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.
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.
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”
In this slide contains introduction, qualification, preventive maintenance, requalification method.
Presented by: Malarvannan M (Department of pharmaceutical analysis).RIPER, anantapur
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.
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.
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”
In this slide contains introduction, qualification, preventive maintenance, requalification method.
Presented by: Malarvannan M (Department of pharmaceutical analysis).RIPER, anantapur
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.
Aseptic process tech & advanced sterile product mfg rashmi nasareRASHMINasare
Aseptic process technology & advanced sterile product manufacturing technology it is done for doing in process quality control test for sterile product
Qualification of Dissolution Test Apparatus and Validation of Utility System this presentation will help to enhance your knowledge in validation and qualification area.
Qualification of tablet compression machinePritam Kolge
Qualification of Tablet Compression Machine ...
This topic comes under Quality Control and Quality Assurance....
This is useful for M.Pharm (Pharaceutical Quality Assurance) Students who studying in First year sem II....
This Presentation Contain following...
#Introduction
#Design Qualification
#Installation Qualification
#Operational Qualification
#Performance Qualification
#Case Study
#Conclusion
#References
Thanks For Help and Guidance of Dr. Mrs. N. M. Bhatia Mam
This presentation includes detail about cleaning levels,equipments for cleaning validation , steps for cleaning method validation and analytical method validation used for cleaning.
Role of quality system and audits in pharmamaceuticalganpat420
Introduction
cGMP Regulations
Quality Assurance Function
Quality Systems Approach
Management Responsibilities
Resources
Manufacturing Operations
Evaluation Activities
Transitioning to Quality Systems Approach
Audit Checklist for Drug Industry
QUALIFICATION OF MANUFACTURING EQUIPMENTSANKUSH JADHAV
it gives the information about qualification of various manufacturing equipment which is used into the pharmaceutical labs. (only for information purpose)
Cleaning validation is one of the major and critical activity in pharmaceutical operations
The four basic requirement of cGmp are …
Identity
Safety*
Strength
Purity*
This presentation consist a consolidated list all Regulatory Guidelines for Cleaning Validation. Hyperlink of the applicable guidelines are also given in the presentation.
Aseptic process tech & advanced sterile product mfg rashmi nasareRASHMINasare
Aseptic process technology & advanced sterile product manufacturing technology it is done for doing in process quality control test for sterile product
Qualification of Dissolution Test Apparatus and Validation of Utility System this presentation will help to enhance your knowledge in validation and qualification area.
Qualification of tablet compression machinePritam Kolge
Qualification of Tablet Compression Machine ...
This topic comes under Quality Control and Quality Assurance....
This is useful for M.Pharm (Pharaceutical Quality Assurance) Students who studying in First year sem II....
This Presentation Contain following...
#Introduction
#Design Qualification
#Installation Qualification
#Operational Qualification
#Performance Qualification
#Case Study
#Conclusion
#References
Thanks For Help and Guidance of Dr. Mrs. N. M. Bhatia Mam
This presentation includes detail about cleaning levels,equipments for cleaning validation , steps for cleaning method validation and analytical method validation used for cleaning.
Role of quality system and audits in pharmamaceuticalganpat420
Introduction
cGMP Regulations
Quality Assurance Function
Quality Systems Approach
Management Responsibilities
Resources
Manufacturing Operations
Evaluation Activities
Transitioning to Quality Systems Approach
Audit Checklist for Drug Industry
QUALIFICATION OF MANUFACTURING EQUIPMENTSANKUSH JADHAV
it gives the information about qualification of various manufacturing equipment which is used into the pharmaceutical labs. (only for information purpose)
Cleaning validation is one of the major and critical activity in pharmaceutical operations
The four basic requirement of cGmp are …
Identity
Safety*
Strength
Purity*
This presentation consist a consolidated list all Regulatory Guidelines for Cleaning Validation. Hyperlink of the applicable guidelines are also given in the presentation.
Cleaning validation for the 21 th century pharmaceutical onlineEmma Aguinaga
This eBook is a collection of articles written from May of 2017 through August 2018 and are part of the cleaning validation for the "Cleaning Validation for teh 21 st Century" series.
In this presentation from CPhi 2014, Elise Gallais outlines the guidelines for cleaning validation: and focuses on analytical methods and their validation.
Challenges using Multiple Single-use Systems: Functionality versus Extractabl...MilliporeSigma
As single-use technologies continue to expand in pharmaceutical manufacturing processes, the risk assessment for extractables and leachables becomes increasingly complex. Join this webinar to obtain guidance on how to perform risk evaluation on a process with multiple single-use components.
A Single-Use System (SUS) is typically designed for a specific process step. In many cases, single-use components are chosen based on their functionality. The challenge arises when there are multiple processing steps-- as the different applications and product matrices are evaluated, the complexity of the risk assessment increases. Complexity includes component evaluation, process conditions, and model solvents streams which ultimately relates to the patient safety risk.
This webinar will evaluate the different single-use components with respect to compatibility and extractables and leachables. A case study will be used to demonstrate the complexity and potential concerns when performing a risk evaluation on the manufacturing process.
In this webinar, you will learn:
- Risk assessment of extractables
- Single-use component evaluation
- Complexity when evaluating multiple assemblies
Challenges using Multiple Single-use Systems: Functionality versus Extractabl...Merck Life Sciences
As single-use technologies continue to expand in pharmaceutical manufacturing processes, the risk assessment for extractables and leachables becomes increasingly complex. Join this webinar to obtain guidance on how to perform risk evaluation on a process with multiple single-use components.
A Single-Use System (SUS) is typically designed for a specific process step. In many cases, single-use components are chosen based on their functionality. The challenge arises when there are multiple processing steps-- as the different applications and product matrices are evaluated, the complexity of the risk assessment increases. Complexity includes component evaluation, process conditions, and model solvents streams which ultimately relates to the patient safety risk.
This webinar will evaluate the different single-use components with respect to compatibility and extractables and leachables. A case study will be used to demonstrate the complexity and potential concerns when performing a risk evaluation on the manufacturing process.
In this webinar, you will learn:
- Risk assessment of extractables
- Single-use component evaluation
- Complexity when evaluating multiple assemblies
this presentation contains information about HACCP implementation in food industry. with example, easy to understand comment below how is this presentation
Pharmacovigilance and complementary medicines - Regulatory requirementsTGA Australia
Presentation on Pharmacovigilance basics – sponsor obligations, Complementary medicine safety – Regulatory perspective and Special considerations for complementary medicine pharmacovigilance
The challenges of regulating direct to consumer digital medical devicesTGA Australia
Presentation on digital medical devices, the role of the regulator, challenges in applying the framework to digital devices, international approaches and what is the TGA doing
Updates from the Pharmacovigilance and Special Access Branch TGA Australia
Presentation on using new sources of data in Pharmacovigilance, Pharmacovigilance Inspection Program (PVIP) update, International collaboration activities, Adverse Event Management System (AEMS)
Q and A
Manufacturing Investigational Medicinal Products - Legislative and GMP requir...TGA Australia
Presentation on Legislative requirements, specific risks for IMP manufacturing, manufacturing authorisations, PIC/S Guide to GMP PE009-13 and common issues
Update on regulatory reforms from the Scientific Evaluation BranchTGA Australia
Presentation on the latest on variations, Generic Medicines Reform Program, Human cells and tissue regulation (excluded goods), Faecal Microbiota Transplantation and 2D DataMatrix codes for medicines
Update on regulatory reforms from the Scientific Evaluation BranchTGA Australia
Presentation on the latest on variations, Generic Medicines Reform Program, Human cells and tissue regulation (excluded goods), Faecal Microbiota Transplantation and 2D DataMatrix codes for medicines
Presentation on the background of medicine shortages, definitions, reporting requirements, assessment and management, Section 19A and the compliance framework
Regulatory updates from the TGA Medical Devices Branch - Part 1TGA Australia
Presentation on the review of medicines and medical devices regulation, proposed changes to some definitions and regulation of some products without a medical purpose, reclassification of medical devices (not IVD), Unique Device Identification System and post-market monitoring
Regulatory updates from the TGA Medical Devices Branch - Part 2TGA Australia
Presentation on the regulation of software including software as a medical device, proposed regulatory scheme for personalised medical devices, including 3D Printed Devices, proposed changes to the Essential Principles, Conformity Assessment Procedures, and the requirements for devices used in clinical trials, and clarifying the requirements for systems and procedure packs
SME Assist: Help to navigate the regulatory mazeTGA Australia
Presentation to provide information on TGA’s SME Assist and what the service offers, details on upcoming SME Assist events and information on where to find more help
Presentation: Updates from the Pharmacovigilance and Special Access BranchTGA Australia
This presentation covers using new sources of data in Pharmacovigilance, Pharmacovigilance Inspection Program update, international collaboration activities and Adverse Event Management System.
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.
Ozempic: Preoperative Management of Patients on GLP-1 Receptor Agonists Saeid Safari
Preoperative Management of Patients on GLP-1 Receptor Agonists like Ozempic and Semiglutide
ASA GUIDELINE
NYSORA Guideline
2 Case Reports of Gastric Ultrasound
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.
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
Recomendações da OMS sobre cuidados maternos e neonatais para uma experiência pós-natal positiva.
Em consonância com os ODS – Objetivos do Desenvolvimento Sustentável e a Estratégia Global para a Saúde das Mulheres, Crianças e Adolescentes, e aplicando uma abordagem baseada nos direitos humanos, os esforços de cuidados pós-natais devem expandir-se para além da cobertura e da simples sobrevivência, de modo a incluir cuidados de qualidade.
Estas diretrizes visam melhorar a qualidade dos cuidados pós-natais essenciais e de rotina prestados às mulheres e aos recém-nascidos, com o objetivo final de melhorar a saúde e o bem-estar materno e neonatal.
Uma “experiência pós-natal positiva” é um resultado importante para todas as mulheres que dão à luz e para os seus recém-nascidos, estabelecendo as bases para a melhoria da saúde e do bem-estar a curto e longo prazo. Uma experiência pós-natal positiva é definida como aquela em que as mulheres, pessoas que gestam, os recém-nascidos, os casais, os pais, os cuidadores e as famílias recebem informação consistente, garantia e apoio de profissionais de saúde motivados; e onde um sistema de saúde flexível e com recursos reconheça as necessidades das mulheres e dos bebês e respeite o seu contexto cultural.
Estas diretrizes consolidadas apresentam algumas recomendações novas e já bem fundamentadas sobre cuidados pós-natais de rotina para mulheres e neonatos que recebem cuidados no pós-parto em unidades de saúde ou na comunidade, independentemente dos recursos disponíveis.
É fornecido um conjunto abrangente de recomendações para cuidados durante o período puerperal, com ênfase nos cuidados essenciais que todas as mulheres e recém-nascidos devem receber, e com a devida atenção à qualidade dos cuidados; isto é, a entrega e a experiência do cuidado recebido. Estas diretrizes atualizam e ampliam as recomendações da OMS de 2014 sobre cuidados pós-natais da mãe e do recém-nascido e complementam as atuais diretrizes da OMS sobre a gestão de complicações pós-natais.
O estabelecimento da amamentação e o manejo das principais intercorrências é contemplada.
Recomendamos muito.
Vamos discutir essas recomendações no nosso curso de pós-graduação em Aleitamento no Instituto Ciclos.
Esta publicação só está disponível em inglês até o momento.
Prof. Marcus Renato de Carvalho
www.agostodourado.com
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
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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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
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.
4. Cleaning validation
“Cleaning validation is documented evidence that an approved cleaning
procedure will reproducibly remove the previous product or cleaning
agents used in the equipment below the scientifically set maximum
allowable carryover level”
PIC/S Guide to GMP for Medicinal Products; Annex 15 Qualification & Validation
RACI & CAPSIG - August 2017 3
5. Current GMP requirements
– GMPs not prescriptive - allowing flexibility and adoption of
new technologies/science.
PE009-8 Section
Part I Personnel, Premises & Equipment,
Documentation, Production, Quality Control,
Contract Manufacture & Analysis
Part II Personnel, Buildings & Facilities, Process
equipment / cleaning, Materials management,
Production & Process controls, Packaging
Cleaning validation, Contract manufacturers,
Repackaging
APIs by cell culture/fermentation
Annexes 1, 2, 3, 6, 7, 8, 9, 10, 13, 15
RACI & CAPSIG - August 2017 4
6. GMP developments
• PIC/S cGMP – PE009-13
– Annex 15
– Annexes 2 & 3
– Part II - Implementation of QRM
– Part I Chapter 3
– Part I Chapter 5
– Annex 1
• PIC/S adoption of setting health
based exposure limit guidelines
(EMA)
RACI & CAPSIG - August 2017 5
7. Key concepts
Health Based Exposure Limits (HBELs)
• A daily dose of a substance below which no adverse effects are anticipated, by
any route, even if exposure occurs for a lifetime.
• Required for cleaning validation of hazardous products in shared facilities.
• Derived from a structured scientific evaluation of relevant data.
EMA/CHMP/CVMP/SWP/169430/2012
RACI & CAPSIG - August 2017 6
8. No Observable Adverse Effect Level (NOAEL)
• NOAEL must be established for all critical effects identified
• The NOAEL is the highest tested dose at which no adverse effect is observed
• If NOAEL is not calculable, the lowest-observed-effect level (LOEL) may be used
• Determined by toxicological expert
RACI & CAPSIG - August 2017 7
9. PDE or ADE?
• Permitted Daily Exposure (PDE) represents a substance-specific dose that is
unlikely to cause an adverse effect if an individual is exposed at or below this
dose every day for a lifetime
• Acceptable Daily Exposure (ADE) represents a dose that is unlikely to cause
an adverse effect if an individual is exposed, by any route, at or below this dose
every
PDE and ADE are effectively synonymous
RACI & CAPSIG - August 2017 8
10. MACO - Maximum Allowable Carryover
Mathematically calculated quantity of residue from a previous product when carried
over into a different product that CAN represent potential harm to the patient.
• toxicity/pharmacology
• mode of administration
• batch size
• shared equipment surface area plus a safety factor
RACI & CAPSIG - August 2017 9
11. Risk-based approach
• Health Based Exposure Limits
• Good knowledge management (ICH Q10)
• Risk based approach (ICH Q9)
Risk assessments for operations
Cross contamination strategy links to protection of patient
Shared facilities - scientific approach to ensure contamination risks are managed appropriately
RACI & CAPSIG - August 2017 10
12. Bracketing for cleaning validation
• Groups typically based on:
– Equipment train
– Cleaning procedure
– Dosage Form
• Rationale explained in SOP or Cleaning Validation document
• Groupings from which ‘worst-case’ will be selected
• Any product that does not conform to ‘bracket’ must be validated individually
RACI & CAPSIG - August 2017 11
14. Worst-case process conditions
• Campaign length (no. of batches or time elapsed)
• Dirty Hold Time
• Minimum limits for manual cleaning:
Time for Cleaning Steps
Temperature
• CIP programs
RACI & CAPSIG - August 2017 13
15. Establishing health based exposure limits
Step 1: Hazard Identification
Hazard
HLD50r
HCarcinogenicityr
HGenotoxicityr
HMechanism of
Action
HRepeat-dose
toxicityr
HReproductive
toxicityr
HDevelopmental toxicityr
RACI & CAPSIG - August 2017 14
16. Establishing health based exposure limits
Step 2: “Critical Effects”
• Clinical & non-clinical studies
• Therapeutic effects
• Adverse effects
Step 3: Determine NOAEL
• Based on Step 1 and 2 evaluation
• Requires toxicological expertise
• Defined as mg/kg/day
RACI & CAPSIG - August 2017 15
17. Establishing health based exposure limits
Step 4: Calculate PDE
NOAEL: Expressed as mg/kg/day
Weight Adjustment: 50 kg
F1: A factor (values between 2 and 12) to account for extrapolation between species
F2: A factor of 10 to account for variability between individuals
F3: A factor 10 to account for repeat-dose toxicity studies of short duration
F4: A factor (1-10) that may be applied in cases of severe toxicity
F5: A variable factor that may be applied if the no-effect level was not established.
PDE (mg/day) =
NOAEL x Weight Adjustment
F1 x F2 x F3 x F4 x F5
RACI & CAPSIG - August 2017 16
18. ADE approach
NOAEL: Expressed as mg/kg/day
Weight Adjustment: 50 kg - 60 kg
UFc: Composite Uncertainty Factor similar to F1-F5 in PDE formula
MF: Modifying Factor
PK: Pharmacokinetic Adjustments
ADE (mg/day) =
NOAEL x Weight Adjustment
UFc x MF x PK
RACI & CAPSIG - August 2017 17
19. MACO determination
PDE: Obtained in Step 4
MBSnext: Min. Batch Size
SF: Safety Factor
TDDnext: Standard Therapeutic Daily Dose (mg/day)
MACO (mg) =
PDE x MBSnext
SF x TDDnext
Safety factors:
Topicals 10 - 100
Oral products 100 - 1000
Parenterals 1000 - 10000
RACI & CAPSIG - August 2017 18
21. Revalidation requirements
• Introduction of new “worst-case” product
• Change in “product contact” equipment
• Change in bracketing approach
̵ Validation should be assessed for impact
• Annex 15 (PE009-13)
̵ Continuous process verification
̵ Effectiveness of manual cleaning should be confirmed at a justified frequency
RACI & CAPSIG - August 2017 20
22. Microbiological risks
• Annex 15 (PE009-13)
– More prescriptive clauses for cleaning validation
– Microbial and endotoxin contamination risks
• Appropriate sampling method
– Represents “worst-case” locations
– Trained personnel
– Sample handling before testing
• Validated Test Methods
– Acceptable recovery
– Objectionable organisms
RACI & CAPSIG - August 2017 21
23. Observed practices
Good Contamination Control Practices
• Documented Contamination Control Strategy
• Relies on good knowledge management (ICH Q10)
• Risk based approach (ICH Q9)
– Risk assessments for operations
– Cross contamination strategy links to protection of patient
– Shared facilities - methods follow scientific approach to ensure contaminants and contamination risks are
understood and managed appropriately.
• Guidance documents:
– APIC “Guidance on Aspects of Cleaning Validation in API Plants” (2014)
– ISPE Baseline® Guide - Risk MaPP
– PDA TR 29 “Points to Consider for Cleaning Validation” (2009)
RACI & CAPSIG - August 2017 22
24. Common inspection deficiencies
Deficiency categorisation:
• Assessment of intrinsic hazards
presented by the products/processes
• Design of facilities, utilities, equipment
and processes
• Controls to address hazards
– Technical and organisational controls
• Periodic review
RACI & CAPSIG - August 2017 23
25. Assessment of intrinsic hazards - issues
Poor assessment of molecules handled by the
facility:
• Limited or no data from product sponsor
• No clear policies on what products are manufactured
in which areas
• Generic evaluation of risks presented by substances
Deficient assessment of processes:
• No risk assessment for new processes
• Campaign practices implemented without due
validation
RACI & CAPSIG - August 2017 24
26. Assessment of intrinsic hazards - issues
There was no completed risk assessment in place to justify the current operation of the facility
as a shared use, multi-product facility. It was noted that the lines and rooms used for the
production of XXXXX were also used for the production of other cytotoxics, steroids, analgesics
and non-β-lactam antibiotics in injectable forms. In addition, the site product range included
hormonal products, e.g. methyl progesterone.
RACI & CAPSIG - August 2017 25
27. Assessment of intrinsic hazards - issues
The validation of all cleaning processes for all products and equipment trains used by the
manufacturer was based on the cleaning validation of a single liquid product only, (“Product X”)
Product X is a flammable liquid product, and the applicability of this specific cleaning validation
exercise to the cleaning of powder, granule, tablet, cream, ointment and other liquid processes had
not been scientifically established, justified and documented by the manufacturer.
• The written instructions for the cleaning of equipment used in the liquids manufacturing areas, differed to that
in the solids manufacturing areas; the methods were not equivalent.
• The limits for allowable residues of Product X were based on a 10ppm carry over into the smallest flammable
liquids batch size. It was not possible to extrapolate this calculated limit to other product types or
equipment trains.
• Product X was a topical product, and the assessment of allowable carry over did not consider the route of
administration for other dosage forms or product types.
RACI & CAPSIG - August 2017 26
28. Design of processes - issues
In relation to cleaning validation:
• There was no risk assessment or justification available to outline the manufacturer’s current approach to
cleaning validation.
• The cleaning validation of the line 2 lyophiliser had been conducted based on the removal of sodium
chloride only; multiple active cytotoxic materials were processed in the common lyophilisers.
• For the cleaning validation of XXXX, the locations for residue swabbing in the mixing vessel were not
regarded as worst case or hard to clean surfaces. Other areas of the vessel, that were regarded by the
inspector as being more difficult to clean, such as inlet ports, sample valves and under the impellor were not
tested.
• Cleaning validation had not been performed on the glass “Schott” bottles used for API slurry formulation;
these bottles were not labelled as dedicated to a specific active.
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29. Design of Processes - issues
In relation to the existing cleaning validation studies XX & YY:
• The existing cleaning validation for the facility was limited to the AAA and BBB machines only; it was not
apparent as to how the cleaning studies were applicable to other equipment trains
• There was no cleaning validation study available for liquids/creams
• There was no clearly defined cleaning method for the study; the cleaning SOP used at the time of the
validation (Version 1) did not contain sufficient details regarding the specific cleaning methods used.
(Also Clause 4.4)
• The cleaning agent used at the time of the validation was “XXXX” but the manufacturer now uses “YYYY” it
was not clear as to whether these solutions were equivalent.
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30. Design of processes - issues
In relation to the existing cleaning validation study:
• The surface area calculation was limited to the filling line equipment only, and did not include
the upstream of filling process (i.e. formulation) equipment train
• The study for the effective removal of detergent residues did not reflect the current practices used
in manufacturing as the concentration of the detergent was not defined in the cleaning process
RACI & CAPSIG - August 2017 29
31. Design of facility / processes - issues
In relation to the proposed cleaning validation study:
• The protocol did not include consideration of product contact parts used in the
manufacture of dosage forms, e.g. plastic jugs, bowls and sieves used in the manufacturing
area
• The cleaning method described in the procedure did not provide detail regarding the soak
times or method of mechanical removal of residues
• Specific swabbing locations (worst case) within equipment trains were not clearly defined
and justified; e.g. locations were identified as “hopper” or “perforated plate”
RACI & CAPSIG - August 2017 30
32. Lack of appropriate controls - issues
• The procedure for label issue (SOP 123) stated that labels for the powders batches
(penicillins) were to be placed in a grey box and secured. The majority of the boxes
used for label issue to the non-penicillin area were grey, and the mechanism to
ensure that boxes that had accessed the penicillin building were not used
in the general facility was not apparent
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33. Lack of Appropriate Controls - issues
The cleaning record for the paclitaxel compounding area indicated that the room
was clean; however the inspector observed:
• A large pool of standing water was observed on the floor
• White powder residue was observed around the balances
• White residue was observed on the floor in the area
RACI & CAPSIG - August 2017 32
34. Lack of appropriate controls - issues
Re-usable equipment for CYTOTOXIC was stated to be dedicated, however the
inspector observed that:
• Although the filling needles and carboy siphon tubes were marked, these filling needles and carboy siphon
tubes were stored mixed up with needles and siphon tubes for other products
• Although the Equipment Preparation List for CYTOTOXIC stated “use CYTOTOXIC dedicated equipment” the
records available did not demonstrate that CYTOTOXIC dedicated equipment was used, and the system
in place did not clearly demonstrate that CYTOTOXIC dedicated equipment was controlled in a manner to
ensure that the dedicated equipment was not used for the manufacture of other products
• The flasks used for the collection of CYTOTOXIC flush and priming solutions were not dedicated to
CYTOTOXIC
RACI & CAPSIG - August 2017 33
35. Ineffective periodic reviews - issues
The (cleaning) studies were last performed in 2007 and were based on the cleaning and carry-over
from PROD A capsules. The cleaning validation had not been modified or reconsidered in light of
new products or equipment introduced to the site since the completion of the study in 2007.
There was no available risk assessment of the current cleaning practices in light of the changes to
the product range manufactured on site, i.e. the process ability to effectively clean residues from
those additional products introduced into manufacturing since the 2007 study. (Also clauses 1.5 &
1.6)
A 2009 review of the cleaning validation study identified several issues with the 2007 study; issues
were noted regarding the swabbing methods used, as well as the spiking of samples. However,
those recommendations had not yet been actioned.
RACI & CAPSIG - August 2017 34
36. Summary
• International GMPs have incorporated HBELs approach to cleaning validation
• Knowledge management and transfer of information is key
• Will need expert advice in establishing PDE limits - sponsors play key role
• This change is important to maintaining patient safety
• Manufacturers and Sponsors need to remain vigilant regarding cleaning
validation
RACI & CAPSIG - August 2017 35