1. 2014 ISPE Annual Meeting
How to Implement ASTM E2500
for Legacy Systems
Andrew Faden, CPIP
Hargrove C+A, Boston, MA
October 13, 2014
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2. 2014 ISPE Annual Meeting
Agenda
• Introductions
• Seminal Events in Manufacturing Quality
• PV Guidance
• E2500 Refresher
• Tools for implementing E2500
• Questions?
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3. 2014 ISPE Annual Meeting
Introductions
My Background
• BS Electrical Engineering
• MS Bioscience Administration
• 20+ years application engineering in high-tech
manufacturing – sensors; instruments; industrial
control systems; automated equipment
• Hi-Rel components and systems, many with
impact to life/safety (medical device, aerospace,
military)
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4. 2014 ISPE Annual Meeting
Introductions
My Background
• 18 years FSE engineering and project
management in pharmaceutical fill-finish
manufacturing including liquid fill parenteral,
aseptic blow-fill-seal, OSD
• CPIP and lots of guidance from ISPE and fellow
members!
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5. 2014 ISPE Annual Meeting
Introductions
Your Background
• ISPE members?
• Undergrad in engineering?
• Work for pharma?
• Work for biotech?
• Work for vendor?
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6. 2014 ISPE Annual Meeting
Introductions
Your Background
• Quality role?
• Engineering role?
• Operations role?
• Company wants to implement E2500?
• Company has implemented E2500?
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7. 2014 ISPE Annual Meeting
Seminal Events - Quality
• 1924
– Walter Shewhart came up with the concept of common
cause and special cause variation to improve the
telephone cable manufacturing process. First use of SPC.
(ASTM adopted his charts in 1933)
• 1939
– Deming introduces new quality concept:
• Quality = results/cost
• If you focus on decreasing costs, costs rise, and quality falls
• If you focus on increasing quality, costs fall, and company results
rise – think Apple, Tesla.
• Note that the relationship between cost and quality is
counterintuitive!
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8. 2014 ISPE Annual Meeting
Seminal Events - Quality
• 1951 – Juran publishes Quality Control Handbook.
– Top management must be involved to effect change
– Pareto principle (80/20) – focus on the vital few
– Project-by-project approach to quality improvement
• 1986
– Bill Smith, Motorola, devised Theory of Latent Defects.
Key concept was Six-sigma, a process capability that
produces fewer than 3.4 defects per 1,000,000.
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9. 2014 ISPE Annual Meeting
Seminal Events – Drug Quality
• 2001 – ISPE Baseline Guide Volume 5: Commissioning and
Qualification for New and Renovated Facilities:
– An engineering approach to provide cost effective facilities in a
timely manner. Includes regulated facilities, utilities and
equipment. Key concepts:
• Impact assessments starting with system, working down to
components
• Traditional IQ, OQ, PQ verification approach
• 2004 – FDA Initiative: Pharmaceutical CGMPs for the 21st
Century: A Risk-Based Approach – target goals:
– Incorporated concepts of risk management and quality systems
into the manufacture of pharmaceuticals to encourage
innovation and improve product quality
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10. 2014 ISPE Annual Meeting
Seminal Events – Drug Quality
• 2007 – ASTM E2500 Standard Guide for
Specification, Design, and Verification of
Pharmaceutical and Biopharmaceutical
Manufacturing Systems and Equipment.
– Applies concepts introduced in Pharmaceutical
CGMPs for the 21st Century: A Risk-Based Approach
– Verification required for acceptance and release of
FSE – not validation
– Too high-level. Caused confusion. An industry built
around validation processes needed more detail
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11. 2014 ISPE Annual Meeting
Seminal Events – Drug Quality
• 2011 - ISPE GPG Science and Risk-based Approach for the Delivery
of Facilities, Systems, and Equipment (FSE Guide). Upgrade of
Volume 5 Baseline guide:
• Incorporated science and risk based approach for delivery of FES from
E2500
• Incorporated QRM concepts from ICH Q8, Q9, and Q10
• Installation, Functional, and Performance Verification; not Validation
• Still too vague!
• 2011 - ISPE GPG Applied Risk Management for Commissioning and
Qualification (ARM Guide)
• Describes how organizations can keep same processes (IQ, OQ, PQ)
and move from established baseline practice (Volume 5) to a more
efficient science- and risk-based framework (FSE)
• Wishy-washy, encourages status quo.
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12. 2014 ISPE Annual Meeting
Seminal Events – Drug Quality
• 2010 to 2015 - ISPE GPG Product Quality Lifecycle
Implementation Guide Series (PQLI Guides) - address
product and process development and manufacture
using science- and risk-based approaches, QbD, QMS.
• 2011 - FDA Process Validation: General Principals and
Practices (PV Guide).
• Update of “Pharmaceutical CGMPs for the 21st Century ―
A Risk-Based Approach,” adds use of technology, risk-
based approach, and modern quality systems
• Ties back to 21CFR 211.100(a) and 21CFR 211.110(a)
• References ASTM E2500 and other relevant standards
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13. 2014 ISPE Annual Meeting
PV Guide – Key Concepts
Start by asking questions:
– “…process validation is… the collection and
evaluation of data, from the process design stage
through commercial production, which establishes
scientific evidence that a process is capable of
consistently delivering quality product. Process
validation involves a series of activities taking
place over the lifecycle of the product and
process.
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14. 2014 ISPE Annual Meeting
PV Guide – Key Concepts
Iterative process to attain reproducible manufacturing
capability:
– Stage 1 – Process Design: The commercial
manufacturing process is defined during this stage
based on knowledge gained through development and
scale-up activities.
– Stage 2 – Process Qualification: During this stage, the
process design is evaluated to determine if the
process is capable of reproducible commercial
manufacturing.
– Stage 3 – Continued Process Verification: Ongoing
assurance is gained during routine production that the
process remains in a state of control.
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15. 2014 ISPE Annual Meeting
PV Guide – Key Concepts
Current mindset is that things don’t change after
process is validated – this is just the beginning!
– After establishing and confirming the process,
manufacturers must maintain the process in a
state of control over the life of the process, even
as materials, equipment, production environment,
personnel, and manufacturing procedures change.
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16. 2014 ISPE Annual Meeting
PV Guide – Key Concepts
Knowing your process variation is key!
• A successful validation program depends upon information
and knowledge from product and process development.
This knowledge and understanding is the basis for
establishing an approach to control of the manufacturing
process that results in products with the desired quality
attributes. Manufacturers should:
– Understand the sources of variation
– Detect the presence and degree of variation
– Understand the impact of variation on the process and
ultimately on product attributes
– Control the variation in a manner commensurate with the risk it
represents to the process and product
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17. 2014 ISPE Annual Meeting
PV Guide – Key Concepts
Once you understand process variation, implement
sufficient process controls:
• Process controls address variability to assure
quality of the product. Controls can consist of
material analysis and equipment monitoring at
significant processing points (§ 211.110(c)).
Decisions regarding the type and extent of
process controls can be aided by earlier risk
assessments, then enhanced and improved as
process experience is gained.
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18. 2014 ISPE Annual Meeting
PV Guide – Key Concepts
It begs for a knowledge management system!
• Documentation is important so that
knowledge gained about a product and
process is accessible and comprehensible to
others involved in each stage of the lifecycle.
• Information transparency and accessibility are
fundamental tenets of the scientific method.
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19. 2014 ISPE Annual Meeting
PV Guide – Key Concepts
A process flow diagram is the first step:
• We recommend that firms diagram the process
flow for the full-scale process. Process flow
diagrams should describe each unit operation, its
placement in the overall process, monitoring and
control points, and the component, as well as
other processing material inputs (e.g., processing
aids) and expected outputs (i.e., in-process
materials and finished product).
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20. 2014 ISPE Annual Meeting
Why E2500?
E2500 Objective
– “The overall objective is to provide manufacturing
capability to support defined and controlled
processes that can consistently produce product
meeting defined quality requirements”
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21. 2014 ISPE Annual Meeting
Why E2500?
Warning letters about controls and variability
are on the rise:
Numerous citations for: 21 CFR 211.110(a)Control
procedures are not established which validate
the performance of those manufacturing
processes that may be responsible for causing
variability in the characteristics of in-process
material and the drug product.
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22. 2014 ISPE Annual Meeting
Significance of ASTM E2500
It’s all about manufacturing!
“Application of the approach…is intended to
satisfy international regulatory expectations in
ensuring that manufacturing systems and
equipment are fit for intended use, and satisfy
requirements for design, installation, operation,
and performance” ASTM E2500 §5.1
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23. 2014 ISPE Annual Meeting
Key concepts of ASTM E2500
- Risk-based approach
The patient comes first!
“The evaluation of risk to quality should be
based on scientific knowledge and ultimately
link to the protection of the patient” ASTM
E2500 §6.2.2.1
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24. 2014 ISPE Annual Meeting
Key concepts of ASTME E2500
- Science-based approach
Knowledge is the practical use of information!
“Product and process information, as it relates
to product quality and patient safety, should be
used as the basis for making science- and risk-
based decisions that ensure that the
manufacturing systems are designed and
verified to be fit for their intended use.” ASTM
E2500 §6.3.1
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25. 2014 ISPE Annual Meeting
Key concepts of ASTME E2500
- Science-based approach
Collect the information in a central location:
“Examples of product and process information
to consider include: CQAs, CPPs, process control
strategy information, and prior production
experience.” ASTM E2500 §6.3.2
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26. 2014 ISPE Annual Meeting
Key concepts of ASTME E2500
- Critical system aspects
Understand the critical aspects:
“Critical aspects of manufacturing systems are
typically functions, features, abilities, and
performance or characteristics necessary for the
manufacturing process and systems to ensure
consistent product quality and patient safety.”
ASTM E2500 §6.4.1
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27. 2014 ISPE Annual Meeting
Key concepts of ASTME E2500
- Quality by Design
Think Cpk, Six Sigma!
“Quality by design concepts should be applied
to ensure that critical aspects are designed into
systems during the specification and design
process.” ASTM E2500 §6.5.1
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28. 2014 ISPE Annual Meeting
Key concepts of ASTME E2500
Specification, Design, Verification
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Acceptance and release is just the beginning!
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29. 2014 ISPE Annual Meeting
Key concepts of ASTME E2500
– Subject Matter Experts
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SME is a relative term – “in the land of the blind…”
“Subject Matter Experts are defined as those
individuals with specific expertise and responsibility
in a particular area or field (for example, quality
unit, engineering, automation, development,
operations…).” ASTM E2500 §6.7.1.

30. 2014 ISPE Annual Meeting
Key concepts of ASTME E2500
– Subject Matter Experts
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Shifts much of verification responsibility from the
Quality unit to FSE SMEs
“Subject Matter Experts should take the lead role in
the verification of manufacturing systems as
appropriate within their area of expertise and
responsibility.” ASTM E2500 §6.7.2.

31. 2014 ISPE Annual Meeting
Hurdles to Achieving E2500
• Traditionally, reducing the COGS for Pharma
had relatively low impact to bottom line
because of high margins for branded drugs
• Global leadership effort has been focused
more on marketing and development
• Manufacturing was not considered a key
competency
• Requires culture change – leadership will back
E2500 only when it grasps the concept…
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32. 2014 ISPE Annual Meeting
Motivators for Achieving E2500
• A warning letter or recall for product quality
or patient safety can suspend operation
causing drug shortages, loss of sales, loss of
market, and/or damaged reputation
• Better understanding and control of variability
• Lower COGS
• Achieve FDA targets of product quality and
patient safety
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33. 2014 ISPE Annual Meeting
Tools for Implementing E2500
• Critical System Aspect Registry – Risk register
linking Critical Systems, CQAs, CPPs, and risk
to patient
• Knowledge Management – Along with CSA
Registry, collect tacit and explicit knowledge,
including knowledge about process variability,
in a transparent, searchable database
organized by drug product and unit operation
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34. 2014 ISPE Annual Meeting
Tools
Knowledge Management
Why KM?
• Knowledge is currently kept in silos, inaccessible
to those who need it
• MHLW (Japanese FDA) study in 2002 identified
poor communication between R&D and
manufacturing as one of the significant problems.
– Dr. Yukio Hiyama
• “The main competitive advantage organizations
now have is the ability to transfer and apply
knowledge.” Fred Miller, Kaleel Jamison
Consulting Group, April 2012
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35. 2014 ISPE Annual Meeting
Tools
Knowledge Management
For current wisdom on implementing KM see
supplement to PEM, May 2014
• http://www.ispe.org/multimedia/publications
/Pharmaceutical_Engineering_Knowledge_Ma
nagement/#/70/
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36. 2014 ISPE Annual Meeting
Tools – Knowledge Management
Don’t underestimate tacit knowledge:
• Problem: low productivity across site due to
“equipment” problems (eight parenteral fill-finish
lines, five blow-fill-seal fill-finish lines and
associated solution and suspension prep)
• Approach: Held “brown-paper fair” to collect
tacit information from operators and techs.
• Result: 145 issues were identified, prioritized, and
scheduled for remediation. Significant
improvement in productivity.
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37. 2014 ISPE Annual Meeting
Tool – CSA Registry
• The CSA Registry is a trace matrix that links
CQAs, CPPs, and critical system aspects to
risk to patient safety to help meet the intent
of ASTM E2500.
• Concept taken from Project Management
Institute’s PMBOK Risk Register
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38. 2014 ISPE Annual Meeting
Tool - CSA Registry
Methodology
• Identify enlightened sponsor with
knowledge, authority, and responsibility
• With sponsor, select an existing
line/product to start with, one that is
problematic, to get biggest returns,
quickly. Think 80/20 rule and go after
the low-hanging fruit, first.
• This is a project – create a charter!
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39. 2014 ISPE Annual Meeting
Tool - CSA Registry
Methodology
• Select team members with specific
subject matter expertise with selected
line and product, e.g.:
– Product CQAs (development scientist)
– Process CPPs (tech services)
– Manufacturing critical systems (line manager)
– FSE (engineering)
– QMS (quality)
• Train team members on CSA methodology
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40. 2014 ISPE Annual Meeting
Tool - CSA Registry
Methodology
• Assign team members to collect product
and process information:
– CQAs (make sure they are current)
– CPPs
– Process flow diagrams and description
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41. 2014 ISPE Annual Meeting
Tool - CSA Registry
Methodology
• Assign team members to collect line
documentation
– ETOPs with vendor docs, P&IDs, commissioning checklists,
etc.
– SLC documents - URS, FS, DS.
– Verification documentation IQ, OQ, PQ, PV
– SOPs and batch record templates
– Operational information – system logs, CAPAs, OEE data,
calibrations
– Current or planned project work
– Customer complaints, shortages, component inspection
results, etc.
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42. 2014 ISPE Annual Meeting
Tool - CSA Registry
Methodology
• Create a taxonomy that breaks lines into
logical sections: e.g. cartridge filling line >
filling machine > fill level control
• With team members, identify the critical
systems that are causing the most problems
on the selected line
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43. 2014 ISPE Annual Meeting
Tool - CSA Registry
Methodology
• Initiate an entry in the CSA Risk Register based
on selected CQA and CSA (see slide #48):
– Select a drug product CQA of interest (80/20 rule)
– Identify a CSA that can impact that CQA (80/20
rule)
– Document the acceptable range for the selected
CQA at that point in the process
– Is there PAT in place to directly monitor and/or
control that CQA?
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44. 2014 ISPE Annual Meeting
Tool - CSA Registry
Methodology
• What is risk to patient?
– Identify the associated hazard (risk to patient)
– What is the risk to the patient if the CQA is OOS?
Capture severity, probability, detectability.
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45. 2014 ISPE Annual Meeting
Tool - CSA Registry
Methodology
• Continue to populate the registry with CPP
information:
– For the selected CSA, identify a CPP that can
impact that CQA
– Document the acceptable range for the selected
CPP at that point in the process
– Identify whether or not PAT exists for that CPP
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46. 2014 ISPE Annual Meeting
Tool - CSA Registry
Methodology
• Control strategy
– Describe the control strategy, both automated and
procedural, including sampling inspections
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47. 2014 ISPE Annual Meeting
Tool - CSA Registry
Methodology
• Perform risk management:
– Perform Risk Management for each identified
hazard/CSA combination focusing on how to
minimize risk to patient
– The common cause variation of the CSA may well
be unknown. This could be the root cause of the
problem and would have to be tested
experimentally. Equipment manufacturers are
usually very helpful here.
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48. 2014 ISPE Annual Meeting
Tool - CSA Registry
Methodology
• Create CSA Registry Template (hypothetical example):
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Line
Unit
Operation System Risk to patient (Hazard)
Impacted
CQA
Acceptable
range PAT
Dental
Cartridge
Filling Bosch filler Oxygen in
headspace
0.5 µg max no O2 in head space degrades
epinephrine over time. Low
epinephrine at time of administration
causes anesthetic to wear off early
resulting in pain to patient.
CQA

49. 2014 ISPE Annual Meeting
Tool - CSA Registry
Methodology
• Continue until you have worked through
each CQA and each system in the line,
prioritizing the 20% of the issues causing
80% of the problems.
• Additional fields can be added, including:
– Numerical risk evaluation for prioritizing
– Associated CAPAs, deviations, customer complaints
– Planned project work to address issue
– Performance benchmarking to show improvements
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50. 2014 ISPE Annual Meeting
Tool - CSA Registry
Methodology
• End result is a better understanding of the
line’s fitness for use along with risk
mitigation strategies that can be prioritized
for implementation and put into a
maintenance or capital plan.
• If retained in a searchable KM system, the
Registry can be accessed for future change
controls, CAPAs, continuous improvement,
preventative maintenance, etc.
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51. 2014 ISPE Annual Meeting
Conclusion
• Share your thoughts today and going forward!
• Thanks to Nuala Calnan and Bill (Doc)
Spanogle for their suggestions!
• Andrew Faden, CPIP
– afaden@hargrove-epc.com
– fadenad1@gmail.com
– 508 846 6700 cell
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