Transcript Risk Management

Quality Risk Management –
ICH Q9, Annex 20 and GMPs
Presented by: Karen S. Ginsbury
For: IFF
March 2010
1/
Define the following
1. Quality
2. Quality of a pharmaceutical
product
3. Risk
4. A Quality System in terms of risk
2/
What is Regulatory Compliance?
Meeting the requirements of the current
Good Manufacturing Practice regulations
as they relate to
your product (s)
throughout the product life cycle
3/
Revision of GMP Guidelines
18/02/08 GMP Revision of GMP Guidelines to
implement concept of Quality Risk Management
• As an implementation measure related to the
ICH Q9 guideline on quality risk management,
the European Commission has reviewed the
existing GMP provisions
• With the revision of GMP Part I, Chapter 1 on
Quality Management quality risk management
becomes an integral part of a manufacturer’s
quality system
Revision of GMP Guidelines
• This concept will also be considered in a future
revision of GMP Part II
• The ICH Q9 guideline as such has been
implemented with the new Annex 20
• It should be noted that the new Annex is not
intended, however, to create any new regulatory
expectations
• It provides an inventory of risk management
methods and tools together with a list of
potential applications at the discretion of
manufacturers
To be discussed….
This morning
• Current EU and US legislation
• Introduction to Preliminary Hazard
Analysis (PHA) as a risk management tool
• Workshop / case study using PHA to
develop a Product Control Strategy
6/
To be discussed…
• This afternoon:
• Introduction to FMEA
• Workshop / case study using FMEA for
assessing risks associated with a vendor
qualification program and in particular with
changing a supplier of an API and a key
excipient
QRM Related Regulations and Guidance
• ICH Q10: Pharmaceutical Quality System
(cf: FDA’s Quality System Guidance)
• EU Chapter 1: July 2008 revision
• EU Annex 20 / ICH Q9: Risk Management
• ICH Q8 + Q8R1
• FDA (draft) Process Validation Guidance
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DEFINITIONS
(ISO)
Harm:
Physical injury and/or damage to the health of
people or damage to property or the
environment
Risk:
Combination of the probability of occurrence
of harm and the severity of that harm
Risk analysis:
Use of available information to identify
hazards and to estimate the risk
9/
Back to basics - DEFINITIONS
Risk evaluation:
Judgement, on the basis of risk analysis,
of whether a risk which is acceptable has
been achieved in a given context based
on the current values of society
Risk assessment:
Overall process of risk analysis and risk
evaluation
10/
Back to basics DEFINITIONS
Risk Control:
The process through which decisions are
reached and implemented for reducing risks
to or maintaining risks within specified
levels.
Risk management:
Systematic application of management policies,
procedures and practices to the tasks of analysing,
evaluating and controlling risk
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RELATIONSHIP BETWEEN RISK ANALYSIS
& OTHER RISK MANAGEMENT ACTIVITIES
risk assessment
Risk analysis
Intended use
Purpose identification
Hazard identification
Risk estimation (likelihood x
consequence)
Risk evaluation:
Risk acceptability decisions
RISK
MANAGEMENT
Risk monitoring
external environment
review of risk management
experience
Risk reduction/control
option analysis
implementation
residual risk evaluation
overall risk acceptance
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Risk Management
(a practical example)
RISK
ASSESSMENT
Probability that
collision
happens and
degree of
severity of the
resulting
damage
RISK CONTROL
Safe design:
Build a bridge
Protection
measures
Trains at night
Cars in the day
Traffic lights
Warnings
Signals/noise
RISK MONITORING
Check if safety measures work
13/
Risk Management in the
Pharmaceutical Industry
Some examples:
 Engineering Design Reviews
 Product and Process design
 (computer) Validation
 Change Management evaluations
 Release / Reject / Recall decisions
 Cross Contamination evaluations
 Investigations & Corrective / preventive actions
 GMP impact assessment
Most of the time we are managing risk………
(without realising this?)
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Cross - Contamination
• Sugar and coffee
• Active ingredient A gets into product
manufactured with active B
• Ingredient A can cause a nasty
reaction
• How can A get into B?
COFFEE
SUGAR
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Case Study in Risk Management –
Cross Contamination Case Study
• Prevention of steroid contamination in
OTC alcohol solution at company that
manufactures both
• Likelihood of occurrence:
high
(initially if no precautions taken)
• Degree of severity if occurs:
high
• Likelihood of detection:
low
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How could alcohol become
contaminated with Steroid?
(Risk assessment)
• During sampling operations – steroid
traces left in sampling area and alcohol
sampled next
• During weighing operations – steroid
traces left in weighing room and alcohol
weighed next
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How could alcohol become
contaminated with potent steroid?
(Risk assessment)
• During production:
– Via the air handling system
– Powder / dust carried from room to room
– Multi-purpose equipment
– Operators
– Operators clothing
– Other?
18/
How can the hazards be reduced
• Risk reduction
• Sample in dedicated area with single use
sampling equipment
• Clean the area and sample for potent
steroid remainders before use for any
other material
• Same for weighing including replacing
curtains
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How can the hazards be reduced
•
•
•
•
•
•
Risk reduction / Control
Produce in dedicated area
With entrance airlock
With double entrance airlock
Alarms
HVAC system with HEPA filters on entry and exit
air
• Differential pressure cascade
• Other
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Pharmaceutical CGMPs For the 21st Century
A Risk Based Approach
FDA final report
September 2004
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New Framework for Regulatory
Oversight Of Manufacturing Quality
• Based on:
– Quality Systems
–Risk Management
– Minimize risk to public health associated with
pharmaceutical manufacturing
– Issue guidance for industry
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Quality Systems Approach to
CGMP Regulation
• Comprehensive quality systems approach
• Encourages continuous improvement
• Encourages risk management
in manufacture of drugs
• Risk based orientation is main principle
behind the GMP initiative
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Quality Systems Approach to
CGMP Regulation - 4
• Reduce variability through process
understanding (application of knowledge
throughout the product life cycle)
• Means using data that your company has
collected to evaluate the risks associated
with changes (or with the failure to make
those changes)
24/
Quality Systems Approach to
CGMP Regulation - 5
• As a result of uncertainties in drug
manufacturing, FDA exercised extensive
control over virtually every aspect of the
manufacturing process
• Consequently companies were reluctant to
make changes to process because of
regulatory hurdles
25/
Quality Systems Approach to
CGMP Regulation
• Detect, analyze, correct and prevent
problems: continuous process
improvement
• Facilitate robust processes
• Reliable production of high quality
pharmaceuticals
• Accommodate process change to
support continuous process improvement
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When to Use Risk Assessment
• Have you seen this situation before ?
– Do you have SOP to cover situation ?
– Do you already understand the risks ?
• Severity, Probability, Detectability
• If YES; structured Risk Assessment may not
add value
• If NO; structured Risk Assessment can add
value
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Continual Improvement
• Even when you think you understand the
risks – if you are still being surprised…
e.g.
– Media fill failure
– Lack of homogeneity
– Product fails Microbial Limit Test
• Time to go back to basics and do a new /
revised / first time Risk Assessment of the
Product Control Strategy
28/
Control Strategy: Definition
• A planned set of controls, derived from current
product and process understanding, that
assures process performance and product
quality
• The controls can include parameters and
attributes related to drug substance and drug
product materials and components, facility and
equipment operating conditions, in-process
controls, finished product specifications, and the
associated methods and frequency of monitoring
and control (ICH Q10)
PCI Pharmaceutical Consulting Israel Ltd
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Aspects to Consider
• Environment: Facility Control Strategy
– Use risk assessment to answer the questions (in a
systematic manner):
What are the potential hazards to patient (through product
and process)?
• Factors to consider:
–
–
–
–
–
User requirement specifications
Design specifications and Design review
Review / design of systems
Review / design / development of processes
Assess, design and develop resources:
• Time
• Personnel
• Equipment
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Cause and Effect: Viracept
Contamination leads to EU-wide Viracept recall
By Anna Lewcock
07-Jun-2007 - Roche has initiated a recall of its HIV drug Viracept (nelfinavir)
right down to the patient level after finding evidence of dangerous
contaminants in the tablets.
Roche informed the European Medicines Agency (EMEA) of its findings late
on Tuesday, and efforts are being made across European Union markets to
recall the tainted drug as quickly as possible before patients are harmed.
Roche was alerted to the possible contamination by patients themselves,
who reported that the company's 250mg tablets had a strange smell. After
investigating the complaints, Roche discovered that the tablets contained
unexpected high levels of ethyl mesylate, a potentially harmful chemical
also known as methane sulfonic acid ethylester.
This contaminant is a well-known genotoxic substance (i.e. harmful to DNA)
and can cause cancer or harm unborn children if used during pregnancy.
The sad story of Viracept
• Root cause: “Unexpected” reaction in hold tank
• A hold tank was cleaned with ethanol but NOT dried
(human error)
• New campaign started with residual ethanol (not normal)
and MSA was added to the tank (normal process)
• Ethanol + MSA = Ethyl Methane Sulfonate (EMS)
• Three batches manufactured with low level of EMS
impurity (1, 3 and 9 ppm)
• Remaining MSA stored for 2 months in the hold tank
during which time more EMS formed
• January 2007: API manufactured with high level of EMS
• EMS was NOT in the end product spec: testing of 20
batches during development showed no detectable level
Could QbD have prevented Viracept recall?
• A genuine risk assessment should have
identified either one of the following:
– DANGEROUS to use ethanol in the process at all?
– IF no alternative: CRITICAL to remove all ethanol
residue
– IF CCP (HACCP) then need to MONITOR which
would include sampling at the end of the cleaning
process
– + LIMITS on hold time in tank?
– + LIMITS on product release specification?
Don’t Forget Basic GMP
• Employee cleaned the hold-tank using
ethanol which is the process solvent
• Supervisor signed record which did NOT
show the tank was dried (human error)
• Leading to reaction in hold tank
DECISION TREE #6: MICROBIOLOGICAL QUALITY ATTRIBUTES OF DRUG SUBSTANCE AND EXCIPIENTS
Is the drug substance/excipient
capable of supporting microbial
growth or viability?
NO
Provide supporting data. Microbial
limits acceptance criteria and testing
may not be necessary.
YES
YES
Is the drug substance/excipient
sterile?
No further microbial limits testing or
acceptance criteria are necessary.
NO
Does drug substance/excipient
synthesis/processing involve
steps which inherently
reduce microorganisms?
YES
Establish microbial limit acceptance criteria
as per the harmonized pharmacopeial
monograph.
NO
Establish microbial limit acceptance
criteria
as per the harmonized pharmacopoeial
monograph.
Are monitoring
microorganism/indicator levels
consistently below acceptance criteria
levels?
YES
Test lots on a skip-lot basis for
microbial limits and freedom from
compendial indicator organisms.
NO
Test each lot for microbial limits
and freedom from compendial
indicator organisms.
Does scientific evidence demonstrate that
reduction steps result in microorganism levels
< acceptance criteria limits (and the absence of
compendial indicator organisms)
in the drug substance/excipient?
NO
YES
Provide supporting data.
Microbial limits acceptance
criteria and testing
may not be necessary.
DECISION TREE #8: MICROBIOLOGICAL ATTRIBUTES OF NON-STERILE DRUG PRODUCTS
NO
Does the drug product contain
antimicrobial preservatives or possess
inherent antimicrobial
activity?
YES
Establish preservative chemical acceptance criteria and
perform preservative effectiveness validation of product
containing less than or equal to the minimum specified
preservative concentration, or demonstrate the inherent
antimicrobial activity of the drug product.
Is the drug product a dry dosage form
(e.g. solid oral or dry powder)?
N
O
Establish microbial limit acceptance criteria
as per the harmonized pharmacopoeial
monograph.
YES
N
O
Does scientific evidence demonstrate
growth inhibitory properties of the
drug product?
YES
Microbial limits acceptance criteria and testing
may not be necessary.
Perform microbial limits testing on a
lot-by-lot basis.
NO
Do production lots consistently meet
microbial limits acceptance criteria?
YES
Perform skip-lot testing for microbial
limits, or provide scientific justification for
no routine microbial limits testing.
ICH Quality Vision (July 2003)
Q8, Q9, Q10 – The Trilogy
“Develop a harmonized pharmaceutical
quality system applicable across the life
cycle of the product emphasizing an
integrated approach to quality risk
management and science.”
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Definitions: Target Product Profile
• A target product profile is a prospective
and dynamic summary of the quality
characteristics of a drug product that
ideally will be achieved to ensure that the
desired quality, and hence the safety and
efficacy, of a drug product is realised
• The target product profile forms the basis
of design for the development of the
product
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Typical TPP
Quality Attribute
Target
Route of
administration
Oral
Dosage form
Capsule, maximum size 2, maximum fill weight 280mg
Strength
0.6mg
Stability
3 yrs at room temperature
Pharmacokinetics
Immediate release enabling tmax in 2 hours or less
Appearance
White opaque cap and body, hard gelatin capsule filled with
white to off-white granulate
Assay
90-110%
Impurities
Impurity A: NMT 0.5%
Impurity B: NMT 0.5%
Total Impurities: NMT 2%
Content Uniformity
Meets USP
Dissolution
NLT 70% of labeled amount is dissolved in 30 min : (500 ml
water; USP apparatus II {paddles}; 5039rpm)
Microbiology
Meets USP criteria
Definitions
Critical Quality Attribute (CQA):
• A physical, chemical, biological or
microbiological property or characteristic that
should be within an appropriate limit, range, or
distribution to ensure the desired product quality
[= safety, efficacy, performance]
Critical Process Parameter:
• A process parameter whose variability has an
impact on a critical quality attribute and therefore
should be monitored or controlled to ensure the
process produces the desired quality
PCI Pharmaceutical Consulting Israel Ltd
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Product vs Process
• Product is defined by:
– Specification
– Patient Population (customer)
– Internal customers (marketing, production, QC...)
• Process is defined by:
– Your company based on:
• Similar products using similar process
• Equipment availability
• Input parameters: materials and methods
Process
Reference Material
Analytical Methods
Lifecycle
Management
Supplier Qualification
Other…
QbD Definition
• Quality by Design: A systematic approach to
development that begins with predefined
objectives [TPP] and emphasizes product
and process understanding [CQAs and
CPPs] and process control, based on sound
science ([multivariate approach / DOE] and
quality risk management [Ishikawa + FMEA]
[Note: parentheses NOT part of formal definition]
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Key Concepts: Q8
Pharmaceutical Development
• Pharmaceutical development is a learning process
• Describe both successes and failures as part of the story
which demonstrates Quality by Design (QbD)
• Information from pharmaceutical development studies is
a basis for risk management (using Q9)
• Critical parameters carry the risk
• Critical formulation and process parameters are
generally identified through an assessment of the extent
to which their variation can impact on the quality of the
drug product
• This assessment helps define ‘design space’
Q8 – Pharmaceutical Development
• Demonstrate understanding of pharmaceutical and
manufacturing sciences
• Knowledge from pharmaceutical development studies
and manufacturing experience provide scientific
understanding to support establishment of the design
space, specifications, and manufacturing controls
• Changes in formulation and manufacturing processes
during development and lifecycle management are
opportunities for additional knowledge
• Inclusion of relevant knowledge gained from experiments
giving unexpected results can also be useful
Q8 – To be considered
• Components of Drug Product
– Drug Substance: e.g. solubility, water content, part. size, crystal properties, biological activity...
– Excipients: e.g. justify ranges
• Drug Product
• Formulation development: identify critical or interacting variables
• Overages
• Physicochemical and biological properties
•
•
•
•
Manufacturing Process Development: critical process parameters
Container Closure System: choice, rationale, shipping etc.
Microbiological Attributes
Compatibility: e.g. with reconstitution diluents and reconstituted shelf-life
QbD or No?
• In all cases, the product should be designed to
meet patients’ needs and the intended product
performance
• A more systematic approach to development
(also defined as quality by design) can include,
for example:
–
–
–
–
incorporation of prior knowledge
results of studies using design of experiments
use of quality risk management
use of knowledge management (ICH Q10)
• throughout the lifecycle of the product
Q8R: Pharmaceutical Development Elements
(For ALL development, not just QbD)
Q8R: Pharmaceutical Development Elements
(For QbD)
Control Parameters vs CQAs
Process Control Parameters
– Risk assessment can be used
to identify material attributes
and process parameters that
can affect CQAs
– Risk assessment tools can be
used to identify and rank
parameters (e.g., operational,
equipment, input material) with
potential to have an impact on
product quality based on prior
knowledge and initial
experimental data
– Batch production records are
developed with paramter ranges
designed to ensure the CQAs
are achieved
Critical Quality Attributes
– physical, chemical, biological,
or microbiological property or
characteristic that should be
within an appropriate limit,
range, or distribution to ensure
the desired product quality
– CQAs are generally associated
with the drug substance,
excipients, intermediates, and
drug product
– Drug product CQAs include the
properties that impart the
desired quality, safety, and
efficacy
Q8 R1: Risk Management in R&D
• A cross-functional team of experts could work together to
develop an Ishikawa (fishbone) diagram that identifies all
potential variables which can have an impact on the
desired quality attribute
• The team could then rank the variables based on
probability, severity, and detectability using failure mode
effect analysis
• (FMEA) or similar tools based on prior knowledge and
initial experimental data
• Design of experiments or other experimental approaches
could then be used to evaluate the impact of the higher
ranked variables, to gain greater understanding of the
process, and to develop a proper control strategy
Control Strategy
• A control strategy is designed to consistently
ensure product quality
[get ready for lifecycle process validation]
• describe and justify how in-process controls and
the controls of:
– input materials (drug substance and excipients)
– container closure system
– intermediates and end products
• contribute to the final product quality
Control Strategy
• Controls should be based on product,
formulation and process understanding and
should include, at a minimum, control of the
critical parameters and attributes
• A comprehensive pharmaceutical development
approach will generate process and formulation
understanding that identifies sources of
variability
• Critical sources of variability that can lead to
product failures should be identified,
appropriately understood, managed or controlled
Control Strategy
• Understanding sources of variability and their
impact on downstream processes or processing,
intermediate products and finished product
quality can provide flexibility for shifting of
controls upstream and
• minimise the need for end product testing
• Control of process parameters allows variability
of raw materials to be compensated for in an
adaptable process to deliver consistent product
quality
Elements of a Control Strategy
• Control of input material attributes (e.g. drug substance,
excipients, primary packaging materials) based on an
understanding of their impact on processability or
product quality
• Product specification(s)
• Controls for unit operations that have an impact on
downstream processing or end-product quality (e.g., the
impact of drying on degradation, particle size distribution
of the granulate on dissolution);
• In-process or real-time release in lieu of end-product
testing;
• A monitoring program (e.g., full product testing at regular
intervals) for verifying multivariate prediction models
Control of Changes
• Change is an inherent part of the R&D
process
• QA needs to be accepting of change
• QA needs to facilitate change
• R&D needs to capture change i.e.
documentation
Control of Deviations in R&D
• Won’t always be sure if a deviation is actually a
deviation or the limit of process capability for this
product
• Need to capture documentation and follow up on
suspected deviations to assess recurrence
• May use these to develop Product Control
Strategy
Quality Systems Approach
Quality By Design and Product Development
Design and develop the manufacturing
processes during product development stage
to consistently ensure a predefined quality at
the end of the manufacturing process.
A quality system provides a sound framework
for transfer of process knowledge from
development to the commercial
manufacturing process and for post
development changes and optimization
58/
Quality Systems Approach
New Terminology – from ISO
• Risk Management and Risk Assessment
– Risk management: used in setting specifications and
process parameters
– Risk assessment: used in determining need for
discrepancy investigations and corrective actions
• CAPA
– Investigate, correct discrepancies, prevent recurrence
• Change Control
– Manage change to prevent unintended consequences
– Guidance encourages continuous improvement which
necessitates (controlled) changes
59/
Definition: Current Guide
• Process validation is establishing
documented evidence which provides a
high degree of assurance that a specific
process will consistently produce a
product meeting its pre-determined
specifications and quality characteristics
Proposed Definition – Draft Guide
Proposed definition:
Process validation is defined as the
collection and evaluation of data, from
the process design stage throughout
production, which establishes
scientific evidence that a process is
capable of consistently delivering
quality products
Pharmaceutical Product Lifecycle
Changes
R&D
CONTROL
Commercialization
Validation
Q10 - Enablers
• Knowledge management
(a systematic approach to acquiring, analyzing, storing
and disseminating information related to products,
processes and components)
• Quality risk management
(Quality risk management can provide a proactive
approach to identifying and controlling potential risks to
quality throughout the lifecycle)
enable a consistent scientific approach to
achieve the Q10 objectives
CONTINUAL IMPROVEMENT of
Process Performance and Product Quality Monitoring
Through Lifecycle
CONTINUAL IMPROVEMENT
of the Quality System
Application of CAPA Through Lifecycle
Change Management Through Lifecycle
Management Review Through the Lifecycle
And in conclusion
• Risk Management is not new to
pharmaceuticals
• Any Quality Assurance system involves
risk management but may not be formal
and documented
• What is new, is an approach that requires
science behind change and innovation and
process understanding
68/
ICH Q9, Annex 1
Risk ManagementMethods and Tools
69/
Methods
•
•
•
•
•
•
•
•
•
Risk Management Facilitation Methods
FMEA
FMECA
FTA
HACCP
HAZOP
PHA
Risk Ranking and Filtering
Supporting Statistical Tools
70/
Important Note in Annex 1
No one tool or set of tools is applicable to
every situation in which a quality risk
management procedure is used
71/
Basic Risk Management
Facilitation Methods
• Some simple techniques used to structure
risk management by organizing data and
facilitating decision-making are:
– Flowcharts
– Check Sheets
– Process Mapping
– Cause and Effect Diagrams
(Ishikawa diagram or fish bone diagram)
72/
Failure Mode Effects Analysis
• Allows evaluation of:
– potential failure modes [what might go wrong] for
processes
– the likely effect on outcomes and/or product performance
• Once failure modes are established, risk reduction
can be used to eliminate, contain, reduce or control
the potential failures
• FMEA relies on product and process understanding
• FMEA methodically breaks down the analysis of
complex processes into manageable steps
• It is a powerful tool for summarizing the important
modes of failure, factors causing these failures and
the likely effects of these failures
73/
Areas of Use of FMEA
• To prioritize risks and monitor the
effectiveness of risk control activities
• FMEA can be applied to equipment and
facilities and might be used to analyze a
manufacturing operation and its effect on
product or process
• It identifies elements/operations within the
system that render it vulnerable
• The output/ results of FMEA can be used as
a basis for design or further analysis or to
guide resource deployment
74/
Failure Mode, Effects and
Criticality Analysis (FMECA)
• Extend FMEA to include severity of effect
if it happens (we did that)
• In order for such an analysis to be
performed, the product or process
specifications should be established
• FMECA can identify places where
additional preventive actions might be
appropriate to minimize risks
75/
Areas of Use (FMECA)
• Mostly used for failures and risks
associated with manufacturing processes;
however, it is not limited to this application
• The output of an FMECA is a relative risk
“score” for each failure mode, which is
used to rank the modes on a relative risk
basis
76/
Fault Tree Analysis (FTA)
• An approach that assumes failure of the
functionality of a product or process
• This tool evaluates system (or sub-system)
failures one at a time but can combine multiple
causes of failure by identifying causal chains
• The results are represented pictorially in the form
of a tree of fault modes
• At each level in the tree, combinations of fault
modes are described with logical operators (AND,
OR, etc). The method relies on expert process
understanding to identify causal factors
77/
Areas of Use (FTA)
• FTA can be used to:
– establish the pathway to the root cause of the failure
– investigate complaints or deviations in order to fully
understand their root cause
– ensure that intended improvements will fully resolve
the issue and not solve one problem yet cause
another (different) problem
• FTA is an effective tool for evaluating how
multiple factors affect a given issue
• The output of an FTA includes a visual
representation of failure modes
• It is useful both for risk assessment and in
developing monitoring programs
78/
Hazard Analysis and Critical
Control Points (HACCP)
• HACCP is a systematic, proactive, and
preventive tool for assuring product
quality, reliability, and safety
• It is a structured approach that applies
technical and scientific principles to
analyze, evaluate, prevent, and control
the risk or adverse consequence(s) of
hazard(s) due to the design, development,
production, and use of products
79/
Potential Uses of HACCP
• (7 steps described in Annex 1 but already
reviewed by Mr Mankar)
• To identify and manage risks associated with
physical, chemical and biological hazards
(including microbiological contamination)
• Most useful when product and process
understanding is sufficiently comprehensive to
support identification of critical control points
• The output of a HACCP analysis is risk
management information that facilitates
monitoring of critical points not only in the
manufacturing process but also in other life cycle
phases
80/
Hazard Operability Analysis
(HAZOP)
• Theory assumes that risk events are caused by
deviations from the design or operating intentions
• A systematic brainstorming technique for
identifying hazards using “guide-words”
e.g. No, More, Other Than, Part of, etc. are
applied to relevant parameters (contamination,
temperature) to identify potential deviations from
normal use or design intentions
• It often uses a team of people with expertise
covering the design of the process or product and
its application
81/
Potential Uses of HAZOP
• Manufacturing processes, including
outsourced production and formulation as
well as the upstream suppliers, equipment
and facilities for drug substances and drug
products
• For evaluating process safety hazards
• The output of a HAZOP analysis is a list of
critical operations for risk management
• This facilitates regular monitoring of critical
points in the manufacturing process
82/
Preliminary Hazard Analysis (PHA)
• A tool of analysis based on applying prior experience
or knowledge of a hazard or failure to identify future
hazards, hazardous situations and events that might
cause harm, as well as to estimate their probability of
occurrence for a given activity, facility, product or
system
• The tool consists of:
1) identification of possibilities that the risk event happens
2) qualitative evaluation of the extent of possible injury or
damage to health that could result
3) a relative ranking of the hazard using a combination of
severity and likelihood of occurrence
4) the identification of possible remedial measures
83/
Potential Uses of PHA
• Useful when analyzing existing systems or prioritizing
hazards where circumstances prevent a more
extensive technique from being used
• It can be used for product, process and facility design
as well as to evaluate the types of hazards for the
general product type, then the product class, and
finally the specific product
• PHA is most commonly used early in the development
of a project when there is little information on design
details or operating procedures
• It will often be a precursor to further studies
• Hazards identified in the PHA are further assessed
with other risk management tools such as those in this
section
84/
Risk Ranking and Filtering
• A tool for comparing and ranking risks
• Risk ranking of complex systems typically
requires evaluation of multiple diverse quantitative
and qualitative factors for each risk. This tool
breaks down a basic risk question into as many
components as needed to capture factors
involved in the risk
• The factors are combined into a single relative
risk score that can then be used for ranking risks
• Filters in the form of weighting factors or cut-offs
for risk scores, can be used to scale or fit the risk
ranking to management or policy objectives
85/
Potential Use of Risk Ranking
• To prioritize manufacturing sites for
inspection/audit by regulators or industry
• Particularly helpful in situations in which the
portfolio of risks and the underlying
consequences to be managed are diverse
and difficult to compare using a single tool
• Risk ranking is useful when management
needs to evaluate both quantitativelyassessed and qualitatively-assessed risks
within the same organizational framework
86/
Supporting Statistical Tools
• Statistical tools can support and facilitate
quality risk management
• They can enable effective data
assessment, aid in determining the
significance of the data set(s), and
facilitate more reliable decision making
• A listing of some of the principal statistical
tools commonly used in the
pharmaceutical industry is provided
87/
Supporting Statistical Tools
• Control Charts, for example
– Acceptance Control Charts
• Control Charts with Arithmetic Average and
Warning Limits
• Cumulative Sum Charts
• Shewhart Control Charts
• Weighted Moving Average.
• Design of Experiments (DOE)
• Histograms
• Pareto Charts
• Process Capability Analysis
88/
FMEA workshop
89/
Failure Mode and Effect Analysis
(FMEA)
• FMEA is a preventative tool (bottom-up
approach) which identifies all potential failures
• Evaluates the potential risks and current controls
• FMEA begins in the early stages of
product/system design and evolves over time
• A cross functional team uses the FMEA to
evaluate products and manufacturing processes
90/
91/
Risk Ranking Table
Risk Category
Ranking /
Definition
Severity
SEV
Likelihood of
Occurrence
OCC
Likelihood of
Detection
DET
Low
Medium
High
If the event occurs
and is not
detected it is NOT
likely to harm the
patient
If the event occurs
and is not detected it
may cause
moderate harm to
the patient
Direct and severe
impact to the
patient; life
threatening
There is a
The possibility that
reasonable
the cause occurs
possibility that the
is rare; unusual
cause may occur
event
from time to time
High possibility of
occurrence;
common / known
event
If the event occurs
If the event occurs If the event occurs
there is a HIGH
it might be
it probably will
likelihood of
detected
NOT be detected
92
detection
Risk Priority Ranking
Detection
High
(Risk)
MED –
HIGH
HIGH
V. HIGH
Med
MED
MED
HIGH
Med
Low
LOW
LOW
MED LOW
Low
High
Med
High
Low
(Risk)
Severity
Occurrence
Risk Ranking Table
Risk Factors
Ranking
Severity
Occurrence Detection
High
Severe
Medium
Moderate 3 Periodic 3 Maybe
Low
Low
5 Often
5 Unlikely
1 Rare
PCI Pharmaceutical Consulting Israel Ltd.
5
3
Readily
1
Detected 1
94/
FMEA
PCI Pharmaceutical
Consulting Israel Ltd.
95/
Mapping the Process
PCI Pharmaceutical
Consulting Israel Ltd.
96/
Assessment
PCI Pharmaceutical
Consulting Israel Ltd.
97/
Task #2 – Current Controls
• Make a list of current controls and then
calculate the RPN
• Is it acceptable or not
Risk Priority Number
Scale 1 - 5
RPN
< 10
SEV x
OCC X
DET
11 - 29
≥ 30
100/