This document discusses cleaning validation for pharmaceutical manufacturing equipment. It defines cleaning validation as removing contaminants from equipment to safely reuse it. Inadequate cleaning can leave residues that contaminate subsequent batches. A cleaning validation protocol should include the equipment, cleaning procedure, sampling methods, analytical testing, and acceptance criteria. Acceptance criteria may be based on visual inspections, chemical residue limits, or microbiological limits. Worst-case considerations and grouping strategies can help determine representative samples for validation.
In this presentation from CPhi 2014, Elise Gallais outlines the guidelines for cleaning validation: and focuses on analytical methods and their validation.
The presentation was an overview of the GMP regulations specific to cleaning validation for medicine manufacturers. New guidelines for Health Based Exposure Limits were discussed along with common GMP deficiencies observed during TGA inspections.
The subject of cleaning validation in active pharmaceutical ingredient manufacturing plants has continued to receive a large amount of attention from regulators, companies and customers alike.
The integration of Cleaning Validation within an effective Quality System supported by Quality Risk Management Processes should give assurance that API Manufacturing Operations are performed in such a way that Risks to patients related to cleaning validation are understood, assessed for impact and are mitigated as necessary.
It is important that the requirements for the finished manufacturing companies are not transferred back in the process to active pharmaceutical ingredient manufacturers without consideration for the different processes that take place at this stage.
This presentation covers the requirements of Cleaning Validation for a Multipurpose API Manufactuirng Plant
It is process of “Establishing documentary evidence that provide a high degree of assurance that a specific process will consistently produce a product meeting its predetermined specifications and quality attributes”.
In the pharmaceutical industry, it is very important that in addition to final testing and compliance of products, it is also assured that the process will consistently produce the expected results.
Validation is action of proving in accordance with the principles of good manufacturing practices, that any procedure, process, equipment, material, activity or system actually leads to expected results.
Cleaning validation is documented evidence with a high degree assurance that one can consistently clean a system or a piece of equipment to predetermined and acceptable limits.
The primary regulatory concern driving the need for cleaning validation is cross contamination of the desired drug substance either by other API from previous batch runs or by residues from the cleaning agents used.
The prime purpose of validating a cleaning process is to ensure compliance with federal and other standard regulations
1. Cross contamination with active ingredients
Contamination of one batch of product with significant levels of residual active ingredients from previous batch cannot be tolerated.
In addition to the obvious problems posed by subjecting consumers or patients to unintended contaminants, potential clinically significant synergistic interactions between pharmacologically active chemicals are a real concern.
2. Contamination with unintended materials or compounds
While inert ingredients used in drug products are generally recognized as safe for human consumption, the routine use, maintenance and cleaning of equipment's provide the potential contamination with such items as equipment parts, lubricants and chemical cleaning agents3. Microbiological contamination
Maintenance , cleaning and storage conditions may provide adventitious microorganisms with the opportunity to proliferate within the processing equipment.
Cleaning validation is one of the major and critical activity in pharmaceutical operations
The four basic requirement of cGmp are …
Identity
Safety*
Strength
Purity*
In this presentation from CPhi 2014, Elise Gallais outlines the guidelines for cleaning validation: and focuses on analytical methods and their validation.
The presentation was an overview of the GMP regulations specific to cleaning validation for medicine manufacturers. New guidelines for Health Based Exposure Limits were discussed along with common GMP deficiencies observed during TGA inspections.
The subject of cleaning validation in active pharmaceutical ingredient manufacturing plants has continued to receive a large amount of attention from regulators, companies and customers alike.
The integration of Cleaning Validation within an effective Quality System supported by Quality Risk Management Processes should give assurance that API Manufacturing Operations are performed in such a way that Risks to patients related to cleaning validation are understood, assessed for impact and are mitigated as necessary.
It is important that the requirements for the finished manufacturing companies are not transferred back in the process to active pharmaceutical ingredient manufacturers without consideration for the different processes that take place at this stage.
This presentation covers the requirements of Cleaning Validation for a Multipurpose API Manufactuirng Plant
It is process of “Establishing documentary evidence that provide a high degree of assurance that a specific process will consistently produce a product meeting its predetermined specifications and quality attributes”.
In the pharmaceutical industry, it is very important that in addition to final testing and compliance of products, it is also assured that the process will consistently produce the expected results.
Validation is action of proving in accordance with the principles of good manufacturing practices, that any procedure, process, equipment, material, activity or system actually leads to expected results.
Cleaning validation is documented evidence with a high degree assurance that one can consistently clean a system or a piece of equipment to predetermined and acceptable limits.
The primary regulatory concern driving the need for cleaning validation is cross contamination of the desired drug substance either by other API from previous batch runs or by residues from the cleaning agents used.
The prime purpose of validating a cleaning process is to ensure compliance with federal and other standard regulations
1. Cross contamination with active ingredients
Contamination of one batch of product with significant levels of residual active ingredients from previous batch cannot be tolerated.
In addition to the obvious problems posed by subjecting consumers or patients to unintended contaminants, potential clinically significant synergistic interactions between pharmacologically active chemicals are a real concern.
2. Contamination with unintended materials or compounds
While inert ingredients used in drug products are generally recognized as safe for human consumption, the routine use, maintenance and cleaning of equipment's provide the potential contamination with such items as equipment parts, lubricants and chemical cleaning agents3. Microbiological contamination
Maintenance , cleaning and storage conditions may provide adventitious microorganisms with the opportunity to proliferate within the processing equipment.
Cleaning validation is one of the major and critical activity in pharmaceutical operations
The four basic requirement of cGmp are …
Identity
Safety*
Strength
Purity*
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.
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.
role of quality system and audit in pharmaceutical manufacturing environment....MridulBindra2
M. pharma quality assurance
role of quality system and audit in pharmaceutical manufacturing environment.
topics covered are as follows
cGMP regulation
quality assurance functions
quality system approach
management responsibility
resources
A vendor audit is a vehicle used by pharmaceutical companies, and other large companies as well, to inspect and evaluate a vendor’s quality management system, as well as its practices, products, and documentation.
The need to conduct vendor audits stems from a higher need for quality control in an industry that needs to be more regulated than any other industry in the world.
Reason why organizations use audits is to reduce cost and improve quality control
The objective of vendor audit is to develop an audit function comprising of qualified resources to effectively perform compliance audits to ensure that the contracts are being executed in accordance with the intent and address the net benefit to include cost recoveries, process improvement savings, fraud improvement and identification of hidden risks.
In order to reduce the cost pharmaceutical companies have increasingly become dependent on their supplier/ out sourcing partners for customer success. Though it has drastically reduced the production cost for companies, there is a heightened supplier risk and lack of visibility into supplier processes.
To gain an insight into supplier process and eliminate the risks, FDA encourages companies to conduct GMP supplier audit at the manufacturing premises of the supplier.
According to GMP code, it is sole responsibility of pharmaceutical industry to ensure that the suppliers manufacturing process, analytical tests and examinations are carried out reliably by the supplier and are in compliances with the applicable standards and regulations.
After the audit supplier must provide an appropriate corrective action plan with measures that that will be implemented by the supplier within a defined time frame to the manufacturer.
Qualification of Dissolution Test Apparatus and Validation of Utility System this presentation will help to enhance your knowledge in validation and qualification area.
According to new syllabus of PCI M.Pharm 1st sem. students can directly utilize this ppt for their study. As per PCI new syllabus QA STUDENTS find this ppt very use full.
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.
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.
role of quality system and audit in pharmaceutical manufacturing environment....MridulBindra2
M. pharma quality assurance
role of quality system and audit in pharmaceutical manufacturing environment.
topics covered are as follows
cGMP regulation
quality assurance functions
quality system approach
management responsibility
resources
A vendor audit is a vehicle used by pharmaceutical companies, and other large companies as well, to inspect and evaluate a vendor’s quality management system, as well as its practices, products, and documentation.
The need to conduct vendor audits stems from a higher need for quality control in an industry that needs to be more regulated than any other industry in the world.
Reason why organizations use audits is to reduce cost and improve quality control
The objective of vendor audit is to develop an audit function comprising of qualified resources to effectively perform compliance audits to ensure that the contracts are being executed in accordance with the intent and address the net benefit to include cost recoveries, process improvement savings, fraud improvement and identification of hidden risks.
In order to reduce the cost pharmaceutical companies have increasingly become dependent on their supplier/ out sourcing partners for customer success. Though it has drastically reduced the production cost for companies, there is a heightened supplier risk and lack of visibility into supplier processes.
To gain an insight into supplier process and eliminate the risks, FDA encourages companies to conduct GMP supplier audit at the manufacturing premises of the supplier.
According to GMP code, it is sole responsibility of pharmaceutical industry to ensure that the suppliers manufacturing process, analytical tests and examinations are carried out reliably by the supplier and are in compliances with the applicable standards and regulations.
After the audit supplier must provide an appropriate corrective action plan with measures that that will be implemented by the supplier within a defined time frame to the manufacturer.
Qualification of Dissolution Test Apparatus and Validation of Utility System this presentation will help to enhance your knowledge in validation and qualification area.
According to new syllabus of PCI M.Pharm 1st sem. students can directly utilize this ppt for their study. As per PCI new syllabus QA STUDENTS find this ppt very use full.
Considerations to Extractables and Leachables Testing SGS
How to organize Extractables Assessments? FDA continues to issue Warning Letters to companies that fail to properly complete Design Verification, Design Validation, and Process Validation, and recently to include failures of manufacturers in Risk Management. The evaluation of extractables and leachables has become an increasingly important aspect in the Quality by Design (QbD) initiative of the FDA in the area of drug product design, including materials used in the drug product production process and container and closure systems used for product packaging. This presentation provides general approaches and practical aspects in E&L testing.
Cleaning Validation Protocol for Cannabis Certificate Programs.docxNACPT Pharma College
The cannabis industry is rapidly growing in Canada, the world industry leader, and there is a lack of skilled workers in the cannabis space. According to the research performed by International Medical Cannabis Association in 2019, many growing cannabis Licensed Producers and related companies are struggling to find skilled workers in the space. Many individuals have a growing experience, but most do not have the appropriate education, credentials, and regulatory updates to be genuinely successful in the cannabis industry. Therefore, educational training is an essential and critical element in the cannabis space.
Comparing and Contrasting Leading Tools for Evaluating ChemicalsSustainable Brands
Brands are increasingly concerned about the chemicals used in their products. Transparency is growing, but knowing something is there doesn't mean you know how it will affect your customers. To fill this void, a number of chemical evaluation tools (e.g. GreenScreen, GoodGuide, GreenWERCS) and product evaluation certifications have emerged. Expert Tony Kingsbury and his team looked at 32 of these tools and certifications to determine how robust their evaluation is, how many hazard endpoints they take into account, how costly they are, how transparent they are, and whether you need a PhD to use them. Find out which tools are right for your organization and what limitations they carry.
EU GMP Annex 1 Draft: Implications on Sterilizing Grade Filter ValidationMerck Life Sciences
Watch the presentation of this webinar here: https://bit.ly/3kk0Qs1
In this webinar, you will learn:
- About the GMP Annex 1 draft regulatory overview
- How to incorporate the integrity testing & PUPSIT in the filtration systems validation
- How to design a bacterial retention test in terms of organism selection and single vs multiple use validation
Detailed description:
In this webinar we will discuss the implications of the EU GMP Annex 1 draft on the filtration of medicinal products and how this impacts the validation studies.
Bacterial Retention Testing is a critical part of the manufacturing validation process and is required by all regulatory bodies worldwide. Using case studies, our experts will explain how the Annex 1 draft is incorporated into the filtration systems validation exercise, specifically for integrity testing & PUPSIT (Pre-Use Post Sterilization Integrity Testing), the selection and justification of the appropriate test organism, and validation implications of single versus multiple use.
EU GMP Annex 1 Draft: Implications on Sterilizing Grade Filter ValidationMilliporeSigma
Watch the presentation of this webinar here: https://bit.ly/3kk0Qs1
In this webinar, you will learn:
- About the GMP Annex 1 draft regulatory overview
- How to incorporate the integrity testing & PUPSIT in the filtration systems validation
- How to design a bacterial retention test in terms of organism selection and single vs multiple use validation
Detailed description:
In this webinar we will discuss the implications of the EU GMP Annex 1 draft on the filtration of medicinal products and how this impacts the validation studies.
Bacterial Retention Testing is a critical part of the manufacturing validation process and is required by all regulatory bodies worldwide. Using case studies, our experts will explain how the Annex 1 draft is incorporated into the filtration systems validation exercise, specifically for integrity testing & PUPSIT (Pre-Use Post Sterilization Integrity Testing), the selection and justification of the appropriate test organism, and validation implications of single versus multiple use.
Pharmaceutical Validation: Role in Phamaceutical Industrykaunainfathema1
This is a brief presentation on various concepts under Pharamaceutical Validation including its importance, scope, history, authorities, types of validation, VMP; along with the ICH and WHO Guidelines to be followed for Calibration of Equipments.
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!
Pulmonary Thromboembolism - etilogy, types, medical- Surgical and nursing man...VarunMahajani
Disruption of blood supply to lung alveoli due to blockage of one or more pulmonary blood vessels is called as Pulmonary thromboembolism. In this presentation we will discuss its causes, types and its management in depth.
Explore natural remedies for syphilis treatment in Singapore. Discover alternative therapies, herbal remedies, and lifestyle changes that may complement conventional treatments. Learn about holistic approaches to managing syphilis symptoms and supporting overall health.
- 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
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.
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.
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Ve...kevinkariuki227
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
These simplified slides by Dr. Sidra Arshad present an overview of the non-respiratory functions of the respiratory tract.
Learning objectives:
1. Enlist the non-respiratory functions of the respiratory tract
2. Briefly explain how these functions are carried out
3. Discuss the significance of dead space
4. Differentiate between minute ventilation and alveolar ventilation
5. Describe the cough and sneeze reflexes
Study Resources:
1. Chapter 39, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 34, Ganong’s Review of Medical Physiology, 26th edition
3. Chapter 17, Human Physiology by Lauralee Sherwood, 9th edition
4. Non-respiratory functions of the lungs https://academic.oup.com/bjaed/article/13/3/98/278874
Prix Galien International 2024 Forum ProgramLevi Shapiro
June 20, 2024, Prix Galien International and Jerusalem Ethics Forum in ROME. Detailed agenda including panels:
- ADVANCES IN CARDIOLOGY: A NEW PARADIGM IS COMING
- WOMEN’S HEALTH: FERTILITY PRESERVATION
- WHAT’S NEW IN THE TREATMENT OF INFECTIOUS,
ONCOLOGICAL AND INFLAMMATORY SKIN DISEASES?
- ARTIFICIAL INTELLIGENCE AND ETHICS
- GENE THERAPY
- BEYOND BORDERS: GLOBAL INITIATIVES FOR DEMOCRATIZING LIFE SCIENCE TECHNOLOGIES AND PROMOTING ACCESS TO HEALTHCARE
- ETHICAL CHALLENGES IN LIFE SCIENCES
- Prix Galien International Awards Ceremony
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.
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
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.
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. Cleaning Validation……………. At a glance
1Quality Assurance
üWorst Case considerations
üWorst Case considerations
ü Acceptance criteria
ü Sampling Methods
ü Analytical Methods
3. The Active Pharmaceutical Ingredient Industry involves (in general) the manufacture of Active
Pharmaceutical Ingredients by both chemical and physical means through a series of multiple
step processes. Plants or individual pieces of equipment, including ancillary equipment, may be
used in Multi-product manufacture or dedicated toindividual products.
The result of inadequate cleaning procedures is that any of a number of contaminants may be
present in the next batch manufactured on the equipment such as:
1. Precursors to the Active Pharmaceutical Ingredient.
2. By-products and/or degradation products of the Active Pharmaceutical Ingredient.
3. The previous product.
4. Solvents and other materials employed during the manufacturing process.
5. Micro-organisms, this is particularly the case where microbial growth may be sustained by theproduct.
6. Cleaning agents themselves and lubricants.
Quality Assurance
5. STAGE 4:
DEVELOP A CLEANING VALIDATION PROTOCOL FOR THE PRODUCT AND THE
EQUIPMENT BEING CLEANED
That should encompass for example:
1. Introduction
2. Scope
3. Equipment
4. Cleaning procedure
5. Sampling procedures
6. Analytical testing procedure
7. Acceptance/Cleaning limits.
8. Acceptance criteria for the validation.
STAGE 5:
GENERATE A CLEANING VALIDATION REPORT DETAILING THE ACCEPTABILITY
OF THE CLEANING PROCEDURE FOR THE EQUIPMENT AND THE PRODUCT
The report should give a full detailed background and introduction to the cleaning Validation study and
should evaluate all data generated with respect to the acceptance criteria employed for the study. The
report should also indicate the
Quality Assurance
6. Cleaning Validation………… The definition
The process of removing contaminants from process equipment and
monitoring the condition of equipment such that the equipment can be
safely used for subsequent product manufacturing.
Dustin A. Leblanc.
2
Quality Assurance
7. Cleaning Validation…………........... Purpose
v Product integrity
Cross contamination
Microbial integrity
Product impurity
Batch integrity
v It is a regulatory requirement in Active Pharmaceutical Ingredient product
manufacture.
v Equipment reuse
v It is a customer requirement - it ensures the safety and purity of the product.
3
Quality Assurance
11. Cleaning Validation……Cleaning Parameters
q Time
q Cleaning chemistry
q Concentration
q Temperature
q Mixing / flow / turbulence
q Water quality
q Rinsing
17
Quality Assurance
12. Parameter interactions :
18
Cleaning Validation……Cleaning Parameters
Time vs Concentration :
Temp. vs Concentration :
Courtesy: Validated Cleaning Technologies for
Pharmaceutical Manufacturing, D. A. LeBlanc
Quality Assurance
13. Parameter interactions :
19
Cleaning Validation….……Cleaning Parameters
Time vs Temperature :
Time (min)
Courtesy: Validated Cleaning Technologies for
Pharmaceutical Manufacturing, D. A. LeBlanc
Quality Assurance
14. Cleaning Validation……Grouping Strategies
22
"Grouping" is the concept of demonstrating that certain elements
of cleaning are of a similar type, and selecting one (or more)
representative object(s) on which to conduct the Cleaning
Validation (Cleaning Process Qualification).
Product grouping :
ü Same manufacturing equipments being used.
ü Same cleaning SOPs being followed.
ü Similar formulations.
ü Similar risk / therapeutic group.
Equipment grouping, Cleaning method grouping, Cleaning
agent grouping, …………….., etc.
Quality Assurance
15. Cleaning Validation.……Grouping Strategies
23
Sr. No. Name of product Formulation
Cleaning
methods
Equipment
train
Risk / Therap.
class
1 Product A Tablet (FC) Method 1 Train A General
2 Product B Tablet Method 1 Train B General
3 Product C Parenteral Method 2 Train C Cytotoxic
4 Product D Tablet Method 3 Train B General
5 Product E Tablet (EC) Method 4 Train A General
6 Product F Parenteral Method 2 Train C Cytotoxic
7 Product G Tablet (FC) Method 1 Train A Cytotoxic
8 Product H Tablet Method 3 Train B General
9 Product I Tablet (EC) Method 4 Train A General
10 Product J Parenteral Method 2 Train C Cytotoxic
All products in a facility (hypothetical):
Quality Assurance
16. Cleaning Validation……Grouping Strategies
24
Sr. No. Name of product Formulation
Cleaning
methods
Equipment
train
Risk / Therap.
class
1 Product A Tablet (FC) Method 1 Train A General
2 Product B Tablet Method 1 Train B General
3 Product C Parenteral Method 2 Train C Cytotoxic
4 Product D Tablet Method 3 Train B General
5 Product E Tablet (EC) Method 4 Train A General
6 Product F Parenteral Method 2 Train C Cytotoxic
7 Product G Tablet (FC) Method 1 Train A Cytotoxic
8 Product H Tablet Method 3 Train B General
9 Product I Tablet (EC) Method 4 Train A General
10 Product J Parenteral Method 2 Train C Cytotoxic
Before Grouping :
Quality Assurance
17. Cleaning Validation…….Grouping Strategies
25
Sr. No. Name of product Formulation
Cleaning
methods
Equipment
train
Risk / Therap.
class
1 Product A Tablet (FC) Method 1 Train A General
2 Product B Tablet Method 1 Train B General
3 Product G Tablet (FC) Method 1 Train A Cytotoxic
4 Product C Parenteral Method 2 Train C Cytotoxic
5 Product F Parenteral Method 2 Train C Cytotoxic
6 Product J Parenteral Method 2 Train C Cytotoxic
7 Product D Tablet Method 3 Train B General
8 Product H Tablet Method 3 Train B General
9 Product E Tablet (EC) Method 4 Train A General
10 Product I Tablet (EC) Method 4 Train A General
After Grouping :
Quality Assurance
18. Cleaning Validation…..Worst Case considerations
Once the product groups have been established, the next step is to
determine the so-called “worst case” representative of each group.
It is that member(s) who shows the highest challenge on
cleaning program.
Worst case product : Toxicity / solubility / Single Therapeutic
Dosage.
Worst case eq. train : Longest train.
Worst case equipment : Larger size equipment (identical design).
Hold time studies : Longest possible duration.
Campaign Mfg. : Highest possible nos. of batches.
26
Quality Assurance
19. Three criteria :
ü It should be scientifically justifiable.
ü Pacifically achievable.
ü Methodically verifiable.
29
Possible types of limits :
v Visual
v Chemical
v Microbiological
v Endotoxin
Cleaning Validation……...Acceptance criteria
Quality Assurance
20. Visual clean criteria :
GMPs require inspection for visual cleanness before manufacture.
Key items to consider :
o Angle of view
o Distance from equipment surface
o Lighting conditions
o Viewer’s knowledge
o Surface usually must be dry
Visual aids :
Additional lighting / Magnifying glass / Mirror / Fiber-optic
scope / UV light
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Cleaning Validation……...Acceptance criteria
Quality Assurance
21. Chemical residue limits (Therapeutically or Toxicologically
safe criteria) :
ü Therapeutic dose based criteria
Most suitable for drug product (finished product)
manufacturing facility.
ü Toxicological criteria (Where Api STD Not Available)
üMost suitable for active drug (API) manufacturing facility.
Where cleaning agents are used (other than water).
ü 10 PPM criteria
CGMP requirement widely applicable.
32
Cleaning Validation……...Acceptance criteria
Quality Assurance
22. Therapeutic dose based criteria :
Based on the assumption that 1/1000 part of therapeutic dose
does not have any clinical impact on human (animal) body.
Determination of MACO (Maximum Allowable Carryover) of
Product A (Previous) to Product B (Next)
STD (A) × BS (B) × SF
MACO = (unit of mass)
LDD (B)
Where, STD = Single Therapeutic Daily Dose (Product A – ACTIVE CONTENT),
BS = batch size (Product B), SF = safety factor and LDD and LRDD = Largest Daily
Dose (Product B – DRUG PRODUCT)
33
Cleaning Validation……...Acceptance criteria
Step 1
Quality Assurance
23. Therapeutic dose based criteria :
Determination of Surface contamination (Shared Equipment)
MACO
L1 = (mass / surface area)
TSA
Where, TSA = Shared Equipment Total Surface Area (for both products)
34
Cleaning Validation……...Acceptance criteria
Step 2
Quality Assurance
24. 35
Cleaning Validation……...Acceptance criteria
Step 3
Therapeutic dose based criteria :
Determination of Sampled residue (for swab sample)
L2 = L1 × Swab Area (mass / swab)
Ø STD (Single therapeutic dose) value represents the ACTIVE drug content only.
e.g. 10 mg, the dose strength.
Ø LDD value represents the mass or volume of entire dose.
e.g. 250 mg three times a day.
Ø BS = batch size (Product B).
e.g. 150 kg.
Quality Assurance
25. Safety Factors :
36
Cleaning Validation……...Acceptance criteria
Approach Approach Typically Applicable To
0.1 to 0.01 Topical products
0.01 to 0.001 Oral products
0.001 to 0.0001 Parenterals products
0.0001 to 0.00001 Research, investigational products
Quality Assurance
26. 37
Cleaning Validation……...Acceptance criteria
Step 1
Therapeutic dose based criteria (an example) :
Determination of Maximum Allowable Carryover
10 mg × 150 kg × 0.001 × 1000000
(250 mg × 3)
= 2000 mg (MACO value)
Quality Assurance
29. 10 PPM criteria :
Based on the hypothesis that 10 parts of previous product is
therapeutically ineffective if presents in million parts of next
product.
Determination of MACO
10 × BS
MACO = (unit of mass)
1000000
Where, BS = batch size (smallest available batch size)
Then use and to derive final swab residue
limit. 45
Cleaning Validation……...Acceptance criteria
Step 1
Step 3Step 2
Quality Assurance
30. 46
Cleaning Validation…………...Acceptance criteria
Step 1
10 PPM criteria (an example) :
Determination of MAC
10 × 150 kg × 1000000
MAC = = 1500 mg
1000000
The final Swab residue (L2) :
1500 mg × 25 cm2
3170 cm2
= 11.83 mg/swab
Quality Assurance
31. 47
Cleaning Validation……...Acceptance criteria
The most stringent acceptance criteria shall be chosen for
cleaning validation study (The worst case approach).
11.831932 63.00
mg / swab
In real life cases, therapeutic or 10 PPM criteria become final
acceptance criterion for cleaning validation. Quality Assurance
32. Microbiological criteria :
§ Internal specifications
§ Official specifications: e.g. USP <1111>, “Microbial
Examination of nonsterile Products: Acceptance criteria for
Pharmaceutical Preparations and Substances for Pharmaceutical
Use”
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Cleaning Validation……...Acceptance criteria
Adminstration route TAMC Endotoxin
Oral 100 CFU/mL -
Liquid 20 CFU/mL -
Injectables 10 CFU/mL 0.25 Unit/mL
Quality Assurance
33. The sampling procedure refers to the method of collecting the
residues from the surface so that they can be measured.
Cleaning Validation…......Sampling Methods
Types Advantages Limitations
Swabs & Wipes
Dissolves & physically removes
sample, adaptable to wide variety
of area
May introduce fibers,
technique dependent, hard-to-
reach areas
Rinse
Easy, quick, non-intrusive, large
surface area
Limited information about
actual surface cleanliness
53
Quality Assurance
34. v Swab sampling techniques:
(⑴)One of the most widely used technique for chemical and
microbial sampling.
(⑵)Swabs are being wet with solvent aiding solubilization and
physical removal of surface residues.
(3) Results are technique dependent.
Cleaning Validation…......Sampling Methods
54
Microbial swab (sterile) Chemical swabs (Texwipe) Cotton wipes
Quality Assurance
35. v Swab sampling techniques:
(⑸)Generally 1 swab sample per location is adequate.
(⑹)Multiple swabs can be taken to improve surface recovery.
(⑺)Typical swabbed per site varies from 25 cm2 to 100 cm2. There
is no “magic” number.
(⑻)PTFE (chemically inert) templates may be used for accurate
swabbing area. e.g. (Teflon)
(⑼)“Difficult to clean” equipment surfaces
shall be identified and sampled.
(10) Representative surfaces of different
materials (MOCs) should be sampled.
Cleaning Validation……......Sampling Methods
55
10 cm
10 cm
Swab area
templates
Quality Assurance
36. v Swab sampling techniques:
(11)10 Nos. Wiping should be unidirectional at a time. Parallel
strokes should be employed to cover entire swab area.
Cleaning Validation……......Sampling Methods
56
Courtesy: Validated Cleaning Technologies for Pharmaceutical Manufacturing, D. A. LeBlanc
Quality Assurance
37. v Swab sampling techniques:
Example of “Difficult to clean” locations of an RMG:
Cleaning Validation……......Sampling Methods
57
Courtesy: Rapid mixer granulator, Kevin.
The design aspect of the equipment should be considered to
identify “difficult to clean” locations. Quality Assurance
38. v Rinse sampling techniques:
Rinse sampling involves using a liquid to cover the surfaces to be
sampled.
(⑴)One of the easy and widely used sampling method.
(⑵)Most preferable liquid for rinsing is water.
Cleaning Validation……......Sampling Methods
58Quality Assurance
39. v Specific vs non-specific methods:
(⑴)A non-specific assay may detect a variety of residues.
(⑵)A specific assay may quantify any anticipated residue.
(⑶)It is essential to correlate the results from a specific method to
the results from other non-specific methods that might be
used for routine monitoring of cleaning effectiveness.
Cleaning Validation……Analytical Methods
61
HPLC pH meter
Quality Assurance
40. Cleaning Validation……Analytical Methods
62
Specific Test Methods Non-Specific Test Methods
UV/Visible Spectrophotometry
Near Infrared Spectrophotometry
(NIR)
High Performance Liquid
Chromatography (HPLC)
Mid Infrared Spectrophotometry (MIR)
Atomic Absorption
Capillary Zone Electrophoresis
Enzyme Linked Immunosorbant Assay
(ELISA)
Total Organic Carbon (TOC)
pH
Titration
Conductivity
Gravimetric
Quality Assurance
41. The analytical methods used for testing cleaning samples
must be validated for [ICH Q2 (R1)]:
ü Limit of Detection (LOD)
ü Limit of Quantification (LOQ)
ü Specificity
ü Accuracy
ü Repeatability
ü Precision
ü Range
ü Linearity
ü Recovery
Cleaning Validation……Analytical Methods
63Quality Assurance
42. Recovery studies :
Procedure :
o Spike coupon with known amount
o Allow to dry
o Remove in swab or simulated rinse procedure
o For swab, desorb
o Analyze sample
o Compare to expected 100% value
This is done at surface acceptance (or below) limit.
Cleaning Validation………Analytical Methods
67
Quality Assurance
43. Minimum acceptable recovery:
v Specify in cleaning validation master plan or master protocol.
v Minimum swab recovery of 70 % - 80 %.
v Carry out recovery study for different material surfaces
(Material Of Constructions).
v Chose right wetting solvent (soluble) and absorbent swab
material to improve recovery.
Cleaning Validation………Analytical Methods
72
Quality Assurance