07 risk analyses tools - dcvmn · • failure mode effects analysis (fmea) ... - suspension -...

May 2015, page 1

Tools for Risk Analyses Dr. Ingrid Walther

May 2015, page 2

Please try to define: What is a „risk“?

May 2015, page 3

What is a „risk“?

Some considerations and possible definitions:

•  Event with potentially negative impact or results

•  Condition, event, or circumstance that could lead to or contribute to an unplanned or undesirable event

•  Event that potentially occurs

•  Likelihood of entry of an event multiplied by the impact of the event

•  Likelihood of entry of an event multiplied by the impact of the event multiplied by the likelihood that the harm it caused will be detected

•  Danger: implies that it is quite likely that there will be a harm / damage

•  Risk: Likelihood of entry not known – dimension / impact of the harm not always clear

•  Residual risk: weaker than a risk

•  Depending on previous events

•  risks may be regarded as hazards

•  residual risks may become risks or hazards

! There is no absolutely clear definition!

May 2015, page 4

What is the risk?

•  sliding on the staircase

•  Flooring / carpet on steps not fixed

•  Injury

Risk

Cause

Consequence

or

or

Risk

Consequence

Risk – cause – consequence is often not easy to define! Confusion during RAs is likely!

May 2015, page 5

Criticality versus Risk versus Harm

Criticality = relevance (critical parameters = relevant parameters) In general, criticality of an aspect does not change! Critical aspects (e.g. critical process parameters, CPPs) may be •  under control •  at risk Risk (hazard) that has occurred ! Harm Risk treatment – preventive Risk Analyses / Risk Assessments !  Identify what could cause a problem / harm in the future Harm – needs curative (corrective) and preventive treatment, in order to prevent re-entry (CAPA) – by Root Cause Analyses

!  Identify causes for an actual problem

Hazard Risk Harm

May 2015, page 6

„Two primary principles of quality risk management are:

•  The evaluation of the risk to quality should be based on scientific knowledge and ultimately link to the protection of the patient;

and

•  The level of effort, formality and documentation of the quality risk management process should be commensurate with the level of risk.“

Part III of the EU-GMP-Guide

ICH Q9 „Quality Risk Management“

May 2015, page 7

4.3 Risk Assessment

..., three fundamental questions are often helpful:

1. What might go wrong?

2. What is the likelihood (probability) it will go wrong?

3. What are the consequences (severity)?

Risk Assessment consists of a.  Risk Identification

b.  Risk Analysis

c.  Risk Evaluation

! Methods are shown in this presentation

May 2015, page 8

Important Statements in ICH Q9

„Risk control ...The purpose of risk control is to reduce the risk to an acceptable level.

The amount of effort used for risk control should be proportional to the significance of the risk.

Risk control might focus on the following questions:

•  Is the risk above an acceptable level?

•  What can be done to reduce or eliminate risks?

•  What is the appropriate balance among benefits, risks and resources?

•  Are new risks introduced as a result of the identified risks being controlled?“

May 2015, page 9

Very important Statement in ICH Q9

Risk acceptance is a decision to accept risk.

Risk acceptance can be a formal decision to accept the residual risk or it can be a passive decision in which residual risks are not specified.

For some types of harms, even the best quality risk management practices might not entirely eliminate risk. In these circumstances, it might be agreed that an appropriate quality risk management strategy has been applied and that quality risk is reduced to a specified (acceptable) level. This (specified) acceptable level will depend on many parameters and should be decided on a case-by-case basis.“

Many companies invest very high effort to eliminate residual risks

! Risk Acceptance strategies are often under-developed!

May 2015, page 10

Risk Analyses ! to identify and evaluate risks / hazards and potential harms

•  Ensure correct design (technical orientation)

•  Define qualification aspects (technical GMP-orientation)

•  Ensure proper operations

•  Define validation and monitoring aspects (operational GMP-orientation)

! Risk Analyses may be carried out in different ways

! Risk Analyses are required by regulatory documents

Murphy‘s law:

If something can go wrong, sooner or later it will go wrong!

An important rule:

Never speculate about things, if precise information is available!

May 2015, page 11

When to perform Risk Analyses? Regulatory Aspects

WHO-Guideline – Quality Assurance of Pharmaceuticals

(some examples)

“… 8.2.5 Critical and non-critical parameters should be determined by means of a risk analysis for all HVAC installation components, subsystems and controls.

“prospective validation

Validation carried out during the development stage on the basis of a risk analysis of the production process, which is broken down into individual steps; these are then evaluated on the basis of past experience to determine whether they may lead to critical situations.”

“Chapter 5

Hazard and risk analysis in pharmaceutical products

!  WHO Guideline mentions „risk-analysis“ more frequently than EU or US Guidelines!

!  New EU Annex 15 on Qualification and Validation mentions „risk“ more than 20 times!

May 2015, page 12

Risk Management Tools – as mentioned in ICH Q9

•  Basic risk management facilitation methods (flowcharts, check sheets etc.)

•  Failure Mode Effects Analysis (FMEA)

•  Failure Mode, Effects and Criticality Analysis (FMECA)

•  Fault Tree Analysis (FTA)

•  Hazard Analysis and Critical Control Points (HACCP)

•  Hazard Operability Analysis (HAZOP)

•  Preliminary Hazard Analysis (PHA)

•  Risk ranking and filtering

•  Supporting statistical tools

The most important and best-applicable methods are selected

May 2015, page 13

ISO 13408 – Aseptic Processing - Risk Management

Reference is made to ICH Q9 Risks shall be

•  identified, •  assessed •  controlled

� establish acceptance criteria for all elements of the aseptic process definition.

Microbiological risk management should follow the following four stages:

a) identification of contamination risks; b) assessment of contamination risks; c) monitoring and detection of contamination; d) prevention of contamination.

� similar to the ideas of ICH Q9

May 2015, page 14

Aspect Examples Examples of specific microbiological risks

Examples of control measures

Ingredients -  Biological origin -  Natural product -  Synthetic origin -  Ingredient with

biocidal activity

-  High numbers of yeast, mould and bacteria

-  Mycoplasma -  Viruses -  Endotoxin level -  Prions

-  Choice of approved suppliers -  Supplier audits -  Supplier certificates -  Control of incoming materials -  Control of pre-filtration bioburden

(yeasts, moulds and bacteria -  ultrafiltration (endotoxins)

Nature of the product

-  Solution (preserved or unpreserved)

-  Suspension -  Crystallized powder -  Lyophilized powder -  Cream or ointment -  Solid device -  Combination product -  Formulations with

biological activity

-  Ability to support -  microbial growth -  Bioburden

increase -  Endotoxin

conamination -  Contamination

during manufacture

-  Perform growth studies on product (if water based, non preserved)

-  Single dose formulation -  Water activity determination -  Holding time limitations of non-

sterile bulk -  Refrigeration of non sterile bulk -  In process bioburden monitoring

ISO 13408 – Excerpt of a table presenting specific risks

Further Aspects: •  product presentation / design •  technical complexity of the manufacturing process •  intended clinical use of the product

May 2015, page 15

Risk Analyses

Engineering Delivery/ Installation

Start-up Test-Runs

Process Optimi-sation

Detail RA Basic RA

Routine Production

Process Validation

Process RA Monitoring RA

Risk Analyses are necessary at different times in a life-cycle!

•  at the stage of planning / engineering ! basis for qualification

•  before process validation

•  before manufacturing ! monitoring

•  in the course of change control

•  in case of deviations

CC- and Deviation RAs

May 2015, page 16

2. Step – after the Impact Assessment ! Risk Analyses

•  profoundly and fundamentally understand your process – involve Subject Matter Experts (SMEs)

•  identyfy potential risks for product quality and patient safety

-  CQAs (Critical Quality Attributes)

-  CPPs (Critical Process Parameters)

•  eliminate the risks via –  technical solutions –  written instructions –  Monitoring of processes

•  veriy that risks are reliably excluded:

! qualify your equipment; consider CQAs and CPPs! ! validate your processes; consider CQAs and CPPs!

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May 2015, page 17

some more considerations around RAs and benefits you have from RAs:

"  Enhance process understanding and learn about your processes

"  have documented evidence for decisions

!  after years you still know what your thoughts were and on which ideas you decisions had been based

!  when new people join the project team or the company, they can READ the RAs

"  If the guidelines do not give precise instruction: analyze your process and justify what you are doing by RAs

•  also for other important matters, RAs can help: project time schedule, cost control

! Different methods for Risk Analyses / Risk Assessments

General Targets of Risk Analyses / Risk Assessments (RA)

May 2015, page 18

Performing Risk Analyses - The Teams -

Risk Analyses should be performed by interdisciplinary teams:

Who should participate? •  QA •  Production •  QC / Microbiology •  Validation •  R&D •  Regulatory Affairs •  Technical Department •  Maintenance •  Suppliers •  IT-Department

in general

depending on the target of the RA

May 2015, page 19

•  allow enough time: minimum 4 - 6 hours per RA, general experience

•  have breaks! •  avoid the team being disturbed

•  do not prevent ideas - allow free-flow of thoughts

•  make any process and equipment knowledge available (right team members!)

•  have the necessary documentation and data present

•  do not try to solve the problems identified - just describe them

Risk Analyses should be performed in a creative atmosphere!

Performing Risk Analyses - The Settings -

May 2015, page 20

Snap-shot of a RA performed in a “creative atmosphere”

May 2015, page 21

Performing Risk Analyses - The Settings -

RA-Teams require a moderator and a writer!

•  the moderator

•  to ask creative and challenging questions •  to co-ordinate the team and make sure that all

statements are heard

•  to prevent disturbing

•  the writer

•  to summarize the results and to perform instant PC-documentation visible for the team via data-beamer

•  gifted with excellent typing-skills!

•  has to understand the process and must be able to put the contributions of the participants into phrases

! in some cases, it may be the same person!

May 2015, page 22

•  PHA – Preliminary Hazard Analysis

•  FMEA – Failure Mode and Effect Analysis

•  HACCP – Hazard Analysis and Critical Control Points

Some Methods

May 2015, page 23

PHA – Preliminary Hazard Analysis

First step to assess risks

•  in general: not very formal

•  initial step at an early stage of a project

•  introduction to an in-depth-analysis for a complex system

•  a complete analysis for a simple system

How to proceed:

•  clearly identify the system (system boundaries – what is included? / what is out of the scope?)

•  have system descriptions, layouts, drawings, process flow diagrams etc. available

•  identify risks in a systematic way – go through the process

•  mark risk points / describe potential failures

•  possibility: evaluate likelihood of entry and severity (may also be done at a later stage)

May 2015, page 24

Preliminary Hazard Analysis

based on a process flow diagram

•  step-by-step-check of risks

•  at the time of a PHA, risks may be “points for clarification”

Remark: This is an example to show a structure, not to show actual results of a PHA

Make sure the PHA is not too detailed!

•  involve people with broad knowledge

•  PHA is not for specialists with detailed knowledge

•  identify major risks

May 2015, page 25

Sources: implemented: US military standard, early 1950 refined: NASA, automotive Industry Targets in engineering / planning: •  reliability •  safety •  quality Different aspects: •  design / planning •  system / functional (existing equipment) •  process

Sometimes FMECA to point out that Criticality is evaluated too, but in general included in FMEA anyhow. It is one of the „forward logic“ systems

Failure Mode and Effect Analysis FMEA

May 2015, page 26

The steps:

•  Description of the process step / equipment function / etc.

•  Failure- or Error-Analysis

•  Risk Review (evaluation by assigning numbers for high – medium – low)

•  Identification of solutions and measures

•  Tasks and responsibilities are fixed

•  Evaluation of the improved situation


May 2015, page 27

Failure-Mode-Effects-AnalysisDesign-FMEA Process-FMEA System-FMEA

Name/Department/Production Unit/Telefon

Potential Error Current SituationRPN RPN

Improved Situation

Part / Unit

Model

Designed by (Name/Dept..)

ActivityCheckPoints

FixedMeasure

Number

Date

Revision

Respons..

Error Result Cause

ComponentProcessSystem

Err

or N

r.

Likelihood of the error(Error may occur)unlikely = 1low = 2 - 3moderate = 4 - 6high = 7 - 8very high = 9 -10

Importance of the error(Effects to production/customer)no effect = 1low = 2 - 3moderate = 4 - 6high = 7 - 8very high = 9 -10

Detection of the error(before shipped to customer)easy = 1useful = 2 - 5demanding = 6 - 8very costly = 9unlikely = 10

Error Analysis RiskReview Solutions,

MeasuresResults

L I D

RPN =L x I x D

L I D


May 2015, page 28

Description of the process step / equipment function / etc.

Clear and precise

Using technical terms

Elaborated enough to be understood

•  by other / future team members

•  after some years!

Performing the Failure- or Error-Analysis

What might go wrong? – Describe failure / error: mention all failure modes!

What are the consequences, when it will go wrong? (importance / impact / severity) ! consequences may be different for different failure modes!

What are the potential causes? ! causes may be different for different failure modes!


May 2015, page 29

Risk Review Evaluate: •  Likelihood (L) / probability of entry of the failure / error •  Importance (I) / impact / severity of the consequences •  Detection (D) / likelihood of detection / possibility of detection of

the of the failure / error OR the consequences (NOT: the cause!) Solutions and measures Identify and describe ways to •  reduce the likelihood of entry and / or •  enhance the possibility of detection •  Tasks and responsibilities are fixed •  Evaluation of the improved situation: projection into the future;

evaluation is done BEFORE the measures are implemented; may be re-evaluated AFTER the measures are implemented.

! FMEAs (as well as other RAs) are life-cycle documents!


May 2015, page 30

Tasks and responsibilities •  define precise tasks •  fix due dates •  assign responsibilities

Evaluation of the improved situation Projection into the future! Evaluation is done BEFORE the measures are implemented; may be re-evaluated AFTER the measures are implemented. ! FMEAs (as well as other RAs) are life-cycle documents!


May 2015, page 31

Impact (Severity) Rating

Definition

with regard to patient with regard to equipment / process

Catastrophic 5 Severe harm to patient – death not unlikely

loss of the system

Critical 4 Severe harm to patient considerable system damage

Major 3 Harm to patient is likely damage to system may occur

Minor 2 Moderate discomfort of the patient – patient may not be able to use the product

Short interruption or limit exceeding of limits expected

None 1 No effect on patient safety Has no effect on safety !

Failure Mode and Effect Analysis FMEA Risk Review and Risk Rating

When assigning the rating ! make sure it is based on knowledge!

May 2015, page 32

FMEA - Risk Priority Numbers - RPN

The RPN is calculated by multiplication of the Risk Review Numbers:

I x L x D = RPN

If I, L and D are between 1 and 10 - RPN may be 1 - 1000!

Most frequent rating: 1 – 5 ! RPN in 1 to 125

➩ Evaluation of RPNs allows to set priorities on severe risks!

Risk Analyses Methods

May 2015, page 33

FMEA – Risk Categories

Impact

Likelihood

1 2 3 4 5

5 5 10 15 20 25

4 4 8 12 16 20

3 3 6 9 12 15

2 2 4 6 8 10

1 1 2 3 4 5 !

no measures required measures required

ALARP = As Low As Reasonably Practicable

ALARP = measures shall be implemented, if they can be implemented with a reasonable technical and financial effort ! Normally not applicable for GMP-risks!

May 2015, page 34

FMEA – Risk Categories

Assigning Risk Levels, taking Detectability into account

I x L RPN (IxLxD) Risk Level

Consequences and Measures

≤ 4 RPN ≤ 8 Low Residual risk, which can be accepted. No further action required

5 ≤ I x L ≤ 10 9 ≤ RPN ≤ 30 Medium Measures to control the risk have to be implemented in general

I xL ≥ 10 RPN ≥ 32 High Risk cannot be accepted and measures have to be implemented to reduce it . Re-evaluation is required taking the planned measures into account.

!

May 2015, page 35

Example

Process Step

Poten-tial error

potential conse-quence

potential cause

Checkpoint L I D RPN Rationale Measure Responsible

L I D RPN Status of comple-tion

Filling Volume too low

Product does not meet specification

Operator has selected wrong program

IPC 2 5

1#

10

IPC allows detection. Impact is high, because of economic and patient risk

Training of operator

xxxx / 31.12.14

1 5 1 5

equipment malfunction

IPC 2 5 1 10 perform equip-ment qualifica-tion

30.09.14 1 5 1 5


strongly recommended: implement a column to document the rationale for rating!

D = detection of the failure or detection of the consequence!

Checkpoint: for potential error or consequence – in general: not for the potential cause!

May 2015, page 36

Systematic method, which still requires

•  definition of the scope and the level of detail

•  a systematic approach

•  there is often a lot of confusion between „cause“ and „consequence“ ... a kind of confusion that does not appear likely to happen at the beginning!

•  process know-how – no guessing and assumptions!

•  clear risk acceptance criteria

•  a lot of writing, explanation and record of rationales

•  time-consuming

.... and at the end, it is sorted into

a)  measures required - red

b)  risk accepted and not reduced further - green


May 2015, page 37

HACCP – Hazard Analysis (and) Critical Control Points mentioned in ISO 14698 as HACCP concept

The HACCP concept has been established for microbiological control in the food industry – it is also applicable for the Pharmaceutical Industry Result: Check-lists for routine check of quality relevant parameters! For the Pharmaceutical Industry, it can be called: GMP-Risk-Analysis

Risk Analyses Methods

A GMP-Risk Analysis is an easy and adequate method if an assessment of a potential future risk shall be made!

! Very formal and quantitative methods are often not adequate to

evaluate a future risk because there may be a lack of information and data

May 2015, page 38

The HACCP-Concept 1. Conduct a hazard analysis. 2. Determine the critical control points (CCPs). 3. Establish target levels and critical limit(s). 4. Establish a system to monitor the CCPs. 5. Establish the corrective action to be taken when monitoring

indicates that a particular CCP is not under control. 6. Establish procedures to verify that the HACCP system is

working effectively. 7. Establish documentation concerning all procedures and keep

records appropriate to these principles and their application.

HACCP - The Basic Principle (WHO-GMP-Guide)

May 2015, page 39

GMP-Risk-Analysis for Validation and Monitoring How to proceed:

Step 1: Identify potentially critical points / process steps (carry out Risk Analysis based on the table)

•  Consider different situations

•  Evaluate and describe what could happen

•  Check, it this is or may be critical / or not!

•  Describe WHY the decision “critical” or “not critical” was made

•  Define measures

Step 2: Perform tests to find out worst-case and critical points / process steps (optional)

Step 3: Improve the situation, if a point or step has been identified as critical (optional)

Step 4: Define validation / monitoring programme

Step 5: Write validation / monitoring plan

The GMP-Risk Analysis

May 2015, page 40

The GMP-Risk Analysis Step 1: Find out worst-case points -

identify and describe points that can and shall be tested*

1

2 3 4 5 6 7 8

9 10

11

No. Description of the point Potential Risk critical

Explanation Measures y n

1. Forehead microbial contamination particle contamination

✔ personnel may touch forehead during operations

include in program

2. Eyes / eye brows microbial contamination particle contamination

✔ personnel may touch eye area during operations

include in program – it may be necessary to decide that full mask has to be worn – depending on the results

3. Mouth mask microbial contamination particle contamination

✔ known source of risk – micro-organism from mouth and breathing

include in program

4. Chest microbial contamination particle contamination

✔ breast is close to product

include in program

…..

8. Knees microbial contamination particle contamination

✔

…

11. Rear parts of the body microbial contamination ✔ not considered as risky because not close to the product

- - -

*The table is an example to show the structure – not necessarily correct decisions for a specific process!

May 2015, page 41

What to consider during a GMP-Risk Analysis during design phase:

•  consider every single process step and/or component •  identify and describe potential errors and risks •  for each point, four different questions should be considered (example: valve

or temperature sensor): -  does the item itself present a specific risk? -  does the absence of the item present a risk? -  does the malfunction of the item present a risk? -  does or may the specific design of the item present a risk?

•  If the answer is “yes” – consider in subsequent qualification phases •  explain the background for the y/n-decision •  describe measures to avoid or circumvent the potential risk

-  re-design -  improve failure detection -  compensate failure and its consequences by procedures (e.g. QC)

The GMP-Risk Analysis

May 2015, page 42

GMP-Risk Analysis Table (HACCP) – Example 1

No. Description of the step Potential Risk / Potential Error

critical Explanation Measures

y n

1. Door to the chamber is opened and visual check for line clearance is performed

Stoppers from previous batch may have remained in the system

y Risky, because stoppers may be of different size and material and multiple treatment of potentially remaining stoppers may be harmful to the material.

Check, during qualification if the system has no areas, where stoppers could “hide”.

2. Stopper bags are opened and stoppers are fed into the chamber

Contamination of chamber and stoppers due to improper handling

y Describe handling in SOP

3. Door of the rotating drum is closed (by two pneumatic cylinders)

Door is not properly closed

n No risk, because closing is surveyed automatically – Malfunction presents a risk - function has to be tested.

Check function of system.

example to show structure!

Excerpt from a HACCP-Analysis Stopper Sterilizer

May 2015, page 43


No. Description of the step Potential failure / Potential error

rele-vant Rationale

at risk

Rationale Measures

1. Door to the chamber is opened and visual check for line clearance is performed

Stoppers from previous batch may have remained in the system

y Stoppers may be of different size and material and multiple treatment of potentially remaining stoppers may be harmful to the material.

y Design is not finalized.

Design review Check, during qualification that the system has no areas, where stoppers can “hide”.

2. Stopper bags are opened and stoppers are fed into the chamber

Particle contamination of chamber and stoppers due to improper handling

y Particles may remain in the system and contaminate the product.

n Handling is done in a Grade C area. personnel is trained.

n/a

Microbial contamination of chamber and stoppers due to improper handling

n Not relevant, because sterilization takes place.

n/a n/a n/a

3. Door of the rotating drum is closed (by two pneumatic cylinders)

Door is not properly closed

y open door may prevent adequate sterilization cycle

n closing is surveyed automatically.

Qualify function.



May 2015, page 44




May 2015, page 45

Methods may be used as stand-alone methods or may be combined - depending on the scope of the RA: Typical sets of combinations:

PHA + 1.  HACCP 2.  FMEA (if more detail is required) HACCP + at a later stage: FMEA

If a problem has occured (in general: deviation) Ishikawa / Fault Tree Analysis, which may be supported by: •  FMEA •  HACCP

Risk Analyses – Which Tools to Combine?

May 2015, page 46

Disclaimer:

•  This presentation has been prepared upon best knowledge and it presents the view and experience of Pharma Consulting Walther.

•  The presentation reflects current guidelines, knowledge and thinking. Changes of regulatory guidelines or interpretation thereof or new regulatory expectations may change the applicability of the contents of this presentation.

•  Parts of the presentation may not be understood or misinterpreted without the verbal explanation given during the seminar.

•  Although the statements made in the presentation in general have been presented to and discussed with inspectors, a different approach may be required and adequate depending on the individual situation.

•  The information contained herein may be changed without prior notice.

Contact: Pharma Consulting Walther Dr. Ingrid Walther Rosenweg 36 61381 Friedrichsdorf – Germany +49-(0)6172-958281 +49-(0)172 654 8834 www.consulting-walther.com [email protected]

07 risk analyses tools - dcvmn · • failure mode effects analysis (fmea) ... - suspension -...

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