
A ‘Traceability Matrix’ summarizes required testing and when it occurs
-Page 29-
Verification Plan Traceability Matrix
Identifies required test functions Identifies when testing will be executed FAT, SAT, IQ, OQ, PQ
-Page 30-
Implementing ASTM E 2500
7. Verification Plan Execution : Subject matter experts perform or oversee activities, and document results (§7.4.3.1)
“Vendor verification documentation may be used” (§7.4.3.2)
Leverage FAT/SAT testing “rather than repeating vendor activities and replicating vendor documentation” (§6.8.2)
Testing occurs across FAT, SAT, IQ, OQ, PQ
The more critical testing or additional testing may occur during IQ/OQ to mitigate risk
-Page 31-
The Role of System Vendors “The key to a competitive parts supply system is the way the assembler works with its suppliers ” – Womack, The Story of Lean Production
-Page 32-
Implementing ASTM E 2500
8. Verification Summary Report
Approved FAT, SAT, ETOP, IOQ and PQ Reports collectively provide documented verification that the manufacturing system is fit for intended use (E 2500 §7.5.1)
Summary Report provides an overview of test results and nonconformances with acceptance criteria (§7.5.2)
Completed verification documentation reviewed by qualified and independent subject matter expert(s) (§7.4.4.1)
SME reviews overview of results and any nonconformance with critical acceptance criteria
Systems with critical aspects should be approved by the quality unit.
SME confirms manufacturing system is fit for intended us (§7.5.3)
Approved by SME and Quality Assurance (§7.5.4). -Page 33-
Implementing ASTM E 2500
9. GMP Operation Acceptance, Release & Change Management:
After Verification Summary Report approval,
Quality Assurance issues authorization to release the system for GMP operational use (§7.5.5).
As part of the system life-cycle, equipment, and procedures are periodically reviewed.
Modifications are controlled via Change Management throughout the system lifecycle (E 2500 §8.4.3). Changes are approved by system subject matter experts. Changes to critical aspects or to aspects that affect system requirements relative to product quality and patient safety are additionally approved by Quality Assurance (§8.4.2, §8.4.3)
-Page 34-
The Role of QA in ASTM E 2500
7.4.1.3 Acceptance criteria of critical aspects (that is, critical to product quality and patient safety) should be approved by the quality unit.
7.4.2.3 The verification plan should be developed and approved by t h g i subject matter experts. Verification plans for systems containing s critical r e v aspects should be approved by the quality unit. O l a n 7.5.4 Such documentation should be prepared and approved by o i t i d d subject matter experts. Such documentation for systems with critical A h aspects should be approved by the quality w i t unit.
i s k R e management should be applied. This t 8.4.2 Before acceptance, change a g process should be managed M i t i by, and changes approved by, subject matter experts. Changes affecting critical aspects of manufacturing systems should be communicated to the quality unit.
8.4.3 After acceptance, prior to manufacturing for commercial use, operational change management should be applied. Under operational change management, all changes related to specific requirements relative to product quality and patient safety require prior approval by the quality unit, unless predefined arrangements are established covering -Page 35-
What Else is Needed?
Risk Management Process
ICH Q9
Perform risk assessments at appropriate stages to evaluate the risks to product quality and patient safety
Performed by an appropriate SME
Identify controls and verification techniques to manage risk to an acceptable level
-Page 36-
Risk Management Program
ICH Published 09 Nov 2005 FDA Published Federal Register, June 2, 2006
“Although there are some examples of the use of quality risk management in the pharmaceutical industry today, they are limited and do not represent the full contributions that risk management has to offer.“
Risk Based Quality Systems Risk Based Validation Risk Based Process Monitoring Risk Based Documentation -Page 37-
ICH Q9 Describes Several Risk Assessment Tools
Basic Risk Management Facilitation Methods (Flowcharts, Check Sheets Etc.)
Failure Mode Effects Analysis (FMEA)
Failure Mode, Effects and Criticality Analysis (FMECA)
Fault Tree Analysis (FTA)
Hazard Analysis And Critical Control Points (HACCP)
Hazard Operability Analysis (HAZOP)
Preliminary Hazard Analysis (PHA)
Risk Ranking and Filtering
Supporting Statistical Tools
-Page 38-
Risk Management - FMEA Method
Severity
Occurrence
assesses the likelihood a parameter will be out of range.
Detection
addresses the impact on a process in the event a parameter is out of range.
addresses the ability of detecting a defect if a parameter is out of range.
Risk Priority Number
RPN = Severity x Occurrence x Detection -Page 39-
FMEA Risk Assessment - Identifying Criticality
Assemble multidisciplinary team
Prepare “FMEA Data Sheet”
Manufacturing, Process Development, Manufacturing Sciences, Engineering and Quality Assurance
All operating inputs and proposed operating ranges What are the potential failure modes (process, equipment, operators) Typical sources of failure in systems What are causes of these failures
Scoring based upon
Knowledge, known equipment capability, maintenance Previous experience and expertise
-Page 40-
Risk Assessment SOP
-Page 41-
FMEA Worksheet Severity x Occurrence x Detection = RPN Failure Modes and Effects Analysis Process
Healgen
Unit Operation
TFF
Leader
John Smith
Participants
Robert S, Bill E, Fred J, Mary S, Jill R
Operational Parameter Preparation Verify TFF-08207 is within cleaning expiration date
Current Range
Failure Mode
Cause(s)
30 days
Out of date
Operator error / Process delay
Incorrect dip tube orientation
Operator error / Incorrect alignment of alignment pin
Install dip tubes Perform pre-use visual inspection
Clean
Set-up TFF for processing per MO173
Not cleaned
Faulty cleaning cycle
System set-up incorrectly
Operator error / Incorrect SOP revision
Incorrect system hose connections Incorrect connection / utilities failure Incorrect connection / utilities failure Incorrect connection / utilities failure
System hose connections Connect chilled water supply Conncect AWFI Conncect CDA Drain the system per MO173
System not drained
Verify Hydraulic Pressure Unit is in the run setting Open and download file "Automated TFF Method VER01"
Incorrect pressure on membranes
Buffer Manifold Flush System AWFI flush
> 1150 psig
Wrong file downloaded Flush valves for > 2 min
Potential Effect(s)
Severity
Occurrence
Detection
RPN
Expired equipment used in process Foaming / Over concentration / Yield loss Dirty equipment used in process Production delay / Product loss
Inadequate flushing of system / Operator error Product loss Temperature spike / Product Utilities failure / Operator error loss Inadequate flushing of system / Utilities failure / Operator error Product loss System will not operate / valves Utilities failure / Operator error will not toggle System not flushed of storage Operator error / Equipment failure solution Wrong setting selected / Faulty Membranes not sealed / Hydraulic Pressure Unit Product loss Operator error
Product Loss
Valves not flushed for sufficient tim
Incorrect flow rate / Valve failure
System not flushed of storage solution
System not adequately flushed with AWFI
Incorrect system connections / Insufficient volume / Incorrect flow path
System not flushed of storage solution / Product loss
-Page 42-
FMEA Worksheet Severity x Occurrence x Detection = RPN
System/Process Failure Mode, Effects and Criticality Analysis (FMECA) System or Process Name:
Compiled by:
Team:
Reference Drawings
System Owner:
Primary SME:
URS
Original Date:
Revision Date: Existing Conditions
Component Description & Function
Potential Failure Mode
Potential Failure Effects
Potential Failure Causes
Compensating Provisions
S E V
O C C
D E T
R P N
Revised Conditions
Recommended Actions
Resp.
Actions Taken
S E V
O C C
D E T
R P N
-Page 43-
FMECA Worksheet Component Description & Function 3
WFI Dis tribut ion S ys tem
Potential Failure Mode
WF I di stribut ion p ipe Contamination
Potential Failure Effects
WFI water quality out of spec
Potential Failure Causes
Compensating Provisions
S E V
O C C
D E T
R P N
8
5
5
200
Dead leg, Non-turbulent flow, Check design, commissioning, wrong surface finishing and/or validation, PM & EM program incompatible material (MOC) for WFI piping
Res Recommended Actions
Commissioning & Qualification Testing (RPN=200 Undesirable) 1. Verify no dead leg L/D >2.0 2. Verify surface finish 3. Verify MOC (elastomers, SS grade) 4. Verify Reynolds number (circulation flowrate) 5. Verify Design Review
p .
Actions Taken
S
O E V
D C C
R E T
P N
Particle Test Program -Yearly by Intarcia?
-Page 44-
Criticality Ranking
100 80 70 High Risk 60 50 42 36 Risk Score 30 24 Moderate Risk 16 12 9 Low Risk 6 1 Number of RISK CRITICALITY RPN's in Range Intolerable 343-1000 37 Undesirable 189-336 26 Tolerable 72-180 23 Negligible 1-70 34
1 Certain 100 80 70 60 50 42 36 30 24 16 12 9 6 1
2 Very High 200 160 140 120 100 84 72 60 48 32 24 18 12 2
Detection Rank 4 6 Moderate Low 400 600 320 480 280 420 240 360 200 300 168 252 144 216 120 180 96 144 64 96 48 72 36 54 24 36 4 6
8 Remote 800 640 560 480 400 336 288 240 192 128 96 72 48 8
10 Uncertain 1000 800 700 600 500 420 360 300 240 160 120 90 60 10
ACTION Design modification required to mitigate risk Qualification testing or design modification required to mitigate risk Qualification testing may be required to mitigate risk Commission -Page 45-
Manufacturing FMEA
RPN’s can range from 1 to 1,000
Manufacturing:
RPN ≥100 indication may be a high risk item
Nine unit operations analyzed FMEA evaluated 445 operational inputs RPN’s ranged from 3 to 158
Only 6 operational inputs received RPN scores ≥100
Indicates robustness, procedural controls and equipment capabilities have minimized the risk of failure Fewer parameters to validate More Targeted Validation Better understanding, better quality, lower cost -Page 46-
FMEA Results Unit Operation
Parameter
RPN
Production Fermentation
Raw Material Addition
111
Production Fermentation
Sampling for Culture Purity Analysis
102
SEC
Elution Buffer (BT018) pH
158
SEC
Elution Buffer (BT018) Conductivity
155
SEC
Load Volume
144
SEC
Remove Bioburden, LAL Samples
113
Validate only CRITICAL & KEY Parameters
From FMEA
From Severity
From Knowledgebase -Page 47-
FMECA Risk Analysis Report
a t io n t n e m u d o c d o o g i th… w e c n o r d a a n c e c d i c u a g n i I C H t e d c h 41 t u i 2 d w n 9 . t o n m “ c e e t s i s yst n S o y . c t s i l s e i a c i u n b e a t io al Q p r a c t d c d i l t n u u e o e m h c o m ma l s s 8 T h i s r e c t r y, Q10 Phar o f t h e c o n t r o N o v 1 8, 2 0 0 c e io n u s t n d a a n c d i i i f i r u t s o G f DA n d j u F a – s ” n d o i n t e e m D e c i s u c o n t ly d e i c i f f u s -Page 48-
E 2500 Implementation Gaps
ASTM E 2500 lays out a ‘standard” roadmap for the overall approach
It is not a ‘how to’ guide,
Firms will need to develop
“Firms should develop appropriate mechanisms to communicate requirement inputs, including product quality considerations, to those responsible for design”
Processes Tools & templates suited to their operations
Not one size fits all – needs to address corporate risk, nature of business, expertise of staff, organization resources
-Page 49-
What Else is Needed?
Design Review Process
Planned and systematic reviews throughout the system lifecycle: −
Specifications
−
Design
−
Design development
−
Continuous improvement changes
Ensure product and process requirements are satisfied by the design
Unacceptable risks are mitigated by design or other means
Design is performed by appropriate SMEs -Page 50-
What Else is Needed?
Change Management Process
Develop a change management plan before releasing the system
Change is good, is expected
Managed by, changes approved by SMEs
Changes affecting critical aspects communicated to the quality unit
Changes related to product quality and patient safety require prior approval by the quality unit, unless predefined plan
PAT – provides scientific data to support changes and manage risk
-Page 51-
ASTM E 2500 – The Role of Vendors
“The key to a competitive parts supply system is the way the assembler works with its suppliers”
(Womack et al., 1990)
Partner with a supplier (LEAN) vs Bid them against each other (MASS)
“Preferred Suppliers ”
Few in number, single sourced? Share information – needs, specifications Supplier becomes the solution provider
Encourages use good vendor documentation and testing to support qualification
-Page 52-
Implementation Gaps
Gaps
How do you do a risk assessment eg. FMEA SOP?
How often, at what points in the process?
How do you qualify to be an SME?
How many QA staff will be needed? What expertise will they need? Where will you find them?
How do you manage changes during design & implementation?
How do you manage change to enable improvements to be implemented?
How do you efficiently address deviations from the Verification Plan?
How do you determine the ‘Critical aspects of the manufacturing system’
How to define & document the verification approach -Page 53-
E 2500 Implementation Gaps
ASTM E 2500 lays out a ‘standard” roadmap for the overall approach
It is not a ‘how to’ guide,
Firms will need to develop
“Firms should develop appropriate mechanisms to communicate requirement inputs, including product quality considerations, to those responsible for design”
Processes Tools & templates suited to their operations
Not one size fits all – needs to address corporate risk, nature of business, expertise of staff, organization resources
-Page 54-
E 2500 Efficiency & Cost Savings
The extent of verification and the level of detail of documentation should be based on risk, including those associated with product quality and patient safety, and the complexity.
“Only companies that achieve a high level of process understanding will have the opportunity to justify a more flexible regulatory path.”
FDA 2004
-Page 55-
Yes, ASTM E 2500 is Being Implemented
Hyde Client, Commercial Device Facility
E2500 Based facility and systems commissioning and qualification
Amgen, Thousand Oaks Clinical Mfg
50-70% reduction in IQ/OQ for chromatography skid − Phil Bowles, ISPE Tampa 2009
Bristol-Myers Squibb Biologics
“Applying ASTM E2500 to a Greenfield Site” − E Bramhall, Director Validation, ISPE 2008 Annual Meeting
Perkin Elmer
Major East Bay Pharmaceutical Company
“Best Practices for Qualification of Laboratory Equipment Utilizing ASTM E2500”
Risk based commissioning & qualification
Major Bay Area Biotech Company
Risk based validation for new facility commissioning -Page 56-
FDA Guidance
“Guidance for Industry Process Validation: General Principles and Practices” - FDA Nov 18 2008 Guidance
In keeping with the spirit of ASTM E 2500 Standard, the document uses the term “verify” rather than “validate” when referring to facility systems.
IQ, OQ, DQ, PQ are industry terms and standards, not FDA mandated. -Page 57-
Summary
ASTM E 2500-07 provides a cutting edge framework for planning and execution of riskbased approach to designing and implementing reliable manufacturing systems
ASTM E 2500 has many parallels to existing approaches, but relies on more risk management and higher expertise
The challenge is to address the implementation gaps and develop the custom tools -Page 58-
