This presentation from IVT's 2nd Annual Validation Week Canada covers the 2011 FDA Process validation and the subsequent statistical processes. Statistics in process validation is introduced as well as the integration with six sigma and solutions to common mistakes.
Validation: Validation is a documented program that provides high degree of assurance that a specific process, method or system consistently produces a result meeting pre-determined acceptance criteria.
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.
FDA’s emphasis on quality by design began with the recognition that increased testing does not improve product quality (this has long been recognized in other industries).In order for quality to increase, it must be built into the product. To do this requires understanding how formulation and manufacturing process variables influence product quality.Quality by Design (QbD) is a systematic approach to pharmaceutical development that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management.
This presentation - Part IV in the series- deals with the concepts of Design Space, Design of experiments and Models. This presentation was compiled from material freely available from FDA , ICH , EMEA and other free resources on the world wide web.
quality assurance, quality control, total quality management UNIT 1, b pharma 6th sem
Quality management in the drug industry
Why quality is important in pharmaceuticals?
Impacts of ignorance on quality
Quality control
Role of quality control in pharmaceutical industry
Objectives of quality control
Components of quality control
Functions of qc in pharmaceutical industry
Quality assurance
Total quality management
Characteristics of tqm
Benefits of tqm:
Process Validation is Key important factor for the Pharmaceutical Industry to maintain Consistent Quality in product which claimed by the manufacturer.
Validation: Validation is a documented program that provides high degree of assurance that a specific process, method or system consistently produces a result meeting pre-determined acceptance criteria.
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.
FDA’s emphasis on quality by design began with the recognition that increased testing does not improve product quality (this has long been recognized in other industries).In order for quality to increase, it must be built into the product. To do this requires understanding how formulation and manufacturing process variables influence product quality.Quality by Design (QbD) is a systematic approach to pharmaceutical development that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management.
This presentation - Part IV in the series- deals with the concepts of Design Space, Design of experiments and Models. This presentation was compiled from material freely available from FDA , ICH , EMEA and other free resources on the world wide web.
quality assurance, quality control, total quality management UNIT 1, b pharma 6th sem
Quality management in the drug industry
Why quality is important in pharmaceuticals?
Impacts of ignorance on quality
Quality control
Role of quality control in pharmaceutical industry
Objectives of quality control
Components of quality control
Functions of qc in pharmaceutical industry
Quality assurance
Total quality management
Characteristics of tqm
Benefits of tqm:
Process Validation is Key important factor for the Pharmaceutical Industry to maintain Consistent Quality in product which claimed by the manufacturer.
FDA Process Validation Guidance (Guidance for Industry: Process Validation- General Principles and Practices, Jan. 2011) outlines process validation activities in three stages - Stage 1: Process Design, Stage 2: Process Qualification and Stage 3: Continued Process Verification. Completion of Stage 2 subsequent to Stage 1 is a major milestone in the Process Validation Lifecycle as it confirms the process design and demonstrates the expected consistent performance of the manufacturing process. Knowledge and information gained from the design stage through the process qualification stage is used to complete this assessment. Stage 2 demonstrates suitability for successful commercial distribution where the data indicates that the process meets the conditions established in the protocol. Continued Process Verification is initiated for the subsequent commercial batches. Stage 3 assures that the process remains in a state of control during commercial manufacture.
This presentation gives a practical approach to implement the stage 3 of the FDA Process Validation Guide.
The presentation is about basic statistical techniques and how statistics can be used effectively in the quality control and process control. It also presents statistical package Minitab version 16 and some of its applications in the field of statistical process control.
Six sigma aims to reduce defects and conform to customer specifications. To make sure that each project adheres to customer specifications Adev Research assists your organization focus on process improvements and variation reduction.
Use SAS to identify what tell-tale signs in consumers’ credit history would best model the bad consumers, and, in turn, use this as a way to prevent potential future bad consumers from getting approved for lines of credit.
Quality Management: Nature of Inspection; Quality Control; Statistical Quality Control (SQC); Types of Control Charts; Acceptance Sampling Technique; Total Quality Management; What is Quality Management? Modern Quality Management;
Measurement System Analysis is the first step of the Measure Phase of an improvement project. Before you can pass judgment on the process, you need to ensure that your measurement system is accurate, precise, capable and in control.
In this presentation from, Janeen Santorosa discusses the best practices for harmonization of GMP auditing, domestic and international regulations for supplier auditing, integration of risk-based practices, and supplier audit practice tools.
In this presentation from IVT's 4th Annual Validation Week EU, Paul Pluta, discussed the differences between the traditional approach to cleaning validation and the lifecycle approach, applicable regulatory guidance, current industry trends, the necessary phases of the lifecycle approach (design and definition, cycle development, validation, and implementation), how to continously monitor the process, change control, and common obstacles to compliance.
This session from the Institute of Validation Technology's 14th Annual CSV Conference looks at B. Braun’s journey in moving from an in-house validated training tracking system to learning management in the cloud.
In this session from the Institute of Validation Technology's Validation Week Europe, Kurtis Epp and John Kandl discuss how to implement QbD to all three stages of process validation.
This presentation from the Institute of Validation Technology's first annual Validation and cGMP Compliance Week Singapore discusses the obstacles to quality such, the key components to improve quality, and the tools for strategic teamwork.
This session from the Institute of Validation Technology's Contamination and Control Week discusses regulatory expectations and industry drivers for aseptic cleaning and environmental monitoring, regulatory expectations for cleanrooms, and current FDA and EU expectations during inspection of sterile and aseptic operations.
In this presentation from the Institute of Validation Technology's Life Sciences Aseptic Processing, Kim Van Antwerpen discusses collecting environmental data, methods for trending, and interpreting and sharing environmental monitoring data.
Regulatory inspections have had a significant impact on the number of drug shortages and companies facing adverse regulatory actions.
Review of the inspection trends can be useful in assessing the regulatory status of your own company and help aid in the preparation for upcoming inspections. This session from IVT's Contamination and Control Week provides an in-depth, practical look at some of the recent Warning Letters and discusses current trends.
The Validation Master Plan is a a valuable opportunity to provide an overview of your company’s validation process, including organization structure, content, and planning.
Regulatory guidelines on stability testing are mainly designed to address studies that will be applied to support NDAs. However, in any pharmaceutical development program, a number of other stability studies are also required, for example, to help select appropriate formulations and to support regulatory applications for clinical programs. This session from the Institute of Validation Technology's Stability Programs Forum outlines a number of examples of early development stability studies.
This presentation from IVT's 4th Annual reviews what to do when you have an exception, critical vs. non-critical exceptions, and learning how to prevent exceptions.
This presentation from IVT's 4th Annual Validation Week Europe provided a thorough explanation of developing a gap analysis, areas in validation that are issues of concern, and FDA expectations of a manufacturer's gap analysis.
In this presentation from Validation Week Europe, Karen Ginsbury discusses the rigors, preparations, strategies, and the do's and the don't of the FDA Inspection process.
This workshop examines the approach to Continued Process Verification and demonstrating that your product and process are operating in a state of control and continue to do so over the life of the product. Without any prior coordination, the theme was elaborated by the afternoon speakers once the conference itself was underway. The concept of “step up step down” for adjusting the level of product scrutiny both for process parameters monitoring and for sampling and testing quality attributes was explored and developed.
In this presentation from IVT's GMP Week, Journal of Validation Technology Editor-in-Chief, Paul Pluta, Ph.D., asks "can compliance be improved by using quality by design [QbD] concepts?" Pluta discussed the QbD application, development of validation master plans, and the lifecycle approach to process validation. Furthermore, he discusses how to incorporate these essential parts of the validation process to implement effective, and efficient, compliance by design into the quality system.
A comprehensive presentation on GMP systems and integration. This includes validations, vendor qualification, preventative maintenance, audits, CAPA, and utilization of system results.
This presentation from IVT Network's Method Validation Conference covers required and suggested regulations and guidances for biological process specifications. It also covers dosage form considerations and specifications for other components.
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
Report Back from SGO 2024: What’s the Latest in Cervical Cancer?bkling
Are you curious about what’s new in cervical cancer research or unsure what the findings mean? Join Dr. Emily Ko, a gynecologic oncologist at Penn Medicine, to learn about the latest updates from the Society of Gynecologic Oncology (SGO) 2024 Annual Meeting on Women’s Cancer. Dr. Ko will discuss what the research presented at the conference means for you and answer your questions about the new developments.
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.
New Directions in Targeted Therapeutic Approaches for Older Adults With Mantl...i3 Health
i3 Health is pleased to make the speaker slides from this activity available for use as a non-accredited self-study or teaching resource.
This slide deck presented by Dr. Kami Maddocks, Professor-Clinical in the Division of Hematology and
Associate Division Director for Ambulatory Operations
The Ohio State University Comprehensive Cancer Center, will provide insight into new directions in targeted therapeutic approaches for older adults with mantle cell lymphoma.
STATEMENT OF NEED
Mantle cell lymphoma (MCL) is a rare, aggressive B-cell non-Hodgkin lymphoma (NHL) accounting for 5% to 7% of all lymphomas. Its prognosis ranges from indolent disease that does not require treatment for years to very aggressive disease, which is associated with poor survival (Silkenstedt et al, 2021). Typically, MCL is diagnosed at advanced stage and in older patients who cannot tolerate intensive therapy (NCCN, 2022). Although recent advances have slightly increased remission rates, recurrence and relapse remain very common, leading to a median overall survival between 3 and 6 years (LLS, 2021). Though there are several effective options, progress is still needed towards establishing an accepted frontline approach for MCL (Castellino et al, 2022). Treatment selection and management of MCL are complicated by the heterogeneity of prognosis, advanced age and comorbidities of patients, and lack of an established standard approach for treatment, making it vital that clinicians be familiar with the latest research and advances in this area. In this activity chaired by Michael Wang, MD, Professor in the Department of Lymphoma & Myeloma at MD Anderson Cancer Center, expert faculty will discuss prognostic factors informing treatment, the promising results of recent trials in new therapeutic approaches, and the implications of treatment resistance in therapeutic selection for MCL.
Target Audience
Hematology/oncology fellows, attending faculty, and other health care professionals involved in the treatment of patients with mantle cell lymphoma (MCL).
Learning Objectives
1.) Identify clinical and biological prognostic factors that can guide treatment decision making for older adults with MCL
2.) Evaluate emerging data on targeted therapeutic approaches for treatment-naive and relapsed/refractory MCL and their applicability to older adults
3.) Assess mechanisms of resistance to targeted therapies for MCL and their implications for treatment selection
Flu Vaccine Alert in Bangalore Karnatakaaddon Scans
As flu season approaches, health officials in Bangalore, Karnataka, are urging residents to get their flu vaccinations. The seasonal flu, while common, can lead to severe health complications, particularly for vulnerable populations such as young children, the elderly, and those with underlying health conditions.
Dr. Vidisha Kumari, a leading epidemiologist in Bangalore, emphasizes the importance of getting vaccinated. "The flu vaccine is our best defense against the influenza virus. It not only protects individuals but also helps prevent the spread of the virus in our communities," he says.
This year, the flu season is expected to coincide with a potential increase in other respiratory illnesses. The Karnataka Health Department has launched an awareness campaign highlighting the significance of flu vaccinations. They have set up multiple vaccination centers across Bangalore, making it convenient for residents to receive their shots.
To encourage widespread vaccination, the government is also collaborating with local schools, workplaces, and community centers to facilitate vaccination drives. Special attention is being given to ensuring that the vaccine is accessible to all, including marginalized communities who may have limited access to healthcare.
Residents are reminded that the flu vaccine is safe and effective. Common side effects are mild and may include soreness at the injection site, mild fever, or muscle aches. These side effects are generally short-lived and far less severe than the flu itself.
Healthcare providers are also stressing the importance of continuing COVID-19 precautions. Wearing masks, practicing good hand hygiene, and maintaining social distancing are still crucial, especially in crowded places.
Protect yourself and your loved ones by getting vaccinated. Together, we can help keep Bangalore healthy and safe this flu season. For more information on vaccination centers and schedules, residents can visit the Karnataka Health Department’s official website or follow their social media pages.
Stay informed, stay safe, and get your flu shot today!
MANAGEMENT OF ATRIOVENTRICULAR CONDUCTION BLOCK.pdfJim Jacob Roy
Cardiac conduction defects can occur due to various causes.
Atrioventricular conduction blocks ( AV blocks ) are classified into 3 types.
This document describes the acute management of AV block.
Tom Selleck Health: A Comprehensive Look at the Iconic Actor’s Wellness Journeygreendigital
Tom Selleck, an enduring figure in Hollywood. has captivated audiences for decades with his rugged charm, iconic moustache. and memorable roles in television and film. From his breakout role as Thomas Magnum in Magnum P.I. to his current portrayal of Frank Reagan in Blue Bloods. Selleck's career has spanned over 50 years. But beyond his professional achievements. fans have often been curious about Tom Selleck Health. especially as he has aged in the public eye.
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Introduction
Many have been interested in Tom Selleck health. not only because of his enduring presence on screen but also because of the challenges. and lifestyle choices he has faced and made over the years. This article delves into the various aspects of Tom Selleck health. exploring his fitness regimen, diet, mental health. and the challenges he has encountered as he ages. We'll look at how he maintains his well-being. the health issues he has faced, and his approach to ageing .
Early Life and Career
Childhood and Athletic Beginnings
Tom Selleck was born on January 29, 1945, in Detroit, Michigan, and grew up in Sherman Oaks, California. From an early age, he was involved in sports, particularly basketball. which played a significant role in his physical development. His athletic pursuits continued into college. where he attended the University of Southern California (USC) on a basketball scholarship. This early involvement in sports laid a strong foundation for his physical health and disciplined lifestyle.
Transition to Acting
Selleck's transition from an athlete to an actor came with its physical demands. His first significant role in "Magnum P.I." required him to perform various stunts and maintain a fit appearance. This role, which he played from 1980 to 1988. necessitated a rigorous fitness routine to meet the show's demands. setting the stage for his long-term commitment to health and wellness.
Fitness Regimen
Workout Routine
Tom Selleck health and fitness regimen has evolved. adapting to his changing roles and age. During his "Magnum, P.I." days. Selleck's workouts were intense and focused on building and maintaining muscle mass. His routine included weightlifting, cardiovascular exercises. and specific training for the stunts he performed on the show.
Selleck adjusted his fitness routine as he aged to suit his body's needs. Today, his workouts focus on maintaining flexibility, strength, and cardiovascular health. He incorporates low-impact exercises such as swimming, walking, and light weightlifting. This balanced approach helps him stay fit without putting undue strain on his joints and muscles.
Importance of Flexibility and Mobility
In recent years, Selleck has emphasized the importance of flexibility and mobility in his fitness regimen. Understanding the natural decline in muscle mass and joint flexibility with age. he includes stretching and yoga in his routine. These practices help prevent injuries, improve posture, and maintain mobilit
Title: Sense of Smell
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 primary categories of smells and the concept of odor blindness.
Explain the structure and location of the olfactory membrane and mucosa, including the types and roles of cells involved in olfaction.
Describe the pathway and mechanisms of olfactory signal transmission from the olfactory receptors to the brain.
Illustrate the biochemical cascade triggered by odorant binding to olfactory receptors, including the role of G-proteins and second messengers in generating an action potential.
Identify different types of olfactory disorders such as anosmia, hyposmia, hyperosmia, and dysosmia, including their potential causes.
Key Topics:
Olfactory Genes:
3% of the human genome accounts for olfactory genes.
400 genes for odorant receptors.
Olfactory Membrane:
Located in the superior part of the nasal cavity.
Medially: Folds downward along the superior septum.
Laterally: Folds over the superior turbinate and upper surface of the middle turbinate.
Total surface area: 5-10 square centimeters.
Olfactory Mucosa:
Olfactory Cells: Bipolar nerve cells derived from the CNS (100 million), with 4-25 olfactory cilia per cell.
Sustentacular Cells: Produce mucus and maintain ionic and molecular environment.
Basal Cells: Replace worn-out olfactory cells with an average lifespan of 1-2 months.
Bowman’s Gland: Secretes mucus.
Stimulation of Olfactory Cells:
Odorant dissolves in mucus and attaches to receptors on olfactory cilia.
Involves a cascade effect through G-proteins and second messengers, leading to depolarization and action potential generation in the olfactory nerve.
Quality of a Good Odorant:
Small (3-20 Carbon atoms), volatile, water-soluble, and lipid-soluble.
Facilitated by odorant-binding proteins in mucus.
Membrane Potential and Action Potential:
Resting membrane potential: -55mV.
Action potential frequency in the olfactory nerve increases with odorant strength.
Adaptation Towards the Sense of Smell:
Rapid adaptation within the first second, with further slow adaptation.
Psychological adaptation greater than receptor adaptation, involving feedback inhibition from the central nervous system.
Primary Sensations of Smell:
Camphoraceous, Musky, Floral, Pepperminty, Ethereal, Pungent, Putrid.
Odor Detection Threshold:
Examples: Hydrogen sulfide (0.0005 ppm), Methyl-mercaptan (0.002 ppm).
Some toxic substances are odorless at lethal concentrations.
Characteristics of Smell:
Odor blindness for single substances due to lack of appropriate receptor protein.
Behavioral and emotional influences of smell.
Transmission of Olfactory Signals:
From olfactory cells to glomeruli in the olfactory bulb, involving lateral inhibition.
Primitive, less old, and new olfactory systems with different path
- Video recording of this lecture in English language: https://youtu.be/lK81BzxMqdo
- Video recording of this lecture in Arabic language: https://youtu.be/Ve4P0COk9OI
- Link to download the book free: https://nephrotube.blogspot.com/p/nephrotube-nephrology-books.html
- Link to NephroTube website: www.NephroTube.com
- Link to NephroTube social media accounts: https://nephrotube.blogspot.com/p/join-nephrotube-on-social-media.html
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.
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
4. PV GUIDELINES
• statistical tools to be used in • Emphasis on process design
the analysis of data elements, and maintaining
• the number of process runs process control based on
carried out and observations knowledge gained throughout
made should be sufficient to commercialization
allow the normal extent of • Emphasize to have good
variation and trends to be knowledge to detect and to
established to provide control variability through use
sufficient data for evaluation. of statistical analysis
4
5. PROCESS VALIDATION LIFE CYCLE
Variation analysis, capability,
Stage 2: Process
stability analysis
Qualification
Stage 1: Process
Design
Statistics to
analyze and
optimize
results (DOE,
variation
analysis, etc)
Process Capability
Stage 3: Process Monitoring Control Charts
and Improvement
5
6. PROCESS UNDERSTANDING
Testing the final
product and passing
specifications does
not give knowledge
of the process
Variation at each production
stage
Knowledge of stability and
capability
6
7. PROCESS UNDERSTANDING – KNOW VARIATION
“Understanding variation is the key to success in
quality and business” W. Edwards Deming (Father of
Modern Process Control)
The customers “feel” variation and lack of
consistency in a product much more so than the
“average” (Jack Welch)
7
8. FDA PV GUIDANCE RECOMMENDATIONS
INTEGRATED TEAM APPROACH
industrial
pharmacy
Recommended that a statistician quality or
process assurance
person with adequate training in
engineering
and statistical process control technique
manufacturing analytical
develop the data collection plan and
chemistry
statistical methods and procedures
used in measuring and evaluating
microbiology
process stability and process
capability. statistics
8
9. DESCRIPTIVE VS INFERENTIAL
STATISTICS
This distinction is based on
what you’re trying to do with The Division Between
your data Descriptive and
Inferential Statistics
9
10. DESCRIPTIVE STATISTICS
• Summarizing or displaying the facts
Mean = Sum of all observations/ # of
observations
Range = Max - Min
Standard Deviation
Variance = std dev2
Relative Standard Deviation or CV = std
dev*100/mean
10
11. RELATIVE STANDARD DEVIATION
Example 1: Example 2:
Group Size Avg St Dev RSD Group Size Avg St Dev RSD
1 10 80 0.8 1.0 1 10 80 1.0 1.4
2 10 90 0.9 1.0 2 10 90 1.0 1.1
3 10 100 1.0 1.0 3 10 100 1.0 1.0
4 10 110 1.1 1.0 4 10 110 1.0 0.9
5 10 120 1.2 1.0 5 10 120 1.0 0.8
Standard deviation is proportional to the %RSD is changing because the average is
average and the %RSD is unchanged changing, not the standard deviation
11
16. INFERENTIAL STATISTICS
• A decision about the batch is based on a relative
small sample taken since it is not realistic to test the
entire batch.
• To confirm that the data is representative of the
batch, inference statistics (confidence and tolerance
intervals) can be used to predict the true mean.
16
17. CONFIDENCE INTERVAL
• A confidence interval is an interval within which
it is believed the true mean lies
CI = ±
where is sample mean, s is sample standard
deviation, N is the sample size, and t value is a
constant obtained from t-distribution tables
based on the level of confidence.
Note the value of t should correspond to N-1.
17
18. TOLERANCE INTERVAL
• A tolerance interval is an interval within which
it is believed the individual values lie,
TI = ± k*s
where is sample mean, s is sample
standard deviation, N is the sample size, and
k value is a constant obtained from factors for
two-sided tolerance limits for normal
distributions table believed the true mean lies.
18
19. EXAMPLE
A batch of tablets was tested for
content uniformity. The mean
value of 10 tablets tested was
99.1% and a standard deviation
was 2.6%.
19
21. EXAMPLE: Confidence Interval
• CI = ± = 99.1 ± =96.4 to 101.8
• Then we can say that we are 99% certain that
the true batch mean will be between 96.4%
and 101.8 %.
21
23. EXAMPLE: TOLERANCE INTERVAL
• N=10, mean=99.1, s =2.6, k =5.594
TI = ± k*s
• Probability of 99% covering 99% of
data:
TI =99.1 ± (5.594*2.6)
TI = 84.6% to 113.6%
23
24. EXAMPLE: Confidence and Tolerance
Interval
• If a sample has the mean value of 10 tablets
at 99.1% and a standard deviation at 2.6%.
• Then we can say that we are 99% certain that
99% of the tablet content uniformity lies
between 80.6 and 117.6% and we are 99%
certain that the true batch mean will be
between 96.4 and 101.8 %.
24
26. SAMPLING
• The cGMPs mention samples, sampling plans,
or sampling methods repeatedly.
• Firms are expected:
– To use a sampling plan that utilizes basic elements
of statistical analysis
– Provide a scientific rationale for sampling that
would vary the amount of samples taken
according to the lot size
– Define a confidence limit to ensure an accurate
and representative sampling of the product
26
27. WARNING LETTER EXAMPLE
211.165 - Testing and release for distribution:
(d) Acceptance criteria for the sampling and testing conducted by the
quality control unit shall be adequate to assure that batches of drug
products meet each appropriate specification and appropriate
statistical quality control criteria as a condition for their approval and
release. The statistical quality control criteria shall include appropriate
acceptance levels and/or appropriate rejection levels.
“For example, your firm's finished product sampling plan product A is
not representative of the batch produced. A total of 13 units are
sampled per lot, with 3 tested for bacterial endotoxin and 10 tested for
bioburden. This sampling of 13 units is irrespective of lot size, which
may vary from X to Z units (vials) per lot”
27
30. SAMPLING RISK
DISPOSITION IMPACT IF LOT IMPACT IF LOT BAD
GOOD
Lot is accepted Correct Decision Incorrect Decision
(Type II or
Consumer’s risk)
Lot is rejected Incorrect Decision Correct Decision
(Type I or Producer’s
risk)
Expressed as Acceptable Quality Level (AQL): maximum average percent
defective that is acceptable for the product being evaluated.
30
31. ACCEPTANCE SAMPLING
Acceptance Sampling is a form of inspection applied to lots or
batches of items before or after a process to judge
conformance to predetermined standards.
Sampling Plans specify the lot size, sample size, number of
samples and acceptance/rejection criteria.
Lot Random sample 31
32. OPERATING CHARACTERISTIC CURVE
• The operating-characteristic (OC) curve measures the
performance of an acceptance-sampling plan.
• The OC curve plots the probability of accepting the lot
versus the lot fraction defective.
• The OC curve shows the probability that a lot
submitted with a certain fraction defective will be
either accepted or rejected.
32
33. OC CURVES
Ideal OC Curve
Reject all lots with more than 2.5%
defective and accept all lots with less
than 2.5% defective
The only way to assure is 100%
inspection
100
90
acceptance (%)
80
Probability of
70
60
50
40
30
20
10
1 1.5 2 2.5 3 3.5
Percent defective (%) 33
34. OCCs for Single Sampling Plans
An Operating Characteristic Curve (OCC) is a probability curve for a sampling plan that
shows the probabilities of accepting lots with various lot quality levels (% defectives).
1
0.9 Under this sampling plan, if the lot has 3% defective
Probability of accepting lot
the probability of accepting the lot is 90%
0.8
the probability of rejecting the lot is 10%
0.7
0.6
0.5 If the lot has 20% defective
0.4 it has a small probability (5%) of being accepted
0.3 the probability of rejecting the lot is 95%
0.2
0.1
0
0 .05 .10 .15 .20 Lot quality (% defective)
34
35. SAMPLING PLANS
Sampling plans involve:
Single sampling
Double sampling
Multiple sampling
Provisions for each type of sampling plan include
1. Normal inspection
2. Tightened inspection
3. Reduced inspection
35
36. SWITCHING RULES
“and” conditions: 2 out of 5
Production Steady Start
consecutive
10 consecutive lots lots rejected
accepted
Approved by
responsibility
authority
Tightened
Reduced Normal
5
consecutive
“or” conditions: lots
accepted 10 consecutive
Lot rejected
lots remain on
Irregular production
tightened
A lot meets neither
inspection
the accept nor the
reject criteria
Other conditions Discontinue
warrant return to inspection
normal inspection
36
37. SAMPLING BY ATTRIBUTES: ANSI Z1.4 2008
• The acceptable quality level (AQL) is a primary
focal point of the standard
• The AQL is generally specified in the contract or
by the authority responsible for sampling.
• Different AQLs may be designated for different
types of defects (critical, major, minor).
• Tables for the standard provided are used to
determine the appropriate sampling scheme.
37
38. ANSI Z1.4 2008
PROCEDURE:
1. Choose the AQL
2. Choose the inspection level
3. Determine the lot size
4. Find the appropriate sample size code
letter from Table I-Sample Size Code Letters
5. Determine the appropriate type of
sampling plan to use (single, double,
multiple)
6. Check the appropriate table to find the
acceptance criteria.
38
39. SAMPLE SIZE DETERMINATION
Table I - Sample Size Letter Codes
Special Inspection Levels General Inspection Levels
Lot or Batch Size S-1 S-2 S-3 S-4 I II III
2 to 8 A A A A A A B
9 to 15 A A A A A B C
16 to 25 A A B B B C D
26 to 50 A B B C C D E
51 to 90 B B C C C E F
91 to 150 B B C D D F G
151 to 280 B C D E E G H
281 to 500 B C D E F H J
501 to 1200 C C E F G J K
1201 to 3200 C D E G H K L
3201 to 10000 C D F G J L M
10001 to 35000 C D F H K M N
35001 to 150000 D E G J L N P
150001 to 500000 D E G J M P Q
500001 to over D E H K N Q R
39
41. SINGLE SAMPLING PLAN - EXAMPLE
Defect: any color except of red
N = lot size = 25 apples
From Sample Size Code Letters:
Lot or batch size General Inspection
Level
16-25 B
From Normal Single Level Inspection
Sampling Sample Size AQL 0.010
Size Code
Letter
B 3 0/1 Scenario 1: Scenario 2:
0 defects 2 defects
n = sample size =3 Accept Reject
41
C=acceptance number = 0 Accept/1 Reject
42. SINGLE SAMPLING PLAN - EXAMPLE
N = lot size = 120,000
From Sample Size Code Letters:
Lot or batch size General Inspection
Level
35,001-150,000 N
Normal Inspection
From Normal Single Level Inspection
Sampling Size Sample Critical Major Minor
Code Letter Size AQL 0.010 AQL 0.65 AQL 4.0
N 500 ACC 0 / REJ 1 ACC 7/ REJ 8 ACC 21 / REJ 22
42
43. STATISTICAL PROCESS CONTROL
• The principle of SPC analysis is to understand
the process and detect the process change.
• Statistical Process Control (SPC) charts are
used to detect process variation.
43
44. STATISTICAL PROCESS CONTROL
• The Current Good Manufacturing Practices for
Process Validation published by the FDA in
January 2011 states "homogeneity within a
batch and consistency between batches are
goals of process validation activities." Control
charts explicitly compare the variation within
subgroups to the variation between
subgroups, making them very suitable tools
for understanding processes over time
(stability).
44
45. VARIABLE CONTROL CHARTS
n=1 2<n<9 n is ‘small’ n is ‘large’
median 3<n<5 n > 10
X & Rm X&R X&R X&S
Used for measured data
45
46. CONTROL CHART SELECTION: ATTRIBUTE DATA
Defect or Defective Data
Nonconformity Data
Constant Variable Constant Variable
Sample Size Sample Size n > 50 n > 50
C chart u chart p or np chart p chart
Used for count (attribute) data 46
47. Stable and Unstable Processes
A stable (or “in
control”) process is UCL
one in which the
key process
responses show no
signs of special LCL
causes.
An unstable (or UCL
“out of control”)
process has both
common and
special causes LCL
present.
47
48. CONTROL CHART
Tablet Weight
305
UCL
303.7
302
300 mean
298.0
296.3 LCL
285
280
1 hr 30 2hr 30
0 min 30 min 1 hr min 2 hr min
48
49. PROCESS CAPABILITY
• Is the process capable of consistently
delivering quality products?
• Is the process design confirmed as being
capable of reproducible commercial
manufacturing?
• Process capability is expressed as a ratio of
specifications/process variability
49
51. PROCESS CAPABILITY
Accurate and precise Accurate but not precise Precise but not accurate
Desired Desired
Desired Current
Current Situation
Situation
LSL T USL LSL T USL LSL T USL
51
52. PROCESS CAPABILITY INDECES
• Short-term (Cp and Cpk) and/or long term (Pp
and Ppk) are commonly used to evaluate
process performance.
• Cpk attempts to answer the question "does
my current production sample meet
specification?"
• Ppk attempts to answer the question "does
my process in the long run meet
specification?"
52
54. PROCESS CAPABILITY
• At a minimum, 50 individual values or 25
subgroups for sub-grouped data are required
to calculate process capability; and 100
individual values provide a stronger basis for
the assessment.
• Use SPC charts to check if the process is stable
• Check the distribution (normal vs not normal)
• Use the Cpk value which represents the
process under consideration
54
55. PROCESS CAPABILITY EXAMPLE
• A client had to meet Cpk requirement of ≥
1.20.
• When data was assumed to be normally
distributed, the Cpk =0.8
• When the non-normal behavior was
accounted for, the Cpk = 1.22
55
56. SIX SIGMA AND PROCESS VALIDATON
• Six Sigma and Process
Validation
• Use the process
knowledge to make
improvements
56
57. SIX SIGMA AND PROCESS VALIDATON
Six Sigma – process improvement methodology
DMAIC
Define Objective To improve compression
process
Measure Measure hardness during PV
Analyze Statistical analysis, calculate Cp/Cpk
Improve Decrease variation
Control Control variation
57
59. COMMON MISTAKES
• Incorrect use of statistical tools:
– ANSI Attribute Sampling for measurement data
(pH)
– Incorrect sampling size
– Distribution is not checked
– Process in not stable
– Incorrect uses of Cpk (equivalency between
equipment, large specification limits, etc)
59
60. WARNING LETTER: EQUIPMENT
COMPARABILITY AND CAPABILITY
• The firm referenced the Cpk values for processes using a double-sided
tablet press and the single-sided tablet press to demonstrate statistical
equivalence.
• FDA evaluation :
– The Cpk value alone was not appropriate metric to demonstrate
statistical equivalence. Cpk analysis requires a normal underlying
distribution and a demonstrated state of statistical process control.
– Statistical equivalence between the two processes could have been
shown by using either parametric or non-parametric (based on
distribution analysis) approaches and comparing means and variances.
– Firm did not use the proper analysis to support their conclusion that
no significant differences existed between the two compression
processes.
60
61. STATISTICAL EVALUATION
• Is required by statute
• Is an expectation of the regulatory inspector
during inspection of the firm as it relates to
process validation of products
• Use statistical tools that are meaningful and
useful to understand the baseline
performance of the process
• Is invaluable as a troubleshooting tool post
validation
61