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Quality Risk Management – ICH Q9, Annex 20 and GMPs

Presented by: Karen S. Ginsbury

For: IFF

March 2010

Define the following

1. Quality

2. Quality of a pharmaceutical product

3. Risk

4. A Quality System in terms of risk

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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

Revision of GMP Guidelines18/02/08 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

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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

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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DEFINITIONSDEFINITIONS(ISO)

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

Harm:Physical injury and/or damage to the health

of people or damage to property or the environment

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Back to basics - DEFINITIONSBack 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

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Back to basics - Back to basics - DEFINITIONSDEFINITIONS

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 RELATIONSHIP BETWEEN RISK ANALYSIS & OTHER RISK MANAGEMENT ACTIVITIES& OTHER RISK MANAGEMENT ACTIVITIES

Risk analysisIntended usePurpose identificationHazard identificationRisk estimation (likelihood x consequence)

Risk evaluation:Risk acceptability decisions

Risk reduction/controloption analysisimplementation

residual risk evaluationoverall risk acceptance

Risk monitoringexternal environment

review of risk management experience

RISK RISK MANAGEMENTMANAGEMENT

risk assessmentrisk assessment

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Risk ManagementRisk Management(a practical example)(a practical example)

RISK CONTROLSafe design:

Build a bridge

Protection measuresTrains at night

Cars in the day

Traffic lights

WarningsSignals/noise

RISK ASSESSMENT

Probability that collision

happens and degree of

severity of the resulting damage

RISK MONITORINGCheck if safety measures work

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Risk Management in the Risk Management in the Pharmaceutical IndustryPharmaceutical Industry

Some examples:Some examples:Engineering Design ReviewsEngineering Design ReviewsProduct and Process designProduct and Process design (computer) Validation(computer) ValidationChange Management evaluationsChange Management evaluationsRelease / Reject / Recall decisionsRelease / Reject / Recall decisionsCross Contamination evaluationsCross Contamination evaluations Investigations & Corrective / preventive actionsInvestigations & Corrective / preventive actionsGMP impact assessmentGMP impact assessment

Most of the time we are managing risk……… Most of the time we are managing risk……… (without realising this?)(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 nastyreaction

• 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?

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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)

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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

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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

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

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29PCI Pharmaceutical Consulting Israel Ltd

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)

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: ViraceptContamination leads to EU-wide Viracept recallBy Anna Lewcock07-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

Is the drug substance/excipientsterile?

Does drug substance/excipientsynthesis/processing involve

steps which inherently reduce microorganisms?

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 ?

Provide supporting data. Microbial limits acceptance criteria and testing

may not be necessary.

No further microbial limits testing or acceptance criteria are necessary.

Test each lot for microbial limits and freedom from compendial

indicator organisms.

Test lots on a skip-lot basis for microbial limits and freedom fromcompendial indicator organisms.

Establish microbial limit acceptance criteriaas per the harmonized pharmacopeial

monograph .

DECISION TREE #6: MICROBIOLOGICAL QUALITY ATTRIBUTES OF DRUG SUBSTANCE AND EXCIPIENTS

Is the drug substance/excipient capable of supporting microbial

growth or viability?

Are monitoring microorganism/indicator levels

consistently below acceptance criteria levels?

Provide supporting data. Microbial limits acceptance

criteria and testing may not be necessary.

NO

NO

NO

NO

NO

YES

YES

YES

YES

YES

Establish microbial limit acceptance criteria

as per the harmonized pharmacopoeial monograph.

Is the drug product a dry dosage form (e.g. solid oral or dry powder)?

Do production lots consistently meet microbial limits acceptance criteria?

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 .

Establish microbial limit acceptance criteriaas per the harmonized pharmacopoeial

monograph.

Perform microbial limits testing on a lot-by-lot basis.

Microbial limits acceptance criteria and testing may not be necessary.

Does the drug product contain antimicrobial preservatives or possess

inherent antimicrobial activity?

Perform skip-lot testing for microbial limits, or provide scientific justification for

no routine microbial limits testing .

DECISION TREE #8: MICROBIOLOGICAL ATTRIBUTES OF NON-STERILE DRUG PRODUCTS

YESNO

YES

YES

NO

NO

Does scientific evidence demonstrategrowth inhibitory properties of the

drug product?

YES

NO

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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 TPPQuality AttributeTarget

Route of administration

Oral

Dosage formCapsule, maximum size 2, maximum fill weight 280mg

Strength0.6mg

Stability3 yrs at room temperature

PharmacokineticsImmediate release enabling tmax in 2 hours or less

AppearanceWhite opaque cap and body, hard gelatin capsule filled with white to off-white granulate

Assay90-110%

ImpuritiesImpurity A: NMT 0.5%Impurity B: NMT 0.5%Total Impurities: NMT 2%

Content UniformityMeets USP

DissolutionNLT 70% of labeled amount is dissolved in 30 min : (500 ml water; USP apparatus II {paddles}; 50 rpm)

MicrobiologyMeets USP criteria

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DefinitionsCritical 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

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

Lifecycle Management

Ref

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Mat

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Ana

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Met

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Pro

cess

Supplier Qualification

Other…

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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: Q8Pharmaceutical 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

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Quality Systems ApproachQuality 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

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Quality Systems ApproachNew 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

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

R&D

ValidationCommercialization

Changes

CONTROLCONTROL

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 ofProcess 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

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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

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ICH Q9, Annex 1Risk Management-Methods and Tools

Methods

• Risk Management Facilitation Methods• FMEA• FMECA• FTA• HACCP• HAZOP• PHA• Risk Ranking and Filtering• Supporting Statistical Tools

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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

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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)

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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 happens2) qualitative evaluation of the extent of possible injury or

damage to health that could result3) a relative ranking of the hazard using a combination of

severity and likelihood of occurrence4) the identification of possible remedial measures

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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

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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

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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 quantitatively-assessed and qualitatively-assessed risks within the same organizational framework

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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

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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

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FMEA workshop

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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

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Risk Ranking Table

Risk Category Ranking / Definition

LowMediumHigh

Severity

SEV

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

Likelihood of Occurrence

OCC

The possibility that the cause occurs is rare; unusual event

There is a reasonable possibility that the cause may occur from time to time

High possibility of occurrence; common / known event

Likelihood of Detection

DET

If the event occurs there is a HIGH likelihood of detection

If the event occurs it might be detected

If the event occurs it probably will NOT be detected

Risk Priority Ranking

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Risk Ranking Table

RankingRisk Factors

SeverityOccurrenceDetection

HighSevere 5Often 5Unlikely 5

MediumModerate 3Periodic 3Maybe 3

LowLow 1Rare 1Readily Detected 1

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FMEA

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Mapping the Process

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Assessment

Task #2 – Current Controls

• Make a list of current controls and then calculate the RPN

• Is it acceptable or not

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Risk Priority Number

Scale 1 - 5RPN

SEV x

OCC X

DET

< 10

11 - 29

≥ 30