“We don’t have time for training.”
Response: “Training is critical to ensure valid results. Without proper training, results cannot be relied upon and regulatory compliance is at risk.”
37
STAGE 2 – PROCESS PERFORMANCE QUALIFICATION
FDA Guidance Topics
1. Demonstrating process capability and performance.
2. Establishing acceptance criteria.
3. Documenting the results.
Application to Cleaning
1. Cleaning process performance qualification batches.
2. Establish acceptance criteria based on analytical method.
3. Document all results and conclusions.
Cleaning process is now qualified and validated.
Maintain process and documentation going forward.
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 full day presentation gives an overview of the process validation lifecycle approach, the FDA PV Guidance, the lifecycle approach to cleaning validation, equipment qualification, and validation quality systems.
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.
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 full day presentation gives an overview of the process validation lifecycle approach, the FDA PV Guidance, the lifecycle approach to cleaning validation, equipment qualification, and validation quality systems.
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.
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.
In this presentation from CPhi 2014, Elise Gallais outlines the guidelines for cleaning validation: and focuses on analytical methods and their validation.
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”
Technology Transfer and Scale-up in Pharmaceutical IndustryPranjalWagh1
Transfer of technology is defined as “a logical procedure that controls the transfer of any process together with its documentation and professional expertise between development and manufacture or between manufacture sites”.
In Pharmaceutical Industry, technology transfer refers to the processes that are needed for successful progress from drug discovery to product development to clinical trials to full scale commercialization.
It is basically divided into three phases - Research Phase, Development Phase and Production Phase. The presentation elaborates on the technology transfer taking place in production phase. Production phase mainly concerns with validation studies and scale-up.
Validation studies such as performance qualification, cleaning validation and process validation is carried out by R&D department.
Scale-up involves the use of results obtained from lab studies for designing prototype of a product and pilot plant process, constructing pilot plant and further using pilot plant data for full-scale commercialization.
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”
Validation of aseptic process should be designed to provide assurance through appropriate testing that all phases and activities of the process remain sterile and it is controlled within the predetermined parameters.
Drug product, container, and closure are subject to sterilization separately, and then brought together.
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.
Pharmaceutical Good Manufacturing PracticesPharmaceutical
When you are in healthcare, Then GMP is must. Regulatory philosophy for product Quality have been changed from "Quality by Testing QbT" to "Quality by Design QbD". Quality is to be built in product and that only can be done by GMP.
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.
In this presentation from CPhi 2014, Elise Gallais outlines the guidelines for cleaning validation: and focuses on analytical methods and their validation.
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”
Technology Transfer and Scale-up in Pharmaceutical IndustryPranjalWagh1
Transfer of technology is defined as “a logical procedure that controls the transfer of any process together with its documentation and professional expertise between development and manufacture or between manufacture sites”.
In Pharmaceutical Industry, technology transfer refers to the processes that are needed for successful progress from drug discovery to product development to clinical trials to full scale commercialization.
It is basically divided into three phases - Research Phase, Development Phase and Production Phase. The presentation elaborates on the technology transfer taking place in production phase. Production phase mainly concerns with validation studies and scale-up.
Validation studies such as performance qualification, cleaning validation and process validation is carried out by R&D department.
Scale-up involves the use of results obtained from lab studies for designing prototype of a product and pilot plant process, constructing pilot plant and further using pilot plant data for full-scale commercialization.
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”
Validation of aseptic process should be designed to provide assurance through appropriate testing that all phases and activities of the process remain sterile and it is controlled within the predetermined parameters.
Drug product, container, and closure are subject to sterilization separately, and then brought together.
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.
Pharmaceutical Good Manufacturing PracticesPharmaceutical
When you are in healthcare, Then GMP is must. Regulatory philosophy for product Quality have been changed from "Quality by Testing QbT" to "Quality by Design QbD". Quality is to be built in product and that only can be done by GMP.
Validation by Vilegave Kailash, Shivajirao S. Jondhle college of Pharmacy Asa...Kailash Vilegave
General aspects
Validation of parenterals
Validation of tablets
component of validation,function of different departments,reasons for validation,shivajirao s jondhle college of pharmacy asangaon,validation of parenterals,validation of tablets,validation priority,vilegave kailash
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.
Presented at length on 23 April and 21 May 2017 at ICCBS, HEJ and Getz Pharma Auditorium, Karachi in a Discussion Forum of about 800 practicing university qualified professionals of various pharmaceutical manufacturing industries
In this slide contains Introduction, levels of cleaning, mechanism, sampling method of cleaning validation.
Presented by: P. VENKATESH (Department of pharmaceutical analysis).RIPER, anantapur
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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.
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.
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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.
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.
A comprehensive presentation on GMP systems and integration. This includes validations, vendor qualification, preventative maintenance, audits, CAPA, and utilization of system results.
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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
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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
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(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
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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
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
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- ADVANCES IN CARDIOLOGY: A NEW PARADIGM IS COMING
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- Prix Galien International Awards Ceremony
1. VALIDATION BOOT CAMP #3
LIFECYCLE APPROACH TO
PHARMACEUTICAL VALIDATION –
PRINCIPLES, IMPLEMENTATION, AND PRACTICE
LIFECYCLE APPROACH
TO CLEANING VALIDATION
Paul L. Pluta, PhD
1
2. MANUAL CLEANING -- Do you really know what is happening?
Q to operator: “Why is there so much foam in the tub?”
A: “I put in extra soap because the equipment was really dirty.”
Q to operator: “Why is there powder on the (clean) equipment?”
A: “No problem -- We’ll get the residue when we set up.”
Q to operator: “Why don’t you follow the cleaning procedure?”
A: “The cleaning procedure really doesn’t work.”
ABOVE NOT ACCEPTABLE – TRAINING NEEDED
2
3. MANUAL CLEANING -- Do you really know what is happening?
Q to operator: “Why is there powder on the clean equipment?”
A: “It’s clean enough.”
Q to QA (equipment inspection person): “Did you approve that the equipment
is clean?”
A: “It’s clean enough.”
Q to management: “Do you know that your equipment is not clean?”
A: “It’s clean enough.”
Q to operator: “You cleaned the gasket with pure soap – this is not the
procedure? Also it is dangerous – these are corrosive chemicals.”
A: “That is the only way to get it clean.”
Q: “So why don’t you tell someone to change the procedure?”
A: “We don’t have time.”
ABOVE NOT ACCEPTABLE – TRAINING NEEDED
3
4. MANUAL CLEANING -- Do you really know what is happening?
Q to management: “Did you finish cleaning the equipment? We are
here to swab for cleaning validation.”
A (very proudly): “We cleaned the equipment three times so that we
won’t have any problems.”
Q to validation person: “Did you know that the manufacturing people
always clean the equipment multiple times before it is swabbed?”
A: “Sure, we knew.
Q: “Why didn’t you stop this?”
A: “These people are our friends. We have to work with these
people.”
ABOVE NOT ACCEPTABLE – TRAINING NEEDED
4
5. OUTLINE
Lifecycle Approach Applied to Cleaning Validation
Stage 1 Activities
• Cleaning Method Development
• Analytical Method Development
• Site equipment
Stage 2 Activities
• Cleaning documentation
• Validation conformance lots
Stage 3 Activities
• Maintaining Validation
• Change Control
• Management review
5
6. OBJECTIVES
1. Application of lifecycle approach to cleaning
validation
2. Cleaning lifecycle stage details
• Process development and understanding
• Process qualification
• Maintaining the validated state
3. Cleaning validation problems
• Global experiences
6
7. Lifecycle Approach to Cleaning Validation –
Value? Does this make sense?
• Cleaning is a process
• Validation lifecycle concepts being applied to equipment,
facilities, utilities, computers, etc., by validation and
technical experts
• Who can argue with understanding, performing, and
maintaining the validated state?
• Consistent with QbD and ICH approaches
• Lifecycle approach (i.e., understanding, performing,
maintaining) vs. traditional approach – Which would
you rather present to an auditor?
7
8. WHAT IS THE CLEANING PROCESS?
Cleaning Process Performance Qualification (PPQ)
Automated CIP System
Process steps Qualification
1. Residue on equipment Equipment
2. Water procedure Purified Water
3. Cleaning agent procedure Computer / software
4. Water procedure Compressed air
5. Purified Water procedure Conductivity analysis
6. Dry TOC analysis
Equipment is clean -- Process is validated
Process parameters à Quality attributes
8
9. WHAT IS THE CLEANING PROCESS?
Cleaning Process Performance Qualification (PPQ)
Manual Cleaning
Process steps Qualification
1. Residue on equipment Personnel
2. Water rinse Purified Water
3. Scrub with cleaning agent Compressed air
4. Water rinse
5. Scrub
6. Water rinse
7. Purified Water rinse
8. Dry
Equipment is clean -- Process is validated
Process parameters à Quality attributes
9
10. CLEANING VALIDATION OVERVIEW
1990s àpresent
1. Defined cleaning procedure (SOP) – basis?
2. Product A batch does not contaminate subsequent
Product B batch
3. Acceptance limit calculated
4. Assume uniform contamination of all equipment
5. Three conformance lots = Validated cleaning procedure
6. Validated analytical method (original API)
7. Worst-case matrix approach
One-time event
10
11. FDA PROCESS VALIDATION GUIDANCE
LIFECYCLE APPROACH TRANSITION
APPPLICATION TO CLEANING VALIDATION
Pre Lifecycle
Cleaning development (?) à PQ à change control
________________________
Lifecycle Approach
Development à PQ à Maintenance
EXPANDED SCOPE OF VALIDATION
INCREASED SPECIFIC STAGE REQUIREMENTS
11
12. LIFECYCLE APPROACH TO CLEANING VALIDATION
Scientific and technical approach
Design and development
– Residue + cleaning agent + cleaning procedure à Clean equipment
Performance demonstration
Monitoring and maintenance
Rationale, responsibility, and accountability
Future process improvements
Not the following:
– Standard site method (no basis or rationale)
– Personnel driven (no control)
– “Do whatever it takes” (high variation)
– SOP (no accountability)
– Validation (?) – One-time event.
12
13. STAGE 1, PROCESS DESIGN (PROCESS UNDERSTANDING)
APPLICATION TO CLEANING
FDA Guidance Topics
1. Building and capturing process knowledge and understanding.
2. Establishing a strategy for process control.
Application to Cleaning
Understand residue chemistry (solubility, stability)
Determine cleaning agent based on residue chemistry
Determine cleaning process
• Identify sources of variability
• Establish methods to control variability
– Process Analytical Technology
Rational analytical method and supporting work
Characterization of equipment to be cleaned and supporting work
Trained sampling personnel
DOCUMENT ALL OF THE ABOVE
13
14. DEVELOPMENT (STAGE 1)
CLEANING PROCESS DEVELOPMENT
• Physical and chemical properties of the residue is basis for cleaning
process
• Considerations for determination of most difficult-to-clean residue
• Residue solubility and stability in determining worst-case soils
• Residue chemistry critical for analytical method
• Cleaning agent chemistry consistent with residue chemistry
• Cleaning process chemistry and engineering and consistent with
residue and cleaning agent.
RESIDUE CHEMISTRY
– BASIS FOR CLEANING PROGRAM
– BASIS FOR ANALYICAL METHOD
14
15. RESIDUE PROPERTIES -- BASIS FOR CLEANING PROCESS
Case study: Antibiotic suspension containing insoluble API (base)
Original cleaning method: Water, PurW, dry
• No documented cleaning validation for many years
• Unknown peaks on original cleaning validation attempts
• API insoluble
Second method: Alkaline soap wash, water, PurW, dry
• Unknown peaks again
• API insoluble
Final method: Acid wash, alkaline soap wash, water, PurW, dry
• No residues
• Unknown peaks determined to be degradants and flavors.
• API dissolves (acid-base neutralization)
Consider active drug and other residue chemistry in development
of cleaning process
15
16. DETERMINATION OF
MOST DIFFICULT TO CLEAN RESIDUE
BASIS FOR CLEANING PROGRAM
Water solubility – USP Tables
• Is this adequate? NO!
pH effect – API with ionizable groups?
Solubility in cleaning agent?
• Determine solubility at range pH 1-12
• Understand solubility at pH of cleaning liquid
• Understand solubility in cleaning agent liquid
16
18. RESIDUE SOLUBILITY AND STABILITY FOR
DETERMINING WORST-CASE SOILS
Solubility considerations
• Hydrophilic and hydrophobic molecules
• Ionization – Effect of pH
• Effect of temperature
• Surface active molecules
• Liquid and semisolid product vehicle polarity
Stability considerations
• Hydrolysis, oxidation, photolysis, physical changes
What residue is really present?
Consider chemistry of residues
18
19. CLEANING MATRIX
Determine Worst-Case Soil
SOLUBILITY (mg / ml)
pH 1 Water pH 12 Alkaline
Cleaning Agent
Drug A 25 25 25 25
Drug B 15 15 15 15
Drug C 5 5 150 250
Drug D 150 10 10 50
Drug E 125 10 100 250
Consider acid cleaning agent for drugs D and E
19
20. WORST CASE CLEANING
Determination of worst-case cleaning based
on API toxicity, worst-case dose, etc.
– Standard calculation
Cleaning procedure may be based on
excipients having greatest effect on
cleaning
– Hydrophilic polymers
– Dyes
– Hydrophobic vehicles
20
21. BIOTECH CLEANING CHEMISTRY -- API
Protein molecules degrade in alkaline conditions
Degradation rate is milder in acidic conditions
Degradation rate increases with temperature
API residues typically consist of protein fragments and
aggregates
Analytical method: Non-specific analysis
Reference: Kendrick, Canhuto, and Kreuze. Analysis of
Degradation Products of Biopharmaceutical API Caused
by Cleaning Agents and Temperature. Journal of
Validation Technology, V15, #3, Summer 2009.
21
22. BIOTECH CLEANING CHEMISTRY – GROWTH MEDIUM
Medium Composition
• Acids or bases
• Monovalent salts
• Polyvalent salts
• Amino acids
• Proteins (polypeptides)
• Carbohydrates
• Aqueous soluble organics
• Non-aqueous soluble organics
Consider medium composition at end of cycle.
Reference: Azadan and Canhoto. A Scientific Approach to the Selection of
Cleaning Validation Worst-Case Soils for Biopharmaceutical manufacturing.
Cleaning and Cleaning Validation, Volume 1. 2011.
22
25. COMPONENTS OF FORMULATED DETERGENTS
• Surfactants
• Alkalis
• Acids
• Sequestrants / chelants
• Dispersants / anti-redeposition agents
• Corrosion inhibitors
• Oxidizing agents
• Enzymes
• Buffers / builders
• Preservatives
MUST HAVE CONTROL OF CLEANING AGENT
HAVE CONFIDENTIALITY AGREEMENT WITH SUPPLIER
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26. CLEANING ENGINEERING
Factors affecting cleaning
• Soil residue
– Soil levels, soil condition, hold times, soil mixing,
water quality and residue,
• Cleaner and parameters (TACT)
– Time, Action, Concentration, Temperature
– Others
• Surface and equipment design
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27. CLEANING PROCESS
SOURCES OF VARIATION
• Cleaning agent preparation – must be exact
• Automated cleaning vs. manual cleaning
• Manual cleaning process variation
• Human physical strength variation
• “Cleaning” between same-product batches in
campaign – residue level build-up
• Campaign length – residue level build-up
• Time to initiate cleaning (dirty hold time)
• Residue chemical and physical changes
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28. EQUIPMENT TO BE CLEANED
Cleaning-related qualification
• Product-contact materials
• Compatibility with cleaning agents
• Surface areas – need for residue calculations
• Equipment equivalence
• Most-difficult-to-clean locations on equipment -- Highest
risk locations for sampling
• Non-uniform contamination equipment
• Non-uniform contamination sampling locations
• Sampling methods (swab / rinse)
Part of IQ/OQ/PQ for manufacturing equipment
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29. PROCEDURE TO DETERMINE SAMPLING
LOCATIONS
Specific documented procedure recommended
• Equipment technical evaluation
• Observation of equipment after processing
• Equipment disassembly review
• Cleaning procedure review
• Equipment evaluation review
• Operator interviews
SOP describing above
Documentation of above for equipment sampling
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30. TIME TO INITIATE CLEANING
“DIRTY HOLD TIME”
1. Make Product A
2. Clean
3. Make Product B
How long between end of #1 and start #2?
Is residue same? Does residue change?
What can happen to the residue?
• Wet and dry processes
• Chemical changes (hydrolysis, oxidation, etc.)
• Physical changes
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31. CAMPAIGN LENGTH
How many lots in manufacturing campaign before
cleaning must be done?
What about “cleaning” between batches?
• Equipment should be visually clean
• Terminology: “Between lot procedure”
• How much residue “build-up?”
DO NOT IDENTIFY AS “BETWEEN LOT CLEANING”
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32. MANUAL CLEANING
• Manual cleaning procedures should be
monitored and maintained with increased
scrutiny compared to non-manual procedures
• More frequent training of cleaning personnel
• Increased supervision
• Periodic (annual?) revalidation batches
Manual cleaning is high risk
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33. ANALYTICAL METHOD DEVELOPMENT
Early stage 1 (development) analysis –
validation not required but must be sound
Validated method when used for Stage 2
cleaning validation and post-validation
testing (change control)
All methods and data (including stage 1) subject to
regulatory audit
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34. ANALYTICAL METHOD DEVELOPMENT
Analytical method must measure actual residue –
what residue is actually present on equipment
surfaces?
• Small molecules
– API
– API degraded – specific or non-specific method
• Biotech molecules
– API degraded – non-specific method
UNDERSTAND RESIDUE CHEMISTRY
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35. ANALYTICAL METHOD DEVELOPMENT
Cleaning agent residue
• Analytical method to determine residual cleaning
agent.
• Information from cleaning agent vendor
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36. ANALYTICAL METHOD DEVELOPMENT
Recovery studies
Can sampling procedure adequately recover residue
from equipment surfaces?
• Product contact materials
• High % of total surface area
• Obtain representative coupons from equipment
fabricators
• High (e.g., >80%) acceptance criteria
• Factor may be used in calculation
– Multiple approaches
– Factor every calculation?
All sampled surfaces must have recovery data
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37. SAMPLING
Sampling methods
• Sampling (swab) critical activity
• Training program
• Trained sampling personnel
– Demonstrated acceptable performance
• Documented training and retraining
• Worst case compounds / procedures in training
– Volatile solvents (importance of rapid technique)
• Worst case sampling equipment
– Extension poles
• Retraining considerations
– Who does sampling? Personnel skills
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38. SAMPLING TRAINING
Sampling is extremely critical to cleaning
validation program
Inadequate sampling = false negative
– Insufficient pressure on surface
– Swab solvent evaporation
– Insufficient area sampled
Auditors routinely ask for sampling program training
methods and training records
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39. STAGE 2, PROCESS QUALIFICATION –
(VALIDATION PERFORMANCE)
APPLICATION TO CLEANING
1. Design of a facility and qualification of utilities and equipment
2. Process performance qualification
3. PPQ protocol
4. PPQ protocol execution and report
Qualification of equipment, utilities, facilities
• Cleaning equipment (CIP)
Process Performance Qualification (PPQ) – commercial scale
Conclusion that process consistently produces clean equipment
Conformance batches
• All support systems, documents, training, personnel, etc. in place
• Target / nominal operating parameters within design space
• Additional testing (swab / rinse)
• Decision to “release cleaning process” for routine commercial use
• Post validation monitoring plan – Based on risk
– Drug residue properties
– Manual or CIP
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40. CLEANING EQUIPMENT
CIP system must be qualified (IQ/OQ/PQ or ASTM
E2500)
Riboflavin (or other) coverage testing
Temperature controls
Flow rates, etc.
PAT inline systems
– Drug disappearance – spectrophotometry, other methods
– Cleaning agent rinse -- conductivity
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41. CLEANING PROCEDURE DOCUMENTATION
(Cleaning Batch Record)
SOP
• Fill tank half full
• Add half scoop of soap
• Scrub as needed
• Rinse until clean
• Re-scrub and re-rinse if needed
CLEANING PROCEDURE RECORD
• Fill tank with 500 L water. Sign/date __________
• Add 20.0 kg cleaning agent. Sign/date __________
• Disassemble Part A. Steps 1,2,3,4,5
• Scrub for 20 minutes. Sign/date __________
• Disassemble Part B. Steps 1,2,3,4,5
• Soak Part B in cleaning liquid for 10 minutes. Sign/date __________
• Rinse Part A and Part B with 50 L water. Sign/date __________
• Rinse with 50 L Purified Water. Sign/date __________
• Dry with compressed air
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42. CLEANING PROCEDURE RECORD
• Fill tank with 500 L water. Sign/date __________
• Add 20.0 kg cleaning agent. Sign/date __________
• Disassemble Part A. Steps 1,2,3,4,5
• Scrub for 20 minutes. Sign/date __________
• Disassemble Part B. Steps 1,2,3,4,5
• Soak Part B in cleaning liquid for 10 minutes. Sign/date __________
• Rinse Part A and Part B with 50 L water. Sign/date __________
• Rinse with 50 L Purified Water. Sign/date __________
• Dry with compressed air
KEY POINTS
Exact concentration of cleaning agent liquid
Signature on quantitative steps
Grouping non-quantitative steps (e.g., disassembly)
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43. VALIDATION REQUEST / PLAN
Initiates cleaning validation
• New cleaning validation or change control process
improvements
• Strategy and approach
• Scientific and technical basis
• Specify required protocols and other work to accomplish
validation
• Risk-based
• References: Stage 1 Design / development reports
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44. VALIDATION PROTOCOL
Cleaning validation protocols and other work
as specified in Validation Plan
– Risk based
Include sampling pages indicating worst
case sampling locations.
Specify acceptance criteria
44
45. VALIDATION RESULTS / REPORT
Test results as required in validation protocol.
• Discussion. Consistency with Stage 1
development work.
• Clear statement the cleaning process is (or is
not) validated.
• Recommendations for Stage 3 monitoring and
maintenance.
– Additional limited testing based on data and risk
– Routine monitoring based on risk
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46. STAGE 3, CONTINUED PROCESS VERIFICATION
(VALIDATION MONITORING AND MAINTENANCE)
APPLICATION TO CLEANING
Activities to assure process remains in validated state
Change control -- evaluate impact of change and validate (test) as
necessary
Trend and assess data
– PAT rinse times
– Conductivity data
Study OOS and OOT (Out of Trend) data
Improve process
Improve control to detect and reduce variability
Cleaning non-conformances and deviations
Re-validation – definition: Actual batch or “paper”
• Is re-testing necessary?
• When should re-testing be considered?
Periodic Management Review
• Documentation reviewed by management
• Documented review
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47. POST-VALIDATION MONITORING AND MAINTENANCE
1. Stage 2 specific requirements
– Additional testing based on actual data
– Ex: One location has high (acceptable result)
2. Routine monitoring and maintenance
– Risk based
3. Change control program
CHANGE CONTROL MOST IMPORTANT AND
DIFFICULT TO ADMINISTER
PERSONNEL MUST RECOGNIZE “CHANGE”
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48. POST-VALIDATION MONITORING AND MAINTENANCE
Residue toxicity risk
• Residue that can be visually seen
– Room lighting must be adequate
– Provide additional lighting if necessary
• Residue that cannot be visually seen
– Swab after each batch?
CONSIDER PATIENT RISK AND COMPANY RISK
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49. CHANGE CONTROL
• All associated personnel must be aware of
change control
• Change control system developed
• Process improvements expected based on
ongoing experience
• Process improvements should be evaluated by
technical people (i.e., Stage 1)
• Stage 2 PPQ conducted when appropriate
based on Stage 1 technical evaluation.
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50. POST-VALIDATION MONITORING
Periodic review of cleaning performance
• Deviations
• Non-conformances (dirty equipment)
• Re-cleaning
• Change control
• Other monitoring (CIP data)
• Product APR data
• Statistical Process Control data treatment
• Management review -- documented
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51. CLEANING DOCUMENTATION
• High level documents
• Specific cleaning validation documents
– Design/Development, performance, monitoring/maintenance
• Specific cleaning validation support documents (equipment
qualifications)
• Cleaning validation approach documents (Worst case matrix,
calculations, sampling locations, etc.)
• Production documents (Cleaning Procedure Records)
– Production cleaning policies
• Management review documents
• Associated documents
– Personnel training in direct and associated areas
– HR records
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52. CLEANING DOCUMENTATION
High level documents
• Corporate policy
• VMP (Cleaning VMP)
Stage 1 documents
• Cleaning process development report
• Analytical method development report
• Supporting equipment documents (materials, surface areas, equivalent equipment,
sampling, etc.)
Stage 2 documents
• Validation PPQ request, protocol, results
• Cleaning equipment qualification
• Cleaning procedure record
Stage 3 documents
• Change control documents
• Process monitoring
• Management review
CONSISTENT LIFECYCLE STRATEGY AND APPROACH
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53. SUMMARY
STAGE 1 -- DESIGN AND DEVELOPMENT
INCLUDING COMMON PROBLEMS
Understanding cleaning process
• Residue properties
– Residue degradation
• Rational cleaning process based on residue
• Scientific and technical cleaning matrix
Understand and control sources of variation
• Dirty hold time
• Campaigns
Rational analytical method based on residue properties
Equipment to be cleaned characterized
• Worst case sampling
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54. SUMMARY – EQUIPMENT TO BE CLEANED
INCLUDING COMMON PROBLEMS
• Equipment characterization
• Residue calculations
• Materials of product contact
• Surface areas
• Worst-case areas for sampling based on risk
– Non-uniform contamination
• Equivalent equipment
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55. SUMMARY – ANALYTICAL
INCLUDING COMMON PROBLEMS
Understand residue
• Solubility and stability
• Validated analytical method for actual residue
– Specific or non-specific analytical methods
• API and cleaning agent residue
Recovery studies from product contact materials
• API and cleaning agent
Swab / rinse testing on equipment
• Most difficult to clean sampling sites
• Use of auxiliary sampling equipment (extension pole)
Swab / rinse training of sampling personnel
55
56. SUMMARY
STAGE 2 – PERFORMANCE
INCLUDING COMMON PROBLEMS
Cleaning Process Conformance Lots
Cleaning equipment qualified
Cleaning procedure specified (Not SOP)
Cleaning documentation
– Request
– Protocol
– Results / Report
Manual cleaning – high risk
56
57. SUMMARY
STAGE 3 -- MAINTAINING VALIDATION
Change control -- evaluate impact of change
and validate (test) as necessary
Improve process
Improve control to detect and reduce
variability
Cleaning non-conformances and deviations
Periodic Management Review
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58. PAUL L. PLUTA, PhD
Editor-in-Chief
Journal of Validation Technology
Journal of GXP Compliance
Advanstar Communications
Adjunct Associate Professor
University of Illinois at Chicago (UIC) College of Pharmacy
Chicago, IL, USA
Pharmaceutical industry experience
Contact: paul.pluta@comcast.net
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