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ASTM E2500 A New Approach to Validation

Peter K. Watler, Ph.D., Principal Consultant and CTO, Hyde Engineering + Consulting, Inc.

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ASTM E 2500 ­ 07, What is it?

"A risk-based and science-based approach to the specification, design, and verification 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 element that affect product quality

"quality", (not Quality Assurance or Quality Unit) appears 44 times "expert" appears 21 times "critical" appears 20 times

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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.

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What the Law Looks Like

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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

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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)

Eliminate Impact Assessment

Replaces sequential Commissioning and Qualification with "Verification"

"Fit for intended use" - Not bound by the formal IQ, OQ PQ phases

Lifecycle Change

Continuous process improvements and real-time monitoring (PAT)

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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!

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What's Driving us to Consider new Validation Approaches

tes as ry W to cient "Pharmaceutical manufacturingst need u will scientific & employ innovation, al Ind edge Ineffi c cutting e tthe way it "If FDA ceuti change o could engineering knowledge." Du ma regulated... g" ar ear "Ph "PATiTeam &a Y n Manufacturing Sciencen Group Report", 2004 ·Source: turi Working ill o anufac 0 Bthe industry could save $5 M

"if we change the way both manufacturers and 10 to P50% of the cost of could savesold." h regulators operate, the industry goods an Pharmaceutical Manufacturing Research Project Benchmarking Study, Georgetown University, October 2006 average of 15 per cent of manufacturing costs".

rgeto , Geo oject ch Pr r esea ng R cturi anufa cal M ceuti arma sity, niver wn U 2006 ober Oct

"Pharmaceutical manufacturing operations are inefficient and costly."

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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

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Focus on Criticality, Ongoing Verification


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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

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Implementing ASTM E 2500 Some will wrongly interpret this as simply shifting validation responsibilities:

"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"

Some will wrongly interpret this as simply changing the terminology:

"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

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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

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Is ASTM E 2500 About This?



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GAMP Validation "V" Model

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ASTM E 2500 Is:

A standard approach for validating equipment, facilities, processes

Streamlined process Risk based ­ reduce costs QbD ­ develop then employ best practices More consistent qualification Supports current regulatory guidance (FDA, ICH) - Knowledge (expert) based - Risk based

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ASTM E 2500 Process Map

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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 Vendor Documentation Site Acceptance Tests Installation/ Operational Qualification Tests Performance Qualification Tests

Verification Summary Report


GMP Operation and Change Management

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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 Science Based Approach Quality by Design (QbD) Process Analytical Technologies (PAT) Design Space Critical Parameters Critical Quality Attributes (CQA) Knowledge & Understanding Subject Matter Experts (SMEs) Good Engineering Practice, (GEP) Lifecycle concepts Change implementation Continuous process improvement Vendor documentation

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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

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Benefits of Implementing E 2500 LEANer manufacturing systems

Remove waste

Elevate our industry to more knowledge, better understanding of our manufacturing systems

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

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Implementing ASTM E 2500

1. Planning and Documentation:

VMP Verification Team and Responsibilities Document Matrix (planning, design & verification) Eligible vendor documentation

Document Matrix

Phase 1 Planning and Definition


Phase 2 Design & Development

Doc. # Status FAT SAT IOQ PQ Enhanced Comm


IOQ PQ Summary Reports


RSK-50058- DRAFT 66







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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?

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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

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Implementing ASTM E 2500

3. Requirements Specification:

Identify specific requirements Basis for specification, design, and verification of the system (§7.2) SMEs

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

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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

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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.

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Potential Design Requirements Requirements Definition: Temperature Shear Flow rate Membrane Area

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Implementing ASTM E 2500 6. Verification Plan (§5.1, §7.4)

Verify the critical aspects of the manufacturing system

Design Properly installed Operating correctly Meets performance requirements "Fit for intended use"

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:

Developed and approved by subject matter experts Critical aspects approved by the quality unit

A `Traceability Matrix' summarizes required testing and when it occurs

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Verification Plan Traceability Matrix

Identifies required test functions Identifies when testing will be executed FAT, SAT, IQ, OQ, PQ

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Implementing ASTM E 2500 7. Verification Plan Execution: Subject matter experts perform or oversee activities, and document results (§ "Vendor verification documentation may be used" (§ 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

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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

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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) (§ 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).

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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)

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The Role of QA in ASTM E 2500 Acceptance criteria of critical aspects (that is, critical to product quality and patient safety) should be approved by the quality unit. The verification plan should be developed and approved by t h subject matter experts. Verification plans for systems containingg si critical ver aspects should be approved by the quality unit. al O by n 7.5.4 Such documentation should be prepared and approved itio subject matter experts. Such documentation for systems with critical Add h aspects should be approved by the quality unit. wit 8.4.2 Before acceptance, ga change management should be applied. This iti by, and changes approved by, subject process should be managed M 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

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Ris te


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

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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

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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

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Risk Management - FMEA Method Severity

addresses the impact on a process in the event a parameter is out of range.


assesses the likelihood a parameter will be 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

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FMEA Risk Assessment - Identifying Criticality Assemble multidisciplinary team

Manufacturing, Process Development, Manufacturing Sciences, Engineering and Quality Assurance

Prepare "FMEA Data Sheet"

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

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Risk Assessment SOP

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FMEA Worksheet Severity x Occurrence x Detection = RPN

Failure Modes and Effects Analysis

Process Unit Operation Leader Participants Operational Parameter Preparation Verify TFF-08207 is within cleaning expiration date Install dip tubes Perform pre-use visual inspection Set-up TFF for processing per MO173 System hose connections Connect chilled water supply Conncect AWFI Conncect CDA Drain the system per MO173 Verify Hydraulic Pressure Unit is in the run setting Open and download file "Automated TFF Method VER01" Buffer Manifold Flush System AWFI flush > 1150 psig Clean Current Range 30 days Healgen TFF John Smith Robert S, Bill E, Fred J, Mary S, Jill R Failure Mode Out of date Incorrect dip tube orientation Not cleaned System set-up incorrectly Incorrect system hose connections Incorrect connection / utilities failure Incorrect connection / utilities failure Incorrect connection / utilities failure System not drained Incorrect pressure on membranes Wrong file downloaded Flush valves for > 2 min Valves not flushed for sufficient tim System not adequately flushed with AWFI Cause(s) Operator error / Process delay Operator error / Incorrect alignment of alignment pin Faulty cleaning cycle Operator error / Incorrect SOP revision Potential Effect(s) Expired equipment used in process Foaming / Over concentration / Yield loss Dirty equipment used in process Production delay / Product loss Severity Occurrence Detection RPN

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 Incorrect flow rate / Valve failure Incorrect system connections / Insufficient volume / Incorrect flow path Product Loss System not flushed of storage solution System not flushed of storage solution / Product loss

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FMEA Worksheet Severity x Occurrence x Detection = RPN

System/Process Failure Mode, Effects and Criticality Analysis (FMECA)

System or Process Name: Reference Drawings URS Compiled by: System Owner: Original Date: Existing Conditions Component Description & Function S E V O C C D E T R P N Recommended Actions Team: Primary SME: Revision Date: Revised Conditions S E V O C C D E T R P N

Potential Failure Mode

Potential Failure Effects

Potential Failure Causes

Compensating Provisions


Actions Taken

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FMECA Worksheet

Component Description & Function

3 WFI Distribution System

Potential Failure Mode

Potential Failure Effects

Potential Failure Causes

Compensating Provisions





WFI distribution pipe Contamination

WFI water quality out of spec

Check design, commissioning, Dead leg, Non-turbulent flow, wrong surface finishing and/or validation, PM & EM program incompatible material (MOC) for WFI piping 8 5 5 200

Res Recommended Actions p .

Actions Taken

Particle Test Program -Yearly by Intarcia?






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

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Criticality Ranking

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 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

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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

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

Manufacturing FMEA

RPN's can range from 1 to 1,000

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

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FMEA Results

Unit Operation Production Fermentation Production Fermentation SEC SEC SEC SEC Parameter Raw Material Addition Sampling for Culture Purity Analysis Elution Buffer (BT018) pH Elution Buffer (BT018) Conductivity Load Volume Remove Bioburden, LAL Samples RPN 111 102 158 155 144 113

Validate only CRITICAL & KEY Parameters

From FMEA From Severity From Knowledgebase

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FMECA Risk Analysis Report

n entatio um od doc go with... ce e cordan uidanc 1 ac in Hg ducted with IC stem.9 24 nt "con y onsiste is c ices. uality S ld be Q tion pract eutical rols shou menda ac m 8 his reco y, Q10 Pharm of the cont T 18, 200 ov dustr ation ance N id fic for in nd justi ed" ­ FDA Gu sa ecision document D ntly sufficie

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E 2500 Implementation Gaps ASTM E 2500 lays out a `standard" roadmap for the overall approach It is not a `how to' guide,

"Firms should develop appropriate mechanisms to communicate requirement inputs, including product quality considerations, to those responsible for design"

Firms will need to develop

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

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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

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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

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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

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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

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E 2500 Implementation Gaps ASTM E 2500 lays out a `standard" roadmap for the overall approach It is not a `how to' guide,

"Firms should develop appropriate mechanisms to communicate requirement inputs, including product quality considerations, to those responsible for design"

Firms will need to develop

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

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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

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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

"Best Practices for Qualification of Laboratory Equipment Utilizing ASTM E2500"

Major East Bay Pharmaceutical Company

Risk based commissioning & qualification

Major Bay Area Biotech Company

Risk based validation for new facility commissioning

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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.

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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

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Contact Info

Peter K Watler, PhD Principal Consultant and Chief Technology Officer Hyde Engineering + Consulting, Inc. [email protected] 415-235-1911

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Microsoft PowerPoint - ASTM E 2500 - Watler.ppt

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