1. Quality Risk Management – ICH Q9, Annex 20 and GMPs
Presented by: Karen S. Ginsbury
For: IFF
March 2010

2. Define the following Quality Quality of a pharmaceutical product Risk
A Quality System in terms of risk

3. 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

4. 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

5. 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

6. 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

7. 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

8. 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

9. 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

10. 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

11. 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

12. 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 reduction/control
option analysis
implementation
residual risk evaluation
overall risk acceptance
Risk monitoring
external environment
review of risk management
experience

13. 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

14. 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?)

15. 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

16. 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

17. 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

18. 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?

19. 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

20. 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

21. Pharmaceutical CGMPs For the 21st Century A Risk Based Approach
FDA final report
September 2004

22. 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

23. 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

24. 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)

25. 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

26. 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

27. 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

28. 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

29. 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)
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30. 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

31. Cause and Effect: Viracept
Contamination leads to EU-wide Viracept recall
By Anna Lewcock
07-Jun 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.

32. 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

33. 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?

34. 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

35. Is the drug substance/excipient sterile?
Does drug substance/excipient synthesis/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 from compendial indicator organisms.
Establish microbial limit acceptance criteria as 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
YES
Establish microbial limit acceptance criteria as per the harmonized pharmacopoeial

36. 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 criteria as 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
YES NO
Does scientific evidence demonstrate growth inhibitory properties of the drug product?

37. 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.” 37

38. 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 38

39. 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}; 50 rpm)
Microbiology
Meets USP criteria 39

40. 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
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41. Product vs Process Product is defined by: Process 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

42. Lifecycle Management Analytical Methods Reference Material Process
Supplier Qualification
Other…

43. 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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44. 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’

45. 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

46. Q8 – To be considered Components of Drug Product 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

47. 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

48. Q8R: Pharmaceutical Development Elements (For ALL development, not just QbD)

49. Q8R: Pharmaceutical Development Elements (For QbD)

50. 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

51. 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

52. 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

53. 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

54. 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

55. 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

56. 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

57. 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

58. 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
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59. 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
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60. 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

61. Proposed Definition – Draft Guide
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

62. Pharmaceutical Product Lifecycle
Changes
R&D
CONTROL
Commercialization
Validation

63. 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

64. CONTINUAL IMPROVEMENT of Process Performance and Product Quality Monitoring Through Lifecycle

65. CONTINUAL IMPROVEMENT of the Quality System Application of CAPA Through Lifecycle

66. Change Management Through Lifecycle

67. Management Review Through the Lifecycle

68. 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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69. ICH Q9, Annex 1 Risk Management- Methods and Tools
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70. Methods Risk Management Facilitation Methods FMEA FMECA FTA HACCP
HAZOP
PHA
Risk Ranking and Filtering
Supporting Statistical Tools
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71. 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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72. 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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73. 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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74. 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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75. 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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76. 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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77. 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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78. 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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79. 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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80. 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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81. 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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82. 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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83. 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:
identification of possibilities that the risk event happens
qualitative evaluation of the extent of possible injury or damage to health that could result
a relative ranking of the hazard using a combination of severity and likelihood of occurrence
the identification of possible remedial measures
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84. 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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85. 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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86. 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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87. 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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88. 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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89. FMEA workshop
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90. 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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91. 91/

92. Risk Ranking Table SEV OCC DET Risk Category Ranking / Definition Low
Medium
High
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 92

93. Risk Priority Ranking Detection Occurrence High Low (Risk) Med
High (Risk)
Severity
MED – HIGH
HIGH
V. HIGH
MED
Low
LOW
MED - LOW

94. PCI Pharmaceutical Consulting Israel Ltd.
Risk Ranking Table
Risk Factors
Ranking
Detection
Occurrence
Severity
Unlikely 5
Often
Severe 5
High
Maybe
Periodic 3
Moderate 3
Medium
Readily Detected 1
Rare
Low
Low
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95. FMEA
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96. Mapping the Process
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97. Assessment
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99. Task #2 – Current Controls
Make a list of current controls and then calculate the RPN
Is it acceptable or not

100. Risk Priority Number Scale 1 - 5 RPN SEV x OCC X DET < 10 11 - 29
≥ 30
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