This document discusses the role of GLP compliance in generating accurate and reproducible bioequivalence data. It provides an overview of the evolution of GLP guidelines and the key fundamentals of GLP, including resources, rules and procedures, test characterization, documentation, and quality assurance. It notes that while BE studies involve human subjects and must comply with GCP, the analytical laboratory work should also adhere to GLP principles. Key regulatory guidelines on applying GLP to bioanalytical methods from the US FDA, EMEA, and ICH are summarized. Maintaining both GCP and GLP compliance through validated methods, quality systems, training and oversight can help ensure the best BE study results and regulatory acceptance.
Analytical method validation as per ich and usp shreyas B R
Analytical method validation is a process of documenting/ proving that an analytical method provides analytical data acceptable for the intended use.After the development of an analytical procedure, it is must important to assure that the procedure will consistently produce the intended a precise result with high degree of accuracy. The method should give a specific result that may not be affected by external matters. This creates a requirement to validate the analytical procedures. The validation procedures consists of some characteristics parameters that makes the method acceptable with addition of statistical tools.
OOS and OOT investigation is always a challenging task. This slide may help for a better understanding of investigation procedure according to regulatory requrement.
Analytical method validation as per ich and usp shreyas B R
Analytical method validation is a process of documenting/ proving that an analytical method provides analytical data acceptable for the intended use.After the development of an analytical procedure, it is must important to assure that the procedure will consistently produce the intended a precise result with high degree of accuracy. The method should give a specific result that may not be affected by external matters. This creates a requirement to validate the analytical procedures. The validation procedures consists of some characteristics parameters that makes the method acceptable with addition of statistical tools.
OOS and OOT investigation is always a challenging task. This slide may help for a better understanding of investigation procedure according to regulatory requrement.
Indian GMP Certification & WHO GMP CertificationVishal Shelke
Indian GMP Certification & WHO GMP Certification by Mr. Vishal Shelke
https://youtube.com/vishalshelke99
https://instagram.com/vishal_stagram
Sub :- Drug Regulatory Affairs
M.Pharm Sem II
Savitribai Phule Pune University
Method validation for drug substances and drug product _remodified_2014Ramalingam Badmanaban
Method validation is the process of proving that an analytical method is acceptable for its intended purposes.
METHOD VALIDATION = ERROR ASSESSMENT
Method validation is the process of demonstrating that analytical procedures are suitable for their intended use and that they support the identity, strength, quality, purity and potency of the drug substances and drug products
Validation: Prior ConsiderationsSuitability of Instrument Status of Qualification and Calibration Suitability of Materials Status of Reference Standards, Reagents, Placebo Lots Suitability of Analyst Status of Training and Qualification Records Suitability of Documentation Written and approved standard test procedure and proper approved protocol with pre-established acceptance criteria
Compendial vs. Non-compendial Methods
Compendial methods-Verification
Regulatory analytical procedure in USP/NF
Non- compendial methods-Validation
Alternative analytical procedure proposed by the applicant for use instead of the regulatory analytical procedure
Chromatographic Methods
Demonstrate Resolution
Impurities/Degradants Available
Spike with impurities/degradants
Show resolution and a lack of interference
Impurities/Degradants Not Available
Stress SamplesFor assay, Stressed and Unstressed Samples should be compared.
Ability of an analytical method to measure the analyte free from interference due to other components.
Selectivity describes the ability of an analytical method to differentiate various substances in a sample
Original term used in USP
Also Preferred by IUPAC and AOAC
Also used to characterize chromatographic columns
Degree of Bias (Used in USP)
The difference in assay results between the two groups
the sample containing added impurities, degradation products, related chemical compounds, placebo ingredients
Selectivity: For impurity test, impurity profiles should be compared.
Temperature (50-60℃)
Humidity (70-80%)
Acid Hydrolysis (0.1 N HCl)
Base Hydrolysis (0.1 N NaOH)
Oxidation (3-30%)
Light (UV/Vis/Fl)
Intent is to create 10 to 30 % Degradation
Change in the analytical procedure, drug substance, drug product, the changes, may necessitate revalidation of the analytical procedures.
“The degree of revalidation depends on the nature of the change.”
“FDA intends to provide guidance in the future on post-approval changes in analytical procedures.”
By Visual Inspection of plot of signals vs. analyte concentration
By Appropriate statistical methods
Linear Regression (y = mx + b)
Correlation Coefficient, y-intercept (b), slope (m)
Acceptance criteria: Linear regression r2 > 0.999
Requires a minimum of 6 concentration levels
Normally derived from Linearity studies.
Established by confirming that the method provides acceptable degree of linearity, accuracy, and precision.
Specific range dependent upon intended application of the procedure.
Indian GMP Certification & WHO GMP CertificationVishal Shelke
Indian GMP Certification & WHO GMP Certification by Mr. Vishal Shelke
https://youtube.com/vishalshelke99
https://instagram.com/vishal_stagram
Sub :- Drug Regulatory Affairs
M.Pharm Sem II
Savitribai Phule Pune University
Method validation for drug substances and drug product _remodified_2014Ramalingam Badmanaban
Method validation is the process of proving that an analytical method is acceptable for its intended purposes.
METHOD VALIDATION = ERROR ASSESSMENT
Method validation is the process of demonstrating that analytical procedures are suitable for their intended use and that they support the identity, strength, quality, purity and potency of the drug substances and drug products
Validation: Prior ConsiderationsSuitability of Instrument Status of Qualification and Calibration Suitability of Materials Status of Reference Standards, Reagents, Placebo Lots Suitability of Analyst Status of Training and Qualification Records Suitability of Documentation Written and approved standard test procedure and proper approved protocol with pre-established acceptance criteria
Compendial vs. Non-compendial Methods
Compendial methods-Verification
Regulatory analytical procedure in USP/NF
Non- compendial methods-Validation
Alternative analytical procedure proposed by the applicant for use instead of the regulatory analytical procedure
Chromatographic Methods
Demonstrate Resolution
Impurities/Degradants Available
Spike with impurities/degradants
Show resolution and a lack of interference
Impurities/Degradants Not Available
Stress SamplesFor assay, Stressed and Unstressed Samples should be compared.
Ability of an analytical method to measure the analyte free from interference due to other components.
Selectivity describes the ability of an analytical method to differentiate various substances in a sample
Original term used in USP
Also Preferred by IUPAC and AOAC
Also used to characterize chromatographic columns
Degree of Bias (Used in USP)
The difference in assay results between the two groups
the sample containing added impurities, degradation products, related chemical compounds, placebo ingredients
Selectivity: For impurity test, impurity profiles should be compared.
Temperature (50-60℃)
Humidity (70-80%)
Acid Hydrolysis (0.1 N HCl)
Base Hydrolysis (0.1 N NaOH)
Oxidation (3-30%)
Light (UV/Vis/Fl)
Intent is to create 10 to 30 % Degradation
Change in the analytical procedure, drug substance, drug product, the changes, may necessitate revalidation of the analytical procedures.
“The degree of revalidation depends on the nature of the change.”
“FDA intends to provide guidance in the future on post-approval changes in analytical procedures.”
By Visual Inspection of plot of signals vs. analyte concentration
By Appropriate statistical methods
Linear Regression (y = mx + b)
Correlation Coefficient, y-intercept (b), slope (m)
Acceptance criteria: Linear regression r2 > 0.999
Requires a minimum of 6 concentration levels
Normally derived from Linearity studies.
Established by confirming that the method provides acceptable degree of linearity, accuracy, and precision.
Specific range dependent upon intended application of the procedure.
Importance of guidelines in regulatory toxicity testingChander K Negi
Importance of Guidelines in Regulatory Toxicity studies
Guidelines are the consensus document accepted by a regulatory body
Prevent duplication of clinical trials in humans
Ensure SAFETY, EFFICACY and QUALITY of medicines
Minimize the use of animal testing without compromising safety and effectiveness
What is the most overlooked step in Quality by Design? QbD Risk Assessment - Learn the common pitfalls and how to prevent it. It's all about the relationship between your process parameter (CPP) and patient (QTPP)
cGMP University - GMP training and Proactive Quality Management | Compliance ...David Muchemu
cGMP University - GMP/CGMP (Good Manufacturing Practice) information, regulations and literature for pharmaceutical industry. cgmp provides state of the art GMP know how that gives guidance in your business.
Quality Management Systems in Radiotherapy based on ISO 9001 standardVal Antoff
Presentation on the main building blocks of a Quality Management System in Radiotherapy based on the international ISO 9001 standard. The presentation provides internal hyperlinks to bookmarked material for easy navigation.
The fundamental purposes of the Principles of Good Laboratory Practice (GLP) is to ensure the quality and integrity of test data related to non-clinical safety studies.
The Principles of Good Laboratory Practice (GLP) are a managerial quality control system covering the organisational process and the conditions under which non-clinical health and environmental studies are planned, performed, monitored, recorded, reported and retained (or archived). The OECD Principles of GLP are followed by test facilities carrying out studies to be submitted to receiving authorities for the purposes of assessing the health and environmental safety of chemicals and chemical products which may also be of natural or biological origin and, in some circumstances, may be living organisms.
The Principles of GLP define the responsibilities of test facility management, study director, study personnel and quality assurance personnel that are operating within a GLP system, and minimum standards concerning the suitability of facilities and equipment to perform studies, the need for standard operating procedures, documentation of raw data, study reports, the archiving of records, etc.
GLP applies to nonclinical studies conducted for the assessment of the safety or efficacy of chemicals (including pharmaceuticals).
GLP helps assure regulatory authorities that the data submitted are a true.
Quality management systems: Good Laboratory Practice (QMS GLP)Dr Ajay Kumar Tiwari
Fundamental knowledge on pharmaceutical
product development and translation from laboratory to market.
Quality management systems: Quality management & Certifications.
1. Introduction to GLP
2. Definition of GLP
3. Fundamentals of GLP
4. GLP Principles
5. Aim of GLP
Good Laboratory Practices (GLP) and USP 1058 Validation.pdfConference Panel
This webinar will define what is the US FDA's expectations for proper laboratory practices, systems, equipment usage, and documentation / record-keeping. It will evaluate the requirements for how basic Quality Management System (QMS) expectations/requirements are addressed in the lab environment. The webinar with evaluate pharma GMPs and 21 CFR 58 and associated regulations to see how the GLPs can be implemented in the real world to achieve FDA requirements and ensure the accuracy and repeatability/reproducibility of lab results.
This webinar is intended to provide guidance regarding Good Laboratory Practices (GMP) and lab equipment and analytical methods validation for use in pharmaceutical manufacturing and clinical trials and for use by contract laboratories that support the regulated medical products industries.
Register,
https://conferencepanel.com/conference/good-laboratory-practices-glp-and-usp-1058-validation
Quality management systems: Good Laboratory Practice (QMS GLP)Dr Ajay Kumar Tiwari
Fundamental knowledge on pharmaceutical
product development and translation from laboratory to market.
Quality management systems: Quality management & Certifications.
1. Introduction to GLP
2. Definition of GLP
3. Fundamentals of GLP
4. GLP Principles
5. Aim of GLP
Good Laboratory Practices (GLPs) are standard regulatory programs that assure the quality and integrity of nonclinical safety test data submitted to regulatory agencies worldwide.
Root cause Analysis (RCA) & Corrective and Preventive action (CAPA) in MRCT d...Bhaswat Chakraborty
This presentation describes Identification & differentiation of Protocol deviation & violation; Different methods of RCA & best suitable method for Multiregional Clinical Trial; CAPA management and CAPA application to other trial sites/CRO/SMO/ Country that is involved in same trial (Strategic Management and application of CAPA in MRCT)
This presentation gives effective solutions to outliers issue in bioequivalence trials. It described what would be acceptable to Regulatory agencies as well as some new approaches.
Equivalence approches for complex generics DIA 11 april 2019 Bhaswat Chakraborty
This is a workshop that i gave a few days ago on bioequivalence of complex generics like peptides, polymers, liposomes, colloids, ophthamic and topical produtcts.
Clinical trials that are needed for efficacy & safety evidence of Medical devices include feasibility (pilot) and Pivotal trials. An extended battery of preclinical trials are also needed for high risk devices.
Writing Science papers for for publication requires something more thatn creativity. Target journals, content organization, wrting style, elegance and referencing are equally important.
Multidisc review of NDAs and BLAs nipicon 2018 Dr. ChakrabortyBhaswat Chakraborty
NDAS and BLAs cannot be authoritatively reviewed these days until experts from different disciplines act together like a team. This presentation give some foundational points and an illustrative example in that regard.
Teaching by stories, anecdotes and historical facts sept 25 2018Bhaswat Chakraborty
Many difficult principles in science and humanities can be taught best by a story (of its discovery), by an anecdote or some historical facts about them.
Orientation and Adaptation for Post-Graduate Pharmacy ProgramsBhaswat Chakraborty
PG Pharmacy programs are more focused and professionally oriented than the undergraduate counterpart. Many soft skills are required along with the curricular competence for excellence at the PG level.
Scientific integrity calls for some basic originality. Plagiarism can destroy this original creativity and ideation. This presentation defines plagiarism (stealing from others' works) and some of the creative and systematic remedies.
Best Practices to Risk Based Data Integrity at Data Integrity Conference, Lon...Bhaswat Chakraborty
Data integrity can be implemented using several approaches. One of the most effective ways to implement DI is a risk based approach. The speaker elaborates this.
There are several dimensions in Pharmaceutical ethics -- Practice-, research- and community oriented. This presentation mainly deals with Clinical research oriented Ethics.
Young pharmaceutical scientists are and can get involved in all aspects of new drug discovery and development. They have to be appropriately qualified, trained and experienced though,
This presentation mainly deals with clinical development of biosimilar products. It also gives enough on non-clinical development so that the audience is well oriented.
High variability in PK can be a characteristic of certain drug products which require different from ordinary strategies and study designs for establishing bioequivalence.
High variability in PK can be a characteristic of certain drug products which require different from ordinary strategies and study designs for establishing bioequivalence.
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.
micro teaching on communication m.sc nursing.pdfAnurag Sharma
Microteaching is a unique model of practice teaching. It is a viable instrument for the. desired change in the teaching behavior or the behavior potential which, in specified types of real. classroom situations, tends to facilitate the achievement of specified types of objectives.
Title: Sense of Taste
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the structure and function of taste buds.
Describe the relationship between the taste threshold and taste index of common substances.
Explain the chemical basis and signal transduction of taste perception for each type of primary taste sensation.
Recognize different abnormalities of taste perception and their causes.
Key Topics:
Significance of Taste Sensation:
Differentiation between pleasant and harmful food
Influence on behavior
Selection of food based on metabolic needs
Receptors of Taste:
Taste buds on the tongue
Influence of sense of smell, texture of food, and pain stimulation (e.g., by pepper)
Primary and Secondary Taste Sensations:
Primary taste sensations: Sweet, Sour, Salty, Bitter, Umami
Chemical basis and signal transduction mechanisms for each taste
Taste Threshold and Index:
Taste threshold values for Sweet (sucrose), Salty (NaCl), Sour (HCl), and Bitter (Quinine)
Taste index relationship: Inversely proportional to taste threshold
Taste Blindness:
Inability to taste certain substances, particularly thiourea compounds
Example: Phenylthiocarbamide
Structure and Function of Taste Buds:
Composition: Epithelial cells, Sustentacular/Supporting cells, Taste cells, Basal cells
Features: Taste pores, Taste hairs/microvilli, and Taste nerve fibers
Location of Taste Buds:
Found in papillae of the tongue (Fungiform, Circumvallate, Foliate)
Also present on the palate, tonsillar pillars, epiglottis, and proximal esophagus
Mechanism of Taste Stimulation:
Interaction of taste substances with receptors on microvilli
Signal transduction pathways for Umami, Sweet, Bitter, Sour, and Salty tastes
Taste Sensitivity and Adaptation:
Decrease in sensitivity with age
Rapid adaptation of taste sensation
Role of Saliva in Taste:
Dissolution of tastants to reach receptors
Washing away the stimulus
Taste Preferences and Aversions:
Mechanisms behind taste preference and aversion
Influence of receptors and neural pathways
Impact of Sensory Nerve Damage:
Degeneration of taste buds if the sensory nerve fiber is cut
Abnormalities of Taste Detection:
Conditions: Ageusia, Hypogeusia, Dysgeusia (parageusia)
Causes: Nerve damage, neurological disorders, infections, poor oral hygiene, adverse drug effects, deficiencies, aging, tobacco use, altered neurotransmitter levels
Neurotransmitters and Taste Threshold:
Effects of serotonin (5-HT) and norepinephrine (NE) on taste sensitivity
Supertasters:
25% of the population with heightened sensitivity to taste, especially bitterness
Increased number of fungiform papillae
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
ARTIFICIAL INTELLIGENCE IN HEALTHCARE.pdfAnujkumaranit
Artificial intelligence (AI) refers to the simulation of human intelligence processes by machines, especially computer systems. It encompasses tasks such as learning, reasoning, problem-solving, perception, and language understanding. AI technologies are revolutionizing various fields, from healthcare to finance, by enabling machines to perform tasks that typically require human intelligence.
Lung Cancer: Artificial Intelligence, Synergetics, Complex System Analysis, S...Oleg Kshivets
RESULTS: Overall life span (LS) was 2252.1±1742.5 days and cumulative 5-year survival (5YS) reached 73.2%, 10 years – 64.8%, 20 years – 42.5%. 513 LCP lived more than 5 years (LS=3124.6±1525.6 days), 148 LCP – more than 10 years (LS=5054.4±1504.1 days).199 LCP died because of LC (LS=562.7±374.5 days). 5YS of LCP after bi/lobectomies was significantly superior in comparison with LCP after pneumonectomies (78.1% vs.63.7%, P=0.00001 by log-rank test). AT significantly improved 5YS (66.3% vs. 34.8%) (P=0.00000 by log-rank test) only for LCP with N1-2. Cox modeling displayed that 5YS of LCP significantly depended on: phase transition (PT) early-invasive LC in terms of synergetics, PT N0—N12, cell ratio factors (ratio between cancer cells- CC and blood cells subpopulations), G1-3, histology, glucose, AT, blood cell circuit, prothrombin index, heparin tolerance, recalcification time (P=0.000-0.038). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and PT early-invasive LC (rank=1), PT N0—N12 (rank=2), thrombocytes/CC (3), erythrocytes/CC (4), eosinophils/CC (5), healthy cells/CC (6), lymphocytes/CC (7), segmented neutrophils/CC (8), stick neutrophils/CC (9), monocytes/CC (10); leucocytes/CC (11). Correct prediction of 5YS was 100% by neural networks computing (area under ROC curve=1.0; error=0.0).
CONCLUSIONS: 5YS of LCP after radical procedures significantly depended on: 1) PT early-invasive cancer; 2) PT N0--N12; 3) cell ratio factors; 4) blood cell circuit; 5) biochemical factors; 6) hemostasis system; 7) AT; 8) LC characteristics; 9) LC cell dynamics; 10) surgery type: lobectomy/pneumonectomy; 11) anthropometric data. Optimal diagnosis and treatment strategies for LC are: 1) screening and early detection of LC; 2) availability of experienced thoracic surgeons because of complexity of radical procedures; 3) aggressive en block surgery and adequate lymph node dissection for completeness; 4) precise prediction; 5) adjuvant chemoimmunoradiotherapy for LCP with unfavorable prognosis.
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1. Role of GLP Compliance in
Generating Accurate & Reproducible
BE Data
Dr. Bhaswat S. Chakraborty
Sr. VP & Chair, R&D Core Committee
Cadila Pharmaceuticals Ltd.
Presented at ACRO India Workshop
AMA, Ahmedabad, India, July 19-20, 2013
1
2. Contents
• GLP, its evolution
• Fundamentals of GLP
– Resources
– Rules & Characterization
– Documentation & QAU
• Regulatory BE studies
• GLP in BE
– USFDA, EU
• Legal & Excellence GLP
• GLP expectations in Bioanalytical
• Best BE Results
• Concluding remarks
2
3. Good Laboratory Practices (GLP)
• Good Laboratory Practices or GLPs were initially invoked in a
reaction to malpractices in laboratories conducting safety
experiments of medicines.
• In early 1970s, research laboratories in the USA were found
doing work in unethical ways, like:
– data generation without conduct of study
– falsification of laboratory work
– replacement of dead animals and fabrication of test results etc.
• As a result, a series of guidelines were issued by US FDA,
Japan and finally by the whole group of OECD countries.
Board and Dent 19963
4. Evolution of GLP
• 1976 – USA: FDA proposals
• 1978 – USA: FDA final rules
• 1980 – USA : FDA amendment to GLP
• 1981 – OECD: Guidelines for testing of chemicals – OECD Paris and
Guidelines for National GLP inspections – Paris
• 1982 – OECD: GLP in testing of chemicals - Paris
• 1984 – Japan: GLP proposals and notification to agricultural
production bureau
• 1987 – USA: FDA amendment final rule
• 1988 – OECD: Final report for working group on mutual
recognition of compliance with GLP
• 1989 – UK: GLP compliance program
Board and Dent 19964
5. Fundamentals of GLP
1) Resources: organization, personnel, facilities
and equipment.
2) Rules: protocols and written procedures
(SOPs).
3) Characterization: test items and test systems.
4) Documentation: raw data, final report and
archives.
5) Quality assurance unit.
5
6. Resources
• Organization and Personnel:
– structure of the research organization and responsibilities of the
research personnel should be clearly defined
– staffing levels must be sufficient to perform the tasks required
– qualifications and the training of staff must also be defined and
documented
• Facilities and Equipment:
– sufficient facilities and equipment must be existent in order to
perform the studies
– all equipment must be in working order.
6
7. Rules & Characterization
• Protocols and Written Procedures:
– main steps of research studies must be described in the
study plan or protocol
– for repeatability of the studies and reproducibility of
results, routine procedures are described in SOPs
• Test item and the Test system
– essential to know as much as possible about the test item
and about the test system (often an animal or plant) to
which it is administered.
7
8. Documentation & QAU
• Raw data must be accurately captured and organized to
reflect the procedures and conditions of the study
• Final report is the responsibility of the study director,
ensuring
– that the contents, results and interpretation thereof are accurate
• Archives should be safe for many years and equipped with
logical and prompt retrieval.
• Quality assurance (QA) is a team assuring GLP compliance
– organized independently of the operational and study program, and
function as witnesses to the whole pre-clinical research process.
8
9. Critical GLP Violations
• Fabrication or falsification of data
• No Quality Assurance
• No study allotment
• No approved written study plans
• Failure to date, initial or sign data entries
• No training records and / or no job descriptions for
study personnel
• Absence of required information in final reports
9
10. Critical GCP Violations
• Fabrication or falsification of data
• Evidence that formal procedure/systems were not in place or rather weak
• Lack of/inadequate Quality Certification.
• Importation and mfg. of investigational product without regulatory licence
• Inaccurate information about investigational product is supplied to
regulatory agency
• Use of expired/recalled/non GMP manufactured investigational product
• Poor/ineffective blinding system
• Poor accountability of investigational product
• Poorly documented/incorrect sponsorship/Legal Representative
arrangements
• Uncontrolled site to site transfer
• Failure to observe IND conditions
• Failure to report serious breaches of trial protocol/GCP
• Little or no oversight of pharmacovigilance requirements
11. Regulatory Bioequivalence (BE)
Studies
• Clinical studies in healthy volunteers
– GCP compliance is a must
• Involves laboratory measurements of drug
concentrations in blood samples
– Logically GLP should be applicable
• They are not non-clinical, safety studies
– Thus may NOT have to CLAIM GLP compliance
11
12. Scope Demarcation: GCP and GLP
• GCP: relate to clinical studies using human volunteers patients and
also relate to most of the clinical procedures that can be carried out
without a laboratory test
– Includes all clinical phase I-IV studies
• GLP apply to all analytical and testing process all safety studies for
human health market approval and include QC assays, clinical
chemistry and tests by instruments and certain bioanalytical
procedures
– Excludes validation studies, cosmetic safety, bioanalytical for
efficacy studies including animal efficacy studies
• Good QA is applicable to all biomedical research practices
12
13. GLP in BE
• Common perceptions
– Confusing
– Only in the testing of non-clinical safety aspects
– Applies to bioanalytical? Or bioanalytical only?
– Wherever there is a lab
• Clinical pathology
• Serology
• Microbiology
• Bioanalytical…
13
14. Guidance for Industry,
USFDA/CDER, May 2001
• “The analytical laboratory conducting
pharmacology/toxicology and other preclinical
studies for regulatory submissions should adhere to
FDA’s Good Laboratory Practices (GLPs) (21 CFR part
58) and to sound principles of quality assurance
throughout the testing process.
• The bioanalytical method for human BA, BE, PK, and
drug interaction studies must meet the criteria in 21
CFR 320.29.”
14
15. 21 CFR 320.29
• “….shall be demonstrated to be accurate and
of sufficient sensitivity to measure, with
appropriate precision, the actual
concentration of the active drug ingredient or
therapeutic moiety, or its active metabolite(s),
achieved in the body. ……”
15
16. EMEA CPMP/EWP/QWP/1401/98
• “The bioanalytical part of bioequivalence
trials should be performed in accordance
with the principles of Good Laboratory
Practice (GLP).
• However, as human bioanalytical studies fall
outside the scope of GLP, the sites conducting
the studies are not required to be monitored
as part of a national GLP compliance
programme.”
16
17. Bioanalytical Guidelines
EMEA/CHMP/EWP/192217/2009
• “The validation of bioanalytical methods and the analysis of
study samples should be performed in accordance with the
principles of Good Laboratory Practice (GLP).
• However, as human bioanalytical studies fall outside of the
scope of GLP, as defined in Directive 2004/10/EC, the sites
conducting the human studies are not required to be
monitored as part of a national GLP compliance programme.
• In addition, for clinical trials in humans the principles of Good
Clinical Practice (GCP) should be followed”.
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19. Excellence vs Legal GLP
• Legal GLP
– Accredited
– Monitored & certified by authorities
• Excellence in GLP
– Protocol & study director
– Proper sample collection, storage and processing
– Validated calibration and QC
– Successful analysis of batches
– High quality data (QC)
– Excellent QA
• Tracing, accountability & accuracy
– Proper reporting
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20. GLP expectations in Bioanalytical
• Pre-study method validation
– precision and accuracy – intra- and inter-batch across calibration
range, including LOQ
– selectivity – test for endogenous/exogenous interferences
– stability under study conditions – freeze/thaw, long-term frozen
storage, bench-top, auto-sampler (extract), stock solution
– recommend freshly prepared samples for comparison
– consider conditions of actual use – for example, increased batch size
during actual use
• Written, thorough documentation of the bioanalytical
method and results of validation
20Source: US FDA Guidelines & Presentations
21. GLP expectations in Bioanalytical..
• During incurred sample analysis
– select calibration range and QCs based on expected concentrations
for the study
– include a standard curve and quality control samples with each batch
of subject samples
– assure consistent integration of all chromatograms within a batch
• prepare complete study reports tabulate results for calibration standards,
QCs, subject samples
• list repeat results and the reason for the repeat
• list deviations and their impact
• description of failed runs
21Source: US FDA Guidelines & Presentations
22. GLP expectations in Bioanalytical...
• Reference standard – record identity, purity, expiration date,
lot number
• Document preparation – of stock solutions, and matrix-
based calibration standards and quality control (QC) samples
• Sample handling – store study samples under conditions that
maintain their integrity
• Document – storage condition, freezer removal/return
• Equipment – record instrumentation problems and
maintenance
22Source: US FDA Guidelines & Presentations
23. GLP expectations in Bioanalytical….
• Written procedures – establish a priori acceptance/rejection
criteria
– calibration standards, QCs, system suitability assessments
• e.g., at least 67% of all QCs in the batch, and at least 50% of the
QC replicates at each level, must be within 15% of intended
concentrations to accept a run
– chromatography acceptance
• define procedures for automatic and manual integrations,
handling interferences at the retention time of the analyte
– repeat analysis
• define basis for identifying samples for repeat analysis and
reporting the results of repeated samples
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24. For Best BE Results
• Effectively incorporate both GCP and GLP
• Follow the relevant regulations & guidelines in both areas
• Set up a QMS that follows the principles of total quality with
QA assuring traceability, integrity, accountability and
compliance of documents and standard procedures
• Be very open during internal & external audits and
inspections
• Address all problem areas (both GCP & GLP violations)
• Implement CAPA and improve systems
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25. Concluding Remarks
• Whether claimed or not, GLP compliance of bioanalytical and
clinical chemistry methods can help generate accurate and
precise data for BE studies
• Not all regulatory jurisdictions want it as a mandatory practice
• Many other authoritative regulations etc. (e.g., guidelines,
21CFR 32.9...) mirror the GLP expectations in essence
• Details of GLP expectations are a combination of GLP principles
and bioanalytical guidelines – if both are upheld, you will have
a first class BE data
• Ultimate common goal: integrity, accuracy and quality of
data
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