This document provides an overview of quality risk management and failure mode and effects analysis (FMEA). It discusses risk as a combination of the probability of harm occurring and the severity of that harm. The quality risk management process includes risk identification, analysis, evaluation, control, and communication. FMEA is presented as a systematic method to identify and prevent product and process problems before they occur. Key aspects of FMEA covered include failure modes, effects, risk priority numbers, and using FMEA to prioritize risks for improvement actions. Scales for rating severity, occurrence, detection, and examples of applying FMEA to a drying process are also presented.
Critical Hazard Management System (CHMS)AnkitVasoya5
TOPIC ~ Critical Hazard Management System
What Is Hazards ?
Why Management ?
The most common hazards
How to prevent workplace from Hazards
Identification of Hazards
Risk Assessment
Controlling risk and Hazards
Risk / Hazard monitoring
References.
Almost all the regulatory bodies are expected to have Risk Based Quality System. Quality Risk and its assessment has tremendous output and benefits towards the Patient Safety.
Aseptic / sterile- “ A state of control attained by using an aseptic work area and performing activities in a manner that precludes microbiological contamination of the exposed sterile product”
Critical Hazard Management System (CHMS)AnkitVasoya5
TOPIC ~ Critical Hazard Management System
What Is Hazards ?
Why Management ?
The most common hazards
How to prevent workplace from Hazards
Identification of Hazards
Risk Assessment
Controlling risk and Hazards
Risk / Hazard monitoring
References.
Almost all the regulatory bodies are expected to have Risk Based Quality System. Quality Risk and its assessment has tremendous output and benefits towards the Patient Safety.
Aseptic / sterile- “ A state of control attained by using an aseptic work area and performing activities in a manner that precludes microbiological contamination of the exposed sterile product”
Corrective Actions and Preventive Actions.Corrective Action Preventive Action (CAPA) is a process which investigates and solves problems, identifies causes, takes corrective action and prevents recurrence of the root causes. The ultimate purpose of CAPA is to assure the problem can never be experienced again. Corrective vs. Preventive Action. Quality professionals frequently express confusion as to the difference between corrective and preventive action. A corrective action deals with a nonconformity that has occurred, and a preventive action addresses the potential for a nonconformity to occur.
Presentation complied by Drug Regulations – a not for profit organization from publicly available material form FDA , EMA, EDQM . WHO and similar organizations.
Visit www.drugregulations.org for the latest in Pharmaceutic
A structured approach to the investigation process should be used with the objective of determining the root cause.
The level of effort, formality, and documentation of the investigation should be commensurate with the level of risk, in line with ICH Q9.
Auditing Manufacturing Process and Product and Process Information.pdfDr. Dinesh Mehta
Manufacturing process audits should ensure that procedures are properly followed, problems are quickly corrected, there is consistency in the process, and there is continuous improvement and corrective action as needed.
This presentation f=gives Overview of Quality Risk Management Process and presents case studies for application of QRM in Manufacturing Operations.
◦ Drug Substance Attributes
◦ Excipient Selection
◦ Process Selection
◦ Formulation Development & Optimisation
◦ “Manufacturing Process Development
Presentation complied by Drug Regulations – a not for profit organization from publicly available material form FDA , EMA, EDQM . WHO and similar organizations.
Visit www.drugregulations.org for the latest in Pharmaceuticals
Corrective Actions and Preventive Actions.Corrective Action Preventive Action (CAPA) is a process which investigates and solves problems, identifies causes, takes corrective action and prevents recurrence of the root causes. The ultimate purpose of CAPA is to assure the problem can never be experienced again. Corrective vs. Preventive Action. Quality professionals frequently express confusion as to the difference between corrective and preventive action. A corrective action deals with a nonconformity that has occurred, and a preventive action addresses the potential for a nonconformity to occur.
Presentation complied by Drug Regulations – a not for profit organization from publicly available material form FDA , EMA, EDQM . WHO and similar organizations.
Visit www.drugregulations.org for the latest in Pharmaceutic
A structured approach to the investigation process should be used with the objective of determining the root cause.
The level of effort, formality, and documentation of the investigation should be commensurate with the level of risk, in line with ICH Q9.
Auditing Manufacturing Process and Product and Process Information.pdfDr. Dinesh Mehta
Manufacturing process audits should ensure that procedures are properly followed, problems are quickly corrected, there is consistency in the process, and there is continuous improvement and corrective action as needed.
This presentation f=gives Overview of Quality Risk Management Process and presents case studies for application of QRM in Manufacturing Operations.
◦ Drug Substance Attributes
◦ Excipient Selection
◦ Process Selection
◦ Formulation Development & Optimisation
◦ “Manufacturing Process Development
Presentation complied by Drug Regulations – a not for profit organization from publicly available material form FDA , EMA, EDQM . WHO and similar organizations.
Visit www.drugregulations.org for the latest in Pharmaceuticals
This presentation presents how Quality Risk management can be applied in Commissioning & Qualification of Facility , System and Equipments in Pharmaceutical Facilities.
Environmental Monitoring describes the microbiological testing under- taken in order to detect changing trends of microbial counts and micro- flora growth within cleanroom or controlled environments. The results obtained provide information about the physical construction of the room, the performance of the Heating, Ventilation, and Air-Conditioning (HVAC) system, personnel cleanliness, gowning practices, the equipment, and cleaning operations.
Over the past decade, environmental monitoring has become more sophisticated in moving from random sampling, using an imaginary grid over the room and testing in each grid, to the current focus on risk assessment and the use of risk assessment tools to determine the most appropriate methods for environmental monitoring.
This presentation gives current trends in the application of risk assessment to the practice of environmental monitoring.
The two most commonly used within microbiology are
HACCP (which originated in the food industry) and FMEA
(developed for engineering). This article explores these two
approaches, first with a description of HACCP, followed by a
description and case study of FMEA in sterility testing.
Risk management tools and techniques for environmental monitoring:
Application of HACCP for selecting environmental monitoring locations; Use of risk filtering to determine frequencies of monitoring ; Applying FMEA to assess risks from process equipment – a sterility testing isolator.
hello there , During M pharm , I have presented this for seminar purpose named as '' QUALITY RISK MANAGEMENT " Hope it will reach your expectations. thank you.
This presentation highlights the reasons which lead to the withdrawal of the 2002 Guidance of the FDA and the current issue with Blend Uniformity and Content Uniformity Determinations.
WHO has recently issued draft document titled "Guidelines on Validation". These guidelines (i.e., the main text included in this working document) cover the general principles of validation and qualification.
These guidelines focus mainly on the overall concept of validation and are not intended to be prescriptive in specific validation requirements. This document serves as general guidance only and the principles may be considered useful in its application in the manufacture and control of starting materials and finished pharmaceutical products (FPPs), as well as other areas. Validation of specific processes and systems, for example, in sterile product manufacture, requires much more consideration and a detailed approach that is beyond the scope of this document. The general text in this document may be applicable to validation and qualification of premises, equipment, utilities, systems, processes, and procedures.
The draft on the specific topics, the appendices to this main text, will follow. The following is an overview on the appendices that are intended to complement the text of this working document:
Appendix 1: Validation of heating, ventilation and air-conditioning systems - will be replaced by cross reference to WHO Guidelines on GMP for HVAC systems for considerations in qualification of HVAC systems (update - working document QAS/15.639/Rev. 1)
Appendix 2: Validation of water systems for pharmaceutical use - will be replaced by cross-reference to WHO Guidelines on water for pharmaceutical use for consideration in qualification of water purification systems
Appendix 3: Cleaning validation - consensus to retain
Appendix 4: Analytical method validation - update in process
Appendix 5: Validation of computerized systems - update in process
Appendix 6: Qualification of systems and equipment - update in process
Appendix 7: Non-sterile process validation - update already published as Annex 3, WHO Technical Report Series, No. 992, 2015
Comments on this draft document are due by July 12, 2016.
A presentation on this guidance is given below:
Presentation on New WHO Guidance on Validations
This presentation is compiled from freely available resources like the websites of FDA, EMA ,WHO and research papers published by experts in this field like Sandle, T Reinmüller, B , Hyde, W,, Costello, E.K., Lauber, C. L., Hamady, M., Fierer, N., Gordon, J.I., Knight, R.
Paper published by T. Sandle on clean room contamination was referred extensively for this presentation. “Drug Regulations” is a non profit organization which provides free online resource to the Pharmaceutical Professional.
Visit http://www.drugregulations.org for latest information from the world of Pharmaceuticals.
This presentation gives an overview of : Validation of microbiological methods , Considering some of the limitations and
Key criteria that may be applicable for assessment.
Title: Sense of Taste
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the structure and function of taste buds.
Describe the relationship between the taste threshold and taste index of common substances.
Explain the chemical basis and signal transduction of taste perception for each type of primary taste sensation.
Recognize different abnormalities of taste perception and their causes.
Key Topics:
Significance of Taste Sensation:
Differentiation between pleasant and harmful food
Influence on behavior
Selection of food based on metabolic needs
Receptors of Taste:
Taste buds on the tongue
Influence of sense of smell, texture of food, and pain stimulation (e.g., by pepper)
Primary and Secondary Taste Sensations:
Primary taste sensations: Sweet, Sour, Salty, Bitter, Umami
Chemical basis and signal transduction mechanisms for each taste
Taste Threshold and Index:
Taste threshold values for Sweet (sucrose), Salty (NaCl), Sour (HCl), and Bitter (Quinine)
Taste index relationship: Inversely proportional to taste threshold
Taste Blindness:
Inability to taste certain substances, particularly thiourea compounds
Example: Phenylthiocarbamide
Structure and Function of Taste Buds:
Composition: Epithelial cells, Sustentacular/Supporting cells, Taste cells, Basal cells
Features: Taste pores, Taste hairs/microvilli, and Taste nerve fibers
Location of Taste Buds:
Found in papillae of the tongue (Fungiform, Circumvallate, Foliate)
Also present on the palate, tonsillar pillars, epiglottis, and proximal esophagus
Mechanism of Taste Stimulation:
Interaction of taste substances with receptors on microvilli
Signal transduction pathways for Umami, Sweet, Bitter, Sour, and Salty tastes
Taste Sensitivity and Adaptation:
Decrease in sensitivity with age
Rapid adaptation of taste sensation
Role of Saliva in Taste:
Dissolution of tastants to reach receptors
Washing away the stimulus
Taste Preferences and Aversions:
Mechanisms behind taste preference and aversion
Influence of receptors and neural pathways
Impact of Sensory Nerve Damage:
Degeneration of taste buds if the sensory nerve fiber is cut
Abnormalities of Taste Detection:
Conditions: Ageusia, Hypogeusia, Dysgeusia (parageusia)
Causes: Nerve damage, neurological disorders, infections, poor oral hygiene, adverse drug effects, deficiencies, aging, tobacco use, altered neurotransmitter levels
Neurotransmitters and Taste Threshold:
Effects of serotonin (5-HT) and norepinephrine (NE) on taste sensitivity
Supertasters:
25% of the population with heightened sensitivity to taste, especially bitterness
Increased number of fungiform papillae
micro teaching on communication m.sc nursing.pdfAnurag Sharma
Microteaching is a unique model of practice teaching. It is a viable instrument for the. desired change in the teaching behavior or the behavior potential which, in specified types of real. classroom situations, tends to facilitate the achievement of specified types of objectives.
Ethanol (CH3CH2OH), or beverage alcohol, is a two-carbon alcohol
that is rapidly distributed in the body and brain. Ethanol alters many
neurochemical systems and has rewarding and addictive properties. It
is the oldest recreational drug and likely contributes to more morbidity,
mortality, and public health costs than all illicit drugs combined. The
5th edition of the Diagnostic and Statistical Manual of Mental Disorders
(DSM-5) integrates alcohol abuse and alcohol dependence into a single
disorder called alcohol use disorder (AUD), with mild, moderate,
and severe subclassifications (American Psychiatric Association, 2013).
In the DSM-5, all types of substance abuse and dependence have been
combined into a single substance use disorder (SUD) on a continuum
from mild to severe. A diagnosis of AUD requires that at least two of
the 11 DSM-5 behaviors be present within a 12-month period (mild
AUD: 2–3 criteria; moderate AUD: 4–5 criteria; severe AUD: 6–11 criteria).
The four main behavioral effects of AUD are impaired control over
drinking, negative social consequences, risky use, and altered physiological
effects (tolerance, withdrawal). This chapter presents an overview
of the prevalence and harmful consequences of AUD in the U.S.,
the systemic nature of the disease, neurocircuitry and stages of AUD,
comorbidities, fetal alcohol spectrum disorders, genetic risk factors, and
pharmacotherapies for AUD.
The prostate is an exocrine gland of the male mammalian reproductive system
It is a walnut-sized gland that forms part of the male reproductive system and is located in front of the rectum and just below the urinary bladder
Function is to store and secrete a clear, slightly alkaline fluid that constitutes 10-30% of the volume of the seminal fluid that along with the spermatozoa, constitutes semen
A healthy human prostate measures (4cm-vertical, by 3cm-horizontal, 2cm ant-post ).
It surrounds the urethra just below the urinary bladder. It has anterior, median, posterior and two lateral lobes
It’s work is regulated by androgens which are responsible for male sex characteristics
Generalised disease of the prostate due to hormonal derangement which leads to non malignant enlargement of the gland (increase in the number of epithelial cells and stromal tissue)to cause compression of the urethra leading to symptoms (LUTS
Lung Cancer: Artificial Intelligence, Synergetics, Complex System Analysis, S...Oleg Kshivets
RESULTS: Overall life span (LS) was 2252.1±1742.5 days and cumulative 5-year survival (5YS) reached 73.2%, 10 years – 64.8%, 20 years – 42.5%. 513 LCP lived more than 5 years (LS=3124.6±1525.6 days), 148 LCP – more than 10 years (LS=5054.4±1504.1 days).199 LCP died because of LC (LS=562.7±374.5 days). 5YS of LCP after bi/lobectomies was significantly superior in comparison with LCP after pneumonectomies (78.1% vs.63.7%, P=0.00001 by log-rank test). AT significantly improved 5YS (66.3% vs. 34.8%) (P=0.00000 by log-rank test) only for LCP with N1-2. Cox modeling displayed that 5YS of LCP significantly depended on: phase transition (PT) early-invasive LC in terms of synergetics, PT N0—N12, cell ratio factors (ratio between cancer cells- CC and blood cells subpopulations), G1-3, histology, glucose, AT, blood cell circuit, prothrombin index, heparin tolerance, recalcification time (P=0.000-0.038). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and PT early-invasive LC (rank=1), PT N0—N12 (rank=2), thrombocytes/CC (3), erythrocytes/CC (4), eosinophils/CC (5), healthy cells/CC (6), lymphocytes/CC (7), segmented neutrophils/CC (8), stick neutrophils/CC (9), monocytes/CC (10); leucocytes/CC (11). Correct prediction of 5YS was 100% by neural networks computing (area under ROC curve=1.0; error=0.0).
CONCLUSIONS: 5YS of LCP after radical procedures significantly depended on: 1) PT early-invasive cancer; 2) PT N0--N12; 3) cell ratio factors; 4) blood cell circuit; 5) biochemical factors; 6) hemostasis system; 7) AT; 8) LC characteristics; 9) LC cell dynamics; 10) surgery type: lobectomy/pneumonectomy; 11) anthropometric data. Optimal diagnosis and treatment strategies for LC are: 1) screening and early detection of LC; 2) availability of experienced thoracic surgeons because of complexity of radical procedures; 3) aggressive en block surgery and adequate lymph node dissection for completeness; 4) precise prediction; 5) adjuvant chemoimmunoradiotherapy for LCP with unfavorable prognosis.
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These lecture slides, by Dr Sidra Arshad, offer a quick overview of physiological basis of a normal electrocardiogram.
Learning objectives:
1. Define an electrocardiogram (ECG) and electrocardiography
2. Describe how dipoles generated by the heart produce the waveforms of the ECG
3. Describe the components of a normal electrocardiogram of a typical bipolar leads (limb II)
4. Differentiate between intervals and segments
5. Enlist some common indications for obtaining an ECG
Study Resources:
1. Chapter 11, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 9, Human Physiology - From Cells to Systems, Lauralee Sherwood, 9th edition
3. Chapter 29, Ganong’s Review of Medical Physiology, 26th edition
4. Electrocardiogram, StatPearls - https://www.ncbi.nlm.nih.gov/books/NBK549803/
5. ECG in Medical Practice by ABM Abdullah, 4th edition
6. ECG Basics, http://www.nataliescasebook.com/tag/e-c-g-basics
2. This presentation will cover
1. Overview of Quality Risk Management
Process & Tools
2. FMEA Overview
3. Calculation of RPN
4. Case Stud
◦ Drying Process
www.drugregulations.org 2
3. Risk
◦ Combination of
◦ Probability of occurrence of harm and
◦ Severity of that harm.
4. Any circumstances which can cause an
adverse health effect.
◦ Research , Pre-clinical , Clinical
◦ Production
◦ Control
◦ Distribution
5. Which consequence is more severe?
◦ 300 lives lost in single, fiery plane crash.
◦ 300 lives lost on roads over a weekend.
◦ 300 lives potentially lost from cancer within the next 20 years
Which probability is probable?
What does a “30% chance of rain tomorrow” mean?
◦ 30% of the days like tomorrow will have at least a trace of rain.
◦ 30% of the area will have rain tomorrow.
◦ 30% of the time tomorrow, it will rain.
7. Time
ProcessParameter
Lower Specification Limit (LSL)
Upper Specification Limit (USL)
today
Uncertainty
RISK: For a given severity of risk event, what are the chances
(probability) of exceeding the USL in the next period of time?
Tomorrow ?
8. Time
ProcessParameter
Lower Specification Limit (LSL)
Upper Specification Limit (USL)
today
Uncertainty
RISK: Control options are scenarios for risk management.
Note that this scenario shows the best estimate is below the USL.
Tomorrow ?
10. Risk Identification
What might go wrong?
Risk Analysis
What is the likelihood (probability) it will go
wrong
What are the consequences (severity)?
Risk Evaluation
What is the level of risk? Any mitigating factors?
Risk Assessment
www.drugregulations.org 10
Risk Review
RiskCommunication
Risk Assessment
Risk Evaluation
unacceptable
Risk Control
Risk Analysis
Risk Reduction
Risk Identification
Review Events
Risk Acceptance
Initiate
Quality Risk Management Process
Output / Result of the
Quality Risk Management Process
RiskManagementtools
Risk Reduction
Mitigation or avoidance of quality risk
Elimination of risks, where appropriate
Risk Control
Risk Acceptance
Acceptance of Residual Risk
11. System Risk (facility & people)
◦ e.g. interfaces, operators risk, environment,
components such as equipment, IT, design elements
System Risk (organisation)
◦ e.g. Quality systems, controls, measurements,
documentation, regulatory compliance
Process Risk
◦ e.g. process operations and quality parameters
Product Risk (safety & efficacy)
◦ e.g. quality attributes:
measured data according to specifications
12. The evaluation of
the risk to quality
should be based on
scientific knowledge
and ultimately link
to the protection
of the patient
The level of effort,
formality and
documentation
of the quality risk
management process
should be
commensurate with the
level of risk
ICH Q9
13.
14. Supporting statistical tools
◦ Acceptance Control Charts (see ISO 7966)
◦ Control Charts (for example)
Control Charts with Arithmetic Average and
Warning Limits (see ISO 7873)
Cumulative Sum Charts; “CuSum” (see ISO 7871)
Shewhart Control Charts (see ISO 8258)
Weighted Moving Average
◦ Pareto Charts
◦ Process Capability Analysis
◦ Histograms
◦ Design of Experiments (DOE)
◦ Use others that you are familiar with….
www.drugregulations.org 14
16. Systematic Method for Identification and
Prevention of
Product & Process Problems before they occur
Focused on Preventing Defects
Ideally conducted in Product & Process Design
Stage
Conducting on existing products & processes
yields substantial results.
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17. First formal FEMA was conducted in Aerospace Industry in
1960’s
Became key tool for improving safety of chemical
processes
Safety FMEA today is a key tool to prevent safety accidents
& incidents
Engineers have always used FMEA to identify potential
failures of product & processes
Automotive Industry used FMEA for Quality Improvement
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18. Essential to have documented Data and Information
about Product & Process
Otherwise it becomes a guessing game based on
opinions.
FMEA will then focus on wrong failure modes
FMEA should be based on facts : on DATA
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19. To look for all different ways in which a product or
process can fail
Failures are not limited to products
Failures can occur when the user makes a mistake
These failures should also be included in FMEA
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20. Ways in which a product or process can fail are called
FAILURE MODES
Each FAILURE MODE has a potential effect
Some effects are more likely to occur than others –
each failure mode has a probability
Each FAILURE MODE has relative RISK associated with
it.
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21. FMEA process is way to identify the failures, effects,
and risks within a process or product and then
eliminate or reduce them.
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22. Process Step : Pre-mixing
Failure Mode : Mixing time
Effect : Not meet specifications of content uniformity
Risk Reduction: IPC measure of content uniformity
Comments: Effect on efficacy
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23. Process Step : Pre-mixing granulation
Failure Mode : speed of adding water
Effect : Not meet specifications of dissolution and
degradation
Risk Reduction: Use of dosing pump
Comments: Appropriate granulation
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24. Process Step : Pre-mixing granulation
Failure Mode : Manner of adding water
Effect : Not meet specifications of dissolution and
degradation
Risk Reduction: Install a spray nozzle
Comments: Appropriate granulation
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25. Process Step : Granulation
Failure Mode : Kneading Time
Effect : Not meet dissolution specification
Risk Reduction: Reduce Personal fluctuations
Comments: Operator knowledge , power
consumption, difficult to automate
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26. Process Step : Granulation
Failure Mode : Power consumption
Effect : Not meet dissolution specification
Risk Reduction: Try to get optimum kneading time
Comments: Depends on material properties
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27. Process Step : Granulation
Failure Mode : Quality of excipients
Effect : All parameters may need re-evaluation
Risk Reduction: Internal specifications for physical
parameters
Comments: Supplier qualification
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28. Process Step : Granulation drying
Failure Mode : Water Content
Effect : Not meet degradation specification
Risk Reduction: On line NIR , IPC measurements,
Comments: Indirect , Time consuming
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29. The relative risk of a failure and its effects is
determined by three factors
Severity: The consequences of the failure should it
occur
Occurrence: The probability or the frequency of the
failure occurring
Detection : The probability of the failure being
detected before the impact of the effect is realized.
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30. Each Potential Failure Mode is rated in each of the
three factors on a scale ranging from 1 to 10 , low to
high.
Risk Priority Number( RPN) is determined by
multiplying the ranking of the three factors ( severity
X occurrence X detection )
The RPN is determined for each potential failure and
each effect.
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31. The RPN is used to rank the need for corrective action
to eliminate or reduce the potential failure modes.
Failure modes with highest RPN should be attended
first
Special attention should be given when the severity
ranking is high : 9 or 10
RPN will range from 1 to 1000 for each failure mode.
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32. Once corrective action is taken , a new RPN is
determined by re-evaluating the severity , occurrence
and detection.
The new RPN is called “ Resulting RPN”
Improvements and corrective actions must continue
until the “ Resulting RPN is at an acceptable level for
all potential failure modes.
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34. Potential Areas of Use(s)
Prioritize risks
Monitor the effectiveness of risk control activities
Equipment and facilities
Analyse a manufacturing process to identify high-risk
steps or critical parameters
RNP: Risk Priority Number
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35. 1. Review the Process or Product
2. Brainstorm potential failure modes
3. List Potential effects of each failure mode
4. Assign a Severity Ranking for each failure mode
5. Assign Occurrence Ranking for each failure mode
6. Assign detection ranking for each failure mode or effect
7. Calculate the RPN for each effect
8. Prioritize the Failure Modes for Action
9. Take action to eliminate or reduce high risk failure modes
10. Calculate the RPN again as the failure modes are reduced or
eliminated.
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37. 10 Dangerously High Failure could lead to death or permanent injury to the customer. Financial:
>$1,000,000
9 Extremely high Failure could lead to injury to the customer. Failure would create non-
compliance with registered specifications. Failure likely to lead to recall.
Financial: $1,000,000
8 Very High Failure could lead to adverse reaction for customer. Failure would create
noncompliance with GMP regulations or product registrations. Failure
possible to lead to recall. Financial: $500,000
7 High Failure leads to customer percept ion of safety issue. Failure renders
individual unit(s) unusable. Failure causes a high degree of customer
dissatisfaction. Recall for business reasons possible but Authority required
recall unlikely. Financial: $100,000
6 Moderate Failure causes a high degree of customer dissatisfaction and numerous
complaints. Failure unlikely to lead to recall. Financial: $50,000
5 Low Failure likely to cause isolated customer complaints. Financial: $10,000
4 Very Low Failure relates to non-dosage form issues (like minor packaging problems)
and can be easily overcome by the customer. Financial: $5,000
3 Minor Failure could be noticed by the customer but is unlikely to be perceived as
significant enough to warrant a complaint.
2 Very Minor Failure not readily apparent to the customer. Financial: <$1,000
1 None Failure would not be noticeable to the customer. Financial: none
38. 10 Very High: Failure
is almost
inevitable
More than one occurrence per day or a probability of more than three
occurrences in 10 units (Cpk < 0.33 or <1σ).
9 One occurrence every three to four days or a probability of three occurrences
in 10 units (Cpk ~ 0.33 or ~1 σ).
8 High: Repeated
failures
One occurrence per week or a probability of 5 occurrences in 100 units (Cpk ~
0.67 or ~2 σ).
7 One occurrence every month or one occurrence in 100 units (Cpk ~ 0.83 ~2.5
σ).
6 Moderate:
Occasional
Failures
One occurrence every three months or three occurrences in 1,000 units (Cpk ~
1.00 or ~ 3 σ).
5 One occurrence every six months to one year or one occurrence in 10,000
units (Cpk ~ 1.17 or ~ 3.5 σ).
4 One occurrence per year or six occurrences in 100,000 units (Cpk ~ 1.33 or ~ 4
σ).
3 Low: Relatively
few Failures
One occurrence every one to three years or six occurrences in 10,000,000
units (Cpk ~ 1.67 or ~5 σ).
2 One occurrence every three to five years or 2 occurrences in 1,000,000,000
units (Cpk ~ 2.00 OR ~6 σ).
1 Remote: Failure is
unlikely
One occurrence in greater than five years or less than two occurrences in
1,000,000,000 units (Cpk > 2.00 OR >6 σ).
For batch failures use the time scale for unit failures use the unit scale.
39. 10 Absolute
Uncertainty
The product is not inspected or the defect caused by the failure is not
detectable.
9 Very Remote Product is sampled, inspected, and released based on Acceptable Quality
Level (AQL) sampling plans.
8 Remote Product is accepted based on no defects in a sample.
7 Very Low Product is 100% manually inspected in the process.
6 Low Product is 100% manually inspected using go/no-go or other mistake-proofing
gauges.
5 Moderate Some Statistical Process Control (SPC) is used in the process and product is
final inspected off-line.
4 Moderately High SPC is used and there is immediate reaction to out-of-control conditions.
3 High An effective SPC program is in place with process capabilities (Cpk) greater
than 1.33.
2 Very High All product is 100% automatically inspected.
1 Almost Certain The defect is obvious and there is 100% automatic inspection with regular
calibration and preventive maintenance of the inspection equipment.
40. • 10 Extreme
• Predicted to cause severe impact to quality (Product out of specifications, no
Expert Statement possible)
• 7 High
• Predicted to cause significant impact on quality (Failure to meet specifications,
no Stability data, Expert Statement possible)
• 3 Moderate
• Predicted to cause minor impact on quality (Failure to meet specifications,
Stability data available)
• 1 Low
• Predicted to have no/minor impact on quality of the product (Quality within
specifications)
9/17/2015. 408/27/2016
41. • 8 Regular failures
• Expected to happen regularly
• 4 Repeated failures
• Expected to happen in a low frequency
• 2 Occasional failures
• Expected to happen infrequently
• 1 Unlikely failures
• Unlikely to happen
9/17/2015. 418/27/2016
42. • 4 Normally not detected
• Failure very likely to be overlooked, hence not detected
(no technical solution, no manual control)
• 3 Likely not detected
• Failure may be overseen
(manual control, spot checks)
• 2 Regularly detected
• Failure will normally be detected
(manual control, routine work with statistical control)
• 1 Always detected
• Failure can and will be detected in all cases
(monitoring, technical solution available)
428/27/2016
44. Severity (S)
◦ Link to end product functional failure
◦ Medical Department involvement
Probability (P)
◦ Use historical data
◦ Similar processes products
Detection
◦ Validation studies
◦ Historical data
Drying Process
448/27/2016
45. Rankin
g
Severity (S) Probability (P) Detection (D)
10 Death More than once a day Impossible to detect
9 ↓ 3 – 4 times a day Remote
8 Permanent injury Once a week Very slight
7 ↓ Once a month Slight
6 Temporary injury Once in three month Low
5 ↓ Once in half – one year Medium
4
Reported/
dissatisfied
Once a year Moderately high
3 ↓ Once in 1 – 3 years High
2 Notice/ no report Once in 3 – 5 years Very High
1 ↓
Less than once in 5
years
Virtually certain
Drying Process
9/17/2015. 45
46. Process
Potential Failure
Mode
Potential Cause S P D RPN
1. Set up Contamination Disheveled gown of operator
Insufficient cleaning of
equipment
2. Start
drying
Contamination Damage of inlet-air filter
Degradation of
product
Damage of thermometer
3. Maintain
temperature
Long drying time Unstable supply-air volume
High Loss On Drying
(LOD)
Damage of timer
Low LOD High dew-point
Non-uniformity of
LOD
Uneven temperature
distribution
Drying Process RPN: Risk Priority Number = S*P*D
47. Existing controls: IPC of LOD and degradation product after drying process
Drying Process
Process
Potential Failure
Mode
Potential Cause S P D RPN
1. Set up Contamination Disheveled gown of operator 3 5 8 120
Insufficient cleaning of
equipment
7 2 8 112
2. Start
drying
Contamination Damage of inlet-air filter 7 3 6 126
Degradation of
product
Damage of thermometer 7 3 3 63
3. Maintain
temperature
Long drying time Unstable supply-air volume 2 4 5 40
High LOD Malfunction of timer 2 2 2 8
Low LOD High due-point 3 3 3 27
Non-uniformity of
LOD
Uneven temperature
distribution
3 5 3 45
RPN: Risk Priority Number = S*P*D
48. Take action when RPN is over 100
Take action when severity is over 5
Remaining critical parameters after taking action; further controls required
Drying Process
Process Potential Cause RPN Recommended Action S P D RPN
1. Set up Disheveled gown of
operator
120 Use long gloves and
goggles
3 2 8 48
Insufficient cleaning of
equipment
112 Change cleaning procedure 7 2 4 56
2. Start
drying
Damage of inlet-air filter 126 Change maintenance
period
7 2 6 84
Damage of thermometer 63 Change calibration period 7 2 3 42
3.Maintain
temperature
Unstable supply-air
volume
40 ― 2 4 5 40
Malfunction of timer 8 ― 2 2 2 8
High dew-point 27 ― 3 3 3 27
Uneven temperature
distribution
45 ― 3 5 3 45
RPN: Risk Priority Number = S*P*D
49. Should risks
be assessed?
Are there clear rules
for decision making?
e.g. regulations
Yes
“no RM“
Risk assessment not required
(No flexibility)
Follow procedures
(e.g. Standard Operating Procedures)
Document results,
decisions and actions
CONSIDERATIONS
www.drugregulations.org 49
50. §211.25 Personnel qualifications. ( a)
◦ Each person engaged in the manufacture, processing, packing, or
holding of a drug product shall have education, training, …………..
◦ Training in cGMP shall be conducted by qualified individuals on a
continuing basis and with sufficient frequency ……………..
§211.160 General requirements.
◦ Any deviation from the written specifications, standards, sampling
plans, test procedures, or other laboratory control mechanisms
shall be recorded and justified.
9/17/2015. 508/27/2016
51. §211.192 Production record review.
◦ Any unexplained discrepancy … shall be thoroughly investigated,
….......
◦ The investigation shall extend to other batches …...........
§211.46 Ventilation, air filtration, air heating and cooling.
◦ (d) Air-handling systems for the manufacture, processing, and
packing of penicillin shall be completely separate from those for
other drug products for human use.
9/17/2015. 518/27/2016
52. Should risks
be assessed?
Are there clear rules
for decision making?
e.g. regulations
Yes
“no RM“
Risk assessment not required
(No flexibility)
Follow procedures
(e.g. Standard Operating Procedures)
Document results,
decisions and actions
CONSIDERATIONS
1. What might go wrong?
2. What is the likelihood (probability)
it will go wrong?
3. What are the consequences (severity)?No or
justification needed
Can you answer
the risk assessment
questions?
Yes
“informal RM“
Initiate Risk assessment
(risk identification, analysis & evaluation)
Run risk control
(select appropriate measures)
Agree on a team
(small project)
Select a Risk Management tool
(if appropriate e.g. see ICH Q9 Annex I)
No
“formal RM“
Carry out the
quality risk management process
Document the steps
www.drugregulations.org 52